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 impact of biologics and tofacitinib on cardiovascular risk factors and outcomes in patients with rheumatic disease: a systematic literature review

Introduction Rheumatic diseases are autoimmune, inflammatory diseases often associated with cardiovascular (CV) disease, a major cause of mortality in these patients. In recent years, treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs), either as monotherapy or in combination with other drugs, have become the standard of treatment. In this systematic literature review, we evaluated the effect of treatment with biologic or tofacitinib on the CV risk and outcomes in these patients. Methods A systematic search was performed in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for articles reporting on CV risk and events in patients with rheumatic disease treated with a biologic agent or tofacitinib. Articles identified were subjected to two levels of screening. Articles that passed the first level based on title and abstract were assessed on full-text evaluation. The quality of randomized clinical trials was assessed by Jadad scoring system and the quality of the other studies and abstracts was assessed using the Downs and Black instrument. The data extracted included study design, baseline patient characteristics, and measurements of CV risk and events. Results Of the 5722 articles identified in the initial search, screening yielded 105 unique publications from 90 unique studies (33 clinical trials, 39 prospective cohort studies, and an additional 18 retrospective studies) that reported CV risk outcomes. A risk of bias analysis for each type of report indicated that they were of good or excellent quality. Importantly, despite some limitations in data reported, there were no indications of significant increase in adverse CV events or risk in response to treatment with the agents evaluated. Conclusions Treatment with biologic or tofacitinib appears to be well-tolerated with respect to CV outcomes in these patients

Exploring the status, benefits, barriers and opportunities of using BIM for advancing prefabrication practice

Building information modelling (BIM) has significantly influenced the construction industry. However, the existing BIM tools and frameworks within prefabricated buildings are minimal. This research study aims to identify the opportunities and barriers of integrating BIM in the Australian prefabrication industry. The research was carried out using a mixed method of literature review and questionnaire survey with 30 indudstry professionals. The literature review identified the key challenges associated with prefabricated buildings including construction discipline-specific, fabrication-specific issues and communication-specific issues. The survey results proved that the most significant BIM opportunities are minimizing design errors and discrepancy of final product model between designers and manufacturers and increasing mass customization. The study revealed that seamless and timely information exchange among key project stakeholders via a BIM system was identified as the most critical success factor to adopt BIM in the prefabrication industry. This research provides practical insights into how to utilize BIM effectively for prefabrication in the housing sector. The survey results document the opportunities and barriers to BIM integration and provide professional insights on how BIM can benefit the prefabrication. The study contributes to the body of knowledge on enhancing the productivity/practice of prefabrication through BIM integration within the Australian housing context.Griffith Sciences, School of Engineering and Built EnvironmentNo Full Tex

Productivity Improvement in the Construction Industry: A Case Study of Mechanization in Singapore

Globally, the construction industry is a key contributor to national economies including Singapore's. However, the industry is a serial productivity underperformer. The literature argues that mechanization, automation and use of advanced technologies help improve construction productivity, but real-world case studies are limited in number. This paper presents a case study of the introduction of mechanization to improve the level of construction productivity in Singapore. The case study under investigation was the production/fabrication of steel gratings, the conventional process of which depends heavily on labor with few workers present on site. The majority of these workers are migrant workers, which contributes to a significant social concern in Singapore. The case study organization introduced a more advanced laser cutting machine to the process. The project team observed the process of using the laser cutting machine, and quantitative and qualitative data were obtained. The researchers observed the processes, both conventional and updated, and recorded the data on both methods. The quantitative data were comparatively analyzed to investigate the relative quality, efficiency and productivity of the two methods. The data revealed that the mechanization process achieved a productivity improvement (or savings) in man-days of at least 78%. Material wastage was reduced, and moreover, less reliance was placed on migrant workers, which helped to mitigate the social concerns created by the influx of foreign workers to Singapore. The findings also shed some light on the positive influence of government incentives to improve the industry's productivity

Kidney claudin-19: Localization in distal tubules and collecting ducts and dysregulation in polycystic renal disease

Tight junction (TJ) constitutes the barrier by controlling the passage of ions and molecules via paracellular pathway and the movement of proteins and lipids between apical and basolateral domains of the plasma membrane. Claudins, occludin, and junctional adhesion molecules are the major three transmembrane proteins at TJ. This study focuses a newly identified mammalian TJ gene, claudin-19, in kidneys. Mouse claudin-19 composes of 224 amino acids and shares 98.2% and 95% amino acid homology with rat and human, respectively; the most evolutionary-related claudins are claudin-1 and -7, which share ∼75% DNA sequence homology with claudin-19. Claudin-19 is abundantly expressed in the mouse and rat kidneys among the organs examined by Northern blots, and to a much less extent, also found in brain by RT-PCR. Claudin-19 and zonula occludens-1 (ZO-1) are localized at junctional regions of Madin-Darby canine kidney (MDCK) cells by immunofluorescent microscopy. In addition, ZO-1 is found in the claudin-19-associated protein complexes in MDCK cells by co-immunoprecipitation. Using aquaporin-1 and aquaporin-2 antibodies as markers for different renal segment, strong expression of claudin-19 was observed in distal tubules of the cortex as well as in the collecting ducts of the medulla. To less extent, claudin-19 is also present in the proximal tubules (cortex) and in the loop of Henle (medulla). Furthermore, intense claudin-19 immunoreactivity is found co-localized with the ZO-1 in kidneys from postnatal day 15, day 45, and adult rats and mice. Similar localizations of claudin-19 and ZO-1 are also observed in human kidneys. Since these renal segments are mainly for controlling the paracellular cation transport, it is suggested that claudin-19 may participate in these processes. In human polycystic kidneys, decreased expression and dyslocalization of claudin-19 are noticed, suggesting a possible correlation between claudin-19 and renal disorders. Taken together, claudin-19 is a claudin isoform that is highly and specifically expressed in renal tubules with a putative role in TJ homeostasis in renal physiology. © 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.link_to_subscribed_fulltex

Consequences of haemolysis without haptoglobin

10.1179/135100001101536571Redox Report66375-378RDRP