Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Circulating microRNAs in sera correlate with soluble biomarkers of immune activation but do not predict mortality in ART treated individuals with HIV-1 infection: A case control study

Introduction: The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals. Materials and Methods: A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed. Results: None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR- 145 correlated with nadir CD4+ T cell count. Discussion: No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Study of 208Po Populated via β+/EC Decay

Data collected during a decay spectroscopy experiment at the ISOLDE Decay Station (IDS) in 2016, were used to investigate the structure of 208Po populated via the β+/EC decay of 208At. This decay, and resulting structure, was most recently studied in experiments which took place in the 1980s. Thus, the aim of this analysis was to take advantage of improvements in detector technology and radioactive beam production to establish an expanded level scheme below QEC = 4999(9) keV. From this work a total of 170 transitions and 58 states were observed, including 27 newly-observed states. Ninety-three of the transitions identified in this analysis differ from prior decay studies. These consist of 43 newly-observed transitions; 33 previously-observed 208Po γ rays placed in the level scheme through this analysis; and 17 transitions moved from previous placements. Spin-parities were assigned through a combination of γ-ray placements, previously-measured αK values, and restrictions resulting from β and γ decay selection rules. In addition, electron conversion coefficients were calculated for all transitions below 1 MeV, and log ft values were determined for all populated states using intensity imbalances. From this analysis, ∼46% of the decays were found to be first-forbidden, a significant increase from the ∼37% measured in the 1980s. It is suggested that the high first-forbidden proportion of 208At and surrounding β+/EC-decaying nuclei could provide a testing ground for models of first-forbidden decay. These can then be incorporated into larger β-decay studies in the region which lack relevant data points, such as models of r-process nucleosynthesis. In addition, a low-lying 3− state at 1995 keV, which had been previously assigned (2−,3−), was identified. Through comparisons with shell model calculations and considering the underlying shell structure, it was concluded that the low energy of the state was the result of configuration mixing of an abundance of 3− states. In particular, the strength of f7/2i13/2 contributions to the octupole from both proton particle and neutron hole excitations results in stronger mixing for 3− states in 208Po with dominant f7/2i13/2 configurations. Strong octupole collectivity in the region, and observed, low-energy, core-excited states in neighbouring nuclei suggest collective character for the 1995 keV state. Although no evidence of this was found in this analysis, it is anticipated that a high statistics Coulex experiment could provide further detail into the nature of the 1995 keV state

Ground-state β-decay spectroscopy of 187 Ta

Beta-decay spectroscopy of the 187 Ta ground state was performed at the KEK Isotope Separation System. β-delayed γ rays corresponding to the previously reported in-beam transitions were observed. The β-decay half-life of the 187 Ta ground state was determined to be 283(10) s by analyzing a time spectrum of β-γ coincidence events. The β-decay branching ratio and log(f t) values were evaluated for the first time. Based on the newly evaluated log(f t) values of >6.0 and a decay scheme, spin-parity values of I π = 7/2 + originating from the odd-proton orbit π 7/2[404] were assigned with high confidence, which is consistent with the systematics of neighboring odd-A nuclides

First direct observation of isomeric decay in neutron-rich odd-odd 186Ta

De-excitation γ rays associated with an isomeric state of 186 Ta were investigated. The isomers were produced in multinucleon transfer reactions between a 136 Xe beam and a natural W target, and were collected and separated by the KEK Isotope Separation System. Two γ transitions with energies of 161.1(2) and 186.8(1) keV associated with an isomeric decay were observed for the first time. The half-life of the isomeric state of the neutral atom 186m Ta was deduced as 17(2) s. Based on the comparison with the previous measurements of the isomeric state using the ESR storage ring at GSI Darmstadt and the coupling of angular momenta of individual particle orbitals in odd-odd nuclei, a decay scheme of 186m Ta was proposed

Competition between allowed and first forbidden β decays of 208 At and expansion of the 208 Po level scheme

The structure of 208 Po populated through the EC/β + decay of 208 At was investigated using γ-ray spectroscopy at the ISOLDE Decay Station. The presented level scheme contains 27 new excited states and 43 new transitions, as well as a further 50 previously-observed γ rays which have been (re)assigned a position. The level scheme was compared to shell model calculations. Through this analysis approximately half of the β decay strength of 208 At was found to proceed via allowed and half via first forbidden decay. The first forbidden transitions predominantly populate core excited states at high excitation energies, which was qualitatively understood using shell model considerations. This mass region provides an excellent testing ground for the competition between allowed and first forbidden β-decay calculations, important for the detailed understanding of the nucleosynthesis of heavy elements