Bibliography: leaves 150-166. / ix, 166, xxii leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / To assess the role of acetylator status and glutathione S-transferase[mu] (GST[mu]) null phenotype on the risk for development of colorectal neoplasms in humans and to determine whether this was influenced by the dietary intake of meat. / Thesis (M.D.)--University of Adelaide, Dept. of Medicine, 1995?

Colorectal cancer (CRC) is a major problem in affluent countries worldwide. In Australia it is the second most commonly diagnosed malignancy with approximately 13,000 new cases diagnosed each year. This disease is also the leading cause of cancer related death in Australia with approximately 4,500 fatalities each year. Epidemiological studies have shown geographical variation in the incidence of disease, with diet considered to be a key contributing factor to CRC risk. In particular, diets high in fibre and low in fat have been demonstrated to reduce the risk of developing CRC. Fibre is heterogeneous in nature and can be categorised into different subtypes. Resistant starch is a component of fibre which remains largely intact throughout the gastrointestinal tract until it reaches the colon. Here it undergoes bacterial fermentation to produce the short chain fatty acids (SCFAs) acetate, propionate and butyrate (BuA). Each of the SCFAs are bioactive in the colon, with the most active being BuA. The beneficial effects of fibre have been linked to BuA’s ability to induce colon cancer cell differentiation, reduce proliferation and initiate apoptosis. Interestingly, in normal cells BuA is utilised as the preferential energy source and has been shown to promote proliferation. With an apparent “paradoxical effect” on normal and cancerous cells BuA has been the subject of much investigation as a potential anticancer agent. Despite numerous studies investigating BuA actions, the exact biological mechanisms remain largely undefined. This thesis explored a possible mechanism for BuA-induced apoptosis and inhibition of proliferation. In 2003, two publications provided evidence that SCFAs, including BuA, were ligands to two members of a previously orphan family of G-protein coupled receptors (GPCRs); GPCR41 and 43. Of the two receptors BuA had the strongest effect on GPCR43. Consequently this thesis investigated the possibility that BuA acts to decrease CRC proliferation and induce apoptosis by binding to and activating GPCR43 on CRC cells. It was hypothesised that GPCR43 acted as a “BuA sensor” on the surface of the cell to mediate the effects of BuA. This experimental work utilised PCR, Q-PCR, measures of apoptosis, proliferation and differentiation and RNAi knockdown. The key areas of investigation included: (1) Determining if GPCR43 was present on a range of CRC cell lines with a cell line to represent adenocarcinoma, carcinoma and metastatic stage of disease. (2) Investigating the expression of GPCR43 with manipulated nutrient media and different levels of cell confluence. (3) Exploring GPCR43 expression in normal and malignant human patient biopsies. (4) Determining if the inhibition of G-protein function using inhibitors influenced BuAinduced changes to apoptosis and proliferation. (5) Using RNAi, investigating the effect that GPCR43 knockdown would have on BuA-induced changes to proliferation and apoptosis. The key findings from this work included: (1) Presence of GPCR43 on some but not all CRC cell lines. (2) Modulation of GPCR43 expression with exposure to BuA and altered glucose concentrations in the media. (3) An influence of G-protein inhibition on BuA-induced apoptosis but not proliferation in some cell lines. (4) GPCR43 knockdown using RNAi indicated that GPCR43 is not exclusively required for BuA to regulate apoptosis and proliferation. The results from this work indicate that GPCR43 is not likely to exclusively mediate BuA’s effects, but opens up new areas of research into the exact role of GPCR43 on CRC cells. / Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2008

Graduation date: 2006

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / Typescript. Vita. Includes bibliographical references (leaves 95-113). Also available on the Internet.

Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2003. / Includes bibliographical references (leaves 95-105). Also available in electronic version. Access restricted to campus users.

published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Colorectal cancer (CRC) is the second most common cancer in Hong Kong. While high-penetrance germline mutations account for up to 6% of cases, much of the variation in genetic risk may be attributable to multiple low-penetrance variants. Previous genome wide association studies (GWAS) have identified a number of CRC susceptibility alleles in Caucasian populations. Our GWAS investigated the association between genetic variants with CRC risk in the Han Chinese population in Hong Kong. In Stage I, genomic DNA samples from 455 female Chinese CRC subjects were genotyped using the Illumina 610 Quad SNP chip. Association analysis was performed on 439 cases and 771 general population female controls recruited for a study on bone mineral density. Population stratification was examined through principal components analysis using EIGENSTRAT version 2.0. From the association results, 46 SNPs (Group 1) were selected for follow-up replication (Stage II), together with 10 SNPs (Group 2) from previous GWAS studies. Genomic DNA samples from 3,571 Chinese subjects were genotyped using Sequenom MassARRAY system. Association analysis was performed on 1,505 cases and 1,452 controls. 5 SNPs (rs835378, rs2652007, rs2139273, rs2139273 and rs9286410) exceeded the genome-wide significance level in stage I, although none replicated in Stage 2, suggesting genotyping error. Results from stage II showed that the three most significant SNP were among those selected from the previous studies, yet their significance levels in Stage I were very weak . None of the SNPs selected from Stage I was significant at p<0.01 in Stage 2. Two composite scores of genetic susceptibility, one for each group of SNPs, were calculated in stage II genotype data, as the total number of high-risk alleles (according to the direction of effect in Stage I results or previous GWAS) present in an individual. Both composite scores were significantly associated with CRC risk in Stage 2 (Group 1, p=2.38 x 10-5, beta=0.046, SE=0.012; Group 2 p=1.06 x 10-7, beta=0.10, SE=0.019), suggesting that while we had insufficient power to confirm individual SNPs identified in our GWAS and the previous GWAS, these findings indicate that the SNP sets selected from Stage I results, as well as those selected from previous GWAS, contain SNPs with genuine effects on CRC risk. One SNP, rs10795668 (OR = 0.79 [CI] 95%:0.71 – 0.87 p=3.78 x 10-6), was significantly associated with CRC risk in Stage II after adjustment for multiple testing. Two further SNPs, rs6983267 and rs4939827, also achieved suggestive p-values in Stage II. All these SNPs were selected from previous GWAS in the Caucasian population, demonstrating that shared genetic factors operate for CRC in diverse populations. / published_or_final_version / Psychiatry / Master / Master of Philosophy

Polycomb group (PcG) proteins governs the regulation of diverse cellular functions, such as cell fate decision, cell cycle progression, maintenance of embryonic stem cell pluripotency, and DNA damage repair. Although aberrant expression of PcG proteins has been frequently reported in different cancer types, CBX8 is one of the least studied PcG family members in cancer. Recently, a study showed that forced expression of CBX8 in normal human and mouse fibroblasts demonstrated that cells could bypass senescence via INK4a-ARF repression; while another report demonstrated that CBX8 was involved in MLL-AF9-linked leukemogenesis. Despite accumulating evidence on CBX8-related carcinogenic functions, the role of CBX8 in solid cancers has not been investigated thus far. This study is therefore initiated to investigate and establish the functional role of CBX8 in colorectal cancer. In this study, expression of CBX8 in 121 pairs of human CRC samples was analyzed by immunohistochemistry; and data were correlated with different clinicopathological parameters. To evaluate the functional effects of CBX8, CBX8 overexpressed and downregulated clones were established from three CRC cell lines. The in vitro effects of CBX8 on cell proliferation, cell cycle progression and apoptosis profiles were investigated; and the effects of CBX8 on tumorigenicity in vivo were further demonstrated in mice xenograft models. The results showed that CBX8 expression was downregulated or loss in approximately 48.8% of human colorectal tumors, and downregulated or loss of CBX8 expression were mainly observed in tumors with intermediate to later stages (stage II to IV). Moreover, expression of CBX8 showed a significant inverse correlation with colorectal tumor sizes (P < 0.0001). Ectopic expression of CBX8 in CRC cell lines resulted in inhibition of cell proliferation, clonogenic ability and anchorage-independent growth, which are hallmarks of tumorigenesis. Conversely, downregulation of CBX8 promoted proliferation and clonogenic ability. Moreover, it was found that restoring CBX8 expression could induce G0/G1 arrest of cell cycle. The tumor suppressive role of CBX8 in colorectal cells was further demonstrated in vivo through subcutaneous and orthotropic mice tumor models; followed by immuno-staining of the proliferation marker Ki-67. To unveil the possible mechanisms behind the tumor suppressing effects of CBX8, two signalling pathways commonly engaged in CRC were evaluated. At least part of the effects could be attributed to the mediation of MAPK signaling pathway; whereas the Wnt signalling was not affected by CBX8. This study demonstrated for the first time the loss of CBX8 expression in intermediate and late stage tumors, and was the first to report the tumor suppressing ability of CBX8 in solid cancers. The effects of CBX8 in this study were different to the functional implications reported in the current literature. This functional divergence in distinct cell types suggested a dynamic role of CBX8 depending on specific cellular context. / published_or_final_version / Surgery / Master / Master of Philosophy

