Medicine (St Vincent's) - Theses
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ItemTowards the integration of palliative care in advanced cancer: an exploration of patient, family and community perceptions of palliative care and views of communication( 2018)Since its inception, palliative care practice has evolved to respond to the emerging evidence base and the needs of the population it serves. This has resulted in the increasing health system focus on models of early integration of palliative care, enabling improved quality of life, prevention of suffering, and the achievement of goals considered important by people with serious illness and their families. Yet, population data from international jurisdictions including those such as Australia with “advanced” systems of integrated care suggest a picture of missed opportunities, with many patients accessing palliative care late in the illness course. This thesis explored patient, carer, and community perceptions of palliative care, and their views of communication about this concept – including at the hospital for those who are experiencing serious illness and in the community more broadly. This was explored with the broader aim to improve engagement with palliative care, and ultimately facilitate the provision of quality care for those with serious illness. Consistent with the Medical Research Council Framework for the development of complex interventions, empirical work was undertaken using mixed methodology over two phases. Exploratory qualitative interviews were undertaken with patients with advanced cancer and their carers. These data informed the development of a public health intervention to communicate information about palliative care to the broader community, which was tested in an online randomised pilot trial. Patients and carers reported inherently negative perceptions of palliative care, understood as inpatient nursing care, relevant only when no other anti-cancer treatment options remained. Patients revealed the difficulties faced in speaking about death other than in implicit terms, with this topic perceived to be outside the realms of medical consultations. Instead, patients perceived health professionals used the term ‘palliative care’ as a tool to talk about dying. ‘Palliative care’ was understood as a euphemism for death, and personified to mean my death, in turn also becoming ‘unspeakable’. Carers reported their needs for communication about palliative care to be ideally staged overtime, providing education about the tasks of palliative care separate from referral. Once death was imminent, carers wanted open communication with their health professionals, including spoken acknowledgement that death was close, using simple, direct language, and including the words ‘death’ and ‘dying’. A narrative communication intervention was demonstrated to be an acceptable approach to provide education about palliative care to community members. Participants reported significant improvement in attitudes to palliative care post intervention compared to baseline. An evidence-based narrative spoken by a health professional was found to hold the most promise for further investigation in a definitive trial. The results of thesis have significant implications for achieving the routine integration of palliative care in clinical practice. They highlight key opportunities to target education and improve communication about palliative care, and can inform future public health efforts to develop a systematic, evidence-based approach to community engagement. As such, this work provides the next steps to begin to transform experiences of end of life care within health systems.
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ItemUnderstanding and manipulating epigenetic deregulations in osteosarcoma( 2016)Osteosarcoma (OS) is the most common cancer of bone and the 5th leading cause of cancer related death in young adults. Current 5-year survival rates have plateaued at ~70% for patients with localised disease. Those with disseminated disease have an ~20% 5-year survival. An improved understanding of the molecular genetics of OS translating into the identification of effective therapeutic targets may yield new approaches to improve outcomes for OS patients. To this end, I applied previously described murine models that replicate human OS to identify and understand dysregulated microRNAs (miRNA) and epigenetic modulators in OS. miRNA and epigenetic modulator expression patterns were profiled in murine primary osteoblasts, osteoblast cultures and primary OS cell cultures (from primary and paired metastatic locations) isolated from two genetically engineered murine models of OS. The differentially expressed miRNA were further assessed by a cross species comparison to human osteoblasts and osteosarcoma cultures. This led to the identification of miR-155-5p, miR-148a-3p and miR 335-5p as deregulated miRNA in OS. Additionally, miR-155-5p suppression or miR-148a-3p overexpression potently reduced proliferation and induced apoptosis in OS cells, yet strikingly, did not impact normal osteoblasts. To define how these miRNAs regulated OS cell fate, I used an integrated computational approach to identify putative candidate targets and then correlated these with the cell biological impact. While I could not resolve the mechanism through which miR-148a-3p or miR-335-5p impact OS, I identified that miR-155-5p overexpression suppressed its target Ripk1 (receptor (TNFRSF)-interacting serine-threonine kinase 1) expression, and miR-155-5p inhibition elevated Ripk1 levels. Ripk1 is