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

Legal matters related to structural damage in the Netherlands

When structural damage occurs and disputes arise, forensic engineers have to search for the causes of this damage to find out who can be held liable for it. Legal systems must provide an adequate, reasonable, effective and complete way to solve these disputes. Each country has its own system with advantages and disadvantages. This paper provides an overview of the Dutch legal system concerning liability, dispute resolution and insurances. These themes will be illustrated by quantitative research data, a comparison between the Netherlands and England and by discussing advantages and disadvantages of rules, such as reasonableness and influences on structural safety. In this way, the aim is to share knowledge and contribute to the discussion regarding the legal and judicial framework relating to structural damage.Structural EngineeringCivil Engineering and Geoscience

Structural incidents in The Netherlands: A comparison of three databases

After several major structural incidents in The Netherlands, various initiatives have been started to improve structural safety. Research studies were initiated on the characteristics, causes and consequences of structural incidents. In this paper the results of three of these research studies are compared. Each study uses different data sources: a confidential reporting system called ABC registration, Dutch arbitration awards on 'structural' failures and a newspaper called Cobouw. It appears that the reliability of the research studies varies due to the quality of both source and analysis. In addition, a comparison of the results shows variations due to the type of sources used. However, general patterns have been derived from the three databases. From this study it can be concluded that contrasting and combining results of different sources has improved the overview of structural incidents and has provided an insight into trends.Structural EngineeringCivil Engineering and Geoscience

The role of bacterial stimuli in inflammation-driven bone formation

Immune cells and their soluble factors regulate skeletal cells during normal bone regeneration and pathological bone formation. Bacterial infections can trigger immune responses that activate pro-osteogenic pathways, but these are usually overshadowed by osteolysis and concerns of systemic inflammation. The aim of this study was to determine whether the transient local inflammatory reaction to non-viable bacterial immune agonists could lead to favourable new bone formation. In a series of rabbit studies, as proof-of-concept, how tibial intramedullary injection of viable or killed bacterial species affected bone remodelling and new bone formation was determined. Application of killed bacteria led to considerable new bone formation after 4 weeks, without the prolonged systemic inflammation and exaggerated bone lysis seen with active infection. The osteo-immunomodulatory effects of various species of killed bacteria and the dose response relationship were subsequently screened in ectopically-implanted ceramic scaffolds. Histomorphometry after 8 weeks showed that a relatively low dose of killed bacteria enhanced ectopic bone induction. Moreover, lipoteichoic acid - the bacterial cell-wall derived toll-like-receptor (TLR)-2 activator - was identified as an osteo-stimulatory factor. Collectively, the data indicated that bacterial stimuli could be harnessed to stimulate osteogenesis, which occurs through a synergy with osteoinductive signals. This finding holds promise for the use of non-viable bacteria, bacterial antigens, or their simplified analogues as immuno-modulatory bone regenerating tools in bone biomaterials.Biomaterials & Tissue Biomechanic