published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

The number of patients with colorectal cancer had increased dramatically in recent years (Hong Kong cancer registry, 2012), and surgical resection is the first line treatment of colorectal. To enhance patients’recovery process, there is a need to develop a comprehensive and user-friendly, with most important, an evidence-based guideline for promoting patients’ recovery process. Traditional post-operative management is associated with different postoperative complications, delayed recovery, and lengthened hospital stay. Recent research documented that using a specific rehabilitation programme focused on education; early mobilization and early diet regime could enhance patients’ recovery. Therefore, this transitional research aims to evaluate the current evidence on the effect of adopting a specific rehabilitation programme, to formulate an evidence-based guideline, assess its implementation potential, and to develop an implementation and evaluation plan. Ten related literature were retrieved from four electronic bibliographical databases. Critical appraisal had been done to ensure the quality and validity of the selected evidences. A clinical guideline is developed based upon the information from the identified high level of literature. The implementation potential is assessed based on the similarity and the readiness of the target setting to the proposed environment. It was found that the transferability of the protocol was high and it was feasible to be implemented into the target site. Little expenditure and input was expected, as the protocol was a systematic reformation of practice, rather that developing a set of totally new practice to current clinical setting. An implementation plan was then planned, which included the communication plan with all the stakeholders. After reaching a consensus among the stakeholders, a two-month pilot study will be carried out for examining the readiness before the full-scale implementation of the program. The evaluation plan of the effectiveness of the proposed program is developed. Result will be used to provide recommendation for further adjustment on the protocol to yield a better outcome. The implementation of this nurse-led rehabilitation program is suggested to be worthy of adoption in the clinical setting for bringing benefits to patients, the hospital and staffs. / published_or_final_version / Nursing Studies / Master / Master of Nursing

MicroRNAs (miRNAs) are a small non-coding RNAs that play a crucial role in cellular proliferation, differentiation and apoptosis by regulating gene expression via post-translation repression or degradation. They are involved in the regulation of various human diseases including colorectal cancer (CRC). CRC is the third most common cancer in the world and second leading cause of cancer death in Hong Kong and United States. Distant metastasis is the main cause of high mortality rate. In most CRC patients, liver is the most common site of distant metastasis, which is often associated with treatment failure and poor prognosis. While some patients with liver metastasis may still be amenable to surgical resection, most patients can only be treated with chemotherapy, which has limited in controlling the tumor progression. The pathological mechanism of metastasis in CRC is poorly understood. Cell motility is important for tumor invasion and metastasis, which require the interaction between tumor cells and their extracellular matrix. This interaction is regulated by the focal adhesion molecules. Recent evidence suggested that miRNAs affect the cell motility and invasiveness of various cancers, and regulate key steps in metastatic cascade. Investigation of the role of miRNAs in tumor development and metastasis can provide potential novel targets for treatment of colorectal liver metastasis or even other advanced cancers. In this study, expression of miR-885-5p was examined in CRC surgical specimens. Overexpression of miR-885-5p was observed in liver metastasis when compared with primary tumor and adjacent non-tumorous colon. The high expression level of miR-885-5p in primary colorectal tumors was positively associated with late TNM stage and development of metastasis, suggesting that its expression level can act a predictive marker for liver metastasis. Functional studies demonstrated that overexpression of miR-885-5p could significantly enhance the invasive phenotypes and metastatic properties of colorectal cancer cells through a series of in vitro and in vivo assays. Overexpression of miR-885-5p was correlated with increased expression of mesenchymal markers such as N-cadherin, vimentin and Snail, and decreased expression of epithelial marker such as E-cadherin. Moreover, overexpression of miR-885-5p enhanced the expression of Rho GTPases, which is a regulator of polarity, protrusion and adhesion. These results suggested that miR-885-5p overexpression might be a key step in tumor progression and metastasis via regulation of EMT pathway and Rho GTPases family. Knockdown of miR-885-5p enhanced chemosensitivity of CRC cells through induction of apoptosis. On the other hand, overexpression of miR-885-5p increased tumor proliferation through upregulation of the expression level of cyclin D1. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

