DNA polymerase B deficiency is linked to aggressive breast cancer: a comprehensive analysis of gene copy number, mRNA and protein expression in multiple cohorts

Short arm of chromosome 8 is a hot spot for chromosomal breaks, losses and amplifications in breast cancer. Although such genetic changes may have phenotypic consequences, the identity of candidate gene(s) remains to be clearly defined. Pol β gene is localized to chromosome 8p12 - p11 and encodes a key DNA base excision repair protein. Pol β may be a tumour suppressor and involved in breast cancer pathogenesis. We conducted the first and the largest study to comprehensively evaluate pol β in breast cancer. We investigated pol β gene copy number changes in two cohorts (n=128 & n=1952), pol β mRNA expression in two cohorts (n=249 & n=1952) and pol β protein expression in two cohorts (n=1406 & n=252). Artificial neural network analysis for pol β interacting genes was performed in 249 tumours. For mechanistic insights, pol β gene copy number changes, mRNA and protein levels were investigated together in 1 28 tumours and validated in 1952 tumours. Low pol β mRNA expression as well as low pol β protein expression was associated high grade, lymph node positivity, pleomorphism, triple negative, basal - like phenotypes and poor survival (ps<0.001). In oestrogen receptor (ER) positive sub - group that received tamoxifen, low pol β protein remains associated with aggressive phenotype and poor survival (ps<0.001). Artificial neural network analysis revealed ER as a top pol β interacting gene. Mechanistically, there was strong positive correlation between pol β gene copy number changes and pol β mRNA expression (p<0.0000001) and between pol β mRNA and pol β protein expression (p<0.0000001). This is the first study to provide evidence that pol β deficiency is linked to aggressive breast cancer and may have prognostic and predictive significance in patients

Antenatal atazanavir: a retrospective analysis of pregnancies exposed to atazanavir.

INTRODUCTION: There are few data regarding the tolerability, safety, or efficacy of antenatal atazanavir. We report our clinical experience of atazanavir use in pregnancy. METHODS: A retrospective medical records review of atazanavir-exposed pregnancies in 12 London centres between 2004 and 2010. RESULTS: There were 145 pregnancies in 135 women: 89 conceived whilst taking atazanavir-based combination antiretroviral therapy (cART), "preconception" atazanavir exposure; 27 started atazanavir-based cART as "first-line" during the pregnancy; and 29 "switched" to an atazanavir-based regimen from another cART regimen during pregnancy. Gastrointestinal intolerance requiring atazanavir cessation occurred in five pregnancies. Self-limiting, new-onset transaminitis was most common in first-line use, occurring in 11.0%. Atazanavir was commenced in five switch pregnancies in the presence of transaminitis, two of which discontinued atazanavir with persistent transaminitis. HIV-VL < 50 copies/mL was achieved in 89.3% preconception, 56.5% first-line, and 72.0% switch exposures. Singleton preterm delivery (<37 weeks) occurred in 11.7% preconception, 9.1% first-line, and 7.7% switch exposures. Four infants required phototherapy. There was one mother-to-child transmission in a poorly adherent woman. CONCLUSIONS: These data suggest that atazanavir is well tolerated and can be safely prescribed as a component of combination antiretroviral therapy in pregnancy

Stringy black holes and energy conditions

The energy condition inequalities for the matter stress energy comprised out of the dilaton and Maxwell fields in the dilaton-Maxwell gravity theories emerging out of string theory are examined in detail. In the simplistic 1+1 dimensional models, $R\le 0$ (where $R$ is the Ricci scalar), turns out to be the requirement for ensuring focusing of timelike geodesics. In 3+1 dimensions, we outline the requirements on matter for pure dilaton theories-these in turn constrain the functional forms of the dilaton. Furthermore, in charged dilaton gravity a curious opposite behaviour of the matter stress energy w.r.t the violation/conservation of the Weak Energy Condition is noted for the electric and magnetic black hole metrics written in the string frame of reference. We also investigate the matter that is necessary for creating certain specific non-asymptotically flat black holes. For the electric and magnetic black hole metrics, strangely, matter satisfies the weak energy condition in the string frame. Finally, the Averaged Null Energy Condition is evaluated along radial null geodesics for each of these black hole spacetimes.Comment: 23 pages, RevTex, no figures, corrected and extended,to appear in Physical Review

