tbuckley/cabot-search huggingface dataset:
High-affinity T cell receptors for adoptive cell transfer
Authors: Ariel Isser, Jonathan P. Schneck
Journal: Journal of Clinical Investigation (2018)

Adoptive cell transfer (ACT) of engineered T cell receptors (TCRs) for cancer immunotherapy has evolved from simple gene transfer of isolated TCRs to various affinity enhancement techniques that overcome limitations imposed by central and peripheral tolerance on TCR affinity. In the current issue of the JCI, Poncette et al. used mice with human TCRαβ and HLA gene loci to discover CD4+ TCRs of optimal affinity for cancer testis antigen (CTA) NY-ESO-1. They combined this TCR with a previously discovered NY-ESO-1-specific CD8+ TCR in an ACT fibrosarcoma tumor model to demonstrate the importance of T cell help in mediating antitumor responses.
Clinical and MRI Features of Cerebral Small-Vessel Disease in Type 1 Diabetes
Authors: Lena M. Thorn, Sara Shams, Daniel Gordin, Ron Liebkind, Carol Forsblom, Paula Summanen, Stefanie Hägg-Holmberg, Turgut Tatlisumak, Oili Salonen, Jukka Putaala, Juha Martola, Per-Henrik Groop
Journal: Diabetes Care (2018)

OBJECTIVE To assess the prevalence of cerebral small-vessel disease (SVD) in subjects with type 1 diabetes compared with healthy control subjects and to characterize the diabetes-related factors associated with SVD. RESEARCH DESIGN AND METHODS This substudy was cross-sectional in design and included 191 participants with type 1 diabetes and median age 40.0 years (interquartile range 33.0–45.1) and 30 healthy age- and sex-matched control subjects. All participants underwent clinical investigation and brain MRIs, assessed for cerebral SVD. RESULTS Cerebral SVD was more common in participants with type 1 diabetes than in healthy control subjects: any marker 35% vs. 10% (P = 0.005), cerebral microbleeds (CMBs) 24% vs. 3.3% (P = 0.008), white matter hyperintensities 17% vs. 6.7% (P = 0.182), and lacunes 2.1% vs. 0% (P = 1.000). Presence of CMBs was independently associated with systolic blood pressure (odds ratio 1.03 [95% CI 1.00–1.05], P = 0.035). CONCLUSIONS Cerebral SVD, CMBs in particular, is more common in young people with type 1 diabetes compared with healthy control subjects.
CCND2 and CCND3 hijack immunoglobulin light-chain enhancers in cyclin D1− mantle cell lymphoma
Authors: David Martín-Garcia, Alba Navarro, Rafael Valdés-Mas, Guillem Clot, Jesús Gutiérrez-Abril, Miriam Prieto, Inmaculada Ribera-Cortada, Renata Woroniecka, Grzegorz Rymkiewicz, Susanne Bens, Laurence de Leval, Andreas Rosenwald, Judith A. Ferry, Eric D. Hsi, Kai Fu, Jan Delabie, Dennis Weisenburger, Daphne de Jong, Fina Climent, Sheila J. O’Connor, Steven H. Swerdlow, David Torrents, Sergi Beltran, Blanca Espinet, Blanca González-Farré, Luis Veloza, Dolors Costa, Estella Matutes, Reiner Siebert, German Ott, Leticia Quintanilla-Martinez, Elaine S. Jaffe, Carlos López-Otín, Itziar Salaverria, Xose S. Puente, Elias Campo, Sílvia Beà
