The pan-cancer analysis of whole genomes The expansion of whole-genome sequencing studies from individual ICGC and TCGA working groups presented the opportunity to undertake a meta-analysis of genomic features across tumour types. To achieve this, the PCAWG Consortium was established. A Technical Working Group implemented the informatics analyses by aggregating the raw sequencing data from different working groups that studied individual tumour types, aligning the sequences to the human genome and delivering a set of high-quality somatic mutation calls for downstream analysis (Extended Data Fig. 1). Given the recent meta-analysis

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Four male subjects aged 23-34 years were studied during 60 days of unilateral strength training and 40 days of detraining. Training was carried out four times a week and consisted of six series of ten maximal isokinetic knee extensions at an angular velocity of 2.09 rad.s-1. At the start and at every 20th day of training and detraining, isometric maximal voluntary contraction (MVC), integrated electromyographic activity (iEMG) and quadriceps muscle cross-sectional area (CSA) assessed at seven fractions of femur length (Lf), by nuclear magnetic resonance imaging, were measured on both trained (T) and untrained (UT) legs. Isokinetic torques at 30 degrees before full knee extension were measured before and at the end of training at: 0, 1.05, 2.09, 3.14, 4.19, 5.24 rad.s-1. After 60 days T leg CSA had increased by 8.5% +/- 1.4% (mean +/- SEM, n = 4, p less than 0.001), iEMG by 42.4% +/- 16.5% (p less than 0.01) and MVC by 20.8% +/- 5.4% (p less than 0.01). Changes during detraining had a similar time course to those of training. No changes in UT leg CSA were observed while iEMG and MVC increased by 24.8% +/- 10% (N.S.) and 8.7% +/- 4.3% (N.S.), respectively. The increase in quadriceps muscle CSA was maximal at 2/10 Lf (12.0% +/- 1.5%, p less than 0.01) and minimal, proximally to the knee, at 8/10 Lf (3.5% +/- 1.2%, N.S.). Preferential hypertrophy of the vastus medialis and intermedius muscles compared to those of the rectus femoris and lateralis muscles was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Quadriceps muscle and fibre cross-sectional areas (CSA), torque and neural activation were studied in seven healthy males during 6 months of weight training on alternate days with six series of eight unilateral leg extensions at 80% of one repetition maximum. After training, the quadriceps cross-sectional area increased by 18.8 +/- 7.2% (P < 0.001) and 19.3 +/- 6.7% (P < 0.001) in the distal and proximal regions respectively, and by 13.0 +/- 7.2% (P < 0.001) in the central region of the muscle. Hypertrophy was significantly different between and within the four constituents of the quadriceps. Biopsies of the vastus lateralis at mid-thigh did not show any increase in mean fibre cross-sectional area. Maximum isometric voluntary torque increased by 29.6 +/- 7.9%-21.1 +/- 8.6% (P < 0.01-0.05) between 100 degrees and 160 degrees of knee extension, but no change in the optimum angle (110 degrees-120 degrees) for torque generation was found. A 12.0 +/- 10.8% (P < 0.02) increase in torque per unit area together with a right shift in the IEMG-torque relation and no change in maximum IEMG were observed. Time to peak isometric torque decreased by 45.8% (P < 0.03) but no change in time to maximum IEMG was observed. In conclusion, strength training of the quadriceps results in a variable hypertrophy of its components without affecting its angle-torque relation. The increase in torque per unit area, in the absence of changes in IEMG, may indicate changes in muscle architecture. An increase in muscle-tendon stiffness may account for the decrease in time to peak torque.

The physiological cross-sectional areas (CSAp) of the vastus lateralis (VL), vastus intermedius (VI), vastus medialis (VM) and rectus femoris (RF) were obtained, in vivo, from the reconstructed muscle volumes, angles of pennation and distance between tendons of six healthy male volunteers by nuclear magnetic resonance imaging (MRI). In all subjects, the isometric maximum voluntary contraction strength (MVC) was measured at the optimum angle at which peak force occurred. The MVC developed at the ankle was 746.0 (SD 141.8) N and its tendon component (Ft), given by a mechanical advantage of 0.117 (SD 0.010), was 6.367 (SD 1.113) kN. To calculate the force acting along the fibres (Ff) of each muscle, Ft was divided by the cosine of the angle of pennation and multiplied for (CSAp.sigma CSAp-1), where sigma CSAp was the sum of CSAp of the four muscles. The resulting Ff values of VL, VI, VM and RF were: 1.452 (SD 0.531) kN, 1.997 (SD 0.187) kN, 1.914 (SD 0.827) kN, and 1.601 (SD 0.306) kN, respectively. The stress of each muscle was obtained by dividing these forces for the respective CSAp which was: 6.24 x 10(-3) (SD 2.54 x 10(-3)) m2 for VL, 8.35 x 10(-3) (SD 1.17 x 10(-3)) m2 for VI, 6.80 x 10(-3) (SD 2.66 x 10(-3)) m2 for VM and 6.62 x 10(-3) (SD 1.21 x 10(-3)) m2 for RF. The mean value of stress of VL, VI, VM and RF was 250 (SD 19) kN m-2; this value is in good agreement with data on animal muscle and those on human parallel-fibred muscle.