tbuckley/cabot-search huggingface dataset:
Modulation of the Tryptophan Hydroxylase 1/Monoamine Oxidase‐A/5‐Hydroxytryptamine/5‐Hydroxytryptamine Receptor 2A/2B/2C Axis Regulates Biliary Proliferation and Liver Fibrosis During Cholestasis
Authors: Konstantina Kyritsi, Lixian Chen, April O’Brien, Heather Francis, Travis W. Hein, Julie Venter, Nan Wu, Ludovica Ceci, Tianhao Zhou, David Zawieja, Anatoliy A. Gashev, Fanyin Meng, Pietro Invernizzi, Luca Fabris, Chaodong Wu, Nicholas J. Skill, Romil Saxena, Suthat Liangpunsakul, Gianfranco Alpini, Shannon S. Glaser
Journal: Hepatology (2019)

Background and Aims Serotonin (5HT) is a neuroendocrine hormone synthetized in the central nervous system (CNS) as well as enterochromaffin cells of the gastrointestinal tract. Tryptophan hydroxylase (TPH1) and monoamine oxidase (MAO‐A) are the key enzymes for the synthesis and catabolism of 5HT, respectively. Previous studies demonstrated that 5‐hydroxytryptamine receptor (5HTR)1A/1B receptor agonists inhibit biliary hyperplasia in bile‐duct ligated (BDL) rats, whereas 5HTR2B receptor antagonists attenuate liver fibrosis (LF) in mice. Our aim was to evaluate the role of 5HTR2A/2B/2C agonists/antagonists in cholestatic models. Approach and Results While in vivo studies were performed in BDL rats and the multidrug resistance gene 2 knockout ( Mdr2–/– ) mouse model of PSC, in vitro studies were performed in cell lines of cholangiocytes and hepatic stellate cells (HSCs). 5HTR2A/2B/2C and MAO‐A/TPH1 are expressed in cholangiocytes and HSCs from BDL rats and Mdr2–/– ‐ mice. Ductular reaction, LF, as well as the mRNA expression of proinflammatory genes increased in normal, BDL rats, and Mdr2–/– ‐ mice following treatment 5HTR2A/2B/2C agonists, but decreased when BDL rats and Mdr2–/– mice were treated with 5HTR2A/2B/2C antagonists compared to BDL rats and Mdr2–/– mice, respectively. 5HT levels increase in Mdr2–/– mice and in PSC human patients compared to their controls and decrease in serum of Mdr2–/– mice treated with 5HTR2A/2B/2C antagonists compared to untreated Mdr2–/– mice. In vitro , cell lines of murine cholangiocytes and human HSCs express 5HTR2A/2B/2C and MAO‐A/TPH1; treatment of these cell lines with 5HTR2A/2B/2C antagonists or TPH1 inhibitor decreased 5HT levels as well as expression of fibrosis and inflammation genes compared to controls. Conclusions Modulation of the TPH1/MAO‐A/5HT/5HTR2A/2B/2C axis may represent a therapeutic approach for management of cholangiopathies, including PSC.
Assessment of Diagnostic Yield of Nonculture Infection Testing on Cerebrospinal Fluid in Immune-Competent Children
Authors: Jennifer L. McGuire, Nichole V. Tuite, Sanjeev K. Swami, Robert A. Avery
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Nonculture infection tests of cerebrospinal fluid (CSF) samples using polymerase chain reaction and antigen or antibody assays are frequently ordered on lumbar puncture specimens concurrently with routine CSF cell counts, but the value of CSF infection testing in otherwise healthy children is unknown. <h3>Objective</h3> To determine the value of nonculture CSF infection testing in immune-competent children with normal CSF cell counts. <h3>Design, Setting, and Participants</h3> This cross-sectional study reviewed screening and diagnostic tests in the electronic medical record system of a large academic tertiary care children’s hospital. Records of children aged 0.5 to 18.9 years (n = 4083) who underwent lumbar puncture (n = 4811 procedures) in an inpatient or outpatient facility of Children's Hospital of Philadelphia between July 1, 2007, and December 31, 2016, were reviewed. Those with indwelling CSF shunts or catheters; those with active or past oncologic, immunologic, or rheumatologic conditions; or those taking immune-suppressing medications were excluded from analysis. This study was conducted from July 20, 2017, to March 13, 2019. <h3>Main Outcomes and Measures</h3> Outcome variables included frequency of nonculture CSF infection testing and frequency of positive results in the entire cohort, and among those with normal cell counts. Normal cell counts were defined as CSF white blood cell counts lower than 5 cells/μL and CSF red blood cell counts lower than 500 cells/μL. <h3>Results</h3> In total, 4811 lumbar puncture procedures were performed on 4083 unique children, with a median (range) age of 7.4 (0.5-18.9) years, 2537 boys (52.7%), and 3331 (69.2%) with normal CSF cell counts. At least 1 nonculture CSF infection test was performed on 1270 lumbar puncture specimens with normal cell counts (38.1%; 95% CI, 36%-40%), and more tests were performed in the summer months. Only 18 (1.4%; 95% CI, 0.9%-2.2%) of 1270 lumbar puncture specimens with normal cell counts had at least 1 nonculture infection test with a positive result; 2 of these 18 children required clinical intervention for their positive results, but each also had other clear clinical signs of infection. <h3>Conclusions and Relevance</h3> Nonculture CSF infection testing appeared to be common in immune-competent children with normal CSF cell counts, but positive results were uncommon and were not independently associated with clinical care; delaying the decision to send nonculture infection tests until CSF cell counts are available could reduce unnecessary diagnostic testing and medical costs, which may improve value-based care.
Abstract 14243: Rolling 600,000 Remote Patients Encounters to STEMI Intervention
Authors: Sameer Mehta, Roberto Botelho, Francisco Fernandez, Jamil Cade, Fausto Feres, Alexandre Abizaid, Cristiano Souza, Nabil Hamdan, Pablo Charry, Marco A Alcocer, Juan C Perez-Alva, Alfredo Estrada, Mario A Torres, Daniel Rodriguez, Lucas Lauar C. Vidal, Daniel Vieira
Journal: Circulation (2018)