Journal: Blood (2018)
Kidney transplantation from donors after uncontrolled circulatory death: the Spanish experience
Authors: Francisco del Río, Amado Andrés, María Padilla, Ana I. Sánchez-Fructuoso, María Molina, Ángel Ruiz, José M. Pérez-Villares, Lorena Z. Peiró, Teresa Aldabó, Rosa Sebastián, Eduardo Miñambres, Lidia Pita, Marcial Casares, Juan Galán, Cristina Vidal, Christel Terrón, Pablo Castro, Marga Sanroma, Elisabeth Coll, Beatriz Domínguez-Gil, Lander Atutxa, María Isabel Delgado, Juan José Egea-Guerrero, Alberto Fernández Carmona, Ana Fernández Rodríguez, Antón Fernández García, Elena Gallego, Carmen de Gracia, José María Manciño, María A. Márquez, Eva Oliver, Teresa Pont, Juan Carlos Ruiz, Sofía Vázquez, Ana Zapatero
Journal: Kidney International (2018)
Cardiac Magnetic Resonance Normal Reference Values of Biventricular Size and Function in Male Athlete’s Heart
Authors: Flavio D’Ascenzi, Francesca Anselmi, Pietro Piu, Caterina Fiorentini, Salvatore Francesco Carbone, Luca Volterrani, Marta Focardi, Marco Bonifazi, Sergio Mondillo
Journal: JACC. Cardiovascular imaging (2018)
OA10 CheckMate 078: Patient-Reported Outcomes (PROs) With Nivolumab vs Docetaxel in Advanced Non-Small Cell Lung Cancer (NSCLC)
Authors: Y. Wu, J. Chang, L. Zhang, H. Tu, L. Wu, J. Feng, S. Lu, C. Zhou, J. Wang, T. Mok, F. Taylor, B. Mossman, J. Penrod, R. Lawrance, S. Blum, P.F. Wang, Y. Cheng
Journal: Journal of Thoracic Oncology (2018)
The HLA ligandome landscape of chronic myeloid leukemia delineates novel T-cell epitopes for immunotherapy
Authors: Tatjana Bilich, Annika Nelde, Leon Bichmann, Malte Roerden, Helmut R. Salih, Daniel J. Kowalewski, Heiko Schuster, Chih-Chiang Tsou, Ana Marcu, Marian C. Neidert, Maren Lübke, Jonas Rieth, Mirle Schemionek, Tim H. Brümmendorf, Vladan Vucinic, Dietger Niederwieser, Jens Bauer, Melanie Märklin, Janet K. Peper, Reinhild Klein, Oliver Kohlbacher, Lothar Kanz, Hans-Georg Rammensee, Stefan Stevanović, Juliane S. Walz
Journal: Blood (2018)
TET2-Dependent Hydroxymethylome Plasticity Reduces Melanoma Initiation and Progression
Authors: Elise Bonvin, Enrico Radaelli, Martin Bizet, Flavie Luciani, Emilie Calonne, Pascale Putmans, David Nittner, Nitesh Kumar Singh, Sara Francesca Santagostino, Valérie Petit, Lionel Larue, Jean Christophe Marine, François Fuks
Journal: Cancer Research (2018)

