ORCID Profile
0000-0003-4163-511X
Current Organisations
MacLin Consulting
,
Westmead Institute for Medical Research
,
Torrens University Australia
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Genetics Not Elsewhere Classified | Gene Expression | Genome Structure | Genetics
Publisher: Springer Science and Business Media LLC
Date: 05-03-2020
Publisher: American Chemical Society (ACS)
Date: 30-06-2022
DOI: 10.1021/ACSINFECDIS.2C00087
Abstract: The escalating issue of multidrug-resistant (MDR) bacteria indicates the urgent need for new and effective strategies to combat this global health challenge. Here, we describe a new combinatorial approach that can be put forward for experimental therapy application against MDR bacteria. Specifically, we have developed a tri-system that includes the coadministration of two different membrane-disrupting-type antimicrobial agents─a synthetic antimicrobial polymer
Publisher: Wiley
Date: 13-01-2014
DOI: 10.1096/FJ.13-244046
Abstract: We previously showed that paternal high-fat diet (HFD) consumption programs β-cell dysfunction in female rat offspring, together with transcriptome alterations in islets. Here we investigated the retroperitoneal white adipose tissue (RpWAT) transcriptome using gene and pathway enrichment and pathway analysis to determine whether commonly affected network topologies exist between these two metabolically related tissues. In RpWAT, 5108 genes were differentially expressed due to a paternal HFD the top 5 significantly enriched networks identified by pathway analysis in offspring of HFD fathers compared with those of fathers fed control diet were: mitochondrial and cellular response to stress, telomerase signaling, cell death and survival, cell cycle, cellular growth and proliferation, and cancer. A total of 187 adipose olfactory receptor genes were down-regulated. Interrogation against the islet transcriptome identified specific gene networks and pathways, including olfactory receptor genes that were similarly affected in both tissues (411 common genes, P<0.05). In particular, we highlight a common molecular network, cell cycle and cancer, with the same hub gene, Myc, suggesting early onset developmental changes that persist, shared responses to programmed systemic factors, or crosstalk between tissues. Thus, paternal HFD consumption triggers unique gene signatures, consistent with premature aging and chronic degenerative disorders, in both RpWAT and pancreatic islets of daughters.
Publisher: Elsevier BV
Date: 09-2016
Publisher: EMBO
Date: 09-08-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-07-2014
DOI: 10.1161/RES.115.SUPPL_1.58
Abstract: 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 .05) and attenuated with antimiR-34 treatment (85% decrease [0.85 of 1], p .05). TAC mice developed pathological cardiac hypertrophy (60% increase [4.8 of 8] in heart weight/tibial length ratio compared to Sham controls, P .05) and treatment with antimiR-34 significantly attenuated heart size (P .05). To uncover the underlying miRNA interactions, we carried out miRNA-Seq to identify other miRNAs that might be dysregulated in response to antimiR-34-based therapy. We identified several miRNAs (e.g., miR-3083 and miR-20b) that were downregulated in hearts from TAC vs Sham but not significantly downregulated in the TAC antimiR-34 group. Conversely, two miRNAs (miR-8103, miR-1933) were increased in response to TAC vs Sham but not significantly upregulated in TAC antimiR-34 treated mice. Our data suggests that miR-34 can regulate other miRNA and that these miRNAs can work together to regulate pathways leading to pathological cardiac hypertrophy. Conclusion: The identification of other miRNAs regulated by miR-34 may improve our understanding of miRNA networks for optimization of better therapeutic targets for treatment of complex diseases such as heart failure.
Publisher: Public Library of Science (PLoS)
Date: 27-02-2014
Publisher: American Thoracic Society
Date: 11-2019
Publisher: Springer Science and Business Media LLC
Date: 17-02-2020
Publisher: Oxford University Press (OUP)
Date: 16-11-2023
Abstract: Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and four disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases, with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene–intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild-type full-length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic Caenorhabditis elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress, which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene–intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.
