Medicine (St Vincent's) - Theses

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    Regulation of bone and fat cells by zinc-finger protein- 467
    Quach, Julie. (University of Melbourne, 2010)
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    The relationship between occupational sunlight exposure and non-melanoma skin cancer
    Tan, Stephanie Soo Hwei ( 2015)
    Aims and Background: Australia has the highest incidence of skin cancer in the world and ultraviolet (UV) radiation exposure is the dominant environmental determinant of all major forms of skin cancer. Two recent systematic reviews and meta-analysis of the available epidemiological evidence clearly indicate that occupational ultraviolet radiation (UVR) exposure is a substantial risk factor for the development of non- melanoma skin cancer. This study is an initial attempt to investigate the role of occupational sunlight exposure in the development of non-melanoma skin cancer in men in Australia. Methods: A case-control study was conducted. One hundred cases were recruited from the Skin and Cancer Foundation Inc. Controls included 14 age- and gender-matched subjects nominated by the cases. A questionnaire was administered through face-to- face interviews to collect information on pigmentary and genetic characteristics, occupational and recreational exposure assessment, and time of first diagnosis of non- melanoma skin cancer, confirmed with histopathological diagnosis. Conditional logistic regression models were implemented. Subsequently, a one-way analysis of variance (ANOVA) was used to investigate the relationship of each risk factor with occupational sun exposure. Results: There was insufficient evidence to conclude that there was a relationship between occupational sun exposure and non-melanoma skin cancer, because of the small sample size of matched case-control pairs. As the results for the small sample size of the matched case-control group were not statistically significant, a one-way analysis of variance (ANOVA) was performed to compare the risk factors. Fitzpatrick Skin Type was the only risk factor that showed a statistically significantly different occupational exposure profile (with a P-value of 0.035) but even then the differences were minor and only between skin phototype 2 and 3. There were no significant relationships between occupation exposure and the other risk factors. Conclusion: Unfortunately, analysis of the small number of matched case-control pairs was not statistically significant and it was not possible to draw any conclusions regarding the role of occupational sunlight exposure in the development of non- melanoma skin cancer. We experienced unexpectedly high levels of reluctance from case subjects to propose control subjects to participate in the study, which impacted on data collection and subsequently the study results. It has been well established that solar UVR is a risk factor for skin cancer. Outdoor workers are potentially exposed to high levels of UVR. More epidemiological studies are needed to improve our understanding and awareness of skin cancer as well as aid the development of prevention strategies at workplaces to reduce outdoor workers’ exposure to UVR.
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    Developing and evaluating a multimodal musical training method to improve music perception in cochlear implant users
    Liu, Timothy James ( 2014)
    The present study investigated the efficacy of a multimodal approach to musical training to improve melody perception in cochlear implant recipients. Five post-lingually deaf cochlear implant recipients were trained for a duration of two weeks with take-home training software for computer tablets. The software included a keyboard interface which facilitated learning of familiar melodies and a closed-set melody recognition task founded on the melodies learnt. The Modified Melodies Test was used to measure melody perceptual skills before and after training. A statistically non-significant trend of improvement (p = 0.173) was found between pretest and posttest overall scores of the Modified Melodies Test. However, limitations imposed on psychometric scoring in the Modified Melodies Test resulted in alternative scoring methods that did not allow conclusions to be aptly applied to melody perceptual skills. Furthermore, the present study had a small sample size that resulted in low statistical power and also prevented a planned comparison of multimodal training to a reference of unimodal training that incorporated listening tasks only. As such, there was insufficient evidence to evaluate the importance of the multimodal approach to musical training in cochlear implant users. While firm conclusions were not drawn from the results, the present study has explored various aspects of its training software and the Modified Melodies Test that could pilot a future comprehensive study of multimodal musical training effects on cochlear implant music perception.
