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

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Racial/Ethnic Disparities in Inadequate Gestational Weight Gain Differ by Pre-pregnancy Weight

OBJECTIVES: Pre-pregnancy body mass index (BMI) varies by race/ethnicity and modifies the association between gestational weight gain (GWG) and adverse pregnancy outcomes, which disproportionately affect racial/ethnic minorities. Yet studies investigating whether racial/ethnic disparities in GWG vary by pre-pregnancy BMI are inconsistent, and none studied nationally representative populations. METHODS: Using categorical measures of GWG adequacy based on Institute of Medicine recommendations, we investigated whether associations between race/ethnicity and GWG adequacy were modified by pre-pregnancy BMI [underweight (<18.5kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)), or obese (≥30.0 kg/m(2)) ] among all births to Black, Hispanic, and White mothers in the 1979 USA National Longitudinal Survey of Youth cohort (n=6849 pregnancies; range=1-10). We used generalized estimating equations, adjusted for marital status, parity, smoking during pregnancy, gestational age, and multiple measures of socioeconomic position. RESULTS: Effect measure modification between race/ethnicity and pre-pregnancy BMI was significant for inadequate GWG (Wald test p-value=0.08). Normal weight Black (Risk Ratio (RR)=1.34, 95% confidence interval (CI): 1.18, 1.52) and Hispanic women (RR=1.33, 95%CI: 1.15, 1.54) and underweight Black women (RR=1.38; 95% CI: 1.07, 1.79) experienced an increased risk of inadequate GWG compared to Whites. Differences in risk of inadequate GWG between minority women, compared to White women, were not significant among overweight and obese women. Effect measure modification between race/ethnicity and pre-pregnancy BMI was not significant for excessive GWG. CONCLUSIONS: The magnitude of racial/ethnic disparities in inadequate GWG appears to vary by pre-pregnancy weight class, which should be considered when designing interventions to close racial/ethnic gaps in healthy GWG

Control of metal-organic framework crystallization by metastable intermediate pre-equilibrium species

There is an increasing amount of interest in metal–organic frameworks (MOFs) for a variety of applications, from gas sensing and separations to electronics and catalysis. However, the mechanisms by which they crystallize remain poorly understood. Herein, an important new insight into MOF formation is reported. It is shown that, prior to network assembly, crystallization intermediates in the canonical ZIF‐8 system exist in a dynamic pre‐equilibrium, which depends on the reactant concentrations and the progress of reaction. Concentration can, therefore, be used as a synthetic handle to directly control particle size, with potential implications for industrial scale‐up and gas sorption applications. These findings enable the rationalization of apparent contradictions between previous studies of ZIF‐8 and opens up new opportunities for the control of crystallization in network solids more generally

Control of metal-organic framework crystallization by metastable intermediate pre-equilibrium species

There is an increasing amount of interest in metal–organic frameworks (MOFs) for a variety of applications, from gas sensing and separations to electronics and catalysis. However, the mechanisms by which they crystallize remain poorly understood. Herein, an important new insight into MOF formation is reported. It is shown that, prior to network assembly, crystallization intermediates in the canonical ZIF‐8 system exist in a dynamic pre‐equilibrium, which depends on the reactant concentrations and the progress of reaction. Concentration can, therefore, be used as a synthetic handle to directly control particle size, with potential implications for industrial scale‐up and gas sorption applications. These findings enable the rationalization of apparent contradictions between previous studies of ZIF‐8 and opens up new opportunities for the control of crystallization in network solids more generally

Epidemiological methods for research with drug misusers: review of methods for studying prevalence and morbidity Métodos: epidemiológicos para pesquisa com usuários de drogas: revisão de métodos para estudo da prevalência e morbidade

Epidemiological studies of drug misusers have until recently relied on two main forms of sampling: probability and convenience. The former has been used when the aim was simply to estimate the prevalence of the condition and the latter when in depth studies of the characteristics, profiles and behaviour of drug users were required, but each method has its limitations. Probability samples become impracticable when the prevalence of the condition is very low, less than 0.5% for example, or when the condition being studied is a clandestine activity such as illicit drug use. When stratified random samples are used, it may be difficult to obtain a truly representative sample, depending on the quality of the information used to develop the stratification strategy. The main limitation of studies using convenience samples is that the results cannot be generalised to the whole population of drug users due to selection bias and a lack of information concerning the sampling frame. New methods have been developed which aim to overcome some of these difficulties, for example, social network analysis, snowball sampling, capture-recapture techniques, privileged access interviewer method and contact tracing. All these methods have been applied to the study of drug misuse. The various methods are described and examples of their use given, drawn from both the Brazilian and international drug misuse literature.<br>São descritos e discutidos os vários métodos de amostragem, de probabilidade e conveniência para estudos epidemiológicos sobre usuários de drogas, e apresentados exemplos de seu uso, com base na literatura brasileira e internacional. Os estudos epidemiológicos sobre usuários de drogas, realizados até recentemente, têm utilizado duas formas principais de amostragem: a de probabilidade e a de conveniência. A primeira tem sido utilizada quando o objetivo é apenas estimar a prevalência da condição sendo pesquisada e a segunda (conveniência) quando as características, perfis e comportamentos de usuários de drogas são os focos do trabalho. Ambos os métodos têm suas limitações, amostras probabilísticas ficam cada vez mais impraticáveis quando a prevalência de determinada condição é muito baixa, menor do que 0,5% por exemplo, ou quando a condição sendo estudada é uma atividade clandestina, como o uso de drogas ilícitas. Por outro lado, os resultados de amostras de conveniência são limitados porque não podem ser generalizados para a população total de usuários de droga, devido ao viés de seleção e a falta de informações a respeito do "sampling frame". Novos métodos têm sido desenvolvidos para superar essas dificuldades, por exemplo, análise da rede social, técnica de amostragem bola-de-neve (snowball sampling), técnica de captura e recaptura, método utilizando um entrevistador com acesso privilegiado à população-alvo (PAI - Privileged Access Interviewer Method) e técnica de investigação epidemiológica chamada de "contact tracing"