Quantum Kinks: Solitons at Strong Coupling

We examine solitons in theories with heavy fermions. These ``quantum'' solitons differ dramatically from semi-classical (perturbative) solitons because fermion loop effects are important when the Yukawa coupling is strong. We focus on kinks in a $(1+1)$--dimensional $\phi^4$ theory coupled to fermions; a large-$N$ expansion is employed to treat the Yukawa coupling $g$ nonperturbatively. A local expression for the fermion vacuum energy is derived using the WKB approximation for the Dirac eigenvalues. We find that fermion loop corrections increase the energy of the kink and (for large $g$) decrease its size. For large $g$, the energy of the quantum kink is proportional to $g$, and its size scales as $1/g$, unlike the classical kink; we argue that these features are generic to quantum solitons in theories with strong Yukawa couplings. We also discuss the possible instability of fermions to solitons.Comment: 21 pp. + 2 figs., phyzzx, JHU-TIPAC-92001

Quantum solitons at strong coupling

We examine the effect of one loop quantum corrections on the formation of nontopological solitons in a strongly coupled scalar-fermionic Yukawa theory. The exact one fermion loop contribution is incorporated by using a nonlocal method to correct the local derivative expansion approximation (DE) of the effective action. As the Yukawa coupling is increased we find that the nonlocal corrections play an increasingly important role. The corrections cause the scalar field to increase in depth while maintaining its size. This increases the energy of the bag configuration, but this is compensated for by more tightly bound fermionic states with lower energy. In contrast to the semi-classical picture without quantum corrections, the binding energy is small, and the total energy scales directly with the Yukawa coupling. This confirms the qualitative behavior found in earlier work using the second order DE, although the quantitative solutions differ.Comment: 17 pages, 4 Postscript figures, REVTe

Right ventricular outflow reconstruction with cryopreserved homografts in pediatric patients: Intermediate-term follow-up with serial echocardiographic assessment

AbstractObjectives. This study was performed to assess by echocardiography the intermediate-term outcome of cryopreserved homografts employed in pulmonary outflow reconstruction in children and to validate the reliability of Doppler echocardiography in their evaluation.Background. Cryopreserved homografts have become the most widely used pulmonary conduits. Previous reports have shown the occurrence of homograft regurgitation in the immediate postoperative period and the propensity of regurgitation to progress. Although Doppler echocardiography has been useful in assessing extracardiac valved conduit stenosis, its reliability in assessing a large series of cryopreserved homografts has not been documented.Methods. Echocardiograms of 41 patients (43 homografts) who underwent operations between December 1986 and October 1992 were retrospectively reviewed. The median age of patients at operation was 37.5 months (range 3 to 333), and the median duration of follow-up was 28.5 months (range 1 to 68). Homograft regurgitation was classified on a scale of 0 to 4+. Pressure gradients across the homografts measured in 23 catheterizations were correlated with corresponding echocardiographic gradients.Results. Regurgitation: Homograft regurgitation occurred in 100% of patients at follow-up. Progression of severity >2 grades occurred during follow-up in 35% and was associated with operation before age 18 months (p < 0.002) and stenosis progression (p < 0.05) but not with homograft type (aortic or pulmonary). These data predict that 50% of patients operated on before 18 months of age will have severe regurgitation by 15 months postoperatively compared with only 15% operated on after 18 months. Stenosis: At follow-up, 51% of homografts had a stenotic gradient ≥25 mm Hg predominantly at the distal anastomosis, and stenosis progression was related to young age at operation (<18 months, p < 0.005) and small conduit size (p < 0.01). Fifty percent of conduits implanted before age 18 months could be predicted to stenose by 21.8 months compared with only 5% of those implanted after age 18 months. The gradient measured from Doppler echocardiography correlated well with the catheterization gradient (r = 0.86).Conclusions. Cryopreserved homograft dysfunction is frequent and progressive. Young age at operation (<18 months) predicts more rapid deterioration. Doppler echocardiography is reliable in assessing the systolic gradients across homografts. Serial echocardiographic assessment in the follow-up of these patients accurately characterizes these problems

Longitudinal grey and white matter changes in frontotemporal dementia and Alzheimer's disease

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD

Effect of tensor couplings in a relativistic Hartree approach for finite nuclei

The relativistic Hartree approach describing the bound states of both nucleons and anti-nucleons in finite nuclei has been extended to include tensor couplings for the $\omega$- and $\rho$-meson. After readjusting the parameters of the model to the properties of spherical nuclei, the effect of tensor-coupling terms rises the spin-orbit force by a factor of 2, while a large effective nucleon mass $m^{*}/M_{N} \approx 0.8$ sustains. The overall nucleon spectra of shell-model states are improved evidently. The predicted anti-nucleon spectra in the vacuum are deepened about 20 -- 30 MeV.Comment: 31 pages, 4 postscript figures include

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

Extensive Copy-Number Variation of Young Genes across Stickleback Populations

MM received funding from the Max Planck innovation funds for this project. PGDF was supported by a Marie Curie European Reintegration Grant (proposal nr 270891). CE was supported by German Science Foundation grants (DFG, EI 841/4-1 and EI 841/6-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript