Dept of Medicine

DEPT OF MEDICINE

Researcher : Au KW

List of Research Outputs

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endothelial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Lian Q. , Zhang Y. , Kang S., Zhang Y. , Lai A.Y.K. , Au K.W. , Zhang J. and Tse H.F. , GENERATION OF MESENCHYMAL STEM CELLS FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (iPSC) FOR THE REATMENT OF LIMB ISCHEMIA, 7th Annunal Meeting of International Society for Stem Cell Research . 2009, 194.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium . Heart Rhythm. , 2010.

Researcher : Au WY

List of Research Outputs

Au W.Y. and Yeung C.K. , Acute promyelocytic leukemia in patients with severe psoriasis vulgaris, Leukemia Research . 2009, 33(11): e189-e190.

Au W.Y. , Kim S.J., Yiu H.H., Ngan R.K., Loong F. , Kim W.S. and Kwong Y.L. , Clinicopathological features and outcome of late relapse s of natural killer cell lymphomas 10–29 years after initial remission, American Journal of Hematology . 2010, 85(5): 362-363.

Au W.Y. , Law M.F., Tung Y. and Shek T.W.H. , Concomitant EBV encoded RNA positive cutaneous nasal- type natural killer-cell lymphoma and EBV encoded RNA negative nasopharyngeal carcinoma., Leukaemia & Lymphoma . 2009, 50(9): 1543-1544.

Au W.Y. , Current management of nasal NK/T-cell lymphoma, Oncology (Williston Park). . 2010, 24(4): 352-8.

Au W.Y. , Lie A.K.W. , Lam K.Y. and Kwong Y.L. , Engraftment of umbilical cord blood with glucose 6-phosphate dehydrogenase deficiency after double-unit unrelated cord blood transplantation, Bone Marrow Transplantation . 2009, 44(1): 57–58.

Au W.Y. , Lam K.K., Leung A.Y.H. , Liang R.H.S. , Lie A.K.W. and Kwong Y.L. , Occult autologous haematopoietic regeneration without disease relapse following myeloablative allogeneic haematopoietic SCT for lymphomas, Bone Marrow Transplantation . 2009, 45: 1377–1378.

Au W.Y. , Trendell-Smith N.J. , Ko B.H., Tong A.C. and Wong R.W.S. , Oral Epstein–Barr virus-related B-cell lymphoma causing persistent paraneoplastic dermatomyositis after nasopharyngea l and cutaneous carcinomas, Leukaemia & Lymphoma . 2010, 51(4): 715-716.

Au W.Y. , Lam W.W., Chu W.W., Tam S. , Wong W.K., Lau J., Yeung Y.M., Liu H.S. and Liang R.H.S. , Organ-specific hemosiderosis and functional correlation in Chinese patients with thalassemia intermedia and hemoglobin H disease, Annals of Hematology . 2009, 88(10): 947-950.

Au W.Y. , Lie A.K.W. , Lam W.W. and Chan J.K., Refractory, concomitant, cutaneous, and systemic lymphomas of discordant B-cell and T-cell lineages, The American Journal of Dermatopathology . 2010, 32(1): 102-4.

Au W.Y. , Hon C. , Yau K. , Lai W.W.K. , Tam S. and Kwong Y.L. , Two cases of monocular visual loss during oral arsenic trioxide therapy of acute promyelocytic leukemia., American Journal of Hematology . 2009, 84: 699.

Chan K.K. , Shen L. , Au W.Y. , Yuen H.F. , Wong K.Y. , Guo T. , Wong M.L.Y. , Shimizu N., Tsuchiyama J., Kwong Y.L. , Liang R.H.S. and Srivastava G. , Interleukin-2 induces NF-kappaB activation through BCL10 and affects its subcellular localization in natu ral killer lymphoma cells, J Pathol . 2010, 221(2): 164-74.

Chen W.Y.W. , Hu X. , Liang C.T., Wong M.L.Y. , Au W.Y. , Wong K.Y. , Choi W.L. , Wan T.S.K. , Chu K.M. , Chim J.C.S. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , Molecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm., 101st Annual Meeting of American Association for Cancer Research (AACR), Washington D.C., USA, April 2010. . 2010.

Cheung J., Au W.Y. , Ha S.Y. , Jensen J., Kim D., Ding A., Zhou I., Guo H., Brown T., Chu W., Rasalkar D. and Khong P.L. , Monitoring iron chelation effect in hearts of thalassaemia patients with improved sensitivity using reduced trans verse relaxation rate (RR2), Joint ISMRM-ESMRMB Annual Scientific Meeting, Stockholm, Sweden, 1-7 May 2010 .

Gu J. , Kwong Y.L. , Chan T. , Au W.Y. , Chan Q., Zhang J. , Liang R.H.S. and Khong P.L. , Comparison of DWIBS and 18F-FDG PET/CT in newly diagnosed lymphoma, Joint ISMRM-ESMRMB Annual Scientific Meeting, Stockholm, Sweden, 1-7 May 2010 .

Guo H. , Au W.Y. , Cheung J.S., Kim D., Jensen J.H., Khong P.L. , Chan Q., Chan K.C., Tosti C., Tang H., Brown T.R., Lam W.W.M., Ha S.Y. , Brittenham G.M. and Wu E.X. , Myocardial T2 quantitation in patients with iron overload at 3 tesla, Journal of Magnetic Resonance Imaging . 2009, 30: 394-400.

Hu X. , Chen W.Y.W. , Liang A.C.T., Au W.Y. , Wong K.Y. , Wan T.S.K. , Wong M.L.Y. , Shen L. , Chan K.K. , Guo T. , Chu K.M. , Tao Q. , Chim J.C.S. , Loong F. , Choi W.L. , Lu L. , So J.C.C. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation, Blood . 2010, 115: 2458-2461.

Hwang Y.Y., Wong K.Y. , Leung R.Y.Y. , Wong S.H.M., Chan S.C. , Srivastava G. and Au W.Y. , Post-rituximab Burkitt transformation of PTLD: loss of CD20 expression accompanied by a switch in light-chain expression, Annals of Hematology . 2010, 89(1): 97-99.

Iqbal J., Weisenburger D.D., Greiner T.C., Vose J.M., McKeithan T., Kucuk C., Geng H., Deffenbacher K., Smith L., Dybkaer K., Nakamura S., Seto M., Delabie J., Berger F., Loong F. , Au W.Y. , Ko Y.H., Sng I., Armitage J.O. and chan W.C., Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma, Blood . 2010, 115(5): 1026-36.

Iqbal J., Weisenburger D.D., Chowdhury A., Srivastava G. , Greiner T.C., Deffenbacher K.E., Kucuk C., Vose J.M., Au W.Y. , Nakamura S., Seto M., Delabie J., Berger F., Loong F. , Ko Y.H., Sng I., Liu X., Loughran T.P., Tsai M., Armitage J.O. and Chan W.C., NK-Cell Lymphoma Shares Strikingly Similar Molecular Features with a Distinct Set of gamma delta T-Cell Lymphoma and Identification of Aurora Kinase A Inhibitor as a Novel Therapeutic Agent, 51st Annual Meeting of the American-Society-of-Hematology , New Orleans, LA, DEC 05-08, 2009 . Blood; 114(22): 132-133.

Kwong Y.L. , Au W.Y. , Leung A.Y.H. and Tse E.W.C. , T-cell large granular lymphocyte leukemia: an Asian perspective, Annals of Hematology . 2010, 89(4) 331-339: 331-339.

Researcher : Bow CHY

List of Research Outputs

Bow C.H.Y. , Tsang S.W.Y., Soong S.S. , Yeung S.C. and Kung A.W.C. , BMD Enhances Clinical Risk Factors in Predicting Ten-Year Risk of Osteoporotic Fractures in Chinese Men: The Hong Kong Osteoporosis Study, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Bow C.H.Y. , Cheung C.L. , Gao Y. , Lau K.S. , Soong S.S. , Yeung S.C. and Kung A.W.C. , Bone Mineral Density and Serum Osteoprotegerin Levels in Pre- and Postmenopausal Women, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Bow C.H.Y. , Loong C., Leung F., Lau T.W., Chan Y.Y. and Soong S.S. , Survival and Re-fracture Rates in Paitents with Osteopo rotic Fractures: The Hong Kong Osteoporosis Study, The 31st Annual Meeting of the American Society for Bone and Mineral Research, Denver, Colorado, USA . 2009.

Cheung E.Y., Bow C.H.Y. and Kung A.W.C. , Rate of Perimenopausal Bone Loss and Its Predictive Factors Among Asian Females, International Osteoporosis Foundation World Congr ess on Osteoporosis & 10th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, Florence, Italy . 2010.

Loong C.H.N., Leung F., Lau T.W., Leung E., Chan Y.Y., Yee A., Ma L.F., Soong S.S. , Bow C.H.Y. , Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Predictive Factors for Re-fracture in Chinese Population with Previous Osteoporotic Fractures, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , A Secondary Fracture Prevention Programme to Reduce Fractures, Hospital Admissions, and Mortality, Hospital Authority Convention 2010, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Evaluation of the Osteoporosis Secondary Fracture Prevention Program at Queen Mary Hospital: Successful Recruitment is Associated with a Lower Re-fracture Rate and Morta lity Rate at One Year, Hospital Authority Convention 2010, Hong Kong . 2010.

Soong S.S. , Loong C.H.N., Bow C.H.Y. , Wu J. and Kung A.W.C. , Factors Associated with Osteoporosis Treatment Adhere nce in Hong Kong, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Tsang S.W.Y., Bow C.H.Y. , Chu E.Y.W. and Kung A.W.C. , Clinical risk factors assessment had better discriminative ability than bone mineral density in identifying subjects with vertebral fracture, Osteoporosis International . 2010, Epub ahead of print.

Researcher : Chan AOO

List of Research Outputs

Cheng C. , Chan T...N..., Chio H.M. , Chan P., Chan A.O.O. and Hui W.M. , Active versus flexible coping in psychological adjustment to gastrointestinal cancer , Paper presentation at the 22nd Annual Convention of the Association for Psychological Science, Boston, U.S.A. . 2010.

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnos tic and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Researcher : Chan CK

List of Research Outputs

Hung I.F.N. , Chan P., Leung S., Chan S.Y. , Hsu A., But D., Seto W.K., Wong S.Y. , Chan C.K. , Gu Q. , Tong T.S.M., Cheung T.K. , Chu K.M. and Wong B.C.Y. , Clarithromycin-amoxycillin-containing triple therapy: A valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong?, Helicobacter . 2009, 14: 505-511.

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Researcher : Chan DTM

Project Title:	Identification of the cross reactive antigen(s) on proximal tubular epithelial cells that mediate anti-DNA antibody binding and subsequent inflammation
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2007
Completion Date:	10/2009

Abstract:

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by loss of tolerance to self-antigens, elevated levels of auto-antibodies, amplification of inflammatory responses and multi-organ injury (1). SLE affects predominantly the female population, especially those of child bearing age, and has a prevalenc e rate of 12-100/100,000 in Hong Kong (2). Lupus nephritis is a severe and debilitating organ manifestation of SLE that affects over 50% of the SLE population, and is often associated with a poor prognosis. Cardinal features of lupus nephritis include immune complex deposition within the glomerular and tubular basement membranes and renal cell proliferation, which precede the more severe lesions such as endocapillary proliferation and crescent formation (3, 4). Anti-DNA antibodies have been implicated in the pathogenesis of lupus nephritis. In many patients increased renal disease activity is associated with elevated titres of anti-DNA antibodies (5). Furthermore, they can be eluted from the kidneys of patients and mice with active nephritis (6, 7). How anti-DNA antibodies mediate tissue injury remain s to be fully elucidated. Evidence suggests that they can bind to intrinsic renal structures either indirectly through chromatin material, or via a direct interaction with cross-reactive non-DNA antigen(s) on the surface of renal cells (8-10). Furthermore, studies have demonstrat ed that sub-sets of murine anti-DNA antibodies can penetrate cells, traverse the cytoplasm and translocate to the nucleus, although the subsequent events that follow remain to be defined (11). To date, much of the research has focused on the immuno-pathogenesis of glomerular lesions in lupus nephritis, whilst less attention has been bestowed to the tubulo-interstitium despite the frequent occurrence of tubulo-interstitial inflammation in lupus patients, and that the extent of tubular injury strongly correlates with unfavorable renal prognosis. Proximal tubular epithelial cells represent the predominant cell type in the tubulo-interstitium, and act as directional regulators of immune-mediated inflammation. We have recently demonstrated the presence of IgG deposition along the tubular basement membrane in renal biopsies obtained from patients with active lupus nephritis. The extent of IgG staining correlated with tubulo-interstitial abnormalities, induction of IL-6 and circulating anti-DNA antibody titres (12). Our in vitro studies showed isolated human polyclonal anti-DNA antibodies to directly bind to proximal tubular epithelial cells in a manner that was independent of cell surface DNA and such binding induced IL-6 and TNF-alpha secretion (12). The cross reactive antigen(s) through which human polyclonal anti-DNA antibodies bind to on the surface of proximal tubular epithelial cells, and the subsequent inflammatory events initiated by anti-DNA antibody binding remain to be determined, and thus constitutes the theme of this project: The Objectives of this project: 1. To identify the protein(s) on the surface of proximal tubular epithelial cells that mediate anti-DNA antibody binding. 2. To determine whether cellular uptake and nuclear localization of anti-DNA antibodies can occur in proximal tubular epithelial cells after anti-DNA antibody binding, and whether this represents a mechanism through which anti-DNA antibodies can initiate inflammation in these cells. 3. To assess functional changes in proximal tubular epithe lial cells after anti-DNA antibody binding (cell proliferation, cell viability and secretion of pro-inflammatory cytokines and chemokines). References 1. Croker JA, Kimberly RP. SLE: challenges and candidates in human disease. Trends Immunol 2005; 26: 580-586. 2. Mok CC, Lau CS. Lupus in Hong Kong Chinese. Lupus 2003; 12: 717-722. 3. Cameron JS. Lupus nephritis. J Am Soc Nephrol 1999; 10: 413-424. 4. Lewis EJ, Schwartz MM. Pathology of lupus nephritis. Lupus 2005; 14: 31-38. 5. Chan TM, Leung JK, Ho SK, Yung S. Mesangial cell-binding anti-DNA antibodies in patients with systemic lupus erythematosus. J Am Soc Nephrol 2002; 13: 1219-1229. 6. Winfield JB, Faiferman I, Koffler D. Avidity of anti -DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis. J Clin Invest 1977; 59: 90-96. 7. Termaat RM, Assmann KJ, van Son JP, Dijkman HB, et al. Antigen-specificity of antibodies bound to glomeruli of mice with systemic lupus erythematosus-like syndromes. Lab Invest 1993; 68: 164-173. 8. Berden JH, Termaat RM, Brinkman K, Smeenk RJ, et al. Binding of anti-DNA antibodies to glomerular heparan sulfate: a new clue for the pathogenesis of SLE nephritis? Nephrologie 1989; 10: 127-132. 9. Termaat RM, Assmann KJ, Dijkman HB, van Gompel F, et al. Anti-DNA antibodies can bind to the glomerulus via two distinct mechanisms. Kidney Int 1992; 42: 1363-1371. 10. Deocharan B, Qing X, Lichauco J, Putterman C. Alpha-actinin is a cross-reactive renal target for pathogenic anti-DNA antibodies. J Immunol 2002; 168: 3072-3078. 11. Yanase K, Smith RM, Puccetti A, Jarett L, et al. Receptor-mediated cellular entry of nuclear localizing anti-DNA antibodies via myosin 1. J Clin Invest 1997; 100: 25-31. 12. Yung S, Tsang RC, Sun Y, Leung JK, et al. Effect of human anti-DNA antibodies on proximal renal tubular epithelial cell cytokine expression: implications on tubulointerstitial inflammation in lupus nephritis. J Am Soc Nephrol 2005; 16: 3281-3294.

Project Title:	The role of anti-dsDNA antibodies in mediating fibrotic processes in human proximal tu bular epithelial cells
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2008

Abstract:

Background Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by a loss of immunologic self-tolerance and the production of auto-antibodies against self antigens (1). Kidney involvement is one of the most severe organ manifestations of this disease and is a leading cause of acute or chronic renal failure, especially in Asian populations (2). Lupus nephritis is characterized by the deposition of auto-antibodies in the mesangial area and along the glomerular and tubular basement membranes, and the local production of mediators that result in inflammation and fibrosis (2, 3). Histological features include mesangial and proximal tubular epithelial cell prolifera tion, inflammatory cell infiltration, kidney damage and replacement of normal structures by extracellular matrix and sclerosis (3). Compelling evidence has highlighted a pathological role for anti-double-stranded (ds) DNA antibodies in lupus nephritis (4) In this respect, anti-dsDNA antibodies have been observed in renal and glomerular eluates obtained from SLE patients and lupus mice (5, 6). The correlation between circulating anti-dsDNA antibodies and disease activity presents further evidence that these antibodies participate in pathogenetic mechanis ms (7, 8). Whilst the immunopathogenesis of glomerular lesions in lupus nephritis has been extensively studied, limited knowledge regarding tubulo-interstitial lesions is known, despite the observation that tubulo-interstitial disease is associated with less favorable long-term renal prognosis. Proximal tubular epithelial cells constitute the predominant cells in the tubulo-interstitium and they are regulators of immune-mediated inflammation and fibrosis (9). Matrix metalloproteinases (MMPs) are zinc-containing endopeptidases that play a crucial role in the remodeling of the extracellular matrix and tissue homeostasis (10). Studies have shown that the expression of MMPs in tissues is tightly regulate d by cytokines and chemokines, and are under strict control at both the transcription and translation levels (10). Recent studies have shown that glomerular expression of MMP-2 and MMP-9 is increased in lupus-prone mice (11), but their expression within the tubulo-interstitium has not been documented. In this study, our aim is to determine whether anti-dsDNA antibodies can med iate fibrotic changes in proximal tubular epithelial cells, and the mechanisms through which matrix protein synthesis/degradatio n is altered. The objectives of this projective are: 1. To compare renal expression of fibrotic and anti-fibrotic markers (fibronectin, collagen type I, TGF-beta1, VEGF, BMP-7 and HGF, MMP-2 and MMP-9) in renal biopsies obta ined from patients with lupus nephritis. 2. To determine whether anti-dsDNA antibodies can induce fibrotic changes in proximal tubular epithelial cells in vitro, and to elucidate the mechanisms through which fibrosis occurs. References 1. Croker JA, Kimberly RP. SLE: challenges and candidates in human disease. Trends Immunol 2005;26:580-6. 2. Cameron JS. Lupus nephritis. J Am Soc Nephrol 1999;10:413-24. 3. Schwartz MM. The pathological classification of lupus nephritis. In: Lewis EJ, Schwartz MM, Korbet SM, eds. Lupus Nephritis. New York: Oxford unviersity Press; 1999:126-58. 4. Hahn BH. Antibodies to DNA. N Engl J Med 1998;338:1359-68. 5. Winfield JB, Faiferman I, Koffler D. Avidity of anti-D NA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis. J Clin Invest 1977;59:90-6. 6. Termaat RM, Assmann KJ, van Son JP, Dijkman HB, Koene RA, Berden JH. Anti gen-specificity of antibodies bound to glomeruli of mice with systemic lupus erythematosus-like syndromes. Lab Invest 1993;68:16 4-73. 7. Chan TM, Leung JK, Ho SK, Yung S. Mesangial cell-binding anti-DNA antibodies in patients with systemic lupus erythematosus. J Am Soc Nephrol 2002;13:1219-29. 8. Isenberg DA, Manson JJ, Ehrenstein MR, Rahman A. Fifty years of anti-ds DNA antibodies: are we approaching journey's end? Rheumatology 2007;46:1052-6. 9. Yung S, Tsang RC, Sun Y, Leung JK, Chan TM. Effect of human anti-DNA antibodies on proximal renal tubular epithelial cell cytokine expression: implications on tubulointerstitial inflammation in lupus nephritis. J Am Soc Nephrol 2005;16 :3281-94. 10. Ram M, Sherer Y, Shoenfeld Y. Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol 2006;26:299-307. 11. Tveita AA, Rekvig OP, Zykova SN. Increased glomerular matrix metalloproteinase activity in murine lupus nephritis. Kidney Int 2008.

Project Title:	42nd Annual Meeting and Scientific Exposition (ASN Renal Week 2009) Effects of mycophenolic acid (MPA) and cyclophosphamide (CTX) on cytokine and matrix protein synthesis and apoptosis in human mesangial cells (HMC)
Investigator(s):	Chan DTM
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	10/2009
Completion Date:	11/2009

Abstract:

N/A

Project Title:	Serum immunoglobulin levels and resident renal cell-binding in patients with severe lupus nephritis
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2009

Abstract:

Background Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect multi-organ systems. Renal involvement is one of the most severe organ manifestations of SLE and can affect up to 60% of the SLE population. Lupus nephritis is characterize d by elevated levels of auto-antibodies, in particular anti-DNA antibodies, and immune complex-mediated glomerular and tubulo-interstitial inflammation that can result in renal failure. Standard immunosuppressive treatment for severe active lupus nephritis entails the combined use of a corticosteroid with cyclophosphamide or mycop henolate mofetil (MMF), while azathioprine or MMF is often used during the maintenance phase. The level of circulating immunoglobulins in patients with lupus nephritis is dependent on the state of immune reactivity, the sever ity of proteinuria, and immunosuppressive treatment. Recent studies have shown that a significant proportion of patients using new immunomodulatory agents have markedly reduced serum immunoglobulin concentrations [1-3]. While suppression of immunoglobulin production by lymphocytes indicates immunosuppressive efficacy, low immunoglobulin levels have been associated with increased risk of infections in patients with autoimmune disease and in kidney transplant recipients [1-4]. There is currently little data on immunoglobulin levels in patients with lupus nephritis during treatment with the different immunosuppressive agents. Such data would be important in optimization of drug dosing to enhance efficacy while minimizing the infective risk. Our group has previously reported that the degree of immunoglobuli n binding to cultured human mesangial cells (HMC) and proximal tubular epithelial cells (PTEC) in serum samples from patients with lupus nephritis correlated with disease activity and the level of anti-DNA antibodies, and that the binding of anti-DNA antibodies to HMC and PTEC could contribute to intra-renal disease pathogenesis [5, 6]. It is therefore relevant to investigate the relationship between HMC- and PTEC-binding activity and the level of circulating immunoglobulins, and the possible differential effects of the various immunosuppressive regimens. The objectives of this study are as follows: 1) To examine the effects of cyclophosphamide, azathioprine, MMF, combined with corticosteroid, and proteinuria on serum immunoglobulin levels in patients with lupus nephritis. 2) To investigate the relationship between serum immunoglobulin levels and clinical outcomes, including both efficacy and adverse events, in these patients. 3) To investigate the relationship between the level of serum immunoglobulins, anti-DNA antibody, and HMC- and PTEC-binding activity. References 1. Ponce R. Preclinical support for combination therapy in the treatment of autoimmunity with atacicept. Toxicol Pathol 2009;37(1):89-99. 2. Carbonatto M, Yu P, Bertolino M, Vigna E, et al. Nonclinical safety, pharmacokinetics , and pharmacodynamics of atacicept.Toxicol Sci 2008;105(1):200-10. 3. Munafo A, Priestley A, Nestorov I, Visich J, Rogge M. Safety, pharmacokinetics and pharmacodynamics of atacicept in healthy volunteers. Eur J Clin Pharmacol 2007; 63(7):647-56. 4. Keven K, Sahin M, Kutlay S, et al. Immunoglobulin deficiency in kidney allograft recipients: comparative effects of mycophenolate mofetil and azathioprine. Transpl Infect Dis 2003;5:181-6. 5. Chan TM, Leung JKH, Ho SKN, Yung S. Mesangial cell-binding anti-DNA antibodies in patients with systemic lupus erythematosus. J Am Soc Nephrol 2002;13: 1219-29. 6. Yung S, Tsang RCW, Sun Y, Leung JKH, Chan TM. Effect of human anti-DNA antibodies on proximal renal tubular epithelial cell cytokine expression:implications on tubulointerstitial inflammation in lupus nephritis. J Am Soc Nephrol 2005; 16: 3281-3295.

Project Title:	The role of annexin II in the pat hogenesis of lupus nephritis
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) Since annexin II expression in the mesangial area is increased in lupus nephritis, one of the objec tives of the present study is to investigate the mechanisms that regulate annexin II expression in mesangial cells. We will determine whether increased cell surface annexin II is dependent on de novo protein synthesis or intracell ular translocation to the cell surface, and the role of post-transcriptional modifications; 2) We shall investigate further the functional alterations in human mesangial cells consequent to the binding and interaction between human polyclonal anti-DNA antibodies and mesangial cell annexin II. We will focus on the cellular effects relevant to inflammatory and fibrosis processes. We will include a proteomics approach as well as the elucidation of signal transduction pathways; 3) Our previous studies focused on the interaction between anti-DNA antibodies and proteins in the mesangial cell membrane. In the present study, we seek to identify the intracellular molecules that are involved in the binding and trans location of internalized anti-DNA antibodies; 4) We shall also ascertain clinical correlations with our in vitro findings. Specifically, we will study the correlation between the annexin II-binding activity of anti-DNA (and also non-anti-DNA) immunoglobulins from lupus nephritis patients with clinical disease activity.

List of Research Outputs

Chan D.T.M. , Hepatitis B and renal disease, Current Hepatitis Reports . 2010, 9(2): 99-105 [Epub 2010 Apr 14].

Chan D.T.M. , Member of Editorial Board (since 2008), Nephrology . 2010.

Chan D.T.M. , Member of Editorial Board (since 2010), Chinese Journal of Internal Medicine . 2010.

Chan D.T.M. , Ng Y.C.C. and Yung S.S.Y. , Mycophenolic acid reduces MAPK activation and fibronec tin synthesis in human proximal tubular epithelial cells (PTEC) induced by anti-DNA antibodies, J Am Soc Nephrol . 2009, 860A.

Chan D.T.M. , Peritoneal Dialysis, Mesothelial Cells, Proteoglycans, Annual Congress of the Chinese Society of Nephrolo gy, July 2-5, Dalian, China . 2009.

Chan D.T.M. , Protocol Reviewer, Cochrane Reviews (Renal Group) [since 2006] . 2010.

Chan D.T.M. , The importance of research and publishing - An Asian perspective, Asian Pacific Colloquium on Organ Transplantation, 15-16 January. Shenzhen, China . 2010.

Chan D.T.M. , Treatment of lupus nephritis (Plenary Lecture), 9th International Congress on Systemic Lupus Erythematosus, 27-27 June, Vancouver, Canada . 2010.

Cheung K.F. , Yung S.S.Y. and Chan D.T.M. , Annexin II on human mesangial cells mediates anti-dsDNA antibody binding, 9th International Congress on Systemic Lupus Erythematos us . 2010.

Kwok J.S.Y. , Chan G.S.W. , Lam M.F. , Yan T., Tang L., Kwong K.M., Chan K.W. and Chan D.T.M. , Determination of mismatched donor HLA in kidney transplant recipients with unknown donor HLA phenotypes, Clinical transplantation . 2010, [Epub ahead of print 2010 Apr 9].

Lam M.F. , Lo W.K. , Tse K.C., Yip T.P.S., Lui S.L. , Chan D.T.M. and Lai K.N. , Retroperitoneal leakage as a cause of acute ultrafiltration failure: its associated risk factors in peritoneal dialysis , Peritoneal Dialysis International . 2009, 29(5): 542-547.

Lui S.L. , Cheng S.W., Yung S.S.Y. , Chan D.T.M. and Lo W.K. , Acute deterioration in residual renal function after CAPD peritonitis is associated with increased interleukin-6 release, J Am Soc Nephrol . 2009, 20: 787A.

Ma K.M., Yap D.Y., Chan D.T.M. and Lai K.N. , A hemodialysis patient with severe vomiting, Hemodialysis International . 2009, 13: 432.

Mok M.M., Yip T., Lui S.L. , Chan D.T.M. , Lai K.N. , Lo W.K. and Lo W.K. , Severe hypocalcemia and hyperphosphatemia caused by oral sodium phosphate fleet solution in a hemodialysis patient after parathyroidectomy, Hemodialysis International . 2009, 13: 395.

Tse K.C., Yap D.Y.H., Tang C.S.O. , Yung S.S.Y. and Chan D.T.M. , Response to adefovir or entecavir in renal allograft recipients with hepatitic flare due to lamivudine-resistant hepatitis B, Clinical transplantation . 2010, 24(2): 207-212.

Tse W.W. , Yung S.S.Y. and Chan D.T.M. , Hyaluronan in the pathogenesis of lupus nephritis in NZB/W mice and the effect of 4-methylumbelliferone, 9th International Congress on Systemic Lupus Erythematosus . 2010.

Yang W. , Shen N., Ye D.Q., Liu Q., Qian X.X., Hirankarn N., Pan H.F., Mok C.C., Chan D.T.M. , Wong R.W.S. , Lee K.W., Wong S.N. , Leung A.M.H., Li X.P., Avihingsanon Y., Wong C.M. , Lee T.L. , Ho M.H.K. , Lee P.P.W. , Chang Y.K., Li P.H., Li R. , Zhang L. , Wong W.H.S. , Ng I.O.L. , Lau W.C.S. , Sham P.C. , Lau Y.L. and Asian Lupus Genetics Consortium A.L.G.C., Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. , PLoS Genetics . 2010, 6: e1000841.

Yap D.Y., Chu F.S., Chu S.S.M. , Tam P.C. , Chan D.T.M. , Lai K.N. and Tang S.C.W. , CT angiography versus conventional digital angiography in pre-operative assessment for Chinese living kidney donors [Epub ahead of print 15 June 2010], Journal of Nephrology . 2010.

Yap D.Y., Chu F.S., Chu S.S.M. , Tam P.C. , Tam S., Lai K.N. , Chan D.T.M. and Tang S.C.W. , CT angiography versus conventional digital angiography in pre-operative assessment for Chinese living kidney donors, Nephrology . 2010, 15 (S3): 54.

Yap D.Y., Ma M.K., Lai K.N. and Chan D.T.M. , Superior vena cava injury after cuffed tunneled cathe ter insertion using a right subclavian approach, Hemodialysis International . 2009, 13: 430.

Yap D.Y.H., Lau S.K.P. , Lamb S., Choy C.B.Y. , Chan D.T.M. , Lai K.N. and Tang S.C.W. , An unusual organism for PD-related peritonitis: Hafnia alvei, Peritoneal Dialysis International . 2010, 30(2): 254-255.

Yap D.Y.H., Tse K.C., Chan D.T.M. and Lai K.N. , Epstein syndrome presenting as renal failure in young patients, Ren Fail . 2009, 31(7): 582-585.

Yip T., Tse K.C., Lam M.F. , Cheng S.W., Lui S.L. , Tang S.C.W. , Mg M., Chan D.T.M. , Lai K.N. and Lo W.K. , Colonic diverticulosis as a risk factor for peritonitis in Chinese peritoneal dialysis patients, Peritoneal Dialysis International . 2010, 30: 187-191.

Yip T.P., Tse K., Ng F., Lam M.F. , Tang S.C.W. , Lui S.L. , Lai K.N. , Chan D.T.M. and Lo W.K. , Clinical course and outcomes of enterococcus peritonitis in peritoneal dialsyisi patients, Nephrology . 2010, 15 (S3): 47.

Yip T.P.S., Lui S.L. , Tse K.C., Xu H., Ng F.S.K. , Cheng S.W. , Chan D.T.M. , Lai K.N. and Lo W.K. , A prospective randomized study comparing tenckhoff catheters inserted using the triple incision method with standard swan neck catheters, Peritoneal Dialysis International . 2010, 30(1): 56-62.

Yung S.S.Y. , Chau K.M. , Yip T.P.S., Li F.K. and Chan D.T.M. , Induction of inflammatory and fibrotic mediators in human peritoneal mesothelial cells (HPMC) by icodextrin-based peritoneal dialysis fluid, J Am Soc Nephrol . 2009, 20: 694A.

Yung S.S.Y. , Ng Y.C.C. and Chan D.T.M. , Mycophenolic acid ameliorates anti-dsDNA antibody binding to proximal tubular epithelial cells and the subsequent induction of inflammatory and fibrotic processes., 9th International Congress on Systemic Lupus Erythematos us . 2010.

Yung S.S.Y. and Chan D.T.M. , Tissue remodeling and inflammation during peritoneal dialysis: catheter versus fluid, Peritoneal Dialysis International . 2010, 39(3): 274-276.

Zhang C. , Yung S.S.Y. and Chan D.T.M. , Rapamycin decreases IL-6 induced inflammatory and fibrotic mediators in human mesangial cells (HMC), J Am Soc Nephrol . 2009, 20: 731A.

Zhang Q. , Yung S.S.Y. and Chan D.T.M. , Effects of mycophenolic acid (MPA) and cyclophospham ide (CTX) on cytokine and matrix protein synthesis and apoptosis in human mesangial cells (HMC), J Am Soc Nephrol . 2009, 20: 562A.

Researcher : Chan FHW

List of Research Outputs

Tang M., Woo J. , Hui E., Chan F.H.W. , Lee J., Sham A. and Chau P.H. , Utilization of emergency room and hospitalization by Chinese nursing home residents: a cross-sectional study, Journal of the American Medical Directors Associat ion . 2010, 11: 325-332.

Researcher : Chan HHL

Project Title:	The role of epidermal cooling in improving the outcome of laser therapy in the treatment of Nevus of Ota
Investigator(s):	Chan HHL, Lam LK
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	12/2000

Abstract:

To assess whether epidermal cooling would reduce pain, swelling, complications but improve clinical response and reduce the number of session required for laser treatment for Nevus of Ota.

Project Title:	The use of vascular lasers in the treatment of port wine stain in chinese
Investigator(s):	Chan HHL, Wei WI
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	11/2001

Abstract:

To establish the importance of epidermal cooling when 585nm pulse dye laser is used for the treatment of port wine stain in Chinese; to compare the clinical efficacy, patients' tolerability and complications of two commerical available vascular lasers that are equipped with different cooling devices in the treatment of port wine stain in Chinese.

Researcher : Chan HT

List of Research Outputs

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H., Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patients with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Researcher : Chan JCK

Project Title:	Application of the APACHE II and III prognostic scoring methods in the 14-bed Intensi ve Care Unit at Queen Mary Hospital
Investigator(s):	Chan JCK, Lam WK
Department:	Medicine
Source(s) of Funding:	Health Services Research Fund - Full Grants
Start Date:	07/1995

Abstract:

To evaluate the usefulness of the APACHE II and III prognostic scoring methods in the 14-bed ICU at Queen Mary Hospital; to compare our ICU performance in terms of actual mortality with the predicted mortality based on the APACHE II predictive equation; to correlate the APACHE II and III severity scores. As the mortality prediction equation for APACHE III is only commercially available, a close correlation between APACHE II and III scores would support using the APACHE II scoring and prediction method as the standard method rather than financially investing in the APACHE III system.

Researcher : Chan K

List of Research Outputs

Chan K. , Yam I.Y.L. , Leung K.Y., Tang M., Chan T.K. and Chan V.N.Y. , Detection of paternal alleles in maternal plasma for non-invasive prenatal diagnosis of beta-thalassemia: a feasibility study in southern Chinese., Eur J Obstet Gynecol Reprod Biol . 2010, 150: 28-33.

Researcher : Chan KH

Project Title:	Clinical outcome of multiple sclerosis in Hong Kong Chinese
Investigator(s):	Chan KH
Department:	Medicine
Source(s) of Funding:	Bayer Pharmaceuticals Ltd. - General Award
Start Date:	01/2008

Abstract:

To study long term clinical outcome of local multiple sclerosis on different treatment regimes.

Project Title:	Study of clinical and immunological characteristics of local multiple sclerosis patients
Investigator(s):	Chan KH, Ho SL
Department:	Medicine
Source(s) of Funding:	Bayer Pharmaceuticals Ltd. - General Award
Start Date:	03/2008

Abstract:

To study the clinical and immunological characteristics of multiple sclerosis patients among Hong Kong Chinese.

Project Title:	Aquaporin-4 autoimmunity in neuromyelit is optica spectrum disorders among Hong Kong Chinese, and aquaporin-4 expression in thymus and thymoma
Investigator(s):	Chan KH, Chu ACY, Ho SL
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2008
Completion Date:	05/2010

Abstract:

The objectives of the project is to study the frequency of aquaporin-4 autoantibody in the sera of local patients with neuromyelitis spectrum disorders, and to find out whether thymus and thymoma from patients with myasthenia gravis express aquaporin-4. Neuromyelitis optica (NMO) is a severe autoimmune inflammatory demyelinating disorder of the central nervous system (CNS) characterized by optic neuritis and transverse myelitis, usually recurrent (Wingerchuk et al., 2007). It is commonly misdiagnosed as multiple sclerosis (MS), and is clas sified by Asian investigators as “optic-spinal MS” (Kira 2003). Histopathologically, spinal cord tissues exhibit necrosis in both grey and white matter, infiltrating leucocytes (macrophages, polymorphonuclear cells and lymphocytes ), activated microglia, demyelination, axonal loss, thickened hyalinized vessel walls and deposits of IgM, IgG and products of complement activation in a vasculocentric pattern (Mandler et al., 1993; Lucchinetti et al; 2002). An advance in understanding the immunopathogenesis of NMO was the discovery of a specific IgG marker for NMO (NMO-IgG) as a specific autoantibody marker in 73% of NMO patients (Lennon et al., 2004). This led to the recognition of a spectrum of immunologically related disorders including recurrent longitudinally extensive transverse myelitis (LETM) and recurrent optic neuritis (Lennon et al., 2004; Weinshenker et al., 2005; Chan et al., 2005). The autoantigen targetted by NMO-IgG is the major CNS water channel protein, aquaporin-4 (AQP4), which is highly expressed in astrocytic endfeet at the glial limitans abutting capillaries in pia, subpia and subependyma (Lennon et al., 2005), and at synapses and nodes of Ranvier (Hinson et al., 2007). AQP4 is critical in the maintenance of blood-brain barrier’s functional integrity, regulation of water transfer across the interfaces between blood and cerebrospinal fluid (CSF), and between blood and brain, and for buff ering of potassium ions released during neurotransmission. It is vital for water homeostasis in the CNS (Nico et al., 2001; Nicchia et al., 2004; Moghaddam et al., 2004). In-vitro studies demonstrated that IgG from NMO patients induces rapid and reversible loss of AQP4 expressed on membranes of viable transfected mammalian cell via endocytosis and endolysosomal degradation. Membrane loss of antigen reflects that NMO-IgG is cytot oxic to AQP4-expressing membrane evidenced by deposition of terminal membrane attack complex of complement (C9 neo) and loss of membrane integrity (Hinson et al., 2007). Confocal microscopic studies have revealed that in spinal cord and optic nerve, paranodal astrocytic endfeet also highly express AQP4. IgG targeting astrocytic processes at nodes of Ranvier could plausibly initia te demyelination. The loss of AQP4 demonstrated in NMO lesions contrast to the increased AQP4 expression in early MS lesions (Roemer et al., 2007), suggesting that NMO-IgG is pathogenic in NMO and is the cause of AQP4 loss and initiating event of inflammatory demyelination (Hinson et al., 2007). NMO is more common among Asians than Caucasians (Kira 2003). Colleagues and I have noticed that among Hong Kong Chinese patient s, NMO spectrum disorders are more common than classical MS after an initial attack of transverse myelitis, and that NMO spectrum disorders are commonly associated with severe neurological diability (paraplegia and/or blindness) (Chan et al., 2006). As treatment for NMO spectrum disorders are different from that of MS, early diagnosis of NMO spectrum disorders are important. Serological testing for the NMO-IgG and AQP4 autoantibod y is useful in this aspect. Information on AQP4 autoantibody status of local patients are not available. In addition, another autoantibody-mediated neurological disease, myasthenia gravis (MG), have been observed to coexist with NMO spectrum disorders in some patients (Chan et al., submitted). This leads us to suspect that the thymus, which plays an important role in the pathogene sis of MG, may be pathogenically involved in the immunopathogenesis of NMO spectrum disorder. We would like to study whether thymus and thymoma from MG patients express AQP4.

Project Title:	Study of pathophysiological effect of anti-aquaporin-4 autoantibodies in neuromyelitis optica by passive transfer into mice
Investigator(s):	Chan KH, Ho SL, Ho WL
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2009

Abstract:

Neuromyelitis optica (NMO) is a serious idiopathic inflammatory demyelinating disorders of the CNS characterized by monophasic or recurrent optic neuritis (ON) and acute transverse myelitis (ATM). It has been regarded as a form of multiple sclerosis (MS), but there are obvious differences between NMO and classical MS (CMS). In CMS, about 85% of patients initially have a relapsing remitting course with recurrent inflammatory demyelination affecting optic nerves, cerebral hemispheres, brainstem and spinal cord. Cerebrospinal fluid (CSF)oligoclonal bands (OCB) are detected in ~90% of MS patients. NMO has relative sparing of the cerebral hemispheres (Wingerchuk et al., 2007), and CSF OCB are rare in NMO patients. Clinically, NMO patients usually have more severe disability ATM typified by longitudinally extensive transverse myelitis (LETM) and severe ON (Ghezzi et al., 2004), less frequent secondary progression (Wingerchuk et al., 2007b) and worse clinical outcome compared to CMS patients (Wingerchuk 1999). Distinction of NMO from MS can be difficult especially in the early stage. An early diagnosis of NMO is important as early frequent relapse with severe disabilities are common (Wingerchuk et al., 2007). First-line disease modifying agents for MS are ineffective in NMO (Bergamaschi 2007). Aggressive immunosuppression by azathioprine and corticosteroids should be initiated early in NMO to prevent relapses (Mandler et al., 1998). Asian patients with recurrent CNS inflammatory demyelination commonly have predominant spinal cord and optic nerv es involvement while cerebral hemispheres are relatively spared, ascribed as having opticospinal MS (OSMS)(Kira 2003). OSMS patients have longitudinally extensive transverse myelitis (LETM) frequently while in CMS patients, spinal cord lesions typically are short and partial. Also frequency of CSF OCB is lower in OSMS compared to CMS. An autoantibody marker, NMO-IgG, is recently identified in serum of ~70% of NMO patients but <5% of CMS patients, and is a useful marker to differentiate NMO from CMS (Lennon et al., 2004). Interesting ~50-60% of Japanese OSMS patients are seropositive for NMO-IgG, suggesting that NMO is distinct from CMS, and OSMS is NMO (Lennon et al., 2004). Importantly, detection of NMO-IgG in patients with first LETM attack predicts relapse of ATM or later development of ON (Weinshenker et al., 2006b). Detection of NMO-IgG facilitates early diagnosis of NMO spectrum disorders and prompt appropriate treatment. The autoantigen targetted by NMO-IgG is the major CNS water channel protein, aquaporin-4 (AQP4), which is highly expressed in astrocytic endfee t processes at the glial limitans abutting capillaries in pia, subpia and subependyma (Lennon et al., 2005). AQP4 is critical in maintaining functional integrity of the blood-brain barrier, regulating water transport across the interfaces between blood and CSF, and between blood and brain (Nico et al., 2001; Nicchia et al., 2004). In-vitro experiments showed that IgG from serum of NMO patients seropositive for NMO-IgG bound to extracellular domain of AQP4 expressed on surface of human embryonic kidney cells transfected with construct encoding AQP4 fused at its cytoplasmic N-terminus with green fluorescent protein. This autoantibody-antigen binding was followed by 1)endocytosis and endolysosomal degradation of bound AQP4 (downregulation of membran e AQP4), and 2) complement activation and deposition of lytic membrane attack complex C9neo which led to increased membrane permeability and cell lysis (Hinson et al., 2007) (Hinson et al., 2007). AQP4 loss in NMO lesions contrasted to increased AQP4 expression in early CMS lesions; suggesting that anti-AQP4 autoantibody-mediate d AQP4 loss may be initiating pathogenic event in NMO (Misu et al., 2006; Roemer et al., 2007). An autoimmune pathogenesis of NMO (autoimmune water channelopathy) is not confirmed yet. We aim to study the potential pathogenic effects of IgG from NMO patients seropositive and seronegative for NMO-IgG by passive transfer of IgG purified from patients' sera to laboratory animals. We hypothesize that during relapse or active NMO, anti-AQP4 autoantibodies in patients' sera cross the blood-brain barrier and bind to extracellular portion of AQP4 in astrocytic endfoot processes; this autoantibodyantigen binding may be pathogenic by three mechanisms: 1) complements activation initiates inflammation which leads to astrocyte injury or death, and demyelination and necrosis of CNS tissues; 2) internalization and endolysosomal degradation of bound AQP4 (downregulation), and AQP4 loss further impairs integrity of the blood-brain barrier, allowing activated autoreactive T cells more anti-AQP4 antibodies to enter the CNS; 3) activated CD8+ T cells may cause CNS damage via antibody-depende nt cytotoxicity. References Ami-Moghaddam M, Ottersen OP. The molecular basis of water transport in the brain. Nat Rev Neurosci 2003;4:991-1001 Chan K H, Tsang K L , Fong G C Y, Cheung R T F , Ho S L. Idiopathic severe recurrent transverse myelitis: a restricted variant of neuromyelitis optica. Clin Neuro Neurosurg 2005a;107(2):132-135 Chan K H, Tsang K L, Fong C Y, Ho S L, Cheung R T F, Mak W. Idiopathic inflammatory demyelinating disorders after acute transverse myelitis. Eur J Neuro 2006;13:862-868 Chan K H, Pittock S J, Lennon V A. Coexisting autoimmune channelopathies: neuromyelitis optica (NMO) with myasthenia gravis (MG). Neurology 2008c (Suppl 1);70:A236 (Abstract) Chan K H, Ramsden D B, Yu Y L, Kwok K H H, Chu A C Y, Ho P W L, Kwan J S C, Lee R, Lim E, Kung M H W, Ho S L. NMO-IgG in idiopathic inflammatory demyelinating disorders among Hong Kong Chinese. Eur J Neuro (in press) Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, et al. Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica . Neurology 2007;69:1-11 Kira J. Multiple sclerosis in the Japanese population. Lancet Neurol 2003;2:117-127 Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoant ibody marker of neuromyelitis optica. Lancet 2004;364:2106-2112 Lennon VA, Kryzer TJ, Pittock SJ, et al. IgG marker of optic-spinal multiple sclerosis binds to aquaporin-4 water channel. J Exp Med 2005;202:473-477 Nico B, Frigeri A, Nicchia GP, et al. Role of aquaporin-4 water channel in the development and integrity of the blood-brain barrier. J Cell Sci 2001;114:1297 Yang B, Ma T, Verkman AS. cDNA cloning, gene organization, and chromosomal localization of a human mercurial insensitive water channel. Evidence for distinct transcriptional units. J Biol Chem 1995;270:22907-22913 Roemer SF, Lennon VA, Benarroch EE, Lassmann H, Bruck W, et al. Pattern-specific loss of aquaporin-4 immunoreactivity distinguish neuromyelitis optical from multiple sclerosis. Brain 2007 Sommer C, Weishaupt A, Brinkhoff, Biko L, Wessig C, Gold R, Toyka KV. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005;365:1406-1411 Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805-815

Project Title:	Study of potential neuroprotective role of adiponectin and APPL1 in beta-amyloid neuroto xicity
Investigator(s):	Chan KH, Lam KSL, Xu A, Ho SL, Ho WL
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2010

Abstract:

Alzheimer disease (AD) is a common neurodegenerative disease with significant morbidity and mortality, and the commonest cause of dementia (Selkoe 1991). The exact pathogenetic mechanisms of AD is uncertain. One of the most accepted potential pathogenesis is neurotoxici ty mediated by β-amyloid (Aβ) protein. Aβ monomers, predominantly the Aβ40 and Aβ42 are peptides derived from cleavage of the membrane protein, amyloid precursor protein (APP). Histopathological studies of brains from AD patients reveal accumulation of extracellular Aβ fibrils (senile plaques) and intracellular accumulation of neurofibrillary tangles. Aβ proteins exist in various forms including the monomer peptides, oligomers (soluble and insoluble) formed from oligomerization of monomers, and protofibrils and fibrils that are formed from further aggregation of the Aβ peptides (Yu et al., 2009). Aβ proteins are neurotoxic (Selkoe 1991). It is postulate d that Aβ cytotoxicity is related to the soluble protofibrils that cause uncontrolled ion flux due to their pore-forming properties (Arispe et al., 1993; Lashuel et al., 2002). Arispe et al. reported that Aβ forms pores acting as calcium channels in bilayer membrane (Arispe et al., 1993). Recent evidences strongly suggest that Aβ oligomers are directly toxic to neurons and probably play important roles in early stage of AD (Selkoe 2002). Most recently, a cleaved amino-terminal fragment of amyloid precursor protein (APP) is found to bind to the death receptor 6 (DR6) and triggers axonal pruning and neuronal death (Nikolaev et al., 2009). Neuroprotection is another important mechanism for potential therapeutic targets in AD. Recently, the endosomal protein APPL1 (adaptor protein containing PH [pleckstrin homology] domain, phosphotyrosine binding domain, and leucine zipper motif) is found to play important role as an endosomal adaptor protein in various signaling pathways, mediati ng signaling from ligand of cell membrane receptors to intracellular biological pathways that control gene transcriptions, cell proliferation and survival via endocytosis. APPL1 mediates induction of endothelial nitric oxide synthase and production of nitric oxide in endothelial cells by adiponectin via interaction with adiponectin receptors (AdipoR1 and AdipoR2) (Cheng et al., 2007). In this study, both APPL1 expression and adiponectin-induced vasodilation were significantly decreased in db/db diabetic mice. Insulin signaling in hepatocytes via interaction with APPL1 leads to increased hepatic insulin sensitivity and alleviates diabetes via activation of Akt (protein kinase B) activity in mice (Cheng et al., 2009). Adiponectin stimulates the interaction between APPL1 and Rab5 (a small GTPase), leading to increased glucose transporter 4 (GLUT4) membrane translocation (Ceddia et al., 2005). APPL1also acts as a critical regulator of the crosstalk between adiponectin signaling and insulin signaling pathways with insulin sensitizing function (Mao et al., 2006). APPL1 also plays important role in the nervous system. APPL1 expression is ubiquitous during development with high levels of expression in the forebrain (telencephalon), pronephros and neural tubes in developing vertebrates (Mao et al., 2006; Schenck et al., 2008). Lin et al. reported that APPL1 associates with TrkA receptor tyrosine kinase and is required for nerve growth factor (NGF) mediated signal transduction in sympathetic neurons. The TrkA receptor tyrosine kinase is essential for development and function of the vertebrate nervous system. NGF binds to TrkA in axon terminals, which are then internalized into endosomes via interaction of APPL1 with TrkA; endosomes are then transported retrogradely to nucleus. Neurons that have received sufficient retrograde survival and growth signals survive and innervate their target, while those that do not are eliminated by apoptosis (Lin D C et al., 2006). Schenck et al. studied the role of APPL1 in zebrafish and found that APPL1 regulates Akt activity and substrate specificity, controlling glycogen storage kinase 3β (GSK-3β); and APPL1 is selectively required for cell survival, most critically in highly expressing tissues (Schenck et al., 2008). Their results suggest that APPL1 functions as a membrane adaptor specifically required for Akt activity and cell survival in multicel lular organism, and that APPL1 selectively regulates apoptosis during development by controlling Akt signalling. The authors proposed that beyond embryonic development, APPL1-dependent segregation of Akt downstream pathways would also be expected to contribute to tissue maintenanc e and homeostasis. Recently, adiponection was reported to block interleukin-18 (IL-18) mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-κB/PTEN suppression (Chandrasker B et al., 2008). In this study, treatment of endothelial cells with IL-18 suppressed Akt phosphor ylation and its associated kinase activity, induced IκB kinase (IKK)-NF-κB-dependent PTEN activation and promoted endothelial cell death; and pretreatment with adiponectin stimulated APPL1-dependent AMPK activation and reversed Akt inhibition in a phophatidylinositol 3-kinase-depe ndent manner via blocking Bax translocation and hence inhibiting endothelial cell death. It has been shown that expression of IL-18 is increased in brains of AD patients (Ojala et al., 2007) and that IL-18 production by periphe ral blood cells is increased in AD patients, the level of which correlates with cognitive impairment (Bossu et al., 2007). These suggest that IL-18 related inflammatory pathways are exacerbated in AD patients and that IL-18 may participate in pathogenic process leading to dementia in AD. In addition, glial cells such as astrocyte play important role in function of CNS and evidences suggest that astrocytes are activated in AD contributing to the inflammation noted on histological studies of AD brain tissues. We would like to study, as the second part of this study, whether how astrocytes are affected by amyloid-beta by coculturing glioblastoma cells or mouse/rat fetal astrocytes with neuroblastoma cells over-expressing amyloid beta protein, and whether adiponectin can protect astrocytes from effect from potential amyloid beta toxicity to astrocytes. We hypothesize that 1) in AD, Aβ neurotoxicity affect normal signaling cascade activities of molecules such as adiponectin by impairing normal physiological action of the adaptor protein APPL1; and 2) that increased APPL1 activity , by enhancing activity of adiponectin signaling, is neuroprotective against Aβ-induced neuronal injury/death in AD, 3) adiponectin and enhanced APPL1 activity may also protect astrocytes against harmful effect from amyloid beta toxicity. We would like to study 1) whether neuroblastoma cells overexpressing amyloid-beta have reduced APPL1 expression, 2) whether human neuroblastoma cells overexpressing APPL1 is protected from Aβ neurotoxicity in the in-vitro model, 3) whether adiponectin is neuroprotective against amyloid-beta neurotoxicity in this in-vitro cultured cell model, 4) if adiponectin is neuroprotective, whether its neuroprotective action is dependent on function of APPL1, and 5) whether adiponectin can protect astrocytes against potential harmful effect from amyloid beta protein.

Project Title:	20th Meeting of the European Neurological Society Aquaporin-4 expression by thymoma of myasthenia gravis patients
Investigator(s):	Chan KH
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	06/2010
Completion Date:	06/2010

Abstract:

N/A

List of Research Outputs

Chan K.H. , A Case Of Postpartum Collapse: Neurologist's Perspective, Obstetrics and Gynaecology Clinical Conference . 2010.

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chan K.H. , Kwan S.C. , Chu A.C.Y. , Ho W.L. , Ho W.M. and Ho S.L. , Aquaporin-4 expression by thymoma of myasthenia gravis patients, 20th Meeting of the European Neurological Society, Berlin, 2010; Journal of Neurology . 2010, 257 (Supplement 1): S50.

Chan K.H. , Brief Talk on Multiple Sclerosis, Metropolis Daily . 2010, 30.

Chan K.H. , Chairmanship at Young Investigators Award Forum II of Fifth International Symposium on Healthy Aging , Fifth International Symposium on Healthy Aging, Research Center of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Chan K.H. , Chairmanship of Oral Session in Clinical Medicine, 15th Medical Research Conference , 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Chan K.H. , Ho S.P., Yeung S.C. , So H.L. , Cho C.H., Koo M.W.L. , Lam W.K. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine . 2009, 103: 1746-1754.

Chan K.H. , Tse C.T., Ho S.L. , Ho W.L. and Ho W.M. , Clinical Outcome of Hong Kong Chinese Relapsing Remit ting Multiple Sclerosis, 20th Meeting of European Neurological Society, Be rlin, 2010 .

Chan K.H. , Yeung S.C. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Effects of Chinese green tea on cigarette smoke-induced lung inflammation, oxidative stress and protease act ivity in rats, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A5062.

Chan K.H. , Yeung S.C. , Yao T.J. , Ip M.S.M. , Cheung A.H.K. , Chan M.M.W. and Mak J.C.W. , Elevated Plasma Adiponectin Levels In Patients With Chronic Obstructive Pulmonary Disease, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 10.

Chan K.H. , Invited Chairmanship at Session on Neurology, Hong Kong Medical Forum, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Chan K.H. , Invited Chairmanship of Alzheimer's Disease Research Seminar: Current Concepts of Immunotherapy for Alzheimer Disease, Hong Kong University Alzheimer's Disease Research Network, Research Center of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Chan K.H. , Member of Organizing Committee, Second Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS) . 2009.

Chan K.H. , Multiple Sclerosis Day: Study on Employment of Multiple Sclerosis Patients by Multiple Sclerosis International Federation, Press Conference on Multiple Sclerosis Day 2010: Employment of Multiple Sclerosis Patients . 2010.

Chan K.H. , Multiple Sclerosis, The Sun (Chinese Newspaper) . 2010.

Chan K.H. , Neuroinflammation in Alzheimer's Disease, Alzheimer's Disease Conference: From Public Health to Therapeutic Insights . 2010.

Chan K.H. , Paraneoplastic Neurological Disorders Part 1: Pathogenesis and Diagnosis, Medical Progress . 2009, 36: 317-322.

Chan K.H. , Paraneoplastic Neurological Disorders Part 2: Clinical Features And Treatment, Medical Progress . 2009, 36: 369-375.

Chan K.H. , Tsang J.W.H. , Mak W. , Liu H.H.W., Ho S.L. and Cheung R.T.F. , Thymomatous myasthenia gravis among Hong Kong Chinese, 20th Meeting of the European Neurological Society , Berlin, 2010. Journal of Neurology . 2010, 257 (Supplement 1): S170.

Goh K.J., Umapathi T., Puvanarajah S.D., Lo Y.L., Goh K.Y., Witoonpanich R., Chandrachang S., Misbach J., Wibowo B.S., Rosales R.L., Damian H.L.F., Chan K.H. , Chiu H.C. and Shahrizaila N., Good clinical practice points on the use of acetylcholinesterase inhibitors in myasthenia gravis: Recommendations from the Special Interest Group in Myasthenia Gravis in Asia, Neurology Asia . 2009, 14(2): 175-176.

Goh K.J., Umapathi T., Puvanarajah S.D., Lo Y.L., Goh K.Y., Witoonpanich R., Chankrachang S., Misbach J., Wibowo B.S., Rosales R.L., Damian H.L.F., Chan K.H. , Chiu H.C. and Shahrizalia N., Good clinical practice points on the use of acetylcholinesteras e inhibitors in myasthenia gravis: recommendation from a South-East Asian regional special interest group on myasthenia gravis, 19th World Congress of Neurology . 2009.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Inves tigator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.L. , Ho W.M. , Liu H. , Chan K.H. , Ramsden D.B. and Ho S.L. , Neuronal mitochondrial uncoupling proteins: implications in the pathology of Parkinson’s disease , The Hong Kong Neurological Society - Annual Scientific Meeting 2009; Kowloon Shangri-La Hotel, Hong Kong; 8 Nov 2009. . 2009.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kim M. , Chan C.W.A. , Mak H.K.F. , Chan Q. and Chan K.H. , Magnetization Transfer MRI measurements of Cervical Spinal Cord abnormalities in patients with Neuromyelitis Optica, Joint ISMRM-ESMRMB Annual Scientific Meeting, Stockholm, Sweden, 1-7 May . Stockholm, Sweden, 2010.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Herpes simplex encephalitis: how good are we in diagnosing this condition?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 29.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Ischaemic stroke related to branch artery disease: a missing link?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 30.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Liu H.H.W., Tsang J.W.H. , Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Chu A.C.Y. , Tse M.M.Y., Mak W. , Ho W.L. and Chan K.H. , Thymomatous myasthenia gravis, 15th Medical Research Conference, Faculty of Medicine, The University of Hong Kong . 2010.

Qian W. , Mak H.K.F. , Chan Q., Chan K.H. and Kim M. , Quantitative assessment of the cervical spinal cord damage in neuromyelitis optica using diffusion tensor imaging at 3T , Joint ISMRM-ESMRMB Annual Scientific Meeting, Stockholm, Sweden, 1-7 May . 2010.

Teo K.C., Mahboobani N.R., Lee R. , Cheung R.T.F. , Ho S.L. , Tse C.T. and Chan K.H. , Intracerebral hemorrhage complicating anticoagulant therapy among Hong Kong Chinese, 15th Medical Research Conference, Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Best Abstract In Clinical Medicine, 15th Medical Research Conference, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Clinical outcome of relapsing remitting multiple sclerosi s among Hong Kong Chinese, 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Researcher : Chan KH

List of Research Outputs

Chan K.H. , A Case Of Postpartum Collapse: Neurologist's Perspec tive, Obstetrics and Gynaecology Clinical Conference . 2010.

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chan K.H. , Brief Talk on Multiple Sclerosis, Metropolis Daily . 2010, 30.

Chan K.H. , Chairmanship of Oral Session in Clinical Medicine, 15th Medical Research Conference , 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Chan K.H. , Tse C.T., Ho S.L. , Ho W.L. and Ho W.M. , Clinical Outcome of Hong Kong Chinese Relapsing Remitting Multiple Sclerosis, 20th Meeting of European Neurological Society, Berlin, 2010 .

Chan K.H. , Yeung S.C. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Effects of Chinese green tea on cigarette smoke-induced lung inflammation, oxidative stress and protease activity in rats, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A5062.

Chan K.H. , Invited Chairmanship at Session on Neurology, Hong Kong Medical Forum, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Chan K.H. , Invited Chairmanship of Alzheimer's Disease Research Seminar: Current Concepts of Immunotherapy for Alzhei mer Disease, Hong Kong University Alzheimer's Disease Research Network, Research Center of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Chan K.H. , Member of Organizing Committee, Second Congress of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS) . 2009.

Chan K.H. , Multiple Sclerosis, The Sun (Chinese Newspaper) . 2010.

Chan K.H. , Neuroinflammation in Alzheimer's Disease, Alzheimer's Disease Conference: From Public Health to Therapeutic Insights . 2010.

Chan K.H. , Paraneoplastic Neurological Disorders Part 1: Pathogenesi s and Diagnosis, Medical Progress . 2009, 36: 317-322.

Chan K.H. , Paraneoplastic Neurological Disorders Part 2: Clinica l Features And Treatment, Medical Progress . 2009, 36: 369-375.

Chan K.H. , Tsang J.W.H. , Mak W. , Liu H.H.W., Ho S.L. and Cheung R.T.F. , Thymomatous myasthenia gravis among Hong Kong Chinese, 20th Meeting of the European Neurological Society, Berlin, 2010. Journal of Neurology . 2010, 257 (Supplement 1): S170.

Goh K.J., Umapathi T., Puvanarajah S.D., Lo Y.L., Goh K.Y., Witoonpanich R., Chandrachang S., Misbach J., Wibowo B.S., Rosales R.L., Damian H.L.F., Chan K.H. , Chiu H.C. and Shahrizaila N., Good clinical practice points on the use of acetylcholinester ase inhibitors in myasthenia gravis: Recommendations from the Special Interest Group in Myasthenia Gravis in Asia, Neurology Asia . 2009, 14(2): 175-176.

Goh K.J., Umapathi T., Puvanarajah S.D., Lo Y.L., Goh K.Y., Witoonpanich R., Chankrachang S., Misbach J., Wibowo B.S., Rosales R.L., Damian H.L.F., Chan K.H. , Chiu H.C. and Shahrizalia N., Good clinical practice points on the use of acetylcholine sterase inhibitors in myasthenia gravis: recommendation from a South-East Asian regional special interest group on myasthenia gravis, 19th World Congress of Neurology . 2009.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Investigator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese, 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Researcher : Chan KHT

List of Research Outputs

Dai Y.L., Luk T.H., Siu D.C.W. , Yiu K.H., Chan K.H.T. , Lee S.W.L. , Li S.W., Fong B., Wong W.K., Tam S. , Lau C.P. and Tse H.F. , Mitochondrial dysfunction induced by statin contributes to endothelial dysfunction in patients with coronary artery disease., Cardiovascular Toxicology . 2010, 10: 130-8.

Researcher : Chan MMW

Project Title:	A surveillance program of tuberculosis in old age homes in Hong Kong
Investigator(s):	Chan MMW, Chu LW, Lam WK
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	11/2001

Abstract:

To conduct a cross-sectional screening examination for tuberculosis in old age homes in several districts in Hong Kong, SAR; to ensure that directly observed therapy (DOT) is given to those with active disease diagnosed through the screening program in collaboration with the Hong Kong Government Tuberculosis and Chest Service (Chest Service); to provide a screening examinatio n for tuberculosis for new residents on entry to the old age homes participating in the program; to participate, in collaboration with the Chest Service, in contact examination on residents in the same home from which an active case of tuberculosis is being diagnosed; to provide education to the staff of old age homes on early recognition of tuberculosis, its treatment and possible side effects to evaluate the effectiveness of the program.

Project Title:	A surveillance program of tuberculosis in old age homes in Hong Kong
Investigator(s):	Chan MMW, Chu LW, Lam WK
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	01/2004

Abstract:

To conduct a cross-sectional screening examination for tuberculosis in old age homes in several districts in Hong Kong, SAR; to ensure that directly observed therapy (DOT) is given to those with active disease diagnosed through the screening program in collaboration with the Hong Kong Tuberculosis and Chest Service, Department of Health (Chest Service); to provide a screening examination for tuberculosis for new residents on entry to the old age homes participating in the program; to participate, in collaboration with the Chest Service, in contact examination on residents in the same home from which an active case of tuberculosis is being diagnosed; to provide education to the staff of old age homes on early recognition of tuberculosis, its treatment and possible side effects; to evaluate the effectiveness of the program.

List of Research Outputs

Carlsten C., Dimich-Ward H., Becker A.B., Ferguson A., Chan H.W., DyBuncio A. and Chan M.M.W. , Indoor allergen exposure, sensitization, and development of asthma in a high-risk birth cohort. , Pediatr Allergy Immunol . 2010, 21(4 Pt 2): e740-6.

Chan K.H. , Yeung S.C. , Yao T.J. , Ip M.S.M. , Cheung A.H.K. , Chan M.M.W. and Mak J.C.W. , Elevated Plasma Adiponectin Levels In Patients With Chronic Obstructive Pulmonary Disease, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 10.

Chan M.M.W. and Pierard C., Lessons on lung diseases in 2009., Int J Tuberc Lung Dis. . 2010, 14(3): 263-8.

Wang J.K., Ho J.C.M. , Mok T.Y., Chan J.W., Yee W.K., Chan M.M.W. , Cheung B.M.Y. , Lam K.S.L. , Lam W.K. and Ip M.S.M. , The relationship of asthma and the pattern of adiposity in adult Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 56.

Researcher : Chan RHW

List of Research Outputs

Ho H.H., Cheung C.W., Jim M.H., Miu R., Lam Y.M. , Chan R.H.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Type A aortic intramural hematoma: clinical features and outcomes in Chinese patients, Clinical Cardiology . 2010, (in press).

Researcher : Chan SY

List of Research Outputs

Lee A.M. , Chu L.W. , Chong C.S.Y., Chan S.Y. , Lam K.S.L. and Lam T.P. , Relationship Between Symptoms of Androgen Deficiency and Psychological Factors and Quality of Life among Chinese Men., International Journal of Andrology. . 2009.

Researcher : Chan TK

List of Research Outputs

Chan K. , Yam I.Y.L. , Leung K.Y., Tang M., Chan T.K. and Chan V.N.Y. , Detection of paternal alleles in maternal plasma for non-invasive prenatal diagnosis of beta-thalassemia: a feasibility study in southern Chinese., Eur J Obstet Gynecol Reprod Biol . 2010, 150: 28-33.

Researcher : Chan VNY

Project Title:	Hepatitis B virus array for genotyping and mutation detection
Investigator(s):	Chan VNY, Lai CL, Chan K, Yuen RMF
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	11/2006

Abstract:

To design a comprehensive hepatitis B virus array for the simultaneous analysis of 8 HBV genotypes, 5 precore, 4 core promoter, 23 S gene and 44 polymerase gene mutations. A total of 88 variants will be assessed; to assess the sensitivity of the system; to monitor 50 patients on anti-viral therapy over a period of 18 months to detect any development of drug resistance by detection of viral mutants in their serum sample

List of Research Outputs

Chan K. , Yam I.Y.L. , Leung K.Y., Tang M., Chan T.K. and Chan V.N.Y. , Detection of paternal alleles in maternal plasma for non-invasive prenatal diagnosis of beta-thalassemia: a feasibility study in southern Chinese., Eur J Obstet Gynecol Reprod Biol . 2010, 150: 28-33.

Chan V.N.Y. , RAD9A (RAD9 homolog A (S. pombe)), Atlas of Genetics and Cytogenetics in Oncology and Haematology . 2010.

Leung K.Y. , Cheong K.B. , Lee C.P. , Chan V.N.Y. , Lam Y.H. and Tang M.H.Y. , Ultrasonographic prediction of homozygous a ^o -thalassemia using placental thickness, fetal cardiothoracic ratio and middle cerebral artery Doppler: alone or in combination? , Ultrasound in Obstetrics & Gynecology . 2010, 35: 149-154.

Li T.K.T. , Leung K.Y. , Lam Y.H., Tang M.H.Y. and Chan V.N.Y. , Does in-utero transfusion for homozygous a ^o -thalassemia depend on hemoglobin level alone? , 19 ^th World Congress on Ultrasound in Obstetrics and Gynecology, Hamburg, Germany, September 13–17 2009. . 2009.

Researcher : Chan WK

List of Research Outputs

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Foxp3 mRNA expression on DC subsets in patients of systemic lupus erythematosus. , IJRD . 2010, 13: S557 p55.

Jin O. , Kavikondala S. , Mok T.M.Y. , Sun L.Y., Gu J.R., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Studies on the function of plasmacytoid dendritic cells in healthy and systemic lupus erythematosus., IJRD . 2010, 13: S554p54.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Study on myeloid dendritic cells in systemic lupus erythematosus, IJRD . 2010, 13: S793 p56.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow-derived dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Wu H. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patients with systemic lupus erythematosus. , HKMJ . 2010, 16: p57 S98.

Wu H. , Lau W.C.S. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patien ts with systemic lupus erythematosus. , IJRD . 2010, 13: S680 p114.

Researcher : Chan WS

List of Research Outputs

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Improvement of myocardial perfusion reserve detected by cardiovascular magnetic resonance after direct endomyocardial implantation of autologous bone marrow cells in patie nts with severe coronary artery disease, Journal of cardiovascular magnetic resonance . 2010, 12(1): 6..

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Therapeutic angiogenesis with direct endomyocardial implantation of autologous bone marrow cells in patients with severe coronary artery diseases: Insight from cardiac magnetic resonance imaging., J Cardiovasc Magn Reson. . 2010, 12: 6.

Researcher : Chan YC

Project Title:	ISSCR 7th ANNUAL MEETING PROMOTION OF MOUSE EMBRYONIC STEM CELL DIFFERENTIATION INTO CARDIOM YOCYTES VIA ELECTRICAL STIMULATION
Investigator(s):	Chan YC
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	07/2009
Completion Date:	07/2009

Abstract:

N/A

Project Title:	Promotion Of Mouse Embryonic Stem Cell Differentiation Into Cardiomyocytes Via Electri cal Stimulation
Investigator(s):	Chan YC, Tse HF, Siu DCW
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	07/2009

Abstract:

Different stem cell populations have been advocated as a promising therapeutic material for myocardial repair (Joggerst SJ and Hatzopoulos AK, 2009). Embyronic stem cell (ESC) derived from inner cell mass of the pre-implantation blastocyst, being pluripotent in nature , can differentiate into cardiomyocytes (CMs) in appropriate conditions (Wobus AM, et al., 1991; Maltsev VA, et al., 1993). ESC-derived CMs had been implanted into injured heart to repair damaged cardiac tissue with encouraging results (Behfar et al., 2007; Laflamme et al., 2007; Min et al., 2002; Yang et al., 2002). Therefore, focus on the methodology to promote differentiation process of ESC to CMs has been drawn to much attenti on. Apart from the application of chemicals, electro-stimulation, previously shown as a trophic factor to elicit phenotypic changes in myoblasts (Genovese JA et al., 2008), may also help differentiating ESC into CMs while at the same time remove any unknown side-effects incurred by chemicals on the cells. The present research project aims to investigate whether electro-stimulation could promote CMs differentiation and examine the electro-physiological, molecular, as well as functional effects underlying. D3 mouse ESCs in the form of embryoid bodies (EBs) are first seeded on 0.1% gelatin-coated glass cover slips. Once the EBs have settled down and well attached to the chamber bottom a day after plating, they are subjected to long-term electric field stimulation with an eight-channel C-Pace chronic stimulator (Ion-Optics Co., MA). Voltages of 10 V have been used in 1 Hz, 2 ms pulses. Cells are then subjected to electro-physiologi cal, molecular and functional data analysis after 7 days of stimulation. References: Behfar A, Perez-Terzic C, Faustino RS, Arrell DK, Hodgson DM, Yamada S, Puceat M, Niederländer N, Alekseev AE, Zingman LV, Terzic A. (2007) Journal of Experimental Medicine 204, 405-420. Genovese JA, Spadaccio C, Langer J, Habe J, Jackson J, Patel AN.(2008) Biochem Biophys Res Commun. Jun 6;370(3):450-5. Joggerst SJ, Hatzopoulos AK. (2009) Expert Rev Mol Med. 8;11:e 20. Laflamme MA, Chen KY, Naumova AV, Muskheli V, Fugate JA, Dupras SK, Reinecke H, Xu C, Hassanipour M, Police S, O'Sullivan C, Collins L, Chen Y, Minami E, Gill EA, Ueno S, Yua n C, Gold J, Murry CE.. (2007) Nature Biotechnology 25, 1015-1024. Maltsev VA, Rohwedel J, Hescheler J, Wobus AM. (1991)Mech Dev. 191:41-50. Min JY, Yang Y, Converso KL, Liu L, Huang Q, Morgan JP, Xiao YF. l. (2002). Journal of Applied Physiology 92, 288-296. Wobus AM, Wallukat G, Hescheler J. Differentiation 48:173-182. Yang Y, Min JY, Rana JS, Ke Q, Cai J, Chen Y, Morgan JP, Xiao YF.. (2002) Journal of Applied Physiology 93, 1140-1151

List of Research Outputs

Chan Y.C. , Lee Y.K. , Ng K.M. , Lai K.W.H. , Yang D. , Tse H.F. and Siu D.C.W. , A Newly-derived Small Synthetic Compound Alleviated Ventricular Fibrillation In A Pig Model With Chronic Myocardial Infarction As Revealed By Optical Mapping, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” (Hong Kong) . 2010.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. and Li R.A. , Automaticity and conduction properties of bio-artifi cial pacemakers assessed in an in vitro monolayer model of neonatal rat ventricular myocytes., Europace. In press. . 2010.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. , Lau C.P. and Tse H.F. , Characterizing the basis of automaticity of neonatal rat ventricular myocytes: Implications for cardiac excitability manipulations., Europace . 2010.

Chan Y.C. , Leung C.F.P. , Wong W.T., Tian X.Y., Yung L.M., Lau C.W., Tsang S.Y., Yao X., Chen Z.Y. and Huang Y., Therapeutically relevant concentrations of raloxifene dilate pressurized rat resistance arteries via calcium-dependent endothelial nitric oxide synthase activation., Arterioscler Thromb Vasc Biol . 2010, 30(5): 992-9.

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai K.W.H. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1alpha promotes cardiac differentiation of embryonic stem cells., Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-37.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embry onic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Researcher : Chan YC

List of Research Outputs

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. and Li R.A. , Automaticity and conduction properties of bio-artific ial pacemakers assessed in an in vitro monolayer model of neonatal rat ventricular myocytes., Europace. In press. . 2010.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embryo nic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Researcher : Chan YY

List of Research Outputs

Guo H. , Leung J.C.K. , Cheung J.S., Chan Y.Y. , Wu E.X. and Lai K.N. , Non-viral Smad7 gene delivery and attenuation of postoperative peritoneal adhesion in an experimental model, Br J Surg . 2009, 96(11): 1323-35.

Tang S.C.W. , Chan Y.Y. , Leung J.C.K. , Cheng A.S. , Chan K.W. , Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote renal tubular inflammation, Nephrol Dial Transplant . 2010, 25(3): 698-710.

Xiao J. , Leung J.C.K. , Chan Y.Y. , Tang S.C.W. and Lai K.N. , Crosstalk between peroxisome proliferator-activated receptor-gamma and angiotensin II in renal tubular epithelial cells in IgA nephropathy, Clinical Immunology . 2009, 132: 266-276.

Researcher : Chau KM

List of Research Outputs

Yung S.S.Y. , Chau K.M. , Yip T.P.S., Li F.K. and Chan D.T.M. , Induction of inflammatory and fibrotic mediators in human peritoneal mesothelial cells (HPMC) by icodextrin-base d peritoneal dialysis fluid, J Am Soc Nephrol . 2009, 20: 694A.

Researcher : Chen C

List of Research Outputs

Chen C. , Xu A. , Tso A.W.K. , Law S.C. , Cheung B.M.Y. , Janus E.D., Wat N.M.S. and Lam K.S.L. , Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study., 5th International Symposium on Healthy Aging . 2010.

Researcher : Chen H

List of Research Outputs

Li X. , Tse H.F. , Yiu K.H., Jia N., Chen H. , Li L.S.W. and Jin L.J. , Increased levels of circulating endothelial progenitor cells in subjects with moderate to severe chronic periodo ntitis, Journal of Clinical Periodontology . 2009, 36: 933-939.

Researcher : Chen J

List of Research Outputs

Chen J. , Tao R. , Sun H. , Tse H.F. , Lau C.P. and Li G.R. , Multiple Ca(2+) signaling pathways regulate intracellular Ca(2+) activity in human cardiac fibroblasts., J Cell Physiol . 2010, 223(1): 68-75.

Chen J. and Li G.R. , Purinoceptor activation and cell proliferation in human cardiac fibroblasts., Biophysical Journal/54th Annual Meeting of Biophysical Society, San Francisco, California, USA. Feb 20-24 . 2010, L166.

Li G.R. , Sun H. , Chen J. , Zhou Y. , Tse H.F. and Lau C.P. , Characterization of Multiple Ion Channels in Cultured Human Cardiac Fibroblasts. , PLoS One . 2009, 4(10): e7307.

Researcher : Chen JY

List of Research Outputs

Salter Menzo D.J. , Chan L.C. and Chen J.Y. , Creating a learning environment to develop students' reflection and communication about medical humanities , Frontiers in Medical and Health Sciences Education "Making Sense in Communication" . 2009.

Researcher : Chen WH

Project Title:	Enoxaparin combined with epitfibatide or abciximab versus unfractionated heparin combined with epitfibatide or abciximab in percutaneous coronary intervention: obersvations on efficacy, safety, anticoagulation profile, and level of platelet inhibition
Investigator(s):	Chen WH, Lau CP
Department:	Medicine
Source(s) of Funding:	Other Funding Scheme
Start Date:	06/2001

Abstract:

To compare the safety, efficacy, anticoagulation profile and level of platelet inhibition in patients undergoing percutaneous coronary intervention using enoxaparin/eptifibatide, unfractionated heparin/epitfib atide, enoxaparin/abciximab, and unfractionated heparin/abciximab.

Project Title:	A prospective study to investigate the determinants of the quantity of embolized debris during native vessel percutaneous coronary intervention
Investigator(s):	Chen WH, Lau CP
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2002

Abstract:

To identity the clinical and lesion characteristics that determine the quantity of embolized debris captured by a distal protection device during native vessel PCI.

Project Title:	A prospective study to evaluate the relation between aspirin resistance and the incidence and magnitude of myonecrosis after percutaneous coronary intervention
Investigator(s):	Chen WH, Lau CP
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2003

Abstract:

To compare the incidence and magnitude of myoecrosis between aspirin-sensitive and -resistant patients undergoing PCI.

Researcher : Chen Y

List of Research Outputs

Cheung K.F. , Ye D. , Yang Z. , Lu L. , Liu C.H., Wang X.L., Poon R.T.P. , Tong Y. , Liu P., Chen Y. and Lau G. , Therapeutic efficacy of Traditional Chinese Medicine 319 recipe on hepatic fibrosis induced by carbon tetrachl oride in rats, Journal of Ethnopharmacology . 2009, 124(1): 142-150.

Researcher : Cheng AS

List of Research Outputs

Tang S.C.W. , Chan Y.Y. , Leung J.C.K. , Cheng A.S. , Chan K.W. , Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote renal tubular inflammation, Nephrol Dial Transplant . 2010, 25(3): 698-710.

Researcher : Cheng CH

List of Research Outputs

Cheng C.H. , Tam J.H. , Wong R., Yik P.Y. , Song Y.Q., Morley J.E. and Lam K.S.L. , Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men: a 1-year cohort study., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 16.

Researcher : Cheng CTK

List of Research Outputs

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Correlation of liver stiffness and histological featu res in healthy persons and in patients with occult hepatitis B, chronic active hepatitis B, or hepatitis B cirrhosis., Am J Gastroenterol . 2009, 105(5): 1116-22.

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Liver stiffness and histological features in healthy persons, and patients with occult hepatitis B, chronic active hepatitis B, and hepatitis B-related cirrhosis., Hepatology . 2009, 50(4) Suppl: 978A.

Fung J.Y.Y. , Lai C.L. , Cheng C.T.K. , Wu C.H. , Wong D.K.H. and Yuen R.M.F. , Mild-to-moderate elevation of alanine aminotransferase may increase liver stiffness measurement by transient elastography in patients with chronic hepatitis B., Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 971A.

Fung J.Y.Y. , Lai C.L. , Yuen J.C.H. , Cheng C.T.K. , Wu C.H. and Yuen R.M.F. , Sequential therapy using lamivudine in entecavir-treated patients with undetectable HBV DNA – results at 48 weeks. , Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 510A.

Researcher : Cheng CW

List of Research Outputs

Cheng C.W. , Pang R.W.C. , Kwong Y.L. and Tse E.W.C. , Pin1 enhances the anti-apoptotic function of survivin in cancer cells, 16th Hong Kong International Cancer Congress . 2009.

Researcher : Cheng SW

List of Research Outputs

Yip T.P.S., Lui S.L. , Tse K.C., Xu H., Ng F.S.K. , Cheng S.W. , Chan D.T.M. , Lai K.N. and Lo W.K. , A prospective randomized study comparing tenckhoff catheters inserted using the triple incision method with standard swan neck catheters, Peritoneal Dialysis International . 2010, 30(1): 56-62.

Researcher : Cheng YY

Project Title:	The role of hypoxia inducible facto r 1 alpha in NK/T-cell lymphoma
Investigator(s):	Cheng YY, Tse EWC
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	12/2008

Abstract:

Natural killer (NK) cell malignancies are aggressive solid tumours that are rare in the United States and Europe but common in Asia and South America [1-4]. Nasal NK-cell lymphoma is aggressive with a median survival period of less than 12 months [5]. One of reasons for the poor prognosis of nasal NK/T-cell lymphoma is its strong tendency to have a widespread relapse or dissemination into distant sites. Another reason is that NK/T-cell lymphomas are refractory to conventional chemotherapy [6-8]. The ineffectiveness of chemotherapy for such lymphoma types can be partially explained by the presence of the multi-drug resistance (MDR) phenotype, which confers cellular resistance to a vari ety of unrelated anticancer agents [7-9]. Hypoxia can also provide solid malignancies with resistance to conventional therapies. This is also linked to the malignancy’s poor prognosis [10-12]. In an attempt to improve the management of NK/T-cell lymphoma with adjuvant therapy, the understanding of the microenvironment of NK/T-cell lymphoma becomes important. Stewart et al showed that hypoxia-inducible factor (Hif) was expresse d in lymphomas [13]. Constitutive Hif activation and elevated Hif levels in solid tumours have been shown to be related to poor prognosis [14]. The role of Hif in NK/T-cell lymphoma has not been well established. An important role for Hif has emerged in cancer biology, including a relationship between elevated Hif-1a expressions with high tumour grade in solid tumours [14, 15]. Hypoxia triggers the transcription of genes responsible for cell survival mainly through hypoxia-inducible factor 1alpha (Hif-1a). Overexpression of this protein has been implicated in carcinogenesis and cancer progression [16, 17]. In addition to the effect of Hif-1a transcript ional activity in a hypoxic environment, it also seems to be involved in the determination of cell fate in a normoxic environment [18]. Many cancers are characterized by enhanced Hif levels and increased expression of hypoxically regulated genes which correlates with both tumour aggression and patient outcome [19, 20]. Although there are a lack of studies that have mentioned the relationship between Hif-1a and NK/T-cell lymphoma, we hypothesize that Hif-1a may play an important role in NK/T-cell lymphoma. This proposal seeks to investigate the expression of Hif-1a and its functional significance in NK/T-cell lymphoma. The major objective of this study is to elucidate the role of Hif-1a in NK/T cell lymphoma. The specific objectives are: 1 To determine the expression of Hif-1a in NK/T-cell lymphoma under normoxic and hypoxic condition: 1.1 Hypoxia treatment of NK/T cell lymophoma lines; 1.2 The mRNA expression of Hif-1a; 1.3 The protein expression level of Hif-1a; 1.4 The localization of Hif-1a expression in primary NK/T cell lymphoma. 2 To determine the effect of Hif-1a knock down in NK/T cell lymphoma: 2.1 To determine the effect of siRNA knock down of Hif-1a in NK/T cell lymphoma, 1. Aozasa, K., et al., Nation-wide study of lethal mid-line granuloma in Japan: frequencies of wegener's granulomatosis, polymorphic reticulosis, malignant lymphoma and other related conditions. Int J Cancer, 1989. 44(1): p. 63-6. 2. Ferry, J.A., et al., Nasal lymphoma. A clinicopathologic study with immunophenotypic and genotypic analysis. Am J Surg Pathol, 1991. 15(3): p. 268-79. 3. Ho, F.C., et al., Polymorphic reticulosis and conventional lymphomas of the nose and upper aerodigestive tract: a clinicopat hologic study of 70 cases, and immunophenotypic studies of 16 cases. Hum Pathol, 1990. 21(10): p. 1041-50. 4. Jaffe, E.S., et al., Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphoma s. Definitions, differential diagnosis, and epidemiology. Am J Surg Pathol, 1996. 20(1): p. 103-11. 5. Kwong, Y.L., Natural killer-cell malignancies: diagnosis and treatment. Leukemia, 2005. 19(12): p. 2186-94. 6. Cheung, M.M., et al., Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophe notype, and treatment outcome in 113 patients. J Clin Oncol, 1998. 16(1): p. 70-7. 7. Kim, G.E., et al., Combined chemotherapy and radiation versus radiation alone in the management of localized angiocentric lymphoma of the head and neck. Radiother Oncol, 2001. 61(3): p. 261-9. 8. Ribrag, V., et al., Early locoregional high-dose radiotherapy is associated with long-term disease control in localized primary angiocentric lymphoma of the nose and nasopharynx. Leukemia, 2001. 15(7): p. 1123-6. 9. Yamaguchi, M., et al., Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells. Cancer, 1995. 76(11): p. 2351-6. 10. Brown, J.M. and A.J. Giaccia, The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res, 1998. 58(7): p. 1408-16. 11. Hockel, M., et al., Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol, 1993. 26(1): p. 45-50. 12. Hockel, M., et al., Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res, 1996. 56(19): p. 4509-15. 13. Stewart, M., et al., Expression of angiogenic factors and hypoxia inducible factors HIF 1, HIF 2 and CA IX in non-Hodgkin's lymphoma. Histopathology, 2002. 40(3): p. 253-60. 14. Zhong, H., et al., Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res, 1999. 59(22): p. 5830-5. 15. Kronblad, A., et al., Hypoxia inducible factor-1alpha is a prognost ic marker in premenopausal patients with intermediate to highly differentiated breast cancer but not a predictive marker for tamoxifen response. Int J Cancer, 2006. 118(10): p. 2609-16. 16. Semenza, G.L., HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol, 2000. 88(4): p. 1474-80. 17. Semenza, G.L., HIF-1 and human disease: one highly involved factor. Genes Dev, 2000. 14(16): p. 1983-91. 18. Wang, F., et al., Inhibitory effects of nitric oxide on invasion of human cancer cells. Cancer Lett, 2007. 257(2): p. 274-82. 19. Chi, J.T., et al., Gene expression programs in response to hypoxia: cell type specificity and prognostic significance in human cancers. PLoS Med, 2006. 3(3): p. e47. 20. Semenza, G.L., HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med, 2002. 8(4 Suppl): p. S62-7.

List of Research Outputs

Liu X., Lam E.K., Wang X., Zhang J., Cheng Y.Y. , Lam Y.W., Ng K.O. , Yu J., Chan F.K., Jin H. and Sung J.J., Promoter Hypermethylation Mediates Downregulation of Thiamine Receptor SLC19A3 in Gastric Cancer, Tumour Biol . 2009, 30(5): 242-248.

Researcher : Cheung AHK

List of Research Outputs

Chan K.H. , Yeung S.C. , Yao T.J. , Ip M.S.M. , Cheung A.H.K. , Chan M.M.W. and Mak J.C.W. , Elevated Plasma Adiponectin Levels In Patients With Chronic Obstructive Pulmonary Disease, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 10.

Researcher : Cheung BMY

Project Title:	The effect of adrenomedullin on gene and protein expression in macrophages stimulated by tumour necrosis factor-alpha
Investigator(s):	Cheung BMY, Tang F, Lau WCS
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2010

Abstract:

Purpose of the proposed project To study the effect of ADM and its binding protein, AMBP-1, on gene and protein expression in a rat macrophage cell line, NR838 3, stimulated by the pro-inflammatory cytokine, TNF-α. Key issues and problems being addressed A. Work done by others Adrenomedullin (ADM) was first isolated from the adrenal medulla and is a powerful vasodilator [1]. We and others have reported elevated plasma ADM levels in hypertension and heart failure [2, 3]. It gradual ly emerges, however, that ADM is expressed throughout the body and plays an important role in counter-regulating inflammation and apoptosis. ADM is remarkably conserved in evolution despite its length, which is necessary for its bactericidal binding to the bacterial cell wall. It is ubiquitous and present in all tissue types (including the eye) and body fluids (including sweat ) as part of the innate immunity system. Circulating ADM is bound to adrenomedullin binding protein-1 (AMBP-1), which is in fact complement factor H [4]. They bind to bacteria and protect normal healthy cells from the attack of inflammatory cytokines and complement. Homozygous deletion of ADM is lethal. Heterozygous mice with reduced ADM are more susceptible to septic shock and ischaemia-reperfusion injury [5], while transgenic mice with augmented ADM expression are very resistant to septic shock [6], and in vivo transfer of the ADM gene protects the myocardium and kidneys of spontaneously hypertensive rats [7]. In the hypotensive phase of septic shock, there is decreased AMBP-1 and responsiveness to ADM. Administration of ADM and AMBP-1 rescued such rats from irreversible and fatal hypotension [8]. Another line of evidence highlighting the critical role of ADM in cell survival is the discovery that ADM is the lead gene in the gene expression signature for hepatocellular carcinoma [9]. This is supported by the experiment using an antibody to ADM receptors to inhibit tumour angiogenesis and suppress the growth of human tumour xenografts in mice [10]. How ADM exerts its protective effects is complex and incompletely understood. Oxidative stress leads to inflammation and apoptosis. ADM is known to have anti-oxidative, anti-inflammatory and anti-apoptotic properties. The anti-inflammatory effects of ADM appear to be mediated through adenylyl cyclase and Pyk-2-ERK1/2-dependent induction of peroxisome proliferator-activated receptor-γ (PPAR-γ). Its anti-apoptotic effect is mediated by the phosphatidylinositol 3-Kinase Akt pathway [11]. In man, the plasma level of ADM has recently emerged as a strong prognostic marker, outperforming many previous biomarkers such as high sensitivity C-reactive protein or B-type natriuretic peptide, in coronary heart disease, heart failure, pneumonia and septic shock [12]. The midregional fragment of pro-adrenomedullin (MR-proADM) predicts mortality in intensive care and coronary event s in the community [13]. These new clinical findings suggest that ADM is of critical importance in maintaining the survival of not only cells but also the whole organism. Despite the remarkable clinical utility of ADM, how it exerts its protective effects is still unclear. B. Work done by us and preliminary data ADM in plasma is difficult to measure because of a short plasma half-life (around 22 minutes) and its binding to AMBP-1 in plasma. We developed a method to measure ADM and proceeded to describe elevation in its levels in patients with hypertension, heart failure, renal failure, chronic liver failure and chronic respiratory failure [2]. However, we found that ADM is also elevated in a variet y of diseases characterised by infection and inflammation, including asthma, bronchiectasis and pneumonia. It is also elevated in diseases in which inflammation is triggered by autoimmunity rather than by infectious agents, such as rheumatoid arthritis [14], systemic lupus erythematosus (SLE) [15] and systemic sclerosis [16]. The most potent stimulation of ADM occurs in infections [17]. With support from RGC (HKU7282/00M), we used a septicaemia model in the rat to study the expression of ADM in endotoxaemia [18]. Lipopolysaccharide (LPS) stimulates immediate production of the pro-inflammatory cytokine tumour necrosis factors- α (TNF-α), and ADM secretion occurs subsequently. TNF-α is known to pote ntly stimulate the production of ADM [19]. We confirmed this in cell culture experiments, and found that ADM also exerts a counter-regulatory role by decreasing the expression of TNF-α and interleukin (IL)-1β [20]. The mechanisms involved are complex; our experiments on NR8383 cells suggest that IL-6 and IL-10 are involved [21]. We found that adenylyl cyclase mediates the increased expression of IL-6 and IL-10, and the decrease d expression of TNF-α. The production of IL-6 is mediated by p38-mitogen-activated protein kinase (MAPK), p42/44-MAPK (ERK 1/2), protein tyrosine kinase (PTK) and protein kinase C (PKC), whereas that of IL-10 is mediated by p38-MAPK and PTK. These findings suggest that the interaction between ADM and TNF-α or IL-1β is complex and best studied using a systems approach looking at pathways rather than individual mediators. In summary, there is evidence to believe that ADM plays an important role in host defence, and in conjunction with its binding protein, AMBP-1, protects the organism from self-injury caused by inflammation and activation of the immune system. How ADM exerts is protective effect is complex and requires clarification. The proposed study may alter our understanding of fundamental mechanisms of cell protection and have diverse clinical applications.

List of Research Outputs

Chen C. , Xu A. , Tso A.W.K. , Law S.C. , Cheung B.M.Y. , Janus E.D., Wat N.M.S. and Lam K.S.L. , Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study., 5th International Symposium on Healthy Aging . 2010.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Jiang C.Q., Thomas G.N. and Lam T.H. , A single nucleotide polymorphism in the gene encoding fibrinogen beta chain is associated with hypertension , British Hypertension Society Annual Meeting, 14-16 September 2009, Cambridge, UK . 2009.

Cheung B.M.Y. , Cardiovascular risk – a view from East to West, Li Ka Shing Faculty of Medicine, University of Hong Kong . 2009.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. and Lam K.S.L. , Gamma-glutamyl transaminase level predicts the development of hypertension., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong, 2010 . 18: 33.

Cheung B.M.Y. , Hong Kong College of Cardiology Best Paper Award , Hong Kong College of Cardiology . 2010.

Cheung B.M.Y. , Metabolic dysfunction in hypertension, 2nd National Conference: Chronic Heart Failure and Hypertension, London . 2010.

Cheung B.M.Y. , The hypertension-diabetes continuum., J Cardiovasc Pharmacol. . 2010, 55: 333-9.

Cheung B.M.Y. , Updates on management of hypertension in Asia, World Congress of Cardiology, Beijing . 2010.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. and Sham P.C. , Using glycosylated hemoglobin to define the metaboli c syndrome in United States adults., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong, 2010 . 18: 33.

Cheung B.M.Y. , Ong K.L. and Tso A.W.K. , Using the Albumin-Globulin Ratio to Identify Individuals with Elevated High-sensitivity C-Reactive Protein Level and High Cardiovascular Risk., Presented at the International Congress of Cardiolog y, Hong Kong, February 26-28, 2010 .

Cheung B.M.Y. , Writing for international journals, Hepatitis B net meeting, Busan . 2009.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Law S.C. , Sham P.C. and Lam K.S.L. , A genetic variant near the GNPDA2 gene is associated with the metabolic syndrome in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Sham P.C. , Xu A. , Ong K.L. , Cheung B.M.Y. and Lam K.S.L. , Implication of the obesity-associated genetic variant s identified from recent genome-wide association studies in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 15.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a Chinese population, J Clin Endocrinol Meta . 2010, 95: 1395-403.

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Li Jin Y., Yue X.J., Ong K.L. , Tam S., Wong K.S., Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese , Eur J Hum Genet . 2010, 18(11): 1255-1260.

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Jin Y.L., Yue X.J., Ong K.L. , Tam S. , Wong K.S. , Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese . , Eur J Hum Genet. . 2010, 1-6.

Jiang C.Q. , Lam T.H. , Lin J.M., Liu B., Yue X.J., Cheng K.K. , Tomlinson B., Wong K.S., Cheung B.M.Y. and Thomas G.N. , An overview of the Guangzhou Biobank Cohort Study-Cardiovas cular Disease Subcohort (GBCS-CVD): A platform for multidisciplinary collaboration, J Hum Hypertens. . 2010, 24(2): 139-150.

Lau C.P. , Tse H.F. , Kumana C.R. and Cheung B.M.Y. , Angiotensin receptor blockers for heart disease: are they the same?, J HK Coll Cardiol 2009 . 2009, 17: 1-3.

Law S.C. , Tso A.W.K. , Tam S.C.F., Wat N.M.S. , Cheung B.M.Y. and Lam K.S.L. , Predictive value of hemoglobin A1c on diabetes incidence over 8 years., 5th International Symposium on Healthy Aging . 2010.

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endothel ial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Li M. and Cheung B.M.Y. , Pharmacotherapy for obesity. , Br J Clin Pharmacol. . 2009, 63: 804-10.

Li M. , Ong K.L. , Tse H.F. and Cheung B.M.Y. , Utilization of lipid lowering medications among adults in the United States 1999-2006. , Atherosclerosis. . 2010, 208: 456-60.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted development of hypertension in Chinese men, Thrombosis and Haemostasis . 2010, 103 (4): 728-735.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted incident hypertension in Chinese men, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Adiponectin gene polymorphisms, plasma adiponectin level and persistent hypertension in Hong Kong Chinese, British Pharmacological Society Winter Meeting, Dec 2009, London, UK . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen beta chain with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 51.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen β chain with hypertension in Hong Kong Chinese, 14th Research Postgraduate Symposium, Faculty of Medicine, HKU, Dec 2009, Hong Kong . 2009.