The majority of sporadic colorectal cancer (CRC) cases affects individuals over the age of 50, but about 10% of cases occur in young adults under 50 in Hong Kong. Apart from germline mutation of the DNA mismatch repair genes that predisposes to early-onset CRC with a high-level of microsatellite instability (MSI-H), it is unknown if the mechanisms that give rise to CRC in other young adults differ from those in older individuals. In an effort to understand the genetic and epigenetic basis of early and late-onset CRC outside the Lynch Syndrome setting, we performed a detailed characterization of 36 MSI-H and 198 non-MSI-H tumours from patients of varying ages. This characterization was based primarily on the presence of the CpG island methylator phenotype (CIMP), as measured by the level of DNA methylation; and presence of genetic instability, as measured by DNA copy number aberrations, as well as mutations in BRAF, KRAS, or TP53. Our findings revealed that early (≤50) and late-onset (>50) CRCs have different genetic and epigenetic features. In non-MSI-H cancers, CIMP-H was associated with early-onset, while CIMP-L and KRAS mutation was associated with late-onset. However, in MSI-H tumours, late-onset disease was associated with CIMP-H and BRAF mutation. In addition, promoter methylation of MLH1 in early-onset MSI-H patients had a higher frequency of occurring in the germline that was locus specific, whereas nearly all late-onset MSI-H patients showed somatic regional methylation at the MLH1 locus, as well as regional methylation on other chromosomes. This is the first study to show regional methylation at chromosome 9p21 and 7p14, which encompass the CIMP markers P16 and ELMO1, respectively. We also observed an association between regional methylation and CIMP-H, but in MSI-H cases it was linked with late-onset, whereas in non-MSI-H cases it was irrespective of age. This suggests that mechanisms of methylation seeding and spreading may be different in early and late-onset disease. Moreover, CIMP-H non-MSI-H cases had significantly worse prognosis (p=0.021 for overall survival, p=0.004 for disease-free survival) and poor response to chemotherapy compared to CIMP-L or CIMP-Neg cases. Lastly, a methylation score assigned to non-MSI-H patients based on the degree of methylation of known CIMP markers was a significant prognostic factor of disease-free survival (p=0.004), and patients with a high methylation score showed a poor response to chemotherapy. Thus, our results suggest that different genetic and epigenetic mechanisms may drive tumourigenesis in early and late-onset disease. Although further research will be needed to elucidate the exact nature of these mechanisms, our findings should help to improve current classification of CRC patients with a goal towards personalized treatment. / published_or_final_version / Pathology / Doctoral / Doctor of Philosophy

