tbuckley/cabot-search huggingface dataset:
Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study
Authors: Michael Wainberg, Anubha Mahajan, Anshul Kundaje, Mark I. McCarthy, Erik Ingelsson, Nasa Sinnott-Armstrong, Manuel A. Rivas
Journal: PLoS Medicine (2019)

Background Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk. Methods and findings We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m2 BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m2 BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12–1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m2) without a family history of diabetes, similar to that in obese individuals (BMI ≥ 30 kg/m2) with a family history (1.21-fold reduction, 95% CI 1.13–1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual's entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life. Conclusions In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk.
Prognostic Significance of Prior Best Response to Imatinib in Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Second Generation Tyrosine Kinase Inhibitors (TKIs).
Authors: Elias Jabbour, Hagop Kantarjian, Jenny Shan, Susan O’Brien, William Wierda, Farhad Ravandi, Gautam Borthakur, Steven Kornblau, Brenda K. Walker, Mary Beth Rios, Jorge Cortes
Journal: Blood (2007)
Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (NMHCT) for Patients Relapsing after Autologous Stem Cell Transplantation (autoHCT) for B Cell Non-Hodgkin Lymphoma (NHL)
Authors: Cesar O Freytes, Jeanette Carreras, Mei-Jie Zhang, Ginna G. Laport, Koen Van Besien, Hillard M. Lazarus, Parameswaran Hari
Journal: Blood (2008)
David Oliver: Hearing loss in hospital
Authors: David Oliver
Journal: BMJ (2019)

One in six people in England has hearing loss—around 42% of people over 50 and 71% of over 70s.1 Increasing age brings greater risk of frailty, dementia, and functional impairment in daily activities, which may be compounded by hearing loss.23 Hospital patients with hearing loss are multiply disadvantaged if we’re not attuned to their needs.

Quality of care may be jeopardised if we don’t document and share knowledge of patients’ pre-existing hearing loss. It can, for example, be a risk factor for developing delirium.4 It can make it harder for patients to understand instructions or information, which could in turn hinder physical examination, functional or …
Pruritus secondary to primary biliary cholangitis
Authors: A.B. Hussain, R. Samuel, V.S. Hegade, D.E. Jones, N.J. Reynolds
Journal: British Journal of Dermatology (2019)

Primary biliary cholangitis (PBC) is a long‐term disease affecting 35 in every 100,000 people in the United Kingdom (UK) and United States. It is driven by the immune system and causes inflammation of bile ducts (tubes carrying bile from the liver to the gut), leading to bile duct destruction and eventual scarring of the liver. For unclear reasons, PBC causes persistent itch (cholestatic itch) that is difficult to suppress with conventional treatments. Several case studies have shown that phototherapy (treatment of the skin with UV light) can be used to reduce cholestatic itch, although the processes behind this treatment remain poorly understood. This review article, written by researchers in the UK, summarises the evidence behind the use of phototherapy to treat cholestatic itch and explores potential reasons (mechanisms) for how it works. Fifty articles were included in this review, alongside the authors’ own expertise. Key theories about potential mechanisms include the effect of phototherapy on bile salt components, enzyme activity and the expression of receptors involved in cholestatic itch pathways. This paper has developed several testable hypotheses (theories) that can be trialled to increase knowledge on this important subject and to aid the development of effective treatments.
Salinomycin effectively eliminates cancer stem-like cells and obviates hepatic metastasis in uveal melanoma
Authors: Jingfeng Zhou, Shenglan Liu, Yun Wang, Wei Dai, Hailin Zou, Shubo Wang, Jing Zhang, Jingxuan Pan
Journal: Molecular Cancer (2019)