Publisher: Public Library of Science (PLoS)
Date: 28-07-2011
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JTHO.2017.10.016
Abstract: Malignant pleural mesothelioma (MPM) is an aggressive malignancy linked to asbestos exposure. On a genomic level, MPM is characterized by frequent chromosomal deletions of tumor suppressors, including microRNAs. MiR-137 plays a tumor suppressor role in other cancers, so the aim of this study was to characterize it and its target Y-box binding protein 1 (YBX1) in MPM. Expression, methylation, and copy number status of miR-137 and its host gene MIR137HG were assessed by polymerase chain reaction. Luciferase reporter assays confirmed a direct interaction between miR-137 and Y-box binding protein 1 gene (YBX1). Cells were transfected with a miR-137 inhibitor, miR-137 mimic, and/or YBX1 small interfering RNA, 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 hypermethylation. High miR-137 expression was linked to poor patient survival. The miR-137 inhibitor did not affect target levels or growth, but interestingly, it increased miR-137 levels by means of mimic transfection suppressed growth, migration, and invasion, which was linked to direct YBX1 downregulation. YBX1 was overexpressed in MPM cell lines and inversely correlated with miR-137. RNA interference-mediated YBX1 knockdown significantly reduced cell growth, migration, and invasion. MiR-137 can exhibit a tumor-suppressive function in MPM by targeting YBX1. YBX1 knockdown significantly reduces tumor growth, migration, and invasion of MPM cells. Therefore, YBX1 represents a potential target for novel MPM treatment strategies.
Publisher: Wiley
Date: 02-12-2014
Publisher: Wiley
Date: 06-2003
DOI: 10.1038/OBY.2003.111
Abstract: To determine whether the N363S variant in the glucocorticoid receptor (encoded by nuclear receptor subfamily 3, group C, member 1: NR3C1) is associated with obesity, type 2 diabetes, or hypertension. This was a cross-sectional case-control study involving 951 Anglo-Celtic/Northern European subjects from Sydney. This study consisted of the following: 1) an obesity clinic group, most of whom had "morbid obesity" (mean BMI for group = 43 +/- 8 kg/m(2) n = 152) 2) a type 2 diabetes clinic group (n = 356) 3) patients with essential hypertension who had a strong family history (n = 141) and 4) normal healthy controls (n = 302). N363S genotype, BMI, and a range of other parameters relevant to each group were measured. Compared with the frequency of 0.04 in nonobese healthy subjects, the S363 allele was significantly higher in obesity clinic patients (0.17 p = 5.6 x 10(-8)), subjects with diabetes who were also obese (0.09 p = 0.0045), subjects with hypertension who were also overweight (0.08 p = 0.0016), and overweight healthy subjects (0.12 p = 0.0004). The NR3C1 N363S variant is associated with obesity and overweight in a range of patient settings but is not associated with hypertension or type 2 diabetes.
Publisher: Mary Ann Liebert Inc
Date: 20-01-2012
Publisher: CSIRO Publishing
Date: 2019
DOI: 10.1071/MA19005
Abstract: The rise of multiple antibiotic resistance in clinically relevant bacteria has created a global crisis with increasing burden on healthcare systems. The need to optimise alternative therapies to antibiotics, particularly in high risk nosocomial settings, is therefore immediate. Bacteriophages are specialised lethal viruses of bacteria, and an underused clinical resource for the treatment of severe infections refractory to antibiotics. Both the gaps in knowledge of bacteriophage biology, particularly the details of host-pathogen dynamic interactions, and legislative hurdles related to the regulation of natural microorganisms for therapy have delayed progress in bacteriophage clinical applications. At the Westmead Institute for Medical Research (WIMR), in collaboration with Westmead Hospital (Western Sydney Local Health District, WSLHD) and the University of Sydney (USyd), we have been investigating rational design protocols for routine bacteriophage application in clinical practice and testing bacteriophage therapeutics on patients suffering from multidrug resistant (MDR) severe infections.
