Medicine & Health

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  • (2021) Wahlroos, Sara
    Thesis
    Exercise following a breast cancer diagnosis is known to improve outcomes. In multiple pre-clinical cancer models, exercise alone has shown to inhibit tumour growth. Some of the suggested mechanisms for this benefit include exercise-induced recruitment and activation of anti-cancer immune cells, release of myokines and alterations in intrinsic metabolic cellular pathways. Exercise has also shown to improve tumour blood flow, which may translate to improved chemotherapy delivery to otherwise hypo-perfused tumour regions. Whether exercise acts an adjunct to our current systemic therapies in improving breast cancer outcomes is a question that remains unanswered. The overall hypothesis of this thesis is that exercise suppresses breast cancer tumour growth. We confirmed this in two different in vivo models of breast cancer. Given our positive results, we proceeded to test a series of questions necessary to move our findings into clinical practice; 1. Does exercise act as an adjunct to systemic breast cancer therapy, 2. Does exercise shift the tumour immune microenvironment (TIME) to an immunosuppressive phenotype, 3. Is it feasible to exercise immediately after and during neoadjuvant chemotherapy for early stage breast cancer. We tested the combination of exercise and doxorubicin chemotherapy in two different in vivo models of breast cancer, and found no additional benefit on tumour growth with the combination treatment compared to doxorubicin alone. We did find an exercise-induced shift in the TIME to include immune cells with cytotoxic properties, associated with tumour growth suppression in one in vivo model of breast cancer. Concordantly, where exercise showed to be ineffective in suppressing breast cancer growth in vivo, no clear shift in the TIME was observed. Our clinical study confirmed that exercising immediately after, and during neoadjuvant chemotherapy using a partially supervised exercise program was feasible, safe and well received by patients. We showed that our exercise intervention maintained quality of life, improved muscle strength and reduced sedentary behaviour. Exploratory findings from our study also suggest that exercise acutely may abrogate immunosuppressive effects of chemotherapy on circulating immune cells. Due to the methodological challenges and complexities involved with conducting exercise-studies in in vivo models, we propose that future studies interrogating the effects of exercise on breast cancer focus on clinical studies in the neoadjuvant setting in order to better understand the underlying mechanisms for the benefits already observed with exercise after a breast cancer diagnosis.

  • (2021) Hanssen, Kimberley
    Thesis
    Multidrug resistance is a leading contributor to treatment failure in cancer patients. As elevated levels of the antioxidant glutathione (GSH) and increased expression of drug efflux pumps may both contribute to chemotherapy resistance, depleting GSH and blocking drug efflux in cancer cells may improve response to treatment. Multidrug resistance protein 1 (MRP1) is a membrane transporter that is frequently overexpressed in cancer cells. By actively effluxing a wide range of chemotherapeutic agents, MRP1 can protect the cancer cell from chemotherapy. GSH is also transported by MRP1 as a low-affinity endogenous substrate. Some small molecules (MRP1 'modulators'), upon binding to MRP1, greatly enhance this innate GSH transport whilst simultaneously blocking the efflux of chemotherapeutics. As this stimulated GSH efflux can deprive the cell of GSH, in parallel with the blocked chemotherapy efflux enhancing intracellular chemotherapy concentrations, MRP1 modulators might be used to exploit the high expression of MRP1 in cancer cells to improve treatment response. MRP1 was found to be frequently expressed in patient tumours of two difficult to treat cancer types: non-small cell lung (NSCLC) and ovarian cancer. As this MRP1 expression might be leveraged with an MRP1 modulator, two modulators were tested on high MRP1-expressing NSCLC and ovarian cancer cell lines. As single agents, the modulators reduced MRP1 drug transport by >85% and improved the efficacy of MRP1-substrate chemotherapeutics (2 5-fold). In combination with the GSH synthesis inhibitor buthionine sulfoximine, complete GSH depletion, diminished clonogenic capacity, enhanced radiosensitivity, and extended chemosensitivity were achievable selectively in high MRP1-expressing cancer cells. As MRP1 expression in NSCLC was also associated with NRF2 activation, a key driver of treatment resistance in NSCLC, the modulator and buthionine sulfoximine combination was tested and found to be effective against cell lines representative of this highly resistant subset of NSCLC. Given the therapeutic potential for MRP1 modulators, their MRP1 binding site and mechanism of action as GSH transport modulators was investigated to provide a basis for future structure-guided design of more potent and selective modulators. Overall, these findings support that the high expression of MRP1 in cancers can be exploited with MRP1 modulators to chemosensitise and radiosensitise NSCLC and ovarian cancers.

