Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype

Background Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types. Methods We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects. Results A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers. Conclusions The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.Peer reviewe

Markers of neutrophil mediated inflammation associate with disturbed continuous electroencephalogram after out of hospital cardiac arrest

Background Achieving an acceptable neurological outcome in cardiac arrest survivors remains challenging. Ischemia-reperfusion injury induces inflammation, which may cause secondary neurological damage. We studied the association of ICU admission levels of inflammatory biomarkers with disturbed 48-hour continuous electroencephalogram (cEEG), and the association of the daily levels of these markers up to 72 h with poor 6-month neurological outcome. Methods This is an observational, post hoc sub-study of the COMACARE trial. We measured serum concentrations of procalcitonin (PCT), high-sensitivity C-reactive protein (hsCRP), osteopontin (OPN), myeloperoxidase (MPO), resistin, and proprotein convertase subtilisin/kexin type 9 (PCSK9) in 112 unconscious, mechanically ventilated ICU-treated adult OHCA survivors with initial shockable rhythm. We used grading of 48-hour cEEG monitoring as a measure for the severity of the early neurological disturbance. We defined 6-month cerebral performance category (CPC) 1-2 as good and CPC 3-5 as poor long-term neurological outcome. We compared the prognostic value of biomarkers for 6-month neurological outcome to neurofilament light (NFL) measured at 48 h. Results Higher OPN (p = .03), MPO (p < .01), and resistin (p = .01) concentrations at ICU admission were associated with poor grade 48-hour cEEG. Higher levels of ICU admission OPN (OR 3.18; 95% CI 1.25-8.11 per ln[ng/ml]) and MPO (OR 2.34; 95% CI 1.30-4.21) were independently associated with poor 48-hour cEEG in a multivariable logistic regression model. Poor 6-month neurological outcome was more common in the poor cEEG group (63% vs. 19% p < .001, respectively). We found a significant fixed effect of poor 6-month neurological outcome on concentrations of PCT (F = 7.7, p < .01), hsCRP (F = 4.0, p < .05), and OPN (F = 5.6, p < .05) measured daily from ICU admission to 72 h. However, the biomarkers did not have independent predictive value for poor 6-month outcome in a multivariable logistic regression model with 48-hour NFL. Conclusion Elevated ICU admission levels of OPN and MPO predicted disturbances in cEEG during the subsequent 48 h after cardiac arrest. Thus, they may provide early information about the risk of secondary neurological damage. However, the studied inflammatory markers had little value for long-term prognostication compared to 48-hour NFL.Peer reviewe

Is global cardiovascular risk considered in current practice? Treatment and control of hypertension, hyperlipidemia, and diabetes according to patients’ risk level

Daria Roccatagliata1, Fausto Avanzini1, Lara Monesi1, Vittorio Caimi2, Davide Lauri1, Paolo Longoni3, Roberto Marchioli4, Massimo Tombesi2, Gianni Tognoni1, Maria Carla Roncaglioni1, on behalf of the Collaborative Group Risk and Prevention Study*1Istituto di Ricerche Farmacologiche &ldquo;Mario Negri&rdquo;, Milano, Italy; 2CSeRMEG Centro Studi e Ricerca in Medicina Generale, Monza, Italy; 3CoS Consorzio Sanit&agrave;, Milano, Italy; 4Consorzio Mario Negri Sud, S. Maria Imbaro, Italy *A full list of investigators is reported in the AppendixObjectives: To assess the pharmacological treatment and the control of major modifiable cardiovascular risk factors in everyday practice according to the patients&rsquo; cardiovascular risk level.Methods: In a cross-sectional study general practitioners (GPs) had to identify a random sample of their patients with cardiovascular risk factors or diseases and collect essential data on the pharmacological treatment and control of hypertension, hyperlipidemia, and diabetes according to the patients&rsquo; cardiovascular risk level and history of cardiovascular disease. Participants were subjects of both sexes, aged 40&ndash;80 years, with at least one known cardiovascular risk factor or a history of cardiovascular diseases.Results: From June to December 2000, 162 Italian GPs enrolled 3120 of their patients (2470 hypertensives, 1373 hyperlipidemics, and 604 diabetics). Despite the positive association between the perceived level of global cardiovascular risk and lipid-lowering drug prescriptions in hyperlipidemic subjects (from 26% for lowest risk to 56% for highest risk p &lt; 0.0001) or the prescription of combination therapy in hypertensives (from 41% to 70%, p &lt; 0.0001) and diabetics (from 24% to 43%, p = 0.057), control was still inadequate in 48% of diabetics, 77% of hypertensives, and 85% of hyperlipidemics, with no increase in patients at highest risk. Trends for treatment and control were similar in patients with cardiovascular diseases.Conclusions: Even in high-risk patients, despite a tendency towards more intensive treatment, pharmacological therapy is still under used and the degree of control of blood pressure, cholesterol level and diabetes is largely unsatisfactory.Keywords: global cardiovascular risk, hypertension, hyperlipideamia, diabetes, general practice