Publisher: Elsevier BV
Date: 08-2023
Publisher: Proceedings of the National Academy of Sciences
Date: 09-10-2012
Abstract: MicroRNAs are dysregulated in a setting of heart disease and have emerged as promising therapeutic targets. MicroRNA-34 family members (miR-34a, -34b, and -34c) are up-regulated in the heart in response to stress. In this study, we assessed whether inhibition of the miR-34 family using an s.c.-delivered seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiR (LNA-antimiR-34) can provide therapeutic benefit in mice with preexisting pathological cardiac remodeling and dysfunction due to myocardial infarction (MI) or pressure overload via transverse aortic constriction (TAC). An additional cohort of mice subjected to MI was given LNA-antimiR-34a (15-mer) to inhibit miR-34a alone as a comparison for LNA-antimiR-34. LNA-antimiR-34 (8-mer) efficiently silenced all three miR-34 family members in both cardiac stress models and attenuated cardiac remodeling and atrial enlargement. In contrast, inhibition of miR-34a alone with LNA-antimiR-34a (15-mer) provided no benefit in the MI model. In mice subjected to pressure overload, LNA-antimiR-34 improved systolic function and attenuated lung congestion, associated with reduced cardiac fibrosis, increased angiogenesis, increased Akt activity, decreased atrial natriuretic peptide gene expression, and maintenance of sarcoplasmic reticulum Ca 2+ ATPase gene expression. Improved outcome in LNA-antimiR-34–treated MI and TAC mice was accompanied by up-regulation of several direct miR-34 targets, including vascular endothelial growth factors, vinculin, protein O -fucosyltranferase 1, Notch1, and semaphorin 4B. Our results provide evidence that silencing of the entire miR-34 family can protect the heart against pathological cardiac remodeling and improve function. Furthermore, these data underscore the utility of seed-targeting 8-mer LNA-antimiRs in the development of new therapeutic approaches for pharmacologic inhibition of disease-implicated miRNA seed families.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2010
DOI: 10.1161/ATVBAHA.109.201988
Abstract: Objective— Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110α)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110α) provides protection in a setting of MI is unknown, and PI3K(p110α) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110α) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110α). Methods and Results— Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110α) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110α) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion— Activation of PI3K(p110α) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110α) represent new drug targets for heart failure.
Publisher: No publisher found
Date: 2011
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2008
Publisher: Elsevier BV
Date: 09-2011
Publisher: Mary Ann Liebert Inc
Date: 06-2022
Publisher: Cold Spring Harbor Laboratory
Date: 06-07-2023
DOI: 10.1101/2023.07.03.23292153
Abstract: Due to the rise in antimicrobial resistance (AMR), there has been an increased interest in phage therapy to treat multi-drug resistant infections. In Australia, phage therapy is predominantly used in small clinical studies or for compassionate use, however, despite its potential expansion in modern medicine, the perception of phage therapy among medical professionals remains largely unknown. Therefore, we conducted a national survey of Australian infectious diseases and clinical microbiology advanced trainees and specialists to assess their knowledge, areas of interest, and concerns around the use of phage therapy in clinical practice in Australia. Our survey received 92 responses from infectious diseases and clinical microbiology professionals across all states of Australia. The majority of those surveyed believed that the current national plan for controlling AMR is inadequate and that phage therapy may be an effective solution with 97% of respondents indicating that they would consider using phage therapy meeting established guidelines for purity and safety (United States Food and Drug Administration and/or European Union guidelines). The respondents indicated a preference for bespoke therapy, with Gram-negative pathogens highlighted as priority targets. Alongside the phage therapy delivery protocols, therapeutic phage monitoring (TPM like therapeutic drug monitoring (TDM)) was considered important. Cystic Fibrosis, lung-infections, prosthetic device related infections, and infections among patients following transplantation and/or immunosuppression were highly ranked in terms of priorities for clinical syndromes. Accessibility was highlighted as a barrier to phage therapy, specifically timely access (72%) and logistics of phage procurement and administration (70%). Altogether, these results suggest the support of phage therapy among infectious diseases and clinical microbiology advanced trainees and specialists in Australia, and highlights areas of focus and priority in order to advance phage therapy in modern medicine.
Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2022
DOI: 10.1101/2022.08.16.504208
Abstract: Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and 4 disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene ( UBE3C ) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion ( UBE3C-IF ) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild type full length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic C. elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2003
DOI: 10.1161/01.HYP.0000055342.40301.DC
Abstract: Overweight is associated with the N363S variant in the glucocorticoid receptor (encoded by nuclear receptor subfamily 3, group C, member 1 gene: NR3C1 ). The present study examined whether the N363S polymorphism might also be associated with coronary artery disease (CAD). This involved 556 patients with CAD, of which 437 were analyzed, and 302 control subjects, all being of Anglo-Celtic descent residing in Sydney. An extensive range of phenotypic parameters was collected from the patients, and leukocyte DNA from all subjects was genotyped by polymerase chain reaction–restriction fragment length polymorphism analysis for the A1218G (N363S) variant. Frequency of the S363 allele was 0.04 in healthy normal-weight control subjects but was 0.15 in patients with CAD ( P =2.0×10 −5 ) and was also elevated in subjects with CAD who were not overweight (0.14) ( P =2.6×10 −5 ), supporting a primary association with CAD. Frequency of S363 allele carriers in subjects with CAD who had angina was particularly high: unstable angina (0.45), stable angina (0.29), and no angina (0.26) ( P for trend=0.016). Elevated cholesterol ( P =0.027), triglycerides ( P =0.005), and total cholesterol/HDL ratio ( P =0.011), after Bonferroni, tracked with the S363 allele, consistent with accentuation of mechanisms that predispose to atheroma formation in coronary vessels. The data suggest a role for glucocorticoid receptor variation in the underlying cause of CAD.
