published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Community Medicine / Doctoral / Doctor of Philosophy

NK-cell malignancies (NKLL) consist of two separate entities: Extranodal NK-cell lymphoma, nasal type (ENKL) and aggressive NK-cell leukemia (ANKL). ENKL is the second most common group of extranodal lymphomas in Hong Kong. Deletions in the 6q21 region in ENKL have been consistently reported in the literature and differential expression data indicated that the transcription factor PRDM1 (PR domain containing 1, with ZNF domain) located at 6q21-q22.1 is a candidate TSG in NK-cell neoplasms. PRDM1 exists as 2 isoforms generated from the same gene by alternative transcription promoter. PRDM1- differs from PRDM1-βin that it lacks the amino-terminal 101 amino acids with a disrupted PR domain. As the PRDM1- is functionally impaired, with a loss of repressive function on multiple target genes while maintaining normal DNA-binding activity, we hypothesize that the  -isoform, which is overexpressed in NKLLs, may act as a negative regulator of the tumor suppressive α-isoform in NKLLs. In this study, we investigated the possible role of PRDM1- as a negative regulator of tumor suppressor PRDM1-α in NK-cell lymphoma by using a gene silencing technique. Short hairpin-RNA (sh-RNA) construct with sequence targeting to PRDM1- purchasing from biotechnology company was used to knockdown of the gene expression. Series of functional assays were then performed to evaluate the effect of the PRDM1-  knockdown in two NK cell line, YT and NKYS, which xpress endogenous PRDM1-. Comparison was made between the 1) shRNA targeting to nt65-nt94 of PRDM1- sequence, sh-PRDM1 -pGFP-V-RS (shV2), and 2) scrambled-pGFPV-RS (scrambled shRNA), negative control with a non-effective shRNA cassette in pGFP-VRS plasmid. Western blot analysis was performed to examine the efficiency of shRNA in knockdown the expression of PRDM1-  in 293T cells (normal human embryonic kidney cells). The protein expression level for ectopic PRMD1- was reduced in cells expressing shV2 when compared with the negative control. NKYS cell line expressed with shV2 showed a significant reduction in the number of colonies. Percentage of dead cells was found higher in these cells. The proliferation rate of shV2 expressing cells started to retarded significantly on the third day of measurement in the MTS proliferation assay. The cell also underwent G1 cell cycle arrest and had lower proliferation rate, as indicated by cell cycle analysis. For YT cell line expressed with shV2, significant reduction in both colony number and size in methylcellulose colony formation assay was observed. Base on the results obtained from the two NK-cell lines, we suggest that the shV2 inhibit the tumor cell growth. The knockdown of the PRDM1-  lead to an increase level of PRDM1- α. PRDM1- α is a tumor suppressor gene with suppressive function by preventing damaged cells from proliferation or inhibiting the clonogenecity of the tumor cells. An imbalance expression of PRDM1- and PRDM1-αplay an important role in tumor growth and formation, and PRDM1 could possibly be the new tumor suppressor gene in NK-cells lymphoma. / published_or_final_version / Pathology / Master / Master of Medical Sciences

