Medicine & Health

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Now showing 1 - 10 of 10
  • (2011) Mao, Limin; Kippax, Susan; Holt, Martin; Prestage, Garrett; Zablotska, Iryna; de Wit, John
    Journal Article
    Objective Three decades into the HIV epidemic and with the advancement of HIV treatments, condom and non-condom-based anal intercourse among gay men in resource-rich countries needs to be re-assessed. Methods The proportions of men engaging in a range of anal intercourse practices were estimated from the ongoing cross-sectional Gay Community Periodic Surveys in six states in Australia from 2007 to 2009. Comparisons were made between HIV-negative men, HIV-positive men with an undetectable viral load and those with a detectable viral load. Results Condoms play a key role in gay men's anal intercourse practices: 33.8% of HIV-negative men, 25.1% of HIV-positive men with an undetectable viral load and 22.5% of those with a detectable viral load reported consistent condom use with all male partners in the 6 months before the survey. Among HIV-negative men, the second largest group were men who had unprotected anal intercourse (UAI) only in the context of HIV-negative seroconcordant regular relationships. Among HIV-positive men, the second largest group was men who had UAI in casual encounters preceded by HIV status disclosure to some, but not all, casual partners. Conclusions A minority, yet sizeable proportion, of men consistently engaged in a number of UAI practices in specific contexts, suggesting they have adopted deliberate HIV risk-reduction strategies. While it is important that HIV behavioural prevention continues to reinforce condom use, it needs to address both the challenges and opportunities of the substantial uptake of non-condom-based risk-reduction strategies.

  • (2011) Hocking, Samantha Louise
    Thesis
    Intra-abdominal (AB) obesity is associated with a higher risk of diabetes than subcutaneous (SC) obesity. To determine whether this is due to differences in anatomical location or intrinsic differences in fat depots, the metabolic effects of transplantation of SC or AB fat into the SC or AB space of recipient mice were determined. Donor inguinal (SC) and epididymal (AB) fat was transplanted into the SC (SC-SC and AB-SC) or AB (SC-AB and AB-AB) space in high fat-fed (45% calories from fat) male C57BL6/J mice. Sham-operated mice underwent surgery without fat transplantation (SHAM). 11-13 weeks after transplantation metabolic studies were performed and adipose tissue harvested for analysis including microarray. Mice receiving SC-AB grafts displayed significantly reduced fat mass, in both transplanted and endogenous fat depots, and improved glucose tolerance compared with SHAM. These metabolic effects were not observed in mice receiving SC-SC, AB-SC or AB-AB grafts. Microarray analysis of transplanted and endogenous fat depots revealed increased expression of genes controlled by the transcription factor myocyte enhancer factor 2 (MEF2-genes) in SC-AB grafts and the endogenous inguinal adipose tissue (ENDOG-SC) from mice receiving a SC-AB graft. Increased uncoupling protein-1 (UCP-1) gene expression was observed uniquely in ENDOG-SC fat. At 13 weeks post-transplantation SC-AB grafts had decreased in mass. Failure of SC grafts to expand in the AB compartment suggests that cross-talk between adipocyte and non-adipocyte components of adipose tissue is depot-specific. Lectin affinity chromatography combined with partial metabolic labelling and mass spectrometry determined quantitative differences in the secretomes of SC and AB whole adipose tissue, preadipocytes and microvascular endothelial cells, suggesting intrinsic depot-specific differences are present in all cell types within adipose tissue. These findings suggest a unique beneficial metabolic effect of SC-AB transplantation that is mediated by a secreted factor acting uniquely on SC fat to increase expression of MEF2-genes and UCP-1. As chronic B3-adrenergic stimulation of white adipose tissue increases UCP-1 and MEF2 expression is increased by adrenergic stimulation in non-adipose adult tissues, increased adrenergic-stimulation of subcutaneous fat is a putative mechanism. The identity of the secreted factor is important as it may provide a novel treatment for obesity-induced metabolic disease.

