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

Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice

Corticotropin releasing factor (CRF) regulates physiological and behavioral responses to stress. Trauma in early life or adulthood is associated with increased CRF in the cerebrospinal fluid and heightened anxiety. Genetic variance in CRF receptors is linked to altered risk for stress disorders. Thus, both heritable differences and environmentally induced changes in CRF neurotransmission across the lifespan may modulate anxiety traits. To test the hypothesis that CRF hypersignaling is sufficient to modify anxiety-related phenotypes (avoidance, startle, and conditioned fear), we induced transient forebrain-specific overexpression of CRF (CRFOE) in mice (1) during development to model early-life stress, (2) in adulthood to model adult-onset stress, or (3) across the entire postnatal lifespan to model heritable increases in CRF signaling. The consequences of these manipulations on CRF peptide levels and behavioral responses were examined in adulthood. We found that transient CRFOE during development decreased startle habituation and prepulse inhibition, and increased avoidance (particularly in females) recapitulating the behavioral effects of lifetime CRFOE despite lower CRF peptide levels at testing. In contrast, CRFOE limited to adulthood reduced contextual fear learning in females and increased startle reactivity in males but did not change avoidance or startle plasticity. These findings suggest that forebrain CRFOE limited to development is sufficient to induce enduring alterations in startle plasticity and anxiety, while forebrain CRFOE during adulthood results in a different phenotype profile. These findings suggest that startle circuits are particularly sensitive to forebrain CRFOE, and that the impact of CRFOE may be dependent on the time of exposure

Controle do dengue em uma área urbana do Brasil: avaliação do impacto do Programa Saúde da Família com relação ao programa tradicional de controle Dengue control in an urban area of Brazil: impact of the Family Health Program on traditional control

Avaliaram-se os resultados da integração do Programa Saúde da Família (PSF) e do Programa de Controle do Dengue em São José do Rio Preto, São Paulo, Brasil. O estudo foi realizado em uma área com PSF e outra sem PSF. Na primeira, os agentes comunitários de saúde, de modo integrado com as suas atribuições, orientavam os moradores sobre as medidas de controle de dengue, incentivando-os a realizá-las. Na segunda área, os agentes de controle de vetores orientavam os moradores e realizavam as atividades de controle de criadouros. Conduziram-se, de outubro de 2001 a janeiro de 2003, levantamentos para mensurar conhecimentos e práticas dos moradores sobre dengue. Na área com PSF comparativamente com a sem PSF as proporções de entrevistados que afirmaram ter como fonte de informação o serviço de saúde apresentaram aumento significante. Nas duas áreas ocorreram mudanças significantes em termos de ganhos de conhecimento e diminuição de recipientes. Os resultados mostraram que a integração entre os dois programas é viável, representa otimização de recursos ao evitar a duplicidade das visitas e possibilita um maior envolvimento da comunidade no controle do dengue.<br>A study was performed in different areas of São José do Rio Preto which include the Family Health Program (FHP) and the Dengue Control Program, and the results of integration between the two programs were evaluated. In addition to other responsibilities, community health agents instructed residents on dengue control measures, encouraging the population to adopt the practices in areas with the FHP. Vector control agents were responsible for breeding site control and instructed local residents on the Dengue Control Program. From 2001 to 2003, surveys were conducted to measure residents' dengue control knowledge and practices. The proportions of residents in the FHP area that reported health services as a source of information increased significantly as compared to the other area. There were significant changes concerning the increase in information about the disease and reduction in vector breeding sites. The results show that integration between the programs is possible and could help optimize resources, avoiding duplicity of procedures and fostering greater community involvement in dengue control