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Xu A. , Cherny S.S., Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive Protein As A Predictor Of Hypertension In The Hong Kong Cardiovascular Risk Prevalence Study (crisps) Cohort, International Congress of Cardiology (ICC), Feb 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Xu A. , Cherny S.S. , Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive protein as a predictor of hypertension in the Hong Kong cardiovascular risk prevalence study (CRISPS) cohort, Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chine se, Annual Scientific Meeting of Hong Kong Society of Endocrinology . 2009.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chine se., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Leung Y.K. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese, 13th Annual Scientific Meeting of the Institute of Cardiovascular Science and Medicine, Co-morbidity Hypertension / Diabetes: which one do we treat, Dec 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. , Lam K.S.L. and Cheung B.M.Y. , Relationship of liver enzymes with hypertension in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated haemoglobin to define the metabolic syndrome in United States adults, Diabetes Care . 2010.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated hemoglobin to define the metabolic syndrome in United States adults., 5th International Symposium on Healthy Aging . 2010.

Wang J.K., Ho J.C.M. , Mok T.Y., Chan J.W., Yee W.K., Chan M.M.W. , Cheung B.M.Y. , Lam K.S.L. , Lam W.K. and Ip M.S.M. , The relationship of asthma and the pattern of adiposity in adult Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 56.

Webber M., Krishnan A., Thomas N.G. and Cheung B.M.Y. , Association between serum alkaline phosphatase and C-reactive protein in the United States National Healt h and Nutrition Examination Survey 2005-2006. , Clin Chem Lab Med. . 2010, 48: 167-73.

Yiu K.H., Cheung B.M.Y. and Tse H.F. , A new paradigm for managing dyslipidemia with combinati on therapy: laropiprant + niacin + simvastatin. , Expert Opin Investig Drugs. . 2010, 19: 437-49.

Yiu K.H., Cheung B.M.Y. and Tse H.F. , Pharmacological treatment for hypertension. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Researcher : Cheung CL

List of Research Outputs

Bow C.H.Y. , Cheung C.L. , Gao Y. , Lau K.S. , Soong S.S. , Yeung S.C. and Kung A.W.C. , Bone Mineral Density and Serum Osteoprotegerin Levels in Pre- and Postmenopausal Women, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Cheung C.L. , Xiao S. , Gao Y. and Kung A.W.C. , Genetic Epidemiology of Osteoporosis and Its Application, 骨質疏鬆症的遺傳流行病學及其臨床應用, Chinese Journal of Osteoporosis and Bone Mineral Research . 2010, 3: 73-86.

Song Y. , Tang L.F. , Cheung C.L. , Sham P.C. , McClurg P., Smith D.K. , Tanner J.A. , Su A.I., Cheah K.S.E. and Kung A.W.C. , Genome-wide haplotype association mapping in mice identifies a genetic variant in CER1 associated with bone mineral density and fracture in southern Chinese women, The American Society of Human Genetics 59th Annual Meeting, Honolulu, Hawaii . 2009.

Researcher : Cheung CYY

List of Research Outputs

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Law S.C. , Sham P.C. and Lam K.S.L. , A genetic variant near the GNPDA2 gene is associated with the metabolic syndrome in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Sham P.C. , Xu A. , Ong K.L. , Cheung B.M.Y. and Lam K.S.L. , Implication of the obesity-associated genetic variants identified from recent genome-wide association studies in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 15.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a Chinese population, J Clin Endocrinol Meta . 2010, 95: 1395-403.

Researcher : Cheung KF

List of Research Outputs

Cheung K.F. , Yung S.S.Y. and Chan D.T.M. , Annexin II on human mesangial cells mediates anti-dsDNA antibody binding, 9th International Congress on Systemic Lupus Eryt hematosus . 2010.

Cheung K.F. , Ye D. , Yang Z. , Lu L. , Liu C.H., Wang X.L., Poon R.T.P. , Tong Y. , Liu P., Chen Y. and Lau G. , Therapeutic efficacy of Traditional Chinese Medicine 319 recipe on hepatic fibrosis induced by carbon tetrachloride in rats, Journal of Ethnopharmacology . 2009, 124(1): 142-150.

Feng Y. , Cheung K.F. , Wang N. , Liu P., Nagamatsu T. and Tong Y. , Chinese medicines as a resource for liver fibrosis treatment , In: Hin Wing Yeung, Chinese Medicine . Macau, International association of Chinese Medicine, 2009, 4(1): 16.

Researcher : Cheung KF

List of Research Outputs

Cheung K.F. , Yung S.S.Y. and Chan D.T.M. , Annexin II on human mesangial cells mediates anti-dsDNA antibody binding, 9th International Congress on Systemic Lupus Erythematosus . 2010.

Cheung K.F. , Ye D. , Yang Z. , Lu L. , Liu C.H., Wang X.L., Poon R.T.P. , Tong Y. , Liu P., Chen Y. and Lau G. , Therapeutic efficacy of Traditional Chinese Medicine 319 recipe on hepatic fibrosis induced by carbon tetra chloride in rats, Journal of Ethnopharmacology . 2009, 124(1): 142-150.

Researcher : Cheung RTF

Project Title:	Role of ischemia in Alzheimer's disease - an experimental study in transgenic mice
Investigator(s):	Cheung RTF
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2004

Abstract:

To study (1) the influence of genotype on the cerebral blood flow and infarct volume of transgenic mice overexpressing amyloid precursor protein (APP) alone or with human mutant presenilin-1 (PS-1) gene following photothromb otic stroke, and to study (2) the effects of photothrombotic stroke on the sensorimotor functions and visuospatial memory in the APP transgenic mice and APP/PS-1 double transgenic mice.

Project Title:	Development of Chinese-language versions of internationally-accepted stroke training materials for healthcare professionals treating Chinese stroke patients
Investigator(s):	Cheung RTF
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	04/2005

Abstract:

To develop Chinese-language versions of internationally-accept ed stroke training materials, and to make them available to healthcare professionals treating Chinese stroke patients.

Project Title:	The effects of self-assembling peptide nanofiber scaffold (SAPNS) in a renovascular hypertensive (RVHT) rat model of intracerebral hemorr hage (ICH). Part II: evaluation of SAPNS in the RVHT rat model of ICH
Investigator(s):	Cheung RTF
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2008

Abstract:

Objective: To evaluate the safety and efficacy of clot aspiration with or without injection of self -assembling peptide nanofiber scaffold (SAPNS) in the renovascular hypertensive (RVHT) rats. Key issues: (1) Stroke can be caused by either blockade or rupture of a blood vessel in the head. The former type is called ischemi c stroke, and the latter type is called intracerebral hemorrhage (ICH). (2) Only 20% of patients are independent at six months after ICH. At present, treatment of ICH is mainly supportive. Although neurosurgical stereotaxic aspiration of blood can rapidly remove the hematoma, one cannot stop re-bleeding into the cavity. (3) High blood pressure, or hypertension, is the most imp ortant risk factor for ICH. Recent studies have indicated that hematoma growth, peri-hematoma edema and inflammation are important factors for a poor outcome after ICH. (4) Self-Assembling Peptide Nanofiber Scaffold (SAPNS) consists of interwoven nanofibers. By forming highly hydrated scaffold in physiological environment, SAPNS is very effective in stopping any bleeding. The biomedical use of SAPNS to repair injured optic tract has been recently reported by colleagues in the Department of Anatomy. It is plausible that SAPNS can achieve rapid arrest of bleeding in ICH as well as facilitate neural repair. (5) We have adopted a renovascular hypertensive (RVHT) rat model of ICH and incorporated clot aspiration with or without injection of SAPNS.

Project Title:	Neuroprotective effects of melatoni n and/or electro-acupuncture (EA) on focal cerebral ischemia in rats
Investigator(s):	Cheung RTF
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2009

Abstract:

Objective: To evaluate the safety and efficacy of electro-acupuncture with or without a single injec tion of melatonin in rats undergoing transient or permanent endovascular middle cerebral artery occlusion Key issues: (1) Stroke can be caused by either blockade or rupture of a blood vessel in the head. The former type, called ischemic stroke, accounts for 80% of all strokes. (2) The mortality rate after ischemic stroke is 20-25%, and half of all survivors have significant disability. (3) Melatonin has been shown to possess beneficial effects in ischemic stroke in both rats and mice. (4) There is some evidence that acupuncture may ameliorate the damages caused by ischemic stroke in rats. More systemic studies are needed. (5) Using the well-established endovascular middle cerebral artery occlusion stroke model in rats, we would like to evaluate the safety and efficacy of electro-acupuncture with or without a single injection of melatonin prior to permanent focal ischemia or focal ischemia for 90 mi nutes.

Project Title:	Evaluation of key mechanisms of brain injury and of a novel hemostatic treatment in a rat model of hypertensive intracerebral hemorrhage
Investigator(s):	Cheung RTF, Ellis-Behnke RG, So KF, Wu EX
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To study how hypertension would affect hematoma growth, re-bleeding after clot aspiration, edema formation, peri-hematoma ischemia, inflammation, neurologic outcome and mortality in a rat model of hypertensive ICH using a 7 Tesla MRI scanner, established histochemical techniques and the Montoya staircase test; 2) To evaluate the safety and efficacy of the SAPN in a rat model of hypertensive ICH in terms of hematoma re-growth post-aspiration, edema formation, peri-hematoma ischemia, inflammation, neurologic outcome and mortality using a 7 Tesla MRI scanner, established histochemical techniques and the Montoya staircase test.

List of Research Outputs

Chan K.H. , Tsang J.W.H. , Mak W. , Liu H.H.W., Ho S.L. and Cheung R.T.F. , Thymomatous myasthenia gravis among Hong Kong Chinese, 20th Meeting of the European Neurological Society, Berlin, 2010. Journal of Neurology . 2010, 257 (Supplement 1): S170.

Chang R.S.K., Chan R.C.L., Chu M.M.Y., Yan C.H., Mak W. , Cheung R.T.F. and Ho S.L. , Risk factors, clinical features and prognosis of perioperative stroke in adults, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 13.

Chang R.S.K., Mak W. , Cheung R.T.F. and Ho S.L. , Short-latency somatosensory-evoked potential in patients with central nervous system space-occupying lesions: a study of 261 cases, Medical Research Conference, LKS Faculty of Medici ne, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 13.

Chau C.M. , Cheung R.T.F. , Jiang X., Au-Yeung P.K.M. and Li L.S.W. , Acupuncture of motor-implicated acupoints on subacute stroke patients: an fMRI evaluation study, Medical Acupuncture . 2009, 21(4): 233-241.

Chau C.M. , Cheung R.T.F. , Jiang X., Au Yeung P.K.M. and Li L.S.W. , An fMRI study showing effect of acupuncture in chronic stage stroke patients with aphasia, Journal of Acupuncture & Meridian Studies . 2010, 3: 53-57.

Chau C.M. , Cheung R.T.F. , Jiang X., Au-Yeung P.K.M. and Li L.S.W. , Increased brain activation in motor cortex after acupunctu re treatment for motor recovery in chronic stroke patients, The Open Rehabilitation Journal . 2009, 2: 89-94.

Cheung R.T.F. , Assistant Editor, Stroke . 2010.

Cheung R.T.F. , Chairman of Free Paper, 19th World Congress of Neurology, Bangkok, Thailand, 24-30 October 2009 . 2009.

Cheung R.T.F. , Chairman of Neurology Symposium on 9 May 2010, 15th Hong Kong Medical Forum, University Department of Medicine, Hong Kong Convention & Exhibition Centre, Wanchai, HK . 2010.

Cheung R.T.F. , Chairman of Symposium III; New Insights in Pain Management, Annual Scientific Meeting 2010, Hong Kong Pain Society, 24-25 April 2010, InterContinental Grand Stanford Hon g Kong . 2010.

Cheung R.T.F. , Chairman, New Strategies of Medical Treatment in Secondary Prevention of Ischemic Stroke, The Hong Kong Neurologic al Society & The Hong Kong Stroke Society, The Royal Garden Hotel, 69 Mody Road, Tsimshatsui, Kowloon . 2009.

Cheung R.T.F. , Editorial Board, Chinese Journal of Neurology . 2010.

Cheung R.T.F. , Editorial Board, Chinese version of Stroke . 2010.

Cheung R.T.F. , Editorial Board, Journal of Pineal Research . Blackwell Publishing, 2010.

Cheung R.T.F. , Editorial Board, Medical Progress . CMPMedica, 2009.

Cheung R.T.F. , Editorial Board, Reviews on Recent Clinical Trials . Bentham Science Publishers, 2010.

Cheung R.T.F. , Editorial Board, Stroke Research and Treatment . 2010.

Cheung R.T.F. , Editorial Board, The Open Medical Imaging Journal . Bentham Science Publishers, 2010.

Cheung R.T.F. , Editorial Board, The Open Neuroimaging Journal . Bentham Science Publishers, 2010.

Cheung R.T.F. , Editorial Board, The Open Nuclear Medicine Journal . 2010.

Cheung R.T.F. , Editorial Board, The Open Physiology Journal . Bentham Science Publishers, 2010.

Cheung R.T.F. , IV Thrombolytics for Acute Ischemic Stroke, Commissioned Training Programme of COC (A&E), HAHO . 2010.

Cheung R.T.F. , IV thrombolytics in acute ischemic stroke, EBM Conference on Emergency Medicine Commissioned Training Programme of COC (A&E) of Hospital Authority, 11-12 February 2010, Lecture Theatre, HAHO. Proceedings . 2010, 13.

Cheung R.T.F. , Imaging of ischemic tolerance in the brain, In: Schaller B, State-of-the-Art Imaging in Stroke . Nova Science Publishers, 2009, 2: 245-264.

Cheung R.T.F. , Member of Organizing Committee & Chairman of Symposium III: Degenerative Diseases, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, Faculty of Medicine, HKU, 6-7 March 2010, Sheraton Hong Kong Hotel & Towers, Tsimshatsui, HK . 2010.

Cheung R.T.F. , Organizer and Chairman of Joint Stroke Symposium, First Hong Kong Neurological Congress cum 22nd Annual Scientific Meeting 2009, The Hong Kong Neurological Society, 6-8 November 2009, Kowloon Shangri-La Hotel , 64 Mody Road, Tsimshatsui, Kowloon . 2009.

Cheung R.T.F. , Lyden P.D., Tsoi T.H. , Huang Y., Liu M., Hon S.F.K. , Raman R. and Liu L., Production and validation of Putonghua- and Cantonese-Chines e language National Institutes of Health Stroke Scale training and certification videos, International Journal of Stroke . 2010, 5: 74-79.

Cheung R.T.F. , Program Coordinator, Moderator & Speaker, Training and Certification Workshop on NIH Strok e Scale Using Materials in Cantonese, Cheung Kung Hai Lecture Theatres, LKS Faculty of Medicine, HKU, Hong Kong . 2009.

Cheung R.T.F. , Recruitment Presentation From Hong Kong, Study 12402A DIAS 3 Investigators’ Meeting, Bangkok, Thailand . 2010.

Cheung R.T.F. , Stroke Registry in Hong Kong, International Symposium on Stroke Registry, Chang Gung Healthcare System, Linkou Chang Gung Memorial Hospital, Taiwan . 2010.

Cheung R.T.F. , Stroke registry in Hong Kong, International Symposium on Stroke Registry, Chang Gung Healthcare System, 15 May 2010, Second Conference Hall, Linkou Chang Gung Memorial Hospital, Taiwan; Proceedings . 2010, 12.

Cheung R.T.F. , Stroke: Consequences, First Aid, Treatment and Patient Management, Public Lecture, Health Exhibition 2009, HKU Medical Students Association, Tuen Mun Town Hall . 2009.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. , Cheung C., Qiu D., Mak H.K.F. and Chan Y.S. , Declined frontal white matter integrity in Alzheimer’s disease: a diffusion tensor imaging study, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 21.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. and Chan Y.S. , Task-induced brain deactivation reflects the altered default model network in normal and abnormal aging, Fifth International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, 6–7 March 2010, The Ballroom, Sheraton Hong Kong Hotel & Towers, Tsimsha tsui, Hong Kong; Abstract Book . 2010, 46.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. , Cheung C., Fung G., Qiu D.G. and Chan Y.S. , The anteroposterior pattern of white matter decline in normal and abnormal aging supports retrogenesis: a diffusion tensor imaging study, Fifth International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, 6–7 March 2010, The Ballroom, Sheraton Hong Kong Hotel & Towers, Tsimshatsui, Hong Kong; Abstract Book . 2010, 46.

Ji J.T., So R.H.Y. and Cheung R.T.F. , Isolating the effects of vection and optokinetic nystagmus on optokinetic rotation-induced motion sickness, Human Factors . 2009, 51: 739-751.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Herpes simplex encephalitis: how good are we in diagnosing this condition?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 29.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Ischaemic stroke related to branch artery disease: a missing link?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 30.

Lam K.Y. , Ong K.L. , Lam K.S.L. , Tso A.W.K. and Cheung R.T.F. , Association of two adiponectin gene variants with ischemic stroke in a Chinese cohort, The 32nd Annual Meeting of the Japan Neuroscience Society, 16-18 September 2009, Nagoya, Japan. Neuroscience Research . 2009, 65: S122.

Liu H.H.W., Tsang J.W.H. , Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Chu A.C.Y. , Tse M.M.Y., Mak W. , Ho W.L. and Chan K.H. , Thymomatous myasthenia gravis, 15th Medical Research Conference, Faculty of Medicine, The University of Hong Kong . 2010.

Sang Y. and Cheung R.T.F. , Brain injury and neurogenesis after intracerebral haem orrhage in hypertensive rats, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 53.

Teo K.C., Mahboobani N.R., Lee R. , Cheung R.T.F. , Ho S.L. , Tse C.T. and Chan K.H. , Intracerebral hemorrhage complicating anticoagulant therapy among Hong Kong Chinese, 15th Medical Research Conference, Faculty of Medicin e, The University of Hong Kong . 2010.

Tse A.C.T. and Cheung R.T.F. , Aspirin failure in noncardioembolic ischemic stroke: a retrospective cohort study on its incidence, choice of antiplatelet treatment and clinical outcome, 62nd Annual Meeting of the American Academy of Neurology, 10–17 April 2010, Toronto, Canada. Neurology . 2010, 74 (suppl): A346.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Best Abstract In Clinical Medicine, 15th Medical Research Conference, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Clinical outcome of relapsing remitting multiple scleros is among Hong Kong Chinese, 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Yiu C.K.Y. , Bridges S.M. and Cheung R.T.F. , Evaluation of Medical Case-based Learning as a Dental Curriculum Enhancement Programme, 6th International Conference on PBL in Dentistry, Hong Kong, 13-15 November 2009 . p.21.

Researcher : Cheung TK

List of Research Outputs

Hung I.F.N. , Chan P., Leung S., Chan S.Y. , Hsu A., But D., Seto W.K., Wong S.Y. , Chan C.K. , Gu Q. , Tong T.S.M., Cheung T.K. , Chu K.M. and Wong B.C.Y. , Clarithromycin-amoxycillin-containing triple therapy: A valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong?, Helicobacter . 2009, 14: 505-511.

Tsang J.W.H. , Lau T.T.S., Lee V.K.H., Yung S.T. , Li V.W.K. , Cheung T.K. , Lam W.W.T. , Lee V.H.F. , Au G.K.H. and Kwong D.L.W. , Higher Education And Younger Age Are Associated With Better Understanding Of Clinical Trials Among Hong Kong Cancer Patients, 16th Hong Kong International Cancer Congress & 6th Annual Meeting Centre For Cancer Researach . 2009.

Tsang J.W.H. , Lau T.T.S., Lee V.K.H., Yung S.T. , Li V.W.K. , Cheung T.K. , Lam W.W.T. , Lee V.H.F. , Au G.K.H. and Kwong D.L.W. , Young Investigator Award In Psychosocial Oncology : Higher Education And Younger Age Are Associated With Better Understanding Of Clinical Trials Among Hong Kong Cancer Patients, 16th Hong Kong International Cancer Congress & 6th Annual Meeting Centre For Cancer Research . 2009.

Researcher : Cheung WH

List of Research Outputs

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Researcher : Cheung WWW

List of Research Outputs

Yeung C.W., Cheung W.W.W. , Leung A.Y.H. and Kwong Y.L. , Spontaneous central venous catheter fracture: Releva nce of the pinch-off sign, Journal of Hospital Medicine . 2010, 5(4): E33.

Researcher : Cheung YY

List of Research Outputs

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Researcher : Chim JCS

Project Title:	The role of aberrant promoter methylation of tumor suppressor micro-RNA in chronic lymphocytic leukemia (CLL)
Investigator(s):	Chim JCS, Liang RHS
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2008

Abstract:

1. To study the frequency of methylation of micr o-RNA (mir) in both CLL cell lines and primary samples in patients with CLL at diagnosis and relapse 2. To verify that the CpG island studied contains promoter activity, and aberrant methylation of the CpG island leads to gene silencing 3. To show that aberrant micro-RNA results in deregulation of cell signaling 4. To show that methylation of micro-RNA contributes to disease pathogenesis and progression of disease 5. To determine the prognostic impact of epigenetic dysregulation of micro-RNA in CLL

Project Title:	FISH study and the use of bortezomib in high-risk multiple myeloma
Investigator(s):	Chim JCS
Department:	Medicine
Source(s) of Funding:	Lee Hysan Foundation - General Award
Start Date:	07/2008

Abstract:

(1) Myeloma patients with high-risk genetic changes will have a much higher chance to achieve complete response, which is a requisite to cure. (2) The adverse impact of these high-risk genetic changes in myeloma patients can be abolished. (3) The prevalence of these high-risk genetic changes will be identified for the first time in Chinese patients.

Project Title:	Study of tumor suppressor function of miR-124a in non-Hodgkin's lymphoma
Investigator(s):	Chim JCS
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2009

Abstract:

1. To analysis the CpG islands and methylation statuses of miR-124a in a complete spectrum of lympho ma cell lines, patient samples, and their normal counterparts. 2. To demonstrate the expression of miR-124a can be restored by the treatment of demethylation drug, 5-Aza-2’-deoxy cytidine (DAC). 3. To determine the tumour suppressor function of miR-124a in lymphoma, by demonstrating their role in the regulation cell cycle, survival, apoptosis, and cellular signaling; and thereafter, the target protein-coding mRNA of miR-124a.

Project Title:	Functional study of the impact of hypermethylation of tumor suppressive micro-RNA in myeloma stem cells
Investigator(s):	Chim JCS, Liang RHS
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To identify multiple myeloma-specific miRNAs that are epigenetically silenced by promoter hypermethylati on; 2) To determine the tumor suppressor function of these epigenetically silenced miRNAs by demonstrating their role in the regulation cell cycle, survival, apoptosis, and cellular signaling; and thereafter, the target protein-coding mRNA of these tumor suppressor miRNAs.

List of Research Outputs

Chen W.Y.W. , Hu X. , Liang C.T., Wong M.L.Y. , Au W.Y. , Wong K.Y. , Choi W.L. , Wan T.S.K. , Chu K.M. , Chim J.C.S. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , Molecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm., 101st Annual Meeting of American Association for Cancer Research (AACR), Washington D.C., USA, April 2010. . 2010.

Chim J.C.S. , Lie A.K.W., Liang R.H.S. and Kwong Y.L. , A staged approach with vincristine, adriamycin and dexamethasone followed by bortezomib, thalidomide and dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed multiple myeloma, 15th Congress of the European Hematology Association (Abstract) . 2010.

Chim J.C.S. , Lie A.K.W., Chan E.Y.T., Leung Y.Y., Cheung S.C.W., Chan S.Y.T., Liang R.H.S. and Kwong Y.L. , A staged approach with vincristine, adriamycin and dexamethasone followed by bortezomib, thalidomide and dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed multiple myeloma, Annals Hematology . 2010.

Chim J.C.S. , Epigenetic alterations of microRNA in hematological cancers, Quangzhou . 2010.

Chim J.C.S. , Wong K.Y. and Qi Y. , Epigenetic alterations of the miR-34a in hematological malignancies, 15th Congress of the European Hematology Association, (Poster) . 2010.

Chim J.C.S. , Wong K.Y. , Qi Y. , Foong F., Lam W.L., Wong L.G., Jin D. , Costello J.F. and Liang R.H.S. , Epigenetic inactivation of the miR-34a in hematological malignancies, Carcinogenesis . 2010, 31(4): 745-50.

Chim J.C.S. and Wong K.Y. , Epigenetic inactivation of the miR-34a in hematological malignancies, Epigenetics, Chromatin & Transcription, Suzhou (Poster) . 2010.

Chim J.C.S. , Epigenetic regulation of miRNA expression in hematologic al malignancies, RNA Silencing 2009: Mechanisms and Applications, Croucher Foundation-sponsored Conference, Hong Kong . 2009.

Chim J.C.S. , Health (http://www.scirp.org/journal/health), 2009.

Chim J.C.S. , Management of refractory myeloma, 第七届全国难治性白血病学术研讨会、第二届全国难治性淋巴瘤学术 : 研讨, 2010.

Chim J.C.S. , Fung T.K. and Liang R.H.S. , Methylation of cyclin-dependent kinase inhibitors, XAF1, JUNB, CDH13 and soluble Wnt inhibitors in Essential Thrombocythemia, Journal of Clinical Pathology . 2010, 63(6): 518-21.

Chim J.C.S. , NK/T-cell lymphoma, Post-American Society Hematology Conference : Cur rent Trends in Leukemia, Lymphoma and Myeloma, New York, USA . 2010.

Chim J.C.S. , National Scientific and Technological Advancement Award, Eipigenetic alterations in acute leukaemia, 國家科學技術進步獎 (二等獎), 白血病表觀遺傳學基礎及臨床應用研究, China . 2009.

Chim J.C.S. , Success of a Staged Approach for Myeloma in Hong Kong, Major newspapers (Apply Daily, Oriental Daily News, Ming Pao Daily News, Sing Tao Daily, Ta Kung Pao, Hong Kong Economic Times, Hong Kong Daily News, The Sun, am730, Metropolis Daily) . 2010.

Chim J.C.S. , The Asia-Pacific Journal of Oncology and Hematology . 2010.

Chim J.C.S. , The State Award for Technology Advances, Major newspapers (Wen Wei Po, Apply Daily, Ta Kung Pao, Ming Pao Daily News Sing, Tao Daily) . 2010.

Chim J.C.S. , Translational Oncology, 2010.

Hu X. , Chen W.Y.W. , Liang A.C.T., Au W.Y. , Wong K.Y. , Wan T.S.K. , Wong M.L.Y. , Shen L. , Chan K.K. , Guo T. , Chu K.M. , Tao Q. , Chim J.C.S. , Loong F. , Choi W.L. , Lu L. , So J.C.C. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation, Blood . 2010, 115: 2458-2461.

Wong K.Y. , Jin D. , Liang R.H.S. and Chim J.C.S. , Epigenetic silencing of miR-203 is a disease initiation event of multiple myeloma, European Association of Cancer Research, Norway (Poster) . 2010.

Researcher : Chow CH

List of Research Outputs

Cheung A.M., Chow C.H. , Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , FLT3/internal tandem duplication subclones in acute myeloid leukemia differ in their engraftment potential in NOD/SCID mice, Leukemia Research . 2010, 34(1): 119-22.

Cheung A.M., Fung T.K. , Fan K.P. , Wan T.S., Chow C.H. , Leung J.C.K. , Chan L.Y., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD/SCID mice., Experimental Hematology . 2010, 38: 3-10.

Huang H., Wu D., Fu J., Chen G., Chang W., Chow C.H. , Leung A.Y.H. and Liang R.H.S. , All-trans retinoic acid can intensify the growth inhibition and differentiation induction effect of rosiglitazone on multiple myeloma cells, European Journal of Haematology . 2009, 83(3): 191–202.

Researcher : Chow WS

List of Research Outputs

Lam J.T.C., Lam K.S.L. , Tan K.C.B. , Chow W.S. , Tso A.W.K. and Kung A.W.C. , A woman with hypophosphataemia and raised alkaline phosphatase, British Medical Journal . 2010, 340: b-5564-.

Tam H.L. , Shiu S.W.M. , Wong Y. , Chow W.S. , Betteridge D.J. and Tan K.C.B. , Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes, Atherosclerosis . 2010, 209: 173-177.

Researcher : Chow YY

List of Research Outputs

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Researcher : Choy CBY

List of Research Outputs

Choy C.B.Y. and Lai K.N. , Bleeding tendency and hepatitis B vaccination, In: Lai KN, A Practical Manual of Renal Medicine: Nephrology, Dialysis and Transplantation . Singapore, Imperial College Press/World Scientific Publisher, 2009, 293-299.

Yap D.Y.H., Lau S.K.P. , Lamb S., Choy C.B.Y. , Chan D.T.M. , Lai K.N. and Tang S.C.W. , An unusual organism for PD-related peritonitis: Hafnia alvei, Peritoneal Dialysis Internationa l . 2010, 30(2): 254-255.

Researcher : Chu ACY

List of Research Outputs

Liu H.H.W., Tsang J.W.H. , Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Chu A.C.Y. , Tse M.M.Y., Mak W. , Ho W.L. and Chan K.H. , Thymomatous myasthenia gravis, 15th Medical Research Conference, Faculty of Medicine, The University of Hong Kong . 2010.

Researcher : Chu JYY

List of Research Outputs

Wang A.Y.M. , Cheung C.W., Chu J.Y.Y. , Fok A.N.Y. , Lo W.K. , Leung J.C.K. , Tso W.K. and Lai K.N. , Is aortic pulse wave velocity a useful screening tes t for vascular and valvular calification in end-stage renal disease patients, Journal of American Society of Nephrology . 2009, 20: 443A-444A.

Researcher : Chu LW

Project Title:	A dementia outreach programme in Central, Western and Southern districts of Hong Kong
Investigator(s):	Chu LW, Lam KSL, Lee PWH
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	09/2003

Abstract:

To achieve early detection of dementia, through an outreach dementia-screening programme.

List of Research Outputs

Chu L.W. , Chan I., Lee P.W.H. , Li S.W. and Yu G.K.K. , Effects of cognitive function and depressive mood on the quality of life in Chinese Alzheimer's disease patients in Hong Hong, Geriatrics and Gerontology International . 2010, 1-8.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. , Cheung C., Qiu D., Mak H.K.F. and Chan Y.S. , Declined frontal white matter integrity in Alzheimer’s disease: a diffusion tensor imaging study, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 21.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. and Chan Y.S. , Task-induced brain deactivation reflects the altered default model network in normal and abnormal aging, Fifth International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, 6–7 March 2010, The Ballroom, Sheraton Hong Kong Hotel & Towers, Tsimshatsui, Hong Kong; Abstract Book . 2010, 46.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. , Cheung C., Fung G., Qiu D.G. and Chan Y.S. , The anteroposterior pattern of white matter decline in normal and abnormal aging supports retrogenesis: a diffusion tensor imaging study, Fifth International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, 6–7 March 2010, The Ballroom, Sheraton Hong Kong Hotel & Towers, Tsimshatsui, Hong Kong; Abstract Book . 2010, 46.

Lee A.M. , Chu L.W. , Chong C.S.Y., Chan S.Y. , Lam K.S.L. and Lam T.P. , Relationship Between Symptoms of Androgen Deficiency and Psychological Factors and Quality of Life among Chinese Men., International Journal of Andrology. . 2009.

Researcher : Chung ACK

Project Title:	Signaling mechanisms of angiotensin II-induced epithelial-mesenchymal transition in renal tubular epithelial cells
Investigator(s):	Chung ACK, Lan HY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2008

Abstract:

Tubulointerstitial fibrosis (TIF) is the common pathway in progressive renal disease leading to functional deterioration and eventual loss of renal function, irrespective of the nature of the initial renal injury (1). TIF is characterized by the accumulation of extracellula r matrix components and loss of tubular architecture (1). The excessive deposition of interstitial matrix components was mainly due to an expansion of interstitial myofibroblast populations that are characterized by de novo activation of α-smooth muscle actin (alpha-SMA). The expansion of interstitial myofibroblast appears to be due to epithelial-to-mesenchymal transition (EMT) derived fibroblasts or bone marrow-derived fibroblast s (1). EMT in the kidney is of significant interest as a therapeutic target, and in this regard, it is vital to understand the mechanisms of tubular epithelial cell to EMT. TGF-beta, a multifunctional cytokines, has been implicated as a “master switch” in induction of fibrosis in many tissues, including the kidney (2). EMT in response to TGF-beta1 and in fibrosis is mediated predominantly via Smad-dependent pathways (2). In the Smad-mediated pathway, TGF-beta binds to its tran s-membrane type II and type I receptors to form tight complexes leading to phosphorylation of Smad2 and Smad3. Phosphorylated Smad2/3 will then activate TGF-beta-responsive genes. Among these activated genes, Smad7, an inhibitory Smad, will negatively regulate TGF-beta/Smad2/3 signaling to form a negative feedback loop to regulate TGF-beta signaling. Our laboratory has made significant contributions to understanding of the critical role of TGF-beta/Smad signaling in renal and vascular fibrosis. We first found that activation of Smad2/3 is associated with human hypertensive/diabetic nephropathy (3) and mediates collagen matrix production induced by Angiotensin II (AngII), TGF-beta, high glucose, and advanced glycation end products (AGEs) in kidney mesangial cells. (MC), tubular epithelial cells (TEC), and vascular smooth muscle cells (VSMC) (3-7). Surprisingly, AngII and AGEs can also rapidly activate Smad2/3 to induce renal and vascular fibrosis independently of TGF-beta via the ERK/p38 MAP kinase-Smad signaling crosstalk pathwa y (3, 4), demonstrating a central role for Smad signaling in hypertensive/diabetic complications. This is a further confirmed by the ability of blocking Smad2/3 with overexpressin g an inhibitory Smad7 to inhibit renal and vascular fibrosis in response to TGF-beta, high glucose, and AGE in vitro (3-6) and in obstructive kidney (8) and particular in a hypertension-associated remnant kidney disease in vivo (9, 10). All these results strongly suggest that Smad signaling may be central pathway in renal fibrosis and provide a solid background for proposed study. AngII is a peptide product of the renin-angiotensin system (11). It plays an important role in regulation of sodium balance and blood pressure, and it exerts its effects by binding to cell membrane receptors on target cells. Circulating AngII has vasoconstrictor activity and stimulates adrenal cortical secretion of aldosterone. Beyond this tradition view of AngII, more evidence suggests that activation of the intra-renal rennin-angiotensin system (RAS) might play a key role in controlling the progression of renal fibrosis. Fi rst, numeral clinical trials have shown that drugs that antagonize the renin-angiotensin system, such as ACE inhibitors (ACE I) and Ang II type-1 receptor-1 blockers (ARB), can prevent or slow down the progression of chronic renal disease in patients with hypertension (12-15). Further more, these drugs are able to ameliorate tubulointerstitial lesions in animal models of chronic renal failure (16, 17). Moreover, infusion of AngII in rats causes renal tubulointerstitial fibrosis (18). The results from these clinical and experimental studies suggest AngII is key mediator of chronic kidney diseases, especially in hypertensive nephropathy. The myriad effects of AngII depend on time (acute vs chronic) and on the cells/tissues upon which it acts (11). In addition to inducing G protein-related pathway, AngII also signals through the AngII type-1 receptor-1 (AT1R) to carry out its function by activating MAP kinases (ERK1/2, p38, and JNK MAPK) (11). Studies focusing on cardiovascular diseases have demonstrated that AngII can cause vascular fibrosis in VSMC and activate Smad signaling via ERK/p38 MAP kinase dependently and independently of TGF-beta (19). In kidney disease, TGF-beta/Smad signaling has been shown to be important (2). However, interaction between Ang II and TGF-beta/Smad signaling in renal fibrosis remains unclear. Our preliminary results demonstrated that AngII was able to induce EMT in renal cells in a time- and dose-dependent manner. Levels of both alpha-SMA mRNA and protein in NRK52E, a rat TEC line, increased after AngII treatment (Fig. 1). In addition, AngII treatment in NRK52E cells also reduced E-Cadherin expression in both mRNA and prote in levels (Fig. 2). Collagen I protein was also up-regulated after treating NRK52E cells with AngII (Fig.3). These results suggest that AngII itself is able to EMT in renal cells. However the detailed is awaited to be investigated. Apart from the established view, our new and important findings showed that AngII is able to mediate renal fibrosis through induction of EMT. However, roles of AngII in renal EMT are not fully understood and its molecular mechanism remains largely unclear. We suspect that AngII action may mediate thr ough both TGF-beta dependent and independent Smad signaling pathways. This study is aimed to examine the role of AngII in renal EMT and elucidate the molecular signaling mechanism as well as the interactions with TGF-beta/Smad signaling pathway in the process of renal EMT. Thus, we hypothesize that AngII induces EMT in NRK52E cell by activating TGF-beta-independent MAPK-Smad crosstalk pathway as well as TGF-beta-dependent Smad signaling pathway. This will be achieved by the execution of the following specific aims. 1. AngII activates MAP kinase pathway as well as crosstalks with Smad signaling pathway. 2. Smad signaling pathway plays a central role in AngII-induced EMT

List of Research Outputs

Zhou L. , Fu P., Huang X.R., Liu F. , Chung A.C.K. , Lai K.N. and Lan H.Y. , Mechanism of chronic aristolochic acid nephropathy: role of Smad3, Am J Physiol Renal Physiol . 2010, 298(4): F1006-17.

Researcher : Chung IS

List of Research Outputs

Ma C.H. , Lin H. , Chung I.S. , Yang D. , Liang R.H.S. and Leung A.Y.H. , Distinctive functions of methionine aminopeptidase II in embryonic hematopoiesis in zebrafish embryos., 15th Medical Research Conference . Hong Kong, 2010.

Researcher : Dai Y

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Researcher : Dai YLE

List of Research Outputs

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H., Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patient s with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Researcher : Dong M

List of Research Outputs

Dong M. , Sun H. , Tang Q. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of human cardiac KCNQ1/KCNE1 channel by epidermal growth factor receptor kinase., Biochim Biophys Acta . 2010, 1798(5): 995-1001.

Researcher : Epstein R

List of Research Outputs

Epstein R. , Visual impairment in myopic patients with breast cancer receiving adjuvant therapy with aromatase inhibitors., Clin Breast Cancer . 2009, 9(3): 184-6.

Wong H., Yau T.C.C. , Chan P., Ng I.O.L. , Chan G.S.W. , Hui P., Law W.L. , Lo C.M. , Hedley A.J. and Epstein R. , PPI-delayed diagnosis of gastrinoma: oncologic victim of pharmacologic success, Pathology and Oncology Research . 2010, 16(1): 87-91.

Yau T.C.C. , Yao T.J. , Chan P., Epstein R. , Ng K.K.C. , Chok K.S.H. , Cheung T.T. , Fan S.T. and Poon R.T.P. , The outcomes of elderly patients with hepatocellular carcinoma treated with transarterial chemoembolization, Cancer . 2009, 115(23): 5507-5515.

Researcher : Fan KP

List of Research Outputs

Cheung A.M., Fung T.K. , Fan K.P. , Wan T.S., Chow C.H. , Leung J.C.K. , Chan L.Y., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD/SCID mice., Experimental Hematology . 2010, 38: 3-10.

Ma C.H. , Fan K.P. , Ward A.C., Liongue C., Lewis R.S., Cheng S.H., Chan P.K., Yip S.F. , Liang R.H.S. and Leung A.Y.H. , A novel zebrafish jak2a(V581F) model shared features of human JAK2(V617F) polycythemia vera., Experimental Hematology . 2009, 37: 1379-1386.

Researcher : Feng Z

Project Title:	30th Annual Meeting of the Society for Neuroscience Identifying and Cloning of B218 Gene, which was Down Regulated by Kainic Acid Treatment and in the Developmental Stages
Investigator(s):	Feng Z
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	11/2000

Abstract:

N/A

Researcher : Fok ANY

List of Research Outputs

Wang A.Y.M. , Cheung C.W., Chu J.Y.Y. , Fok A.N.Y. , Lo W.K. , Leung J.C.K. , Tso W.K. and Lai K.N. , Is aortic pulse wave velocity a useful screening test for vascular and valvular calification in end-stage renal disease patients, Journal of American Society of Nephrology . 2009, 20: 443A-444A.

Researcher : Fong HY

List of Research Outputs

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a Chinese population, J Clin Endocrinol Meta . 2010, 95: 1395-403.

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Researcher : Fung FMY

List of Research Outputs

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Researcher : Fung JYY

List of Research Outputs

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Correlation of liver stiffness and histological features in healthy persons and in patients with occult hepatitis B, chronic active hepatitis B, or hepatitis B cirrhosis., Am J Gastroenterol . 2009, 105(5): 1116-22.

Fung J.Y.Y. , Lai C.L. and Yuen R.M.F. , Hepatitis B and C virus-related carcinogenesis., Clin Microbiol Infect . 2009, 15(11): 964-70.

Fung J.Y.Y. , Lai C.L. and Yuen R.M.F. , Hepatitis B virus DNA and hepatitis B surface antigen levels in chronic hepatitis B., Expert Rev Anti Infect Ther . 2010, 8(6): 717-26.

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Liver stiffness and histological features in healthy persons, and patients with occult hepatitis B, chronic active hepatitis B, and hepatitis B-related cirrhosis. , Hepatology . 2009, 50(4) Suppl: 978A.

Fung J.Y.Y. , Lai C.L. , Cheng C.T.K. , Wu C.H. , Wong D.K.H. and Yuen R.M.F. , Mild-to-moderate elevation of alanine aminotransferase may increase liver stiffness measurement by transient elastography in patients with chronic hepatitis B., Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 971A.

Fung J.Y.Y. , Seto W.K., Lai C.L. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , Profiles of HBV DNA in a large population of chinese chronic hepatitis B patients: implications for antiviral therapy. , Hepatol Int . The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010., 2010, 4: 53-4.

Fung J.Y.Y. , Lai C.L. , Yuen J.C.H. , Cheng C.T.K. , Wu C.H. and Yuen R.M.F. , Sequential therapy using lamivudine in entecavir-treated patients with undetectable HBV DNA – results at 48 weeks. , Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 510A.

Fung J.Y.Y. , Treatment of Different Genotypes in Chronic Hepatitis C, 3rd Ditan International Conference on Infectious Disease, Beijing, China . 2009.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , A three-year study on viral suppression and resistance profile for treatment-naive chronic hepatitis B patients receiving continuous entecavir treatment. , Hepatol Int. The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010 . 4: 58.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , HBV DNA levels predict significant liver histology for HBeAg-negative chronic hepatitis B patients., Gastroenterology. Digestive Disease Week, New Orleans, May 2010 . 138 (5 Supp1): S-788.

Yuen R.M.F. , Fung J.Y.Y. , Seto W.K., Wong D.K.H. , Yuen J.C.H. and Lai C.L. , Combination of baseline parameters and on-treatment hepatitis B virus DNA levels to start and continue patients with lamivudine therapy. , Antivir Ther . 2009, 14(5): 679-85.

Researcher : Fung TK

List of Research Outputs

Cheung A.M., Fung T.K. , Fan K.P. , Wan T.S., Chow C.H. , Leung J.C.K. , Chan L.Y., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD/SCID mice., Experimental Hematology . 2010, 38: 3-10.

Chim J.C.S. , Fung T.K. and Liang R.H.S. , Methylation of cyclin-dependent kinase inhibitors, XAF1, JUNB, CDH13 and soluble Wnt inhibitors in Essentia l Thrombocythemia, Journal of Clinical Pathology . 2010, 63(6): 518-21.

Researcher : Fung TK

Project Title:	The role of NUP98 in hematopoiesis in zebrafish and generation of zebrafish model for NUP98-HOXA9 overexpression
Investigator(s):	Fung TK, Leung AYH
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	09/2008
Completion Date:	02/2010

Abstract:

See Attachment.

List of Research Outputs

Chim J.C.S. , Fung T.K. and Liang R.H.S. , Methylation of cyclin-dependent kinase inhibitors, XAF1, JUNB, CDH13 and soluble Wnt inhibitors in Essential Thrombocythemia, Journal of Clinical Pathology . 2010, 63(6): 518-21.

Researcher : Gao J

List of Research Outputs

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. , Cheung C., Qiu D., Mak H.K.F. and Chan Y.S. , Declined frontal white matter integrity in Alzheimer’s disease: a diffusion tensor imaging study, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 21.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. and Chan Y.S. , Task-induced brain deactivation reflects the altered default model network in normal and abnormal aging, Fifth International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, 6–7 March 2010, The Ballroom, Sheraton Hong Kong Hotel & Towers, Tsimshatsui, Hong Kong; Abstract Book . 2010, 46.

Gao J. , Cheung R.T.F. , Lee T.M.C. , Chu L.W. , Cheung C., Fung G., Qiu D.G. and Chan Y.S. , The anteroposterior pattern of white matter decline in normal and abnormal aging supports retrogenesis: a diffusion tensor imaging study, Fifth International Symposium on Healthy Aging, Research Centre of Heart, Brain, Hormone and Healthy Aging, The University of Hong Kong, 6–7 March 2010, The Ballroom, Sheraton Hong Kong Hotel & Towers, Tsimshatsui, Hong Kong; Abstract Book . 2010, 46.

Researcher : Gao Y

List of Research Outputs

Bow C.H.Y. , Cheung C.L. , Gao Y. , Lau K.S. , Soong S.S. , Yeung S.C. and Kung A.W.C. , Bone Mineral Density and Serum Osteoprotegerin Levels in Pre- and Postmenopausal Women, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Cheung C.L. , Xiao S. , Gao Y. and Kung A.W.C. , Genetic Epidemiology of Osteoporosis and Its Application, 骨質疏鬆症的遺傳流行病學及其臨床應用, Chinese Journal of Osteoporosis and Bone Mineral Research . 2010, 3: 73-86.

Kung A.W.C. , Xiao S. , Cherny S.S. , Li H.Y. , Gao Y. , Tso G., Lau K. , Luk K.D.K. , Liu J.M., Cui B., Zhang M.J., Zhang Z.L., He J.W., Yue H., Xia W.B., Luo L.M., He S.L., Kiel D.P., Karasik D., Hsu Y.H., Cupples L.A., Demissie S., Styrkarsdottir U., Halldorsson B.V., Sigurdsson G., Thorsteinsdottir U., Stefansson K., Richards B., Zhai G., Soranzo N., Valdes A., Spector T.D. and Sham P.C. , Association of JAG1 with Bone Mineral Density and Osteo porotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies, American Journal of Human Genetics . 2010, 86 (2): 229-239.

Researcher : Ge X

List of Research Outputs

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Researcher : Gu Q

List of Research Outputs

Hung I.F.N. , Chan P., Leung S., Chan S.Y. , Hsu A., But D., Seto W.K., Wong S.Y. , Chan C.K. , Gu Q. , Tong T.S.M., Cheung T.K. , Chu K.M. and Wong B.C.Y. , Clarithromycin-amoxycillin-containing triple therapy: A valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong?, Helicobacter . 2009, 14: 505-511.

Tu S.P., Sun R.W.Y. , Lin M.C. , Cui J.T., Zou B. , Gu Q. , Kung H.F., Che C.M. and Wong B.C.Y. , Gold (III) Porphyrin Complexes Induce Apoptosis and Cell Cycle Arrest and Inhibit Tumor Growth in Colon Cancer, Cancer . 2009, 115(19): 4459-4469.

Tu S.P., Sun Y.W., Cui J.T., Zou B. , Lin M.C. , Gu Q. , Jiang S.H., Kung H.F., Korneluk R.G. and Wong B.C.Y. , Tumor Suppressor XIAP-associated Factor 1 (XAF1) Cooperates with Tumor Necrosis Factor-related Apoptosis-inducing Ligand to Suppress Colon Cancer Growth and Trigger Tumor Regression, Cancer . 2010, 116(5): 1252-1263.

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnosti c and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Researcher : Guo H

List of Research Outputs

Guo H. , Leung J.C.K. , Cheung J.S., Chan Y.Y. , Wu E.X. and Lai K.N. , Non-viral Smad7 gene delivery and attenuation of postoperative peritoneal adhesion in an experimental model, Br J Surg . 2009, 96(11): 1323-35.

Researcher : Han Q

List of Research Outputs

Han Q. , Yeung S.C. , Ho S.P. , Ip M.S.M. and Mak J.C.W. , Differential Effects Of Intermittent Hypoxia And/or Cigarette Smoking On The Expression Levels Of Fatty Acid-binding Protein In Rat Heart And Lung: An In Vivo Pilot Study, Respirology . 2009, 14 (Suppl. 3): A171.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Effects Of Intermittent Hypoxia On A-/e-fabp Expression In Human Aortic Endothelial Cells, International Journal of Cardiology . 2010, Epub ahead of print.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification Of Serum Adiponectin And Cinc-1 Levels By Intermittent Hypoxia And/or Hyperlipidemia In Vivo, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 22.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification of circulating and cardiac expressions of adiponectin and CINC-1 by intermittent hypoxia in vivo, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A3702.

Researcher : He F

List of Research Outputs

He F. , Kwong Y.L. and Ho J.C.M. , In-vitro growth inhibitory effects of arsenic trioxide in non-small cell lung cancer with different epidermal growth factor receptor mutations, 15th Medical Research Conference, Hong Kong Medical Journal. . 2010, 16: 22.

Researcher : He H

List of Research Outputs

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Researcher : Ho JCM

Project Title:	MERIT – A phase II marker identification trial for TarcevaTM in second line NSCLC patients
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	F Hoffmann-La Roche and Co. Ltd. - General Award
Start Date:	07/2005

Abstract:

To study the identification of differentially exp ressed genes that are predictive for benefit of TarcevaTMtreatment.

Project Title:	A Phase III, radonmized, double-bli nded, parallel group, multi centre study to access the efficacy and safety of ZD6474 (ZACTIMA TM) in combination with pemetrexed (Alimta) versus pemetrexed alone in patients with locally-advanced or metastatic (stage IIIB or IV) non-small cell lung cancer (NSCLC) after failure of 1st line anti-cancer therapy
Investigator(s):	Ho JCM, Wong MKY
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	02/2007

Abstract:

to access the efficacy and safety of ZD6474 (ZACTIMA TM) in combination with pemetrexed (Alimta) verus pemetrexed alone

Project Title:	A rabdomized, double blind, placebo controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib after completion of chemotherapy with bevacizumab for the first line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	08/2007

Abstract:

to compare bevacizumab therapy with or with erlotinib after completion of chemotherapy with bevacizumab

Project Title:	The effect of inhaled corticosteroi ds on the risk of diabetes, impaired glucose tolerance and characteristics of glucose regulation in adults with asthma: a population based matched controlled study
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Lee Wing Tat Fund
Start Date:	08/2007

Abstract:

(A) Primary Objectives: To investigate the ICS effect on the risk of DM/IGT/insulin resistance: (1) prevalence and prevalence odds ratio of diabetes in asthma patients using ICS, (2) prevalence and prevalence odds ratio of IGT in asthma patients using ICS, (3) characteristics of glucose tolerance and insulin resistance in ICS users. (B) Secondary Objectives: To study the dose response relationship and effect odifying factors if risk is present: (1) cumulative dose response relationship of ICS on the risk of diabetes, (2) Cumulative dose response relationship of ICS on the risk of IGT, (3) The impact of ICS dosages on ICS induced insulin resist ance, (4) The impact of positive family history of diabetes, BMI and age on ICS induced insulin resistance.

Project Title:	The effect of inhaled corticosteroids on the risk of diabetes, impaired glucose tolerance and characteristics of glucose regulation in adults with asthma : a population based matched controlled study
Investigator(s):	Ho JCM, Ip MSM, Chan MMW, Lam WK, Lam KSL
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	08/2007

Abstract:

Background: Inhaled corticosteroids have been shown to have many side effects that are consistent with systemic corticosteroids, suggesting that its systemic absorption can lead to adverse effects in the long term users. ICS can pose a major health impact in the community , especially when its use has become widely accepted as mainstay treatment for asthma and chronic obstructive airway diseases in recent decades. In 1997 , inhaled corticosteroids was shown to increase the risk of nuclear cataracts by 1.5 fold and posterior subcapsular cataracts by 1.9 fold respectively. Besides, high dose ICS use for more than 3 months increased risk of open angle glaucoma with OR 1.44. In 1998 , a case control study demonstrated positive association of cataract extraction in elderly ICS users. ICS use of more than 3 years increased cataract by 3 folds in high dose users (> 1mg daily budesonide diproprionate ). Whereas low dose use ( <1mg daily budesonide diproprionate ) for more than 2 years increased cataract by 1.6 fold. Subsequent studies also found increased risk of osteoporosis in long term ICS users. It has been well known that systemic corticosteroids causes diabetes by inducing insulin resistance. Previous study showed a 2-fold increased risk of diabetes in patients using systemic corticosteroids. Nevertheless, of the many systemic side effects that are known to inhaled corticosteroids , its effect on the risk of diabetes has not been es tablished yet. There have also been 2 small scale studies about the effect of ICS on insulin resistance profile , however, the study findings were also inconclusive. In 1987, a study of 9 subjects, given 4 weeks of inhaled budesonide diproprionate 1mg daily , were shown to have increase in 2 hour peak glucose level in oral glucose tolerance test, and also increased fasting serum insulin concentration, suggesting that ICS use was associated with glucose dysregulation and increase insulin resistance. Subsequently, in 1993, another study of 15 subjects with unstable asthma compared to 15 normal control subjects, a reduction in insulin resistance in patients with uncontrolled asthma was noted upon 1 month of ICS treatment; while the insulin resistance profile became static at 5 and 8 months of therapy. This study suggests that insulin resistance profile are increased in subjects with unstable asthma in relation to the stress induced during exacerbation. ICS can reduce insulin resistance profile by stabilizi ng asthma control. In terms of researches relating ICS to diabetes, there are limited studies in the elderly . In 1998, a study showed dose dependent worsening of diabetic control in the diabetic elderly using high dose ICS. However, 2 subsequent case control studies conducted in 2002 failed to demonstrate any association of diabetes in elderly with either current use of ICS or 3 years uses of ICS. These study results are subjected to confounding by concurrent systemic cort icosteroid usage, lack of long term users of ICS, as well as the effect of other competing causes of diabetes ( ie. aging and obesity ) being so strong in the elderly that the impact of ICS on the risk of diabetes might have been masked in this particular group of patients. So far, data is lacking in terms of the association between inhaled corticosteroids and diabetes, as well as impaired glucose tolerance – the pre-diabetic condition. Moreover, the profile of glucose regulation and potential hyperinsu linemia in ICS users with normal glucose tolerance is largely unexplored. As Asians are at increased risk of developing NIDDM, the effect of ICS in inducing diabetes in the Chinese might be more prominent than that for subjects in the western countries. Therefore, we shall investigate the effect of ICS , trying to understand its impact on the whole disease spectrum of insulin resistance. We shall begin with study on the risk of diabetes, then move on to that of impaired glucose tolerance and finally to explore potential hyperinsulinemia in subjects with normal glucose tolerance who have used ICS . We will also put particular emphasis on the younger Chinese population, where the impact of age and obesit y is less marked, and therefore, the effect of ICS on the risk of DM/ IGT/ hyperinsulinemia can be better manifestated and delineated. About 10% of our population has asthma and of these, 50% are on long term inhaled corticosteroids . While asthma is not known to cause diabetes and hence not a confounder for the association of ICS and DM, we shall therefore target at the adult Chinese asthma patients using ICS as our study subjects, and compare the risk of diabetes/ IGT/ hyperinsulinemia of this group of patients with that of the general population. Since diabetes mellitus is a major health problem that is strongly associated with multiple cardiovas cular morbidity and mortality, and inhaled corticosteroid being the most commonly prescribed drug in treating chronic airway diseases. Knowledge regarding the risk of DM in association with chronic ICS use will be of major impact on public health. Study Objectives: A. Primary Objectives: ICS effect on the risk of DM/IGT/insulin resistance 1) Prevalence and prevalence odds ratio of diabetes in asthma patients using ICS 2) Prevalence and prevalence odds ratio of IGT in asthma patients using ICS 3) Characteristics of glucose tolerance and insulin resistance in ICS users B. Secondary Objectives: Dose response relationship and effect modifying factors if risk present 1) Cumulative dose response relationship of ICS on the risk of diabetes 2) Cumulative dose response relationship of ICS on the risk of IGT 3) The impact of ICS dosages on ICS induced insulin resistance 4) The impact of positive family history of diabetes , BMI and age on ICS induced insulin resistance

Project Title:	A Phase 3, multicentre, randomized, placebo-controlled, double-bind trial of AMG 706 in combination with paclitaxel and carboplatin for advanced non-small cell lung cancer
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	11/2007

Abstract:

to study AMG 706 in combination with paclitax and carboplatin

Project Title:	A phase III, randomized, double-blind, active-controlled, parallel-group study, conducted under in-house building conditions, to examine the safety, tolerability, and efficacy of a single dose of intravenous MK-0517 for the prevention of chemother apy-induced nausea and vomiting (CINV) associated wtih Cisplatin chemotheray
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	06/2008

Abstract:

to examine the efficacy of a single dose of intravenou se MK0-517

Project Title:	The association of asthma with systemic inflammation and oxidative stress, and its effect on the risk of cardiovascular morbidity in adult with stable asthma
Investigator(s):	Ho JCM, Ip MSM, Chan MMW, Cheung BMY, Lam KSL, Lam WK
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	09/2008

Abstract:

Asthma is a chronic inflammatory airway disorder, associated with airflow obstruction and bronchial hyper responsiveness (1), which affects about 10% of population in Hong Kong. (2) It has been a major respiratory disease in Hong Kong that carries significant morbidity and high hospitalization burden in asthmatics of all ages. (3-5) The use of long-term inhaled corticosteroid treatment in recent decades has become the cornerstone in the treatment of most patients with persistent asthma with reduction in its mortality. The ultimate goal of treatment is to achieve optimal control of airway inflammation and asthma-related mortality and morbidity. (1) In recent studies on the evaluation of airway and systemic inflammation in patients with asthma, various biomarkers have been measured in exhaled breath condensate (EBC ), like nitric oxide, nitrates/nitrites and 8-isoprostane. (6) Similarly, measurement of biomarkers in blood, notably high-sensitivity c-reactive protein (hs-CRP), 8-isoprostane and antioxidants (catalase, superoxide dismutase, glutathione peroxidase, glutathione), has also been used to reflect the levels of systemic inflammatio n (7-11) and oxidative stress. (12) There has been substantial evidence from landmark epidemiological studies in the past 10 years, predominantly based on plasma hs-CRP, that chronic low grade systemic inflammation is an independent predictor for the development of hypertension, myocardial infarction, stroke, cardiovascular death and peripheral vascular disease. (13-16) A dose- dependent risk association between hs-CRP and these cardiovascular morbidities have also been consistently demonstrated. (13) Moreover, there has been overwhelming data to suggest the association between oxidative stress and the development cardiovascular disease. (17-19) This association is easily understood in light of the cellu lar damages and endothelial dysfunction due to oxidative stress, which may lead to the development of atherosclerosis and cardiovascular morbidity. In chronic obstructive pulmonary disease (COPD), a chronic inflammatory airway disorder characterized by irreversible airflow obstruction induced mainly by tobacco smoking (20), studies have demonstrated that, in acute exacerbations of COPD and smoking , there is a marked imbalance of redox status. (21) The increase oxidative stress result in the inactivati on of alveolar antiproteases, airspace epithelial damage , increased influx of neutrophils into lung tissue and the expression of pro-inflammatory mediators. (22, 23) Similarly, patients with COPD also have increase inflammatory neutrophils, lymphocytes and TNF-α in the peripheral blood. (24, 25) In fact, many studies have demonstrated the existence of low grade systemic inflammation (15, 26-28) and oxidative stress (29-31) in patients with COPD. Important studies published in recent 5 years have also linked the elevation of these systemic biomarkers, in a dose-dependent manner, to COPD severity (28, 32) and increased prevalence of cardiovascular and cerebrovascular morbidity and mortality in patients with COPD. (33-35) On the other hand, chronic airway inflammation is also the hallmark of asthma which involves the interplay of different types of inflammatory cells, including T- lymphocytes, eosinophils, neutrophils , macrophages and cytokines in the airway. (1) Although the pathogenesis of asthma is incompletely understood, studies have shown that it is associated with a state of increased free radical formation, because cells derived from lungs and peripheral blood of patients with asthma generate increased amount of reactive oxygen species, the level of which is related to severity of asthma. (36-38) Besides, airway biomarkers indicating airway inflammation and oxidative stress has been consistently shown to be positively related to asthma severity and asthma control (6), which can be alleviated with treatment by inhaled corticosteroids. (6) Additionally, recent preliminary studies have indicated that, apart from the presence of chronic airway inflammation (elevated EBC nitric oxide , EBC nitrites/ nitrates and EBC 8- isoprostane), asthma may also be associated with chronic low grade systemic inflammation (7-11) (elevation of plasma hs-CRP) and increased oxidative stress (8-isoprostane , erythrocyte superoxide dismutase, catalase, glutathione peroxidase and glutathione). (12) Whether the presence of systemic inflammation and oxidative stress in asthma is actually a consequence of “overspill” of uncontrolled airway inflammation or the existence of an extrapulmonary source of inflammation remains unknown. At the moment, there is only little evidence on the correlation of airway and systemic inflammation in asthma, as well as the relation of systemic inflammation and oxidativ e stress to asthma severity. Intuitively, as in COPD, asthma-related systemic inflammation may as well increase the propensity for development of cardiovascular and cerebrovascular diseases. However, there is also a lack of study that describes the risk of cardiovascular outcomes of asthma-related systemic inflammation and oxidative stress. Therefore, we conduct the current study with the primary objective to investigate the association of asthma severity with systemic inflamma tion and oxidative stress, and its effect on the risk of various cardiovascular morbidities. The secondary objective is to correlate airway inflammation and oxidative stress with systemic inflammation and oxidative stress in stable asthmatics. Primary Objectives: The association of asthma severity with systemic inflammation and oxidative stress, and its effect on the risk of cardiovascular morbidity 1. The association of asthma severity with biomarkers of systemic inflammation ( plasma hs-CRP and 8-isoprostane ) and oxidative stress (erythrocyte superoxide dismutase, catalase, glutathione peroxidase and glutathione ) in stable asthmatics. 2. The independent effect of asthma related systemic inflammation and oxidative stress ( plasma hs-CRP, plasma 8-isoprostane and erythrocyte superoxide dismutase, catalase , glutathi one peroxidase and glutathione ) on the risk of cardiovascular morbidity . Secondary Objectives: Correlation of airway inflammation and oxidative stress with systemic inflammation and oxidative stress in stable asthmatics ; evaluation of interaction between airway and syst emic inflammation on asthma severity, risk of cardiovascular morbidity , 1. Correlation of biomarkers of airway inflammation ( EBC nitrites/nitrates) and oxidative stress ( EBC 8-isoprostane ) with biomarkers of systemic inflammation and oxidative stress (plasma hs-CRP, pl asma 8-isoprostance and erythrocyte superoxide dismutase, catalase , glutathione peroxidase and glutathione) in stable asthmatics 2. Interaction between airway and systemic inflammation on asthma severity, risk of cardiovascular morbidity in stable asthmatics

Project Title:	A randomized, multicenter phase II study to explore whether biomarkers correlate with treatment outcome in chemo-naive patients with advanced or recurrent non-squamous non-small cell lung cancer, who receive treatment with bevacizumab (at a dose of either 7,5mg.kg or 15mg/kg) in addition to carboplain-based chemotherapy (gemcitabine or paclitaxed)
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	12/2008

Abstract:

to explore biomarkers correlation with non-small cell lung cancer

Project Title:	In-vitro combination of arsenic trioxide and chemotherapy in non-small cell lung cancer
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Hong Kong Lung Foundation Research Grant
Start Date:	02/2009

Abstract:

Arsenic trioxide as a novel epidermal growth factor receptor inhibitor in non-small cell lung cancer

Project Title:	A randomised, placebo-controlled, double-blind phase III study of sequential administra tion of Tarceva (erlotinib) or placebo in combination with gemcitabine/platinum as first-line treatment in patients with stage IIIB/V non-small cell lung cancer (NSCLC)
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	04/2009

Abstract:

Gemcitabine / carboplain chemotherapy with sequential Tarceva or placebo

Project Title:	Multicenter, randomized, double-blind, phase III trial to investigate the efficacy and safety of oral BIBF 1120 plus standard pemetrexed therapy compared to placebo plus standard pemetrexed therapy in patients with stage IIIB/IV or recurrent non small cell lung cancer after failure of first line chemotherapy
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	04/2009

Abstract:

second-line treatment of premetrexed + BIBF 1120

Project Title:	A Phase III, multi-center, placebo–controlled trial of Sorafenib (BAY 43-9006) in patients with relapsed or refractory advanced predominantly non squamous Non-Small Cell Lung Cancer (NSCLC) after 2 or 3 previous treatment regimens.
Investigator(s):	Ho JCM, Lam CLD, Lam CM, Wang JKL, Wong MKY
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	08/2009

Abstract:

The objective of this phase III study is to compare the efficacy and safety of sorafenib monotherapy plus best supportive care (BSC) versus placebo plus BSC for the treatment of patients with relapsed or refractory advanced predominantly non squamous NSCLC after two or 3 prior treatment regimens. The primary efficacy variable is overall survival (OS). Secondary efficacy variables are progression-free-survival (PFS), disease control rate (DCR), best overall response rate (ORR), time to progression (TTP), and patient reported outcomes (PRO) on health related quality of life (HRQOL), lung cancer symptoms and utilities. Biomarkers will be assessed as exploratory variables. Other exploratory variables are metabolic disease control rate (MDCR) and metabolic overall response rate (MORR). These variables will be assessed for patients who underwent Positron Emission Tomography (PET) tumor assessment at those participating sites, where PET is used as part of routine clinical practice. In addition, safety variables will be assessed.

Project Title:	In-vitro combination of arsenic trioxide and chemotherapy in non-small cell lung cancer
Investigator(s):	Ho JCM
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	10/2009

Abstract:

Lung cancer, predominantly non-small cell carcin oma (NSCLC), has remained the top cancer killer in Hong Kong and many other parts of the world over the past decade, accounting for a global incidence of 1.2 million new cases yearly and a staggering mortality of 1.1 million deaths in 2001. [1] Based on the Hong Kong Cancer Registry in 2005, there were 4,135 new cases and 3,686 deaths due to lung cancer in the whole year. The high mortality of lung cancer is mainly related to predominance of advanced disease upon clinical presenta tion and the relatively ineffective treatment for advanced or metastatic disease. Systemic chemotherapy has been the cornerstone in palliative treatment for advanced NSCLC, which however was largely limited by its toxicities and rather short duration of disease control. The major breakthrough in lung cancer treatment over the past 5 years is the discovery and clinical application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI). It has been made possible with the increased understanding of biological importance of EGFR pathway in lung carcinogenesis. The clinical use of EGFR TKI in advanced NSCLC has resulted in improved overall survival and quality of life in a selected subgroup of patients, especially those with tumours carrying EGFR sensitizing mutations. In fact, the prevalence of such EGFR mutations in lung cancers has been found to be much enriched in the East Asian population (including Chinese), females and neversmokers. [2] Among those with such epidemiological characteristics and adenocarcinoma histology, the EGFR mutation rate has been commonly reported to be around 50-70%. [2] This is especially relevant to Hong Kong as our recent local studies have demonstrated significant time trends of increasing non-smoking related adenocarcinoma of lung. [3-5] As a result, EGFR TKI has now become a major armamentarium in the first-, second-, or even third-line treatment of lung cancer in Hong Kong. Since the clinical benefit of systemic chemotherapy remains modest, there is theoreti cal advantage in combining chemotherapy with other classes of anti-cancer drugs in the treatment of NSCLC. However, the previous landmark clinical trials have failed to demonstrate clinical benefit of combining standard chemotherapy and EGFR TKI in the first-line setting. [6-8] In this study, arsenic trioxide (ATO) is being investigated in vitro as a novel agent in combination with chemotherapy for lung cancer treatment. ATO has established its important role in the treatment of leukaemia especially acute promyelocytic leukaemia in the past decade, with its mechanisms mainly via oxidative stress and apoptosis. Based on our preliminary findings in NSCLC cell lines with different EGFR mutation status, including those mutations conferring drug sensitivity or resistance, ATO preferentially works in those with EGFR sensitizing mutation compared to wild type, suggesting potential mechanism that works on EGFR pathway. Therefore the key objective of this study is to determine and compare the in vitro drug sensitivity to ATO, chemother apy or combination of both agents in lung cancer cell lines with different EGFR mutation status. References: 1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001: 94(2) : 153-156. 2. Yang CH. EGFR tyrosine kinase inhibitors for the treatment of NSCLC in East Asia: present and future. Lung Cancer 2008: 60 Suppl 2: S23-30. 3. Chan-Yeung M, Koo LC, Ho JC, Tsang KW, Chau WS, Chiu SW, Ip MS, Lam WK. Risk factors associated with lung cancer in Hong Kong. Lung Cancer 2003: 40(2): 131-140. 4. Lam WK. Lung cancer in Asian women-the environment and genes. Respirology 2005: 10(4): 408-417. 5. Au JS, Mang OW, Foo W, Law SC. Time trends of lung cancer incidence by histologic types and smoking prevalence in Hong Kong 1983-2000. Lung Cancer 2004: 45(2): 143 -152. 6. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. J Clin Oncol 2004: 22(5): 777-784. 7. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. J Clin Oncol 2004: 22(5): 785-794. 8. Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res 2004: 10(12 Pt 2): 4238s-4240s.

Project Title:	Phase 3, randomized, open-label study of the efficacy and safety of PF-02341066 versus standard of care chemotherapy (pemetrexed or docetaxel) in patients with advanced nonsmall cell lung cancer (NSCLC) harbouring a translocation or inversion event involving the anaplastic lymphoma kinase (ALK) gene locus
Investigator(s):	Ho JCM, Lam CLD, Wong MKY, Lam CM, Ip MSM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	04/2010

Abstract:

Primary Objective: ‧To demonstrate that PF-02341066 (Arm A) is superior to standard of care chemotherapy, pemetrexed or docetaxel (Arm B), in prolonging PFS in patients with advanced NSCLC whose tumors harbor a translocation or inversion event involving the ALK gene locus and who have received only one prior chemotherapy regimen for advanced NSCLC and this regimen must have been platinum -based Secondary Objectives: ‧To compare secondary measures of clinical efficacy including overal l survival (OS), objective response rate (ORR), and disease control rate (DCR) between the two treatment groups, and evaluate duration of response (DR) ‧To assess the safety and tolerability of PF-02341066 compared to pemetrexed or docetaxel ‧To compare PRO of HRQoL, disease/treatment-related symptoms of lung cancer, and general health status in both treatment arms ‧To characterize the effects of PF -02341066 at therapeutic doses on QTc interval in this patient population ‧To determine PK in this patient population using POPPK methods and explore correlations between PK, response and/or safety findings ‧To explore the relationship of ALK gene fusion to the presence of ALK protein and fusion transcript ‧To correlate modulation of soluble biomarkers to PK and outcome measures

Project Title:	Phase 2, open-label single arm study of the efficacy and safety of PF 02341066 in patients with advanced non-small cell lung cancer (NSCLC) harboring a translocation or inversion involving the anaplastic lymphoma kinase (ALK) gene locus
Investigator(s):	Ho JCM, Lam CLD, Wong MKY, Lam CM, Ip MSM
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	04/2010

Abstract:

Primary Objectives: • To assess the anti-tumor efficacy of oral single agent PF-02341066 administered to patients with advanced NSCLC after failure of at least one line of chemotherapy and harbor a translocation or inversion event involving the ALK gene locus as measured by ORR • To assess the safety and tolerability of oral PF-02341066 Secondary Objectives: • To assess secondary measures of clinical efficacy including overall survival (OS), duration of response (DR), disease control rate (DCR) at 6 and 12 weeks, and progression-fre e survival (PFS) • To determine PK in this patient population using POPPK methods and explore correlations between PK, response and/or safety findings • To explore the relationship of ALK gene fusion to the presence of ALK protein and fusion transcript • To correlate changes from baseline in expression of biomarkers in signaling pathways (including JAK/STAT, MEK/ERK, and PI3K/AKT pathways) to pharmacokinetic and outcome measures • To assess PRO of HRQoL, disease/treatment-related symptoms of lung cancer, and general health status

List of Research Outputs

Chiu C.N. , Liao S. , Lam K.W. , Tang F. , Ho J.C.M. , Ho P.C. , O W.S. , Yao Q.Y. and Yeung W.S.B. , Adrenomedullin regulates sperm motility and oviductal ciliary beat via cyclic adenosine 5'-monophosphate/protein kinase A and nitric oxide, Endocrinology . 2010, 151(7): 3336-3347.

He F. , Kwong Y.L. and Ho J.C.M. , In-vitro growth inhibitory effects of arsenic trioxide in non-small cell lung cancer with different epidermal growth factor receptor mutations, 15th Medical Research Conference, Hong Kong Medical Journal. . 2010, 16: 22.

Ho J.C.M. , Ho S.P. , Mak J.C.W. , Wong M.K.Y. , Ip M.S.M. and Lam W.K. , Alterations of systemic antioxidants and 8-isoprostane during chemotherapy for lung cancer. , 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S909.

Ho J.C.M. , Lam C.L. , Wong M.K.Y. , Lam B. , Ip M.S.M. and Lam W.K. , Capecitabine as salvage treatment for lymphoepithelioma -like carcinoma of lung, Journal of Thoracic Oncology . 2009, 4(9): 1174-1177.

Ho J.C.M. , EGFR mutation status as biomarker for advanced NSCLC: latest data, Roundtable discussion. AstraZeneca. . 2010.

Ho J.C.M. , New hopes for COPD: How far have we gone? , Macau International Forum of Hospital Medicine and the 9th Doctor Training Conference . 2009.

Ho J.C.M. , Targeted and novel treatments for non-small cell lung cancer, Hong Kong International Cancer Conference 2009, HKU . 2009.

Li R.H.W. , Liao S. , Chiu C.N. , Tam W.W., Ho J.C.M. , Ng E.H.Y. , Ho P.C. , Yeung W.S.B. , Tang F. and O W.S. , Expression of adrenomedullin in human oviduct, its regulaton by the hormonal cycle and contact with spermatozoa, and its effect on ciliary beat frequency of the oviductal epithelium, Journal of Clinical Endocrinology and Metabolism . 2010, 95(9): E18-E25.

O W.S. , Liao S. , Sun J.Z. , Ho J.C.M. , Chiu C.N. , Ng E.H.Y. , Yeung W.S.B. , Li R.H.W. and Tang F. , Adrenomedullin and oviduct function in human and rats, Biology of Reproduction . 2009, 81: 99.

Wang J.K., Ho J.C.M. , Mok T.Y., Chan J.W., Yee W.K., Chan M.M.W. , Cheung B.M.Y. , Lam K.S.L. , Lam W.K. and Ip M.S.M. , The relationship of asthma and the pattern of adiposity in adult Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 56.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to first-line gefitinib in non-small cell lung cancer. , Cancer Chemotherapy and Pharmacology . 2010, 65: 1023-1028.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to gefitinib in non-small cell lung cancer, 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S719.

Zheng C. , Kwong Y.L. and Ho J.C.M. , In-vitro combination of arsenic trioxide and chemotherapy in small-cell lung cancer, 15th Medical Research Conference, HKU. Hong Kong Medical Journal . 2010, 16: 56.

Researcher : Ho JCY

Project Title:	Functional significance of Connexin in Regenerated Endothelial Cells
Investigator(s):	Ho JCY, Tse HF
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	12/2008

Abstract:

Atherosclerosis is the leading cause of death in the world. The integrity and functional activity of the endothelial cells monolayer play a critical role in pathogenesis of atherosclerosis. Endothelium continuously expose to shear stress and given rise to endothelial dysfunction and ultimately leading to arthrosclerosis. The endothelium is able to regenerate upon injury, however, it is often accompanied by manifest dysfunction or desquamation leading to proatherogenic processes. In addition, damage of the endothelium after coronary interventions may also contribute to restenosis and thrombosis after procedures. Regulation of endothelial cell integrity is mediated by a range of cell-cell signaling process. The communications between indivi dual neighborhood cells are mediated by the presence of gap-junction. Gap-junction exists as a cluster of transmembrane channel that allows intracellular exchange of ions and small signaling molecules between cells. The major components of this channel, connexins (CX), belongs to a multigene family consists of nearly 20 members in mammalian cells. Connexin 37 (CX37), Connexin 40 (CX40) and Connexin 43 (CX43) are predominately expr essed in various types of endothelial cells (Ko et al, 1999). In particular, CX43 has been reported to be heterogeneously expressed in area with disturbed blood flow (Gabriels & Paul, 1998) which may play a more crucial role in endothelial regeneration and maintenance of endotheli al integrity. Unlike other connexins, CX43 has shown to possess distinct properties in addition to its ability for forming gap junction. CX43 forms hemichannels present in the cell member and function as channel that connects the cytosol and extracellular space (Vergara et al, 2003). It also possesses channel-independent function as its C-terminal tail can also interact with other signaling molecules that modulate cell-cycle regulation and modification of transcription (Singh et al, 2005). During atherosclerosis, down-regulation of gap-junctions is a common phenomenon (Hou et al, 2008). Reduced expression of endothelial gap-junctions is a potential indicator of endothelial dysfunction and unraveling the underlying molecular mechanisms may explore novel therapeutic implications of this deadly disease. Recently, we have established a porcine model to study the regeneration of endothelium of the coronary artery upon endothelial denudation (Lee et al, 2007). In an effort to identif y therapeutics targets for restoring the endothelium, we hypothesized that aberrant expression of the gap-junction protein, CX43, in particular, may contribute to the phenotypic alteration of the regenerated endothelium. Gabriels JE & Paul DL (1998) Circ. Res. 83:636-43. Hou CJ, Tsai CH, Yeh HI. (2008)Front Biosci. 13:3549-57. Ko YS, Yeh HI, Rothery S, Dupont E, Coppen SR, Severs NJ. (1999) J. Histochem Cytochem, 47:683-92. Lee MY, Tse HF, Siu CW, Zhe SG, Man RY, Vanhoutte PM (2007) Arteroscler Thromb Vasc Biol,27:2443-49. Singh D, Solan JL, Taffet SM, Javier R, Lampe PD (2005) J Biol Chem, 280:30416-421. Vergara L, Bao X, Cooper M, Bello-Reuss E, Reuss L (2003) J Membr Biol 196:173-84.

Project Title:	International Society for Stem Cell Research 7th Annual Meeting POTENTIAL USE OF ENDOTHELIAL-LIKE CELLS DERIVED FROM HUMAN EMBRYONIC STEM CELLS FOR VASCULAR REGENERATION
Investigator(s):	Ho JCY
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	07/2009
Completion Date:	07/2009

Abstract:

N/A

List of Research Outputs

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endothelial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Skilton A., Ho J.C.Y. , Mercer B., Outwin E. and Watts F.Z., SUMO Chain Formation Is Required for Response to Replication Arrest in S. pombe, PLoS One . 2009, 25: 6750.

Researcher : Ho SL

Project Title:	Biochemical markers in a large Chinese kindred with autosomal dominant motor neurone disease associated with SOD1 mutation
Investigator(s):	Ho SL, Song Y, Wang Y
Department:	Medicine
Source(s) of Funding:	Liu Po Shan/Dr Vincent Liu Endowment Fund for Motor Neuron diseases - General Award
Start Date:	04/2007

Abstract:

We now have biological samples over 30 non-symptomatic members with the SOD1 mutation, and 15 members who have features of MND and the SOD1 mutation, and these samples will increase with not only from new members but also from our 6 monthly followup. In collaboratio n with the Genome Research Center and the Dept of Biochemistry, we aim to discover biochemical markers associated with MND. Although human serum and plasma have an important clinical value for identification of biomarkers, the analysis of these samples is technically challenging due to the high dynamic concentration range (over 10 orders of magnitude) of the protein/peptide components. In particular, about 0.1% of the total proteins are the most abundant blood proteins, which constitute ~95% of the bulk mass of plasma proteins. These high abundant proteins produce signals interfering with the detection of the other low amount protein components. Hence, the discovery of new proteins or peptides biomarkers in blood is challenging. We have designed a systemat ic approach to resolve these problems to widen the range of detection, and optimized the detection of low concentration candidate biomarkers from our biological samples.

Project Title:	The role of neuronal uncoupling proteins (UCPs) in mitochondrial dysfunction in Parkins on's disease (PD)
Investigator(s):	Ho SL, Ho WL
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2007

Abstract:

(1) To study the roles of neuronal UCPs (UCP4 and 5) in mitochondrial dysfunction in PD by determining the localization and expression profiles of UCP4 and 5 in normal and parkinsonian brains, and MPTP-induced PD models. Because of the reduced funding, the above original objectives will be revised accordingly as follows: a) Knockdown of UCP4 will be omitted. b) Insitu hybridization of UCP4 and UCP5 in human post-mortem brain slides will be omitted; (2) explore the functio n of neuronal UCPs by manipulating their expression in MPTP models, and determining their links to ATP levels, MMP, oxidative stress, and cell viability.

List of Research Outputs

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chan K.H. , Kwan S.C. , Chu A.C.Y. , Ho W.L. , Ho W.M. and Ho S.L. , Aquaporin-4 expression by thymoma of myasthenia gravis patients, 20th Meeting of the European Neurological Society, Berlin, 2010; Journal of Neurology . 2010, 257 (Supplement 1): S50.

Chan K.H. , Tse C.T., Ho S.L. , Ho W.L. and Ho W.M. , Clinical Outcome of Hong Kong Chinese Relapsing Remitting Multiple Sclerosis, 20th Meeting of European Neurological Society, Berlin, 2010 .

Chan K.H. , Tsang J.W.H. , Mak W. , Liu H.H.W., Ho S.L. and Cheung R.T.F. , Thymomatous myasthenia gravis among Hong Kong Chinese, 20th Meeting of the European Neurological Society, Berlin, 2010. Journal of Neurology . 2010, 257 (Supplement 1): S170.

Chang R.S.K., Chan R.C.L., Chu M.M.Y., Yan C.H., Mak W. , Cheung R.T.F. and Ho S.L. , Risk factors, clinical features and prognosis of peri operative stroke in adults, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 13.

Chang R.S.K., Mak W. , Cheung R.T.F. and Ho S.L. , Short-latency somatosensory-evoked potential in patients with central nervous system space-occupying lesions: a study of 261 cases, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 13.

Ho S.L. , Invited Speaker, “Treatment of hallucinations in Parkinson’s disease: Atypical neuroleptics or cholinesterase inhibitor s?” , Asian Scientific Symposium on Parkinson’s disease and Restless Legs syndrome, Tokyo, Japan . Japan, 2009.

Ho S.L. , Neuroprotection in Parkinson’s disease: a clinical perspective , In: Invited Speaker, Shanghai Jiaotong University International Neurodegenera tive Diseases Symposium. . PR China, 2009.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Invest igator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong. (6-7 March 2010) . 2010, 46.

Ho W.L. , Ho S.L. and Ramsden D.B. , Human Catechol-O-methyltransferase (COMT) assay., In: Listed inventers: PWL Ho, SL Ho, DB Ramsden, World Intellectual Property Organization under the Patent Cooperation Treaty (PCT); PCT application no. PCT/CN2009/001011 filed on 8 Sept. 2009; International publication no. WO2010/034183 (1 Apr. 2010). . 2010.

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.L. , Ho W.M. , Liu H. , Chan K.H. , Ramsden D.B. and Ho S.L. , Neuronal mitochondrial uncoupling proteins: implications in the pathology of Parkinson’s disease , The Hong Kong Neurological Society - Annual Scientific Meeting 2009; Kowloon Shangri-La Hotel, Hong Kong; 8 Nov 2009. . 2009.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Herpes simplex encephalitis: how good are we in diagnosing this condition?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 29.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Ischaemic stroke related to branch artery disease: a missing link?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 30.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Liu H.H.W., Tsang J.W.H. , Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Chu A.C.Y. , Tse M.M.Y., Mak W. , Ho W.L. and Chan K.H. , Thymomatous myasthenia gravis, 15th Medical Research Conference, Faculty of Medi cine, The University of Hong Kong . 2010.

Teo K.C., Mahboobani N.R., Lee R. , Cheung R.T.F. , Ho S.L. , Tse C.T. and Chan K.H. , Intracerebral hemorrhage complicating anticoagulant therapy among Hong Kong Chinese, 15th Medical Research Conference, Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Best Abstract In Clinical Medicine, 15th Medical Research Conference, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Clinical outcome of relapsing remitting multiple sclerosis among Hong Kong Chinese, 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Researcher : Ho SP

List of Research Outputs

Han Q. , Yeung S.C. , Ho S.P. , Ip M.S.M. and Mak J.C.W. , Differential Effects Of Intermittent Hypoxia And/or Cigarette Smoking On The Expression Levels Of Fatty Acid-binding Protein In Rat Heart And Lung: An In Vi vo Pilot Study, Respirology . 2009, 14 (Suppl. 3): A171.

Ho J.C.M. , Ho S.P. , Mak J.C.W. , Wong M.K.Y. , Ip M.S.M. and Lam W.K. , Alterations of systemic antioxidants and 8-isoprostane during chemotherapy for lung cancer. , 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S909.

Researcher : Ho WL

Project Title:	Identification and characterizati on of the promoter region of human neuronal uncoupling protein-4, and its regulation to neuroprotection
Investigator(s):	Ho WL, Ho SL, Chan KH
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2009

Abstract:

Objectives: We plan to characterize the gene structure of human neuronal-specific uncoupling protein-4 by 1) determining the 5’- and 3’-RACE (rapid amplification of cDNA ends), 2) cloning and identifying the promote r region, 3) searching for regulatory transcriptional elements in the promoter region, and 4) comparing the structure and regulatory elements of UCP4 to the better described UCP2 (which is ubiquitously expressed) to understand their differences that may give each UCP their distinct functional characteristics in neurons. Key issues: Parkinson's disease (PD) is a common neurodegenerative disorder, and is a major burden in an aging population. Its pathogenesis is unknown. Current treatment of PD does not address the underlying dopa minergic nigrostriatal neuronal degeneration, or alleviate the progressive non-motor disability associated with degeneration of non-dopaminergic pathways. Neuroprotective strategi es which can modify the course of PD may delay its progression. One such strategy involves alleviating the deleterious effects of mitochondrial dysfunction which exist in PD (Lin et al., 2006). Mitochondria provide ATP, source of cellular energy. ATP production is coupled to oxida tive phosphorylation (OxiPhos), which generates mitochondrial membrane potential (MMP) from electron flow through electron transport chain (ETC), producing reactive oxygen species (ROS) as byproducts. Hence, mitochondrial ROS and ATP production are inextricably linked. Uncoupling proteins (UCPs), solute carriers in inner mitochondrial membrane, may be this vital link (Brookes et al., 2005; Kim-Han et al., 2005) by regulating MMP and cellular ROS levels through “mild uncoupling” (Miwa et al., 2003). Uncoupling occurs when ATP production is delinked from OxiPhos resulting in less ATP, but also less ROS and oxidative stress. Five homologs (UCP1 to UCP5) exist. UCP2, 4 and 5 are expressed in neurons (Mao et al., 1999; Sanchis et al., 1998). MPTP is commonly used in parkinsonian experimental models (Dauer et al., 2003). MPTP is converted to toxic MPP+ in neuro ns, which is concentrated in mitochondria. MPP+ specifically inhibits Complex I and hence OxPhos, thus decreasing ATP production, and generating harmful ROS especially superoxides (Markey et al., 1984; Hasegawa et al., 1990). Excess ROS levels and ATP deficiency lead to neuronal cell death. The neuroprotective effects of UCP2 and its uncoupling activity are well-described (Andrews et al., 2005; Conti et al., 2005). Unlike UCP2, the neuroprotective mechanisms of UCP4 are unclear. The vast majority of existing studies on UCPs is based on UCP1, 2 and 3. The few studies on UCP4 assume that the neuroprotective properties are due to uncoupling activities, based on the assumption of its homology to UCP2. Recently, UCP4 was shown to regulate calcium homeostasis to preserve mitochondrial function, which was correlated with reduced ROS generation, oxidative stress, and increased resistance to cell death (Chan et al., 2006). Knockdown of UCP4 in primary hippocampal neurons resulted in calcium overload and cell death (Liu et al., 2006). Ectopic UCP4 expression in human kidney cells reduces MMP (Mao et al., 1999), but this “uncoupling” by UCP4 has not been replicated. Previously, we observed a differential modulation of UCP2, 4 and 5 expressions in MPP+-induced toxicity in a human neuronal cell line, which we hypothesized as a potential protec tive cellular response to counteract the toxic insults (Ho et al., 2005). We have also demonstrated significant protection against MPP+ and dopamine-induced cell death after stable overexpression of UCP4, by reducing oxidative stress and preventing ATP deficiency (*resubmitted after revision). The neuroprotective effects of UCP4 overexpression seem functionally linked with UCP2 ex pression (*resubmitted after revision). We have identified a potential NF-B response element in the 5’-flanking region of UCP4, which significantly modulated the UCP4 mRNA expression by NF-B activators and inhibitors. Our findings are the first evidence to illustrate regulation of UCP4 expression via NF-B pathway (unpublished data). NF-κB is an important transcription factor in eukaryotic cells as a regulator of genes that control cell proliferation and survival, and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens (Gilmore, 2006). Our results will help to understand the physiological role and protective mechanisms of UCP4 in the neuronal system. Problems being addressed: There is growing evidence to show that UCP4 is neuroprotective in both in vitro and in vivo parkinsonian models, including MPP+. The physiological role and regulation of UCP4 are unknown. We plan to characterize the gene structure and promoter region of UCP4, explore its regulation by elucidating transc riptional elements that regulate the gene expression, e.g. NF-B response element; determining the extent they play in the gene regulation; discover what agents, e.g. leptin, can affect UCP4 expression; and whether they provide neuroprotection.

Project Title:	Development of a novel human catechol -O-methyltransferase (COMT) assay to detect estrogenic inhibitors and inducer s
Investigator(s):	Ho WL, Ho SL
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Applied Research
Start Date:	06/2010

Abstract:

Purposes of this proposal: We aim to develop a novel high-throughput assay in measuring human COMT level in tissue and cellular extracts to determine potential estrogenic properties of any testing compounds. The creation of this novel assay for COMT protein expression includes: 1. A novel recognition antibody against a novel synthetic epitope (NE) not present in any kn own protein sequence; 2. Novel artificially produced COMT recombinant proteins containing one or more copies of the novel epitope (COMT-NE). 3. A novel mammalian expression construct containing the COMT epitope recognized by our anti-COMT antibody and the NE epitope recognized by anti-NE antibody. Our previously developed COMT antibody has been shown to be specific to this COMT epitope. 4. A standard ELISA which consists of two unique antibodies (anti-COMT and anti-NE), and two purified recombinant proteins (COMT-FLAG and COMT-NE). Key issues: Catechol-O-methyltransferase (COMT) catalyzes the methylation of various catecholamines such as dopamine, noradrenaline and adrenaline (Zhu, 2002). COMT is expressed ubiquitously and may play an important role in the pathophysiology of different human disorders including estrogen-induced cancers, Parkinson’s disease, depression, schizophrenia, and hypertension (Bonifácio et al., 2007; Houston, 2007; Lewandowski, 2007; Tom et al., 1998; Xie et al, 1998). This is because the COMT methylates other substrates such as catechol estrogens (e.g., carcinogenic 4-hydro xyestradiol), xenobiotic catechols (e.g., carcinogenic flavonoids), and drugs (e.g., levodopa). Previously, we reported the COMT gene in human is powerfully regulated by estrad iol in a non-classical manner involving the estradiol alpha-receptor (Xie et al., 1999; Jiang et al., 2003). The expression of COMT is not only influenced by estradiol but also by compounds of widely different chemical structure but which have the capacity to either mimic or antag onize the actions of estradiol. These compounds include polychlorinated biphenyls (PCBs) and plasticizers such as bis-isohexyl phthalate and related compounds such as bisphenol A (BPA) and octylphenol (Ho et al., 2008a,b). The regulation of transcription of human genes is often complex and that other non-estrogenic agents may well be capable of modulating transcription of the COMT gene via other direct and indirect pathways. COMT may play an etiologic role in tumor formation (Salama et al., 2006; Thompson et al., 2000). Our previous research focused on the distribution of COMT in the central nervous system (Jiang et al, 1998), its role in Parkinson’s disease (Xie et al, 1997), and assay of COMT gene and protein expression, with detailed investigation of the regulation of the human COMT gene (Xie et al., 1999; Jiang et al., 2003) to elucidate factors involved in the etiology of Parkinson’s disease in an attempt to explain the slight male versus female bias in the incidence of the disease. This has led to the recognition of the possibility of using COMT assay to assess endocrine disruptor potential (Ho et al., 2008a,b). Because va rious COMT inducers and inhibitors such as xenoestrogens and existing drugs (e.g., Entacapone and Tolcapone used in the treatment of Parkinson’s disease), and drugs (which affect COMT expression as an adverse event), can affect COMT expression, this assay can be used to assess the effects of such compounds. We have shown that a variety of compounds such as polychlorinated biphenyls (PCBs), plasticizers and related compounds including bisphenol A (BPA), can affect COMT expression in human cells (Ho et al., 2008a,b). Thus this assay may also be used to assess the estrogenic effects of such compounds. It can be envisaged that pharmaceutical companies involved in the production of anti-hypertensive, anti-depressants, and anti-parkinsonian drugs, and oral contraceptives, would have an interest in assaying COMT protein expression. In addition, the growing con cern of environmentalists over the effects of industrial pollutants has led to the European Union to pass legislation, coming into effect in 2008 (REACH Program), requiring manufacturers to assay the endocrine disrupting effects of chemicals used in their processes. Currently the list stands at approximately 30,000 chemicals. A COMT assay in conjunction with a human cell-line which expresses both COMT and the estradiol receptor (e.g., MCF-7 cells) would provide a cheap initial screen of estrogenic activity. Problems to address: The endocrine disrupting effects of environmental estrogenic compounds have drawn substantial attention from the public (see attached articles). Long term exposure to these compounds in widely used plastic containers may cause cancer and developmental disorders. Because these compounds can affect COMT expression, a COMT ELISA assay can be used to screen for the effects of such compounds in a large number of samples efficiently. Currently, there is no similar ELISA assay available. The current assessment of long term adverse effects of estrogenic compounds requires the Two-Generation rodent assay, which is substantially more expensive and less efficient than using an ELISA assay. To address this deficiency, we have developed this human COMT ELISA assay to provide an inexpensive and fast screening method to detect COMT inhibitors and inducers, which may have potential toxic estrogenic properties, e.g. in the manufacture of plastic products. References: Bonifácio MJ, Palma PN, Almeida L, et al. (2007) CNS Drug Review. 13(3):352-79. Ho PWL, Chu ACY, Kwok KHH, Liu HF, Kung MHW, Ramsden DB, Ho SL. (2008a) Current Drug Metabolis m. 9(4):276-9. Ho PWL, Garner CE, Ho JWM, Leung KC, Kwok KHH, Chu ACY, Kung MHW, Burka LT, Ramsden DB, Ho SL. (2008b) Current Drug Metabolism. 9(4):304-9. Houston MC. (2007) Alternative Therapy Health Medicine. 13(2):S128-33. Jiang H, Ho SL, Xie T, Young LP. (1998) NeuroReport. 9(12):2861-4. Jiang H, Xie T, Ramsden DB, Ho SL. (2003) Neuropharmacology. 45:1011 8. Lewandowski KE. (2007) Harvard Review of Psychiatry. 15(5):233-44. Salama SA, Ho SL, Hui Q, et al. (2006) Fertility & Sterility. 86(1):259-62. Thompson PA, Ambrosone C. (2000) Journal National Cancer Institute Monograph. 125-34. Tom T, Cummings JL. (1998) Drugs Aging. 12(1):55-74. Xie T, Ho SL, Li LSW, Ma OCK. (1997) Movement Disorders. 12:426-7. Xie T, Ho SL, Ramsden DB. (1998) Lancet. 351:1966. Xie T, Ho SL, Ramsden DB. (1999) Molecular Pharmacology. 56:31-8. Zhu BT. (2002) Current Drug Metabolism. 3(3):321-49.

List of Research Outputs

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chan K.H. , Kwan S.C. , Chu A.C.Y. , Ho W.L. , Ho W.M. and Ho S.L. , Aquaporin-4 expression by thymoma of myasthenia gravis patients, 20th Meeting of the European Neurological Society, Berlin, 2010; Journal of Neurology . 2010, 257 (Supplement 1): S50.

Chan K.H. , Tse C.T., Ho S.L. , Ho W.L. and Ho W.M. , Clinical Outcome of Hong Kong Chinese Relapsing Remitting Multiple Sclerosis, 20th Meeting of European Neurological Society, Berlin, 2010 .

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Investigator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong. (6-7 March 2010) . 2010, 46.

Ho W.L. , Ho S.L. and Ramsden D.B. , Human Catechol-O-methyltransferase (COMT) assay., In: Listed inventers: PWL Ho, SL Ho, DB Ramsden, World Intellectual Property Organization under the Patent Cooperation Treaty (PCT); PCT application no. PCT/CN2009/001011 filed on 8 Sept. 2009; International publication no. WO2010/034183 (1 Apr. 2010). . 2010.

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.L. , Ho W.M. , Liu H. , Chan K.H. , Ramsden D.B. and Ho S.L. , Neuronal mitochondrial uncoupling proteins: implications in the pathology of Parkinson’s disease , The Hong Kong Neurological Society - Annual Scientific Meeting 2009; Kowloon Shangri-La Hotel, Hong Kong; 8 Nov 2009. . 2009.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Liu H.H.W., Tsang J.W.H. , Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Chu A.C.Y. , Tse M.M.Y., Mak W. , Ho W.L. and Chan K.H. , Thymomatous myasthenia gravis, 15th Medical Research Conference, Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Best Abstract In Clinical Medicine, 15th Medical Research Conference, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Clinical outcome of relapsing remitting multiple scl erosis among Hong Kong Chinese, 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Researcher : Ho WM

List of Research Outputs

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chan K.H. , Kwan S.C. , Chu A.C.Y. , Ho W.L. , Ho W.M. and Ho S.L. , Aquaporin-4 expression by thymoma of myasthenia gravis patients, 20th Meeting of the European Neurological Society, Berlin, 2010; Journal of Neurology . 2010, 257 (Supplement 1): S50.