  • (2011) Chang, David
    Thesis
    Defining phenotypes of prognosis and therapeutic responsiveness is the basis of modern oncology and underpins personalised medicine. Significant improvements in outcomes have been achieved in some cancer types, such as breast and colon, through defining specific phenotypes. Pancreatic cancer (PC) is the fourth leading cause of cancer death in western societies, and as yet has no well-defined phenotypes. This thesis aims to define molecular biomarkers with clinical utility that predict prognosis and therapeutic responsiveness in PC. A systematic approach for biomarker discovery and development based on NCI guideline was applied. First, multiple large independent cohorts of patients with resectable PC were analysed and prognostic factors important to clinical decision making were extensively characterised as the basis for biomarker studies. One key findings demonstrated that surgical margin clearance of more than 1.5mm is important for long-term survival. The results added to our current understanding of microscopic margin involvement definitions and potentially identifies a subgroup of patients who may benefit from aggressive loco-regional therapy such as adjuvant radiotherapy. Aberrant expression of two candidate biomarkers (S100A4 and S100A2 calcium-binding proteins) with potential roles in metastatic processes were identified as independent prognostic factors using these multiple patient cohorts. Differential expression of these two biomarkers categorised patients with resected PC into three distinct prognostic groups. A pre-operative molecular prognostic nomogram was developed using these two biomarkers and tumour size. These markers predicted survival as well as the published post-operative nomogram and can potentially be tested pre-operatively. To implement this strategy, a proof-of-principle study demonstrated that biomarker expression can be reliably assessed in pre-operative EUS-FNAB samples. S100A4 expression was then assessed for its contribution in chemoresistance in clinical cohorts based on previous functional data. S100A4 was identified as a predictive biomarker of adjuvant chemotherapeutic responsiveness in two large cohorts of patients. In addition, the candidate made significant contribution to the Australian Pancreatic Cancer Genome Initiative (APGI), a part of the International Cancer Genome Consortium. The genomic mutational landscape of resected PC using exome sequencing as part of the APGI project was also presented.

  • (2011) Pandit, Sonali
    Thesis
    The main goals of this thesis are: • To investigate the survival of adult human olfactory stem cells xenotransplanted into a mouse model of early-onset hearing loss (A/J mice). • To evaluate the ability of the stem cells to rescue hearing in early-onset progressive sensorineural hearing loss. The main results of this thesis are: • Xenotransplanted adult human olfactory stem cells survived for 4 weeks after the surgery (end point of the study). • The stem cells were mainly found in perilymphatic compartments of the cochlea (scala vestibuli and scala tympani) while only a few stem cells were present in scala media. • The stem cells did not integrate into cochlear tissues. • Post-surgery hearing threshold levels in stem cell-transplanted mice were found to be significantly lower than threshold levels of sham-injected mice (P < .05) for both click and pure tone stimuli. In addition, the threshold shift (difference between pre and post-surgery hearing thresholds) was significantly less in the stem cell transplanted animals than the sham-injected animals for click stimulus. Overall, adult human olfactory stem cell transplantation can help preserve hearing during early-onset sensorineural hearing loss.This improvement in hearing could be due to paracrine effect of adult human olfactory stem cells.

  • (2011) Colvin, Emily Kate
    Thesis
    Pancreatic cancer (PC) is the fourth leading cause of cancer death in western societies, with a 5-year survival rate of approximately 5%. There is an urgent need to develop novel therapeutic strategies. Activation of embryonic signalling pathways quiescent in the adult pancreas is a feature of PC and has been implicated in the regulation of stem cells, with components of these signalling pathways representing both novel drug targets and candidate biomarkers. Aberrant expression of several molecules, identified by global analysis of gene expression, particularly those involved in retinoic acid (RA) signalling, were explored in PC. Their potential utility as biomarkers of prognosis and therapeutic responsiveness was assessed in a large cohort of patients and their function further investigated using in vitro and in vivo models. Bone marrow transplantation models were also developed to assess the potential of bone marrow derived cells (BMDC) as candidate pancreatic stem cells in the pancreas, since embryonic signalling pathways also regulate the stem cell niche Several RA signalling components were aberrantly expressed in PC. The calcium-binding protein S100A2 was an independent predictor of survival following pancreatectomy. Active RA signalling was present in rare exocrine cells of the normal adult pancreas, with marked activation during pancreatic regeneration. Loss of CRBP1, a key component of RA signalling occurred frequently in PC and was present in the earliest precursor lesions, however loss of function studies suggest that loss of CRBP1 alone was not sufficient to induce carcinogenesis. Bone marrow transplantation experiments demonstrated contribution of BMDC to the normal exocrine pancreas, however these cells were not responsible for pancreatic acinar regeneration. BMDC contributed to the activated stellate cell population in chronic pancreatitis and PC, but not to the epithelial component. This study identified two biomarkers predictive of response to therapy in PC with potential clinical utility, S100A2 and hENT, while also delineating the potential role of RA signalling in pancreatic regeneration and PC. Finally, a novel model of investigating tumour-host interactions was developed using bone marrow transplantation in mice.

  • (2011) Millar, Ewan
    Thesis
    Aim: To identify new prognostic and predictive biomarkers for clinical breast cancer, thereby improving patient selection for currently available therapies. Methods: Data derived from gene expression profiling of human breast cancer or human breast cancer cell lines, were interrogated to identify putative biomarkers in ER positive and ER negative disease. These findings were validated using immunohistochemistry on tissue microarrays constructed from the development of two independent clinical breast cancer cohorts (n=292 and n=498). Results: Prognosis in ER+ disease can be predicted by expression of BAG-1, PUMA, c-Myc and an improved biomarker signature for Luminal A and B cancer which includes Ki67 and p53. Studies identifying abnormalities in signalling pathways (PI3-kinase, Hedgehog, STARD10), HIF-1α (CAIX, FOXP3/CXCR4, SIAH2), proliferation (cyclin D1b) and DNA repair pathways (Rad21) have also identified potential biomarkers and therapeutic targets for ER negative and basal-like breast cancer. Conclusions: New biomarkers for clinical breast cancer have been identified which have the potential to improve patient selection and therapeutic decision making. Validation studies are underway in independent international randomised clinical trials to confirm these findings. The use of immunohistochemistry allows the potential rapid translation of these findings into routine Hospital Pathology clinical practice.

  • (2011) Akerfeldt, Mia
    Thesis
    The failure of β-cells to provide sufficient amounts of insulin to maintain blood glucose levels within a narrow physiological range is central to the development of all forms of diabetes. β-cell failure is characterised by both functional defects and loss of β-cell mass through apoptosis; however, the underlying mechanisms are not well defined. The broad aim of this thesis was to gain further insight into the mechanisms leading to β-cell dysfunction and death in type 1 and type 2 diabetes. Pro-inflammatory cytokines and saturated fatty acids are suggested mediators of β-cell apoptosis in type 1 diabetes and type 2 diabetes, respectively. Endoplasmic reticulum (ER) stress is induced by cytokines and saturated fatty acids in vitro. Studies in this thesis tested the hypothesis that ER stress provides a common mechanism for β-cell death induced by cytokines and the saturated fatty acid, palmitate. The research demonstrated for the first time that chemical chaperones are able to relieve ER stress in β-cells. This was associated with protection against death induced by palmitate, but not by cytokines. These findings indicated that ER stress activation is selectively necessary for palmitate- and not for cytokine-mediated β-cell death. The studies suggest that improving ER folding capacity is a promising therapeutic strategy for type 2 diabetes. Previous studies have found that β-cell dysfunction in animal models of diabetes is associated with increased expression of the helix-loop-helix protein Id1. Studies in this thesis investigated the role of Id1 in insulin secretion and glucose homeostasis. The research demonstrates a novel role of Id1 as a negative regulator of insulin secretion. Studies with Id1 knockout mice demonstrated that Id1 expression plays an essential role in the aetiology of glucose intolerance, insulin secretory dysfunction and β-cell dedifferentiation under conditions of insulin resistance and chronic lipid oversupply. The findings suggest that Id1 expression may provide a molecular link between chronic lipid oversupply and β-cell dedifferentiation and dysfunction. Id1 may therefore represent a new target for therapeutic interventions aimed at improving β-cell dysfunction and restoring disordered glucose homeostasis.

  • (2011) Chan, Brian
    Thesis
    Parkinson's disease (PD) is a neurodegenerative movement disorder that affects approximately 1% of people over the age of 60. Majority of PD cases are sporadic or have no known cause while the underlying basis of neurodegeneration is unclear. Common forms of treatment only reduce motor symptoms and there is no cure. Insight can be gained towards understanding the cause of neurodegeneration in PD by studying the function of PARK genes. SNCA (PARK1/4) encodes for alpha-synuclein which is a major component of Lewy bodies, a hallmark of PD. While mutations in or overproduction of alpha-synuclein may cause PD. Importantly, alpha-synuclein causes dosage dependent toxicity in model organisms while the toxic mechanisms are unknown. A second gene is PARK9, mutations are associated with the earliest onset of PD. PARK9 was found to be overexpressed greater than tenfold in surviving dopaminergic neurons of sporadic PD patients, separately, the yeast orthologue of PARK9 was found to significantly reduce alpha-synuclein toxicity in a yeast PD model, suggesting a neuroprotective role for PARK9. The aim of this thesis was to investigate the function of PARK9 and how PARK9 can reduce alpha-synuclein toxicity. PARK9 is a P-ATPase, a family of inorganic cation pumps. Data from yeast, rat primary foetal cortical neurons, human SH-SY5Y neuroblastoma models and PARK patients indicate PARK9 is a zinc pump. PARK9 closely associates with the autophagic marker LC3 and zinc is crucial for autophagy. These data suggest that PARK9 aids in autophagy regulation and defective PARK9 may result in defective autophagy. Importantly, it is shown for the first time, that alpha-synuclein disrupts zinc homeostasis, thus alpha-synuclein may inhibit autophagy partly through perturbing zinc homeostasis. Separately, PARK9 overexpression reduced alpha-synuclein levels in SH-SY5Y neuroblastoma suggesting that the neuroprotective properties of PARK9 may be achieved through restoring autophagy impairment due to alpha-synuclein. Hence, defective autophagy due to a PARK9 deficiency provides a mechanistic explanation for accelerated neurodegeneration in PARK9 mutation PD patients. While data from this thesis suggests that restoring neuronal zinc balance may be a novel therapeutic approach to reduce alpha-synuclein associated neurodegeneration.

