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

Exercise at different ages and appendicular lean mass and strength in later life: results from the Berlin Aging Study II

Excessive loss of muscle mass in advanced age is a major risk factor for decreased physical ability and falls. Physical activity and exercise training are typically recommended to maintain muscle mass and prevent weakness. How exercise in different stages of life relates to muscle mass, grip strength, and risk for weakness in later life is not well understood.Baseline data on 891 participants at least 60 years old from the Berlin Aging Study II (BASE-II) were analyzed. Linear and logistic regressions of self-reported exercise in early adulthood, old age, or both on appendicular lean mass (ALM), grip strength, and a risk indicator for weakness (ALM/ body mass index cutoff) were calculated. In addition, treatment bounds are analyzed to address potential confounding using a method proposed by Oster.Analyses indicate that for men only, continuous exercise is significantly associated with higher muscle mass (SD = 0.24, p < .001), grip strength (SD = 0.18, p < .05), and lower risk for clinically relevant low muscle mass (odds ratio = 0.36, p < .01). Exercise in early adulthood alone is not significantly associated with muscle mass or strength. No significant associations were observed for women.The results of the current study underscore the importance of health programs to promote physical activity with a focus on young adults, a group known to be affected from environmentally associated decline of physical activity, and to promote the continuation of physical exercise from early adulthood into later life in general

Impact of Aspirin Dosing on the Effects of P2Y12 Inhibition in Patients with Acute Coronary Syndromes

The discovery of the antiplatelet effect of low-dose aspirin led to the hugely successful strategy of dual antiplatelet therapy in patients with acute coronary syndromes (ACS). Increasing the dose of aspirin beyond 75-100 mg has never been shown to offer additional efficacy in ACS patients but could possibly increase the risk of bleeding. In the Platelet Inhibition and Patients Outcome (PLATO) study, higher doses of aspirin appeared to neutralise the additional benefit of the potent P2Y12 inhibitor ticagrelor compared to clopidogrel (Circulation 124: 544-554, 2011). However, higher doses of aspirin have not been shown to have an adverse interaction with the potent P2Y12 inhibition provided by prasugrel and double-dose clopidogrel (Journal of the American College of Cardiology, 2013, in press; N Engl J Med 363: 930-942, 2010). This potentially suggests that the mechanism for this interaction is not related to the inhibition of platelet P2Y12 receptors or could simply be a chance finding.</p

Nano metal fluorides: small particles with great properties

The recently developed fluorolytic sol–gel route to metal fluorides opens a very broad range of both scientific and technical applications of the accessible high surface area metal fluorides, many of which have already been applied or tested. Specific chemical properties such as high Lewis acidity and physical properties such as high surface area, mesoporosity and nanosize as well as the possibility to apply metal fluorides on surfaces via a non-aqueous sol make the fluorolytic synthesis route a very versatile one. The scope of its scientific and technical use and the state of the art are presented.Peer Reviewe