tbuckley/cabot-search huggingface dataset:
Preexposure Prophylaxis for the Prevention of HIV Infection
Authors: Douglas K. Owens, Karina W. Davidson, Alex H. Krist, Michael J. Barry, Michael Cabana, Aaron B. Caughey, Susan J. Curry, Chyke A. Doubeni, John W. Epling, Martha Kubik, C. Seth Landefeld, Carol M. Mangione, Lori Pbert, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2019)

<h3>Importance</h3> An estimated 1.1 million individuals in the United States are currently living with HIV, and more than 700 000 persons have died of AIDS since the first cases were reported in 1981. In 2017, there were 38 281 new diagnoses of HIV infection reported in the United States; 81% of these new diagnoses were among males and 19% were among females. Although treatable, HIV infection has no cure and has significant health consequences. <h3>Objective</h3> To issue a new US Preventive Services Task Force (USPSTF) recommendation on preexposure prophylaxis (PrEP) for the prevention of HIV infection. <h3>Evidence Review</h3> The USPSTF reviewed the evidence on the benefits of PrEP for the prevention of HIV infection with oral tenofovir disoproxil fumarate monotherapy or combined tenofovir disoproxil fumarate and emtricitabine and whether the benefits vary by risk group, population subgroup, or regimen or dosing strategy; the diagnostic accuracy of risk assessment tools to identify persons at high risk of HIV acquisition; the rates of adherence to PrEP in primary care settings; the association between adherence and effectiveness of PrEP; and the harms of PrEP when used for HIV prevention. <h3>Findings</h3> The USPSTF found convincing evidence that PrEP is of substantial benefit in decreasing the risk of HIV infection in persons at high risk of HIV acquisition. The USPSTF also found convincing evidence that adherence to PrEP is highly associated with its efficacy in preventing the acquisition of HIV infection; thus, adherence to PrEP is central to realizing its benefit. The USPSTF found adequate evidence that PrEP is associated with small harms, including kidney and gastrointestinal adverse effects. The USPSTF concludes with high certainty that the magnitude of benefit of PrEP with oral tenofovir disoproxil fumarate–based therapy to reduce the risk of acquisition of HIV infection in persons at high risk is substantial. <h3>Conclusions and Recommendation</h3> The USPSTF recommends offering PrEP with effective antiretroviral therapy to persons at high risk of HIV acquisition. (A recommendation)
Sarah-Maria Fendt: Driving scientific discovery through collaboration
Authors: Stephanie Houston
Journal: The Journal of Experimental Medicine (2019)

Sarah-Maria Fendt is a principal investigator at the Flemish Institute for Biotechnology (VIB) in Belgium, and her laboratory focuses on cellular metabolism and metabolic regulation. Recent work from Sarah’s laboratory has shown that pyruvate available in the metastatic niche enables cancer cells to shape their environment and promote metastatic outgrowth. We contacted Sarah to find out more about her journey in science so far.
Abstract 16970: Strain-specific Differences in the Response to SU5416 in the Rat Model of Severe Pulmonary Arterial Hypertension
Authors: BaoHua Jiang, Yupu Deng, Mohamad Taha, Sophie Wen, David W Courtman, Duncan J Stewart
Journal: Circulation (2013)

INTRODUCTION: Inhibition of VEGFR2 with SU5416 (SU), in combination with chronic hypoxia (CH) causes severe, irreversible pulmonary arterial hypertension (PAH) in rats associated with complex intim...
A machine learning approach to predicting short-term mortality risk for patients starting chemotherapy.
Authors: Ravi Bharat Parikh, Aymen Elfiky, Maximilian J. Pany, Ziad Obermeyer
Journal: Journal of Clinical Oncology (2017)

6538 Background: Patients who die soon after starting chemotherapy incur symptoms and financial costs without survival benefit. Prognostic uncertainty may contribute to increasing chemotherapy use near the end of life, but few prognostic aids exist to guide physicians and patients in the decision to initiate chemotherapy. Methods: We obtained all electronic health record (EHR) data from 2004-14 from a large national cancer center, linked to Social Security data to determine date of death. Using EHR data before treatment initiation, we created a machine learning (ML) model to predict 180-day mortality from the start of chemotherapy. We derived the model using data from 2004-11 and report predictive performance on data from 2012-14. Results: 26,946 patients initiated 51,774 discrete chemotherapy regimens over the study period; 49% received multiple lines of chemotherapy. The most common cancers were breast (23.6%), colorectal (17.6%), and lung (16.6%). 18.4% of patients died within 180 days after chemotherapy initiation. Model predictions were used to rank patients in the validation cohort by predicted risk. Patients in the highest decile of predicted risk had a 180-day mortality of 74.8%, vs. 0.2% in the lowest decile (area under the receiver-operating characteristic curve [AUC] 0.87). Predictions were accurate for patients with metastatic disease (AUC 0.85) and for individual primary cancers and chemotherapy regimens—including experimental regimens not present in the derivation sample. Model predictions were valid for 30- and 90-day mortality (AUC 0.94 and 0.89, respectively). ML predictions outperformed regimen-based mortality estimates from randomized trials (RT) (AUC 0.77 [ML] vs. 0.56 [RT]), and National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) estimates (AUC 0.81 [ML] vs. 0.40 [SEER]). Conclusions: Using EHR data from a single cancer center, we derived a machine learning algorithm that accurately predicted short-term mortality after chemotherapy initiation. Further research is necessary to determine applications of this algorithm in clinical settings and whether this tool can improve shared decision making leading up to chemotherapy initiation.
Is there a causal relationship between vitamin D and melanoma risk? A Mendelian randomization study
Authors: U.E. Liyanage, M.H. Law, J.H. Barrett, M.M. Iles, S. MacGregor
Journal: British Journal of Dermatology (2019)

Several preclinical studies have identified the antiproliferative effects of 25-hydroxyvitamin D [25(OH)D; vitamin D]. Ultraviolet radiation (UVR) is essential for vitamin D synthesis yet increases the risk of melanoma. Observational studies on the association of vitamin D levels with melanoma risk have reported inconclusive results, and are difficult to interpret owing to the potential confounding from the dual role of UVR.To determine whether there is a causal association between genetically predicted 25(OH)D concentrations and melanoma using a Mendelian randomization (MR) approach.We performed MR using summary data from a large genome-wide association study (GWAS) meta-analysis of melanoma risk, consisting of 12 874 cases and 23 203 controls. Five single nucleotide polymorphisms associated with 25(OH)D concentration - rs12785878, rs10741657, rs2282679, rs6013897 and rs116970203 - were selected as instrumental variables. An inverse variance weighted method was used to access the evidence for causality. MR results from the melanoma meta-analysis were combined with results from an MR study based on a melanoma risk GWAS using UK Biobank data.A 20 nmol L-1 decrease in 25(OH)D was not associated with melanoma risk [odds ratio (OR) 1·06, 95% confidence interval (CI) 0·95-1·19]. Results from the UK Biobank were concordant with this, with meta-analysis of our and UK Biobank-derived MR causal estimates showing no association (OR 1·02, 95% CI 0·92-1·13 for a 20 nmol L-1 decrease).The results suggest that vitamin D levels may not be causally associated with the risk of melanoma. What's already known about this topic? Antitumour activity of vitamin D has been identified in preclinical studies. Observational studies link vitamin D deficiency with an increased risk of a range of cancers. There is a growing public interest for vitamin D supplementation. Observational studies of melanoma are fraught with difficulties because while higher ultraviolet radiation levels increase vitamin D levels, such exposure is also associated with increased melanoma risk. Results from observational studies are inconclusive regarding the effect of vitamin D on melanoma risk. What does this study add? Using Mendelian randomization, an approach to causal inference, which is analogous to a natural randomized controlled trial, we found no causal association between vitamin D levels and melanoma.
PF214 CRISPR/CAS9 IN VIVO SCREEN REVEALS A CRUCIAL ROLE FOR TMEM63A IN ENGRAFTMENT OF PRIMARY HUMAN ACUTE MYELOID LEUKEMIA CELLS
Authors: L. He, S. Garg, J. Xia, P. Jagdhane, C. Müller-Tidow, C. Pabst
Journal: HemaSphere (2019)

Background: Acute myeloid leukemia (AML) is a hematologic malignancy, which is sustained by a small fraction of leukemia stem cells (LSCs). In previous work, we determined LSC frequencies of primary AML specimens by xenograft assays and correlated engraftment capacity with gene expression determined by RNA-Sequencing (RNA-Seq). Here, we performed a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas) in vivo screen targeting 189 selected genes to identify novel regulators of LSC activity. Aims: In this study, we aimed to identify crucial leukemia drivers and suppressors via single-guide (sgRNA) library in vivo screening in a humanized NRGS mouse xenograft model. Methods: We performed a pooled, unbiased two-step lentiviral single-guide (sgRNA) library screen in vitro and simultaneously in mice. Furthermore, we performed knockdown (KD) experiments using small hairpin (sh) RNAs and single-guide (sg) RNAs to confirm screen results in single assays. Lentivirally transduced AML cells were analyzed in vivo for engraftment capacity and simultaneously in vitro for proliferative output, differentiation, viability and cell cycle. RNA sequencing (RNA-Seq) was used to determine how KD of the top candidate gene affected gene expression. Moreover, we tracked protein localization by immunofluorescence (IF) imaging and performed global proteomics experiments to gain insight into the mechanism of action. Results: We found that knockdown of TMEM63A inhibited cell proliferation, enhanced differentiation ex vivo and impaired engraftment capacity of AML cells in vivo. Gene Ontology (GO) term enrichment analysis on RNA-Seq data showed enrichment for pathways associated with immune response. Summary/Conclusion: We found that knockdown of TMEM63A inhibited cell proliferation, enhanced differentiation ex vivo and impaired engraftment capacity of AML cells in vivo. Gene Ontology (GO) term enrichment analysis on RNA-Seq data showed enrichment for pathways associated with immune response.
Polycystin-1 Assembles With Kv Channels to Govern Cardiomyocyte Repolarization and Contractility
Authors: Francisco Altamirano, Gabriele G. Schiattarella, Kristin M. French, Soo Young Kim, Felipe Engelberger, Sergii Kyrychenko, Elisa Villalobos, Dan Tong, Jay W. Schneider, Cesar A. Ramirez-Sarmiento, Sergio Lavandero, Thomas G. Gillette, Joseph A. Hill
Journal: Circulation (2019)