Publisher: Elsevier BV
Date: 12-2020
Publisher: Cold Spring Harbor Laboratory
Date: 26-04-2019
DOI: 10.1101/619999
Abstract: The effect of IV administration of a bacteriophage cocktail produced under GMP conditions on patients with severe S. aureus infection, including complicated bacteraemia, endocarditis and septic shock, is unknown. To assess safety and tolerability of adjunctive bacteriophage therapy in patients with severe S. aureus infections. Observational, open-label clinical trial of thirteen critically-ill patients admitted to a tertiary-referral hospital with S. aureus bacteraemia (including infective endocarditis, n=6) were assessed by the treating clinician and two consulting infectious diseases physicians to independently verify that routine medical and surgical therapy was optimal and that a poor outcome remained likely. Compassionate access to therapy was approved by both US and Australian regulators and by the Westmead Hospital Human Research Ethics Committee. A GMP-quality preparation of three combined Myoviridae bacteriophages with specific activity against S. aureus (AB-SA01), was administered intravenously in conjunction with optimal antibiotic therapy. Physiological, haematological and biochemical markers of infection, bacterial and bacteriophage kinetics in blood, development of resistance to bacteriophages, and mortality at 28 (D28) and 90 (D90) days were measured. Main outcomes were safety and tolerability. Bacteriophage therapy was initiated 4-10 days after antibiotic commencement, at 10 9 plaque-forming units (PFU) twice daily. Infecting staphylococci were typical of common local subtypes. Initial input ratio of phages to bacteria in the bloodstream (MOI input ) was . Five of the thirteen patients died by D28 and a sixth patient suffered sudden cardiac death on D90. Bacteriophage therapy coincided with a marked reduction in staphylococcal bacterial DNA in the blood and in sepsis-associated inflammatory responses in almost all cases. No bacteriophage-attributable adverse events were identified. Development of bacteriophage resistance was not observed. Population analysis revealed no significant effect of bacteriophage therapy on the gut microflora. Adjunctive bacteriophage therapy appears to be safe and well-tolerated in critically ill patients with severe S. aureus infection. Two weeks of twice daily intravenous administration may be a suitable protocol. Controlled trials are needed. Westmead Hospital Human Research Ethics Committee approval July 11, 2017 ClinicalTrials.gov Identifier: NCT03395769 , AB-SA01-EAP01 (January 10, 2018) Clinical Trials Notification (Australian Therapeutic Goods Association): CT-2018-CTN-02372-1 (July 23, 2018). Is intravenous (IV) administration of investigational bacteriophage (phage) therapy safe and well-tolerated in patients with severe Staphylococcus aureus infection? Thirteen patients with severe S. aureus infections received AB-SA01, a bacteriophage product prepared according to Good Manufacturing Practices (GMP), as adjunctive therapy to antibiotics. AB-SA01 was well-tolerated with no adverse events identified. Bacterial burden and inflammatory responses were reduced and no phage-resistant staphylococci were isolated during or after therapy. Our results will inform future randomised controlled trials assessing the antibacterial and anti-inflammatory potential of bacteriophages in the treatment of severe S. aureus infection.
Publisher: Frontiers Media SA
Date: 11-02-2021
DOI: 10.3389/FMICB.2020.599906
Abstract: Approximately 10% of global health research is devoted to 90% of global disease burden (the so-called “10/90 Gap”) and it often neglects those diseases most prevalent in low-income countries. Antibiotic resistant bacterial infections are known to impact on healthcare, food security, and socio-economic fabric in the developing countries. With a global antibiotic resistance crisis currently reaching a critical level, the unmet needs in the developing countries are even more striking. The failure of traditional antimicrobials has led to renewed interest in century-old bacteriophage (phage) therapy in response to the urgent need to develop alternative therapies to treat infections. Phage therapy may have particular value in developing countries where relevant phages can be sourced and processed locally and efficiently, breaking specifically the economic barrier of access to expensive medicine. Hence this makes phage therapy an attractive and feasible option. In this review, we draw our respective clinical experience as well as phage therapy research and clinical trial, and discuss the ways in which phage therapy might reduce the burden of some of the most important bacterial infections in developing countries.
