Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western societies. Despite significant progress in understanding the molecular pathology of PC and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility. Affymetrix Genechipfi oligonucleotide microarrays were used to interrogate mRNA expression of PC and normal pancreas to identify molecular pathways dysregulated in PC. Analysis of these data identified altered expression of numerous components of the S100 Calcium Binding Protein Family, Retinoic Acid signalling pathway and the HOX transcriptional network in PC compared to normal pancreas. These pathways were assessed using immunohistochemistry (IHC) and in-situ hybridisation (ISH) in a cohort of patients with PC. Increased protein expression, of S100A2, S100A6 and S100P was observed in 43%, 60% and 48% of PC respectively. Expression of S100A2 was associated with a poor outcome (p = 0.009), whilst increased expression of S100A6 (p = 0.0008) and S100P (p = 0.0005) were associated with an improved outcome. Additionally, S100A2 expression was identified as an independent marker of outcome in resected tumours. Aberrant expression of retinoic acid signalling components was demonstrated in PC cell lines using semi-quantitative RT-PCR. ISH demonstrated expression of Retinoic Acid Induced 3 (RAI3), an orphan G protein coupled receptor normally expressed in the fetal lung, in 68% of PC, and this co-segregated with an improved overall survival (p = 0.026).Ectopic protein expression of HOXB2, a transcription factor normally expressed in the developing hindbrain and modulated by retinoic acid, was observed in 15% of early PanIN lesions and 38% of PC specimens. Expression of HOXB2 was associated with non-resectable tumours and was an independent predictor of poor survival in resected tumours. Suppression of HOXB2 protein expression using small interfering RNA, resulted in epithelioid trans-differentiation in the Panc-1 PC cell line, however no alteration in proliferation rates were observed compared to controls. This thesis has shown that transcript profiling and tissue validation has identified potential markers of early diagnosis and outcome in PC. Furthermore, pathways and molecules previously thought to be associated with normal human development have been implicated to play a role in the development and progression of PC. Further analyses of these markers will determine any potential role in future diagnostic and therapeutic strategies.

Diversity analysis of Escherichia coli have routinely utilised isolates obtained by culture of faeces on MacConkey selective media, under the assumption that the diversity identified in faecal isolates are representative of similar diversity in E. coli in the gastrointestinal tract (GIT). This study has addressed this important issue by specifically isolating E. coli from different regions of the gut in pigs and subjecting them to enzymatic multilocus enzyme electrophoresis (MLEE) and molecular virulence factor (VF) analysis to ascertain whether E. coli populations inhabiting different regions of the gut are different from each other. Combination of these results showed that on average, E. coli strains isolated from the upper GIT region (small intestine) of the pig are distinctly different from the E. coli strains isolated from the lower GIT region (large intestine). An important aspect of the finding that faecal E. coli are not truly representative of the diversity in the GIT is the mechanism used by specific clonotypes that have adapted to different geographical habitats to survive challenge from incoming strains. / Doctor of Philosophy (PhD)

Transpyloric flow is the final step in gastric emptying prior to intestinal absorption of nutrients and medications. The details of this process are still incompletely understood. Transpyloric flow is bi-directional, contrasting with the general perception of solely forward flow implied by studies of gross gastric emptying. The degree to which the patterns of bi-directional transpyloric flow reflect emptying of meals of varied physicochemical composition, its mechanical determinants and effect on delivery of oral medications have been evaluated by the studies presented in this thesis.

Bibliography: leaves 209-252. / xvi, 252 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to develop and apply accurate methods of measurement of pyloric motor function and gastric emptying to an unsedated large animal preparation. / Thesis (D.M.)--University of Adelaide, Dept. of Surgery, 1994?

Thesis (Ph. D.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 169-184). Also available on the Internet.

Thesis (M.S.)--Virginia Polytechnic Institute and State University, 2000. / Title from PDF t.p. (viewed on Dec. 11, 2005). Vita. Includes bibliographical references (p. 36-40).

Thesis (Ph. D.)--University of Missouri-Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 169-184). Also available on the Internet.

published_or_final_version / abstract / toc / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Zoology / Doctoral / Doctor of Philosophy