Abstract Background Uveal melanoma (UM) is the most common primary intraocular tumor. Hepatic metastasis is the major and direct death-related reason in UM patients. Given that cancer stem-like cells (CSCs) are roots of metastasis, targeting CSCs may be a promising strategy to overcome hepatic metastasis in UM. Salinomycin, which has been identified as a selective inhibitor of CSCs in multiple types of cancer, may be an attractive agent against CSCs thereby restrain hepatic metastasis in UM. The objective of the study is to explore the antitumor activity of salinomycin against UM and clarify its underlying mechanism. Methods UM cells were treated with salinomycin, and its effects on cell proliferation, apoptosis, migration, invasion, CSCs population, and the related signal transduction pathways were determined. The in vivo antitumor activity of salinomycin was evaluated in the NOD/SCID UM xenograft model and intrasplenic transplantation liver metastasis mouse model. Results We found that salinomycin remarkably obviated growth and survival in UM cell lines and in a UM xenograft mouse model. Meanwhile, salinomycin significantly eliminated CSCs and efficiently hampered hepatic metastasis in UM liver metastasis mouse model. Mechanistically, Twist1 was fundamental for the salinomycin-enabled CSCs elimination and migration/invasion blockage in UM cells. Conclusions Our findings suggest that targeting UM CSCs by salinomycin is a promising therapeutic strategy to hamper hepatic metastasis in UM. These results provide the first pre-clinical evidence for further testing of salinomycin for its antitumor efficacy in UM patients with hepatic metastasis.
Genetic of Sporadic Hemophagocytic Lymphohistiocytosis
Authors: Coralie Bloch, Jean-Philippe Jais, Marine Gil, Marouane Boubaya, Felipe Suarez, Brigitte Bader-Meunier, Nizar Malhaoui, Alain Fischer, Genevieve de Saint Basile, Olivier Hermine
Journal: Blood (2019)
Novel Mechanism of Activated FLT3-Associated Leukemogenisis: FLT3 Regulates Wnt Signaling by Phosphorylating β-Catenin and Promoting β-Catenin Nuclear Localization.
Authors: Tomohiro Kajiguchi, Eun Joo Chung, Hitoshi Kiyoi, Tomoki Naoe, Len Neckers, Jane Trepel
Journal: Blood (2005)
Analysis of JAK2V617F Mutation, PRV-1 Overexpression and Endogenous Erythroid Colony (EEC) Formation Show Different Coexpression Patterns among Ph-Negative Chronic Myeloproliferative Disorders.
Authors: Beatriz Bellosillo, Carles Besses, Lourdes Florensa, Raquel Longaron, Gemma Navarro, Eva Gimeno, Francesc Sole, Rosa M. Vila, Sergi Serrano
Journal: Blood (2005)
Small Populations of PNH-Type Cells in Aplastic Anemia Patients Are Derived from PIG-A Mutant Stem Cell Clones without Proliferative Advantage.
Authors: Kanako Mochizuki, Chiharu Sugimori, Xingmin Feng, Xuzhang Lu, Gudrun H. Reed, Carl T. Wittwer, Shinji Nakao
Journal: Blood (2006)
Core Competencies in Echocardiography for Imaging Structural Heart Disease Interventions
Authors: Rebecca T Hahn, Feroze Mahmood, Susheel Kodali, Roberto Lang, Mark Monaghan, Linda D Gillam, Madhav Swaminathan, Robert O Bonow, Ralph Stephan von Bardeleben, Jeroen J Bax, Paul Grayburn, William A Zoghbi, Partho P Sengupta, Y Chandrashekhar, Stephen H Little
Journal: JACC. Cardiovascular imaging (2019)
Abstract 148: Installation and Deployment of Automated External Defibrillators in New York State Schools
Authors: Milla Arabadjian, Alexandra Stepanovic, Mark Sherrid
Journal: Circulation (2019)

Introduction: AHA recommends that automated external defibrillators (AEDs) be made available in public areas with high likelihood of a sudden cardiac arrest (SCA). Only 18 US states have regulations requiring AEDs in schools and the legislation varies. There is no comprehensive evaluation of the epidemiology of sudden death in schools. School nurses are often the only healthcare providers within a school. New York State (NYS) enrolls almost 3.5 million students with New York City (NYC) being the largest school system in the US; legislation requires AEDs in all public but not in private schools. Purpose: Our aims were threefold: to gain epidemiologic data on SCAs in NYS schools, to evaluate the availability and utilization of AEDs, and to identify factors affecting deployment of AEDs. Methods: Electronic surveys were sent to school nurse members of the NYS Association of School Nurses and NYC school nurses. We also conducted structured interviews with a representative sample of NYS school nurses. Results: Nurses representing 750 public schools and 116 private schools responded, a response rate of 36.4%. There were 71 SCA events, with majority affecting adults on school grounds 41 (58%). AEDs were deployed in 59 (73%). Short term survival occurred in 50 (69%) with 40 (56%) returning to regular activity. While not required to have AEDs available, most private schools had them 69(60%). There were 21 (30%) SCA events in private schools with 8 (11%) occurring in private schools with no AEDs. Of these, 6 (75%) had a negative outcome. Interviews revealed that staff attitude, fear, and training adequacy were factors influencing AED utilization. Conclusions: AEDs in schools improve survival outcomes. There has been no comprehensive evaluation of SCA events in US schools and no uniformity in AED legislation among states. While focus is on students, NYS data suggests that attention should also encompass adult SCAs in schools. Comparisons of AED utilization and SCA outcomes in states with and without AED legislation will be of interest, and may have health policy implications.
Abstract 15232: Iron Deficiency and Elevated Hepcidin Predict Abnormal Pulmonary Vascular Responses to Exercise in Patients With Preserved Ejection Fraction Undergoing Evaluation of Dyspnea
Authors: Thomas F Cunningham, Charles L Slocum, Kathryn M Hardin, Robyn M Farrell, Cole S Bailey, Luke T Wooster, Jennifer N Rouvina, Casey G White, Hanna J Barnes, Jennifer E Ho, Gregory D Lewis, Rajeev Malhotra
Journal: Circulation (2018)

