Prince Henrys Institute for Medical Research

Melbourne, Australia

Prince Henrys Institute for Medical Research

Melbourne, Australia
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Pereira-Fantini P.M.,Murdoch Childrens Research Institute | Lapthorne S.,Murdoch Childrens Research Institute | Joyce S.A.,Alimentary Pharmabiotic Center | Dellios N.L.,Murdoch Childrens Research Institute | And 17 more authors.
Journal of Hepatology | Year: 2014

Background & Aims: Despite the mortality associated with liver disease observed in patients with short bowel syndrome (SBS), mechanisms underlying the development of SBS-associated liver disease (SBS-ALD) are poorly understood. This study examines the impact of bacterially-mediated bile acid (BA) dysmetabolism on farnesoid X receptor (FXR) signalling pathways and clinical outcome in a piglet model of SBS-ALD. Methods: 4-week old piglets underwent 75% small bowel resection (SBR) or sham operation. Liver histology and hepatic inflammatory gene expression were examined. Abundance of BA biotransforming bacteria was determined and metabolomic studies detailed the alterations in BA composition of stool, portal serum and bile samples. Gene expression of intestinal and hepatic FXR target genes and small heterodimer partner (SHP) transrepression targets were assessed. Results: Histological evidence of SBS-ALD included liver bile duct proliferation, hepatocyte ballooning and fibrosis. Inflammatory gene expression was increased. Microbiota changes included a 10-fold decrease in Clostridium and a two-fold decrease in Bacteroides in SBS-ALD piglets. BA composition was altered and reflected a primary BA dominant composition. Intestinal and hepatic regulation of BA synthesis was characterised by a blunted intestinal FXR activation response and a failure of SHP to repress key hepatic targets. Conclusions: We propose a pathological scenario in which microbial dysbiosis following SBR results in significant BA dysmetabolism and consequent outcomes including steatorrhoea, persistent diarrhoea and liver damage. Furthermore alterations in BA composition may have contributed to the observed disturbance in FXR-mediated signalling pathways. These findings provide an insight into the complex mechanisms mediating the development of liver disease in patients with SBS. © 2014.


Dowhan D.H.,University of Queensland | Harrison M.J.,University of Queensland | Eriksson N.A.,University of Queensland | Bailey P.,University of Queensland | And 9 more authors.
Endocrine-Related Cancer | Year: 2012

Protein arginine methyltransferase-6 (PRMT6) regulates steroid-dependent transcription and alternative splicing and is implicated in endocrine system development and function, cell death, cell cycle, gene expression and cancer. Despite its role in these processes, little is known about its function and cellular targets in breast cancer. To identify novel gene targets regulated by PRMT6 in breast cancer cells, we used a combination of small interfering RNA and exon-specific microarray profiling in vitro coupled to in vivo validation in normal breast and primary human breast tumours. This approach, which allows the examination of genome-wide changes in individual exon usage and total transcript levels, demonstrated that PRMT6 knockdown significantly affected i) the transcription of 159 genes and ii) alternate splicing of 449 genes. The PRMT6-dependent transcriptional and alternative splicing targets identified in vitro were validated in human breast tumours. Using the list of genes differentially expressed between normal and PRMT6 knockdown cells, we generated a PRMT6-dependent gene expression signature that provides an indication of PRMT6 dysfunction in breast cancer cells. Interrogation of several well-studied breast cancer microarray expression datasets with the PRMT6 gene expression signature demonstrated that PRMT6 dysfunction is associated with better overall relapse-free and distant metastasis-free survival in the oestrogen receptor (ER (ESR1)) breast cancer subgroup. These results suggest that dysregulation of PRMT6-dependent transcription and alternative splicing may be involved in breast cancer pathophysiology and the molecular consequences identifying a unique and informative biomarker profile. © 2012 Society for Endocrinology.


