tbuckley/cabot-search huggingface dataset:
Abstract 18299: De Novo Leukotriene B4 Production From High-Density Lipoprotein (HDL) in Recurrent Cardiovascular Disease Patients Deteriorates Anti-Inflammatory Properties of HDL
Authors: Shigeyasu Tsuda, Masakazu Shinohara, Toshihiko Oshita, Manabu Nagao, Nobuaki Tanaka, Takeshige Mori, Tetsuya Hara, Yasuhiro Irino, Ryuji Toh, Tatsuro Ishida, Ken-ichi Hirata
Journal: Circulation (2016)

Introduction: We recently reported that serum myeloperoxidase/paraoxonase 1 (MPO/PON1) ratio could be used as a useful marker for high density lipoprotein (HDL) function and elevated MPO/PON1 ratio...
The Bicarbonate Transporter SLC4A7 Plays a Key Role in Macrophage Phagosome Acidification
Authors: Vitaly Sedlyarov, Ruth Eichner, Enrico Girardi, Patrick Essletzbichler, Ulrich Goldmann, Paula Nunes-Hasler, Ismet Srndic, Anna Moskovskich, Leonhard X. Heinz, Felix Kartnig, Johannes W. Bigenzahn, Manuele Rebsamen, Pavel Kovarik, Nicolas Demaurex, Giulio Superti-Furga
Journal: Cell Host & Microbe (2018)

Macrophages represent the first line of immune defense against pathogens, and phagosome acidification is a necessary step in pathogen clearance. Here, we identified the bicarbonate transporter SLC4A7, which is strongly induced upon macrophage differentiation, as critical for phagosome acidification. Loss of SLC4A7 reduced acidification of phagocytosed beads or bacteria and impaired the intracellular microbicidal capacity in human macrophage cell lines. The phenotype was rescued by wild-type SLC4A7, but not by SLC4A7 mutants, affecting transport capacity or cell surface localization. Loss of SLC4A7 resulted in increased cytoplasmic acidification during phagocytosis, suggesting that SLC4A7-mediated, bicarbonate-driven maintenance of cytoplasmic pH is necessary for phagosome acidification. Altogether, we identify SLC4A7 and bicarbonate-driven cytoplasmic pH homeostasis as an important element of phagocytosis and the associated microbicidal functions in macrophages.
Calcium and Vitamin D Supplements and Fractures in Community-Dwelling Adults
Authors: Xerxes Pundole, Maria A. Lopez-Olivo, Huifang Lu
Journal: JAMA (2018)

To the Editor Dr Zhao and colleagues1 concluded that the findings of their review did not support the routine use of calcium or vitamin D supplementation in community-dwelling older adults. This broad conclusion is potentially weakened by several aspects of the study.
From lipid locus to drug target through human genomics
Authors: Sander W van der Laan, Eric L Harshfield, Daiane Hemerich, David Stacey, Angela M Wood, Folkert W Asselbergs
Journal: Cardiovascular Research (2018)

