Medicine & Health

Publication Search Results

Now showing 1 - 10 of 101
  • (2011) Apte, Minoti; Pirola, Romano; Wilson, Jeremy
    Journal Article
    Significance : Prominent fibrosis is a major histological feature of chronic pancreatitis, a progressive necroinflammatory condition of the pancreas, most commonly associated with alcohol abuse. Patients with this disease often develop exocrine and endocrine insufficiency characterised by maldigestion and diabetes. Up until just over a decade ago, there was little understanding of the pathogenesis of pancreatic fibrosis in chronic pancreatitis. Recent Studies : In recent times, significant progress has been made in this area, mostly due to the identification, isolation and characterisation of the cells, namely pancreatic stellate cells (PSCs) that are now established as key players in pancreatic fibrogenesis. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. During pancreatic injury, PSCs transform into an activated phenotype that secretes excessive amounts of the ECM proteins that comprise fibrous tissue. Critical Issues : This Review summarises current knowledge and critical aspects of PSC biology which have been increasingly well characterised over the past few years, particularly with respect to the response of PSCs to factors that stimulate or inhibit their activation and the intracellular signalling pathways governing these processes. Based on this knowledge, several therapeutic strategies have been examined in experimental models of pancreatic fibrosis, demonstrating that pancreatic fibrosis is a potentially reversible condition, at least in early stages. Future Directions : These will involve translation of the laboratory findings into effective clinical approaches to prevent/inhibit PSC activation so as to prevent, retard or reverse the fibrotic process in pancreatitis.

  • (2012) Apte, Minoti; Pirola, Romano; Wilson, Jeremy
    Journal Article
    While the morphology and function of cells of the exocrine and endocrine pancreas have been studied over several centuries, one important cell type in the gland, the pancreatic stellate cell (PSC), had remained undiscovered until as recently as twenty years ago. Even after its first description in 1982, it was to be another 16 years before its biology could begin to be studied, because it was only in 1998 that methods were developed to isolate and culture PSCs from rodent and human pancreas. PSCs are now known to play a critical role in pancreatic fibrosis, a consistent histological feature of two major diseases of the pancreas - chronic pancreatitis and pancreatic cancer. In health, PSCs maintain normal tissue architecture via regulation of the synthesis and degradation of extracellular matrix (ECM) proteins. Recent studies have also implied other additional functions for PSCs as progenitor cells, immune cells or intermediaries in exocrine pancreatic secretion in humans. During pancreatic injury, PSCs transform from their quiescent phase into an activated, myofibroblast-like phenotype that secretes excessive amounts of ECM proteins leading to the fibrosis of chronic pancreatitis and pancreatic cancer. An ever increasing number of factors that stimulate and/or inhibit PSC activation via paracrine and autocrine pathways are being identified and characterized. It is also now established that PSCs interact closely with pancreatic cancer cells to facilitate cancer progression. Based on these findings, several therapeutic strategies have been examined in experimental models of chronic pancreatitis as well as pancreatic cancer, in a bid to inhibit/retard PSC activation and thereby alleviate chronic pancreatitis or reduce tumour growth in pancreatic cancer. The challenge that remains is to translate these pre-clinical developments into clinically applicable treatments for patients with chronic pancreatitis and pancreatic cancer.

  • (2008) Ahern, Nicole; Short, Alison E.
    Journal Article
    A process evaluation was applied to the development and implementation of a receptive music therapy tool, with a view to promoting evidence-based practice via clear linkage from theory to practice. This music tool was required for a research project in the noisy emergency department (ED) of a large urban hospital. The process evaluation focuses on questions about the suitability, planning, application, and effectiveness of this tool used within the research project protocol. The music tool intervention was applied to fifteen selected patients who received a choice of four genre-based relaxation playlists (GRP) over a two-hour period via headphones and MP3 players. The process evaluation method utilized data sources including key informant interactive interviews, observational data, reflective practices, patient feedback and an independent music review. Responses from patients (aged 23-91 years) indicated that most patients listened to multiple genres and most patients (n=14) indicated that the music made them feel better, thereby indicating suitability and effectiveness. Independent music reviewers confirmed that the music playlists contained relaxing musical elements, based on established music therapy criteria. This project was innovative in clearly documenting a music tool development process (GRP) and in turn applying a process evaluation to systematically review both the development and implementation of the tool. In doing so, linkage from theory to practice was established, contributing to understandings about music for relaxation in healthcare.

  • (2010) Xu, Zhihong; Vonlaufen, Alain; Phillips, Phoebe; Fiala-Beer, Eva; Zhang, Xuguo; Yang, Lu; Biankin, Andrew; Goldstein, David; Pirola, Romano; Wilson, Jeremy; Apte, Minoti
    Recorded/Rendered Creative Work
    ABSTRACT Pancreatic stellate cells (PSCs) produce the stromal reaction of pancreatic cancer (PC) and their interaction with cancer cells facilitates cancer progression. This study investigated the role of human PSCs (hPSCs) in the metastatic process and tumor angiogenesis using an in vivo (orthotopic model) and in vitro (cultured PSC and PC cells) approach. A gender mismatch study [injection of male hPSCs + female PC cells into the pancreas of female mice] was conducted to determine whether hPSCs accompany cancer cells to metastatic sites. Metastatic nodules were examined by fluorescent in situ hybridization for the presence of the y chromosome. Angiogenesis was assessed by i) immunostaining tumors for CD31, an endothelial cell marker; and ii) in vitro quantifying human microvascular endothelial cell (HMEC-1) tube formation upon exposure to conditioned media from hPSCs. Transendothelial migration was assessed by examining the movement of fluorescently labeled hPSCs through an endothelial cell monolayer. Human PSCs i) were found in multiple metastatic sites in each mouse injected with male hPSCs + female PC cells; ii) increased CD31 expression in primary tumors from mice injected with MiaPaCa-2 and hPSCs and stimulated tube formation by HMEC-1 in vitro; iii) exhibited transendothelial migration which was stimulated by cancer cells. Human PSCs accompany cancer cells to metastatic sites, stimulate angiogenesis and have the capacity to intravasate/extravasate to and from blood vessels.

  • (2018) Fung, Matle
    Cardiovascular 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.

  • (2017) Lim, Stephanie
    The 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.

  • (2017) Pothula, Srinivasa
    Pancreatic 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.

  • (2014) Leung, Melissa
    This 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.

  • (2014) Adie, Sam
    Randomised 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.

  • (2015) Yau, Yunki
    Background: 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.