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    Bioimaging in colorectal cancer - prediction of response to neoadjuvant treatment
    Memon, Sameer ( 2015)
    Over the last decade the management of colorectal cancer has changed significantly with the benefits of neoadjuvant therapies and new adjuvant treatments becoming apparent. Surgical strategies have also evolved with initial evidence that some patients can be successfully managed with local excision or omission of any surgery at all, resulting in a shift towards the individualisation of cancer management. The management of rectal cancer is based on primary staging assessment which relies on imaging techniques such as CT, MRI and ERUS. Recent advances in technology have improved the accuracy and widened the applications of these techniques. With the progress in medical and surgical treatments for rectal cancer, the optimal management of rectal cancer has become more complex. The evolving ability to tailor optimal treatment to the individual has created new roles for imaging such as prediction of response to treatment, restaging with assessment of response to treatment and prediction of prognosis. Consequently, prediction of response will become an important component of modern pre-operative assessment of rectal cancer to optimise individualisation of medical and surgical treatment. Beyond the established role of primary staging of malignancies, the role of conventional imaging techniques in re-staging following neoadjuvant treatment may be of increasing importance. Novel functional imaging techniques such as FDG-PET, DW (diffusion weighted) MRI are also emerging, the roles of which are yet to be determined. This thesis will examine the current status of bio-imaging and explore new imaging techniques in rectal cancer. At the Peter MacCallum Cancer Centre, we have been routinely performing staging and restaging imaging with CT, MRI and PET for the last 5 years which has resulted in a cohort of patients in whom these imaging techniques can be evaluated. This thesis also aims to evaluate a recent and evolving functional imaging technique- DW-MRI, in the prediction of response of rectal cancer to chemo-radiation.
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    Coronary microcirculatory function in patients with ischaemic heart disease: a focus on novel assessment, management and outcomes of coronary microcirculatory function
    Palmer, Sonny ( 2015)
    Although there have been improvements in pharmacotherapy and percutaneous coronary intervention, patients with ischaemic heart disease, still pose a significant health burden. It has become increasingly evident that cardiovascular outcomes are impacted upon by dysfunction of the coronary microvasculature. Novel direct invasive measures, such as the index of microcirculatory resistance (IMR), have recently been developed. This index of microvascular function has been shown to have significant clinical utility in patients with ischaemic heart disease. However, to date, the body of knowledge on the state of the microcirculation as assessed by IMR in subsets of patients, such as thrombolysed ST-segment elevation myocardial infarction (STEMI) and Non-ST segment elevation myocardial infarction (NSTEMI), is lacking. Furthermore, in patients with NSTEMI, the effect of targeted therapies on IMR and hence microvascular function, is unknown. Finally, no test is perfect and the development of supplementary invasive measures of microvascular function may improve the management of patients with ischaemic heart disease and further enhance our understanding of microvascular dysfunction. The aim of this thesis was to examine microvascular function in patients with ischaemic heart disease. Specifically, I will examine and compare microvascular function, as assessed in particular by IMR, in patients presenting with thrombolysed ST-segment elevation myocardial infarction undergoing a pharmacoinvasive strategy and non-ST segment elevation myocardial infarction. I will examine the relationship between measures of microvascular function, including the IMR, and left ventricular recovery in patients presenting with ST-segment elevation myocardial infarction and undergoing a pharmacoinvasive strategy. I will also examine microvascular function, as assessed by IMR, and the role of the antiplatelet agent, abciximab, in patients presenting with Non-ST segment elevation myocardial infarction. Finally, I will examine and evaluate a novel measure of microvascular function, the coronary artery augmentation index, in patients with stable angina undergoing percutaneous coronary intervention. A full representation of patients with ischaemic heart disease undergoing percutaneous coronary intervention (PCI) were studied; 31 patients with STEMI, 36 patients with NSTEMI and 40 patients with stable angina. Invasive coronary physiological measurements in the culprit vessel were taken during the index procedure at