Publisher: Elsevier BV
Date: 2015
Publisher: American Diabetes Association
Date: 14-06-2014
DOI: 10.2337/DB13-0729
Abstract: Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2) is the most severe form of human lipodystrophy, characterized by an almost complete loss of adipose tissue and severe insulin resistance. BSCL2 is caused by loss-of-function mutations in the BSCL2/SEIPIN gene, which is upregulated during adipogenesis and abundantly expressed in the adipose tissue. The physiological function of SEIPIN in mature adipocytes, however, remains to be elucidated. Here, we generated adipose-specific Seipin knockout (ASKO) mice, which exhibit adipocyte hypertrophy with enlarged lipid droplets, reduced lipolysis, adipose tissue inflammation, progressive loss of white and brown adipose tissue, insulin resistance, and hepatic steatosis. Lipidomic and microarray analyses revealed accumulation/imbalance of lipid species, including ceramides, in ASKO adipose tissue as well as increased endoplasmic reticulum stress. Interestingly, the ASKO mice almost completely phenocopy the fat-specific peroxisome proliferator–activated receptor-γ (Pparγ) knockout (FKO-γ) mice. Rosiglitazone treatment significantly improved a number of metabolic parameters of the ASKO mice, including insulin sensitivity. Our results therefore demonstrate a critical role of SEIPIN in maintaining lipid homeostasis and function of adipocytes and reveal an intimate relationship between SEIPIN and PPAR-γ.
Publisher: Wiley
Date: 20-07-2016
DOI: 10.1113/JP272512
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 04-2021
Publisher: Research Square Platform LLC
Date: 19-11-2020
DOI: 10.21203/RS.3.RS-110673/V1
Abstract: 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.
Publisher: Cold Spring Harbor Laboratory
Date: 04-2019
DOI: 10.1101/MCS.A003764
Abstract: Adrenocortical carcinoma is a rare malignancy with a poor prognosis and few treatment options. Molecular characterization of this cancer remains limited. We present a case of an adrenocortical carcinoma (ACC) in a 37-yr-old female, with dual lung metastases identified 1 yr following commencement of adjuvant mitotane therapy. As standard therapeutic regimens are often unsuccessful in ACC, we undertook a comprehensive genomic study into this case to identify treatment options and monitor disease progress. We performed targeted and whole-genome sequencing of germline, primary tumor, and both metastatic tumors from this patient and monitored recurrence over 2 years using liquid biopsy for ctDNA and steroid hormone measurements. Sequencing revealed the primary and metastatic tumors were hyperhaploid, with extensive loss of heterozygosity but few structural rearrangements. Loss-of-function mutations were identified in MSH2 , TP53 , RB1 , and PTEN , resulting in tumors with mismatch repair signatures and microsatellite instability. At the cellular level, tumors were populated by mitochondria-rich oncocytes. Longitudinal ctDNA mutation and hormone profiles were unable to detect micrometastatic disease, consistent with clinical indicators of disease remission. The molecular signatures in our ACC case suggested immunotherapy in the event of disease progression however, the patient remains free of cancer. The extensive molecular analysis presented here could be applied to other rare and/or poorly stratified cancers to identify novel or repurpose existing therapeutic options, thereby broadly improving diagnoses, treatments, and prognoses.
Publisher: No publisher found
Date: 2000
Publisher: Informa UK Limited
Date: 06-2016
Publisher: Hindawi Limited
Date: 2000
DOI: 10.1002/1098-1004(200007)16:1<96::AID-HUMU33>3.0.CO;2-S
Publisher: Frontiers Media SA
Date: 26-08-2022
Abstract: 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 ch ioned 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 s les. We confirmed via SEM analysis that 3D cells grown using the spheroid methods expressed highly interconnected cell-to-cell junctions. The 3D spheroids were revealed to be an improved mini-tumor model as indicated by the TEM visualization of cell junctions and microvilli, features not seen in the 2D models. Growing 3D cell models using decellularized lung scaffold provided a platform for cell growth and infiltration for all cell types including primary cell lines. The most time-effective method was growing cells in spheroids using low-adhesive U-bottom plates. However, not every cell type grew into a 3D model using the the other methods of hanging drop or poly-HEMA. Cells grown in 3D showed more resistance to chemotherapeutic drugs, exhibiting reduced apoptosis. 3D cells stained with H& E showed cell-to-cell interactions and internal architecture that better represent that of in vivo patient tumors when compared to 2D cells. IHC staining revealed increased protein expression in 3D spheroids compared to 2D culture. Lastly, cells grown in 3D showed very different microRNA expression when compared to that of 2D counterparts. In conclusion, 3D cell models, regardless of which method is used. Showed a more realistic tumor microenvironment for architecture, gene expression and drug response, when compared to 2D cell models, and thus are superior preclinical cancer models.