Substantial studies have investigated homogeneity of psychological distress level among cancer patients by using cross-sectional and longitudinal study design. Nonetheless, as proposed by Bonnano (2004), heterogeneity characteristics of psychological distress following stressful event could not be neglected and he further suggested that the majority of individuals were resilient in response to stressful events. To test this postulation, recent studies employed growth mixture modelling method to examine the heterogeneity characteristics of psychological distress trajectory among cancer patients. Furthermore, identifying relevant factors differentiate the psychological distress trajectories is an integral part for developing effective interventions for cancer patients in dealing with illness demands. However, only a few studies have examined these issues among Chinese colorectal cancer patients, a second most common cancer in Hong Kong. Therefore, it is of important need to address this knowledge gap. This study had two major aims: 1) to explore the patterns of psychological distress among Chinese patients with colorectal cancer from shortly after diagnosis but before surgery (i.e. 1-day prior operation) to 1-year post-surgery and to testify Bonnano’s theory on resilience; 2) to identify the effects of cancer-related intrusive thoughts, physical symptom intrusiveness and dispositional optimism on differentiating psychological distress trajectories. A total of 246 Chinese patients with colorectal cancer were recruited for the current study. Altogether, 5 consecutive face-to-face interviews were conducted on one day prior to surgery (baseline), 1-, 4-, 8- and 12-month post-surgery (T2-T5). Patients’ psychological distress (i.e. anxiety and depression), physical symptom intrusiveness, cancer-related intrusive thoughts, dispositional optimism, demographic and medical information were assessed by a standardised questionnaire with valid and reliable psychometric instruments. Growth mixture modelling was used to estimate and specify the psychological distress trajectories. Multinomial logistic regression was adopted to assess the proposed factors in relation to differentiate the trajectory patterns. Growth mixture modelling suggested three distinct trajectories were identified for both anxiety and depression model. The majority of patients with colorectal cancer were identified as resilient (i.e. maintaining low and stable distress level across time) for both models (anxiety: 82.3%, depression: 82.7%). Additionally, for anxiety trajectory model, the remaining 12.3% and 5.4% of patients were classified as moderately-low anxiety group (i.e. maintaining moderate to low distress level) and increasing anxiety group (i.e. increased from moderate level of distress at initial to subsequently high distress level) respectively. For depression trajectory model, the remaining 12.6% and 4.7% of the patients were grouped as delayed depression (i.e. delayed level of distress over time) and recovery depression (i.e. recovered from high distress level to low across time). Multinomial logistic regression showed that cancer-related negative intrusive thoughts, physical symptom intrusiveness and dispositional optimism were significant factors to differentiate anxiety and depression trajectories respectively. This study highlighted the heterogeneous feature of psychological distress among Chinese patients with colorectal cancer. Physical symptom intrusiveness, cancer-related negative intrusive thoughts and dispositional optimism played important role on predicting cancer patient’s psychological distress respectively. Nonetheless, further investigations are much needed to clarify the underlying mechanism. / published_or_final_version / Public Health / Master / Master of Philosophy

Cancer stem cells are a subpopulation of cells needed for cancer initiation and progression. Previous works have revealed CD26-expressing colorectal cancer (CRC) stem cells are not only endowed with tumor-initiating properties, but also capable of conferring metastasis. However, whether the CD26 molecule plays role in metastasis and the underlying mechanism by which CD26 may mediate metastasis remain unclear. This study aims to reveal the biology and the molecular characteristics of the CD26-expressing CRC stem cells. Here, by the gene manipulation experiment, we showed that CD26 molecule is a functional marker that confers metastasis as transient and stable knock-down of the CD26 molecule in the CRC stem cells resulted in reduced wound healing, migration and invasion abilities in vitro and the capability to generate metastatic liver nodules in vivo, respectively. With the use of genome-wide expression array and immuno-blotting analysis, Smad-dependent TGF-β signaling, orchestrated by the SMAD2, SMAD3 and SMAD4 molecules, was up-regulated and activated in the CD26 expressing colorectal CSCs. In addition, expressions of the SMAD2 and SMAD3 molecules were found to be positively correlated with the CD26 molecule in clinical samples by qPCR and immunohistochemistry studies. Furthermore, no metastasis through EMT could be achieved once the Smad-dependent TGF-β signaling was down-regulated in the CD26 expressing CRC stem cells, which suggested that Smad-dependent TGF-β signaling was necessary for CD26-expressing CRC stem cells to induce metastasis. Finally, our result showed that the Smad-dependent TGF-β signaling was regulated by the CD26 molecule possibly through the down-regulation of CAV1 protein. To conclude, our findings have not only revealed the functional role of CD26 molecule, but have also unveiled a linkage between the CD26 molecule and Smad-dependent TGF-β signaling. Further study of this connection may introduce a novel mechanism, through which CRC metastasis can be induced by this functional CD26 marker of CRC stem cells. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / toc / Medicine / Master / Doctor of Medicine

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

published_or_final_version / Anatomy / Master / Master of Philosophy

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