SETD2 haploinsufficiency for microtubule methylation is an early driver of genomic instability in renal cell carcinoma

Loss of the short arm of chromosome 3 (3p) occurs early in >95% of clear cell renal cell carcinoma (ccRCC). Nearly ubiquitous 3p loss in ccRCC suggests haploinsufficiency for 3p tumor suppressors as early drivers of tumorigenesis. We previously reported methyltransferase SETD2, which trimethylates H3 histones on lysine 36 (H3K36me3) and is located in the 3p deletion, to also trimethylate microtubules on lysine 40 (aTubK40me3) during mitosis, with aTubK40me3 required for genomic stability. We now show that monoallelic, Setd2-deficient cells retaining H3K36me3, but not aTubK40me3, exhibit a dramatic increase in mitotic defects and micronuclei count, with increased viability compared with biallelic loss. In SETD2-inactivated human kidney cells, rescue with a pathogenic SETD2 mutant deficient for microtubule (aTubK40me3), but not histone (H3K36me3) methylation, replicated this phenotype. Genomic instability (micronuclei) was also a hallmark of patient-derived cells from ccRCC. These data show that the SETD2 tumor suppressor displays a haploinsufficiency phenotype disproportionately impacting microtubule methylation and serves as an early driver of genomic instability. Significance: Loss of a single allele of a chromatin modifier plays a role in promoting oncogenesis, underscoring the growing relevance of tumor suppressor haploinsufficiency in tumorigenesis

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis

Background: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. Methods and findings: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. Conclusion: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.info:eu-repo/semantics/publishedVersio

Growth and CD4 patterns of adolescents living with perinatally acquired HIV worldwide, a CIPHER cohort collaboration analysis

Introduction: Adolescents living with HIV are subject to multiple co-morbidities, including growth retardation and immunodeficiency. We describe growth and CD4 evolution during adolescence using data from the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) global project. Methods: Data were collected between 1994 and 2015 from 11 CIPHER networks worldwide. Adolescents with perinatally acquired HIV infection (APH) who initiated antiretroviral therapy (ART) before age 10 years, with at least one height or CD4 count measurement while aged 10–17 years, were included. Growth was measured using height-for-age Z-scores (HAZ, stunting if <-2 SD, WHO growth charts). Linear mixed-effects models were used to study the evolution of each outcome between ages 10 and 17. For growth, sex-specific models with fractional polynomials were used to model non-linear relationships for age at ART initiation, HAZ at age 10 and time, defined as current age from 10 to 17 years of age. Results: A total of 20,939 and 19,557 APH were included for the growth and CD4 analyses, respectively. Half were females, two-thirds lived in East and Southern Africa, and median age at ART initiation ranged from <3 years in North America and Europe to >7 years in sub-Saharan African regions. At age 10, stunting ranged from 6% in North America and Europe to 39% in the Asia-Pacific; 19% overall had CD4 counts <500 cells/mm3. Across adolescence, higher HAZ was observed in females and among those in high-income countries. APH with stunting at age 10 and those with late ART initiation (after age 5) had the largest HAZ gains during adolescence, but these gains were insufficient to catch-up with non-stunted, early ART-treated adolescents. From age 10 to 16 years, mean CD4 counts declined from 768 to 607 cells/mm3. This decline was observed across all regions, in males and females. Conclusions: Growth patterns during adolescence differed substantially by sex and region, while CD4 patterns were similar, with an observed CD4 decline that needs further investigation. Early diagnosis and timely initiation of treatment in early childhood to prevent growth retardation and immunodeficiency are critical to improving APH growth and CD4 outcomes by the time they reach adulthood

Oxidation Behaviors of Porous Ferritic Stainless Steel Support for Metal-supported SOFC

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IMPROVEMENT OF OVERALL SURVIVAL WITH PRIMARY BREAST CANCER WITH MICROMESTASES TO THE BONE MARROW BY ADJUVANT CLODRONATE THERAPY

Supplementation of oral clodronate to postoperative adjuvant treatment for breast cancer (BC) considerably improves overall and relapse-free survival rates. The paper gives the results of a long-term follow-up of patients during a prospective randomized controlled study.Subjects and methods. The study included patients with primary BC receiving clodronate in a dose of 1600 mg/day in combination with the conventional adjuvant therapy for BC.Results. An analysis of 290 of 302 patients indicated a significant increase in overall survival in the clodronate group at a median fol- low-up of 103±12 months; during 8.5 years after primary surgical treatment, 20.4% and 40.7% of patients died in the clodronate and control groups, respectively (p = 0.04). The clodronate group did not show a considerable reduction in the rate of metastatic lesions in the bone and visceral organs or an increase in the relapse-free period following 36- and 55-month follow-ups.Conclusions. The findings of better late overall survival rates confirm the results of earlier studies of oral clodronate in combination with the conventional adjuvant therapy for BC

Human epithelial model systems for the study of Candida infections in vitro. Pt.I: Adhesion to epithelial models

Adhesion to host tissue represents one of the first steps during the early phase of fungal infections. In order to mediate pathogenesis in the infected host, this process is crucial for colonization and subsequent penetration of the respective tissue. In vivo analyses of the adhesion process in whole organisms are limited because of difficulties in providing reproducible and comparable conditions in the host environment. Therefore, in vitro assays provide the opportunity to study such processes under more defined conditions thus allowing for the analysis of events that are involved in more detail. Here we describe an in vitro adhesion assay making use of human epithelial cell lines to study fungal associations with host epithelia. This assay not only is suited to determine the rate of adhesion in a time-dependent manner but also facilitates global transcriptional profiling in order to determine the fungal response during adhesion at the molecular level