Abstract Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcytosine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease progression–associated epigenetic remodeling remains to be established. Here, we show that NRAS-driven melanomagenesis in mice is accompanied by an overall decrease in 5hmC and specific 5hmC gains in selected gene bodies. Strikingly, genetic ablation of Tet2 in mice cooperated with oncogenic NRASQ61K to promote melanoma initiation while suppressing specific gains in 5hmC. We conclude that TET2 acts as a barrier to melanoma initiation and progression, partly by promoting 5hmC gains in specific gene bodies. Significance: This work emphasizes the importance of epigenome plasticity in cancer development and highlights the involvement of druggable epigenetic factors in cancer.
Single cell analysis of clonal architecture in acute myeloid leukaemia
Authors: Nicola Potter, Farideh Miraki-Moud, Luca Ermini, Ian Titley, Gowri Vijayaraghavan, Elli Papaemmanuil, Peter Campbell, John Gribben, David Taussig, Mel Greaves
Journal: Leukemia (2018)

We used single cell Q-PCR on a micro-fluidic platform (Fluidigm) to analyse clonal, genetic architecture and phylogeny in acute myeloid leukaemia (AML) using selected mutations. Ten cases of NPM1c mutant AML were screened for 111 mutations that are recurrent in AML and cancer. Clonal architectures were relatively simple with one to six sub-clones and were branching in some, but not all, patients. NPM1 mutations were secondary or sub-clonal to other driver mutations (DNM3TA, TET2, WT1 and IDH2) in all cases. In three of the ten cases, single cell analysis of enriched CD34+/CD33− cells revealed a putative pre-leukaemic sub-clone, undetectable in the bulk CD33+ population that had one or more driver mutations but lacked NPM1c. Cells from all cases were transplanted into NSG mice and in most (8/10), more than one sub-clone (#2-5 sub-clones) transplanted. However, the dominant regenerating sub-clone in 9/10 cases was NPM1+ and this sub-clone was either dominant or minor in the diagnostic sample from which it was derived. This study provides further evidence, at the single cell level, for genetic variegation in sub-clones and stem cells in acute leukaemia and demonstrates both a preferential order of mutation accrual and parallel evolution of sub-clones.
Abstract 20593: In vivo Cardiac Effects of Mavacamten (MYK-461): Evidence for Negative Inotropy and Improved Compliance
Authors: Carlos L del Rio, Yukie Ueyama, Dale C Baker, Shana R Dalton, Laurence Lucats, Philip Janiak, Bari Olivier, Joseph Lambing, Marc J Evanchik, Eric M Green
Journal: Circulation (2017)

Background: Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility and impaired ventricular relaxation. Conventional negative inotropes can alleviate ...
Genetic and observational evidence supports a causal role of sex hormones on the development of asthma
Authors: Ryan Arathimos, Raquel Granell, Philip Haycock, Rebecca C Richmond, James Yarmolinsky, Caroline L Relton, Kate Tilling
Journal: Thorax (2019)

Introduction Males have a higher prevalence of asthma in childhood, whereas females have a higher prevalence in adolescence and adulthood. The ‘adolescent switch’ observed between sexes during puberty has been hypothesised to be due to fluctuating sex hormones. Robust evidence of the involvement of sex hormones in asthma could lead to development of therapeutic interventions. Methods We combine observational evidence using longitudinal data on sex hormone-binding globulin (SHBG), total and bioavailable testosterone and asthma from a subset of males (n=512) in the Avon Longitudinal Study of Parents and Children, and genetic evidence of SHBG and asthma using two-sample Mendelian randomisation (MR), a method of causal inference. We meta-analysed two-sample MR results across two large data sets, the Trans-National Asthma Genetics Consortium genome-wide association study of asthma and UK Biobank (over 460 000 individuals combined). Results Observational evidence indicated weak evidence of a protective effect of increased circulating testosterone on asthma in males in adolescence, but no strong pattern of association with SHBG. Genetic evidence using two-sample MR indicated a protective effect of increased SHBG, with an OR for asthma of 0.86 (95% CI 0.74 to 1.00) for the inverse-variance weighted approach and an OR of 0.83 (95% CI 0.72 to 0.96) for the weighted median estimator, per unit increase in natural log SHBG. A sex-stratified sensitivity analysis suggested the protective effect of SHBG was mostly evident in females. Conclusion We report the first suggestive evidence of a protective effect of genetically elevated SHBG on asthma, which may provide a biological explanation behind the observed asthma sex discordance. Further work is required to disentangle the downstream effects of SHBG on asthma and the molecular pathways involved.
Reduced prevalence of latent tuberculosis infection in diabetes patients using metformin and statins
Authors: Matthew J. Magee, Argita D. Salindri, Hardy Kornfeld, Amit Singhal
Journal: European Respiratory Journal (2018)

<b>New data indicate metformin and statin use reduce incidence of active TB, but if they prevent TB infection (LTBI) is unknown. We used national data to report LTBI prevalence was highest among participants with diabetes who did not use statins or metformin.</b>http://ow.ly/W21v30nehnt
Intellectual engagement and cognitive ability in later life (the “use it or lose it” conjecture): longitudinal, prospective study
Authors: Roger T Staff, Michael J Hogan, Daniel S Williams, L J Whalley
Journal: BMJ (2018)

