1,412 research outputs found

    Malic enzyme 1 absence in synovial sarcoma shifts antioxidant system dependence and increases sensitivity to ferroptosis induction with ACXT-3102

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    PURPOSE: To investigate the metabolism of synovial sarcoma (SS) and elucidate the effect of malic enzyme 1 absence on SS redox homeostasis. EXPERIMENTAL DESIGN: ME1 expression was measured in SS clinical samples, SS cell lines, and tumors from an SS mouse model. The effect of ME1 absence on glucose metabolism was evaluated utilizing Seahorse assays, metabolomics, and C13 tracings. The impact of ME1 absence on SS redox homeostasis was evaluated by metabolomics, cell death assays with inhibitors of antioxidant systems, and measurements of intracellular reactive oxygen species (ROS). The susceptibility of ME1-null SS to ferroptosis induction was interrogated in vitro and in vivo. RESULTS: ME1 absence in SS was confirmed in clinical samples, SS cell lines, and an SS tumor model. Investigation of SS glucose metabolism revealed that ME1-null cells exhibit higher rates of glycolysis and higher flux of glucose into the pentose phosphate pathway (PPP), which is necessary to produce NADPH. Evaluation of cellular redox homeostasis demonstrated that ME1 absence shifts dependence from the glutathione system to the thioredoxin system. Concomitantly, ME1 absence drives the accumulation of ROS and labile iron. ROS and iron accumulation enhances the susceptibility of ME1-null cells to ferroptosis induction with inhibitors of xCT (erastin and ACXT-3102). In vivo xenograft models of ME1-null SS demonstrate significantly increased tumor response to ACXT-3102 compared with ME1-expressing controls. CONCLUSIONS: These findings demonstrate the translational potential of targeting redox homeostasis in ME1-null cancers and establish the preclinical rationale for a phase I trial of ACXT-3102 in SS patients. See related commentary by Subbiah and Gan, p. 3408

    Association of the Type 2 Diabetes Mellitus Susceptibility Gene, TCF7L2, with Schizophrenia in an Arab-Israeli Family Sample

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    Many reports in different populations have demonstrated linkage of the 10q24–q26 region to schizophrenia, thus encouraging further analysis of this locus for detection of specific schizophrenia genes. Our group previously reported linkage of the 10q24–q26 region to schizophrenia in a unique, homogeneous sample of Arab-Israeli families with multiple schizophrenia-affected individuals, under a dominant model of inheritance. To further explore this candidate region and identify specific susceptibility variants within it, we performed re-analysis of the 10q24-26 genotype data, taken from our previous genome-wide association study (GWAS) (Alkelai et al, 2011). We analyzed 2089 SNPs in an extended sample of 57 Arab Israeli families (189 genotyped individuals), under the dominant model of inheritance, which best fits this locus according to previously performed MOD score analysis. We found significant association with schizophrenia of the TCF7L2 gene intronic SNP, rs12573128, (p = 7.01×10−6) and of the nearby intergenic SNP, rs1033772, (p = 6.59×10−6) which is positioned between TCF7L2 and HABP2. TCF7L2 is one of the best confirmed susceptibility genes for type 2 diabetes (T2D) among different ethnic groups, has a role in pancreatic beta cell function and may contribute to the comorbidity of schizophrenia and T2D. These preliminary results independently support previous findings regarding a possible role of TCF7L2 in susceptibility to schizophrenia, and strengthen the importance of integrating linkage analysis models of inheritance while performing association analyses in regions of interest. Further validation studies in additional populations are required

    Measurement of the dependence of transverse energy production at large pseudorapidity on the hard-scattering kinematics of proton-proton collisions at √s=2.76 TeV with ATLAS

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    The relationship between jet production in the central region and the underlying-event activity in a pseudorapidity-separated region is studied in 4.0 pb-1 of s=2.76 TeV pp collision data recorded with the ATLAS detector at the LHC. The underlying event is characterised through measurements of the average value of the sum of the transverse energy at large pseudorapidity downstream of one of the protons, which are reported here as a function of hard-scattering kinematic variables. The hard scattering is characterised by the average transverse momentum and pseudorapidity of the two highest transverse momentum jets in the event. The dijet kinematics are used to estimate, on an event-by-event basis, the scaled longitudinal momenta of the hard-scattered partons in the target and projectile beam-protons moving toward and away from the region measuring transverse energy, respectively. Transverse energy production at large pseudorapidity is observed to decrease with a linear dependence on the longitudinal momentum fraction in the target proton and to depend only weakly on that in the projectile proton. The results are compared to the predictions of various Monte Carlo event generators, which qualitatively reproduce the trends observed in data but generally underpredict the overall level of transverse energy at forward pseudorapidity

    Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

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    BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

    Study of the B-c(+) -> J/psi D-s(+) and Bc(+) -> J/psi D-s*(+) decays with the ATLAS detector

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    The decays B-c(+) -> J/psi D-s(+) and B-c(+) -> J/psi D-s*(+) are studied with the ATLAS detector at the LHC using a dataset corresponding to integrated luminosities of 4.9 and 20.6 fb(-1) of pp collisions collected at centre-of-mass energies root s = 7 TeV and 8 TeV, respectively. Signal candidates are identified through J/psi -> mu(+)mu(-) and D-s(()*()+) -> phi pi(+)(gamma/pi(0)) decays. With a two-dimensional likelihood fit involving the B-c(+) reconstructed invariant mass and an angle between the mu(+) and D-s(+) candidate momenta in the muon pair rest frame, the yields of B-c(+) -> J/psi D-s(+) and B-c(+) -> J/psi D-s*(+), and the transverse polarisation fraction in B-c(+) -> J/psi D-s*(+) decay are measured. The transverse polarisation fraction is determined to be Gamma +/-+/-(B-c(+) -> J/psi D-s*(+))/Gamma(B-c(+) -> J/psi D-s*(+)) = 0.38 +/- 0.23 +/- 0.07, and the derived ratio of the branching fractions of the two modes is B-Bc+ -> J/psi D-s*+/B-Bc+ -> J/psi D-s(+) = 2.8(-0.8)(+1.2) +/- 0.3, where the first error is statistical and the second is systematic. Finally, a sample of B-c(+) -> J/psi pi(+) decays is used to derive the ratios of branching fractions B-Bc+ -> J/psi D-s*+/B-Bc+ -> J/psi pi(+) = 3.8 +/- 1.1 +/- 0.4 +/- 0.2 and B-Bc+ -> J/psi D-s*+/B-Bc+ -> J/psi pi(+) = 10.4 +/- 3.1 +/- 1.5 +/- 0.6, where the third error corresponds to the uncertainty of the branching fraction of D-s(+) -> phi(K+ K-)pi(+) decay. The available theoretical predictions are generally consistent with the measurement

    Measurements of the charge asymmetry in top-quark pair production in the dilepton final state at s √ =8  TeV with the ATLAS detector

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    Measurements of the top-antitop quark pair production charge asymmetry in the dilepton channel, characterized by two high-pT leptons (electrons or muons), are presented using data corresponding to an integrated luminosity of 20.3  fb−1 from pp collisions at a center-of-mass energy s√=8  TeV collected with the ATLAS detector at the Large Hadron Collider at CERN. Inclusive and differential measurements as a function of the invariant mass, transverse momentum, and longitudinal boost of the tt¯ system are performed both in the full phase space and in a fiducial phase space closely matching the detector acceptance. Two observables are studied: AℓℓC based on the selected leptons and Att¯C based on the reconstructed tt¯ final state. The inclusive asymmetries are measured in the full phase space to be AℓℓC=0.008±0.006 and Att¯C=0.021±0.016, which are in agreement with the Standard Model predictions of AℓℓC=0.0064±0.0003 and Att¯C=0.0111±0.0004

    Measurement of W boson angular distributions in events with high transverse momentum jets at s√= 8 TeV using the ATLAS detector

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    The W boson angular distribution in events with high transverse momentum jets is measured using data collected by the ATLAS experiment from proton–proton collisions at a centre-of-mass energy at the Large Hadron Collider, corresponding to an integrated luminosity of . The focus is on the contributions to processes from real W emission, which is achieved by studying events where a muon is observed close to a high transverse momentum jet. At small angular separations, these contributions are expected to be large. Various theoretical models of this process are compared to the data in terms of the absolute cross-section and the angular distributions of the muon from the leptonic W decay.Fil: Aaboud, M.. Université Mohamed Premier and LPTPM; MarruecosFil: Aad, G.. Aix-Marseille Université ; FranciaFil: Abbott, B.. Oklahoma State University; Estados UnidosFil: Abdallah, J.. Academia Sinica; ChinaFil: Abdinov, O.. Azerbaijan Academy of Sciences; AzerbaiyánFil: Alconada Verzini, María Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Alonso, Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Arduh, Francisco Anuar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Dova, Maria Teresa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Hoya, Joaquín. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Monticelli, Fernando Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Wahlberg, Hernan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; ArgentinaFil: Bossio Sola, Jonathan David. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Marceca, Gino. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Otero y Garzon, Gustavo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Piegaia, Ricardo Nestor. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Sacerdoti, Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Zibell. A.. Julius-Maximilians-Universität ; AlemaniaFil: Zieminska, D.. Indiana University; Estados UnidosFil: Zimine, N. I.. Joint Institute for Nuclear Research; RusiaFil: Zimmermann, C.. Universität Mainz ; AlemaniaFil: Zimmermann, S.. Albert-Ludwigs-Universität ; AlemaniaFil: Zinonos, Z.. Georg-August-Universität ; AlemaniaFil: Zinser, M.. Universität Mainz ; AlemaniaFil: Ziolkowski, M.. Universität Siegen ; AlemaniaFil: Živković, L.. University of Belgrade ; SerbiaFil: Zobernig, G.. University of Wisconsin; Estados UnidosFil: Zoccoli, A.. Università di Bologna ; ItaliaFil: Nedden, M. zur. Humboldt University; AlemaniaFil: Zurzolo, G.. Università di Napoli; ItaliaFil: Zwalinski, L.. Cern - European Organization For Nuclear Research; SuizaFil: The ATLAS Collaboration. No especifica

    Rare coding variants and X-linked loci associated with age at menarche.

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    More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.UK sponsors (see article for overseas ones): This work made use of data and samples generated by the 1958 Birth Cohort (NCDS). Access to these resources was enabled via the 58READIE Project funded by Wellcome Trust and Medical Research Council (grant numbers WT095219MA and G1001799). A full list of the financial, institutional and personal contributions to the development of the 1958 Birth Cohort Biomedical resource is available at http://www2.le.ac.uk/projects/birthcohort. Genotyping was undertaken as part of the Wellcome Trust Case-Control Consortium (WTCCC) under Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data is available at www.wtccc.org.uk ... The Fenland Study is funded by the Wellcome Trust and the Medical Research Council, as well as by the Support for Science Funding programme and CamStrad. ... SIBS - CRUK ref: C1287/A8459 SEARCH - CRUK ref: A490/A10124 EMBRACE is supported by Cancer Research UK Grants C1287/A10118, C1287/A16563 and C1287/A17523. Genotyping was supported by Cancer Research - UK grant C12292/A11174D and C8197/A16565. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. ... Generation Scotland - Scottish Executive Health Department, Chief Scientist Office, grant number CZD/16/6. Exome array genotyping for GS:SFHS was funded by the Medical Research Council UK. 23andMe - This work was supported in part by NIH Award 2R44HG006981-02 from the National Human Genome Research Institute.This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/ncomms875
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