varying times depending on the study protocol. Left ventricular function was assessed by either transthoracic echocardiography or cardiac MRI and compared with measures of microvascular function. Cardiac biomarker levels were taken pre-procedure, at the time of procedure and post procedure for up to 24 hours post intervention. In summary, the main findings of this thesis are: • Invasive measures of microvascular function, such as IMR, are significantly higher in a pharmacoinvasive STEMI population than in a clinically stable NSTEMI population. • In a STEMI population undergoing a pharmacoinvasive strategy, in contrast to other traditional markers of microvascular dysfunction, post PCI IMR correlates with left ventricular function and has the potential to predict left ventricular recovery at three months post STEMI. • In patients with NSTEMI undergoing PCI, a bolus dose of intracoronary abciximab improves coronary microvascular function as assessed by IMR. • Coronary augmentation index is a valid and reproducible measure of microvascular function in patients with stable angina undergoing PCI. • Coronary augmentation index is a predictor of periprocedural myocardial injury and may be able to identify those patients who are at greater risk of such injury following intervention. The findings of this Doctor of Medical Science are novel and have important clinical implications for the clinician. The work in this thesis supports the notion that it is important to consider microvascular dysfunction in patients with ischaemic heart disease undergoing PCI. With accurate assessment and appropriate management clinical outcomes may be improved. The work presented does warrant further investigation in larger multicentre trials. I anticipate that these will support the findings of this thesis and by measuring microvascular function will can aid risk-stratification and enable a more intensive therapeutic strategy not only within the catheterisation laboratory, but post procedure in the short and medium term.
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    Roles of cyclin-dependent kinase substrates: cell cycle and beyond
    binte Roesley, Siti Nur Ain ( 2015)
    The cyclin-dependent kinases (CDKs) are serine/threonine specific kinases that are key regulators of the cell cycle. However, several reports indicated their roles in other pathways. Therefore, it is important to identify novel CDK substrates in order to gain a better understanding of the pathways they regulate and in turn, the diseases where they are deregulated. In this thesis, I describe two substrates; Brahma (Brm), an ATPase subunit of the SWI/SNF chromatin remodeling complex and Breast Cancer Metastasis Suppressor 1 (BRMS1), a metastasis suppressor in human cancers. Brm has long been modeled to be part of the pRb/E2F complex, regulating entry into S phase of the cell cycle. In addition, several studies have indicated that Brm interacts with Cyclin E and CDKs. Here, I demonstrate that Drosophila Brm is phosphorylated in vitro by both Cyclin A and Cyclin E/CDK2. Furthermore, using Drosophila as an animal model, a phospho-mimic of Brm was able to bypass the developmental G1 arrest in the wing discs’ zone of non-proliferating cells (ZNC), indicating its role in inhibiting S phase entry. In addition, based on the phenotypes obtained from the expression of Brm phospho-mutants and the current literature, I postulate that CDK-mediated phosphorylation of Brm also has roles in maintaining genomic stability, cell signaling and expression of cell adhesion systems. Our laboratory had previously identified the regulation of Drosophila EGFR/Ras signaling by Brm-DN and its antagonism by Gem. In this thesis, I have further characterised the roles of Brm-DN and Gem in Drosophila development and have identified Rhomboid (a positive regulator of EGFR/Ras signaling) to be the target gene that is transcriptionally regulated by Brm and Gem. Finally, BRMS1 is a metastasis suppressor, better known to exert its functions by being a part of the SAP30/mSin3/HDAC complex to modulate transcription. Furthermore, it was previously reported to be in complex with RBP1, a CDK substrate, which inhibits S phase entry. In this thesis, we have found that BRMS1 is phosphorylated by CDKs both in vivo and in vitro. Using Mass Spectrometry, we have further identified the phosphorylated site to be Serine 237. Interestingly, mutation of this phosphorylation site had no impact on cell cycle progression and BRMS1’s role as a transcriptional regulator, however, it modulated BRMS1’s role in inhibiting cell migration. Taken together, this thesis confirms the CDK-mediated phosphorylation of two proteins and has expanded our understanding of the various roles that CDK substrates have beyond the cell cycle. Overall, this work provides further insights into the role of CDK substrates in cellular behaviour, tissue growth and differentiation, and the development of cancer and metastasis.