  • (2020) Liu, Yue
    Thesis
    Alzheimer’s disease (AD) and cerebrovascular disease (CVD) are the two most prevalent causes of dementia. However, the molecular basis of AD and Vascular dementia (VaD) remains incompletely understood, and effective treatments are still not available. In the last three decades, the interaction(s) between CVD and AD have attracted considerable interest. Mixed AD/CVD pathology is commonly seen in patients with clinically diagnosed AD dementia. Combined vascular and AD pathology is the leading cause of dementia in the very old, and there is a debate on whether this is due to an additive effect of both pathologies on cognitive impairment, and whether it represents an interaction between the two pathologies. This thesis explored the association and interaction between cerebrovascular disease and AD pathology/dementia from the perspectives of plasma lipid profiles, imaging biomarkers, post-mortem pathology, and animal models. In addition, studies on plasma biomarkers of AD and VaD and their independent contribution to dementia and cognitive decline were interpreted. In chapter 2, a systematic review and meta-analyses of several cerebral small vessel disease (CSVD) imaging biomarkers and AD found that CSVDs alone were not able to predict AD incidence but were associated with AD dementia and AD pathology. The strength of relationship increased with the presence of Apolipoprotein E (APOE ε4) genotype. Periventricular and parietal white matter hyperintensities (WMHs) and cortical microbleeds (CMBs) had stronger association with AD than CSVDs in other regions. Microinfarcts were less well studied in related imaging studies. We also further explored CSVDs and other cerebral vascular injuries in the aspect of neuropathology. In chapter 3, a cross-sectional study of autopsy brain pathology from National Alzheimer’s Coordinating Center (NACC) showed that CVD pathology had an additive effect with AD pathology in the development and progression of Alzheimer’s dementia. The relationship between the plasma lipidome and VaD and AD has received little attention. In chapter 4, liquid chromatography mass spectrometry was used to demonstrate that plasma ceramides and cholesterol-esters had the highest accuracy for the classification of VaD from controls, while in chapter 5, I showed that AD could be best discriminated by plasma cholesterols esters, sphingomyelins and triglycerides. The results obtained from clinical samples were supported by my preclinical animal model work which involved the induction of cerebral vascular lesions in AD transgenic mice. These mice were double transgenic rodents containing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both directed to neurons. In chapter 6, neuroinflammation and cognitive deficits were significantly worse in APP/PS1 mice injected with endothelin-1 – a neuropeptide and vasoconstrictor – in the internal capsule compared to APP/PS1 controls. Finally, the neuroprotective effects of the glutathione precursor against biomarkers of oxidative stress, inflammation, Aβ pathology and ferroptosis, and its outcome on spatial memory in APP/PS1 mice were reported in chapter 7. Our findings on imaging and neuropathological biomarkers of cerebral vascular lesions collectively suggested that vascular lesions had a potentially additive effect on AD pathology in Alzheimer’s dementia. The result was supported by our animal study on interaction of induced brain infarcts and AD-like pathological hallmarks in transgenic mice. The two pathologies might have distinct profiles, especially at the lipid level. Strategies aimed at replenishing GSH levels using GGC may have beneficial effects in AD and other neurodegenerative diseases as well as on the ageing brain.

  • (2020) Jain, Pankaj
    Thesis
    Continuous-flow left ventricular assist devices (cf-LVADs) now form a cornerstone of the treatment of advanced heart failure. With their increasing use, improving our understanding of the mechanical, histopathological and physiological interactions between these devices and the patients in whom they are implanted is paramount. Initially, through non-invasive assessment of the impact of dynamic manoeuvres on the pump flow waveform and left ventricular dimensions, I demonstrate that changes in afterload pressure, posture and intrathoracic pressure have significant and highly variable effects on pump flow. The relationship between the intrathoracic pressure changes, loading conditions and pump flow is then assessed invasively, with low preload, low arterial resistance and increased ventricular-arterial coupling predictive of pulsatility loss and suction events during modified Valsalva manoeuvre. Using a pulsatile mock loop circulation, I assess the contribution of the outflow conduit to pump afterload. Haemodynamically significant gradients can be generated across an unobstructed HVAD outflow graft, and their magnitude predicted using an empirically derived model incorporating conduit diameter, mean pump flow, systolic dQdt and conduit length. I then demonstrate in vivo that some degree of tissue ingrowth into the cf-LVAD outflow graft due to acute inflammatory, chronic inflammatory, fibrotic or neointimal reaction is a near-universal phenomenon and is associated with a small but measurable decrease in pump flow and flow pulsatility over time. In order to enable an integrated assessment of left ventricular contractility, energetics and loading conditions, I describe a method to derive pressure-volume loops using non-invasive inputs that are readily available in the clinic setting. This method is validated invasively by assessing its ability to detect predictable pharmacodynamic effects of intravenous Milrinone. Finally, I utilise this pressure-volume derivation in order to assess the haemodynamic effects of exercise, revealing increased left ventricular contraction that is likely driven by increased preload, and profoundly diminished unloading effect of increased pump speed during exercise. Overall, this thesis sheds light on the complex interplay between ventricular contractility, loading conditions and cf-LVAD performance under ‘real-world’ conditions, with significant implications for both clinical practice and future research in this area.

