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

Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms

Varicella zoster virus (VZV) causes chickenpox in humans and, subsequently, establishes latency in the sensory ganglia from where it reactivates to cause herpes zoster. Infection of rhesus macaques with simian varicella virus (SVV) recapitulates VZV pathogenesis in humans thus representing a suitable animal model for VZV infection. While the type I interferon (IFN) response has been shown to affect VZV replication, the virus employs counter mechanisms to prevent the induction of anti-viral IFN stimulated genes (ISG). Here, we demonstrate that SVV inhibits type I IFN-activated signal transduction via the JAK-STAT pathway. SVV-infected rhesus fibroblasts were refractory to IFN stimulation displaying reduced protein levels of IRF9 and lacking STAT2 phosphorylation. Since previous work implicated involvement of the VZV immediate early gene product ORF63 in preventing ISG-induction we studied the role of SVV ORF63 in generating resistance to IFN treatment. Interestingly, SVV ORF63 did not affect STAT2 phosphorylation but caused IRF9 degradation in a proteasome-dependent manner, suggesting that SVV employs multiple mechanisms to counteract the effect of IFN. Control of SVV ORF63 protein levels via fusion to a dihydrofolate reductase (DHFR)-degradation domain additionally confirmed its requirement for viral replication. Our results also show a prominent reduction of IRF9 and inhibition of STAT2 phosphorylation in VZV-infected cells. In addition, cells expressing VZV ORF63 blocked IFN-stimulation and displayed reduced levels of the IRF9 protein. Taken together, our data suggest that varicella ORF63 prevents ISG-induction both directly via IRF9 degradation and indirectly via transcriptional control of viral proteins that interfere with STAT2 phosphorylation. SVV and VZV thus encode multiple viral gene products that tightly control IFN-induced anti-viral responses

Characterization of the tautometric equilibrium of triazolium ylids by NMR spectroscopy

The monitoring by 1H NMR of the kinetics of the tautomeric equilibrium between the triazolium ylids lf-h and 2f-h confirms the existence of a dynamic equilibrium and corroborates the results obtained by the chemically induced perturbation of the equilibrimn

Preparation and characterization of flax, hemp and sisal fiber-derived mesoporous activated carbon adsorbents

The first aim of this study was to investigate mesoporous activated carbon adsorbents from sisal, hemp, and flax fibers by cost-effective methods. Fibers were impregnated with low concentration (20-‰wt.%) phosphoric acid. Carbonization temperatures were defined by thermal analysis. Bast fibers (hemp, flax) decompose at lower temperatures (419.36℃, 434.96℃) than leaf fibers (sisal, 512.92℃). The second aim was to compare bast and leaf fibers-derived activated carbon adsorbents by determining physical adsorption properties, chemical compositions, scanning electron microscope, and Fourier transform infrared spectroscopy. Results showed that natural fibers have good candidates to prepare mesoporous activated carbon adsorbents with high surface area (1186--1359-‰m2/g), high mesopore percentage (60--72%), and high C content (80--86%). Even though leaf-derived activated carbon developed more mesoporous structure (72%), bast-derived activated carbons provided higher surface areas (Shemp-‰=-‰1359-‰m2/g; Sflax-‰=-‰1257-‰m2/g) and C content. Fourier transform infrared spectra for bast fibers-derived activated carbon adsorbents were quite similar while leaf fiber-derived activated carbon adsorbent had a different spectrum