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O'Brien K.,Trinity College Dublin | Lowry M.C.,Trinity College Dublin | Corcoran C.,Trinity College Dublin | Martinez V.G.,Trinity College Dublin | And 6 more authors.
Oncotarget | Year: 2015

Exosomes (EVs) have relevance in cell-to-cell communication carrying protumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer. Source

Stead D.A.,University of Aberdeen | Walker J.,University of Aberdeen | Holcombe L.,Imperial College London | Gibbs S.R.S.,Imperial College London | And 5 more authors.
Proteomics | Year: 2010

Candida glabrata is a major fungal pathogen of humans, and the virulence of C. glabrata is increased by inactivation of the transcription factor, Ace2. Our previous examination of the effects of Ace2 inactivation upon the intracellular proteome suggested that the hypervirulence of C. glabrata ace2 mutants might be caused by differences in the secretome. Therefore in this study we have characterised the C. glabrata secretome and examined the effects of Ace2 inactivation upon this extracellular proteome. We have identified 31 distinct proteins in the secretome of wild-type C. glabrata cells by MS/MS of proteins that were precipitated from the growth medium and enriched by affinity chromatography on concanavalin A. Most of these proteins are predicted to be cell wall proteins, cell wall modifying enzymes and aspartyl proteinases. The endochitinase Cts1 and the endoglucanase Egt2 were not detected in the C. glabrata secretome following Ace2 inactivation. This can account for the cell separation defect of C. glabrata ace2 cells. Ace2 inactivation also resulted in the detection of new proteins in the C. glabrata secretome. The release of such proteins might contribute to the hypervirulence of ace2 cells. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA. Source

Buhmann H.,University of Zurich | Le Roux C.W.,Conway Institute | Le Roux C.W.,Gothenburg University | Bueter M.,University of Zurich
Best Practice and Research: Clinical Gastroenterology | Year: 2014

Currently the only effective treatment for morbid obesity with a proven mortality benefit is surgical intervention. The underlying mechanisms of these surgical techniques are unclear, but alterations in circulating gut hormone levels have been demonstrated to be at least one contributing factor. Gut hormones seem to communicate information from the gastrointestinal tract to the regulatory appetite centres within the central nervous system (CNS) via the so-called 'Gut-Brain-Axis'. Such information may be transferred to the CNS either via vagal or non-vagal afferent nerve signalling or directly via blood circulation. Complex neural networks, distributed throughout the forebrain and brainstem, are in control of feeding and energy homoeostasis. This article aims to review how appetite is potentially regulated by these gastrointestinal hormones. Identification of the underlying mechanisms of appetite and weight control may pave the way to develop better surgical techniques and new therapies in the future. © 2014 Elsevier Ltd. All rights reserved. Source

Dakna M.,Mosaiques Diagnostics and Therapeutics | Harris K.,University of Glasgow | Kalousis A.,University of Geneva | Carpentier S.,Catholic University of Leuven | And 9 more authors.
BMC Bioinformatics | Year: 2010

Background: The purpose of this manuscript is to provide, based on an extensive analysis of a proteomic data set, suggestions for proper statistical analysis for the discovery of sets of clinically relevant biomarkers. As tractable example we define the measurable proteomic differences between apparently healthy adult males and females. We choose urine as body-fluid of interest and CE-MS, a thoroughly validated platform technology, allowing for routine analysis of a large number of samples. The second urine of the morning was collected from apparently healthy male and female volunteers (aged 21-40) in the course of the routine medical check-up before recruitment at the Hannover Medical School.Results: We found that the Wilcoxon-test is best suited for the definition of potential biomarkers. Adjustment for multiple testing is necessary. Sample size estimation can be performed based on a small number of observations via resampling from pilot data. Machine learning algorithms appear ideally suited to generate classifiers. Assessment of any results in an independent test-set is essential.Conclusions: Valid proteomic biomarkers for diagnosis and prognosis only can be defined by applying proper statistical data mining procedures. In particular, a justification of the sample size should be part of the study design. © 2010 Dakna et al; licensee BioMed Central Ltd. Source

Newsholme P.,Conway Institute
Advances in Experimental Medicine and Biology | Year: 2010

Pancreatic β-cells are often referred to as "fuel sensors" as they continually monitor and respond to dietary nutrients, under the modulation of additional neurohormonal signals, in order to secrete insulin to best meet the needs of the organism. β-cell nutrient sensing requires metabolic activation, resulting in production of stimulus-secretion coupling signals that promote insulin biosynthesis and release. The primary stimulus for insulin secretion is glucose, and islet β-cells are particularly responsive to this important nutrient secretagogue, It is important to consider individual effects of different classes of nutrient or other physiological or pharmacological agents on metabolism and insulin secretion. However, given that β-cells are continually exposed to a complex milieu of nutrients and other circulating factors, it is important to also acknowledge and examine the interplay between glucose metabolism and that of the two other primary nutrient classes, the amino acids and fatty acids. It is the mixed nutrient sensing and outputs of glucose, amino and fatty acid metabolism that generate the metabolic coupling factors (MCFs) involved in signaling for insulin exocytosis. Primary MCFs in the β-cell include ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol and are discussed in detail in this article. © Springer Science+Business Media B.V. 2010. Source

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