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Forrester H.B.,Monash Institute of Medical Research | Forrester H.B.,MIMR PHI Institute of Medical Research | Leong T.,Peter MacCallum Cancer Center | McKay M.J.,University of Sydney | And 2 more authors.
Radiotherapy and Oncology | Year: 2014

Background and purpose During radiotherapy, normal tissue is unavoidably exposed to radiation which results in severe normal tissue reactions in a small fraction of patients. Because those who are sensitive cannot be determined prior to radiotherapy, the doses are limited to all patients to avoid an unacceptable number of severe adverse normal tissue responses. This limitation restricts the optimal treatment for individuals who are more tolerant to radiation. Genetic variation is a likely source for the normal tissue radiosensitivity variation observed between individuals. Therefore, understanding the radiation response at the genomic level may provide knowledge to develop individualized treatment and improve radiotherapy outcomes. Material and methods Exon arrays were utilized to compare the basal expression profile between cell lines derived from six cancer patients with and without severe fibrosis. These data were supported by qRT-PCR and RNA-Seq techniques. Results A set of genes (FBN2, FST, GPRC5B, NOTCH3, PLCB1, DPT, DDIT4L and SGCG) were identified as potential predictors for radiation-induced fibrosis. Many of these genes are associated with TGFβ or retinoic acid both having known links to fibrosis. Conclusion A combinatorial gene expression approach provides a promising strategy to predict fibrosis in cancer patients prior to radiotherapy. © 2014 Elsevier Ireland Ltd. All rights reserved.


Gargett C.E.,Monash University | Schwab K.E.,MIMR PHI Institute of Medical Research | Brosens J.J.,University of Warwick | Puttemans P.,Leuven Institute for Fertility and Embryology | And 2 more authors.
Molecular Human Reproduction | Year: 2014

The pathogenesis of early-onset endometriosis has recently been revisited, sparked by the discovery of endometrial stem/progenitor cells and their possible role in endometriosis, and because maternal pregnancy hormone withdrawal following delivery induces uterine bleeding in the neonate. The neonatal uterus has a large cervix to corpus ratio which is functionally blocked with mucous, supporting the concept of retrograde shedding of neonatal endometrium. Only 5% show overt bleeding. Furthermore, the presence of endometriosis in premenarcheal girls and even in severe stage in adolescents supports the theory that earlyonset endometriosis may originate from retrograde uterine bleeding soon after birth. Endometrial stem/progenitor cells have been identified in menstrual blood suggesting they may also be shed during neonatal uterine bleeding. Thus, we hypothesised that stem/progenitor cells present in shedding endometrium may have a role in the pathogenesis of early-onset endometriosis through retrograde neonatal uterine bleeding. During the neonatal and pre-pubertal period, shed endometrial stem/progenitor cells are postulated to survive in the pelvic cavity in the absence of circulating oestrogens supported by niche cells also shed during neonatal uterine bleeding. According to this hypothesis, during thelarche, under the influence of rising oestrogen levels, endometrial stem/progenitor cells proliferate and establish ectopic endometrial lesions characteristic of endometriosis. This New Research Horizon review builds on recent discussions on the pathogenesis of early-onset endometriosis and raises new avenues for research into this costly condition. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.


O'Donnell L.,MIMR PHI Institute of Medical Research | O'Donnell L.,Monash University | O'Bryan M.K.,Monash University
Seminars in Cell and Developmental Biology | Year: 2014

Microtubules are dynamic polymers of tubulin subunits that underpin many essential cellular processes, such as cell division and migration. Spermatogenesis is the process by which spermatogenic stem cells undergo mitotic and meiotic division and differentiation to produce streamlined spermatozoa capable of motility and fertilization. This review summarizes the current knowledge of microtubule-based processes in spermatogenesis. We describe the involvement of microtubule dynamics in Sertoli cell shape and function, as well as in the mitotic and meiotic division of germ cells. The roles of microtubules in sperm head shaping, via the development and function of the manchette, and in sperm flagella development are also discussed. The review brings together data from microscopy studies and genetically modified mouse models, and reveals that the regulation of microtubule dynamics is essential for male fertility. © 2014 Elsevier Ltd.