Colorectal cancer has been a major health issue worldwide. Not only it affects the patients but it also carries physical and psychological influences to their caregivers. Despite the concerns of the psychological needs of caregivers of colorectal cancer patients, there has been a lack of a good understanding of their needs, and how to intervene in order to alleviate their psychological problems and burdens. Therefore, this thesis aimed at designing and evaluating a nurse-led telephone based psychosocial education program for improving the psychological conditions and quality of life among Chinese caregivers of patients with colorectal cancer. The nurse-led telephone based psycho-educational program was designed based on the transactional model of stress and copying. It was piloted on 6 caregivers and refined. Its efficacy over the patients discharged under the ‘usual routine hospital standard discharge care procedure’ was assessed in a randomized controlled trial on 140 Chinese caregivers of colorectal cancer patients. Caregivers in the intervention group received three telephone calls from an experienced Nurse Interventionist at 1, 3 and 5 weeks after the patients’ discharge. Each call addressed any unmet needs of the caregivers with the provision of education and psychological support. At baseline, 2 weeks, 4 weeks and 8 weeks, all caregivers were assessed for the primary outcome of depression measured by the Depression Anxiety Stress Scale (DASS), and for the secondary outcomes of anxiety, stress, burden of care and quality of life. The mixed effects model, which takes into account the extra-covariance among repeated measurements, and which is consistent with the intention-to-treat principle, was used in the efficacy analysis. Of the 140 caregivers recruited in the randomized controlled study, 5 dropped out before the end of the study. However, all the caregivers were included in the analysis. There was no significant baseline difference between the intervention and ‘usual care’ groups. The psycho-education program reduced depression more than the ‘usual care’ group by2.7 (95% CI = 0.6 to 4.8, p=0.013) units in DASS at 2 weeks, and even more by 3.5 (95% CI = 1.7 to 5.24, p<0.001) at 4 weeks. However, the ‘usual care’ group caught up at 8 weeks, and no significant effect of the psycho-education program was found (p=0.144). Moreover, the program also reduced anxiety and stress more than the ‘usual care’ group by1.83 (95% CI = 0.61 to 3.50, p=0.004) and 3.50 (95% CI = 1.74 to 5.25, p<0.001) respectively at follow-up. In addition, the burden of care and quality of life were also generally improved more in the psycho-education program group. Furthermore, strong positive associations among depression, stress, anxiety, and burden of care were found. Caregivers perceived to have a high burden of care would be associated with more depression, stress or anxiety(r = 0.53, p<0.001). Moreover, depression, anxiety, and stress had a strong negative association with the physical, psychological, social relationship and environmental well-being but not with social relationships(r = -0.16, p = 0.550). In conclusion, this thesis has developed the first nurse-led telephone based psycho-education program for caregivers of colorectal cancer patients. The program can effectively help caregivers in reducing their feelings of stress from depression, anxiety, stress and the burden of care, as well as improving their quality of life. It paves the way for a new direction for a comprehensive colorectal cancer care service in addressing the caregivers’ needs. / published_or_final_version / Nursing Studies / Doctoral / Doctor of Nursing