Age-related macular degeneration (AMD) causes vision impairment which is not recoverable under existing treatment options. It has been a major leading cause of blindness in the aged population. To ameliorate the self-care ability for AMD patients, educational interventions to mediate negative impacts of the disease on quality of life have become a research interest. Current practice in the proposed Hong Kong setting, Elderly Health Centre A and Elderly Health Centre B, depends on nurses giving general advice which is lack of scientific support and non-specific to AMD. Purpose of this dissertation is to translate the best evidence to practice for improving the care of older adults with AMD in the proposed setting. Evidences showed that self-management education programmes were effective in improving emotional distress and self-efficacy. Electronic searches located 9 relevant RCTs of high level and methodologically strong evidences. Data was extracted into tables of evidence. Data summary and synthesis was presented. Assessment on the implementation potential indicated that the SEP was worth to try in the local setting. Twelve recommendations for the practice guidelines of SEP were presented and a communication process to facilitate the change in a top-down approach was introduced. A pilot study plan in Centre A followed by a main study in Centre A and Centre B was presented. A total of 98 elderly patients with AMD will be recruited as 10 SEP groups. Approximately 1.8 years will be used to finish the main study. Outcomes will be measured at the 6th week follow-up. ‘Emotional distress’ will be measured as primary outcome and ‘self-efficacy’ will be measured as secondary outcome. ‘Client satisfaction’, ‘staff satisfaction’ and the ‘utilization rate of the innovation’ will also be assessed in evaluation. A two-tailed paired (one-sample) t-test will be adopted for analysis, with a 95% confidence interval. The basis for effectiveness for the outcome measurements and basis for adoption of the clinical guidelines were stated. Adoption of the developed guidelines in the local setting will optimistically improve the substantial clinical outcomes for AMD patients, mediating the negative impacts of vision impairment or vision loss on their quality of life. / published_or_final_version / Nursing Studies / Master / Master of Nursing

Breast cancer comprises of 22.9% of all cancers worldwide in females. In the year 2008, it has caused 458,503 deaths worldwide. De-regulation of transcription factors has been shown to play an important role in the progression of breast cancers. Snail and TWIST genes have been found to promote epithelial-mesenchymal transition (EMT). It has been suggested that the level of expression of each of these genes correlates with poor prognosis in different types of solid tumors. For breast cancer, the up-regulation of Snail was associated with recurrence and higher tumor grade, while the up-regulation and up-regulation of TWIST was associated with shorter survival and metastatic development. However, in recent studies conflicting results have been observed. Our collaborator had analyzed mRNA expression data obtained from the Gene Expression Omnibus (GEO) database together with patient survival data from the breast cancer cohort datasets, and found that expression of Snail when stratified against TWIST expression levels or vice versa, gave more significant association with survival than when expression levels of Snail or TWIST was considered on their own. To investigate whether these findings could be demonstrated at a protein level, we performed imrnuno-histochemisty analysis on breast cancer samples in tissue microarray blocks. Nuclear and cytoplasmic scores of TWIST were successfully assessed separately in 114 invasive breast cancer patients. The Snail scores were obtained from previous studies. As Snail and TWIST are both transcription factors, nuclear expression of each was examined for correlation of Snail and TWIST with pathological features and patient survival. Our results showed that nuclear Snail expression did not correlate with survival (p=0.498) but when stratified with nuclear TWIST, high levels of nuclear Snail expression associated with poorer survival in patients with low nuclear TWIST expression (p=O.2l2), though not statistically significant which agreed with the mRNA results of our collaborator. For nuclear TWIST expression, association with survival was in reverse from that of the mRNA findings. Low expression levels of TWIST mRNA was associated with shorter survival, however immuno-histochemistry showed that high levels of nuclear TWIST expression marginally correlated with poorer survival (p=O.079). Low levels of cytoplasmic TWIST expression on the other hand, correlated with poorer survival in patients (p=O.024), and when stratified against high nuclear Snail, expression was associated with shorter survival (p=O.022), which is in keeping with mRNA findings. The results show that Snail and TWIST expression gave more prognostic value when considered together than when considered individually, which suggests that Snail and TWIST might be functionally similar in the promoting of EMT mediated breast. It also highlights the importance of nuclear and cytoplasmic localization by immuno-histochemistry in evaluating results and in assessing its role in promoting breast cancer progression. In conclusion Snail and TWIST should be considered together for prognostication of breast cancer as they may complement each other in predicting the progression of the disease. / published_or_final_version / Pathology / Master / Master of Medical Sciences

 As a neuropeptide, both secretin and secretin receptor are expressed in the central nervous system (CNS). It has been revealed that the activities of secretin on hypothalamic cells of rodents are important for osmoregulation and food intake. In the present study, embryonic mouse hypothalamic cell line N42 was used to study the promoter activity of mouse secretin receptor (mSR). By 5′ deletion analysis, a promoter element was identified within ?282 to ?443, relative to the ATG codon, and it contains a GC-box (-297 to -286), a ras responsive element (RRE) (-289 to -276) and an E-box (-416 to -411). Electrophoretic mobility shift assay (EMSA) and supershift analyses showed that Sp1 interacted with the GC-box, another zinc finger As a neuropeptide, both secretin and secretin receptor are expressed in the central nervous system (CNS). It has been revealed that the activities of secretin on hypothalamic cells of rodents are important for osmoregulation and food intake. In the present study, embryonic mouse hypothalamic cell line N42 was used to study the promoter activity of mouse secretin receptor (mSR). By 5′ deletion analysis, a promoter element was identified within ?282 to ?443, relative to the ATG codon, and it contains a GC-box (-297 to -286), a ras responsive element (RRE) (-289 to -276) and an E-box (-416 to -411). Electrophoretic mobility shift assay (EMSA) and supershift analyses showed that Sp1 interacted with the GC-box, another zinc finger / published_or_final_version / Biological Sciences / Doctoral / Doctor of Philosophy

Background: As many studies, women are more vulnerable to contract HIV through sex behavior than men from women. The low status of women also make women are more at risk of infecting with HIV. South Africa now is one of the most rapidly growing HIV epidemics in the world. In Africa, 74% of youth who get HIV/AIDS are young women and young girls. In 2005, there were 16.9 per cent women aged 15-24 years got HIV and only 4.4% men got HIV in South Africa. Objective: To identify the main internal risk factors and interventions/external factors of HIV/AIDS on young women in Africa. Data Source: Pub Med, Medline and Cochrane Library were searched for English articles from 1990 to 2011. (Keywords: HIV, AIDS, young women or girl or adolescent girl.) Results: Initial search produced 2888 articles. According to the inclusion and exclusion criteria, 9 articles were for the final systematic review. 5 papers were about risk factors of HIV/AIDS and 4 papers were about the interventions or the factors influenced the risk factors. We identified four risk factors: intimate partner violence (IPV) and relationship power inequity, number of partners and last sexual activities, age of partner, alcohol consumption before sex. Two interventions/external factors: Microfinance with gender and HIV training curriculum and SES neighborhoods (Community level). Conclusions: We have two policy implications. First, we should ensure that preventive services, including education of young women have more accessibility. Secondly, because many young women who with older men have sex were more likely to infect with HIV, Therefore, we should make greater efforts to encourage them to adopt safer behavior. As the man play leading role in Africa, our prevention programs should focus more on men. / published_or_final_version / Public Health / Master / Master of Public Health

