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(2018)ThesisCardiovascular disease is the leading cause of morbidity and mortality globally. Left ventricular (LV) and left atrial (LA) dysfunction are both independent predictors of adverse cardiac outcomes. LV and LA structural and functional remodelling can result from increased LV wall stress consequent to chronic pressure overload. The studies in this thesis aimed to examine the alterations in LV and LA mechanics in chronic pressure overload conditions, especially focusing on early detection of subtle and subclinical abnormalities using newer echocardiographic techniques. Aortic stenosis (AS) and hypertension, the two most common cardiovascular conditions associated with chronic pressure overload, have been chosen for evaluation. Myocardial fibres are organised in layers with subendocardial strain being significantly higher than subepicardial strain in all three (longitudinal, circumferential and radial) axes. There was progressive global longitudinal strain (GLS) and global circumferential strain (GCS) impairment with increasing AS severity. Subendocardial longitudinal strain correlated better with indices of AS severity than other strain parameters. The degree of aortic valve calcification correlated with AS severity as well as strain impairment, with stronger correlation with GLS than GCS. There was no correlation between the degree of myocardial fibrosis assessed on histopathology and AS severity or LV strain impairment in patients undergoing surgical aortic valve replacement (AVR). For AS patients who were managed conservatively, there was progressive strain impairment, detectable earlier in subendocardial than subepicardial layer, and earlier in GLS than GCS. LV GLS improvement was detected from 3 months after AVR, with GCS improvement detected from 6 months post-surgery. Hypertensive patients, compared with normotensive patients, had impaired LV GLS at rest and at low-dose dobutamine, and impaired GCS at low-dose dobutamine despite preserved GCS at rest. They also had impaired LV GLS contractile reserve (CR) to inotropic stimulation, despite normal LVEF at rest and normal LV CR assessed by LVEF. Furthermore, hypertensive patients had impaired LA reservoir, conduit and atrial contractile strains, in addition to more prolonged electromechanical delay (EMD) in the absence of LA enlargement. LA EMD correlated significantly with all 3 LA phasic strains, with LA atrial contractile strain being an independent correlate of LA EMD.
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(2017)ThesisThe main component of treatment for locally advanced rectal cancer is neoadjuvant chemoradiation, which carries morbidity. Hence, biomarkers are urgently needed to better select patients to undergo this therapy. This work evaluates selected, rational and primarily biologically-based biomarker changes during chemoradiation. These include circulating tumour cell (CTC)-based, serum and solid tissue biomarkers, as well as patient-related biomarkers such as quality of life. Novel aspects include tracking of CTCs during chemoradiation, description of microRNA (miRNA) profiles in CTCs, tracking changes in miRNA expression during treatment, comparison of miRNA profiles across tissue types and correlation of biological and patient-related markers. CTCs were found in almost two-thirds of patients with locally advanced rectal cancer. Overall, CTC counts fell during chemoradiation. Patients with a complete pathological response to treatment had lower CTCs at baseline. We report a positive correlation between CEA and CTC counts, and between CTC counts and the neutrophil-lymphocyte ratio. We found that natural killer cell counts were reduced in locally advanced rectal cancer tissue compared to normal tissue and this correlated with tumour regression. Rectal tissue lymphocyte counts increased with neoadjuvant chemoradiotherapy, with the CD8 subset most likely responsible. Upregulated polo-like kinase 1 expression in the periphery of the primary tumour tissue correlates with inferior survival in rectal cancer. Hypothesis-generating correlations were found between CTCs and quality of life. MicroRNA profiles exist in CTCs, serum and solid tissue and were compared between treatment time-points. miR-542-3p in CTCs was upregulated during chemoradiation. Out of 112 candidates, 13 serum miRNAs were differentially expressed between patients and controls and 11 were also altered with treatment. Comparing across tissue types, miR-1183, miR-125b-1*, miR-223, miR-375 were differentially expressed from pre- to post-treatment in both serum and solid tissue. miR-195 and miR-342-3p in CTCs, and serum miR-720 and mir-628-5p may be promising markers of non-response. In solid tissue, miR-25 was downregulated only in responders. We believe that a comprehensive profile incorporating these novel biomarkers will help us better understand the disease process during neoadjuvant chemoradiation in locally advanced rectal cancer, and can potentially serve as an adjunct to conventional histopathological variables.