  • (2011) Wright, Lauren Emily
    Thesis
    The prevalence of obesity and insulin resistance has increased at an alarming rate in recent years. Many studies published in the last decade have implicated defective mitochondrial metabolism as a possible factor driving the development of lipid-induced insulin resistance. The studies described in this thesis have investigated the effect of manipulating mitochondrial function on skeletal muscle insulin action. In the first study, the effect of broadly increasing mitochondrial metabolism via Peroxisome proliferator-activated receptor γ coactivator-1β (PGC-1β), a master regulator of mitochondrial biogenesis and function, was investigated. Acute, PGC-1β-mediated increases in mitochondrial function and antioxidant defences partially ameliorated lipid-induced insulin resistance, in association with reductions in the reactive lipid species long-chain acyl-CoA (LCACoA) and reduced oxidative stress. The subsequent study investigated the possibility of achieving a similar result by specifically upregulating lipid metabolism pathways via upregulation of a known regulator of lipid metabolism and a downstream effector of PGC-1β, estrogen-related receptor α (ERRα). Overexpression of ERRα increased markers of lipid metabolism; however this had no effect on high-fat-diet induced insulin resistance, LCACoA accumulation or oxidative stress within the muscle. In an attempt to further increase the beneficial effects of PGC-1β, PGC-1β and ERRα were simultaneously overexpressed. Unexpectedly, dual PGC-1β/ERRα upregulation did not induce any of the metabolic pathways induced by overexpression of PGC-1β or ERRα alone and thus did not prevent lipid-induced insulin resistance. Lastly, the effect of post-translational protein modifications (PTMs) on mitochondrial function was investigated in the genetically obese ob/ob mouse, identifying an association between protein hyperacetylation and reduced mitochondrial oxidative capacity. This was further correlated with the expression of mitochondrial deacetylases SIRT3 and SIRT5, indicating that sirtuin-mediated protein acetylation may be an additional level of regulation of mitochondrial function, and potentially insulin action. These studies suggest that changing mitochondrial capacity can influence insulin action in skeletal muscle, and that protein acetylation is associated with mitochondrial function and muscle insulin action. While it remains unknown whether defective mitochondrial metabolism may be a causative factor in the development of insulin resistance, these studies suggest that targeting manipulation of mitochondrial metabolism may be beneficial for the treatment of insulin resistance.

  • (2011) Wong, Poh Ling Iris
    Thesis
    Neural regulation of bone via the neuropeptide Y (NPY) dependent pathway has marked inhibitory effect on osteoblast activity. The anti-anabolic actions of NPY on bone involve hypothalamic Y2 receptors in the brain and osteoblastic Y1 receptors in the periphery. This thesis examines whether peripheral signals, in particular, peptide YY (PYY) and leptin, also modulate bone homeostasis via the NPY system. The contrasting effect of knockout and transgenic mouse models indicates that PYY regulates bone mass through suppression of osteoblast activity in cancellous and cortical bone, similar to the recently described skeletal actions of NPY. Mineral apposition rate (MAR) was greater in PYY knockout (PYY-/-) and reduced in PYY transgenic (PYYtg). Conversely, osteoclast activity was elevated in PYYtg. These alterations in bone cell activities resulted in changes in cancellous bone volume: greater in PYY-/- of both genders, and lower in female PYYtg. Interestingly, attenuating both PYY and NPY signalling abolishes the beneficial skeletal effect in cancellous bone volume observed in PYY-/- and NPY-/-, highlighting the complexity of the skeletal regulation by the NPY system. Nonetheless, the anti-anabolic actions of PYY on bone are consistent with clinical observations in anorexia nervosa and exercising amenorrhea, suggesting that the increased PYY levels may contribute to the reduced BMD observed in these disorders, providing a possible therapeutic target for the treatment of low bone mass. In addition, we show that the diminished cortical bone of leptin-deficient (ob/ob) mice is mediated by increased NPY signalling, as demonstrated by the improved cortical bone of ob/ob mice towards wildtype levels following NPY deletion. NPY-deficient ob/ob exhibited thicker and denser cortical bone, associated with greater endocortical and periosteal MAR, compared to ob/ob. These effects of NPY deficiency in the cortical compartment are consistent with the role of NPY in co-ordinating bone homeostasis with energy homeostasis and are likely to be neural-mediated. Together these findings clearly demonstrate that signals arises from the periphery, namely PYY and leptin, can modulate bone formation via the NPY signalling pathway, reinforcing the NPY system as a powerful modulator of bone homeostasis and as a potential therapeutic target for the development of skeletal anabolic agents.