Publisher: Springer Science and Business Media LLC
Date: 10-2010
DOI: 10.1038/NATURE09491
Abstract: 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 any contribution of obese fathers is unclear, particularly the role of non-genetic factors in the causal pathway. Here we show that paternal high-fat-diet (HFD) exposure programs β-cell 'dysfunction' in rat F(1) female offspring. Chronic HFD consumption in Sprague-Dawley fathers induced increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had an early onset of impaired insulin secretion and glucose tolerance that worsened with time, and normal adiposity. Paternal HFD altered the expression of 642 pancreatic islet genes in adult female offspring (P < 0.01) genes belonged to 13 functional clusters, including cation and ATP binding, cytoskeleton and intracellular transport. Broader pathway analysis of 2,492 genes differentially expressed (P < 0.05) demonstrated involvement of calcium-, MAPK- and Wnt-signalling pathways, apoptosis and the cell cycle. Hypomethylation of the Il13ra2 gene, which showed the highest fold difference in expression (1.76-fold increase), was demonstrated. This is the first report in mammals of non-genetic, intergenerational transmission of metabolic sequelae of a HFD from father to offspring.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 09-2009
Publisher: Wiley
Date: 04-2020
DOI: 10.5694/MJA2.50355
Abstract: Bacteriophage (phage) therapy is re-emerging a century after it began. Activity against antibiotic-resistant pathogens and a lack of serious side effects make phage therapy an attractive treatment option in refractory bacterial infections. Phages are highly specific for their bacterial targets, but the relationship between in vitro activity and in vivo efficacy remains to be rigorously evaluated. Pharmacokinetic and pharmacodynamic principles of phage therapy are generally based on the classic predator-prey relationship, but numerous other factors contribute to phage clearance and optimal dosing strategies remain unclear. Combinations of fully characterised, exclusively lytic phages prepared under good manufacturing practice are limited in their availability. Safety has been demonstrated but randomised controlled trials are needed to evaluate efficacy.
Publisher: Wiley
Date: 10-2007
Abstract: The natural polyphenol resveratrol stimulates sirtuins and extends lifespan. Here resveratrol inhibited expression of replicative senescence marker INK4a in human dermal fibroblasts, and 47 of 19,000 genes from microarray experiments were differentially expressed. These included genes for growth, cell ision, cell signaling, apoptosis, and transcription. Genes involved in Ras and ubiquitin pathways, Ras-GRF1, RAC3, and UBE2D3, were downregulated. The changes suggest resveratrol might alter sirtuin-regulated downstream pathways, rather than sirtuin activity. Serum deprivation and high confluency caused nuclear translocation of the SIRT1-regulated transcription factor FOXO3a. Our data indicate resveratrol's actions might cause FOXO recruitment to the nucleus.
Publisher: Springer Science and Business Media LLC
Date: 06-2001
Abstract: 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 25 mean 29+/-5) and controls (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% in (ii) and 28% in (iii), but the differences were not statistically significant. Slight tracking of the T allele with elevation in BMI was, however, observed, in the obesity clinic group (P=0.018). The C825T splice variant of GNB3 makes little if any contribution to obesity in the groups we tested.
Publisher: American College of Physicians
Date: 17-09-2019
DOI: 10.7326/L19-0369
Publisher: Springer Science and Business Media LLC
Date: 05-09-2017
Abstract: Vitamin D co-regulates cell proliferation, differentiation and apoptosis in numerous tissues, including cancers. The known anti-proliferative and pro-apoptotic actions of the active metabolite of vitamin D, 1,25-dihydroxy-vitamin D [1,25(OH) 2 D] are mediated through binding to the vitamin D receptor (VDR). Here, we report on the unexpected finding that stable knockdown of VDR expression in the human breast and prostate cancer cell lines, MDA-MB-231 and PC3, strongly induces cell apoptosis and inhibits cell proliferation in vitro. Implantation of these VDR knockdown cells into the mammary fat pad (MDA-MB-231), subcutaneously (PC3) or intra-tibially (both cell lines) in immune-incompetent nude mice resulted in reduced tumor growth associated with increased apoptosis and reduced cell proliferation compared with controls. These growth-retarding effects of VDR knockdown occur in the presence and absence of vitamin D and are independent of whether cells were grown in bone or soft tissues. Transcriptome analysis of VDR knockdown and non-target control cell lines demonstrated that loss of the VDR was associated with significant attenuation in the Wnt/β-catenin signaling pathway. In particular, cytoplasmic and nuclear β-catenin protein levels were reduced with a corresponding downregulation of downstream genes such as Axin2, Cyclin D1, interleukin-6 (IL-6), and IL-8. Stabilization of β-catenin using the GSK-3β inhibitor BIO partly reversed the growth-retarding effects of VDR knockdown. Our results indicate that the unliganded VDR possesses hitherto unknown functions to promote breast and prostate cancer growth, which appear to be operational not only within but also outside the bone environment. These novel functions contrast with the known anti-proliferative nuclear actions of the liganded VDR and may represent targets for new diagnostic and therapeutic approaches in breast and prostate cancer.
