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

Discovery of a hot, transiting, Earth-sized planet and a second temperate, non-transiting planet around the M4 dwarf GJ 3473 (TOI-488)

International audienceWe present the confirmation and characterisation of GJ 3473 b (G 50–16, TOI-488.01), a hot Earth-sized planet orbiting an M4 dwarf star, whose transiting signal (P = 1.1980035 ± 0.0000018 d) was first detected by the Transiting Exoplanet Survey Satellite (TESS). Through a joint modelling of follow-up radial velocity observations with CARMENES, IRD, and HARPS together with extensive ground-based photometric follow-up observations with LCOGT, MuSCAT, and MuSCAT2, we determined a precise planetary mass, Mb = 1.86 ± 0.30 M⊕, and radius, Rb = 1.264 ± 0.050 R⊕. Additionally, we report the discovery of a second, temperate, non-transiting planet in the system, GJ 3473 c, which has a minimum mass, Mc sin i = 7.41 ± 0.91 M⊕, and orbital period, Pc = 15.509 ± 0.033 d. The inner planet of the system, GJ 3473 b, is one of the hottest transiting Earth-sized planets known thus far, accompanied by a dynamical mass measurement, which makes it a particularly attractive target for thermal emission spectroscopy

Preserving accuracy in GenBank

GenBank, the public repository for nucleotide and protein sequences, is a critical resource for molecular biology, evolutionary biology, and ecology. While some attention has been drawn to sequence errors, common annotation errors also reduce the value of this database. In fact, for organisms such as fungi, which are notoriously difficult to identify, up to 20% of DNA sequence records may have erroneous lineage designations in GenBank. Gene function annotation in protein sequence databases is similarly error-prone. Because identity and function of new sequences are often determined by bioinformatic analyses, both types of errors are propagated into new accessions, leading to long-term degradation of the quality of the database. Currently, primary sequence data are annotated by the authors of those data, and can only be reannotated by the same authors. This is inefficient and unsustainable over the long term as authors eventually leave the field. Although it is possible to link third-party databases to GenBank records, this is a short-term solution that has little guarantee of permanence. Similarly, the current third-party annotation option in GenBank (TPA) complicates rather than solves the problem by creating an identical record with a new annotation, while leaving the original record unflagged and unlinked to the new record. Since the origin of public zoological and botanical specimen collections, an open system of cumulative annotation has evolved, whereby the original name is retained, but additional opinion is directly appended and used for filing and retrieval. This was needed as new specimens and analyses allowed for reevaluation of older specimens and the original depositors became unavailable. The time has come for the public sequence database to incorporate a community-curated, cumulative annotation process that allows third parties to improve the annotations of sequences when warranted by published peer-reviewed analyses.Fil: Bidartondo, Martin I.. Imperial College London; Reino Unido. Royal Botanic Gardens; Reino UnidoFil: Bruns, Thomas D.. University of California at Berkeley; Estados UnidosFil: Blackwell, Meredith. Louisiana State University; Estados UnidosFil: Edwards, Ivan. University of Michigan; Estados UnidosFil: Taylor, Andy F. S.. Swedish University of Agricultural Sciences; SueciaFil: Bianchinotti, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Centro de Recursos Naturales Renovables de la Zona Semiárida. Universidad Nacional del Sur. Centro de Recursos Naturales Renovables de la Zona Semiárida; Argentina. Universidad Nacional del Sur; ArgentinaFil: Padamsee, Mahajabeen. University of Minnesota; Estados UnidosFil: Callac, Philippe. Institut National de la Recherche Agronomique; FranciaFil: Lima, Nelson. Universidade do Minho; PortugalFil: White, Merlin M.. Boise State University; Estados UnidosFil: Barreau Daly, Camila. Centre National de la Recherche Scientifique; Francia. Institut National de la Recherche Agronomique; FranciaFil: Juncai, M. A.. Chinese Academy of Sciences; República de ChinaFil: Buyck, Bart. Museum National d'Histoire Naturelle; FranciaFil: Rabeler, Richard K.. University of Michigan; Estados UnidosFil: Liles, Mark R.. Auburn University; Estados UnidosFil: Estes, Dwayne. Austin Peay State University; Estados UnidosFil: Carter, Richard. Valdosta State University; Estados UnidosFil: Herr Jr., J. M.. University of South Carolina; Estados UnidosFil: Chandler, Gregory. University of North Carolina; Estados UnidosFil: Kerekes, Jennifer. University of California at Berkeley; Estados UnidosFil: Cruse Sanders, Jennifer. Salem College Herbarium; Estados UnidosFil: Galán Marquez, R.. Universidad de Alcalá; EspañaFil: Horak, Egon. Zurich Herbarium; SuizaFil: Fitzsimons, Michael. University of Chicago; Estados UnidosFil: Döering, Heidi. Royal Botanic Gardens; Reino UnidoFil: Yao, Su. China Center of Industrial Culture Collection; ChinaFil: Hynson, Nicole. University of California at Berkeley; Estados UnidosFil: Ryberg, Martin. University Goteborg; SueciaFil: Arnold, A. E.. University of Arizona; Estados UnidosFil: Hughes, Karen. University of Tennessee; Estados Unido

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)