In the last decade, over 175 genetic loci have robustly been associated to levels of major circulating blood lipids. Most loci are specific to one or two lipids, whereas some (SUGP1, ZPR1, TRIB1, HERPUD1, and FADS1) are associated to all. While exposing the polygenic architecture of circulating lipids and the underpinnings of dyslipidaemia, these genome-wide association studies (GWAS) have provided further evidence of the critical role that lipids play in coronary heart disease (CHD) risk, as indicated by the 2.7-fold enrichment for macrophage gene expression in atherosclerotic plaques and the association of 25 loci (such as PCSK9, APOB, ABCG5-G8, KCNK5, LPL, HMGCR, NPC1L1, CETP, TRIB1, ABO, PMAIP1-MC4R, and LDLR) with CHD. These GWAS also confirmed known and commonly used therapeutic targets, including HMGCR (statins), PCSK9 (antibodies), and NPC1L1 (ezetimibe). As we head into the post-GWAS era, we offer suggestions for how to move forward beyond genetic risk loci, towards refining the biology behind the associations and identifying causal genes and therapeutic targets. Deep phenotyping through lipidomics and metabolomics will refine and increase the resolution to find causal and druggable targets, and studies aimed at demonstrating gene transcriptional and regulatory effects of lipid associated loci will further aid in identifying these targets. Thus, we argue the need for deeply phenotyped, large genetic association studies to reduce costs and failures and increase the efficiency of the drug discovery pipeline. We conjecture that in the next decade a paradigm shift will tip the balance towards a data-driven approach to therapeutic target development and the application of precision medicine where human genomics takes centre stage.
Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial
Authors: David E Kandzari, Michael Böhm, Felix Mahfoud, Raymond R Townsend, Michael A Weber, Stuart Pocock, Konstantinos Tsioufis, Dimitrios Tousoulis, James W Choi, Cara East, Sandeep Brar, Sidney A Cohen, Martin Fahy, Garrett Pilcher, Kazuomi Kario, Jiro Aoki, Bryan Batson, Michael Böhm, James W. Choi, Debbie L. Cohen, George Dangas, Shukri David, Justin Davies, Chandan M. Devireddy, David Kandzari, Kazuomi Kario, David P. Lee, Philipp C. Lurz, Vasilios Papademetriou, Manesh Patel, Kiritkumar Patel, Roland E. Schmieder, Andrew S.P. Sharp, Jasvindar Singh, Konstantinos Tsioufis, Antony Walton, Thomas Weber, Joachim Weil, Thomas Zeller, Khaled Ziada, Kengo Tanabe, Robert Wilkins, Felix Mahfoud, Cara East, Robert Wilensky, Johanna Contreras, Susan Steigerwalt, Neil Chapman, Janice P. Lea, Denise Reedus, Satoshi Hoshide, Adrian Ma, Karl Fengler, Ping Li, Laura Svetkey, Anjani Rao, Axel Schmid, Anthony F Watkinson, Angela Brown, Dimitrios Tousoulis, Ingrid Hopper, Markus Suppan, Tolga Agdirlioglu, Elias Noory, Craig Chasen
Journal: The Lancet (2018)
Scotland to target junk food promotions to cut childhood obesity
Authors: Bryan Christie
Journal: BMJ (2018)

Ambitious plans are being drawn up in Scotland aimed at halving the number of children with obesity by 2030.

Details of the plan will be announced later in the summer, but it will include action against supermarket promotions of high sugar and high fat foods that encourage overeating. Children will also be encouraged to become more active by taking part in initiatives such as Scotland’s Daily Mile,1 which aims to get schoolchildren to run or walk a mile …
Abstract 16942: Alternatively Spliced Tissue Factor promotes plaque progression, inflammation and angiogenesis in experimental atherosclerosis
Authors: Daniel Alicea, Aleksey Chudnovskiy, David T Rodriguez, Dong Kwon Yang, Dongtak Jeong, Jason C Kovacic, Juan J Badimon, Thomas Weber, Miriam Merad, Roger J Hajjar, Valentin Fuster, Chiara Giannarelli
Journal: Circulation (2014)

Introduction: Alternatively Spliced Tissue Factor (asTF) is novel isoform of tissue factor with angiogenic activity mediated via HIF-1α signaling (Giannarelli, AHA 13). asTF is highly expressed in human complicated atherosclerotic plaques (Giannarelli, ACC 13); however, it is unknown whether asTF has a functional role in atherogenesis. Hypothesis: asTF promotes atherosclerotic plaque progression, inflammation and angiogenesis. Methods: ApoE-/- mice (8-weeks old; n=15) were fed a Western-type diet from 2 weeks before surgery continuing through the experiment. Immediately after transluminal wire injury of the left common carotid artery (LCCA), LCCA was incubated with lentivirus encoding asTF-GFP (asTF+ group; n=10) or GFP (asTF- control group; n=5). Four weeks after, blood and spleen were collected for flow cytometry analysis of neutrophils and monocytes. LCCA was removed and processed for H&amp;E, Oil-Red O staining and immunostaining for macrophages (MOMA-2 and MAC-3), vascular smooth muscle cells (VSMC, α-actin), endothelial cells (CD31) and HIF-1α. Results: Neointimal thickness and plaque lipid accumulation were significantly greater in asTF+ vs asTF- mice (Fig 1, A-C). An increase in plaque macrophages, neovessels and HIF-1α was observed in asTF+ vs asTF- (Fig 1, D-F). Medial thickness and VSMC density were similar between groups. Increased circulating neutrophils and Ly6C high (classical/inflammatory) monocytes were observed in asTF+ vs asTF- mice (Fig 1, G,H). In contrast, circulating Ly6C low (patrolling) monocytes were significantly reduced (Fig 1, I). Similar findings were observed in the spleen (Fig 1, J-L). Conclusions: Our results demonstrate that asTF expressed within atherosclerotic lesions promotes plaque progression towards a more advanced phenotype and is associated with systemic proinflammatory status. These data makes asTF an attractive marker of plaque vulnerability and a potential therapeutic target for plaque stabilization.
Abstract 16529: Usefulness of Left Ventricle Global Longitudinal Strain to Predict Cardiovascular Outcomes in Patients With Chagas Cardiomyopathy
Authors: Minna M Romano, Henrique T Moreira, Fawaz Alenezi, Luciano A Saraiva, Andre Schmidt, Benedito C Maciel, Anis Rassi, Jose A Marin-Neto, Eric J Velazquez
Journal: Circulation (2017)

