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Chu Wai Kit. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 87-96). / Abstracts in English and Chinese. / Acknowledgments --- p.ii / Publication --- p.iii / List of Abbreviations --- p.iv / List of Tables --- p.v / List of Figures --- p.vi / Abstract --- p.vii / 摘要 --- p.x / Table of Contents --- p.xii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Epidemiology of gastric cancer --- p.1 / Chapter 1.2 --- Risk factors associated with gastric cancer --- p.7 / Chapter 1.3 --- Prevention of Gastric Cancer --- p.9 / Chapter 1.4 --- H. pylori eradication and gastric cancer development --- p.11 / Chapter 1.5 --- Non-steroidal anti-inflammatory drugs and gastric cancer prevention --- p.13 / Chapter 1.6 --- COX-2 independent pathway --- p.14 / Chapter 1.7 --- Animal model of gastric cancer --- p.15 / Chapter 1.8 --- Microarray system --- p.16 / Chapter 1.9 --- Hypothesis --- p.18 / Chapter 1.10 --- Aim of study --- p.19 / Chapter Chapter 2 --- Chemoprevention of gastric cancer by celecoxib --- p.20 / Chapter 2.1 --- Introduction --- p.20 / Chapter 2.2 --- Material and Methods --- p.22 / Chapter 2.2.1 --- Animals --- p.22 / Chapter 2.2.2 --- Chemicals --- p.22 / Chapter 2.2.3 --- Study design --- p.23 / Chapter 2.2.4 --- Cell Culture --- p.24 / Chapter 2.2.5 --- Celecoxib treatment --- p.24 / Chapter 2.2.6 --- Cell proliferation assay --- p.25 / Chapter 2.3 --- Results --- p.26 / Chapter 2.3.1 --- Chemoprevention of gastric cancer by celecoxib in rats --- p.26 / Chapter 2.3.2 --- Effects of celecoxib on growth of human gastric cancer cells --- p.29 / Chapter 2.4 --- Discussion --- p.30 / Chapter 2.4.1 --- MNNG induced gastric cancer effectively --- p.30 / Chapter 2.4.2 --- Celecoxib significantly suppressed gastric carcinogenesis in rats --- p.31 / Chapter 2.4.3 --- Celecoxib inhibited the growth of MKN 45 in a concentration-dependent manner --- p.31 / Chapter 2.4.4 --- Celecoxib may exert its anti-tumor property through COX independent pathway --- p.32 / Chapter Chapter 3 --- Gene expression profiles of celecoxib treated rat gastric tumor and human gastric cells --- p.34 / Chapter 3.1 --- Introduction --- p.34 / Chapter 3.2 --- Material and Methods --- p.34 / Chapter 3.2.1 --- RNA extraction --- p.34 / Chapter 3.2.2 --- Target preparation and Array hybridization --- p.35 / Chapter 3.2.3 --- Post-hybridization processing and Scanning --- p.36 / Chapter 3.2.4 --- Microarray data analysis --- p.36 / Chapter 3.2.5 --- Quantitative RT-PCR --- p.37 / Chapter 3.3 --- Results --- p.39 / Chapter 3.3.1 --- Gene expression profiles of rat gastric tumors --- p.39 / Chapter 3.3.1.1 --- Genes differentially expressed in MNNG induced gastric tumors --- p.39 / Chapter 3.3.1.2 --- Genes differentially expressed in celecoxib treated group --- p.42 / Chapter 3.3.1.3 --- Mechanisms underlying chemoprevention of celecoxib --- p.43 / Chapter 3.3.2 --- Verification of gene expression by quantitative RT-PCR --- p.55 / Chapter 3.3.3 --- Confirmation of the gene expression profiles in human by quantitative RT-PCR --- p.59 / Chapter 3.4 --- Discussions --- p.63 / Chapter Chapter 4 --- Effects of celecoxib on Akt pathway in gastric cancer cells --- p.68 / Chapter 4.1 --- Introduction --- p.68 / Chapter 4.2 --- Material and methods --- p.72 / Chapter 4.2.1 --- Protein extraction --- p.72 / Chapter 4.2.2 --- Western blotting --- p.72 / Chapter 4.3 --- Results --- p.74 / Chapter 4.3.1 --- Expression of the Akt pathway after treatment with celecoxib --- p.74 / Chapter 4.4 --- Discussions --- p.78 / Chapter Chapter 5 --- Conclusion --- p.82 / References --- p.87