To examine the association between intellectual engagement and cognitive ability in later life, and determine whether the maintenance of intellectual engagement will offset age related cognitive decline.Longitudinal, prospective, observational study.Non-clinical volunteers in late middle age (all born in 1936) living independently in northeast Scotland.Sample of 498 volunteers who had taken part in the Scottish Mental Health Survey of 1947, from one birth year (1936).Cognitive ability and trajectory of cognitive decline in later life. Typical intellectual engagement was measured by a questionnaire, and repeated cognitive measurements of information processing speed and verbal memory were obtained over a 15 year period (recording more than 1200 longitudinal data points for each cognitive test).Intellectual engagement was significantly associated with level of cognitive performance in later life, with each point on a 24 point scale accounting for 0.97 standardised cognitive performance (IQ-like) score, for processing speed and 0.71 points for memory (both P<0.05). Engagement in problem solving activities had the largest association with life course cognitive gains, with each point accounting for 0.43 standardised cognitive performance score, for processing speed and 0.36 points for memory (both P<0.05). However, engagement did not influence the trajectory of age related decline in cognitive performance. Engagement in intellectual stimulating activities was associated with early life ability, with correlations between engagement and childhood ability and education being 0.35 and 0.22, respectively (both P<0.01).These results show that self reported engagement is not associated with the trajectory of cognitive decline in late life, but is associated with the acquisition of ability during the life course. Overall, findings suggest that high performing adults engage and those that engage more being protected from relative decline.
Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements
Authors: Jason C. Chang, Lei Zhang, Alexander E. Drilon, Ping Chi, Rita Alaggio, Laetitia Borsu, Ryma Benayed, William D. Travis, Marc Ladanyi, Cristina R. Antonescu
Journal: Journal of Thoracic Oncology (2018)

IntroductionHalf of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next-generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMTs.MethodsIn this study, we have investigated a series of pediatric and adult thoracic IMTs for abnormalities in a wide spectrum of actionable kinases by applying a variety of molecular and next-generation sequencing techniques, including fluorescence in situ hybridization (FISH), targeted RNA sequencing, and NanoString assay.ResultsThere were 33 patients with thoracic IMTs, including five children; their mean age was 37. The tumors showed a monomorphic spindle cell phenotype, except for one with an epithelioid morphologic pattern and moderate to severe atypia. By immunohistochemistry, 24 tumors were ALK positive, and 19 of the 24 showed ALK rearrangements and one ret proto-oncogene gene (RET) rearrangement by FISH. RNA sequencing was performed in the remaining four cases lacking ALK abnormalities by FISH, revealing ALK fusions involving tropomyosin 4 gene (TMP4) and echinoderm microtubule associated protein like 4 gene (EML4) as partner in three cases. NanoString assay was performed in the remaining case, revealing ALK alternative transcription initiation (ALKATI). Nine cases lacking ALK abnormalities were further tested by FISH or targeted RNA sequencing, revealing ROS1 rearrangement in six cases and ETS variant 6 gene (ETV6)–neurotrophic receptor tyrosine kinase 3 gene (NTRK3) fusion in three cases, respectively.ConclusionsBy using a battery of complementary molecular techniques, we have shown that all the thoracic IMTs harbored a tyrosine kinase abnormality, with 30% involving a kinase gene other than ALK, including ROS1, NTRK3, and RET gene fusions. We have also described for the first time ALKATI-induced ALK oncogenic activation in IMTs.
Histopathologic Characterization of Peripheral Arteries in Subjects With Abundant Risk Factors
Authors: Sho Torii, Jihad A. Mustapha, Jagat Narula, Hiroyoshi Mori, Fadi Saab, Hiroyuki Jinnouchi, Kazuyuki Yahagi, Atsushi Sakamoto, Maria E. Romero, Navneet Narula, Frank D. Kolodgie, Renu Virmani, Aloke V. Finn
Journal: JACC. Cardiovascular imaging (2018)
Physical activity less than the recommended amount may prevent the onset of major biological risk factors for cardiovascular disease: a cohort study of 198 919 adults
Authors: David Martinez-Gomez, Irene Esteban-Cornejo, Esther Lopez-Garcia, Esther García-Esquinas, Kabir P Sadarangani, Oscar L Veiga, Fernando Rodriguez-Artalejo
Journal: British Journal of Sports Medicine (2018)