Introduction: Major disparities exist between developed and developing countries in the outcomes of patients presenting with AMI. Telemedicine has emerged as a powerful, cost-efficient, and scalabl...
Implications of Early Decline in eGFR due to Intensive BP Control for Cardiovascular Outcomes in SPRINT
Authors: Srinivasan Beddhu, Jincheng Shen, Alfred K. Cheung, Paul L. Kimmel, Glenn M. Chertow, Guo Wei, Robert E. Boucher, Michel Chonchol, Farid Arman, Ruth C. Campbell, Gabriel Contreras, Jamie P. Dwyer, Barry I. Freedman, Joachim H. Ix, Kent Kirchner, Vasilios Papademetriou, Roberto Pisoni, Michael V. Rocco, Paul K. Whelton, Tom Greene
Journal: Journal of the American Society of Nephrology (2019)

The Systolic BP Intervention Trial (SPRINT) found that intensive versus standard systolic BP control (targeting <120 or <140 mm Hg, respectively) reduced the risks of death and major cardiovascular events in persons with elevated cardiovascular disease risk. However, the intensive intervention was associated with an early decline in eGFR, and the clinical implications of this early decline are unclear.In a post hoc analysis of SPRINT, we defined change in eGFR as the percentage change in eGFR at 6 months compared with baseline. We performed causal mediation analyses to separate the overall effects of the randomized systolic BP intervention on the SPRINT primary cardiovascular composite and all-cause mortality into indirect effects (mediated by percentage change in eGFR) and direct effects (mediated through pathways other than percentage change in eGFR).About 10.3% of the 4270 participants in the intensive group had a ≥20% eGFR decline versus 4.4% of the 4256 participants in the standard arm (P<0.001). After the 6-month visit, there were 591 cardiovascular composite events during 27,849 person-years of follow-up. The hazard ratios for total effect, direct effect, and indirect effect of the intervention on the cardiovascular composite were 0.67 (95% confidence interval [95% CI], 0.56 to 0.78), 0.68 (95% CI, 0.57 to 0.79), and 0.99 (95% CI, 0.95 to 1.03), respectively. All-cause mortality results were similar.Although intensive systolic BP lowering resulted in greater early decline in eGFR, there was no evidence that the reduction in eGFR owing to intensive systolic BP lowering attenuated the beneficial effects of this intervention on cardiovascular events or all-cause mortality.
Author Correction: Deep learning versus human graders for classifying diabetic retinopathy severity in a nationwide screening program
Authors: Paisan Ruamviboonsuk, Jonathan Krause, Peranut Chotcomwongse, Rory Sayres, Rajiv Raman, Kasumi Widner, Bilson J. L. Campana, Sonia Phene, Kornwipa Hemarat, Mongkol Tadarati, Sukhum Silpa-Archa, Jirawut Limwattanayingyong, Chetan Rao, Oscar Kuruvilla, Jesse Jung, Jeffrey Tan, Surapong Orprayoon, Chawawat Kangwanwongpaisan, Ramase Sukumalpaiboon, Chainarong Luengchaichawang, Jitumporn Fuangkaew, Pipat Kongsap, Lamyong Chualinpha, Sarawuth Saree, Srirut Kawinpanitan, Korntip Mitvongsa, Siriporn Lawanasakol, Chaiyasit Thepchatri, Lalita Wongpichedchai, Greg S. Corrado, Lily Peng, Dale R. Webster
Journal: npj Digital Medicine (2019)

[This corrects the article DOI: 10.1038/s41746-019-0099-8.].
Abstract 31: Nifedipine Increases Vascular Formations in Skin Wounds
Authors: Dinaldo C Oliveira, Augusto Brasileiro, Lais Dantas, Danielle Oliveira, Vitor Nunes, Maria Isabel Gadelha, Jessica Amorim
Journal: Circulation Research (2017)

Introduction: Loss of skin integrity can result in a wound. Wounds are associated with high cost and disability for patients. Peripheral arterial disease may be the cause of wounds that infect and lead to amputations. Our objective was to evaluate whether the use of nifedipine in wounds is associated with greater amounts of new vascular formations and collagen when compared to placebo. Hypothesis: The new vascular formation in wounds is greater in those treated with nifedipine than in those treated with placebo. Methods: We performed 32 wounds in pigs and locally applied placebo or nifedipine (1%, 10% or 20%). Wounds were evaluated macro and microscopically at 6 different moments. A logistic longitudinal model of mixed effects was applied. For this purpose, the response to moderate or marked polymorphonuclear cells was considered as a dependend variable, with the comparison groups (placebo, nifedipine 1%, 10% and 20%) as the explanatory variable. Based on the placebo group, the OR was estimated with its respective confidence interval for the nifedipine groups at the different doses. Value of p &lt;0.05 was considered significant. This study was approved by the animal research ethics committee. Results: The figure below shows the comparison of new vascular formation and collagen between groups at six different times. Conclusions: The use of nifedipine in wounds was associated with greater vascular formation when compared to placebo. There were differences in the production of collagen between the groups evaluated (in the groups of nifedipine 10% and 20% less amount of collagen). Nifedipine may have a positive impact on the healing of skin wounds.
Project Switch: Docetaxel as a potential synthetic control in metastatic non-small cell lung cancer (mNSCLC) trials.
Authors: Michael E. Menefee, Yutao Gong, Pallavi Shruti Mishra-Kalyani, Rajeshwari Sridhara, Bindu Kanapuru, Gideon Michael Blumenthal, Richard Pazdur
Journal: Journal of Clinical Oncology (2019)

9105 Background: Docetaxel is a common comparator arm to test novel therapies in post-platinum mNSCLC trials. The advent of Real World Evidence (RWE) has renewed interest in the use of synthetic control arms (control arms from previously conducted randomized trials) to improve accrual to trials and increase patient access of promising experimental agents. We reviewed legacy second-line (2L) mNSCLC trials to assess the impact of switching docetaxel control arms from one trial to another and compare to an experimental regimen. Methods: We identified 5 contemporary 2L trials that enrolled 2013 patients receiving an experimental therapy vs. docetaxel: 5 immunoncology head-to-head trials (one with 2 arms) and one anti-VEGF add-on trial. Kaplan-Meier curves of overall survival (OS) and progression-free survival (PFS) were produced for docetaxel controls. We calculated OS and PFS hazard ratios and 95% confidence intervals for each synthetic trial. A pooled doc arm was also compared with each experimental agent. Results: See Table. Conclusions: Both individual and pooled docetaxel switching of control arms approximated the original OS HR and 95% CI. Methods such as bootstrapped sampling and propensity score matching will be performed in an effort to more closely approximate the original trial characteristics. [Table: see text]
Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation
Authors: Timothy Kinsella, Howard Safran, Susan Wiersma, Thomas DiPetrillo, Andrew Schumacher, Kayla Rosati, John Vatkevich, Lawrence W. Anderson, Kimberly D. Hill, Charles Kunos, Jerry M. Collins
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Iododeoxyuridine (IUdR) is a potent radiosensitizer; however, its clinical utility is limited by dose-limiting systemic toxicities and the need for prolonged continuous infusion. 5-Iodo-2-pyrimidinone-2′-deoxyribose (IPdR) is an oral prodrug of IUdR that, compared with IUdR, is easier to administer and less toxic, with a more favorable therapeutic index in preclinical studies. Here, we report the clinical and pharmacologic results of a first-in-human phase I dose escalation study of IPdR + concurrent radiation therapy (RT) in patients with advanced metastatic gastrointestinal (GI) cancers. Patients and Methods: Adult patients with metastatic GI cancers referred for palliative RT to the chest, abdomen, or pelvis were eligible for study. Patients received IPdR orally once every day × 28 days beginning 7 days before the initiation of RT (37.5 Gy in 2.5 Gy × 15 fractions). A 2-part dose escalation scheme was used, pharmacokinetic studies were performed at multiple time points, and all patients were assessed for toxicity and response to Day 56. Results: Nineteen patients were entered on study. Dose-limiting toxicity was encountered at 1,800 mg every day, and the recommended phase II dose is 1,200 mg every day. Pharmacokinetic analyses demonstrated achievable and sustainable levels of plasma IUdR ≥1 μmol/L (levels previously shown to mediate radiosensitization). Two complete, 3 partial, and 9 stable responses were achieved in target lesions. Conclusions: Administration of IPdR orally every day × 28 days with RT is feasible and tolerable at doses that produce plasma IUdR levels ≥1 μmol/L. These results support the investigation of IPdR + RT in phase II studies.
Glasdegib with Low-Dose Cytarabine: A New Upfront Option for the Vulnerable AML Patient
Authors: Amir T. Fathi
Journal: Clinical Cancer Research (2019)

