Medicine & Health

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  • (1992) Farrell, Caroline
    Thesis


  • (1999) Brighton, Timothy Andrew
    Thesis




  • (2012) Kurniawan, Monica
    Thesis
    T cells are a type of white blood cell that are able to recognise and kill virally infected cells. T cells have receptors on their cell surface that facilitates the recognition of a viral peptide bound to the major histocompatibility complex (MHC) of an infected cell. An enormous diversity of T cell receptors (TCR) is needed to ensure the recognition of a wide variety of pathogens and immune control of infections. Therefore, many previous studies have attempted to understand the different factors that shape the T cell repertoire including the mechanisms that generate T cell receptor diversity. TCRs are generated by a somatic recombination process that involves somewhat random and imprecise mechanisms, including the selection and joining of up to three different types of gene segments (that is, the variable (V), diversity (D) and joining (J) genes), the addition of gene-templated palindromic nucleotides (P-nucleotides) at the gene ends, the deletion of nucleotides from the gene ends, and the addition of non-templated nucleotides (N-nucleotides). The prevalence and the contributions of each of these mechanisms to the generation of TCR diversity are generally well-studied and well-understood, with the exception of P-nucleotide addition. In this study, we examined more than 100,000 T cell receptor beta chain (TRB) sequences in order to investigate the prevalence of P-nucleotides in expressed TRB repertoires. These TCR sequences were obtained from various studies of T cell responses to infectious diseases in mice, rhesus macaques, and humans, as well as naive T cell repertoires. We implemented previously published approaches and developed novel bioinformatics algorithms to estimate the prevalence of palindromic nucleotides at either the intact V and J gene ends and to assess the likelihood that these nucleotides could have been contributed by the other genes or N-nucleotides involved in the V(D)J recombination rather than P-nucleotides arising from the hairpin splicing. Our results demonstrate a high prevalence of P-nucleotides (>5% of TRB sequences per species), even when attributing the palindromic nucleotides at the intact gene ends to other possible sources. Thus, P-nucleotide addition appears to make a non-trivial contribution to the generation of the TRB repertoire.

  • (2012) An, Siwei
    Thesis
    Background. Cardiovascular disease is a major cause of death and disability and treatment options are limited. Abnormal vascular smooth muscle cell (VSMC) proliferation is a key pathological feature in atherosclerosis, hypertension, and stenosis and restenosis. In order to design new and effective strategies to cure or prevent cardiovascular disease, it is important to better understand mechanisms of gene transcription, mRNA translation and related signaling pathways. Objective. The aims of this thesis were (i) to understand the function of YrdC in translational control in VSMC, and (ii) to dissect the signal transduction pathways underlying IL-1β-induced Egr-1 expression via MEK in VSMC. Results. In the first study, YrdC, which is upregulated after VSMC injury, was found to play a role in translational regulation, i.e. YrdC positively regulates protein synthesis. In the second study, the involvement of EGFR (tyrosine 845 phosphorylation) in IL-1β-induced Egr-1 expression was demonstrated in both VSMCs and mouse embryonic fibroblasts (MEF) and to mediate IL-1β-induced VSMC migration and proliferation. Conclusion. YrdC, once induced, may play a key role in promoting cell migration or proliferation by mediating protein synthesis in the reparative response to injury in VSMCs. IL-1β-induced Egr-1 expression is mediated through EGFR in VSMCs. These findings provide important insights on signaling responses to vascular cell injury.

  • (2021) Cheng, Lap
    Thesis
    Chronic kidney disease (CKD) is a major public health issue affecting 10% of the global population and resulting in 1.2 million deaths. The risk of all-cause and cardiovascular mortality is inversely proportional to declining eGFR such that individuals with CKD are more likely to die, primarily due to a cardiovascular cause, than survive to the point of requiring dialysis. These poor outcomes are related to a myriad of factors including multimorbidity, medial vascular calcification and underlying haemostatic dysfunction. Polypharmacy is a key consequence of the disease burden experienced by CKD patients. It is linked with poor adherence, adverse drug reactions, falls and increased hospitalisations. A post-hoc analysis of the CKD-FIX study was conducted to assess the prevalence and predictors of polypharmacy in CKD patients. It found that polypharmacy, defined as ≥5 medications, and hyperpolypharmacy, defined as ≥10 medications, were found in 77.5% and 34.3% of patients respectively. Age ≥65 yrs, diabetes, cardiovascular disease and hyperlipidemia were independently associated with polypharmacy. However, limiting polypharmacy via appropriate prescribing is hampered by the lack of data in patients with advanced CKD. Despite the disproportionate cardiovascular disease burden in CKD, the benefits and risks of dual antiplatelet therapy are not known. Therefore a systematic review of randomised controlled trials on the effectiveness of dual antiplatelet therapy in CKD was conducted. Nineteen trials with 27,308 participants were analysed with all but 3 trials excluding participants with dialysis-dependent kidney failure. Compared with aspirin monotherapy or no study medication, P2Y12 inhibitor-based dual antiplatelet therapy significantly reduced the risks of major adverse cardiovascular events, myocardial infarction and stroke; but increased the risk of major bleeding. There was insufficient evidence to conclude whether patients with advanced stages of CKD and dialysis-dependent kidney failure derived benefit. In conclusion, CKD patients represent an expanding population that is at high risk of adverse outcomes. Polypharmacy is common in patients with CKD and is related to age and multimorbidity. Further research on medication appropriateness and deprescribing are needed. In particular, adequately powered randomized trials are required to evaluate the effectiveness of dual antiplatelet therapy in patients with advanced stages of CKD and cardiovascular disease.