Medicine & Health

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  • (2022) Kokkinos, John
    Thesis
    Less than 10% of patients with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years. One of the characteristic features that drive the aggressive nature of PDAC is its multicellular, heterogeneous, and fibrotic microenvironment. We previously identified a cytoskeletal protein, βIII-tubulin, as a novel therapeutic target in PDAC. However, the PDAC cell survival mechanisms controlled by βIII-tubulin were previously unknown. We also identified a major gap in the ability of human PDAC preclinical models to accurately mimic the 3D multicellular architecture and stroma of the disease. Thus, the aims of this work were (1) to evaluate the pro-survival role of βIII-tubulin in PDAC; (2) to establish a new patient derived tumour explant model that maintains all features of the PDAC microenvironment; and (3) to use the tumour explant model to test the clinical potential of silencing βIII-tubulin expression as well as two stromal targets that had been previously explored by our lab: solute carrier 7A11 (SLC7A11) and heat shock protein 47 (HSP47) Here, we identified that silencing βIII-tubulin in pancreatic cancer cells activated extrinsic apoptosis and increased their sensitivity to extrinsic apoptosis inducers including tumour necrosis factor-α (TNFα), Fas-ligand (FasL), and TNF-related apoptosis inducing factor (TRAIL). We next established the patient derived PDAC tumour explant model. We cultured whole-tissue tumour explants from PDAC patients for 12 days and demonstrated that explants maintained their 3D multicellular architecture, proliferative state, and collagen fibrosis. We also demonstrated the ability to deliver chemotherapeutics and siRNA-nanoparticles to the tumour explants. Finally, we tested the utility of this model to investigate the clinical potential of silencing three different therapeutic targets. We showed that therapeutic silencing of βIII-tubulin combined with TRAIL increased extrinsic apoptosis, decreased cell proliferation, and decreased tumour cell number. Inhibition of the stromal target SLC7A11 reduced tumour cell number and inhibited activity of stromal cancer-associated fibroblasts. Silencing of another target, HSP47, also led to a reduction in tumour cells and decreased cell proliferation. Overall, this work has discovered a previously unexplored role of βIII-tubulin as a brake on extrinsic cell death and has developed a new human PDAC preclinical model with utility in the drug development and precision medicine pipeline.

  • (2022) O'Hagan, Edel
    Thesis
    Low back pain is common and burdensome. The economic burden of low back pain in Australia includes total costs that exceed A$8 billion per year, costs which are projected to increase by 60% over the next 10 years. Less is known about the personal burden of low back pain. The first-line treatment consistently recommended for people with low back pain is patient education and advice. Regardless of the duration of low back pain, clinicians should provide advice to remain active, education on the benign nature of low back pain, and reassurance about the absence of a serious medical condition. Little guidance is available on how best this can be achieved. New treatments are urgently required to stem the rising costs of low back pain. Two proposed strategies are repurposing medicines, such as sleep medicines and media campaigns to target unhelp behaviours and beliefs. The overarching aim of this thesis was to investigate the personal burden of low back pain, evaluate attitudes toward education and advice for low back pain and explore contemporary options for managing low back pain. The methods used included qualitative content analysis, an observational study, development and evaluation of a new measurement tool, a systematic review and a randomised controlled trial. People with and without low back pain, online and in-person were recruited to participate across the five studies. The findings from each study are presented in individual chapters. The evidence in this thesis provides a scientific basis for understanding the personal burden of low back pain. The results describe how evaluating attitude toward education and advice could enable clinicians to tailor the patient education and advice they provide. Specific messages of reassurance rather than information about staying active should be prioritised. The Attitude toward Education and advice for Low back pain Questionnaire (AxEL-Q) is a valid and reliable tool to provide clinicians with an insight into attitudes toward education and advice at the outset of a clinical encounter. Sleep medicines should be further investigated before being endorsed to reduce pain intensity in people with acute low back pain. Social media and digital health interventions such as conversational agents provide options for supplementing low back pain management in the future.