Chan K.H. , Tse C.T., Ho S.L. , Ho W.L. and Ho W.M. , Clinical Outcome of Hong Kong Chinese Relapsing Remitting Multiple Sclerosis, 20th Meeting of European Neurological Society, Berlin, 2010 .

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Investigator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain , Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong. (6-7 March 2010) . 2010, 46.

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.L. , Ho W.M. , Liu H. , Chan K.H. , Ramsden D.B. and Ho S.L. , Neuronal mitochondrial uncoupling proteins: implicat ions in the pathology of Parkinson’s disease , The Hong Kong Neurological Society - Annual Scientifi c Meeting 2009; Kowloon Shangri-La Hotel, Hong Kong; 8 Nov 2009. . 2009.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Best Abstract In Clinical Medicine, 15th Medical Research Conference, Department of Medicine, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Tse C.T., Tse M.M.Y., Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Ho W.L. , Ho W.M. and Chan K.H. , Clinical outcome of relapsing remitting multiple sclerosi s among Hong Kong Chinese, 15th Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong . 2010.

Researcher : Hon SFK

List of Research Outputs

Cheung R.T.F. , Lyden P.D., Tsoi T.H. , Huang Y., Liu M., Hon S.F.K. , Raman R. and Liu L., Production and validation of Putonghua- and Cantonese-Chinese language National Institutes of Health Stroke Scale training and certification videos, International Journal of Stroke . 2010, 5: 74-79.

Researcher : Hoo RLC

List of Research Outputs

Hoo R.L.C. , Wong Y.L. , Xu A. and Lam K.S.L. , Adipocyte fatty acid binding protein (AFABP) in kupffer cells as the novel player in the pathogenesis of non-alcoholic fatty liver disease, 14th Medical Research Conference, The University of Hong Kong . 2009.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Inactivation Of Toll-like Receptor 4 Improves Reendothelialisation In Apoe-deficient Mice – Impact Of Oxidative Stress On Endothelial Progenitor Cells, 15th Medical Research Conference, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Outstanding Abstract Prize, Fifth International Symposium On Healthy Aging: Is Aging A Disease?, Research Centre Of Heart, Brain, Hormone & Healthy Aging, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Toll-like Receptor 4 Inactivation Ameliorates Impair ed Reendothelialisation Through The Improvement In Endothelial Progenitor Cell Adhesion, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” . 2010.

Researcher : Hu H

List of Research Outputs

Hu R. , He M. , Hu H. , Yuan B.X., Zang W.J., Lau C.P. , Tse H.F. and Li G.R. , Characterization of calcium signaling pathways in human preadipocytes, J Cell Physiol . 2009, 220(3): 765-770.

Researcher : Hu HC

Project Title:	A study to validate a symptom severity questionnaire for patents with functional dyspepsia
Investigator(s):	Hu HC, Lam CLK
Department:	Medicine
Source(s) of Funding:	Health Services Research Fund - Full Grants
Start Date:	10/1998

Abstract:

To develop and validate an instrument to measure the severity of symptoms in patients with functional dyspepsia.

Researcher : Hu R

List of Research Outputs

Hu R. , He M. , Hu H. , Yuan B.X., Zang W.J., Lau C.P. , Tse H.F. and Li G.R. , Characterization of calcium signaling pathways in hum an preadipocytes, J Cell Physiol . 2009, 220(3): 765-770.

Researcher : Huang Q

Project Title:	Systematic evaluation and screen of the regions previously linked to osteoporosis in Southern Chinese
Investigator(s):	Huang Q, Kung AWC, Sham PC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	10/2006
Completion Date:	12/2009

Abstract:

To determine whether the genomic regions previou sly identified in genome scans contribute to osteoporosis/BMD in Southern Chinese by performing genetic linkage analyses; to investigate whether genetic variability in candidate genes in the region of linkage is associated with BM D variation.

Project Title:	Large scale association studies of osteoporosis in Chinese
Investigator(s):	Huang Q, Kung AWC, Sham PC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) Evaluate the association between osteoporosis and 30 most likely candidate osteoporosis susceptibil ity genes predicted by computational disease gene identification strategy; (2) Identify osteoporosis susceptibility genes on chromosomes 7p that showed good evidence of linkage to osteoporosis in our recent linkage study by peak wide association study.

Researcher : Hui CK

Project Title:	Significance of occult hepatitis B infection in patients undergoing autologous HSCT
Investigator(s):	Hui CK, Liang RHS, Lau G, Lie AKW
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	10/2006

Abstract:

(1) The occurrence of de novo HBV or occult HBV infection with or without clinical hepatitis after HSCT in HBsAg negative patients pre-HSCT; (2) the risk of transmitting de novo or occult HBV from occult HBV infected blood products to HBsAg negative immunocomprom ised patients.

List of Research Outputs

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Researcher : Hui WM

List of Research Outputs

Cheng C. , Chan T...N..., Chio H.M. , Chan P., Chan A.O.O. and Hui W.M. , Active versus flexible coping in psychological adjustment to gastrointestinal cancer , Paper presentation at the 22nd Annual Convention of the Association for Psychological Science, Boston, U.S.A. . 2010.

Researcher : Hui X

List of Research Outputs

Hui X. , Li H. , Zhou Z., Lam K.S.L. , Xiao Y., Wu D., Ding K., Wang Y. , Vanhoutte P.M.G.R. and Xu A. , Adipocyte fatty acid-binding protein modulates inflammator y responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1, J Biol Chem . 2010, 285(14): 10273-80.

Hui X. , Lam K.S.L. , Wang Y. , Xu A. , Li H. , Vanhoutte P.M.G.R. and Wu D. , Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1., The Journal of Biological Chemistr y . the United States, American Society for Biochemistry and Molecular Biology, 2010, 285: 10273.

Hui X. , Best Trainee Scientist Award., 15th Medical Research Conference . 2010.

Researcher : Hung IFN

Project Title:	Harvesting convalescent plasma for hyperimmune intravenous globulin production: a multicentres, randomised double-blind controlled trial for treatment of patients with serious S-OIV H1N1 infection
Investigator(s):	Hung IFN, Chan KH, Liang RHS, Lai ST, Yuen KY
Department:	Medicine
Source(s) of Funding:	Commissioned Studies on Human Swine Influenza Research
Start Date:	08/2009

Abstract:

To collect and prepare hyperimmune intravenous immunoglobulins (H-IVIG) from patients recovered from S-OIV H1N1 infection and to treat patients with severe S-OIV H1N1 infection with the prepared S-OIV H-IVIG. Patients' clinical outcome and adverse effects from the H-IVIG would be compared to patients who received simple IVIG.

List of Research Outputs

Cheng V.C.C. , Tai J.W.M., Wong L.M.W., Chan J.F.W. , Li W.S. , To K.K.W. , Hung I.F.N. , Chan K.H. , Ho P.L. and Yuen K.Y. , Prevention of nosocomial transmission of swine-origin pandemic influenza virus A/H1N1 by infection control bundle. , J Hosp Infect 2010 . 2010, 74: 271-7.

Hung I.F.N. , Chan P., Leung S., Chan S.Y. , Hsu A., But D., Seto W.K., Wong S.Y. , Chan C.K. , Gu Q. , Tong T.S.M., Cheung T.K. , Chu K.M. and Wong B.C.Y. , Clarithromycin-amoxycillin-containing triple therapy: A valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong?, Helicobacter . 2009, 14: 505-511.

Hung I.F.N. , Epidemiology & Advances in Screening Methods for Colorectal Cancer, Hong Kong Colorectal Symposium 2010 . 2010.

Hung I.F.N. and Wong B.C.Y. , The relevance of new Helicobacter pylori guidelines to Asia. , US Gastroenterology and Hepatology Review. Volume 1 Issue 2 2009. . 2009.

Hung I.F.N. , Two Patients With Fever, Hong Kong-Beijing-Xian Medical Forum 2010 . 2010.

Li W.S. , Hung I.F.N. , To K.K.W. , Chan K.H. , Wong S.S.Y. , Chan J.F.W. , Cheng V.C.C. , Tsang O.T., Lai S.T., Lau Y.L. and Yuen K.Y. , The natural viral load profile of patients with pandemi c swine-origin influenza A H1N1 2009 (pH1N1) and the effect of oseltamivir treatment., Chest . 2010, 137: 759-768.

Seto W.K., Mak C.M. , BUT D., Hung I.F.N. , Lam C.W. , Tam S., Yuen R.M.F. and Lai C.L. , Mutational analysis for Wilson's disease, Lancet . 2009, 374(9690): 662.

Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Chemoprophylaxis in colorectal cancer: current concepts and a practical algorithm for use., Exper Opin Investig Drugs . 2010, Suppl 1: S57-66.

To K.K.W. , Hung I.F.N. , Li W.S. , Lee K.L., Koo C.K., Yan W.W., Liu R., Ho K.Y., Chu K.H., Watt C.L., Luk W.K., Lai K.Y., Chow F.L., Mok T., Buckley T., Chan J.F.W. , Wong S.S.Y. , Zheng B. , Chen H. , Tse H. , Cheng V.C.C. , Chan K.H. and Yuen K.Y. , Delayed clearance of viral load and marked cytokine activation in severe cases of pandemic H1N1 2009 influenza virus infection, Clinical Infectious Disease . 2010, 50: 850-9.

To K.K.W. , Chan K.H. , Li W.S. , Tsang T.Y., Tse H. , Chan J.F.W. , Hung I.F.N. , Lai S.T., Leung C.W., Kwan Y.W., Lau Y.L. , Ng T.K., Cheng V.C.C. , Peiris J.S.M. and Yuen K.Y. , Viral load in patients infected with pandemic H1N1 2009 influenza A virus, J Med Virol . 2010, 82: 1-7.

Wong H.K., Lee C.K., Hung I.F.N. , Leung J.N.S., Hong J., Yuen K.Y. and Lin C.K., Practical limitations of convalescent plasma collection: a case scenario in pandemic preparation for influenza A (H1N1) infection., Transfusion . 2010, 50: 1967-71.

Yee Y.K., Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Epidemiology of colorectal cancer in Asia. , J Gastroenterol Hepatol . 2009, 24: 1810-6.

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Yee Y.K., Gu Q., Hung I.F.N. , Tan V.P.Y. , Chan P., Hsu A., Pang R.W.C. , Lam S.C. and Wong B.C.Y. , Trend of colorectal cancer in Hong Kong:1983-2006. , J Gastroenterol Hepatol . 2010, 25: 923-7.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presentation) , 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Ip MSM

Project Title:	The efficacy of the modified oral appliance in the treatment of mild and moderate obstruct ive Sleep Apnoea
Investigator(s):	Ip MSM
Department:	Medicine
Source(s) of Funding:	Other Funding Scheme
Start Date:	02/1997

Abstract:

To assess the efficacy, side effects and patient acceptance of an oral appliance in the treatment of obstructive sleep apnoea; to define the clinical, anthrop ometric, polysomnographic and cephalometric characteristics that determine treatment response.

Project Title:	The effect of oral appliance (OA) in treatment of obstructive sleep apnoea
Investigator(s):	Ip MSM, Peh WCG, Cooke MS
Department:	Medicine
Source(s) of Funding:	Other Funding Scheme
Start Date:	06/1997

Abstract:

To study the efficacy of OA in teatment of mild/moderate OSA; to study the safety profile of OA.

Project Title:	Role of adiponectin in obstructive sleep apnoea
Investigator(s):	Ip MSM, Lam KSL
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2002

Abstract:

To investigate serum adiponectin levels in OSA patients with a spectrum of body mass index (BMI) and sleep disordered breathing (no OSA to severe OSA) and define correlative parameters; to investigate for any difference in adiponectin levels in patients with OSA and BMI-matched subjects with no OSA (3) the impact of nasal Continuous Positive Airway pressure (nCPAP) treatment on adiponectin secretion in subjects with OSA.

Project Title:	Candidate genes of obstructive sleep apnoea syndrome in Hong Kong Chinese
Investigator(s):	Ip MSM, Lam KSL, Song Y, Sham PC, Lam CL
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2005

Abstract:

The main objectives of this project are: 1) To study the presence and role of genetic polymorphism of selected candidate genes relating to the obesity phenotypes in the OSA patients in Hong Kong 2) As an initiating project, to provide pilot data on the role of genetic changes in selected candidate genes in Chinese OSA patients, and to prepare for future in-depth studies in family cohorts

Project Title:	Endothelial damage and atheroscl erosis in obstructive sleep apnea: the role of advanced glycation end products
Investigator(s):	Ip MSM, Tse HF, Tan KCB, Ooi CGC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2006
Completion Date:	08/2009

Abstract:

To explore the relationship between insulin resistance and the formation of advanced glycation end products (AGE) in obstructive sleep apnea (OSA); to evaluate the role of AGE in vascular endothelial damage in OSA; to investigate the relationship between AGE and atheros clerosis in OSA.

Project Title:	Exploration of the role of adipocyt e fatty acid binding protein in the association of obstructive sleep apnea and metabolic dysfunction
Investigator(s):	Ip MSM, Mak JCW, Xu A
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	11/2007

Abstract:

To further evaluate the finding of elevated circulati ng A-FABP in OSA subjects; to investigate the effect of intermittent hypoxia, simulating hypoxia-reoxygenation in OSA, on the expression of A-FABP from cultured adipocytes and macrophages.

List of Research Outputs

Chan C.H. , Leung V.O.Y. , Lam C.L.D. , Mak J.C.W. , Freeman C., Ip M.S.M. and Shum D.K.Y. , Sulfated maltoheptaose reduces neutrophilic airway inflammation in a smoking rat model of chronic obstru ctive pulmonary disease , Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” 6-7 March 2010 . 2010.

Chan K.H. , Ho S.P., Yeung S.C. , So H.L. , Cho C.H., Koo M.W.L. , Lam W.K. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine . 2009, 103: 1746-1754.

Chan K.H. , Yeung S.C. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Effects of Chinese green tea on cigarette smoke-induce d lung inflammation, oxidative stress and protease activity in rats, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A5062.

Chan K.H. , Yeung S.C. , Yao T.J. , Ip M.S.M. , Cheung A.H.K. , Chan M.M.W. and Mak J.C.W. , Elevated Plasma Adiponectin Levels In Patients With Chronic Obstructive Pulmonary Disease, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 10.

Chan L.K. , Patil N.G. and Ip M.S.M. , Enhancement of student learning in PBL by video triggers, 7th Asian Pacific Medical Education Conference (APMEC), Singapore, 6-7 February 2010, Medical Education . 2010, 44 (Suppl 1): 1.

Eastwood P.R., Malhotra D.R., Palmer L.J., Kezirian E.J., Horner R.L., Ip M.S.M. , Thurnheer R., Antic N.A. and Hillman D.R., Obstructive sleep apnoea: From pathogenesis to treatment - Current controversies and future directions, Respirology . 2010, 15: 587-595.

Han Q. , Yeung S.C. , Ho S.P. , Ip M.S.M. and Mak J.C.W. , Differential Effects Of Intermittent Hypoxia And/or Cigarette Smoking On The Expression Levels Of Fatty Acid-binding Protein In Rat Heart And Lung: An In Vivo Pilot Study, Respirology . 2009, 14 (Suppl. 3): A171.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Effects Of Intermittent Hypoxia On A-/e-fabp Expression In Human Aortic Endothelial Cells, International Journal of Cardiology . 2010, Epub ahead of print.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification Of Serum Adiponectin And Cinc-1 Levels By Intermittent Hypoxia And/or Hyperlipidemia In Vivo, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 22.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification of circulating and cardiac expressions of adiponectin and CINC-1 by intermittent hypoxia in vivo, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A3702.

Ho J.C.M. , Ho S.P. , Mak J.C.W. , Wong M.K.Y. , Ip M.S.M. and Lam W.K. , Alterations of systemic antioxidants and 8-isoprostane during chemotherapy for lung cancer. , 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S909.

Ho J.C.M. , Lam C.L. , Wong M.K.Y. , Lam B. , Ip M.S.M. and Lam W.K. , Capecitabine as salvage treatment for lymphoepithelioma-like carcinoma of lung, Journal of Thoracic Oncology . 2009, 4(9): 1174-1177.

Ip M.S.M. , Chairman, New insights on COPD management, Asia Pacific Respiratory Summit Aug 2009 . 2009.

Ip M.S.M. , Chairman, Symposium, 14th Congress of the Asian Pacific Society of Respirol ogy & 3rd Joint Congress of the Asian Pacific Society of Respirology/American College of Chest Physicians, Korea, Seoul, Nov 2009 . 2009.

Ip M.S.M. , Diaphragmatic Pacing, Symposium on Trauma Rehabilitation - a multidiscip linary approach 2010 in Hong Kong, Central Committee on Trauma Service, HAHO . 2010.

Ip M.S.M. , Honorary Advisor, The Hong Kong Asthma Society . 2010.

Ip M.S.M. , Member of Editorial Board, Sleep Medicine . 2009.

Ip M.S.M. , Member, Public Affairs Forum, Home Affairs Bureau, HKSAR . 2010.

Ip M.S.M. , Member, Steering Committee of European Respiratory Society Global Lung Taskforce . 2010.

Ip M.S.M. , OSA and metabolic syndrome, 2009 Annual Meeting of Taiwan Society of Pulmonary and Critical Care Medicine, Taipei, Taiwan, Dec 2009 . 2009.

Ip M.S.M. , Obstructive sleep apnea and its related morbidity in Western and Asian countries (Meet the Professor), American Thoracic Society International Conference, New Orleans, USA, May 2010 . 2010.

Ip M.S.M. , Obstructive sleep apnea and its related morbidity in western and Asian countries, American Thoracic Society International Conferenc e, New Orleans, USA, May, 2010 (Meet the Professor Seminar) . 2010.

Ip M.S.M. , Sleep apnea and disorders of glucose metabolism (Symposium Lecture), Annual Scientific Meeting, Hong Kong Society of Sleep Medicine, October . 2009.

Ip M.S.M. , Sleep-disordered breathing and glucose metabolism, 14th Congress of the Asian Pacific Society of Res pirology & 3rd Joint Congress of the Asian Pacific Society of Respirology/American College of Chest Physicians, Seoul, Korea, Nov 2009 . 2009.

Ip M.S.M. , Sleep-disordered breathing in Asia, CHEST 2009, San Diego, USA, Oct/Nov 2009 . 2009.

Ip M.S.M. , Sleepless in Asia: Cardiovcascular risk profile in patients with sleep-related breathing disorders, 29th Annual Chest Convention, Philippines College of Chest Physicians, Manila, Philippines, Mar 2010 . 2010.

Ko F.W.S., Ip M.S.M. , Chu C.M., So L.K.Y. and Lam C.L.D. , A milti-centre study of the prevalence of allergic rhinitis and its associated morbidity among adults with asthma, 14th Congress of the Asian Pacific Society of Respirology & 3rd Joint Congress of the Asian Pacific Society of Respirology/American College of Chest Physicians, Seoul, Korea, Nov 2009, Respirology . 2009, 14 (Supp 3): A223 (PD 10-20).

Lam C.L.D. , Girard L., Sihoe A., Cheng L.C., Lui M.M.S., Wong M.P. , Chung L.P. , Ip M.S.M. , Lam W.K. and Minna J.D., Gene expression profiling in lung adenocarcinomas reflects possible different molecular pathogenesis with respe ct to gender and smoking status, 14th Congress of the Asian Pacific Society of Respirology & 3rd Joint Congress of the Asian Pacific Society of Respirology/American College of Chest Physicians, Seoul, Korea, Nov 2009, Respirology . 2009, 14(Suppl 3): A128 (OS 03-05).

Lam C.L.D. , Girard L., Sihoe A.D.L. , Cheng L.C. , Lui M.A.C.Y., Wong M.P. , Chung L.P. , Ip M.S.M. , Lam W.K. and Minna J.D., Gene expression signatures associated with combination of female non-smokers in lung adenocarcinomas bearing activating epidermal growth factor receptor (EGFR) gene mutations in Chinese, The American Thoracic Society Annual Meeting 2010 .

Lam C.L.D. , Lam C.M. , Tan K.C.B. , Lui M.M.S. and Ip M.S.M. , Serum advanced glycation endproducts (AGE) levels correlated with severity of obstructive sleep apnea but not insulin resistance, 14th Congress of the Asian Pacific Society of Respirology & 3rd Joint Congress of the Asian Pacific of Respirology/American College of Chest Physicians, Seoul, Korea, November, 2009, Respirology . 2009, 14 (Suppl 3): A168 (OS 32-01).

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S., Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensitivity in obstructive sleep apnea, Eur Respir J. . 2009.

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S. , Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin se nsitivity in obstructive sleep apnea, European Respiratory Journal . 2010, 35(1): 138-145.

Lam C.M. , Yan C.S.W., Lai A.Y.K. , Tam S., Fong D.Y.T. , Lam C.L.D. and Ip M.S.M. , Determinants of Daytime Blood Pressure in Relation to Obstructive Sleep Apnea in Men, Lung . 2009, 187: 291-298.

Lam C.M. and Ip M.S.M. , Sleep and the metabolic syndrome, The Indian Journal of Medical Research . 2010, 131: 206-216.

Lam D., Lam J., Tan K.C.B. , Lui M. and Ip M.S.M. , Serum advanced glycation end products levels correlated with severity of obstructive sleep apnea but not with insulin resistance, 14th Congress of the Asian Pacific Society of Respirology, Seoul, Korea . 2009.

Lam T.P. , Wong J.G.W.S. , Ip M.S.M. , Lam K.F. and Pang S.L. , Psychological wellbeing of interns in Hong Kong: What causes them stress and what helps them, Medical Teacher . Taylor & Francis, 2010, 32: e120-e126.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Blockage of serotonin receptor 2 attenuates cigarette- induced IL-8 release in human bronchial epithelial cells, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A1399.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Involvement of Serotonin in Cigarette Smoke-Induced IL-8 Release in Airway Epithelial Cells, ATS 2010 International Conference, New Orleans, USA (May 14-19, 2010) . 2010.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Involvement of serotoninergic system in cigarette-induced inflammatory responses in human bronchial epithelial cells, HKU 14th Research Postgraduate Symposium, Hong Kong (December 2-3, 2009) . 2010.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Ketanserin Attenuates Cigarette-mediated Oxidative Stress In Human Bronchial Epithelial Cells, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 34.

Lui M.M.S. and Ip M.S.M. , Disorders of glucose metabolism in sleep-disordered breathing, Clinics in Chest Medicine . 2010, 31(2): 271-285.

Shum D.K.Y. , Ip M.S.M. , Chan C.H. and Leung O.Y.V. , Compositions and Methods for Treating chronic Respiratory Inflammation. U.S. Provisional Application No. 61/308,597 filed on Feb 26, 2010 with the U.WS. Patent and Trademark Office. , 2010.

Tang S.C.W. , Lam B. , Yap D.Y., Ip M.S.M. and Lai K.N. , Conversion between hemodialysis and continuous ambulatory peritoneal dialysis may impact on sleep apnea in favor of CAPD, Hemodialysis International . 2009, 13: 395.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea as a novel risk predictor for cardiovascular morbidity and death in peritoneal dialysis patients, Kidney International . 2010, 77: 1031-1038.

Tang S.C.W. , Lam B. , Yao T.J. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is a novel risk predictor of cardiovascular morbidity and death in patients receiving peritoneal dialysis, Kidney International . 2010, 77(11): 1031-8.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is an independent risk predictor for all-cause and cardiovascular mortality in peritoneal dialysis patients, Peritoneal Dialysis International . 2009, 29: S7.

Wang J.K., Ho J.C.M. , Mok T.Y., Chan J.W., Yee W.K., Chan M.M.W. , Cheung B.M.Y. , Lam K.S.L. , Lam W.K. and Ip M.S.M. , The relationship of asthma and the pattern of adiposity in adult Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 56.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to first-lin e gefitinib in non-small cell lung cancer. , Cancer Chemotherapy and Pharmacology . 2010, 65: 1023-1028.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to gefitinib in non-small cell lung cancer, 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S719.

Researcher : Jin O

List of Research Outputs

Jin O. , Sushima K., Mok T.M.Y. and Lau W.C.S. , Abnormalities in circulating plasmacytoid dendritic cells in patients with systemic lupus erythematosus, Arthritis Res Ther . 2010, in press.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Foxp3 mRNA expression on DC subsets in patients of systemic lupus erythematosus. , IJRD . 2010, 13: S557 p55.

Jin O. , Kavikondala S. , Mok T.M.Y. , Sun L.Y., Gu J.R., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Studies on the function of plasmacytoid dendritic cells in healthy and systemic lupus erythematosus., IJRD . 2010, 13: S554p54.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Study on myeloid dendritic cells in systemic lupus erythematosus, IJRD . 2010, 13: S793 p56.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow-derived dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Researcher : Jin O

List of Research Outputs

Jin O. , Sushima K., Mok T.M.Y. and Lau W.C.S. , Abnormalities in circulating plasmacytoid dendritic cells in patients with systemic lupus erythematosus, Arthritis Res Ther . 2010, in press.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow-deri ved dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Researcher : Jin Y

Project Title:	Cytogenetic and molecular genetic characterization of esophageal carcinomas
Investigator(s):	Jin Y, Kwong YL, Tsao GSW
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	10/2002

Abstract:

To identify, by cytogenetic, fluorescence in situ hybridization (FISH), and molecular genetic approaches, the genetic changes that are important in the malignant transformation of esophageal epithelium; to investigate genetic differences and similarity between immortalized, preneoplastic esophageal epithelial cells and aquamous cell carcinoma (SCC) of the esophagus.

Researcher : Kavikondala S

List of Research Outputs

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Foxp3 mRNA expression on DC subsets in patients of systemic lupus erythematosus. , IJRD . 2010, 13: S557 p55.

Jin O. , Kavikondala S. , Mok T.M.Y. , Sun L.Y., Gu J.R., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Studies on the function of plasmacytoid dendritic cells in healthy and systemic lupus erythematosus., IJRD . 2010, 13: S554p54.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow-der ived dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Researcher : Kng CPL

List of Research Outputs

Ng F.H. , Wong S.Y. , Lam K.F. , Chu W.M., Chan P., Ling Y.H., Kng C.P.L. , Yuen W.C., Lau Y.K. , Kwan A. and Wong B.C.Y. , Famotidine is inferior to Pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions, Gastroenterology . Elsevier, 2010, 138: 82-88.

Researcher : Kong SL

List of Research Outputs

Lee S.W.L. , Ho H.H., Kong S.L. , Lam Y.M., Siu D.C.W. , Miu K.M., Lam L. and Chan H.W., Long term clinical outcomes after deployment of femo ral vascular closure devices in coronary angiography and percutaneous coronary intervention., Catheterization and Cardiovascular Interventions . 2009, 75(3): 345-348.

Researcher : Kumana CR

List of Research Outputs

Lau C.P. , Tse H.F. , Kumana C.R. and Cheung B.M.Y. , Angiotensin receptor blockers for heart disease: are they the same?, J HK Coll Cardiol 2009 . 2009, 17: 1-3.

Researcher : Kung AWC

Project Title:	To identify susceptibility gene(s) at the BMND2 locus on chromosome 1q21-23 for bone mineral density variation in Chinese
Investigator(s):	Kung AWC, Sham PC, Smith DK
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2007
Completion Date:	08/2009

Abstract:

To identify the candidate gene(s) at BMND2 locus in chromosome 1q21-23 responsible for BMD variation at the spine and hip in Southern Chinese using linkage and association approaches: a.To perform a high density linkage and association screen of the 1q21-23 region using a set of optimally selected tag SNP on sibpair s from 306 pedigrees. b. To replicate the significant SNPs identified from the sibpair study with an independent case-control sample of subjects with low and high BMD; to elucidate the DNA variants responsible for the association by sequencing and additional genotyping of the susceptible genes identified; to study the structure and function of the candidate genes and their normal and variant products using computational and bioinformatics approaches.

Project Title:	To identify osteoporosis suscept ibility gene(s) at chromosome 2q,5q,7p, and 13q in Chinese
Investigator(s):	Kung AWC, Sham PC, Huang Q
Department:	Medicine
Source(s) of Funding:	NSFC/RGC Joint Research Scheme
Start Date:	01/2008
Completion Date:	12/2009

Abstract:

To confirm and fine-map the putative genomic regions that are recently found to linked to BMD in genome-wide scans using linkage analysis with dense microsatellite markers (at 5 cM or less apart) in 2,719 subjects fro m Chinese families; to identify osteoporosis susceptibility gene(s) in the confirmed regions by tag SNP-based haplotype association study in 1,617 age- and sex- matched unrelated case-control subjects.

Project Title:	Gene Identification for Osteoporosis using a Two Stage Genome-wide Association Strategy in the Chinese Population
Investigator(s):	Kung AWC, Huang Q, Sham PC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	10/2008

Abstract:

(1) To identify the genes and their variants that give rise to low bone mass and osteoporosis using a two-step genome-wide association strategy: first, a genome-wide association analysis in a large case-control Chinese female population (n=800) to uncover the potentia l SNPs and candidate genes associated with low BMD and osteoporotic fractures; (2) To validate the findings obtained from genome-wide association scan by genotyping the top 100 SNPs in a separate sample consisted of 306 Hong Kong Chinese extended families (total number of subjects=1,459); (3) To replicate the findings in another population consisted of an unrelated sample of 1,500 Shanghai Chinese women.

Project Title:	Functional study of the Lys3Asn polymorphism in the osteoprotegerin gene on bone mineral density
Investigator(s):	Kung AWC, Gao Y
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2009
Completion Date:	03/2010

Abstract:

Osteoporosis is a systemic skeletal disease characte rized by a combination of low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures. It is a complex disease in which not only environmental factors such as diet, smoking and exercise, but also genetic factors play a very important role. Genetic factors have been shown by family and twin studies to be responsible for 75–80% of the inter-individual variance in bone mineral density (BMD) [1]. Despite major efforts and different strategies used to find the responsible genes, the majority of candidate genes require examination of their contribution to explain the genetic basis of osteoporosis [2,3]. Osteoprotegerin (OPG) (TNFRSF11B) is a key regulator of bone remodeling. It protects bone from excessive resorption by inhibi ting the terminal stages of osteoclastogenesis , suppressing mature osteoclast activation and inducing their apoptosis. These effects are a consequence of OPG acting as a soluble decoy receptor for receptor activator of nuclear factor κ-β ligand(RANKL), a potent inducer of osteocl ast differentiation and activation, when bound to its functional receptor (κ-β)RANK. In addition to in vitro studies, there are also several in vivo studies confirming the bone protective role of OPG. Overexpression of OPG in transgenic mice resulted in osteopetrosis [4], whereas OPG knock-out mice developed severe osteoporosis [5,6]. Administration of OPG prevented ovariectomy-induced bone loss in rats [4]. Its important role in the control of bone resorption ranks the OPG gene among the promising candidate genes for osteoporosis. Our recent genetic epidemiology study had identified one single nucleot ide polymorphism (SNP) in the OPG gene which was associated with BMD variation in Southern Chinese women (n=1,600). The polymorphism rs2073618 is a G to C transversion at codon 3 in exon 1of OPG which results in the substitution of the third amino acid from lysine to asparagine (L ys3Asn). Our association results showed that the Lys3Asn genotype was significantly associated with the prevalence of osteoporosis, with Asn-allele being significantly more common in normal subjects than osteoporotic subjects. Our data replicated previous smaller studies conducted in other populations [7,8]. The mechanism by which different alleles of polymorphism Lys3Asn could affect BMD is not known. The first exon of the OPG gene encodes the signal peptide of OPG, which is necessary for OPG to be secreted from the cell. Mutations in the signal peptide can affect targeting and transport of the precur sor protein to the endoplasmic reticulum or removal of the signal peptide by signal peptidase. The extract mechanism with which this SNP in the first exon of the OPG gene possibly affects the OPG secretory kinetics needs to be elucidates by further functional studies. The aim of our work is to investigate the possible contribution of Lys3Asn variant in OPG gene to the genetic susceptibility to osteoporosis and also its molecular mechanism, and finally identify a novel genetic marker for diagnosis of osteoporosis. In this study, firstly, we wish to investigate the functional influe nce of Lys3Asn SNP in OPG gene in in vitro system, and secondly, we will also measure human serum level of OPG, which is a crucial regulator for maintaining a balance of bone resorption and bone formation, and to correlate serum OPG level and Lys3Asn genotype in human subjects in vivo. These results will enable us to determine the functionality of the variant Lys-allele in the determination of risk for osteoporosis.

Project Title:	ASBMR 31st Annual Meeting Risk Factors Associated with 10-year Risk of Osteoporosis Fractures in Hong Kong Southern Chinese Men: A Prospecti ve Study
Investigator(s):	Kung AWC
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	09/2009
Completion Date:	09/2009

Abstract:

N/A

Project Title:	Cost-effective osteoporosis interv ention thresholds for Hong Kong Southern Chinese postmenopausal women
Investigator(s):	Kung AWC, McGhee S
Department:	Medicine
Source(s) of Funding:	Health and Health Services Research Fund - Full Grants
Start Date:	10/2009

Abstract:

To define the intervention thresholds for osteoporosis in Hong Kong southern Chinese postmenopausal women based on estimates of fracture incidence, morbidity, mortality and costs that are specific to Hong Kong, at which the absolute 10-year risk of osetoporotic fracture becomes cost-effective.

List of Research Outputs

Bow C.H.Y. , Tsang S.W.Y., Soong S.S. , Yeung S.C. and Kung A.W.C. , BMD Enhances Clinical Risk Factors in Predicting Ten-Year Risk of Osteoporotic Fractures in Chinese Men: The Hong Kong Osteoporosis Study, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Bow C.H.Y. , Cheung C.L. , Gao Y. , Lau K.S. , Soong S.S. , Yeung S.C. and Kung A.W.C. , Bone Mineral Density and Serum Osteoprotegerin Levels in Pre- and Postmenopausal Women, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Chen W., Gao Q., Chan B., Fan N. and Kung A.W.C. , Ginsenoside Rg1 exerts selective estrogenic effects in human endometrial tumor Ishikawa cells but not pre-osteob lastic MC3T3-E1 cells, The 31st Annual Meeting of the American Society for Bone and Mineral Research, Denver, Colorado, USA . 2009.

Cheung C.L. , Xiao S. , Gao Y. and Kung A.W.C. , Genetic Epidemiology of Osteoporosis and Its Application, 骨質疏鬆症的遺傳流行病學及其臨床應用, Chinese Journal of Osteoporosis and Bone Mineral Research . 2010, 3: 73-86.

Cheung E.Y., Bow C.H.Y. and Kung A.W.C. , Rate of Perimenopausal Bone Loss and Its Predictive Factors Among Asian Females, International Osteoporosis Foundation World Congres s on Osteoporosis & 10th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, Florence, Italy . 2010.

Kung A.W.C. , Xiao S. , Cherny S.S. , Li H.Y. , Gao Y. , Tso G., Lau K. , Luk K.D.K. , Liu J.M., Cui B., Zhang M.J., Zhang Z.L., He J.W., Yue H., Xia W.B., Luo L.M., He S.L., Kiel D.P., Karasik D., Hsu Y.H., Cupples L.A., Demissie S., Styrkarsdottir U., Halldorsson B.V., Sigurdsson G., Thorsteinsdottir U., Stefansson K., Richards B., Zhai G., Soranzo N., Valdes A., Spector T.D. and Sham P.C. , Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies, American Journal of Human Genetics . 2010, 86 (2): 229-239.

Kung A.W.C. , Coticosteroid-induced osteoporosis, 2009 IOF Asia Osteoporosis Conference, 26 September 2009, Beijing . 2009.

Kung A.W.C. , Diagnostic Tools for Fracture Prediction in Asian Popu lations., The First Scientific Meeting of Asian Federation of Osteoporosis Societies, 13 November 2009, Guangzhou . 2009.

Kung A.W.C. , Diagnostic Tools for Fracture Prediction, Osteoporosis Society of Macau Annual Meeting, 1 December 2009, Macau . 2009.

Kung A.W.C. , Fracture Risk Assessment and Application of WHO FRAX Assessment Tool, 2009 IOF Asia Osteoporosis Conference, 25 September 2009, Beijing . 2009.

Kung A.W.C. , Fan T., Xu L., Xia W.B., Park I.H., Kim H.S., Chan S.P., Lee J.K., Koh L., Soong Y.K., Soontrapa S., Songpatanasilp T., Turajane T., Yates M. and Sen S.S., Gaps in Post-fracture Osteoporosis Care in Asian Countries: A Preliminary Report, The 31st Annual Meeting of the American Society for Bone and Mineral Research, Denver, Colorado, USA . 2009.

Kung A.W.C. , Rachman I.A., Adam J.M.F., Roeshadi D., Torralba T., De Rosa M., Canete A., Lin H.Y., Soong Y.K., Lan J.L., Hsu H.C., Tu S.T., Lin R.M., Yuktanandana P., Songpatanasilp T., Ngarmukos S., Soontrapa S., Soontrapa S., Rojanasthien S., Albert A. and Vanbelle S., Impact of bone marker feedback on adherence to once monthly ibandronate for osteoporosis among Asian postmenopausal women, International Journal of Rheumatic Diseases . 2009, 12: 216–24.

Kung A.W.C. , John Bilezikian ISCD Global Leadership Award, The International Society for Clinical Densitometry (ISCD) . 2010.

Kung A.W.C. , Member of Editoral Board, Chinese Medical Journal . 2009.

Kung A.W.C. , Member of Editorial Board, Osteoporosis International . 2009.

Kung A.W.C. , Osteoporosis Management and ISCD course in Hong Kong, Asia Pacific Consensus Meeting for ISCD Position,25-26 July 2009, Taipei . 2009.

Kwan S.H. , Cherny S.S. , Kung A.W.C. and Sham P.C. , Novel Sib Pair Selection Strategy Increases Power in Quantitative Association Analysis, Behavior Genetics . 2010, 39 (5): 571-579.

Lam J.T.C., Lam K.S.L. , Tan K.C.B. , Chow W.S. , Tso A.W.K. and Kung A.W.C. , A woman with hypophosphataemia and raised alkaline phosphatase, British Medical Journal . 2010, 340: b-5564-.

Leung R., Lopes D., Lam C., Wong K.F., Kung A.W.C. and Kwong Y.L. , Diffuse Osteosclerosis Complicating Hairy Cell Leukemia, J Clin Oncol . 2010, 28(13): e203-4.

Li G.H.Y., Kung A.W.C. and Huang Q. , Common variants in FLNB/CRTAP, not ARHGEF3 at 3p are associated with osteoporosis in southern Chinese Women, Osteoporosis International . 2010, 21(6): 1009-20.

Loong C.H.N., Leung F., Lau T.W., Leung E., Chan Y.Y., Yee A., Ma L.F., Soong S.S. , Bow C.H.Y. , Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Predictive Factors for Re-fracture in Chinese Population with Previous Osteoporotic Fractures, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W. , Leung F.K.L. and Kung A.W.C. , A Secondary Fracture Prevention Programme to Reduce Fractures, Hospital Admissions, and Mortality Rates at One and Five Years Osteoporosis Society of Hong Kong, 11th Regional Osteoporosis Conference, Hong Kong, 15-16 May, 2010, 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , A Secondary Fracture Prevention Programme to Reduce Fractures, Hospital Admissions, and Mortality, Hospital Authority Convention 2010, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Evaluation of the Osteoporosis Secondary Fracture Prevention Program at Queen Mary Hospital: Successful Recruitment is Associated with a Lower Re-fracture Rate and Mortality Rate at One Year, Hospital Authority Convention 2010, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W. , Leung F.K.L. , Luk K.D.K. and Kung A.W.C. , Evaluation of the Osteoporosis Secondary Fracture Prevention Program at Queen Mary Hospital: Successful Recruitment is associated with Lower Re-fracture and Mortality Rates at One and Five years Osteoporosis Society of Hong Kong, 11th Regional Osteoporosis Conference, Hong Kong, 15-16 May, 2010, 2010.

Ryan D.P., Dias da Silva MR M.R., Soong T.W., Fontaine B., Kung A.W.C. , Donaldson M.R., Jongjaroenprasert W., Bernstein H.S., Maciel R.M.B., Brown Jr. R.H. and Ptacek L.J., Mutations in a novel potassium channel (Kir2.6) cause susceptibility to thyrotoxic hypokalemic periodic paralysis, Cell . 2010, 140(1): 88-98.

Song Y. , Tang L.F. , Cheung C.L. , Sham P.C. , McClurg P., Smith D.K. , Tanner J.A. , Su A.I., Cheah K.S.E. and Kung A.W.C. , Genome-wide haplotype association mapping in mice identifies a genetic variant in CER1 associated with bone mineral density and fracture in southern Chinese women, The American Society of Human Genetics 59th Annual Meeting, Honolulu, Hawaii . 2009.

Soong S.S. , Loong C.H.N., Bow C.H.Y. , Wu J. and Kung A.W.C. , Factors Associated with Osteoporosis Treatment Adherence in Hong Kong, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Tsang S.W.Y. and Kung A.W.C. , Associated With 10-Year Risk of Osteoporotic Fractures in Hong Kong Southern Chinese Men: A Prospectvie Study, The 31st Annual Meeting of the American Society for Bone and Mineral Research, Denver, Colorado, USA . 2009.

Tsang S.W.Y., Bow C.H.Y. , Chu E.Y.W. and Kung A.W.C. , Clinical risk factors assessment had better discriminative ability than bone mineral density in identifying subjects with vertebral fracture, Osteoporosis International . 2010, Epub ahead of print.

Xiao S. , Sham P.C. and Kung A.W.C. , Periostin Gene is Associated with BMD Variation and Risk of Vertebral Fracture, The 31st Annual Meeting of the American Society for Bone and Mineral Research, Denver, Colorado, USA . 2009.

Researcher : Kung MHW

List of Research Outputs

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Investigator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong. (6-7 March 2010) . 2010, 46.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and re ducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Researcher : Kwan SC

List of Research Outputs

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chan K.H. , Kwan S.C. , Chu A.C.Y. , Ho W.L. , Ho W.M. and Ho S.L. , Aquaporin-4 expression by thymoma of myasthenia gravis patients, 20th Meeting of the European Neurological Society, Berlin, 2010; Journal of Neurology . 2010, 257 (Supplement 1): S50.

Researcher : Kwok HH

List of Research Outputs

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and red ucing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Researcher : Kwong YL

Project Title:	Provision of purine analogues for the treatment of patients with chronic lymphoid malignancies
Investigator(s):	Kwong YL, Liang RHS
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	07/1997

Abstract:

To provide purine analogues for the treatment of patients with chronic lymphoid malignancies who cannot otherwise afford the drugs.

Project Title:	Molecular mechanisms and consequences of downregulation of p73 in natural killer cell lymphoma
Investigator(s):	Kwong YL
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2002

Abstract:

To define if p73 acts as a tumor suppressor gene in natural killer (NK) cell lymphomas; to define the biologic significance of re-expression of p73 in NK lumphoma cells that have p73 inactivated due to aberrant promoter methylation; to define the potential significance of p21 inactivation in NK lymphoma cells.

Project Title:	Molecular basis of arsenic resistance in tumours
Investigator(s):	Kwong YL, Tse EWC
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2003

Abstract:

To define the molecular basis of arsenic resistance in tumour cells.

Project Title:	Provision of free cytogenetic and molecular testing for monitoring of disease relapse after bone marrow transplantation
Investigator(s):	Kwong YL, Liang RHS, Lie AKW, Au WY
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	11/2004

Abstract:

To establish provisions of (a) free molecular / cytogenetic tests for monitoring of BMT patients, (b) free molecular / cytogenetic tests for BMT patients who have relapsed, so that their treatment can be guided and optimized, (c) free molecular / cytogenetic tests for referral patients from other hospitals.

Project Title:	Provision of ibritumomab for the treatment of lymphoma
Investigator(s):	Kwong YL, Liu KY
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	01/2008

Abstract:

Provide yttrium-90 ibritumomab tiuxetan (Zevalin) treatment to patients with relapsed or refractory follicular lymphoma that is resistant to rituximab.

Project Title:	Provision of oral arsenic trioxide free to patients with cancers
Investigator(s):	Kwong YL, Au WY, Chim JCS
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	01/2008

Abstract:

(1) Oral-arsenic is a pioneer development in Hong Kong; (2) Production of oral-arsenic has been funded exclusively by the S.K. Yee Medical Foundation; (3) Funding from the S.K. Yee Foundation will help to provide oral-arsenic to patients with cancers other than leukemia; (4) It will also be an excellent example of a philanth ropic cause.

Project Title:	The role of Pin1 in tumour invasion and metastasis in hepatocellular carcinoma
Investigator(s):	Kwong YL, Tse EWC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2008

Abstract:

To study the relationship of Pin1 expression with tumour angiogenesis and metastasis in HCC; to define the role of Pin1 in the regulation of VEGF, and the underlying mechanisms and function significance; to examine the effects of Pin1 up/down regulation on tumour angiogenesis in HCC.

Project Title:	Provision of ibritumomab for the treatment of Iymphoma
Investigator(s):	Kwong YL, Liu KY
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	05/2010

Abstract:

n/a

List of Research Outputs

Anthony M. , Kwong Y.L. and Khong P.L. , FDG-PET/CT for the assessment of type II enteropathy-associated T-cell lymphoma, 3rd Joint Scientific Meeting of The RCR & HKCR and 17th ASM of HKCR, 31 October-1 November 2009 .

Au W.Y. , Kim S.J., Yiu H.H., Ngan R.K., Loong F. , Kim W.S. and Kwong Y.L. , Clinicopathological features and outcome of late relapses of natural killer cell lymphomas 10–29 years after initial remission, American Journal of Hematology . 2010, 85(5): 362-363.

Au W.Y. , Lie A.K.W. , Lam K.Y. and Kwong Y.L. , Engraftment of umbilical cord blood with glucose 6-phosphate dehydrogenase deficiency after double-unit unrelated cord blood transplantation, Bone Marrow Transplantation . 2009, 44(1): 57–58.

Au W.Y. , Lam K.K., Leung A.Y.H. , Liang R.H.S. , Lie A.K.W. and Kwong Y.L. , Occult autologous haematopoietic regeneration without disease relapse following myeloablative allogeneic haematopoietic SCT for lymphomas, Bone Marrow Transplantation . 2009, 45: 1377–1378.

Au W.Y. , Hon C. , Yau K. , Lai W.W.K. , Tam S. and Kwong Y.L. , Two cases of monocular visual loss during oral arsenic trioxide therapy of acute promyelocytic leukemia., American Journal of Hematology . 2009, 84: 699.

Chan J.K. and Kwong Y.L. , Common misdiagnoses in lymphomas and avoidance strategies, The Lancet Oncology . 2010, 11(6): 579-588.

Chan K.K. , Shen L. , Au W.Y. , Yuen H.F. , Wong K.Y. , Guo T. , Wong M.L.Y. , Shimizu N., Tsuchiyama J., Kwong Y.L. , Liang R.H.S. and Srivastava G. , Interleukin-2 induces NF-kappaB activation through BCL10 and affects its subcellular localization in natural killer lymphoma cells, J Pathol . 2010, 221(2): 164-74.

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Improvement of myocardial perfusion reserve detected by cardiovascular magnetic resonance after direct endomyocardial implantation of autologous bone marrow cells in pati ents with severe coronary artery disease, Journal of cardiovascular magnetic resonance . 2010, 12(1): 6..

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Therapeutic angiogenesis with direct endomyocardial implantation of autologous bone marrow cells in patients with severe coronary artery diseases: Insight from cardiac magnetic resonance imaging., J Cardiovasc Magn Reson. . 2010, 12: 6.

Chen W.Y.W. , Hu X. , Liang C.T., Wong M.L.Y. , Au W.Y. , Wong K.Y. , Choi W.L. , Wan T.S.K. , Chu K.M. , Chim J.C.S. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , Molecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm., 101st Annual Meeting of American Association for Cancer Research (AACR), Washington D.C., USA, April 2010. . 2010.

Cheng C.W. , Pang R.W.C. , Kwong Y.L. and Tse E.W.C. , Pin1 enhances the anti-apoptotic function of survivin in cancer cells, 16th Hong Kong International Cancer Congress . 2009.

Cheung A.M., Chow C.H. , Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , FLT3/internal tandem duplication subclones in acute myeloid leukemia differ in their engraftment potentia l in NOD/SCID mice, Leukemia Research . 2010, 34(1): 119-22.

Cheung A.M., Fung T.K. , Fan K.P. , Wan T.S., Chow C.H. , Leung J.C.K. , Chan L.Y., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD/SCID mice., Experimental Hematology . 2010, 38: 3-10.

Chim J.C.S. , Lie A.K.W., Liang R.H.S. and Kwong Y.L. , A staged approach with vincristine, adriamycin and dexamethasone followed by bortezomib, thalidomide and dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed multiple myeloma, 15th Congress of the European Hematology Association (Abstract) . 2010.

Chim J.C.S. , Lie A.K.W., Chan E.Y.T., Leung Y.Y., Cheung S.C.W., Chan S.Y.T., Liang R.H.S. and Kwong Y.L. , A staged approach with vincristine, adriamycin and dexamethasone followed by bortezomib, thalidomide and dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagn osed multiple myeloma, Annals Hematology . 2010.

Fung T.K. , Cheung A.M., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Differential NOD/SCID mouse engraftment of peripheral blood CD34(+) cells and JAK2V617F clones from patients with myeloproliferative neoplasms., Leukemia Research . 2010.

Gill H., Trendell-Smith N.J. , Loong F. , Yeung C.K. and Kwong Y.L. , Paraneoplastic pemphigus due to CD8-positive cytotoxic T-cell lymphoma, British Journal of Haematology . 2010, 149(4): 464.

Gu J. , Kwong Y.L. , Chan T. , Au W.Y. , Chan Q., Zhang J. , Liang R.H.S. and Khong P.L. , Comparison of DWIBS and 18F-FDG PET/CT in newly diagnosed lymphoma, Joint ISMRM-ESMRMB Annual Scientific Meeting, Stockholm, Sweden, 1-7 May 2010 .

He F. , Kwong Y.L. and Ho J.C.M. , In-vitro growth inhibitory effects of arsenic trioxide in non-small cell lung cancer with different epidermal growth factor receptor mutations, 15th Medical Research Conference, Hong Kong Medic al Journal. . 2010, 16: 22.

Hu X. , Chen W.Y.W. , Liang A.C.T., Au W.Y. , Wong K.Y. , Wan T.S.K. , Wong M.L.Y. , Shen L. , Chan K.K. , Guo T. , Chu K.M. , Tao Q. , Chim J.C.S. , Loong F. , Choi W.L. , Lu L. , So J.C.C. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation, Blood . 2010, 115: 2458-2461.

Kwong Y.L. , Azathioprine: association with therapy-related myelodysplastic syndrome and acute myeloid leukemia, The Journal of Rheumatology . 2010, 37(3): 485-90.

Kwong Y.L. , High-dose chemotherapy and hematopoietic SCT in the management of natural killer-cell malignancies, Bone Marrow Transplantation . 2009, 44: 709–714.

Kwong Y.L. , Anderson B.O., Advani R., Kim W.S., Levine A.M. and Lim S.T., Management of T-cell and natural-killer-cell neoplasms in Asia: consensus statement from the Asian Oncology Summit 2009, The Lancet Oncology . 2009, 10(11): 1093-1101.

Kwong Y.L. and Tse E.W.C. , Rivaroxaban: an oral factor Xa inhibitor in the manag ement of thrombotic diseases, Medical Progress . 2010, 37(4): 188-92.

Kwong Y.L. , Au W.Y. , Leung A.Y.H. and Tse E.W.C. , T-cell large granular lymphocyte leukemia: an Asian perspective, Annals of Hematology . 2010, 89(4) 331-339: 331-339.

Kwong Y.L. , T-cell lymphoma forum, Expert Review of Anticancer Therapy . 2010, 10(4): 493-498.

Leung A.Y.H. and Kwong Y.L. , Haematopoietic stem cell transplantation: current concepts and novel therapeutic strategies, British Medical Bulletin . 2009, 93(1): 85-103.

Leung R., Lopes D., Lam C., Wong K.F., Kung A.W.C. and Kwong Y.L. , Diffuse Osteosclerosis Complicating Hairy Cell Leukemia, J Clin Oncol . 2010, 28(13): e203-4.

So J.C.C. , Hwang Y.Y., Shek T.W.H. , Lam C.C.K. , Lai C.L. and Kwong Y.L. , Transfusion-refractory anaemia in liver cirrhosis, Gut . 2010, 59(1): 5.

Yeung C.K. , Trendell-Smith N.J. , Mak H.K.F. , Lam C.C.K. and Kwong Y.L. , ‘Western’ or ‘Asian’ intravascular large B-cell lymphoma?, Clinical and Experimental Dermatology . 2009, 34(7): e482–e483.

Yeung C.W., Cheung W.W.W. , Leung A.Y.H. and Kwong Y.L. , Spontaneous central venous catheter fracture: Relevance of the pinch-off sign, Journal of Hospital Medicine . 2010, 5(4): E33.

Zheng C. , Kwong Y.L. and Ho J.C.M. , In-vitro combination of arsenic trioxide and chemotherapy in small-cell lung cancer, 15th Medical Research Conference, HKU. Hong Kong Medical Journal . 2010, 16: 56.

Researcher : Lai AYK

List of Research Outputs

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S., Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensitivit y in obstructive sleep apnea, Eur Respir J. . 2009.

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S. , Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensitivity in obstructive sleep apnea, European Respiratory Journal . 2010, 35(1): 138-145.

Lam C.M. , Yan C.S.W., Lai A.Y.K. , Tam S., Fong D.Y.T. , Lam C.L.D. and Ip M.S.M. , Determinants of Daytime Blood Pressure in Relation to Obstructive Sleep Apnea in Men, Lung . 2009, 187: 291-298.

Lian Q. , Zhang Y. , Kang S., Zhang Y. , Lai A.Y.K. , Au K.W. , Zhang J. and Tse H.F. , GENERATION OF MESENCHYMAL STEM CELLS FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (iPSC) FOR THE REATMENT OF LIMB ISCHEMIA, 7th Annunal Meeting of International Society for Stem Cell Research . 2009, 194.

Researcher : Lai CL

Project Title:	A preliminary assessment of safety and antiviral activity of open-label entecavir plus lamivudine therapy in subjects with chronic hepatitis B who have viremia on monotherapy in other entecavir trials
Investigator(s):	Lai CL, Yuen RMF
Department:	Medicine
Source(s) of Funding:	Bristol-Myers-Squibb (HK) - General Award
Start Date:	01/2003

Abstract:

To assess the safety of a combination of oral ente cavir (1.0 mg QD) plus oral lamivudine (100 mg QD) as measured by the incidence of clinical adverse events and laboratory abnormalities.

Project Title:	Long-term assessment of treatment outcomes with entecavir and lamivudine for chronic hepatitis B infection in patients who have enrolled in phase iii entecavir trials
Investigator(s):	Lai CL, Yuen RMF
Department:	Medicine
Source(s) of Funding:	Bristol-Myers-Squibb (HK) - General Award
Start Date:	10/2003

Abstract:

Primary Objectives: to determine in each treatment cohort (entecavir vs lamivudine) the number of weeks of exposure to anti-HBV therapy; to determine in each treatment cohort, the proportion of subjects who achieve a complete response (HBV DNA by PCR of smaller or equal to 10000 copies/mL and absence of e antigen and normaliz ation of ALT) to anti-HBV therapy over the follow-up period. Secondary objectives: to determine the following in each treatment cohort (a) the proportion of subjects who achieve a sustained HBV DNA by PCR of smaller or equal to 10000 copies/mL over the follow-up period, (b) the proportion of subjects who achieve ALT normalization by the end of blinded dosing and who remain ALT normal [ < 1.25 x Upper Limit of Normal (ULN)] during the follow-up period, (c) the proportion of subjects who were HBeAg positive at the beginning of Phase III trials who achieve loss of HBeAg or seroconversion by the end of blinde d dosing and who remain HBeAg negative during the follow-up period.

Project Title:	A randomized, double-blind trial of Telbivudine (LdT) versus Lamivudine in adults with decompensated chronic hepatitis B and evidence of cirrhosis
Investigator(s):	Lai CL, Yuen RMF
Department:	Medicine
Source(s) of Funding:	Idenix Pharmaceuticals, Inc - General Award
Start Date:	01/2004

Abstract:

To compare the antiviral and clinical efficacy of telbivudine (LdT) versus lamivudine in adults with decompensated chronic hepatitis B, over two years (104 weeks); to compare the safety and tolerability of telb ivudine (LdT) versus lamivudine in patients with decompensated chronic hepatitis B, over two years (104 weeks); to determine the comparative frequency of resistance-related virologic breakthrough during two years of treatment with LdT or lamivudine, and the clinical correlates of virologic breakthrough with regard to efficacy and safety; to characterize treatment-emergent HBV viral genotypes associated with virologic breakthrough, for the two study treatments.

List of Research Outputs

Antak N., Craxi A., Kamal S., Moucari R., Van de Merwe S., Haffar S., Gadano A., Zein N., Lai C.L. , Pawlotsky J.M., Heathcote E.J., Dusheiko G. and Marcellin P., The neglected hepatitis C virus genotypes 4, 5 and 6: an international consensus report., Liver Int. . 2010, 30(3): 342-55.

Chang T.T., Lai C.L. , Kew Y.S., Lee S.S., Coelho H.S., Carrilho F.J., Poordad F., Halota W., Horsmans Y., Tsai N., Zhang H., Tenney D.J., Tamez R. and Iloeje U., Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B., Hepatology . 2010, 51(2): 422-30.

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Correlation of liver stiffness and histological features in healthy persons and in patients with occult hepatitis B, chronic active hepatitis B, or hepatitis B cirrhosis., Am J Gastroenterol . 2009, 105(5): 1116-22.

Fung J.Y.Y. , Lai C.L. and Yuen R.M.F. , Hepatitis B and C virus-related carcinogenesis., Clin Microbiol Infect . 2009, 15(11): 964-70.

Fung J.Y.Y. , Lai C.L. and Yuen R.M.F. , Hepatitis B virus DNA and hepatitis B surface antigen levels in chronic hepatitis B., Expert Rev Anti Infect Ther . 2010, 8(6): 717-26.

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Liver stiffness and histological features in healthy persons, and patients with occult hepatitis B, chronic active hepatitis B, and hepatitis B-related cirrhosis., Hepatology . 2009, 50(4) Suppl: 978A.

Fung J.Y.Y. , Lai C.L. , Cheng C.T.K. , Wu C.H. , Wong D.K.H. and Yuen R.M.F. , Mild-to-moderate elevation of alanine aminotransferase may increase liver stiffness measurement by transient elastography in patients with chronic hepatitis B., Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 971A.

Fung J.Y.Y. , Seto W.K., Lai C.L. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , Profiles of HBV DNA in a large population of chinese chronic hepatitis B patients: implications for antivir al therapy. , Hepatol Int . The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010., 2010, 4: 53-4.

Fung J.Y.Y. , Lai C.L. , Yuen J.C.H. , Cheng C.T.K. , Wu C.H. and Yuen R.M.F. , Sequential therapy using lamivudine in entecavir-treated patients with undetectable HBV DNA – results at 48 weeks. , Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 510A.

Gish R.G., Chang T.T., Lai C.L. , de Man R., Gadano A., Poordad F., Yang J., Brett-Sm ith H. and Tamez R., Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naïve HBeAg-positive pat ients with chronic hepatitis B*, Journal of Viral Hepatitis . 2009, 17(1): 16-22.

Gish R.G., Chang T.T., Lai C.L. , De Man R.A., Poordad F., Xu D., Brett-Smith H., Harris M., Iloeje U. and Tang H., Loss of HBsAg in nucleoside-naive HBeAg(+) chronic hepatitis B patients following treatment with entecavir or lamivudine: evaluation of HBV genotypes., Hepatology . 2009, 50(4) Suppl: 487A.

Lai C.L. , 'Cases Studies and Panel Discussion’ (Facilitator), Evening Symposium, GlaxoSmithKline, Hong Kong, Oct ober 15, 2009 . 2009.

Lai C.L. , Antiviral Therapy for Chronic Hepatitis B: Resistance, Fibrosis, Clinical Trials with Entecavir, Scientific Meeting – From durable viral suppression to disease regression, Hong Kong Association for the Study of Liver Diseases and Hong Kong Medical Association, Hong Kong, November 26, 2009 . 2009.

Lai C.L. , Antiviral Therapy for Chronic Hepatitis B: Resistance, Fibrosis, Clinical Trials with Entecavir, Symposium of Infection Control Association of Macao, Macau, January 8, 2010 . 2010.

Lai C.L. , Bristol Myers Squibb FACE B Speaker Training Meeting in Hoboken, NJ; Manhattan; Brooklyn; and Chicago; USA, May 21-26, 2010 . 2010.

Lai C.L. , Chronic Hepatitis B: Natural History, Treatment Guidelines and Treatment Options – Focus: Asian-Pacific Region, AiCuris GmbH & Co. KG, Wuppertal, Germany, August 14, 2009 . 2009.

Lai C.L. , Duration of Therapy for Chronic Hepatitis B, GSK Evening Symposium, Hong Kong, April 29, 2010. . 2010.

Lai C.L. , Management of Chronic Hepatitis B, 15 ^th Hong Kong Medical Forum. Faculty of Medicine, The University of Hong Kong, Hong Kong, May 8-9, 2010 . 2010.

Lai C.L. , Management of Chronic Hepatitis B, Seminar on Viral Hepatitis for Nurses 2010, Department of Health, Hong Kong, May 13, 2010 . 2010.

Lai C.L. , Monitoring and Minimizing Resistance to Antiviral Therapy in Chronic Hepatitis B, 20 ^th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China, March 26, 2010 . 2010.

Lai C.L. , Occult Hepatitis B Infection: Incidence, Detection and Clinical Implications, International Symposium on Hepatology 2009/22 ^nd Annual Scientific Meeting of the Hong Kong Association for the Study of Liver Diseases in Hong Kong, November 8, 2009 . 2009.

Lai C.L. , Occult hepatitis B Infection: Incidence, Detection and Clinical Implications, Plenary Session: TTI, the XX ^th Regional Congress of the International Society of Blood Transfusion (ISBT), Asia, Nagoya, Japan, November 17, 2009 . 2009.

Lai C.L. and Yuen R.M.F. , Occult hepatitis B infection: Incidence, detection and clinical implications., ISBT Science Series (An affiliated publiction to Vox Sanguinis) . 2009, 4: 347-51.

Lai C.L. , Reinventing Chronic Hepatitis B in Canada, Gilead Sciences Canada Inc., Vancouver, Toronto and Montreal, Canada, October 2-6, 2009 . 2009.

Lai C.L. , Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B Patient, 16 ^th Hong Kong International Cancer Congress/6 ^th Annual Meeting of Cetnre for Cancer Research, Centre for Cancer Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, November 4-6, 2009 . 2009.

Lai C.L. and Yuen R.M.F. , The saga of entecavir. , Hepatol Int . 2009, 3(3): 421-4.

Lai C.L. , 乙型肝炎, Hepatitis B Public Education Outreach Program, The Hong Kong Liver Foundation , Hong Kong, May 16, 2010 . 2010.

Lam T.P. , Lam C.L.K. , Lai C.L. , Yuen R.M.F. and Fong D.Y.T. , Psychometrics of the chronic liver disease questionna ire for Southern Chinese patients with chronic hepatitis B virus infection, World Journal of Gastroenterology . 2009, 15: 3288-97.

Lam T.P. , Lam C.L.K. , Lai C.L. , Fong D.Y.T. , So T.M.K. and Yuen R.M.F. , The Effect of Health-related Quality of Life on Health Service utilization and Willingness to Pay for Treatment of Chinese with Chronic Hepatitis B Infection, Oral, 2009 International Society for Quality of Life Research Annual Meeting . New Orleans, USA, 2009.

Mukaide M., Tanaka Y., Shin-I T., Yuen R.M.F. , Kurbanov F., Yokosuka O., Sata M., Karino Y., Yamada G., Sakaguchi K., Orito E., Inoue M., Baqai S., Lai C.L. and Mizokami M., Mechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation. , Antimicrob Agents Chemother . 2009, 54(2): 882-9.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , A three-year study on viral suppression and resistance profile for treatment-naive chronic hepatitis B patients receiving continuous entecavir treatment. , Hepatol Int. The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010 . 4: 58.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , HBV DNA levels predict significant liver histology for HBeAg-negative chronic hepatitis B patients., Gastroenterology. Digestive Disease Week, New Orleans , May 2010 . 138 (5 Supp1): S-788.

Seto W.K., Mak C.M. , BUT D., Hung I.F.N. , Lam C.W. , Tam S., Yuen R.M.F. and Lai C.L. , Mutational analysis for Wilson's disease, Lancet . 2009, 374(9690): 662.

So J.C.C. , Hwang Y.Y., Shek T.W.H. , Lam C.C.K. , Lai C.L. and Kwong Y.L. , Transfusion-refractory anaemia in liver cirrhosis, Gut . 2010, 59(1): 5.

Tung K.K. , Mak K.M. , Lee M.F. , Li J.J., Poon R.T.P. , Lai C.L. , Luk J.M.C. and Ng I.O.L. , Serum level of DKK1 as a marker for predicting tumor recurrence of hepatocellular carcinoma , American Association for Cancer Research 101st Annual Meeting 2010 .

Wu I.C., Lai C.L. , Han S.H., Han K.H., Gordon S.C., Chao Y.C., Tan C.K., Sievert W., Tanwandee T., Xu D., Neo B.L. and Chang T.T., Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy-proven histological damage., Hepatology . 2010, 51(4): 1185-9.

Yuen R.M.F. , Han K.H., Um S.H., Yoon S.K., Kim H.R., Kim J., Kim C.R. and Lai C.L. , Antiviral activity and safety of LB80380 in hepatitis B e antigen-positive chronic hepatitis B patients with lamivudine-resistant disease. , Hepatology . 2010, 51(3): 767-76.

Yuen R.M.F. , Fung J.Y.Y. , Seto W.K., Wong D.K.H. , Yuen J.C.H. and Lai C.L. , Combination of baseline parameters and on-treatment hepatitis B virus DNA levels to start and continue patients with lamivudine therapy. , Antivir Ther . 2009, 14(5): 679-85.

Researcher : Lai KN

Project Title:	The role of the renin-angiotensin system in the tubulointerstitial injury of IgA nephropathy (IgAN)
Investigator(s):	Lai KN, Leung JCK
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2004

Abstract:

To define the role of RAS in inducing PTEC/MC damage and; to elucidate the cross-talk between resident cells and infiltrating cells (T-cells/monocytes).

Project Title:	Endothelial progenitor cells in renal failure patients and its modulation by treatment with the peroxisome proliferator-activated receptor-gamma agonist in relation to clinical atherosclerosis
Investigator(s):	Lai KN, Wang AYM
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2007

Abstract:

To test the hypothesis that endothelial progenitor cells (EPCs) are reduced and show impaired angiogenic function and that contribute to endothelial dysfunction and atherosclerosis in chronic renal failure (CRF) patients; to test the hypothesis that the number and functional activity of EPCs increase with amelioration of uremia by dialysis and that correspond to an improvement in flow-mediated dilatation in CRF patients; to study the short-term and longer-term effects of treatment with the peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist on the proliferation and func tional activity of EPCs in relation to endothelial dysfunction and progression of atherosclerosis in chronic renal failure patients.

Project Title:	The tubular peroxisome proliferator - activated receptors (PPAR) -γ system in IgA nephropathy: a potential therapeutic target
Investigator(s):	Lai KN
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2007

Abstract:

To test whether the PPAR system in renal tubules is suppressed due to the glomerulo-tubular "cross-talk" that operates in IgAN; to test whether PPAR-γ agonist suppresses the expression of ATR1 in proximal tubular epithelial cells and hence improves the therapeutic efficacy of ATR1 blockade; to test the new therapeutic regimen derived from an in vitro model be applied to an animal model of IgAN

Project Title:	Podocyte injury in IgA nephropathy
Investigator(s):	Lai KN, Leung JCK
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2008

Abstract:

(1) Are there functional/structural abnormalities of podocytes in IgAN? (2) How do mediators released following mesangial IgA deposition lead to glomerular filtration barrier failure in IgAN? (3) Will the renin-angiotensin system be activated in podocytes? Will this be abolished by ACEI or AngII receptor blockade? (4) Is apoptosis an important form of podocyte injury in IgAN? (5) If apoptosis were operational in podocyte injury in IgAN, what are the mechanisms through which AngII is involved?

Project Title:	Infiltrating leukocytes in the tubulointerstitium of IgA nephropathy: Their role in pathogenesis
Investigator(s):	Lai KN, Leung JCK
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To define the nature of infiltrating leukocy tes in the tubulointerstitium in IgAN; (2) To determine how infiltrating leukocytes are recruited in the tubulointerstitium through production of chemokines by TEC and the express ion of specific chemokine receptors; (3) To determine the mechanism that controls the chemokine production by TEC in IgAN. 4 To explore the potential therapeutic intervention of tubular inflammation by targeting specific chemokine receptors expressed on infiltrating leukocyt es.

List of Research Outputs

Choy C.B.Y. and Lai K.N. , Bleeding tendency and hepatitis B vaccination, In: Lai KN, A Practical Manual of Renal Medicine: Nephrology, Dialysis and Transplantation . Singapore, Imperial College Press/World Scientific Publisher, 2009, 293-299.

Guo H. , Leung J.C.K. , Cheung J.S., Chan Y.Y. , Wu E.X. and Lai K.N. , Non-viral Smad7 gene delivery and attenuation of postoperat ive peritoneal adhesion in an experimental model, Br J Surg . 2009, 96(11): 1323-35.

Hsu S.I., Niu Y., Davila S., Leung J.C.K. , Lam M.F. , Tang S.C.W. and Lai K.N. , Genome-wide linkage scan for familial IgA nephropathy among southeast Asian Chinese: evidence for a suggestive novel susceptibility locus on chromosome 8p23, Journal of American Society Nephrology . 2009, 20: 434A.

Lai K.N. , Acute renal failure, In: Lai KN, A Practical Manual of Renal Medicine: Nephrology, Dialysis and Transplantation . Singapore, Imperial College Press/World Scientific Publisher, 2009, 89-107.

Lai K.N. , Chan L.Y., Guo H., Tang S.C.W. and Leung J.C.K. , Additive effect of peroxisome proliferator-activated receptor- g agonist and angiotensin receptor blocker in treatment of experimental IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 149-150A.

Lai K.N. , Lai A.S. and Tang S.C.W. , Chronic Kidney Disease and Infectious Disease, In: El Nahas M and Levin A, Chronic Kidney Disease: a practical guide to understanding and management. Oxford University Press, Oxford . 2010, 155-183.

Lai K.N. and Tang S.C.W. , Hepatitis B Associated Renal Diseases., Rheumatology and the Kidney, 2nd edition. Oxford University Press, Oxford . 2010.

Lai K.N. , IgA nephropathy, In: Kurma and Clark, Online Appendix in Textbotok of Medicine 7 ^th Edition . Edinburgh, Elservier Saunders, 2009.

Lai K.N. and Leung J.C.K. , Inflammation in Peritoneal Dialysis., Nephron Clin Pract . 2010, 116(1): c11-c18.

Lai K.N. and Leung J.C.K. , Peritoneal adipocytes and their role in inflammation during peritoneal dialysis, Mediators Inflamm . 2010, 2010: 164954.

Lai K.N. , Lai A.S., Yap D.Y. and Ng M.M., Recurrent oral ulcers and diarrhea in a renal transp lant patient. Behcet's disease (associated with IgA nephropathy) and acute tacrolimus nephrotoxicity, Kidney International . 2009, 76(11): 1211-2.

Lai K.N. , Selected glomerular disorders, In: Lai KN, A Practical Manual of Renal Medicine: Nephrology, Dialysis and Transplantation . Singapore, Imperial College Press/World Scientific Publisher, 2009, 109-126.

Lai K.N. , Selected problems in general nephrology, In: Lai KN, A Practical Manual of Renal Medicine: Nephrology, Dialysis and Transplantation . Singapore, Imperial College Press/World Scientific Publisher, 2009, 137-147.

Lai K.N. , Severe acute respiratory syndrome, In: Kurma and Clark, Online Appendix in Textbook of Medicine 7 ^th Edition . Edinburgh, Elservier Saunders, 2009.

Lam M.F. , Lo W.K. , Tse K.C., Yip T.P.S., Lui S.L. , Chan D.T.M. and Lai K.N. , Retroperitoneal leakage as a cause of acute ultrafiltration failure: its associated risk factors in peritoneal dialysis , Peritoneal Dialysis Internation al . 2009, 29(5): 542-547.

Leung J.C.K. , Chan L.Y., Tam K.Y., Tang S.C.W. and Lai K.N. , Inhibition of renin-angiotensin-aldosterone system abolishes polymeric-IgA induced TGF- synthesis by human mesangial cells in IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 294A.

Lim V., Stubbs J.W., Nahar N., Amarasena N., Chaudry Z.U., Weng S.C., Mayosi B., Van der Spuy Z., Liang R.H.S. , Lai K.N. , Metz G., Fitzgerald G.W., Williams B., Douglas N., Donohoe J., Darnchaivijir S., Coker P. and Gilmore I., Politicians must heed health effects of climate change, Bone Marrow Transplantation . 2009, 339:b3672.

Lin M. , Chan A.W., Chan L.Y., Leung J.C.K. , Lai K.N. and Tang S.C.W. , Toll-like receptor 4 mediates tubular inflammation in diabetic nephropathy, Hong Kong Medical Journal . 2010, 16: 39.

Lou T., Zhang J., Gale D.P., Rees A.J., Rhodes B., Feehally J., Li C., Li Y., Li R., Huang W., Hu B., Leung J.C.K. , Lam M.F. , Lai K.N. , Wang Y. and Maxwell P.H., Variation in IGHMBP2 is not associated with IgA nephropathy in independent studies of UK Caucasian and Chinese Han patients, Nephrology Dialysis Transplantation . 2009, 25(5): 1547-54.

Ma K.M., Yap D.Y., Chan D.T.M. and Lai K.N. , A hemodialysis patient with severe vomiting, Hemodialysis International . 2009, 13: 432.

Mok M.M., Yip T., Lui S.L. , Chan D.T.M. , Lai K.N. , Lo W.K. and Lo W.K. , Severe hypocalcemia and hyperphosphatemia caused by oral sodium phosphate fleet solution in a hemodialysi s patient after parathyroidectomy, Hemodialysis International . 2009, 13: 395.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , In vitro enhanced chemotaxis of CD25+ mononuclear cells in patients with familial IgAN through glomerulotubular interaction, American Journal of Physiology-Renal Physiology . 2010.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , Increased chemotaxis of CD25+ PBMC to tubular epithelial cells through glomerulotubular interaction in patients with familial IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 307A.

Tang S.C.W. , Chan A.W., Chan L.Y., Leung J.C., Lan H.Y. and Lai K.N. , Anti-inflammatory effects of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) in protein-overloaded renal tubule cells, Journal of American Society Nephrology . 2009, 20: 858-868A.

Tang S.C.W. , Chan L.Y., Leung J.C.K. , Cheng A.S., Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote diabetic renal tubular injury , Nephrology Dialysis Transplantation . 2010, 25: 698-710.

Tang S.C.W. , Chan Y.Y. , Leung J.C.K. , Cheng A.S. , Chan K.W. , Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote renal tubular infl ammation, Nephrol Dial Transplant . 2010, 25(3): 698-710.

Tang S.C.W. , Lam B. , Yap D.Y., Ip M.S.M. and Lai K.N. , Conversion between hemodialysis and continuous ambulatory peritoneal dialysis may impact on sleep apnea in favor of CAPD, Hemodialysis International . 2009, 13: 395.

Tang S.C.W. , Tang A.W., Wong S.S., Ho Y.W. and Lai K.N. , Long-term study of mycophenolate mofetil in IgA nephropathy, Journal of American Society of Nephrology . 2009, 20: 233A.

Tang S.C.W. , Tang A.W., Wong S.H., Leung J.C., Ho Y.W. and Lai K.N. , Long-term study of mycophenolate mofetil treatment in IgA nephropathy, Kidney International . 2010, 77: 543-549.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea as a novel risk predictor for cardiovascul ar morbidity and death in peritoneal dialysis patients, Kidney International . 2010, 77: 1031-1038.

Tang S.C.W. , Lam B. , Yao T.J. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is a novel risk predictor of cardiovascu lar morbidity and death in patients receiving peritoneal dialysis, Kidney International . 2010, 77(11): 1031-8.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is an independent risk predictor for all-cause and cardiovascular mortality in peritoneal dialysis patients, Peritoneal Dialysis International . 2009, 29: S7.

Tang S.C.W. , Leung V.T., Chan L.Y., Wong S.H., Chu D.W., Leung J.C.K. , Lai K.N. , Ma L., Elbein S.C., Bowden D.W., Hicks P.J., Comeau M.E., Langefeld and Freedman B.I., The acetyl-Coenzyme A carboxylase beta gene (ACACB) is associated with nephropathy in Chinese patients with type 2 diabetes, Nephrology Dialysis Transplantation . 2010.

Wang A.Y.M. , Cheung C.W., Chu J.Y.Y. , Fok A.N.Y. , Lo W.K. , Leung J.C.K. , Tso W.K. and Lai K.N. , Is aortic pulse wave velocity a useful screening test for vascular and valvular calification in end-stage renal disease patients, Journal of American Society of Nephrology . 2009, 20: 443A-444A.

Xiao J. , Leung J.C.K. , Chan Y.Y. , Tang S.C.W. and Lai K.N. , Crosstalk between peroxisome proliferator-activated receptor-gamma and angiotensin II in renal tubular epithelial cells in IgA nephropathy, Clinical Immunology . 2009, 132: 266-276.

Yap D.Y., Chu F.S., Chu S.S.M. , Tam P.C. , Chan D.T.M. , Lai K.N. and Tang S.C.W. , CT angiography versus conventional digital angiography in pre-operative assessment for Chinese living kidney donors [Epub ahead of print 15 June 2010], Journal of Nephrology . 2010.

Yap D.Y., Chu F.S., Chu S.S.M. , Tam P.C. , Tam S., Lai K.N. , Chan D.T.M. and Tang S.C.W. , CT angiography versus conventional digital angiograp hy in pre-operative assessment for Chinese living kidney donors, Nephrology . 2010, 15 (S3): 54.

Yap D.Y. and Lai K.N. , Cytokines and their roles in the pathogenesis of systemic lupus erythematosus: from basics to recent advances., J Biomed Biotechnol . 2010, 2010: 365083.

Yap D.Y., Ma M.K., Lai K.N. and Chan D.T.M. , Superior vena cava injury after cuffed tunneled catheter insertion using a right subclavian approach, Hemodialysis International . 2009, 13: 430.

Yap D.Y.H., Lau S.K.P. , Lamb S., Choy C.B.Y. , Chan D.T.M. , Lai K.N. and Tang S.C.W. , An unusual organism for PD-related peritonitis: Hafnia alvei, Peritoneal Dialysis Internatio nal . 2010, 30(2): 254-255.

Yap D.Y.H., Tse K.C., Chan D.T.M. and Lai K.N. , Epstein syndrome presenting as renal failure in young patients, Ren Fail . 2009, 31(7): 582-585.

Yip T., Tse K.C., Lam M.F. , Cheng S.W., Lui S.L. , Tang S.C.W. , Mg M., Chan D.T.M. , Lai K.N. and Lo W.K. , Colonic diverticulosis as a risk factor for peritonitis in Chinese peritoneal dialysis patients, Peritoneal Dialysis International . 2010, 30: 187-191.

Yip T.P., Tse K., Ng F., Lam M.F. , Tang S.C.W. , Lui S.L. , Lai K.N. , Chan D.T.M. and Lo W.K. , Clinical course and outcomes of enterococcus peritonitis in peritoneal dialsyisi patients, Nephrology . 2010, 15 (S3): 47.

Yip T.P.S., Lui S.L. , Tse K.C., Xu H., Ng F.S.K. , Cheng S.W. , Chan D.T.M. , Lai K.N. and Lo W.K. , A prospective randomized study comparing tenckhoff catheters inserted using the triple incision method with standard swan neck catheters, Peritoneal Dialysis Internationa l . 2010, 30(1): 56-62.

Zhou L. , Fu P., Huang X.R., Liu F. , Lai K.N. and Lan H.Y. , Activation of p53 promotes renal injury in acute aristolo chic acid nephropathy, Journal of American Society of Nephrology . 2010, 21(1): 31-41.

Zhou L. , Fu P., Huang X.R., Liu F. , Chung A.C.K. , Lai K.N. and Lan H.Y. , Mechanism of chronic aristolochic acid nephropathy: role of Smad3, Am J Physiol Renal Physiol . 2010, 298(4): F1006-17.

Researcher : Lai KWH

List of Research Outputs

Chan Y.C. , Lee Y.K. , Ng K.M. , Lai K.W.H. , Yang D. , Tse H.F. and Siu D.C.W. , A Newly-derived Small Synthetic Compound Alleviated Ventricular Fibrillation In A Pig Model With Chronic Myocardial Infarction As Revealed By Optical Mapping, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” (Hong Kong) . 2010.

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Lee Y.K. , Ng K.M. , Lai K.W.H. , Tse H.F. and Siu D.C.W. , Triiodothyronine enhances cardiac differentiation of embryonic stem cells and maturation via classical pathway., Molecular Endocrinology . 2010, (in press).

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endothelial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Mok T.M.Y. , Tse H.F. , Wong C.Y., Qiuwaxi J. , Lai K.W.H. , Lo Y. , Wong R.W.S. and Lau W.C.S. , Endothelial dysfunction is associated with decreased circulating endothelial progenitor cells in patients with systemic sclerosis, Annals of the Rheumatic Diseases . 2009, S337.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai K.W.H. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1alpha promotes cardiac differentiation of embryonic stem cells., Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-37.

Siu D.C.W. , Waston T., Lai K.W.H. , Lee Y.K. , Chan Y.H. , Ng K.M. , Lau C.P. , Lip G.Y. and Tse H.F. , Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm., Europace . 2009, 12(4): 460-1.

Researcher : Lai WHK

List of Research Outputs

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embryonic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Researcher : Lai WW

List of Research Outputs

Yiu K.H., Wang S. , Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Lau C.P. , Lai W.W. , Wong L.Y. , Lam K.F. , Lau W.C.S. and Tse H.F. , Role of circulating endothelial progenitor cells in patients with rheumatoid arthritis with coronary calcification, Journal of Rheumatology . 2010, 37: 529-535.

Researcher : Lam B

List of Research Outputs

Ho J.C.M. , Lam C.L. , Wong M.K.Y. , Lam B. , Ip M.S.M. and Lam W.K. , Capecitabine as salvage treatment for lymphoepithelioma-like carcinoma of lung, Journal of Thoracic Oncology . 2009, 4(9): 1174-1177.

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S., Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sen sitivity in obstructive sleep apnea, Eur Respir J. . 2009.

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S. , Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensitivity in obstructive sleep apnea, European Respiratory Journal . 2010, 35(1): 138-145.

Siu D.C.W. , Pong V., Ho H.H., Liu S., Lam B. , Lau C.P. , Li S.W. and Tse H.F. , Does MADIT II criteria for implantable cardioverter defibrillator implantation applicable to Chinese patients? , J Cardiovasc Electrophysiol. . 2010, 21: 231-5.

Tang S.C.W. , Lam B. , Yap D.Y., Ip M.S.M. and Lai K.N. , Conversion between hemodialysis and continuous ambulatory peritoneal dialysis may impact on sleep apnea in favor of CAPD, Hemodialysis International . 2009, 13: 395.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea as a novel risk predictor for cardiovascular morbidity and death in peritoneal dialysis patients, Kidney International . 2010, 77: 1031-1038.

Tang S.C.W. , Lam B. , Yao T.J. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is a novel risk predictor of cardiovascular morbidity and death in patients receiving peritoneal dialysis, Kidney International . 2010, 77(11): 1031-8.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is an independent risk predictor for all-c ause and cardiovascular mortality in peritoneal dialysis patients, Peritoneal Dialysis International . 2009, 29: S7.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to first-l ine gefitinib in non-small cell lung cancer. , Cancer Chemotherapy and Pharmacology . 2010, 65: 1023-1028.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to gefitinib in non-small cell lung cancer, 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S719.

Researcher : Lam CL

Project Title:	The role of nicotinic acetylcholi ne receptor (nAChR) in bronchial epithelium in relation to lung carcinogenesis
Investigator(s):	Lam CLD, Ip MSM, Tsao GSW, Lam WK
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2010

Abstract:

Overall hypotheses 1. That nicotine can stimulate expression and activation of nAChR with downstream activation of signaling pathways important in tumorigenesis and relevant airway inflammation. 2. That these nAChR and relevant pathway activation can be detected in bronchial epithelium of smokers with or without lung cancer. Objectives 1. In in vitro experiments, to evaluate the effects of chronic nicotine exposure on normal bronchial epithelial cells and lung cancer cell lines in terms of nAChR activation and relevant tumor igenic and growth signaling pathways 2. To test and confirm in vitro experimental findings in clinical samples and to understand the functional role of nAChR activation in relation to smoking-related airflow obstruction and lung cancer.

List of Research Outputs

Ho J.C.M. , Lam C.L. , Wong M.K.Y. , Lam B. , Ip M.S.M. and Lam W.K. , Capecitabine as salvage treatment for lymphoepithelioma-like carcinoma of lung, Journal of Thoracic Oncology . 2009, 4(9): 1174-1177.

Researcher : Lam CLD

Project Title:	The role of nicotinic acetylcholin e receptor (nAChR) in bronchial epithelium in relation to lung carcinogenesis
Investigator(s):	Lam CLD, Ip MSM, Tsao GSW, Lam WK
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2010

Abstract:

Overall hypotheses 1. That nicotine can stimulate expression and activation of nAChR with downstream activation of signaling pathways important in tumorigenesis and relevant airway inflammation. 2. That these nAChR and relevant pathway activation can be detected in bronchial epithelium of smokers with or without lung cancer. Objectives 1. In in vitro experiments, to evaluate the effects of chronic nicotine exposure on normal bronchial epithelial cells and lung cancer cell lines in terms of nAChR activation and relevant tumori genic and growth signaling pathways 2. To test and confirm in vitro experimental findings in clinical samples and to understand the functional role of nAChR activation in relation to smoking-related airflow obstruction and lung cancer.

List of Research Outputs

Chan C.H. , Leung V.O.Y. , Lam C.L.D. , Mak J.C.W. , Freeman C., Ip M.S.M. and Shum D.K.Y. , Sulfated maltoheptaose reduces neutrophilic airway inflammation in a smoking rat model of chronic obstructi ve pulmonary disease , Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” 6-7 March 2010 . 2010.

Ko F.W.S., Ip M.S.M. , Chu C.M., So L.K.Y. and Lam C.L.D. , A milti-centre study of the prevalence of allergic rhinitis and its associated morbidity among adults with asthma, 14th Congress of the Asian Pacific Society of Respirology & 3rd Joint Congress of the Asian Pacific Society of Respirology/American College of Chest Physicians, Seoul , Korea, Nov 2009, Respirology . 2009, 14 (Supp 3): A223 (PD 10-20).

Lam C.L.D. , APSR Travel Award to attend American Thoracic Society Meeting, May, 2010, Asian Pacific Society of Respirology (APSR) . 2010.

Lam C.L.D. , Girard L., Sihoe A., Cheng L.C., Lui M.M.S., Wong M.P. , Chung L.P. , Ip M.S.M. , Lam W.K. and Minna J.D., Gene expression profiling in lung adenocarcinomas reflects possible different molecular pathogenesis with respect to gender and smoking status, 14th Congress of the Asian Pacific Society of Respirology & 3rd Joint Congress of the Asian Pacific Society of Respirology/American College of Chest Physicians, Seoul, Korea, Nov 2009, Respirology . 2009, 14(Suppl 3): A128 (OS 03-05).

Lam C.L.D. , Girard L., Sihoe A.D.L. , Cheng L.C. , Lui M.A.C.Y., Wong M.P. , Chung L.P. , Ip M.S.M. , Lam W.K. and Minna J.D., Gene expression signatures associated with combination of female non-smokers in lung adenocarcinomas bearing activating epidermal growth factor receptor (EGFR) gene mutations in Chinese, The American Thoracic Society Annual Meeting 2010 .

Lam C.L.D. , In: David CL Lam, Respirology . Wiley-Blackwell, 2010.

Lam C.L.D. , Lam C.M. , Tan K.C.B. , Lui M.M.S. and Ip M.S.M. , Serum advanced glycation endproducts (AGE) levels corr elated with severity of obstructive sleep apnea but not insulin resistance, 14th Congress of the Asian Pacific Society of Res pirology & 3rd Joint Congress of the Asian Pacific of Respirology/American College of Chest Physicians, Seoul, Korea, November, 2009, Respirology . 2009, 14 (Suppl 3): A168 (OS 32-01).

Lam C.M. , Yan C.S.W., Lai A.Y.K. , Tam S., Fong D.Y.T. , Lam C.L.D. and Ip M.S.M. , Determinants of Daytime Blood Pressure in Relation to Obstructive Sleep Apnea in Men, Lung . 2009, 187: 291-298.

Researcher : Lam CLK

List of Research Outputs

Chan S.S.C. , Leung Y.P. , Leung A.Y.M. , Lam C.L.K. , Hung I., Yuen K.Y. , Liang R.H.S. , Johnston J.M. , Chan C.K., Chu D., Liu S.H. and Lam T.H. , Predictors of influenza vaccination in Chinese older patients with chronic disease in Hong Kong, The First Asia-Pacific Conference on Health Promotion and Education, 18-20 July, Chiba, Japan . 2009, 186.

Lam T.P. , Lam C.L.K. , Lai C.L. , Yuen R.M.F. and Fong D.Y.T. , Psychometrics of the chronic liver disease questionnair e for Southern Chinese patients with chronic hepatitis B virus infection, World Journal of Gastroenterology . 2009, 15: 3288-97.

Researcher : Lam CM

List of Research Outputs

Lam C.L.D. , Lam C.M. , Tan K.C.B. , Lui M.M.S. and Ip M.S.M. , Serum advanced glycation endproducts (AGE) levels correlated with severity of obstructive sleep apnea but not insulin resistance, 14th Congress of the Asian Pacific Society of Respirology & 3rd Joint Congress of the Asian Pacific of Respirology/Am erican College of Chest Physicians, Seoul, Korea, November, 2009, Respirology . 2009, 14 (Suppl 3): A168 (OS 32-01).

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S., Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensit ivity in obstructive sleep apnea, Eur Respir J. . 2009.

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S. , Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensitivity in obstructive sleep apnea, European Respiratory Journal . 2010, 35(1): 138-145.

Lam C.M. , Yan C.S.W., Lai A.Y.K. , Tam S., Fong D.Y.T. , Lam C.L.D. and Ip M.S.M. , Determinants of Daytime Blood Pressure in Relation to Obstructive Sleep Apnea in Men, Lung . 2009, 187: 291-298.

Lam C.M. and Ip M.S.M. , Sleep and the metabolic syndrome, The Indian Journal of Medical Research . 2010, 131: 206-216.

Researcher : Lam JBB

List of Research Outputs

Chow H.M. , Sun R.W.Y. , Lam J.B.B. , Li C.K.L. , Xu A. , Abagyan R., Wang Y. and Che C.M. , A Gold(III) Porphyrin Complex with Antitumor Properties Targets the Wnt/ b -catenin Pathway, Cancer Research . 2010, 70: 329-337.

Researcher : Lam KSL

Project Title:	The Endocrine Society's 88th Annual Meeting Adipocyte Fatty Acid Binding Protein as a Potential Circulating Metabolic Hormone: Clinical and Functional Studies
Investigator(s):	Lam KSL
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	06/2006

Abstract:

N/A

Project Title:	Adipocyte fatty acid binding protei ns: new mediators of the metabolic syndrome and coronary atherosclerosis
Investigator(s):	Lam KSL, Xu A, Sham PC, Lao TTH
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	08/2006
Completion Date:	07/2009

Abstract:

(1) To investigate the genetic regulation of circulating FABP4 and FABP5 levels in man by examining the effects of genetic variants detected from a systematic analysis of the two genes (2) To investigate (a) the associations of genetic variants/serum levels of FABP4 and FABP5 with the metabolic syndrome or its components (Obesity, insulin resistance, dyslipidaemia, glucose intolerance/diabetes, hypertension, chronic inflammation), and coronary atherosc lerosis, in cross-sectional and prospective studies, and (b) whether FABP4 and FABP5 interact at genetic or circulating protein levels in such associations (3) To examine the relationship of circulating FABP4 and FABP5 levels with their gene and protein expressions in visceral and subcutaneous adipose tissues, and insulin sensitiv ity indices (4) To investigate why circulating FABP4 levels are higher in women.

Project Title:	Do biomarkers of inflammation and obesity predict the development of hypertension in Hong Kong Chinese?
Investigator(s):	Lam KSL, Lam TH, Lau CP, Sham PC, Tse HF, Cheung BMY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	07/2007
Completion Date:	09/2009

Abstract:

To determine the cumulative incidence of hypertension since 1995-6; to identify baseline factors predictive of the incidence of hypertension and its complications and to quantify the risk; to determine the utility of four biomarkers, C-reactive protein, interleukin-6, adiponectin and adrenomedullin, in predicting the deve lopment of hypertension, in addition to baseline blood pressure.

Project Title:	Role of adipocyte-fatty acid binding protein (A-FABP) in the development of non-alcoholic steatohepatitis (NASH)
Investigator(s):	Lam KSL, Xu A, Hoo RLC
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2008

Abstract:

Major objective: To elucidate the role of A-FABP in the development of non-alcoholic steatohepatitis. The specific objectives are: 1. To investigate whether the enhanced expression of A-FABP in the liver of db/db diabetic mice is mainly attributable to Kupffer cells. 2. To generate adenovirus that over-expresses A-FABP or luciferase (control), and investigate the mechanisms whereby ectopic hepatic expression of A-FABP may lead to the development of NASH including, specifically, whether adenovirus-mediated ectopic expression of A-FABP leads to the activation of major pro-inflammatory pa thways, including NF-kappaB and the JNK (c-Jun NH2- terminal kinase) pathways.

Project Title:	Healthy Ageing
Investigator(s):	Lam KSL
Department:	Medicine
Source(s) of Funding:	Seed Funding for Strategic Research Theme
Start Date:	06/2008
Completion Date:	05/2011

Abstract:

n/a

Project Title:	Clinical implications of genetic variants of the newly discovered type 2 diabetes sus ceptibility genes in Southern Chinese
Investigator(s):	Lam KSL, Sham PC, Tso AWK
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2009

Abstract:

Type 2 diabetes (T2DM) is a complex disease under the influence of multiple genes (1) which interact with environmental factors, leading to clinical manifestation in the susceptible individual. The advances in genome-wide association studies have dramatically expanded the number of genetic variants that show a significant association with T2DM (2). Recently, a meta-analysis of genome-wide association data obtained from the Eur opean populations has detected eleven additional T2DM associated variants (3). These SNPs are located within JAZF1 (rs864745), THADA (rs7578597), ADAMTS9 (rs4607103), NOTCH2 (rs10 923931), DCD (rs1153188), ADAM30 (rs2641348), VEGFA (rs9472138), BCL11A (rs10490072) and between CDC123/CAMK1D (rs12779790), TSPAN8/LGR5 (rs7961581) and SYN2/PPARG (rs17036101) respectively. The clinical significance of these new ly identified T2DM associated genes on the susceptibility to T2DM in Chinese is currently unknown. The purpose of this study is to elucidate the implications of these newly identified genes in our population and whether they can be usefully employed for the prediction of T2DM in Hong Kong Chinese. Objectives: 1. To validate the association of these newly identified T2DM gene loci with T2DM in Hong Kong Chinese by performing a cross-sectional case control association study. 2. To investigate the impact of these variants to the T2DM related quantitative traits. 3. To examine whether the genetic polymorphisms with positive associations with T2DM, or related quantitative traits, identified in the above studies can predict the progression to diabetes in an 8-year prospective follow up study of a non-diabetic Chinese cohort.

Project Title:	Role of JNK in adipose tissue inflammation, adipokine production and systemic insulin resistance
Investigator(s):	Lam KSL, Xu A, Zhang X
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To generate and propagate the transgenic mice with adipose tissue specific over-expression of dominant negative (DN) form of JNK; (2) To test whether selective suppression of JNK in adipose tissue of obese mice is sufficient to prevent the metabolic disorders associated with diet-induced or genetic obesity, and type 2 diabetes; (3) To use these transgenic mice to investigate the role of JNK in obesity-induced macrophage infiltration, aberrant production of adipokines in adipose tissues and systemic inflammation, in the context of diet-in duced and genetic obesity.

Project Title:	Adipocyte fatty acid binding protein as a novel mediator of obesity-related fatty liver disease
Investigator(s):	Lam KSL, Xu A
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To investigate whether or not A-FABP knockout mice are resistant to develop neo-inflammation and liver injury following high fat diet/LPS; 2) To evaluate whether the pharmacological inhibitor of A-FABP can be used for the treatment of NASH in mice; 3) To study the role of A-FABP in LPS/FFA-induced inflammation and production of pro-inflammatory cytokines in primary Kupffer cells using gain-of-function.