  • (2020) Lau, Derrick
    Thesis
    The HIV-1 capsid is a protein shell utilised by the virus as a binding platform to hijack host machineries to promote infection. Characterisation of novel cofactors binding to capsid demands sensitive and quantitative assays to better understand their underlying binding mechanisms. Here, I have developed three complementary fluorescence microscopy-based platforms for quantitative characterisation of capsid binding analytes using tubular, spherical or conical lattices self-assembled from recombinant capsid protein (CA) with engineered cysteine residues for cross-linking as surrogates for the authentic capsid. The first approach focused on the development of a TIRFM biosensor using CA tubes immobilised on a glass surface as the biorecognition substrate for sensitive single-molecule binding studies. The biosensor was assessed in its ability to measure binding affinity, stoichiometry and kinetics using known capsid-binding cofactors as part of its validation process. Biosensor measurements confirmed that binding of the host cell protein cyclophilin A (CypA) to the tubular lattice is substoichiometric due to steric hindrance between CypA molecules. Binding analysis of cleavage and polyadenylation specificity factor subunit 6 (CPSF6) expressed as a full-length protein in a cell-free expression system suggested a role of oligomerisation to enhance binding via avidity. In the second approach, the biosensor surface was modified with cross-linked CA spheres as an alternative substrate containing pentameric defects and highly curved regions that are lacking in CA tubes. Binding of CypA to spheres revealed a significantly higher CypA to CA binding ratio at saturation suggesting a role of curvature in accommodating specific host cofactors. The third approach utilises confocal microscopy-based single molecule spectroscopy and was developed as a medium-throughput capsid interactor screening platform that uses conical CA self-assemblies as the substrate. Fluorescence-tagged analytes are identified as capsid binders when they accumulate on the surface of the CA cones, which can be detected in the fluorescence intensity traces as the appearance of spikes in the analyte channel or as an increase in the coincidence between the analyte signal and CA signal. The assay can be adapted for competition studies by using antagonistic molecules or different CA mutants to dissect binding interfaces on the capsid. The three assays developed herein are complementary methods to accelerate characterisation of novel capsid binders.

  • (2020) Chen, Kerrie-Anne
    Thesis
    This thesis examines the clinical translation of two novel therapeutic drugs in rare paediatric neurological disease via expanded access programs (EAP). Patients with rare diseases commonly encounter barriers to care and lack of disease-modifying treatments. EAPs help address this need by providing access to therapeutic drugs before commercial availability, however, there is usually limited knowledge regarding the safety and full impact of the drug. Two drugs were recently made available via an EAP for children in New South Wales: cannabidiol for paediatric drug-resistant epilepsy (DRE) and nusinersen for spinal muscular atrophy (SMA). In a time when there was no evidence regarding the use of cannabidiol in paediatric DRE, an EAP was established due to unprecedented patient demand. Our study analysed the safety, adverse effects and preliminary efficacy of cannabidiol in patients with DRE. Cannabidiol was well tolerated, with sedation commonly reported (37.5%). Elevated transaminases were seen in 5% and demonstrated the necessity of medical monitoring. Although many patients reported improved overall health, indirect measures of seizure control did not show improvement, thus signifying the need for larger, randomised-controlled trials. In children with SMA type 1 (SMA1) treated with nusinersen, respiratory, bulbar and nutritional outcomes were analysed, as previous studies had demonstrated increased survival and motor function but had not assessed the broader impact on the burden of disease. Our study demonstrated substantial ongoing comorbidities due to respiratory and bulbar weakness, with the need for ongoing nocturnal noninvasive ventilation, gastrostomy feeding and recurrent acute hospitalisations. Greater burden of disease was seen more in patients with two SMN2 copies. Most children showed improvement in motor outcome assessments, a stark change in the natural history of SMA. These findings show the impact of nusinersen in modifying the phenotype of children with SMA1, yet ongoing significant morbidities and requirement for multidisciplinary supportive medical care. In conclusion, these studies provide additional real-world clinical data on the implementation and extent of efficacy of two novel drugs for rare neurological diseases. EAPs serves to address an unmet clinical need and facilitate the translation of research into practice to advance future health practice and research in rare diseases.

  • (2020) Ashari Kandy, Divya Jagadeesh
    Thesis
    Aim: To explore the association of optic disc and retinal parameters with myopia, and to determine if models incorporating these parameters can discriminate between myopic versus non-myopic eyes as well as aid in predicting future onset/incidence and increased progression. Methods: Optic nerve head and retinal parameters were systematically analysed using retinal images, spherical equivalent refraction, and axial length data obtained from two pilot studies (n=58 adults; n=56 myopic children, respectively). Thereafter, an association of optic disc and retinal parameters with myopic versus non-myopic eyes were analysed using data from a large population study of Asian children (n= 2995; 6 to 9 years). Multiple logistic regression analysis was performed and receiver operating characteristic (ROC) curves used to determine the ability of optic disc/retinal features to a) differentiate myopes and non-myopes at baseline; b) predict 12-month myopia incidence c) predict 12-month spherical equivalent and axial length change of ≥-1.00D and ≥0.50 mm respectively. The models were validated in a small, independent sample of 380 Asian children aged 5 to 14 years. Results: Optic disc and retinal parameters such as disc rotation, tilt from Vertical, ovality, reduced short axis of the disc, temporal crescent, tessellations, temporal > nasal pRNFL thickness, reduced fovea to disc distance as well a thinner macular thickness were associated with myopia and/or incidence and/or progression. Models incorporating one or more of these parameters had sensitivity/specificity of 77%/83% to discriminate between myopic versus non-myopic eye; 69%/68% to predict the incidence of myopia, and 58%/ 82% and 66%/79% to predict spherical equivalent and axial length change of ≥ 1D and ≥ 0.50 mm respectively. In an independent sample, the sensitivity/specificity of the models to discriminate between myopic versus non-myopic eyes was 90%/79%; to predict the incidence of myopia was 83%/ 50%; whereas models to predict progression had low sensitivity but high specificity. Conclusion: This body of work adds to the knowledge on the optic disc and retinal features associated with myopia and demonstrates that models incorporating such parameters can successfully discriminate between myopic versus non-myopic eyes. These features are also associated with future incidence and/or progression; however, further work is needed to improve the accuracy of models to predict incidence and/or progression.

  • (2020) Bijker, Rimke
    Thesis
    The introduction of effective antiretroviral therapy (ART) has dramatically increased life expectancy of people living with HIV (PLHIV). However, due to lifestyle factors, side effects of ART, ongoing inflammation and immune activation, and ageing, non-communicable diseases (NCDs) are becoming more apparent in this population. This will prove challenging in some countries in the Asian region, where health systems are already strained by a high HIV burden and limited resources are available to provide optimal care for all PLHIV. The aim of this thesis was to investigate NCDs – primarily cardiovascular disease (CVD), diabetes and kidney disease – and related outcomes in PLHIV in the Asian region. All analyses were based on routinely collected data from the TREAT Asia cohorts, two large adult observational cohorts of PLHIV in 12 countries across the Asia-Pacific region. Similar to what is happening at the global level, ART uptake across this region has increased over time. Among those on ART in the TREAT Asia cohorts, there was a considerable burden of comorbid CVD, diabetes and kidney disease. Risk factors for CVD were primarily of modifiable nature, such as hypertension, unfavourable lipid levels and overweight. It was estimated that the CVD incidence might double in the next decade, although this could be largely addressed by implementing interventions that target CVD risk factors. Diabetes and prediabetes were strongly associated with mortality. When assessing risk factors of mortality after long-term exposure to ART, the findings showed that diabetes, kidney disease, and hepatitis were associated with increased mortality, while treatment continuity remained important to improve survival. Overall, the findings indicate that there was suboptimal monitoring for NCDs in the TREAT Asia cohorts. With the growing population of PLHIV who are on life-long ART, there is an urgent need for integrated NCD and HIV care. Timely interventions are key to reducing the unnecessary morbidity and mortality. Future efforts to improve NCD-related outcomes in PLHIV in the Asian region should thus have a clear focus on screening and monitoring for NCDs with appropriate diagnostic tools and access to affordable treatment options.

