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Tebbutt N.,Ludwig Oncology Unit | Pedersen M.W.,Symphogen | Johns T.G.,Monash Institute of Medical Research
Nature Reviews Cancer | Year: 2013

The ERBB family of receptor tyrosine kinases has a central role in the tumorigenesis of many types of solid tumour. Various therapeutics targeting these receptors have been approved for the treatment of several cancers. Considerable preclinical data have shown that the administration of two inhibitors against an individual ERBB family member-particularly epidermal growth factor receptor (EGFR) or ERBB2-leads to markedly higher antitumour activity than the administration of single agents. This Opinion article describes the preclinical and clinical performance of these dual-targeting approaches, discusses the key mechanisms that mediate their increased efficacy and highlights areas for ongoing investigation. © 2013 Macmillan Publishers Limited. All rights reserved.


Schroder K.,University of Lausanne | Schroder K.,Monash Institute of Medical Research | Tschopp J.,University of Lausanne
Cell | Year: 2010

Inflammasomes are molecular platforms activated upon cellular infection or stress that trigger the maturation of proinflammatory cytokines such as interleukin-1β to engage innate immune defenses. Strong associations between dysregulated inflammasome activity and human heritable and acquired inflammatory diseases highlight the importance this pathway in tailoring immune responses. Here, we comprehensively review mechanisms directing normal inflammasome function and its dysregulation in disease. Agonists and activation mechanisms of the NLRP1, NLRP3, IPAF, and AIM2 inflammasomes are discussed. Regulatory mechanisms that potentiate or limit inflammasome activation are examined, as well as emerging links between the inflammasome and pyroptosis and autophagy. © 2010 Elsevier Inc.


St. John J.,Monash Institute of Medical Research
Biochimica et Biophysica Acta - General Subjects | Year: 2014

Background Mitochondrial DNA (mtDNA) is important for energy production as it encodes some of the key genes of electron transfer chain, where the majority of cellular energy is generated through oxidative phosphorylation (OXPHOS). MtDNA replication is mediated by nuclear DNA-encoded proteins or enzymes, which translocate to the mitochondria, and is strictly regulated throughout development. It starts with approximately 200 copies in each primordial germ cell and these copies undergo expansion and restriction events at various stages of development. Scope of review I describe the patterns of mtDNA replication at key stages of development. I explain that it is essential to regulate mtDNA copy number and to establish the mtDNA set point in order that the mature, specialised cell acquires the appropriate numbers of mtDNA copy to generate sufficient adenosine triphosphate (ATP) through OXPHOS to undertake its specialised function. I discuss how these processes are dependent on the controlled expression of the nuclear-encoded mtDNA-specific replication factors and that this can be modulated by mtDNA haplotypes. I discuss how these events are altered by certain assisted reproductive technologies, some of which have been proposed to prevent the transmission of mutant mtDNA and others to overcome infertility. Furthermore, some of these technologies are predisposed to transmitting two or more populations of mtDNA, which can be extremely harmful. Major conclusions The failure to regulate mtDNA replication and mtDNA transmission during development is disadvantageous. General significance Manipulation of oocytes and embryos can lead to significant implications for the maternal-only transmission of mtDNA. This article is part of a Special Issue entitled Frontiers of mitochondrial research. © 2013 Elsevier B.V.


St John J.C.,Monash Institute of Medical Research
Acta neuropathologica communications | Year: 2014

BACKGROUND: Mitochondrial DNA (mtDNA) encodes key proteins of the electron transfer chain (ETC), which produces ATP through oxidative phosphorylation (OXPHOS) and is essential for cells to perform specialised functions. Tumor-initiating cells use aerobic glycolysis, a combination of glycolysis and low levels of OXPHOS, to promote rapid cell proliferation and tumor growth. Glioblastoma multiforme (GBM) is an aggressively malignant brain tumor and mitochondria have been proposed to play a vital role in GBM tumorigenesis.RESULTS: Using next generation sequencing and high resolution melt analysis, we identified a large number of mtDNA variants within coding and non-coding regions of GBM cell lines and predicted their disease-causing potential through in silico modeling. The frequency of variants was greatest in the D-loop and origin of light strand replication in non-coding regions. ND6 was the most susceptible coding gene to mutation whilst ND4 had the highest frequency of mutation. Both genes encode subunits of complex I of the ETC. These variants were not detected in unaffected brain samples and many have not been previously reported. Depletion of HSR-GBM1 cells to varying degrees of their mtDNA followed by transplantation into immunedeficient mice resulted in the repopulation of the same variants during tumorigenesis. Likewise, de novo variants identified in other GBM cell lines were also incorporated. Nevertheless, ND4 and ND6 were still the most affected genes. We confirmed the presence of these variants in high grade gliomas.CONCLUSIONS: These novel variants contribute to GBM by rendering the ETC. partially dysfunctional. This restricts metabolism to anaerobic glycolysis and promotes cell proliferation.


Hertzog P.J.,Monash Institute of Medical Research | Williams B.R.G.,Monash Institute of Medical Research
Cytokine and Growth Factor Reviews | Year: 2013

Interferon responses are balanced between protection against pathogens and other disease agents versus toxicity and development of chronic diseases. Optimal outcomes are achieved by regulating the nature, strength and duration of Interferon (IFN) production, IFN-receptor interaction and signalling pathways modulated in a manner appropriate for particular target cells. Modification of cell behaviour is mediated by regulation of positive and negative signalling pathways and by proteins encoded by selected groups of IFN-regulated genes. Understanding how these pathways are regulated and how to measure them by biomarkers or gene signatures will enable us to better understand the role of IFN pathways in the pathogenesis of infectious and inflammatory diseases and cancer. This will lead to improved patient stratification and disease treatment. © 2013 Elsevier Ltd.