Project Title:	To Establish a Metabolic Study Center in Hong Kong: Focusing on the liver-derived hormones
Investigator(s):	Lam KSL, Xu A, Leung PS, Wang Y, Tso AWK
Department:	Medicine
Source(s) of Funding:	Collaborative Research Fund (CRF) - Group Research Project
Start Date:	06/2010

Abstract:

1) To establish a Hong Kong Mouse Metabolic Phenotyp ing Center (HKMMPC) providing the standardized; methodologies for metabolic characterization of rodent models related to obesity and diabetes; 2) To apply the platform established in objective-1 to comprehensively investigate the physiological roles of the two liver-secreted hormones in regulating energy metabolism and insulin sensitivity in FGF21 and adropin knockout mice; 3): To elucidate in depth the molecular pathways underlying the metabolic actions of FGF21 and adropin in their target organs; 4) To conduct both cross-sectional and longitudinal studie s to evaluate the association of serum FGF21 and adropin with various metabolic parameters and indexes of insulin sensitivity in human subjects.

List of Research Outputs

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chen C. , Xu A. , Tso A.W.K. , Law S.C. , Cheung B.M.Y. , Janus E.D., Wat N.M.S. and Lam K.S.L. , Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospec tive study., 5th International Symposium on Healthy Aging . 2010.

Cheng C.H. , Tam J.H. , Wong R., Yik P.Y. , Song Y.Q., Morley J.E. and Lam K.S.L. , Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men: a 1-year cohort study ., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 16.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Jiang C.Q., Thomas G.N. and Lam T.H. , A single nucleotide polymorphism in the gene encoding fibrinogen beta chain is associated with hypertension, British Hypertension Society Annual Meeting, 14-16 September 2009, Cambridge, UK . 2009.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. and Lam K.S.L. , Gamma-glutamyl transaminase level predicts the development of hypertension., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong, 2010 . 18: 33.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. and Sham P.C. , Using glycosylated hemoglobin to define the metabolic syndrome in United States adults., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong, 2010 . 18: 33.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Law S.C. , Sham P.C. and Lam K.S.L. , A genetic variant near the GNPDA2 gene is associated with the metabolic syndrome in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Sham P.C. , Xu A. , Ong K.L. , Cheung B.M.Y. and Lam K.S.L. , Implication of the obesity-associated genetic variants identified from recent genome-wide association studies in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 15.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implica tions in a Chinese population, J Clin Endocrinol Meta . 2010, 95: 1395-403.

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Hoo R.L.C. , Wong Y.L. , Xu A. and Lam K.S.L. , Adipocyte fatty acid binding protein (AFABP) in kupffer cells as the novel player in the pathogenesis of non-alcoh olic fatty liver disease, 14th Medical Research Conference, The University of Hong Kong . 2009.

Hui X. , Li H. , Zhou Z., Lam K.S.L. , Xiao Y., Wu D., Ding K., Wang Y. , Vanhoutte P.M.G.R. and Xu A. , Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1, J Biol Chem . 2010, 285(14): 10273-80.

Hui X. , Lam K.S.L. , Wang Y. , Xu A. , Li H. , Vanhoutte P.M.G.R. and Wu D. , Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1., The Journal of Biological Chemistry . the United States, American Society for Biochemistry and Molecular Biology, 2010, 285: 10273.

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Li Jin Y., Yue X.J., Ong K.L. , Tam S., Wong K.S., Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese , Eur J Hum Genet . 2010, 18(11): 1255-1260.

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Jin Y.L., Yue X.J., Ong K.L. , Tam S. , Wong K.S. , Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese. , Eur J Hum Genet. . 2010, 1-6.

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S., Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensitivity in obstructive sleep apnea, Eur Respir J. . 2009.

Lam C.M. , Lam B. , Yao T.J. , Lai A.Y.K. , Ooi C.G.C. , Tam S. , Lam K.S.L. and Ip M.S.M. , A randomized controlled trial of nCPAP on insulin sensitiv ity in obstructive sleep apnea, European Respiratory Journal . 2010, 35(1): 138-145.

Lam J.T.C., Lam K.S.L. , Tan K.C.B. , Chow W.S. , Tso A.W.K. and Kung A.W.C. , A woman with hypophosphataemia and raised alkaline phosphatase, British Medical Journal . 2010, 340: b-5564-.

Lam K.S.L. , Associate Editor, Journal of Diabetes Investigation . 2009.

Lam K.S.L. , Associate Editor, Obesity Research & Clinical Practice . 2009.

Lam K.S.L. , Fighting the obesity epidemic - What’s on the horizon? , The 1st Richard Yu Lecture in Medicine, Medical Forum, University of Hong Kong . 2010.

Lam K.S.L. , Member, Advisory Panel on International Outreach, The Endocrine Society . 2009.

Lam K.S.L. , Zhang X. and Xu A. , Selective Inactivation Of C-jun Nh2 Terminal Kinase (jnk) In Adipose Tissue Is Sufficient To Alleviate Metabolic Disorders Associated With Dietary Obesity In Mice , The 5th Scientific Meeting of the Asia-Pacific Diabetes and Obesity Study Group, Japan . 2009.

Lam K.S.L. , Zhang X. , Wong L.C. and Xu A. , Selective Inactivation of c-Jun NH2 Terminal Kinase (JNK) in the Adipose Tissue Is Sufficient To Protect Against Diet-Induced-Obesity and Its Associated Metabolic Disorders in Mice, Endocrine Society Annual Meeting, 19-22 June, San Diego, USA . 2010.

Lam K.Y. , Ong K.L. , Lam K.S.L. , Tso A.W.K. and Cheung R.T.F. , Association of two adiponectin gene variants with ischemic stroke in a Chinese cohort, The 32nd Annual Meeting of the Japan Neuroscience Society, 16-18 September 2009, Nagoya, Japan. Neuroscience Research . 2009, 65: S122.

Lau G.S.K., Lang B.H.H. , Lo C.Y. , Tso A., Garcia-Barcelo M.M. , Tam P.K.H. and Lam K.S.L. , Prohylactic thyroidectomy in ethnic Chinese patients with multiple endocrine neoplasia type 2A syndrome after the introduction of genetic testing, Hong Kong Medical Journal . 2009, 15(5): 326-331.

Law K.M. , Xu A. , Lam K.S.L. , Berger T., Mak T., Vanhoutte P.M.G.R. , Liu T.C. , Sweeney G. and Wang Y. , Lipocalin-2 deficiency attenuates insulin resistance associated with ageing and obesity., Diabetes . 2010, 59: 872-82.

Law K.M. , Xu A. , Lam K.S.L. , Berger T., Mak T.W., Liu T.C. , Sweeney G., Zhou M. and Wang Y. , Mice Lacking Lipocalin-2 are Protected from Developing Insulin Resistance Associated with Aging and Obesity, 45th Annual Meeting of The European Association for the Study of Diabetes, September 29-October 2, 2009. Vienna - Austria. Diabetologia 2009 . 52 supp:1: S20.

Law S.C. , Tso A.W.K. , Tam S.C.F., Wat N.M.S. , Cheung B.M.Y. and Lam K.S.L. , Predictive value of hemoglobin A1c on diabetes incidence over 8 years., 5th International Symposium on Healthy Aging . 2010.

Lee A.M. , Chu L.W. , Chong C.S.Y., Chan S.Y. , Lam K.S.L. and Lam T.P. , Relationship Between Symptoms of Androgen Deficiency and Psychological Factors and Quality of Life among Chinese Men., International Journal of Andrology. . 2009.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Inactivation Of Toll-like Receptor 4 Improves Reendot helialisation In Apoe-deficient Mice – Impact Of Oxidative Stress On Endothelial Progenitor Cells, 15th Medical Research Conference, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Outstanding Abstract Prize, Fifth International Symposium On Healthy Aging: Is Aging A Disease?, Research Centre Of Heart, Brain, Hormone & Healthy Aging, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Toll-like Receptor 4 Inactivation Ameliorates Impaired Reendothelialisation Through The Improvement In Endotheli al Progenitor Cell Adhesion, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” . 2010.

Li H. , Lam A.K.Y. , Xu A. , Lam K.S.L. and Chung S.K. , High dosage of Exendin-4 increased early insulin secretion in differentiated beta cells from mouse embryonic stem cells, Acta Pharmacol Sin . 2010, 31(5): 570-7.

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endothelial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Melmed S., Cook D., Schopohl J., Goth M.I., Lam K.S.L. and Marek J., Rapid and sustained reduction of serum growth hormone and insulin-like growth factor-1 in patients with acromegaly receiving lanreotide Autogel® therapy: a randomized, placebo-controlled, multicenter study with a 52 week open extension, Pituitary . 2009, E28: E28-52030-717 (Epub).

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted development of hypertension in Chinese men, Thrombosis and Haemostasis . 2010, 103 (4): 728-735.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen be ta chain predicted incident hypertension in Chinese men, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Adiponectin gene polymorphisms, plasma adiponectin level and persistent hypertension in Hong Kong Chinese, British Pharmacological Society Winter Meeting, Dec 2009, London, UK . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene en coding fibrinogen beta chain with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 51.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen β chain with hypertension in Hong Kong Chines e, 14th Research Postgraduate Symposium, Faculty of Medicine, HKU, Dec 2009, Hong Kong . 2009.

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Xu A. , Cherny S.S., Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive Protein As A Predictor Of Hypertension In The Hong Kong Cardiovascular Risk Prevalence Study (crisps) Cohort, International Congress of Cardiology (ICC), Feb 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Xu A. , Cherny S.S. , Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive protein as a predictor of hypertension in the Hong Kong cardiovascular risk prevalence study (CRISPS) cohort, Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants gene encoding adrenome dullin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting of Hong Kong Society of Endocrinology . 2009.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenome dullin with hypertension and dysglycaemia in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Leung Y.K. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chine se, 13th Annual Scientific Meeting of the Institute of Cardiovascular Science and Medicine, Co-morbidity Hypertension / Diabetes: which one do we treat, Dec 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. , Lam K.S.L. and Cheung B.M.Y. , Relationship of liver enzymes with hypertension in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated haemoglobin to define the metabolic syndrome in United States adults, Diabetes Care . 2010.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated hemoglobin to define the metabolic syndrome in United States adults., 5th International Symposium on Healthy Aging . 2010.

Wang J.K., Ho J.C.M. , Mok T.Y., Chan J.W., Yee W.K., Chan M.M.W. , Cheung B.M.Y. , Lam K.S.L. , Lam W.K. and Ip M.S.M. , The relationship of asthma and the pattern of adiposity in adult Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 56.

Wang Y. , Huang Y., Lam K.S.L. , Li Y., Wong W.T., Ye H., Lau C.W., Vanhoutte P.M.G.R. and Xu A. , Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosph ate-activated protein kinase and endothelial nitric oxide synthase, Cardiovascular Research . 2009, 82: 484-492.

Xia F. , Lam K.S.L. , Zhang J. , Zhou P. and Xu A. , Serum Levels Of Fibroblast Growth Factor 21 Are Elevated In Both Rodents And Humans In Response To Acute Fasting, Diabetes . 2010, 59 supplement: 1661-P.

Zhang X. , Lam K.S.L. , Chung S.K. and Xu A. , Hypoxia Inducible Factor 1α Plays An Indispensible Role In Maintaining The Thermogenic Functions Of Bro wn Adipose Tissue In Mice, Endocrine Society Annual Meeting, 19-22 June, San Diego, USA . 2010.

Zhang X. , Lam K.S.L. , Chung S.K. and Xu A. , Hypoxia Inducible Factor 1 Plays an Indispensible Role in the Thermogenic Functions of Brown Adipose Tissue in Mice, Diabetes . 2010, 59 supplement 1: A47.

Zhou M. , Xu A. , Tam P.K.H. , Lam K.S.L. and Wang Y. , Adiponectin deficiency diminishes the anti-inflammatory activities of rosiglitazone in liver , The American Association for the Study of Liver Diseases . 2009.

Zu Y. , Liu L. , Xu A. , Lam K.S.L. , Lee M.Y.K. , Vanhoutte P.M.G.R. and Wang Y. , SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells, 34th FEBS Congress, Czech Republic, July 2009 . 2009.

Researcher : Lam KY

List of Research Outputs

Lam K.Y. , Ong K.L. , Lam K.S.L. , Tso A.W.K. and Cheung R.T.F. , Association of two adiponectin gene variants with ischemic stroke in a Chinese cohort, The 32nd Annual Meeting of the Japan Neuroscience Society, 16-18 September 2009, Nagoya, Japan. Neuroscience Research . 2009, 65: S122.

Researcher : Lam MF

List of Research Outputs

Hsu S.I., Niu Y., Davila S., Leung J.C.K. , Lam M.F. , Tang S.C.W. and Lai K.N. , Genome-wide linkage scan for familial IgA nephropathy among southeast Asian Chinese: evidence for a suggestive novel susceptibility locus on chromosome 8p23, Journal of American Society Nephrology . 2009, 20: 434A.

Kwok J.S.Y. , Chan G.S.W. , Lam M.F. , Yan T., Tang L., Kwong K.M., Chan K.W. and Chan D.T.M. , Determination of mismatched donor HLA in kidney transplant recipients with unknown donor HLA phenotypes, Clinical transplantation . 2010, [Epub ahead of print 2010 Apr 9].

Lam M.F. , Lo W.K. , Tse K.C., Yip T.P.S., Lui S.L. , Chan D.T.M. and Lai K.N. , Retroperitoneal leakage as a cause of acute ultrafiltration failure: its associated risk factors in peritoneal dialysis , Peritoneal Dialysis International . 2009, 29(5): 542-547.

Lou T., Zhang J., Gale D.P., Rees A.J., Rhodes B., Feehally J., Li C., Li Y., Li R., Huang W., Hu B., Leung J.C.K. , Lam M.F. , Lai K.N. , Wang Y. and Maxwell P.H., Variation in IGHMBP2 is not associated with IgA nephropathy in independent studies of UK Caucasian and Chinese Han patients, Nephrology Dialysis Transplantation . 2009, 25(5): 1547-54.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , In vitro enhanced chemotaxis of CD25+ mononuclear cells in patients with familial IgAN through glomerulotubular interaction, American Journal of Physiology-Renal Physiology . 2010.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , Increased chemotaxis of CD25+ PBMC to tubular epithelial cells through glomerulotubular interaction in patients with familial IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 307A.

Yip T., Tse K.C., Lam M.F. , Cheng S.W., Lui S.L. , Tang S.C.W. , Mg M., Chan D.T.M. , Lai K.N. and Lo W.K. , Colonic diverticulosis as a risk factor for peritonit is in Chinese peritoneal dialysis patients, Peritoneal Dialysis International . 2010, 30: 187-191.

Yip T.P., Tse K., Ng F., Lam M.F. , Tang S.C.W. , Lui S.L. , Lai K.N. , Chan D.T.M. and Lo W.K. , Clinical course and outcomes of enterococcus peritoniti s in peritoneal dialsyisi patients, Nephrology . 2010, 15 (S3): 47.

Researcher : Lam SC

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Yee Y.K., Gu Q., Hung I.F.N. , Tan V.P.Y. , Chan P., Hsu A., Pang R.W.C. , Lam S.C. and Wong B.C.Y. , Trend of colorectal cancer in Hong Kong:1983-2006. , J Gastroenterol Hepatol . 2010, 25: 923-7.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presentation), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Lam SC

List of Research Outputs

Researcher : Lam SK

Project Title:	Biotech Company in the Faculty of Medicine, The University of Hong Kong
Investigator(s):	Lam SK
Department:	Medicine
Source(s) of Funding:	The University of Hong Kong Foundation Seed Grant
Start Date:	07/2003

Abstract:

To enable the Faculty of Medicine of The University of Hong Kong to establish itself as the regional centre of excellence in the provision of complete solutions to industry from laboratory research services to clinical trials, setting standards and quality benchmarks comparable to the best international practices for other similar centres in the region to follow.

Project Title:	Treatment of gastrointestinal cancer by targeting survivin using adeno-associated virus gene delivery system
Investigator(s):	Lam SK, Wong BCY, Lin MC
Department:	Medical Faculty
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2004

Abstract:

To elucidate the molecular mechanisms of survivin in tumor angiogenesis, to will investigater the effect of overexpression of survivin on the migration and capillary tuber-like networks of endothelial cells, expression of angiogenic factors in gastrointestinal cancer cells and angiogenesis in Chorioallantoic membrane angiogenesis (CAM) model and nude mice xenograft; to establish a novel gene therapy for gastrointestinal cancer by targeting survivin gene with adeno-associated virus vector. We will further study the therapeutic effect of rAAV-mediated survivin mutant on gastrointestin al cancer in vivo and evaluate long-term effect and safety of the rAAV virus.

Researcher : Lam TP

List of Research Outputs

Lam C.L.K. , Wong K.H. , Lam T.P. and Lo Y.Y.C. , Population norm of Chinese (HK) SF-12 Health Survey_version 2 of Chinese adults in Hong Kong. , HK Practitioner . 2010, 32: 77-86.

Lam T.P. , Lam C.L.K. , Lai C.L. , Yuen R.M.F. and Fong D.Y.T. , Psychometrics of the chronic liver disease questionnaire for Southern Chinese patients with chronic hepatitis B virus infection, World Journal of Gastroenterology . 2009, 15: 3288-97.

Researcher : Lam TP

List of Research Outputs

Lam C.L.K. , Wong K.H. , Lam T.P. and Lo Y.Y.C. , Population norm of Chinese (HK) SF-12 Health Survey_ver sion 2 of Chinese adults in Hong Kong. , HK Practitioner . 2010, 32: 77-86.

Researcher : Lam WK

List of Research Outputs

Chan K.H. , Ho S.P., Yeung S.C. , So H.L. , Cho C.H., Koo M.W.L. , Lam W.K. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine . 2009, 103: 1746-1754.

Ho J.C.M. , Ho S.P. , Mak J.C.W. , Wong M.K.Y. , Ip M.S.M. and Lam W.K. , Alterations of systemic antioxidants and 8-isoprostane during chemotherapy for lung cancer. , 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S909.

Ho J.C.M. , Lam C.L. , Wong M.K.Y. , Lam B. , Ip M.S.M. and Lam W.K. , Capecitabine as salvage treatment for lymphoepithelioma-l ike carcinoma of lung, Journal of Thoracic Oncology . 2009, 4(9): 1174-1177.

Lam C.L.D. , Girard L., Sihoe A., Cheng L.C., Lui M.M.S., Wong M.P. , Chung L.P. , Ip M.S.M. , Lam W.K. and Minna J.D., Gene expression profiling in lung adenocarcinomas reflects possible different molecular pathogenesis with respect to gender and smoking status, 14th Congress of the Asian Pacific Society of Respir ology & 3rd Joint Congress of the Asian Pacific Society of Respirology/American College of Chest Physicians, Seoul, Korea, Nov 2009, Respirology . 2009, 14(Suppl 3): A128 (OS 03-05).

Lam C.L.D. , Girard L., Sihoe A.D.L. , Cheng L.C. , Lui M.A.C.Y., Wong M.P. , Chung L.P. , Ip M.S.M. , Lam W.K. and Minna J.D., Gene expression signatures associated with combination of female non-smokers in lung adenocarcinomas bearing activating epidermal growth factor receptor (EGFR) gene mutations in Chinese, The American Thoracic Society Annual Meeting 2010 .

Wang J.K., Ho J.C.M. , Mok T.Y., Chan J.W., Yee W.K., Chan M.M.W. , Cheung B.M.Y. , Lam K.S.L. , Lam W.K. and Ip M.S.M. , The relationship of asthma and the pattern of adiposity in adult Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 56.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to first-line gefitinib in non-small cell lung cancer. , Cancer Chemotherapy and Pharmacology . 2010, 65: 1023-1028.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to gefitinib in non-small cell lung cancer, 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S719.

Researcher : Lam YM

List of Research Outputs

Ho H.H., Cheung C.W., Jim M.H., Miu R., Lam Y.M. , Chan R.H.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Type A aortic intramural hematoma: clinical features and outcomes in Chinese patients, Clinical Cardiology . 2010, (in press).

Researcher : Lan HY

Project Title:	Essential role of SMAD3 in cardiac repair and fibrosis
Investigator(s):	Lan HY
Department:	Medicine
Source(s) of Funding:	Sun Chieh Yeh Heart Foundation - General Award
Start Date:	08/2006

Abstract:

To investigate the signaling mechansims of TGF-beta/Smad3 in cardiac fibrosis induced in Smad3 knockout mice by angiotensin II infusion or by cardiac ischemic injury.

Project Title:	Role of Smad signalling in the pathogenesis of hypertensive nephropathy and a novel therapeutic potential using ultrasound-microbubble-mediated transfer of inducible Smad7
Investigator(s):	Lan HY
Department:	Medicine
Source(s) of Funding:	Baxter Health Care Ltd. - General Award
Start Date:	05/2008

Abstract:

To explore the role of TGF-beta/Smad signaling mechanisms in hypertensive nephropathy and develop a novel gene therapy for the hypertensive nephropathy using ultrsound-microbubble-mediated inducible Smad7 strategy.

Project Title:	Gene therapy for diabetic nephropathy using ultrasound-microbubble-mediated transfer of inducible smad7
Investigator(s):	Lan HY
Department:	Medicine
Source(s) of Funding:	Pharmaceutical Industry - General Award
Start Date:	05/2008

Abstract:

To explore the therapeutic potential to retard the progression of established diabetic nephropathy by inducing overexpression of Smad7.

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Tang S.C.W. , Chan Y.Y. , Leung J.C.K. , Cheng A.S. , Chan K.W. , Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote renal tubular infl ammation, Nephrol Dial Transplant . 2010, 25(3): 698-710.

Zhang R. , Zhang S.Y. , Lan X.R. , Wu Y. , Szalai ..J..., Wong B.C.Y. , Lau C.P. , Wu E.X. and Lan H.Y. , C-reactive Protein Promotes Cardiac Inflammation and Fibrosis in Angiotensin II-Induced Hypertensive Cardiovas cular Diseases, In: American Heart Association, Basic Cardiovascular Science Conference, July 20-23 , 2009, Las Vegas, USA; Circulation Research . 2009.

Zhou L. , Fu P., Huang X.R., Liu F. , Lai K.N. and Lan H.Y. , Activation of p53 promotes renal injury in acute aristolochic acid nephropathy, Journal of American Society of Nephrology . 2010, 21(1): 31-41.

Zhou L. , Fu P., Huang X.R., Liu F. , Chung A.C.K. , Lai K.N. and Lan H.Y. , Mechanism of chronic aristolochic acid nephropathy: role of Smad3, Am J Physiol Renal Physiol . 2010, 298(4): F1006-17.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presentation), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Lan XR

Project Title:	Mechanisms of Peritoneal Fibrosis: Role of TGF-beta Signaling
Investigator(s):	Lan XR, Lan HY, Leung JCK
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2008

Abstract:

(1) To determine the specific role of Smad3 in PD-associated peritoneal fibrosis in vitro in Smad 3 KO MSC and in vivo in Smad3 KO mice; (2) To examine the specific role of Smad2 in PD-associated peritoneal fibrosis in vitro in conditional Smad2 KO or double Smad2 and Smad3 KO MSC and in vivo in mice that have conditional KO for Smad2 or double KO for Smad2 and Smad3; (3) To develop an effective and specific therapeut ic strategy for PD-related peritoneal fibrosis by blocking Smad3 using an ultrasound-microbubble-mediated Smad3 siRNA technique.

List of Research Outputs

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastati c Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Zhang R. , Zhang S.Y. , Lan X.R. , Wu Y. , Szalai ..J..., Wong B.C.Y. , Lau C.P. , Wu E.X. and Lan H.Y. , C-reactive Protein Promotes Cardiac Inflammation and Fibrosis in Angiotensin II-Induced Hypertensive Cardiovascular Diseases, In: American Heart Association, Basic Cardiovascular Science Conference, July 20-23, 2009, Las Vegas, USA; Circulation Research . 2009.

Researcher : Lau CP

Project Title:	Evaluation of the antianginal efficacy and safety of oral chronic administration of ivabradine (5mg b.i.d. then 7.5mg b.i.d or 10mg b.i.d) compared to atenolol (50mg o.d then 100mg o.d), in patients with stable effort angina pectorals
Investigator(s):	Lau CP, Lee KLF
Department:	Medicine
Source(s) of Funding:	Other Funding Scheme
Start Date:	05/2000

Abstract:

To demonstrate the non-inferiority of invabradine 7.5mg b.i.d then 10mg b.i.d in improving exercise capacity in comparison to atenolol given by oral route for 4 and a half months to out-patients with chronic stable angina; to determine pharmacokinetic parameters.

Project Title:	Roles of macrophage migration inhibitory factor (MIF) in acute myocardial infarction
Investigator(s):	Lau CP, Yu CM, Lan HY
Department:	Medicine
Source(s) of Funding:	Low Budget High Impact Programme
Start Date:	11/2000

Abstract:

To investigate the pathogenic role and mechanism of macrophage migration inhibitory factor (MIF) after myocardial infarction (AMI).

List of Research Outputs

Chan S.S.C. , Leung Y.P. , Lau C.P. , Wong V. and Lam T.H. , A stage-matched smoking cessation intervention for cardiac outpatients: A randomized controlled trial, Book of Abstract. The Hong Kong Public Health Forum 2009, The University of Hong Kong, 20 September . Hong Kong, 2009, 46.

Chan S.S.C. , Leung Y.P. , Lau C.P. , Wong V. and Lam T.H. , Cost-effectiveness analysis of a low intensity nurse-l ed stage-matched smoking cessation intervention to cardiac patients in Hong Kong, Circulation . , American Heart Association, 2010, 122(2): e87.

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Improvement of myocardial perfusion reserve detected by cardiovascular magnetic resonance after direct endomyocardia l implantation of autologous bone marrow cells in patients with severe coronary artery disease, Journal of cardiovascular magnetic resonance . 2010, 12(1): 6..

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Therapeutic angiogenesis with direct endomyocardial implantation of autologous bone marrow cells in patients with severe coronary artery diseases: Insight from cardiac magnetic resonance imaging., J Cardiovasc Magn Reson. . 2010, 12: 6.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. , Lau C.P. and Tse H.F. , Characterizing the basis of automaticity of neonatal rat ventricular myocytes: Implications for cardiac excitability manipulations., Europace . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W. , Tam S. , Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke (abstract and poster presentation), EuroPRevent 2010, Prague, 5-7 May 2010 . Prague, European Society of Cardiology.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W., Tam S., Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke, EuroPrevent 2010. European Journal of Cardiovascular Prevention and Rehabilitation 2010 Jun P480 . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W. , Lau C.P. , Lam T.H. and Tse H.F. , Selenium deficiency is associated with adverse vascular function in patients with high risk for vascular even ts (abstract and poster presentation), EuroPRevent 2010, 5-7 May 2010, Prague . Prague, European Society of Cardiology, 2010.

Chen J. , Tao R. , Sun H. , Tse H.F. , Lau C.P. and Li G.R. , Multiple Ca(2+) signaling pathways regulate intracellular Ca(2+) activity in human cardiac fibroblasts., J Cell Physiol . 2010, 223(1): 68-75.

Dai Y.L., Luk T.H., Siu D.C.W. , Yiu K.H., Chan K.H.T. , Lee S.W.L. , Li S.W., Fong B., Wong W.K., Tam S. , Lau C.P. and Tse H.F. , Mitochondrial dysfunction induced by statin contributes to endothelial dysfunction in patients with coronary artery disease., Cardiovascular Toxicology . 2010, 10: 130-8.

Dong M. , Sun H. , Tang Q. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of human cardiac KCNQ1/KCNE1 channel by epidermal growth factor receptor kinase., Biochim Biophys Acta . 2010, 1798(5): 995-1001.

He M. , Lau C.P. , Tse H.F. and Li G.R. , Regulation of cell proliferation by large-conductance calcium-activated potassium and volume-sensitive chloride channels in human cardiac fibroblasts, 15th Medical Research Conference . 2010, 16(1): 23.

Ho H.H., Cheung C.W., Jim M.H., Miu R., Lam Y.M. , Chan R.H.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Type A aortic intramural hematoma: clinical features and outcomes in Chinese patients, Clinical Cardiology . 2010, (in press).

Ho L.Y., Siu D.C.W. , Lau C.P. , Lip G.Y. and Tse H.F. , Safety and efficacy of oral anticoagulation therapy in chinese patients with concomitant atrial fibrillation and hypertension. , J Hum Hypertens. 2010 . 2010.

Hu R. , He M. , Hu H. , Yuan B.X., Zang W.J., Lau C.P. , Tse H.F. and Li G.R. , Characterization of calcium signaling pathways in human preadipocytes, J Cell Physiol . 2009, 220(3): 765-770.

Jim M.H., Chan A.O., Tse H.F. , Barold S.S. and Lau C.P. , Clinical and Angiographic findings of complete atrioventricular block in acute inferior myocardial infarction. , Ann Acad Med Singap. . 2010, 39: 185-9.

Jim M.H., Ho H.H., Ko R.L., Siu D.C.W. , Yiu K.H., Lau C.P. and Chow W.H., Paclitaxel-eluting stents for chronically occluded saphenous vein grafts (EOS) study, Journal of Interventional Cardiology . 2010, 23(1): 40-45.

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lau C.P. , Tse H.F. , Kumana C.R. and Cheung B.M.Y. , Angiotensin receptor blockers for heart disease: are they the same?, J HK Coll Cardiol 2009 . 2009, 17: 1-3.

Lau C.P. and Siu D.C.W. , Pacing technology and its indications: Advances in threshold management, automatic mode switching, and sensors, In: Saksena S, Camm AJ, Boyden PA, Dorian P, Goldschla ger N, Electrophysiological Disorders of the Heart . Elsevier Churchill Livingstone, 2010.

Lau C.P. , Siu D.C.W. and Tse H.F. , Sensor Driven Pacing, In: Ellenbogen KA, Natale A, Al-Ahmad Amin, Wang PJ , Pacemakers and Implantable Cardioverter Defibrillators: An Expert’s Manual . 2010.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Li G.R. , Sun H. , Chen J. , Zhou Y. , Tse H.F. and Lau C.P. , Characterization of Multiple Ion Channels in Cultured Human Cardiac Fibroblasts. , PLoS One . 2009, 4(10): e7307.

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with passive epicardial patch in porcine model of chronic myocardial infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H., Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patients with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Siu D.C.W. , Pong V., Ho H.H., Liu S., Lam B. , Lau C.P. , Li S.W. and Tse H.F. , Does MADIT II criteria for implantable cardioverter defibrillator implantation applicable to Chinese patients? , J Cardiovasc Electrophysiol. . 2010, 21: 231-5.

Siu D.C.W. , Pong V., Ho H.H., Liu S., Lau C.P. and Tse H.F. , Are MADIT II criteria for implantable cardioverter defibrillator in Chinese. , Journal of Cardiovascular Electrophysiology . 2009, 21: 231-5.

Siu D.C.W. , Pong V., Jim M.H., Yue W. , Ho H.H., Li L.S.W. , Lau C.P. and Tse H.F. , Beta-blocker in post-myocardial infarct survivors with preserved left ventricular systolic function, Pacing and Clinical Electrophysiology . 2010, 33(6): 675-80.

Siu D.C.W. and Lau C.P. , Cardiac Pacemaker, In: Lip GY, Tse HF, Coats , Oxford Desk Reference. . Oxford University Press, 2010.

Siu D.C.W. , Lau C.P. , Lee S.W.L. , Lam K.F. and Tse H.F. , Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation, Critical Care Medicine . MD Consult, LLC, 2009, 37(7): 2174-2179.

Siu D.C.W. , Waston T., Lai K.W.H. , Lee Y.K. , Chan Y.H. , Ng K.M. , Lau C.P. , Lip G.Y. and Tse H.F. , Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm., Europace . 2009, 12(4): 460-1.

Tse H.F. , Saha S., Garg A., Bohn D., Lee Y.L. and Lau C.P. , Muscle noise effects on atrial evoked response sensi ng: implications on atrial auto-threshold and auto-capture determination. , Pacing Clin Electrophysiol. . 2010.

Tse H.F. , Siu D.C.W. and Lau C.P. , Impact of Right Ventricular Pacing Sites on Exercise Capacity during Ventricular Rate Regularization in Patients with Permanent Atrial Fibrillation., Pacing and Clinical Electrophysiology . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical Function only in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation Existing Atrial Dyssynchrony , European Society of Cardiology Congress, Spain. August 29 –September 2, . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchrony and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Submitted) . 2010.

Wang S. , Yiu K.H., Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Mak H.K.F. , Lau C.P. , Lam K.F. , Lau W.C.S. and Tse H.F. , Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis, Journal of Internal Medicine . 2009, 266: 445-452.

Wu W. , Lau C.P. , Tse H.F. and Li G.R. , Beta 1 subunit-dependent modulation of BK channel by membrane cholesterol, In: 15th Medical Research Conference, Department of Medicine, HKU, 15th Medical Research Conference . 2010, 16(1): 58.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Elevated Pulmonary Artery Systolic Pressure in Patients with Coronary Artery Disease and Left Ventricular Dyssynchrony , European Journal of Heart Failure . 2010, (in press).

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Relation of T-wave Alternans to Left Ventricular Dyssynchr ony in Patients with Coronary Heart Disease, ESC Congress, 2010 .

Yiu K.H., Wang S. , Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Lau C.P. , Lai W.W. , Wong L.Y. , Lam K.F. , Lau W.C.S. and Tse H.F. , Role of circulating endothelial progenitor cells in patients with rheumatoid arthritis with coronary calcification, Journal of Rheumatology . 2010, 37: 529-535.

Zhang R. , Zhang S.Y. , Lan X.R. , Wu Y. , Szalai ..J..., Wong B.C.Y. , Lau C.P. , Wu E.X. and Lan H.Y. , C-reactive Protein Promotes Cardiac Inflammation and Fibrosis in Angiotensin II-Induced Hypertensive Cardiovascular Diseases, In: American Heart Association, Basic Cardiovascular Science Conference, July 20-23, 2009, Las Vegas, USA; Circulation Research . 2009.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , large-conductance Ca-activated Potassium and Ether-a-go-go Potassium Channels Regulate Proliferation of Human Mesenchymal Stem Cells, J HK Coll Cardiol . 2009, 17(2): 59.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Human cardiac KV4.3 channels are regulated by protei n tyrosine kinases, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 64.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Protein Tyrosine Kinases Regulate Human Cardiac KV4.3 Channel, J HK Coll Cardiol . 2009, 17(2): 58.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of cell proliferation by ion channels in human mesenchymal stem cells, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 65.

Researcher : Lau G

Project Title:	Prevalence and Natural History of Non-Alcoholic Fatty Liver Diseases in Hong Kong Chinese
Investigator(s):	Lau G
Department:	Medicine
Source(s) of Funding:	Hong Kong Liver Foundation - General Award
Start Date:	02/2005

Abstract:

To define teh prevalence of non-alcoholic fatty liver diseases (NAFLD) in Hong Kong Chinese; to charaterize the natural history of NAFLD in patients with and without chronic HBV infection.

Project Title:	Basic science study on the disease mechanism, clinical surveillance and outcomes of seve re hepatitis B infection
Investigator(s):	Lau G
Department:	Medicine
Source(s) of Funding:	Matching Fund for National Key Basic Research Developm ent Scheme (973 Projects)
Start Date:	12/2007

Abstract:

Refer to hard copy

List of Research Outputs

Cheung K.F. , Ye D. , Yang Z. , Lu L. , Liu C.H., Wang X.L., Poon R.T.P. , Tong Y. , Liu P., Chen Y. and Lau G. , Therapeutic efficacy of Traditional Chinese Medicine 319 recipe on hepatic fibrosis induced by carbon tetrachlo ride in rats, Journal of Ethnopharmacology . 2009, 124(1): 142-150.

Researcher : Lau GKK

Project Title:	Prevalence and Natural History of Non-Alcoholic Fatty Liver Diseases in Hong Kong Chinese
Investigator(s):	Lau G
Department:	Medicine
Source(s) of Funding:	Hong Kong Liver Foundation - General Award
Start Date:	02/2005

Abstract:

To define teh prevalence of non-alcoholic fatty liver diseases (NAFLD) in Hong Kong Chinese; to charaterize the natural history of NAFLD in patients with and witho ut chronic HBV infection.

Project Title:	Basic science study on the disease mechanism, clinical surveillance and outcomes of severe hepatitis B infection
Investigator(s):	Lau G
Department:	Medicine
Source(s) of Funding:	Matching Fund for National Key Basic Research Development Scheme (973 Projects)
Start Date:	12/2007

Abstract:

Refer to hard copy

List of Research Outputs

Researcher : Lau K

List of Research Outputs

Kung A.W.C. , Xiao S. , Cherny S.S. , Li H.Y. , Gao Y. , Tso G., Lau K. , Luk K.D.K. , Liu J.M., Cui B., Zhang M.J., Zhang Z.L., He J.W., Yue H., Xia W.B., Luo L.M., He S.L., Kiel D.P., Karasik D., Hsu Y.H., Cupples L.A., Demissie S., Styrkarsdottir U., Halldorsson B.V., Sigurdsson G., Thorsteinsdottir U., Stefansson K., Richards B., Zhai G., Soranzo N., Valdes A., Spector T.D. and Sham P.C. , Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies, American Journal of Human Genetics . 2010, 86 (2): 229-239.

Researcher : Lau KS

List of Research Outputs

Bow C.H.Y. , Cheung C.L. , Gao Y. , Lau K.S. , Soong S.S. , Yeung S.C. and Kung A.W.C. , Bone Mineral Density and Serum Osteoprotegerin Levels in Pre- and Postmenopausal Women, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Researcher : Lau KW

List of Research Outputs

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Blockage of serotonin receptor 2 attenuates cigarette-induced IL-8 release in human bronchial epithelial cells, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A1399.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Involvement of serotoninergic system in cigarette-induced inflammatory responses in human bronchial epithelial cells, HKU 14th Research Postgraduate Symposium, Hong Kong (December 2-3, 2009) . 2010.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Ketanserin Attenuates Cigarette-mediated Oxidative Stress In Human Bronchial Epithelial Cells, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 34.

Researcher : Lau KW

List of Research Outputs

Researcher : Lau WCS

Project Title:	Prospective study of the clinical pattern of systemic lupus erythematosus in Hong Kong
Investigator(s):	Lau WCS
Department:	Medicine
Source(s) of Funding:	Other Funding Scheme
Start Date:	01/1993

Abstract:

To study the clinical pattern of systemic lupus erythematosus in Hong Kong.

Project Title:	Effects of sex hormones on lymph ocyte function in systemic lupus erythematosus
Investigator(s):	Lau WCS, Mok TMY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2002

Abstract:

To examine the effects of estrogen, testrogen, testosterone and prolactin on SLE peripheral T- and B-lymphocyte apoptosis and function. Menstruating and postmenopausal female patients and male patients will be studied.

Project Title:	A study to evaluate the immunopathology of Severe Acute Respiratory Syndrome
Investigator(s):	Lau WCS, Chan EYT, Cheung BMY
Department:	Medicine
Source(s) of Funding:	VCO SARS Research Fund
Start Date:	07/2003

Abstract:

To investigate the time course of changes in cyto kines in patients with SARS; to investigate the relationship between clinical deterioration and changes in the serum/plasma levels of cytokines; to evaluate the cytokine expressio n in post-mortem lung tissues of patients with SARS will be studied.

Project Title:	Evaluation of the effects of sex hormones on neutrophils and macrophage apoptosis and macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus
Investigator(s):	Lau WCS
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2003

Abstract:

To study the effects of oestrogen and progesterone on the rate of apoptosis and secondary necrosis of PMN and M[phi] in SLE patients and controls; to study the effects of oestrogen and progesterone on the abilit y of phagocytic M[phi] to clear apoptotic bodies in patients with SLE and controls.

Project Title:	Dendritic cell function and their effects on B cell activation in systemic lupus erythematosus
Investigator(s):	Lau WCS
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	12/2005

Abstract:

Disturbances in the process of apoptosis and the clearance of apoptotic cells, a major source of auto-antigens, have been suggested as the fundamental pathoaetiological mechanism of systemic lupus erythematosus (SLE) which is characterised by T and B cell activation. Excess apoptotic cells may be captured by dendritic cells (DCs) which may then undergo functional changes and influence the activity of other immune cells, particularly T cells. Previous studies on DCs in SLE have yielded conflicting results with some demonstrating a deficiency in DC function, particularly CD11c+ cells, while others showing SLE serum was capable of inducing DC differen tiation and presentation of dying cells to CD4+ T cells. These discrepancies are probably related to the fact that (1) peripheral blood DCs exist in different subtypes with different roles in immune regulation; and (2) previous studies have generally generated DCs from peripheral blood mononuclear cells (PBMCs) cultured with granulocyte-macrophage colony-stimulating factor and interleukin-4, and stimulation with lipopolysaccharid e. DCs generated and isolated by this method are not representative of circulating DCs. We now know that there are two main subtypes of peripheral blood DCs - plasmacytoid DCs (pDCs) and myeloid DCs (mDCs). pDCs are characterised by cell surface expression of CD4+, Lin-, CD11C-, CD123bright, CD45RA+, CD2- and BDCA-2+1, while mDCs have cell surface expression of CD4+, CD11cbright, CD123dim, CD45RO+ and CD2+. It is now possible to isolate pDCs and mDCs by positive selection. In one of our recent studies, we showed that mDCs were responsible for the maintenance of immune homoestasis by inducing Th-1 cytokine response, and pDCs in the induction of tolerance in healthy subjects. The number and functional activities of these 2 types of DCs appeared to be altered in SLE. SLE blood had a lower % of mDCs and higher % of pDCs of PBMCs, and SLE mDCs had lower surface CD83 expression when compared with controls. Unlike in healthy subjects, mDCs from SLE patients were less able to present non-self antigens to autologous T cells. On the other hand, SLE pDCs were capable of stimulating T cells in SLE. These results suggest that SLE pDCs have increased activit y and this may contribute to the development of autoimmunity in this condition. Recent investigations have also shown DCs may directly interact with B cells in healthy subjects. However, this has not been studied in SLE. The primary objective of this investigation is to evaluate if DCs are capable of interacting directly with B-cells in the absence of T-cells in patients with SLE.

Project Title:	Evaluation of the effects of micro-RNA146a on the function of bone marrow dendritic cells in system ic lupus erythematosus
Investigator(s):	Lau WCS
Department:	Medicine
Source(s) of Funding:	Travel Grants for NSFC/RGC JRS
Start Date:	12/2009

Abstract:

Travel grants for NSFC/RGC JRS

List of Research Outputs

Jin O. , Sushima K., Mok T.M.Y. and Lau W.C.S. , Abnormalities in circulating plasmacytoid dendritic cells in patients with systemic lupus erythematosus, Arthritis Res Ther . 2010, in press.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Foxp3 mRNA expression on DC subsets in patients of systemic lupus erythematosus. , IJRD . 2010, 13: S557 p55.

Jin O. , Kavikondala S. , Mok T.M.Y. , Sun L.Y., Gu J.R., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Studies on the function of plasmacytoid dendritic cells in healthy and systemic lupus erythematosus., IJRD . 2010, 13: S554p54.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Study on myeloid dendritic cells in systemic lupus erythematosus, IJRD . 2010, 13: S793 p56.

Mok T.M.Y. , Chiu S.S.H. , Lo Y. , Mak H.K.F. , Wong R.W.S. , Khong P.L. and Lau W.C.S. , Coronary atherosclerosis using CT coronary angiogram in patients with systemic sclerosis. Rely letter to Editor., Scand J Rheumatol . 2010, 38(5): 381-385.

Mok T.M.Y. , Yiu K.H., Wong C.Y., Lai W.H., Lo Y. , Wong R.W.S. , Tse H.F. and Lau W.C.S. , Endothelial Dysfunction is Associated with Low Level of Circulating Endothelial Progenitor Cells in Patients with Systemic Sclerosis, Clin Exp Rheumatol . 2010, in press.

Mok T.M.Y. , Tse H.F. , Wong C.Y., Qiuwaxi J. , Lai K.W.H. , Lo Y. , Wong R.W.S. and Lau W.C.S. , Endothelial dysfunction is associated with decreased circulating endothelial progenitor cells in patients with systemic sclerosis, Annals of the Rheumatic Diseases . 2009, S337.

Mok T.M.Y. , Wu H. , Lo Y. and Lau W.C.S. , Serum IL-17 and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus, J Rheumatol . 2010, in press.

Mok T.M.Y. and Lau W.C.S. , The burden and measurement of cardiovascular disease in systemic sclerosis, Nat Rev Rheumatol . 2010, 6:430-4.

Nie Y. , Lau W.C.S. , Lie A.K.W. , Chan G.C.F. and Mok T.M.Y. , Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus, Lupus . 2010, 19: 850-9.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow-derive d dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Wang S. , Yiu K.H., Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Mak H.K.F. , Lau C.P. , Lam K.F. , Lau W.C.S. and Tse H.F. , Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis, Journal of Internal Medicine . 2009, 266: 445-452.

Wu H. , Lau W.C.S. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patient s with systemic lupus erythematosus. , IJRD . 2010, 13: S680 p114.

Yang W. , Shen N., Ye D.Q., Liu Q., Qian X.X., Hirankarn N., Pan H.F., Mok C.C., Chan D.T.M. , Wong R.W.S. , Lee K.W., Wong S.N. , Leung A.M.H., Li X.P., Avihingsanon Y., Wong C.M. , Lee T.L. , Ho M.H.K. , Lee P.P.W. , Chang Y.K., Li P.H., Li R. , Zhang L. , Wong W.H.S. , Ng I.O.L. , Lau W.C.S. , Sham P.C. , Lau Y.L. and Asian Lupus Genetics Consortium A.L.G.C., Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. , PLoS Genetics . 2010, 6: e1000841.

Yiu K.H., Wang S.L., Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Mak H.K.F. , Lam K.F. , Lau W.C.S. and Tse H.F. , Pattern on atherosclerosis for coronary, carotid and aortic arteries calcification in rheumatoid arthritis: a multidetector CT study, Journal of American College of Cardiology . 2009, 53: A432.

Yiu K.H., Wang S. , Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Lau C.P. , Lai W.W. , Wong L.Y. , Lam K.F. , Lau W.C.S. and Tse H.F. , Role of circulating endothelial progenitor cells in patients with rheumatoid arthritis with coronary calcification, Journal of Rheumatology . 2010, 37: 529-535.

Researcher : Lau YK

List of Research Outputs

Ng F.H. , Wong S.Y. , Lam K.F. , Chu W.M., Chan P., Ling Y.H., Kng C.P.L. , Yuen W.C., Lau Y.K. , Kwan A. and Wong B.C.Y. , Famotidine is inferior to Pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions, Gastroenterology . Elsevier, 2010, 138: 82-88.

Researcher : Law SC

List of Research Outputs

Chen C. , Xu A. , Tso A.W.K. , Law S.C. , Cheung B.M.Y. , Janus E.D., Wat N.M.S. and Lam K.S.L. , Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Law S.C. , Sham P.C. and Lam K.S.L. , A genetic variant near the GNPDA2 gene is associated with the metabolic syndrome in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Law S.C. , Tso A.W.K. , Tam S.C.F., Wat N.M.S. , Cheung B.M.Y. and Lam K.S.L. , Predictive value of hemoglobin A1c on diabetes incidence over 8 years., 5th International Symposium on Healthy Aging . 2010.

Researcher : Lee KLF

List of Research Outputs

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical Function only in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation Existing Atrial Dyssynchrony , European Society of Cardiology Congress, Spain. August 29 –September 2, . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchrony and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Submitted) . 2010.

Researcher : Lee SWL

List of Research Outputs

Dai Y.L., Luk T.H., Siu D.C.W. , Yiu K.H., Chan K.H.T. , Lee S.W.L. , Li S.W., Fong B., Wong W.K., Tam S. , Lau C.P. and Tse H.F. , Mitochondrial dysfunction induced by statin contributes to endothelial dysfunction in patients with coronary artery disease., Cardiovascular Toxicology . 2010, 10: 130-8.

Hai J.J., Siu D.C.W. , Ho H.H., Li S.W., Lee S.W.L. and Tse H.F. , Relationship between changes in heart rate recovery after cardiac rehabilitation on cardiovascular mortal ity in patients with myocardial infarction. , Heart Rhythm . 2010, 7: 929-936.

Ho H.H., Cheung C.W., Jim M.H., Miu R., Lam Y.M. , Chan R.H.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Type A aortic intramural hematoma: clinical features and outcomes in Chinese patients, Clinical Cardiology . 2010, (in press).

Lee S.W.L. , Ho H.H., Kong S.L. , Lam Y.M., Siu D.C.W. , Miu K.M., Lam L. and Chan H.W., Long term clinical outcomes after deployment of femoral vascular closure devices in coronary angiography and percutaneous coronary intervention., Catheterization and Cardiovascular Interventions . 2009, 75(3): 345-348.

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H., Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patients with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Siu D.C.W. , Lau C.P. , Lee S.W.L. , Lam K.F. and Tse H.F. , Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation, Critical Care Medicine . MD Consult, LLC, 2009, 37(7): 2174-2179.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Submitted) . 2010.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Elevated Pulmonary Artery Systolic Pressure in Patients with Coronary Artery Disease and Left Ventricular Dyssynchrony , European Journal of Heart Failure . 2010, (in press).

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Relation of T-wave Alternans to Left Ventricular Dyssynchrony in Patients with Coronary Heart Disease, ESC Congress, 2010 .

Researcher : Lee YK

List of Research Outputs

Chan Y.C. , Lee Y.K. , Ng K.M. , Lai K.W.H. , Yang D. , Tse H.F. and Siu D.C.W. , A Newly-derived Small Synthetic Compound Alleviated Ventricular Fibrillation In A Pig Model With Chronic Myocardial Infarction As Revealed By Optical Mapping, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” (Hong Kong) . 2010.

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation an d Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Lee Y.K. , Ng K.M. , Lai K.W.H. , Tse H.F. and Siu D.C.W. , Triiodothyronine enhances cardiac differentiation of embryonic stem cells and maturation via classical pathway., Molecular Endocrinology . 2010, (in press).

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai K.W.H. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1alpha promotes cardiac differentiation of embryonic stem cells., Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-37.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embr yonic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Ng K.M. , Lee Y.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Hypoxia promotes cardiac differentiation of human embry onic stem cells, Physiology Symposium 2009, HKU, Hong Kong 5/2009 .

Siu D.C.W. , Waston T., Lai K.W.H. , Lee Y.K. , Chan Y.H. , Ng K.M. , Lau C.P. , Lip G.Y. and Tse H.F. , Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm., Europace . 2009, 12(4): 460-1.

Researcher : Lee YK

List of Research Outputs

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embryonic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Ng K.M. , Lee Y.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Hypoxia promotes cardiac differentiation of human em bryonic stem cells, Physiology Symposium 2009, HKU, Hong Kong 5/2009 .

Researcher : Leung AYH

Project Title:	Provision of free alemtuzumab (a nti-CD52) to patients with chronic lymphocytic leukemia refractory to conventional chemotherapy
Investigator(s):	Leung AYH, Kwong YL
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	11/2007

Abstract:

To provide free alemtuzumab for the treatment of refractory CLL to patients cannot afford this drug; to impove microbiological surveillance against fungal infection among patients who receive this drug.

Project Title:	The role of aldehyde dehydrogenase in primitive hematopoiesis during embryonic development
Investigator(s):	Leung AYH
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2008
Completion Date:	02/2010

Abstract:

Embryonic hematopoiesis During embryonic development, hematopoiesis occurs in two successive waves known as the primitive and definitive hematopoiesis. These fundamental processes are conserved among vertebrate s, including humans, mice and zebrafish. In zebrafish embryos, primitive hematopoiesis occurs within 24 hours-post-fertilizatio n (hpf) and definitive hematopoiesis begins at 48 hpf. The identity of genes associated with specific lineage differentiation has been reported and such information has been useful to delineate hematopoietic stem and lineage-committed cell populations in this organism. However, the regulatory mechanisms of these processes are not completely understood. Aldehyde dehydrogenase and hematopoietic stem cells Aldehyde dehydrogenase (ALDH) is a family of enzymes involved in the metabo lism of aldehydes to their corresponding carboxylic acids. It is highly expressed in human and murine hematopoietic stems (HSC) and has been widely used in their enumeration. Diethylaminobenzaldehyde (DEAB) has been shown to inhibit ALDH activity in-vitro. It remains unclear if DEAB may be useful as an inhibitor of ALDH in-vivo and if so, it may provide a means to examine the functional role of ALDH during hematopoiesis. Zebrafish as a model of embryonic hematopoiesis To address this issue, we make use of the zebrafish model and examine if inhibition of ALDH with DEAB may perturb embryonic hematopoiesis in this organism. The model is uniquely suitable for this proposal based on the following featur es: 1. The embryos are externally fertilized, so that the embryos can be bathed in water containing accurately defined concentration of DEAB; 2. The embryos are optically transparent, allowing direct visual inspection of hematop oiesis; 3. Quantitative as well as qualitative assays of embryonic hematopoi esis at both cellular and molecular levels have been established in our laboratory. Objectives of the research proposal The proposal aims to address two core questions pertainin g to the role of ALDH in embryonic hematopoiesis. 1. Will inhibition of ALDH perturb embryonic hematopoiesis? If so, how? 2. Is ALDH involved at hematopoietic stem cells or lineage-committed progenitors level? Answers to these questions will shed novel lights to the regulatory mechanism of embryonic hematopoiesis and the cell-fate decision made by hematopoietic stem and progenitor cells.

Project Title:	Provision of free service for serum polyoma BK virus quantification to kidney transplant recipients in Hong Kong
Investigator(s):	Leung AYH, Kwong YL, Tang SCW
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	01/2009

Abstract:

Provide free serum BKV monitoring to kidney transplantatio n patients to prevent and treat PAN. The patients will benefit from BKV monitoring in the following ways: (1) early detection of a rise in serum BKV will allow timely and cautious reduction of immunosuppression, whereby facilitating clearance of the virus and preventing the occurrence of PAN; (2) established PAN, quantification of serum BKV will enable clinicians to withdraw immu nosuppression to the appropriate level.

Project Title:	Identification of novel human polyomav iruses from patients with acute respiratory tract infections in Hong Kong
Investigator(s):	Leung AYH, Kwong YL
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	01/2009

Abstract:

(1) The novel K.I. and W.U. viruses can be identified in the respiratory tract of people in Hong Kong; (2) the viruses may remain dormant in the respiratory tract of patients without ARTI; (3) These viruses may play a pathogenetic role in ARTI.

Project Title:	Is Jak2V617F mutation a stem cell event in chronic myeloproliferative disease ?
Investigator(s):	Leung AYH, Liang RHS
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To determine if the specific loss of Jak2V617F cells in NOD/SCID mice after transplanting bone marr ow CD34+ cells from patients with polycythemia vera results from deficiency of human erythropoietin signaling in erythroid-skewed Jak2V617F HSC; (2) Revised Objectives: The Objective 2 has been revised as: To determine the lineage differentiation of the engrafting Jak2V617F negative cells in NOD/SCID mice based on flow cytometry; (3) To determine if the loss of Jak2V617F cells in NOD/SCID mice occurs also for cases of essential thrombocythemia and chronic idiopathic myelofibrosis.

Project Title:	Provision of free molecular tests for patients with acute myeloid leukemia with normal cytogenetics
Investigator(s):	Leung AYH
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	01/2010

Abstract:

n/a

Project Title:	Is aldehyde dehydrogenase a negative regulator of primitive hematopoiesis during embryonic development?
Investigator(s):	Leung AYH
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) What is the effect of aldh inhibition on primitive hematopoiesis? i. What is the development stage at which aldh regulate primitive hematopoiesis? ii. Is the effect of aldh inhibition linked to endogenous retinoic acid synthesis? (The third part of this obje ctive as proposed in the original proposal: "iii. What is the hierarchical relationship of aldh to other signalling pathways during embryonic hematopoiesis?" would have to be left to a separate project due to the significant reduction in funding obtained from this proposal) 2 What are the specific aldh isoforms involved? i. Is aldh1a2 regulating hematopoiesis? ii. If not, what are the specific aldh isoforms? (The third part of this objective as proposed in the original proposal: "iii. What are the potential regulators of aldh expression in zebrafish?" would have to be left to a separate project due to the significant reduction in funding obtained from this proposal)

Project Title:	Study of Microglia and Acute Myeloi d Leukemia in Zebrafish
Investigator(s):	Leung AYH
Department:	Medicine
Source(s) of Funding:	Collaborative Research Fund (CRF) - Group Research Project
Start Date:	05/2010

Abstract:

(1) elucidate the origin of microglia and the mechanisms regulating microglia cell development; (2) uncover the role of microglia in CNS infection, CNS regenerat ion and Alzheimer‟s disease; (3) understand the cellular and molecular basis underlying the onset and development of AML; (4) establish an AML zebrafish model that can be used for drug discovery.

List of Research Outputs

Au W.Y. , Lam K.K., Leung A.Y.H. , Liang R.H.S. , Lie A.K.W. and Kwong Y.L. , Occult autologous haematopoietic regeneration without disease relapse following myeloablative allogeneic haematopoietic SCT for lymphomas, Bone Marrow Transplantation . 2009, 45: 1377–1378.

Cheng V.C.C. , Chan J.F.W. , Ngan H.Y. , To K.K.W. , Leung S.Y. , Tsoi H.W. , Yam W.C. , Tai J.W.M. , Wong S.S.Y. , Tse H. , Li W.S. , Lau S.K.P. , Woo P.C.Y. , Leung A.Y.H. , Lie A.K.W. , Liang R.H.S. , Que T.L., Ho P.L. and Yuen K.Y. , Outbreak of Intestinal Infection due to Rhizopus microsporus., Journal of Clinical Microbiology . 2009, 47: 2834-43.

Cheung A.M., Chow C.H. , Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , FLT3/internal tandem duplication subclones in acute myeloid leukemia differ in their engraftment potential in NOD/SCID mice, Leukemia Research . 2010, 34(1): 119-22.

Cheung A.M., Fung T.K. , Fan K.P. , Wan T.S., Chow C.H. , Leung J.C.K. , Chan L.Y., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD/S CID mice., Experimental Hematology . 2010, 38: 3-10.

Fung T.K. , Cheung A.M., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Differential NOD/SCID mouse engraftment of peripheral blood CD34(+) cells and JAK2V617F clones from patien ts with myeloproliferative neoplasms., Leukemia Research . 2010.

Fung T.K. , Liang R.H.S. and Leung A.Y.H. , Functional characterization of novel gene NUP98 in zebrafish embryo, 15th Medical Research Conference, 2010.

Fung T.K. and Leung A.Y.H. , Functional characterization of novel gene NUP98 in zebrafish embryo, 16th Hong Kong International Cancer Congresss 6th Annual Meeting Centre for Cancer Research . 2009.

Gill H., Leung A.Y.H. , Trendell-Smith N.J. , Yeung C.K. and Liang R.H.S. , Sweet Syndrome due to Myelodysplastic Syndrome: Possible Therapeutic Role of Intravenous Immunoglobulin in Addition to Standard Treatment, Advances in Hematology . 2010, 2010:328316: Epub.

Huang H., Wu D., Fu J., Chen G., Chang W., Chow C.H. , Leung A.Y.H. and Liang R.H.S. , All-trans retinoic acid can intensify the growth inhibiti on and differentiation induction effect of rosiglitazone on multiple myeloma cells, European Journal of Haematology . 2009, 83(3): 191–202.

Huang H.W., Chen G.H., Chang H.R., Chow H.C., Leung A.Y.H. , Liang R.H.S. and Wu D.P., Differentiating effect of PPARgamma ligand rosiglitazone and all trans-retinoic acid on myeloma cells and its possible mechanism, Zhonghua Zhong Liu Za Zhi, 2009, 31(12): 885-9.

Kwong Y.L. , Au W.Y. , Leung A.Y.H. and Tse E.W.C. , T-cell large granular lymphocyte leukemia: an Asian perspective, Annals of Hematology . 2010, 89(4) 331-339: 331-339.

Leung A.Y.H. and Kwong Y.L. , Haematopoietic stem cell transplantation: current concep ts and novel therapeutic strategies, British Medical Bulletin . 2009, 93(1): 85-103.

Ma C.H. , Fan K.P. , Ward A.C., Liongue C., Lewis R.S., Cheng S.H., Chan P.K., Yip S.F. , Liang R.H.S. and Leung A.Y.H. , A novel zebrafish jak2a(V581F) model shared features of human JAK2(V617F) polycythemia vera., Experimental Hematology . 2009, 37: 1379-1386.

Ma C.H. , Lin H. , Chung I.S. , Yang D. , Liang R.H.S. and Leung A.Y.H. , Distinctive functions of methionine aminopeptidase II in embryonic hematopoiesis in zebrafish embryos., 15th Medical Research Conference . Hong Kong, 2010.

Ma C.H. , Liang R.H.S. and Leung A.Y.H. , The effect of Diethylaminobenzaldehyde (DEAB), an inhibitor of Aldehyde Dehydrogenase (Aldh), on Primitive Henatopoiesis during Zebrafish Embryonic Development, 16th Hong Kong International Cancer Congress . 2009, Abs#A5.

Ma C.H. , Liang R.H.S. and Leung A.Y.H. , The effect of diethylaminobenzaldehyde (DEAB), an inhi bitor of aldehyde dehydrogenase (Aldh), on primitive hematopoiesis during zebrafish embryonic development. , The 16th Hong Kong Internation Cancer Congress . 2009.

Yeung C.W., Cheung W.W.W. , Leung A.Y.H. and Kwong Y.L. , Spontaneous central venous catheter fracture: Relevance of the pinch-off sign, Journal of Hospital Medicine . 2010, 5(4): E33.

Researcher : Leung JCK

Project Title:	IgA1 molecules from familial IgA N: a more pathogenetic entity?
Investigator(s):	Leung JCK, Lai KN
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2008
Completion Date:	12/2009

Abstract:

(1) Examine the molecular nature of IgA1 molecules from human familial and sporadic IgAN; (2) Explore the cytokine cascade and signaling events of kidney mesangial cell and proximal tubular epithelial cells in response to activation by IgA1 molecules from familial IgAN; (3) Examine the expression of megsin and its regulation by IgA1 from familial IgAN in mesangial cells.

Project Title:	The role of aldosterone in the pathogenesis of IgA nephropathy
Investigator(s):	Leung JCK, Lai KN
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) Elucidation of the distribution of components for aldosterone system including aldosterone, 11ß-HSD2, aldosterone synthase and MR in kidney biopsies from patients with IgAN; (2) Investigation of the regulation of aldosterone synthesis (CYP11B2) in HMC activated by pIgA and proximal tubular epithelial cells (PTEC) exposed to pIgA directly or mediators released by mesangial cells after pIgA activation. (3) Examination of the mechanisms of HMC and PTEC activation by pIgA-induced aldosterone and the related signaling pathways; (4)Ex amination of the effects of specific aldosterone blockade alone, or in combination with AngII inhibition by ACEI or ARB, on pIgA-induced immune injury.

List of Research Outputs

Cheung A.M., Fung T.K. , Fan K.P. , Wan T.S., Chow C.H. , Leung J.C.K. , Chan L.Y., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD/SCID mice., Experimental Hematology . 2010, 38: 3-10.

Guo H. , Leung J.C.K. , Cheung J.S., Chan Y.Y. , Wu E.X. and Lai K.N. , Non-viral Smad7 gene delivery and attenuation of postoperative peritoneal adhesion in an experimental model, Br J Surg . 2009, 96(11): 1323-35.

Hsu S.I., Niu Y., Davila S., Leung J.C.K. , Lam M.F. , Tang S.C.W. and Lai K.N. , Genome-wide linkage scan for familial IgA nephropathy among southeast Asian Chinese: evidence for a suggestive novel susceptibility locus on chromosome 8p23, Journal of American Society Nephrology . 2009, 20: 434A.

Lai K.N. , Chan L.Y., Guo H., Tang S.C.W. and Leung J.C.K. , Additive effect of peroxisome proliferator-activated receptor- g agonist and angiotensin receptor blocker in treatment of experimental IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 149-150A.

Lai K.N. and Leung J.C.K. , Inflammation in Peritoneal Dialysis., Nephron Clin Pract . 2010, 116(1): c11-c18.

Lai K.N. and Leung J.C.K. , Peritoneal adipocytes and their role in inflammation during peritoneal dialysis, Mediators Inflamm . 2010, 2010: 164954.

Leung J.C.K. , Chan L.Y., Tam K.Y., Tang S.C.W. and Lai K.N. , Inhibition of renin-angiotensin-aldosterone system abolishes polymeric-IgA induced TGF- synthesis by human mesangial cells in IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 294A.

Lin M. , Chan A.W., Chan L.Y., Leung J.C.K. , Lai K.N. and Tang S.C.W. , Toll-like receptor 4 mediates tubular inflammation in diabetic nephropathy, Hong Kong Medical Journal . 2010, 16: 39.

Lou T., Zhang J., Gale D.P., Rees A.J., Rhodes B., Feehally J., Li C., Li Y., Li R., Huang W., Hu B., Leung J.C.K. , Lam M.F. , Lai K.N. , Wang Y. and Maxwell P.H., Variation in IGHMBP2 is not associated with IgA nephro pathy in independent studies of UK Caucasian and Chinese Han patients, Nephrology Dialysis Transplantatio n . 2009, 25(5): 1547-54.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , In vitro enhanced chemotaxis of CD25+ mononuclear cells in patients with familial IgAN through glomerulotubular interaction, American Journal of Physiology-Renal Physiology . 2010.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , Increased chemotaxis of CD25+ PBMC to tubular epithelial cells through glomerulotubular interaction in patients with familial IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 307A.

Tang S.C.W. , Chan L.Y., Leung J.C.K. , Cheng A.S., Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote diabetic renal tubular injury , Nephrology Dialysis Transplantation . 2010, 25: 698-710.

Tang S.C.W. , Chan Y.Y. , Leung J.C.K. , Cheng A.S. , Chan K.W. , Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote renal tubular inflammation , Nephrol Dial Transplant . 2010, 25(3): 698-710.

Tang S.C.W. , Leung V.T., Chan L.Y., Wong S.H., Chu D.W., Leung J.C.K. , Lai K.N. , Ma L., Elbein S.C., Bowden D.W., Hicks P.J., Comeau M.E., Langefeld and Freedman B.I., The acetyl-Coenzyme A carboxylase beta gene (ACACB) is associated with nephropathy in Chinese patients with type 2 diabetes, Nephrology Dialysis Transplantation . 2010.

Wang A.Y.M. , Cheung C.W., Chu J.Y.Y. , Fok A.N.Y. , Lo W.K. , Leung J.C.K. , Tso W.K. and Lai K.N. , Is aortic pulse wave velocity a useful screening test for vascular and valvular calification in end-stage renal disease patients, Journal of American Society of Nephrology . 2009, 20: 443A-444A.

Xiao J. , Leung J.C.K. , Chan Y.Y. , Tang S.C.W. and Lai K.N. , Crosstalk between peroxisome proliferator-activated receptor-gamma and angiotensin II in renal tubular epithelial cells in IgA nephropathy, Clinical Immunology . 2009, 132: 266-276.

Researcher : Leung YH

List of Research Outputs

Ong K.L. , Tso A.W.K. , Leung Y.H. , Xu A. , Cherny S.S. , Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive protein as a predictor of hypertension in the Hong Kong cardiovascular risk prevalence study (CRISPS) cohort, Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants gene encoding adrenom edullin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting of Hong Kong Society of Endocrinology . 2009.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenom edullin with hypertension and dysglycaemia in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Researcher : Li FK

List of Research Outputs

Yung S.S.Y. , Chau K.M. , Yip T.P.S., Li F.K. and Chan D.T.M. , Induction of inflammatory and fibrotic mediators in human peritoneal mesothelial cells (HPMC) by icodextrin-based peritoneal dialysis fluid, J Am Soc Nephrol . 2009, 20: 694A.

Researcher : Li FYL

Project Title:	TLR4 as a novel mediator of impaired vascular repair in obesity and diabetes.
Investigator(s):	Li FYL, Lam KSL, Xu A
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	10/2008
Completion Date:	03/2010

Abstract:

In the Western populations, obesity has been linked to cardiovascular diseases and related diabetic complications. The increased risk for cardiovascular disease in obese subjects is partially associated with increased blood cholesterol, yet other risk factors may also play a part. During the progression of atherosclerosis, oxidised low density lipoprotein (oxLDL) stimulates the recruitment of monocytes which in turn induces the scavenging of oxidised lipids by macrophages, leading to foam cell formation. This process is mediated by pro-inflammatory cytokines such as MCP-1 and TNFα, and adhesion molecu les such as VCAM-1 and ICAM-1. Advanced lesions are formed as foam cells undergo necrosis and release oxidised lipids to necrotic core, involving pro-inflammatory mediators and cytokines to form calcified fibrous cap (plague formation). As the lesions expand, a thrombus may form to cause plague rupture or erosion, leading to myocardial infarction, stroke or tissue ischaemia (Lusis 2000). Endothelial dysfunction results from endothelial damage induced by oxidised lipids, free radicals, cytokines and high concentrations of blood cholesterol. This causes apoptosis/necrosis of the endothelial cellular layer accompanied by a loss of anti-thrombotic properties. An emerging theory of obesity-induced inflammation in the vasculature further illustrates the relationship between high fat intake and cardiovascular risks. Toll-like receptor 4 (TLR4) is well known to mediate inflammatory response in numerous tissue types (Shi et al., 2004). To highlight, vascular tissues from mice fed with high fat diets were found to express high levels of inflammatory markers, such as ICAM and IL-6, which were not evident in tissues from TLR4 lacking mice (Kim et al., 2007). Free fatty acid (FFA) contained in the diet and hence in the blood flow has been shown to activate TLR4 to mediate the activation of the a adipocyte-specific fatty acid binding protein (A-FABP) expressed in macrophage and thence the transcription factor NFkB which in turn activates downstream signalling cascades, leading to an increase in the expression of pro-inflammatory and pro-atherogenic cytokines (Shi et al., 2004). These cytokines, such as MCP-1 and TNFα, are known to potentiate the progression of atherosclerosis. Of note, by the mechanism by which FFA activates TLR4 is still under controversies (Lee et al., 2003; Nguyen et al., 2007). However, it has been shown that lipopolysaccharides (LPS), a specific TLR4 ligand, can activate TLR4 via activation of LPS-binding protein, co-receptors MD-2 and CD14, both of which can be found on the surface of macrophage (Jerala, 2007; Lu et al., 2008; Miller et al., 2005). Previous studies have provided grounds that TLR4 plays a part in atherosclerotic progression. Endothelial cells isolated from TLR4 lacking mice showed limited changes in expression of MCP-1 and VCAM-1 when compared to control mouse endothelium, which have been detect ed a marked increased expression of these cytokines (Shi et al., 2000). Furthermore, cytokine interferon α sensitises antigen presenting cells by up-regulating TLR4 expression and intensifies TNFα and IL-12 production, in turn destablising atherosclerotic plaque (Niessner et al., 2007). In atherosclerosis, vascular endothelial dysfunction caused by oxidised lipids, free radicals, cytokines and high concentrations of blood cholesterol complicates disease progression. Moreover, endothelial damage is accompanied with a reduced antithrombotic property of blood vessels (Ross, 1999). Therefore, endothelial repair is crucial in possibly reversing the drastic effect of atherosclerotic damage in the vasculature. In this aspect, endothelial progenitor cells (EPC) are key players in repairing damaged endothelia l cells. It has been demonstrated that EPC are incorporated into endothelial layer, expressing endothelial markers. The recruitment, homing and subsequent attachment of EPC at site of injury involves several mediators, namely nitric oxide (NO), stromal cell-derived factor and vascular endothelial growth factor (Xu, 2007). Patients with cardiovascular diseases, including coronary artery disease, heart failure, hypertension, and diabetes, have been shown to exhibit reduced number and functional capacity of EPCs (Tousoulis et al., 2008). In addition, inflammation further abrogates the repair capacity and number of EPC. Several studies have demonstrated that incubation of EPC with pro-inflammatory mediators such as C-reactive protein (Verma et al., 2004) and TNFα (Seeger et al., 2005) reduced EPC surviv al and number. Reendothelialisation capacity of EPC derived from diabetic subjects is markedly impaired as a result of increased reactive oxygen species production and hence reduced NO bioavailability. Howeve r, it is yet to be established that whether vascular repair by EPC is also attenuated by the activation of TLR4, leading to a diminished repair mechanism and hence potentiated atherosclerotic progression. Conclusively, atherosclerosis is an inflammatory disease which can be at least in part mediated by TLR4. Endothelial inju ry in atherosclerosis can be repaired by EPC activation, which has been shown to diminish in patients with diabetes and/or vascular diseases. Vascular inflammation appears to impair the capacity of EPC in reendothelialisation process, which is not known whether TLR4 is involved. Therefore in the current study, we aim to address th e key issues with three objectives: Objective 1: To investigate whether TLR4 plays a causative role in impaired vascular repair in animal model with spontaneous atherosclerosis; Objective 2: To address whether TLR4 deficiency leads to increased number and functionality of circulating endothelial progenitor cells; Objective 3: To study the molecular mechanisms whereby free fatty acids activate TLR4 in endothelial cells. References: see attachment

List of Research Outputs

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Inactivation Of Toll-like Receptor 4 Improves Reendotheli alisation In Apoe-deficient Mice – Impact Of Oxidative Stress On Endothelial Progenitor Cells, 15th Medical Research Conference, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Outstanding Abstract Prize, Fifth International Symposium On Healthy Aging: Is Aging A Disease?, Research Centre Of Heart, Brain, Hormone & Healthy Aging, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Toll-like Receptor 4 Inactivation Ameliorates Impaired Reendothelialisation Through The Improvement In Endothelial Progenitor Cell Adhesion, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” . 2010.

Researcher : Li GR

Project Title:	Volume-sensitive chloride current and cell volume regulation in human atrial myocytes
Investigator(s):	Li GR, Lau CP, Chiu SW, Tse HF
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	12/2001

Abstract:

To determine the intracellular signaling pathways that regulate I _Cl.vol and cell volume in human atrium; to determine whether I _Cl.vol is persistently activated in atrial myocytes from patients with dilated atrial cardiomyopathy.

Project Title:	Studies on ion channels and cell proliferation in human cardiac fibroblasts
Investigator(s):	Li GR, Lau CP
Department:	Medical Faculty
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2007
Completion Date:	12/2009

Abstract:

To analyze the molecular identities of I _KCa, IK _DR, I _CI.vol, and I _Na, in human cardiac fibroblasts with RT-PCR, Western blot analysis, and patch clamp technique; to test the hypothesis that these four types of channels (I _KCa, IK _DR, I _CI.vol, and I _Na are involved in the proliferation of human cardiac fibroblasts. Cell proliferation assays will be conducted in the absence and presence of channel blockers, short interfering RNA (siRNA) oligos targeted to IK _DR, I _KCa, I _CI.vol, and I _Na and channels, and/or signal modulators.

Project Title:	Calcium Signals and Cell Proliferation in Human Cardiac Fibroblasts
Investigator(s):	Li GR, Lau CP, Lee HC, Tse HF
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To determine the effects of calcium signals on proliferation and the modulation of calcium signals and cell cycle progression by extracellular ATP in human cardiac fibroblasts.

Project Title:	Calcium Signaling Pathways in Human Preadipocytes
Investigator(s):	Li GR
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2009
Completion Date:	02/2010

Abstract:

It is well known that calcium (Ca2+) is a universal second messenger that modulates numerous diverse cellular processes in excitable, non-excitable and proliferative cells. In excitable cells Ca2+ signal participates in motility, secretion, and learning and memory: in proliferative cells it plays an important role in maintaining physiological homeostasis and regulating proliferati on. It is well known that white adipose tissue plays a crucial role in the regulation of energy balance and acts as a secretory/endocrine (leptin, adiopnectin, resistin, etc.) organ that mediates numerous physiological and pathological processes. Dysregulation of adipose mass (i.e. size and number of white adipocyte) causes obesity and lipatrophy, that are closely associated with life-threatening pathologies including cardiovascu lar disease and type 2 diabetes. Preadipocytes (i.e. pre-fat cells) are a type of highly proliferating cell and the origin of fat cells (adipocytes); however, cell biology of this type of cell is not fully understood, especially in human preadipocytes. An understanding of Ca signals and their physiological activity is important in the study on obesity, the major risk factor for type 2 diabetes and cardiovascular disease. Nonethe less, little or no study appears to have been made of Ca signal pathways of preadipocytes. In a preliminary experiment we found that spontaneous intracellular Ca oscillations were observed in a small population of human preadipocytes without any inducing agent. Fetal bovine serum (FBS) in the bath medium increased the cell number with Ca oscillations (please refer the attached Research Background), suggesting that Ca activity is significant in human preadipocytes. However, it is unknown what Ca signal pathways are involved in the Ca oscillations. The objectives of the present proposal are therefore: 1) to characterize calcium signal pathways in human cardiac fibroblasts; and 2) to determine whether calcium signals regulate proliferation of human cardiac fibroblasts.

Project Title:	Biophysical Society 54th Annual Meeting PURINOCEPTOR ACTIVATION AND CELL PROLIFERATION IN HUMAN CARDIAC FIBROBLAST
Investigator(s):	Li GR
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	02/2010
Completion Date:	02/2010

Abstract:

N/A

Project Title:	Study on the Natural Anti-Atrial Fibrillation Compound Acacetin and Its Analogues/Derivatives
Investigator(s):	Li GR, Vanhoutte PMGR
Department:	Medicine
Source(s) of Funding:	Innovation and Technology Support Programme (Tier 3)
Start Date:	03/2010

Abstract:

1) To investigate pharmacokinetic profile of acacetin. The bioavailability, metabolites of acacetin will be studied in the two animal species, the non-rodent dog and the rodent rat, using classical approaches of pharmacokinetics to provide pharmacokinetic information for the potential clinical trial, in addition, tissue distribution wull be determined in rats. 2) To determine pharmacological efficacy and ion channel selectivity of acacetin's analogues/derivatives. The pharmacological efficacy of analogues/derivatives (including its major metabolite) on Kv1.5 channel and Kv4.3 will be studied to find out the compound(s) that has more potent inhibitory effect on Kv1.5 and Kv4.3 channels than acacetin, and ion channel selectivity will be then studied for the selected compound(s) using patch clamp technique.

List of Research Outputs

Chen J. , Tao R. , Sun H. , Tse H.F. , Lau C.P. and Li G.R. , Multiple Ca(2+) signaling pathways regulate intracellular Ca(2+) activity in human cardiac fibroblasts., J Cell Physiol . 2010, 223(1): 68-75.

Chen J. and Li G.R. , Purinoceptor activation and cell proliferation in human cardiac fibroblasts., Biophysical Journal/54th Annual Meeting of Biophysical Society, San Francisco, California, USA. Feb 20-24 . 2010, L166.

Dong M. , Sun H. , Tang Q. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of human cardiac KCNQ1/KCNE1 channel by epidermal growth factor receptor kinase., Biochim Biophys Acta . 2010, 1798(5): 995-1001.

He M. , Lau C.P. , Tse H.F. and Li G.R. , Regulation of cell proliferation by large-conductance calcium-activated potassium and volume-sensitive chloride channels in human cardiac fibroblasts, 15th Medical Research Conference . 2010, 16(1): 23.

Hu R. , He M. , Hu H. , Yuan B.X., Zang W.J., Lau C.P. , Tse H.F. and Li G.R. , Characterization of calcium signaling pathways in human preadipocytes, J Cell Physiol . 2009, 220(3): 765-770.

Li G.R. , Chairman, Oral Session IV, Cancer and Animal Model of Human Diseases, 15th Medical Research Conference . 2010.

Li G.R. , Sun H. , Chen J. , Zhou Y. , Tse H.F. and Lau C.P. , Characterization of Multiple Ion Channels in Cultured Human Cardiac Fibroblasts. , PLoS One . 2009, 4(10): e7307.

Li G.R. , Development of a selective potassium channel blocker from TCM used for anti-atrial fibrillation, International drug discovery science and technology. Oct 22-25, 2009. Shanghai, China . 2009.

Li G.R. , Multiple ion channel currents and their role in proliferation of human cardiac fibroblasts, The 7th scientific conference on cardiovascular sciences across the strait. Aug 14-16. Kunming, Yunnan, China. . 2009.

Li G.R. , Patch Clamp Applications-from Excitable Cells To Non-excitable Cells, Department of Physiology and Pathophysiology, Medical School of Xi'an Jiaotong University, Xi'an China . 2010.

Li G.R. , Study on natural selective anti-atrial fibrillation drug, 3rd Annual meeting of Hubei province pharmacology society. July 3-5, 2009. Xianning. Hube. China . 2009.

Wu H. , Tse H.F. and Li G.R. , Effects of acacetin on kv1.5 channels and rat atrial repolarization potassium currents, 14th Research postgraduate symposium, HKU . 2009, 58.

Wu W. , Lau C.P. , Tse H.F. and Li G.R. , Beta 1 subunit-dependent modulation of BK channel by membrane cholesterol, In: 15th Medical Research Conference, Department of Medicine, HKU, 15th Medical Research Conference . 2010, 16(1): 58.

Zhang X. , Jin M.W. and Li G.R. , Ion Channels and Their Role in Cell Proliferration of 3T3-L1 Preadipocytes, J HK Coll Cardiol . 2009, 17(2): 68.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , large-conductance Ca-activated Potassium and Ether-a-go -go Potassium Channels Regulate Proliferation of Human Mesenchymal Stem Cells, J HK Coll Cardiol . 2009, 17(2): 59.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Human cardiac KV4.3 channels are regulated by protein tyrosine kinases, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 64.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Protein Tyrosine Kinases Regulate Human Cardiac KV4.3 Channel, J HK Coll Cardiol . 2009, 17(2): 58.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of cell proliferation by ion channels in human mesenchymal stem cells, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 65.

Zhou Y. , Wong T.M. and Li G.R. , Ionic mechanisms of chloroform induced arrhythmia, FEBS Journal . 2009, 276(Suppl. 1): 354-5.

Researcher : Li HY

List of Research Outputs

Kung A.W.C. , Xiao S. , Cherny S.S. , Li H.Y. , Gao Y. , Tso G., Lau K. , Luk K.D.K. , Liu J.M., Cui B., Zhang M.J., Zhang Z.L., He J.W., Yue H., Xia W.B., Luo L.M., He S.L., Kiel D.P., Karasik D., Hsu Y.H., Cupples L.A., Demissie S., Styrkarsdott ir U., Halldorsson B.V., Sigurdsson G., Thorsteinsdottir U., Stefansson K., Richards B., Zhai G., Soranzo N., Valdes A., Spector T.D. and Sham P.C. , Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow -up Replication Studies, American Journal of Human Genetics . 2010, 86 (2): 229-239.

Researcher : Li LSW

List of Research Outputs

Chau C.M. , Cheung R.T.F. , Jiang X., Au-Yeung P.K.M. and Li L.S.W. , Acupuncture of motor-implicated acupoints on subacute stroke patients: an fMRI evaluation study, Medical Acupuncture . 2009, 21(4): 233-241.

Chau C.M. , Cheung R.T.F. , Jiang X., Au Yeung P.K.M. and Li L.S.W. , An fMRI study showing effect of acupuncture in chronic stage stroke patients with aphasia, Journal of Acupuncture & Meridian Studies . 2010, 3: 53-57.

Chau C.M. , Cheung R.T.F. , Jiang X., Au-Yeung P.K.M. and Li L.S.W. , Increased brain activation in motor cortex after acupuncture treatment for motor recovery in chronic stroke patients, The Open Rehabilitation Journal . 2009, 2: 89-94.

Li X. , Tse H.F. , Yiu K.H., Jia N., Chen H. , Li L.S.W. and Jin L.J. , Increased levels of circulating endothelial progenitor cells in subjects with moderate to severe chronic periodontitis, Journal of Clinical Periodonto logy . 2009, 36: 933-939.

Li X. , Tse H.F. , Li L.S.W. and Jin L.J. , Salivary MIF is associated with gingival inflammation and periodontopathogens, Journal of Dental Research . 2009, 88 (Spec Iss B): 288 (PAPF/APR).

Liu K.P.Y., Chan C.C.H., Wong R.S.M., Kwan I.W.L., Yau C.S.F., Li L.S.W. and Lee T.M.C. , A randomized controlled trial of mental imagery augment generalization of learning in acute post-stroke patient s., Stroke . 2009, 40: 2222-2225.

Siu D.C.W. , Pong V., Jim M.H., Yue W. , Ho H.H., Li L.S.W. , Lau C.P. and Tse H.F. , Beta-blocker in post-myocardial infarct survivors with preserved left ventricular systolic function, Pacing and Clinical Electrophysio logy . 2010, 33(6): 675-80.

Researcher : Li M

List of Research Outputs

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endothe lial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Li M. and Cheung B.M.Y. , Pharmacotherapy for obesity. , Br J Clin Pharmacol. . 2009, 63: 804-10.

Li M. , Ong K.L. , Tse H.F. and Cheung B.M.Y. , Utilization of lipid lowering medications among adults in the United States 1999-2006. , Atherosclerosis. . 2010, 208: 456-60.

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Researcher : Li M

List of Research Outputs

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endotheli al Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Li M. and Cheung B.M.Y. , Pharmacotherapy for obesity. , Br J Clin Pharmacol. . 2009, 63: 804-10.

Li M. , Ong K.L. , Tse H.F. and Cheung B.M.Y. , Utilization of lipid lowering medications among adults in the United States 1999-2006. , Atherosclerosis. . 2010, 208: 456-60.

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chine se, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Researcher : Li RA

List of Research Outputs

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. and Li R.A. , Automaticity and conduction properties of bio-artificial pacemakers assessed in an in vitro monolayer model of neonatal rat ventricular myocytes., Europace. In press. . 2010.

Fu J., Rushing S., Lieu D., Wu J.C. and Li R.A. , Differential effects of microRNAs on ventricular specification and maturation of Human Embryonic Stem Cells., 2010.

Fu J.D., Kong M.C.W. , Rushing S.N., Lieu D.K., Chan C.W.Y. , Tse H.F. , Wilson K., Chiamvimonvat N., Boheler K.R., Wu J.C., Keller G. and Li R.A. , Distinct Roles of MicroRNA-1 and -499 in ventricular specification and maturation of human embryonic stem cells, Fifth International Symposium on Healthy Aging . 2010.

Fu J.D., Li R.A. , Peng J., Ha T. and Jing L., Na+/Ca2+ exchanger in hESC-derived ventricular cardiomyocytes is a functional determinant of excitation-contraction coupling during cardiac development., Stem Cell & Development. . 2009.

Jiang P., Rushing S.N., Kong M.C.W. , Fu J., Lieu D.K., Chan C.W.Y. , Deng W. and Li R.A. , Electrophysiological Properties of Human induced Pluripotent Stem Cells (iPSCs), Fifth International Symposium on Healthy Aging . 2010.

Jiang P., Rushing S.N., Kong M.C.W. , Fu J., Lieu D.K., Chan C.W.Y. , Deng W. and Li R.A. , Electrophysiological properties of human induced pluri potent stem cells, Am J Physiol Cell Physiol . 2010, 298: 486-495.

Kong M.C.W. , Jiang P., Rushing S.N., Tse H.F. and Li R.A. , MicroRNA and cell cycle of embryonic stem (ES) and induced pluripotent stem (iPS) cells: Insights for eliminating tumorgenicity, Fifth International Symposium on Healthy Aging . 2010.

Li R.A. , Convener for the field of Stem Cell & Regenerative Medicine in Hong Kong, appointed by the Research Grant Council of HK, Theme-based Research., Research Grant Council of HK . 2010.

Li R.A. , Department of Molecular Genetics, Biochemistry and Microbiolog., U of Cincinnati. . 2009.

Li R.A. , Gene- and Cell-based Heart Therapies, MSSM . 2009.

Li R.A. , SY and HY Cheng Endowed Professorship in Stem Cell & Regenerative Medicine (nominated by Professors Sum Lee and Karen S. Lam, pending Committee Approval). , The University of Hong Kong, The University of Hong Kong . 2010.

Li R.A. , Stem Cell Institute, U of Miami. . 2009.

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with passive epicardial patch in porcine model of chronic myocardial infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai K.W.H. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1alpha promotes cardiac differentiation of embryonic stem cells., Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-37.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embryonic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Ng K.M. , Lee Y.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Hypoxia promotes cardiac differentiation of human embryonic stem cells, Physiology Symposium 2009, HKU, Hong Kong 5/2009 .

Wilson K.D., Hu S., Venkatasubrahmanyam S., Fu J.D., Sun N., Abilez O.J., Baugh J.J., Jia F., Ghosh Z., Li R.A. , Butte A.J. and Wu J.C., Dynamic MicroRNA Expression Programs during Cardiac Differentiation of Human Embryonic Stem Cells: Role for miR-499. Circ Cardiovasc Genet., 2010.

Xue T., Cho H.C., Akar A., Tsang S.Y., Jones S., Marbán E., Tomaselli G.F. and Li R.A. , Functional integration of electrically-active cardiac derivatives from genetically-engineered human embryonic stem cells with quiescent recipient ventricular cardiomyoc ytes: Insights into the development of cell-based pacemakers., Circulation. 111(1):11-20. See Comments 112(6):e82-83. BEST BASIC STUDY OF 2005. . 2009, 111(1): 11-20.

Researcher : Li SW

List of Research Outputs

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W. , Tam S. , Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke (abstract and poster presentation), EuroPRevent 2010, Prague, 5-7 May 2010 . Prague, European Society of Cardiology.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W. , Lau C.P. , Lam T.H. and Tse H.F. , Selenium deficiency is associated with adverse vascul ar function in patients with high risk for vascular events (abstract and poster presentation), EuroPRevent 2010, 5-7 May 2010, Prague . Prague, European Society of Cardiology, 2010.

Researcher : Lian Q

Project Title:	Comparing differentiation propensity among mescenchymal stem cells derived from sources of human embryonic stem cell lines, term placenta and bone morrow
Investigator(s):	Lian Q, Tse HF
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	10/2008

Abstract:

Human mescenchymal stem cells (MSCs) have been emerged as very valuable cell sources in regenerative medicine. Different tissue-origin derived MSCs share many common properties including conventional capacity of cartilage, fat and bone differentiation. However, there are many biologically differences including multiline age differentiation potential. The different tissue origin-derived MSC with distinct differentiation propensity is one of the most interesting issues and is largely unclear at present. To eventually provide the best MSC source for tissue regeneration in clinical applications and research purpose, therefore the central objective of this proposal is to systematically compare propensity of multilineage differentiation among MSCs derived from sources of human embryonic stem cells (from early embryonic-like stage ,hESC-MSCs), term placenta (from neonatal stage ,PL-MSCs) and adult bone marrow (from adult stage ,BM-MSCs). The specific aims to achieve central goal are to 1. Identifying molecular bases for specific lineage or cell type differentiation potenti al among hESC-MSCs, PL-MSCs and BM-MSCs by fluorescence-activated cell sorting (FACS), microarray and quantitative PCR analysis. 2. Determining propensity of multilineage differentiation (mesoderm, ectoderm and endoderm differen tiation) among hESC-MSCs, PL-MSCs and BM-MSCs by in vitro differentiation studies. 3. Verifying functional characteristics of differentially differentiation potential among hESC -MSCs, PL-MSCs and BM-MSCs by in vivo transplantation studies. These studies will facilitate our understanding of biological characteristics among MSCs derived from different tissue-origins for the development of stem cell-based therapies.

Project Title:	ISSCR 7th Annual Meeting GENERATION OF MESENCHYMAL STEM CELLS FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (iPSC) FOR THE TREATMENT OF LIMB ISCHEMIA
Investigator(s):	Lian Q
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	07/2009
Completion Date:	07/2009

Abstract:

N/A

Project Title:	Generation of corneal epithelial stem cells from human induced pluripotent stem cells (iPSC) and application for corneal epithelial tissue engineering
Investigator(s):	Lian Q, Tse HF, Wong DSH, Siu DCW, Yu CS
Department:	Medicine
Source(s) of Funding:	NSFC/RGC Joint Research Scheme
Start Date:	01/2010

Abstract:

1) Generation of induced pluripotent stem cells (iPSC) from ocular surface epithelial cells or fibroblasts from patients with total limbal stem cell deficiency (LSCD); 2) Differentiation of iPSC into corneal epithelial stem cells (iPSC-CESC) and characterization of iPSC-C ESC; 3) Construction and assessment of iPSC-ESC tissue enginee

Project Title:	Generation of mesenchymal stem cells from human induced pluripotent stem cells (iPS) for the treatment of limb ishcemia
Investigator(s):	Lian Q, Tse HF
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	01/2010

Abstract:

Human mesenchymal stem cells (MSCs), also named multipotent stromal cells have emerged as a promising cell type in regenerative medicine, including in the treatment of myocardial and limb ischemia(Kim et al., 2006; Minguell and Erices, 2006; Pittenger and Marti n, 2004). In the majority of pre-clinical and clinical studies, MSCs are derived from bone marrow (BM). However, there are several potential shortcomings in using BM derived-MSCs (BM-MSCs). BM-MSCs have a limited capacity of proliferation, quickly loss of differentiation potenti al and production of protective factors during ex-vivo expansion before possible therapeutic use (Crisostomo et al., 2006; Kretlow et al., 2008; Wagner W, 2009 ). Importantly, it has been shown that aging and aging-related disorders significantly impair the survival and differenti ation potential of BM-MSCs, and thus limit their therapeutic efficacy (Heeschen et al., 2004; Jiang et al., 2008; Roobrouck et al., 2008; Xin et al., 2009). As a result, there is an emerging interest in the identification of alternative cell sources for MSCs. Recent breakthrough in the generation of induced pluripotent stem cells (iPSCs) from adult somatic cells by reprogramming techniques (Takahashi et al., 2007; Yu et al., 2007) provides a possibility to generate high yield of patient-specific MSCs. However, the differentiation potential of human iPSC into functional MSC and their therapeutic efficacy have never been demonstrated. This study was aimed to generate and characterize human iPSCs-derived MSC and to investigate its biological functions for the treatment of limb ischemia. Our specific objectives are summarized as following: Objective 1: To generate MSCs from human iPSC (iPSC-MSC ) Objective 2: To study basic biology and multipotency of iPSC-MSC. Objective 3: To transplant iPSC-MSC into mice with severe limb ischemia to determine protective effects of iPSC-MSC . Reference Crisostomo, P.R., Wang, M.J., Wairiuko, G.M., Morrell, E.D., Terrell, A.M., Seshadr i, P., Nam, U.H., and Meldrum, D.R. (2006). High passage number of stem cells adversely affects stem cell activation and myocardial protection. Shock 26, 575-580. Heeschen, C., Lehmann, R., Honold, J., Assmus, B., Aicher, A., Walter, D.H., Martin, H., Zeiher, A.M., and Dimmeler, S. (2004). Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease. Circulation 109, 1615-1622. Jiang, S., Kh Haider, H., Ahmed, R.P., Idris, N.M., Salim, A., and Ashraf, M. (2008). Transcriptional profiling of young and old mesenchymal stem cells in response to oxygen deprivation and reparability of the infarcted myocardium. J Mol Cell Cardiol 44, 582-596. Kim, S.W., Han, H., Chae, G.T., Lee, S.H., Bo, S., Yoon, J.H., Lee, Y.S., Lee, K.S., Park, H.K., and Kang, K.S. (2006). Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger's disease and ischemic limb disease animal model. Stem Cells 24, 1620-1626. Kretlow, J.D., Jin, Y.Q., Liu, W., Zhang, W.J., Hong, T.H., Zhou, G., Baggett, L.S., Mikos, A.G., and Cao, Y. (2008). Donor age and cell passage affects differentiation potential of murine bone marrow-derived stem cells. BMC Cell Biol 9, 60. Minguell, J.J., and Erices, A. (2006). Mesenchymal stem cells and the treatment of cardiac disease. Exp Biol Med (Maywood) 231, 39-49. Pittenger, M.F., and Martin, B.J. (2004). Mesenchymal stem cells and their potent ial as cardiac therapeutics. Circ Res 95, 9-20. Roobrouck, V.D., Ulloa-Montoya, F., and Verfaillie, C.M. (2008). Self-renewal and differentiation capacity of young and aged stem cells. Exp Cell Res 314, 1937-1944. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., and Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861-872. Wagner W, B.S., Horn P, Krunic D, Walenda T, Diehlmann A, Benes V, Blake J, Huber FX, Eckstein V, Boukamp P, Ho AD. (2009 ). Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One Jun 9;4(6):e5846. Xin, Y., Wang, Y.M., Zhang, H., Li, J., Wang, W., Wei, Y.J., and Hu, S.S. (2009). Aging Adversely Impacts Biological Properties of Human Bone Marrow-derived Mesenchymal Stem Cells: Implications for Tissue Engineering Heart Valve Construction. Artif Organs. Yu, J.Y., Vodyanik, M.A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane , J.L., Tian, S., Nie, J., Jonsdottir, G.A., Ruotti, V., Stewart, R., et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917-1920.

List of Research Outputs

Lian Q. , Establishing mesenchymal stem cells from human ESC/iPSC and applications in cardiovascular diseases , 1st International Course on Stem Cell Biology and Regenerative Medicine ( HKU- Toronto U) 2009 . 2009.

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Lian Q. , Zhang Y. , Kang S., Zhang Y. , Lai A.Y.K. , Au K.W. , Zhang J. and Tse H.F. , GENERATION OF MESENCHYMAL STEM CELLS FROM HUMAN INDUC ED PLURIPOTENT STEM CELLS (iPSC) FOR THE REATMENT OF LIMB ISCHEMIA, 7th Annunal Meeting of International Society for Stem Cell Research . 2009, 194.

Researcher : Liang RHS

List of Research Outputs

Au W.Y. , Lam K.K., Leung A.Y.H. , Liang R.H.S. , Lie A.K.W. and Kwong Y.L. , Occult autologous haematopoietic regeneration without disease relapse following myeloablative allogeneic haematopoietic SCT for lymphomas, Bone Marrow Transplantation . 2009, 45: 1377–1378.

Au W.Y. , Lam W.W., Chu W.W., Tam S. , Wong W.K., Lau J., Yeung Y.M., Liu H.S. and Liang R.H.S. , Organ-specific hemosiderosis and functional correlation in Chinese patients with thalassemia intermedia and hemoglobin H disease, Annals of Hematology . 2009, 88(10): 947-950.