  • (2021) Hailemariam, Tewodros
    Thesis
    Couples HIV Testing and Counselling (CHTC) is recommended by the World Health Organisation to increase uptake of testing in Sub-Saharan Africa (SSA). There is limited evidence about whether people in heterosexual relationships consider CHTC to be a viable HIV testing option compared to other approaches, or the perceived risks and benefits of CHTC. This thesis examined the uptake, beliefs, intentions, and experiences associated with CHTC in SSA, and in Ethiopia specifically. The thesis includes four studies in a mixed methods design: a systematic review and meta-analysis of CHTC uptake in SSA (n=14 peer-reviewed studies); a qualitative elicitation study (n=21 people in heterosexual relationships and n=11 key informants) of beliefs and intentions; a qualitative experience study (n=19 in-depth interviews) of people who had used CHTC; and the development and pilot of a survey informed by the elicitation study (n=100 individuals). New empirical findings from this research include 1) a modest (24%) uptake of CHTC among heterosexual couples in SSA, with variability by country and population sub-groups; 2) that although CHTC was regarded as important to prevent HIV transmission, some participants stated they preferred to first ‘test alone, then together’ to avoid the perceived risks of being diagnosed with HIV in the presence of their partner — including accusations of infidelity and relationship break-up; 3) key reasons for undertaking CHTC included requests by third parties, such as religious institutions, before marriage, frequent sickness, as part of antenatal care, visa application, or mistrust between partners; 4) for some couples, consequences following an HIV-positive result included ongoing disputes, abuse, and relationship breakdown. Lastly, the elicitation study findings informed the development of a new survey tool for population-level use. Pilot psychometric testing found acceptable internal constancy, discriminant validity, and predictive ability of individuals’ behavioural intentions towards CHTC. The collective findings in this thesis provide evidence that individuals are cautious of undertaking CHTC because of fears about confidentiality and potential risks to their relationships. Testing programs should monitor and assure adherence to the principles of confidentiality and voluntary testing. For individuals who decide to undertake CHTC, individual-based pre-test counselling is important to ensure informed decisions about HIV testing options.

  • (2021) Padeniya, Seneviratne Mudiyanselage Thilini Nisansala
    Thesis
    Gonorrhoea notifications have been increasing among young Australian heterosexuals since 2009 and the reasons for this are unclear. Gonorrhoea incidence has also increased in female sex workers (FSW) since 2009. Previous studies indicate that condom-use among FSW-clients declined from 2009-2017, mainly for oral sex and a high proportion of infections in heterosexual males arise from condomless oral sex with FSW. Thus, we hypothesise that an increase in condomless sex by FSW-clients may have contributed to the rising incidence of gonorrhoea among heterosexuals in Australia. In this thesis, mathematical modelling is used to provide insights to the role of the FSW-client interaction for heterosexual gonorrhoea transmission, to explore whether the increasing notifications can be explained, even partly, by decreasing condom-use among FSW-clients, and to evaluate the potential impact of providing gonorrhoea vaccination for FSW on gonorrhoea incidence/prevalence. A deterministic compartmental model was developed to address the stated objectives and was calibrated to reported female notifications and FSW incidence data for 2009. Using adaptations of the model that included/excluded FSW-client strata, we evaluated the role of FSW-client interactions in model dynamics and sensitivity of the reproduction number (Rt) in this population to changes in key parameters. We then estimated the annual percentage decline in condom-use between 2009 and 2017 that resulted in a model-produced notification rate that is consistent with the reported increase in heterosexual notifications using the model with FSW-client strata. Finally, the potential impact of a gonococcal vaccine for FSW on heterosexual gonorrhoea rates was assessed under different assumptions regarding the mode of vaccine conferred protection. Our results suggest that Rt and the heterosexual notification rate are highly sensitive to changes in parameters that govern transmission in the model that accommodates FSW-client interactions and infection rates are consequently highly sensitive to changes in condom-use by FSW-clients. An annual decline of only 0.26% in condom-use by FSW-clients is predicted to lead to an increase in heterosexual notifications that is consistent with the observed increase in notifications. Vaccinating FSW with a partially efficacious vaccine has the potential to substantially reduce gonorrhoea prevalence over time in the heterosexual population in Australia. These findings suggest that increasing condomless sex among FSW-clients can result in marked increases in heterosexual notifications. Therefore, promoting condom-use in commercial sex may help reduce the gonorrhoea burden in young heterosexuals. Additionally, targeted vaccination of FSW may be an effective means of controlling gonorrhoea in this population.