abstract / Surgery / Master / Master of Philosophy

Fibroblast Growth Factor (FGF) 21 is a liver-derived endocrine factor with multiple metabolic effects on glucose and lipid homeostasis in animals. The adipose tissue has been proposed as a major target of FGF21, where it enhances glucose uptake and modulates lipolysis as well as thermogenesis. However, the molecular mechanisms underlying the pleiotropic effects of FGF21 in adipocytes and the physiological roles of FGF21 in regulating energy homeostasis remain poorly characterized. Therefore, the present study aimed to investigate: 1) the signal transduction pathway whereby FGF21 enhances glucose uptake in white adipocytes; 2) the role of FGF21 in lipolysis in both mouse and human white adipose tissues (WAT) and its underlying mechanisms involved; 3) the phenotypes of FGF21 knockout (KO) mice with respect to energy expenditure and adiposity under both standard chow and high fat diet. Key findings: 1. In vitro studies demonstrated that extracellular signal-regulated kinases (ERK1/2) play an obligatory role in mediating FGF21-induced upregulation of glucose transporter-1 (GLUT1) expression and hence elevation of glucose uptake in 3T3-L1 adipocytes. 2. Chromatin immunoprecipitation assay revealed that Serum Response Factor (SRF) and ETS-like protein-1 (Elk-1), the two transcription factors which are known as the downstream targets of ERK1/2, were recruited to the endogenous GLUT1 promoter in adipocytes. A conserved binding motif for these two transcription factors was also identified in the GLUT1 promoter responsive to FGF21 stimulation in 3T3-L1 adipocytes by site-directed mutagenesis and luciferase assay. 3. In WAT of diet-induced obese mice, FGF21-evoked downstream signaling events, including the phosphorylation of ERK1/2 and SRF/Elk-1, the upregulation of GLUT1, and the increased glucose uptake, were markedly blunted compared to lean controls, suggesting the existence of “FGF21 resistance” in obesity. 4. In vivo and ex vivo studies on fasted wild type and FGF21 KO mice demonstrated that FGF21 acutely suppressed basal and forskolin-stimulated lipolysis in WAT. 5. FGF21-inhibited lipolysis was mediated by Akt-dependent reduction of cyclic adenosine monophosphate (cAMP) levels in both mouse and human WAT. 6. FGF21 KO mice were resistant to diet- and aging-induced obesity, which was attributed to decreased fat mass. The increased lipolysis and fatty acid oxidation in FGF21 KO mice may explain in part the lean phenotype of FGF21 KO mice. Conclusions: These results collectively suggest FGF21 as a key modulator of glucose and lipid metabolism in WAT, by activation of ERK1/2 kinase and Akt respectively. FGF21 and its signaling components may represent potential targets for the future development of new strategies for treating obesity and its medical complications. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Research on risk factor for suicidal behaviors has been broadly conducted to enhance knowledge of suicide prevention. However, there are still challenges for risk factor research. Four major research gaps have been identified: (1) uncertain effectiveness of the population approach versus the high-risk approach for suicide prevention; (2) lack of a valid and convenient Chinese-version screening tool for the severity of suicidal ideation among adolescents; (3) demand for testing the prospective associations of risk factors with suicidal ideation using a longitudinal designed population-based sample; and (4) necessity of pathway analysis to explore and confirm how risk factors interact with each other and lead to suicidality. This thesis aims to address these gaps through a combination of five studies. Study 1 introduces an illness and death model to suicide prevention research. Elasticity and sensitivity analyses were performed. The findings revealed that the control of suicide incidence among the healthy population is the most effective prevention strategy whereas treatment of mental illness appears to be the least effective approach to suicide prevention. Study 2 validates the psychometric properties of the Chinese versions of Reynolds’s Suicidal Ideation Questionnaire (SIQ) and Suicidal Ideation Questionnaire Junior (SIQ-JR, a short version of the SIQ) in a sample of Hong Kong adolescents. A short, four-item version of the SIQ-JR has been suggested as an alternative to the SIQ and the SIQ-JR. Study 3 identifies the history of psychiatric treatment, depression, anxiety, hopelessness, unstable marital status, poor economic circumstance, and a recent death of a first-degree relative as significant risk factors for the incidence of suicidal ideation. The associations of change in risk factors with the development of suicidal ideation have been tested. There are gender and age differences in the patterns of such associations. Study 4 focuses on psychological factors associated with the first-ever incidence of suicidal ideation. Psychological factors have been detected generally to differ in their associations with the incidence and persistence of suicidality. The idea that depression partially mediates the effect of average life distress on the persistence of suicidal ideation has clinical value. Study 5 introduces and tests a stressor and illness model as a theoretical framework reference for future risk factor research. Risk factors are classified into stressor, illness, and pattern factors. Both the simple and complex models are tested. Evidence supported the proposed mediating role of mental disorders between negative life events and severity of suicidal ideation. A gender-specific pattern of associations between stressors, illness, and severity of suicidal ideation has also been detected. This thesis has made substantial theoretical, psychometric, and empirical contributions to the existing knowledge of suicide research. / published_or_final_version / Social Work and Social Administration / Doctoral / Doctor of Philosophy