Chan G.C.F. , Fung K.L. and Liang R.H.S. , Vincristine but not imatinib could suppress mesenchymal niche’s support to acute lymphoid leukemic (ALL) cells., 41th Congress of the International Society of Paedi atric Oncology, Sao Paulo, Brazil, 5 – 9 October 2009. . 2009.

Chan K.K. , Shen L. , Au W.Y. , Yuen H.F. , Wong K.Y. , Guo T. , Wong M.L.Y. , Shimizu N., Tsuchiyama J., Kwong Y.L. , Liang R.H.S. and Srivastava G. , Interleukin-2 induces NF-kappaB activation through BCL10 and affects its subcellular localization in natural killer lymphoma cells, J Pathol . 2010, 221(2): 164-74.

Chan S.S.C. , Leung Y.P. , Leung A.Y.M. , Lam C.L.K. , Hung I., Yuen K.Y. , Liang R.H.S. , Johnston J.M. , Chan C.K., Chu D., Liu S.H. and Lam T.H. , Predictors of influenza vaccination in Chinese older patients with chronic disease in Hong Kong, The First Asia-Pacific Conference on Health Promotion and Education, 18-20 July, Chiba, Japan . 2009, 186.

Chen W.Y.W. , Hu X. , Liang C.T., Wong M.L.Y. , Au W.Y. , Wong K.Y. , Choi W.L. , Wan T.S.K. , Chu K.M. , Chim J.C.S. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , Molecular features and functional consequence of CD44 activation by a novel recurrent IGH translocation t(11;14) (p13;q32) in mature B-cell lymphoid neoplasm., 101st Annual Meeting of American Association for Cancer Research (AACR), Washington D.C., USA, April 2010. . 2010.

Cheng K.K., Leung S.F., Liang R.H.S. , Tai J.W., Yeung R.M. and Thompson D.R., Oropharyngeal mucositis-specific quality-of-life measure in patients with cancer therapy, Hong Kong Medical Journal . 2010, 16(13): 42-46.

Cheng K.K., Leung S.F., Liang R.H.S. , Tai J.W., Yeung R.M. and Thompson D.R., Severe oral mucositis associated with cancer therapy: impact on oral functional status and quality of life, 2009, Epub.

Cheng V.C.C. , Chan J.F.W. , Ngan H.Y. , To K.K.W. , Leung S.Y. , Tsoi H.W. , Yam W.C. , Tai J.W.M. , Wong S.S.Y. , Tse H. , Li W.S. , Lau S.K.P. , Woo P.C.Y. , Leung A.Y.H. , Lie A.K.W. , Liang R.H.S. , Que T.L., Ho P.L. and Yuen K.Y. , Outbreak of Intestinal Infection due to Rhizopus microsporus., Journal of Clinical Microbiology . 2009, 47: 2834-43.

Cheung A.M., Chow C.H. , Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , FLT3/internal tandem duplication subclones in acute myeloid leukemia differ in their engraftment potential in NOD/SCID mice, Leukemia Research . 2010, 34(1): 119-22.

Cheung A.M., Fung T.K. , Fan K.P. , Wan T.S., Chow C.H. , Leung J.C.K. , Chan L.Y., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Successful engraftment by leukemia initiating cells in adult acute lymphoblastic leukemia after direct intrahepatic injection into unconditioned newborn NOD /SCID mice., Experimental Hematology . 2010, 38: 3-10.

Chim J.C.S. , Lie A.K.W., Liang R.H.S. and Kwong Y.L. , A staged approach with vincristine, adriamycin and dexamethasone followed by bortezomib, thalidomide and dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagno sed multiple myeloma, 15th Congress of the European Hematology Association (Abstract) . 2010.

Chim J.C.S. , Lie A.K.W., Chan E.Y.T., Leung Y.Y., Cheung S.C .W., Chan S.Y.T., Liang R.H.S. and Kwong Y.L. , A staged approach with vincristine, adriamycin and dexamethasone followed by bortezomib, thalidomide and dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed multiple myeloma, Annals Hematology . 2010.

Chim J.C.S. , Wong K.Y. , Qi Y. , Foong F., Lam W.L., Wong L.G., Jin D. , Costello J.F. and Liang R.H.S. , Epigenetic inactivation of the miR-34a in hematological malignancies, Carcinogenesis . 2010, 31(4): 745-50.

Chim J.C.S. , Fung T.K. and Liang R.H.S. , Methylation of cyclin-dependent kinase inhibitors, XAF1, JUNB, CDH13 and soluble Wnt inhibitors in Essentia l Thrombocythemia, Journal of Clinical Pathology . 2010, 63(6): 518-21.

Fung K.L. , Liang R.H.S. and Chan G.C.F. , Vincristine But Not Imatinib Could Suppress Mesenchy mal Niche’s Support to Lymphoid Leukemic Cells, Leukemia Lymphoma . 2010, 51(3): 515-522.

Fung T.K. , Cheung A.M., Kwong Y.L. , Liang R.H.S. and Leung A.Y.H. , Differential NOD/SCID mouse engraftment of peripheral blood CD34(+) cells and JAK2V617F clones from patients with myeloproliferative neoplasms., Leukemia Research . 2010.

Fung T.K. , Liang R.H.S. and Leung A.Y.H. , Functional characterization of novel gene NUP98 in zebrafish embryo, 15th Medical Research Conference, 2010.

Gill H., Leung A.Y.H. , Trendell-Smith N.J. , Yeung C.K. and Liang R.H.S. , Sweet Syndrome due to Myelodysplastic Syndrome: Possible Therapeutic Role of Intravenous Immunoglobulin in Addition to Standard Treatment, Advances in Hematology . 2010, 2010:328316: Epub.

Gu J. , Kwong Y.L. , Chan T. , Au W.Y. , Chan Q., Zhang J. , Liang R.H.S. and Khong P.L. , Comparison of DWIBS and 18F-FDG PET/CT in newly diagn osed lymphoma, Joint ISMRM-ESMRMB Annual Scientific Meeting, Stockholm, Sweden, 1-7 May 2010 .

Hu X. , Chen W.Y.W. , Liang A.C.T., Au W.Y. , Wong K.Y. , Wan T.S.K. , Wong M.L.Y. , Shen L. , Chan K.K. , Guo T. , Chu K.M. , Tao Q. , Chim J.C.S. , Loong F. , Choi W.L. , Lu L. , So J.C.C. , Chan L.C. , Kwong Y.L. , Liang R.H.S. and Srivastava G. , CD44 activation in mature B-cell malignancies by a novel recurrent IGH translocation, Blood . 2010, 115: 2458-2461.

Huang H., Wu D., Fu J., Chen G., Chang W., Chow C.H. , Leung A.Y.H. and Liang R.H.S. , All-trans retinoic acid can intensify the growth inhibition and differentiation induction effect of rosiglitazone on multiple myeloma cells, European Journal of Haematology . 2009, 83(3): 191–202.

Huang H.W., Chen G.H., Chang H.R., Chow H.C., Leung A.Y.H. , Liang R.H.S. and Wu D.P., Differentiating effect of PPARgamma ligand rosiglita zone and all trans-retinoic acid on myeloma cells and its possible mechanism, Zhonghua Zhong Liu Za Zhi, 2009, 31(12): 885-9.

Hwang Y.Y. and Liang R.H.S. , Antifungal prophylaxis and treatment in patients with hematological malignancies, Expert Review of Anti-infective Therapy . 2010, 8: 397-404.

Liang R.H.S. , Allogeneic Haematopoietic stem cell transplantation. An Asian perspective, 20th Regional Congress of the International Society of Blood Transfusion . 2009, Abs# AC08.

Lim V., Stubbs J.W., Nahar N., Amarasena N., Chaudry Z.U., Weng S.C., Mayosi B., Van der Spuy Z., Liang R.H.S. , Lai K.N. , Metz G., Fitzgerald G.W., Williams B., Douglas N., Donohoe J., Darnchaivijir S., Coker P. and Gilmore I., Politicians must heed health effects of climate change, Bone Marrow Transplantation . 2009, 339:b3672.

Ma C.H. , Fan K.P. , Ward A.C., Liongue C., Lewis R.S., Cheng S.H., Chan P.K., Yip S.F. , Liang R.H.S. and Leung A.Y.H. , A novel zebrafish jak2a(V581F) model shared features of human JAK2(V617F) polycythemia vera., Experimental Hematology . 2009, 37: 1379-1386.

Ma C.H. , Lin H. , Chung I.S. , Yang D. , Liang R.H.S. and Leung A.Y.H. , Distinctive functions of methionine aminopeptidase II in embryonic hematopoiesis in zebrafish embryos., 15th Medical Research Conference . Hong Kong, 2010.

Ma C.H. , Liang R.H.S. and Leung A.Y.H. , The effect of Diethylaminobenzaldehyde (DEAB), an inhi bitor of Aldehyde Dehydrogenase (Aldh), on Primitive Henatopoiesis during Zebrafish Embryonic Development, 16th Hong Kong International Cancer Congress . 2009, Abs#A5.

Ma C.H. , Liang R.H.S. and Leung A.Y.H. , The effect of diethylaminobenzaldehyde (DEAB), an inhibitor of aldehyde dehydrogenase (Aldh), on primitive hematopoiesis during zebrafish embryonic development. , The 16th Hong Kong Internation Cancer Congress . 2009.

Wong K.Y. , Jin D. , Liang R.H.S. and Chim J.C.S. , Epigenetic silencing of miR-203 is a disease initiation event of multiple myeloma, European Association of Cancer Research, Norway (Poster) . 2010.

Researcher : Liao S

List of Research Outputs

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with passive epicardial patch in porcine model of chronic myocard ial infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Siu D.C.W. , Liao S. , Liu Y. and Tse H.F. , Stem cells for myocardial repair. , Thromb Haematol . 2010, 104(1).

Researcher : Lie AKW

List of Research Outputs

Au W.Y. , Lie A.K.W. , Lam K.Y. and Kwong Y.L. , Engraftment of umbilical cord blood with glucose 6-phosphate dehydrogenase deficiency after double-unit unrelated cord blood transplantation, Bone Marrow Transplantation . 2009, 44(1): 57–58.

Au W.Y. , Lam K.K., Leung A.Y.H. , Liang R.H.S. , Lie A.K.W. and Kwong Y.L. , Occult autologous haematopoietic regeneration without disease relapse following myeloablative allogeneic haematopoietic SCT for lymphomas, Bone Marrow Transplantation . 2009, 45: 1377–1378.

Au W.Y. , Lie A.K.W. , Lam W.W. and Chan J.K., Refractory, concomitant, cutaneous, and systemic lymphomas of discordant B-cell and T-cell lineages, The American Journal of Dermatopathology . 2010, 32(1): 102-4.

Cheng V.C.C. , Chan J.F.W. , Ngan H.Y. , To K.K.W. , Leung S.Y. , Tsoi H.W. , Yam W.C. , Tai J.W.M. , Wong S.S.Y. , Tse H. , Li W.S. , Lau S.K.P. , Woo P.C.Y. , Leung A.Y.H. , Lie A.K.W. , Liang R.H.S. , Que T.L., Ho P.L. and Yuen K.Y. , Outbreak of Intestinal Infection due to Rhizopus microsporus., Journal of Clinical Microbiology . 2009, 47: 2834-43.

Kwan T.K., Ma E.S.K. , Chan Y.Y., Wan T.S.K. , Liu H.S.Y., Sim J.P.Y., Yeung Y.M., Lie A.K.W. and Yip S.F. , BCR-ABL mutational studies for predicting the respon se of patients with chronic myeloid leukaemia to second-generation tyrosine kinase inhibitors after imatinib fail, Hong Kong Medical Journal . 2009, 15(5): 365-73.

Nie Y. , Lau W.C.S. , Lie A.K.W. , Chan G.C.F. and Mok T.M.Y. , Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus, Lupus . 2010, 19: 850-9.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow-derived dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Researcher : Lin H

List of Research Outputs

Ma C.H. , Lin H. , Chung I.S. , Yang D. , Liang R.H.S. and Leung A.Y.H. , Distinctive functions of methionine aminopeptidase II in embryonic hematopoiesis in zebrafish embryos., 15th Medical Research Conference . Hong Kong, 2010.

Researcher : Lin M

List of Research Outputs

Lin M. , Chan A.W., Chan L.Y., Leung J.C.K. , Lai K.N. and Tang S.C.W. , Toll-like receptor 4 mediates tubular inflammation in diabetic nephropathy, Hong Kong Medical Journal . 2010, 16: 39.

Researcher : Liu F

List of Research Outputs

Zhou L. , Fu P., Huang X.R., Liu F. , Lai K.N. and Lan H.Y. , Activation of p53 promotes renal injury in acute aristolochic acid nephropathy, Journal of American Society of Nephrology . 2010, 21(1): 31-41.

Zhou L. , Fu P., Huang X.R., Liu F. , Chung A.C.K. , Lai K.N. and Lan H.Y. , Mechanism of chronic aristolochic acid nephropathy: role of Smad3, Am J Physiol Renal Physiol . 2010, 298(4): F1006-17.

Researcher : Liu H

List of Research Outputs

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Investigator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong. (6-7 March 2010) . 2010, 46.

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.L. , Ho W.M. , Liu H. , Chan K.H. , Ramsden D.B. and Ho S.L. , Neuronal mitochondrial uncoupling proteins: implicatio ns in the pathology of Parkinson’s disease , The Hong Kong Neurological Society - Annual Scientific Meeting 2009; Kowloon Shangri-La Hotel, Hong Kong; 8 Nov 2009. . 2009.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Researcher : Liu H

List of Research Outputs

Ho W.L. , Ho W.M. , Liu H. , Chan K.H. , Ramsden D.B. and Ho S.L. , Neuronal mitochondrial uncoupling proteins: implications in the pathology of Parkinson’s disease , The Hong Kong Neurological Society - Annual Scientific Meeting 2009; Kowloon Shangri-La Hotel, Hong Kong; 8 Nov 2009. . 2009.

Researcher : Liu L

List of Research Outputs

Zu Y. , Liu L. , Xu A. , Lam K.S.L. , Lee M.Y.K. , Vanhoutte P.M.G. R. and Wang Y. , SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells, 34th FEBS Congress, Czech Republic, July 2009 . 2009.

Researcher : Liu Y

List of Research Outputs

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with passive epicardial patch in porcine model of chronic myocardial infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Siu D.C.W. , Liao S. , Liu Y. and Tse H.F. , Stem cells for myocardial repair. , Thromb Haematol . 2010, 104(1).

Researcher : Lo WK

List of Research Outputs

Lam M.F. , Lo W.K. , Tse K.C., Yip T.P.S., Lui S.L. , Chan D.T.M. and Lai K.N. , Retroperitoneal leakage as a cause of acute ultrafiltration failure: its associated risk factors in peritoneal dialysis , Peritoneal Dialysis International . 2009, 29(5): 542-547.

Lui S.L. , Cheng S.W., Yung S.S.Y. , Chan D.T.M. and Lo W.K. , Acute deterioration in residual renal function after CAPD peritonitis is associated with increased interleukin-6 release, J Am Soc Nephrol . 2009, 20: 787A.

Mok M.M., Yip T., Lui S.L. , Chan D.T.M. , Lai K.N. , Lo W.K. and Lo W.K. , Severe hypocalcemia and hyperphosphatemia caused by oral sodium phosphate fleet solution in a hemodialysis patient after parathyroidectomy, Hemodialysis International . 2009, 13: 395.

Wang A.Y.M. , Cheung C.W., Chu J.Y.Y. , Fok A.N.Y. , Lo W.K. , Leung J.C.K. , Tso W.K. and Lai K.N. , Is aortic pulse wave velocity a useful screening test for vascular and valvular calification in end-stage renal disease patients, Journal of American Society of Nephrology . 2009, 20: 443A-444A.

Yip T., Tse K.C., Lam M.F. , Cheng S.W., Lui S.L. , Tang S.C.W. , Mg M., Chan D.T.M. , Lai K.N. and Lo W.K. , Colonic diverticulosis as a risk factor for peritonitis in Chinese peritoneal dialysis patients, Peritoneal Dialysis International . 2010, 30: 187-191.

Yip T.P., Tse K., Ng F., Lam M.F. , Tang S.C.W. , Lui S.L. , Lai K.N. , Chan D.T.M. and Lo W.K. , Clinical course and outcomes of enterococcus peritonitis in peritoneal dialsyisi patients, Nephrology . 2010, 15 (S3): 47.

Yip T.P.S., Lui S.L. , Tse K.C., Xu H., Ng F.S.K. , Cheng S.W. , Chan D.T.M. , Lai K.N. and Lo W.K. , A prospective randomized study comparing tenckhoff catheters inserted using the triple incision method with standard swan neck catheters, Peritoneal Dialysis Internation al . 2010, 30(1): 56-62.

Researcher : Lo Y

List of Research Outputs

Mok T.M.Y. , Chiu S.S.H. , Lo Y. , Mak H.K.F. , Wong R.W.S. , Khong P.L. and Lau W.C.S. , Coronary atherosclerosis using CT coronary angiogram in patients with systemic sclerosis. Rely letter to Editor., Scand J Rheumatol . 2010, 38(5): 381-385.

Mok T.M.Y. , Yiu K.H., Wong C.Y., Lai W.H., Lo Y. , Wong R.W.S. , Tse H.F. and Lau W.C.S. , Endothelial Dysfunction is Associated with Low Level of Circulating Endothelial Progenitor Cells in Patients with Systemic Sclerosis, Clin Exp Rheumatol . 2010, in press.

Mok T.M.Y. , Tse H.F. , Wong C.Y., Qiuwaxi J. , Lai K.W.H. , Lo Y. , Wong R.W.S. and Lau W.C.S. , Endothelial dysfunction is associated with decreased circulating endothelial progenitor cells in patients with systemic sclerosis, Annals of the Rheumatic Diseases . 2009, S337.

Mok T.M.Y. , Wu H. , Lo Y. and Lau W.C.S. , Serum IL-17 and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus, J Rheumatol . 2010, in press.

Mok T.M.Y. , Huang F.P., Ip W.K., Lo Y. , Wong F.Y., Chan E.Y.T., Lam K.F. and Xu D., Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus, Rheumatology . Oxford, 2010, 49: 520-527.

Mok T.M.Y. , Yao T.J. , Lo Y. and Tam S. , Southern Chinese patients with systemic lupus erythematosus in Hong Kong have low vitamin D levels. , HKMJ . 2010, 16: p46 S77.

Mok T.M.Y. , Wu H. and Lo Y. , The relation of cytokines of IL-17/IL-23 axis to Th1/Th2 cytokines and disease activity in systemic lupus eryt hematosus, HKMJ . 2010, 16: p45 S75.

Researcher : Lo YYC

Project Title:	Why are patients willing to pay for chronic disease care?
Investigator(s):	Lo YYC, Lam CLK
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	12/2009
Completion Date:	12/2009

Abstract:

Like many countries in the West, ageing of the population and changes in the socioeconomic structure are coupled with changes in the primary care morbidity pattern. [1,2] The World Health Organization has expected that chronic diseases will be the major burden of illness in the 21st century.[3] Hong Kong is of no exception. Four primary care morbidity surveys have been carried out in Hong Kong since 1980 and have already shown that general practitioners were increasingly taking care of patients with chronic disease.[4] In Hong Kong, primary health care is provided by both the government and the private sector, and is funded in a variety of ways. Preliminary results from a recent territory wide primary care morbidity survey found that the public health care sector was much burdened with patients having chronic disease while the private sector encountered more acute illness and performed more preventive care.[5] Such disparity in morbidity is not unexpected as the public sector is subsidized heavily by the government. Patients only need to pay a very low fee for consultation, medication and investigation. On the other hand, there are various types of primary care providers within the private sector, such as doctors working in solo practice, in group practice, in outpatient clinics of private hospital or in clinics of non-governmental organization (NGO). Differences in morbidity pattern were observed from the survey among these various types of primary care providers on further data analysis. While hypertension, diabetes and lipid disorder accounted for over 40% of all health problems in the public sector, they accounted for 23% in the NGO and less than 10% in either private solo and private group practice. Among all patients with such chronic diseases in the public sector, 77% paid out of their own pocket to have their illness managed while in the NGO clinics, 95% of such patients paid for medical care in the NGO. The aim of the study was to explore the reasons why patients were willing to pay more and out of pocket for chronic disease care in the private sector. Specific objectives are to: 1.Explore the views of patients with chronic disease on the current health care system 2.Explore their attitudes towards health and self-care 3.Measure their enablement in coping with health and illness after consultation 4.Measure their health related quality of life References 1.Fleming DM, Cross KW, Barley MA. Recent changes in the prevalence of diseases presenting for health care. British Journal of General Practice 2005; 55:589-595. 2.Jones R, Schellevis FG, Westert G. The changing face of primary care: the secon d Dutch national survey. Family Practice 2004 Dec; 21(6):597-598. 3.Strong K., Bonita R. The SuRF Report 1. Surveillance of ris k factors related to non-communicable diseases: current status of global data. WHO, 2003. 4.Lee A, Wun YT, Chan KKC. Changing family medicine / general practice morbidity patterns in Hong Kong adults. The Hong Kong Practitioner 1997; 19:508-517. 5.Lo YYC, Lam CLK, Mercer S, et al. Morbidity and management patterns of community based primary health care services in Hong Kong. Studies in Health Services [SHS-P-11]. [Personal communication] 6.Lam, C.L.K., Tse, E.Y.Y., and Gandek , B., Is the standard SF-12 Health Survey valid and equivalent for a Chinese population? Qual Life Res, 2005. 14: p. 539-547. 7.Howie, J.G.R., et al., Quality at general practice consultations: cross sectional survey. BMJ, 1999. 319: p. 738-743. 8.Wong W, Lam CLK, Ho SWW, Choi YS, Sze HH. Effectiveness of western medicine outpatient consultations in primary care – a comparison with Chinese medicine consultations. Event: TWHGs Eddie Wang Chinese Medicine Postgraduate Forum cum Integrated Health Management Conference 2009. Hong Kong. 9.Devers K. How will we know ‘good’ qualitative research when we see it? Beginning the dialogue in health services research. Health Services Research 1999; 34:1153-1188. 10.Sofaer S. Qualitative methods: what are they and why use them? Health Services Research 1999; 34:461-483.

List of Research Outputs

Lo Y.Y.C. , member, In: Dr. Samuel Wong, The Hong Kong Practitioner . The Hong Kong College of Family Physicians, 2009.

Researcher : Lu L

List of Research Outputs

Cheung K.F. , Ye D. , Yang Z. , Lu L. , Liu C.H., Wang X.L., Poon R.T.P. , Tong Y. , Liu P., Chen Y. and Lau G. , Therapeutic efficacy of Traditional Chinese Medicine 319 recipe on hepatic fibrosis induced by carbon tetrac hloride in rats, Journal of Ethnopharmacology . 2009, 124(1): 142-150.

Researcher : Lui SL

List of Research Outputs

Lam M.F. , Lo W.K. , Tse K.C., Yip T.P.S., Lui S.L. , Chan D.T.M. and Lai K.N. , Retroperitoneal leakage as a cause of acute ultrafiltratio n failure: its associated risk factors in peritoneal dialysis , Peritoneal Dialysis International . 2009, 29(5): 542-547.

Lui S.L. , Cheng S.W., Yung S.S.Y. , Chan D.T.M. and Lo W.K. , Acute deterioration in residual renal function after CAPD peritonitis is associated with increased interleukin-6 release, J Am Soc Nephrol . 2009, 20: 787A.

Mok M.M., Yip T., Lui S.L. , Chan D.T.M. , Lai K.N. , Lo W.K. and Lo W.K. , Severe hypocalcemia and hyperphosphatemia caused by oral sodium phosphate fleet solution in a hemodialysis patient after parathyroidectomy, Hemodialysis International . 2009, 13: 395.

Yip T., Tse K.C., Lam M.F. , Cheng S.W., Lui S.L. , Tang S.C.W. , Mg M., Chan D.T.M. , Lai K.N. and Lo W.K. , Colonic diverticulosis as a risk factor for peritoni tis in Chinese peritoneal dialysis patients, Peritoneal Dialysis International . 2010, 30: 187-191.

Yip T.P., Tse K., Ng F., Lam M.F. , Tang S.C.W. , Lui S.L. , Lai K.N. , Chan D.T.M. and Lo W.K. , Clinical course and outcomes of enterococcus peritonit is in peritoneal dialsyisi patients, Nephrology . 2010, 15 (S3): 47.

Yip T.P.S., Lui S.L. , Tse K.C., Xu H., Ng F.S.K. , Cheng S.W. , Chan D.T.M. , Lai K.N. and Lo W.K. , A prospective randomized study comparing tenckhoff catheters inserted using the triple incision method with standard swan neck catheters, Peritoneal Dialysis International . 2010, 30(1): 56-62.

Researcher : Luk JKH

List of Research Outputs

Chan J.F.W. , Lau S.K.P. , Woo P.C.Y. , Fan Y.Y. , Ip J.J.K., Chan C.F., Luk J.K.H. and Yuen K.Y. , Lactobacillus rhamnosus hepatic abscess associated with Mirizzi syndrome: a case report and review of the literature, Diagnostic Microbiology and Infectious Disease . 2010, 66: 94-97.

Researcher : Luk TH

List of Research Outputs

Dai Y.L., Luk T.H. , Siu D.C.W. , Yiu K.H., Chan K.H.T. , Lee S.W.L. , Li S.W., Fong B., Wong W.K., Tam S. , Lau C.P. and Tse H.F. , Mitochondrial dysfunction induced by statin contributes to endothelial dysfunction in patients with coronary artery disease., Cardiovascular Toxicology . 2010, 10: 130-8.

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H., Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patients with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Researcher : Ma CH

Project Title:	Which aldehyde dehydrogenase isoform(s) is/are important for primitive hematopoiesis during zebrafish embryonic development
Investigator(s):	Ma CH, Leung AYH
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	08/2009

Abstract:

Please refer to the attached file "Section V".

List of Research Outputs

Ma C.H. , Fan K.P. , Ward A.C., Liongue C., Lewis R.S., Cheng S.H., Chan P.K., Yip S.F. , Liang R.H.S. and Leung A.Y.H. , A novel zebrafish jak2a(V581F) model shared features of human JAK2(V617F) polycythemia vera., Experimental Hematology . 2009, 37: 1379-1386.

Ma C.H. , Lin H. , Chung I.S. , Yang D. , Liang R.H.S. and Leung A.Y.H. , Distinctive functions of methionine aminopeptidase II in embryonic hematopoiesis in zebrafish embryos., 15th Medical Research Conference . Hong Kong, 2010.

Ma C.H. , Liang R.H.S. and Leung A.Y.H. , The effect of Diethylaminobenzaldehyde (DEAB), an in hibitor of Aldehyde Dehydrogenase (Aldh), on Primitive Henatopoiesis during Zebrafish Embryonic Development, 16th Hong Kong International Cancer Congress . 2009, Abs#A5.

Ma C.H. , Liang R.H.S. and Leung A.Y.H. , The effect of diethylaminobenzaldehyde (DEAB), an inhibito r of aldehyde dehydrogenase (Aldh), on primitive hematopoiesis during zebrafish embryonic development. , The 16th Hong Kong Internation Cancer Congress . 2009.

Researcher : Ma J

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Researcher : Mak JCW

Project Title:	Role of transforming growth factor- beta1 variants in susceptibility to tuberculosis in Hong Kong Chinese population
Investigator(s):	Mak JCW, Chan MMW
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2005

Abstract:

i) To study the role of two common single nucleotide polymorphisms (SNPs) at the promoter (C-509T) and coding regions (T869C) of the TGF-beta1 gene in conferring susceptibility to the development of tuberculosis (TB) in Hong Kong Chinese population. ii) To perform functional analysis in correlating the associated polymorphisms with the plasma level of TGF-beta1 in TB patients and healthy controls. iii) To conduct a study in determining the proportion of patients with chronic obstructive pulmonary disease (COPD) with a past history of tuber culosis since COPD is a major cause of respiratory disability in Hong Kong.

Project Title:	Effects of intermittent hypoxia and/or cigarette smoke on oxidative stress-induced apoptotic markers in human endothelial cells
Investigator(s):	Mak JCW, Ip MSM
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2008
Completion Date:	09/2009

Abstract:

Obstructive sleep apnoea (OSA) is an increasingly common disorder. Including “subclinical” subjects who do not claim overt symptoms, the condition is estimated to affect as many as a quarter of the middle-aged men in some Caucasian populations, and at least 8% of Chinese men in Hong Kong [1,2]. It is a condition characterized by repeated interruptions in the airflow due to partial or complete collapse of the upper airway during sleep, leading to chronic intermittent hypoxia (CIH). There is growing evidence that it may constitute an independent risk factor for cardiovascular disease (CVD)[3]. Cigarette smoking is a well-established cardiovascular risk factor [4]. It has been reported that cigarette smoking (CS) is independently associated with an increased risk of OSA [5], and smoking is not an uncommon prevailing habit among OSA subjects, depending on the smoking prevalence of the population as well. It is highly plausible that OSA and cigarette smoking both contribute independently as well as interact in vascular pathogenesis. Recently, a synergistic effect has been reported between OSA and cigarette smoking (CS) on some of the biochemical cardiovascular risk markers such as ceruloplasmin and high density lipoprotein (HDL)[6]. The mechanistic pathways leading to vascular dysfunction in OSA or CS exposure, and in particular their potential interaction s have not been fully elucidated. Endothelial cells provide a permeable barrier between circulating blood cells and the underlying vascular tissue, and play a pivotal role in the regulation of vascular tone and cellular growth. Endothelial cell homeostasis is maintained by balancing proliferation and apoptosis. Increased detection of endothelial apoptotic cells has been reported ex vivo in patients with OSA[7]. Endothelial cell ap optosis has also been implicated in smoking-related endothelial dysfunction [8], in which cigarette smoke induces necrosis of endothelial cells [9]. In both OSA and CS, there is now evidence that oxidative stress may be important intermediary mechanisms of endothelial injury. In OSA, the repetitive periods of hypoxia and reoxygenation may promote cell stress, while cigarette smoke contains a large number of different oxidants and radicals that are known to cause a pro-oxidative state in the circulating system [10]. We hypothesize that either intermittent hypoxia (IH) or cigarette smoke (CS) exposure could increase endothelial cell death through Bcl-2/Bax expression, and the combined exposure would be additive or synergistic. The Bcl-2 family of protein comprising both anti- and pro-apoptotic members plays pivotal roles in regulating apoptosis [11]. The 26 kDa Bcl-2 membrane-associated antiapoptic member who prevents apoptosis and necrotic death by inhibiting the release of cytochrome c from the mitochondria [12]. In contrast Bax, the binding partner protein for Bcl-2 [13], mainly induces cytochrome c release from mitochondria [14]. Actually, the balance of Bcl-2/Bax in a cell is regarded as one of the crucial factors determining whether or not the cell will undergo apoptosis. Objectives The specific aims of the study are: · To construct a novel in vitro endothelial cell system to explore features of apoptosis underlying the molecular response in cultured cells exposed to IH and CS. · To characterize whether IH- and/or CS-induced alterations in O2·- and H2O2 production play a role in apoptosis. · To examine the effects of IH and CS on proteins of Bcl-2 family. References 1. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. A population health perspective. Am J Respir Crit Care Med 2002;165:1217-1239. 2. Ip MS, Lam B, Tang LC, Lauder IJ, Ip TY, Lam WK. A community study of sleep-disordered breathing in middle-aged Chinese women in Hong Kong. Chest 2004;125:127-134. 3. McNicholas WT, Bonsignore MR. Sleep apnea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;129:156-178. 4. Barnoya J, Glantz SA. Cardiovascular effects of secondhand smoke: nearly as large as smoking. Circulation 2005;111:2684-2698. 5. Kashyap R, Hock LM, Bowman TJ. Higher prevalence of smoking in patients diagnosed as having obstructive sleep apnea. Sleep Breath 2001;5:167-172. 6. Lavie L, Lavie P. Smoking interacts with sleep apnea to increase cardiovascular risk. Sleep Med 2007 May 18 [Epub ahead of print] 7. El Solh AA, Akinnusi ME, Baddoura FH, Mankowski CR. Endothelial cell apoptosis in obstructive sleep apnea. A link to endothelial dysfunction. Am J Respir Crit Care Med 2007;175:1186-91. 8. Yang YM, Liu GT. Damaging effect of cigarette smoke extract on primary cultured human umbilical vein endothelial cells and its mechanism . Biomed Environ Sci 2004;17:121-34. 9. Wickenden JA, Clarke MC, Rossi AG, Rahman I, Faux SP, Donaldson K, MacNee W. Cigarette smoke prevents apoptosis through inhibition of caspase activation and induces necrosis. Am J Respir Cell Mol Biol 2003;29:562-70. 10. Bernhard D, Wang XL. Smoking, oxidative stress and cardiovascular diseases – do anti-oxidative therapies fail? Curr Med Chem 2007;14:1703-1712. 11. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998;81:1322-1326. 12. Kuwana T, Newmeyer DD. Bcl-2 family proteins and the role of mitochondria in apoptosis. Curr Opin Cell Biol 2003;15:691-699. 13. Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74:609-619. 14. Jurgensmeier JM, Xie Z, Deveraux Q et al. Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA 1998;95:4997-5002.

Project Title:	Effects of intermittent hypoxia and/or cigarette smoking on endothelial injury in vivo - relevant to obstructive sleep apnea
Investigator(s):	Mak JCW, Ip MSM
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	10/2008

Abstract:

(1) To set up an in vivo experimental rat model of exposure to CIH in OxyCycler A84 System and/or exposure to CS in a specially designed smoking chamber; (2) To compare the vascular morphological changes over time (4, 8 and 12 weeks) in rats exposed to CIH and/or CS; (3) To evaluate apoptotic markers in serum and/or vascular tissues in this rat model; (4) To determine the oxidative/antioxidative, and inflammatory/anti-inflammatory status in serum and/or vascular tissues in this rat model; (5) To study endothelial dysfunction in clinical subjects (measuring peripheral arterial tone response to reactive hyperemia; and circulating biomarkers of interest), with reference to their OSA and smoking status.

Project Title:	Pre- and post-operation sputum and serum tumor markers in non-small cell lung cancer patients
Investigator(s):	Mak JCW, Lam B
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2009

Abstract:

Lung cancer is the leading cause of cancer mortality with a 5-year survival of 14% (1). In Hong Kong, it accounts for about 30% of all cancer death (2). For patients with early stage non-small cell lung cancer (stage I or II), surgery provides the best prospect of cure with 5 year survival ~ 70%. Despite curative operation, clinically significant second primary lung cancer is diagnosed in patients with prior NSCLC at a rate of 1 to 3% per patient per year (3-5). Despite postoperative follow-up, only 50% of second primary lung cancers are resectable either due to late presenta tion or limited lung reserve. Routine postoperative chest roentgenograms (CXR) are neither sensitive nor specific for detection of second lung cancer. Computed tomography (CT) is superior to CXR in detecting parenchymal nodules but CT is not sensitive in detecting early endobronch ial lesions. Newer bronchoscopy systems are able to detect early endobronchial lesions (7) but because of the invasive nature of the bronchoscopy, this is unlikely a primary tool for early detection of lung cancer. As lung cancer arises from the epithelium of the bronchial tree, sputum examination could be the earliest way of detecting lung cancer non-invasively. Sputum cytolog y, however, has a low sensitivity for peripheral lung cancer, i.e. adenocarcinoma, the commonest type of lung cancer (8). It has been showed that respiratory secretions from lung cancer patients contained high levels of tumor markers (9).By using micro sampling probe tools (which can collect bronchial epithelial lining fluid), tumor markers in fluid from tissues surrounding lung cancer are significantly higher than that of the contra lateral sides and that of the corresponding serum level (10). However, the technology still needs to be applied via bronchoscopy, i.e. invasively. A recent published paper demonstrated that tumor markers from induced sputum were significantly higher in lung cancer patients suggesting tumor markers in the sputum could be used as a tool for early detection of lung cancer (11). We hypothesize that sputum tumor markers would have a good correlation with lung cancer status and could be used as a clinical tool for early detection of second primary lung cancer in patients with cured non-small cell lung cancer (NSCLC) patients. This could improve the prognosis of lung cancer. Objectives • To evaluate carcinoembryonic antigen (CEA) and cytokeratin fragment 19 (CYFRA 21-1) levels in sputum and serum before operation, 3 months and 1 year after operation • To compare the diagnostic utility of sputum with that of serum tumor markers References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer J Clin 1999;49:8-31. 2. Hong Kong Cancer Registry: Cancer Incidence & Mortality in Hong Kong. Hospital Authority 1999. 3. Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998;90:1335-1345. 4. Thomas PA, Rubinstein L. Malignant disease appearing late after operation for T1 N0 non-small cell lung cancer. J Thorac Cardiovsc Surg 1993;106:1053-1058. 5. Woolner LB, Fontana RS, Cortese DA, et al. Roentgenographically occult lung cancer: pathologic findings and frequency of multicentricity during a 10-year period. Mayo Clin Proc 1984;59:453-466. 6. Athanassiadou P, Psyhoyou H, Kyrkou K et al. Expression of keratins and carcino embryonic antigen in bronchial squamous metaplasma and lung carcinomas. Acta Cytol 1995;39:1161-1166. 7. Lam S et al. Fluorescence tumor detection, in Hetzel MR (ed): Minimally invasive Techniques in Thoracic Medicine and Surgery; pp 179-191. London, Chapman & Hall, 1995. 8. Kennedy TC, Hirsch FR. Using molecular markers in sputum for the early detection of lung cancer: a review. Lung Cancer 45(Suppl 2): S21-S27. 9. Khajotia RR, Mohn A, Pokieser L et al. Induced sputum and cytological diagnosis of lung cancer. Lancet 1991;338:976-977. 10. Watanabe M, Ishizaka A, Ikeda E, Ohashi A, Kobayashi K. Contributions of Bronchoscopic Microsampling in the Supplemental Diagnosis of Small Peripheral Lung Carcinoma Ann Thorac Surg 2003;76:1668 –73 11. Hillas G, Moschos C, Dimakou K et al. Carcinoembryonic antigen, neuron-specific enolase and cytokeratin fragment 19 (CYFRA 21-1) levels in induced sputum of lung cancer patients. Scandinavia n Journal of Clinical and Laboratory Investigation, 2008;68:542-547

Project Title:	Involvement of serotoninergic system in cigarette smoke-induced inflammatory responses in human airway epithelial cells
Investigator(s):	Mak JCW
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	05/2010

Abstract:

Background Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway limitation together with abnormal inflammation in the lung. Cigarette smoke (CS) is one of the major causes to this disease, which is involved in the induction of inflammatory responses in the airway by elevating pro-inflammatory cytokines, i.e. interleukin-8 (IL-8). As the first site of contacting CS, airway epithelial cells play an important role in monitoring the airway inflammation process. Exposure to CS has been reported to elevate interleukin-8 (IL-8) release in epithelial cells which is positively correlated to airway dysfunction (1). Serotonin (5-hydroxytryptamine; 5-HT) is a neuroimmunomodul ator which is present in brain and peripheral tissues. 5-HT has a variety of physiological functions including regulation of temperature, learning and memory, and can affect the activities of the gastrointestinal tract, the cardiovascular and respiratory systems. 5-HT is released during inflammatory processes and may interact with circulating immune cells. Evidences such as increa sed systemic serotonin levels in non-smokers after smoking (2) and improved lung function by applying selective serotonin receptor 2 antagonist, ketanserin, to COPD patients (3,4), suggest the involvement of serotoninergic system in COPD. Recently, activation of 5-HTR subtypes with selective 5-HTR agonists elevates the release of pro-inflammatory markers, IL-6 and IL-8, in BEAS-2B and alveolar epithelial cells type II (AEC-II), further indicating the involvement of peripheral serotoninergic system in lung epithelial inflammation process (5). Of the 7 different 5-HT receptor families (5-HTR1-7), each of these are G-protein-coupled receptors with the exception of the 5-HTR3, which is a ligand-gated ion channel (6). 5-HTR2 including 5-HTR2A, 5-HTR2B and 5-HTR2C, has been shown in regulating inflammatory responses in different cell types (7-9). Activation of 5-HTR2A can result in stimulating mitogen-activat ed protein kinases (MAPKs) signaling cascade via inositol 1, 4, 5-triphosphate (IP3) and diacylglycerol pathways (10-13). MAPKs, including p38, extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminus kinase (JNK), have recently been shown to be involved in cig arette smoking elicited IL-8 release in human cultured epithelial cells (14). Nevertheless, the presence of serotonin itself has been demonstrated to be necessary for expressi on of the inflammatory markers IL-6 and TNF-α, with lower serotonin levels inducing, and higher levels decreasing, expression of these markers (15). This inverted U-shaped response clearly indicates that serotonin may play an important role in modulating molecular components of the inflammatory process. Rationale for the proposed study It is unclear whether exposure to CS will release 5-HT from airway epithelial cells in the modulation of IL-8 release. We hypothesize that activation of 5-HT2 receptors may contribute to CS-induced IL-8 release via MAPK signaling pathways in human airway epithelial cells. The proposed study is designed to address these important issues in the inflammatory process. A bett er understanding of these mechanisms may aid us in providing potential platforms for novel therapies in CS-induced lung diseases such as COPD. Objectives • To study whether CS-induced 5-HT causes pro-inflammatory IL-8 release • To investigate the mechanisms on how CS modulates the 5-HT levels leading to IL-8 release References 1. Kodama T, Kanazawa H, Tochino Y, Kyoh S, Asai K, Hirata K. A technological advance comparing epithelial lining fluid from different regions of the lung in smokers. Respir Med 2009; 103:35-40. 2. Racké K, Schwörer H, Simson G. Effects of cigarette smoking or ingestion of nicotine on platelet 5-hydroxytryptamine (5-HT) levels in smokers and non-smokers. Clin Investig 199 2; 70:201-204. 3. Cazzola M, D’Amato G, Lobefalo G, Guillaro B, Sepe J, Assogna G, Pietroletti R, Lauria D. Ketanserin, a new blocking agent of serotonin S2-receptors. Respirator y functional effects in chronic obstruction of the airways. Chest 1987; 92:863-866. 4. Cazzola M, Guidetti E, Sepe J, Assogna G, Lucchetti G, Santangelo G, D'Amato G. Acute respiratory and cardiovascular effects of inhaled ketanserin in chronic obstructive pulmonary disease. A comparative study with intravenously administered ketanserin. Chest 1990; 97:901-905. 5. Bayer H, Müller T, Myrtek D, Sorichter S, Ziegenhagen M, Norgauer J, Zissel G, Idzko M. Serotoninergic receptors on human airway epithelial cells. Am J Respir Cell Mol Biol 2007; 36:85-93. 6. Nichols DE, Nichols CD. Serotonin receptors. Chem Rev 2008; 108:1614-1641. 7. Ito T, Ikeda U, Shimpo M, Yamamoto K, Shimada K. Serotonin increases interleukin-6 synthesis in human vascular smooth muscle cells. Circulation 2000; 102:2522-2527. 8. Cloez-Tayarani I, Petit-Bertron A-F, Venters HD, Cavaillon J-M. Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors. Int Immunol 2003; 15:233-240. 9. Marconi A, Darquenne S, Boulmerka A, Mosnier M, D’Alessio P. Naftidrofuryl-driven regulation of endothelial ICAM- 1 involves nitric oxide. Free Rad Biol Med 2003; 34:616-625. 10. Porter RH, Benwell KR, Lamb H, Malcolm CS, Allen NH, Revell DF, Adams DR, Sheardown MJ. Functional characterizati on of agonists at recombinant human 5-HT2A, 5-HT2B, and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 1999; 128:13-20. 11. Greene EL, Houghton O, Collinsworth G, Garnovskaya MN, Nagai T, Sajjad T, Bheemanathini V, Grewal JS, Paul RV, Raymond JR. 5-HT2A receptors stimulate mitogen-activated protein kinase via H2O2 generation in rat renal mesangial cells. Am J Physiol Renal Physiol 2000; 278:F650-F658. 12. Jerman JC, Brough SJ, Gager T, Wood M, Coldwell MC, Smart D, Middlemiss DN. Pharmacological characterization of human 5-HT2 receptor subtypes. Eur J Pharmacol 2001; 414:23-30. 13. Knauer CS, Campbell JE, Chio CL, Fitzgerald LW. Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors. Naunyn-Schmied Arch Pharmacol 2009; 379:461-471. 14. Moretto N, Facchinetti F, Southworth T, Civelli M, Singh D, Patacchini R. α,-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol 2009; 296:L839-L848. 15. Kubera M, Maes M, Kenis G, Kim YK, Lason W. Effects of serotonin and serotonergic agonists and antagonists on the production of tumor necrosis factor alpha and interleukin-6. Psychiartry Res 2005; 134:251-258.

List of Research Outputs

Chan C.H. , Leung V.O.Y. , Lam C.L.D. , Mak J.C.W. , Freeman C., Ip M.S.M. and Shum D.K.Y. , Sulfated maltoheptaose reduces neutrophilic airway inflammation in a smoking rat model of chronic obstructive pulmonary disease , Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” 6-7 March 2010 . 2010.

Chan K.H. , Ho S.P., Yeung S.C. , So H.L. , Cho C.H., Koo M.W.L. , Lam W.K. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine . 2009, 103: 1746-1754.

Chan K.H. , Yeung S.C. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Effects of Chinese green tea on cigarette smoke-induced lung inflammation, oxidative stress and protease activity in rats, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A5062.

Chan K.H. , Yeung S.C. , Yao T.J. , Ip M.S.M. , Cheung A.H.K. , Chan M.M.W. and Mak J.C.W. , Elevated Plasma Adiponectin Levels In Patients With Chronic Obstructive Pulmonary Disease, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 10.

Chang R.C.C. , Yang X. , Ho Y.S. , Yeung S.C. and Mak J.C.W. , Alzheimer-like pathology in rat receiving passive smoking, Society for Neuroscience 2009 . Program No. 626.13: Poster No. H26.

Han Q. , Yeung S.C. , Ho S.P. , Ip M.S.M. and Mak J.C.W. , Differential Effects Of Intermittent Hypoxia And/or Cigarette Smoking On The Expression Levels Of Fatty Acid-binding Protein In Rat Heart And Lung: An In Vivo Pilot Study, Respirology . 2009, 14 (Suppl. 3): A171.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Effects Of Intermittent Hypoxia On A-/e-fabp Expression In Human Aortic Endothelial Cells, International Journal of Cardiology . 2010, Epub ahead of print.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification Of Serum Adiponectin And Cinc-1 Levels By Intermittent Hypoxia And/or Hyperlipidemia In Vivo, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 22.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification of circulating and cardiac expressions of adiponectin and CINC-1 by intermittent hypoxia in vivo, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A3702.

Ho J.C.M. , Ho S.P. , Mak J.C.W. , Wong M.K.Y. , Ip M.S.M. and Lam W.K. , Alterations of systemic antioxidants and 8-isoprostane during chemotherapy for lung cancer. , 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S909.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Blockage of serotonin receptor 2 attenuates cigarette-induced IL-8 release in human bronchial epithelial cells, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A1399.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Involvement of Serotonin in Cigarette Smoke-Induced IL-8 Release in Airway Epithelial Cells, ATS 2010 International Conference, New Orleans, USA (May 14-19, 2010) . 2010.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Involvement of serotoninergic system in cigarette-induced inflammatory responses in human bronchial epithelial cells, HKU 14th Research Postgraduate Symposium, Hong Kong (December 2-3, 2009) . 2010.

Lau K.W. , Law A.C.K. , Ip M.S.M. and Mak J.C.W. , Ketanserin Attenuates Cigarette-mediated Oxidative Stress In Human Bronchial Epithelial Cells, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 34.

Mak J.C.W. , Oxidative Stress In Airway Diseases, Department Of Pharmacology, National University Of Singapore . 2010.

Researcher : Mak W

List of Research Outputs

Chan K.H. , Tsang J.W.H. , Mak W. , Liu H.H.W., Ho S.L. and Cheung R.T.F. , Thymomatous myasthenia gravis among Hong Kong Chinese, 20th Meeting of the European Neurological Society, Berlin, 2010. Journal of Neurology . 2010, 257 (Supplement 1): S170.

Chan S.H.S. , Mak W. and Wong V.C.N. , A girl with atypical chronic inflammatory demyelinat ing polyneuropathy, Annual Scientific Meeting 2009, The Hong Kong Neurolog ical Society, Hong Kong, 7 November 2009 .

Chang R.S.K., Chan R.C.L., Chu M.M.Y., Yan C.H., Mak W. , Cheung R.T.F. and Ho S.L. , Risk factors, clinical features and prognosis of perioperative stroke in adults, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 13.

Chang R.S.K., Mak W. , Cheung R.T.F. and Ho S.L. , Short-latency somatosensory-evoked potential in patients with central nervous system space-occupying lesions: a study of 261 cases, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 13.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Herpes simplex encephalitis: how good are we in diagnosing this condition?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 29.

Kwan M.W.W., Mak W. , Chan K.H. , Cheung R.T.F. and Ho S.L. , Ischaemic stroke related to branch artery disease: a missing link?, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 30.

Liu H.H.W., Tsang J.W.H. , Pang S.Y.Y., Ho S.L. , Cheung R.T.F. , Chu A.C.Y. , Tse M.M.Y., Mak W. , Ho W.L. and Chan K.H. , Thymomatous myasthenia gravis, 15th Medical Research Conference, Faculty of Medicine, The University of Hong Kong . 2010.

Researcher : Mok TMY

Project Title:	Interleukin-33 and its relation with Th1/Th2 cytokine and disease activity in systemic lupus erythematosus
Investigator(s):	Mok TMY, Ip WK, Chan EYT
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	05/2009
Completion Date:	02/2010

Abstract:

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects young women leading to significant morbidity and mortality. This disease is more prevalent in the Chinese population including Hong Kong compared to Caucasian. Current therapy involves high dose corticosteroids and immunosuppressants that are associated with significant adverse effects includin g predisposition to infection. Targeted therapy towards molecules that are pivotally involved in the disease pathogenesis is appealing and may offer higher efficacy and lesser side effects. The pathogenesis of SLE involves production of autoantibodies by autoreactive B lymphocytes activated by autoreactive T cells. Autoantibodies bind to autoantigens leading to immune complex formation that deposit in major organs causing inflammation and damage. Various cytokines, mediators for immune cell interactions, have been found to be involved in the pathogenesis in SLE. High serum levels of both T helper 1 (Th1) pro-inflammatory cytokines including tumour necrosis factor (TNF-α) and interferon (IFN)-γ and T helper 2 (Th2) anti-inflammatory cytokines including interleukin (IL)-4 and IL-10 have been demonstrated in SLE(1). However, serum levels of Th2 cytokines pred ominate and thus SLE is generally regarded as a Th2 disease(2-4). However, the interaction between Th1 and Th2 cytokines in the pathogenesis of SLE has not been fully elucidated. IL-33 is a newly described cytokine that belongs to the IL-1 family that includes IL-1ß and IL-18(5, 6). Unlike other IL-1 family members that mediate production of other pro-inflammatory cytokines that have been shown to play an important role in inflammatory diseases(5), IL-33 has been found to drive production of Th2-associa ted cytokines from in vitro polarised Th2 cells(7). Stimulation of cells with IL-33 leads to production of IL-5 and IL-13 and increased serum immunoglobulin levels that are typical of Th2 immunity(4). IL-33 has been linked to airway hyperresponsiveness and asthma, a Th2 predominan t condition(8). Thus, IL-33 has been postulated to be an important mediator of Th2 rather than Th1 immunity(9). On the other hand, IL-33 has also been shown to induce production of Th1 cytokines from human natural killer (NK) cells in addition to its effect on basophils in the production of Th2 cytokines(10). IL-33 has recently been found to be a ligand for the orphan IL-1 family receptor ST2 which is expressed primarily on mast cells and on Th2 cells(11) and is linked to Th2 effector functions(12). IL-33 has been demonstrated to bind to ST2 and promote cytokine production via a MyD88- and NF-κB-dependent manner in mouse model of allergic airway inflammation(8, 13). Other than the transmembrane form, the IL-33 receptor is also alternatively spliced to produce a secreted soluble form (sST2)(12). sST2 has been found to be elevated in serum and to correlate with severity of asthmatic exacerbation(14) and septic shock(15). sST2 has been shown to possess negative regulatory effect on IL-33 by inhibiting the induction of NF-κB and may have treatment implication in allergic airway conditions(16). IL-33 has not been studied before in SLE, a Th2 predominant disease. On the other hand, sST2 level has previously been found to be elevated in autoimmune diseases including SLE(17) compared to controls. However, the relation of serum level of sST2 to that of IL-33 and SLE disease activity has not been explored. Our study aims to examine the role of IL-33 in correlation with Th1/Th2 cytoki ne profile and sST2 expression and disease activity in SLE patients. The hypothesis of our study is that IL-33 is involved in the mediation of Th2 immune response in SLE and that sST2 may be a regulatory factor for IL-33. Indeed, our preliminary study measuring serum IL-33 and sST2 levels in SLE patients revealed decreased IL-33 and elevated sST2 levels compared to normal controls (Figure 1 and Figure 2 in appendix). This leads us to the postulation that IL-33 may have a role in the pathophysiology of SLE that is counteracted by sST2. Objectives This study aims to examine the role of IL-33 and its regulation by sST2 in the pathogenesis of SLE. Other than serum IL-33 and sST2 levels that we have already measured in SLE serum and controls, we would like to examine: 1. the correlation between IL-33, sST2 and other Th1 and Th2 cytokines and disease activity in SLE patients 2. the effect of human recombinant IL-33 on SLE peripheral blood mononuclear cells (PBMCs) in regard to production of Th1 and Th2 cytokines in vitro 3. the expression of ST2 on PBMCs in SLE patients compared to healthy controls 4. Signal transduction pathway mediating IL-33 effect via ST2 on SLE PBMCs

Project Title:	Polarization of Th17 cells by ac tivated dendritic cells in systemic lupus erythematosus
Investigator(s):	Mok TMY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	05/2010

Abstract:

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects predominantly young women and is associated with significant morbidity and mortality. This disease is more prevalent among Chinese than Caucasian populations. SLE is characterised by a phlethora of autoantibodies against nuclear antigens and organ inflamm ation secondary to immune complex deposition. Increased apoptosis and deficient clearance of apoptotic material have been implicated as key processes in the pathogenesis that provides a source of autoantigens leading to induction of autoantibodies and autoimmune response(1). We have previously demonstrated impaired phagocytosis of apoptotic neutrophils by macrophages in SLE patients(2). Apoptotic cells may undergo secondary necrosis if not removed swiftly(3). The cellular contents released by necrotic cells have been shown to act as endogenous danger signa ls and activate dendritic cells (DCs)(4, 5). DCs are professional antigen presenting cells that play a key role linking the innate and adaptive immune systems. The maturity status of DCs determines tolerance or activation of immune response. Immature DCs capture antigens without eliciting immune response because of production of anti-inflammatory cytokines such as transforming growth factor (TGF)-β and interleukin (IL)-10. In contrast, fully matured and activated DCs induce antigen-specific immunity, associated with production of pro-inflammatory cytokines such as tumour necrosis factor (TNF)-α and IL-6(6). DCs polarise naïve T cells towards a particular T-helper (Th) cell phenotype depending on the cytokine millieu in which DC-T cell interaction occurs. T cell mediated immune response has traditionall y been believed to be controlled by Th1 and Th2 cells(7). Recently, DC activation has also been shown to elicit Th17 response with production of IL-17(8) which has pro-inflammatory effects. Th17 cells have been identified to be a new subset of Th effector cells with distinct requirement of inducing cytokines and transcriptional factor for differentiation and produce IL-17, their signature cytokine(9, 10). The differentiation of Th17 cells excludes the acquisition of Th1 or Th2 phenotypes, and the transcription factor, retinoid-related orphan receptor (RORγt), is expressed exclusively in these cells(11). In human, IL-1β appears to be an important factor in the development of Th17 cells from naïve T cells(12). IL-23, a cytokine of the IL-12 family, has been found to play a crucial role in the expansion and maintenance of Th17 cells and mediates the full acquisition of function of these cells(13). IL-23 is primarily involved in immune defence against microbial infection by rapid recruitment of neutrophils to the sites of acute infection(14). IL-23 is produced by DCs within a few hours after microbial encounter which triggers rapid IL-17 response from tissue resident T cells. IL-17 then promotes the production of IL-1, IL-6, IL-8, chemokines and TNF-α by stromal cells, endothelial cells and monocytes(15). This capability of IL-17 in the induction of other pro-inflammatory cytokines, chemokines and acute-phase proteins(14) has been linked to the pathogenesis of many inflammatory diseases such as rheumatoid arthritis(16), psoriasis(17 ) and inflammatory bowel disease(18). IL-17 has recently been linked to pathogenesis of murine model of SLE as well as human lupus(19). Our group (Appendix I) and others have reported elevated serum IL-17 in SLE patients (20-23). Our preliminary data also demonstrated higher number of terminally committed Th17 cells that express IL23 receptor among peripheral blood CD4+ T cell population in SLE patients compared to controls (Appendix II). Th17 cells were also found in renal tissue from patients with active lupus nephritis(24, 25) and in the spleen, kidneys and other involved organs in murine lupus model(24, 26, 27). A higher frequency of these IL-17 producing cells was found in patients with active disease compared to those with inactive disease and controls(21, 22) suggesting a role of IL-17 in inflammatory response in the lupus pathophysiology. Little is known about the physiological conditions needed for human Th17 development and maintenance, particularly the role of DCs. DCs stimulated with various toll like receptor (TLR) ligands have been found to elicit both Th1 and Th17 memory responses(8). TLRs are pattern recognition receptors on DCs that recognize pathogen-associated molecular patterns on surface of micro-organisms. Some TLRs have been implicated in the pathogenesis of SLE(28). Triggering of TLRs by pathogenic molecules results in maturation and activation of DCs with expression of co-stimulatory molecules, which together with secretion of cytokines by DCs, determines effector Th cell differentiation(6). Stimul ation via the c-type lectin receptors on DCs, dectin-1, has also been shown to induce Th17 response in the immune defense against fungal infection(29), which is not uncommon infective complications in SLE patients(30). Dectin-1 directs Th cell differentiation by controlling non-canonical NF-κB activation through Syk(31, 32) and Raf-signaling, the latter is essential to induce Th1 and Th17 dependent immune responses and hence linki ng adaptive immunity(33). Furthermore, a recent study showed that ingestion of apoptotic blebs by DCs led to a mature phenotype that induced T cells to produce IL-17 in a murine lupus model(34). Previous studies have suggested that early apoptotic cells are efficiently removed by macrophages and DCs but late apoptotic or secondary necrotic cells may lead to maturation of DCs which are capable of presenting altered self antigens to T cells(6, 35). DCs that have captured necrotic but not apoptotic cells were shown to induce systemic autoimmune disease in susceptible murine lupus model(36). The role of DCs in the induction of Th17 in the pathogenesis of SLE has not been studied. The differential effects of (1) TLR stimulation, (2) dectin-1 stimulation and (3) apoptotic or necrotic material uptake on the maturation and activation of DCs with resultant polarisation of naïve and memory T cells into Th17 phenotype and production of IL-17 will provide useful information with treatment implications. The objective of our study is to exami ne the effect of DCs on polarization of Th17 cells with production of IL-17 after treatment with (1) TLR agonists (2) dectin-1 agonists and (3) apoptotic or necrotic cells in SLE patients compared to healthy controls. These results will contribute to further research plan studying the signal transduction pathways involved in the activation of DCs that polarize Th17 cells induced by these stimulants (application for Research Grant Council funding in 2010/2011).

List of Research Outputs

Chung H.Y., Wong R.W.S. and Mok T.M.Y. , A comparison of the performance of the Assessment of SpondyloArhritis international Society classification criteria, European Spondyloarthropathy Study Group classification criteria, and Modified New York criteria in a cohort of Chinese Spondyloarthritis patients. , HKMJ . 2010, 16: p18 S20.

Fu Q., Zhao J., Qian X.X., Wang J., Kaufman K.M., Yu Y., Howe H.S., Mok T.M.Y. , Harley J.B., Guthridge J.M., Song Y.W., Bae S.C., Grossman J.M., Hahn B.H., Arnett F.C., Shen N. and Tsao B.P., Association of a functional IRF7 variant with systemic lupus erythematosus., IJRD . 2010, 13: S693 p9.

Jin O. , Sushima K., Mok T.M.Y. and Lau W.C.S. , Abnormalities in circulating plasmacytoid dendritic cells in patients with systemic lupus erythematosus, Arthritis Res Ther . 2010, in press.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Foxp3 mRNA expression on DC subsets in patients of systemic lupus erythematosus. , IJRD . 2010, 13: S557 p55.

Jin O. , Kavikondala S. , Mok T.M.Y. , Sun L.Y., Gu J.R., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Studies on the function of plasmacytoid dendritic ce lls in healthy and systemic lupus erythematosus., IJRD . 2010, 13: S554p54.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Study on myeloid dendritic cells in systemic lupus erythematosus, IJRD . 2010, 13: S793 p56.

Leung W.K. , Chu C.H. , Mok T.M.Y. and Ng S.K.S. , Periodontal status of adults with systemic sclerosis in Hong Kong, Journal of Dental Research . 2009, 88 (Spec Iss B): 655 (PAPF/APR).

Mok T.M.Y. , B-cell and T-cell targeted therapy in rheumatoid arthritis, Hong Kong Society of Physicians, Hong Kong . 2010.

Mok T.M.Y. , Clinical usefulness of anti-CCP in rheumatoid arthritis, Hong Kong Association of Medical Laboratories Limited, Hong Kong . 2010.

Mok T.M.Y. , Chiu S.S.H. , Lo Y. , Mak H.K.F. , Wong R.W.S. , Khong P.L. and Lau W.C.S. , Coronary atherosclerosis using CT coronary angiogram in patients with systemic sclerosis. Rely letter to Editor., Scand J Rheumatol . 2010, 38(5): 381-385.

Mok T.M.Y. , Development of biomarkers: basic science perspective (Plenary lecture), APLAR Review course. The Asia Pacific League of Associations for Rheumatology, the Philippines . 2009.

Mok T.M.Y. and Li W.L., Do Asians have worst lupus? , Lupus . 2010, 1: in press.

Mok T.M.Y. , Elderly onset rheumatic diseases, The Hong Kong Medical Forum. Department of Medicine, The University of Hong Kong . 2010.

Mok T.M.Y. , Yiu K.H., Wong C.Y., Lai W.H., Lo Y. , Wong R.W.S. , Tse H.F. and Lau W.C.S. , Endothelial Dysfunction is Associated with Low Level of Circulating Endothelial Progenitor Cells in Patients with Systemic Sclerosis, Clin Exp Rheumatol . 2010, in press.

Mok T.M.Y. , Tse H.F. , Wong C.Y., Qiuwaxi J. , Lai K.W.H. , Lo Y. , Wong R.W.S. and Lau W.C.S. , Endothelial dysfunction is associated with decreased circulating endothelial progenitor cells in patients with systemic sclerosis, Annals of the Rheumatic Diseases . 2009, S337.

Mok T.M.Y. , Managing difficult patients with rheumatoid arthritis, The Hong Kong Medical Forum, Department of Medicine, The University of Hong Kong . 2010.

Mok T.M.Y. , Novel cytokines in systemic lupus erythematosus, 4th Asian Congress on Autoimmunity, 11-13 September 2009, Singapore . 2009.

Mok T.M.Y. , Novel cytokines in systemic lupus erythematosus, Infectious disease and immunology research center, The University of Hong Kong . 2010.

Mok T.M.Y. , Novel cytokines in systemic lupus erythematosus, The 7th Jiangsu Rheumatology Meeting. Nanjing, China . 2010.

Mok T.M.Y. , Wu H. , Lo Y. and Lau W.C.S. , Serum IL-17 and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus, J Rheumatol . 2010, in press.

Mok T.M.Y. , Huang F.P., Ip W.K. , Wong F.Y., Chan E.Y.T. and Xu D., Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. , HKMJ . 2010, 16: p46 S76.

Mok T.M.Y. , Yao T.J. , Lo Y. and Tam S. , Southern Chinese patients with systemic lupus erythematosus in Hong Kong have low vitamin D levels. , HKMJ . 2010, 16: p46 S77.

Mok T.M.Y. , Tackling B lymphocytes in the treatment of rheumatic diseases (Plenary lecture), The Annual Scientific Meeting of the Hong Kong Society of Rheumatology, Hong Kong . 2009.

Mok T.M.Y. and Lau W.C.S. , The burden and measurement of cardiovascular disease in systemic sclerosis, Nat Rev Rheumatol . 2010, 6:430-4.

Mok T.M.Y. , The clinical spectrum and diagnosis of psoriatic arthropath y, The Hong Kong Medical Diary . 2010.

Mok T.M.Y. , The effect of hormonal contraceptives in patients with systemic lupus erythematosus and related diseases. , Postgraduate Study Day, Department of Obstetrics and Gynaecology, Queen Mary Hospital, Hong Kong. . 2009.

Mok T.M.Y. , The immunological basis of B cell therapy in systemic lupus erythematosus, Internal Journal of Rheumatic Diseases . 2010, 13: 3-11.

Mok T.M.Y. , Wu H. and Lo Y. , The relation of cytokines of IL-17/IL-23 axis to Th1/Th2 cytokines and disease activity in systemic lupus erythematos us, HKMJ . 2010, 16: p45 S75.

Mok T.M.Y. , The role of B lymphocytes in rheumatic diseases (Plenary lecture), Ten topics in Rheumatology, the Philippines . 2009.

Mok T.M.Y. , Update in Neuropsychiatric lupus, Guangzhou-Hong Kong Rheumatology Meeting, Shenzhen, China . 2009.

Mok T.M.Y. , Update in the management of psoriatic arthropathy, The Hong Kong Medical Diary . 2010, 1.

Mok T.M.Y. , 中國香港特別行政區風濕病專科的現狀和發展, Chin J Rheumatol . 2010, 14:3-4.

Nie Y. , Lau W.C.S. , Lie A.K.W. , Chan G.C.F. and Mok T.M.Y. , Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus, Lupus . 2010, 19: 850-9.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow -derived dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Tsang H.H., Wong R.W.S. , Trendell-Smith N.J. , Wu A.K.P. and Mok T.M.Y. , Diffuse large B-cell lymphoma of the central nervous system in mycophenolate mofetil-treated patients with systemic lupus erythematosus., HKMJ . 2010, 16: p54 S92.

Tsang H.H.L., Nigel T., Wu A.K.P. and Mok T.M.Y. , Diffuse large B-cell lymphoma of the central nervous system in mycophenolate mofetil treated patients with systemic lupus erythematosus [Epub 2009 Nov 6], Lupus . 2009, 19(3): 330-333.

Wang S. , Yiu K.H., Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Mak H.K.F. , Lau C.P. , Lam K.F. , Lau W.C.S. and Tse H.F. , Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis, Journal of Internal Medicine . 2009, 266: 445-452.

Wu H. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from pa tients with systemic lupus erythematosus. , HKMJ . 2010, 16: p57 S98.

Wu H. , Lau W.C.S. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patient s with systemic lupus erythematosus. , IJRD . 2010, 13: S680 p114.

Xu J., Taylor A.L., Louthrenoo W., Mok T.M.Y. , Kissel K., Vernon E. and Van Vollenhoven R.F., Safety of tocilizumab in patients with rheumatoid arthritis and a median treatment duration of 2.6 years. , IJRD . 2010, 13: S207 p98.

Yiu K.H., Wang S.L., Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Mak H.K.F. , Lam K.F. , Lau W.C.S. and Tse H.F. , Pattern on atherosclerosis for coronary, carotid and aortic arteries calcification in rheumatoid arthritis: a multidetector CT study, Journal of American College of Cardiology . 2009, 53: A432.

Yiu K.H., Wang S. , Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Lau C.P. , Lai W.W. , Wong L.Y. , Lam K.F. , Lau W.C.S. and Tse H.F. , Role of circulating endothelial progenitor cells in patients with rheumatoid arthritis with coronary calcification, Journal of Rheumatology . 2010, 37: 529-535.

Researcher : Ng FH

List of Research Outputs

Ng F.H. , Wong S.Y. , Lam K.F. , Chu W.M., Chan P., Ling Y.H., Kng C.P.L. , Yuen W.C., Lau Y.K. , Kwan A. and Wong B.C.Y. , Famotidine is inferior to Pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions, Gastroenterology . Elsevier, 2010, 138: 82-88.

Researcher : Ng FSK

List of Research Outputs

Yip T.P.S., Lui S.L. , Tse K.C., Xu H., Ng F.S.K. , Cheng S.W. , Chan D.T.M. , Lai K.N. and Lo W.K. , A prospective randomized study comparing tenckhoff catheters inserted using the triple incision method with standard swan neck catheters, Peritoneal Dialysis International . 2010, 30(1): 56-62.

Researcher : Ng KM

List of Research Outputs

Chan Y.C. , Lee Y.K. , Ng K.M. , Lai K.W.H. , Yang D. , Tse H.F. and Siu D.C.W. , A Newly-derived Small Synthetic Compound Alleviated Ventricular Fibrillation In A Pig Model With Chronic Myocardial Infarction As Revealed By Optical Mapping, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” (Hong Kong) . 2010.

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system wit h defined factors., Cellular Reprogramming (in press) . 2010.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Lee Y.K. , Ng K.M. , Lai K.W.H. , Tse H.F. and Siu D.C.W. , Triiodothyronine enhances cardiac differentiation of embryonic stem cells and maturation via classical pathway., Molecular Endocrinology . 2010, (in press).

Researcher : Ng L

List of Research Outputs

Chen W.J., Ng L. , Chow A.K., Chu A.C.Y., Wong B.C.Y. and Pang R.W.C. , Identification of CD44+ Cancer Cells in Gastric Cancer by Chemotherapeutic Enrichment, 16th Hong Kong International Cancer Congress . 2009.

Ng L. , Poon R.T.P. , Wong B.C.Y. and Pang R.W.C. , A novel regulator of cell migration and invasion in human hepatocellular carcinoma, 16th Hong Kong INternational Cancer Congress . 2009.

Ng L. , Poon R.T.P. , Wong B.C.Y. and Pang R.W.C. , Actopaxin: A Novel Regulator Of Cell Migration And Invasion In Human Hepatocellular Carcinoma , 15th Medical Research Conference, Hong Kong . 2010.

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metas tatic Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Researcher : Ng YCC

List of Research Outputs

Chan D.T.M. , Ng Y.C.C. and Yung S.S.Y. , Mycophenolic acid reduces MAPK activation and fibronectin synthesis in human proximal tubular epithelial cells (PTEC) induced by anti-DNA antibodies, J Am Soc Nephrol . 2009, 860A.

Yung S.S.Y. , Ng Y.C.C. and Chan D.T.M. , Mycophenolic acid ameliorates anti-dsDNA antibody binding to proximal tubular epithelial cells and the subsequent induction of inflammatory and fibrotic processes., 9th International Congress on Systemic Lupus Erythematosus . 2010.

Researcher : Nie Y

List of Research Outputs

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Foxp3 mRNA expression on DC subsets in patients of systemic lupus erythematosus. , IJRD . 2010, 13: S557 p55.

Jin O. , Kavikondala S. , Mok T.M.Y. , Sun L.Y., Gu J.R., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Studies on the function of plasmacytoid dendritic cells in healthy and systemic lupus erythematosus., IJRD . 2010, 13: S554p54.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Study on myeloid dendritic cells in systemic lupus erythematosus, IJRD . 2010, 13: S793 p56.

Nie Y. , Lau W.C.S. , Lie A.K.W. , Chan G.C.F. and Mok T.M.Y. , Defective phenotype of mesenchymal stem cells in patients with systemic lupus erythematosus, Lupus . 2010, 19: 850-9.

Nie Y. , Mok T.M.Y. , Chan G.C.F. , Chan W.K. , Jin O. , Kavikondala S. , Lie A.K.W. and Lau W.C.S. , Phenotypic and functional abnormalities of bone marrow-derived dendritic cells in systemic lupus erythematosus, Arthritis Res Ther . 2010, 12: R91.

Researcher : Ong KL

List of Research Outputs

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Jiang C.Q., Thomas G.N. and Lam T.H. , A single nucleotide polymorphism in the gene encoding fibrinogen beta chain is associated with hypertension, British Hypertension Society Annual Meeting, 14-16 September 2009, Cambridge, UK . 2009.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. and Lam K.S.L. , Gamma-glutamyl transaminase level predicts the development of hypertension., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong, 2010 . 18: 33.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. and Sham P.C. , Using glycosylated hemoglobin to define the metabolic syndrome in United States adults., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong, 2010 . 18: 33.

Cheung B.M.Y. , Ong K.L. and Tso A.W.K. , Using the Albumin-Globulin Ratio to Identify Individuals with Elevated High-sensitivity C-Reactive Protein Level and High Cardiovascular Risk., Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Law S.C. , Sham P.C. and Lam K.S.L. , A genetic variant near the GNPDA2 gene is associated with the metabolic syndrome in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Sham P.C. , Xu A. , Ong K.L. , Cheung B.M.Y. and Lam K.S.L. , Implication of the obesity-associated genetic variants identified from recent genome-wide association studies in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 15.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a Chinese population, J Clin Endocrinol Meta . 2010, 95: 1395-403.

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Li Jin Y., Yue X.J., Ong K.L. , Tam S., Wong K.S., Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese , Eur J Hum Genet . 2010, 18(11): 1255-1260.

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Jin Y.L., Yue X.J., Ong K.L. , Tam S. , Wong K.S. , Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese. , Eur J Hum Genet. . 2010, 1-6.

Lam K.Y. , Ong K.L. , Lam K.S.L. , Tso A.W.K. and Cheung R.T.F. , Association of two adiponectin gene variants with ischemic stroke in a Chinese cohort, The 32nd Annual Meeting of the Japan Neuroscience Society, 16-18 September 2009, Nagoya, Japan. Neuroscience Research . 2009, 65: S122.

Li M. , Ong K.L. , Tse H.F. and Cheung B.M.Y. , Utilization of lipid lowering medications among adults in the United States 1999-2006. , Atherosclerosis. . 2010, 208: 456-60.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted development of hypertension in Chinese men, Thrombosis and Haemostasis . 2010, 103 (4): 728-735.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted incident hypertension in Chinese men, Annual Scientific Meeting and Annual General Meetin g of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Adiponectin gene polymorphisms, plasma adiponectin level and persistent hypertension in Hong Kong Chinese, British Pharmacological Society Winter Meeting, Dec 2009, London, UK . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen beta chain with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 51.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen β chain with hypertension in Hong Kong Chinese, 14th Research Postgraduate Symposium, Faculty of Medicine, HKU, Dec 2009, Hong Kong . 2009.

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Xu A. , Cherny S.S., Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive Protein As A Predictor Of Hypertension In The Hong Kong Cardiovascular Risk Prevalence Study (crisps) Cohort, International Congress of Cardiology (ICC), Feb 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Xu A. , Cherny S.S. , Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive protein as a predictor of hypertension in the Hong Kong cardiovascular risk prevalence study (CRISPS) cohort, Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chin ese, Annual Scientific Meeting of Hong Kong Society of Endocrinology . 2009.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chin ese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Leung Y.K. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese, 13th Annual Scientific Meeting of the Institute of Cardiovascular Science and Medicine, Co-morbidity Hypertension / Diabetes: which one do we treat, Dec 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meetin g of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. , Lam K.S.L. and Cheung B.M.Y. , Relationship of liver enzymes with hypertension in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated haemoglobin to define the metabolic syndrome in United States adults, Diabetes Care . 2010.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated hemoglobin to define the metabolic syndrome in United States adults., 5th International Symposium on Healthy Aging . 2010.

Researcher : Ong KL

List of Research Outputs

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Jiang C.Q., Thomas G.N. and Lam T.H. , A single nucleotide polymorphism in the gene encoding fibrinogen beta chain is associated with hypertensio n, British Hypertension Society Annual Meeting, 14-16 September 2009, Cambridge, UK . 2009.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. and Lam K.S.L. , Gamma-glutamyl transaminase level predicts the develop ment of hypertension., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong , 2010 . 18: 33.

Lam K.Y. , Ong K.L. , Lam K.S.L. , Tso A.W.K. and Cheung R.T.F. , Association of two adiponectin gene variants with isch emic stroke in a Chinese cohort, The 32nd Annual Meeting of the Japan Neuroscience Society, 16-18 September 2009, Nagoya, Japan. Neuroscience Research . 2009, 65: S122.

Li M. , Ong K.L. , Tse H.F. and Cheung B.M.Y. , Utilization of lipid lowering medications among adults in the United States 1999-2006. , Atherosclerosis. . 2010, 208: 456-60.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted development of hypertension in Chines e men, Thrombosis and Haemostasis . 2010, 103 (4): 728-735.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted incident hypertension in Chinese men, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encod ing fibrinogen beta chain with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 51.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen β chain with hypertension in Hong Kong Chinese, 14th Research Postgraduate Symposium, Faculty of Medicine, HKU, Dec 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meetin g of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants gene encoding adrenomedul lin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting of Hong Kong Society of Endocrinology . 2009.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedul lin with hypertension and dysglycaemia in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chines e, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated haemoglobin to define the metabolic syndrome in United States adults, Diabetes Care . 2010.

Researcher : Pang RWC

Project Title:	Isolation and Characterization of Cancer Stem Cells of Colorectal Cancer with Capability of Tumour Initiation and Metastasis
Investigator(s):	Pang RWC, Wong BCY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2008

Abstract:

Objectives: 1. To isolate cancer stem cells capable of tumor initiation from human colorectal cancer. 2. To study the gene expression profile of the cancer stem cells as compared with mature cancer cells. 3. To isolate and characterize cancer stem cells capable of initiating metastasis of the tumor in colorectal cancer. Background, key issues and problems being addressed: Colorectal cancer is the second most common cause of cancer death worldwide, and the incidence of colorectal cancer in Hong Kong is rising rapidly in recent years due to westernization of lifestyle, now being one of the third most common cancers in Hong Kong. While there are several well-established systemic therapy regimens for colorectal cancer, treatment failure is common and the prognosis of patients with advanced cancer remains unsatisfactory. Even after surgical resection for patients with relatively early colorectal cancer, tumor recurrence due to distant metastasis is common, which is the main cause of death in most patients. The exact biological mechanisms of uncontrolled cancer growth and metastasis remains unclear. It is believed that colorectal cancer, like many other cancers, develops from the accumulation of mutations in genes critical to processes such as self-renewal, cell growth, and other functions. It has been estimated that approximately 3 to 6 genetic events are necessary to transform a normal cell into a cancer cell.1 If this hypothesis holds true, stem cells of the coloni c mucosa, which have the highest potential for proliferation and a much longer life span compared with their progeny, are possibly the only cells that have the ability to accumulate the requisite number of mutations necessary to perturb intrinsic mechanisms regulating normal cell proliferation and differentiation while remaining viable. Mutations in the components of regulatory pathways of these intestinal stem cells may then lead to the development of colorectal cancer.2 In the last few years, a growing body of evidence increasingly supports the notion that human cancers can be considered as a stem cell disease. 3,4 Tumour cells are organized in a hierarchy of heterogeneous cell populations with different biological properties; and the capability to sustain tumour formation and growth is exclusively driven by a minority, pathological pool of cells, cal led cancer stem cells (CSCs). Studies have shown that these cells have not only acquired tumour-related features such as uncontrolled growth and the ability to metastasize, but have also maintained its inherent stem/progenitor cell properties to self-renew and generate mature cell s of a particular lineage through differentiation. To date, the existence of CSCs has been proven in the context of leukemia, 5,6 breast cancer, 7,8 glioblastoma, 9 and more recently, prostate,10 gastric, 11 lung, 12 and colon cancer. 13,14 These cells are important target for future therapeutic strategies to more completely eradicate the cancer in treatment of colorectal cancer. While a few preliminary studies have demonstrated the presence of cancer stem cells in colorectal cancer that is capable of initiating tumor growth in mice model, the exact phenotypic characteristics of the cancer stem cells remains far from clear. Furthermore, it is unknown if some cancer stem cell subpopulation may be responsible for the metastatic property of the cancer. We propose a study to isolate cancer stem cells from human colorectal cancer specimens, characterize the cell surface markers of the stem cells and to elucid ate the gene expression in such cells compared with the mature cancer cells by microarray analysis. We also aim to isolate a subpopulation of cancer stem cells that may be responsible for the metastatic potential of the cancer by comparing the cancer stem cells in primary and matched metastatic human colorectal cancer specimens. 1. W.C. Hahn, C.M. Counter, A.S. Lundberg, et al. Creation of human tumour cells with defined genetic elements, Nature 400 (1999), 464–468. 2. SA McDonald, SL Preston, MJ Lovell, et al Mechanisms of disease: from stem cells to colorectal cancer, Nat Clin Pract Gastroenterol Hepatol, 5 (2006), 267-74 3. T. Reya, S.J. Morrison, M.F. Clarke and I.L. Weissman, Stem cells, cancer and cancer stem cells, Nature 414 (2001), 105–111. 4. T. Lapidot, C. Sirard, J. Vormoor, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice, Nature 367 (1994), 645–648. 5. T. Lapidot, C. Sirard, J. Vormoor, et al. A cell initiating human acute Myeloid leukaemia after transplantation into SCID mice, Nature 367 (1994), 645–648. 6. D. Bonnet and J.E. Dick. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell, Nat Med 3 (1997), 730–737. 7. D. Ponti, A. Costa, N. Zaffaroni, et al. Isolation and in vitro propagation of tumourigenic breast cancer cells with stem/progenitor cell properties, Cancer Res 65 (2005), pp. 5506– 5511. 8. M. Al-Hajj, M.S. Wicha, A. Benito-Hernandez et al.Prospective identification of tumourigenic breast cancer cells, Proc Natl Acad Sci U S A 1000 (2003), 3983–3988. 9. S.K. Singh, I.D. Clarke, M. Terasaki, et al. Identification of a cancer stem cell in human brain tumours, Cancer Res 63 (2003), 5821–5828. 10. A.T. Collins, P.A. Berry, C. Hyde, M.J. Stower and N.J. Maitland, Prospective identification of tumourigenic prostate cancer stem cells, Cancer Res 65 (2005), 10946–10951. 11. J Houghton, C. Stoicov, S. Nomura, et al., Gastric cancer originating from bone marrow derived cells, Science 306 (2004), 1568–1571. 12. C.F. Kim, E.L. Jackson, A.E. Woolfenden, et al, Identification of bronchioalveolar stem cells in normal lung and lung cancer, Cell 121 (2005), 823–835. 13. O’brien, A. Pollett, S. Gallinger and J.E. Dick, A human colon cancer cell capable of initiating tumour growth in immunodeficient mice, Nature 445 (2007), 106–110. 14. L. Ricci-Vitiani, D.G. Lombardi, E. Pilozzi, et al. Identification and expansion of human colon-cancer-initiating cells, Nature 445 (2007), 111–115.

Project Title:	A study of the modulatory effects of p53 on Pin1-mediated tumor growth, invasion and metastasis in hepatocellular carcinoma
Investigator(s):	Pang RWC, Kwong YL, Tse EWC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	12/2008

Abstract:

(1) To study the effect of p53 on Pin1-mediated tumour growth in HCC; (2) To study the effect of p53 on Pin1-mediated invasiveness and metastasis in HCC; (3) To study the clinical significance of p53 abnormalities in relation to Pin1 overexpression in clinical specimens of HCC.

Project Title:	Study of a novel role of Pin1 in regulating invasiveness and metastasis of hepatocellular carcinoma via Rho signaling
Investigator(s):	Pang RWC, Kwong YL, Tse EWC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) to study the molecular mechanisms and downstream pathways of Pin1-mediated RhoA activation; to study the functional effect of Pin1-mediated RhoA activation on HCC cell migration, invasion and metastasis; to correlate Pin1 and PhoA expression with clinicopathological features of invasiveness and metastasis of HCC.

List of Research Outputs

Chen W.J., Ng L. , Chow A.K., Chu A.C.Y., Wong B.C.Y. and Pang R.W.C. , Identification of CD44+ Cancer Cells in Gastric Cancer by Chemotherapeutic Enrichment, 16th Hong Kong International Cancer Congress . 2009.

Cheng C.W. , Pang R.W.C. , Kwong Y.L. and Tse E.W.C. , Pin1 enhances the anti-apoptotic function of survivin in cancer cells, 16th Hong Kong International Cancer Congress . 2009.

Chow K.M. , Chu A.C.Y. , Poon R.T.P. and Pang R.W.C. , Blockade of Raf/MEK/ERK Pathway by Raf265 Inhibits Tumor Growth in Colorectal Cancer, 101st Annual Meeting 2010 of American Association for Cancer Research . Washington DC, 2010.

Chow K.M. , Chu A.C.Y. , Poon R.T.P. and Pang R.W.C. , Inhibition of Tumour Growth by Raf265 Via Blockade of Raf/MEK/ERK Pathway in Colorectal Cancer, 15th Medical Research Conference . Hong Kong, 2010.

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhib itor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Ng E.K.O. , Leung C.P.H. , Au S., Chan A., Wong L.P. , Ma E.S.K. , Pang R.W.C. , Chua D.T.T. , Chu K.M. , Law W.L. , Poon R.T.P. and Kwong A. , Plasma microRNA as a potential marker for breast cancer detection, The 101st Annual Meeting of the American Association for Cancer Research Annual Meeting, Washington D.C., U.S.A., 17 - 21 April 2010 .

Ng L. , Poon R.T.P. , Wong B.C.Y. and Pang R.W.C. , A novel regulator of cell migration and invasion in human hepatocellular carcinoma, 16th Hong Kong INternational Cancer Congress . 2009.

Ng L. , Poon R.T.P. , Wong B.C.Y. and Pang R.W.C. , Actopaxin: A Novel Regulator Of Cell Migration And Invasion In Human Hepatocellular Carcinoma , 15th Medical Research Conference, Hong Kong . 2010.

Pang R.W.C. , A Subpopulation of CD26+ Cancer Stem Cells Responsible for Metastasis in Colorectal Cancer, In: Seoul University, Korea, International Symposium on Cancer Stem Cells . 2009.

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Chemoprophylaxis in colorectal cancer: current concepts and a practical algorithm for use., Exper Opin Investig Drugs . 2010, Suppl 1: S57-66.

Yau W.L. , Pang R.W.C. and Poon R.T.P. , Identification Of Mir-106b And Mir-21 Overexpression In Hepactocellular Carcinoma By An Orthotopic Metastasis Mouse Model , Hong Kong International Cancer Congress, November 2009, Hong Kong . 2009.

Yee Y.K., Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Epidemiology of colorectal cancer in Asia. , J Gastroenterol Hepatol . 2009, 24: 1810-6.

Yee Y.K., Gu Q., Hung I.F.N. , Tan V.P.Y. , Chan P., Hsu A., Pang R.W.C. , Lam S.C. and Wong B.C.Y. , Trend of colorectal cancer in Hong Kong:1983-2006. , J Gastroenterol Hepatol . 2010, 25: 923-7.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presentation), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Qi Y

List of Research Outputs

Chim J.C.S. , Wong K.Y. and Qi Y. , Epigenetic alterations of the miR-34a in hematologica l malignancies, 15th Congress of the European Hematology Association, (Poster) . 2010.

Chim J.C.S. , Wong K.Y. , Qi Y. , Foong F., Lam W.L., Wong L.G., Jin D. , Costello J.F. and Liang R.H.S. , Epigenetic inactivation of the miR-34a in hematological malignancies, Carcinogenesis . 2010, 31(4): 745-50.

Researcher : Qiao L

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Liu S., Chan K.W. , Tong J., Wang Y., Wang B.Y. and Qiao L. , Fibrolamellar hepatocellular carcinoma detected by PET-CT scan: A case report., Hepato-Gastroenterology . 2009, In press.

Liu S., Chan K.W. , Wang B.Y. and Qiao L. , Fibrolamellar hepatocellular carcinoma. , Am J Gastroenterol . 2009, In press.

Qiao L. and Wong B.C.Y. , Experimental therapeutics of colon cancer., In: Manfred Schwab, Encyclopedia of Cancer . Springer Reference, 2009, LXXXVII.

Zou B. , Qiao L. and Wong B.C.Y. , Current Understanding of the Role of PPARgamma in Gas trointestinal Cancers, PPAR Research . 2009, 2009: 816957.

Researcher : Qiuwaxi J

List of Research Outputs

Mok T.M.Y. , Tse H.F. , Wong C.Y., Qiuwaxi J. , Lai K.W.H. , Lo Y. , Wong R.W.S. and Lau W.C.S. , Endothelial dysfunction is associated with decreased circulating endothelial progenitor cells in patients with systemic sclerosis, Annals of the Rheumatic Diseases . 2009, S337.

Researcher : Ramsden DB

List of Research Outputs

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Investigator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong. (6-7 March 2010) . 2010, 46.

Ho W.L. , Ho S.L. and Ramsden D.B. , Human Catechol-O-methyltransferase (COMT) assay., In: Listed inventers: PWL Ho, SL Ho, DB Ramsden, World Intellectual Property Organization under the Patent Cooperation Treaty (PCT); PCT application no. PCT/CN2009/001011 filed on 8 Sept. 2009; International publication no. WO2010/034183 (1 Apr. 2010). . 2010.

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.L. , Ho W.M. , Liu H. , Chan K.H. , Ramsden D.B. and Ho S.L. , Neuronal mitochondrial uncoupling proteins: implicatio ns in the pathology of Parkinson’s disease , The Hong Kong Neurological Society - Annual Scientific Meeting 2009; Kowloon Shangri-La Hotel, Hong Kong; 8 Nov 2009. . 2009.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Researcher : Sang Y

List of Research Outputs

Sang Y. and Cheung R.T.F. , Brain injury and neurogenesis after intracerebral haemorrhage in hypertensive rats, Medical Research Conference, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, 2010. Hong Kong Medical Journal . 2010, 16 (suppl 1): 53.

Researcher : Shen J

Project Title:	Biochemical Society Meeting 679 University of Essex UK - Stress, Signalling and Control Reactive Oxygen Species Mediate Intracellular Cholesterol Accumulation via Modulating Caveolin-1 Pathway in Chinese Hamster Ovary Cells
Investigator(s):	Shen J
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	07/2003

Abstract:

N/A

Project Title:	Development of Nano-salvianic Acids for Protecting Neural Cells from Oxidative Injury
Investigator(s):	Shen J
Department:	School of Chinese Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2008
Completion Date:	12/2009

Abstract:

Background: Ischemic stroke is the third killer in human diseases. Disruption of blood brain barrier (BBB) and enlargement of infarction volume are frequently found in stroke patients after blood circulation is restored. This phenomenon is commonly called cerebral ischemia-reperfusion injury. Free radicals, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), are found in ischemic brains. Both ROS and RNS are important cytotoxic factors in cerebral ischemia-reperfusion injury. ROS, including superoxide (O2.-) and hydroxyl radicals (OH.), etc., induces lipid peroxidation of plasma membrane and destroys membrane structures and functions of neural cells and brain microvascular endothelial cells, resulting in BBB breakdown, enlargement of infarction and neural apoptotic cell death. RNS, including nitric oxide (NO) and peroxynitrite (ONOO-), contributes to neural oxidative damage as well. High concentration of NO produced from inducible NOS (iNOS) and neuronal NOS (nNOS) is detrimental to ischemic brain, inducing inflamma tion, cell death, BBB hyperpermeability, and infarction enlargement. NO reacts with superoxide (O2.-) to generate ONOO-. The later can easily penetrate lipid bilayers, leading to peroxidation of membrane lipids and apoptotic cell death during cerebral ischemia-reperfusion injury. Therefore, development of novel antioxidants for scavenging free radicals becomes a critical therapeutic strategy for the treatment of ischemic stroke. Danshen, the dried root of salvia miltiorrhiza, is a commonly used traditional Chinese Medicine (TCM) for the treatment of ischemic heart disease and ischemic cerebrovascula r diseases. A number of clinical trials have reported its efficacy on improving clinical outcome and quality of life in the treatment of ischemic stroke. The chemical constituents of Danshen have been studied and at least 50 hydrophilic compounds and 30 lipophilic compounds have been identified. Among them, salvianolic acids and tanshinones are considered as the major constituents contributing to Danshen's neuroprotective effects. Salvianolic acids have showed to scavenge free radicals, inhibit lipid peroxidation and mitochondrial membrane permeability transition, improve regional cerebral blood flow, protect neural cells and improve neurogenesis in experimental stroke models. Salvianolic acids can be potentially developed into new botanical drugs for stroke treatment. However, as hydrophilic compounds, salvianolic acids are difficult to penetrate BBB, gre atly limiting its application. Development of novel antioxidants based on the traditional antioxidants form herbal medicine like salvianolic acids with enhanced antioxidant capac ity and BBB permeability is an important stretegy of drug discovery for the treatment of ischemic stroke. Current research in neuro nanomedicine have proposed to use nanotechnology for featuring brain repair, brain imaging and drug delivery for crossing the BBB. Recent progress in the development of new biological material s nanotechnology provides great opportunities for drugs and small molecular delivery across the BBB. The promise of nanotechnology is that the selective delivery of therapeutics can be delivered through to the brain without causing secondary damage. In our recent study, we found that the antioxidant activity and bioavailability of tocopherol can be dramatically enhanced by assembling it on the surface of nanoparticles (see Free Rad Biol Med 43:1243-1254, 2007). Therefore, with the discovery, we hypothesize that the assembly of antioxidant ligands on nanoparticles could provide the possiblity of improvin g antioxidant activity and enhancing drug delivery into the brains. In this proposal we will design self-assembled nanoantioxidants based on salvianolic acid A and evaluate its antioxidant and neuroprotective effects on neural cells under oxidative stress. Objectives: (1) To design and prepare self-assembled nano-salvianolic acids. (2) To compare the antioxidant effects of the nano-salvianolic acids and natural salvianolic acid A in human neuroblastoma SK-N-MC cells under oxidative stress. (3) To compare the effects of the nano-salvianolic acid A and natural salvianolic acid A against apoptoti c cell death in human neuroblastoma SK-N-MC cells under oxidative stress.

Project Title:	Interactions of Reactive Nitrogen Species, Caveolins and Matrix Metalloproteinases: A Novel Signal Mechanism in Disruption of Blood Brain Barrier during Ischemic Stroke
Investigator(s):	Shen J, Chung SK, So KF, Yang D
Department:	School of Chinese Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2008

Abstract:

(1) To test the hypothesis that ONOO- would contribute to NO-induced down-regulation of caveolin-1 and activation of MMPs in cerebral ischemia-reperfusion injury. The experiments will be conducted in hypoxia-reoxygenated brain microvascular endothelial cells (BMECs) in vitro and middle cerebral artery occlusion (MCAO)-induced cerebral ischemia-reperfusion injury in vivo; (2) To address the question whether diminished caveolin-1 expression will be linked to activation of MMPs, increase of BBB permeability and enlargement of infarction volume in cerebral ischemia-reperfusion injury. Several con ventional approaches including caveolin-1 knockdown BMECs, caveolin-1 knockout mice and cell-permeable peptide encoding caveolin -1 scaffolding domain will be used to elucidate the roles of caveolin-1 in regulating MMPs expression and BBB permeability; (3) To test the hypothesis that caveolin-1 will control BBB peremability via protecting tight junction-associated proteins from degradation of MMPs in ischemia-reperfused BMECs and brain tissues.

Project Title:	Development of caveolin-1 as a target molecule for screening active compounds from herbal medicine in promoting neurogenesis for ischemic stroke
Investigator(s):	Shen J
Department:	School of Chinese Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2008

Abstract:

Stroke is the third leading cause of death and a major human disease associated with disability. Curr ently, no reliable therapy is available to improve the regeneration of neurons and the recovery of neurological functions for the treatment of ischemic brain injury, inducing long-term disability in post-stroke patients. Mammalian central nervous system (CNS) was believed to be incapable of self-repair or regeneration. Recent evidence found that stem/progenitors cells in adult CNS could potentially generate new functional neurons and repair the damaged CNS. Adult CNS in dentate gyrus of hippocampus, subventricular zone (SVZ) of lateral ventricle and cortex contains a range of progenitors or stem cells with limited capacities of growth and differentiation. As pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, they are selectively destroyed after cerebral ischemia. After transient global ischemia, newborn cells migrate into the granule cells. Enhanced neurogenesis in the dentate gyrus could promote functional recovery of the ischemia brain injury. However, only one neuronal subtype, granule cells in the dentate gyrus, is able to regenerate, and the production of new neurons in other hippocampal regions appears to be very limited in adults. Growth-factors showed to stimulate massive regeneration of hippocampal pyramidal neurons after ischemia injury. The result is interpreted as an evidence for direct migration of neuronal precursors toward injured areas, possibly triggering brain repair. Neuronal replacement strategies to rely on endogenous progenitors avoid many potential technical ethical limitations associated with fetal or stem cell transplantation. The mechanisms of neural regeneration at ischemic brains are largely unknown. Recent studies bring attentions to the connection between hypoxia and the proliferation of neural stem/progenitor cells. Enhanced proliferation of stem cells in response to hypoxia has been shown in vivo in neural stem/progenitor cells after hypoxic brain injury in neonatal mice, in adult rats and in aged humans. Hypoxia could be a proliferation stimulus in neural stem/progenitor cells. However, most of proliferated neural stem/progenitor cells in ischemia area could not be finally developed into newly formed neurons and integrated in neurological network. It is important to find out why the newly proliferated neural stem/progenitor cells could not further developed into neurons in the ischemic brains. Neural stem/progenitor cells are found in close proximity to blood vessels and surrounded by glial cells in the hippocampus and SVZ. The proliferation and differentiation of neural stem/progenitor cells depend on microenvironment niche signals, including a number of growth factors. Recent studies have drawn attention to the roles of vascular endothelial growth factors (VEGF) and its receptors in neural regeneration. VEGF was originally identified as a major mediator of angiogenesis. VEGF exerts its action via its receptor, VEGFR-2/Flk-1, in endothelial cells, hematopoietic stem/progenitor cells and tumor cells. VEGF stimulates the expension of neural stem/progenitor cells and neurogenesis in various animal models, resulting in improved learn ing ability. VEGF-overexpressing transgenic mice show enhanced post-ischemic neurogenesis, neuromigration, angiogenesis and functional recovery. Both vascular endothelial cells and glial cells expressing VEGF and bFGF serve as niche signals for neural stem/progenitor cells. Neural stem/progenitor cells proliferate in response to bFGF during neurogenic phase. In addition, VEGF and brain-drived neurotrophic factor (BDNF) mediate cross-talk between neural stem cells and endothelial cells in the niche. Therefore, VEGF and its receptor Flk-1 could be therapeutic target for brain repair in post-stroke treatment. Caveolae, invaginations of the plasma membrane, participates in many cellular events. Caveolins are integral membrane proteins located at the caveolae. The subtypes of caveolin-1 and -2 are widely expressed in neuronal cell types and brain regions, while caveolin-3 is specifically expressed in skeleton muscle cells and cardiomyocytes. Caveolins are cholesterol trafficking proteins as well as negat ive regulating protein in a variety of signal transduction pathways, such as G proteins, nitric oxide synthases (NOS), Src tyrosine kinases, ras, esterogen receptors, PKC, intergrins, EGF-R, etc. Caveolin-1 suppresses MAP kinase activation and cell proliferation induced by bFGF and PDGF in mesangial cells. Upregulation of VEGFR-2/Fik-1 by bFGF treatment is essential for VEGF-media ted promotion of neural stem/progenitor cell proliferation. Overexpression of caveolin-1 inhibits the activity of VEGFR-2/Fik-1, resulting in G0/G1 arrest in endothelial cells. Caveolin-1 appears to play important roles on post-injury reactive neural plasticity. Caveolin-1 can inhibit the bFGF signal pathway and block the formatio n of neurites upon bFGF treatment in N2a cells. Caveolin-1 is present in neural stem/progenitor cells. However, whether caveolin-1 modulates the proliferation and differentiation of neural stem/progenitor cells are unknown yet. In Traditional Chinese Medicine (TCM), many formulae have clinically used for treating stroke-induced disability for centuries. Buyang Huanwu Decoction (BHD), a representative formul a, has been commonly used for functional recovery of stroke-induced disability for more than 300 years. BHD is composed of Astragalus membranaceus, Angelica sinensis, Paeonia lactiflora, Ligusticum chuanxiong, Carthamus tinctorius , Prunus persica and Lumbricus. The neuroprotective effects of BHD on ischemic stroke patients were reported clinically. Experimental evidence shows that BHD could promote growth and differentiation of neural progenitor cells [44]. BHD can promote neurite outgrowth and differenti ation of neuroepithelial stem cells. However, the mechanisms for promoting neural growth and regeneration and its active ingredients with promoting neural regeneration are unclear yet. Further studies in those aspects would lead to drug discovery for the treatment of post-stroke disability. The purpose of the proposal is to verify the roles played by caveolin-1 in inhibiting VEGF signal and neurogenesis. Following key issues will be addressed: Central Hypothesis Caveolin-1 is a critical negative regulation protein for proliferation and differentiation of neural stem cells via inhibiting neural growth signals including VEGF and its receptor VEGFR-2/Flk-1. Key issues and problem to be addressed: 1. To understand the roles played by caveolin-1 in modulating proliferation and differentiation of neural stem cell s under hypoxia /ischemia 2. To test the hypothesis that caveolin-1 could inhibit the expression and activity of VEGF and its receptor VEGFR-2/Flk-1 3. To use caveolin-1 as a target protein for screening bioactive ingredients with promoting neural regeneration properties from Buyang Huanwu Decoction, a classic TCM formula for recovery of neurological functions in post-stroke treatment

Project Title:	Effects of Baicalin on promoting differentiation of neural stem cells into neurons in post-ischemic stroke rats
Investigator(s):	Shen J, Tong Y
Department:	School of Chinese Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2009
Completion Date:	03/2010

Abstract:

Mammalian central nervous system (CNS) has long been believed to be incapable of neuronal repair or regeneration. In the past decade, one of the most im portant discoveries in Neurobiology is that ischemia-injured brains have the potential capability to repair itself by stimulating the proliferation and differentiation of neural stem/progenitor cells, and by the direct migration of the neuronal precursors toward injured areas and replaced damaged neurons. The compensatory replacement of striatal neurons from resident progenitors and neuronal recruitment into the neostriatum have been identified in experimental stroke models. Appar ent compensatory neurogenesis has been also found in the striatum of Huntington’s disease patients and in the dentate gyrus of hippocampus of Alzheimer’s patients, indicating the potentials for recruiting new neurons from resident neural progenitor cells as a means of treating degenerative conditions. Those discoveries offer a hope for the development of therapeutic approaches for the recovery of neurological functions in post-str oke patients and in those with neurodegenerative diseases. The strategy of cell replacement by endogenitors raises optimism for regenerative therapies, avoiding many potential technical and ethical limitations associated with fetal or stem cell transplantation. Therefore, recent efforts have focused on stimulating the formation and preventing the death of neurons and glial cells produced by endogenous stem cells in the adult CNS. Neurogenesis is a multistep process including proliferation, fate determination, migration, and neuronal maturation of endogenous neural progenitor cells. Among these processes, one of critical steps during NSCs differentiation is the decision to generate neuronal or glial cells. Recent evidences indicate that Stat3 could maintain the propagation and pluripotency of embryonic stem cells. Targeted disruption of the Jak/Stat3 gene in mice results in early embryonic lethality. Especially, suppression of Jak/Stat3 directly induced neurogenesis and inhibited astrogliogenesis in neural stem cells. In contrast, the activator-type bHLH genes including Mash1, Math and Neurogenin are expressed by differentiating neurons. Misexpression of these genes in neural stem cells induces the pan-neuronal gene expression and determines the neuronal fate. In addition, Mice lacking Mash1 present defects in the specification of progenitors in the autonomic ganglia, olfactory epithelium, and ventral forebrain, while Neurogenin 1 and Neurogenin 2 mutant mice present similar phenotypes in the dorsal root and cranial ganglia and in the dorsal telencephalons. Those studies suggest that Stat 3 and Mash1 participate in the signal modulations during the differentiations of neural progenitors. The natural plant world is a vast resource that can be used in drug discovery for neurogenesis. Many botanical ingredients such as ginsenoside Rb1, M1, and withanolide A, have been reported to improve neuritic regeneration and synaptic reconstruction in cultured neurons in vitro. Baicalin, a flavonoid isolated from the root of Scutellaria baicalensis G, has showed multiple biological functions, such as anti-inflammatory activity, and inhibition of nitric oxide producing activity. Baicalin has neuroprotective effects on the oxygen/glucos e deprivation- and NMDA-induced injuries in primary cultured neurons and rat hippocampus slice. Recent experiments indicate that Baicalin can pass through BBB and reach the CNS. Interestingly, Baicalin has been shown to promote the differentiation of human umbilical cord blood mesenchymal stem cells and rat bone marrow stromal cells into neuron. Those results lead us hypothesize that Baicalin could promote the differentiation of neural progenitor cells in post-ischemic brains. To verify this hypothesis, we conducted pilot studies on primiary cultured neural progenitor cells and found that baicalin could promote the differentiation of neural progenitor cells but inhibit glial generation of neural progenitor cells. Baicalin can suppress Stat3 pathway and activate the Mash1 gene expression in the neural progenitor cells. This proposal is specifically designed to further verify this hypothesis in both in vitro neural progenitor cells and in vivo animal model. Central hypothesis: Baicalin could promote the differentiation of neural progenitor cells but inhibit glial generation of neural progenitor cells in post-ischemic brains via suppressing Stat3 pathway and activating the basic helix-loop-helix (bHLH) transcription factors in the neural progenitor cells.

Project Title:	6th World Congress for Brain Mapping and Image Guided Therapy 1. Development of 3-actoxymethoxycarbonyl-2,2,5,5-tetramethyl-1 -pyrrolid as an electron paramagnetic resonance imaging reagent for in vivo mapping brain oxygen distribution and infarction in ischemic brain 2. INTERACTION OF CAVEOLIN-1, NITRIC OXIDE AND NITRIC OXIDE SYNTHASES IN HYPOXIC HUMAN SK-N-MC NEUROBLASTOMA CELLS AND RAT ISCHEMIC BRAINS
Investigator(s):	Shen J
Department:	School of Chinese Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	08/2009
Completion Date:	08/2009

Abstract:

N/A

Project Title:	Elucidating Effects and Mechanisms of Isoflavonoids from Astragalus Mongholicus in Improving Neurogenesis for Post-stroke Treatment
Investigator(s):	Shen J, Fu S
Department:	School of Chinese Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	01/2010

Abstract:

Mammalian central nervous system (CNS) has long been believed to be incapable of neuronal repair or regeneration. However, in the past decade, one of the most important discoveries in Neurobiology is that ischemic injured brains have the potential capability to repair itself by stimulating the proliferation and differentiation of neural stem/progenitor cells, and by the direct migration of the neuronal precursors toward injured areas. This discovery offers a hope for the development of therapeutic approaches for the recovery of neurological functions in post-stroke patients and in those with neurodegenerative diseases. The production of new neurons in the ischemic brai n itself appears to be very limited in adults. Neural stem/progenitor cells within the adult brain germinal centers reside in a specialized microenvironmental niche. These cells are found in close proximity to blood vessels and are surrounded by glial cells in the adult hippocampus and the SVZ. The proliferation and differentiation of neural stem/progenitor cells and neural growth depend on the microenvironment niche signals, which include a number of growth factors such as basic fibroblast growth factor (bFGF), nerve growth factor (NGF), and epidermal growth factor (EGF) [1]. Vascular endothelial growth factor (VEGF) seems to play a key role in neural regeneration. Originally, VEGF was identified as a major mediator of angiogenes is, but it can also mediate vascular permeability and tissue regeneration. VEGF exerts its action via phosphotyrosine kinase receptors including VEGFR1/fms-like tyrosine kinase (Flt) and Flk-1 in endothelial cells, in hematopoieti c stem/progenitor cells, and in tumor cells. VEGF binds to Flk-1 in brain cells. The VEGF stimulates the extension of neural stem/progenitor cells and neurogenesis, consequently improving the learning ability in several animal mod els [1-4]. VEGF has the enhanced neurogenesis, neuromigration, angiogenesis, and improves recovery of sensorimotor and cognitive deficits in post focal cerebral ischemic rats [5-7]. Both vascular endothelial cells and glial cells expressing VEGF and bFGF function as niche signals for neural stem/progenitor cells, which proliferate in response to bFGF signal during neurogenic phase [8-11]. Both VEGF and BDNF mediate cross-talking between neural stem cells and endothelial cells in the niche [12]. Hypoxia-induced up-regulation of VEGF and Flk-1 stimulates proliferation and differentiation of adult neural stem cells in vitro and promotes neurogenesis in vivo [4,7,13]. Therefore, the niche signals are important cellular signal molecules mediating neural regeneration. Traditional Chinese Medicine is potentially useful for recovery of neurological functions in post-stroke treatment. Astragalus mongholicus (AM), which is a commonly used Chinese medicinal plant, has been reported to improve recovery of neurological function and promote neural regeneration in the rat brains. AM can reverse A beta(25-35)-induced memory loss and prevent the loss of axons and synapses in the cerebral cortex and hippocampus in mice [14]. The mechanisms of AM on promotion of neural regeneration are still unclear. AM is reported to promote the differentiatio n of rat bone marrow mesenchymal stem cells (BMSCs) into neuron-like cells [15]. DNA microarray analysis showed that AM remarkably up-regulated the expressions of epiregulin, fibroblast growth factor, and basic helix-loop-helix (bHLH) transcription factors (Mash1, Neurogenin1, Neu rogenin2) in the induction of BMSCs into neuronal cells [16]. Astragalosides, the major components of AM, can improve memory in aged mice [17]. Astragaloside IV, a representative compound of Astragalosides, can reduce brain infarction in mice after focal ischemia [18]. The active herbal ingredients of AM could hold promise for the discovery of novel drugs that could promote neurogenesis. However, the active ingredients and molecular mechanisms of AM for promoting neurogenesis are largely unclear. Isoflavonoids are one of the important active components in AM. Previous studies suggest that the isoflavonoids isolated from AM. have strong antioxidant activities and can protect neural cells from toxicity induced by L-glutamine (19-20). Our preliminary data showed that the isoflavonoids including formononetin, calycosin and 9,10-dimethoxypterocarpan-3-O-b- D-glucoside, could promote proliferation and differentiation of neural stem cells in vitro. In this proposal, we will further investigate the effects of formononetin, 9,10-di methoxypterocarpan-3-O-b-D-glucoside, and calycosin on promoting neural regeneration and its mechanisms involved. Objectives: To test the hypothesis that AM isoflavonoids can promote proliferation and differentiation of neural stem cells via regulating niche signals Special Aim 1. To investigate the effects of the AM isoflavonoids on improving proliferation and differentiation in cultured neural progenitor cells in vitro. Special Aim 2. To explore the molecular mechanisms of the AM isoflavonoids for promoting proliferation and differentiation of neural progenitor/stem cells under normoxic and hypoxic conditions. Special Aim 3. To study the effects of the AM isoflavonoids on improving neural progenitors / stem cells to develop into new neurons in ischemia rat brains in vivo References: 1. Mocchetti I, Wrathall JR. J Neurotrauma 1995; 12:853-870 . 2. Jin K, Zhu Y, Sun Y, et al. PNAS 2002; 99:11946-11950. 3. Fabel K, Tam B, Kaufer D, et al. Eur J Neurosci 2003; 18:2803-2812. 4. Cao L, Jiao X, Zuzga DS, et al. Nat Genet 2004; 36:827-835. 5. Schänzer A, Wachs FP, Wilhelm D, et al. Brain Pathol 2004; 14:237-248. 6. Wang Y, Galvan V, Gorostiza O, et al. Brain Res 2006; 1115(1):186-193. 7. Wang Y, Jin K, Mao XO, et al. Neurosci Res 2007; 85(4):740-7. 8. Lee HJ, Kim KS, Park IH, et al. PLoS One 2007; 2(1):e156. 9. Ciccolini F, Svendsen CN. J Neurosci 1998; 18:7869-7880. 10. Vaccarino FM, Schwartz ML, Raballo R, et al. Nat Neurosci 1999; 2:246-253. 11. Raballo R, Rhee J, Lyn-Cook R, et al. J Neurosci 2000; 20:5012-5023. 12. Li Q, Ford MC, Lavik EB, et al. J Neurosci 2006; 84:1656-1668. 13. Meng H, Zhang Z, Zhang R, et al. Neurosci lett 2006; 393:97-101. 14. Tohda C, Matsuyama S, Komatsu K. Br J Pharmacol 2006; 149:532-541. 15. Yang XW, Wang Y, Tissues Engineering Research 2008: 12(25):4996-5000. 16. Leng S, Dong X. Nervous Diseases and Mental Health 2005: 5(4): 251-256. 17. Lei H, Wang B, Li WP, et al. Acta Pharmacol Sin 2003; 24: 230-234. 18. Luo Y, Qin Z, Hong Z, et al. Neurosci Lett 2004; 363:218-223. 19. Yu D, Duan Y, Bao Y, et al. J Ethnopharmacol 2005; 98(1-2):89-94; 20. Yu DH, Bao YM, Wei CL, et al. Biomed Environ Sci 2005; 18(5):297-301

Project Title:	Development of Hydroxysafflor Yellow A (HSYA) as a Botanical Drug for Reducing Blood Brain Barrier Permeability and Preventing Infarction Enlarge ment in Stroke Treatment
Investigator(s):	Shen J
Department:	School of Chinese Medicine
Source(s) of Funding:	Seed Funding Programme for Applied Research
Start Date:	06/2010

Abstract:

Stroke is the third major cause of death worldwide and is the leading cause of disability in human diseases. Few therapeutic drugs are available for saving neura l cells from cerebral ischemic injury. Recombinant tissue-plasminogen activator (rt-PA) is the only thrombolytic drug approved for rebuilding cerebral circulation in the treatment of acute ischemic stroke. However, rt-PA has the restraint of use within 3 hours after stroke with potential risk of hemorrhagic transformation. It is desirable to develop new drugs for saving neural cells from ischemic brain injury. After stroke, elevated blood brain barrier (BBB) permeability and infarction enlargement are major complications contributing to ischemic bra in injury. Activating matrix metalloproteinases (MMPs) is a key step in BBB disruption during stroke [1-3]. MMPs are a large family of proteolytic zinc-containing enzymes responsible for degradation of extracellular matrix around cerebral blood vessels and neurons, and their action leads to BBB opening, brain edema, hemorrhage and cell death. MMP-2, -3, and -9 are the main soluble MMPs in brain. MMP-3 has a broad spectrum of activity against extracellular matrix, while MMP-2 and -9 show narrow ranges of substrates, but these include important elements of the basement membrane. MMP-2 is normally present in astrocytic end feet surrounding cerebral blood vessels. Ischemia-reperfusion causes the induction of MMP-9 in blood vessels and subsequent invasion of neutrophils. Increased activation of MMPs contribute s to BBB opening following thrombolysis with rt-PA in focal cerebral ischemic experiments [4]. Development of new drugs particularly targeting on protection of BBB integrity is an attractive strategy for drug discovery to protect ischemic brains in stroke treatment. Free radicals are important mediators for activating MMPs and inducing BBB breakdown and infarction enlargem ent. Fee radicals include reactive oxygen species (ROS) like superoxide (O2.-) and hydroxyl radicals (.OH) and reactive nitrogen species (RNS) such as nitric oxide (NO) and peroxynitrite (ONOO-), etc. Both ROS and RNS are important cytotoxic factors in neural oxidative damage. NO mediates BBB disruption through MMPs activation [3]. NOS inhibitor L-NAME shows to reduce both the disruption of BBB and MMP-9 expression [5]. NO can react with superoxide (O2.-) to generate ONOO-. Pero xynitrite mediates NO-induced BBB damage. Peroxynitrite can easily penetrate lipid bilayers, leading to peroxidation of membrane lipids. More and more evidences indicate that the formation of peroxynitrite is a key pathway of ischemic brain injury, inducing inflammation, cell death, BBB high-permeability and infarction enlargement . For example, 3-nitrotyrosine (3-NT), an oxidative product of tyrosine by ONOO–, is widely used as a biomarker for ONOO– detection. The increase of 3-NT was found in the penumbral cortex of ischemic brains [5,6]. By co-localizing of 3-NT, MMP-9 and Evans blue leakage, a recent study suggests that ONOO- is associated with MMP-9 activation and BBB opening in focal cerebral ischemia-reperfusion rats [7]. Peroxynitrite decomposition catalysts (PDCs) potentates the reduction of NO and O2.- and isomerizes ONOO- to nitrate and decreases its decomposition to other reactive intermediates. Even delayed treatments of PDCs can reduce apoptosis, infarction volume, edema and neurological deficits in focal ischemic rat brains [8]. Those results suggest a role of NO and ONOO- in activation of MMPs and BBB opening during cerebral ischemia-reperfusion injury. Therefore, seeking for the drugs with the properties of scavenging ONOO- and inhibiting MMPs activation can lead to drug discovery for preventing BBB breakdown and infarction enlargement in stroke treatment. The dried flower of the safflower plant, Carthamus tinctorius L. (紅花), a herbal medicine with the prope rties of improving circulation, has been used extensively in Traditional Chinese Medicine (TCM) to treat ischemic heart diseases, hypertension, cerebrovascular and gynecological diseases [9, 10]. Phytochemical studies have proved that safflower yellow is the main constituent in water soluble extracts of safflower. Safflower yellow consists of hydroxysafflor yellow A, safflor yellow B, safflomin A, etc, and has a wide range of pharmacological activities, including coronary dilation, platelet activator facto r antagonists, antioxidation, myocardial and cerebral protection, and immunosuppression, etc. Hydroxysafflor yellow A (HSYA) is considered as the main active component of safflor yellow contributing to the myocardial and cerebral protective effects and is chosen as an active marker component for controlling the quality of safflowe r in Chinese Pharmacopoeia [9]. The chemical structure of HSYA is showed in Fig 1 of Attachment. HSYA can extend the coagulation time and has anti-thrombotic effect. Accumulating evidence indicates that HSYA can be potentially developed into a new drug for the treatment of ischemic stroke. HSYA has showed the neuroprotective effects against ischemic brain injury in vivo and in vitro. Previous studies have showed the multiple phar macological activities of HSYA such as scavenging active oxygen species, suppressing p65 binding activity and inflammatory cytokines including TNF-alpha, IL-1beta and IL-6, promot ing anti-inflammatory cytokine IL-10, and inhibiting mitochondrial permeability transition pores, etc.[11-14]. HSYA can reduce infarction size, edema and improve the neurological deficit scores in focal cerebral ischemic rats [11]. HSYA has showed to significantly inhibit glutamate and sodium cyanide (NaCN)-mediated neuronal injury in the in vitro cultured fetal cortical cells and remarkably attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mediated neurotoxicity in mice [15-16]. In our pilot study, we found that HSYA reduced infarction volumes in the ischemic brains in vivo and protected brain microvascular endothelial cells from oxidative injury in vitro. Further study showed that HYSA inhib ited MMPs activation and degradation of tight-junction proteins (key proteins in BBB permeability). In order to develop HSYA as a potential drug for protecting BBB from oxidative damage in ischemic stroke treatment, we propose to further investigate the effects of HSYA on inhibiting RNS production, MMPs activation-induced degradation of the tight junction proteins and preventing blood brain barrier disruption in focal brain ischemia-reperfusion injury. References 1. Gasche Y, et al. Front Biosci. 2006;11:1289-301. 2. Rosenberg GA, Yang Y. Neurosurg Focus. 2007;22(5):E4. 3. Liu KJ, Rosenberg GA. Free Rad Biol Med 2005; 39: 71-80 4. Kelly MA, et al. Exp Neurol. 2006; 200(1):38-49 5. Gursoy-Ozdemir Y, et al.Stroke 2000;31:1974-81 6. Suzuki M, et al. Brain Res 2002; 951: 113-20 7. Gursoy-Ozdemir Y, et al. Stroke. 2004; 35(6):1449-53. 8. Thiyagarajan M, et al. Br J Pharmacol 2004; 142, 899-911 9. The State Pharmacopoeia Commission of China, Pharmacopoeia of the People’s Republic of China, Part I. Chemical Industury Press. Beijing, China. 2005. p10 10. Nie QR. Shizhen Med Materia Med Res 2003 14(8): 503-5 11. Ye SY, Gao WY. Arch Pharm Res 2008; 31(8): 1010-5 12. Li ZY, Tu XH. Tradit Chin Drug Res Clin Pharmacol 2005;16(2) : 153-6 13. Tian J, et al. Pharmacology 2008:82(2);121-6 14. Chen TT, et al. Yao Xue Xue Bao 2008; 43(6):570-5. 15. Zhu H, et al. Planta Med 2003; 69(5): 429-33. 16. Han B, Zhao H. Neurochem Res 2010; 35(1):107-13

Researcher : Shiu SWM

List of Research Outputs

Shiu S.W.M. , Zhou H., Wong Y. and Tan K.C.B. , Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus, J Diabetes Invest . 2010, 1: 111-116.

Shiu S.W.M. , Wong Y. , Zhou H.L. and Tan K.C.B. , Roles of lipid transfer proteins in determining cellular cholesterol efflux to serum in type 2 diabetes mellitus, 53rd Annual Meeting of the Japan Diabetes Society, Okayama, Japan . 2010.

Tam H.L. , Shiu S.W.M. , Wong Y. , Chow W.S. , Betteridge D.J. and Tan K.C.B. , Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes, Atherosclerosis . 2010, 209: 173-177.

Tan K.C.B. , Tam H.L. , Yuen M.A.M., Shiu S.W.M. and Betteridge D.J., Association between expression of receptor for advanced glycation end products in peripheral blood monocytes and circulating soluble isoforms of the receptor in type 2 diabetes, The Endocrine Society’s 92th Annual Meeting, San Diego . 2010.

Tan K.C.B. , Shiu S.W.M. , Zhou H.L. and Wong Y. , Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus, The International Diabetes Federation 20th World Diabetes Congress, Montreal, Canada . 2009.

Researcher : Siu DCW

Project Title:	Dynamic Conformational Changes of the P-S6 linker of the Pacemaker (HCN) Channels Identified by Sulfhydryl Modification: Pore-to-Gate Coupling Model
Investigator(s):	Siu DCW, Tse HF
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	10/2008

Abstract:

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel gene family encodes the pacemaker current If (f for funny), one of the key players in cardiac pacing (1,2). Recently, HCN channels have been emerging as a new pharmacological target for cardiac arrhythmias. Structurally, HCN channels resemble voltage-gated K+ (Kv) channels, consisting of four monomeric subunits arranged around a central pore, and each subunit comprises six transmembrane segments (S1-S6) with a pore-forming P-loop between the S5 and S6 (3-6). Despite the presumed structural similarity, much less is known about how the structure relates to the HCN channel functions, in which holds significances for the development of novel pharmacological agents. Previous experimental evidences have shown that the activation gating behavior of HCN channels can be modified by missense mutations near the P-loop (7-9) suggesting that ion permeation (pore) and activation gating (gate) though primarily controlled by structures on opposite sides of the per meation pathway, may actually interact with each other similar to the C-type inactivation of Kv channels. In fact, plausible mechanisms for the pore-to-gate coupling may involve: 1) dynamic state-dependent conformational changes/movements of the pore region that are directly coupled to the voltage-sensor and/or activation gate, 2) movement of the rest of channels with respect to the pore such that structures outside of an inflexib le pore region interact with structures within the pore region in a state-dependent manner, or 3) a combination of both. However, direct evidence regarding the existence of these conformational changes/movements of the P-loop is in generally lacking. In this proposal, we aim to dissect the structure and function interaction betw een the pore (permeation pathway) and the activation gate of HCN channels. This will be accomplished by systematical introduction of cysteine residues (scanning cysteine mutagenesis) into the pore segment of the HCN1 channels (putatively exposed to the extracellular milieu), which would then be probed by the permanently charged, membrane-impermeant 2-trimethylammoniumethylmethane thiosulfonate (MTSET) from external application. The functional consequences of the cysteine mutagenesis and the MTSET modification will be studied using two-electrode voltage clamp to record the hyperpolarization-activated current in Xenopus oocyte expression system. The results of the proposed study may shed light onto the structure of the outer pore of the HCN channel, as well as the dynamic conformatio nal movement during channel gating; this will be of significance in understanding the structure and function of this important pacemaker channel, and may ultimately provide important groundwork data for the development of pharmac ological agents tackling this channel.

Project Title:	Long-term Efficacy and Safety of a Gene-based Bio-artificial Pacemaker tested in a large animal Sick Sinus Syndrome Model
Investigator(s):	Siu DCW, Lau CP, Li RA, Tse HF
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To test the hypothesis that HCN-channel gene-based bio-artificial pacemaker performs long-term pacing function for treatment of SSS. This will be accomplished by in-vivo AAV mediated gene-transfer of a gating-en gineered version of HCN-channels to create bio-artificial pacemaker in a clinically relevant swine SSS model, followed by detailed, long-term assessment. The endpoint is a) reduction of the electronic pacemaker dependence at whole animal level for 1 year, and b) sustained phenotypic shift at cellular level; (2) To test the hypothesis that bio-artificial pacemaker exhibits physiolo gical neurohumeral responsiveness. This will be accomplished by standard autonomic tests of bio-artificial pacemaker in SSS model. The endpoints are a) to demonstrate normal intrinsic heart rate, b) to exhibit appropriate heart rate variability, and c) to exhibit response to auton omic interventions; (3) to test the hypothesis that bio-artificial pacemaker confers no arrhythmogenic risk. This will be accomplished by continuous telemetry monitoring, programmed electrical stimulation, and cellular electrophys iological studies. The endpoints are a) the occurrence of spontaneous atrial tachyarrhythmia, b) the inducibility of atrial tachyarrhythmia, and c) the occurrence of trigger activ ities of transduced cells.

Project Title:	Cardiac hypertrophic signals for cardiac differentiation of embryonic stem cells
Investigator(s):	Siu DCW
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	08/2009

Abstract:

Objective 1: To investigate whether adult hypertrophic signals including cardiotonic steroid (ouabain) on cardiac differentiation of mESCs. Objective 2: To investigate whether the phenotypes of cardiac derivatives from embryonic stem cells can be matured by cardiotonic steroid.

List of Research Outputs

Chan Y.C. , Lee Y.K. , Ng K.M. , Lai K.W.H. , Yang D. , Tse H.F. and Siu D.C.W. , A Newly-derived Small Synthetic Compound Alleviated Ventricular Fibrillation In A Pig Model With Chronic Myocardial Infarction As Revealed By Optical Mapping, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” (Hong Kong) . 2010.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. and Li R.A. , Automaticity and conduction properties of bio-artifici al pacemakers assessed in an in vitro monolayer model of neonatal rat ventricular myocytes., Europace. In press. . 2010.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. , Lau C.P. and Tse H.F. , Characterizing the basis of automaticity of neonatal rat ventricular myocytes: Implications for cardiac excitability manipulations., Europace . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W. , Tam S. , Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke (abstract and poster presentation), EuroPRevent 2010, Prague, 5-7 May 2010 . Prague, European Society of Cardiology.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W., Tam S., Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke, EuroPrevent 2010. European Journal of Cardiovascular Prevention and Rehabilitation 2010 Jun P480 . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W., Lam T.H. and Tse H.F. , Selenium Deficiency is Associated with Adverse Vascular Function in Patients with High Risk for Vascular Events, EuroPrevent 2010. European Journal of Cardiovascular Prevention and Rehabilitation 2010 Jun P334 . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W. , Lau C.P. , Lam T.H. and Tse H.F. , Selenium deficiency is associated with adverse vascular function in patients with high risk for vascular events (abstract and poster presentation), EuroPRevent 2010, 5-7 May 2010, Prague . Prague, European Society of Cardiology, 2010.

Dai Y.L., Luk T.H., Siu D.C.W. , Yiu K.H., Chan K.H.T. , Lee S.W.L. , Li S.W., Fong B., Wong W.K., Tam S. , Lau C.P. and Tse H.F. , Mitochondrial dysfunction induced by statin contributes to endothelial dysfunction in patients with coronary artery disease., Cardiovascular Toxicology . 2010, 10: 130-8.

Hai J.J., Siu D.C.W. , Ho H.H., Li S.W., Lee S.W.L. and Tse H.F. , Relationship between changes in heart rate recovery after cardiac rehabilitation on cardiovascular mortality in patients with myocardial infarction. , Heart Rhythm . 2010, 7: 929-936.

Ho H.H., Pong V., Siu D.C.W. , Yiu K.H., Ko R., Tse H.F. , Jim M.H. and Chow W.H., Long-term outcomes of drug-eluting stents versus bare- metal stents in Chinese. , Clinical Cardiology . 2009, In press.

Ho L.Y., Siu D.C.W. , Lau C.P. , Lip G.Y. and Tse H.F. , Safety and efficacy of oral anticoagulation therapy in chinese patients with concomitant atrial fibrillation and hypertension. , J Hum Hypertens. 2010 . 2010.

Jim M.H., Ho H.H., Ko R.L., Siu D.C.W. , Yiu K.H., Lau C.P. and Chow W.H., Paclitaxel-eluting stents for chronically occluded saphenous vein grafts (EOS) study, Journal of Interventional Cardiology . 2010, 23(1): 40-45.

Jim M.H., Yiu K.H., Ko R.L., Siu D.C.W. and Chow W.H., Virtual histology of aneurysmal lesion in aortocoronary saphenous vein graft, Asian Cardiovascular Thoracic Annals . 2009.

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lau C.P. and Siu D.C.W. , Pacing technology and its indications: Advances in threshold management, automatic mode switching, and sensors, In: Saksena S, Camm AJ, Boyden PA, Dorian P, Goldschlager N, Electrophysiological Disorders of the Heart . Elsevier Churchill Livingstone, 2010.

Lau C.P. , Siu D.C.W. and Tse H.F. , Sensor Driven Pacing, In: Ellenbogen KA, Natale A, Al-Ahmad Amin, Wang PJ , Pacemakers and Implantable Cardioverter Defibrillators: An Expert’s Manual . 2010.

Lee S.W.L. , Ho H.H., Kong S.L. , Lam Y.M., Siu D.C.W. , Miu K.M., Lam L. and Chan H.W., Long term clinical outcomes after deployment of femora l vascular closure devices in coronary angiography and percutaneous coronary intervention., Catheterization and Cardiovascular Interventions . 2009, 75(3): 345-348.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Lee Y.K. , Ng K.M. , Lai K.W.H. , Tse H.F. and Siu D.C.W. , Triiodothyronine enhances cardiac differentiation of embryonic stem cells and maturation via classical pathway., Molecular Endocrinology . 2010, (in press).

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with pas sive epicardial patch in porcine model of chronic myocardial infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H., Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patients with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai K.W.H. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1alpha promotes cardiac differentiation of embryonic stem cells., Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-37.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embryonic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Ng K.M. , Lee Y.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Hypoxia promotes cardiac differentiation of human em bryonic stem cells, Physiology Symposium 2009, HKU, Hong Kong 5/2009 .

Siu D.C.W. , Pong V., Ho H.H., Liu S., Lam B. , Lau C.P. , Li S.W. and Tse H.F. , Does MADIT II criteria for implantable cardioverter defibrillator implantation applicable to Chinese patients? , J Cardiovasc Electrophysiol. . 2010, 21: 231-5.

Siu D.C.W. and Tse H.F. , Predicting recurrence of atrial fibrillation after electrical cardioversion: gauging atrial damage. Europace. , Europace . 2010, 12: 764-5.

Siu D.C.W. , A Safety and Efficacy Trial Evaluating the Use of Apixaban in the Treatment of Symptomatic Deep Vein Thrombosis and Pulmonary Embolism, 2009.

Siu D.C.W. , Are MADIT II criteria for ICD implantation applicable to Japanese and Chinese?, Cardiostim, Nice France, 2010 . 2010.

Siu D.C.W. , Pong V., Ho H.H., Liu S., Lau C.P. and Tse H.F. , Are MADIT II criteria for implantable cardioverter defibrillator in Chinese. , Journal of Cardiovascular Electrophysiology . 2009, 21: 231-5.

Siu D.C.W. , Atrial Fibrillation: Old Wars, New Weapons, Atrial selective anti-arrhythmic therapy, The Hong Kong Society of Congenital and Structural Heart Disease . 2010.

Siu D.C.W. , Atrial Selective Anti-arrhythmic drug, 2nd Asia Pacific Heart Rhythm Society Scientific Session . 2009.

Siu D.C.W. , Atrial Selective Therapy for Atrial Fibrillation, 12th South China International Congress of Cardiology . 2010.

Siu D.C.W. , Atrial fibrillation: Beyond Rhythm and Rate Management, 12th South China International Congress of Cardiology . 2010.

Siu D.C.W. and Tse H.F. , Atrial flutter and fibrillation. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Siu D.C.W. , Pong V., Jim M.H., Yue W. , Ho H.H., Li L.S.W. , Lau C.P. and Tse H.F. , Beta-blocker in post-myocardial infarct survivors with preserved left ventricular systolic function, Pacing and Clinical Electrophysiology . 2010, 33(6): 675-80.

Siu D.C.W. and Lau C.P. , Cardiac Pacemaker, In: Lip GY, Tse HF, Coats , Oxford Desk Reference. . Oxford University Press, 2010.

Siu D.C.W. and Tse H.F. , Cryoablation for Atrial Fibrillation, In: Bredikis, Wiber , Cryoablation of Cardiac Arrhythmias. . Elsevier Churchill Livingstone, 2010.

Siu D.C.W. , Lau C.P. , Lee S.W.L. , Lam K.F. and Tse H.F. , Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation, Critical Care Medicine . MD Consult, LLC, 2009, 37(7): 2174-2179.

Siu D.C.W. , New antithrombotic therapy for management of atrial fibrillation and venous thromboembolism., Fifth International Symposium on Healthy Aging . 2010.

Siu D.C.W. , Optimal anticoagulation therapy for atrial fibrillatio n., CME Anaesthesology (2010) . 2010.

Siu D.C.W. , Pharmacological Therapy for Atrial Fibrillation , Hong Kong Interhospital Network of Pacing and Cardiac Electrophysiology (11th Annual Scientific Meeting) . 2009.

Siu D.C.W. , Pharmacological therapy for Atrial fibrillation, 11th Annual Scientific Meeting, Hong Kong Interhospital Network of Pacing and Cardiac Electrophysiology . 2010.

Siu D.C.W. and Tse H.F. , Predicting recurrence of atrial fibrillation after cardioversion: gauging atrial damage, Europace . 2010, 12: 764-5.

Siu D.C.W. , Waston T., Lai K.W.H. , Lee Y.K. , Chan Y.H. , Ng K.M. , Lau C.P. , Lip G.Y. and Tse H.F. , Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm., Europace . 2009, 12(4): 460-1.

Siu D.C.W. , Liao S. , Liu Y. and Tse H.F. , Stem cells for myocardial repair. , Thromb Haematol . 2010, 104(1).

Siu D.C.W. , The Society of Physicians of Hong Kong, Sunday Symposium in Cardiology, What constitutes appropriate cardiac risk screening? . 2010.

Siu D.C.W. , Update in management of atrial fibrillation and venous thromboembolism, Annual Scientific Meeting of Hong Kong Society of Hematology . 2010.

Tse H.F. , Siu D.C.W. and Lau C.P. , Impact of Right Ventricular Pacing Sites on Exercise Capacity during Ventricular Rate Regularization in Patients with Permanent Atrial Fibrillation., Pacing and Clinical Electrophysiology . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical Function only in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation Existing Atrial Dyssynchrony , European Society of Cardiology Congress, Spain. August 29 –September 2, . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchrony and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Submitte d) . 2010.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Elevated Pulmonary Artery Systolic Pressure in Patients with Coronary Artery Disease and Left Ventricular Dyssync hrony , European Journal of Heart Failure . 2010, (in press).

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Relation of T-wave Alternans to Left Ventricular Dyssynchrony in Patients with Coronary Heart Disease, ESC Congress, 2010 .

Yiu K.H., Siu D.C.W. , Yiu Y.F. and Tse H.F. , Electrocardiogram, In: Lip GY, Tse HF, Coats , Oxford Desk Reference . Oxford University Press, 2010.

Researcher : Soong SS

List of Research Outputs

Bow C.H.Y. , Tsang S.W.Y., Soong S.S. , Yeung S.C. and Kung A.W.C. , BMD Enhances Clinical Risk Factors in Predicting Ten-Year Risk of Osteoporotic Fractures in Chinese Men: The Hong Kong Osteoporosis Study, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Bow C.H.Y. , Cheung C.L. , Gao Y. , Lau K.S. , Soong S.S. , Yeung S.C. and Kung A.W.C. , Bone Mineral Density and Serum Osteoprotegerin Levels in Pre- and Postmenopausal Women, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Bow C.H.Y. , Loong C., Leung F., Lau T.W., Chan Y.Y. and Soong S.S. , Survival and Re-fracture Rates in Paitents with Osteoporot ic Fractures: The Hong Kong Osteoporosis Study, The 31st Annual Meeting of the American Society for Bone and Mineral Research, Denver, Colorado, USA . 2009.

Loong C.H.N., Leung F., Lau T.W., Leung E., Chan Y.Y., Yee A., Ma L.F., Soong S.S. , Bow C.H.Y. , Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Predictive Factors for Re-fracture in Chinese Population with Previous Osteoporotic Fractures, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , A Secondary Fracture Prevention Programme to Reduce Fractures, Hospital Admissions, and Mortality, Hospital Authority Convention 2010, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Evaluation of the Osteoporosis Secondary Fracture Prevention Program at Queen Mary Hospital: Successful Recruitment is Associated with a Lower Re-fracture Rate and Mortality Rate at One Year, Hospital Authority Convention 2010, Hong Kong . 2010.

Soong S.S. , Loong C.H.N., Bow C.H.Y. , Wu J. and Kung A.W.C. , Factors Associated with Osteoporosis Treatment Adherence in Hong Kong, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Researcher : Sun H

List of Research Outputs

Chen J. , Tao R. , Sun H. , Tse H.F. , Lau C.P. and Li G.R. , Multiple Ca(2+) signaling pathways regulate intracellul ar Ca(2+) activity in human cardiac fibroblasts., J Cell Physiol . 2010, 223(1): 68-75.

Dong M. , Sun H. , Tang Q. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of human cardiac KCNQ1/KCNE1 channel by epidermal growth factor receptor kinase., Biochim Biophys Acta . 2010, 1798(5): 995-1001.

Li G.R. , Sun H. , Chen J. , Zhou Y. , Tse H.F. and Lau C.P. , Characterization of Multiple Ion Channels in Cultured Human Cardiac Fibroblasts. , PLoS One . 2009, 4(10): e7307.

Researcher : Sun JZ

List of Research Outputs

O W.S. , Liao S. , Sun J.Z. , Ho J.C.M. , Chiu C.N. , Ng E.H.Y. , Yeung W.S.B. , Li R.H.W. and Tang F. , Adrenomedullin and oviduct function in human and rats, Biology of Reproduction . 2009, 81: 99.

Researcher : Tam HL

List of Research Outputs

Tam H.L. , Shiu S.W.M. , Wong Y. , Chow W.S. , Betteridge D.J. and Tan K.C.B. , Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes, Atherosclerosis . 2010, 209: 173-177.

Tan K.C.B. , Tam H.L. , Yuen M.A.M., Shiu S.W.M. and Betteridge D.J., Association between expression of receptor for advanced glycation end products in peripheral blood monocytes and circulating soluble isoforms of the receptor in type 2 diabetes, The Endocrine Society’s 92th Annual Meeting, San Diego . 2010.

Researcher : Tam JH

List of Research Outputs

Cheng C.H. , Tam J.H. , Wong R., Yik P.Y. , Song Y.Q., Morley J.E. and Lam K.S.L. , Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men: a 1-year cohort study., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 16.

Researcher : Tam S

List of Research Outputs

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W. , Tam S. , Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke (abstract and poster presentation), EuroPRevent 2010, Prague, 5-7 May 2010 . Prague, European Society of Cardiology.

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Jin Y.L., Yue X.J., Ong K.L. , Tam S. , Wong K.S. , Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese. , Eur J Hum Genet. . 2010, 1-6.

Researcher : Tan KCB

Project Title:	Regulation of Receptor for Advanced Glycation End Products Isoforms in Diabetes
Investigator(s):	Tan KCB
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2007
Completion Date:	10/2009

Abstract:

The receptor for advanced glycation end products (RAGE) belongs to the immunoglobulin superfamily of cell-surface molecules and is a multi-ligand receptor (1). Activation of RAGE by advanced glycation end products (AGEs) has been shown to play an important role in the pathogenesis of diabetic vascular complications. The engagement of the full-length RAGE by AGEs activat es key cell signaling pathways and result in a perturbation of a variety of homeostatic functions of the vasculature and induction of cellular oxidant stress (2,3). Blocking the activation of RAGE by using recombinant soluble form of the receptor (sRAGE) or function-blocking antib odies suppresses vascular hyperpermeability and atherosclerotic lesion development in diabetic rodents (4,5). The soluble form of RAGE can be produced endogenously by alternative splicing of the RAGE gene (6). The C-trunc ated sRAGE has AGE-binding properties in the absence of a signalling cascade and is capable of neutralizing RAGE signalling in cells. Hence, sRAGE can act as a decoy for RAGE ligands and have cytoprotective properties against AGEs. Very little is known about the endogenous production of sRAGE and the regulation of alternative splicing of the RAGE gene. RAGE transcription is contro lled by several transcription factors and RAGE expression occurs in both a constitutive and inducible manner depending on the cell type and developmental stage (7). Schlueter et al have shown that the relative expression ratios for the full length RAGE transcript to the sum of its splice variants encoding C-truncated soluble variants varied strongly among tissues (8). They suggest ed that the pre-mRNA of RAGE must be subjected to regulated alternative splicing activated by extracellular cues of yet unknown cellular signalling pathways. In vitro studies have demonstrated that AGEs can stimulate the RAGE gene expression through activation of nuclear factor-κB (NF-κB) in human vascular endothelial cells (9) although whether AGEs directly influence sRAGE expression and its secretion by endothelial cells has not been determined. We have recently shown that there is an association between serum levels of AGEs and sRAGE in diabetic patients (10). Our data suggest that AGEs may be involved in the regulation of endogenous sRAGE and we intend to investigate the underlying mechansims. The objectives of this study are to determine (i) whether AGEs can modulate the pattern of RAGE gene expressio n and alter sRAGE production by endothelial cells and macrophages and the cell signaling pathways involved; and (ii) the effects of statins on AGEs-RAGE system and sRAGE production as statin has been shown to prevent the AGE-induced increase in NF-κB in endothelial cells (11).

Project Title:	Lectin-like oxidized low-density-lipoprotein receptor-1 in diabetes
Investigator(s):	Tan KCB
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	12/2008

Abstract:

The lectin-like oxidized low density lipoprotein receptor (LOX-1), a class E scavenger receptor, is a newly identified oxidized LDL receptor mainly expressed by endothelial cells (1). It is also expressed by mac rophages and vascular smooth muscle cells (2). LOX-1 has been implicated in vascular inflammation and atherosclerotic plague formation and destablisation (3,4). LOX-1 expression has been demonstrated in animal and human atheroscle rotic lesions (5,6). Levels of LOX-1 are elevated both within the intima and in the endothelium surrounding the lesion in early atherosclerotic lesions, suggesting that the LOX-1 is involved in the initiation and formation of atherosclerotic plaques. Transgenic mouse models for LOX-1 overexpression or gene knockout further confir m that LOX-1 contributes to the development of atherosclerosis. Overexpression of LOX-1 in apolipoprotein E-deficient mice increases atherosclerotic plaque formation, consistent with a role for LOX-1 in plaque development and prog ression (7). In double LDL-receptor- and LOX-1-null mice fed a high cholesterol diet, there was a significant reduction in atherosclerotic plaque formation in comparison with LDL-receptor-null mice alone (8). These findings would support the notion that oxLDL and LOX-1 interaction accelerates atherosclerosis. Binding of oxidized LDL (oxLDL) to LOX-1 in endothelial cells stimulates intracellular signaling and activates pro-atherogenic gene expression and causes endothelial dysfunction (9-11). Similar to other scavenger receptors, LOX-1 has broad ligand specificity and LOX-1 can bind structurally diverse ligands. In addition to oxLDL, LOX-1 recognizes other modified lipoprotein particles but not native LDL. LOX-1 also binds anionic phospholipids, apoptotic bodies, aged cells, activated platelets, advanced glycation end products (AGEs) and both gram-positive and gram-negative bacteria (3,4). We have recently shown that LOX-1 expres sion is increased in human diabetes (12). Since there is increased formation and accumulation of AGEs in diabetes mellitus, AGEs may act as major ligands for LOX-1 in diabetes in additional to oxLDL. Although oxLDL/LOX-1 activation and intracellular signaling has been extensively studied, it is unclear what pathways are activated upon LOX-1 binding to other ligands like AGEs and the subsequent effects on the vasculature. The objectives of this study are to determine (i) whether binding of AGEs to LOX-1 increases intracellular reactive oxygen species (ROS), activates NF-κB and stimulates adhesion molecules expression (ii) whether AGEs induces endothelial cells apoptosis via LOX-1.

Project Title:	Soluble receptor for advanced glycation end products and diabetic complications
Investigator(s):	Tan KCB
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	12/2008

Abstract:

(1) To determine whether circulating levels of esRAGE and sRAGE reflect levels of RAGE expression in peripheral blood monocytes in type 2 diabetic subjects It is not clear at present from which tissue or cell type plasma sRAGE or esRAGE is originated and it is difficult to determine in humans whether circulating levels of sRAGE or esRAGE is related to tissue RAGE expression. Hence, we will evaluate the relationship between RAGE expression in peripheral blood monocytes and circulating sRAGE and esRAGE concentrations in type 2 diabetic patients. Although peripheral blood monoctyes may not be the only source of esRAGE and sRAGE, these cells are easily accessible and it has been shown that RAGE expression in peripheral blood monocytes can be upregulated in conditions where ligands for RAGE accumulate (8); (2) To investigate the potential use of sRAGE and esRAGE as a biomarker We have recently shown that there is an association between sRAGE and circulating AGEs and the severity of nephropathy in type 2 diabetic patients (9). The relationship betwe en sRAGE and diabetic complications has so far only been investigated in cross-sectional studies and the roles of the different splice variants of sRAGE have not been addressed. Prospective studies are very much needed to further determine whether sRAGE is a good marker of diabetic vascular complications and whether it can potentially predict and influence the development of complications. Whether esRAGE is a better marker than sRAGE is not known and the usefulness of measuring of sRAGE compared to esRAGE needs to be investigated. We will determine the relationship between sRAGE, esRAGE and diabetic microvascular complications in a prospective manner in a large group of type 2 diabetic patients that we have been following up from our previous cross-section al studies on the association between AGEs and diabetic complications; (3) To investigate the effect of thiazolidinedione on the generation of esRAGE and sRAGE and the underlying mechanisms We have recently shown that treating diabetic subjects with thiazolidinedione increases serum esRAGE levels (10). We will explore the potential underlying mechasnism(s) whereby thiazolidinedione may influence RAGE expression and stimulate the production of sRAGE and esRAGE in vitro. It is important to determine whether the effect of thiazolidinedione on these soluble receptors differ from that of the full length cell surface receptor. The results from our study will answer some very crucial questions on the clinical relevance of measuring the circulating levels of the soluble receptors of RAGE and its potential usefulness as a biomarker. Determi nation of the level or the ratio of individual RAGE isoforms may help to predict an individual’s susceptibility to diabetic complications caused by RAGE activation. If sRAGE turns out to be not just a biomarker, but also plays a role in the endogenous defence of tissue to AGEs, measurement of serum sRAGE can be used to monitor diabetic vascular disease as well as to evaluate the effect of potential intervention. Improving our understanding on the regulation of the production of esRAGE and sRAGE and how this may differ from the reg ulation of full length RAGE will help to devise future therapeutic approaches to modulate sRAGE.

Project Title:	MircoRNA and reverse cholesterol transport
Investigator(s):	Tan KCB
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	12/2009

Abstract:

MicroRNAs (MiRNAs) are a novel group of universally present small non-coding RNAs that have been implicated in a wide range of physiological processes (1,2). Thes e short non-coding RNA molecules (about 22 nt) are highly conserved and regulate gene expression on the post-transcriptional level. They suppress protein synthesis by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA, thereby silencing gene expression. Hence, miRNAs add a new level of regulation and fine tuning for gene expression and cellular function. Although the function of most miRNAs is currently unknown, several studies indicate that they may play important roles in diverse aspects of signaling and metabolic control (3). Emerging evidences suggest that miRNAs play a significant role in cardiovascular biology and lipid metabolism and may therefore influence atherosclerosis (4,5). Let7-f, miR-27b, and miR-130a have been identified as pro-angiogenic miRNAs; and miR-221 and miR-222 have been shown to inhibit in vitro endothelial cell migrati on, proliferation, and angiogenesis (6). miR-21, miR-155, and miR-126 are important modulators of vessel remodelling and vascular inflammation (7,8). The uptake of modified LDL (eg oxidized LDL) leading to focal accumulation of lipid in foam cells derived from macrophages is recognized as a critical early event in atherogenesis . The amount of cholesterol retained in macrophages/foam cells depends not only on the uptake of oxidized lipoproteins by scavenger receptors but also by the process of degradatio n and efflux. Efflux of free cholesterol from cells can occur by a number of mechanisms including regulated transporter-facilitated processes by the ATP-binding cassette transporter A1 (ABCA1), ABCG1 and scavenger receptor class B type I (SR-BI) as well as by aqueous diffusion (9). Chen at al have recently shown that miR-125a-5p is involved in the regulation of lipid uptake and the inflammatory response in macrophages stimulated by oxidized LDL (10). We hypothesize that miRNA may also be involved in cholesterol efflux and reverse cholesterol transport in macrophages as one of the target genes of miR-125a-5p in macrophages is oxysterol binding protein (OSBP) (10). Recent studies have shown that OSBP is involved in the regulation of ATP-binding cassette transporter A1 (ABCA1) and reduces the expression and protein stability of the cholesterol transporter (11,12). miR-125a-5p may the refore be able to increase ABCA1 expression by suppressing ORBP. In addition, using bioinformatics analysis (http://www.targetsc an.org), we have found potential target sites of miR-125a-5p on the 3’ untranslated regions (3’ UTR) of SR-BI gene. Hence, we intend to evaluate the role of miR-125a-5p on the regulation of cholesterol transporters and cholesterol efflux in macrophages.

Project Title:	Reverse cholesterol transport and diabetic nephropathy
Investigator(s):	Tan KCB, Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To investigate serum capacity to induce ABCG1-mediated cholesterol efflux in type 2 diabetic patients with and without diabetic nephropathy and the impact of advanced glycation of HDL on cholesterol efflux; 2) To investigate the relative roles of ABCA1 and ABCG1 in human monocyte/macrophage cholesterol efflux and to determine whether both ABCA1 and ABCG1 expression is reduced in peripheral blood monocytes in type 2 diabetic patients with diabetic nephropathy and their regulation; 3) To examine cholesterol efflux in mesan gial cells and proximal tubular cells and renal expression of cholesterol transporters in diabetic nephropathy.

List of Research Outputs

Colhoun H.M., Betteridge D.J., Durrington P.N., Hitman G.A., Neil A.W., Livingstone S.J., Charlton-Menys V., Bao W.H., DeMicco D.A., Preston G.M., Tan K.C.B. and Fuller J.H., Comparison of Factors Associated with total sRAGE and esRAGE in Patients with Type 2 Diabetes, American Diabetes Association 70th Scientific Sessions, Florida. . 2010.

Lam C.L.D. , Lam C.M. , Tan K.C.B. , Lui M.M.S. and Ip M.S.M. , Serum advanced glycation endproducts (AGE) levels correlated with severity of obstructive sleep apnea but not insulin resistance, 14th Congress of the Asian Pacific Society of Respirology & 3rd Joint Congress of the Asian Pacific of Respirolog y/American College of Chest Physicians, Seoul, Korea, November, 2009, Respirology . 2009, 14 (Suppl 3): A168 (OS 32-01).

Lam D., Lam J., Tan K.C.B. , Lui M. and Ip M.S.M. , Serum advanced glycation end products levels correlated with severity of obstructive sleep apnea but not with insulin resistance, 14th Congress of the Asian Pacific Society of Respirology, Seoul, Korea . 2009.

Lam J.T.C., Lam K.S.L. , Tan K.C.B. , Chow W.S. , Tso A.W.K. and Kung A.W.C. , A woman with hypophosphataemia and raised alkaline phosphatase, British Medical Journal . 2010, 340: b-5564-.

Shiu S.W.M. , Zhou H., Wong Y. and Tan K.C.B. , Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus, J Diabetes Invest . 2010, 1: 111-116.

Shiu S.W.M. , Wong Y. , Zhou H.L. and Tan K.C.B. , Roles of lipid transfer proteins in determining cellular cholesterol efflux to serum in type 2 diabetes mellitus, 53rd Annual Meeting of the Japan Diabetes Society, Okayama, Japan . 2010.

Tam H.L. , Shiu S.W.M. , Wong Y. , Chow W.S. , Betteridge D.J. and Tan K.C.B. , Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes, Atherosclerosis . 2010, 209: 173-177.

Tan K.C.B. , Tam H.L. , Yuen M.A.M., Shiu S.W.M. and Betteridge D.J., Association between expression of receptor for advanced glycation end products in peripheral blood monocytes and circulating soluble isoforms of the receptor in type 2 diabetes, The Endocrine Society’s 92th Annual Meeting, San Diego . 2010.

Tan K.C.B. , Beijing Baishideng BioMed Scientific Co. Ltd., World Journal of Diabetes . 2009.

Tan K.C.B. , Bentham Science Publishers, The Open Diabetes Journal . 2009.

Tan K.C.B. , Bentham Science Publishers, The Open Translational Medicine Journal . 2009.

Tan K.C.B. , Cardiovascular disease protection for patients with diabetes, Hong Kong Cardiovascular Task Force Workshop, Hong Kong . 2010.

Tan K.C.B. , Shiu S.W.M. , Zhou H.L. and Wong Y. , Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus, The International Diabetes Federation 20th World Diabetes Congress, Montreal, Canada . 2009.

Tan K.C.B. , Hypothyrodism, CME Meeting for Chinese Medical Association of Macau, Macau . 2010.

Tan K.C.B. , Journal of Diabetes Investigation, 2009.

Tan K.C.B. , MediMedia, MIMS Endocrinology Guide . 2009.

Tan K.C.B. , Member of the Organising Committee, 5th International Symposium on Healthy Aging, Hong Kong . 2010.

Tan K.C.B. , Reducing cardiovascular risk in type 2 diabetes melli tus, CME Meeting for Physicians, Baptist Hospital, Hong Kong . 2010.

Tan K.C.B. , The vascular wall & diabetes, Asia-Europe Expert Dialogue on Diabetes & Vascular Protection, organized by the Physicians’ Academy for Cardiovascular Education, London, UK. . 2009.

Tan K.C.B. , Towards an improved outcome in type 2 diabetes: challenges and gaps in care, 15th Hong Kong Medical Forum, Hong Kong . 2010.

Researcher : Tan VPY

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Chemoprophylaxis in colorectal cancer: current concept s and a practical algorithm for use., Exper Opin Investig Drugs . 2010, Suppl 1: S57-66.

Yee Y.K., Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Epidemiology of colorectal cancer in Asia. , J Gastroenterol Hepatol . 2009, 24: 1810-6.

Yee Y.K., Gu Q., Hung I.F.N. , Tan V.P.Y. , Chan P., Hsu A., Pang R.W.C. , Lam S.C. and Wong B.C.Y. , Trend of colorectal cancer in Hong Kong:1983-2006. , J Gastroenterol Hepatol . 2010, 25: 923-7.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presen tation), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Tang CSO

List of Research Outputs

Tse K.C., Yap D.Y.H., Tang C.S.O. , Yung S.S.Y. and Chan D.T.M. , Response to adefovir or entecavir in renal allograft recipients with hepatitic flare due to lamivudine-resista nt hepatitis B, Clinical transplantation . 2010, 24(2): 207-212.

Researcher : Tang CW

Project Title:	Mapping the molecular footprints and therapeutic targets of diabetic nephropathy
Investigator(s):	Tang SCW, Lan HY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2008

Abstract:

1. To map out the molecular culprits of DN and to define their signaling mechanisms of injury 2. To map out novel therapeutic targets by studying the in vitro and in vivo effects of PPAR-γ activation, B2KR blockade, and toll-like receptor inhibition in cultured PTEC and MC, and in a murine model of type 2 diabetes

Project Title:	Role of N-acetyl-seryl-aspartyl-lysyl-proline in nephropathies
Investigator(s):	Tang SCW, Lan HY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To explore the in vitro anti-inflammatory and anti-fibrotic potential of Ac-SDKP and the associated signaling pathways in protein-overloaded PTEC; (2) To investigate the potential in vivo renoprotective efficacy of exogenously applied Ac-SDKP in the ADR model of renal injury that resemble CKD in human.

Project Title:	Genetic analysis in Chinese patients with nephropathy due to type 2 diabetes
Investigator(s):	Tang SCW, Leung JCK, Chu DWS
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2009

Abstract:

To investigate the contribution of genetic factors in association with the development of diabetic nephropathy in Chinese subjects with type 2 diabetes mellitus (T2DM), and the ensuing systemic inflammatory responses. Key Issues and problems It was previously thought that individuals who had diabetes and developed progressive diabetic nephropathy (DN) and/or end-stage renal disease (ESRD) were simply exposed to long durations of diabetes with relatively poor glycemic control. In other words, all individuals with diabetes were assumed to be at essentially equivalent risk for developing nephropathy, allowing for differences in their ambient serum glucose concentration. In support of the concept that exposure to a hyperglycemic environment led to DN (often with coexisting obesity, metabolic syndrome, hypertension, and hyperlipidemia), clinical trials have conclusively demonstrated that improving glycemic control delays and, in some cases, may prevent the subsequent development of albuminuria, DN, and macrovascular complications such as coronary artery disease (1,2). The concept that select individuals with diabetes were at differe ntial risk for developing nephropathy on the basis of familial aggregation of kidney disease was initially reported in 1989 but has only recently gained broad acceptance among nephrologists and diabetologists (3). To date, six complete genome-wide scans (GWS) have been published in type 2 DN. However, most of these reports were fr om patients of European-American, African-American, and Hispanic descent (4). Data from Chinese subjects are scarce in the literature. It is therefore the objective of this proposal to study genetic contributions to type 2 DN in Chinese subjects. Methods: Unrelated adult patients with diabetic nephropathy and control subjects will be recruited. The former will be defined accordingly to published standards. Presumed type 1 diabetic patients will be excluded on the basis of a history of diabetic ketoacidosis or diabetes diagnosis before age 25 years with continuous insulin therapy since diagnosis. A diagnosis of type 2 diabetes will be based on participants reporting an initial diagnosis of diabetes after age 35 years, receiving oral hypoglycemic agents or dietary therapy without insulin for at least 1 year after initial diagnosis, and active treatment with diabetes medications. Case subjects are those who either have ESRD with kidney biopsy revealing typic al diabetic nephropathy in the presence of overt proteinuria or have ESRD attributed to diabetic nephropathy as defined by either 1) onset of diabetes > 5 years before renal replacement therapy (in form of dialysis or renal transplantation) with diabetic retinopathy, 2) onset of diabetes > 5 years before renal replacement therapy with historic 24-h urine protein >/=3 g (protein-to-creatinine ratio >/= 3.0 g/g or 339 mg/mmol), or 3) diabetic retinopathy with historic 24-h urine protein >/= 3 g (protein-to-c reatinine ratio >/= 3.0 g/g or 339 mg/mmol). In other words, if case subjects have type 2 diabetes diagnosed > 5 years before initiating renal replacement therapy, they must also have background or greater diabetic retinopathy, and/or overt proteinuria in the absence of other causes of nephropathy; if they have T2DM for < 5 years, they need to have both retinopathy and overt proteinuria. The diagnosis of diabetic retinopathy will be based on medical record documentation of an ophthalmologic exam demonstrating microaneurysms, proli ferative diabetic retinopathy, or macular edema. Alternatively, the subject may have had a history of retinal laser surgery (photocoagulation) for diabetic retinopathy. Control subjects will be divided into 2 groups: diabetic non-nephropathy and normal subjects. Diabetic non-nephr opathy will be defined as subjects with spot urine albumin-to-creatinine ratio (ACR) < 30 mg/g or urine dipstix being negative for microalbumin, and normal serum creatinine concentrations ( 10 years of type 2 diabetes. Normal controls are those without overt renal disease. WBCs will be harvested from blood samples for retrieval of genomic DNA (gDNA). Genetic analysis will be performed by shipping gDNA samples from case and control subjects to the research laboratory of Dr. Barry Freedman, Wake Forest University School of Medicine, North Carolina, USA. Dr Freedman is a world expert in this field (4). Key references: 1. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR, UKPDS Group: Development and progression of nephropathy in type 2 diabetes: The United Kingdo m Prospective Diabetes Study (UKPDS 64). Kidney Int 63 :225 –232,2003 2. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complicatio ns Research Group. N Engl J Med 342 :381 –389,2000 3. Seaquist ER, Goetz FC, Rich SS, Barboso J: Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320 :1161 –1165,1989 4. Freedman BI, Bostrom M, Daeihagh P, Bowden DW. Genetic factors in diabetic nephropathy. Clin J Am Soc Nephrol. 2:1306-16, 2007

Project Title:	4th Asian Chapter Meeting of Internat ional Society of Peritoneal Dialysis Sleep apnea is an independent risk predictor for all-cause and cardiovascular mortality in peritoneal dialysis patients
Investigator(s):	Tang SCW
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	10/2009
Completion Date:	10/2009

Abstract:

N/A

Project Title:	Role of bone morphogenetic protein-7 in diabetic nephropathy
Investigator(s):	Tang SCW
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To explore the in vitro anti-inflammatory potential of BMP-7 and the associated signaling pathways in PTEC overloaded with AGE, HG, or BK; 2) To investigate the potential in vivo renoprotective efficacy of exogenousl y applied rhBMP-7 in a model of uninephrectomized genetically diabetic db/db mice with renal injuries that resemble human type 2 DN.

List of Research Outputs

Researcher : Tang Q

List of Research Outputs

Dong M. , Sun H. , Tang Q. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of human cardiac KCNQ1/KCNE1 channel by epidermal growth factor receptor kinase., Biochim Biophys Acta . 2010, 1798(5): 995-1001.

Researcher : Tang SCW

Project Title:	Mapping the molecular footprints and therapeutic targets of diabetic nephropathy
Investigator(s):	Tang SCW, Lan HY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2008

Abstract:

Project Title:	Role of N-acetyl-seryl-aspartyl-lysyl -proline in nephropathies
Investigator(s):	Tang SCW, Lan HY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

Project Title:	Genetic analysis in Chinese patients with nephropathy due to type 2 diabetes
Investigator(s):	Tang SCW, Leung JCK, Chu DWS
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2009

Abstract:

To investigate the contribution of genetic factors in association with the development of diabetic nephropathy in Chinese subjects with type 2 diabetes mellitus (T 2DM), and the ensuing systemic inflammatory responses. Key Issues and problems It was previously thought that individuals who had diabetes and developed progressive diabetic nephropathy (DN) and/or end-stage renal disease (ESRD) were simply exposed to long durations of diabete s with relatively poor glycemic control. In other words, all individuals with diabetes were assumed to be at essentially equivalent risk for developing nephropathy, allowing for differences in their ambient serum glucose concentration. In support of the concept that exposure to a hyperglycemic environment led to DN (often with coexisting obesity, metabolic syndrome, hypertension, and hyperlipidemia), clinical trials have conclusively demonstrated that improving glycemic control delays and, in some cases, may prevent the subsequent development of albuminuria, DN, and macrovascular complications such as coronary artery disease (1,2). The concept that select individuals with diabetes were at differential risk for developing nephropathy on the basis of familia l aggregation of kidney disease was initially reported in 1989 but has only recently gained broad acceptance among nephrologists and diabetologists (3). To date, six complete genome-wide scans (GWS) have been published in type 2 DN. However, most of these reports were from patients of European-American, African-American, and Hispanic descent (4). Data from Chinese subjects are scarce in the literature. It is therefore the objectiv e of this proposal to study genetic contributions to type 2 DN in Chinese subjects. Methods: Unrelated adult patients with diabetic nephropathy and control subjects will be recruited. The former will be defined accordingly to published standards. Presumed type 1 diabetic patients will be excluded on the basis of a history of diabetic ketoacidosis or diabetes diagnosis before age 25 years with continuous insulin therapy since diagnosis. A diagnosis of type 2 diabetes will be based on participants reporting an initial diagnosis of diabetes after age 35 years, receiving oral hypogly cemic agents or dietary therapy without insulin for at least 1 year after initial diagnosis, and active treatment with diabetes medications. Case subjects are those who either have ESRD with kidney biopsy revealing typical diabetic nephropathy in the presence of overt proteinuria or have ESRD attributed to diabetic nephropathy as defined by either 1) onset of diabetes > 5 years before renal replacement therapy (in form of dialysis or renal transplantation) with diabetic retinopathy, 2) onset of diabetes > 5 years before renal replacement therapy with historic 24-h urine protein >/=3 g (protein-to-creatinin e ratio >/= 3.0 g/g or 339 mg/mmol), or 3) diabetic retinopathy with historic 24-h urine protein >/= 3 g (protein-to-creatinine ratio >/= 3.0 g/g or 339 mg/mmol). In other words, if case subjects have type 2 diabetes diagnosed > 5 years before initiating renal replacement therapy, they must also have background or greater diabetic retinopathy, and/or overt proteinuria in the absence of other causes of nephropathy; if they have T2DM for < 5 years, they need to have both retinopathy and overt proteinuria. The diagnosis of diabetic retinopathy will be based on medical record documentation of an ophthalmologic exam demonstrating microaneurysms, proliferative diabetic retinopathy, or macular edema. Alternativel y, the subject may have had a history of retinal laser surgery (photocoagulation) for diabetic retinopathy. Control subjects will be divided into 2 groups: diabetic non-nephropathy and normal subjects. Diabetic non-nephropathy will be defined as subjects with spot urine albumin-to -creatinine ratio (ACR) < 30 mg/g or urine dipstix being negative for microa lbumin, and normal serum creatinine concentrations ( 10 years of type 2 diabetes. Normal controls are those without overt renal disease. WBCs will be harvested from blood samples for retrieval of genomic DNA (gDNA). Genetic analysis will be performed by shipping gDNA samples from case and control subjects to the research laboratory of Dr. Barry Freedman, Wake Forest University School of Medicine, North Carolina, USA. Dr Freedman is a world expert in this field (4). Key references: 1. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR, UKPDS Group: Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63 :225 –232,2003 2. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. The Diabetes Control and Compli cations Trial/Epidemiology of Diabetes Intervention and Complications Research Group. N Engl J Med 342 :381 –389,2000 3. Seaquist ER, Goetz FC, Rich SS, Barboso J: Familial clustering of diabetic kidney disease: Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320 :1161 –1165,1989 4. Freedman BI, Bostrom M, Daeihagh P, Bowden DW. Genetic factors in diabetic nephropathy. Clin J Am Soc Nephrol. 2:1306-16, 2007

Project Title:	4th Asian Chapter Meeting of International Society of Peritoneal Dialysis Sleep apnea is an independent risk predictor for all-cause and cardiovas cular mortality in peritoneal dialysis patients
Investigator(s):	Tang SCW
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	10/2009
Completion Date:	10/2009

Abstract:

N/A

Project Title:	Role of bone morphogenetic protein-7 in diabetic nephropathy
Investigator(s):	Tang SCW
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To explore the in vitro anti-inflammatory poten tial of BMP-7 and the associated signaling pathways in PTEC overloaded with AGE, HG, or BK; 2) To investigate the potential in vivo renoprotective efficacy of exogenously applied rhBMP-7 in a model of uninephrectomized genetically diabetic db/db mice with renal injuries that resemble human type 2 DN.

List of Research Outputs

Hsu S.I., Niu Y., Davila S., Leung J.C.K. , Lam M.F. , Tang S.C.W. and Lai K.N. , Genome-wide linkage scan for familial IgA nephropathy among southeast Asian Chinese: evidence for a suggest ive novel susceptibility locus on chromosome 8p23, Journal of American Society Nephrology . 2009, 20: 434A.

Lai K.N. , Chan L.Y., Guo H., Tang S.C.W. and Leung J.C.K. , Additive effect of peroxisome proliferator-activated receptor- g agonist and angiotensin receptor blocker in treatment of experimental IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 149-150A.

Lai K.N. , Lai A.S. and Tang S.C.W. , Chronic Kidney Disease and Infectious Disease, In: El Nahas M and Levin A, Chronic Kidney Disease: a practical guide to understanding and management. Oxford University Press, Oxford . 2010, 155-183.

Lai K.N. and Tang S.C.W. , Hepatitis B Associated Renal Diseases., Rheumatology and the Kidney, 2nd edition. Oxford University Press, Oxford . 2010.

Leung J.C.K. , Chan L.Y., Tam K.Y., Tang S.C.W. and Lai K.N. , Inhibition of renin-angiotensin-aldosterone system abolishes polymeric-IgA induced TGF- synthesis by human mesangial cells in IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 294A.

Lin M. , Chan A.W., Chan L.Y., Leung J.C.K. , Lai K.N. and Tang S.C.W. , Toll-like receptor 4 mediates tubular inflammation in diabetic nephropathy, Hong Kong Medical Journal . 2010, 16: 39.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , In vitro enhanced chemotaxis of CD25+ mononuclear cells in patients with familial IgAN through glomerulotubular interaction, American Journal of Physiology-Renal Physiology . 2010.

Tam K.Y., Leung J.C.K. , Chan L.Y., Lam M.F. , Tang S.C.W. and Lai K.N. , Increased chemotaxis of CD25+ PBMC to tubular epithelial cells through glomerulotubular interaction in patients with familial IgA nephropathy, Journal of American Society Nephrology . 2009, 20: 307A.

Tang S.C.W. , APD: a new choice to improve quality of life in dialysis? , Baxter Satellite Symposium at the Chinese Society of Nephrology Annual Meeting, Chinese Medical Association, Dalian, China, 3 July . 2009.

Tang S.C.W. , Chan A.W., Chan L.Y., Leung J.C., Lan H.Y. and Lai K.N. , Anti-inflammatory effects of N-acetyl-seryl-aspartyl-lysyl -proline (Ac-SDKP) in protein-overloaded renal tubule cells, Journal of American Society Nephrology . 2009, 20: 858-868A.

Tang S.C.W. , Assessment of Patients with Renal Diseases. In: Manual of Nephrology, edited by Lai KN, World Scientific Press, London . 2009, 3-13.

Tang S.C.W. , Chan L.Y., Leung J.C.K. , Cheng A.S., Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote diabetic renal tubular injury , Nephrology Dialysis Transplantation . 2010, 25: 698-710.

Tang S.C.W. , Chan Y.Y. , Leung J.C.K. , Cheng A.S. , Chan K.W. , Lan H.Y. and Lai K.N. , Bradykinin and high glucose promote renal tubular inflammation, Nephrol Dial Transplant . 2010, 25(3): 698-710.

Tang S.C.W. , Lam B. , Yap D.Y., Ip M.S.M. and Lai K.N. , Conversion between hemodialysis and continuous ambulato ry peritoneal dialysis may impact on sleep apnea in favor of CAPD, Hemodialysis International . 2009, 13: 395.

Tang S.C.W. , Diabetic tubulopathy: does it exist?, Quadrangular Chinese Nephrology Conference (Shanghai, China) . 2010.

Tang S.C.W. , Diabetic tubulopathy: is it real?, Visiting Scholar, Wake Forest University School of Medicine (Winston Salem, NC, USA) . 2010.

Tang S.C.W. , Faculty Teaching Medal, LKS Faculty of Medicine, The University of Hong Kong . 2009.

Tang S.C.W. , History of Anticoagulation in Hemodialysis. In: History of Dialysis, edited by Kjellstrand C and Todd I, World Scientific Press, London . 2010.

Tang S.C.W. , IgA nephropathy: 40 years on, Lecture tour to (i) Taipei Veterans General Hospital, National Yang-Ming University (Taipei, Taiwan) and (ii) Kaohsiung Medical University (Kaohsiung, Taiwan) . 2010.

Tang S.C.W. , Tang A.W., Wong S.S., Ho Y.W. and Lai K.N. , Long-term study of mycophenolate mofetil in IgA nephrop athy, Journal of American Society of Nephrology . 2009, 20: 233A.

Tang S.C.W. , Tang A.W., Wong S.H., Leung J.C., Ho Y.W. and Lai K.N. , Long-term study of mycophenolate mofetil treatment in IgA nephropathy, Kidney International . 2010, 77: 543-549.

Tang S.C.W. , Routine Investigations for Dialysis Patients. In: Manual of Nephrology, edited by Lai KN, World Scientific Press, London . 2009, 301-305.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea as a novel risk predictor for cardiovascula r morbidity and death in peritoneal dialysis patients, Kidney International . 2010, 77: 1031-1038.

Tang S.C.W. , Sleep apnea in PD patients, Visiting Scholar, Wake Forest University School of Medicine (Winston Salem, NC, USA) . 2010.

Tang S.C.W. , Lam B. , Yao T.J. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is a novel risk predictor of cardiovascular morbidity and death in patients receiving peritoneal dialysis, Kidney International . 2010, 77(11): 1031-8.

Tang S.C.W. , Lam B. , Leung W.S., Chu C.M., Ho Y.W., Ip M.S.M. and Lai K.N. , Sleep apnea is an independent risk predictor for all-cause and cardiovascular mortality in peritoneal dialysis patients, Peritoneal Dialysis International . 2009, 29: S7.

Tang S.C.W. , Leung V.T., Chan L.Y., Wong S.H., Chu D.W., Leung J.C.K. , Lai K.N. , Ma L., Elbein S.C., Bowden D.W., Hicks P.J., Comeau M.E., Langefeld and Freedman B.I., The acetyl-Coenzyme A carboxylase beta gene (ACACB) is associated with nephropathy in Chinese patients with type 2 diabetes, Nephrology Dialysis Transplantation . 2010.

Tang S.C.W. , Updates on management of diabetic nephropathy, World Kidney Day 2010 Special Symposium . 2010.

Tang S.C.W. , Visiting scholar and keynote speaker, Sun Yat-sen International Forum, Sun Yat-sen University, Guangzhou, China, August . 2009.

Xiao J. , Leung J.C.K. , Chan Y.Y. , Tang S.C.W. and Lai K.N. , Crosstalk between peroxisome proliferator-activated receptor-gamma and angiotensin II in renal tubular epithelial cells in IgA nephropathy, Clinical Immunology . 2009, 132: 266-276.

Yap D.Y., Chu F.S., Chu S.S.M. , Tam P.C. , Chan D.T.M. , Lai K.N. and Tang S.C.W. , CT angiography versus conventional digital angiography in pre-operative assessment for Chinese living kidney donors [Epub ahead of print 15 June 2010], Journal of Nephrology . 2010.

Yap D.Y., Chu F.S., Chu S.S.M. , Tam P.C. , Tam S., Lai K.N. , Chan D.T.M. and Tang S.C.W. , CT angiography versus conventional digital angiography in pre-operative assessment for Chinese living kidney donors, Nephrology . 2010, 15 (S3): 54.

Yap D.Y.H., Lau S.K.P. , Lamb S., Choy C.B.Y. , Chan D.T.M. , Lai K.N. and Tang S.C.W. , An unusual organism for PD-related peritonitis: Hafnia alvei, Peritoneal Dialysis International . 2010, 30(2): 254-255.

Yip T., Tse K.C., Lam M.F. , Cheng S.W., Lui S.L. , Tang S.C.W. , Mg M., Chan D.T.M. , Lai K.N. and Lo W.K. , Colonic diverticulosis as a risk factor for peritonitis in Chinese peritoneal dialysis patients, Peritoneal Dialysis International . 2010, 30: 187-191.

Yip T.P., Tse K., Ng F., Lam M.F. , Tang S.C.W. , Lui S.L. , Lai K.N. , Chan D.T.M. and Lo W.K. , Clinical course and outcomes of enterococcus peritonitis in peritoneal dialsyisi patients, Nephrology . 2010, 15 (S3): 47.

Researcher : Tao R

List of Research Outputs

Chen J. , Tao R. , Sun H. , Tse H.F. , Lau C.P. and Li G.R. , Multiple Ca(2+) signaling pathways regulate intracellul ar Ca(2+) activity in human cardiac fibroblasts., J Cell Physiol . 2010, 223(1): 68-75.

Researcher : Tsang SWY

Project Title:	Determination of Risk Factors and Treatment Thresholds for Osteoporotic Fractures in Hong Kong Southern Chinese Men
Investigator(s):	Tsang SWY, Kung AWC
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2008
Completion Date:	05/2010

Abstract:

Objectives a) To determine the clinical risk factors for osteoporotic fractures in Hong Kong Southern Chinese men; b) To establish the cut-off level which will identify the majority of the fracture cases for Hong Kong Southern Chinese men using local normative databas e; c) To compare bone mineral density (BMD) standard deviations (SD) with the NHANES III study to determine whether the use of Caucasian derived T-scores would greatly affect the identification of osteoporotic fracture in Southern Chinese men; d) To determine therapeutic threshold for Southern Chinese men based on the actual fracture risk data. Osteoporosis is defined as “an asymptomatic systemic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture” (1). The importance of this disease arises from its complication of fragility fractures which are associated with high morbidity and mortality. Among all osteoporotic fractures, hip fracture accounts for higher rates of morbidity and mortality for men than women (2). For example, it has been reported that men are twice as likely to die in hospital after a hip fracture than women (3). Other studies have shown that up to 50% of men may need institutionalized care after hip fracture (4) and that men are less likely to return to autonomous living circumstances than women at 1 yr post hip frac ture (5). Taken together, with the increasing size of our aging population and the improving longevity of men, osteoporosis in men will soon become a significant burden to society and health care systems worldwide. Based on the World Health Organization (WHO) guideline establis hed in 1994, osteoporosis is defined operationally as a bone mineral density (BMD) 2.5 standard deviation (SD) or more below the peak young adult mean (6). Low BMD measurements has since been used worldwide as a diagnostic criterion for osteoporotic pharmacological intervention (7). However, an increasing number of studies have demonstrated that the use of femoral neck BMD measure ment alone is insufficient to identify all individuals at high risk for osteoporotic fracture risk. A prospective study, for example, has shown that around 58% of hip fracture occurred in men with a T-score between -1 and -2.5 (8). Thus, there is a need for the development of more sensitive osteoporotic fracture risk assessment tool. This is of particular importance in Asia where resources are limited and medications need to be targeted to the most needy patients. Recent studies have suggested that an individual’s 10-yr absolute risk of osteoporotic fracture is likely to be a more reliable predictor of osteoporotic fracture than BMD measurement alone (9, 10). At present, combinations of clinical risk factors with BMD to determine diagnostic and therapeu tic thresholds in Hong Kong population, especially in men, have received scant research attention. Nevertheless, our group has identified six independent clinical risk factors (CRFs) for osteoporotic fractures in Hong Kong Southern Chinese postmenopausal women (11). Some of them are related to risk of falls such as one or more falls in 12 months, being homebound, use of walking aids; while others are related to osteoporosis and low BMD such as prior fragility fracture, low body mass index <19kg/m2, smoking and alcohol, calcium intake <400mg/day. Epidemiological data on osteoporosis in men are scanty. It would be interesting to find out whether Hong Kong Southern Chinese men share the same CRFs profile for osteoporotic fractures as in women. Furthermore, World Health Organization (WHO) recommends the use of a uniform Caucasian (non-race adjusted) female normative database for women and men of all ethnic groups as reference for BMD T-scores determination and fracture risk assessment. However, it is still not clear whether the use of Caucasian female or mal e normative data can be applied to Chinese men and whether the use of the WHO definition of osteoporosis as cut-off level for osteoporotic fracture prediction and intervention thresholds.

Researcher : Tse EWC

Project Title:	Post-translational regulation of survivin by peptidy-proplyl-isomerase Pin1 in hepatocellular carcinoma
Investigator(s):	Tse EWC, Kwong YL, Pang RWC
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	11/2007
Completion Date:	10/2009

Abstract:

To characterize the interaction between Pin1 and survivin; to investigate the properties or functional changes of survivin in the presence and absence of Pin1 over-expression; to investigate the role of this interaction in the pathogenesis and treatment of hepatocellular carcinoma.

Project Title:	The role of nucleophosmin (NPM1) in the pathogenesis of acute myeloid leukaemia
Investigator(s):	Tse EWC
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	09/2008
Completion Date:	02/2010

Abstract:

The purpose of this project is to characterize the function of mutated nucelophosmin (NPMc+) in the pathogenesis of acute myeloid leukaemia (AML). The central hypothesis of the proposed thesis work is that cytoplasmic expression of mutated NPM (NPMc+) directly and/or indirectly induces oncogenic transformation of normal hematopoietic cells via blockage of myeloid cell differentiation and aberrant cytoplasmic protein- protein interactions. The objectives of the project are as follows: (1)To investigate the effects of NPMc+ in myeloid cell differentiation in vitro. (2)To define the molecular mechanism(s) by which NPMc+ mediates abnormal myeloid cell differentiation and leukemogenesis by identifying protein binding partners of NPMc+.

Project Title:	Identification and characterizat ion of Pin1 binding proteins
Investigator(s):	Tse EWC
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	01/2010

Abstract:

1. To identify important cellular proteins that are regulated by Pin1 and involved in hepatocarcinogenesis 2. To characterize and to define the role of these proteins in hepatocarcinogenesis

List of Research Outputs

Cheng C.W. , Pang R.W.C. , Kwong Y.L. and Tse E.W.C. , Pin1 enhances the anti-apoptotic function of survivin in cancer cells, 16th Hong Kong International Cancer Congress . 2009.

Gill H., Hwang Y.Y. and Tse E.W.C. , Primary immune thrombocytopenia responding to antithyroid treatment in a patient with Graves’ disease, Annals of Hematology . 2010, E Pub.

Kwong Y.L. and Tse E.W.C. , Rivaroxaban: an oral factor Xa inhibitor in the managemen t of thrombotic diseases, Medical Progress . 2010, 37(4): 188-92.

Kwong Y.L. , Au W.Y. , Leung A.Y.H. and Tse E.W.C. , T-cell large granular lymphocyte leukemia: an Asian perspective, Annals of Hematology . 2010, 89(4) 331-339: 331-339.

Researcher : Tse HF

Project Title:	Direct intramyocardial implantation of autologous bone marrow cells for enhancement of neovascularization in patients with "End-Staged" corona ry artery disease
Investigator(s):	Tse HF, Lau CP, Kwong YL
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	01/2004

Abstract:

To determine the safety and efficacy of direct intramyocardial delivery of bone marrow cells using electromechanical guided injection; to investigate the angiogenic ability of implanting autologous bone marrow cells in patients with end-stage coronary artery disease.

Project Title:	Hypoxia-mediated differentiation of murine and human embryonic stem cells into cardiomyocytes: mechanistic roles of calcium and ion channels
Investigator(s):	Tse HF, Li RA, Fung ML, Wong TM, Lau CP
Department:	Medicine
Source(s) of Funding:	NSFC/RGC Joint Research Scheme
Start Date:	01/2006

Abstract:

The main objectives of this project are: 1/ To determine whether hypoxia is a critical physiological stimulus for the differentiation of CMCs 2/ To determine the role of calcium and its key regulatory protein RyR2 in hypoxia-mediated differentiation of ESCs 3/ To investigate the effect of hypoxia on the development changes of ionic channels during cardiac differentiation of ESCs

Project Title:	Effect of Isoflavone Supplement on Endothelial Function in Patients with Ischaemic Stroke
Investigator(s):	Tse HF
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	09/2008
Completion Date:	08/2009

Abstract:

In recent years, epidemiological studies have demonstr ated that populations with higher legume, fruit and vegetable consumption had a lower incidence of cardiovascular events (1-3). This led to immense interests in the potential role of plant-derived polyphenolic chemicals for prevention of cardiovascular diseases (4-7). Biochemicall y characterized by the presence of more than one phenol unit per molecule, the diverse family of polyphenols has been recognized for its subclasses of phytoestrogens and flavanols. Phytoestrogens are mainly found in soybeans, chick peas and clovers. Experimental studies suggested that they exhibit versatile biochemical actions (8), including anti-oxidant and hypocholesterolaemic effects, direct action on vaso-relaxation and platelet function modulation. These and their peculiar function as partial estrogen agonist provided potential mechanisms for cardiovascular protection. Indeed, our recent study also showed that a higher intake level of isoflavone, a major class of phytoestrogens, was associated with better vascular endothelial function and lower caroti d atherosclerotic burden in patients with high risk for cardiovascular events (9). Despite previous studies which documented the potentiating effect of isoflavone on vascular endothelial function in healthy subjects, no studies to date had yet provided an answer to as whether isoflavone exerted cardiovascular benefits in patients with established atherosclerosis and endothelial dysfunction. Moreover, whether subjects who were alre ady on regular conventional medical treatments received additional benefits from this novel intervention also remained unclear. Therefore, this study was carried out to investigate the effects of 12-week supplementation of isoflavone on the brachial flow-mediated dilatation (FMD) in a group of patients with clinically manifest atherosclerosis and impaired endothelial function. References: 1. Vanharanta M, et al. Risk of acute coronary events according to serum concentrations of enterolactone: a prospective population-based case-control study. Lancet 1999;354:2112-5. 2. Bazzano LA, et al. Legume consumption and risk of coronary heart disease in US men and women: NHANES I Epidemiologic Follow-up Study. Arch Intern Med 2001;161:2573-8. 3. He FJ, et al. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet 2006;367:320- 6. 4. Taubert D, et al. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA 2007;298:49-60. 5. Heiss C, et al. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol 2005;46:1276-83. 6. Anthony MS. Phytoestrogens and cardiovascular disease: where's the meat? Arterioscler Thromb Vasc Biol 2002;22:1245-7. 7. Sacks FM, et al. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulati on 2006;113:1034-44. 8. Lissin LW, Cooke JP. Phytoestrogens and cardiovascular health. J Am Coll Cardiol 2000;35:1403-10. 9. Chan YH, et al. Isoflavone intake in persons at high risk of cardiovascular events: implications for vascular endothelial function and the carotid atherosclerotic burden. Am J Clin Nutr 2007;86:938-45.

Project Title:	Outstanding Researcher Award 2007-2008
Investigator(s):	Tse HF
Department:	Medicine
Source(s) of Funding:	Outstanding Researcher Award
Start Date:	10/2008

Abstract:

The Awards are intended to recognize, reward, and promote exceptional research accomplishments of academic and research staff.

Project Title:	Direct endomyocardial injection of autologous bone marrow cells for treatment of pat ients with "end-stage" ischaemic heart failure
Investigator(s):	Tse HF, Lau CP, Kwong YL, Siu DCW, Lee SWL, Chan FHW, Lam L, Lee KLF, Chan WS, Lam YM
Department:	Medicine
Source(s) of Funding:	S.K. Yee Medical Foundation - General Award
Start Date:	01/2009

Abstract:

To determine the effect of direct endomyocardial injection of autologous bone marrow cells on left ventr icular ejection fraction in patients with ischaemic heart failure; to assess the effect on symptoms, exercise capacity, infarct and peri-infarct region function and perfusion, combined clinical endpoint of heart failure hospitalization, myocardial infarction and cardiovascular death, and the safety and efficacy of the endomyocardial injection technique.

Project Title:	Transplantation of Bioengineered Human Embryonic Stem Cell-derived Cardiomyocytes with Mature Electrical Phenotype in Post-infarction Heart Failure Improves Cardiac Function Without Proarrhythmia
Investigator(s):	Tse HF, Lau CP, Siu DCW, Wu EX
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To test the hypothesis that transplantation of genetically manipulated human embryonic stem cell(hESC )-derived cardiomyocyte(hESC-CM) with over-expression of inwardly rectifying K current(IK1), a resting membrane potential(RMP) stabilizer encoded by the Kir2 gene family can rende r their electrophysiological phenotype adult-like and eliminate the susceptibility of developing lethal ventricular arrhythmias post-transplantation in heart failure(HF); (2) To test the hypothesis that transplantation of hESC-CM can integrate with the host myocardium and improve left ventricular(LV) function in a large animal model of HF after myocardium infarction(MI).

Project Title:	Relationship between mitochondrial dysfunction and vascular function in patients with cardiovascular diseases
Investigator(s):	Tse HF
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	01/2010

Abstract:

We hypothesize that mitrochondrial dysfunction is closely linked with vascular endothelial dysfuncti on in patients with coronary artery disease. Objective 1: To study the effect of statin therapy on mitrochondrial and vascular function in patients with coronary artery disease Objective 2: To study the effect of physical activity on mitrochondrial and vascular function in patients with coronary artery disease

Project Title:	Pluripotent Human Stem Cell Platform for Tissue Regeneration and Drug Screening for Cardiovascu lar Diseases
Investigator(s):	Tse HF, Li RA, Siu DCW, Li GR, Lian Q
Department:	Medicine
Source(s) of Funding:	Collaborative Research Fund (CRF) - Group Research Project
Start Date:	03/2010

Abstract:

1) To generate human patient-specific iPSC lines from their skin fibroblasts that can serve well as i) novel disease models, ii) drug-screening and iii) ground work for subsequent human trials. 2) To direct the differentiation of hESC and iPSC to cardiac lineages and MSC and to study their basic biology and multipotency. 3) To study the functional and electrophysiological effects of transplantation of CMC and MCS derived from iPSC for cardiac and vascular regeneration. 4) To setup an in-vitro human disease-specific stem-cell system for studying of disease pathophysiology of cardiac diseases as well as drug/cardiotoxicity screening.

List of Research Outputs

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Improvement of myocardial perfusion reserve detected by cardiovascular magnetic resonance after direct endomyocar dial implantation of autologous bone marrow cells in patients with severe coronary artery disease, Journal of cardiovascular magnetic resonance . 2010, 12(1): 6..

Chan W.S. , Kwong Y.L. , Kwong R.Y., Lau C.P. and Tse H.F. , Therapeutic angiogenesis with direct endomyocardial implantation of autologous bone marrow cells in patients with severe coronary artery diseases: Insight from cardiac magnetic resonance imaging., J Cardiovasc Magn Reson. . 2010, 12: 6.

Chan Y.C. , Lee Y.K. , Ng K.M. , Lai K.W.H. , Yang D. , Tse H.F. and Siu D.C.W. , A Newly-derived Small Synthetic Compound Alleviated Ventricular Fibrillation In A Pig Model With Chronic Myocardial Infarction As Revealed By Optical Mapping, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” (Hong Kong) . 2010.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. and Li R.A. , Automaticity and conduction properties of bio-artifici al pacemakers assessed in an in vitro monolayer model of neonatal rat ventricular myocytes., Europace. In press. . 2010.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. , Lau C.P. and Tse H.F. , Characterizing the basis of automaticity of neonatal rat ventricular myocytes: Implications for cardiac excitability manipulations., Europace . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W. , Tam S. , Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke (abstract and poster presentation), EuroPRevent 2010, Prague, 5-7 May 2010 . Prague, European Society of Cardiology.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W., Tam S., Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke, EuroPrevent 2010. European Journal of Cardiovascular Prevention and Rehabilitation 2010 Jun P480 . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W., Lam T.H. and Tse H.F. , Selenium Deficiency is Associated with Adverse Vascular Function in Patients with High Risk for Vascular Events, EuroPrevent 2010. European Journal of Cardiovascular Prevention and Rehabilitation 2010 Jun P334 . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W. , Lau C.P. , Lam T.H. and Tse H.F. , Selenium deficiency is associated with adverse vascular function in patients with high risk for vascular events (abstract and poster presentation), EuroPRevent 2010, 5-7 May 2010, Prague . Prague, European Society of Cardiology, 2010.

Chen J. , Tao R. , Sun H. , Tse H.F. , Lau C.P. and Li G.R. , Multiple Ca(2+) signaling pathways regulate intracellular Ca(2+) activity in human cardiac fibroblasts., J Cell Physiol . 2010, 223(1): 68-75.

Dai Y.L., Luk T.H., Siu D.C.W. , Yiu K.H., Chan K.H.T. , Lee S.W.L. , Li S.W., Fong B., Wong W.K., Tam S. , Lau C.P. and Tse H.F. , Mitochondrial dysfunction induced by statin contributes to endothelial dysfunction in patients with coronary artery disease., Cardiovascular Toxicology . 2010, 10: 130-8.

Dong M. , Sun H. , Tang Q. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of human cardiac KCNQ1/KCNE1 channel by epidermal growth factor receptor kinase., Biochim Biophys Acta . 2010, 1798(5): 995-1001.

Fu J.D., Kong M.C.W. , Rushing S.N., Lieu D.K., Chan C.W.Y. , Tse H.F. , Wilson K., Chiamvimonvat N., Boheler K.R., Wu J.C., Keller G. and Li R.A. , Distinct Roles of MicroRNA-1 and -499 in ventricular specification and maturation of human embryonic stem cells, Fifth International Symposium on Healthy Aging . 2010.

Hai J.J., Siu D.C.W. , Ho H.H., Li S.W., Lee S.W.L. and Tse H.F. , Relationship between changes in heart rate recovery after cardiac rehabilitation on cardiovascular mortality in patients with myocardial infarction. , Heart Rhythm . 2010, 7: 929-936.

Hai J.J. and Tse H.F. , Sudden cardiac death. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Hai J.J. and Tse H.F. , Ventricular tachyarrhythmias. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

He M. , Lau C.P. , Tse H.F. and Li G.R. , Regulation of cell proliferation by large-conductance calcium-activated potassium and volume-sensitive chlo ride channels in human cardiac fibroblasts, 15th Medical Research Conference . 2010, 16(1): 23.

Ho H.H., Pong V., Siu D.C.W. , Yiu K.H., Ko R., Tse H.F. , Jim M.H. and Chow W.H., Long-term outcomes of drug-eluting stents versus bare-m etal stents in Chinese. , Clinical Cardiology . 2009, In press.

Ho H.H., Cheung C.W., Jim M.H., Miu R., Lam Y.M. , Chan R.H.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Type A aortic intramural hematoma: clinical features and outcomes in Chinese patients, Clinical Cardiology . 2010, (in press).

Ho L.Y., Siu D.C.W. , Lau C.P. , Lip G.Y. and Tse H.F. , Safety and efficacy of oral anticoagulation therapy in chinese patients with concomitant atrial fibrillation and hypertension. , J Hum Hypertens. 2010 . 2010.

Hu R. , He M. , Hu H. , Yuan B.X., Zang W.J., Lau C.P. , Tse H.F. and Li G.R. , Characterization of calcium signaling pathways in human preadipocytes, J Cell Physiol . 2009, 220(3): 765-770.

Jim M.H., Chan A.O., Tse H.F. , Barold S.S. and Lau C.P. , Clinical and Angiographic findings of complete atrioventricular block in acute inferior myocardial infarction. , Ann Acad Med Singap. . 2010, 39: 185-9.

Kong M.C.W. , Jiang P., Rushing S.N., Tse H.F. and Li R.A. , MicroRNA and cell cycle of embryonic stem (ES) and induced pluripotent stem (iPS) cells: Insights for eliminating tumorgenicity, Fifth International Symposium on Healthy Aging . 2010.

Lai K.W.H. , Ho J.C.Y. , Lee Y.K. , Ng K.M. , Au K.W. , Chan Y.C. , Lau C.P. , Tse H.F. and Siu D.C.W. , Generation of human induced pluripotent stem cells in feeder-independent, serum-free culture system with defined factors., Cellular Reprogramming (in press) . 2010.

Lau C.P. , Tse H.F. , Kumana C.R. and Cheung B.M.Y. , Angiotensin receptor blockers for heart disease: are they the same?, J HK Coll Cardiol 2009 . 2009, 17: 1-3.

Lau C.P. , Siu D.C.W. and Tse H.F. , Sensor Driven Pacing, In: Ellenbogen KA, Natale A, Al-Ahmad Amin, Wang PJ , Pacemakers and Implantable Cardioverter Defibrillators: An Expert’s Manual . 2010.