Includes list of publications arising from this thesis / Erratum attached to inside back cover. / "25/03/2004." / Includes bibliographical references (leaves 185-257) / xii, 257 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine and Royal Adelaide Hospital, Rheumatology Unit, 2004

[Truncated abstract] Hepatocellular carcinoma (HCC) is the major malignancy complicating chronic liver disease. New therapies for the prevention of HCC are required due to the limited success and high tumour recurrence rates of existing treatments. Emerging evidence suggests that HCC arise from the transformation of adult liver progenitor cells (LPCs), which have the capacity to differentiate into hepatocytes and biliary cells during liver regeneration. LPC activation precedes neoplasia in experimental hepatocarcinogenesis. LPCs share antigenic epitopes with HCCs, including α-fetoprotein (AFP) and M2- pyruvate kinase (M2PK). In animal models of hepatocarcinogenesis, attenuation of the LPC response reduces the incidence of HCC following prolonged liver injury via a tumour necrosis factor (TNF) dependent mechanism. As TNF is a pro-inflammatory cytokine, these data suggest that anti-inflammatory agents may be effective in inhibiting LPC activation and hepatocarcinogenesis. Cyclo-oxygenase-2 (COX-2) is an inducible enzyme that mediates the production of many prostaglandins during inflammation and carcinogenesis. Recent investigations show that the administration of selective COX-2 inhibitors (SC2Is) may reduce the incidence of a variety of tumours including breast, colon and skin. The broad aim of this thesis was to conduct a series of detailed studies on the effects of a SC2I on LPC activation and the hepatic pathologies associated with hepatocarcinogenesis in order to test the hypothesis that S2CIs may be a beneficial therapy that can reduce liver injury and pre-neoplastic changes in the choline-deficient, ethionine supplemented (CDE) murine model of hepatocarcinogenesis. Administration of a SC2I (SC-236) significantly inhibited a variety of hepatic cell populations that expand during the first month of the CDE mouse model of hepatocarcinogenesis (a choline deficient, ethionine supplemented diet). Numbers of M2PK-positive LPCs (which are more hepatocytic in morphology and are also COX-2 positive) and inflammatory cells were all significantly reduced by SC-236. In contrast, numbers of A6-positive LPCs (which are more biliary cell-like in morphology and do not express COX-2) were unchanged. ... In summary, these data suggest that COX-2 inhibitors such as SC-236 inhibit LPC activation and a variety of pre-neoplastic liver pathologies as a result of COX-2 dependent and independent mechanisms that may be mediated through inhibition of Akt phosphorylation and induction of apoptosis. Moreover, SC2Is may be useful as preventative treatment strategies for HCC in patients with chronic liver disease.

Ho Toi Sze Joyce. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (leaves 65-74). / Abstracts in English and Chinese. / Acknowledgement --- p.ii / Contents --- p.iii / Abstract --- p.viii / List of Abbreviations --- p.xvii / List of Tables --- p.xix / List of Figures --- p.xx / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- The role of Non-steroidal anti-inflammatory drugs (NSAIDs) --- p.1 / Chapter 1.2 --- NSAID-induced gastrointestinal (GI) toxicity --- p.1 / Chapter 1.2.1 --- Pathogenesis of NSAID-induced GI toxicity --- p.2 / Chapter 1.2.2 --- GI symptoms --- p.4 / Chapter 1.2.3 --- GI ulcers --- p.4 / Chapter 1.2.4 --- GI complications --- p.5 / Chapter 1.2.5 --- Risk factor for GI complications --- p.6 / Chapter 1.2.6 --- Ulcerogenicity of different NSAIDs in upper GI events --- p.6 / Chapter 1.3 --- Prevention of NSAID-induced