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

The Diversity of Trajectories of Large Housing Estates in Madrid, Spain

Public and private housing developments between 1940 and 1990 shaped the City of Madrid by differentiating urban area types according to social composition, location and development type. Spanish housing policies over these decades fostered public housing stock that, unlike in European cities, ended up being transformed into owned rather than rented homes; closely linking certain disadvantaged groups to the most vulnerable areas of the city. In this chapter, current processes of physical and social vulnerability are analysed using data from the 2001 and 2011 Population and Housing Censuses using a multivariate analysis. Our analysis differentiates between two stages of social housing estates in Madrid (under Francoism and in the democratic period) and private housing developments. These analyses show significant differences both in the trajectories of each of the types analysed in relation to contemporary vulnerability processes, as well as in the composition of the population that resides in them. Lastly, we examine challenges and proposals for the future of these urban areas, considering their social composition and the urban policies that seek to rebalance Madrid’s neighbourhoods and paying attention to the insertion of the immigrant population into the most vulnerable neighbourhoods of the city.Depto. de Sociología AplicadaFac. de Estudios EstadísticosFac. de Ciencias Políticas y SociologíaTRUEpu

Quality of life measurement in alopecia areata. Position statement of the European Academy of Dermatology and Venereology Task Force on Quality of Life and Patient Oriented Outcomes

New treatment options may lead to an increased interest in using reliable and sensitive instruments to assess health-related quality of life in people with alopecia areata (AA). The purpose of this paper is to present current knowledge about quality of life assessment in AA. The dermatology-specific Dermatology Life Quality Index (DLQI) was the most widely reported health-related quality of life instrument used in AA. Three AA-specific (Alopecia Areata Symptom Impact Scale, Alopecia Areata Quality of Life Index and Alopecia Areata Patients' Quality of Life) and three hair disease-specific instruments (Hairdex, Scalpdex and ‘hair-specific Skindex-29’) were identified with a range of content and validation characteristics: there is little evidence yet of the actual use of these measures in AA. Scalpdex is the best-validated hair disease-specific instrument. Further extensive validation is needed for all of the AA-specific instruments. The European Academy of Dermatology and Venereology Task Force on Quality of Life and Patient Oriented Outcomes recommends the use of the dermatology-specific DLQI questionnaire, hair disease-specific Scalpdex and the alopecia areata-specific instruments the Alopecia Areata Symptom Impact Scale or Alopecia Areata Quality of Life Index, despite the limited experience of their use. We hope that new treatment methods will be able to improve both clinical signs and health-related quality of life in patients with AA. In order to assess the outcomes of trials on these new treatment methods, it would be helpful when further development and validation of AA-specific instruments is being encouraged and also conducted

Multi-actor networks and innovation niches: university training for local Agroecological Dynamization

Unidad de excelencia María de Maeztu MdM-2015-0552The global environmental and social-economic crises of industrialized agriculture have led to the emergence of agroecology as an alternative approach aiming to increase the ecological, social and economic sustainability of agri-food systems. The 'multi-level perspective' is now a widely used framework to understand and promote the upscaling of local innovation niches, such as agroecology, to broader scales (e.g., regional, national, international), thus reconfiguring the dominant socio-technical regimes. Additionally, emergent 'hybrid forums' can provide a space between niche and regime where niche innovators can become important actors in scaling up and out emergent innovations. In this paper, we examine a university training program (Postgraduate Diploma in Local Agroecological Dynamization at the Universitat Autònoma de Barcelona), to better understand its role as a 'hybrid forum'. Our analysis focuses especially on how the program, as an example of a hybrid forum, worked to reconfigure practices, concepts, and tools of local development practitioners. We also assess to what extent the program contributed to transitioning local development institutions toward agroecology. An online survey (n = 46) and in-depth interviews (n = 16) were carried out to determine how the training program has impacted the student's opinions and their respective institutions. The results show that most of the students consider that they have acquired new theoretical frameworks and useful methods to re-framing their local development projects, that new alliances with multi-actor networks have been perceived, and that some internal changes of the local development practices have taken place. We conclude that the training program, as a hybrid forum, is capable of outscaling niche innovations through linkages with different kind of actors both from the niche and the regime. Political changes in the socio-technical landscape level offer an opportunity to amplify the impact of the innovations which are being generated by those multi-actor networks, but with a limited multi-level impact as far as institutional regime-actors not aligned with agroecological transition keep the most of the competencies on agri-food systems

