Melbourne Medical School Collected Works - Theses
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ItemThe role of the renin-angiotensin system in portal hypertension and hepatic fibrosis(University of Melbourne, 2008)
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ItemCoagulation and inflammation in experimental colitis(University of Melbourne, 2008)
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ItemFactors controlling the differentiation of macrophage lineage cells into osteoclasts(University of Melbourne, 2007)
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ItemSuperantigens and the innate immune response in human sepsis(University of Melbourne, 2006)
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ItemSuperantigens and the innate immune response in human sepsis(University of Melbourne, 2006)
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ItemThe role of Dlk1 in haematopoiesis, leukaemia and angiogenesis( 2017)Delta-Like Homologue 1 (DLK1), also known as Preadipocyte Factor 1 (PREF-1), is a non-canonical EGF-like NOTCH ligand. It is maternally imprinted at the Dlk1-Dio3 imprinted locus, and has been shown to regulate embryonic growth, lipid metabolism and skeletal development. However, the precise role of Dlk1 in haematopoiesis, leukaemia and angiogenesis, processes in which it has been previously implicated, is unknown. We generated Dlk1 knockout and conditional knockout mice and used a constitutive overexpression system via retroviral transduction to specifically study Dlk1 in these contexts. Dlk1 knockout mice showed distinctive phenotype of increased perinatal mortality and growth retardation. In foetal livers, significant expression of Dlk1 was detected in the haematopoietic cells, with higher level of expression in the haematopoietic stem cells compared to lineage positive mature cells, with overall expression decreasing with embryonic age. Dlk1 knockout mice were not significantly different from wild type mice in the mature haematopoietic lineages, but serial competitive transplant assays demonstrated Dlk1 knockout bone marrow cells were inferior to controls in reconstituting lethally irradiated recipient mice in short term haematopoietic reconstitution assays, suggesting that Dlk1 knockout led to a defect in adult short term haematopoietic stem cells. Despite frequent overexpression of DLK1 found in many human acute myeloid leukaemias, constitutive overexpression of Dlk1 did not lead to increase in acute leukaemia or death in reconstituted mice. However, Dlk1-overexpressing haematopoietic cells demonstrated competitive repopulation advantage compared to MIG-transduced controls. Using a retinal model of angiogenesis, Dlk1 was found to be expressed by the pericytes rather than endothelium of newly developing blood vessels in postnatal murine pups, in contrast to the published data. Conditional knockout of Dlk1 in endothelial cells using the endothelial specific Tie2 Cre transgene did not lead to significant abnormality in postnatal retina, confirming that Dlk1 did not have a functional role in the retinal endothelium. These new findings add to our current knowledge of stem cell biology and leukaemia, and the role of Dlk1 in angiogenesis.
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ItemTargeting cyclin-dependent kinase 9 and myeloid cell leukaemia 1 in MYC-driven B-cell lymphoma( 2016)Aggressive B-cell lymphomas include diffuse large B-cell lymphoma, Burkitt lymphoma and intermediate forms. Despite high response rates to conventional immuno-chemotherapeutic approaches, an unmet need for novel therapeutic strategies is required in the setting of relapsed and refractory disease, typified by resistance to chemotherapy and radiotherapy. The proto-oncogene MYC is frequently dysregulated in the aggressive B-cell lymphomas, however, it has proven an elusive direct therapeutic target. A significant body of evidence is accumulating to suggest that MYC-dysregulated disease maintains a ‘transcriptionally-addicted’ state, whereby perturbation of RNA polymerase II activity may indirectly antagonise MYC activity. Furthermore, very recent studies implicate anti-apoptotic myeloid cell leukaemia 1 (MCL-1) as a critical survival determinant of MYC-driven lymphoma. This thesis utilises pharmacologic and genetic techniques in MYC-driven models of aggressive B-cell lymphoma to demonstrate that cyclin-dependent kinase 9 (CDK9) and MCL-1 are oncogenic dependencies of this subset of disease. The cyclin-dependent kinase inhibitor, dinaciclib, and more selective CDK9 inhibitors are used to demonstrate efficient apoptosis induction conferred at least in part by downregulation of MCL1 transcription. Furthermore, a genetic screen identifies other transcriptional cyclin-dependent kinases that are required for viability of MYC-driven lymphoid disease. Finally, having established MCL-1 as a critical oncogenic dependency of MYC-driven lymphoma, this thesis demonstrates the significant activity that is conferred by direct pharmacologic antagonism of MCL-1 using a small molecule BH3-mimetic inhibitor of MCL-1. These findings confirm a druggable pathway of oncogenic cMYC dependency involving CDK9 regulated RNA polymerase II-mediated transcription of MCL-1, and proposes pharmacologic inhibition of CDK9 and MCL-1 as novel anti-lymphoma strategies.