Introduction:  Chagas cardiomyopathy (CC) is associated with a high incidence of cardiovascular events. Global longitudinal strain (GLS) has been shown to be useful in predicting adverse cardiovascular outcomes in various patient populations. However, its prognostic value in CC is unknown.   Hypothesis:  Left ventricle global longitudinal strain (GLS), a more sensitive marker of myocardial damage, can predict outcomes in CC.   Methods:  This study was a prospective analysis of CC subjects with echocardiographic examinations from 2011-2014. GLS was defined as the average of three apical peak longitudinal strain measurements of the LV using a vendor-independent software. Lower GLS reflects better systolic function. GLS groups were defined according to tertiles: (1) GLS ≤ -18.9%, (2) GLS > -18.9% and    Results:  GLS was obtained in 85 subjects, 52% were males and mean age was 55±14 years. There were 7.3% losses of follow-up and the mean LVEF was 52±14 %. . After a follow up period of 28±19 months, 39 subjects reached the composite outcome. Hospitalization was the most frequent outcome (n=15), followed by death (n=12), decrease of LVEF (n=8), new heart failure (n=3), stroke (n=3) and STV (n=1). The GLS group 3 was associated with worse prognosis when compared with the GLS groups 1 and 2 (logrank-p-value = 0.001 for both comparisons),  figure 1 .On multivariate Cox proportional hazard model, adjusting for age, gender and LVEF, GLS was an independent predictor of outcomes with HR 2.7 per 5% absolute change in GLS (CI=1.31-5.54;p=0.007).   Conclusion:  Left ventricle GLS is an independent predictor of cardiovascular outcomes in patients with Chagas cardiomyopathy. GLS may be an important tool to Chagas disease risk stratification, independent of ejection fraction.
RUNX1 mutations in pediatric acute myeloid leukemia are associated with distinct genetic features and an inferior prognosis
Authors: Genki Yamato, Norio Shiba, Kenichi Yoshida, Yusuke Hara, Yuichi Shiraishi, Kentaro Ohki, Jun Okubo, Myoung-ja Park, Manabu Sotomatsu, Hirokazu Arakawa, Nobutaka Kiyokawa, Daisuke Tomizawa, Souichi Adachi, Takashi Taga, Keizo Horibe, Satoru Miyano, Seishi Ogawa, Yasuhide Hayashi
Journal: Blood (2018)
Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma
Authors: Yiru Zhang, Chiaki Tsuge Ishida, Wataru Ishida, Sheng-Fu L. Lo, Junfei Zhao, Chang Shu, Elena Bianchetti, Giulio Kleiner, Maria J. Sanchez-Quintero, Catarina M. Quinzii, Mike-Andrew Westhoff, Georg Karpel-Massler, Peter Canoll, Markus D. Siegelin
Journal: Clinical Cancer Research (2018)

