Using State Space Exploration to Determine How Gene Regulatory Networks Constrain Mutation Order in Cancer Evolution

Cancer develops via the progressive accumulation of somatic mutations, which subvert the normal operation of the gene regulatory network of the cell. However, little is known about the order in which mutations are acquired in successful clones. A particular sequence of mutations may confer an early selective advantage to a clone by increasing survival or proliferation, or lead to negative selection by triggering cell death. The space of allowed sequences of mutations is therefore constrained by the gene regulatory network. Here, we introduce a methodology for the systematic exploration of the effect of every possible sequence of oncogenic mutations in a cancer cell modelled as a qualitative network. Our method uses attractor identification using binary decision diagrams and can be applied to both synchronous and asynchronous systems. We demonstrate our method using a recently developed model of ER-negative breast cancer. We show that there are differing levels of constraint in the order of mutations for different combinations of oncogenes, and that the effects of ErbB2/HER2 over-expression depend on the preceding mutations

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Framework development of hydrometeorological observational network and hazard mitigation modelling systems in respect of floods and cyclones

An appropriate real-time hydrometeorological observational network is designed and established for developing a full-scale hazard mitigation modelling system in respect of floods covering 24 river systems and cyclones covering nine coastal districts of Andhra Pradesh, east coast of India with an objective to develop an enhanced technical capacity to deal with the floods and cyclones in future using all available technologies and modelling tools. The framework includes set of hydrological and hydrodynamic models, set of regional specific models of cyclone prediction, wind hazard assessment, storm surge inundation assessment along with suitable Geographical Information System (GIS) interfacing for facilitating the quantification and spatial description of the impact of flooding and cyclone damage (in terms of storm surge inundation and wind damage on structures/infrastructure) with a sufficient lead-time so as to plan for effective relief routing plans/ rehabilitation strategies. Performance evaluation of the hazard mitigation modelling systems for the past flood and cyclone events is presented in this study

Wound healing: a new perspective on glucosylated tetrahydrocurcumin

Adari Bhaskar Rao,1 Ernala Prasad,1 Seelam Siva Deepthi,1 Vennapusa Haritha,1 Sistla Ramakrishna,1 Kuncha Madhusudan,1 Mullapudi Venkata Surekha,2 Yerramilli Sri Rama Venkata Rao3 1Medicinal Chemistry and Pharmacology Division, Council of Scientific and Industrial Research – Indian Institute of Chemical Technology, 2Pathology Division, National Institute of Nutrition, 3Ashian Herbex Ltd, Hyderabad, AP, India Abstract: Wound healing represents a dynamic set of coordinated physiological processes observed in response to tissue injury. Several natural products are known to accelerate the process of wound healing. Tetrahydrocurcumin (THC), an in vivo biotransformed product/metabolite of curcumin, is known to exhibit a wide spectrum of biological activities similar to those of native curcuminoids. The poor bioavailability of these curcuminoids limits their clinical applications. The present study highlights the percutaneous absorption and wound healing activity of glucosyl-conjugated THC (glucosyl-THC) in male Wistar rats. A high plasma concentration of glucosyl-THC (4.35 µg/mL) was found in rats 3 hours after application. A significant enhanced wound healing activity and reduced epithelialization time were observed in rats that received glucosyl-THC. This may have been due to the improved bioavailability of the glucosyl compound. The nonstaining and lack of skin-sensitive side effects render the bioconjugated glucosyl-THC a promising therapeutic compound in the management of excision wounds and in cosmetic applications, in the near future. Keywords: glucosylation, epithelialization, granulation tissue, cosmetic, therapeuti