Integrated genomic characterization of oesophageal carcinoma

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular features differentiated oesophageal squamous cell carcinomas from oesophageal adenocarcinomas. Oesophageal squamous cell carcinomas resembled squamous carcinomas of other organs more than they did oesophageal adenocarcinomas. Our analyses identified three molecular subclasses of oesophageal squamous cell carcinomas, but none showed evidence for an aetiological role of human papillomavirus. Squamous cell carcinomas showed frequent genomic amplifications of CCND1 and SOX2 and/or TP63, whereas ERBB2, VEGFA and GATA4 and GATA6 were more commonly amplified in adenocarcinomas. Oesophageal adenocarcinomas strongly resembled the chromosomally unstable variant of gastric adenocarcinoma, suggesting that these cancers could be considered a single disease entity. However, some molecular features, including DNA hypermethylation, occurred disproportionally in oesophageal adenocarcinomas. These data provide a framework to facilitate more rational categorization of these tumours and a foundation for new therapies.ope

Mental health consultations in a prison population: a descriptive study

BACKGROUND: The psychiatric morbidity among prison inmates is substantially higher than in the general population. We do, however, have insufficient knowledge about the extent of psychiatric treatment provided in our prisons. The aim of the present study was to give a comprehensive description of all non-pharmacological interventions provided by the psychiatric health services to a stratified sample of prison inmates. METHODS: Six medium/large prisons (n = 928) representing 1/3 of the Norwegian prison population and with female and preventive detention inmates over-sampled, were investigated cross-sectionally. All non-pharmacological psychiatric interventions, excluding pure correctional programs, were recorded. Those receiving interventions were investigated further and compared to the remaining prison population. RESULTS: A total of 230 of the 928 inmates (25 %) had some form of psychiatric intervention: 184 (20 %) were in individual psychotherapy, in addition 40 (4 %) received ad hoc interventions during the registration week. Group therapy was infrequent (1 %). The psychotherapies were most often of a supportive (62 %) or behavioural-cognitive (26 %) nature. Dynamic, insight-oriented psychotherapies were infrequent (8 %). Concurrent psychopharmacological treatment was prevalent (52 %). Gender and age did not correlate with psychiatric interventions, whereas prisoner category (remanded, sentenced, or preventive detention) did (p < 0.001). Most inmates had a number of defined problem areas, with substance use, depression, anxiety, and personality disorders most prevalent. Three percent of all inmates were treated for a psychotic disorder. Remand prisoners averaged 14 sessions per week per 100 inmates, while sentenced inmates and those on preventive detention averaged 22 and 25 sessions per week per 100 inmates, respectively. Five out of six psychiatric health services estimated the inmates' psychiatric therapy needs as adequately met, both overall and in the majority of individual cases. CONCLUSION: Our results pertain only to prisons with adequate primary and mental health services and effective diversion from prison of individuals with serious mental disorders. Given these important limitations, we do propose that the service estimates found may serve as a rough guideline to the minimum number of sessions a prison's psychiatric health services should be able to fulfil in order to serve the inmates psychiatric needs. The results rely on the specialist services' own estimates only. Future studies should take other important informants, including the inmates themselves, into consideration

Host Immune Transcriptional Profiles Reflect the Variability in Clinical Disease Manifestations in Patients with Staphylococcus aureus Infections

Staphylococcus aureus infections are associated with diverse clinical manifestations leading to significant morbidity and mortality. To define the role of the host response in the clinical manifestations of the disease, we characterized whole blood transcriptional profiles of children hospitalized with community-acquired S. aureus infection and phenotyped the bacterial strains isolated. The overall transcriptional response to S. aureus infection was characterized by over-expression of innate immunity and hematopoiesis related genes and under-expression of genes related to adaptive immunity. We assessed individual profiles using modular fingerprints combined with the molecular distance to health (MDTH), a numerical score of transcriptional perturbation as compared to healthy controls. We observed significant heterogeneity in the host signatures and MDTH, as they were influenced by the type of clinical presentation, the extent of bacterial dissemination, and time of blood sampling in the course of the infection, but not by the bacterial isolate. System analysis approaches provide a new understanding of disease pathogenesis and the relation/interaction between host response and clinical disease manifestations

Cartography of Methicillin-Resistant S. aureus Transcripts: Detection, Orientation and Temporal Expression during Growth Phase and Stress Conditions

BACKGROUND: Staphylococcus aureus is a versatile bacterial opportunist responsible for a wide spectrum of infections. The severity of these infections is highly variable and depends on multiple parameters including the genome content of the bacterium as well as the condition of the infected host. Clinically and epidemiologically, S. aureus shows a particular capacity to survive and adapt to drastic environmental changes including the presence of numerous antimicrobial agents. Mechanisms triggering this adaptation remain largely unknown despite important research efforts. Most studies evaluating gene content have so far neglected to analyze the so-called intergenic regions as well as potential antisense RNA molecules. PRINCIPAL FINDINGS: Using high-throughput sequencing technology, we performed an inventory of the whole transcriptome of S. aureus strain N315. In addition to the annotated transcription units, we identified more than 195 small transcribed regions, in the chromosome and the plasmid of S. aureus strain N315. The coding strand of each transcript was identified and structural analysis enabled classification of all discovered transcripts. RNA purified at four time-points during the growth phase of the bacterium allowed us to define the temporal expression of such transcripts. A selection of 26 transcripts of interest dispersed along the intergenic regions was assessed for expression changes in the presence of various stress conditions including pH, temperature, oxidative shocks and growth in a stringent medium. Most of these transcripts showed expression patterns specific for the defined stress conditions that we tested. CONCLUSIONS: These RNA molecules potentially represent important effectors of S. aureus adaptation and more generally could support some of the epidemiological characteristics of the bacterium

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

Company-level family policies: Who has access to it and what are some of its outcomes

Despite the increase in number of studies that examine the cross-national variation in the policy configuration that allow a better work-family integration, very few look beyond the national levels. It is also crucial to examine occupational level welfare since companies may restrict or expand the existing national level regulations, defining the “final availability” workers actual have towards various arrangements. In addition, companies may provide various additional arrangements through occupational policies which are not set out in the national level agreements that are crucial in addressing reconciliation needs of workers. This chapter examines what types of arrangements are provided at the company level to address work-family demands of workers. It further provides a synthesis of studies that examine both national level contexts and individual level characteristics that explain who gets access to company level family-friendly policies, which is linked to the possible outcomes of these policies