PubMed | Murdoch Childrens Research Institute, University College Cork, Prince Henrys Institute for Medical Research and Alimentary Pharmabiotic Center
Type: Journal Article | Journal: Journal of hepatology | Year: 2014

Despite the mortality associated with liver disease observed in patients with short bowel syndrome (SBS), mechanisms underlying the development of SBS-associated liver disease (SBS-ALD) are poorly understood. This study examines the impact of bacterially-mediated bile acid (BA) dysmetabolism on farnesoid X receptor (FXR) signalling pathways and clinical outcome in a piglet model of SBS-ALD.4-week old piglets underwent 75% small bowel resection (SBR) or sham operation. Liver histology and hepatic inflammatory gene expression were examined. Abundance of BA biotransforming bacteria was determined and metabolomic studies detailed the alterations in BA composition of stool, portal serum and bile samples. Gene expression of intestinal and hepatic FXR target genes and small heterodimer partner (SHP) transrepression targets were assessed.Histological evidence of SBS-ALD included liver bile duct proliferation, hepatocyte ballooning and fibrosis. Inflammatory gene expression was increased. Microbiota changes included a 10-fold decrease in Clostridium and a two-fold decrease in Bacteroides in SBS-ALD piglets. BA composition was altered and reflected a primary BA dominant composition. Intestinal and hepatic regulation of BA synthesis was characterised by a blunted intestinal FXR activation response and a failure of SHP to repress key hepatic targets.We propose a pathological scenario in which microbial dysbiosis following SBR results in significant BA dysmetabolism and consequent outcomes including steatorrhoea, persistent diarrhoea and liver damage. Furthermore alterations in BA composition may have contributed to the observed disturbance in FXR-mediated signalling pathways. These findings provide an insight into the complex mechanisms mediating the development of liver disease in patients with SBS.


Ahmed N.,Royal Womens Hospital | Ahmed N.,University of Melbourne | Ahmed N.,Prince Henrys Institute for Medical Research | Stenvers K.L.,Prince Henrys Institute for Medical Research | Stenvers K.L.,Monash University
Frontiers in Oncology | Year: 2013

More than one third of ovarian cancer patients present with ascites at diagnosis, and almost all have ascites at recurrence. The presence of ascites correlates with the peritoneal spread of ovarian cancer and is associated with poor disease prognosis. Malignant ascites acts as a reservoir of a complex mixture of soluble factors and cellular components which provide a pro-inflammatory and tumor-promoting microenvironment for the tumor cells. Subpopulations of these tumor cells exhibit cancer stem-like phenotypes, possess enhanced resistance to therapies and the capacity for distal metastatic spread and recurrent disease. Thus, ascites-derived malignant cells and the ascites microenvironment represent a major source of morbidity and mortality for ovarian cancer patients. This review focuses on recent advances in our understanding of the molecular, cellular, and functional characteristics of the cellular populations within ascites and discusses their contributions to ovarian cancer metastasis, chemoresistance, and recurrence. We highlight in particular recent translational findings which have used primary ascites-derived tumor cells as a tool to understand the pathogenesis of the disease, yielding new insights and targets for therapeutic manipulation. © 2013 Ahmed and Stenvers.


Latifi A.,Royal Womens Hospital | Latifi A.,University of Melbourne | Luwor R.B.,Royal Melbourne Hospital | Bilandzic M.,Prince Henrys Institute for Medical Research | And 14 more authors.
PLoS ONE | Year: 2012

Tumor cells in ascites are a major source of disease recurrence in ovarian cancer patients. In an attempt to identify and profile the population of ascites cells obtained from ovarian cancer patients, a novel method was developed to separate adherent (AD) and non-adherent (NAD) cells in culture. Twenty-five patients were recruited to this study; 11 chemonaive (CN) and 14 chemoresistant (CR). AD cells from both CN and CR patients exhibited mesenchymal morphology with an antigen profile of mesenchymal stem cells and fibroblasts. Conversely, NAD cells had an epithelial morphology with enhanced expression of cancer antigen 125 (CA125), epithelial cell adhesion molecule (EpCAM) and cytokeratin 7. NAD cells developed infiltrating tumors and ascites within 12-14 weeks after intraperitoneal (i.p.) injections into nude mice, whereas AD cells remained non-tumorigenic for up to 20 weeks. Subsequent comparison of selective epithelial, mesenchymal and cancer stem cell (CSC) markers between AD and NAD populations of CN and CR patients demonstrated an enhanced trend in mRNA expression of E-cadherin, EpCAM, STAT3 and Oct4 in the NAD population of CR patients. A similar trend of enhanced mRNA expression of CD44, MMP9 and Oct4 was observed in the AD population of CR patients. Hence, using a novel purification method we demonstrate for the first time a distinct separation of ascites cells into epithelial tumorigenic and mesenchymal non-tumorigenic populations. We also demonstrate that cells from the ascites of CR patients are predominantly epithelial and show a trend towards increased mRNA expression of genes associated with CSCs, compared to cells isolated from the ascites of CN patients. As the tumor cells in the ascites of ovarian cancer patients play a dominant role in disease recurrence, a thorough understanding of the biology of the ascites microenvironment from CR and CN patients is essential for effective therapeutic interventions. © 2012 Latifi et al.


