IntroductionThere has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.Methods and... more
IntroductionThere has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy.Methods and analysisWe propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia’s Therapeutic Goods Administration Special Access Scheme. A phage product with highin vitroactivity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50–100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of...
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Traditional studies using cancer cell lines are often performed on a two-dimensional (2D) cell culture model with a low success rate of translating to Phase I or Phase II clinical studies. In comparison, with the advent of developments... more
Traditional studies using cancer cell lines are often performed on a two-dimensional (2D) cell culture model with a low success rate of translating to Phase I or Phase II clinical studies. In comparison, with the advent of developments three-dimensional (3D) cell culture has been championed as the latest cellular model system that better mimics in vivo conditions and pathological conditions such as cancer. In comparison to biospecimens taken from in vivo tissue, the details of gene expression of 3D culture models are largely undefined, especially in mesothelioma – an aggressive cancer with very limited effective treatment options. In this study, we examined the veracity of the 3D mesothelioma cell culture model to study cell-to-cell interaction, gene expression and drug response from 3D cell culture, and compared them to 2D cell and tumor samples. We confirmed via SEM analysis that 3D cells grown using the spheroid methods expressed highly interconnected cell-to-cell junctions. The ...
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Introduction: MicroRNAs (miRNAs) are altered in heart disease and have emerged as promising therapeutic targets. We recently reported that therapeutic inhibition of the miR-34 family (with an 8 mer antimiR) was effective in attenuation of... more
Introduction: MicroRNAs (miRNAs) are altered in heart disease and have emerged as promising therapeutic targets. We recently reported that therapeutic inhibition of the miR-34 family (with an 8 mer antimiR) was effective in attenuation of pathological cardiac remodeling. We hypothesized the efficacy of antimiR-34 may be due to its regulation of other miRNAs, producing direct and indirect target effects. Objectives: To identify miRNAs regulated by miR-34 and understand miRNA networks involved in miR-34 inhibition therapy for pathological cardiac hypertrophy. Methods: MiRNA sequencing (Illumina HiSeq 2000) was performed on hearts of mice subjected to transverse aortic constriction (TAC) for 5 weeks, and subcutaneously administered a locked nucleic acid (LNA)-antimiR-34 for 6 weeks (n=3-4). Results: Expression of miR-34 family members (miR-34a, miR-34b, miR-34c) is increased in the hearts of TAC mice compared to Sham controls (1.7, 2.5, 4-fold, P<0.05) and attenuated with antimiR-34...
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Information about reprints can be found online at: Reprints: document. Permissions and Rights Question and Answer this process is available in the click Request Permissions in the middle column of the Web page under Services. Further... more
Information about reprints can be found online at: Reprints: document. Permissions and Rights Question and Answer this process is available in the click Request Permissions in the middle column of the Web page under Services. Further information about Office. Once the online version of the published article for which permission is being requested is located, can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialHypertensionin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions: by guest on February 26,
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Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and... more
Introduction: Targeting microRNAs differentially regulated in settings of stress and protection could represent a new approach for the treatment of heart failure. miR-652 expression increased in hearts of a cardiac stress mouse model and was downregulated in a model of cardiac protection. Aim: To assess the therapeutic potential of silencing miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Methods: Mice were subjected to a sham operation (n=10) or transverse aortic constriction (TAC, n=14) for 4 weeks to induce hypertrophy and cardiac dysfunction. Mice were subcutaneously administered a locked nucleic acid (LNA)-antimiR-652 or LNA-control. Cardiac function was assessed by echocardiography before and 8 weeks post treatment, followed by molecular and histological analyses. Results: Expression of miR-652 increased in hearts subjected to pressure overload compared to sham operated mice (2.9 fold, n=3-5, P<0.05), but ...
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Top 20 Enriched microRNA Families Extracted from the Four Gene Expression Datasets. Table S2. Pathway Enrichment Analysis of Gene Targets of the miR-17 family members. Table S3. Primers and TaqMan Assay IDs for RT-qPCR and siRNA and Mimic... more
Top 20 Enriched microRNA Families Extracted from the Four Gene Expression Datasets. Table S2. Pathway Enrichment Analysis of Gene Targets of the miR-17 family members. Table S3. Primers and TaqMan Assay IDs for RT-qPCR and siRNA and Mimic Sequences. Table S4. Characteristics of Patients Analyzed in Fig. 2h and i. Table S5. Individual P values for Fig. 3a, f and g. Figure S1. TGFBR2 mRNA down regulated followed miR-17-5p transfection. Figure S2. MPM cell viability was not affected by transfection with miR-17-5p mimic or siRNA. Figure S3. Effect of KCNMA1 down-regulation on cell cycle in MPM cells. Figure S4. KCNMA1 down-regulation and miR-17-5p did not induce MPM cell apoptosis. Figure S5. Migration of MPM cell lines treated with miR-17-5p mimic or KCNMA1 siRNAs. Figure S6. Invasion of MPM cell lines treated with miR-17-5-5p mimic or KCNMA1 siRNAs. Figure S7. Paxilline did not sensitize MPM cells to cisplatin or gemcitabine. (DOCX 10063 kb)
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Successful phage therapy for extensive chronic osteoarticular infection in a child resulted in an initial flush of bacterial contents into the bloodstream with an inflammatory response marked by fever, local pain and upregulation of genes... more
Successful phage therapy for extensive chronic osteoarticular infection in a child resulted in an initial flush of bacterial contents into the bloodstream with an inflammatory response marked by fever, local pain and upregulation of genes associated with autophagy and innate immunity. Monitoring of phage and bacterial kinetics and the human host response allowed early dose adjustment and indicated a strong therapeutic effect within two weeks.
