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André Uitterlinden and colleagues report a genome-wide association study for age at natural menopause, from the Rotterdam Study and TwinsUK, with replication in additional cohorts. They report three loci associated with age at natural menopause, which is a known risk factor for several cancers, osteoporosis and cardiovascular disease. We conducted a genome-wide association study for age at natural menopause in 2,979 European women and identified six SNPs in three loci associated with age at natural menopause: chromosome 19q13.4 (rs1172822; –0.4 year per T allele (39%); P = 6.3 × 10 −11 ), chromosome 20p12.3 (rs236114; +0.5 year per A allele (21%); P = 9.7 × 10 −11 ) and chromosome 13q34 (rs7333181; +0.5 year per A allele (12%); P = 2.5 × 10 −8 ). These common genetic variants regulate timing of ovarian aging, an important risk factor for breast cancer, osteoporosis and cardiovascular disease.

Among patients with leiomyosarcoma, a combination of doxorubicin and trabectedin with prolonged trabectedin maintenance therapy led to longer overall survival than doxorubicin alone (median, 33 vs. 24 months).

Metastatic leiomyosarcomas have a poor prognosis, and currently doxorubicin alone is used as the standard first-line treatment. Doxorubicin combined with trabectedin has shown promising results in phase 1 and 2 studies. We aimed to identify and compare the progression-free survival of patients with metastatic or unresectable uterine or soft tissue leiomyosarcoma treated with doxorubicin and trabectedin combined as first-line therapy versus doxorubicin alone in a phase 3 trial. LMS-04 was a randomised, multicentre, open-label, superiority phase 3 trial, which included patients from 20 centres of the French Sarcoma Group (anticancer centers or hospitals with an oncological unit) in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–1, and had metastatic or relapsed unresectable leiomyosarcomas that had not previously been treated with chemotherapy. Patients were randomly assigned (1:1), by means of an interactive web response system (permuted blocks of different sizes from two to six), to receive either intravenous doxorubicin alone (75 mg/m2) once every 3 weeks for up to six cycles or of intravenous doxorubicin (60 mg/m2) plus intravenous trabectedin (1·1 mg/m2) once every 3 weeks up to six cycles followed by maintenance with trabectedin alone. Surgery for residual disease was allowed in both groups after six cycles of treatment. Randomisation was stratified by tumour location (uterine vs soft tissue) and disease (locally advanced vs metastatic). The primary endpoint was progression-free survival assessed by blinded independent central review and according to Response Evaluation Criteria in Solid Tumours 1.1 criteria. Efficacy analyses were performed on all randomly assigned patients, based on the intention-to-treat principle. The safety population included all randomly assigned patients who received at least one cycle of treatment. This trial is registered with ClinicalTrials.gov, NCT02997358, and is closed to enrolment. Between Jan 18, 2017, and March 21, 2019, 150 patients were enrolled (67 with uterine leiomyosarcomas and 83 with soft tissue leiomyosarcomas) and included in the intention-to-treat population: 76 in the doxorubicin alone group and 74 in the doxorubicin plus trabectedin group. The median duration of follow-up was 36·9 months (IQR 30·0–43·2) in the doxorubicine group and 38·8 months (32·7–44·2) in the doxorubicin plus trabectedin group. Median progression-free survival was significantly longer with doxorubicin plus trabectedin versus doxorubicin alone (12·2 months [95% CI 10·1–15·6] vs 6·2 months [4·1–7·1]; adjusted hazard ratio 0·41 [95% CI 0·29–0·58]; p<0·0001). The most common grade 3–4 adverse events were neutropenia (ten [13%] of 75 patients in the doxorubicin alone group vs 59 [80%] in the doxorubicin plus trabectedin group), anaemia (four [5%] vs 23 [31%]), thrombocytopenia (0 vs 35 [47%]), and febrile neutropenia (seven [9%] vs 21 [28%]). Nine (12%) patients in the doxorubicin alone group and 15 (201%) patients in the doxorubicin plus trabectedin group has serious adverse events. There was only one treatment-related death, reported in the doxorubicin alone group (cardiac failure). Doxorubicin plus trabectedin in first-line therapy was found to significantly increase progression-free survival in patients with metastatic or unresectable leiomyosarcomas compared with doxorubicin alone, despite a higher but manageable toxicity, and could be considered an option for the first-line treatment of metastatic leiomyosarcomas. PharmaMar.