Njamen D.,University of Yaounde I | Mvondo M.A.,University of Yaounde I | Mvondo M.A.,University of Dschang | Djiogue S.,University of Yaounde I | And 3 more authors.
Planta Medica | Year: 2013

Approximately 80 % of the population in Africa use traditional medicinal plants to improve their state of health. The reason of such a wide use of medicinal plants has been mainly attributed to their accessibility and affordability. Expectation of little if any side effects, of a "naturalo" and therefore safe treatment regimen, as well as traditional beliefs additionally contribute to their popularity. Several of these plants are used by women to relieve problems related to their reproductive health, during or after their reproductive life, during pregnancy, or following parturition. The African pharmacopoeia thus provides plants used for preventing and/or treating gynecological infections, dysmenorrhea, irregular menstruations, oligomenorrhea or protracted menstruation, and infertility. Such plants may then be used as antimicrobians, emmenagogues, or as suppressors of uterine flow. African medicinal plants are also used during pregnancy for prenatal care, against fetal malposition or malpresentation, retained dead fetus, and against threatened abortion. Some others are used as anti-fertilizing drugs for birth control. Such plants may exert various activities, namely, anti-implantation or early abortifacient, anti-zygotic, blastocytotoxic, and anti-ovulatory effects. Some herbs could also act as sexual drive suppressors or as a post-coital contraceptive by reducing the fertility index. A number of these plants have already been subject to scientific investigations and many of their properties have been assessed as estrogenic, oxytocic, or anti-implantation. Taking into account the diversity of the African pharmacopoeia, we are still at an early stage in the phytochemical and pharmacological characterization of these medicinal plants that affect the female reproductive system, in order to determine, through in vitro and in vivo studies, their pharmacological properties and their active principles. © Georg Thieme Verlag KG Stuttgart New York.


Weisberg E.,Sydney Center for Reproductive Health Research | Weisberg E.,University of Sydney | Croxatto H.B.,University of Santiago de Chile | Findlay J.K.,Prince Henrys Institute for Medical Research | And 3 more authors.
Contraception | Year: 2011

Background: Mifepristone alone or in combination with ethinyl estradiol (EE) can effectively stop an episode of uterine bleeding in women using the etonogestrel-releasing contraceptive implant, Implanon® but could impair contraceptive efficacy. Aim: To examine the effects of administration of mifepristone alone or with EE on ovarian function and cervical mucus consistency in women using Implanon. Study Design: Women using Implanon were randomized to mifepristone 25 mg twice daily on day 1 plus placebo 1 daily for 4 days or plus EE 20 mcg daily for days 2-5. Measurements of serum estradiol (E 2), progesterone (P 4), luteinizing hormone (LH), follicle-stimulating hormone (FSH), cervical mucus examination and maximal follicle size (by vaginal ultrasound) were carried out at various times. Results: Following mifepristone intake, there was a dramatic increase in E 2 levels ranging from 543 to 1183 pmol/L (p=.000), which was not correlated with maximal follicle size or preceded by LH or FSH increase. The increase in E 2 triggered an LH increase resulting in development of a luteinized follicle in four women with no evidence of ovulation. One of these women had estradiol and progesterone levels suggestive of ovulation, but no corpus luteum was seen. Almost all women had very low mucus scores, which did not correlate with E 2 levels. Discussion: Despite a transient increase in E 2 levels after mifepristone, there was no evidence of subsequent ovulation irrespective of whether they also received EE. The mechanism by which mifepristone in the presence of etonogestrel results in a rapid increase in E 2 levels remains unclear and could not be related to any significant changes in FSH, LH, ovarian follicle dynamics or subsequent possible ovulation. Conclusion: Pregnancy is very unlikely to occur if mifepristone and EE are given during use of Implanon to stop an episode of bleeding. © 2011 Elsevier Inc. All rights reserved.