Funder J.W.,Monash Institute of Medical Research
Progress in Cardiovascular Diseases | Year: 2010

Aldosterone is currently thought to exert its physiologic effects by activating epithelial mineralocorticoid receptors, and its pathologic effects on the cardiovascular system via mineralocorticoid receptors in the heart and blood vessels. Recent studies have extended this understanding to include a reevaluation of the roles of aldosterone and mineralocorticoid receptor activation in blood pressure control; the rapid, nongenomic effects of aldosterone; the role of cortisol as a mineralocorticoid receptor agonist under conditions of redox change/tissue damage/reactive oxygen species generation; the growing consensus that primary aldosteronism accounts for approximately 10% of all essential hypertension; recent new insights into the cardioprotective role of spironolactone; and the development of third- and fourth-generation mineralocorticoid receptor antagonists for use in cardiovascular and other inflammatory disease. These findings on aldosterone action and mineralocorticoid receptor blockade are analyzed in the context of the prevention and treatment of cardiovascular disease. © 2010.


Kaitu'u-Lino T.J.,Monash Institute of Medical Research
Biology of reproduction | Year: 2012

The human endometrium is incredibly dynamic, undergoing monthly cycles of growth and regression during a woman's reproductive life. Endometrial repair at the cessation of menstruation is critical for reestablishment of a functional endometrium receptive for embryo implantation; however, little is understood about the mechanisms behind this rapid and highly efficient process. This study utilized a functional mouse model of endometrial breakdown and repair to assess changes in endometrial vasculature that accompany these dynamic processes. Given that adult endometrial stem/progenitor cells identified in human and mouse endometrium are likely contributors to the remarkable regenerative capacity of endometrium, we also assessed label-retaining cells (LRC) as candidate stromal stem/progenitor cells and examined their relationship with endometrial vasculature. Newborn mouse pups were pulse-labeled with bromodeoxyuridine (BrdU) and chased for 5 wk before decidualization, endometrial breakdown, and repair were induced by hormonal manipulation. Mean vessel density did not change significantly throughout breakdown and repair; however, significantly elevated endothelial cell proliferation was observed in decidual tissue. Stromal LRC were identified throughout breakdown and repair, with significantly fewer observed during endometrial repair than before decidualization. A significantly higher percentage of LRC were associated with vasculature during repair than before decidualization, and a proportion were undergoing proliferation, indicative of their functional capacity. This study is the first to examine the endometrial vasculature and candidate stromal stem/progenitor cells in a functional mouse model of endometrial breakdown and repair and provides functional evidence suggesting that perivascular LRC may contribute to endometrial stromal expansion during the extensive remodeling associated with this process.


Forster S.,Monash Institute of Medical Research
Immunology and Cell Biology | Year: 2012

The interferon (IFN) family and the type-I IFNs specifically have an important and well-characterized role in antiviral defence, immune modulation and cell-cycle control and are regularly applied in the clinical context. Advances in high-content technologies have facilitated an enhanced understanding of the global IFN response capable of being induced. Recent application of these technologies is improving our understanding of the specificity and subtleties associated with this response. This review considers our current understanding of the temporal gene profile induced through IFN stimulation across a diversity of disease conditions including autoimmune diseases, bacterial and viral infections. Understanding these signatures, the disease-specific differences and the biological effects induced has the potential to facilitate IFN-driven therapeutic development. © 2012 Australasian Society for Immunology Inc. All rights reserved.


Funder J.W.,Monash Institute of Medical Research
Science | Year: 2011

Adrenal gland tumor growth and increased aldosterone production are linked to mutations in a potassium channel.


Quinn T.A.,Monash Institute of Medical Research
The Journal of endocrinology | Year: 2014

Antenatal stress disturbs the development of the fetal hypothalamic-pituitary-adrenal axis and adrenal steroidogenesis. We investigated the effect of brief maternal exposure to high glucocorticoids (dexamethasone (DEX)) at mid- and late-pregnancy on adrenal structure and production of steroids in spiny mouse. Pregnant spiny mice were treated for 60 h with 125 μg/kg DEX or saline s.c. by osmotic minipump at day 20 (0.5) or 30 (0.75) of gestation. Immunohistochemical expression of steroidogenic acute regulatory-protein (StAR), 3β-hydroxysteroid dehydrogenase (3βHSD), 17-hydroxylase,17-20lyase (P450C17), and cytochromeb5 (CYTB5) was determined in adrenals on postnatal (P) day 170±20. DHEA, testosterone, and cortisol were measured by RIA. Maternal DEX at 20 days significantly reduced the expression of STAR, P450C17 (CYP17A1), and CYTB5 in the adrenal zona reticularis (ZR) of adult offspring, with greater change in male vs female offspring (P<0.05). Plasma DHEA was decreased in male offspring from DEX-treated (6.84±1.24 ng/ml) vs saline-treated (13±0.06 ng/ml; P=0.01) dams, and the DHEA:cortisol ratio was lower in males (P<0.05). Testosterone levels increased in male offspring from DEX (266.03±50.75 pg/ml) vs saline (83.47±32.3 pg/ml, P<0.05)-treated dams. DEX treatment at 0.75 gestation had no significant effect on any parameters measured. This study shows that brief exposure to excess glucocorticoid has long-term impacts on the ZR and adrenal steroidogenesis, affecting the secretion of DHEA and testosterone in male offspring, an effect produced at 0.5 but not at 0.75 gestation. DHEA is important for brain development, and its suppression in adult life might contribute to the neurobehavioral pathologies that can arise after illness and stress during pregnancy.

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