Sclerotinia sclerotiorum and Botrytis cinerea are closely related necrotrophic plant pathogenic fungi notable for their wide host ranges and environmental persistence. These attributes have made these species models for understanding the complexity of necrotrophic, broad host-range pathogenicity. Despite their similarities, the two species differ in mating behaviour and the ability to produce asexual spores. We have sequenced the genomes of one strain of S. sclerotiorum and two strains of B. cinerea. The comparative analysis of these genomes relative to one another and to other sequenced fungal genomes is provided here. Their 38-39 Mb genomes include 11,860-14,270 predicted genes, which share 83% amino acid identity on average between the two species. We have mapped the S. sclerotiorum assembly to 16 chromosomes and found large-scale co-linearity with the B. cinerea genomes. Seven percent of the S. sclerotiorum genome comprises transposable elements compared to <1% of B. cinerea. The arsenal of genes associated with necrotrophic processes is similar between the species, including genes involved in plant cell wall degradation and oxalic acid production. Analysis of secondary metabolism gene clusters revealed an expansion in number and diversity of B. cinerea-specific secondary metabolites relative to S. sclerotiorum. The potential diversity in secondary metabolism might be involved in adaptation to specific ecological niches. Comparative genome analysis revealed the basis of differing sexual mating compatibility systems between S. sclerotiorum and B. cinerea. The organization of the mating-type loci differs, and their structures provide evidence for the evolution of heterothallism from homothallism. These data shed light on the evolutionary and mechanistic bases of the genetically complex traits of necrotrophic pathogenicity and sexual mating. This resource should facilitate the functional studies designed to better understand what makes these fungi such successful and persistent pathogens of agronomic crops.

A large set of genes was identified in the phytopathogenic fungus Botrytis cinerea by using an expressed sequence tag approach. The fungus was grown in axenic culture and a cDNA library was produced. From this library, 6559 ESTs were obtained. The combined sequences represent 3026 unisequences that corresponds to approximately one-quarter of the estimated total number of genes in B. cinerea. Approximately 18% of the ESTs showed significant similarities with genes coding for proteins with known functions, approximately 56% were similar to genes coding for proteins with unknown functions and approximately 26% were orphans. A substantial B. cinerea gene inventory including putative virulence factors was therefore obtained and is now available at the Génoplante-Info Database interface (http://urgi.infobiogen.fr///Projects/GPiDB/Interface/).

OBJECTIVES. We studied the risk and circumstances of separation (due to either maternal death or drug use) between women infected by human immunodeficiency virus (HIV) type 1 and their children. METHODS. This analysis was based on the French Prospective Study of Infants Born to HIV-seropositive Women (1986 through 1993). Data recorded at each follow-up visit included the mother's effective presence with the child and the child's care after separation. RESULTS. A child's cumulative risk of long-term or permanent separation from his or her mother was 37% at 60 months. Maternal drug use was associated with an added risk during the child's first years (adjusted relative risk [RR]=3.4, 95% confidence interval [CI]=2.3, 5.0). The risk among drug users was even higher when the mother used injection drugs during pregnancy (adjusted RR=2.9, 95% CI=1.9, 4.3). Risk of early separation related to drug use tended to diminish since survey initiation. After separation, 57% of the children were placed through child welfare services and 43% were cared for by relatives. CONCLUSIONS. In the French Prospective Study, 2% to 3% of HIV-infected children were separated each year from their mothers as a result of the mothers death from acquired immunodeficiency syndrome (AIDS). Separations related to drug use have decreased over the years, and the family is becoming the most frequent carer after separation.