Novel germline variant in the histone demethylase and transcription regulator KDM4C induces a multi-cancer phenotype

Background Genes involved in epigenetic regulation are central for chromatin structure and gene expression. Specific mutations in these might promote carcinogenesis in several tissue types.Methods We used exome, whole-genome and Sanger sequencing to detect rare variants shared by seven affected individuals in a striking early-onset multi-cancer family. The only variant that segregated with malignancy resided in a histone demethylase KDM4C. Consequently, we went on to study the epigenetic landscape of the mutation carriers with ATAC, ChIP (chromatin immunoprecipitation) and RNA-sequencing from lymphoblastoid cell lines to identify possible pathogenic effects.Results A novel variant in KDM4C, encoding a H3K9me3 histone demethylase and transcription regulator, was found to segregate with malignancy in the family. Based on Roadmap Epigenomics Project data, differentially accessible chromatin regions between the variant carriers and controls enrich to normally H3K9me3-marked chromatin. We could not detect a difference in global H3K9 trimethylation levels. However, carriers of the variant seemed to have more trimethylated H3K9 at transcription start sites. Pathway analyses of ChIP-seq and differential gene expression data suggested that genes regulated through KDM4C interaction partner EZH2 and its interaction partner PLZF are aberrantly expressed in mutation carriers.Conclusions The apparent dysregulation of H3K9 trimethylation and KDM4C-associated genes in lymphoblastoid cells supports the hypothesis that the KDM4C variant is causative of the multi-cancer susceptibility in the family. As the variant is ultrarare, located in the conserved catalytic JmjC domain and predicted pathogenic by the majority of available in silico tools, further studies on the role of KDM4C in cancer predisposition are warranted.</p

Bioeconomy perception by future stakeholders: Hearing from European forestry students

This article provides useful information for universities offering forestry programs and facing the growing demand for bioeconomy education. An explorative survey on bioeconomy perception among 1400 students enrolled in 29 universities across nine European countries offering forestry programs was performed. The data have been elaborated via descriptive statistics and cluster analysis. Around 70% of respondents have heard about the bioeconomy, mainly through university courses. Students perceive forestry as the most important sector for bioeconomy; however, the extent of perceived importance of forestry varies between countries, most significantly across groups of countries along a North–South European axis. Although differences across bachelor and master programs are less pronounced, they shed light on how bioeconomy is addressed by university programs and the level of student satisfaction with this. These differences and particularities are relevant for potential development routes towards comprehensive bioeconomy curricula at European forestry universities with a forestry focus.Peer reviewe

Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma

One in four women suffers from uterine leiomyomas (ULs)-benign tumours of the uterine wall, also known as uterine fibroids-at some point in premenopausal life. ULs can cause excessive bleeding, pain and infertility(1), and are a common cause of hysterectomy(2). They emerge through at least three distinct genetic drivers: mutations in MED12 or FH, or genomic rearrangement of HMGA2(3). Here we created genome-wide datasets, using DNA, RNA, assay for transposase-accessible chromatin (ATAC), chromatin immunoprecipitation (ChIP) and HiC chromatin immunoprecipitation (HiChIP) sequencing of primary tissues to profoundly understand the genesis of UL. We identified somatic mutations in genes encoding six members of the SRCAP histone-loading complex(4), and found that germline mutations in the SRCAP members YEATS4 and ZNHIT1 predispose women to UL. Tumours bearing these mutations showed defective deposition of the histone variant H2A.Z. In ULs, H2A.Z occupancy correlated positively with chromatin accessibility and gene expression, and negatively with DNA methylation, but these correlations were weak in tumours bearing SRCAP complex mutations. In these tumours, open chromatin emerged at transcription start sites where H2A.Z was lost, which was associated with upregulation of genes. Furthermore, YEATS4 defects were associated with abnormal upregulation of bivalent embryonic stem cell genes, as previously shown in mice(5). Our work describes a potential mechanism of tumorigenesis-epigenetic instability caused by deficient H2A.Z deposition-and suggests that ULs arise through an aberrant differentiation program driven by deranged chromatin, emanating from a small number of mutually exclusive driver mutations.Peer reviewe

Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans

Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.Peer reviewe

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio