Genomic and immune landscape Of metastatic pheochromocytoma and paraganglioma

The mechanisms triggering metastasis in pheochromocytoma/paraganglioma are unknown, hindering therapeutic options for patients with metastatic tumors (mPPGL). Herein we show by genomic profiling of a large cohort of mPPGLs that high mutational load, microsatellite instability and somatic copy-number alteration burden are associated with ATRX/TERT alterations and are suitable prognostic markers. Transcriptomic analysis defines the signaling networks involved in the acquisition of metastatic competence and establishes a gene signature related to mPPGLs, highlighting CDK1 as an additional mPPGL marker. Immunogenomics accompanied by immunohistochemistry identifies a heterogeneous ecosystem at the tumor microenvironment level, linked to the genomic subtype and tumor behavior. Specifically, we define a general immunosuppressive microenvironment in mPPGLs, the exception being PD-L1 expressing MAML3-related tumors. Our study reveals canonical markers for risk of metastasis, and suggests the usefulness of including immune parameters in clinical management for PPGL prognostication and identification of patients who might benefit from immunotherapy

Genetic diversity in Mediterranean Brassica vegetables: seed phenotyping could be useful for sustainable crop production

The European BrasExplor project aims to explore the genetic diversity present in two economically important Brassica crop species, Brassica oleracea and B. rapa, for sustainable crop production. This diversity is present in wild populations but also in cultivated landraces and has been shaped by contrasting environments. An international consortium of 11 partners has begun to collect and multiply wild populations extending from the French North Atlantic coast to the southern Algerian desert as well as local cultivars from 6 contributing countries in order to characterize the genetic diversity available over a wide soil-climate gradient. A total of 100 populations has been obtained for each species. Identifying the genetic variation and understanding the basis for it will allow the development of breeding strategies for a better adaptation of turnip (Brassica rapa) and cabbage (Brassica oleracea var. capitata) to climate change. One third of the collection has been already phenotyped for its germination traits of native seeds harvested in 2020 for wild populations or of local landraces provided by farmers and seed banks. In favourable conditions, a high diversity in germination capacity and germination rate was observed independently of seed age. The two species have a different germination profile: some turnip seeds can stand higher temperature and lower water potential than most cabbage seeds. Variation in flowering time has also been documented in these plants.We are grateful to Benjamin Foltran for his contribution to the project during his internship, Anne-Sophie Grenier for her input in communication and project website. We also thank Hakima Arrar, Fariza Boussad, Thouraya Rhim, Ilahy Riadh who are involved in field phenotyping. BrasExplor project is funded by the PRIMA programme supported under Horizon ? ? ? ? the European Union’s framework programme for research and innovation.Peer reviewe

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

E‐cigarettes and expectancies: why do some users keep smoking?

BACKGROUND AND AIMS: Many smokers who have tried electronic cigarettes (“e-cigarettes”) continue to smoke, perhaps influenced by their beliefs about the outcomes of using e-cigarettes (“e-cigarette expectancies”). The primary aims of this study were to compare expectancies of dual users to former smokers, and to examine the association between expectancies and intentions to quit or reduce “vaping” among former smokers. DESIGN AND SETTING: A large cross-sectional online survey of e-cigarette users conducted in the USA. PARTICIPANTS: We surveyed current e-cigarette users (N=1815), including both current cigarette smokers (“dual users,” n=381) and former smokers (n=1434). We further subdivided former smokers into those with (n=686) and without (n=748) intentions to reduce or quit e-cigarette use. MEASUREMENTS: The primary outcomes were self-reported past-month smoking status and, among former smokers, current intentions to reduce or quit e-cigarette use, both adjusted for potential confounders. E-cigarette expectancy items were primarily derived from a previously validated measure of smoking expectancies. FINDINGS: Dual users reported less positive expectancies than former smokers about e-cigarettes, rating e-cigarettes as more physically irritating (β=−0.10, p<0.001) and addictive (β=0.06, p=0.016), as well as less satisfying (β= −0.11, p<0.001). Former smokers with intentions to quit e-cigarettes also rated e-cigarettes less positively than former smokers without intentions to quit e-cigarettes, rating them more likely to damage health (β=0.16, p<0.001) and cause addiction (β=0.10, p<0.001), but less likely to taste good (β= −0.08, p=0.006). CONCLUSIONS: Positive e-cigarette expectancies among e-cigarette users are associated with a greater likelihood of having quit smoking, but lower likelihood of intention to quit e-cigarette use

E-cigarettes and Expectancies: Why Do Some Users Keep Smoking?

Background and aims: Many smokers who have tried electronic cigarettes (‘e-cigarettes’) continue to smoke, perhaps influenced by their beliefs about the outcomes of using e-cigarettes (‘e-cigarette expectancies’). The primary aims of this study were to compare expectancies of dual users to former smokers, and to examine the association between expectancies and intentions to quit or reduce ‘vaping’ among former smokers. Design and Setting Design and Setting: A large cross-sectional online survey of e-cigarette users conducted in the United States. Participants: We surveyed current e-cigarette users (n = 1815), including both current cigarette smokers (‘dual users’, n = 381) and former smokers (n = 1434). We further subdivided former smokers into those with (n = 686) and without (n = 748) intentions to reduce or quit e-cigarette use. Measurements: The primary outcomes were self-reported past-month smoking status and, among former smokers, current intentions to reduce or quit e-cigarette use, both adjusted for potential confounders. E-cigarette expectancy items were derived primarily from a previously validated measure of smoking expectancies. Findings: Dual users reported less positive expectancies than former smokers about e-cigarettes, rating e-cigarettes as more physically irritating (β = 0.10, P \u3c 0.001) and addictive (β = 0.06, P = 0.016), as well as less satisfying (β = –0.11, P \u3c 0.001). Former smokers with intentions to quit e-cigarettes also rated e-cigarettes less positively than former smokers without intentions to quit e-cigarettes, rating them more likely to damage health (β = 0.16, P \u3c 0.001) and cause addiction (β = 0.10, P \u3c 0.001), but less likely to taste good (β = –0.08, P = 0.006). Conclusions: Positive e-cigarette expectancies among e-cigarette users are associated with a greater likelihood of having quit smoking, but lower likelihood of intention to quit e-cigarette use