A multitude of regulatory approvals has recently changed the therapeutic landscape of acute myeloid leukemia. Among these was upfront therapy with the Hedgehog inhibitor glasdegib with low-dose cytarabine. Understanding the process of and rationale for approval of this promising combination is timely and valuable for the oncology community.See related article by Norsworthy et al., p. 6021.
Charles van der Horst: physician, clinical researcher, political activist, and accomplished swimmer
Authors: Rebecca Wallersteiner
Journal: BMJ (2019)

Photo credit: David Wohl

An emeritus professor of medicine and infectious diseases at the University of North Carolina at Chapel Hill, and a global health consultant, Charles van der Horst was born in Hilversum, Netherlands. His parents were Sonja Eichenbaum, a Holocaust survivor, and Johannes Martines Arnold van der Horst. Academic and athletic, van der Horst shone at high school, where he developed an interest in activism as well as science. In his spare time, he worked for the Vietnam anti-war movement.

Explaining the roots of his political activism, van der Horst said: “My parents arrived in the United States in 1952, just after I was born. That was the McCarthy era and Jim Crow laws (which enforced racial segregation in the southern states), and they were horrified. When I was in middle school, my father took me to march for the Voting Rights Act and the Civil Rights Act.

Van der Horst married fellow medical student Laura Svetkey, now a professor at Duke University, and they had two daughters, Anna and Sarah. He was a devoted, fun loving husband, father, and brother.

A passionate athlete, as well as physician, van der Horst loved to challenge himself and ran many marathons as well as competing in open air swims. He marked turning 60 by competing in 35 events in that year alone. He went missing at …
Alteration of factors associated with coagulation in provoked pulmonary embolism
Authors: Won-Il Choi
Journal: European Respiratory Journal (2014)

Purpose:  Pulmonary embolism (PE) regarded as a form of deep vein thrombosis. Although the recurrence rate of venous thrombosis in provoked embolism is lower than unprovoked vein thrombosis, proteins associated with coagulation have not been well studied in provoked pulmonary embolism. This study is aimed to evaluate factors associated with coagulation between provoked and unprovoked PE.   Methods:  This restrospective cohort study included 207 PE patients. Patients had transient risk factors at the diagnosis regarded as provoked PE, the others were classified as unprovoked PE. Evaluation of proteins associated with coagulation included protein C, protein C activity, protein S, protein S free form, protein S activity, antithrombin III, factor VIII and factor IX.   Results:  Among 207 PE cases, 65 (31.4%) cases were provoked PE. Clinical characteristics between provoked and unprovoked PE were not different. However, RV/LV ratio was significantly higher in provoked than unprovoked PE. Proteins and activity associated with coagulation were significantly lower in provoked PE than unprovoked PE; protein C antigen (33% vs. 54%,  P  = 0.01), protein S antigen (31% vs 53%,  P  = 0.001), protein S activity (55% vs 71%,  P   P   P  = 0.01).   Conclusion:  Provoked PE had significant lower anti-coagulation proteins level or activity than unprovoked PE.
Abstract P203: Serum Metabolites Associate With Blood Pressure Phenotypes in the Bogalusa Heart Study
Authors: William He, Changwei Li, Xuenan Mi, Shengxu Li, Lydia Bazzano, Wei Chen, Jiang He, Tanika Kelly
Journal: Circulation (2018)