Polycystin-1 (PC1) is a transmembrane protein originally identified in autosomal dominant polycystic kidney disease where it regulates the calcium-permeant cation channel polycystin-2. Autosomal dominant polycystic kidney disease patients develop renal failure, hypertension, left ventricular hypertrophy, and diastolic dysfunction, among other cardiovascular disorders. These individuals harbor PC1 loss-of-function mutations in their cardiomyocytes, but the functional consequences are unknown. PC1 is ubiquitously expressed, and its experimental ablation in cardiomyocyte-specific knockout mice reduces contractile function. Here, we set out to determine the pathophysiological role of PC1 in cardiomyocytes.Wild-type and cardiomyocyte-specific PC1 knockout mice were analyzed by echocardiography. Excitation-contraction coupling was assessed in isolated cardiomyocytes and human embryonic stem cell-derived cardiomyocytes, and functional consequences were explored in heterologous expression systems. Protein-protein interactions were analyzed biochemically and by means of ab initio calculations.PC1 ablation reduced action potential duration in cardiomyocytes, decreased Ca2+ transients, and myocyte contractility. PC1-deficient cardiomyocytes manifested a reduction in sarcoendoplasmic reticulum Ca2+ stores attributable to a reduced action potential duration and sarcoendoplasmic reticulum Ca2+ ATPase (SERCA) activity. An increase in outward K+ currents decreased action potential duration in cardiomyocytes lacking PC1. Overexpression of full-length PC1 in HEK293 cells significantly reduced the current density of heterologously expressed Kv4.3, Kv1.5 and Kv2.1 potassium channels. PC1 C terminus inhibited Kv4.3 currents to the same degree as full-length PC1. Additionally, PC1 coimmunoprecipitated with Kv4.3, and a modeled PC1 C-terminal structure suggested the existence of 2 docking sites for PC1 within the N terminus of Kv4.3, supporting a physical interaction. Finally, a naturally occurring human mutant PC1R4228X manifested no suppressive effects on Kv4.3 channel activity.Our findings uncover a role for PC1 in regulating multiple Kv channels, governing membrane repolarization and alterations in SERCA activity that reduce cardiomyocyte contractility.
PS1045 INDIRECT NUMBER NEEDED TO TREAT: COMPARATIVE EFFECTIVENESS OF GLASDEGIB + LOW-DOSE CYTARABINE VS AZACITIDINE OR DECITABINE IN ACUTE MYELOID LEUKEMIA PATIENTS INELIGIBLE FOR INTENSIVE CHEMOTHERAPY
Authors: G. Tremblay, T. Westley, S.A. Garib, T. Bell, J.C. Cappelleri, G. Chan, A. Forsythe
Journal: HemaSphere (2019)

