Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer

Background: Defects in BRCA1, BRCA2, and other members of the homologous recombination pathway have potential therapeutic relevance when used to support agents that introduce or exploit double-stranded DNA breaks. This study examines the association between homologous recombination defects and genomic patterns of loss of heterozygosity (LOH). Methods: Ovarian tumours from two independent data sets were characterised for defects in BRCA1,BRCA2, and RAD51C, and LOH profiles were generated. Publically available data were downloaded for a third independent data set. The same analyses were performed on 57 cancer cell lines. Results: Loss of heterozygosity regions of intermediate size were observed more frequently in tumours with defective BRCA1 or BRCA2 (P=10−11). The homologous recombination deficiency (HRD) score was defined as the number of these regions observed in a tumour sample. The association between HRD score and BRCA deficiency was validated in two independent ovarian cancer data sets (P=10−5 and 10−29), and identified breast and pancreatic cell lines with BRCA defects. Conclusion: The HRD score appears capable of detecting homologous recombination defects regardless of aetiology or mechanism. This score could facilitate the use of PARP inhibitors and platinum in breast, ovarian, and other cancers

CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis.

Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive founder mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients

Assessment of anthelmintic efficacy of mebendazole in school children in six countries where soil-transmitted helminths are endemic

BACKGROUND: Robust reference values for fecal egg count reduction (FECR) rates of the most widely used anthelmintic drugs in preventive chemotherapy (PC) programs for controlling soil-transmitted helminths (STHs; Ascaris lumbricoides, Trichuris trichiura, and hookworm) are still lacking. However, they are urgently needed to ensure detection of reduced efficacies that are predicted to occur due to growing drug pressure. Here, using a standardized methodology, we assessed the FECR rate of a single oral dose of mebendazole (MEB; 500 mg) against STHs in six trials in school children in different locations around the world. Our results are compared with those previously obtained for similarly conducted trials of a single oral dose of albendazole (ALB; 400 mg). METHODOLOGY: The efficacy of MEB, as assessed by FECR, was determined in six trials involving 5,830 school children in Brazil, Cambodia, Cameroon, Ethiopia, United Republic of Tanzania, and Vietnam. The efficacy of MEB was compared to that of ALB as previously assessed in 8,841 school children in India and all the above-mentioned study sites, using identical methodologies. PRINCIPAL FINDINGS: The estimated FECR rate [95% confidence interval] of MEB was highest for A. lumbricoides (97.6% [95.8; 99.5]), followed by hookworm (79.6% [71.0; 88.3]). For T. trichiura, the estimated FECR rate was 63.1% [51.6; 74.6]. Compared to MEB, ALB was significantly more efficacious against hookworm (96.2% [91.1; 100], p CONCLUSIONS/SIGNIFICANCE: A minimum FECR rate of 95% for A. lumbricoides, 70% for hookworm, and 50% for T. trichiura is expected in MEB-dependent PC programs. Lower FECR results may indicate the development of potential drug resistance

CD8+ T-cells count in acute myocardial infarction in HIV diseases in a predominantly male cohort

Human Immunodeficiency Virus- (HIV-) infected persons have a higher risk for acute myocardial infarction (AMI) than HIV-uninfected persons. Earlier studies suggest that HIV viral load, CD4+ T-cell count, and antiretroviral therapy are associated with cardiovascular disease (CVD) risk. Whether CD8+ T-cell count is associated with CVD risk is not clear. We investigated the association between CD8+ T-cell count and incident AMI in a cohort of 73,398 people (of which 97.3% were men) enrolled in the U.S. Veterans Aging Cohort Study-Virtual Cohort (VACS-VC). Compared to uninfected people, HIV-infected people with high baseline CD8+ T-cell counts (\u3e1065 cells/mm3) had increased AMI risk (adjusted , 95% CI: 1.46 to 2.28). There was evidence that the effect of CD8+ T-cell tertiles on AMI risk differed by CD4+ T-cell level: compared to uninfected people, HIV-infected people with CD4+ T-cell counts ≥200 cells/mm3 had increased AMI risk with high CD8+ T-cell count, while those with CD4+ T-cell counts \u3c200 cells/mm3 had increased AMI risk with low CD8+ T-cell count. CD8+ T-cell counts may add additional AMI risk stratification information beyond that provided by CD4+ T-cell counts alone

The Role of Chest Imaging in Patient Management During the COVID-19 Pandemic: A Multinational Consensus Statement From the Fleischner Society.