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ItemExploring the qualities of Electronic Health Record medical student documentation( 2016)Written communication within the health professions has been rapidly changing over the last decade. Implementation of Electronic Health Records (EHR) in health services is now widespread. Medical student teaching and learning of the skills specifically required for EHRs has lagged behind the implementation. Very few original studies have focused on EHR skills and there are no validated measures by which to assess any of the EHR skills students are expected to develop. Our study explored the attributes of quality EHR documentation recorded by medical students, with the purpose of the EHR documentation being the communication between health care professionals to share or transfer the clinical care of a patient. Recently there have been published validated instruments for measuring quality in physician EHR documentation, one being Physician Documentation Quality Instrument (PDQI-9). The purpose of this study was to explore the attributes of quality of EHR documentation written by first-year clinical medical students by building upon existing literature. The PDQI-9 was used as a basis for defining the attributes of quality in EHR documentation as a foundation for assessing and providing feedback on the performance of documentation to medical students. With the focus on assessment, and providing a content validated test domain for assessment in quality EHR documentation, we utilised Kane’s framework for validity to structure the study and a mixed method study design to achieve the depth of exploration required to examine the performance of quality documentation fully. The study was conducted in two stages. In the first stage of the study, an expert panel of assessors applied the PDQI-9 to existing EHR data recorded by first clinical year medical students in a graduate entry program. The assessors both scored the records and justified their grading. Descriptive statistics and thematic analysis were undertaken on the data collected, and the findings triangulated with the literature review. The second stage employed explanatory semi-structured interviews with the expert assessors to better understand the findings of the first stage and reach consensus on a test domain for assessing quality documentation recorded by medical students. Outcomes from our study indicated that the PDQI-9 in its current format was not valid in a medical student setting, however most of the attributes assessed by the PDQI-9 were deemed relevant and meaningful to assess if their interpretations were clarified. In addition, Professionalism of documentation was regarded as a quality attribute. Consensus was reached on modifications that have the potential to improve the validity of the assessment of quality documentation recorded by medical students. Further studies need to complete Kane’s framework of validity for an assessment instrument and collect evidence to broaden the validity of the scoring, the generalization of the assessment items, the extrapolation to the real world and the implications of this assessment for students and health services.
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ItemLinguistic change in an online support group( 2016)Online support groups (OSGs) are popular sources of both health information and social support. Though early research into OSGs highlighted a concern that non-expert members may give harmful advice, more recent studies have typically shown that engagement with OSGs can increase consumer satisfaction with the treatment process, enhance wellbeing, and ultimately improve health outcomes. OSGs are well-researched within applied linguistics. Qualitative studies have focussed on member roles within OSGs, as well as the ways in which group members discursively construct their identities, especially with respect to their illness. These approaches have generated rich insights into consumer healthcare discourse that can inform strategies for fostering consumer-centred care. Qualitative approaches, however, are resource-intensive, di cult to reproduce, and limited in terms of generalisability and representativeness. Quantitative and computational approaches are able to overcome these shortcomings, adding transparency, reproducibility, scalability, and reducing the potential for researcher bias. Current computational approaches to consumer healthcare discourse, however, tend to rely on simplified conceptualisations of language, prioritising lexis over grammar, and thus ignoring the central role played by grammar in the meaning-making process. To address current methodological shortcomings in OSG discourse research, this thesis presents an interdisciplinary, corpus-based investigation of lexicogrammatical and discourse-semantic choices made by members over the course of membership in an online bipolar disorder support community. 8.2 million words in over 66,000 posts from approximately 3,500 members were transformed into a metadata-rich, grammatically annotated corpus and investigated from a systemic-functional linguistic (SFL) perspective using purpose-built corpus/computational linguistic tools. An analysis of MOOD and MODALITY choices made over ten stages of membership highlights differences in the ways members negotiate role-relationships, with changes in Mood Type, Modality and Speech Function reflecting a longitudinal increase in the provision of advice and social support. An analysis of the TRANSITIVITY system shows longitudinal changes in the kinds of participants and processes construed by Forum members, as well as changes in how these participants and processes behave lexicogrammatically. The diagnosis Event, for example, is represented by newcomers as a process and modi ed temporally; at later stages of membership, it is more often reconstrued as a participant in discourse, framed in terms of veracity. Longitudinal shifts were also observed in the preferred ways of ascribing/attributing bipolar disorder to Forum members: new members use bing forms (I’m bipolar), while veteran members prefer having constructions (I have bipolar). The thesis has implications for corpus linguistics, systemic-functional linguistic theory, and healthcare communication research. For corpus linguistics and corpus-assisted discourse studies, the main contribution is corpkit, an open-source software tool designed to build and analyse parsed and metadata-rich corpora. it is suggested that the developed tools and methods can circumvent theoretically problematic current practices, and increase the accuracy and automatability of the analytical process. For healthcare communication research, the case study demonstrates the importance of expanding the conceptualisation and analysis of the consumer healthcare journey to include intra–consumer communication that occurs outside of hospitals and clinics. The thesis also advances an argument that the emerging eld of clinical natural language processing stands to benefit from increased engagement with functional linguistic theory and insights generated within the qualitative paradigm. I argue that combining the insights from functional linguistics and discourse analysis with automated computational workflows is a step toward an important future goal of improvement of consumer health outcomes through analysis of large, digital collections of spoken and written healthcare discourse.
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ItemThe malaria vaccine candidate Apical Membrane Antigen 1 – antigenic diversity and its potential as effective multi-allele vaccine( 2016)Understanding naturally acquired immunity to malaria and how human antibodies protect against clinical malaria is essential for vaccine development. Antibodies against Plasmodium falciparum apical membrane antigen 1 (AMA1), a leading vaccine candidate, can inhibit merozoite invasion of erythrocytes and protect from P. falciparum malaria. However, polymorphism in antigens like AMA1 is a common mechanism for immune evasion and presents major challenges in vaccine development. This study aims to understand antigenic diversity of AMA1, the correlation between sequence polymorphism and antigenic differences, the impact of polymorphism on potential vaccine escape, and the structural differences of the protein amongst various alleles, with the goal to ultimately ascertain which AMA1 alleles should be included in an effective multi-allele vaccine.