Publisher: BMJ
Date: 12-2022
DOI: 10.1136/BMJOPEN-2022-065401
Abstract: There 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. We 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 high in vitro activity 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 s ling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with % of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics. Participant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children’s Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website ( www.phageaustralia.org/ ). Registered on ANZCTR, 10 November 2021 (ACTRN12621001526864 WHO Universal Trial Number: U1111-1269-6000).
Publisher: Oxford University Press (OUP)
Date: 23-02-2018
Abstract: 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. Inhibition of MMP1 prevented FGF2-induced scattering and invasiveness. Moreover, in MPM cells with sarcomatoid morphology, inhibition of FGF/MAP-kinase signaling induced a more epithelioid morphology and gene expression pattern. Our findings suggest a critical role of the MAP-kinase axis in the morphological and behavioral plasticity of mesothelioma.
Publisher: Cold Spring Harbor Laboratory
Date: 11-03-2023
DOI: 10.1101/2023.03.10.532157
Abstract: There is a growing appreciation that the direct interaction between bacteriophages and the mammalian host can facilitate erse and unexplored symbioses. Yet the impact these bacteriophages may have on mammalian cellular and immunological processes is poorly understood. Here we applied highly purified phage T4, free from bacterial by-products and endotoxins to mammalian cells and analyzed the cellular responses using luciferase reporter and antibody microarray assays. Phage preparations were applied in vitro to either A549 lung epithelial cells, MDCK-I kidney cells, or primary mouse bone marrow derived macrophages with the phage-free supernatant serving as a comparative control. Highly purified T4 phages were rapidly internalized by mammalian cells and accumulated within macropinosomes but did not activate the inflammatory DNA response TLR9 or cGAS-STING pathways. Following eight hours of incubation with T4 phage, whole cell lysates were analyzed via antibody microarray that detected expression and phosphorylation levels of human signaling proteins. T4 phage internalization led to the activation of AKT-dependent pathways, resulting in an increase in cell metabolism, survival, and actin reorganization, the last being critical for macropinocytosis and potentially regulating a positive feedback loop to drive further phage internalization. T4 phages additionally down-regulated CDK1 and its downstream effectors, leading to an inhibition of cell cycle progression and an increase in cellular growth through a prolonged G1 phase. These interactions demonstrate that highly purified T4 phages do not activate DNA-mediated inflammatory pathways but do trigger protein phosphorylation cascades that promote cellular growth and survival. We conclude that mammalian cells are internalizing bacteriophages as a food source to promote cellular growth and metabolism.
Publisher: Future Science Ltd
Date: 09-2015
DOI: 10.4155/FMC.15.107
Abstract: 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.
Publisher: Wiley
Date: 12-2002
DOI: 10.1038/OBY.2003.214
Publisher: Springer Science and Business Media LLC
Date: 06-2016
Publisher: Wiley
Date: 21-08-2014
DOI: 10.1096/FJ.14-253856
Abstract: Expression of microRNA-652 (miR-652) increases in the diseased heart, decreases in a setting of cardioprotection, and is inversely correlated with heart function. The aim of this study was to assess the therapeutic potential of inhibiting miR-652 in a mouse model with established pathological hypertrophy and cardiac dysfunction due to pressure overload. Mice were subjected to a sham operation or transverse aortic constriction (TAC) for 4 wk to induce hypertrophy and cardiac dysfunction, followed by administration of a locked nucleic acid (LNA)-antimiR-652 (miR-652 inhibitor) or LNA control. Cardiac function was assessed before and 8 wk post-treatment. Expression of miR-652 increased in hearts subjected to TAC compared to sham surgery (2.9-fold), and this was suppressed by ∼95% in LNA-antimiR-652-treated TAC mice. Inhibition of miR-652 improved cardiac function in TAC mice (fractional shortening:29±1% at 4 wk post-TAC compared to 35±1% post-treatment) and attenuated cardiac hypertrophy. Improvement in heart function was associated with reduced cardiac fibrosis, less apoptosis and B-type natriuretic peptide gene expression, and preserved angiogenesis. Mechanistically, we identified Jagged1 (a Notch1 ligand) as a novel direct target of miR-652. In summary, these studies provide the first evidence that silencing of miR-652 protects the heart against pathological remodeling and improves heart function.