Effects of Organic Selenium Supplementation on Growth, Accumulation, Haematology and Histopathology of Juvenile Barramundi (Lates calcarifer) Fed High Soybean Meal Diets

Soybean meal (SBM) has been commonly utilised as a substitute for fishmeal (FM) in the diets of several fish species. However, little is known regarding their effects on trace element availability and thus their importance to fish. The present study employed two feeding trials to evaluate the implications of dietary selenium (Se) on the growth, accumulation, antioxidant, and histopathological responses of juvenile barramundi (Lates calcarifer). In the first trial, each of three basal diets containing 0, 15 and 43 % SBM as replacements for 0, 25 and 75 % of FM protein on an isoproteic and isocalorific basis were either supplemented or not supplemented with 2 mg kg-1 organic Se (OS). In the second trial, the potential effect of OS supplementation in a high SBMdiet was investigated in a feeding trial with five experimental diets: 75 % SBM protein as replacement of FM was supplemented with 2, 3, 4, 5 or 7 mg OS kg-1. Growth was independently influenced by the SBM level and the OS supplementation level but not by their interaction. Glutathione peroxidase (GPx) activity, haematocrit, Se accumulation and muscle tissue integrity were significantly enhanced in fish fed on OS-supplemented diets. Furthermore, when high SBM was included in diets, elevated Se tended to lower the barramundi’s performance. These findings suggest that dietary supplementation of OS at 2–3 g kg-1 diet is necessary when high plant protein ingredients are incorporated in the diet, in order to maintain better growth and to afford protection against oxidative stress

Serious Asthma Events with Fluticasone plus Salmeterol versus Fluticasone Alone

BACKGROUND: The safe and appropriate use of long-acting beta-agonists (LABAs) for the treatment of asthma has been widely debated. In two large clinical trials, investigators found a potential risk of serious asthma-related events associated with LABAs. This study was designed to evaluate the risk of administering the LABA salmeterol in combination with an inhaled glucocorticoid, fluticasone propionate. METHODS: In this multicenter, randomized, double-blind trial, adolescent and adult patients (age, ≥12 years) with persistent asthma were assigned to receive either fluticasone with salmeterol or fluticasone alone for 26 weeks. All the patients had a history of a severe asthma exacerbation in the year before randomization but not during the previous month. Patients were excluded from the trial if they had a history of life-threatening or unstable asthma. The primary safety end point was the first serious asthma-related event (death, endotracheal intubation, or hospitalization). Noninferiority of fluticasone-salmeterol to fluticasone alone was defined as an upper boundary of the 95% confidence interval for the risk of the primary safety end point of less than 2.0. The efficacy end point was the first severe asthma exacerbation. RESULTS: Of 11,679 patients who were enrolled, 67 had 74 serious asthma-related events, with 36 events in 34 patients in the fluticasone-salmeterol group and 38 events in 33 patients in the fluticasone-only group. The hazard ratio for a serious asthma-related event in the fluticasone-salmeterol group was 1.03 (95% confidence interval [CI], 0.64 to 1.66), and noninferiority was achieved (P=0.003). There were no asthma-related deaths; 2 patients in the fluticasone-only group underwent asthma-related intubation. The risk of a severe asthma exacerbation was 21% lower in the fluticasone-salmeterol group than in the fluticasone-only group (hazard ratio, 0.79; 95% CI, 0.70 to 0.89), with at least one severe asthma exacerbation occurring in 480 of 5834 patients (8%) in the fluticasone-salmeterol group, as compared with 597 of 5845 patients (10%) in the fluticasone-only group (P<0.001). CONCLUSIONS: Patients who received salmeterol in a fixed-dose combination with fluticasone did not have a significantly higher risk of serious asthma-related events than did those who received fluticasone alone. Patients receiving fluticasone-salmeterol had fewer severe asthma exacerbations than did those in the fluticasone-only group