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    Anatomical study of the arrector pili muscle in normal and diseased hair
    Torkamani, Niloufar ( 2015)
    The arrector pili muscle (APM) comprises a small band of smooth muscle that connects the hair follicle to the connective tissue of the adjacent upper dermis. The APM mediates thermoregulation by contracting to increase air-trapping within the pelage, but has been thought to be vestigial in humans. The APM regresses in androgenic alopecia (AGA), where hair loss is permanent, but not in alopecia areata (AA), where hair loss can be reversed. These observations suggest that the human APM plays an important role in maintaining hair follicle function. This thesis aimed to characterise the biology of the proximal APM (which attaches to the follicle), the anatomy and biology of the distal APM (which attaches to the upper dermis), the potential role of the APM as a regulator of stem cells, and the involvement of the APM in hair loss disorders. This thesis characterised novel staining techniques that allowed visualization of extensive branching of the distal APM. The data obtained confirms an arborized APM structure and demonstrates that the distal APM attaches to the dermal-epidermal junction. Moreover interfollicular epidermal stem cell populations were studied. These stem cell groups are restricted to basal keratinocytes, mostly near an attachment site of APM to the epidermal basement membrane. Hence this study suggests that the distal APM may contribute to the formation of a niche for epidermal stem cells, as the proximal muscle does for follicular stem cells. Signals from the APM may contribute to the regulation of both stem cell populations. The APM may be involved in epidermal renewal, homeostasis, and in wound healing, in addition to its recognized function in piloerection. Finally the APM was studied in hair loss conditions. Results demonstrated that the APM degenerates and is replaced by adipose tissue in AGA. A novel model for APM degeneration is proposed. In summary, this study describes the anatomical structure of the APM in detail. This thesis suggests that the human APM plays an important role in maintaining hair follicle function and supports the proposition that APM degeneration is associated with permanency of hair loss. The distal muscle helps to define a niche for epidermal stem cells, as the proximal end of the muscle does for hair follicle stem cells.
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    The natural history of inflammatory bowel disease in an Australian community cohort: investigating the aetiology, clinical course, predictors of severe disease and health cost
    Niewiadomski, Olga ( 2015)
    Inflammatory Bowel Disease (IBD), including Crohn’s Disease (CD), Ulcerative colitis (UC) and IBD undifferentiated (IBDU), are chronic disorders of the gastrointestinal tract that exert a major impact on an individual’s quality of life and result in very high usage of health care resources. The aetiology of IBD remains unknown. Clinical course can vary from mild to severe and debilitating, and it remains unclear at diagnosis what disease progression will be. Identifying early clinical prognostic factors that predict a severe course is important, thereby enabling early medical therapy to minimize complications of disease. In recent years there has been greater emphasis on intensive therapy and disease monitoring. The greatest impact has been the introduction of biological therapy. However, it remains unclear if these advances are translating into better disease outcomes in the community and at what cost. A population based inception cohort study of patients with IBD was set up in Barwon, Victoria. The aims of the study were to validate the previously reported high incidence, to identify environmental exposures that are associated with disease aetiology, to assess the early course of disease as measured by objective markers such as surgery and hospitalization rates, to identify early clinical prognostic factors associated with severe disease and to determine the health care cost early in the course of IBD. Incident cases from 2007/2008 and 2010-2013 in a well-defined geographical area were prospectively identified through a multifaceted approach to ensure complete capture. Cases were subsequently enrolled into the IBD registry that was used as a basis to collect outcome data on the disease progression, environmental exposures and health care cost. A number of environmental exposures were found to be associated with increased risk of CD included smoking, frequent fast food intake and childhood events such as tonsillectomy and chicken pox infection. In UC, the risk factors included smoking, childhood chicken pox infection as well as frequent fast food. In UC, high caffeine intake was protective (a novel finding), while frequent fruit intake and pets