Kassahn K.S.,University of Queensland | Ragan M.A.,University of Queensland | Funder J.W.,Prince Henrys Institute for Medical Research
Endocrinology | Year: 2011

Mineralocorticoid receptors (MR), glucocorticoid receptors (GR), progesterone receptors (PR), and androgen receptors (AR) comprise a closely related subfamily within the human 49-mem-ber nuclear receptor family. These receptors and their cognate ligands play major roles in homeostasis, reproduction, growth, and development, despite which their evolution and diversification remains incompletely understood. Several conflicting models have been advanced for the evolution of this subfamily. We have thus undertaken Bayesian and maximum likelihood phylogeneticanalyses of thissubfamily. The Bayesian consensus and maximum likelihood trees support a basal position for MR, with the PR and AR forming a sister clade. We next performed analyses using topological constraints to directly contrast the likelihood of seven phylogenetic models. In these analyses, three models have similar support: one proposes two sister clades (MR and GR, PR and AR); the other two propose a different subfamily member (MR or GR) to be the first to have diverged. Ancestral state reconstructions at sites critical for physiological function show that the S810L mutation in the MR, which results in the MR being similar to estrogen receptors and the more distantly related retinoic acid receptor-α is likely to reflect the ancestral receptor sequence before the divergence of this subfamily and provides further support for MR having been the first of the subfamily to diverge. Finally, we drew on pathophysiological comparisons to help to distinguish the different models. On the basis of our phylogeneticanalyses and pathophysiological considerations, we propose that the MR was the first to diverge from the ancestral gene lineage from which this subfamily derived. Copyright © 2011 by The Endocrine Society.


Bagheri-Fam S.,Prince Henrys Institute for Medical Research | Sinclair A.H.,Murdoch Childrens Research Institute | Koopman P.,University of Queensland | Harley V.R.,Prince Henrys Institute for Medical Research
International Journal of Biochemistry and Cell Biology | Year: 2010

While the primary sex determining switch varies between vertebrate species, a key downstream event in testicular development, namely the male-specific up-regulation of Sox9, is conserved. To date, only two sex determining switch genes have been identified, Sry in mammals and the Dmrt1-related gene Dmy (Dmrt1bY) in the medaka fish Oryzias latipes. In mice, Sox9 expression is evidently up-regulated by SRY and maintained by SOX9 both of which directly activate the core 1.3 kb testis-specific enhancer of Sox9 (TESCO). How Sox9 expression is up-regulated and maintained in species without Sry (i.e. non-mammalian species) is not understood. In this study, we have undertaken an in-depth comparative genomics approach and show that TESCO contains an evolutionarily conserved region (ECR) of 180 bp which is present in marsupials, monotremes, birds, reptiles and amphibians. The ECR contains highly conserved modules that predict regulatory roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination/differentiation. Our data suggest that tetrapods share common aspects of Sox9 regulation in the testis, despite having different sex determining switch mechanisms. They also suggest that Sox9 autoregulation is an ancient mechanism shared by all tetrapods, raising the possibility that in mammals, SRY evolved by mimicking this regulation. The validation of ECR regulatory sequences conserved from human to frogs will provide new insights into vertebrate sex determination. © 2009 Elsevier Ltd. All rights reserved.


PubMed | Prince Henrys Institute for Medical Research
Type: Journal Article | Journal: The international journal of biochemistry & cell biology | Year: 2010

While the primary sex determining switch varies between vertebrate species, a key downstream event in testicular development, namely the male-specific up-regulation of Sox9, is conserved. To date, only two sex determining switch genes have been identified, Sry in mammals and the Dmrt1-related gene Dmy (Dmrt1bY) in the medaka fish Oryzias latipes. In mice, Sox9 expression is evidently up-regulated by SRY and maintained by SOX9 both of which directly activate the core 1.3 kb testis-specific enhancer of Sox9 (TESCO). How Sox9 expression is up-regulated and maintained in species without Sry (i.e. non-mammalian species) is not understood. In this study, we have undertaken an in-depth comparative genomics approach and show that TESCO contains an evolutionarily conserved region (ECR) of 180 bp which is present in marsupials, monotremes, birds, reptiles and amphibians. The ECR contains highly conserved modules that predict regulatory roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination/differentiation. Our data suggest that tetrapods share common aspects of Sox9 regulation in the testis, despite having different sex determining switch mechanisms. They also suggest that Sox9 autoregulation is an ancient mechanism shared by all tetrapods, raising the possibility that in mammals, SRY evolved by mimicking this regulation. The validation of ECR regulatory sequences conserved from human to frogs will provide new insights into vertebrate sex determination.

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