GI toxicity --- p.7 / Chapter 1.3.1 --- H2-receptor antagonists --- p.8 / Chapter 1.3.2 --- Misoprostol --- p.8 / Chapter 1.3.3 --- Proton Pump Inhibitor (PPI) --- p.9 / Chapter 1.3.4 --- Selective COX-2 Inhibitors --- p.10 / Chapter 1.3.4.1 --- GI safety of selective COX-2 inhibitors --- p.11 / Chapter 1.3.4.1.1 --- Gastrointestinal outcomes research of rofecoxib --- p.13 / Chapter 1.3.4.1.2 --- Celecoxib Long term Arthritis Safety Study --- p.14 / Chapter 1.3.4.2 --- Cardiovascular toxicity of NSAIDs --- p.15 / Chapter 1.3.4.2.1 --- Cardiovascular toxicity of non-selective NSAIDs --- p.15 / Chapter 1.3.4.2.2 --- Cardiovascular toxicity of selective COX-2 inhibitors --- p.16 / Chapter 1.4 --- Guidelines on the management of osteoarthritis (OA) and rheumatoid arthritis (RA) --- p.21 / Chapter 1.4.1 --- American College of Rheumatology (ACR) Subcommittee --- p.22 / Chapter 1.4.2 --- National Institute for Clinical Excellence (NICE) --- p.23 / Chapter 1.4.3 --- Hong Kong Hospital Authority (HA) --- p.23 / Chapter 1.5 --- Cost of illness of upper GI events in the setting of an emergency room of a regional hospital in Hong Kong and cost analysis of selective COX-2 inhibitor with non-selective NSAID plus gastroprotective agent --- p.24 / Chapter 1.6 --- Objectives --- p.25 / Chapter Chapter 2 --- Cost of illness of upper GI events in the setting of an emergency room of a regional hospital in Hong Kong --- p.26 / Chapter 2.1 --- Methods --- p.28 / Chapter 2.1.1 --- Study site --- p.28 / Chapter 2.1.2 --- Cohort participants --- p.28 / Chapter 2.1.3 --- Resource data collection --- p.29 / Chapter 2.1.4 --- Cost data --- p.30 / Chapter 2.1.5 --- Statistical Methods --- p.31 / Chapter 2.1.6 --- Study perspective --- p.31 / Chapter 2.2 --- Results --- p.31 / Chapter 2.2.1 --- Demographic data --- p.31 / Chapter 2.2.2 --- Total direct medical cost of upper GI complaints in UCH --- p.33 / Chapter 2.3 --- Discussion --- p.35 / Chapter 2.3.1 --- Total direct medical cost of upper GI events --- p.35 / Chapter 2.3.2 --- Cost of upper GI events associated with NSAID usage --- p.38 / Chapter 2.3.3 --- Low dose aspirin on NSAID-induced GI toxicity --- p.38 / Chapter 2.3.4 --- Limitation --- p.39 / Chapter 2.3.5 --- Future study --- p.41 / Chapter 2.4 --- Conclusion --- p.41 / Chapter Chapter 3 --- Cost analysis of selective COX-2 inhibitor versus non-selective NSAID with gastroprotective agent --- p.43 / Chapter 3.1 --- Methods --- p.46 / Chapter 3.1.1 --- Local randomized clinical trial --- p.46 / Chapter 3.1.1.1 --- Study population --- p.46 / Chapter 3.1.1.2 --- Cost data --- p.47 / Chapter 3.1.1.3 --- Statistical Methods --- p.48 / Chapter 3.1.1.4 --- Sensitivity analysis --- p.49 / Chapter 3.1.2 --- Large randomized clinical trial --- p.49 / Chapter 3.1.2.1 --- Study population --- p.49 / Chapter 3.1.2.2 --- Cost data --- p.50 / Chapter 3.2 --- Results --- p.50 / Chapter 3.2.1 --- Local randomized clinical trial --- p.51 / Chapter 3.2.1.1 --- Demographic data --- p.51 / Chapter 3.2.1.2 --- Cost analysis --- p.52 / Chapter 3.2.1.3 --- Sensitivity analysis --- p.53 / Chapter 3.2.2 --- Large randomized clinical trial --- p.54 / Chapter 3.2.2.1 --- Demographic data --- p.54 / Chapter 3.2.2.2 --- Cost analysis --- p.55 / Chapter 3.3 --- Discussion --- p.55 / Chapter 3.3.1 --- Cost analysis --- p.55 / Chapter 3.3.2 --- Sensitivity analysis --- p.59 / Chapter 3.3.3 --- Low dose aspirin on NSAID-induced GI toxicity --- p.59 / Chapter 3.3.4 --- Limitation --- p.60 / Chapter 3.4 --- Future study --- p.62 / Chapter 3.5 --- Conclusion --- p.62 / Chapter Chapter 4 --- Conclusion --- p.63 / Chapter Chapter 5 --- Reference --- p.65 / Appendix Data collection form --- p.75