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

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO-), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.published_or_final_versio

Ultra-small Nd3+-doped nanoparticles as near-infrared luminescent biolabels of hemin in bacteria

Near-infrared (NIR) luminescent Nd3+-doped nanoparticles (NPs) have attracted considerable attention in bioimaging and biodetection. Here, we demonstrate sub-6 nm NaGdF4:Nd3+, Fe3+ NPs as luminescent biolabels of hemin molecules that act as the exogenous electron carriers in microbial communities. Contrary to the severe quenching of the visible luminescence for either upconverting or downconverting NPs, the Nd3+-doped NPs show superior properties in avoiding the optical absorption of hemin within the UV and visible spectral regions. A detailed examination showed that the Nd3+-doped NPs exhibit no obvious toxic effects on the microbial communities and show scarce influence on the characteristics of labeled hemin molecules in enhancing the reducing power of the fermentation system. More importantly, by monitoring the NIR luminescence of Nd3+-doped NPs, the selective accumulation of exogenous electron carriers in bacteria that are lacking reducing power has been revealed for the first time. The application of Nd3+-doped NPs as biolabels in bacteria would provide new opportunities for further unravelling the role of exogenous electron carriers in anaerobic digestion

Redox-induced reversible luminescence switching of cerium-doped upconversion nanoparticles

Smart upconversion nanophosphors (UCNPs) that can be reversibly switched between two or more luminescent states by certain external stimuli have attracted considerable attention due to their great potential in biological applications. Here we report for the first time a type of redox-switchable UCNPs by codoping NaGdF4:Yb/Er nanorods with the redox-active Ce3+/Ce4+ ion pairs. A reversible switching of their UC luminescence intensity was observed upon the variation of the surrounding redox environments. We show solid proof that the luminescence switching is caused by the tailoring of the NaGdF4 host crystal structure in response to changing redox state of the codoped cerium ions. A proof-of-concept example is further demonstrated by using these UCNPs for probing the dynamical variation of redox environments in biological tissues. (C) 2016 Elsevier B.V. All rights reserved