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

Residual stress distribution of roller bending of steel rectangular structural hollow sections

Curved steel rectangular structural hollow sections, which have a wide range of applications in construction industry, are commonly produced by cold roller bending using pyramid-type 3-roller machine on hot finished steel hollow sections. The roller bending process induces local deformations and residual stress in the hot finished section walls. While the residual stress magnitude and distribution could have sufficient influence on the member's stability and buckling resistance, few studies have paid attention to the residual stress distribution caused by roller bending. In this paper, a proper numerical modelling procedure is employed to simulate the rolling process and reproduce the residual stress. In addition, a small scale parametric study is conducted to investigate the effects of some key roller bending parameters, including the rolling boundary conditions, the bending ratio, the steel yield stress, the thickness ratio and the shape factor, on the resulted residual stress distribution of the bended sections. Based on the results obtained from the parametric studies, a simple residual stresses model which could predict the residual stress distribution of the curved member is proposed

Emergence of unusual species of enterococci causing infections, South India

<p>Abstract</p> <p>Background</p> <p>Enterococci tend to be one of the leading causes of nosocomial infections, with <it>E. faecalis </it>and <it>E. faecium </it>accounting up to 90% of the clinical isolates. Nevertheless, the incidence of other species of enterococci from clinical sources shows an alarming increase with the properties of intrinsic resistance to several antibiotics including beta-lactams and glycopeptides. Thus proper identification of enterococci to species level is quintessential for management and prevention of these bacteria in any healthcare facility. Hence this work was undertaken to study the prevalence of unusual species of enterococci causing human infections, in a tertiary care hospital in South India.</p> <p>Methods</p> <p>The study was conducted in a tertiary care hospital in South India from July 2001 to June 2003. Isolates of enterococci were collected from various clinical specimens and speciated using extensive phenotypic and physiological tests. Antimicrobial susceptibility testing were performed and interpreted as per NCCLS guidelines. Whole cell protein (WCP) fingerprinting of enterococci were done for species validation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and analyzed computationally.</p> <p>Results</p> <p>Our study showed the prevalence of unusual (non-faecalis and non-faecium enterococci) and atypical (biochemical variant) species of enterococci as 19% (46 isolates) and 5% (12 isolates) respectively. The 7 unusual species (46 isolates) isolated and confirmed by phenotypic characterization includes: 15 <it>E. gallinarum </it>(6.2%), 10 <it>E. avium </it>(4.1%), 6 <it>E. raffinosus </it>(2.5%), 6 <it>E. hirae </it>(2.5%), 4 <it>E. mundtii </it>(1.7%), 3 <it>E. casseliflavus</it>-including the two atypical isolates (1.2%) and 2 <it>E. durans </it>(0.8%). The 12 atypical enterococcal species (5%) that showed aberrant sugar reactions in conventional phenotyping were confirmed as <it>E. faecalis, E. faecium </it>and <it>E. casseliflavus </it>respectively by WCP fingerprinting. The antimicrobial susceptibility testing depicted the emergence of high-level aminoglycoside and beta-lactam resistance among different species apart from intrinsic vancomycin resistance by some species, while all the species tested were susceptible for linezolid and teicoplanin.</p> <p>Conclusion</p> <p>Our study reveals the emergence of multi-drug resistance among unusual species of enterococci posing a serious therapeutic challenge. Precise identification of enterococci to species level enables us to access the species-specific antimicrobial resistance characteristics, apart from knowing the epidemiological pattern and their clinical significance in human infections.</p

Can better prescribing turn the tide of resistance?

In the wake of concerns about the level of antibiotic resistance, governments worldwide are pressing for reduced antibiotic use, hoping thereby to reverse resistance trends. Is success likely? The evidence is mixed, and expectations should be tempered by the growing realization that many resistant bacteria are biologically fit, making them difficult to displace. If resistance is unlikely to be reduced significantly by changing prescription practices, how can clinicians outpace increased resistance, particularly when much of 'big pharma' is abandoning antibiotic development

INVESTIGATION OF BIOFILM FORMATION IN COAGULASE-NEGATIVE STAPHYLOCOCCI ISOLATED FROM PLATELET CONCENTRATE BAGS

Platelet Concentrates (PCs) are the blood components with the highest rate of bacterial contamination, and coagulase-negative staphylococci (CoNS) are the most frequently isolated contaminants. This study investigated the biofilm formation of 16 contaminated units out of 691 PCs tested by phenotypic and genotypic methods. Adhesion in Borosilicate Tube (ABT) and Congo Red Agar (CRA) tests were used to assess the presence of biofilm. The presence of icaADC genes was assessed by means of the Polymerase Chain Reaction (PCR) technique. With Vitek(r)2, Staphylococcus haemolyticus was considered the most prevalent CoNS (31.25%). The CRA characterized 43.8% as probable biofilm producers, and for the ABT test, 37.5%. The icaADC genes were identified in seven samples by the PCR. The ABT technique showed 85.7% sensitivity and 100% specificity when compared to the reference method (PCR), and presented strong agreement (k = 0.8). This study shows that species identified as PCs contaminants are considered inhabitants of the normal skin flora and they might become important pathogens. The results also lead to the recommendation of ABT use in laboratory routine for detecting biofilm in CoNS contaminants of PCs