Knower K.C.,MIMR PHI Institute of Medical Research | To S.Q.,MIMR PHI Institute of Medical Research | To S.Q.,Monash University | Leung Y.-K.,University of Cincinnati | And 3 more authors.
Endocrine-Related Cancer | Year: 2014

The heritable component of breast cancer accounts for only a small proportion of total incidences. Environmental and lifestyle factors are therefore considered to among the major influencing components increasing breast cancer risk. Endocrine-disrupting chemicals (EDCs) are ubiquitous in the environment. The estrogenic property of EDCs has thus shown many associations between ongoing exposures and the development of endocrine-related diseases, including breast cancer. The environment consists of a heterogenous population of EDCs and despite many identified modes of action, including that of altering the epigenome, drawing definitive correlations regarding breast cancer has been a point of much discussion. In this review, we describe in detail well-characterized EDCs and their actions in the environment, their ability to disrupt mammary gland formation in animal and human experimental models and their associations with exposure and breast cancer risk.We also highlight the susceptibility of early-life exposure to each EDC to mediate epigenetic alterations, and where possible describe how these epigenome changes influence breast cancer risk. © 2014 Society for Endocrinology.


Hooper S.B.,MIMR PHI Institute of Medical Research | Hooper S.B.,Monash University | Polglase G.R.,MIMR PHI Institute of Medical Research | Polglase G.R.,Monash University | And 3 more authors.
Paediatric Respiratory Reviews | Year: 2015

The newborn's transition from fetal to neonatal life includes aeration of the lungs, establishment of pulmonary gas exchange and changing the fetal circulation into the adult phenotype. This review summarizes the latest research findings, which show that lung aeration, airway liquid clearance and cardiovascular changes are directly interconnected at birth. The mechanisms of airway liquid clearance at birth are reviewed and the particular importance of the transpulmonary pressure gradient during lung aeration is discussed. Further, we summarize research findings which prove that lung aeration triggers the increase in pulmonary blood flow (PBF) at birth, and how the increase in PBF secures the preload for left ventricular output. Consequently, we review animal experiments which suggest that delaying umbilical cord clamping until breathing commences facilitates hemodynamic stability during transition. These data are reviewed with respect to the clinical applicability: As lung aeration is the key to successful transition to newborn life, providing adequate respiratory support at birth must be the primary objective of neonatal staff attending to the newborn infant. Clinical studies are needed to demonstrate whether the obvious benefits of delaying cord clamping until breathing commences hold true in human babies. © 2015 Elsevier Ltd.


Krishnan S.M.,Monash University | Sobey C.G.,Monash University | Latz E.,University of Bonn | Latz E.,University of Massachusetts Medical School | And 3 more authors.
British Journal of Pharmacology | Year: 2014

Chronic inflammation in the kidneys and vascular wall is a major contributor to hypertension. However, the stimuli and cellular mechanisms responsible for such inflammatory responses remain poorly defined. Inflammasomes are crucial initiators of sterile inflammation in other diseases such as rheumatoid arthritis and gout. These pattern recognition receptors detect host-derived danger-associated molecular patterns (DAMPs), such as microcrystals and reactive oxygen species, and respond by inducing activation of caspase-1. Caspase-1 then processes the cytokines pro-IL-1β and pro-IL-18 into their active forms thus triggering inflammation. While IL-1β and IL-18 are known to be elevated in hypertensive patients, no studies have examined whether this occurs downstream of inflammasome activation or whether inhibition of inflammasome and/or IL-1β/IL-18 signalling prevents hypertension. In this review, we will discuss some known actions of IL-1β and IL-18 on leukocyte and vessel wall function that could potentially underlie a prohypertensive role for these cytokines. We will describe the major classes of inflammasome-activating DAMPs and present evidence that at least some of these are elevated in the setting of hypertension. Finally, we will provide information on drugs that are currently used to inhibit inflammasome/IL-1β/IL-18 signalling and how these might ultimately be used as therapeutic agents for the clinical management of hypertension. © 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.


Rastetter R.H.,Monash University | Bernard P.,Monash University | Palmer J.S.,University of Queensland | Chassot A.-A.,University of Nice Sophia Antipolis | And 7 more authors.
Developmental Biology | Year: 2014

