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

External heating garments used post-warm-up improve upper body power and elite sprint swimming performance

This paper was accepted for publication in Proceedings of the Institution of Mechanical Engineers, Part P: Journal of Sports Engineering and Technology. The definitive version is available at: http://dx.doi.org/10.1177/1754337116650322The aim of this study was to determine the effects of using an electrical heating garment during a 30-minute recovery period after a standardized swimming warm-up on subsequent swimming performance and upper-body power output. On two occasions, eight male and four female elite competitive swimmers completed a standardized swimming warm-up, followed by a 30-minute passive recovery period before completing maximal plyometric press-ups and a 50m Freestyle swim. Plyometric press-ups determined starting strength (SS), peak force (PF) and peak concentric power (PCP). During the recovery period, participants wore tracksuit bottoms and (i) a standard tracksuit top (CON) or (ii) jacket with integrated electric heating elements (HEAT). The overall results demonstrated a trend of a relevant (>0.4%) improvement in the 50m Freestyle performance of 0.83% (P = 0.06) in HEAT vs. CON. In male participants, performance in the 50m Freestyle significantly improved by 1.01% (CON 25.18 ± 0.5s vs. HEAT 24.93 ± 0.4s; P < 0.05), whereas female participants only showed a trend for an improvement of 0.38% (29.18 ± 0.5s vs. 29.03 ± 1.0s; P = 0.09), in HEAT compared with CON, though statistical power for the latter test was low. Male participants’ starting strength, peak force and peak concentric power were 16.5 ± 13%, 18.1 ± 21% and 16.2 ± 21% greater, respectively, in HEAT compared with CON (all P<0.01). In conclusion, external heating of the upper body between completion of the warm-up and performance through the utilization of an electrically heated jacket improves plyometric press-up power output and force production, as well as sprint swimming performance in males. This provides justification for future enhancement opportunities in sporting performance through the utilization of external heating systems. Optimization of the heating system for specific sports is required

Human Neutrophil Elastase-Mediated Cleavage Sites of MMP-9 and TIMP-1: Implications to Cystic Fibrosis Proteolytic Dysfunction

Cystic fibrosis (CF) is a lethal genetic disorder characterized by airway remodeling and inflammation, leading to premature death. Recent evidence suggests the importance of protease activity in CF pathogenesis. One prominent protease, matrix metalloprotease (MMP)-9, demonstrates increased activity in CF individuals undergoing acute pulmonary exacerbation. This is thought to be mediated by both direct MMP-9 activation and the degradation of its natural inhibitor, tissue inhibitor of metalloprotease-1 (TIMP-1). To examine if this relationship exists in nonexacerbating CF individuals, we examined protease activity in sputum from these individuals compared with nondisease controls. We demonstrated increased gelatinolytic activity in CF sputum. These samples had elevated human neutrophil elastase (HNE) levels which correlated with an increased MMP-9/TIMP-1 ratio. To determine if HNE could discretely cleave and activate MMP-9, these enzymes were coincubated and two specific cleavage sites, between Valine38 and Alanine39, and between Alanine 39 and glutamic acid40 were observed. These sites corresponded with appropriate molecular weight for the activated MMP-9 isoform in CF sputum. Using N-terminal sequencing of cleavage fragments obtained with TIMP-1 incubation with HNE, we confirmed the TIMP-1 cleavage site for HNE is at Valine69-Cysteine70. We also show for the first time that human neutrophils were capable of degrading TIMP-1 ex vivo and that a 16 kDa TIMP-1 fragment was identified in CF sputum, consistent with the expected cleavage of TIMP-1 by HNE. These results demonstrate increased MMP-9 activity in stable CF lung disease, and the presence of specific protease products in CF sputum highlights that HNE-mediated activity plays a role in this dysregulation