Signalling pathway activation analysis is a powerful approach for extracting biologically relevant features from large-scale transcriptomic and proteomic data. However, modern pathway-based methods often fail to provide stable pathway signatures of a specific phenotype or reliable disease biomarkers. In the present study, we introduce the in silico Pathway Activation Network Decomposition Analysis (iPANDA) as a scalable robust method for biomarker identification using gene expression data. The iPANDA method combines precalculated gene coexpression data with gene importance factors based on the degree of differential gene expression and pathway topology decomposition for obtaining pathway activation scores. Using Microarray Analysis Quality Control (MAQC) data sets and pretreatment data on Taxol-based neoadjuvant breast cancer therapy from multiple sources, we demonstrate that iPANDA provides significant noise reduction in transcriptomic data and identifies highly robust sets of biologically relevant pathway signatures. We successfully apply iPANDA for stratifying breast cancer patients according to their sensitivity to neoadjuvant therapy.

Vive la radiorsistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization Vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Andreyan N. Osipov1, 2, 3, 4, Margarita Pustovalova1, 2, Anna Grekhova1, 5, Petr Eremin1, Natalia Vorobyova1, 3, Andrey Pulin1, Alex Zhavoronkov4, 6, 7, Sergey Roumiantsev3, 4, 8, Dmitry Y. Klokov9, Ilya Eremin1 1State Research Center - Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency (SRC-FMBC), Moscow, Russia 2Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow, Russia 3Dmitry Rogachev Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia 4Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, Russia 5Emanuel Institute for Biochemical Physics, Russian Academy of Sciences, Moscow, Russia 6Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, Maryland, USA 7The Biogerontology Research Foundation, BGRF, London, UK 8N.I. Pirogov Russian National Research Medical University, Moscow, Russia 9Canadian Nuclear Laboratories, Chalk River, Ontario, Canada Correspondence to: Andreyan N. Osipov, e-mail: andreyan.osipov@gmail.com Keywords: mesenchymal stem cells, DNA double-strand breaks, DNA repair, X-rays, low doses Received: April 08, 2015 Accepted: July 10, 2015 Published: July 23, 2015

DNA double-strand breaks (DSB) are among the most harmful DNA lesions induced by ionizing radiation (IR). Although the induction and repair of radiation-induced DSB is well studied for acute irradiation, responses to DSB produced by chronic IR exposures are poorly understood, especially in human stem cells. The aim of this study was to examine the formation of DSB markers (γH2AX and phosphorylated kinase ATM, pATM, foci) in human mesenchymal stem cells (MSCs) exposed to chronic gamma-radiation (0.1 mGy/min) in comparison with acute irradiation (30 mGy/min) at cumulative doses of 30, 100, 160, 240 and 300 mGy. A linear dose-dependent increase in the number of both γH2AX and pATM foci, as well as co-localized γH2AX/pATM foci (“true” DSB), were observed after an acute radiation exposure. In contrast, the response of MSCs to a chronic low dose-rate IR exposure deviated from linearity towards a threshold model, for γH2AX, pATM foci and γH2AX/pATM foci, with an indication of a “plateau”. The state of equilibrium between newly formed DSB at a low rate during the protracted exposure time and the elimination of a fraction of DSB is proposed as a mechanistic explanation of the non-linear DSB responses following a low dose-rate irradiation. This notion is supported by the observation of the elimination of a substantial fraction of DSB 6 h after the cessation of the exposures. Our results demonstrate non-linear dose responses for γH2AX and pATM foci in human MSCs exposed to low dose-rate IR and showed the existence of a threshold, which may have implications for radiation protection in humans.