Lee C.H., Tse H.F. , Tai B.C., Chen Z., Chan M.Y. and Tan H.C., Procedure-related myonecrosis after bare and drug-eluting stent implantation. , Asian Cardiovasc Thorac Ann. . 2010, 18: 272-8.

Lee C.H. and Tse H.F. , Microvascular obstruction after percutaneous coronary intervention. , Catheter Cardiovasc Interv. . 2010, 75: 369-77.

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Lee Y.K. , Ng K.M. , Lai K.W.H. , Tse H.F. and Siu D.C.W. , Triiodothyronine enhances cardiac differentiation of embryonic stem cells and maturation via classical pathway., Molecular Endocrinology . 2010, (in press).

Li G.R. , Sun H. , Chen J. , Zhou Y. , Tse H.F. and Lau C.P. , Characterization of Multiple Ion Channels in Cultured Human Cardiac Fibroblasts. , PLoS One . 2009, 4(10): e7307.

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endoth elial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Li M. , Ong K.L. , Tse H.F. and Cheung B.M.Y. , Utilization of lipid lowering medications among adults in the United States 1999-2006. , Atherosclerosis. . 2010, 208: 456-60.

Li X. , Tse H.F. , Yiu K.H., Jia N., Chen H. , Li L.S.W. and Jin L.J. , Increased levels of circulating endothelial progenit or cells in subjects with moderate to severe chronic periodontitis, Journal of Clinical Periodontology . 2009, 36: 933-939.

Li X. , Tse H.F. , Li L.S.W. and Jin L.J. , Salivary MIF is associated with gingival inflammation and periodontopathogens, Journal of Dental Research . 2009, 88 (Spec Iss B): 288 (PAPF/APR).

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Lian Q. , Zhang Y. , Kang S., Zhang Y. , Lai A.Y.K. , Au K.W. , Zhang J. and Tse H.F. , GENERATION OF MESENCHYMAL STEM CELLS FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (iPSC) FOR THE REATMENT OF LIMB ISCHEMIA, 7th Annunal Meeting of International Society for Stem Cell Research . 2009, 194.

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with passive epicardial patch in porcine model of chronic myocardial infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H., Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patient s with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Mok T.M.Y. , Yiu K.H., Wong C.Y., Lai W.H., Lo Y. , Wong R.W.S. , Tse H.F. and Lau W.C.S. , Endothelial Dysfunction is Associated with Low Level of Circulating Endothelial Progenitor Cells in Patients with Systemic Sclerosis, Clin Exp Rheumatol . 2010, in press.

Mok T.M.Y. , Tse H.F. , Wong C.Y., Qiuwaxi J. , Lai K.W.H. , Lo Y. , Wong R.W.S. and Lau W.C.S. , Endothelial dysfunction is associated with decreased circulating endothelial progenitor cells in patients with systemic sclerosis, Annals of the Rheumatic Diseases . 2009, S337.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai K.W.H. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1alpha promotes cardiac differentiation of embryonic stem cells., Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-37.

Ng K.M. , Lee Y.K. , Chan Y.C. , Lai W.H.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Exogenous expression of HIF-1 a promotes the cardiac differentiation of embryonic stem cells, Journal of Molecular and Cellular Cardiology . 2010, 48(6): 1129-1137.

Ng K.M. , Lee Y.K. , Fung M.L. , Li R.A. , Siu D.C.W. and Tse H.F. , Hypoxia promotes cardiac differentiation of human em bryonic stem cells, Physiology Symposium 2009, HKU, Hong Kong 5/2009 .

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Ong K.L., Li M., Tso A.W., Xu A., Cherny S.S., Sham P.C., Tse H.F. , Lam T.H., Cheung B. and Lam K., Association of genetic variants in the adiponectin gene with adiponectin level and hypertension in Hong Kong Chinese. , Eur J Endocrinol. . 2010.

Pei D., Xu J., Zhuang Q., Tse H.F. and Esteban M.A., Induced pluripotent stem cell technology in regenerative medicine and biology. , Adv Biochem Eng Biotechnol. . 2010.

Siu D.C.W. , Pong V., Ho H.H., Liu S., Lam B. , Lau C.P. , Li S.W. and Tse H.F. , Does MADIT II criteria for implantable cardioverter defibrillator implantation applicable to Chinese patients? , J Cardiovasc Electrophysiol. . 2010, 21: 231-5.

Siu D.C.W. and Tse H.F. , Predicting recurrence of atrial fibrillation after electrical cardioversion: gauging atrial damage. Europace. , Europace . 2010, 12: 764-5.

Siu D.C.W. , Pong V., Ho H.H., Liu S., Lau C.P. and Tse H.F. , Are MADIT II criteria for implantable cardioverter defibrillator in Chinese. , Journal of Cardiovascular Electrophysiology . 2009, 21: 231-5.

Siu D.C.W. and Tse H.F. , Atrial flutter and fibrillation. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Siu D.C.W. , Pong V., Jim M.H., Yue W. , Ho H.H., Li L.S.W. , Lau C.P. and Tse H.F. , Beta-blocker in post-myocardial infarct survivors with preserved left ventricular systolic function, Pacing and Clinical Electrophysiology . 2010, 33(6): 675-80.

Siu D.C.W. and Tse H.F. , Cryoablation for Atrial Fibrillation, In: Bredikis, Wiber , Cryoablation of Cardiac Arrhythmias. . Elsevier Churchill Livingstone, 2010.

Siu D.C.W. , Lau C.P. , Lee S.W.L. , Lam K.F. and Tse H.F. , Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation, Critical Care Medicine . MD Consult, LLC, 2009, 37(7): 2174-2179.

Siu D.C.W. and Tse H.F. , Predicting recurrence of atrial fibrillation after cardioversion: gauging atrial damage, Europace . 2010, 12: 764-5.

Siu D.C.W. , Waston T., Lai K.W.H. , Lee Y.K. , Chan Y.H. , Ng K.M. , Lau C.P. , Lip G.Y. and Tse H.F. , Relationship of circulating endothelial progenitor cells to the recurrence of atrial fibrillation after successful conversion and maintenance of sinus rhythm ., Europace . 2009, 12(4): 460-1.

Siu D.C.W. , Liao S. , Liu Y. and Tse H.F. , Stem cells for myocardial repair. , Thromb Haematol . 2010, 104(1).

Tse H.F. , Invited Speaker, Right ventricular lead placement: What and where” “Atrial selective anti-arrhythmia”, 2nd Asia Pacific Heart Rhythm Society Scentific Session, Singapore . 2009.

Tse H.F. , Invited Speaker, “ Stem Cell in cardiology”, The 18th Annual Scientific meeting of the Indonesian Heart Association . 2009.

Tse H.F. , Saha S., Garg A., Bohn D., Lee Y.L. and Lau C.P. , Muscle noise effects on atrial evoked response sensing: implications on atrial auto-threshold and auto-capture determination. , Pacing Clin Electrophysiol. . 2010.

Tse H.F. , 2010 Public talk – Primula Study Hong Kong Data, 香港公立醫院心臟醫生協會, 2010.

Tse H.F. , Asia Pacific The Raise educators’ Workshop, Hong Kong, 2010.

Tse H.F. , Chairman, Asia Pacific Heart Rhythm society Scientific Session APHRS 2009, Beijing, China , 2010.

Tse H.F. , Chairman, Plenary Session II, 15th Medical Research Conference, 2010.

Tse H.F. , Elite Reviewer 2009 for The Journal of the American College of Cardiology., 2010.

Tse H.F. , Siu D.C.W. and Lau C.P. , Impact of Right Ventricular Pacing Sites on Exercise Capacity during Ventricular Rate Regularization in Patients with Permanent Atrial Fibrillation., Pacing and Clinical Electrophysiology . 2009.

Tse H.F. , Invited Chairman, Faculty Member, Provocative Cases for the Device Physician” , Heart Rhythm 31st Annual Scientific Session, Denver, USA” . 2010.

Tse H.F. , Invited Speaker, Bio-medical therapy for Ventricula r Arrhythmia”, The 2nd National Ventricular Arrhythmia Symposium, Nanjing, China, . 2010.

Tse H.F. , Invited Speaker, “RAAS inhibition for CVD protection: Current Insights & future direction” , Hong Kong Cardiovascular Task Force, . 2010.

Tse H.F. , Invited Speaker, ' Chinese amlodipine besylate specialsts’ opinion recommendation (CLASSIC), The Primary Care Clinic Macau . 2009.

Tse H.F. , Invited Speaker, EP Physician Education Program in Vietnam Heart Institute, Bach Mai Hospital, Vietnam, 2010.

Tse H.F. , Invited Speaker, PRIMULA Workshop, MSD, 2010.

Tse H.F. , Invited Speaker, Palliative Therapy for Head and Neck Cancer, Head and Heck Course, ‘ . 2010.

Tse H.F. , Invited Speaker, RVOT Experience Sharing and Workshop on Shaing the ‘Mond Stylet’, Right Ventricular Septal Pacing Hand-on Workshop HK,” . 2010.

Tse H.F. , Invited Speaker, The 13th Congress of the International Society for Holter and Nonivasive Electrocardiology, “ State of the Art: Catheter Ablation for AF”2009, 2009.

Tse H.F. , Invited Speaker, “ Novel Antithrombotic Agents for Prevention of Thromboembolic Diseases”, Shatin International Medial Centre Union Hospital . 2009.

Tse H.F. , Invited Speaker, “ Optimal site ventricular pacing: where, when and how, “ Are MADIT indications applicab le globally?” , World Congress of Cardiology, Beijing, China “Stem Cell therapy for cardiovascular diseases,”, . 2010.

Tse H.F. , Invited Speaker, “New Echo techniques: focus on mechanical activity, Europace, 2009 . 2009.

Tse H.F. , Invited Speaker, “Palliative Therpay for Head and Ne ck Cancer” – Medical assessment of surgical risk , Head and Neck Course, Department of Surgery, Univ ersity of Hong Kong . 2010.

Tse H.F. , Invited Speaker, “Practical approach on pre-operative cardiac assessment”, Postgraduate Diploma in Diagnosis and Therapeutics in Internal Medicine, . 2010.

Tse H.F. , Invited Speaker, ”Cardiac Resynchronization therapy: Does evolving technology enhance efficacy”, European Society of Cardiology Congress, 2009, Barcelona, Spain . 2009.

Tse H.F. , Invited Speaker, 本地及海外大學升學講座, 聖保羅男女中學家教會， . 2010.

Tse H.F. , nvited Speaker, William MW Mong Professor in Cardiogy, “Clinical Applications of Stem Cells in Cardiovascular Diseases”, 2010.

Tse H.F. , 幹細胞科技科幻與現實之間, MingPao Weekly . 2010.

Tse H.F. , 重新睇健康, Metro Radio- . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical Function only in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation Existing Atrial Dyssynchrony , European Society of Cardiology Congress, Spain. August 29 –September 2, . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchrony and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Subm itted) . 2010.

Wang S. , Yiu K.H., Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Mak H.K.F. , Lau C.P. , Lam K.F. , Lau W.C.S. and Tse H.F. , Prevalence and extent of calcification over aorta, coronary and carotid arteries in patients with rheumatoid arthritis, Journal of Internal Medicine . 2009, 266: 445-452.

Wu H. , Tse H.F. and Li G.R. , Effects of acacetin on kv1.5 channels and rat atrial repolarization potassium currents, 14th Research postgraduate symposium, HKU . 2009, 58.

Wu W. , Lau C.P. , Tse H.F. and Li G.R. , Beta 1 subunit-dependent modulation of BK channel by membrane cholesterol, In: 15th Medical Research Conference, Department of Medicine, HKU, 15th Medical Research Conference . 2010, 16(1): 58.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Elevated Pulmonary Artery Systolic Pressure in Patie nts with Coronary Artery Disease and Left Ventricular Dyssynchrony , European Journal of Heart Failure . 2010, (in press).

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Relation of T-wave Alternans to Left Ventricular Dyssynchrony in Patients with Coronary Heart Disease, ESC Congress, 2010 .

Yiu K.H. and Tse H.F. , Cardiac gene and stem cell therapy. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. , Oxford: Oxford University Press (in press). . 2010.

Yiu K.H., Cheung B.M.Y. and Tse H.F. , A new paradigm for managing dyslipidemia with combinat ion therapy: laropiprant + niacin + simvastatin. , Expert Opin Investig Drugs. . 2010, 19: 437-49.

Yiu K.H., Siu D.C.W. , Yiu Y.F. and Tse H.F. , Electrocardiogram, In: Lip GY, Tse HF, Coats , Oxford Desk Reference . Oxford University Press, 2010.

Yiu K.H., Lee C.H. and Tse H.F. , Non-pharmacological treatment for hypertension. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Yiu K.H., Wang S.L., Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Mak H.K.F. , Lam K.F. , Lau W.C.S. and Tse H.F. , Pattern on atherosclerosis for coronary, carotid and aortic arteries calcification in rheumatoid arthritis: a multidetector CT study, Journal of American College of Cardiology . 2009, 53: A432.

Yiu K.H., Cheung B.M.Y. and Tse H.F. , Pharmacological treatment for hypertension. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Yiu K.H., Wang S. , Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Lau C.P. , Lai W.W. , Wong L.Y. , Lam K.F. , Lau W.C.S. and Tse H.F. , Role of circulating endothelial progenitor cells in patients with rheumatoid arthritis with coronary calcification, Journal of Rheumatology . 2010, 37: 529-535.

Yiu Y.F. , Yiu K.H. and Tse H.F. , Inappropriate sinus tachcyardia. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , large-conductance Ca-activated Potassium and Ether-a-go-go Potassium Channels Regulate Proliferation of Human Mesenchymal Stem Cells, J HK Coll Cardiol . 2009, 17(2): 59.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Human cardiac KV4.3 channels are regulated by protein tyrosine kinases, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 64.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Protein Tyrosine Kinases Regulate Human Cardiac KV4.3 Channel, J HK Coll Cardiol . 2009, 17(2): 58.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of cell proliferation by ion channels in human mesenchymal stem cells, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 65.

Researcher : Tse WW

List of Research Outputs

Tse W.W. , Yung S.S.Y. and Chan D.T.M. , Hyaluronan in the pathogenesis of lupus nephritis in NZB/W mice and the effect of 4-methylumbelliferone, 9th International Congress on Systemic Lupus Erythematosus . 2010.

Researcher : Tso AWK

Project Title:	A population-based prospective study to investigate the associations of obesity and adipokines with the incidence of cardiovascular disease and cancer
Investigator(s):	Tso AWK, Cheung BMY, Lam KSL, Lam TH, Lo SV, Tse HF, Wat NMS
Department:	Medicine
Source(s) of Funding:	Health and Health Services Research Fund - Full Grants
Start Date:	12/2008

Abstract:

To investigate the associations of obesity indices , insulin resistance index and adipokines with the incidence of (1) cardiovascular disease and (2) cancer in a community-based prospectively followed-up cohort in Hong Kong.

Project Title:	Adipocyte fatty acid-binding pro tein – an adipocytokine with a role in diabetic nephropathy ?
Investigator(s):	Tso AWK, Lam KSL, Chan DTM, Xu A
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2009

Abstract:

Adipocyte fatty acid-binding protein (A-FABP) belongs to a family of small cytoplasmic proteins important in mediating intracellular fatty-acid trafficking and energy metabolism. It is expressed predominantly in adipocytes but is also found in macrophages. A-FABP has been shown to influence various metabolic and inflam matory pathways. In mice, deletion of the A-FABP gene (aP2-/-) is associated with partial protection against glucose and lipid dysregulation in genetic and diet-induced obesity models1,2. An oral selective competitive inhibitor of A-FABP, BMS309403, has also been developed3, and treatment with BMS309403 led to significant improvement in glucose intolerance, insulin resistance and fatty infiltration of the liver in obese leptin-deficient mice3. At the cellular level, inhibition of A-FABP was associated with significant suppression of c-jun N-terminal kinase-1 (JNK) activity in adipose tissue and liver, resulting in improved insulin-stimulated tyrosine and Akt phosphorylation, and hence enhanced insulin signaling3. Furthermore, A-FABP is also likely to have pro-inflammatory effects. Macrophages from aP2-/- mice had reduced NFkB activity and reduced expre ssion of inflammatory cytokines, such as tumour necrosis factor-, monocyte chemoattractant protein (MCP-1), interleukin-6 (IL-6) and interleukin-1(IL-1)4, as well as suppression of inducible nitric oxide synthase and cyclo-oxygenase 2 pathways5. In humans, we found that A-FABP is released into the circulation, and A-FABP levels were predictive of the development of type 2 diabetes6 and the metabolic syndrome7. Recently, in a cohort of patients with type 2 diabetes, we found that serum A-FABP level was significantly associated with the severity of diabetic nephropathy, and correlated positively with albumin excretion rate and serum creatinine but negatively with glomerular filtration rate8. Seru m A-FABP level was independently associated with the presence of microalbuminuria and macroalbuminuria independent of age, sex, hypertension, waist circumference and LDL cholesterol8. However, whether A-FABP plays a direct role in the pathogenesis of diabetic nephropathy remains to be elucidated. Diabetic nephropathy is characterized by the progressive development of albuminur ia, initially associated with glomerular hyperfiltration, followed by progressive decline in glomerular function. Histologically, there is thickening of glomerular basement membrane, mesangial expansion, glomerulosclerosis, tubulo-interstitial fibrosis and tubular atrophy. There is significant monocyte/ macrophage infiltration9, and inflammatory stress has been suggested to play an important role in the pathogenesis of diabetic nephropathy. In support of this, it has been found that progressive diabetic nephropathy is associated with increased NFkB and JNK10 activation, increased production of MCP-111 and tumour growth factor-1 (TGF1)12, and increasin g macrophage accumulation parallels the development of renal injury and fibrosis10,13. On the other hand, suppression of macrophage infiltration, either by genetic or immunosuppressive approaches, significantly reduced the severity of diabetic nephropathy14. A-FABP is expressed in macrophages, and may modulate their pro-inflam matory cytokine productions4. In atherosclerosis-prone apolipoprotein-E-defi cient mice, macrophage-restricted ablation of A-FABP resulted in significant reduction in atherosclerotic lesions, regardless of its expressions in adipocytes, suggesting that macrophage A-FABP plays a direct role in the pathogene sis in atherosclerosis4,15. Whether A-FABP released from macrophages may have a similar pathogenic role in diabetic nephropathy remains unknown. In this project, we propose to examine the relevance of A-FABP in the pathogenesi s of diabetic renal disease in mice in both type 1 and type 2 diabetic mouse models: (1)Type 1 diabetes model: streptozotocin-induced diabetes, comparing the progression of nephropathy in A-FABP knockout mice with their wild-type littermate as controls. (2)Type 2 diabetes model: KK-Ay mice (a model of type 2 diabetes with spontaneous development of progressive albuminuria and nephropathy) will be used, and the effects of the administration of A-FABP inhibitor, BMS309403, on th e progression of nephropathy as well as reversal of established nephropathy as compared to vehicle will be examined. Objectives To investigate the effects of 1. the genetic deletion of A-FABP in type 1 diabetes mouse model, and 2. the use of a selective inhibitor of A-FABP in type 2 diabetes mouse model on diabetic nephropathy, in particular looking for: A) progressive albuminuria B) macrophage infiltration and pro-inflammatory cytokine productions in kidneys C) histological changes associated with diabetic nephropathy.

List of Research Outputs

Chen C. , Xu A. , Tso A.W.K. , Law S.C. , Cheung B.M.Y. , Janus E.D., Wat N.M.S. and Lam K.S.L. , Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study., 5th International Symposium on Healthy Aging . 2010.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Jiang C.Q., Thomas G.N. and Lam T.H. , A single nucleotide polymorphism in the gene encoding fibrinogen beta chain is associated with hypertension, British Hypertension Society Annual Meeting, 14-16 September 2009, Cambridge, UK . 2009.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. and Lam K.S.L. , Gamma-glutamyl transaminase level predicts the development of hypertension., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kong, 2010 . 18: 33.

Cheung B.M.Y. , Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. and Sham P.C. , Using glycosylated hemoglobin to define the metabolic syndrome in United States adults., Presented at the Hong Kong College of Cardiology 18th Annual Scientific Congress, May 14-16, Hong Kon g, 2010 . 18: 33.

Cheung B.M.Y. , Ong K.L. and Tso A.W.K. , Using the Albumin-Globulin Ratio to Identify Individuals with Elevated High-sensitivity C-Reactive Protein Le vel and High Cardiovascular Risk., Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Law S.C. , Sham P.C. and Lam K.S.L. , A genetic variant near the GNPDA2 gene is associated with the metabolic syndrome in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Sham P.C. , Xu A. , Ong K.L. , Cheung B.M.Y. and Lam K.S.L. , Implication of the obesity-associated genetic variants identified from recent genome-wide association studies in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 15.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a Chinese population, J Clin Endocrinol Meta . 2010, 95: 1395-403.

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Lam J.T.C., Lam K.S.L. , Tan K.C.B. , Chow W.S. , Tso A.W.K. and Kung A.W.C. , A woman with hypophosphataemia and raised alkaline phosphatase, British Medical Journal . 2010, 340: b-5564-.

Lam K.Y. , Ong K.L. , Lam K.S.L. , Tso A.W.K. and Cheung R.T.F. , Association of two adiponectin gene variants with ischemic stroke in a Chinese cohort, The 32nd Annual Meeting of the Japan Neuroscience Society, 16-18 September 2009, Nagoya, Japan. Neuroscience Research . 2009, 65: S122.

Law S.C. , Tso A.W.K. , Tam S.C.F., Wat N.M.S. , Cheung B.M.Y. and Lam K.S.L. , Predictive value of hemoglobin A1c on diabetes incidence over 8 years., 5th International Symposium on Healthy Aging . 2010.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted development of hypertension in Chinese men, Thrombosis and Haemostasis . 2010, 103 (4): 728-735.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , A genetic variant in the gene encoding fibrinogen beta chain predicted incident hypertension in Chinese men, Annual Scientific Meeting and Annual General Meeti ng of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Adiponectin gene polymorphisms, plasma adiponectin level and persistent hypertension in Hong Kong Chinese, British Pharmacological Society Winter Meeting, Dec 2009, London, UK . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q., Thomas G.N., Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen beta chain with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 51.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam K.S.L. , Jiang C.Q. , Thomas G.N. , Lam T.H. and Cheung B.M.Y. , Association of a genetic polymorphism in the gene encoding fibrinogen β chain with hypertension in Hong Kong Chinese, 14th Research Postgraduate Symposium, Faculty of Medicine, HKU, Dec 2009, Hong Kong . 2009.

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Leung R.Y., Xu A. , Cherny S.S., Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive Protein As A Predictor Of Hypertension In The Hong Kong Cardiovascular Risk Prevalence Study (crisps) Cohort, International Congress of Cardiology (ICC), Feb 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Xu A. , Cherny S.S. , Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive protein as a predictor of hypertension in the Hong Kong cardiovascular risk prevalence study (CRISPS) cohort, Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting of Hong Kong Society of Endocrinology . 2009.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adrenomedullin with hypertension and dysglycaemia in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Leung R.Y., Cherny S.S., Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of genetic variants in gene encoding adre nomedullin with hypertension and dysglycaemia in Hong Kong Chinese, Annual Scientific Meeting and Annual General Meeting of Hong Kong Society of Endocrinology, Metabolism and Reproduction, Nov 2009, Hong Kong . 2009.

Ong K.L. , Tso A.W.K. , Cherny S.S. , Sham P.C. , Lam T.H. , Lam K.S.L. and Cheung B.M.Y. , Relationship of liver enzymes with hypertension in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Cherny S.S. , Sham P.C. , Cheung B.M.Y. and Lam K.S.L. , Relationship of plasma interleukin-6 and its genetic variants with hypertension in Hong Kong Chinese., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 50.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated haemoglobin to define the metabolic syndrome in United States adults, Diabetes Care . 2010.

Ong K.L. , Tso A.W.K. , Lam K.S.L. , Cherny S.S. , Sham P.C. and Cheung B.M.Y. , Using glycosylated hemoglobin to define the metabolic syndrome in United States adults., 5th International Symposium on Healthy Aging . 2010.

Tso A.W.K. , Asian data report on phaeochromocytoma and paraganglio ma in Hong Kong, First Asian Symposium on Phaeochromocytoma and Paragangli oma, University of Santa Tomas, Philippines, in collaboration with National Institutes of Health, USA. . 2010.

Tso A.W.K. , Improving glycaemic control by islet enhancement, 5th International Symposium on Healthy Aging, Res earch Centre of Heart, Brain, Hormone & Healthy Aging . 2010.

Tso A.W.K. , Management of diabetes mellitus and diabetes insipidus: A neurosurgical perspective, Hong Kong Society of Neurosurgeons . 2009.

Tso A.W.K. , Peptides in Appetite Regulation, Take Control - Peaks & Valleys, Barcelona . 2010.

Tso A.W.K. , Peptides in appetite regulation, Take Control - Peaks & Valleys . 2010.

Tso A.W.K. , When and how to start novel insulin - an overview and case sharing, Hong Kong Doctors' Union . 2010.

Researcher : Tsoi TH

List of Research Outputs

Cheung R.T.F. , Lyden P.D., Tsoi T.H. , Huang Y., Liu M., Hon S.F.K. , Raman R. and Liu L., Production and validation of Putonghua- and Cantonese-Chi nese language National Institutes of Health Stroke Scale training and certification videos, International Journal of Stroke . 2010, 5: 74-79.

Researcher : Wang AYM

Project Title:	An epidemiologic survey of vitamin D deficiency in Chinese patients with moderate to severe chronic kidney disease
Investigator(s):	Wang AYM, Kwan CW, Lai KN
Department:	Medicine
Source(s) of Funding:	Health and Health Services Research Fund - Full Grants
Start Date:	07/2008

Abstract:

To determine the prevalance of vitamin D deficency in Chinese patients with moderate to severe chronic kidney disease.

List of Research Outputs

Wang A.Y.M. , Cheung C.W., Chu J.Y.Y. , Fok A.N.Y. , Lo W.K. , Leung J.C.K. , Tso W.K. and Lai K.N. , Is aortic pulse wave velocity a useful screening test for vascular and valvular calification in end-stage renal disease patients, Journal of American Society of Nephrology . 2009, 20: 443A-444A.

Researcher : Wang J

Project Title:	Characterization of the interaction between XAF1 and FHL2 in carcinogenesis and differentiation of gastrointestinal cancers
Investigator(s):	Wang J, Wong BCY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2008

Abstract:

Inhibitor of apoptosis (IAPs) family proteins are over-expressed by most of the cancers (1). They exert effects through inhibiting caspases activation and apoptosis, thus account for the development of cancers and tolerance to anti-cancer therapy (2). X-linked IAPs (XIAP) is the most potent member of IAPs. Several clinical or preclinical trails targeting the interferenc e of XIAP and its interacting protein, smac or omi are under assessment now around the world (3). XAF1 (XIAP associated factor 1) is the latest identified XIAP interacting protein that is able to antagonize the effect of XIAP (4). XAF1 has been defined as a novel tumor suppressor. First, it is expressed by all normal adult and fetal tissues, whereas its expression is absent or only at extremely low level in cancer cells (4). Secondly, others and we have shown that XAF1 gene is hypermethylated in cancerous but not the normal gastrointestinal (GI) tissues (5). Abnormal reduction of XAF1 expression strongly correlated with the stage and grade of gastric tumors (6). Thirdly, we have reported that an anti-apoptotic protein, Heat Shock Factor 1 (HSF1), negatively regulated the expr ession of XAF1 through transcription regulation (7), indicating that XAF1 was excluded during the protective stress responses of cancer cells. Finally, XAF1 has been implicated in the regulation of cancer cell differentiation. XAF 1 has been identified as an interferon-stimulating genes (ISGs). XAF1 stable transfectants of either Hela or melanoma cells behave as the terminal differentiated cells characterized by the loss of division capacity (8). We also identified an interferon response factor 1 (IRF-1) binding element adjacent to the transcription starting site of XAF1 gene (10). XAF1 expression in colon cancer cells is up-regulated by all-trans retinoic acid (ATRA) via IRF-1-mediated transcriptional regulation (9) By using yeast two hybrid assay, we identified four and a half of LIM-only protein 2 (FHL2) as an interacting protein of XAF1 (Attached figure 1). FHL2 is the second member of a small family of five proteins with four and a half LIM domains (10). This domain is a specialized double zinc finger protein motif that has versatile cellular roles as regulators of gene expression, cyto-architecture, cell adhesion, cell motility and signal transduction. Accumulated evidences indicated that FHL2 might function as an oncogene in cancer cells. First, FHL2 is highly expre ssed by various types of cancer cells including colon, cervical, prostate cancer cells and some breast cancer cells (10-12, 16). Moreover, expression of FHL2 protein in epithelial ovarian cancer and hepatoblastoma tissues was markedly up-regulated (11, 13), compared with the matched normal tissues. Secondly, high expression of FHL2 predicted bad prognosis for cancers patients. Gabriel reported that breast cancer patients with tumo rs expressing low amounts of FHL2 had significantly better survival compared with those with high FHL2 expression (14). Similarly, Philip considered FHL2 as a novel biomarker in predicting prostate cancer recurrence (11). Thirdly, over-expression of FHL2 stimulated cell proliferation and inhibited apoptosis in melanocyte or prostate cancer cells (14). Finally, FHL2 interacted with and activated oncogenic proteins, AP-1 (c-jun, c-fos) and TCF/-catenin in cancer cells (14, 16). We have shown that FHL2 expression is pivotal in maintenance of the malignant phenotype of GI cancers (16). FHL2 is only expressed by most of cancerous but not normal GI tissues. Suppression of FHL2 expression by either antisense or siRNA strategies induced GI cancer cell differentiation, and abrogated the ability of anchorage-dependent, independent or serum-dependent cell growth and in vivo tumorigenicity in nude mice. However, all studies published focus on the expression and transactivation function of FHL2 protein; neither other investigators nor we define the regula tion of FHL2 function itself before. Base on the fact that XAF1 and FHL2 interacted with each other in nucleus (Attached figure 1) and exert opposite roles in cancer cells, we hypothesized that XAF1 suppressed the transactivation function of FHL2 through physical interaction. Clarification of the nature of XAF1 and FHL2 interaction will broaden our knowledge about tumorigenesis and de-differentiation of GI cancers and may provide novel targets for treatmen t. Reference (The references with full title are published by the applicants) 1.Nachmias B, Ashhab Y, Ben-Yehuda D. Semin Cancer Biol. 2004;14(4):231-43 2.Yang L, Cao Z, Yan H, et al. Cancer Res. 2003;63(20):6815-24 3.Vaux DL, Silke J. Biochem Biophys Res Commun. 2003 May 9; 304(3):499-504 4.Liston P, Fong WG, Kelly NL, et al. Nat Cell Biol. 2001;3(2 ):128-33 5.Zou B, Chim CS, Zeng H. Correlation between the Single-Site CpG and Expression Silencing of the XAF1 Gene in Human Gastric and Colon Cancers Gastroenterology, 2006; 131(6):1835-43 6.Byun DS, Cho K, Ryu BK, et al. Cancer Res. 2003;63(21):7068-75 7.Wang J, He H, Yu L, et al. Heat shock factor 1 (HSF1) downregulates X-linked inhibitor of apoptosis protein-associated factor 1 (XAF1) through transcriptional regulation. Journal of Biological Chemistry, 2006; 281(5): 2451-9 8.Leaman DW, Chawla-Sarkar M, Vyas K et al. J Biol Chem. 2002;277(32):2 8504-11 9.Wang J, Peng Y, Sun YW, et al. All-trans retinoic acid induces XAF1 expression through an interferon regulatory facto r-1 element in colon cancer. Gastroenterology, 2006, 130(3):747-758 10.Chan KK, Tsui SK, Lee SM, et al. Gene. 1998;210(2):345-50 11.Yang Y, Hou H, Haller EM, et al. EMBO J. 2005; 24(5): 1021-32 12.Philip K, Lucia G,1Lukas CH, et al. Cancer Res 2006, 66 (23): 11341-11347 13.Chen D, Xu W, Bales E, et al. Cancer Res. 2003;63(20):6626-3 14.Gabriel B, Fischer DC, Orlowska-Volk M, et al. J Soc Gynecol Investig. 2006;13(1):69-75 15.Chen D, Xu W, Bales E, et al. Cancer Res. 2003;63(20):6626-34 16.Wang J, Yang Y, Xia HHX, et al. Suppression of FHL2 expression induces cell differentiation and inhibits gastrointestinal carcinogenesis Gastroenterology, 2007;132(3):1066-1076

Project Title:	Elucidation of the role of Sp1 in maintaining the survival and renewal of colon cancer stem cells
Investigator(s):	Wang J, Wong BCY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2009

Abstract:

1.Cancer stem cell contributes to the initiation, metastasis and drug-resistance of cancers. Cancer is constituted of a heterogeneous population of cells differing in morphology, marker expression, proliferation capacity and tumorigenicity. Cancer stem cells (CSCs ) have been defined as a cell fraction in analogy to normal stem cells that have the capacity to self-renew, undergo divisions that allow the generation of more CSCs and give rise to the variety of differentiated cells found in the malignancy. The gold standard for showing 'stemness' of cancer cells is the ability to generate a phenocopy of the original malignancy in immuno-compromised mice. In addition, the xenotransplanted tumor must be serially transplanted into new recipient mice, which is believed to address the issue of self -renewal in this subset of cancer cells (1). Cancer stem cell is not only the initiator of primary tumors but also the only cell subset that is capable of initiating and driving tumor metastases. This notion has been confirmed by several facts. The first is that cancer cells with the phenotype of CSCs have high potential of developing metastasis. Secondly, the percentage of cancer cells detected in bone marrow of several solid tumors is highly enriched for the CSCs phenotype. These phenomena indicate that the cells bearing CSCs markers are either better capable of disseminating from the tumor or better suited for survival outside of the primary malignancy. In addition, the CSCs are relatively resistant to chemotherapeutic and radiotherapeutic approaches. Most of CSCs are in a quiescent state, which means they are non-dividing and subsequently much less sensitive to classical antiproliferative chemotherapeutic regimens. Moreover, CSCs express high level of drug transporters that can efflux cytotoxic drugs. 2.CSCs possess unique growth property and surface marker. Unlike proliferation, CSCs possess the ability of self-renewal. It is a unique cell divis ion in which the capacity of one or both progeny to proliferate and differentiate is similar to those of the parental cell. Although a committed progenitor cell might have an extensive ability to proliferate, it is destined to eventually become terminally differentiated and stop dividing. On the other hand, a self-renewing cell division of a CSCs results in a cell that maintains its proliferative capacity and can regenerate tumors . Another common growth property of CSCs is their ability to form spheroid. So far, reports of successful culture of CSCs were all cultured in low adhesion flasks (dishes) with medium enriched EGF and bFGF (1-2). No characteristic gene signature of CSCs has been well-accepted up to now. CSCs share some common properties with normal stem cells such as the expression of CD133 and/or CD34. They display more similarity with the differentiated cancer cells such as the aberrant accumulation of normal or mutant -catenin. The surface marker to be used in identifying CSCs remains controversial. However, a few of molecules such as CD133, CD44, CD166, EpCAM, CD26 or Mushashi-1 have been accepted in more than one type of cancers. As for colon cancer, CD44 and CD166 have been defined as the specific surface markers for stem cells (3-4). 3. Cancer cell lines can be used as the source of CSCs Although it is obvious that tumors are the primary source of CSCs for their characterization, cancer cell lines may have the potential to act as alternative sources of CSCs. Many cancer cell lines can be maintained indefinitely in culture and form tumors like the original one when transplanted in vivo. As it seems likely that a number of cell lines were derived from single cancer cells, they do not contain any contaminating normal stem cells, such as hematopoietic stem cells, bone marrow (BM)-derived mesenchymal stem cells, or neural stem cells, all of which are recruited to tumors in vivo. Several groups have already shown that many cancer cell lines contain CSCs. A number of established cancer cell lines, including human and rodent glioma, breast cancer, prostate cancer, hepatocellularcarcinoma, pancreatic carcinoma and colo n cancer cell lines contain a small SP. These findings make cell lines attractive models for investigating the characteristics of CSCs. 4. Sp1 might be pivotal in maintaining the survival and renewal of cancer stem cell The transcription factor Sp1 (specificity protein 1) possesses three C2H2-type zinc fingers as DBD (DNA-bin ding domain). Sp1 binds to GC-boxes with the consensus sequence 5′-G/T-GGGCGG-G/A-G/A-C/T-3′ or 5′-G/T-G/A-GGCG-G/T-G/A-G/A-C/T -3′. Sp1 protein is higher expressed in gastric and colon cancer tissues than that of adjacent normal tissues. Moreover, the survival of patients with high Sp1 expression was significantly decreased compared to patients with weak to non-detectable Sp1 expression (5). However, the role of Sp1 in cancer stem cell has not been report ed. In our preliminary experiments, we generated cancer stem cells under the standard culture condition. We showed that Sp1 expressions in colon cancer stem cells (Fig 1A) and magnetic beads-sorted pure CD44+ cells (Fig 1B) were increased significantly. Suppression of Sp1 expression by siRNA or its DNA-binding activity by mithramycin A (MIA) not only inhibited the expression of CD44 and CD166 as determined by real time PCR (Fig 2), but also decreased the percentage of CD44+/CD166 + cell subset (Fig 3). Based on our preliminary observations, we hypothesized that Sp1 might play important role in maintaining the survival and renewal of colon cancer stem cells. The objectives of this proposal are to confirm our preliminary findings using more cell lines and with more functional assays. The result obtained will give us insight into the survival mechanism of CSCs and subsequently provide putative target for ca ncer management. Reference 1.Lobo NA, Shimono Y, Qian D, et al. Annu Rev Cell Dev Biol. 2007;23:675-99 2.Al-Hajj M, Clarke MF. Oncogene. 2004;23(43):7274-82 3.P. Dalerba, S.J. Dylla and I.K. Park et al. Proc. Nat. Acad. Sci. USA 2007, 104: 10158–10163 4.Vermeulen L, Todaro M, de Sousa Mello F, et al. Proc Natl Acad Sci U S A. 2008;105(36):13427-32. 5.Wierstra I. Biochem Biophys Res Commun. 2008, 18;372(1):1-13

Project Title:	Characterization of the role and mechanisms of FHL2 in promoting epithelial mesenchymal transition of colon cancer
Investigator(s):	Wang J, Wong BCY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) The correlation between FHL2 expression and EMT, metastasis and invasion of colon cancer by using clinical cancer tissues with primary and metastatic sites; 2) The effect and underlying mechanism of FHL2 on E-cadherin expression; 3) The influence of E-cadheri n/ -catenin complex re-constitution on FHL2-induced EMT.

List of Research Outputs

An X. , Ng S.M. , Xie D., Zeng Y.X., Sze J. , Wang J. , Chen Y.C., Chow B.K.C. , Lu G., Poon W.S., Kung H.F., Wong B.C.Y. and Lin M.C. , Functional characterisation of cell cycle-related kinase (CCRK) in colorectal cancer carcinogenesis. , European Journal of Cancer . 2010, 46: 1752-1761.

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Li M. , Wang J. , Ng S.M. , Chan C.Y., He M.L., Yu F. , Lai L., Shi C. , Chen Y.C., Yew D.T., Kung H.F. and Lin M.C. , Adenosine Diphosphate-ribosylation Factor 6 is Required for Epidermal Growth Factor-induced Glioblastoma Cell Proliferation, Cancer . 2009, 115(21): 4959-4972.

Zhang W. , Wang J. , Zou B. and Wong B.C.Y. , Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer, Hong Kong Medical Journal . 2010, 16: 64.

Researcher : Wang K

List of Research Outputs

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. and Li R.A. , Automaticity and conduction properties of bio-artificial pacemakers assessed in an in vitro monolayer model of neonatal rat ventricular myocytes., Europace. In press. . 2010.

Chan Y.C. , Tse H.F. , Siu D.C.W. , Wang K. , Lau C.P. and Tse H.F. , Characterizing the basis of automaticity of neonatal rat ventricular myocytes: Implications for cardiac excitability manipulations., Europace . 2010.

Researcher : Wang MM

Project Title:	Prevalence and clinical implications of exercise-induced left ventricular dyssynchrony de tected by echocardiography in patients with coronary artery disease
Investigator(s):	Wang MM, Lau CP, Tse HF
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2008

Abstract:

To estimate the prevalence of exercise-induced LV dyssynchrony in patients with CAD; to investigate the mechanism of exercise-induced dyssynchrony, we propose to compare the extent of LV dyssynchrony in CAD patients with or without active myocardial ischemia, and to determine the extent of LV dyssynchrony before and after coronary revascularisation intervention in patients with active myocardial ischaemia; to examine the functional significance of exercise-induced LV dyssynchrony, we plan to compare the exercise capacity with cardiopulmonary exercise in CAD patients with or without exercise-induced LV dyssynchrony.

Project Title:	Atrial Mechanical Dyssynchrony and Function in Sinus Node Disease Patients With And Without Atrial Fibrillation: Impacts of Different Modes of Atrial and Ventricular Pacing
Investigator(s):	Wang MM, Lau CP, Tse HF
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To compare the atrial mechanical function and synchronicity in SND patients with or without AF and age-matched normal subjects; (2) To assess the effec t of ventricular pacing on atrial mechanical function and dyssynchrony in SND patients with dual chamber pacing; (3) To assess the effect of atrial pacing sites (septal versus appendage) on improvement atrial mechanical function and dyssynchrony in SND patients with dual chamber pacing; (4) To assess if atrial dyssynchrony and mechanical function are predictors for the occurrence of AF (AF burden), independent of other clinical risk factors including hypertension, diabetes.

List of Research Outputs

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical Function only in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation Existing Atrial Dyssynchrony , European Society of Cardiology Congress, Spain. August 29 –September 2, . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchrony and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Submitted) . 2010.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Elevated Pulmonary Artery Systolic Pressure in Patients with Coronary Artery Disease and Left Ventricular Dy ssynchrony , European Journal of Heart Failure . 2010, (in press).

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Relation of T-wave Alternans to Left Ventricular Dyssynchrony in Patients with Coronary Heart Disease, ESC Congress, 2010 .

Researcher : Wang Y

List of Research Outputs

Wang Y. , Huang Y., Lam K.S.L. , Li Y., Wong W.T., Ye H., Lau C.W., Vanhoutte P.M.G. R. and Xu A. , Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-act ivated protein kinase and endothelial nitric oxide synthase, Cardiovascular Research . 2009, 82: 484-492.

Researcher : Wat NMS

List of Research Outputs

Chen C. , Xu A. , Tso A.W.K. , Law S.C. , Cheung B.M.Y. , Janus E.D., Wat N.M.S. and Lam K.S.L. , Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study., 5th International Symposium on Healthy Aging . 2010.

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implicati ons in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Law S.C. , Tso A.W.K. , Tam S.C.F., Wat N.M.S. , Cheung B.M.Y. and Lam K.S.L. , Predictive value of hemoglobin A1c on diabetes inciden ce over 8 years., 5th International Symposium on Healthy Aging . 2010.

Researcher : Wong BCY

Project Title:	Effect of XAF1 gene on tumor growth in gastric and colon cancer
Investigator(s):	Wong BCY, Tu S
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2003

Abstract:

To study the effect of XAF1 on tumor growth.

Project Title:	Role of Bcl-2 family proteins in non-steroidal anti-inflammatory drug-induced apoptosis of gastric cancer
Investigator(s):	Wong BCY, Xia HHX
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2004

Abstract:

To clarify the role of Bcl-2 family proteins in NSAID-induced apoptosis in vitro in this proposal using gastric cancer cell lines.

List of Research Outputs

An X. , Ng S.M. , Xie D., Zeng Y.X., Sze J. , Wang J. , Chen Y.C., Chow B.K.C. , Lu G., Poon W.S., Kung H.F., Wong B.C.Y. and Lin M.C. , Functional characterisation of cell cycle-related kinase (CCRK) in colorectal cancer carcinogenesis. , European Journal of Cancer . 2010, 46: 1752-1761.

Chen W.J., Ng L. , Chow A.K., Chu A.C.Y., Wong B.C.Y. and Pang R.W.C. , Identification of CD44+ Cancer Cells in Gastric Cancer by Chemotherapeutic Enrichment, 16th Hong Kong International Cancer Congress . 2009.

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibit or of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Hung I.F.N. , Chan P., Leung S., Chan S.Y. , Hsu A., But D., Seto W.K., Wong S.Y. , Chan C.K. , Gu Q. , Tong T.S.M., Cheung T.K. , Chu K.M. and Wong B.C.Y. , Clarithromycin-amoxycillin-containing triple therapy: A valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong?, Helicobacter . 2009, 14: 505-511.

Hung I.F.N. and Wong B.C.Y. , The relevance of new Helicobacter pylori guidelines to Asia. , US Gastroenterology and Hepatology Review. Volume 1 Issue 2 2009. . 2009.

Ng F.H. , Wong S.Y. , Lam K.F. , Chu W.M., Chan P., Ling Y.H., Kng C.P.L. , Yuen W.C., Lau Y.K. , Kwan A. and Wong B.C.Y. , Famotidine is inferior to Pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosion s, Gastroenterology . Elsevier, 2010, 138: 82-88.

Ng L. , Poon R.T.P. , Wong B.C.Y. and Pang R.W.C. , A novel regulator of cell migration and invasion in human hepatocellular carcinoma, 16th Hong Kong INternational Cancer Congress . 2009.

Ng L. , Poon R.T.P. , Wong B.C.Y. and Pang R.W.C. , Actopaxin: A Novel Regulator Of Cell Migration And Invasion In Human Hepatocellular Carcinoma , 15th Medical Research Conference, Hong Kong . 2010.

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastatic Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Qiao L. and Wong B.C.Y. , Experimental therapeutics of colon cancer., In: Manfred Schwab, Encyclopedia of Cancer . Springer Reference, 2009, LXXXVII.

Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Chemoprophylaxis in colorectal cancer: current concepts and a practical algorithm for use., Exper Opin Investig Drugs . 2010, Suppl 1: S57-66.

Tu S.P., Sun R.W.Y. , Lin M.C. , Cui J.T., Zou B. , Gu Q. , Kung H.F., Che C.M. and Wong B.C.Y. , Gold (III) Porphyrin Complexes Induce Apoptosis and Cell Cycle Arrest and Inhibit Tumor Growth in Colon Cancer, Cancer . 2009, 115(19): 4459-4469.

Tu S.P., Sun Y.W., Cui J.T., Zou B. , Lin M.C. , Gu Q. , Jiang S.H., Kung H.F., Korneluk R.G. and Wong B.C.Y. , Tumor Suppressor XIAP-associated Factor 1 (XAF1) Coopera tes with Tumor Necrosis Factor-related Apoptosis-inducing Ligand to Suppress Colon Cancer Growth and Trigger Tumor Regression, Cancer . 2010, 116(5): 1252-1263.

Wong B.C.Y. , Fatty liver, Next Magazine, book A, 2 Jul . 2009, 94-98.

Wong B.C.Y. , Treatment of H pylori in prevention of gastric cancer, 6th Shanghai International Conference of Gastroenterology, Shanghai, 1-4 July, 2009 . 2009.

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Yee Y.K., Tan V.P.Y. , Chan P., Hung I.F.N. , Pang R.W.C. and Wong B.C.Y. , Epidemiology of colorectal cancer in Asia. , J Gastroenterol Hepatol . 2009, 24: 1810-6.

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Yee Y.K., Gu Q., Hung I.F.N. , Tan V.P.Y. , Chan P., Hsu A., Pang R.W.C. , Lam S.C. and Wong B.C.Y. , Trend of colorectal cancer in Hong Kong:1983-2006. , J Gastroenterol Hepatol . 2010, 25: 923-7.

Zhang R. , Zhang S.Y. , Lan X.R. , Wu Y. , Szalai ..J..., Wong B.C.Y. , Lau C.P. , Wu E.X. and Lan H.Y. , C-reactive Protein Promotes Cardiac Inflammation and Fibrosis in Angiotensin II-Induced Hypertensive Cardiovascular Diseases, In: American Heart Association, Basic Cardiovascular Science Conference, July 20-23, 2009, Las Vegas, USA; Circulation Research . 2009.

Zhang W. , Wang J. , Zou B. and Wong B.C.Y. , Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer, Hong Kong Medical Journal . 2010, 16: 64.

Zou B. , Qiao L. and Wong B.C.Y. , Current Understanding of the Role of PPARgamma in Ga strointestinal Cancers, PPAR Research . 2009, 2009: 816957.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presenta tion), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Wong DKH

Project Title:	Identification of hepatitis B vi rus DNA polymerase sequences to predict virological response to entecavir therapy
Investigator(s):	Wong DKH, Lai CL, Yuen RMF, Fung JYY
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	05/2009

Abstract:

To identify possible HBV DNA sequences of predictive value of entecavir treatment response

Project Title:	Identification of aberrantly methylated CpG loci in hepatitis B virus-related hepatocellular carcinoma
Investigator(s):	Wong DKH, Yuen RMF, Lai CL, Fung JYY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	04/2010

Abstract:

Hepatocellular carcinoma (HCC) is one of the most common liver cancers in the world and, according to the Hong Kong Cancer Registry, liver cancer is the third leading cause of cancer death in Hong Kong. In Hong Kong, more than 80% of HCC cases are related to chronic hepatitis B virus (HBV) infection. Curative therapy to HCC is limited. Although the molecular and cellular mechanisms of hepatocarcinogenesis have been extensively studied, the exact pathways remain unclear. Therefore, there is a need for a better understanding of the molecular biology of HCC for the identification of potential new molecular therapeutic targets and markers for early diagnosis. As with many other tumors, development of HCC is a multistep process with genetic and epigenetic alterations in regulatory genes. Recently, more data are available on the genetic changes in hepatocarcinogenesis, giving clues to the molecular pathway, potential therapeutic targets and early diagnost ic markers of HCC. Beside genetic changes, epigenetic alterations can modulate gene expression without changing the genetic sequence. In particular, site-specific hypermethylation, signified by the addition of a 5´-methyl group to the cytosine residues in the CpG dinucleotide-rich areas (CpG islands) at the promoter region, results in transcriptional gene inactivation. As epigenetic silencing of tumor suppressor genes by promoter CpG island hypermethylation is commonly observed in various human cancers, understanding DNA methylation can provide means to elucidate the molecular mechanism of HCC and identify potential therapeutic targets and markers for early diagnosis and/or prognosis assessment of HCC. Studies on promoter CpG island methylation in HCC have mostly been done with a candidate gene approach, in which the promoter methylation status of selected classical tumor suppressor genes, or genes which are differentially methylated in other cancers, are studied by techniques such as methylation-specific PCR (MS-PCR) and/or bisulfite sequencing. One pitfall in this approach is that some genes which are of importance to cancer development may be missed in the initial selection process. A systematic global study of the CpG promoter hypermethylation in HCC has not been done. We propose to study the CpG promoter methylation profile in HCC in surgically resected tumor and adjacent non-tumor liver tissues obtained from patients with HBV-related HCC, using differential methylation hybridization CpG microarray. The key issues of this proposed study are as follow: 1) The effect of epigenetic modifications in hepatocarcinogenesis is still poorly understood, and the study of CpG island promoter methylation in HCC remains a great challenge 2) Although it has been reported that CpG island promoter methylation regulates the expression of several tumor-related genes in HCC, the aberrant CpG island methylation involved in hepatocarcin ogenesis has not been studied in a genome-wide scale 3) There is a need for the identification of molecular and methylation markers for the early diagnosis and classification of HCC 4) Identifying new candidate HCC-related genes by epigenetic analysis may provide insights into the development of new therapeutic target for HCC We hypothesize that potential tumor-related genes that have not been identified using candidate gene approach can be identified through this genome-wide CpG island promoter methylation profiling. These new findings will add value to the understanding of the molecular mechanism and epigenetic regulation of HCC. More importantly, understanding the regulation of these genes by promoter methylation will provide clues to the identification of potential molecular therapeutic targets and novel markers for early diagnosis of HCC and assessment of prognosis in HCC patients. Objectives 1. To identify aberrantly methylated promoter loci in HCC using a genome-wide microarray approach 2. To verify aberrantly methylation of candidate genes by MS-PCR 3. To verify the differential expression of these candidate tumor-related genes in liver tissue samples and cell lines

Project Title:	Application of COLD-PCR sequencing for the early detection of HBV antiviral drug resistant mutations
Investigator(s):	Wong DKH, Fung JYY, Lai CL, Yuen RMF
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	04/2010

Abstract:

To develop a modified co-amplification at lower denaturation temperature PCR (COLD-PCR) method for the detection of low level of HBV antiviral drug resistant mutations ( <20% of the viral population); to apply this method for the early detection of drug resistant mutations in patients with lamivudine and telbivudine therapy.

List of Research Outputs

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Correlation of liver stiffness and histological feat ures in healthy persons and in patients with occult hepatitis B, chronic active hepatitis B, or hepatitis B cirrhosis., Am J Gastroenterol . 2009, 105(5): 1116-22.

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Liver stiffness and histological features in healthy persons, and patients with occult hepatitis B, chronic active hepatitis B, and hepatitis B-related cirrhosis., Hepatology . 2009, 50(4) Suppl: 978A.

Fung J.Y.Y. , Lai C.L. , Cheng C.T.K. , Wu C.H. , Wong D.K.H. and Yuen R.M.F. , Mild-to-moderate elevation of alanine aminotransferase may increase liver stiffness measurement by transient elastography in patients with chronic hepatitis B., Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 971A.

Fung J.Y.Y. , Seto W.K., Lai C.L. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , Profiles of HBV DNA in a large population of chinese chronic hepatitis B patients: implications for antiviral therapy. , Hepatol Int . The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010., 2010, 4: 53-4.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , A three-year study on viral suppression and resistance profile for treatment-naive chronic hepatitis B patients receiving continuous entecavir treatment. , Hepatol Int. The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010 . 4: 58.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , HBV DNA levels predict significant liver histology for HBeAg-negative chronic hepatitis B patients., Gastroenterology. Digestive Disease Week, New Orleans, May 2010 . 138 (5 Supp1): S-788.

Yuen R.M.F. , Fung J.Y.Y. , Seto W.K., Wong D.K.H. , Yuen J.C.H. and Lai C.L. , Combination of baseline parameters and on-treatment hepatitis B virus DNA levels to start and continue patients with lamivudine therapy. , Antivir Ther . 2009, 14(5): 679-85.

Researcher : Wong KH

List of Research Outputs

Lam C.L.K. , Wong K.H. , Lam T.P. and Lo Y.Y.C. , Population norm of Chinese (HK) SF-12 Health Survey_version 2 of Chinese adults in Hong Kong. , HK Practitioner . 2010, 32: 77-86.

Wong K.H. , Audit of Diabetes Dependent Quality of Life (ADDQoL19) Chinese for Hong Kong (Cantonese) 11.9.06, Health Psychology Research Limited . 2009.

Wong K.H. , Lam C.L.K. and Lam T.P. , Comparison of SF-6D and SF-36v2-derived Health Preference Values among Chinese Chronic Hepatitis B Patients., 14th Research Postgraduate Symposium. . The University of Hong Kong, Hong Kong, 2009.

Wong K.H. and Lo Y.Y.C. , Normative Data and Factors Associated with SF-12 Health Survey in Chinese Patients with Type 2 Diabetes Mell itus., International Conference on Promoting Chronic Care 2010. . Hong Kong Polytechnic University, Hong Kong, 2010.

Wong K.H. and Lam C.L.K. , Primary Care Service Utilization Rates and Pattern of the Hong Kong Population., 15th Medical Research Conference. . Department of medicine, the University of Hong Kong, Hong Kong, 2010.

Wong K.H. and Lam C.L.K. , Primary Care Service Utilization Rates and Pattern of the Hong Kong Population., Hong Kong Med J . 2010, 16 (Suppl 1): S57.

Researcher : Wong KS

List of Research Outputs

Jiang C.Q., Liu B., Cheung B.M.Y. , Lam T.H. , Lin J.M., Jin Y.L., Yue X.J., Ong K.L. , Tam S. , Wong K.S. , Tomlinson B., Lam K.S.L. and Thomas G.N., A single nucleotide polymorphism in APOA5 determines triglyceride levels in Hong Kong and Guangzhou Chinese. , Eur J Hum Genet. . 2010, 1-6.

Researcher : Wong KW

List of Research Outputs

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Researcher : Wong KY

List of Research Outputs

Chim J.C.S. , Wong K.Y. and Qi Y. , Epigenetic alterations of the miR-34a in hematological malignancies, 15th Congress of the European Hematology Associat ion, (Poster) . 2010.

Chim J.C.S. , Wong K.Y. , Qi Y. , Foong F., Lam W.L., Wong L.G., Jin D. , Costello J.F. and Liang R.H.S. , Epigenetic inactivation of the miR-34a in hematological malignancies, Carcinogenesis . 2010, 31(4): 745-50.

Chim J.C.S. and Wong K.Y. , Epigenetic inactivation of the miR-34a in hematological malignancies, Epigenetics, Chromatin & Transcription, Suzhou (Post er) . 2010.

Wong K.Y. , Jin D. , Liang R.H.S. and Chim J.C.S. , Epigenetic silencing of miR-203 is a disease initiation event of multiple myeloma, European Association of Cancer Research, Norway (Poster) . 2010.

Researcher : Wong LC

List of Research Outputs

Lam K.S.L. , Zhang X. , Wong L.C. and Xu A. , Selective Inactivation of c-Jun NH2 Terminal Kinase (JNK) in the Adipose Tissue Is Sufficient To Protect Against Diet-Induced-Obesity and Its Associated Metabolic Disorders in Mice, Endocrine Society Annual Meeting, 19-22 June, San Diego, USA . 2010.

Researcher : Wong LY

List of Research Outputs

Lee Y.K. , Ng K.M. , Chan Y.C. , Lai K.W.H. , Au K.W. , Ho J.C.Y. , Wong L.Y. , Lau C.P. , Tse H.F. and Siu D.C.W. , Triiodothyronine Promotes Cardiac Differentiation and Maturation of Embryonic Stem Cells via the Classical genomic and ERK1/2 Pathway., Molecular Endocrinology . 2010, 24(9): 1728-36.

Yiu K.H., Wang S. , Mok T.M.Y. , Ooi C.G.C. , Khong P.L. , Lau C.P. , Lai W.W. , Wong L.Y. , Lam K.F. , Lau W.C.S. and Tse H.F. , Role of circulating endothelial progenitor cells in patients with rheumatoid arthritis with coronary calcificatio n, Journal of Rheumatology . 2010, 37: 529-535.

Researcher : Wong LYF

Project Title:	Involvement of NF-κB and cAMP-dependent protein kinase pathways in adrenomedullin-induc ed cytokine responses in macrophages
Investigator(s):	Wong LYF, Cheung BMY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2004

Abstract:

To assess the involvement of NF-[kappa]B pathway as the link between AM and inflammation; to confirm that AM exerts its effect on cytokine production in macrophages through cyclic-AMP; to identify the cAMP-dependent protein kinase pathway involved in the AM-induced cytokine response in LPS-stimulated macrophages.

Project Title:	Mechanism of the modulation of cytokine responses by adrenomedullin and adrenomedullin binding protein-1 in macrophages: a novel pathway in sepsis with therapeutic implications
Investigator(s):	Wong LYF, Cheung BMY
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	10/2006

Abstract:

To investigate the expression of AMBP-1 and AM receptor proteins in the inflammatory process in a rat alveolar macrophage cell line; to examine the effect of AMBP-1 on LPS-induced inflammatory cytokine produc tions in macrophages and determine whether feedback loops or desensitization of AM receptor may affect the production of AM and AMBP-1; to identify the role of second messenger-de pendent kinases involved in the regulation of expression of AM and AMBP-1 and AM-induced cytokine response in LPS-stimulated macrophages

Researcher : Wong MKY

List of Research Outputs

Ho J.C.M. , Ho S.P. , Mak J.C.W. , Wong M.K.Y. , Ip M.S.M. and Lam W.K. , Alterations of systemic antioxidants and 8-isoprostane during chemotherapy for lung cancer. , 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S909.

Ho J.C.M. , Lam C.L. , Wong M.K.Y. , Lam B. , Ip M.S.M. and Lam W.K. , Capecitabine as salvage treatment for lymphoepithelioma- like carcinoma of lung, Journal of Thoracic Oncology . 2009, 4(9): 1174-1177.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to first-line gefitinib in non-small cell lung cancer. , Cancer Chemotherapy and Pharmacology . 2010, 65: 1023-1028.

Wong M.K.Y. , Lo A.I., Lam B. , Lam W.K. , Ip M.S.M. and Ho J.C.M. , Erlotinib as salvage treatment after failure to gefiti nib in non-small cell lung cancer, 13th World Conference on Lung Cancer. Journal of Thoracic Oncology . 2009, 4(9): S719.

Researcher : Wong RWS

List of Research Outputs

Au W.Y. , Trendell-Smith N.J. , Ko B.H., Tong A.C. and Wong R.W.S. , Oral Epstein–Barr virus-related B-cell lymphoma causing persistent paraneoplastic dermatomyositis after nasopharyngeal and cutaneous carcinomas, Leukaemia & Lymphoma . 2010, 51(4): 715-716.

Chung H.Y., Wong R.W.S. and Mok T.M.Y. , A comparison of the performance of the Assessment of SpondyloArhritis international Society classification criteria, European Spondyloarthropathy Study Group classification criteria, and Modified New York criteria in a cohort of Chinese Spondyloarthritis patients. , HKMJ . 2010, 16: p18 S20.

Mok T.M.Y. , Chiu S.S.H. , Lo Y. , Mak H.K.F. , Wong R.W.S. , Khong P.L. and Lau W.C.S. , Coronary atherosclerosis using CT coronary angiogram in patients with systemic sclerosis. Rely letter to Editor., Scand J Rheumatol . 2010, 38(5): 381-385.

Mok T.M.Y. , Yiu K.H., Wong C.Y., Lai W.H., Lo Y. , Wong R.W.S. , Tse H.F. and Lau W.C.S. , Endothelial Dysfunction is Associated with Low Level of Circulating Endothelial Progenitor Cells in Patients with Systemic Sclerosis, Clin Exp Rheumatol . 2010, in press.

Mok T.M.Y. , Tse H.F. , Wong C.Y., Qiuwaxi J. , Lai K.W.H. , Lo Y. , Wong R.W.S. and Lau W.C.S. , Endothelial dysfunction is associated with decreased circulating endothelial progenitor cells in patients with systemic sclerosis, Annals of the Rheumatic Diseases . 2009, S337.

Tsang H.H., Wong R.W.S. , Trendell-Smith N.J. , Wu A.K.P. and Mok T.M.Y. , Diffuse large B-cell lymphoma of the central nervous system in mycophenolate mofetil-treated patients with systemic lupus erythematosus., HKMJ . 2010, 16: p54 S92.

Yang W. , Shen N., Ye D.Q., Liu Q., Qian X.X., Hirankarn N., Pan H.F., Mok C.C., Chan D.T.M. , Wong R.W.S. , Lee K.W., Wong S.N. , Leung A.M.H., Li X.P., Avihingsanon Y., Wong C.M. , Lee T.L. , Ho M.H.K. , Lee P.P.W. , Chang Y.K., Li P.H., Li R. , Zhang L. , Wong W.H.S. , Ng I.O.L. , Lau W.C.S. , Sham P.C. , Lau Y.L. and Asian Lupus Genetics Consortium A.L.G.C., Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus. , PLoS Genetics . 2010, 6: e1000841.

Researcher : Wong SY

List of Research Outputs

Hung I.F.N. , Chan P., Leung S., Chan S.Y. , Hsu A., But D., Seto W.K., Wong S.Y. , Chan C.K. , Gu Q. , Tong T.S.M., Cheung T.K. , Chu K.M. and Wong B.C.Y. , Clarithromycin-amoxycillin-containing triple therapy: A valid empirical first-line treatment for Helicobacter pylori eradication in Hong Kong?, Helicobacter . 2009, 14: 505-511.

Ng F.H. , Wong S.Y. , Lam K.F. , Chu W.M., Chan P., Ling Y.H., Kng C.P.L. , Yuen W.C., Lau Y.K. , Kwan A. and Wong B.C.Y. , Famotidine is inferior to Pantoprazole in preventing recurrence of aspirin-related peptic ulcers or erosions, Gastroenterology . Elsevier, 2010, 138: 82-88.

Researcher : Wong W

List of Research Outputs

Lam C.L.K. , Wong W. and Fong D.Y.T. , Chinese Herbal Medicine in the Treatment of Acute Upper Respiratory Tract Infections, a Double Blind, Placebo Controlled Trial, HK Med J . 2009, 15 (Supple 6): S30-4.

Wong W. , District Champion. Title: Effectiveness of Western Medicine Outpatient Consultations in Primary Care-A Comparison with Chinese Medicine Consultations. , The Postgraduate Symposium of the 2009 TWGHs Eddie Wang Symposium on Integrated Chinese and Western Medicine . 2009.

Researcher : Wong WM

List of Research Outputs

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Researcher : Wong Y

List of Research Outputs

Shiu S.W.M. , Zhou H., Wong Y. and Tan K.C.B. , Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus, J Diabetes Invest . 2010, 1: 111-116.

Shiu S.W.M. , Wong Y. , Zhou H.L. and Tan K.C.B. , Roles of lipid transfer proteins in determining cellular cholesterol efflux to serum in type 2 diabetes mellitus, 53rd Annual Meeting of the Japan Diabetes Society, Okayama, Japan . 2010.

Tam H.L. , Shiu S.W.M. , Wong Y. , Chow W.S. , Betteridge D.J. and Tan K.C.B. , Effects of atorvastatin on serum soluble receptors for advanced glycation end-products in type 2 diabetes, Atherosclerosis . 2010, 209: 173-177.

Tan K.C.B. , Shiu S.W.M. , Zhou H.L. and Wong Y. , Endothelial lipase and reverse cholesterol transport in type 2 diabetes mellitus, The International Diabetes Federation 20th World Diabetes Congress, Montreal, Canada . 2009.

Researcher : Wong YL

List of Research Outputs

Hoo R.L.C. , Wong Y.L. , Xu A. and Lam K.S.L. , Adipocyte fatty acid binding protein (AFABP) in kupffer cells as the novel player in the pathogenesis of non-alcoho lic fatty liver disease, 14th Medical Research Conference, The University of Hong Kong . 2009.

Researcher : Wu CH

List of Research Outputs

Fung J.Y.Y. , Lai C.L. , Cheng C.T.K. , Wu C.H. , Wong D.K.H. and Yuen R.M.F. , Mild-to-moderate elevation of alanine aminotransferase may increase liver stiffness measurement by transient elastography in patients with chronic hepatitis B., Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 971A.

Fung J.Y.Y. , Lai C.L. , Yuen J.C.H. , Cheng C.T.K. , Wu C.H. and Yuen R.M.F. , Sequential therapy using lamivudine in entecavir-treated patients with undetectable HBV DNA – results at 48 weeks. , Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 510A.

Researcher : Wu D

List of Research Outputs

Gao Y., Zhou Y., Xu A. and Wu D. , Effects of an AMP-activated protein kinase inhibitor, compound C, on adipogenic differentiation of 3T3-L1 cells., Biol Pharm Bull. . 2009, 31: 1716-22.

Hui X. , Lam K.S.L. , Wang Y. , Xu A. , Li H. , Vanhoutte P.M.G.R. and Wu D. , Adipocyte fatty acid-binding protein modulates inflam matory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1., The Journal of Biological Chemistry . the United States, American Society for Biochemistry and Molecular Biology, 2010, 285: 10273.

Researcher : Wu EX

Project Title:	Magnetic resonance imaging for biomedical research
Investigator(s):	Wu EX
Department:	Engineering Faculty
Source(s) of Funding:	Seed Funding for New Staff
Start Date:	02/2004

Abstract:

To develop and acquire the basic and necessary software and hardware required for the MRI research at HKU.

Project Title:	Magnetic Resonance Measurement of Heart and Liver Iron
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	The National Institute of Diabetes and Digestive and Kidney Diseases
Start Date:	11/2006

Abstract:

1. Implementation and optimization of projection-rec onstruction, gradient- and spin-echo imaging sequences to map T2 and T2* in test phantoms. The work initially will be performed at 7 Tesla for testing and then implemented for clinical imaging at 3 Tesla. This component of the research work will also include development of necessary software toolkits for image data analysis. 2.Optimization of clinical protocols at 3 Tesla for T2 and T2* measurements using projection-reconstru ction, gradient- and spin-echo sequences in the anterior pituitary, pancreas and gonads. 3. Estimates of iron deposition in the anterior pituitary, pancreas and gonads using the optimized MRI protocols will be compared with th e results of clinical evaluation of endocrine function in a group of thalassaemia patients with a wide range of body iron burdens.

Project Title:	Cell labeling for In Vivo MRI Monitoring after Transplantation in Cell Based Therapies
Investigator(s):	Wu EX
Department:	Engineering Faculty
Source(s) of Funding:	Small Project Funding
Start Date:	01/2007

Abstract:

In vivo monitoring of stem cells after grafting is essential for a better understanding of their migr ational dynamics and differentiation processes and of their therapeutic potential. High-field magnetic resonance imaging (MRI) is potentially capable of tracking transplanted stem cells, and characterizing resulting anatomical, physiological and functional recovery in vivo, intac t, and with high spatial resolution. We propose to develop such cellular imaging methodology on a 7 Tesla MRI scanner by (i) designing various techniques to label cells in vitro and quantitatively monitoring their in vivo distribution and activity after transplantation in stem cell therapy in rat stroke model; (ii) characterizing the therapeutic outcome in terms of anatomical structures and physiological functions using various MRI methods.

Project Title:	International Bioiron Society (IBIS) 2007 Meeting MRI CHARACTERIZATION OF FERRITIN-LIKE AND HEMOSIDERIN-LIKE IRON
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	04/2007

Abstract:

N/A

Project Title:	Thalassaemia Major: A new MRI method for monitoring heart and liver iron deposition
Investigator(s):	Wu EX, Au WY, Ha SY
Department:	Electrical & Electronic Engg
Source(s) of Funding:	Children's Thalassaemia Foundation - General Awards
Start Date:	09/2007

Abstract:

To develop a new magnetic resonance imaging (MRI) method for detection and monitoring of heart iron depos ition in patients with thalassaemia major and other forms of iron overload.

Project Title:	Thalassaemia major: a new MRI method for detection and monitoring of heart and liver iron deposition
Investigator(s):	Wu EX, Ha SY, Khong PL, Tse HF
Department:	Electrical & Electronic Engg
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2007

Abstract:

To develop and optimize new MRI pulse sequences to separately measure ferritin and hemosiderin iron by their distinctive effects on CPMG signal decay in phantoms containing water soluble nanometer-sized (ferritin-like) iron particles and water insoluble micron-sized (hemosiderin-l ike) iron particles and validate the MRI method by studies ex vivo of heart and liver samples from patients with iron overload in which ferritin and hemosiderin iron concentrations will be determined by biochemical measurement; to assess the new MRI determinations of tissue ferrit in and hemosiderin iron in cross-sectional and prospective longitudinal studies of cardiac and hepatic function in thalassaemia patients with iron overload.

Project Title:	MR Study of High-order Water Molecule Diffusion in Biological Systems
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	Small Project Funding
Start Date:	12/2007

Abstract:

Diffusion tensor magnetic resonance imaging (DTI) has great potential to provide detailed information regarding central nervous system (CNS) tissue morphology and pathology. Often, the results of DTI studies are presented using summary parameters such as apparent diffusion coefficient (ADC) or fractional anisotropy (RA) that allow a simplified expression of water diffusion characteristics. While these summary parameters are convenient and are often highly correlated with disease progression, they fail to capture the specific, directional information inherent in the full DTI experiment. This project aims to develop, evaluate and validate a new in vivo and non-invasive MR diffusion kurtosis imaging (DKI) technique to charaterize CNS tissue. The specific objectives are: 1. Develop and implement MR data acquisition sequences. 2. Comprehensive analysis of the 2nd-order (conventional DTI approach) and 4th-orde r diffusion tensors. 3. Correlation of MRI DTI and DKI images with histology. 4. Monte Carlo simulation of diffusion kurtosis characteristics.

Project Title:	16th Scientific Meeting of Internat ional Society for Magnetic Resonance in Medicine (ISMRM) Relation of myocardial fiber structure with cardiac wall motion using DTI and MR tagging Myocardium structural remodeling with relation of infarct location and size in porcine model using DTI MR study of postnatal development of left ventricular myocardium structure and function in rats
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	05/2008

Abstract:

N/A

Project Title:	30th Annual International Confer ence of the IEEE Engineering in Medicine and Biology Society Magnetic Resonance Imaging of Migrating Neuronal Precursors in Normal and Hypoxic-ischemic Neonatal Rat Brains by Intraventricular MPIO Labeling Preliminary In Vitro Study of Ultrasound Sonoporation Cell Labeling with Superparamagnetic Iron Oxide Particles for MRI Cell Tracking
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	08/2008

Abstract:

N/A

Project Title:	Manganese-enhanced MRI for In Vivo Detection of Neurodegeneration in Neonatal Hypoxic-isc hemic Brain Injury
Investigator(s):	Wu EX, Khong PL
Department:	Electrical & Electronic Engg
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2008

Abstract:

(1) Quantitative and longitudinal characterization of MEMRI, Mn-SOD and GS levels and Mn concentrations in two established neonatal rat H-I brain injury models (severe and mild H-I models): The purpose is to establish the spatiotemporal correlations between MEMRI measuremen ts, enzyme levels and Mn levels; and (ii) assess the effect of Mn injection time and gradual clearance of Mn-SOD, GS and Mn in vivo; (2) Evaluation of MnDPDP for MEMRI in mild H-I model: The purpose is to experimentally evaluate MnDPDP, a clinically approved chelated Mn2+ contrast agent for liver MRI, for detection of Mn-SOD or/and GS activities in noncystic PVL model and assessme nt of any apparent toxicity.

Project Title:	Neuroimaging of Spontaneous Brain Activities in Anaesthetized Rodents
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	Small Project Funding
Start Date:	11/2008

Abstract:

In this study, electrophysiologicalrecordings and resting-state fMRI measurements will be conducted in anesthetized rats upon different isoflurane gas concentra tions at various ages. The blood oxygenation level-dependent signal fluctuations will be correlated with the EEG power variations of delta, theta, alpha, beta, and gamma rhythms to investigate the relationship between hemodynamic and electrical oscillations.

Project Title:	Diffusion Kurtosis Imaging For Improved Neural Tissue Characterization By Magnetic Resonance
Investigator(s):	Wu EX, Khong PL, Wu W
Department:	Electrical & Electronic Engg
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	09/2009

Abstract:

1) Implement and optimize our DKI method on a 7T rodent MRI scanner with a twice-refocused spin-echo sequence to minimize eddy current distortions, and to compute a complete set of DKI index maps using our directional kurtosis analysis protocol; 2) Evaluate our DKI method and analysis protocol by monitoring postnatal rodent brain development between postnatal day 0 and 360. Voxel-wise and ROI analysis will be performed to determine regional DKI index changes with time and to compare DKI with conventional DTI in detect ing subtle microstructural alterations; 3) Evaluate our DKI method and analysis protocol by monitoring rodent brain aging longitudinally from postnatal year 1 to 2.5 with similar procedures and objectives.

Project Title:	31st Annual International Conference of the IEEE Engineering in Medicine and Biology Society Gas-filled Microbubbles – A Novel Susceptibility Contrast Agent for Brain and Liver MRI
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	09/2009

Abstract:

N/A

Project Title:	In Vivo MRI of Endogenous Stem/Progenitor Cell Migration in Developing Brains
Investigator(s):	Wu EX
Department:	Electrical & Electronic Engg
Source(s) of Funding:	Small Project Funding
Start Date:	11/2009

Abstract:

The general objective of the present study is to employ the in situ cell labeling approach to characterize the migration of the endogenous NSPs from the SVZ in the postnatal developing rat brains in normal and HI-injured developing conditions. We further hypothesize that the NSP migrating patterns in normal and HI-injured developing brains will differ and can be detected by serial high-resolution in vivo MRI in addition to po stmortem immunohistochemical analysis. Such in vivo MRI analysis can improve our understanding of NSP behavior in the developing mammalian brains and its alterations during injuries. The specific aims are: 1. MRI Determination of Migrating NSPs, Migration Patterns and Histologica l Colocalization in the Normal Developing Brains; 2. MRI Determination of Migrating NSPs, Migrating Patterns and Histological Colocalization in the HI-Injured Developing Brains; 3. Evaluation of Alteration of Migrating Pathways in HI-Injured Brains in Response to Injury.

List of Research Outputs

Guo H. , Leung J.C.K. , Cheung J.S., Chan Y.Y. , Wu E.X. and Lai K.N. , Non-viral Smad7 gene delivery and attenuation of posto perative peritoneal adhesion in an experimental model, Br J Surg . 2009, 96(11): 1323-35.

Researcher : Wu H

List of Research Outputs

Mok T.M.Y. , Wu H. , Lo Y. and Lau W.C.S. , Serum IL-17 and IL-23 to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus, J Rheumatol . 2010, in press.

Mok T.M.Y. , Wu H. and Lo Y. , The relation of cytokines of IL-17/IL-23 axis to Th1/Th2 cytokines and disease activity in systemic lupus erythematosus, HKMJ . 2010, 16: p45 S75.

Wu H. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patien ts with systemic lupus erythematosus. , HKMJ . 2010, 16: p57 S98.

Wu H. , Lau W.C.S. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patients with systemic lupus erythematosus. , IJRD . 2010, 13: S680 p114.

Wu H. , Tse H.F. and Li G.R. , Effects of acacetin on kv1.5 channels and rat atrial repolarization potassium currents, 14th Research postgraduate symposium, HKU . 2009, 58.

Researcher : Wu H

List of Research Outputs

Mok T.M.Y. , Wu H. , Lo Y. and Lau W.C.S. , Serum IL-17 and IL-23 to Th1/Th2 cytokines and disea se activity in systemic lupus erythematosus, J Rheumatol . 2010, in press.

Mok T.M.Y. , Wu H. and Lo Y. , The relation of cytokines of IL-17/IL-23 axis to Th1/Th2 cytokines and disease activity in systemic lupus eryth ematosus, HKMJ . 2010, 16: p45 S75.

Wu H. , Chan W.K. and Mok T.M.Y. , 1, 25-dihydroxyvitamin D3 suppresses differentiation, maturation and activation of dendritic cells from patients with systemic lupus erythematosus. , HKMJ . 2010, 16: p57 S98.

Wu H. , Tse H.F. and Li G.R. , Effects of acacetin on kv1.5 channels and rat atrial repolarization potassium currents, 14th Research postgraduate symposium, HKU . 2009, 58.

Researcher : Wu W

List of Research Outputs

Wu W. , Lau C.P. , Tse H.F. and Li G.R. , Beta 1 subunit-dependent modulation of BK channel by membrane cholesterol, In: 15th Medical Research Conference, Department of Medicine, HKU, 15th Medical Research Conference . 2010, 16(1): 58.

Researcher : Wu X

List of Research Outputs

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Researcher : Xia HHX

Project Title:	Homeobox genes in gastric carcinogen esis: an in vivo and in vitro study
Investigator(s):	Xia HHX, Wong BCY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	01/2003

Abstract:

To investigate the expression of gastric-related homeobox genes in human normal, precancerous and cancerous gastric tissues in vivo, and in non-malignant and malignant gastric cancer cell lines in vitro; to determine the effect of gastric-related homeobox genes on the secretion of gastric endocrine hormones.

Project Title:	Role of cyclooxygenase in helicobacter pylori-induced gastric carcinogenesis
Investigator(s):	Xia HHX, Wong BCY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2004

Abstract:

To reveal the precise mechanism of COX and interrelationship between COX and H. pylori infection in the pathogenesis of gastric cancer; to provide insights into whether specific targets can be dealth with by new drugs, or a combination of drugs on different cellular targets to potentiate the chemoprevention effects; to develop effective strategies in the prevention of gastric cancer, for which no active agent or drug is available at present.

Project Title:	Role of macrophage migration inhibi tory factor in Helicobacter pylori-induced gastric carcinogenesis
Investigator(s):	Xia HHX, Wong BCY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	05/2005

Abstract:

To determine the effect of MIF deficiency on H. pylori-induced inflammation and expression of inflammato ry cytokines, cell proliferation and apoptosis and expression of related genes; to determine the difference in the incidence of gastric precancerous and cancerous lesions between MIF-knockout mice and wild-type mice after long-term infection with H. pylori.

List of Research Outputs

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Researcher : Xiao J

List of Research Outputs

Xiao J. , Leung J.C.K. , Chan Y.Y. , Tang S.C.W. and Lai K.N. , Crosstalk between peroxisome proliferator-activated receptor-gamma and angiotensin II in renal tubular epithelial cells in IgA nephropathy, Clinical Immunology . 2009, 132: 266-276.

Researcher : Xiao S

List of Research Outputs

Cheung C.L. , Xiao S. , Gao Y. and Kung A.W.C. , Genetic Epidemiology of Osteoporosis and Its Application, 骨質疏鬆症的遺傳流行病學及其臨床應用, Chinese Journal of Osteoporosis and Bone Mineral Research . 2010, 3: 73-86.

Kung A.W.C. , Xiao S. , Cherny S.S. , Li H.Y. , Gao Y. , Tso G., Lau K. , Luk K.D.K. , Liu J.M., Cui B., Zhang M.J., Zhang Z.L., He J.W., Yue H., Xia W.B., Luo L.M., He S.L., Kiel D.P., Karasik D., Hsu Y.H., Cupples L.A., Demissie S., Styrkarsdottir U., Halldorsson B.V., Sigurdsson G., Thorsteinsdottir U., Stefansson K., Richards B., Zhai G., Soranzo N., Valdes A., Spector T.D. and Sham P.C. , Association of JAG1 with Bone Mineral Density and Osteoporotic Fractures: A Genome-wide Association Study and Follow-up Replication Studies, American Journal of Human Genetics . 2010, 86 (2): 229-239.

Xiao S. , Sham P.C. and Kung A.W.C. , Periostin Gene is Associated with BMD Variation and Risk of Vertebral Fracture, The 31st Annual Meeting of the American Society for Bone and Mineral Research, Denver, Colorado, USA . 2009.

Researcher : Xiong J

Project Title:	2008 NCRI Cancer Conference Growth inhibitory effect of 5-aza-2'-deoxycytidine on cancer cells is independent of p16 ink4a and p14ARF
Investigator(s):	Xiong J
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	10/2008

Abstract:

N/A

Researcher : Xu A

Project Title:	The use of adiponectin as a biomarker to identify novel anti-diabetic and anti-atherogenic agents from Chinese herbs
Investigator(s):	Xu A, Qin GW, Lam KSL
Department:	Medicine
Source(s) of Funding:	NSFC/RGC Joint Research Scheme
Start Date:	01/2006

Abstract:

To determine and optimize the chemical structures for the three bioactive compounds isolated from Rhizoma Dioscoreae and Radix Astragali; to study the molecular mechanisms by which the three bioactive compounds in duce adiponectin production from fat cells; to explore the therapeutic potentials of the three bioactive compounds in the treatment of T2DM, endothelial dysfunction, atherosclerosis and other obesity-related metabolic disorders in several well-established animal models.

Project Title:	Hypoxia inducible factor 1α as a mediator of obesity-induced chronic inflammatio n, aberrant production of adipokines, and insulin resistance
Investigator(s):	Xu A, Lam KSL, Chung SK
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2007
Completion Date:	12/2009

Abstract:

To generate the transgenic mice with adipose tissue specific over-expression of the dominant negative form of HIF 1α to investigate the role of HIF 1α in obesity-induced macrophage infiltration and aberrant production of adipokines in adipose tissue, systemic inflammation and insulin resistance in the transgenic mouse models; to evaluate whether berberine, a compound with potent HIF 1α inhibitor activity, has therapeutic effects on obesity-associated chronic inflammation, insulin resistance and other metabolic abnormalities in mice.

Project Title:	Molecular mechanism underlaying the pathogenesis of type 2 diabetes
Investigator(s):	Xu A
Department:	Medicine
Source(s) of Funding:	Matching Fund for National Key Basic Research Development Scheme (973 Projects)
Start Date:	05/2007

Abstract:

To study molecular mechanism underlaying the pathogenesis of type 2 diabetes.

Project Title:	APPL1 as a novel modulator of endothelial nitric oxide production and endothelium-dependent vasodi lation
Investigator(s):	Xu A, Chung SK, Wang Y
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2008

Abstract:

To further define the role of APPL1 in the AMPK/eNOS signaling pathway, and to study the structural basis that underlies APPL1 actions; to characterize the phosphorylation sites of APPL1 and to investigate the role of phosphorylation in APPL1-mediated activation of AMPK/eNOS signaling cascade in endothelial cells; to test whether transgenic overexpression of APPL1 alleviates endothelial dysfunction associated with obese and diabetic mice.

Project Title:	Vascular dysfunction in obesity and diabetes: from risk prediction to therapeutic interv ention
Investigator(s):	Xu A, Lam KSL, Vanhoutte PMGR, Tse HF, Wong KB, Wang Y
Department:	Medicine
Source(s) of Funding:	Collaborative Research Fund (CRF) - Group Researc h Project
Start Date:	06/2008

Abstract:

To establish an integrated platform for in vivo and ex vivo evaluation of metabolic and vascular functions in transgenic rodent models; to examine in depth the roles of different oligomeric forms of adiponectin in preventing vascular diseases associated with obesity and diabetes, and to elucidate the receptor and postreceptor signaling pathways underlying the vasculo-protective properties of adiponectin; to investigate whether or not lipocalin-2 and A-FABP play an etiological role in the pathogenesis of vascular dysfunctions associated with obesity and diabetes, and to test the effects of the selective inhibitor of A-FABP in treating these diseases in mice; to evaluate the prospective and cross-sectional association of adiponectin, A-FABP and lipocalin-2, and their interactions, with the development of inflammat ion and vascular diseases in Chinese population.

Project Title:	Adipocyte fatty acid binding protein as a novel diagnostic marker and therapeutic target to combat vascular complications of diabetes: mechanisms and clinical implications
Investigator(s):	Xu A, Vanhoutte PMGR, Lam KSL
Department:	Medicine
Source(s) of Funding:	NSFC/RGC Joint Research Scheme
Start Date:	01/2009

Abstract:

To use A-FABP knockout mouse model to elucidate the pathological role of A-FABP in the development of endothelial dysfunction associated with diabetes; to investigate whether or not the selective chemical inhibitor of A-FABP can be used the treatment of vascular dysfunction in diabetic animal models; to study the detailed molecular mechanisms whereby A-FABP induces vascular inflammation and endothelial dysfunction; to conduct a joint clinical investigation to evaluate whether or not elevated serum A-FABP is causally associated.

Project Title:	Protective roles of AMP-activated protein kinase against vascular disease in diabetes: Molecular mechanisms and therapeutic intervention
Investigator(s):	Xu A, Vanhoutte PMGR
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To use both in vivo and ex vivo approaches to study the physiological roles of AMPK in modulating the number and functionality of endothelial progenitor cells (EPCs), and to elucidate the molecular mechanism underlying AMPK actions in EPCs; (2) To investigate whether endothelium-specific activation of AMPK can alleviate diabetes-induced impairment in reendothelialization following carotid arterial injury; (3) To evaluate whether the selective activation of AMPK in endothel ial cells is sufficient to reverse the impaired vasodilatation and augmented vasoconstriction in diabetic animal models.

Project Title:	Roles of APPL1 and APPL2 in insuli n-mediated inhibition of hepatic glucose production: the serine/theonine kinase Akt as a common downstream target
Investigator(s):	Xu A, Xia F, Wang Y
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2009
Completion Date:	05/2010

Abstract:

The liver is the primary organ responsible for endogenous glucose production, which is tightly controlled by various metabolic and nutritional factors. In the fasted state, hepatic glucose production is enhanced by glucagon to maintain euglycemia, thus ensuring that glucose-dependent tissues such as the brain have access to an energy supply. When blood glucose levels are elevated after nutrient ingestion, hepatic glucose production is suppressed by insulin. The inhibitory effect of insulin on hepatic glucose production is mediated by activation of Akt (also known as protein kinase B). Akt reduces the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) by suppressing the activity of FOXO1, a member of the forkhead family of transcription factors. In the absence of insulin, FOXO1 is localized in the nucleus where it transactivates the two glucon eogenic genes. Upon insulin stimulation, activated Akt phosphorylates FOXO1 at three conserved sites, inducing FOXO1 translocati on to the cytoplasm and thereby reducing its transcriptional activity. In addition, activated Akt also inhibits the gluconeogenic program through a phosphorylation-dependent inhibition of the peroxisome proliferator-activated receptor-γ coactivator 1 α (PGC-1α) and TORC2, both of which act in concert with FOXO1 in transactivating the gluconeogenic genes (Dentin et al., 2007; Li et al., 2007; Puigserver et al., 2003). Hepatic insulin resistance, which leads to excessive hepatic glucose production, is the major contributor to fasting hyperglycemia in patients with type 2 diabetes mellitus (T2DM) (Biddinger and Kahn, 2006; Magnusson et al., 1992). The central role of excessive hepatic glucose production in the pathogenesis of T2DM is underscored by the fact that current antidiabetic drugs such as metformin decrease blood glucose levels through inhibiting hepatic gluconeogenesis. Therefore, identification of novel molecules involved in regulating the hepatic insulin signaling pathway leading to the inhibition of glucose production might provide potential new targets for novel therapeutic intervention in the treatment of T2DM, a major health burden worldwide. APPL1, an adaptor protein containing an NH2-terminal Bin/Amphiphiphysin/Rvs (BAR) domain, a central pleckstrin homology (PH) domain and a COOH-termina l phosphotyrosine binding (PTB) domain (Hosch et al., 2006), was originally identified as an interacting partner of Akt in a yeast two-hybrid assay using Akt2 as a bait (Mitsuuchi et al., 1999) (see Figure 1 in the attachment). Subsequent studies demonstrate that APPL1 binds to a number of cell surface receptors [TrkA(Lin et al., 2006; Varsano et al., 2006), DCC and adiponectin (Cheng et al., 2007; Mao et al., 2006), FSH) and intr acellular signaling molecules (small GTPase Rab5(Miaczynska et al., 2004) and inositol 5-phosphatase(Erdmann et al., 2007), suggesting that APPL1 may act as a common relay to coordinate diverse signaling cascades. Notably, we have recently found that the interaction of APPL1 with adiponectin receptors is essential in mediating its insulin-sensitizing actions of adiponectin in musc le (Mao et al., 2006) and endothelial cells (Cheng et al., 2007). A more recent study on zebrafish demonstrates that APPL1 not only plays an essential role in Akt activation, but also determines Akt substrate specificity (Schenck et al., 2008). In mammalian cells, APPL1 has also been implicated in Akt activation by several extrace llular stimuli including androgen and NGF-1 (Lin et al., 2006). Furthermore, APPL1 is required for insulin-stimulated translocation of GLUT4 from cytoplasm to plasma membrane and glucose uptake in adipocytes and myotubes (Saito et al., 2007). In primary rat hepatocytes, we showed that knockdown of APPL1 expression abolishes insulin-stimulated phosphorylation of Akt and its downstream targets, leading to impaired actions of insulin on inhibition of glucose production. Conversely, adenovirus-mediated APPL1 overexpression in liver reverses hyperglycemia, hyperinsulinemia and insulin resistance in db/db obese mice with frank diabetes. This data collectively suggests that APPL1 might be a physiological regulator of insulin sensitivity by activating the Akt signaling pathway. However, the molecular mechanisms whereby APPL1 potentiates insulin-evoked PI3K/Akt signaling remain elusive. APPL2 is cloned as a close homolog of APPL1. It shares 54% identity, 72% similarity and the same domain organization with APPL1 (See Figure-1 in the attachment). APPL2 forms a heterodimer with APPL1 through its BAR domain, and may play a similar role with APPL1 in mediating EGF-induced cell proliferation (Miaczynska et al., 2004) and cell survival(Schenck et al., 2008). By contras t, a recent study shows that some signaling molecules only bind to APPL1 but not APPL2, suggesting that these two adaptor proteins may possess distinct roles (Erdmann et al., 2007). The functions of APPL2 in regulating insulin sensitivity have never been explored so far. The primary objective of this study is to further define the role of APPL1 and APPL2 in modulating insulin sensitivity and hepatic glucose production, and to elucidate the detailed mechanisms involved in the actions of APPL1 and APPL2. Our specific objectives are: 1. To study in detail the structural basis and molecular pathways whereby APPL1 potentiates insulin-evoked Akt activation and inhibition of glucose production in rat primary hepatocytes. 2. To test our hypothesis that APPL1 activates Akt through competing with the endogenous inhibitor of Akt in primary hepatocytes, and to map the detailed domain of Akt involved in its interaction with APPL1. 3. To elucidate the role of APPL2, a close homolog of APPL1, in regulating hepatic insulin sensitivity and glucose metabolism in primary hepatocytes and various mouse models. Key references cited: Biddinger, S.B.et al (2006). Annu Rev Physiol 68, 123-158. Cheng, K.K., et al. (2007). Diabetes 56, 1387-1394. Dentin, R., et al. (2007). Nature 449, 366-369. Erdmann, K.S., et al. (2007). Dev Cell 13, 377-390. Hosch, S.E., et al (2006). Cell Metab 4, 5-6. Li, X., et al (2007). Nature 447, 1012-1016. Lin, D.C., et al (2006). Mol Cell Biol 25, 25. Magnusson, I.et al. J Clin Invest 90, 1323-1327. Mao, X., et al. (2006). Nat Cell Biol. 8, 516-523. Epub 2006 Apr 2016. Miaczynska, M. et al. (2004). Cell. 116, 445-456. Mitsuuchi, Y., et al (1999). Oncogene. 18, 4891-4898. Puigserver, P. et al. (2003). Nature 423, 550-555. Saito, T. et al. (2007). J Biol Chem 282, 32280-32287. Schenck, A., et al. (2008). Cell 133, 486-497. Varsano, T., et al. (2006). Mol Cell Biol 26, 8942-8952.

Project Title:	Characterization of Novel Adaptor Proteins Involved in Regulating Insulin Sensitivity and Glucose Homeostasis: from Molecular Mechanism to Physiological Implication
Investigator(s):	Xu A
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

Refer to hard copy

Project Title:	Characterization of the receptor and postreceptor signaling events underlying the met abolic actions of FGF21, a potential therapeutic agent for treating obesity-related medical complications
Investigator(s):	Xu A, Hoo RLC, Wang Y
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	06/2010

Abstract:

With the rapid rise in the prevalence of overweight and obesity, diabetes has now reached an epidemic level and become a major public health threat worldwide. The latest report of the World Health Organization (WHO) suggested that over 250 million people are curre ntly living with this disease. Without concerted actions to prevent diabetes, this figure will reach 380 million within a generation. In Hong Kong, the prevalence rate of diabetes exceeds 10% among adults, and is increasing rapidly in our ageing population. Diabetes is the primary risk factor for cardiovascular diseases (such as coronary artery disease and stroke), now the leading cause of death and disability among the elderly population. The current therapies for diabetes and its complications are suboptimal. Therefore, there is an urgent need to identify new therapeutic targets and to develop more effective therapies against diabetes and its complicatio ns. FGF21 is a secreted polypeptide with 210 amino acid residues that is expressed predominantly in the liver (Nishimura et al., 2000). It was first suggested as a metabolic regulator with potential antidiabetic properties during a high throughput screening for agents capabl e of increasing glucose uptake in 3T3-L1 adipocytes (Kharitonenkov et al., 2005). When administrated systemically to rodents and nonhuman primates with obesity and T2DM, recombina nt FGF21 causes a variety of beneficial metabolic effects, including body weight loss, sustained decrease of plasma glucose and triglyceride to nearly normal levels, and also alleviation of insulin resistance (Kharitonenkov et al., 2005; Kharitonenkov et al., 2007). In rodent models with both dietary and genetic obesity, recombina nt FGF21 has been shown to preserve beta-cell mass and functions (Wente et al., 2006), and to alleviate hepatosteatosis (Xu et al., 2009). Consistently, transgenic mice with overexpression of human or mouse FGF21 also exhibit significantly decreased levels of blood glucose, insuli n, triglyceride and cholesterol, and improved insulin sensitivity and glucose clearance, as well as smaller adipocyte size compared to their wild type controls (Kharitonenkov and Shanafelt, 2008; Kharitonenkov et al., 2005) (Inagaki et al., 2007). Transgenic mice expressing human FGF21 were also resistant to high fat diet-induced weight gain and fat accumulation despite an increase in food intake (Kharitonenkov et al., 2005). The beneficial metabolic effects of FGF21 on hyperglyce mia, hyperlipidemia and insulin resistance have also been observed in nonhuman primates with diabetes (Kharitonenkov et al., 2007). Noticeably, in nonhuman primates, recombinant FGF21 administration also leads to significant impro vements in lipoprotein profiles, including lowering of low-density lipoprotein (LDL), cholesterol and raising low-density lipoprotein (HDL) cholesterol, and beneficial changes in the circulating levels of several cardiovascular risk markers (Kharitonenkov et al., 2007). Several unique biological properties of FGF21 make it an attractive drug candidate for the treatment of insulin resistance and diabetes. Firstly, although FGF21 structurally belongs to the FGF superfamily, both in vitro and in vivo experiments demonstrate that FGF21 does not possess mitogenic activities (Kharitonenkov and Shanafelt, 2008; Ryden, 2009). FGF21 transgenic mice do not dev elop neoplasia, tumor or any other overt abnormalities throughout their lifespan. In fact, transgenic mice with liver-specific overexpression of FGF21 display a markedly delayed process of tumor initiation in liver as measured by the frequency of diethylnitrosamine-induced adenomas and hepatocellular carcinoma (Huang et al., 2006). Secondly, despite its potent effects on decreasing hyperglycemia, FGF21 does not cause hypoglycemia events in any of the studies published so far (Kharitonenkov et al., 2005; Kharitonenkov et al., 2007). Thirdly, FGF21 does not induce weight gain and edema, which is a big caveat with many currently used anti-diabetic drugs.(Kharitonenkov and Shanafelt, 2008; Ryden, 2009). In addition to its insulin sensitizing and glucose-l owering activities, FGF21 has recently been found to play a key role in mediating the body’s adaptive responses to fasting and was proposed as a primary factor initiating the production of ketone bodies (ketogenesis) in the liver (Moore, 2007; Reitman, 2007). FGF21 expression in the liver is under the control of perioxisome prolif erator-activated receptor  (PPAR), a transcription factor that is activated during starvation (Badman et al., 2007; Inagaki et al., 2007). In rodents fed ketogenic diets, upon overnight fasting, or treated with the PPAR agonist s, FGF21 mRNA expression in the liver is markedly elevated, but this effect is abrogated in PPAR-deficient diet. Elevated FGF21 causes adipose lipolysis, providing fatty acids to the liver for ketogenesis. FGF21 also induces torpor, a state characterized by physical inactivity and a low body temperature. Despite these promising findings, the receptor and postreceptor signaling events that underlie the metabolic actions of FGF21 remain poorly characterized. FGFs are known to mediate their actions via a set of FGF receptors that are expressed in multiple splice variants in (FGFR1-4). However, unlike classical FGFs that use heparin as a co-receptor, FGF21 does not possess heparin-binding properties (Ry den, 2009). In 3T3-L1 adipocytes, the metabolic actions of FGF21 have been shown to be dependent on β-klotho, a type I transmembrane protein that constitutively forms a complex with several members of FGFRs (Kharitonenkov and Shanafelt, 2008; Kurosu et al., 2007; Ogawa et al., 2007; Suzuki et al., 2008). FGF21 bind to the β-klotho- FGFR complexes through its NH2-terminus and COOH-terminus respectively, resulting in activation of the receptor complex. However, the specific subtypes of FGFRs involved and the downstream signaling pathways mediating the metabolic responses of FGF21 are yet to be established. Therefore, the current study is designed to identify the key targets of FGF21, and to investigate the molecular mechanisms underlying the metabolic actions of FGF21 in the liver. Our specific objectives are: 1. To investigate whether betaklotho is an essential receptor component mediating the hepatic actions of FGF21. 2. To determine the specific type of FGF receptors involved in the hepatic actions of FGF21. 3. To identify the proximal postrecptor signaling components involved in the hepatic actions of FGF21. 4. To elucidate the major metabolic pathways and target genes/proteins associated with acute or chronic FGF21 actions in the liver.