as a child reduced the risk of UC. Objective clinical outcomes were measured for a median of 18 months from diagnosis (range 12-60 months) for 252 patients comprising 146 CD, 96 with Ulcerative colitis UC and 10 IBDU. Immunomodulators (IM) were prescribed in 57% of CD patients, and 19% with UC; biological therapy in 13% of CD patients. A third of all CD patients were hospitalised, the majority (77%) in the first 12 months. Risk factors for hospitalisation included penetrating, perianal and ileocolonic disease. A quarter of UC patients were hospitalized, most within the first 12 months. Resective surgery rates were 13% at 1 year in CD, and 26% at 5 years. Risk factors at diagnosis included penetrating, stricturing and ileal disease. Colectomy rates in UC were 2% and 13% at 1 and 5 years. High CRP at diagnosis was associated with colectomy. Health cost analysis in the first year of disease showed that per patient cost was higher in CD than UC; and that there has been a shift from inpatient to outpatient resources driving the majority of health cost in IBD compared to older studies. This was primarily due to the expense from medications. This first Australian population based study of an inception cohort confirms a high incidence of IBD in Barwon, Victoria that has remained stable over 6 years. A number of environmental risk factors associated with an increased risk of IBD were identified, as well as protective factors, of which high caffeine intake is a novel finding. Disease progress in this cohort was optimistic, compared to historical cohorts, with low rates of intestinal surgery. This was associated with high rates of IM and biological therapy. Early clinical predictors of severe disease were identified that can be used in clinical practice to tailor therapy. Health cost analysis in the first year shows a shift from inpatient to outpatient resources, with medications and investigations contributing the most.
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    Economic evaluation of domiciliary long-term non-invasive positive pressure ventilation in Duchenne muscular dystrophy
    Colgan, Stephen James ( 2015)
    Duchenne muscular dystrophy (DMD) is a rare X-linked recessive, incurable and invariably fatal disease that affects approximately one in every 3300 live male births. It is the result of the failure of the body to produce a protein called dystrophin that stabilises and protects the plasma membranes of muscle cells from the mechanical stresses induced by muscle fibre contraction. In the absence of this protein muscle contraction disrupts the cell membranes, triggering a process that results in cell death and a reduction in muscle strength and function. There is a rapid decline in respiratory muscle strength approximately 1 year after the loss of independent ambulation. The first manifestations of this are seen during sleep, which is disrupted by periods of abnormal breathing (sleep disordered breathing). As respiratory function worsens this disruption increases in frequency and severity and unless some form of long-term mechanical ventilation (LTMV) is used to support respiratory function, it inevitably results in respiratory failure and death in the early 20s. The aim of the thesis was to produce an estimate of the Cost-effectiveness (CEA) and Cost-utility (CUA) of two alternative timings for the initiation of LTMV in three identical cohorts of 100 hypothetical individuals with DMD. The alternative timings were: (i) from the onset of the sleep disordered breathing (SDB) in rapid eye movement (REM) sleep, without hypercapnia (Intervention 1) and; (ii) from the onset of SDB in REM sleep, with hypercapnia (Intervention 2). The comparator was the current practice initiation of LTMV from the onset of diurnal hypercapnia. In the base-case analysis of the CEA (all costs and outcomes discounted by 3%) Intervention 1 and 2 were dominated by the comparator. The probability (for a maximum acceptable ratio of 100,000 a lifeyear) that the comparator would be cost-effective was approximately 0.50 to 0.74; for Intervention 2 it was approximately 0.28 to 0.33 and; for Intervention 1 it was 0.04 to 0.18. In the base-case of the CUA (all costs and outcomes discounted by 3%) there were no strategies that were clearly dominated by any other. The probability (for a maximum acceptable ratio of $ 100,000 a QALY), that the comparator would be cost-effective was approximately 0.35 to 0.52; for Intervention 2 it was approximately 0.29 to 0.33 and; for Intervention 1 it was approximately 0.17 to 0.42. The limited evidence for the effectiveness of the intervention, the inability of the small scale study to recruit and retain a statistically significant sample and the use of a researcher developed model of LTMV service delivery, mean that the results of the economic evaluation cannot be seen to be anything other than exploratory in nature.