directly involved in apoptosis/necroptosis. In OS cells, siRNA or small molecule inhibition against Ripk1 prevented cell death induced by the sequestration of miR-155-5p. Collectively I have shown that miR-148a-3p and miR-155-5p are species-conserved deregulated miRNA in OS. Modulation of these miRNA was specifically toxic to tumour cells but not to normal osteoblasts, raising the possibility that these may be tractable targets for miRNA based therapies for OS. Additionally, I investigated the outcome of targeting deregulate epigenetic modulators to achieve therapeutic efficacy in OS. The serine/threonine p21-activating kinases (Pak) are dysregulated in multiple cancers; however, their role in osteosarcoma (OS) is yet unknown. Using primary and metastatic OS tumour propagated cultures from murine models of OS I identified Pak1 and Pak2 as deregulated in OS. While reduced Pak1 expression in murine OS was not found conserved in human OS, the increased expression of Pak2, consistently existed across human and mouse OS. By inhibiting Pak2 gene expression levels using siRNA or pharmacological inhibition using 1,1′-Disulfanediyldinaphthalen-2-ol (IPA-3) and FRAX486, I demonstrated Pak2 inhibition to induce apoptosis in fibroblastic and osteoblastic murine OS cells in addition to primary human OS xenograft derived OS cells. The effects of Pak2 reduction or inhibition on cell proliferation and viability were proportional to the magnitude of Pak2 overexpression. Pak2 inhibition in normal osteoblasts, which have low basal Pak2 expression, did not induce changes in cell viability or proliferation. These findings demonstrate the efficacy of targeting Pak2 activity as a potential therapeutic strategy in OS. Finally, I investigated the effects of osteoblast restricted deletion of the oncogenic miR-17-92 cluster in delaying the onset of OS in Osx-Cre+ p53fl/fl Rbfl/fl murine models. While within my timeline I was unable to resolve the effects of conditional deletion of miR-17-92 cluster on OS onset, my parallel investigation of this deletion on skeletal and haematopoietic development in Osx-Cre+ R26eYFPki/+ miR17+/+, Osx-Cre+ R26eYFPki/+ miR17fl/+ and Osx-Cre+ R26eYFPki/+ miR17fl/fl models demonstrated unaltered parameters.
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ItemThe contribution of genetic variations in the region of the parathyroid hormone-like hormone, PTHLH, gene to breast cancer susceptibility( 2016)Aims: • Analyse the evidence for PTHLH and PTHrP, its protein product, playing a role in breast cancer and update the empirical definition of the gene. • Describe the 3-Dimensional structure of the PTHLH region and determine its system of regulatory interactions, including remote regulatory elements affecting PTHLH. • Integrate existing tools in addition to the novel perspectives generated above to enable a comprehensive annotation and analysis of genetic variants identified through molecular epidemiological techniques including Genome-Wide Association Studies (GWAS) and somatic DNA sequencing of tumour tissue to derive putative molecular mechanisms for the region’s involvement in breast cancer susceptibility. Methodology: • Review published studies and databases, integrating findings from diverse sources. • Acquire and analyse DNA and RNA sequencing, regulatory, expression, algorithm-inferred, and proximity-ligation data from multiple public data sources including ENCODE, ROADMAP, dbGAP, COSMIC and other to update the definition of PTHLH, and advance concepts of structure and regulatory function in the region. • Acquire and analyse primary GWAS data, performing imputation with multiple algorithms and references, and annotating associated variants with a suite of tools. • Use genome browsers including UCSC, WUSTL, and Golden Helix SVS, and their associated databases and tools, to analyse and visually integrate findings. Results: • PTHrP has multiple discretely functional segments active throughout the cell. It likely plays a bivalent and context-dependent role in cancer biology. Analysis of somatic variation in cancer suggests PTHrP may have a tumourigenic role within the nucleus. • PTHLH sits within a 1.3Mb TAD featuring multiple sub-structures that are integrated with the region’s regulatory function. There are activated chromatin hubs (ACHs) at protein-coding genes with evidence of extensive interaction between them. This is facilitated by the TAD’s structure, collocating them at the neck of the TAD. • The ACHs at MRPS35, KLHL42, and CCDC91 each monopolise a subordinate regulatory sub-net with a hierarchical structure. They each appear to act as important remote regulatory elements that integrate regulatory signals generated within their respective sub-nets, transferring them to PTHLH, and other genes, via ACH-ACH interactions. • There appear to be multiple discrete GWAS breast cancer association signals in the PTHLH region. Annotation of the associated variants suggests three particular regulatory elements may be its key drivers. In the context of the regulatory concepts developed in this thesis, the variants may affect a particular regulatory signal at multiple points in its assembly. PTHLH is the likely downstream target of this signal. • There are multiple poorly-describe coding, and non-coding, genes in the region that are also potential actors in breast cancer and should be investigated. Conclusion: • The PTHLH region is likely involved in the pathogenesis of breast cancer through the modification of PTHLH expression. There are likely to be other mechanisms in parallel that are yet to be fully described.