The two main functions of the ovary are the production of oocytes, which allows the continuation of the species, and secretion of female sex hormones, which control many aspects of female development and physiology. Normal development of the ovaries during embryogenesis is critical for their function and the health of the individual in later life. Although the adult ovary has been investigated in great detail, we are only starting to understand the cellular and molecular biology of early ovarian development. Here we show that the adult stem cell marker Lgr5 is expressed in the cortical region of the fetal ovary and this expression is mutually exclusive to FOXL2. Strikingly, a third somatic cell population can be identified, marked by the expression of NR2F2, which is expressed in LGR5- and FOXL2 double-negative ovarian somatic cells. Together, these three marker genes label distinct ovarian somatic cell types. Using lineage tracing in mice, we show that Lgr5-positive cells give rise to adult cortical granulosa cells, which form the follicles of the definitive reserve. Moreover, LGR5 is required for correct timing of germ cell differentiation as evidenced by a delay of entry into meiosis in Lgr5 loss-of-function mutants, demonstrating a key role for LGR5 in the differentiation of pre-granulosa cells, which ensure the differentiation of oogonia, the formation of the definitive follicle reserve, and long-term female fertility. © 2014 Elsevier Inc.


Kaparakis-Liaskos M.,MIMR PHI Institute of Medical Research
Cytokine | Year: 2015

The host has developed an array of systems that enables protection against infection and response to injury, ultimately resulting in the generation of a pro-inflammatory response. The most rapid immune response is mediated via the innate immune system, which is comprised of germ line encoded pathogen recognition receptors (PRRs). This PRR mediated system functions by specifically recognizing conserved structures of microbial molecules or products, known as microbial-associated molecular patterns (MAMPs), ultimately enabling transduction of signaling cascades, gene transcription and the development of a pro-inflammatory innate immune response. The intracellular PRRs nucleotide-binding oligomerization domain protein 1 (NOD1) and NOD2 will be the focus of this review. A brief overview of NOD1 and NOD2 and recent advances in the field regarding the intracellular location and mechanisms of NOD1 signaling will be discussed. These new findings have broadened our understanding of the mechanisms whereby NOD1 signaling results in the induction of the cellular degradation pathway of autophagy and the development of pro-inflammatory responses that activate the adaptive immune system. © 2015 Elsevier Ltd.


Lin S.C.,MIMR PHI Institute of Medical Research | Davey M.J.,Monash Childrens Hospital | Horne R.S.C.,MIMR PHI Institute of Medical Research | Nixon G.M.,MIMR PHI Institute of Medical Research | Nixon G.M.,Monash Childrens Hospital
Journal of Pediatrics | Year: 2014

Objective To compare symptoms of obstructive sleep apnea (OSA) and polysomnography (PSG) results in children with Down syndrome and typically developing children. Study design A total of 49 children with Down syndrome referred for PSG between 2008 and 2012 were matched with typically developing children of the same sex, age, and OSA severity who had undergone PSG in the same year. A parent completed a sleep symptom questionnaire for each child. Sleep quality and measures of gas exchange were compared between the matched groups. Results The 98 children (46 females, 52 males) had mean age of 6.2 years (range, 0.3-16.9 years). Fourteen children had primary snoring, and 34 had OSA (9 mild, 7 moderate, and 19 severe). Children with Down syndrome had more severe OSA compared with 278 typically developing children referred in 2012. Symptom scores were not different between the matched groups. Those with Down syndrome had a higher average pCO2 during sleep (P =.03) and worse McGill oximetry scores. Conclusion Compared with closely matched typically developing children with OSA of comparable severity, children with Down syndrome had a similar symptom profile and slightly worse gas exchange. Referred children with Down syndrome had more severe OSA than referred typically developing children, suggesting a relative reluctance by parents or doctors to investigate symptoms of OSA in children with Down syndrome. These findings highlight the need for formal screening tools for OSA in children with Down syndrome to improve detection of the condition in this high-risk group. © 2014 Elsevier Inc. All rights reserved.


West A.C.,MIMR PHI Institute of Medical Research | Jenkins B.J.,MIMR PHI Institute of Medical Research
Current Pharmaceutical Design | Year: 2015

Collectively, cancers of the gastrointestinal (GI) tract (including the esophagus, stomach, duodenum, colon, rectum, liver, gall bladder and bile ducts) are the most prevalent and deadly worldwide. A common denominator in the pathogenesis of these GI tract cancers is chronic inflammation, as evidenced by the fact that sufferers of inflammatory bowel disease (IBD) are significantly more susceptible to colon cancer than healthy individuals. However, since only a relatively small proportion of individuals with chronic inflammatory conditions such as IBD go on to develop cancer, research has focused on identifying discrepancies in the host immune system that may be responsible for promoting carcinogenesis in inflamed tissue. To this end, molecular pathways linking inflammation and cancer are emerging, with one series of candidates being members of the Toll-like receptor family. © 2015 Bentham Science Publishers.

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