Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Determination of the strong coupling constant αs from transverse energy–energy correlations in multijet events at s√=8 TeV using the ATLAS detector

Measurements of transverse energy–energy correlations and their associated asymmetries in multi-jet events using the ATLAS detector at the LHC are presented. The data used correspond to s√=8 TeV proton–proton collisions with an integrated luminosity of 20.2 fb−1 . The results are presented in bins of the scalar sum of the transverse momenta of the two leading jets, unfolded to the particle level and compared to the predictions from Monte Carlo simulations. A comparison with next-to-leading-order perturbative QCD is also performed, showing excellent agreement within the uncertainties. From this comparison, the value of the strong coupling constant is extracted for different energy regimes, thus testing the running of αs(μ) predicted in QCD up to scales over 1 TeV . A global fit to the transverse energy–energy correlation distributions yields αs(mZ)=0.1162±0.0011(exp.) +0.0084−0.0070(theo.) , while a global fit to the asymmetry distributions yields a value of αs(mZ)=0.1196±0.0013(exp.) +0.0075−0.0045(theo.)

Future archiver for CERN SCADA systems

The paper presents the concept of a modular and scalable archiver (historian) for SCADA systems at CERN. By separating concerns of archiving from specifics of data-storage systems at a high abstraction level, using a clean and open interface, it will be possible to integrate various data handling technologies without a big effort. The frontend part, responsible for business logic, will communicate with one or multiple backends, which in turn would implement data store and query functionality employing traditional relational databases as well as modern NOSQL and big data solutions, opening doors to advanced data analytics and matching the growing performance requirements for data storage

Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

Isocitrate dehydrogenases (IDH) 1 and 2 are key metabolic enzymes that generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) to maintain a pool of reduced glutathione and peroxiredoxin, and produce α-ketoglutarate, a co-factor of numerous enzymes. IDH1/2 is mutated in ~70–80% of lower-grade gliomas and the majority of secondary glioblastomas. The mutant IDH1 (R132H), in addition to losing its normal catalytic activity, gains the function of producing the d-(R)-2-hydroxyglutarate (2-HG). Overproduction of 2-HG in cancer cells interferes with cellular metabolism and inhibits histone and DNA demethylases, which results in histone and DNA hypermethylation and the blockade of cellular differentiation. We summarize recent findings characterizing molecular mechanisms underlying oncogenic alterations associated with mutated IDH1/2, and their impact on tumor microenvironment and antitumor immunity. Isoform-selective IDH inhibitors which suppress 2-HG production and induce antitumor responses in cells with IDH1 and IDH2 mutations were developed and validated in preclinical settings. Inhibitors of mutated IDH1/2 enzymes entered clinical trials and represent a novel drug class for targeted therapy of gliomas. We describe the development of small-molecule compounds and peptide vaccines targeting IDH-mutant gliomas and the results of their testing in preclinical and clinical studies. All those results support the translational potential of strategies targeting gliomas carrying IDH1 mutations

Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats

Background: Ghrelin is a novel peptide involved in the control of appetite, but its role in vascular pathologies remains to be elucidated. Ghrelin was shown to decrease blood pressure (BP) and improve endothelial function. Its plasma levels are correlated with BP in humans. Mechanisms of these effects are unknown. Because oxidative stress and increased superoxide production by NAD(P)H oxidases (Nox) are critical in the pathogenesis of hypertension, we aimed to study the effects of ghrelin on vascular superoxide production and NAD(P)H oxidase activity in spontaneously hypertensive rats (SHR). Methods: Aortic superoxide production and NAD(P)H oxidase activity were measured using lucigenin (5 μmol/L) chemiluminescence. Aortas from Wistar-Kyoto rats (WKY) were used as control. Direct superoxide scavenging properties of ghrelin were tested using xanthine–xanthine oxidase system. Results: Both basal superoxide production and vascular NADPH oxidase activity were significantly higher in aortas from SHR, than from WKY. Preincubation of aortic segments from SHR or WKY with ghrelin caused concentration-dependent (from 50 pg/mL to 5 ng/mL) decrease of basal superoxide production. Vascular NAD(P)H oxidase activity was inhibited by ghrelin, abolishing the difference between SHR and basal WKY. Ghrelin did not affect superoxide release from the in vitro xanthine–xanthine oxidase system, indicating lack of direct superoxide scavenging properties or inhibitory effects on xanthine oxidase in vitro. Nitric oxide synthase (NOS) inhibition, using Nω-nitro-L-arginine methyl ester (L-NAME), partially blunted the effects of ghrelin on NADPH oxidase activity indicating potential role of nitric oxide. Conclusions: Ghrelin inhibits vascular oxidative stress in SHR. This effect is likely related to the inhibition of vascular NAD(P)H oxidases

Novel Use of Hypoxia-Inducible Polymerizable Protein to Augment Chemotherapy for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies and is the fourth leading cause of cancer-related deaths in the United States. Unfortunately, 80–85% of patients are diagnosed with unresectable, advanced stage tumors. These tumors are incurable and result in a median survival less than approximately six months and an overall 5-year survival rate of less than 7%. Whilst chemotherapy is a critical treatment, cure is not possible without surgical resection. The poor clinical outcomes in PDAC can be partially attributed to its dense desmoplastic stroma, taking up roughly 80% of the tumor mass. The stroma surrounding the tumor disrupts the normal architecture of pancreatic tissue leading to poor vascularization, high intratumoral pressure along with hypoxia and an acidic tumor microenvironment. This complicated microenvironment presents a significant challenge for drug delivery. The current manuscript discusses a novel approach to overcome many of these various obstacles. A complex of gemcitabine (GEM) and hemoglobin S (HbS) was formulated, which self-polymerizes under hypoxic and acidic conditions. When polymerized, HbS has the potential to break the tumor stroma, decrease intratumoral pressure, and therefore improve the treatment efficacy of standard therapy. Intratumoral injection of HbS with a fluorescent small molecule surrogate for GEM into a pancreatic tumor xenograft resulted in improved dissemination of the small molecule throughout the pancreatic tumor. The self-polymerization of HbS + GEM was significantly more effective than either agent individually at decreasing tumor size in an in vivo PDAC mouse model. These findings would suggest a clinical benefit from delivering the complex of GEM and HbS via direct injection by endoscopic ultrasound (EUS). With such a treatment option, patients with locally advanced disease would have the potential to become surgical candidates, offering them a chance for cure

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TIB Hannover: RN 5973(2106) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Mapping chromatin accessibility and active regulatory elements reveals pathological mechanisms in human gliomas

Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer development or progression. Gliomas are brain tumors frequently associated with epigenetics-related gene deregulation. We perform whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples to unravel epigenetic dysfunctions driving gliomagenesis. Based on the results of the integrative analysis of the acquired profiles, we create an atlas of active enhancers and promoters in benign and malignant gliomas. We explore these elements and intersect with Hi-C data to uncover molecular mechanisms instructing gene expression in gliomas. Gliomas are tumors often associated with epigenetics-related gene deregulation. Here the authors reveal an atlas of active enhancers and promoters in benign and malignant gliomas by performing whole-genome mapping of chromatin accessibility, histone modifications, DNA methylation patterns and transcriptome analysis simultaneously in multiple tumor samples

Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma

High-grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and \u3c10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next-generation sequencing with a custom panel of 664 cancer- and epigenetics-related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH-wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high-grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH-wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology