NTHL1 biallelic mutations seldom cause colorectal cancer, serrated polyposis or a multi-tumor phenotype, in absence of colorectal adenomas

In 2015 Weren et al. described a hereditary cancer syndrome caused by biallelic mutations in the DNA base excision repair gene NTHL1, characterized by attenuated adenomatous polyposis and increased colorectal cancer (CRC) risk, largely resembling the recessive syndrome caused by MUTYH mutations1. To date, 33 homozygous or compound heterozygous NTHL1 mutation carriers have been reported (21 families)1,2,3,4,5,6,7,8. More than 5 colonic adenomas (range: 6 to >50) were identified in 24 of the 28 (85%) mutation carriers who underwent colonoscopy screening, and CRC was diagnosed in 19 (68%) of them. Noteworthy, 17 carriers (57%) were diagnosed with multiple primary malignant tumors in extracolonic locations, being the most recurrently found breast and endometrial tumors, head neck squamous cell carcimomas, meningiomas, and bladder and basal cell carcinomas, suggesting that the NTHL1-associated syndrome is a multi-tumor disease rather than a solely CRC syndrome. On the other hand, the fact that at least ¼ (7/28) of the reported biallelic mutation carriers who underwent colonoscopy screening had ≤10 adenomas, and that ≥5 hyperplastic polyps were detected in five carriers (polyp number range: 5->30), lead us to suspect a possible association of NTHL1 mutations with nonpolyposis CRC and serrated/hyperplastic polyposis. Based on previous evidence and with the aim of refining the phenotypic characteristics of the NTHL1-associated syndrome, here we evaluated the implication of NTHL1 biallelic mutations in the predisposition to personal or familial history of multiple tumor types, familial/early-onset nonpolyposis CRC, and serrated/hyperplastic polyposis

Searches for transverse momentum dependent flow vector fluctuations in Pb-Pb and p-Pb collisions at the LHC

CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPThe measurement of azimuthal correlations of charged particles is presented for Pb-Pb collisions at root S-NN 2.76 TeV and p-Pb collisions at root S-NN 5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. These correlations are measured for the second, third and fourth order flow vector in the pseudorapidity region vertical bar eta vertical bar 0.8 as a function of centrality and transverse momentum pT using two observables, to search for evidence of PT-dependent flow vector fluctuations. For Ph-Ph collisions at 2.76 TeV, the measurements indicate that PT-dependent fluctuations are only present for the second order flow vector. Similar results have been found for p-Pb collisions at 5.02 TeV. These measurements are compared to hydrodynamic model calculations with event-by-event geometry fluctuations in the initial state to constrain the initial conditions and transport properties of the matter created in Ph-Ph and p-Pb collisions.9133CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPCONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFINANCIADORA DE ESTUDOS E PROJETOS - FINEPFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informaçãoSem informaçãoSem informaçãoThe ALICE collaboration would like to thank all its engineers and technicians for their invaluable contributions to the construction of the experiment and the CERN accelerator teams for the outstanding performance of the LHC complex. The ALICE collaboration gratefully acknowledges the resources and support provided by all Grid centres and the Worldwide LHC Computing Grid (WLCG) collaboration. The ALICE collaboration acknowledges the following funding agencies for their support in building and running the ALICE detector: A.I. Alikhanyan National Science Laboratory (Yerevan Physics Institute) Foundation (ANSL), State Committee of Science and World Federation of Scientists (WFS), Armenia; Austrian Academy of Sciences and Nationalstiftung fur Forschung, Technologie und Entwicklung, Austria; Ministry of Communications and High Technologies, National Nuclear Research Center, Azerbaijan; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Universidade Federal do Rio Grande do Sul (UFRGS), Financiadora de Estudos e Projetos (Finep) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Brazil; Ministry of Science & Technology of China (MSTC), National Natural Science Foundation of China (NSFC) and Ministry of Education of China (MOEC), China; Ministry of Science, Education and Sport and Croatian Science Foundation, Croatia; Ministry of Education, Youth and Sports of the Czech Republic, Czech Republic; The Danish Council for Independent Research Natural Sciences, the Carlsberg Foundation and Danish National Research Foundation (DNRF), Denmark; Helsinki Institute of Physics (HIP), Finland; Commissariat a l'Energie Atomique (CEA) and Institut National de Physique Nucleaire et de Physique des Particules (IN2P3) and Centre National de la Recherche Scientifique (CNRS), France; Bundesministerium fur Bildung, Wissenschaft, Forschung und Technologie (BMBF) and GSI Helmholtzzentrum fur Schwerionenforschung GmbH, Germany; General Secretariat for Research and Technology, Ministry of Education, Research and Religions, Greece; National Research, Development and Innovation Office, Hungary; Department of Atomic Energy Government of India (DAE) and Council of Scientific and Industrial Research (CSIR), New Delhi, India; Indonesian Institute of Science, Indonesia; Centro Fermi Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi and Istituto Nazionale di Fisica Nucleare (INFN), Italy; Institute for Innovative Science and Technology, Nagasaki Institute of Applied Science (IIST), Japan Society for the Promotion of Science (JSPS) KAKENHI and Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; Consejo Nacional de Ciencia (CONACYT) y Tecnologia, through Fondo de Cooperacion Internacional en Ciencia y Tecnologia (FONCICYT) and Direccion General de Asuntos del Personal Academico (DGAPA), Mexico; Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO), Netherlands; The Research Council of Norway, Norway; Commission on Science and Technology for Sustainable Development in the South (COMSATS), Pakistan; Pontificia Universidad Catolica del Peril, Peru; Ministry of Science and Higher Education and National Science Centre, Poland; Korea Institute of Science and Technology Information and National Research Foundation of Korea (NRF), Republic of Korea; Ministry of Education and Scientific Research, Institute of Atomic Physics and Romanian National Agency for Science, Technology and Innovation, Romania; Joint Institute for Nuclear Research (JINR), Ministry of Education and Science of the Russian Federation and National Research Centre Kurchatov Institute, Russia; Ministry of Education, Science, Research and Sport of the Slovak Republic, Slovakia; National Research Foundation of South Africa, South Africa; Centro de Aplicaciones Tecnologicas y Desarrollo Nuclear (CEADEN), Cubaenergia, Cuba, Ministerio de Ciencia e Innovacion and Centro de Investigaciones Energeticas, Medioambientales y Tecnologicas (CIEMAT), Spain; Swedish Research Council (VR) and Knut & Alice Wallenberg Foundation (KAW), Sweden; European Organization for Nuclear Research, Switzerland; National Science and Technology Development Agency (NSDTA), Suranaree University of Technology (SUT) and Office of the Higher Education Commission under NRU project of Thailand, Thailand; Turkish Atomic Energy Agency (TAEK), Turkey; National Academy of Sciences of Ukraine, Ukraine; Science and Technology Facilities Council (STFC), United Kingdom; National Science Foundation of the United States of America (NSF) and United States Department of Energy, Office of Nuclear Physics (DOE NP), United States of America

Measurements of differential cross-sections in top-quark pair events with a high transverse momentum top quark and limits on beyond the Standard Model contributions to top-quark pair production with the ATLAS detector at √s = 13 TeV

Cross-section measurements of top-quark pair production where the hadronically decaying top quark has transverse momentum greater than 355 GeV and the other top quark decays into ℓνb are presented using 139 fb−1 of data collected by the ATLAS experiment during proton-proton collisions at the LHC. The fiducial cross-section at s = 13 TeV is measured to be σ = 1.267 ± 0.005 ± 0.053 pb, where the uncertainties reflect the limited number of data events and the systematic uncertainties, giving a total uncertainty of 4.2%. The cross-section is measured differentially as a function of variables characterising the tt¯ system and additional radiation in the events. The results are compared with various Monte Carlo generators, including comparisons where the generators are reweighted to match a parton-level calculation at next-to-next-to-leading order. The reweighting improves the agreement between data and theory. The measured distribution of the top-quark transverse momentum is used to search for new physics in the context of the effective field theory framework. No significant deviation from the Standard Model is observed and limits are set on the Wilson coefficients of the dimension-six operators OtG and Otq(8), where the limits on the latter are the most stringent to date. [Figure not available: see fulltext.]

Searches for transverse momentum dependent flow vector fluctuations in Pb-Pb and p-Pb collisions at the LHC

The measurement of azimuthal correlations of charged particles is presented for Pb-Pb collisions at sNN=2.76 TeV and p-Pb collisions at sNN=5.02 TeV with the ALICE detector at the CERN Large Hadron Collider. These correlations are measured for the second, third and fourth order flow vector in the pseudorapidity region |η| < 0.8 as a function of centrality and transverse momentum pT using two observables, to search for evidence of pT-dependent flow vector fluctuations. For Pb-Pb collisions at 2.76 TeV, the measurements indicate that pT-dependent fluctuations are only present for the second order flow vector. Similar results have been found for p-Pb collisions at 5.02 TeV. These measurements are compared to hydrodynamic model calculations with event-by-event geometry fluctuations in the initial state to constrain the initial conditions and transport properties of the matter created in Pb–Pb and p–Pb collisions

CDK6 is activated by the atypical cyclin I to promote E2F‐mediated gene expression and cancer cell proliferation

Cyclin‐dependent kinases (CDKs), together with their cyclin partners, are the master cell cycle regulators. Remarkably, the cyclin family was extended to include atypical cyclins, characterized by distinctive structural features, but their partner CDKs remain elusive. Here, we conducted a yeast two‐hybrid screen to identify new atypical cyclin–CDK complexes. We identified 10 new complexes, including a complex between CDK6 and cyclin I (CCNI), which was found to be active against retinoblastoma protein. CCNI upregulation increased the proliferation of breast cancer cells in vitro and in vivo, with a magnitude similar to that seen upon cyclin D upregulation, an effect that was abrogated by CDK6 silencing or palbociclib treatment. In line with these findings, CCNI downregulation led to a decrease in cell number and a reduction in the percentage of cells reaching S phase. Finally, CCNI upregulation correlated with the high expression of E2F target genes in large panels of cancer cell lines and tissue samples from breast cancer patients. In conclusion, we unveil CCNI as a new player in the pathways that activate CDK6, enriching the wiring of cell cycle control

Role of POLE and POLD1 in familial cancer

[Purpose]: Germline pathogenic variants in the exonuclease domain (ED) of polymerases POLE and POLD1 predispose to adenomatous polyps, colorectal cancer (CRC), endometrial tumors, and other malignancies, and exhibit increased mutation rate and highly specific associated mutational signatures. The tumor spectrum and prevalence of POLE and POLD1 variants in hereditary cancer are evaluated in this study. [Methods]: POLE and POLD1 were sequenced in 2813 unrelated probands referred for genetic counseling (2309 hereditary cancer patients subjected to a multigene panel, and 504 patients selected based on phenotypic characteristics). Cosegregation and case–control studies, yeast-based functional assays, and tumor mutational analyses were performed for variant interpretation. [Results]: Twelve ED missense variants, 6 loss-of-function, and 23 outside-ED predicted-deleterious missense variants, all with population allele frequencies <1%, were identified. One ED variant (POLE p.Met294Arg) was classified as likely pathogenic, four as likely benign, and seven as variants of unknown significance. The most commonly associated tumor types were colorectal, endometrial and ovarian cancers. Loss-of-function and outside-ED variants are likely not pathogenic for this syndrome. [Conclusions]: Polymerase proofreading–associated syndrome constitutes 0.1–0.4% of familial cancer cases, reaching 0.3–0.7% when only CRC and polyposis are considered. ED variant interpretation is challenging and should include multiple pieces of evidence.This work was funded by the Spanish Ministry of Science and Innovation, cofunded by FEDER funds (SAF2016-80888-R, SAF2015-68016-R, Severo Ochoa SVP-2014-068895 contract [L.M.-P.]); Instituto de Salud Carlos III (PI16/00563, PI16/00588, PI14/00613, PI19/00553, CIBERONC CB16/12/00234, CIBERESP, Sara Borrell contract [P.M.]); Government of Catalonia [AGAUR 2017SGR1282, CERCA Program]; and Fundación Olga Torres. This study was facilitated by COST Action CA17118, supported by COST (European Cooperation in Science and Technology)

Antimicrobial management of Tropheryma whipplei endocarditis: the Spanish Collaboration on Endocarditis (GAMES) experience

OBJECTIVES: Tropheryma whipplei has been detected in 3.5% of the blood culture-negative cases of endocarditis in Spain. Experience in the management of T. whipplei endocarditis is limited. Here we report the long-term outcome of the treatment of previously reported patients who were diagnosed with infective endocarditis (IE) caused by T. whipplei from the Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis Infecciosa en Espana (GAMES) and discuss potential options for antimicrobial therapy for IE caused by T. whipplei. PATIENTS AND METHODS: Seventeen patients with T. whipplei endocarditis were recruited between 2008 and 2014 in 25 Spanish hospitals. Patients were classified according to the therapeutic regimen: ceftriaxone and trimethoprim/sulfamethoxazole, doxycycline + hydroxychloroquine and other treatment options. RESULTS: Follow-up data were obtained from 14 patients. The median follow-up was 46.5 months. All patients completed the antibiotic treatment prescribed, with a median duration of 13 months. Six patients were treated with ceftriaxone and trimethoprim/sulfamethoxazole (median duration 13 months), four with doxycycline + hydroxychloroquine (median duration 13.8 months) and four with other treatment options (median duration 22.3 months). The follow-up after the end of the treatments was between 5 and 84 months (median 24 months). CONCLUSIONS: All treatment lines were effective and well tolerated. Therapeutic failures were not detected during the treatment. None of the patients died or experienced a relapse during the follow-up. Only six patients received antibiotic treatment in accordance with guidelines. These data suggest that shorter antimicrobial treatments could be effective

Prosthetic Valve Candida spp. Endocarditis: New Insights into Long-term Prognosis-The ESCAPE Study

Background. Prosthetic valve endocarditis caused by Candida spp. (PVE-C) is rare and devastating, with international guidelines based on expert recommendations supporting the combination of surgery and subsequent azole treatment. Methods. We retrospectively analyzed PVE-C cases collected in Spain and France between 2001 and 2015, with a focus on management and outcome. Results. Forty-six cases were followed up for a median of 9 months. Twenty-two patients (48%) had a history of endocarditis, 30 cases (65%) were nosocomial or healthcare related, and 9 (20%) patients were intravenous drug users. "Induction" therapy consisted mainly of liposomal amphotericin B (L-amB)-based (n = 21) or echinocandin-based therapy (n = 13). Overall, 19 patients (41%) were operated on. Patients &lt;66 years old and without cardiac failure were more likely to undergo cardiac surgery (adjusted odds ratios [aORs], 6.80 [95% confdence interval [CI], 1.59-29.13] and 10.92 [1.15-104.06], respectively). Surgery was not associated with better survival rates at 6 months. Patients who received L-amB alone had a better 6-month survival rate than those who received an echinocandin alone (aOR, 13.52; 95% CI, 1.03-838.10). "Maintenance" fluconazole therapy, prescribed in 21 patients for a median duration of 13 months (range, 2-84 months), led to minor adverse effects. Conclusion. L-amB induction treatment improves survival in patients with PVE-C. Medical treatment followed by long-term maintenance fluconazole may be the best treatment option for frail patients

Outpatient Parenteral Antibiotic Treatment for Infective Endocarditis: A Prospective Cohort Study From the GAMES Cohort

BACKGROUND: Outpatient parenteral antibiotic treatment (OPAT) has proven efficacious for treating infective endocarditis (IE). However, the 2001 Infectious Diseases Society of America (IDSA) criteria for OPAT in IE are very restrictive. We aimed to compare the outcomes of OPAT with those of hospital-based antibiotic treatment (HBAT). METHODS: Retrospective analysis of data from a multicenter, prospective cohort study of 2000 consecutive IE patients in 25 Spanish hospitals (2008-2012) was performed. RESULTS: A total of 429 patients (21.5%) received OPAT, and only 21.7% fulfilled IDSA criteria. Males accounted for 70.5%, median age was 68 years (interquartile range [IQR], 56-76), and 57% had native-valve IE. The most frequent causal microorganisms were viridans group streptococci (18.6%), Staphylococcus aureus (15.6%), and coagulase-negative staphylococci (14.5%). Median length of antibiotic treatment was 42 days (IQR, 32-54), and 44% of patients underwent cardiac surgery. One-year mortality was 8% (42% for HBAT; P < .001), 1.4% of patients relapsed, and 10.9% were readmitted during the first 3 months after discharge (no significant differences compared with HBAT). Charlson score (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.04-1.42; P = .01) and cardiac surgery (OR, 0.24; 95% CI, .09-.63; P = .04) were associated with 1-year mortality, whereas aortic valve involvement (OR, 0.47; 95% CI, .22-.98; P = .007) was the only predictor of 1-year readmission. Failing to fulfill IDSA criteria was not a risk factor for mortality or readmission. CONCLUSIONS: OPAT provided excellent results despite the use of broader criteria than those recommended by IDSA. OPAT criteria should therefore be expanded