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Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells,... more
Malignant pleural mesothelioma (MPM), an aggressive malignancy affecting pleural surfaces, occurs in three main histological subtypes. The epithelioid and sarcomatoid subtypes are characterized by cuboid and fibroblastoid cells, respectively. The biphasic subtype contains a mixture of both. The sarcomatoid subtype expresses markers of epithelial-mesenchymal transition (EMT) and confers the worst prognosis, but the signals and pathways controlling EMT in MPM are not well understood. We demonstrate that treatment with FGF2 or EGF induced a fibroblastoid morphology in several cell lines from biphasic MPM, accompanied by scattering, decreased cell adhesion and increased invasiveness. This depended on the MAP-kinase pathway but was independent of TGFβ or PI3-kinase signaling. In addition to changes in known EMT markers, microarray analysis demonstrated differential expression of MMP1, ESM1, ETV4, PDL1 and BDKR2B in response to both growth factors and in epithelioid versus sarcomatoid MPM...
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Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterised by frequent chromosomal deletions of tumour suppressors, including microRNAs. MiR-137 plays a tumour... more
Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterised by frequent chromosomal deletions of tumour suppressors, including microRNAs. MiR-137 plays a tumour suppressor role in other cancers, so the aim of this study was to characterise it and its target Y-box binding protein-1 (YB-1) in MPM. Expression, methylation and copy number status of miR-137 and its host gene MIR137HG were assessed by PCR. Luciferase reporter assays confirmed a direct interaction between miR-137 and YBX1. Cells were transfected with a miR-137 inhibitor, miR-137 mimic and/or YBX1 siRNA, and growth, colony formation, migration and invasion assays were conducted. MiR-137 expression varied among MPM cell lines and tissue specimens, which was associated with copy number variation and promoter hyper-methylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth but i...
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Repopulation of brain circuits by neural precursors is a potential therapeutic strategy for neurodegenerative disorders; however, choice of cell is critical. Previously, we introduced a two-step culture system that generates a high yield... more
Repopulation of brain circuits by neural precursors is a potential therapeutic strategy for neurodegenerative disorders; however, choice of cell is critical. Previously, we introduced a two-step culture system that generates a high yield of neural precursors from small samples of adult canine skin. Here, we probe their gene and protein expression profiles in comparison with dermal fibroblasts and brain-derived neural stem cells and characterize their neuronal potential. To date, we have produced >50 skin-derived neural precursor (SKN) lines. SKNs can be cultured in a highly replicable fashion and uniformly express a panel of identifying markers. Upon differentiation, they self-upregulate neural specification genes, generating neurons with basic electrophysiological functionality. This unique population of neural precursors, derived from mature skin, overcomes many of the practical issues that have limited clinical translation of alternative cell types. Easily accessible, neuronal...
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Research Interests: Aging, Cell Cycle, Diet, Childhood Obesity, Fathers, and 15 moreApoptosis, Gene expression, Cytoskeleton, Female, Animals, DNA methylation, Body Weight, Cations, Gene Expression Regulation, Gene expression profiling, Adenosine Triphosphate, Differential expression, Dietary fats, Adiposity, and Genetic factors
Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression... more
Malignant pleural mesothelioma (MPM) is an aggressive, locally invasive, cancer elicited by asbestos exposure and almost invariably a fatal diagnosis. To date, we are one of the leading laboratory that compared microRNA expression profiles in MPM and normal mesothelium samples in order to identify dysregulated microRNAs with functional roles in mesothelioma. We interrogated a significant collection of MPM tumors and normal pleural samples in our biobank in search for novel therapeutic targets. Utilizing mRNA-microRNA correlations based on differential gene expression using Gene Set Enrichment Analysis (GSEA), we systematically combined publicly available gene expression datasets with our own MPM data in order to identify candidate targets for MPM therapy. We identified enrichment of target binding sites for the miR-17 and miR-30 families in both MPM tumors and cell lines. RT-qPCR revealed that members of both families were significantly downregulated in MPM tumors and cell lines. In...
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Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting... more
Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription factor (TF)-miRNA regulatory networks has added complexity to understanding the therapeutic potential of miRNA-based therapies. Here, we sought to determine whether antimiR-34 targets secondary miRNAs via TFs which could contribute to antimiR-34-mediated protection. Using miRNA-Seq we identified differentially regulated miRNAs in hearts from mice with cardiac pathology due to transverse aortic constriction (TAC), and focused on miRNAs which were also regulated by antimiR-34. Two clusters of stress-responsive miRNAs were classified as "pathological" and "cardioprotective", respectively. Using ChIPBase we identified 45 TF bi...