Purpose: Glioblastoma remains a challenge in oncology, in part due to tumor heterogeneity.Experimental Design: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems.Results: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that the combination of histone deacetylase (HDAC) inhibition and bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells. Transcriptome-based GSEA analysis suggests that metabolic reprogramming is involved with synergistic reduction of oxidative and glycolytic pathways in the combination treatment. Extracellular flux analysis confirms that combined HDAC inhibition and BRD inhibition blunts oxidative and glycolytic metabolism of cancer cells, leading to a depletion of intracellular ATP production and total ATP levels. In turn, energy deprivation drives an integrated stress response, originating from the endoplasmic reticulum. This results in an increase in proapoptotic Noxa. Aside from Noxa, we encounter a compensatory increase of antiapoptotic Mcl-1 protein. Pharmacologic, utilizing the FDA-approved drug sorafenib, and genetic inhibition of Mcl-1 enhanced the effects of the combination therapy. Finally, we show in orthotopic patient-derived xenografts of GBM, that the combination treatment reduces tumor growth, and that triple therapy involving the clinically validated compounds panobinostat, OTX015, and sorafenib further enhances these effects, culminating in a significant regression of tumors in vivoConclusions: Overall, these results warrant clinical testing of this novel, efficacious combination therapy. Clin Cancer Res; 24(16); 3941-54. ©2018 AACR.
Association of Patient Sex With Chemotherapy-Related Toxic Effects
Authors: Valerie Cristina, Jestinah Mahachie, Murielle Mauer, Thierry Buclin, Eric Van Cutsem, Arnaud Roth, Anna D. Wagner
Journal: JAMA Oncology (2018)

This secondary analysis of the PETACC-3 trial examines the association of sex with incidence and severity of chemotherapy-related toxic effects in patients with stage II and III colorectal cancer treated with fluorouracil and leucovorin with or without irinotecan hydrochloride.
Non-invasive prediction of esophageal varices by stiffness and platelet in non-alcoholic fatty liver disease cirrhosis
Authors: Salvatore Petta, Giada Sebastiani, Elisabetta Bugianesi, Mauro Viganò, Vincent Wai-Sun Wong, Annalisa Berzigotti, Anna Ludovica Fracanzani, Quentin M. Anstee, Fabio Marra, Marco Barbara, Vincenza Calvaruso, Calogero Cammà, Vito Di Marco, Antonio Craxì, Victor de Ledinghen
Journal: Journal of Hepatology (2018)
Severe osteoporosis and stridor
Authors: Vanushia Thirumal, Kim To, Athena Togo, Jonathan Brodie
Journal: BMJ (2018)

An 88 year old woman presented with progressive stridor, dysphonia, and dysphagia. She had severe osteoporosis, with loss of height and thoracic kyphosis. Fibreoptic laryngoscopy showed a right …
Sons must abide by decision not to allow their father to have a nasogastric at home
Authors: Clare Dyer
Journal: BMJ (2018)

The four sons of an elderly man with end stage dementia have lost a legal battle for the right to have him at home with a nasogastric (NG) tube in place, in the latest acrimonious dispute between treating doctors and patients’ relatives over end of life care.1

Three Appeal Court judges refused permission for the family to appeal against Mrs Justice Parker’s High Court ruling that it would not be in RW’s best interests to be discharged with the nasogastric tube.

Chelsea and Westminster Hospital NHS Foundation Trust in London, which is caring for RW, agreed with his sons that he should be discharged home. The local clinical commissioning group …
Surgeon General Urges Expanded Availability of Naloxone
Authors: Rita Rubin
Journal: JAMA (2018)

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Erratum. Impact of Liraglutide on Amylase, Lipase, and Acute Pancreatitis in Participants With Overweight/Obesity and Normoglycemia, Prediabetes, or Type 2 Diabetes: Secondary Analyses of Pooled Data From the SCALE Clinical Development Program. Diabetes Care 2017;40:839–848
Authors: William M. Steinberg, Julio Rosenstock, Thomas A. Wadden, Morten Donsmark, Christine B. Jensen, J. Hans DeVries
Journal: Diabetes Care (2018)
Implications of Nine Risk Prediction Models for Selecting Ever-Smokers for Computed Tomography Lung Cancer Screening
Authors: Hormuzd A. Katki, Stephanie A. Kovalchik, Lucia C. Petito, Li C. Cheung, Eric Jacobs, Ahmedin Jemal, Christine D. Berg, Anil K. Chaturvedi
Journal: Annals of Internal Medicine (2018)