We examined the dose-response relationship between physical activity (PA) and incidence of cardiovascular disease (CVD) risk factors in adults in Taiwan.This study included 1 98 919 participants, aged 18-97 years, free of CVD, cancer and diabetes at baseline (1997-2013), who were followed until 2016. At baseline, participants were classified into five PA levels: inactive' (0 metabolic equivalent of task (MET)-h/week), 'lower insufficiently active' (0.1-3.75 MET-h/week), 'upper insufficiently active' (3.75-7.49 MET-h/week), 'active' (7.5-14.99 MET-h/week) and 'highly active' (≥15 MET-h/week]. CVD risk factors were assessed at baseline and at follow-up by physical examination and laboratory tests. Analyses were performed with Cox regression and adjusted for the main confounders.During a mean follow-up of 6.0±4.5 years (range 0.5-19 years), 20 447 individuals developed obesity, 19 619 hypertension, 21 592 hypercholesterolaemia, 14 164 atherogenic dyslipidaemia, 24 275 metabolic syndrome and 8548 type 2 diabetes. Compared with inactive participants, those in the upper insufficiently active (but not active) category had a lower risk of obesity (HR 0.92; 95% CI 0.88 to 0.95), atherogenic dyslipidaemia (0.96; 0.90 to 0.99), metabolic syndrome (0.95; 0.92 to 0.99) and type 2 diabetes (0.91; 0.86 to 0.97). Only highly active individuals showed a lower incidence of CVD risk factors than their upper insufficiently active counterparts.Compared with being inactive, doing half the recommended amount of PA is associated with a lower incidence of several common biological CVD risk factors. Given these benefits, half the recommended amount of PA is an evidence based target for inactive adults.
Salt reduction: food companies fail to achieve half of government targets, report finds
Authors: Susan Mayor
Journal: BMJ (2018)

Only half of the targets for cutting salt content in the foods that contribute most to UK adults’ salt intake have been met, a progress assessment by Public Health England has reported.1

The salt reduction targets apply to 28 broad categories of foods including meat products, bread, breakfast cereals, crisps, and ready meals. These cover 76 subcategories of food that contribute most to adults’ salt intake, providing around 54% of salt in the average diet.

The Department of Health and Social …
Influence of HIV Infection on the Natural History of Hepatocellular Carcinoma: Results From a Global Multicohort Study
Authors: David J. Pinato, Elias Allara, Ting-Yi Chen, Franco Trevisani, Beatriz Minguez, Marco Zoli, Marianne Harris, Alessia Dalla Pria, Nicolás Merchante, Heather Platt, Mamta Jain, Eugenio Caturelli, Luciana Kikuchi, Juan Pineda, Mark Nelson, Fabio Farinati, Gian Ludovico Rapaccini, Ayse Aytaman, Michael Yin, Chee-Kiat Tan, Mark Bower, Edoardo G. Giannini, Norbert Bräu
Journal: Journal of Clinical Oncology (2018)

Conflicting evidence indicates that HIV seropositivity may influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC, independent of treatment and geographic origin.We designed an international multicohort study of patients with HCC accrued from four continents who did not receive any anticancer treatment. We estimated the effect of HIV seropositivity on patients' OS while accounting for common prognostic factors and demographic characteristics in uni- and multivariable models.A total of 1,588 patients were recruited, 132 of whom were HIV positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C or D criteria (n = 1,168 [74%]) and Child-Turcotte-Pugh (CTP) class B (median score, 7; interquartile range [IQR], 3). At HCC diagnosis, the majority of patients who were HIV-positive (n = 65 [64%]) had been on antiretrovirals for a median duration of 8.3 years (IQR, 8.59 years) and had median CD4+ cell counts of 256 (IQR, 284) with undetectable HIV RNA (n = 68 [52%]). OS decreased significantly throughout BCLC stages 0 to D (16, 12, 7.5, 3.1, and 3 months, respectively; P < .001). Median OS of patients who were HIV-positive was one half that of their HIV-uninfected counterparts (2.2 months [bootstrap 95% CI, 1.2 to 3.1 months] v 4.1 months [95% CI, 3.6 to 4.4 months]). In adjusted analyses, HIV seropositivity increased the hazard of death by 24% ( P = .0333) independent of BCLC ( P < .0001), CTP ( P < .0001), α-fetoprotein ( P < .0001), geographical origin ( P < .0001), and male sex ( P = .0016). Predictors of worse OS in patients who were HIV-positive included CTP ( P = .0071) and α-fetoprotein ( P < .0001).Despite adequate antiretroviral treatment, HIV seropositivity is associated with decreased survival in HCC, independent of stage, anticancer treatment, and geographical origin. Mechanistic studies investigating the immunobiology of HIV-associated HCC are urgently required.