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(2017)ThesisPancreatic cancer (PC) is the fourth leading cause of cancer related deaths with a 5-year survival rate as low as 5%. It is now acknowledged that the desmoplastic / stromal reaction, a characteristic feature of PC, contributes to progression of this cancer, by facilitating local growth and distant metastasis. Our laboratory was the first to demonstrate that pancreatic stellate cells (PSCs), i) produce the collagenous stroma of PC, and ii) interact closely with cancer cells to facilitate cancer progression. A candidate growth factor pathway that may mediate this PSC-cancer cell interaction is the hepatocyte growth factor (HGF) /c-MET (receptor for HGF) pathway. This thesis studies the effects of inhibiting HGF and c-MET, in the presence and absence of chemotherapy, on PC progression using (i) an orthotopic model of PC (in vivo approach), and (ii) human PC cells (AsPC-1) and PSCs (hPSCs) in culture (in vitro approach). My novel data have demonstrated that HGF inhibition (with neutralising antibody AMG102) as well as c-MET inhibition (using Compound A, a small molecule c-MET inhibitor), either singly or together were as effective as standard chemotherapy (gemcitabine) in inhibiting local tumour growth. Combining either HGF or c-MET inhibition with gemcitabine also reduced tumour growth. However, the combination of all three approaches (HGF inhibition + c-MET inhibition + chemotherapy) reduced tumour growth most, and more importantly, virtually eliminated metastasis. Another important observation was that gemcitabine treatment by itself failed to prevent metastasis, but instead, induced epithelial-mesenchymal transition and stemness (as assessed by increased expression of stem cell markers) in a sub-population of cancer cells. In vitro studies demonstrated that hPSC secretions not only induce proliferation and migration, but also inhibit apoptosis of cancer cells. These effects were countered by pre-treatment of hPSC secretions with HGF inhibitor or c-MET inhibitor indicating a key role for the HGF/c-MET pathway in PSC-PC interactions. The above findings suggest that targeted therapy to inhibit stromal-tumour interactions mediated by the HGF-c-MET pathway may represent a novel therapeutic approach in PC, which could be used with existing treatment modalities as a multi-pronged approach, to significantly improve the clinical outcome of patients with pancreatic cancer.
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(2014)ThesisThis thesis examined the central concepts of left ventricular (LV) deformation and functional reserve in patients with diabetes (DM). The studies evaluated LV systolic contractile reserve (CR) and coronary microvascular function and identified determinants and patterns of coronary microvascular dysfunction. LV diastolic reserve and its relationship with endothelial function and impact of strict metabolic control on LV mechanics were studied. LV systolic CR at low dose dobutamine of ≥10% identified an index of microcirculatory resistance (IMR) of <25 with 100% accuracy. There was differential involvement of coronary vascular beds in patients with vascular risk factors: DM patients had worse microvascular function in the anterior circulation than patients without DM. The opposite was observed in those without DM. DM patients with dyslipidaemia, hypertension, worse glycaemic control and higher body mass index had worse microvascular function, whereas those treated with metformin had better microvascular function. Flow mediated dilatation (FMD) of the brachial artery was an independent predictor of LV diastolic reserve and exercise capacity. Patients with DM had impaired ability to improve LV diastolic function and maintain normal LV pressures with exercise. This is demonstrated by a higher increase in E/e , after adjusting for differences in the resting values, with the increase in the ratio persisting up to 10 minutes into recovery. Patients with DM and hypertension, longer duration of insulin therapy, worse glycaemic control, worse renal function and lower septal e had more impaired diastolic reserve. Patients with DM have impaired LV systolic and diastolic function manifested by an impaired LV global longitudinal strain of -14.9±3.2% and septal e velocities of 6±2 cm/sec, respectively, despite a normal LV ejection fraction. Improvements in glycaemic control over a 12-month period were associated with improvements in LV systolic and diastolic function measured by LV ejection fraction as well as GLS and septal e velocities. There were significant linear relationships between improvement in HbA1c and improvement in LV systolic and diastolic function. Furthermore, improvements in systolic function and HbA1c were associated with improvement in exercise tolerance. Improving glycemic control appears to be beneficial in reversing to some degree the cardiotoxic effects of hyperglycemia.
