Adverse prognostic and predictive significance of low DNA-dependent protein kinase catalytic subunit (DNA-PKcs) expression in early-stage breast cancers

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a serine threonine kinase belonging to the PIKK family (phosphoinositide 3-kinase-like-family of protein kinase), is a critical component of the non-homologous end joining (NHEJ) pathway required for the repair of DNA double strand breaks. DNA-PKcs may be involved in breast cancer pathogenesis. Methods: We evaluated clinicopathological significance of DNA-PKcs protein expression in 1161 tumours and DNA-PKcs mRNA expression in 1950 tumours. We correlated DNA-PKcs to other markers of aggressive phenotypes, DNA repair, apoptosis and cell cycle regulation. Results: Low DNA-PKcs protein expression was associated with higher tumour grade, higher mitotic index, tumour de-differentiation and tumour type (ps<0.05). Absence of BRCA1, low XRCC1/SMUG1/APE1/Polβ were also more likely in low DNA-PKcs expressing tumours (ps<0.05). Low DNA-PKcs protein expression was significantly associated with worse breast cancer specific survival (BCCS) in univariate and multivariate analysis (ps<0.01). At the mRNA level, low DNA-PKcs was associated with PAM50.Her2 and PAM50.LumA molecular phenotypes (ps<0.01) and poor BCSS. In patients with ER positive tumours who received endocrine therapy, low DNA-PKcs (protein and mRNA) was associated with poor survival. In ER negative patients, low DNA-PKcs mRNA remains significantly associated with adverse outcome. Conclusions: Our study suggests that low DNA-PKcs expression may have prognostic and predictive significance in breast cancers

Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality: The CAP Randomized Clinical Trial

IMPORTANCE Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. OBJECTIVE To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer-specific mortality. DESIGN, SETTING, AND PARTICIPANTS The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. INTERVENTION An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. MAIN OUTCOMES AND MEASURES Primary outcome: prostate cancer-specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. RESULTS Among 415 357 randomizedmen(mean [SD] age, 59.0[5.6] years), 189 386 in the intervention group and 219 439 in the control groupwere included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%)attended the PSAtesting clinic and 67 313 (36%) underwent PSAtesting. Of 64 436 with a valid PSAtest result, 6857 (11%) had a PSA level between 3 ng/mLand 19.9 ng/mL, ofwhom5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, -0.013 per 1000 person-years [95%CI, -0.047 to0.022]; rate ratio [RR] ,0.96 [95%CI,0.85 to 1.08]; P = .50). The number diagnosed with prostate cancerwas higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95%CI, 1.14 to 1.25] ; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lowerwere identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%] ) (difference per 1000 men, 6.11 [95%CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, therewere 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR,0.99 [95%CI,0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RRwas0.93 (95%CI,0.67 to 1.29; P = .66). CONCLUSIONS AND RELEVANCE Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. TRIAL REGISTRATION ISRCTN Identifier: ISRCTN92187251

Selected static foot assessments do not predict medial longitudinal arch motion during running

Background: Static assessments of the foot are commonly advocated within the running community to classify the foot with a view to recommending the appropriate type of running shoe. The aim of this work was to determine whether selected static foot assessment could predict medial longitudinal arch (MLA) motion during running. Methods: Fifteen physically active males (27 ± 5 years, 1.77 ± 0.04m, 80 ± 10kg) participated in the study. Foot Posture Index (FPI-6), MLA angle and rearfoot angle were measured in a relaxed standing position. MLA motion was calculated using the position of retro-reflective markers tracked by a VICON motion analysis system, while participants ran barefoot on a treadmill at a self-selected pace (2.8 ± 0.5m.s-1). Bivariate linear regression was used to determine whether the static measures predicted MLA deformation and MLA angles at initial contact, midsupport and toe off. Results: All three foot classification measures were significant predictors of MLA angle at initial contact, midsupport and toe off (p < .05) explaining 41-90% of the variance. None of the static foot classification measures were significant predictors of MLA deformation during the stance phase of running. Conclusion: Selected static foot measures did not predict dynamic MLA deformation during running. Given that MLA deformation has theoretically been linked to running injuries, the clinical relevance of predicting MLA angle at discrete time points during the stance phase of running is questioned. These findings also question the validity of the selected static foot classification measures when looking to characterise the foot during running. This indicates that alternative means of assessing the foot to inform footwear selection are required