Publisher: Wiley
Date: 02-2002
DOI: 10.1002/AJMG.10177
Abstract: Infection with microorganisms such as Helicobacter pylori and Chlamydia pneumoniae has been associated with coronary heart disease (CAD) and hypertension (HT). Infection increases the release of pro-inflammatory cytokines, thus facilitating interactions that lead to vascular damage and other effects. We hypothesized that genetically determined differences in activity or responsiveness of cytokine(s) might contribute to HT. The interleukin-1 gene (IL1) cluster on chromosome 2q14 contains three related genes (IL1A, IL1B, and IL1RN) located within a 430-kb region. These encode IL-1alpha and IL-1beta, as well as their endogenous receptor antagonist, IL-1ra. The IL1RN gene has a penta-allelic 86-bp tandem repeat in intron 2. Allele IL1RN* 2 is associated with a wide range of chronic inflammatory and autoimmune conditions, and its combination with the -31T variant of an IL1B C(-31)T polymorphism constitutes a pro-inflammatory haplotype that leads to vigorous IL-1beta production. We therefore tested each of these polymorphisms for association with HT. Subjects were white Anglo-Celtic residents of Sydney, Australia. Frequencies of IL1B C(-31)T genotypes CC, CT, and TT were 0.50, 0.40, and 0.10 in normotensive (NT) and 0.46, 0.46, and 0.08 in HT, respectively (chi(2) = 1.2, P = 0.55). T allele frequency in NT (0.30) was similar to that in HT (0.31). For the IL1RN variant, frequencies of alleles IL1RN* 1 and * 2 and combined minor alleles * 3, * 4, and * 5 were 0.61, 0.36, and 0.03 in NT and 0.54, 0.36, and 0.10 in HT, respectively (chi(2) = 11, P = 0.004). In conclusion, no association of the IL1B C(- 31)T with HT was found, whereas combined frequency of the minor alleles of the IL1RN polymorphism was increased in the HT cohort studied.
Publisher: Elsevier BV
Date: 02-2011
Publisher: Public Library of Science (PLoS)
Date: 26-10-2023
Publisher: Springer Science and Business Media LLC
Date: 03-2016
DOI: 10.1038/SREP22442
Abstract: 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 cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.
Publisher: No publisher found
Date: 2002
Publisher: Wiley
Date: 04-2020
DOI: 10.5694/MJA2.50355
Abstract: Bacteriophage (phage) therapy is re-emerging a century after it began. Activity against antibiotic-resistant pathogens and a lack of serious side effects make phage therapy an attractive treatment option in refractory bacterial infections. Phages are highly specific for their bacterial targets, but the relationship between in vitro activity and in vivo efficacy remains to be rigorously evaluated. Pharmacokinetic and pharmacodynamic principles of phage therapy are generally based on the classic predator-prey relationship, but numerous other factors contribute to phage clearance and optimal dosing strategies remain unclear. Combinations of fully characterised, exclusively lytic phages prepared under good manufacturing practice are limited in their availability. Safety has been demonstrated but randomised controlled trials are needed to evaluate efficacy.
Publisher: Springer Science and Business Media LLC
Date: 06-2016
Publisher: Elsevier BV
Date: 08-2017
Publisher: Walter de Gruyter GmbH
Date: 21-01-2003
Publisher: American Thoracic Society
Date: 10-2007
Start Date: 2015
End Date: 2016
Funder: CI NSW REG
View Funded ActivityStart Date: 2005
End Date: 2008
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2009
End Date: 2014
Funder: University of New South Wales
View Funded ActivityStart Date: 2013
End Date: 2015
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2005
End Date: 2006
Funder: Cancer Council NSW
View Funded ActivityStart Date: 2005
End Date: 2007
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2010
End Date: 2012
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2021
End Date: 2022
Funder: Medical Research Future Fund
View Funded ActivityStart Date: 02-2006
End Date: 12-2006
Amount: $850,000.00
Funder: Australian Research Council
View Funded Activity