Introduction: Hepcidin is a master regulator of iron homeostasis that reduces iron absorption when circulating levels are elevated. In preclinical models, iron deficiency and inappropriately elevat...
Fludarabine Combination Therapy Response, Progression and Toxicity Profile in a Minority Predominant Population with Chronic Lymphocytic Leukemia from a Public Health Hospital
Authors: Bety Ciobanu, Shylendra B Sreenivasappa, Barbara Yim, Tracy Smiley, Victoria Angelova, Paula Kovarik, Samuel Ofori, Mousami Shah, Rafid Kouz, Margaret Clare Telfer, Rosalind Catchatourian
Journal: Blood (2008)
Six Novel Mutations Including Triple Heterozygosity for Phe31Ser, 514delT and 516T→G Mutations in Factor X Gene Is Responsible for Congenital Factor X Deficiency in Patients of Indian and Nepali Origin.
Authors: G Jayandharan, RV Shaji, Auro Viswabandhya, Sukesh C. Nair, Joy Mammen, Biju George, Vikram Mathews, Mammen Chandy, Alok Srivastava
Journal: Blood (2004)
LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis
Authors: Yirong Wang, Siqi Wu, Xun Zhu, Liyuan Zhang, Jieqiong Deng, Fang Li, Binbin Guo, Shenghua Zhang, Rui Wu, Zheng Zhang, Kexin Wang, Jiachun Lu, Yifeng Zhou
Journal: The Journal of Experimental Medicine (2019)

Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) with the most aggressive phenotype and poor overall survival. Using bioinformatics tools, we identified LINC00908 encoding a 60–aa polypeptide and differentially expressed in TNBC tissues. We named this endogenously expressed polypeptide ASRPS (a small regulatory peptide of STAT3). ASRPS expression was down-regulated in TNBCs and associated with poor overall survival. We showed that LINC00908 was directly regulated by ERα, which was responsible for the differential down-regulation of LINC00908 in TNBCs. ASRPS directly bound to STAT3 through the coiled coil domain (CCD) and down-regulated STAT3 phosphorylation, which led to reduced expression of VEGF. In human endothelial cells, a mouse xenograft breast cancer model, and a mouse spontaneous BC model, ASRPS expression reduced angiogenesis. In a mouse xenograft breast cancer model, down-regulation of ASRPS promoted tumor growth, and ASRPS acted as an antitumor peptide. We presented strong evidence that LINC00908-encoded polypeptide ASRPS represented a TNBC-specific target for treatment.
The Path to Cure: Using Haploidentical (haplo) Donors and High-Dose Post-Transplant Cyclophosphamide (PTCy) for Treatment-Naïve and Refractory Severe Aplastic Anemia (SAA)
Authors: Amy E. DeZern, Marianna Zahurak, Kenneth R. Cooke, David Margolis, Richard J. Jones, Robert A. Brodsky
Journal: Blood (2019)
DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis
Authors: Barbara Rivera, Javad Nadaf, Somayyeh Fahiminiya, Maria Apellaniz-Ruiz, Avi Saskin, Anne-Sophie Chong, Sahil Sharma, Rabea Wagener, Timothée Revil, Vincenzo Condello, Zineb Harra, Nancy Hamel, Nelly Sabbaghian, Karl Muchantef, Christian Thomas, Leanne de Kock, Marie-Noëlle Hébert-Blouin, Angelia V. Bassenden, Hannah Rabenstein, Ozgur Mete, Ralf Paschke, Marc P. Pusztaszeri, Werner Paulus, Albert Berghuis, Jiannis Ragoussis, Yuri E. Nikiforov, Reiner Siebert, Steffen Albrecht, Robert Turcotte, Martin Hasselblatt, Marc R. Fabian, William D. Foulkes
Journal: Journal of Clinical Investigation (2019)

BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.
B Cell Tetherin: A Flow Cytometric Cell‐Specific Assay for Response to Type I Interferon Predicts Clinical Features and Flares in Systemic Lupus Erythematosus
Authors: Yasser M. El‐Sherbiny, Md Yuzaiful Md Yusof, Antonios Psarras, Elizabeth M. A. Hensor, Kumba Z. Kabba, Katherine Dutton, Alaa A. A. Mohamed, Dirk Elewaut, Dennis McGonagle, Reuben Tooze, Gina Doody, Miriam Wittmann, Paul Emery, Edward M. Vital
Journal: Arthritis & Rheumatology (2019)