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(2014)ThesisRandomised controlled trials (RCTs) provide clinicians with the best evidence for interventions, but are subject to systematic errors (bias) when methodology is not optimal. These biases occur at any time from the inception, execution, data collection, analysis, and dissemination of results. Performing RCTs for surgical interventions is additionally challenging, given the relative complexities of surgical interventions and patients, and the culture of surgical training. This thesis examined the epidemiology and quality characteristics of RCTs of surgical interventions. A systematic search was conducted to locate recently published surgical RCTs and meta-analyses, in order to attain a sample that would be reflective of the current state of surgical evidence. Data was piloted and collected according to a proforma. The first study assessed the epidemiology and methodological quality of surgical RCTs, and compared these characteristics with what is known about general medical RCTs. The second study assessed reporting quality by compliance with the Consolidated Standards of Reporting Trials (CONSORT) statement. The third study investigated the association between methodological quality and treatment effects in surgical RCTs. The fourth and fifth studies examined patterns of outcome reporting. The association between statistical significance and reporting of outcomes (outcome reporting bias) was explored. The extent to which outcomes measured in surgical RCTs are patient important was also assessed. Finally, the sixth study assessed the epidemiology, reporting and methodological quality of meta-analyses of surgical RCTs. The results show that there is substantial room for improvement in the conduct and reporting of RCTs of surgical interventions. Inadequate methodology was common, and was associated with an exaggeration of treatment effects. There was concerning evidence of unreported outcomes, and complete outcome reporting was associated with statistical significance. Only two thirds of primary outcomes were patient important. If the truth about surgical interventions is to be discerned, the conduct and reporting of surgical trials must improve. Much of this responsibility lies with study authors, but journal editors and reviewers, and the funders of research also have an important role. Existing guidelines need to be promoted and imposed, and existing multicentre models for the conduct of surgical trials should be further explored.
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(2015)ThesisBackground: Stricturing and fistulizing intestinal complications are largely responsible for the significant morbidity of Crohn’s disease (CD). The inability to predict the development of these complicated phenotypes of CD (CCD) remains the bottleneck to evaluating the efficacy of early escalation therapies, which could change the natural history of CD. Proteomic methodologies may be able to identify important mechanisms in these pathologies. This thesis comprised a series of studies conducted under the framework of the biomarker development pipeline to examine the low-mass serum proteome of the behavioural phenotypes of CD. Methods: Untargeted and targeted Mass Spectrometry (MS) was used for global metabolite profiling and quantification of immunoregulating Kynurenine Pathway (KP) metabolites in proof-of-principle metabolomics studies. In a discovery phase proteomics study, in-solution electrophoresis was used to enrich the low-mass (<25kDa) serum fraction of CD behavioural phenotypes for untargeted MS analysis. Elements affecting accuracy in Multiple Reaction Monitoring (MRM) MS assays were evaluated in research assay optimisation phase study, and MRM and immunoblotting were used in qualification phase proteomics studies to quantify discovery phase-identified biomarker candidates in cross-sectional and longitudinal cohorts. Results: Proof-of-principle metabolomic studies demonstrated the ability of MS to identify unique plasma profiles between distinct pathologies of intestinal inflammation. Th1/17 inflammatory metabolites Angiotensin IV, diphthamide and GM3 gangliosides were associated with CD and KP metabolite Quinolinic acid was increased in CD and correlated with biochemical and clinical measures of disease activity. In discovery phase proteomics study, a low-mass serum profile typified by an overabundance of epithelial component proteins was identified in CCD. In research assay optimisation, peptide-centric matrix effects that caused deleterious effects on quantitative accuracy in MRM assays were identified, and a novel Reverse-Polynomial Dilution (RPD) calibration technique that reduced error in multiplexed MRM assays was established. Finally, a serological biomarker candidate panel with discriminative ability for intestinal complications in CD was demonstrated in qualification phase. Conclusions: An enrichment of serological epithelial component proteins in CCD was identified in this work that can classify CCD against intestinal and Th1/17 systemic inflammation controls. These proteins may be serological biomarkers of transmural intestinal tissue integrity that could predict progression to CCD.
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(2021)ThesisChronic respiratory disease (CRD), including chronic obstructive pulmonary disease (COPD), asthma, and less common respiratory diseases, is one of the four major noncommunicable diseases worldwide. Tobacco smoking is a major, avoidable risk factor for CRD. In low- and middle-income countries, there are important barriers preventing people affected by CRD from gaining access to effective, evidence-based prevention and disease management. In Vietnam, little is known about the gap between evidence-based practice and actual clinical management for CRD and cigarette smoking. This thesis aims to assess the current practice for CRD and tobacco smoking in the Vietnamese healthcare system and to evaluate the feasibility of two interventions to reduce the burden of CRD and tobacco smoking. The first part of the thesis includes two cross-sectional studies conducted at all four levels of healthcare facilities in Vietnam. In the first study, I used a syndromic approach to assess patients visiting healthcare facilities due to respiratory symptoms. The findings suggested that COPD and asthma were often misdiagnosed and more than half of patients with the diseases did not receive maintenance inhaled medicines for airways disease. In the second study, we found a high prevalence of current smoking among male patients seeking healthcare. The majority of those who attempted to quit had never used any evidence-based method to help them quit. The second part of the thesis reports pilot studies for two trials that were conducted in three rural district hospitals in Hanoi. The first trial assessed the feasibility of a novel stepped approach to treatment of patients with undifferentiated CRD (asthma and/or COPD) using inhaled budesonide-formoterol. Our data collected over 12 months follow-up period suggested that this intervention is feasible in a rural setting in Vietnam. The second trial focused on tobacco smoking and the interventions included the implementation of smoke-free hospital policy, brief advice from doctors, and follow-up counselling phone calls and text messaging. We found a high rate of self-reported smoking cessation. However, many of the participants did not consent to biochemical verification of their quit status, limiting the interpretation of the trial. Finally, I conducted a process evaluation to assess various aspects of implementing the intervention for CRD that may affect patients’ outcomes. The process evaluation shows barriers and challenges to implementing the components of the intervention, such as insufficient inhaler education from pharmacists and underutilisation of management plan by patients. The findings from this process evaluation will help to improve the implementation of interventions for COPD and asthma in Vietnam.
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(2020)ThesisBackground: Randomised clinical trials describe the benefit of chemotherapy (CT) for cancer patients with selected patient and disease characteristics. The overall survival (OS) benefits for the whole population of cancer patients in Australia, if evidence-based guidelines for CT were implemented, are unknown. The purpose of this thesis was to estimate the absolute improvements in overall survival that might result from systematically applying evidence‐based guidelines about the optimal use of a first course of chemotherapy to the whole population of people with cancer in Australia. Methods and Materials: Decision trees with evidence-based indications for CT have been previously defined. Each branch of the tree corresponds to a specific cohort who have, or do not have, defined indication for curative and palliative CT. CT OS benefit was defined as the absolute incremental OS of first-course CT over best supportive care for palliative indications or over radiotherapy or surgery with or without radiotherapy in curative indications. Multiple electronic citation databases were systematically queried, including Medline and Cochrane library. In cases where there were multiple sources of the same level of evidence, then hierarchical meta-analysis was performed. A literature search was updated with a cut-off of December 2017. The OS benefits of CT were estimated for one year, five years and ten years. To assess the robustness of our estimates, sensitivity analyses were performed. Results: The estimated one-year, five-year, ten-year absolute population-based OS benefits of optimally-used first-course CT for cancer were 5.9% (95% Confidence Interval, CI 4.8%-7.0%), 4.5% (95% CI, 4.4%-4.5%) and 3.3% (95% CI, 3.3%-3.4%) respectively. The additional benefit of CT over other modality for five-year OS ranged from 0% (malignant pleural mesothelioma) to 26.7% (testes). Sixty one percent of OS benefit was attributed to first-course palliative CT at one year, and 24% at five years. Conclusion: This is the first comprehensive study, using robust modelling methodologies, to estimate the population-based overall survival benefits from first-course CT for all cancers in Australia. The model can be adapted for other jurisdictions readily. First-course CT offers vital benefits to the cancer population. The population survival benefit can serve as an evidenced-based benchmark as part of the consensus quality standard in the treatment of cancer in Australia. Consequently, it can further aid decision making for cancer treatment. As a result, future studies may utilise this approach to estimate the population benefits for surgery and other endpoints. This model is flexible, enabling the consideration of any future changes to the population benefits of CT in the management of cancer within Australia or can be altered to address other jurisdictions where differing prevalence and stage data may exist.