Research Interests: Genetics and RNA biology
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Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac... more
Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks, and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardi...
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The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood... more
The global prevalence of obesity is increasing across most ages in both sexes. This is contributing to the early emergence of type 2 diabetes and its related epidemic. Having either parent obese is an independent risk factor for childhood obesity. Although the detrimental impacts of diet-induced maternal obesity on adiposity and metabolism in offspring are well established, the extent of
Research Interests: Genetics, Cell Cycle, Childhood Obesity, Type 2 Diabetes, Nature, and 14 moreInsulin Secretion, Risk factors, Pathway Analysis, FGF SIGNALLING PATHWAY, Body Weight, Risk Factors, Intergenerational Transmission, Intracellular Transport, High fat diet, Differential expression, Pancreatic islets, Impaired Glucose Tolerance, Glucose tolerance, and Genetic factors
miRNAs are small non-coding RNAs (ncRNAs), which regulate gene expression. Here, the authors describe the contribution of miRNAs to cardiac biology and disease. They discuss various strategies for manipulating miRNA activity including... more
miRNAs are small non-coding RNAs (ncRNAs), which regulate gene expression. Here, the authors describe the contribution of miRNAs to cardiac biology and disease. They discuss various strategies for manipulating miRNA activity including antisense oligonucleotides (antimiRs, blockmiRs), mimics, miRNA sponges, Tough Decoys and miRNA mowers. They review developments in chemistries (e.g., locked nucleic acid) and modifications (sugar, ‘ZEN’, peptide nucleic acids) and miRNA delivery tools (viral vectors, liposomes, nanoparticles, pHLIP). They summarize potential miRNA therapeutic targets for heart disease based on preclinical studies. Finally, the authors review current progress of miRNA therapeutics in clinical development for HCV and cancer, and discuss challenges that will need to be overcome for similar therapies to enter the clinic for patients with cardiac disease.
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Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments worldwide and frequently occurs in combination with heart failure. AF and heart failure may share common mechanisms and treatment... more
Atrial fibrillation (AF) is the most common sustained arrhythmia presenting at cardiology departments worldwide and frequently occurs in combination with heart failure. AF and heart failure may share common mechanisms and treatment strategies. The objective of this study was to assess whether reduced activation of a cardioprotective signaling protein, phosphoinositide 3-kinase (PI3K, p110a), can accelerate heart failure in a setting of dilated cardiomyopathy (DCM) and, if so, whether this makes the heart susceptible to AF. A cardiac-specific transgenic mouse model of DCM due to cardiac overexpression of the stress-activated protein kinase, mammalian sterile 20-like kinase 1 (Mst1), was genetically crossed with a cardiac-specific transgenic mouse model expressing a dominant negative mutant of PI3K (dnPI3K; reduces PI3K activity in myocytes). Double transgenic mice (Mst1-dnPI3K; DTg), single transgenics (Mst1 and dnPI3K) and non-transgenic littermates were subjected to morphological, ...
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Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish... more
Malignant pleural mesothelioma (MPM) is an asbestos-induced cancer with poor prognosis that displays characteristic alterations in microRNA expression. Recently it was reported that the expression of a subset of microRNAs can distinguish between MPM and adenocarcinoma of the lung. However, the functional importance of these changes has yet to be investigated. We compared expression of miR-192, miR-193a-3p and the miR-200 family in normal pleura and MPM tumor specimens and found a statistically significant reduction in the levels of miR-193a-3p (3.1-fold) and miR-192 (2.8-fold) in MPM. Transfection of MPM cells with a miR-193a-3p mimic resulted in inhibition of growth and an induction of apoptosis and necrosis in vitro. The growth inhibitory effects of miR-193a-3p were associated with a decrease in MCL1 expression and were recapitulated by RNAi-mediated MCL1 silencing. Targeted delivery of miR-193a-3p mimic using EDV minicells inhibited MPM xenograft tumour growth, and was associated...
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To determine whether the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) is associated with overweight and obesity. This polymorphism leads to a splice variant (Gbeta3-s) with higher activity and very strong association with... more
To determine whether the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) is associated with overweight and obesity. This polymorphism leads to a splice variant (Gbeta3-s) with higher activity and very strong association with essential hypertension. A cross-sectional case-control study. The sets of affected and control British/European Caucasian subjects used were: (i) an obesity clinic group most of whom had "morbid obesity" (mean body mass index (BMI) for group=43+/-8 kg/m(2)) and non-obese controls (BMI< or =30); (ii) a group of overweight/obese healthy normotensive community volunteers (BMI>25; mean 29+/-5) and controls (BMI< or =25; mean 23+/-1); (iii) a group of overweight/obese hypertensive patients (BMI>25; mean 30+/-4) and lean hypertensive controls (BMI< or =25; mean=23+/-2). BMI, blood pressure, serum lipids, alleles of GNB3 polymorphism. Compared with control, frequency of the T allele in obese subjects was higher by 12% in (i), 17% ...