Type I interferon (IFN) responses are broadly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Given the cardinal role of autoantibodies in SLE, this study was undertaken to investigate whether the findings of a B cell-specific IFN assay correlate with SLE activity.B cells and peripheral blood mononuclear cells (PBMCs) were stimulated with type I IFN and type II IFN. Gene expression was analyzed, and the expression of pathway-related membrane proteins was determined. A flow cytometry assay for tetherin (CD317), an IFN-induced protein ubiquitously expressed on leukocytes, was validated in vitro and then clinically against SLE diagnosis, plasmablast expansion, and the British Isles Lupus Assessment Group (BILAG) 2004 score in a discovery cohort (n = 156 SLE patients, 30 rheumatoid arthritis [RA] patients, and 25 healthy controls). A second, longitudinal validation cohort of 80 SLE patients was also evaluated for flare prediction.In vitro, a close cell-specific and dose-response relationship between type I IFN-responsive genes and cell surface tetherin was observed in all immune cell subsets. Tetherin expression on multiple cell subsets was selectively responsive to stimulation with type I IFN compared to types II and III IFNs. In patient samples from the discovery cohort, memory B cell tetherin showed the strongest associations with diagnosis (SLE:healthy control effect size 0.11 [P = 0.003]; SLE:RA effect size 0.17 [P < 0.001]), plasmablast numbers in rituximab-treated patients (R = 0.38, P = 0.047), and BILAG 2004. These associations were equivalent to or stronger than those for IFN score or monocyte tetherin. Memory B cell tetherin was found to be predictive of future clinical flares in the validation cohort (hazard ratio 2.29 [95% confidence interval 1.01-4.64]; P = 0.022).Our findings indicate that memory B cell surface tetherin, a B cell-specific IFN assay, is associated with SLE diagnosis and disease activity, and predicts flares better than tetherin on other cell subsets or whole blood assays, as determined in an independent validation cohort.
An Updated Safety and Efficacy Results of Phase 1 Study of HQP1351, a Novel 3rd Generation of BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI Resistant Chronic Myeloid Leukemia
Authors: Qian Jiang, Xiaojun Huang, Zi Chen, Qian Niu, Lichuang Men, Hengbang Wang, Jiao JI, Bo Huang, Dayu Shi, Ting Zhao, Yue Hou, Dajun Yang, Yifan Zhai
Journal: Blood (2019)
Abstract P100: Identification of Patients with Familial Hypercholesterolemia (FH) Using the Dutch Lipid Network (DLN) Criteria in Electronic Health Records (EHR)
Authors: Sarah S Cohen, Jana Shirey-Rice, Jill Hardin, Keri Monda, Jon P Fryzek, Sergio Fazio, Joshua C Denny, Wei-Qi Wei, Loren Lipworth
Journal: Circulation (2016)

Introduction: Heterozygous FH is common but under-diagnosed. No uniformly accepted diagnostic criteria for FH exist, and the ability of current algorithms to identify patients using EHR data remains largely untested. Here we present results and challenges in using the DLN criteria to identify FH patients in an EHR. Methods: In the Vanderbilt University Medical Center de-identified EHR, patients &gt; 18 years with 1+ low-density lipoprotein cholesterol (LDL-C) measure from 1996 to 2014 were eligible for study. Using diagnostic and procedure codes, narrative text from clinical care, and laboratory data, patients were assigned points for DLN components (see Table), which were summed to classify definite (DLN≥8) or probable (DLN=6-7) FH. LDL-C values were extracted directly from structured laboratory records. Evidence of physical signs or testing for LDL-C receptor mutations were assessed via keyword searches with simple negation detection rules, the latter including vendor names known to conduct such mutation analyses. Results: Among 218,652 eligible patients, 10,812 (5%) had 1+ LDL-C &gt; 190 mg/dl. We identified 622 probable and 430 definite FH patients (overall prevalence 0.48%). Family history was not ascertainable in a systematic way for most patients and thus not used in scoring. Physical exam signs minimally impacted DLN scores as they were noted infrequently. No definite or probable FH patient records included mention of LDL-C receptor mutation status. Only 5 definite and 3 probable FH patients had narrative keywords noting the presence or suspicion of FH. Conclusions: EHRs may be useful to identify FH patients but existing algorithms lack sensitivity when applied to EHRs as they rely on key elements rarely captured. Further, the sizable population with LDL-C &gt; 190 suggests that FH in this group may not be adequately captured by the DLN criteria. Work is needed to determine how best to utilize EHRs to reliably ascertain FH, via development of new algorithms or by clarifying the positive predictive value of existing algorithms.
Frontline High-Dose Therapy (HDT) for Adults with Disseminated Aggressive Lymphoma (NHL): Analysis of 327 Patients Included in 3 Prospective Trials (GOELAMS 071, 072, 074) over 12 Years.
Authors: Noel-jean Milpied, Eric Deconinck, Thierry Lamy, Philippe Colombat, Goelams Goelams
Journal: Blood (2005)