Limits on WWZ and WW\gamma couplings from p\bar{p}\to e\nu jj X events at \sqrt{s} = 1.8 TeV

We present limits on anomalous WWZ and WW-gamma couplings from a search for WW and WZ production in p-bar p collisions at sqrt(s)=1.8 TeV. We use p-bar p -> e-nu jjX events recorded with the D0 detector at the Fermilab Tevatron Collider during the 1992-1995 run. The data sample corresponds to an integrated luminosity of 96.0+-5.1 pb^(-1). Assuming identical WWZ and WW-gamma coupling parameters, the 95% CL limits on the CP-conserving couplings are -0.33<lambda<0.36 (Delta-kappa=0) and -0.43<Delta-kappa<0.59 (lambda=0), for a form factor scale Lambda = 2.0 TeV. Limits based on other assumptions are also presented.Comment: 11 pages, 2 figures, 2 table

Search For Heavy Pointlike Dirac Monopoles

We have searched for central production of a pair of photons with high transverse energies in $p\bar p$ collisions at $\sqrt{s} = 1.8$ TeV using $70 pb^{-1}$ of data collected with the D\O detector at the Fermilab Tevatron in 1994--1996. If they exist, virtual heavy pointlike Dirac monopoles could rescatter pairs of nearly real photons into this final state via a box diagram. We observe no excess of events above background, and set lower 95% C.L. limits of $610, 870, or 1580 GeV/c^2$ on the mass of a spin 0, 1/2, or 1 Dirac monopole.Comment: 12 pages, 4 figure

The Dijet Mass Spectrum and a Search for Quark Compositeness in bar{p}p Collisions at sqrt{s} = 1.8 TeV

Using the DZero detector at the 1.8 TeV pbarp Fermilab Tevatron collider, we have measured the inclusive dijet mass spectrum in the central pseudorapidity region |eta_jet| < 1.0 for dijet masses greater than 200 Gev/c^2. We have also measured the ratio of spectra sigma(|eta_jet| < 0.5)/sigma(0.5 < |eta_jet| < 1.0). The order alpha_s^3 QCD predictions are in good agreement with the data and we rule out models of quark compositeness with a contact interaction scale < 2.4 TeV at the 95% confidence level.Comment: 11 pages, 4 figures, 2 tables, submitted to Phys. Rev. Let

Search for High Mass Photon Pairs in p-pbar --> gamma-gamma-jet-jet Events at sqrt(s)=1.8 TeV

A search has been carried out for events in the channel p-barp --> gamma gamma jet jet. Such a signature can characterize the production of a non-standard Higgs boson together with a W or Z boson. We refer to this non-standard Higgs, having standard model couplings to vector bosons but no coupling to fermions, as a "bosonic Higgs." With the requirement of two high transverse energy photons and two jets, the diphoton mass (m(gamma gamma)) distribution is consistent with expected background. A 90(95)% C.L. upper limit on the cross section as a function of mass is calculated, ranging from 0.60(0.80) pb for m(gamma gamma) = 65 GeV/c^2 to 0.26(0.34) pb for m(gamma gamma) = 150 GeV/c^2, corresponding to a 95% C.L. lower limit on the mass of a bosonic Higgs of 78.5 GeV/c^2.Comment: 9 pages, 3 figures. Replacement has new H->gamma gamma branching ratios and corresponding new mass limit

Zgamma Production in pbarp Collisions at sqrt(s)=1.8 TeV and Limits on Anomalous ZZgamma and Zgammagamma Couplings

We present a study of Z +gamma + X production in p-bar p collisions at sqrt{S}=1.8 TeV from 97 (87) pb^{-1} of data collected in the eegamma (mumugamma) decay channel with the D0 detector at Fermilab. The event yield and kinematic characteristics are consistent with the Standard Model predictions. We obtain limits on anomalous ZZgamma and Zgammagamma couplings for form factor scales Lambda = 500 GeV and Lambda = 750 GeV. Combining this analysis with our previous results yields 95% CL limits |h{Z}_{30}| < 0.36, |h{Z}_{40}| < 0.05, |h{gamma}_{30}| < 0.37, and |h{gamma}_{40}| < 0.05 for a form factor scale Lambda=750 GeV.Comment: 17 Pages including 2 Figures. Submitted to PR