Background: Lung cancer screening guidelines recommend using individualized risk models to refer ever-smokers for screening. However, different models select different screening populations. The performance of each model in selecting ever-smokers for screening is unknown. Objective: To compare the U.S. screening populations selected by 9 lung cancer risk models (the Bach model; the Spitz model; the Liverpool Lung Project [LLP] model; the LLP Incidence Risk Model [LLPi]; the Hoggart model; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 [PLCOM2012]; the Pittsburgh Predictor; the Lung Cancer Risk Assessment Tool [LCRAT]; and the Lung Cancer Death Risk Assessment Tool [LCDRAT]) and to examine their predictive performance in 2 cohorts. Design: Population-based prospective studies. Setting: United States. Participants: Models selected U.S. screening populations by using data from the National Health Interview Survey from 2010 to 2012. Model performance was evaluated using data from 337 388 ever-smokers in the National Institutes of Health–AARP Diet and Health Study and 72 338 ever-smokers in the CPS-II (Cancer Prevention Study II) Nutrition Survey cohort. Measurements: Model calibration (ratio of model-predicted to observed cases [expected–observed ratio]) and discrimination (area under the curve [AUC]). Results: At a 5-year risk threshold of 2.0%, the models chose U.S. screening populations ranging from 7.6 million to 26 million ever-smokers. These disagreements occurred because, in both validation cohorts, 4 models (the Bach model, PLCOM2012, LCRAT, and LCDRAT) were well-calibrated (expected–observed ratio range, 0.92 to 1.12) and had higher AUCs (range, 0.75 to 0.79) than 5 models that generally overestimated risk (expected–observed ratio range, 0.83 to 3.69) and had lower AUCs (range, 0.62 to 0.75). The 4 best-performing models also had the highest sensitivity at a fixed specificity (and vice versa) and similar discrimination at a fixed risk threshold. These models showed better agreement on size of the screening population (7.6 million to 10.9 million) and achieved consensus on 73% of persons chosen. Limitation: No consensus on risk thresholds for screening. Conclusion: The 9 lung cancer risk models chose widely differing U.S. screening populations. However, 4 models (the Bach model, PLCOM2012, LCRAT, and LCDRAT) most accurately predicted risk and performed best in selecting ever-smokers for screening. Primary Funding Source: Intramural Research Program of the National Institutes of Health/National Cancer Institute.
Machine Learning–Based Radiomics for Molecular Subtyping of Gliomas
Authors: Chia-Feng Lu, Fei-Ting Hsu, Kevin Li-Chun Hsieh, Yu-Chieh Jill Kao, Sho-Jen Cheng, Justin Bo-Kai Hsu, Ping-Huei Tsai, Ray-Jade Chen, Chao-Ching Huang, Yun Yen, Cheng-Yu Chen
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The new classification announced by the World Health Organization in 2016 recognized five molecular subtypes of diffuse gliomas based on isocitrate dehydrogenase (IDH) and 1p/19q genotypes in addition to histologic phenotypes. We aim to determine whether clinical MRI can stratify these molecular subtypes to benefit the diagnosis and monitoring of gliomas. Experimental Design: The data from 456 subjects with gliomas were obtained from The Cancer Imaging Archive. Overall, 214 subjects, including 106 cases of glioblastomas and 108 cases of lower grade gliomas with preoperative MRI, survival data, histology, IDH, and 1p/19q status were included. We proposed a three-level machine-learning model based on multimodal MR radiomics to classify glioma subtypes. An independent dataset with 70 glioma subjects was further collected to verify the model performance. Results: The IDH and 1p/19q status of gliomas can be classified by radiomics and machine-learning approaches, with areas under ROC curves between 0.922 and 0.975 and accuracies between 87.7% and 96.1% estimated on the training dataset. The test on the validation dataset showed a comparable model performance with that on the training dataset, suggesting the efficacy of the trained classifiers. The classification of 5 molecular subtypes solely based on the MR phenotypes achieved an 81.8% accuracy, and a higher accuracy of 89.2% could be achieved if the histology diagnosis is available. Conclusions: The MR radiomics-based method provides a reliable alternative to determine the histology and molecular subtypes of gliomas. Clin Cancer Res; 24(18); 4429–36. ©2018 AACR.