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

mTOR signaling in proteostasis and its relevance to autism spectrum disorders

Proteins are extremely labile cellular components, especially at physiological temperatures. The appropriate regulation of protein levels, or proteostasis, is essential for all cells. In the case of highly polarized cells like neurons, proteostasis is also crucial at synapses, where quick confined changes in protein composition occur to support synaptic activity and plasticity. The accurate regulation of those cellular processes controlling protein synthesis and degradation is necessary for proteostasis, and its deregulation has deleterious consequences in brain function. Alterations in those cellular mechanisms supporting synaptic protein homeostasis have been pinpointed in autism spectrum disorders such as tuberous sclerosis, neurofibromatosis 1, PTEN-related disorders, fragile X syndrome, MECP2 disorders and Angelman syndrome. Proteostasis alterations in these disorders share the alterations in mechanistic/mammalian target of rapamycin (mTOR) signaling pathway, an intracellular pathway with key synaptic roles. The aim of the present review is to describe the recent literature on the major cellular mechanisms involved in proteostasis regulation in the synaptic context, and its association with mTOR signaling deregulations in various autism spectrum disorders. Altogether, the cellular and molecular mechanisms in synaptic proteostasis could be the foundation for novel shared therapeutic strategies that would take advantage of targeting common disorder mechanisms.This review was supported by grant BFU2015-68568-P (MINECO/FEDER, EU) to AO

Search for the lepton flavor violating decay Z -> e mu in pp collisions at root s=8 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for the lepton flavor violating process Z -> e mu in pp collisions using 20.3 fb(-1) of data collected at root s = 8 TeV. An enhancement in the e mu invariant mass spectrum is searched for at the Z-boson mass. The number of Z bosons produced in the data sample is estimated using events of similar topology, Z -> ee and mu mu, significantly reducing the systematic uncertainty in the measurement. There is no evidence of an enhancement at the Z-boson mass, resulting in an upper limit on the branching fraction, B(Z -> e mu) < 7.5 x 10(-7) at the 95% confidence level

Search for pair and single production of new heavy quarks that decay to a Z boson and a third-generation quark in pp collisions at root s=8 TeV with the ATLAS detector

A search is presented for the production of new heavy quarks that decay to a Z boson and a third-generation Standard Model quark. In the case of a new charge +2/3 quark (T), the decay targeted is T -> Zt, while the decay targeted for a new charge -1/3 quark (B) is B -> Zb. The search is performed with a dataset corresponding to 20.3 fb(-1) of p p collisions at root s = 8TeV recorded in 2012 with the ATLAS detector at the CERN Large Hadron Collider. Selected events contain a high transverse momentum Z boson candidate reconstructed from a pair of oppositely charged same-flavor leptons (electrons or muons), and are analyzed in two channels defined by the absence or presence of a third lepton. Hadronic jets, in particular those with properties consistent with the decay of a b-hadron, are also required to be present in selected events. Different requirements are made on the jet activity in the event in order to enhance the sensitivity to either heavy quark pair production mediated by the strong interaction, or single production mediated by the electroweak interaction. No significant excess of events above the Standard Model expectation is observed, and lower limits are derived on the mass of vector-like T and B quarks under various branching ratio hypotheses, as well as upper limits on the magnitude of electroweak coupling parameters

Measurement of the forward-backward asymmetry of electron and muon pair-production in pp collisions at s ? =7

This paper presents measurements from the ATLAS experiment of the forward-backward asymmetry in the reaction pp -> Z/gamma* -> l(+)l(-), with l being electrons or muons, and the extraction of the effective weak mixing angle. The results are based on the full set of data collected in 2011 in pp collisions at the LHC at root s = 7 TeV, corresponding to an integrated luminosity of 4.8 fb(-1). The measured asymmetry values are found to be in agreement with the corresponding Standard Model predictions. The combination of the muon and electron channels yields a value of the effective weak mixing angle of sin(2) theta(lept)(eff) = 0.2308 +/- 0.0005(stat.)+/- 0.0006(syst.)+/- 0.0009(PDF), where the first uncertainty corresponds to data statistics, the second to s ystematic effects and the third to knowledge of the parton density functions. This result agrees with the current world average from the Particle Data Group fit

Flavor tagged time-dependent angular analysis of the B-s(0) -> J/psi phi decay and extraction of Delta Gamma(s) and the weak phase phi(s) in ATLAS

A measurement of the B-s(0) -> J/psi phi decay parameters, updated to include flavor tagging is reported using 4.9 fb(-1) of integrated luminosity collected by the ATLAS detector from root s = 7 TeV pp collisions recorded in 2011 at the LHC. The values measured for the physical parameters are phi(s) = 0.12 +/- 0.25(stat) +/- 0.05(syst) rad Delta Gamma(s) = 0.053 +/- 0.021(stat) +/- 0.010(syst) ps(-1) Gamma(s) = 0.677 +/- 0.007(stat) +/- 0.004(syst) ps(-1) vertical bar A(parallel to)(0)vertical bar(2) = 0.220 +/- 0.008(stat) +/- 0.009(syst) vertical bar A(0)(0)vertical bar(2) = 0.529 +/- 0.006(stat) +/- 0.012(syst) delta(perpendicular to) = 3.89 +/- 0.47(stat) +/- 0.11(syst) rad where the parameter Delta Gamma(s) is constrained to be positive. The S-wave contribution was measured and found to be compatible with zero. Results for phi(s) and Delta Gamma(s) are also presented as 68% and 95% likelihood contours, which show agreement with the Standard Model expectations

Search for squarks and gluinos with the ATLAS detector in final states with jets and missing transverse momentum using root s=8 TeV proton-proton collision data

A search for squarks and gluinos in final states containing high-pT jets, missing transverse momentum and no electrons or muons is presented. The data were recorded in 2012 by the ATLAS experiment in root s = 8 TeV proton-proton collisions at the Large Hadron Collider, with a total integrated luminosity of 20.3 fb(-1). Results are interpreted in a variety of simplified and specific supersymmetry-breaking models assuming that R-parity is conserved and that the lightest neutralino is the lightest supersymmetric particle. An exclusion limit at the 95% confidence level on the mass of the gluino is set at 1330 GeV for a simplified model incorporating only a gluino and the lightest neutralino. For a simplified model involving the strong production of first- and second-generation squarks, squark masses below 850 GeV (440 GeV) are excluded for a massless lightest neutralino, assuming mass degenerate ( single light-flavour) squarks. In mSUGRA/CMSSM models with tan beta = 30, A(0) = -2m(0) and mu > 0, squarks and gluinos of equal mass are excluded for masses below 1700 GeV. Additional limits are set for non-universal Higgs mass models with gaugino mediation and for simplified models involving the pair production of gluinos, each decaying to a top squark and a top quark, with the top squark decaying to a charm quark and a neutralino. These limits extend the region of supersymmetric parameter space excluded by previous searches with the ATLAS detector

Search for the b(b)over-bar decay of the Standard Model Higgs boson in associated (W/Z)H production with the ATLAS detector

A search for the b (b) over bar decay of the Standard Model Higgs boson is performed with the ATLAS experiment using the full dataset recorded at the LHC in Run 1. The integrated luminosities used are 4.7 and 20.3 fb(-1) from pp collisions at root s = 7 and 8 TeV, respectively. The processes considered are associated (WIZ)H production, where W -> e nu/mu nu, Z -> ee/mu mu, and Z -> nu nu. The observed (expected) deviation from the backgroundonly hypothesis corresponds to a significance of 1.4 (2.6) standard deviations and the ratio of the measured signal yield to the Standard Model expectation is found to be mu = 0.52 +/- 0.32 (stat.) +/- 0.24 (syst.) for a Higgs boson mass of 125.36 GeV. The analysis procedure is validated by a measurement of the yield of (W/Z)Z production with Z -> b (b) over bar in the same final states as for the Higgs boson search, from which the ratio of the observed signal yield to the Standard Model expectation is found to be 0.74 +/- 0.09 (stat.) +/- 0.14 (syst.)

Centrality and rapidity dependence of inclusive jet production in root(NN)-N-S=5.02 TeV proton-lead collisions with the ATLAS detector

Measurements of the centrality and rapidity dependence of inclusive jet production in root(NN)-N-S = 5.02 TeV proton-lead (p + Pb) collisions and the jet cross-section in root s = 2.76 TeV proton-proton collisions are presented. These quantities are measured in datasets corresponding to an integrated luminosity of 27.8 nb(-1) and 4.0 pb(-1), respectively, recorded with the ATLAS detector at the Large Hadron Collider in 2013. The p + Pb collision centrality was characterised using the total transverse energy measured in the pseudorapidity interval -4.9 < eta < -3.2 in the direction of the lead beam. Results are presented for the double-differential per-collision yields as a function of jet rapidity and transverse momentum (p(T)) for minimum-bias and centrality-selected p + Pb collisions, and are compared to the jet rate from the geometric expectation. The total jet yield in minimum-bias events is slightly enhanced above the expectation in a p(T)-dependent manner but is consistent with the expectation within uncertainties. The ratios of jet spectra from different centrality selections show a strong modification of jet production at all p(T) at forward rapidities and for large pT at mid-rapidity, which manifests as a suppression of the jet yield in central events and an enhancement in peripheral events. These effects imply that the factorisation between hard and soft processes is violated at an unexpected level in proton-nucleus collisions. Furthermore, the modifications at forward rapidities are found to be a function of the total jet energy only, implying that the violations may have a simple dependence on the hard parton-parton kinematics. (C) 2015 CERN for the benefit of the ATLAS Collaboration. Published by Elsevier B.V