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(2021)ThesisGene expression can be regulated from transcriptional initiation to RNA processing and turnover time and post translational modification of a protein. The majority of studies of gene expression have focussed on transcription. However, it is also important to understand how post-transcriptional pathways are regulated in response to inflammatory stimuli. Chapter 1 introduces background to gene expression during post transcriptional regulation and its regulation related to inflammatory diseases. The innate immune response to LPS is highly dynamic yet tightly regulated. RNA decay pathways include nonsense-mediated decay, the RNA decay exosome, P-body localised deadenylation, decapping and degradation and AU-rich element targeted decay mediated by tristetraprolin. Chapter 2, we examined the regulation of RNA degradation pathways during the lipopolysaccharide response in macrophages and these results have been published. Alternative splicing has been identified as a key process in post-transcriptional regulation of gene expression in higher eukaryotes. In the immune system, alternative splicing provides a major role in regulating gene expression and generating the diverse mRNA transcripts and protein isoforms, therefore giving rise to protein diversity.Intron retention (IR) is a form of alternative splicing where an intron is not removed during transcription coupled splicing and is considered a widely regulated process during gene expression. Chapter 3 we examined its regulation during inflammation. Also, gene expression can be regulated via nonsense-mediated decay, which can precisely control the timing and level of gene expression as well as eliminating unstable or toxic protein production. SMG1 is a member of the PIKK (phosphoinisitide 3-kinase related kinases) family and plays an important role in NMD. For Chapter 4 we investigated the role of SMG1 in the regulating in response to inflammatory stimuli. We generated a novel animal model of total SMG1 loss in macrophages to address this question. For Chapter 5, we showed how to analyse RNA-seq. of BMM from LysM+/CreSmg1fl/fl (Cre) and Smg1fl/fl (wild-type) mice treated with LPS treatment at dedicated time points by gene ontology tools to discover gene enriched clusters during an LPS treatment between LysM+/CreSmg1fl/fl (Cre) and Smg1fl/fl (wild-type) mice. A final discussion and future directions for this field of study are provided in Chapter 6.
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(2020)ThesisPrediction of chemoradiotherapy (CRT) response in rectal cancer would enable stratification of management whereby responders could undergo ‘watch-and-wait’ to avoid surgical morbidity, and non-responders could have early treatment intensification to improve therapeutic outcomes. Functional MRI can assess tumour function and heterogeneity, and may improve therapeutic response prediction. The aims of this PhD were to (i) prospectively evaluate multi-parametric MRI at 3.0 tesla in vivo combining diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) MRI for prediction of CRT response and 2 year disease-free survival (DFS), and (ii) examine diffusion tensor imaging (DTI) MRI biomarkers of rectal cancer extent and heterogeneity at ultra-high field 11.7 tesla ex vivo in order to establish a pipeline for MRI biomarker discovery from ultra-high field to clinical field. Patients with locally advanced rectal cancer undergoing CRT followed by surgery underwent multi-parametric MRI before, during, and after CRT. A whole tumour voxelwise histogram analysis of apparent diffusion co-efficient (ADC) and Ktrans heterogeneity was performed and correlated with histopathology tumour regression grade. After CRT (before surgery) ADC 75th and 90th quantiles were significantly higher in responders than non-responders. Patients with higher Ktrans values after CRT or greater increase in Ktrans values from before to after CRT had a significantly higher risk of distant metastases, and lower 2 year DFS. Biobank tissue from patients with rectal cancer were examined at 11.7 tesla and DTI-MRI results correlated with histopathology. This work established a discovery framework for screening Biobank cancer tissue for novel MRI biomarkers of tumour extent and heterogeneity, and resulted in good preservation of tissue integrity and MRI-histopathology alignment. DTI-MRI derived fractional anisotropy (FA) was able to differentiate between tumour and desmoplasia, fibrous tissue, and muscularis propria, allowing for more accurate delineation of rectal cancer tumour extent and stromal heterogeneity ex vivo. In conclusion, DWI-MRI was predictive of CRT response, DCE-MRI was predictive of 2 year DFS, and DTI-MRI was able to more accurately define tumour extent and heterogeneity in rectal cancer. These findings could be useful for stratification of patients for individualised treatment based on accurate assessment of tumour extent and therapeutic response prediction.