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    The role of ADAR1 in haematopoiesis and leukaemia
    Liddicoat, Brian ( 2015)
    RNA editing by members of the Adenosine Deaminase Acting on RNA (ADAR) gene family is a form of post-transcriptional modification, which converts genomically encoded adenosine to inosine (A-to-I) in double-stranded RNA (dsRNA). A-to-I editing by ADAR directly changes the sequence of the RNA substrate and can alter the structure, function, processing, and localization of the targeted RNA. Adar1-/- embryos die in utero from foetal liver (FL) disintegration and widespread apoptosis, associated with a significant upregulation of interferon (IFN) stimulated genes (ISGs). A cellintrinsic requirement for ADAR1 has been reported in haematopoiesis. However, the specific cell types that require ADAR1 within haematopoiesis and its physiological requirement in vivo remains largely unexplored. ADAR1 is essential for the survival of haematopoietic stem cells (HSCs), but dispensable for B-lymphocytes. I was able to demonstrate that ADAR1 was dispensable for myeloid development, but essential for both foetal and postnatal erythropoiesis in a cell-autonomous manner, demonstrating a cell-type specific requirement for ADAR1 within haematopoiesis. Loss of ADAR1 caused significant upregulation of ISGs in ADAR1-null erythroid cells. Despite evidence related to regulation of miRNA function by ADARs, there were only subtle changes to the expression pattern and levels of mature miRNAs. I found ADAR1 regulated ISGs independently of IFN receptor signalling. There were no changes in A-to-I editing of known annotated editing sites between erythroid cells and B-lymphocytes despite their differential requirement for ADAR1. When assessing RNA-sequencing data of FL erythroid cells, clusters of novel hyperediting sites were found in retrotransposons embedded within the 3’UTRs of erythroid-specific transcripts, which may explain the cell-type specific requirement for ADAR1 in erythroid cells. Although A-to-I editing was presumed to be the primary function of ADAR1, experimental evidence was lacking. To determine the role of A-to-I editing by ADAR1, mice with an editing dead knock-in allele of ADAR1 (ADAR1E861A) were generated. I demonstrated that ADAR1-mediated A-to-I editing was essential for both foetal and postnatal haematopoiesis and erythropoiesis. I observed a profound upregulation of ISGs in Adar1E861A/E861A FL. Therefore; A-to-I editing by ADAR1 is required to suppress the inappropriate activation of ISGs in haematopoietic cells in a cell autonomous manner. RNA-sequencing analysis confirmed that hyperediting in erythroid-specific transcripts were mediated exclusively by ADAR1. Hyperediting was predicted to act to destabilise dsRNA structures that form from paired retrotransposons. Interestingly, I found that MDA5, the cytosolic sensor of dsRNA, recognises these structures in the absence of ADAR1 editing. Pevious studies have reported essential roles of ADAR1 in chronic myeloid leukaemia. In order to determine if ADAR1 was required for other types of leukaemia, the contributions of ADAR1 and it’s editing were assessed in MLL-AF9 transformed leukaemic cells. ADAR1 A-to-I editing was essential for the maintenance and cell survival of leukaemic cells. This requirement for ADAR1 was akin to that observed in haematopoiesis. Taken together, the primary in vivo function of ADAR1 is to edit endogenous transcripts in order to prevent their sensing by MDA5 as non-self.