With more than 900,000 confirmed cases worldwide and nearly 50,000 deaths during the first three months of 2020, the COVID-19 pandemic has emerged as an unprecedented healthcare crisis. The spread of COVID-19 has been heterogeneous, resulting in some regions having sporadic transmission and relatively few hospitalized patients with COVID-19 and others having community transmission that has led to overwhelming numbers of severe cases. For these regions, healthcare delivery has been disrupted and compromised by critical resource constraints in diagnostic testing, hospital beds, ventilators, and healthcare workers who have fallen ill to the virus exacerbated by shortages of personal protective equipment. While mild cases mimic common upper respiratory viral infections, respiratory dysfunction becomes the principal source of morbidity and mortality as the disease advances. Thoracic imaging with chest radiography (CXR) and computed tomography (CT) are key tools for pulmonary disease diagnosis and management, but their role in the management of COVID-19 has not been considered within the multivariable context of the severity of respiratory disease, pre-test probability, risk factors for disease progression, and critical resource constraints. To address this deficit, a multidisciplinary panel comprised principally of radiologists and pulmonologists from 10 countries with experience managing COVID-19 patients across a spectrum of healthcare environments evaluated the utility of imaging within three scenarios representing varying risk factors, community conditions, and resource constraints. Fourteen key questions, corresponding to 11 decision points within the three scenarios and three additional clinical situations, were rated by the panel based upon the anticipated value of the information that thoracic imaging would be expected to provide. The results were aggregated, resulting in five main and three additional recommendations intended to guide medical practitioners in the use of CXR and CT in the management of COVID-19

Expression and prognostic impact of lncRNAs in acute myeloid leukemia

Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged \u3e/=60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene (FLT3-ITD) and mutations in the NPM1, CEBPA, IDH2, ASXL1, and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [P \u3c 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [P \u3c 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) (P \u3c 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival

Epidemiological and clinical characteristics of international travelers with enteric fever and antibiotic resistance profiles of their isolates: A GeoSentinel analysis

Copyright © 2020 American Society for Microbiology. All Rights Reserved. Enteric fever, caused by Salmonella enterica serovar Typhi (S. Typhi) and S. enterica serovar Paratyphi (S. Paratyphi), is a common travel-related illness. Limited data are available on the antimicrobial resistance (AMR) patterns of these serovars among travelers. Records of travelers with a culture-confirmed diagnosis seen during or after travel from January 2007 to December 2018 were obtained from GeoSentinel. Traveler demographics and antimicrobial susceptibility data were analyzed. Isolates were classified as nonsusceptible if intermediate or resistant or as susceptible in accordance with the participating site’s national guidelines. A total of 889 travelers (S. Typhi infections, n = 474; S. Paratyphi infections, n = 414; coinfection, n = 1) were included; 114 (13%) were children of (41%) traveled to visit friends and relatives (VFRs) and acquired the infection in South Asia (71%). Child travelers with S. Typhi infection were most frequently VFRs (77%). The median trip duration was 31 days (interquartile range, 18 to 61 days), and 448 of 691 travelers (65%) had no pretravel consultation. Of 143 S. Typhi and 75 S. Paratyphi isolates for which there were susceptibility data, nonsusceptibility to antibiotics varied (fluoroquinolones, 65% and 56%, respectively; co-trimoxazole, 13% and 0%; macrolides, 8% and 16%). Two S. Typhi isolates (1.5%) from India were nonsusceptible to third-generation cephalosporins. S. Typhi fluoroquinolone nonsusceptibility was highest when infection was acquired in South Asia (70 of 90 isolates; 78%) and sub-Saharan Africa (6 of 10 isolates; 60%). Enteric fever is an important travel-associated illness complicated by AMR. Our data contribute to a better understanding of region-specific AMR, helping to inform empirical treatment options. Prevention measures need to focus on high-risk travelers including VFRs and children

A Role for Noncoding Variation in Schizophrenia

A large portion of common variant loci associated with genetic risk for schizophrenia reside within noncoding sequence of unknown function. Here, we demonstrate promoter and enhancer enrichment in schizophrenia variants associated with expression quantitative trait loci (eQTL). The enrichment is greater when functional annotations derived from the human brain are used relative to peripheral tissues. Regulatory trait concordance analysis ranked genes within schizophrenia genome-wide significant loci for a potential functional role, based on colocalization of a risk SNP, eQTL, and regulatory element sequence. We identified potential physical interactions of noncontiguous proximal and distal regulatory elements. This was verified in prefrontal cortex and -induced pluripotent stem cell-derived neurons for the L-type calcium channel (CACNA1C) risk locus. Our findings point to a functional link between schizophrenia-associated noncoding SNPs and 3D genome architecture associated with chromosomal loopings and transcriptional regulation in the brain

Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data

Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 35months to 10years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action