We conducted a metabolome-wide association study to identify blood pressure (BP)-related metabolites among 825 white and 436 African-American Bogalusa Heart Study (BHS) participants. After quality control, 1,202 metabolites were tested for association with systolic BP (SBP), diastolic BP (DBP), and hypertension in race-stratified analyses. Multiple regressions were used to adjust for age, sex, education, cigarette smoking, alcohol drinking, physical activity, and body mass index. Weighted correlation network analysis was utilized to identify modules of co-abundant metabolites that associated with covariable adjusted BP phenotypes. After Bonferroni corrections, 16 metabolites from amino acid, cofactor and vitamin, lipid, carbohydrate, and peptide pathways in whites and one from the carbohydrate pathway in African-Americans significantly associated with BP phenotypes. Two novel and one previously reported metabolite consistently associated with hypertension across race groups ( Table ). Among whites, modules consisting primarily of lipid metabolites including phosphatidylcholines, phosphatidylinositol and lysophospholipids ( P =1.0х10 -3 and 6.0х10 -4 for SBP and DBP, respectively), monoacylglycerols and lysophospholipids ( P =3.0х10 -4 and 7.0х10 -5 for SBP and DBP, respectively), and phosphatidylethanolamines, mono- and diacylglycerols, and lysophospholipids ( P =4.0х10 -4 and 4.9х10 -4 for SBP and hypertension, respectively) were identified. In addition, modules consisting primarily of amino acids and peptides such as gamma-glutamyl amino acid metabolites and those involved in leucine, isoleucine and valine metabolism were significant in both African-Americans (P= 2.0х10 -3 and 1.5х10 -3 for DBP and hypertension, respectively) and whites ( P =7.1х10 -4 for hypertension). In aggregate, the current analysis identified novel metabolites and metabolite modules involved in BP regulation. These data add to the accumulating evidence that serum metabolites may play an important role in BP.
Fatty acid-induced CD36 expression via O-GlcNAcylation drives gastric cancer metastasis
Authors: Mingzuo Jiang, Nan Wu, Bing Xu, Yi Chu, Xiaowei Li, Song Su, Di Chen, Wenjiao Li, Yanting Shi, Xiaoliang Gao, Haohao Zhang, Zhao Zhang, Wei Du, Yongzhan Nie, Jie Liang, Daiming Fan
Journal: Theranostics (2019)

Metastasis is the primary cause of death in patients with advanced cancer. Recently, a high-fat diet was shown to specifically promote the metastatic potential of specific cancer cells in a CD36-dependent manner. However, the molecular basis of the fatty acid (FA)-induced upregulation of CD36 has remained unclear. Methods: RT-qPCR, FACS analysis, immunoblotting and immunohistochemistry, as well as retrieving TCGA database, were carried out to quantitate CD36 expression in gastric cancer (GC) tissues and cell lines. Transwell assay and xenografts were used to assess cell metastasis abilities in vitro and in vivo after indicated treatment. Luciferase reporter assay was carried out to evaluate the changes in signaling pathways when O-GlcNAcylation level was increased in GC cells and in vitro O-GlcNAcylation assay was utilized for wild and mutant types of CD36 protein to explore the potential O-GlcNAcylation sites. Results: High CD36 expression is a predictor of poor survival and promotes metastasis of GC cells and the use of neutralizing antibodies to block CD36 inhibits GC metastasis in mice. FA or a HFD promotes the metastatic potential of GC cells by upregulating CD36 via increasing the O-GlcNAcylation level. Increased O-GlcNAcylation levels promote the transcription of CD36 by activating the NF-κB pathway and also increase its FA uptake activity by directly modifying CD36 at S468 and T470. Conclusion: FA-induced hyper-O-GlcNAcylation promotes the transcription and function of CD36 by activating the NF-κB pathway and directly modifying CD36 at S468 and T470, which drives GC metastasis.
Building machines that adapt and compute like brains
Authors: Nikolaus Kriegeskorte, Robert M. Mok
Journal: Behavioral and Brain Sciences (2017)

Abstract Building machines that learn and think like humans is essential not only for cognitive science, but also for computational neuroscience, whose ultimate goal is to understand how cognition is implemented in biological brains. A new cognitive computational neuroscience should build cognitive-level and neural-level models, understand their relationships, and test both types of models with both brain and behavioral data.