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

Defining Participant Exposure Measures in Web-Based Health Behavior Change Programs

BACKGROUND: Published research on the use of Web-based behavior change programs is growing rapidly. One of the observations characterized as problematic in these studies is that participants often make relatively few website visits and spend only a brief time accessing the program. Properly structured websites permit the unobtrusive measurement of the ways in which participants access (are exposed to) program content. Research on participant exposure to Web-based programs is not merely of interest to technologists, but represents an important opportunity to better understand the broader theme of program engagement and to guide the development of more effective interventions. OBJECTIVES: The current paper seeks to provide working definitions and describe initial patterns of various measures of participant exposure to ChewFree.com, a large randomized controlled trial of a Web-based program for smokeless tobacco cessation. METHODS: We examined measures of participant exposure to either an Enhanced condition Web-based program (interactive, tailored, and rich-media program) or a Basic condition control website (static, text-based material). Specific measures focused on email prompting, participant visits (number, duration, and pattern of use over time), and Web page viewing (number of views, types of pages viewed, and Web forum postings). RESULTS: Participants in the ChewFree.com Enhanced condition made more visits and spent more time accessing their assigned website than did participants assigned to the Basic condition website. In addition, exposure data demonstrated that Basic condition users thoroughly accessed program content, indicating that the condition provided a meaningful, face-valid control to the Enhanced condition. CONCLUSIONS: We recommend that researchers conducting evaluations of Web-based interventions consider the collection and analysis of exposure measures in the broader context of program engagement in order to assess whether participants obtain sufficient exposure to relevant program content

Rapid Enhancement of Glutamatergic Neurotransmission in Bipolar Depression Following Treatment with Riluzole

Glutamatergic abnormalities may underlie bipolar disorder (BD). The glutamate-modulating drug riluzole may be efficacious in bipolar depression, but few in vivo studies have examined its effect on glutamatergic neurotransmission. We conducted an exploratory study of the effect of riluzole on brain glutamine/glutamate (Gln/Glu) ratios and levels of N-acetylaspartate (NAA). We administered open-label riluzole 100–200 mg daily for 6 weeks to 14 patients with bipolar depression and obtained imaging data from 8-cm3 voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) at baseline, day 2, and week 6 of treatment, using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 T. Imaging data were analyzed using the spectral-fitting package, LCModel; statistical analysis used random effects mixed models. Riluzole significantly reduced Hamilton Depression Rating Scale (HAM-D) scores (d=3.4; p<0.001). Gln/Glu ratios increased significantly by day 2 of riluzole treatment (Cohen's d=1.2; p=0.023). NAA levels increased significantly from baseline to week 6 (d=1.2; p=0.035). Reduction in HAM-D scores was positively associated with increases in NAA from baseline to week 6 in the ACC (d=1.4; p=0.053), but was negatively associated in the POC (d=9.6; p<0.001). Riluzole seems to rapidly increase Gln/Glu ratios—suggesting increased glutamate–glutamine cycling, which may subsequently enhance neuronal plasticity and reduce depressive symptoms. Further investigation of the Gln/Glu ratio as a possible early biomarker of response to glutamate-modulating therapies is warranted