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

A model study of muscle forces and joint-force direction in normal and dysplastic neonatal hips

Orthopaedic treatment of congenital hip dysplasia does not always give the desired result. With the present model, prediction of the effects of various treatments on the force direction in the hip joint could help to improve and select treatment (the force direction is presumed to control the collum growth direction). The model contains three-dimensional mathematical descriptions of all muscles passing the hip joint, for various degrees of femoral dysplasia, and for various hip postures. Muscles run straight or curve round some skeletal parts. Muscle forces (all isometric) are calculated from muscle mass, density, pennation angle, mean fibre length, muscle elongation, and assumed activation levels. The latter serve as parameters for optimization. Resting lengths are taken from an assumed fetal posture, and from the observed neonatal posture. Differences between force directions before and after birth, as calculated with the model, agree with collum direction changes described by von Lanz and Mayet (1953).</p

Authenticity at Work: A Matter of Fit?

Authenticity at work refers to the extent to which a worker feels in touch with their true self while at work. At first sight this concept seems to overlap with the concept of person-environment (P-E) fit, that is, the degree to which an individual experiences good fit with their work environment. Drawing on a sample of 867 Dutch gifted workers, structural equation modeling was used to investigate (i) whether authenticity at work and P-E fit can be distinguished, and (ii) how authenticity at work and P-E fit were associated with employee well-being. As expected, confirmatory factor analysis revealed that authenticity at work and P-E fit were distinct from each other. Moreover, the mediated effect of authenticity at work was stronger for two negative forms of well-being (burnout and boredom) than for two positive forms of well-being (work engagement and job satisfaction). The theoretical and practical implications of these findings are discussed, especially focusing on the distinction between authenticity and P-E fit.status: publishe

An experimental setup for the measurement of forces on a human cadaveric foot during inversion

An experimental setup was developed for statically measuring seven vertical and three horizontal reaction forces on the foot. In the setup, the leg can be simultaneously loaded (1) by a vertical force, (2) by an externally applied axial moment, and (3) by simulated muscle forces. The foot is free to invert under influence of the external loads. Statical analysis and test experiments were used for evaluation. The setup can be used in combination with Roentgen photogrammetry to measure bone positions simultaneously with forces.</p

Succinate Dehydrogenase Deficiency Is Rare in Pituitary Adenomas

Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor. It has recently been suggested that pituitary adenomas may also be a component of this syndrome. We sought to determine the incidence of SDH mutation in pituitary adenomas. We performed screening immunohistochemistry for SDHB and SDHA on all available pituitary adenomas resected at our institution from 1998 to 2012. In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood. One of 309 adenomas (0.3%) demonstrated an abnormal pattern of staining, a 30 mm prolactin-producing tumor from a 62-year-old man showing loss of staining for both SDHA and SDHB. Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA). Neither of these mutations was present in the germline. We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation. SDH-deficient pituitary adenomas may be larger and more likely to produce prolactin than other pituitary adenomas. Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas. Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy