Clonality and evolutionary history of rhabdomyosarcoma.

To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. We discover several early mutations in non-RAS mutated samples and predict them to be drivers in PFN-RMS including recurrent mutation of PKN1. In contrast, we find that PAX-fusion-positive (PFP) subtype tumors have undergone whole-genome duplication in the late stage of cancer evolutionary history and have acquired fewer mutations and subclones than PFN-RMS. Moreover we predict that the PAX3-FOXO1 fusion event occurs earlier than the whole genome duplication. Our findings provide information critical to the understanding of tumorigenesis of RMS

P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

An exploratory randomised controlled trial of a premises-level intervention to reduce alcohol-related harm including violence in the United Kingdom

<b>Background</b><p></p> To assess the feasibility of a randomised controlled trial of a licensed premises intervention to reduce severe intoxication and disorder; to establish effect sizes and identify appropriate approaches to the development and maintenance of a rigorous research design and intervention implementation.<p></p> <b>Methods</b><p></p> An exploratory two-armed parallel randomised controlled trial with a nested process evaluation. An audit of risk factors and a tailored action plan for high risk premises, with three month follow up audit and feedback. Thirty-two premises that had experienced at least one assault in the year prior to the intervention were recruited, match paired and randomly allocated to control or intervention group. Police violence data and data from a street survey of study premises’ customers, including measures of breath alcohol concentration and surveyor rated customer intoxication, were used to assess effect sizes for a future definitive trial. A nested process evaluation explored implementation barriers and the fidelity of the intervention with key stakeholders and senior staff in intervention premises using semi-structured interviews.<p></p> <b>Results</b><p></p> The process evaluation indicated implementation barriers and low fidelity, with a reluctance to implement the intervention and to submit to a formal risk audit. Power calculations suggest the intervention effect on violence and subjective intoxication would be raised to significance with a study size of 517 premises.<p></p> <b>Conclusions</b><p></p> It is methodologically feasible to conduct randomised controlled trials where licensed premises are the unit of allocation. However, lack of enthusiasm in senior premises staff indicates the need for intervention enforcement, rather than voluntary agreements, and on-going strategies to promote sustainability

Childhood leukaemia: long-term excess mortality and the proportion ‘cured'

Survival from childhood leukaemia has increased, but the proportion of children cured is unknown. The proportion ‘cured' is defined as the proportion of survivors for whom, as a group, there is no longer excess mortality compared to the general population. Average time to cure is defined as the time since diagnosis at which the excess mortality rate has declined to or below a predetermined small value. Data on children diagnosed with leukaemia during 1971–2000 in Great Britain were used to estimate trends in survival, the proportion cured and the average time to cure. Five-year survival for all types of leukaemia combined rose from 33 to 79% by 2000. The percentage cured rose from 25 to 68% by 1995; it is predicted to increase to 73% for those diagnosed more recently. Average time to cure increased from 12 years (95% confidence interval (CI): 11–14) to 19 years (95% CI: 14–26) for lymphoid leukaemia (average annual increase of 0.3 years; P<0.001), but remained at about 5 years for acute nonlymphoblastic leukaemia. The proportion of children cured of leukaemia has risen dramatically, but the period of excess mortality associated with lymphoid leukaemia has also increased, possibly because of late relapse, secondary malignancy and toxicity from treatment

Of monkeys and men:Impatience in perceptual decision-making

For decades sequential sampling models have successfully accounted for human and monkey decision-making, relying on the standard assumption that decision makers maintain a pre-set decision standard throughout the decision process. Based on the theoretical argument of reward rate maximization, some authors have recently suggested that decision makers become increasingly impatient as time passes and therefore lower their decision standard. Indeed, a number of studies show that computational models with an impatience component provide a good fit to human and monkey decision behavior. However, many of these studies lack quantitative model comparisons and systematic manipulations of rewards. Moreover, the often-cited evidence from single-cell recordings is not unequivocal and complimentary data from human subjects is largely missing. We conclude that, despite some enthusiastic calls for the abandonment of the standard model, the idea of an impatience component has yet to be fully established; we suggest a number of recently developed tools that will help bring the debate to a conclusive settlement

Hemiarthroplasty versus angle-stable locking compression plate osteosynthesis in the treatment of three- and four-part fractures of the proximal humerus in the elderly: design of a randomized controlled trial

ABSTRACT: BACKGROUND: The optimal surgical management of dislocated three- and four-part fractures of the proximal humerus in elderly patients remains unclear. Most used techniques are hemiarthroplasty and angle-stable locking compression plate osteosynthesis. In the current literature there is no evidence available presenting superior results between hemiarthroplasty and angle-stable locking compression plate osteosynthesis in terms of speed of recovery, pain, patient satisfaction, functional outcome, quality of life or complications. METHODS/DESIGN: A randomized controlled multicenter trial will be conducted. Patients older than 60 years of age with a dislocated three- or four-part fracture of the proximal humerus as diagnosed by X-rays and CT-scans will be included. Exclusion criteria are a fracture older than 14 days, multiple comorbidity, multitrauma, a pathological fracture, previous surgery on the injured shoulder, severely deranged function caused by a previous disease, "head-split" proximal humerus fracture and unwillingness or inability to follow instructions. Participants will be randomized between surgical treatment with hemiarthroplasty and angle-stable locking compression plate osteosynthesis. Measurements will take place preoperatively and 3 months, 6 months, 9 months, 12 months and 24 months postoperatively. Primary outcome measure is speed of recovery of functional capacity of the affected upper limb using the Disabilities of Arm, Shoulder and Hand score (DASH). Secondary outcome measures are pain, patient satisfaction, shoulder function, quality of life, radiological evaluation and complications. Data will be analyzed on an intention-to-treat basis, using univariate and multivariate analyses. DISCUSSION: Both hemiarthroplasty and angle-stable locking compression plate osteosynthesis are used in the current treatment of dislocated three-and four-part fractures of the proximal humerus. There is a lack of level-1 studies comparing these two most-used surgical treatment options. This randomized controlled multicenter trial has been designed to determine which surgical treatment option provides the fastest recovery of functional capacity of the affected upper limb, and will provide better outcomes in pain, satisfaction, shoulder function, quality of life, radiological evaluation and complications. TRIAL REGISTRATION NUMBER: The trial is registered in the Netherlands Trial Registry (NTR2461)

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models