Project Title:	The 70th Scientific Sessions of American Diabetes Association Hypoxia Inducible Factor 1alpha Plays an Indispensible Role in the The rmogenic Functions of Brown Adipose Tissue in Mice
Investigator(s):	Xu A
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	06/2010
Completion Date:	06/2010

Abstract:

N/A

Project Title:	Pharmacological inhibition of adipocyte fatty acid binding protein as a new strategy for treating obesity-related cardio-metabolic disorders
Investigator(s):	Xu A, Vanhoutte PMGR, Lam KSL
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Applied Research
Start Date:	06/2010

Abstract:

Obesity and diabetes are known major risk factors for cardiovascular disease, including stroke, atherosclerotic heart disease, as well as diabetic nephropathy, neuro pathy and retinopathy. Chronic inflammation, characterized by elevated concentrations of inflammatory biomarkers, is a “common soil” for these closely related diseases. In obese subjects, free fatty acids and a large number of pro-inflammatory factors released from adipose tissue can directly exert their actions on the vasculature to induce insulin resistance, endothelial dysfunction and inflammation, ultimately leading to diabetes and atherosclerosis. Therefore, pharmacological intervention with the inflammatory pathways that link adipose tissues and the vascular system represent an attractive therapeutic strategy for the treatment and/or prevention of obesity-related insulin resistance, type II diabetes as well as vascular disease. Adipocyte fatty acid binding protein (A-FABP), a 15 kDa lipid-binding protein predominantly expressed in adipose tissue, has been identified as a key pro-inflammatory mediator that links obesity with diabetes and its vascul ar complications (Hotamisligil and Erbay, 2008). Although traditionally recognized as an intracellular protein, we have recently identified a circulating form of A-FABP in the human bloodstream (Xu et al., 2006). We found that plasma levels of A-FABP are markedly elevated in obesity and correlate positively with insulin resistance , several classical cardio-metabolic risk factors and atherosclerosis (Tso et al., 2007; Xu et al., 2007; Yeung et al., 2008; Yeung et al., 2007; Yeung et al., 2009). A prospective study in our local Chinese community in Hong Kong has shown that serum A-FABP predicts the development of diabetes and metabolic syndrome, independentl y of sex, age, adiposity and other classical risk factors (Tso et al., 2007; Xu et al., 2007). Furthermore, a reduced risk for hypertriglyceridemia, type 2 diabetes and coronary artery disease was found in subjects who carry a functional genetic variant of the A-FABP gene that results in reduced A-FABP gene expression. Consistent with these clinical and genetic observations, the targeted disruption of the A-FABP gene in mice protects against obesity-induced dyslipidemia, hyperglycemia and insulin resistance, and results in a remarkable reduction (~88%) of atherosclerotic plaque formation in a rodent model with spontaneous development of atherosclerosis(Makowski et al., 2001). Double ablation of A-FABP and E-FABP (another minor form of FABP in adipose tissue) renders almost a complete protection against the development of metabolic syndrome in both dietary and genetic obesity(Maeda et al., 2005). Most importantly, an orally active pharmacological inhibitor of A-FABP appears to be effective for the treatment and prevention of diabetes and atherosclerosis in experimental animals ((Furuhashi et al., 2007). These clinical and animal studies suggest that A-FABP may represent a viable therapeutic target for the treatment and prevention of obesity-related medical complications, including type II diabetes and cardiovascular disease. Indeed, there are a number of advantages in using A-FABP as a therapeutic target: Firstly, since the expressi on of A-FABP is mainly restricted to adipose tissue (adipocytes and macrophages), the chemical inhibitors of A-FABP might be highly selective and do not have adverse effects; Secondly, because changes in A-FABP activity occurs at the very early stage of obesity, its chemical inhib itors can be potentially used for prevention of obesity-related diabetes and cardiovascular disease. As our research group has made significant contribution in discovery of circulating form of A-FABP and in confirming the clinical relevance of A-FABP in the pathogenesis of metabolic syndrome, diabetes and atherosclerosis in humans, we have recently signed a strategic alliance with the Servier Pharmaceuticals in France and we were granted with 450,000 Euro$ (~5 million HKD) to validate whether A-FABP is a viable therapeutic target in animal models. In collaboration with Guangzhou Institute of Biomedicine & Health, Chinese Academy of Sciences, we have identified three lead compounds using computer simulation technology. Our in vitro studies in macrophage s found that two of the chemical compounds we have obtained are more potent in inhibition of lipid-induced inflammation than the commercially available compound BMS309403. The objective of this study is to establish an integrated platform for high throughput screening of A-FABP selective inhibitors and to test the therapeutic efficacy in animal models. The results obtained will be used to support the application of patents and external grants from ITF and other industrial sources. The specific objectives of this study are: 1) To establish a high throughput in vitro platform to test the specificity and bioactivity of A-FABP inhibitors; 2) To evaluate whether the three lead compounds are the selective inhibitors of A-FABP and to define the structural bas is underlying the inhibitory effects of these compounds on lipid binding properties of A-FABP; 3) To investigate whether the lead compounds can alleviate obesity-related metabolic and vascular disorders in rodent models. (NOTE that Key references are listed in section VI).

List of Research Outputs

Chan K.H. , Ho W.L. , Kwan S.C. , Xu A. , Ho S.L. , Ho W.M. and Lam K.S.L. , Amyloid Beta Neurotoxicity, Frontiers in Biomedical Research HKU 2009 . 2009.

Chen C. , Xu A. , Tso A.W.K. , Law S.C. , Cheung B.M.Y. , Janus E.D., Wat N.M.S. and Lam K.S.L. , Plasma level of pigment epithelium-derived factor is independently associated with the development of the metabolic syndrome in Chinese men: a 10-year prospective study., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Law S.C. , Sham P.C. and Lam K.S.L. , A genetic variant near the GNPDA2 gene is associated with the metabolic syndrome in Hong Kong Chinese., 5th International Symposium on Healthy Aging . 2010.

Cheung C.Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a Chinese population, J Clin Endocrinol Meta . 2010, 95: 1395-403.

Cheung Y.Y. , Tso A.W.K. , Cheung B.M.Y. , Xu A. , Ong K.L. , Fong H.Y. , Wat N.M.S. , Janus E.D., Sham P.C. and Lam K.S.L. , Obesity susceptibility genetic variants identified from recent genome-wide association studies: implications in a chinese population., J Clin Endocrinol Metab. . 1403, 2010, 95: 1395.

Gao Y., Zhou Y., Xu A. and Wu D. , Effects of an AMP-activated protein kinase inhibitor, compound C, on adipogenic differentiation of 3T3-L1 cells., Biol Pharm Bull. . 2009, 31: 1716-22.

Hoo R.L.C. , Wong Y.L. , Xu A. and Lam K.S.L. , Adipocyte fatty acid binding protein (AFABP) in kupffer cells as the novel player in the pathogenesis of non-alcoholic fatty liver disease, 14th Medical Research Conference, The University of Hong Kong . 2009.

Hui X. , Li H. , Zhou Z., Lam K.S.L. , Xiao Y., Wu D., Ding K., Wang Y. , Vanhoutte P.M.G.R . and Xu A. , Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1, J Biol Chem . 2010, 285(14): 10273-80.

Hui X. , Lam K.S.L. , Wang Y. , Xu A. , Li H. , Vanhoutte P.M.G.R . and Wu D. , Adipocyte fatty acid-binding protein modulates inflammatory responses in macrophages through a positive feedback loop involving c-Jun NH2-terminal kinases and activator protein-1., The Journal of Biological Chemistry . the United States, American Society for Biochemistry and Molecular Biology, 2010, 285: 10273.

Lam K.S.L. , Zhang X. and Xu A. , Selective Inactivation Of C-jun Nh2 Terminal Kinase (jnk) In Adipose Tissue Is Sufficient To Alleviate Metabolic Disorders Associated With Dietary Obesity In Mice , The 5th Scientific Meeting of the Asia-Pacific Diabetes and Obesity Study Group, Japan . 2009.

Lam K.S.L. , Zhang X. , Wong L.C. and Xu A. , Selective Inactivation of c-Jun NH2 Terminal Kinase (JNK) in the Adipose Tissue Is Sufficient To Protect Against Diet-Induced-Obesity and Its Associated Metabolic Disorders in Mice, Endocrine Society Annual Meeting, 19-22 June, San Diego, USA . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Inactivation Of Toll-like Receptor 4 Improves Reendotheli alisation In Apoe-deficient Mice – Impact Of Oxidative Stress On Endothelial Progenitor Cells, 15th Medical Research Conference, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Outstanding Abstract Prize, Fifth International Symposium On Healthy Aging: Is Aging A Disease?, Research Centre Of Heart, Brain, Hormone & Healthy Aging, University of Hong Kong . 2010.

Li F.Y.L. , Hoo R.L.C. , Lam K.S.L. and Xu A. , Toll-like Receptor 4 Inactivation Ameliorates Impaired Reendothelialisation Through The Improvement In Endothelial Progenitor Cell Adhesion, Fifth International Symposium on Healthy Aging: “Is Aging a Disease?” . 2010.

Li H. , Lam A.K.Y. , Xu A. , Lam K.S.L. and Chung S.K. , High dosage of Exendin-4 increased early insulin sec retion in differentiated beta cells from mouse embryonic stem cells, Acta Pharmacol Sin . 2010, 31(5): 570-7.

Li J. , Fung M.L. , Xu A. , Tsao G.S.W. and Leung W.K. , Lipopolysaccharide causes hypoxia-inducible factor 1-alpha accumulation in gingival fibroblasts, 39 ^th Annual Meeting of the American Association for Dental Research, Washington DC, 3/2010 .

Li M. , Ho J.C.Y. , Lai K.W.H. , Au K.W. , Xu A. , Cheung B.M.Y. , Lam K.S.L. and Tse H.F. , Hypoadiponectinemia and Its Impact on Circulating Endothelial Progenitor Cells in Patients with Type 2 Diabetes - Adiponectin and Endothelial Progenitor Cells (under revision), Diabetes/Metabolism Research and Reviews . 2010.

Man K. , Ng T.P. , Xu A. , Cheng Q. , Lo C.M. , Xiao J. , Sun B. , Lim Z.X.H. , Cheung J.S., Wu E.X. , Sun K.W. , Poon R.T.P. and Fan S.T. , Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of Rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling, Clinical Cancer Research . 2010, 16(3): 967-977.

Milner K.L., van der Poorten D., Trenell M., Jenkins A.B., Xu A. , Smythe J., Dore G.J., Zekry A., Weltman M., Fragomeli V., George J. and Chisholm D.J., Chronic Hepatitis C Is Associated With Peripheral Rather Than Hepatic Insulin Resistance., Gastroenterology . 2010, 49: 1926-34.

Ong K.L. , Li M. , Tso A.W.K. , Xu A. , Cherny S.S., Sham P.C. , Tse H.F. , Cheung B.M.Y. and Lam K.S.L. , Association of a genetic variant in the adiponectin gene with persistent hypertension in Hong Kong Chinese, 1st International Congress on Abdominal Obesity, Jan 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung R.Y., Xu A. , Cherny S.S., Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive Protein As A Predictor Of Hypertension In The Hong Kong Cardiovascular Risk Prevalence Study (crisps) Cohort, International Congress of Cardiology (ICC), Feb 2010, Hong Kong . 2010.

Ong K.L. , Tso A.W.K. , Leung Y.H. , Xu A. , Cherny S.S. , Sham P.C. , Lam K.S.L. and Cheung B.M.Y. , C-reactive protein as a predictor of hypertension in the Hong Kong cardiovascular risk prevalence study (CRISPS) cohort, Presented at the International Congress of Cardiology, Hong Kong, February 26-28, 2010 .

Richards A.A., Colgrave M.L., Zhang J. , Webster J., Simpson F., Preston E., Wilks D., Hoehn K.L., Stephenson M., Macdonald G.A., Prins J.B., Cooney G.J., Xu A. and Whitehead J.P., Sialic Acid Modification Of Adiponectin Is Not Required For Multimerization Or Secretion But Determines Half-life In Circulation., Molecular Endocrinology . Highwire press, 2010, 24: 229-39.

Wang Y. , Huang Y., Lam K.S.L. , Li Y., Wong W.T., Ye H., Lau C.W., Vanhoutte P.M.G.R. and Xu A. , Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-ac tivated protein kinase and endothelial nitric oxide synthase, Cardiovascular Research . 2009, 82: 484-492.

Xia F. , Lam K.S.L. , Zhang J. , Zhou P. and Xu A. , Serum Levels Of Fibroblast Growth Factor 21 Are Elevate d In Both Rodents And Humans In Response To Acute Fasting, Diabetes . 2010, 59 supplement: 1661-P.

Xu A. , A-fabp As A Key Mediator Between Obesity And Cardio-metabolic Syndrome: Mechanism And Clinical Implication, The Secnd Scientific Meeting Of The Asian Association For The Study Of Diabetes (aasd) . Asian Society of Diabetes, 2010.

Xu A. , Adipocyte fatty acid binding protein as a novel link between obesity and cardiovascular disease, The 12th Chinese Diabetes Society (CDS)Annual Confere nce , Xiamen, China . 2009.

Xu A. , Lipid Chaperones As A Novel Mediator Of Obesity-related Inflammation And Cardio-metabolic Disorders: Molecular Basis And Clinical Implication, The 5th Xiang-ya International Diabetes Immunology Symposium . Chinese Diabetes Association, 2010.

Xu A. , The protective effect of adiponectin against vascular complications of diabetes: Molecular basis and therapeut ic implication, 2010 Oriental Conference Of Endocrinology And Metabolism . Shanghai, 2010.

Zhang X. , Lam K.S.L. , Chung S.K. and Xu A. , Hypoxia Inducible Factor 1α Plays An Indispensible Role In Maintaining The Thermogenic Functions Of Brown Adipose Tissue In Mice, Endocrine Society Annual Meeting, 19-22 June, San Diego, USA . 2010.

Zhang X. , Lam K.S.L. , Chung S.K. and Xu A. , Hypoxia Inducible Factor 1 Plays an Indispensible Role in the Thermogenic Functions of Brown Adipose Tissue in Mice, Diabetes . 2010, 59 supplement 1: A47.

Zu Y. , Liu L. , Xu A. , Lam K.S.L. , Lee M.Y.K. , Vanhoutte P.M.G. R. and Wang Y. , SIRT1 promotes cell proliferation and prevents cellular senescence through targeting LKB1 in primary porcine aortic endothelial cells, 34th FEBS Congress, Czech Republic, July 2009 . 2009.

Researcher : Xu J

Project Title:	Search for susceptibility gene loci for maturity-onset diabetes of the young in Southern Chinese
Investigator(s):	Xu J, Lam KSL, Sham PC
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2004

Abstract:

To further study the extended MODYX families recruited from our previous project and screen for MODY loci in Southern Chinese, starting with MODY loci reported in other populations; to investigate whether there is overlap between MODY loci and reported T2DM loci in Chinese, based on studies with predilection of early onset T2DM diagnosed before 40 years of age.

Researcher : Yam IYL

List of Research Outputs

Chan K. , Yam I.Y.L. , Leung K.Y., Tang M., Chan T.K. and Chan V.N.Y. , Detection of paternal alleles in maternal plasma for non-invasive prenatal diagnosis of beta-thalassemia: a feasibility study in southern Chinese., Eur J Obstet Gynecol Reprod Biol . 2010, 150: 28-33.

Researcher : Yan G

List of Research Outputs

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchron y and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Submitted) . 2010.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Elevated Pulmonary Artery Systolic Pressure in Patien ts with Coronary Artery Disease and Left Ventricular Dyssynchrony , European Journal of Heart Failure . 2010, (in press).

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Relation of T-wave Alternans to Left Ventricular Dyssynchrony in Patients with Coronary Heart Disease, ESC Congress, 2010 .

Researcher : Yang Y

List of Research Outputs

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnostic and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Researcher : Yau TCC

List of Research Outputs

Pang R.W.C. , Law W.L. , Chu A.C.Y. , Poon J.T.C. , Lam S.C. , Chow K.M. , Ng L. , Cheung W.H. , Lan X.R. , Lan H.Y. , Tan V.P.Y. , Yau T.C.C. , Poon R.T.P. and Wong B.C.Y. , A Subpopulation of CD26+ Cancer Stem Cells with Metastati c Capacity in Human Colorectal Cancer, Cell Stem Cell . 2010, 6: 603-615.

Wong H., Yau T.C.C. , Chan P., Ng I.O.L. , Chan G.S.W. , Hui P., Law W.L. , Lo C.M. , Hedley A.J. and Epstein R. , PPI-delayed diagnosis of gastrinoma: oncologic victim of pharmacologic success, Pathology and Oncology Research . 2010, 16(1): 87-91.

Yau T.C.C. , Yao T.J. , Chan P., Epstein R. , Ng K.K.C. , Chok K.S.H. , Cheung T.T. , Fan S.T. and Poon R.T.P. , The outcomes of elderly patients with hepatocellular carcinoma treated with transarterial chemoembolization, Cancer . 2009, 115(23): 5507-5515.

Researcher : Ye D

List of Research Outputs

Cheung K.F. , Ye D. , Yang Z. , Lu L. , Liu C.H., Wang X.L., Poon R.T.P. , Tong Y. , Liu P., Chen Y. and Lau G. , Therapeutic efficacy of Traditional Chinese Medicine 319 recipe on hepatic fibrosis induced by carbon tetrachlori de in rats, Journal of Ethnopharmacology . 2009, 124(1): 142-150.

Researcher : Yee YK

List of Research Outputs

Yee Y.K. , Wong K.W. , Hui C.K. , Chan C.K. , Chan A.O.O. , Lam S.K. , Fung F.M.Y. , Hung I.F.N. and Wong B.C.Y. , Prevalence and time trend of intestinal metaplasia in Hong Kong, J Gastorenterol Hepatol . 2009, 24: 896-9.

Researcher : Yeung CK

List of Research Outputs

Au W.Y. and Yeung C.K. , Acute promyelocytic leukemia in patients with severe psoriasis vulgaris, Leukemia Research . 2009, 33(11): e189-e190.

Gill H., Trendell-Smith N.J. , Loong F. , Yeung C.K. and Kwong Y.L. , Paraneoplastic pemphigus due to CD8-positive cytotoxic T-cell lymphoma, British Journal of Haematology . 2010, 149(4): 464.

Gill H., Leung A.Y.H. , Trendell-Smith N.J. , Yeung C.K. and Liang R.H.S. , Sweet Syndrome due to Myelodysplastic Syndrome: Possible Therapeutic Role of Intravenous Immunoglobulin in Addition to Standard Treatment, Advances in Hematology . 2010, 2010:328316: Epub.

Yeung C.K. , Trendell-Smith N.J. , Mak H.K.F. , Lam C.C.K. and Kwong Y.L. , ‘Western’ or ‘Asian’ intravascular large B-cell lymphoma?, Clinical and Experimental Dermatology . 2009, 34(7): e482–e483.

Researcher : Yeung JSL

List of Research Outputs

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Foxp3 mRNA expression on DC subsets in patients of systemic lupus erythematosus. , IJRD . 2010, 13: S557 p55.

Jin O. , Kavikondala S. , Mok T.M.Y. , Sun L.Y., Gu J.R., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Studies on the function of plasmacytoid dendritic cells in healthy and systemic lupus erythematosus., IJRD . 2010, 13: S554p54.

Jin O. , Kavikondala S. , Mok T.M.Y. , Gu J.R., Sun L.Y., Fu R., Chan W.K. , Yeung J.S.L. , Nie Y. and Lau W.C.S. , Study on myeloid dendritic cells in systemic lupus erythematosus, IJRD . 2010, 13: S793 p56.

Researcher : Yeung SC

List of Research Outputs

Bow C.H.Y. , Tsang S.W.Y., Soong S.S. , Yeung S.C. and Kung A.W.C. , BMD Enhances Clinical Risk Factors in Predicting Ten-Year Risk of Osteoporotic Fractures in Chinese Men: The Hong Kong Osteoporosis Study, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Bow C.H.Y. , Cheung C.L. , Gao Y. , Lau K.S. , Soong S.S. , Yeung S.C. and Kung A.W.C. , Bone Mineral Density and Serum Osteoprotegerin Levels in Pre- and Postmenopausal Women, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Chan K.H. , Ho S.P., Yeung S.C. , So H.L. , Cho C.H., Koo M.W.L. , Lam W.K. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Chinese Green Tea Ameliorates Lung Injury In Cigarette Smoke-exposed Rats, Respiratory Medicine . 2009, 103: 1746-1754.

Chan K.H. , Yeung S.C. , Ip M.S.M. , Man R.Y.K. and Mak J.C.W. , Effects of Chinese green tea on cigarette smoke-induced lung inflammation, oxidative stress and protease activity in rats, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A5062.

Chan K.H. , Yeung S.C. , Yao T.J. , Ip M.S.M. , Cheung A.H.K. , Chan M.M.W. and Mak J.C.W. , Elevated Plasma Adiponectin Levels In Patients With Chronic Obstructive Pulmonary Disease, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 10.

Chang R.C.C. , Yang X. , Ho Y.S. , Yeung S.C. and Mak J.C.W. , Alzheimer-like pathology in rat receiving passive smoking, Society for Neuroscience 2009 . Program No. 626.13: Poster No. H26.

Han Q. , Yeung S.C. , Ho S.P. , Ip M.S.M. and Mak J.C.W. , Differential Effects Of Intermittent Hypoxia And/or Cigarette Smoking On The Expression Levels Of Fatty Acid-binding Protein In Rat Heart And Lung: An In Vivo Pilot Study, Respirology . 2009, 14 (Suppl. 3): A171.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Effects Of Intermittent Hypoxia On A-/e-fabp Expression In Human Aortic Endothelial Cells, International Journal of Cardiology . 2010, Epub ahead of print.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification Of Serum Adiponectin And Cinc-1 Levels By Intermittent Hypoxia And/or Hyperlipidemia In Vivo, Hong Kong Medical Journal . 2010, 16 (Suppl. 1): 22.

Han Q. , Yeung S.C. , Ip M.S.M. and Mak J.C.W. , Modification of circulating and cardiac expressions of adiponectin and CINC-1 by intermittent hypoxia in vivo, American Journal of Respiratory and Critical Care Medicine . 2010, 181: A3702.

Loong C.H.N., Leung F., Lau T.W., Leung E., Chan Y.Y., Yee A., Ma L.F., Soong S.S. , Bow C.H.Y. , Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Predictive Factors for Re-fracture in Chinese Population with Previous Osteoporotic Fractures, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , A Secondary Fracture Prevention Programme to Reduce Fractures, Hospital Admissions, and Mortality, Hospital Authority Convention 2010, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Evaluation of the Osteoporosis Secondary Fracture Prevention Program at Queen Mary Hospital: Successful Recruitment is Associated with a Lower Re-fracture Rate and Mortalit y Rate at One Year, Hospital Authority Convention 2010, Hong Kong . 2010.

Researcher : Yeung SC

List of Research Outputs

Bow C.H.Y. , Tsang S.W.Y., Soong S.S. , Yeung S.C. and Kung A.W.C. , BMD Enhances Clinical Risk Factors in Predicting Ten-Y ear Risk of Osteoporotic Fractures in Chinese Men: The Hong Kong Osteoporosis Study, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Chang R.C.C. , Yang X. , Ho Y.S. , Yeung S.C. and Mak J.C.W. , Alzheimer-like pathology in rat receiving passive sm oking, Society for Neuroscience 2009 . Program No. 626.13: Poster No. H26.

Loong C.H.N., Leung F., Lau T.W., Leung E., Chan Y.Y ., Yee A., Ma L.F., Soong S.S. , Bow C.H.Y. , Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Predictive Factors for Re-fracture in Chinese Population with Previous Osteoporotic Fractures, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Loong H.N.C., Chan Y.Y., Lau T.W., Leung F., Bow C.H.Y. , Soong S.S. , Ma L.F., Leung E., Yee A., Yeung S.C. , Luk K.D.K. and Kung A.W.C. , Evaluation of the Osteoporosis Secondary Fracture Prevention Program at Queen Mary Hospital: Successful Recruitment is Associated with a Lower Re-fracture Rate and Mortality Rate at One Year, Hospital Authority Convention 2010, Hong Kong . 2010.

Researcher : Yik PY

List of Research Outputs

Cheng C.H. , Tam J.H. , Wong R., Yik P.Y. , Song Y.Q., Morley J.E. and Lam K.S.L. , Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men: a 1-year cohort study., 15th Medical Research Conference, HKU. Hong Kong Medical Journal. . 2010, 16: 16.

Researcher : Yiu CW

List of Research Outputs

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , "Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival" - Young Invest igator Award for the Oral Category, Fifth International Symposium on Healthy Aging: Is Aging a Disease? The Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong, 6-7 March 2010. . 2010.

Ho W.L. , Ho W.M. , Liu H. , Yiu C.W. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Emerging role of mitochondrial uncoupling protein-4 in neuronal differentiation and survival, Fifth International Symposium on Healthy Aging: Is Aging a Disease? Research Centre of Heart, Brain, Hormone & Healthy Aging, The University of Hong Kong. (6-7 March 2010) . 2010, 46.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Kwok H.H. , Ho W.L. , Chu A.C.Y. , Ho W.M. , Liu H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Mitochondrial UCP5 is neuroprotective by preserving mitochondrial membrane potential, ATP levels, and reducing oxidative stress in MPP+ and dopamine toxicity., Free Radical Biology and Medicine . 2010, 49(6): 1023-1035.

Researcher : Yiu KH

List of Research Outputs

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W. , Tam S. , Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerate s worsening carotid atherosclerosis in patients with ischemic stroke (abstract and poster presentation), EuroPRevent 2010, Prague, 5-7 May 2010 . Prague, European Society of Cardiology.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Li S.W., Tam S., Lam T.H. , Lau C.P. and Tse H.F. , Heightened systemic oxidative stress critically accelerates worsening carotid atherosclerosis in patients with ischemic stroke, EuroPrevent 2010. European Journal of Cardiovascular Prevention and Rehabilitation 2010 Jun P480 . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W., Lam T.H. and Tse H.F. , Selenium Deficiency is Associated with Adverse Vascular Function in Patients with High Risk for Vascular Events, EuroPrevent 2010. European Journal of Cardiovascular Prevention and Rehabilitation 2010 Jun P334 . 2010.

Chan Y.H. , Siu D.C.W. , Yiu K.H. , Chan H.T., Li S.W. , Lau C.P. , Lam T.H. and Tse H.F. , Selenium deficiency is associated with adverse vascular function in patients with high risk for vascular events (abstract and poster presentation), EuroPRevent 2010, 5-7 May 2010, Prague . Prague, European Society of Cardiology, 2010.

Luk T.H. , Dai Y.L.E. , Siu D.C.W. , Yiu K.H. , Chan H.T. , Fong D.Y.T. , Lee S.W.L. , Tam S., Lau C.P. and Tse H.F. , Habitual physical activity is associated with endothelial function and endothelial progenitor cells in patients with stable coronary artery disease, European Journal of Cardiovascular Prevention & Rehabilitation . 2009, 16: 464-471.

Researcher : Yiu YF

List of Research Outputs

Yiu K.H., Siu D.C.W. , Yiu Y.F. and Tse H.F. , Electrocardiogram, In: Lip GY, Tse HF, Coats , Oxford Desk Reference . Oxford University Press, 2010.

Yiu Y.F. , Yiu K.H. and Tse H.F. , Inappropriate sinus tachcyardia. In Lip GY, Tse HF, Coats (eds): Oxford Desk Reference. Oxford: , Oxford University Press (in press). . 2010.

Researcher : Yue W

List of Research Outputs

Siu D.C.W. , Pong V., Jim M.H., Yue W. , Ho H.H., Li L.S.W. , Lau C.P. and Tse H.F. , Beta-blocker in post-myocardial infarct survivors with preserved left ventricular systolic function, Pacing and Clinical Electrophysiology . 2010, 33(6): 675-80.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchrony and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Wang M.M. , Siu D.C.W. , Lee K.L.F. , Yue W. , Yan G. , Lee S.W.L. , Lau C.P. and Tse H.F. , Effects of Right Low Atrial Septal versus Right Atrial Appendage Pacing on Atrial Mechanical Function and Dyssynchrony in Patients with Sinus Node Dysfunction and Paroxysmal Atrial Fibrillation , Journal of Cardiovascular Electrophysiology (Submit ted) . 2010.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Elevated Pulmonary Artery Systolic Pressure in Patients with Coronary Artery Disease and Left Ventricular Dyssy nchrony , European Journal of Heart Failure . 2010, (in press).

Yan G. , Wang M.M. , Yue W. , Siu D.C.W. , Chan H.T. , Dai Y.L.E. , Luk T.H. , Lau C.P. and Tse H.F. , Left Ventricular Systolic Dyssynchrony Is Associated With Pulmonary Arterial Hypertension In Patients With Coronary Artery Disease , ESC Congress . 2009.

Yan G. , Wang M.M. , Yue W. , Yiu K.H., Siu D.C.W. , Lee S.W.L. , Lau C.P. and Tse H.F. , Relation of T-wave Alternans to Left Ventricular Dyssynchrony in Patients with Coronary Heart Disease, ESC Congress, 2010 .

Researcher : Yuen JCH

List of Research Outputs

Fung J.Y.Y. , Seto W.K., Lai C.L. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , Profiles of HBV DNA in a large population of chinese chronic hepatitis B patients: implications for antiviral therapy. , Hepatol Int . The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010., 2010, 4: 53-4.

Fung J.Y.Y. , Lai C.L. , Yuen J.C.H. , Cheng C.T.K. , Wu C.H. and Yuen R.M.F. , Sequential therapy using lamivudine in entecavir-treated patients with undetectable HBV DNA – results at 48 weeks. , Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 510A.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , A three-year study on viral suppression and resistance profile for treatment-naive chronic hepatitis B patients receiving continuous entecavir treatment. , Hepatol Int. The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beiji ng, China 25-28 March 2010 . 4: 58.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , HBV DNA levels predict significant liver histology for HBeAg-negative chronic hepatitis B patients., Gastroenterology. Digestive Disease Week, New Orl eans, May 2010 . 138 (5 Supp1): S-788.

Yuen R.M.F. , Fung J.Y.Y. , Seto W.K., Wong D.K.H. , Yuen J.C.H. and Lai C.L. , Combination of baseline parameters and on-treatment hepatitis B virus DNA levels to start and continue patients with lamivudine therapy. , Antivir Ther . 2009, 14(5): 679-85.

Researcher : Yuen MF

Project Title:	An open label study of adefovir dipivoxil for the treatment of patients with chronic hepatitis B (CHB) related advanced fibrosis or cirrhosi s
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	Glaxo Wellcome Hong Kong Ltd. - General Award
Start Date:	07/2005

Abstract:

To examine the long-term effect of adefovir dipivoxil with respect to the liver histology.

Project Title:	Randomized, open-label, comparat ive study to evaluate early viral load reductions and exploratory viral kinetics following administration of entecavir or adefovir in nucleoside-naïve adults with chronic hepatitis B infection
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	Bristol-Myers-Squibb (HK) - General Award
Start Date:	01/2006

Abstract:

To compare the viral load reduction between patients receiving entecavir and adefovir.

Project Title:	A phase I, multi-centre, randomised, placebo-controlled, dose escalation study to assess the local and systemic tolerability of the therapeutic DNA plasmid pdpSC18 vaccine administered by particle mediated epidermal delivery using the powderject ND 10 delivery system in subjects with chronic hepatitis B infection
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	PowderMed Ltd - General Award
Start Date:	11/2006

Abstract:

To study the safety and efficacy of the HBV DNA vaccine in chronic hepatitis B patients.

Project Title:	Significance of HBV DNA in the natural history of chronic hepatitis B: impact on disease outcome including significant fibrosis and hepatocellular carcinoma
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	Bristol-Myers-Squibb (HK) - General Award
Start Date:	09/2007

Abstract:

To study the relationship between the HBV DNA levels and the development of fibrosis and hepatocellular carcinoma in chronic hepatitis B patients.

Project Title:	Transmissibility of hepatitis B virus infection from blood donors with occult hepatitis B infection
Investigator(s):	Yuen RMF, Lai CL, Wong DKH, Yao TJ
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	12/2008

Abstract:

(1) To determine the transmissibility of HBV from donated blood of subjects with occult HBV in general; (2) To determine whether the transmissible rates are different in recipients with different status of body immunity; (3) To determine the virological and liver histological status of blood donors with occult HBV infection; (4) To determine the viraemic level and liver function for recipients who acquired the HBV from the blood of donors with occult HBV.

Project Title:	Virological and clinico-pathological factors in estimating the chance of recurrence of hepatocellular carcinoma after surgical resection in patients with Chronic Hepatitis B
Investigator(s):	Yuen RMF, Hung IFN, Poon RTP, Fong DYT, Wong DKH, Lai CL
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	01/2010

Abstract:

To predict the chance of recurrence of the HCC after resection; to determine the screening strategy for patients after resection; to reduce the chance of recurrence by correcting the risk factors possible.

Project Title:	Genetic and epigenetic analyses of occult hepatitis B virus infection
Investigator(s):	Yuen RMF, Fung JYY, Lai CL, Wong DKH, Yao TJ
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To identify any variation in the HBV DNA sequence in both the coding and regulatory regions that is un ique to patients with occult HBV by comparison with patients with overt HBV; 2) To study, in vitro, the HBV promoter activities of specific regulatory sequences identified in objective 1) in patients with overt and occult HBV.

List of Research Outputs

Researcher : Yuen RMF

Project Title:	An open label study of adefovir dipivoxil for the treatment of patients with chronic hepatitis B (CHB) related advanced fibrosis or cirrhosis
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	Glaxo Wellcome Hong Kong Ltd. - General Award
Start Date:	07/2005

Abstract:

To examine the long-term effect of adefovir dipivoxil with respect to the liver histology.

Project Title:	Randomized, open-label, comparative study to evaluate early viral load reductions and explorat ory viral kinetics following administration of entecavir or adefovir in nucleoside-naïve adults with chronic hepatitis B infection
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	Bristol-Myers-Squibb (HK) - General Award
Start Date:	01/2006

Abstract:

To compare the viral load reduction between patients receiving entecavir and adefovir.

Project Title:	A phase I, multi-centre, randomised, placebo-controlled, dose escalation study to assess the local and systemic tolerability of the therapeutic DNA plasmid pdpSC18 vaccine administered by particle mediated epidermal delivery using the powderject ND 10 delivery system in subjects with chronic hepatitis B infection
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	PowderMed Ltd - General Award
Start Date:	11/2006

Abstract:

To study the safety and efficacy of the HBV DNA vaccine in chronic hepatitis B patients.

Project Title:	Significance of HBV DNA in the natural history of chronic hepatitis B: impact on disease outcome including significant fibrosis and hepatocellular carcinoma
Investigator(s):	Yuen RMF
Department:	Medicine
Source(s) of Funding:	Bristol-Myers-Squibb (HK) - General Award
Start Date:	09/2007

Abstract:

To study the relationship between the HBV DNA leve ls and the development of fibrosis and hepatocellular carcinoma in chronic hepatitis B patients.

Project Title:	Transmissibility of hepatitis B virus infection from blood donors with occult hepatitis B infection
Investigator(s):	Yuen RMF, Lai CL, Wong DKH, Yao TJ
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	12/2008

Abstract:

Project Title:	Virological and clinico-pathological factors in estimating the chance of recurrence of hepatocellul ar carcinoma after surgical resection in patients with Chronic Hepatitis B
Investigator(s):	Yuen RMF, Hung IFN, Poon RTP, Fong DYT, Wong DKH, Lai CL
Department:	Medicine
Source(s) of Funding:	Research Fund for the Control of Infectious Diseases - Full Grants
Start Date:	01/2010

Abstract:

Project Title:	Genetic and epigenetic analyses of occult hepatitis B virus infection
Investigator(s):	Yuen RMF, Fung JYY, Lai CL, Wong DKH, Yao TJ
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) To identify any variation in the HBV DNA sequence in both the coding and regulatory regions that is unique to patients with occult HBV by comparison with patients with overt HBV; 2) To study, in vitro, the HBV promo ter activities of specific regulatory sequences identified in objective 1) in patients with overt and occult HBV.

List of Research Outputs

Ahn S.H., Kweon Y.O., Paik S.W., Sohn J.H., Lee K.S., Kim D.J., Piratvisuth T., Yuen R.M.F. , Trylesinski A. and Avila C., Telbivudine combination with adefovir versus adefovir monotherapy in HBeAg-positive chronic hepatitis B (CHB) patients with lamivudine resistance. , Hepatol Int. The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010. . 2010, 4: 143.

Farrell G.C., Chan H.L., Yuen R.M.F. , Amarapurkar D.N., Chutaputti A., Fan J.G., Hou J.L., Han K.H., Kao J.H., Lim S.G., Mohamed R., Sollano J. and Ueno Y., (Asia-Pacific Working Party on Prevention of Hepatocellular Carcinoma). Prevention of hepatocellular carcinoma in the Asia-Pacific region: consensus statements., J Gastroenterol Hepatol . 2010, 25(4): 657-63.

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Correlation of liver stiffness and histological features in healthy persons and in patients with occult hepat itis B, chronic active hepatitis B, or hepatitis B cirrhosis., Am J Gastroenterol . 2009, 105(5): 1116-22.

Fung J.Y.Y. , Lai C.L. and Yuen R.M.F. , Hepatitis B and C virus-related carcinogenesis., Clin Microbiol Infect . 2009, 15(11): 964-70.

Fung J.Y.Y. , Lai C.L. and Yuen R.M.F. , Hepatitis B virus DNA and hepatitis B surface antigen levels in chronic hepatitis B., Expert Rev Anti Infect Ther . 2010, 8(6): 717-26.

Fung J.Y.Y. , Lai C.L. , Chan S.C. , But D., Seto W.K., Cheng C.T.K. , Wong D.K.H. , Lo C.M. , Fan S.T. and Yuen R.M.F. , Liver stiffness and histological features in healthy persons, and patients with occult hepatitis B, chronic active hepatitis B, and hepatitis B-related cirrhosis., Hepatology . 2009, 50(4) Suppl: 978A.

Fung J.Y.Y. , Lai C.L. , Cheng C.T.K. , Wu C.H. , Wong D.K.H. and Yuen R.M.F. , Mild-to-moderate elevation of alanine aminotransferase may increase liver stiffness measurement by transient elastography in patients with chronic hepatitis B., Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 971A.

Fung J.Y.Y. , Seto W.K., Lai C.L. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , Profiles of HBV DNA in a large population of chinese chronic hepatitis B patients: implications for antiviral therapy. , Hepatol Int . The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010., 2010, 4: 53-4.

Fung J.Y.Y. , Lai C.L. , Yuen J.C.H. , Cheng C.T.K. , Wu C.H. and Yuen R.M.F. , Sequential therapy using lamivudine in entecavir-treated patients with undetectable HBV DNA – results at 48 weeks. , Hepatology. The 60th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) October 30 - November 3, 2009, Boston, USA. . 2009, 50(4 Suppl): 510A.

Lai C.L. and Yuen R.M.F. , Occult hepatitis B infection: Incidence, detection and clinical implications., ISBT Science Series (An affiliated publiction to Vox Sanguinis) . 2009, 4: 347-51.

Lai C.L. and Yuen R.M.F. , The saga of entecavir. , Hepatol Int . 2009, 3(3): 421-4.

Lam T.P. , Lam C.L.K. , Lai C.L. , Yuen R.M.F. and Fong D.Y.T. , Psychometrics of the chronic liver disease questionnaire for Southern Chinese patients with chronic hepatitis B virus infection, World Journal of Gastroenterology . 2009, 15: 3288-97.

Lam T.P. , Lam C.L.K. , Lai C.L. , Fong D.Y.T. , So T.M.K. and Yuen R.M.F. , The Effect of Health-related Quality of Life on Health Service utilization and Willingness to Pay for Treatment of Chinese with Chronic Hepatitis B Infection, Oral, 2009 International Society for Quality of Life Research Annual Meeting . New Orleans, USA, 2009.

Lim S.G., Mohammed R., Yuen R.M.F. and Kao J.H., Prevention of hepatocellular carcinoma in hepatitis B virus infection. . , J Gastroenterol Hepatol . 2009, 24(8): 1352-7.

Mukaide M., Tanaka Y., Shin-I T., Yuen R.M.F. , Kurbanov F., Yokosuka O., Sata M., Karino Y., Yamada G., Sakaguchi K., Orito E., Inoue M., Baqai S., Lai C.L. and Mizokami M., Mechanism of entecavir resistance of hepatitis B virus with viral breakthrough as determined by long-term clinical assessment and molecular docking simulation. , Antimicrob Agents Chemother . 2009, 54(2): 882-9.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , A three-year study on viral suppression and resistance profile for treatment-naive chronic hepatitis B patients receiving continuous entecavir treatment. , Hepatol Int. The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010 . 4: 58.

Seto W.K., Lai C.L. , Fung J.Y.Y. , Yuen J.C.H. , Wong D.K.H. and Yuen R.M.F. , HBV DNA levels predict significant liver histology for HBeAg-negative chronic hepatitis B patients., Gastroenterology. Digestive Disease Week, New Orleans, May 2010 . 138 (5 Supp1): S-788.

Seto W.K., Mak C.M. , BUT D., Hung I.F.N. , Lam C.W. , Tam S., Yuen R.M.F. and Lai C.L. , Mutational analysis for Wilson's disease, Lancet . 2009, 374(9690): 662.

Xia H.H.X. , Yang Y. , Chu K.M. , Gu Q. , Zhang Y.Y., He H. , Wong W.M. , Leung S.Y. , Yuen S.T. , Yuen R.M.F. , Chan A.O.O. and Wong B.C.Y. , Serum macrophage migration-inhibitory factor as a diagnos tic and prognostic biomarker for gastric cancer, Cancer . 2009, 115: 5441-5449.

Yang H.I., Yuen R.M.F. , Chan H.L., Han K.H., Chen P.J., Kim D.Y., Ahn S.H. and Chen C.J., Development and validation of a predictive risk score for hepatocellular carcinoma in patients with chronic hepatitis B., Hepatol Int. The 20th Conference of the Asian Pacific Association for the Study of the Liver (APASL), Beijing, China 25-28 March 2010 . 4: 113.

Yuen R.M.F. , Han K.H., Um S.H., Yoon S.K., Kim H.R., Kim J., Kim C.R. and Lai C.L. , Antiviral activity and safety of LB80380 in hepatitis B e antigen-positive chronic hepatitis B patients with lamivudine-resistant disease. , Hepatology . 2010, 51(3): 767-76.

Yuen R.M.F. , Fung J.Y.Y. , Seto W.K., Wong D.K.H. , Yuen J.C.H. and Lai C.L. , Combination of baseline parameters and on-treatment hepatitis B virus DNA levels to start and continue patients with lamivudine therapy. , Antivir Ther . 2009, 14(5): 679-85.

Researcher : Yung SSY

Project Title:	The role of mammalian target of rapamycin in anti-DNA antibody-mediated induction of cytokine secretion in human mesangial cells
Investigator(s):	Yung SSY, Chan DTM
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	02/2008
Completion Date:	01/2010

Abstract:

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that affects predominantly the fe male population (1). It has a wide spectrum of clinical manifestations and can result in multi-organ injury (1). Lupus nephritis is a severe and debilitating organ manifestation of SLE that affects up to 65% of SLE patients, and is the principal cause of death in these patients. Hallmarks of lupus nephritis include the induction of immune-mediated inflammatory processes, increased release of pro-inflammatory and pro-fibrotic mediators, mesangial cell proliferation, recruitment of inflammatory cells to sites of injury, and the depo sition of matrix proteins resulting ultimately in scarring and loss of nephrons (2-4). Cytokines are essential molecules that are involved in the differentiation and activation of cells, and play a critical role in renal immuno-inflammatory responses during disease progression when their levels are raised (5). The increased levels of these peptides not only play an important role in the aberration of normal immune responses, but also in local inflammatory processes that ultimately leads to tissue destruction. We and others have demonstrated that amongst the numerous cytokines, TNF-alpha, IFN-gamma, IL-1beta, IL-6, IL-10, IL-18 and TGF-beta1 play a pivotal role in the pathogenesis of lupus nephritis (5-8). Antibodies to native DNA have been implicated in the pathogenesis of lupus nephritis. In this respect, increased renal disease activity is often associated with elevated levels of anti-DNA antibodies (9-11). Moreover, anti-DNA antibodies can be eluted from the kidneys of patients with active lupus nephritis, and from active lupus-prone mice (12, 13). That lupus-like glomerulonephritis can be induced in non-autoimmune mice after the inoculation of a transgene encoding a secreted form of an anti-DNA antibody provide further compelling evidence that anti-D NA antibodies play a pivotal role in the pathogenesis of lupus nephritis (14). Conventional treatment for lupus nephritis entails the use of corticosteroids and cytotoxic agents such as cyclophosphamide, azathioprine and more recently mycophenolate mofetil (MMF) (15-20). Such therapeutic regimens, though largely effective, are associated with considerable side-effects. Further studies are therefore warranted for the identification and development of novel therapeutic strategies essential for the management of lupus nephritis. Rapamycin is a macrolide antibiotic that possesses potent immunosuppressive and anti-proliferative properties (21, 22). It has proven efficacy in the prophylaxis of liver or kidney transplant rejection (23, 24). Rapamycin binds to its intracellular target the immunophilin FK506-binding protein 12 (FKBP12) and inhibits phosphorylation at Ser-2448 of the mammalian target of rapamycin (mTOR), a serine threonine kinase and common effector protein shared by several signal transduction pathways (25). Inhibition of mTOR results in the suppression of cytokine-dr iven cell proliferation, ribosomal protein synthesis, and translation initiation, thereby resulting in cell cycle arrest at the G1 phase. T cells, and lymphocytes responsive to pro-inflammatory mediators are the main targets of rapamycin (26, 27). Recent data show that rapamycin can abrogate PDGF-mediated collagen synthesis in non -immune cells of the kidney (28). Current data also suggest a role for rapamycin in the treatment of autoimmune diseases such as experimental allergic encephalomyelitis, adjuvant arthritis, and rheumatoid arthritis (29, 30). In an animal model of protein overload nephropathy, rapamycin was associated with the deterioration of renal function and intratubular cast formation (31). However, in an animal model of lupus nephritis, rapam ycin reduced circulating anti-DNA antibody levels and proteinuria, prolonged the survival of lupus mice, and restored IL-2 expression (32). We have previously demonstrated that anti-DNA antibodies can induce cytokine secretion in mesangial and tubular epithelial cells (7, 8). Whether rapamycin can alter cytokine secretion in anti-DNA antibody-stimulated mesangial cells, and the mechanism through which rapamycin alters cytokine release have not been investigated and constitutes the aim of this proposal. The Objectives of this proposal are: 1. To determine the levels of cytokines (TNF-alpha, IFN-gam ma, IL-1beta, IL-6, IL-10, IL-18 and TGF-beta1) secreted from human mesangial cells (HMC) after stimulation with purified anti-DNA antibodies or control human IgG. 2. To determine the order/cytokine cascade through which the synthesis of the aforementioned cytokines are induced. 3. To determine whether the mTOR pathway is involved in the induction of cytokine release and cell activation during pathogenesis of disease, and whether mTOR may represent a potential target for pharmac eutical intervention. References 1. Croker JA, Kimberly RP. Trends Immunol 2005; 26: 580-586. 2. Kiberd BA. J Am Soc Nephrol 1992; 3: 930-939. 3. Cameron JS. J Am Soc Nephrol 1999; 10: 413-424. 4. Lewis EJ, Schwartz MM. Lupus 2005; 14: 31-38. 5. Aringer M, Smolen JS. Lupus 2005; 14: 13-18. 6. Herrera-Esparza R, Barbosa-Cisneros O, Villalobos-Hurtado R, Avalos-Diaz E. Lupus 1998; 7: 154-158. 7. Yung S, Tsang RC, Sun Y, Leung JK, et al. J Am Soc Nephrol 2005; 16: 3281-3294. 8. Yung S, Tsang RC, Leung JK, Chan TM. Kidney Int 2006; 69: 272-280. 9. Chan TM, Leung JK, Ho SK, Yung S. J Am Soc Nephrol 2002; 13: 1219-1229. 10. Deshmukh US, Bagavant H, Fu SM. Autoimmun Rev 2006; 5: 414-418. 11. Isenberg DA, Manson JJ, Ehrenstein MR, Rahman A. 2007; 46: 1052-1056. 12. Winfield JB, Faiferman I, Koffler D. J Clin Invest 1977; 59: 90-96. 13. Termaat RM, Assmann KJ, Dijkman HB, van Gompel F, et al. Kidney Int 1992; 42: 1363-1371. 14. Tsao BP, Ohnishi K, Cheroutre H, Mitchell B, et al. J Immunol 1992; 149: 350-358. 15. Chan TM. Arthritis Rheum 2007; 56: 702-704. 16. Chan TM, Tse KC, Tang CS, Mok MY, et al. J Am Soc Nephrol 2005; 16: 1076-1084. 17. Tse KC, Tang CS, Lio WI, Lam MF, et al. Lupus 2006; 15: 371-379. 18. Chan TM, Li FK, Tang CS, Wong RW, et al. N Engl J Med 2000; 343: 1156-1162. 19. Boumpas DT, Austin HA, 3rd, Vaughn EM, Klippel JH, et al. Lancet 1992; 340: 741-745. 20. Chan TM, Li FK, Wong RW, Wong KL, et al. Nephron 1995; 71: 321-327. 21. Burkhardt H, Kalden JR. Rheumatol Int 1997; 17: 85-90. 22. Marone R, Cmiljanovic V, Giese B, Wymann MP. Biochim Biophys Acta 2007. 23. Watson CJ, Friend PJ, Jamieson NV, Frick TW, et al. Transplantation 1999; 67: 505-509. 24. Vu MD, Qi S, Xu D, Wu J, et al. Transplantation 1998; 66: 1575-1580. 25. Chiang GG, Abraham RT. J Biol Chem 2005; 280: 25485-25490. 26. Rovira P, Mascarell L, Truffa-Bachi P. Curr Med Chem 2000; 7: 673-692. 27. Teachey DT, Obzut DA, Axsom K, Choi JK, et al. Blood 2006; 108: 1965-1971. 28. Kim MS, Park J, Ha H, Kim YS, et al. Yonsei Med J 2004; 45: 1121-1126. 29. Forre O, Haugen M, Hassfeld WG. Scand J Rheumatol 2000; 29: 73-84. 30. Martel RR, Klicius J, Galet S. Can J Physiol Pharmacol 1977; 55: 48-51. 31. Coombes JD, Mreich E, Liddle C, Rangan GK. Rapamycin Kidney Int 2005; 68: 2599-2607. 32. Warner LM, Adams LM, Sehgal SN. Arthritis Rheum 1994; 37: 289-297.

Project Title:	Role of high and low molecular weight hyaluronan in the pathogenesis of lupus nephritis
Investigator(s):	Yung SSY, Chan DTM
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2009

Abstract:

(1) To investigate the potential roles of high and low molecular weight HA in disease manifestation; (2) To investigate HA synthesis during lupus nephritis, and to correlate such changes with phenotypic clinical, histological, and serological disease manifestations; (3) To investigate mechanisms by which HA fragments are generated during disease progression and how they regulate the inflammatory response within the kidney; (4) To investigate potential therapeutic effects of inhibiting HA synthesis with 4-methylumbelliferone, pertaining to phenotypic, serological, and histological parameters.

Project Title:	The role of Pseudomonas aerugino sa in mediating inflammatory and fibrotic processes in human peritoneal mesothelial cells - implications in peritoneal dialysis.
Investigator(s):	Yung SSY, Chan DTM
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2009

Abstract:

Peritoneal dialysis (PD) is an established renal replacement therapy for patients with end-stage renal failure, and it is the first-line renal replacement therapy in Hong Kong. Despite improvements in the methods through which dialysis solutions are instilled into the peritoneal cavity, peritonitis is still a major complication of PD and remains the single most importa nt cause of technique failure (1-3). Peritonitis due to Pseudomonas aeruginosa (P. aeruginosa) contributes significantly to additional hospitalization, catheter removal and increased mortality in PD patients (4, 5). The efficacy of PD relies on the integrity of the peritoneal membrane, which consists of a monolayer of mesothelial cells, an interstitium and a capillary network (6-8). Injury to the peritoneal mesothelium results from the continuous exposure to bio-incompatible PD solutions and bacterial peritonitis (9-13). The mechanism through which mesothelial cells respond to injury and inflammation, and the factors that govern the reparative process are poorly understood. There is increasing evidence that mesothelial cells transdifferentiate during PD into a more fibroblastic phenotype, a process that involves TGF-beta1, HGF and pro-inflammatory media tors (13, 14). This phenotypic change is accompanied by cellular activation, diminished cell contact inhibition, reduced expression of epithelial markers, increased proliferative and migratory properties, and a concomitant increase in pro-inflammatory and fibrotic markers (13, 14). These changes precede peritoneal fibrosis and loss of the structural and functional integrity of the peritoneum as a dialyzing membrane. How P. aeruginosa peritonitis mediates functional alterations in mesothelial cells has not been investigated. This microbe is highly adaptive and can survive in a variety of limiting enviro nments. The extensive host range and complex pathophysiology of infection that is associated with P. aeruginosa results from its ability to synthesize a large repertoire of virulence determinants and toxic exoproducts (15). Pyocyanin is a blue redox-active secondary metabolite produced by P. aeruginosa and belongs to a large famil y of tricyclic compounds known as phenazines (15, 16). The effect of pyocyanin on mesothelial cell function remains to be defined. In this study, our aim is to determine how spent dialysis effluent from patients with P. aeruginosa peritonitis can mediate inflammatory, fibrotic and morphologic changes in human peritoneal mesothelial cells (HPMC), and the mechanisms through which P. aeruginosa provoke such changes. The objectives of this projective are: 1. To assess the effect of spent dialysis effluent obtained from patients with P. aeruginosa peritonitis on cell morphology, apoptosis, cell activation, induction of cytokines and growth factors and matrix protein synthesis in HPMC. 2. To assess whether changes that are observed in HPMC consequent to stimulation with spent dialysis effluent is attributed to pyocyanin. 3. To assess the mechanism through which P. aeruginosa / pyocyanin mediate changes to the mesothelium. References 1. Brunier G. Peritonitis in patients on peritoneal dialysis: a review of pathophysiology and treatment. ANNA J 19 95;22:575-584; quiz 585-576. 2. Brown EA. Peritonitis: limiting the damage. Nephrol Dial Transplant 2005;20:1539-1541. 3. Piraino B, Bailie GR, Bernardini J, Boeschoten E, Gupta A, Holmes C, Kuijper EJ, Li PK, Lye WC, Mujais S, Paterson DL, Fontan MP, Ramos A, Schaefer F, Uttley L. Peritoneal dialysis-related infections recommendations: 2005 update. Perit Dial Int 2005;25:107-131. 4. Piraino B. Peritonitis as a complication of peritoneal dialysis. J Am Soc Nephrol 1998;9:1956-1964. 5. Szeto CC, Chow KM, Leung CB, Wong TY, Wu AK, Wang AY, Lui SF, Li PK. Clinical course of peritonitis due to Pseudomonas species complicating peritoneal dialysis: a review of 104 cases. Kidney Int 2001;59:2309-2315. 6. Williams JD, Craig KJ, Topley N, Williams GT. Peritoneal dialysis: changes to the structure of the peritoneal membrane and potential for biocompatible solutions. Kidney Int Suppl 2003:S158-161. 7. Digenis GE. Anatomy of the peritoneal membrane. Perit Dial Bull 1984;4:63-69. 8. Dobbie J. Ultrastructure and pathology of the peritoneum in peritoneal dialysis In: Gokal R, ed. Textbook of peritoneal dialysis. Dordrecht: Kluwer Academic Publishers; 1994:17-44. 9. Topley N. The cytokine network controlling peritoneal inflammation. Perit Dial Int 1995;15:S35-39; discussion S39-40. 10. Yung S, Chen XR, Tsang RC, Zhang Q, Chan TM. Reductio n of perlecan synthesis and induction of TGF-beta1 in human peritoneal mesothelial cells due to high dialysate glucose concentration: implication in peritoneal dialysis. J Am Soc Nephrol 2004;15:1178-1188. 11. Ha H, Cha MK, Choi HN, Lee HB. Effects of peritoneal dialysis solutions on the secretion of growth factors and extracellu lar matrix proteins by human peritoneal mesothelial cells. Perit Dial Int 2002;22:171-177. 12. Mortier S, De Vriese AS, McLoughlin RM, Topley N, Schaub TP, Passlick-Deetjen J, Lameire NH. Effects of conventional and new peritonea l dialysis fluids on leukocyte recruitment in the rat peritoneal membrane. J Am Soc Nephrol 2003;14:1296-1306. 13. Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M, Dominguez-Jimenez C, Jimenez-Heffernan JA, Aguilera A, Sanchez-Tomero JA, Bajo MA, Alvarez V, Castro MA, del Peso G, Cirujeda A, Gamallo C, Sanchez-Madrid F, Lopez-Cabrera M. Peritoneal dialysis and epithelial-to- mesenchymal transition of mesothelial cells. N Engl J Med 2003;348:403-413. 14. Rampino T, Cancarini G, Gregorini M, Guallini P, Maggio M, Ranghino A, Soccio G, Dal Canton A. Hepatocyte growth factor/scatter factor released during peritonitis is active on mesothelial cells. Am J Pathol 2001;159:1275-1285. 15. Ran H, Hassett DJ, Lau GW. Human targets of Pseudomonas aeruginosa pyocyanin. Proc Natl Acad Sci U S A 2003;100:14315-1432 0. 16. Rada B, Lekstrom K, Damian S, Dupuy C, Leto TL. The pseudomonas toxin pyocyanin inhibits the dual oxidase-based antimicrobial system as it imposes oxidative stress on airway epithelial cells. J Immunol 2008;181:4883-4893.

Project Title:	42nd Annual Meeting and Scientific Exposition (ASN Renal Week 2009) Induction of Inflammatory and Fibrotic Mediators in Human Peritoneal Mesothelial Cells (HPMC) by Icodextrin-Based Peritoneal Dialysis Fluid
Investigator(s):	Yung SSY
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	10/2009
Completion Date:	11/2009

Abstract:

N/A

Project Title:	The role of decorin in peritoneal inflammation and fibrosis
Investigator(s):	Yung SSY, Chan DTM
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010

Abstract:

1) Studies have demonstrated that decorin can influence the behavior of cells through its ability to bind and inactive a number of growth factors. Since we have observed a correlation between dialysate levels of decorin and IL-1beta, IL-6, IL-8, TNF-alpha, and HGF, we will determine whether decorin can regulate their activities. If decorin can bind these peptides, we will delineate the physiological relevance of these interactions in HPMC, and how they can affect peritoneal inflammation and fibrosis; 2) We shall investigate the functional consequence of decorin-cytokine interactions in HPMC during peritoneal inflammation. We will focus on cellular effects that are applicable to cell prol iferation, signaling transduction pathway, activation of nuclear transcription factors, markers of EMT, and induction/reduction of inflammatory and fibrotic mediators; 3) We will determine the regulatory mechanism of decorin synthesis and secretion in HPMC during peritoneal inflammation and fibrosis. We will ascertain whether mediators of peritoneal inflammation and fibrosis can induce qualitative and quantitative changes in the core protein and dermatan sulfate glycosaminoglycan of decorin.

Project Title:	The effect of heparin on inflammatory and fibrotic processes in human mesothelial cells duri ng peritoneal dialysis
Investigator(s):	Yung SSY, Chan DTM
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2010

Abstract:

Background The peritoneum is the most extensive serous membrane in the body, covering the visceral organs and lines the abdominal cavity (1). It comprises a monolayer of mesothelial cells that rests upon a thin basal lamina, underneath which is the interstitium containing a capillary network (1). Mesothelial cells are specialized epithelial cells that provide an anatomica l barrier and a frictionless interface for the movement of organs and tissues. There is compelling evidence that far from being passive cells, mesothelial cells play a critical role in the control of peritoneal homeostasis, inflammation and fibrosis (2, 3). The introduction of peritoneal dialysis (PD) as a treatment for patients with end-stage renal failure has resulted in much interest in the biology of mesothelial cells. These cells provide the first line of defence in peritoneal protection during chronic exposure to unphysiological PD solutions and bacterial infection (4). In Hong Kong, 80% of patient s with end-stage renal disease are managed with PD. This technique involves the infusion of a hyperosmolar dialysis solution that contains elevated levels of glucose into the peritoneal cavity, where the solution is allowed to dwell for 4 to 8h, after which time it is replaced by a fresh bag of dialysis solution. Typically 3 to 4 exchanges are required each day. Metabolic waste, electrolytes, and excessive water are removed from the circulation by diffusion or convection across th e peritoneal membrane. Conventional PD solutions utilize dextrose at high concentrations, usually 15 to 40 times that of physiological levels, to provide the osmotic drive for the removal of solutes. This ‘bio-incompatible’ glucose milieu is a major insult to the structural and functional integrity of the peritoneal membrane, and these changes are exacerbated during peritonitis (5-8). Repeated chemical or bacterial injury to the peritoneal mesothelium triggers inflammatory responses and initiates a multitude of reparative processes that aim to heal but which often result in fibrosis. In this respect, many patients on long-term PD, exhibits re-duplication of the basal lamina, increased synthesis and deposition of matrix within the submesothelium, epithelial-to-mesenchymal transdifferentiation of mesotheli al cells, and progressive subendothelial hyalinization, with narrowing or obliteration of the vascular lumen (8-15). These structural changes are accompanied by deranged transport properties. Precisely how these changes in the peritoneal membrane are regulated is unclear. Heparin is often added to PD solutions to prevent fibrin formation (16). Animal and clinical PD studies have demonstrated that intraperitoneal administration of heparin can improve ultrafiltration, inhibit the formation of thrombin and abrogate peritoneal fibros is, although there is discordance in the data (17-20). In vitro studies have also shown that at clinically relevant dose, heparin is non-toxic to mesothelial cells and has no effect of cell proliferation (21). Whether heparin can improve inflammatory and fibrotic processes in mesothelial cells upon exposure to PD solutions remains to be defined. The objectives of this study are as follows: 1) To determine the effect of spent dialysate with or without heparin on cell proliferation, viability, morphology and senescence. 2) To determine the effect of spent dialysate with or without heparin on the secretion of inflammatory marker s in mesothelial cells. 3) To determine the effect of spent dialysate with or without heparin on the deposition of matrix proteins and cell activation in mesothelial cells. 4) To determine the mechanism through which heparin can influence the inflammatory and fibrotic pathways, focusing on signaling pathways that include PKC, ERK, JNK and p38 MAPK activation. References 1. Mutsaers SE. Mesothelial cells: their structure, function and role in serosal repair. Respirology (Carlton, Vic 2002; 7: 171-191. 2. Yung S, Li FK, Chan TM. Peritoneal mesothelial cell culture and biology. Perit Dial Int 2006; 26: 162-173. 3. Yung S, Chan TM. Intrinsic cells: mesothelial cells -- central players in regulating inflammation and resolution. Perit Dial Int 2009; 29 Suppl 2: S21-27. 4. Chan TM, Yung S. Studying the effects of new peritoneal dialysis solutions on the peritoneum. Perit Dial Int 2007; 27 Suppl 2: S87-93. 5. Davies SJ, Bryan J, Phillips L, Russell GI. Longitudinal changes in peritoneal kinetics: the effects of peritoneal dialysis and peritonitis. Nephrol Dial Transplant 1996; 11: 498-506. 6. Devuyst O, Topley N, Williams JD. Morphological and functional changes in the dialysed peritoneal cavity: impact of more biocompatible solutions. Nephrol Dial Transplant 2002; 17 Suppl 3: 12-15. 7. Dobbie J. Ultrastructure and pathology of the peritoneum in peritoneal dialysis In: Gokal R (ed). Textbook of peritoneal dialysis. Kluwer Academic Publishers: Dordrecht, 1994, pp 17-44. 8. Williams JD, Craig KJ, Topley N, Von Ruhland C, et al. Morphologic changes in the peritoneal membrane of patients with renal dise ase. J Am Soc Nephrol 2002; 13: 470-479. 9. Ha H, Yu MR, Lee HB. High glucose-induced PKC activation mediates TGF-beta 1 and fibronectin synthesis by peritoneal mesothelial cells. Kidney Int 2001; 59: 463-470. 10. Ha H, Cha MK, Choi HN, Lee HB. Effects of peritoneal dialysis solutions on the secretion of growth factors and extracellular matrix proteins by human peritoneal mesothelial cells. Perit Dial Int 2002; 22: 171-177. 11. Kim JJ, Li JJ, Kim KS, Kwak SJ, et al. High glucose decreases collagenase expression and increases TIMP expression in cultured human peritoneal mesothelial cells. Nephrol Dial Transplant 2008; 23: 534-541. 12. Chan TM, Leung JK, Sun Y, Lai KN, et al. Different effects of amino acid-based and glucose-based dialysate from peritoneal dialysis patients on mesothelial cell ultrastructure and function. Nephrol Dial Transplant 2003; 18: 1086-1094. 13. Chan TM, Leung JK, Tsang RC, Liu ZH, et al. Emodin ameliorates glucose-induced matrix synthesis in human peritoneal mesothelial cells. Kidney Int 2003; 64: 519-533. 14. Coles GA, Topley N. Long-term peritoneal membrane changes. Adv Ren Replace Ther 2000; 7: 289-301. 15. Mateijsen MA, van der Wal AC, Hendriks PM, Zweers MM, et al. Vascular and interstitial changes in the peritoneum of CAPD patients with peritone al sclerosis. Perit Dial Int 1999; 19: 517-525. 16. Yung S, Chan TM. Peritoneal proteoglycans: much more than ground substance. Perit Dial Int 2007; 27: 375-390. 17. Pawlaczyk K, Kuzlan-Pawlaczyk M, Anderstam B, Heimburger O, et al. Effects of intraperitoneal heparin on peritone al transport in a chronic animal model of peritoneal dialysis. Nephrol Dial Transplant 2001; 16: 669-671. 18. Fracasso A, Baggio B, Ossi E, Del Prete D, et al. Glycosaminoglycans prevent the functional and morphological peritoneal derangement in an experimental model of peritoneal fibrosis. Am J Kidney Dis 1999; 33: 105-110. 19. Sjoland JA, Pedersen RS, Jespersen J, Gram J. Intraperitoneal heparin ameliorates the systemic inflammatory response in PD patients. Nephron Clin Pract 2005; 100: c105-110. 20. Sjoland JA, Smith Pedersen R, Jespersen J, Gram J. Intraperitoneal heparin reduces peritoneal permeability and increases ultrafiltration in peritoneal dialysis patients. Nephrol Dial Transplant 2004; 19: 1264-1268. 21. Manalaysay MT, Kumano K, Hyodo T, Sakai T. Inhibition of mesothelial cell growth and protein synthesis by heparin. Adv Perit Dial 1995; 11: 239-242.

List of Research Outputs

Chan D.T.M. , Ng Y.C.C. and Yung S.S.Y. , Mycophenolic acid reduces MAPK activation and fibronectin synthesis in human proximal tubular epithelial cells (PTEC) induced by anti-DNA antibodies, J Am Soc Nephrol . 2009, 860A.

Cheung K.F. , Yung S.S.Y. and Chan D.T.M. , Annexin II on human mesangial cells mediates anti-ds DNA antibody binding, 9th International Congress on Systemic Lupus Erythem atosus . 2010.

Lui S.L. , Cheng S.W., Yung S.S.Y. , Chan D.T.M. and Lo W.K. , Acute deterioration in residual renal function after CAPD peritonitis is associated with increased interleukin-6 release, J Am Soc Nephrol . 2009, 20: 787A.

Tse K.C., Yap D.Y.H., Tang C.S.O. , Yung S.S.Y. and Chan D.T.M. , Response to adefovir or entecavir in renal allograft recipients with hepatitic flare due to lamivudine-resistant hepatitis B, Clinical transplantation . 2010, 24(2): 207-212.

Tse W.W. , Yung S.S.Y. and Chan D.T.M. , Hyaluronan in the pathogenesis of lupus nephritis in NZB/W mice and the effect of 4-methylumbelliferone, 9th International Congress on Systemic Lupus Erythe matosus . 2010.

Yung S.S.Y. , Chau K.M. , Yip T.P.S., Li F.K. and Chan D.T.M. , Induction of inflammatory and fibrotic mediators in human peritoneal mesothelial cells (HPMC) by icodextrin-based peritoneal dialysis fluid, J Am Soc Nephrol . 2009, 20: 694A.

Yung S.S.Y. , Ng Y.C.C. and Chan D.T.M. , Mycophenolic acid ameliorates anti-dsDNA antibody binding to proximal tubular epithelial cells and the subsequent induction of inflammatory and fibrotic processes., 9th International Congress on Systemic Lupus Erythematosu s . 2010.

Yung S.S.Y. and Chan D.T.M. , Tissue remodeling and inflammation during peritoneal dialysis: catheter versus fluid, Peritoneal Dialysis International . 2010, 39(3): 274-276.

Zhang C. , Yung S.S.Y. and Chan D.T.M. , Rapamycin decreases IL-6 induced inflammatory and fibrotic mediators in human mesangial cells (HMC), J Am Soc Nephrol . 2009, 20: 731A.

Zhang Q. , Yung S.S.Y. and Chan D.T.M. , Effects of mycophenolic acid (MPA) and cyclophosphami de (CTX) on cytokine and matrix protein synthesis and apoptosis in human mesangial cells (HMC), J Am Soc Nephrol . 2009, 20: 562A.

Researcher : Zhang C

List of Research Outputs

Zhang C. , Yung S.S.Y. and Chan D.T.M. , Rapamycin decreases IL-6 induced inflammatory and fibrot ic mediators in human mesangial cells (HMC), J Am Soc Nephrol . 2009, 20: 731A.

Researcher : Zhang J

List of Research Outputs

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y., Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Richards A.A., Colgrave M.L., Zhang J. , Webster J., Simpson F., Preston E., Wilks D., Hoehn K.L., Stephenson M., Macdonald G.A., Prins J.B., Cooney G.J., Xu A. and Whitehead J.P., Sialic Acid Modification Of Adiponectin Is Not Required For Multimerization Or Secretion But Determines Half-life In Circulation., Molecular Endocrinology . Highwire press, 2010, 24: 229-39.

Xia F. , Lam K.S.L. , Zhang J. , Zhou P. and Xu A. , Serum Levels Of Fibroblast Growth Factor 21 Are Elevated In Both Rodents And Humans In Response To Acute Fasting, Diabetes . 2010, 59 supplement: 1661-P.

Researcher : Zhang J

List of Research Outputs

Richards A.A., Colgrave M.L., Zhang J. , Webster J., Simpson F., Preston E., Wilks D., Hoehn K.L., Stephenson M., Macdonald G.A., Prins J.B ., Cooney G.J., Xu A. and Whitehead J.P., Sialic Acid Modification Of Adiponectin Is Not Required For Multimerization Or Secretion But Determines Half-life In Circulation., Molecular Endocrinology . Highwire press, 2010, 24: 229-39.

Researcher : Zhang Q

List of Research Outputs

Zhang Q. , Yung S.S.Y. and Chan D.T.M. , Effects of mycophenolic acid (MPA) and cyclophosphamide (CTX) on cytokine and matrix protein synthesis and apoptosis in human mesangial cells (HMC), J Am Soc Nephrol . 2009, 20: 562A.

Researcher : Zhang R

Project Title:	Role of Smad3 in regulating differentiatio n of T helper cells in experimental autoimmune encephalomyelitis
Investigator(s):	Zhang R, Lan HY
Department:	Medicine
Source(s) of Funding:	Seed Funding Programme for Basic Research
Start Date:	03/2008
Completion Date:	08/2009

Abstract:

Experimental autoimmune encephalomyelitis (EAE) is a well established and widely used animal model that mimics the pathological features of multiple sclerosis (MS). Although the pathogenesis is incompletely unde rstood, MS or EAE is believed to be a T cell-mediated autoimmune disease. CD4+ T cells can be divided into different subsets with distinct differentiation profiles and functional characteristics. The best-characterized subsets are T helper cell (Th) Th1, Th2, and regulatory T cell (Treg), whose development is specified by the transcription factors T-bet, GATA-3, and Foxp3, respect ively [1-3]. Recently, a unique subset Th17 characterized by production of IL-17 whose development through the transcription factors RORγt play important role in pathogenesis of certain autoimmune diseases such as EAE [4-6]. While Th1 mediated EAE has been well studied, growing evidence implicates that Th17 also play a key role in pathogenesis of EAE. Transforming growth factor-β (TGF-β) is a key immunoregulator governing T cell mediated immune response including Th1, Th2, T-reg, and recently Th17 differentiation. The recent findings that TGF-β control the tolerance of T cell and regulates immune response by regulate Th1- and Th17- cell differentiation in EAE and colitis [7, 8]. While study of TGF-β in controls tolerance and immunity is overwhelming, little attention has been paid to its downstream signaling in regulation of immune response in EAE [9]. It is clear that TGF-β signals through the two downstream mediators, Smad2 and 3, to mediate autoimmune response, but the signaling mechanisms whereby TGF-β exerts its immunomodulatory effect on EAE are poorly understood. Since Smad2 deletion is embryonic lethal while Smad3 knockout (KO) mice survive but display impaired immunity, we postulate that Smad3 is a key factor through which TGF-β modulates T cell mediated autoimmune responses in EAE. This postulate was tested in our preliminary studies in vitro Th cell polarization. Compare with Smad3 WT mice, Smad3 KO significantly promotes the Th2 and Th17 cell differentiation by enhanc e the Th2 cytokine IL-4 production and Th17 cytokine IL-17A, IL-17F and IL-22. Our interpretation of these preliminary data is that TGF-β acts by regulating Smad3 to regulate the Th1, Th2 and Th17 response in EAE. Target disruption of Smad3 impairs the inhibitory effects of TGF-β on T cell mediated EAE. Hence, the central hypothesis underlying this application is that TGF-β/Smad3 signaling is a key determinant of Th-cell mediated brain inflammation in EAE. We plan to test this hypothesis by pursuing the two specific aims: 1. To determine the role of Smad3 in regulating pathogenesis of Th cell-mediated EAE. Our working hypothesis is that TGF-β/Smad3 signaling is a key determinant of Th17-cell mediated brain inflammation in EAE. This will be examined in an accelerated EAE in Smad3 KO vs WT mice. The outcom e of disease will be assessed in terms of: clinical score, histological analysis of inflammation, cellular immunity (infiltration of CD4+, CD8+ cells, neutrophils and macrophages), and brain expression of proinflammatory cytokines (IL-17, IL-1β,TNF-alpha, Il-6) and adhesion/chemot atic molecules (ICAM-1, MCP-1). 2. To determine the Smad3 regulated differentiation of Th cell lineages in EAE. Our working hypothesis is that TGF-β signals through Smad3 to regulate Th1/Th2/Th17 differentiation and proliferation in EAE. This hypothesis will be investigated in mouse EAE and in vitro using antigen primed or naïv e T cells. First, we will investigate the regulating role of Smad3 in T cell proliferation in spinal cord and lymphoid tissues in EAE and in CD4+ cells isolated from antigen-primed Smad3 KO and WT mice. Second, we will study the differentiation of Th1,Th2 and Th17 in Smad3 regulated EAE by examining: (i) Th1 (INF-gamma, IL-12), Th2 (IL-4, IL-10) and Th17 (IL-17 and IL-23) cytokine production in EAE in Smad3 KO and WT mice and in CD4+ T cells isolated from Smad3 KO or WT mice under the influence of Ag, TGF-β, and Th1/Th2/Th17 polarization conditions; (iii) regulation of Th1 (T-bet ), Th2 (GATA-3), Th17 (RORγt) transcription factor expression in EAE in Smad3 KO and WT mice and in CD4+ T cells isolated from Smad3 KO or WT mice that are cultured under conditions of Th1 or Th2 differentiation +/- the presence of TGF-β. Reference: 1. Fontenot J, et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22 (2005), pp. 329–341. 2. Szabo S, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100 (2000), pp. 655–669. 3. Zheng W, et al. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89 (1997), pp. 587–596. 4. Cua DJ, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421 (2003), pp. 744–748. 5. Kolls J and Linden A. Interleukin-17 family members and inflammation. Immunity 21 (2004), pp. 467–476. 6. Langrish CL, et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201 (2005), pp. 233–240. 7. Li MO et al. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. (2006), 24:99-146. 8. Li MO, et al. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity. (2007), 26(5):579-91. 9. Li MO, et al. Transforming growth factor-beta control s development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. (2006), 25(3):455-71.

Project Title:	Basic Cardiovascular Sciences Confe rence 2009 - Molecular Mechanisms of Cardiovascular Disease C-reactive Protein Promotes Cardiac Inflammation and Fibrosis in Angiotensin II-Induced Hypertensive Cardiovascular Diseases
Investigator(s):	Zhang R
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	07/2009
Completion Date:	07/2009

Abstract:

N/A

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibitor of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Zhang R. , Zhang S.Y. , Lan X.R. , Wu Y. , Szalai ..J..., Wong B.C.Y. , Lau C.P. , Wu E.X. and Lan H.Y. , C-reactive Protein Promotes Cardiac Inflammation and Fibrosis in Angiotensin II-Induced Hypertensive Cardiovascu lar Diseases, In: American Heart Association, Basic Cardiovascular Science Conference, July 20-23, 2009, Las Vegas, USA; Circulation Research . 2009.

Researcher : Zhang SY

List of Research Outputs

Zhang R. , Zhang S.Y. , Lan X.R. , Wu Y. , Szalai ..J..., Wong B.C.Y. , Lau C.P. , Wu E.X. and Lan H.Y. , C-reactive Protein Promotes Cardiac Inflammation and Fibrosis in Angiotensin II-Induced Hypertensive Cardiovascu lar Diseases, In: American Heart Association, Basic Cardiovascular Science Conference, July 20-23, 2009, Las Vegas, USA; Circulation Research . 2009.

Researcher : Zhang W

List of Research Outputs

Ho W.L. , Liu H. , Ho W.M. , Zhang W. , Chu A.C.Y. , Kwok H.H. , Ge X. , Chan K.H. , Ramsden D.B. and Ho S.L. , Mitochondrial Uncoupling Protein-2 (UCP2) Mediates Leptin Protection Against MPP+ Toxicity in Neuronal Cells , Neurotoxicity Research . 2010, 17(4): 332-343.

Ho W.M. , Ho W.L. , Zhang W. , Liu H. , Kwok H.H. , Yiu C.W. , Chan K.H. , Kung M.H.W. , Ramsden D.B. and Ho S.L. , Transcriptional Regulation of UCP4 by Nuclear Factor kappaB and its Role in Mediating Protection Against MPP(+) Toxicity, Free Radical Biology and Medicine . 2010, 49: 192-204.

Zhang W. , Wang J. , Zou B. and Wong B.C.Y. , Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer, Hong Kong Medical Journal . 2010, 16: 64.

Researcher : Zhang W

List of Research Outputs

Zhang W. , Wang J. , Zou B. and Wong B.C.Y. , Four-and-a-half LIM protein 2 promotes invasive potenti al and epithelial-mesenchymal transition in colon cancer, Hong Kong Medical Journal . 2010, 16: 64.

Researcher : Zhang X

List of Research Outputs

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical Function only in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation Existing Atrial Dyssynchrony , European Society of Cardiology Congress, Spain. August 29 –September 2, . 2009.

Wang M.M. , Lau C.P. , Lee K.L.F. , Zhang X. , Siu D.C.W. , Yan G. , Yue W. and Tse H.F. , Atrial Pacing Improves Atrial Mechanical dyssynchrony and Function in Patient with Sinus Nodes Disease with Paroxysmal Atrial Fibrillation, ESC Congress 2009 . 2009.

Zhang X. , Jin M.W. and Li G.R. , Ion Channels and Their Role in Cell Proliferration of 3T3-L1 Preadipocytes, J HK Coll Cardiol . 2009, 17(2): 68.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of huma n colon cancer via DPPIV signaling pathway.(Oral presentation), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Zhang X

List of Research Outputs

Zhang X. , Jin M.W. and Li G.R. , Ion Channels and Their Role in Cell Proliferration of 3T3-L1 Preadipocytes, J HK Coll Cardiol . 2009, 17(2): 68.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presentation ), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Zhang X

List of Research Outputs

Zhang X. , Jin M.W. and Li G.R. , Ion Channels and Their Role in Cell Proliferration of 3T3-L1 Preadipocytes, J HK Coll Cardiol . 2009, 17(2): 68.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presentation), 15th Medical Research Conference. Hong Kong . 2010.

Researcher : Zhang Y

List of Research Outputs

Lian Q. , Zhang Y. , Zhang J. , Zhang H.K., Wu X. , Zhang Y. , Lam F.F., Kang S., Xia J.C., Lai K.W.H. , Au K.W. , Chow Y.Y. , Siu D.C.W. , Lee C.N. and Tse H.F. , Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemic in mice. , Circulation . 2010, 121: 1113-23.

Lian Q. , Zhang Y. , Kang S., Zhang Y. , Lai A.Y.K. , Au K.W. , Zhang J. and Tse H.F. , GENERATION OF MESENCHYMAL STEM CELLS FROM HUMAN INDUCED PLURIPOTENT STEM CELLS (iPSC) FOR THE REATMENT OF LIMB ISCHEMIA, 7th Annunal Meeting of International Society for Stem Cell Research . 2009, 194.

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with passive epicardial patch in porcine model of chronic myocardial infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Liao S. , Liu Y. , Siu D.C.W. , Zhang Y. , Lai K.W.H. , Au K.W. , Lee Y.K. , Chan Y.C. , Yip P.M.C. , Wu E.X. , Lau C.P. , Wu Y., Li R.A. and Tse H.F. , Pro-arrhythmic Risk of Embryonic Stem Cell-Derived Cardiomyocytes Transplantation in Infarcted Myocardium. Heart Rhythm. , 2010.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , large-conductance Ca-activated Potassium and Ether-a-go-go Potassium Channels Regulate Proliferation of Human Mesenchymal Stem Cells, J HK Coll Cardiol . 2009, 17(2): 59.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Human cardiac KV4.3 channels are regulated by protein tyrosine kinases, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 64.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Protein Tyrosine Kinases Regulate Human Cardiac KV4.3 Channel, J HK Coll Cardiol . 2009, 17(2): 58.

Zhang Y. , Tse H.F. , Lau C.P. and Li G.R. , Regulation of cell proliferation by ion channels in human mesenchymal stem cells, 15th Medical Research Conference, Department of Medicine, HKU. . 2010, 16(1): 65.

Researcher : Zhang Y

List of Research Outputs

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Protein Tyrosine Kinases Regulate Human Cardiac KV4.3 Channel, J HK Coll Cardiol . 2009, 17(2): 58.

Researcher : Zhang Y

List of Research Outputs

Lian Q. , Zhang Y. , Kang S., Zhang Y. , Lai A.Y.K. , Au K.W. , Zhang J. and Tse H.F. , GENERATION OF MESENCHYMAL STEM CELLS FROM HUMAN INDU CED PLURIPOTENT STEM CELLS (iPSC) FOR THE REATMENT OF LIMB ISCHEMIA, 7th Annunal Meeting of International Society for Stem Cell Research . 2009, 194.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Protein Tyrosine Kinases Regulate Human Cardiac KV4.3 Channel, J HK Coll Cardiol . 2009, 17(2): 58.

Researcher : Zhang Y

List of Research Outputs

Liao S. , Siu D.C.W. , Liu Y. , Zhang Y. , Chan W.S., Wu E.X. , Wu Y., Nicholls J.M., Li R.A. , Benser M., Stuart R., Park E., Lau C.P. and Tse H.F. , Attenuation of left ventricular remodelling with passive epicardial patch in porcine model of chronic myocardia l infarction. , Journal of Cardiac Failure . 2010, 16(7): 590-8.

Zhang Y. , Lau C.P. , Tse H.F. and Li G.R. , Protein Tyrosine Kinases Regulate Human Cardiac KV4.3 Channel, J HK Coll Cardiol . 2009, 17(2): 58.

Researcher : Zheng C

List of Research Outputs

Zheng C. , Kwong Y.L. and Ho J.C.M. , In-vitro combination of arsenic trioxide and chemothera py in small-cell lung cancer, 15th Medical Research Conference, HKU. Hong Kong Medical Journal . 2010, 16: 56.

Researcher : Zhou L

List of Research Outputs

Zhou L. , Fu P., Huang X.R., Liu F. , Lai K.N. and Lan H.Y. , Activation of p53 promotes renal injury in acute ari stolochic acid nephropathy, Journal of American Society of Nephrology . 2010, 21(1): 31-41.

Zhou L. , Fu P., Huang X.R., Liu F. , Chung A.C.K. , Lai K.N. and Lan H.Y. , Mechanism of chronic aristolochic acid nephropathy: role of Smad3, Am J Physiol Renal Physiol . 2010, 298(4): F1006-17.

Researcher : Zhou P

List of Research Outputs

Xia F. , Lam K.S.L. , Zhang J. , Zhou P. and Xu A. , Serum Levels Of Fibroblast Growth Factor 21 Are Elevated In Both Rodents And Humans In Response To Acute Fasting, Diabetes . 2010, 59 supplement: 1661-P.

Researcher : Zou B

Project Title:	The study of XAF1 as a novel target gene of p53
Investigator(s):	Zou B, Wong BCY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	08/2008
Completion Date:	01/2010

Abstract:

Apoptosis, also termed programmed cell death, involves a series of biochemical events leading to a character istic cell morphology and death. IAPs (Inhibitor of apoptosis proteins) are a new family of intrinsic regulators of cell death, which function as key proteins in the control of cell death (1). X chromosome-linked inhibitor of apoptosis protein (XIAP) has been shown to be the most potent and versatile inhibitor of caspases and apoptosis of IAP members, and then could selected as a prominent target for anti-cancer therapy(2). In fac t, previous studies from our lab have also demonstrated the crucial role of an IAP member, survivin, in gastric and colon cancer; corroborating the critical role of IAPs in gastric and colorectal carcinogenesis (3,4). The XIAP-associated factor 1 (XAF1) was first identified as a novel negative regulator of XIAP (5). Our group has previously demonstrated the apoptotic effects of XAF1 (6,7), and elucidated the molecular mechanism governing the transcription regulation of XAF1 in gastric and colorectal cancers (8,9). Intriguingly, a subsequent study demonstrated that XAF1 is an IFN stimulated gene that sensitizes TRAIL-induced apoptosis in several tumor cell lines, suggesting that the combination of XAF1 with other cell death triggers may be a feasible approach for cancer therapy. A more recent study demon strated that XAF1 interaction activates E3 activity of XIAP and targets survivin by direct ubiquitination (10). In summary, the functions and underlying mechanisms of proapoptotic effect of XAF1 are more versatile than originally thought, suggesting that a critical role for XAF1 in the regulation of apoptosis and mitotic catastrophe. p53 is an important transcription factor that regulates numerous target genes controlling apopt osis, cell cycle arrest, senescence and DNA repair in response to genotoxic and oncogenic stress. The p53 pathway is composed of a network of genes and their products that are targeted to respond to a variety of intrinsic and extrinsic stress signals that impact upon cellular homeostatic mechanisms that monitor DNA replication, chromosome segregation and cell division (11). In res ponse to a stress signal, the p53 protein is activated in a specific manner by post-translational modifications, and this leads to either cell cycle arrest, a program that induces cell senescence or cellular apoptosis (12). Finally, activation of the p53 protein and its network of genes sets in motion an elaborate process of positive or negative feedback loops, which connect the p53 pathway to other signal transduction pathways within the cell, and through this broader communicati on permits the completion or the reversal of the p53 programmed responses to stress (13). By our preliminary experiments, we found the promoter activity of XAF1 can be down regulated by p53, which suggested the putative intera ction between p53 and XAF1, as well as form the basis of a negative feedback loop, facilitating the regulation of p53-mediated apoptosis by XAF1. Objectives of this proposed study: 1.To confirm and characterize the interaction and mechanism of inhibition of XAF1 induced by p53 and identify new p53 target genes. 2.To identify the fragments or novel elements in XAF1 responsibl e for p53 binding. 3.To map possible effectors and downstream functions responsible for p53 and XAF1 interaction. References: 1.Liston P, Fong WG, Korneluk RG. The inhibitors of apoptosis: there is more to life than Bcl2. Oncogene. 2003 22(53):8568- 80. Review. 2.Eckelman BP, Salvesen GS, Scott FL. Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep. 2006 Oct;7(10):988-94. 3.Tu S., Cui J., Liston P., Jiang X., Xu R., Lin M.C., Zhu Y.B., Zou B., Ng S.M., Jiang S.H., Xia H.H.X., Wong R.W.M., Chan O.O., Yuen R.M.F., Lam S.K., Kung H. and Wong B.C.Y. Gene Therapy for Colon Cancer by Adeno-Associated Viral Vector-Mediated Transfer of Survivin Cys84Ala Mutant, Gastroenterology, 2005, 128, 361-375. 4.Tu S., Jiang X., Lin M.C., Cui J., Yang Y., Lum C.T., Zou B., Zhu Y.B., Jiang S.H., Wong W.M., Chan O.O., Yuen M.F., Lam S.K., Kung H. and Wong B.C.Y. Suppressio n of Survivin Expression Inhibits in vivo Tumorigenicity and Angiogenesis in Gastric Cancer, Cancer Research, 2003, 63(22), 7724-7732. 5.Liston P, Fong WG, Kelly NL, Toji S, Miyazaki T, Conte D, Tamai K, Craig CG, McBurney MW, Korneluk RG. Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol. 2001 3(2):128-33. 6.Yu L., Wang J., Zou B., Lin M.C., Wu Y.L., Xia H.H.X., Sun Y., Gu Q., He H., Lam S.K., Kung H.F. and Wong B.C.Y. XAF1 Mediates Apoptosis Through an Extracellular Signal-regulated Kinase Pathway in Colon Cancer, Cancer, 2007, 109(10), 1996-2003. 7.Wang J., Peng Y., Sun Y., He H., Zhu S., An X.M., Li M., Lin M.C., Zou B., Xia H.H.X., Jiang B., Chan O.O., Yuen R.M.F., Kung H.F. and Wong B.C.Y. All-Trans Retinoic Acid Induces XAF1 Expression Through an Interferon Regulatory Factor-1 Element in Colon Cancer, Gastroenterology, 2006, 130(3), 747-758. 8.Wang J., He H., Yu L., Xia H.H.X., Lin M.C., Gu Q., Li M. , Zou B., An X.M., Jiang B., Kung H.F. and Wong B.C.Y. HSF1 down-regulates XAF1 through transcriptional regulation, Journal of Biological Chemistry, 2006, 281(5), 2451-2459. 9.Zou B, Chim CS, Zeng H, Leung SY, Yang Y, Tu SP, Lin MC, Wang J, He H, Jiang SH, Sun YW, Yu LF, Yuen ST, Kung HF and Wong B.C.Y. Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. Gastroenterology. 2006 131(6):1835-43. 10.Arora V, Cheung HH, Plenchette S, Micali OC, Liston P, Korneluk RG. Degradation of survivin by the X-linked inhibitor of apoptosis (XIAP)-XAF1 complex. J Biol Chem. 2007 Sep 7;282(36):26202-9. 11.Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000, 408(6810):307-10. 12.Jin S, Levine AJ. The p53 functional circuit. J Cell Sci. 2001 Dec;114(Pt 23):4139-40. 13.Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005 24(17):2899-908.

List of Research Outputs

Dai Y. , Qiao L. , Chan K.W. , Yang M. , Ye J. , Zhang R. , Ma J. , Zou B. , Lam S.C. , Wang J. , Pang R.W.C. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Adenovirus-mediated down-regulationof X-linked inhibito r of apoptosis protein inhibits colon cancer, Molecular Cancer Therapeutics . 2009, 8(9): 2762-2770.

Tu S.P., Sun R.W.Y. , Lin M.C. , Cui J.T., Zou B. , Gu Q. , Kung H.F., Che C.M. and Wong B.C.Y. , Gold (III) Porphyrin Complexes Induce Apoptosis and Cell Cycle Arrest and Inhibit Tumor Growth in Colon Cancer, Cancer . 2009, 115(19): 4459-4469.

Tu S.P., Sun Y.W., Cui J.T., Zou B. , Lin M.C. , Gu Q. , Jiang S.H., Kung H.F., Korneluk R.G. and Wong B.C.Y. , Tumor Suppressor XIAP-associated Factor 1 (XAF1) Cooperates with Tumor Necrosis Factor-related Apoptosis-inducing Ligand to Suppress Colon Cancer Growth and Trigger Tumor Regression, Cancer . 2010, 116(5): 1252-1263.

Zhang W. , Wang J. , Zou B. and Wong B.C.Y. , Four-and-a-half LIM protein 2 promotes invasive potential and epithelial-mesenchymal transition in colon cancer, Hong Kong Medical Journal . 2010, 16: 64.

Zou B. , Qiao L. and Wong B.C.Y. , Current Understanding of the Role of PPARgamma in Gastrointestinal Cancers, PPAR Research . 2009, 2009: 816957.

Zou B. , Lam S.C. , Zhang X. , Pang R.W.C. , Hung I.F.N. , Tan V.P.Y. , Lan H.Y. and Wong B.C.Y. , Krit1 inhibited proliferation and metastasis of human colon cancer via DPPIV signaling pathway.(Oral presentation), 15th Medical Research Conference. Hong Kong . 2010.

-- End of Listing -- Dept of Medicine

DEPT OF MEDICINE

Researcher : Au KW

List of Research Outputs

Researcher : Au WY

List of Research Outputs

Au W.Y. and Yeung C.K. , Acute promyelocytic leukemia in patients with severe psoriasis vulgaris, Leukemia Research . 2009, 33(11): e189-e190.

Au W.Y. , Current management of nasal NK/T-cell lymphoma, Oncology (Williston Park). . 2010, 24(4): 352-8.

Kwong Y.L. , Au W.Y. , Leung A.Y.H. and Tse E.W.C. , T-cell large granular lymphocyte leukemia: an Asian perspective, Annals of Hematology . 2010, 89(4) 331-339: 331-339.

Researcher : Bow CHY

List of Research Outputs

Soong S.S. , Loong C.H.N., Bow C.H.Y. , Wu J. and Kung A.W.C. , Factors Associated with Osteoporosis Treatment Adhere nce in Hong Kong, 11th Regional Osteoporosis Conference, Hong Kong . 2010.

Researcher : Chan AOO

List of Research Outputs

Researcher : Chan CK

List of Research Outputs

Researcher : Chan DTM

Project Title:	Identification of the cross reactive antigen(s) on proximal tubular epithelial cells that mediate anti-DNA antibody binding and subsequent inflammation
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2007
Completion Date:	10/2009

Abstract:

Project Title:	The role of anti-dsDNA antibodies in mediating fibrotic processes in human proximal tu bular epithelial cells
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2008

Abstract:

Project Title:	42nd Annual Meeting and Scientific Exposition (ASN Renal Week 2009) Effects of mycophenolic acid (MPA) and cyclophosphamide (CTX) on cytokine and matrix protein synthesis and apoptosis in human mesangial cells (HMC)
Investigator(s):	Chan DTM
Department:	Medicine
Source(s) of Funding:	URC/CRCG - Conference Grants for Teaching Staff
Start Date:	10/2009
Completion Date:	11/2009

Abstract:

N/A

Project Title:	Serum immunoglobulin levels and resident renal cell-binding in patients with severe lupus nephritis
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	Small Project Funding
Start Date:	11/2009

Abstract:

Project Title:	The role of annexin II in the pat hogenesis of lupus nephritis
Investigator(s):	Chan DTM, Yung SSY
Department:	Medicine
Source(s) of Funding:	General Research Fund (GRF)
Start Date:	01/2010