Background: Acute promyelocytic leukemia (APL) has a characteristic peculiar morphologic, genetic features and more favorable outcome. Aims: is to study the differential effect of BCR-1 and BCR-3 isoforms of PML-RARA together with FLT3-ITD mutational status on outcome of APL patients. Methods: All patients referred to the outpatient medical and pediatric oncology clinic, National cancer institute (NCI), Cairo University, Egypt in the period from May 2012 to January 2018. The diagnosis of APL was based on morphologic examination of the bone marrow and peripheral blood smears and was confirmed by the detection of the PML-RARA transcript by FISH and RT-PCR. Results: the study included 118 patients with newly diagnosed de novo APL (71 (60%) adults and 47 (39.8%) children). Based on the initial TLC, pediatric APL patients have higher (48.9%) risk than adults (30%) (p = 0.044). The CR rate was 91% (77/84), after excluding early induction related deaths (18) and patients who did not receive treatment at NCI (no beds available) (16). All pediatric patients (both BCR-1 and BCR-3) and all adult patients with BCR-3 achieved CR while 22/28 (78.5%) of patients with BCR-1 achieved CR (p = 0.04). Adult patients with FLT3 mutation (5/8 = 62.5%) received more high-risk regimen than patients with wild FLT3-ITD (10/38 = 26.3%)(p = 0.047). FLT3-ITD mutation was associated with more hemorrhage and DIC (p = 0.038), and lower 2-year OS (96% v 44.6%)(p = 0.001) in pediatric patients. Also DIC and Hemorrhage are associated with lower 2-year OS in pediatric patients (91.4% v 48.6%)(p < 0.001). The 1-year and 2-year OS for pediatric patients were better than adults (56.2% v 83% and 80.7 % v 49.8% respectively) with a median of 39.4 month versus 12month respectively (p = 0.005). On multivariate analysis, Age was an independent prognostic variable affecting survival, HR 2.6 (95% CI 1.3–5.3, P = 0.007)(adults had hazards ratio of death 2.6 times higher than pediatrics). DIC & FLT3-ITD were independent prognostic variables affecting survival in the pediatric APL with HR 12.3 (95% CI 1.46–104.61, P = 0.021) and 5.2 (95% CI 1.01–26.95, P = 0.048) respectively.Summary/Conclusion: BCR-1 isoform of PML-RARA is associated with decreased response to ATRA-based regimens in adult APL patients. DIC & FLT3-ITD are adverse prognostic factors in pediatric APL patients. Age is an independent prognostic factor in APL patients (whole group). Despite higher high risk groups in pediatric patients, the outcome is better than adult patients.
Abstract 18687: Peripheral Artery Disease Predicts Adverse Outcomes In PCI-naive Patients but Not in Patients Undergoing Repeat Revascularization
Authors: Shawn X Li, Jiyong Lee, Hannah I Chaudry, Theodore B Curran, Vishesh Kumar, Bruce W Andrus, James T DeVries
Journal: Circulation (2017)

Introduction: Previous studies showed that peripheral artery disease (PAD) is an independent predictor of poor in-hospital outcomes following PCI. This has been attributed to extensive underlying a...
Mutation Status of <i>RAS, TP53</i>, and <i>SMAD4</i> is Superior to Mutation Status of <i>RAS</i> Alone for Predicting Prognosis after Resection of Colorectal Liver Metastases
Authors: Yoshikuni Kawaguchi, Scott Kopetz, Timothy E. Newhook, Mario De Bellis, Yun Shin Chun, Ching-Wei D. Tzeng, Thomas A. Aloia, Jean-Nicolas Vauthey
Journal: Clinical Cancer Research (2019)

Somatic gene mutations have been increasingly recognized to impact prognosis following resection of colorectal liver metastases (CLM). We aimed to determine the impact of combinations of somatic mutations on survival in patients undergoing CLM resection.We identified patients who underwent initial CLM resection during 2007-2017 and had genetic sequencing data available. Risk factors for overall survival (OS) and recurrence-free survival (RFS) were determined using Cox proportional hazards models.Of 1460 patients who underwent CLM resection during the study period, 507 met the inclusion criteria. Multigene testing revealed mutation rates greater than 10% for TP53 (mutated in 70.8% of patients), APC (53.5%), RAS (50.7%), PIK3CA (15.8%), and SMAD4 (11.0%). BRAF was mutated in 2.0% of patients. BRAF, RAS, TP53, and SMAD4 mutations were significantly associated with OS, and RAS, TP53, and SMAD4 mutations were significantly associated with RFS. Coexisting mutations in RAS, TP53, and SMAD4 were associated with significantly worse OS and RFS than coexisting mutations in any 2 of these genes and mutations in 1 or none of these genes. Coexisting mutations in 2 genes conferred significantly worse OS and RFS than single mutation or no mutations. OS and RFS did not differ significantly between patients with RAS mutation and wild-type TP53 and SMAD4 and patients with wild-type RAS (P = 0.858 and 0.729, respectively).RAS mutation status alone is not sufficient for precisely predicting prognosis after CLM resection.
Prevalence and risk factors for allergic rhinitis in adults and children living in different grassland regions of Inner Mongolia
Authors: Tingting Ma, Xiangdong Wang, Yan Zhuang, Haiyun Shi, Huiyu Ning, Tianfei Lan, Tiejun Zhang, Zhenxiang Kang, Bate SiQin, Bate Yang, Xiuzhi Bao, Weijun Yan, Tong Lei, Deyun Wang, Guangliang Shan, Biao Zhang, Xueyan Wang, Luo Zhang
Journal: Allergy (2019)

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Abstract 118: Public Access Defibrillation in Vienna
Authors: Elisabeth Lobmeyr, Mario Krammel, Markus Winnisch, David Weidenauer, Harald Herkner, Wolfgang Schreiber, Alexander Nürnberger, Philip Datler, Markus Keferböck, Michael Poppe, Patrick Sulzgruber, Sebastian Zeiner, Fritz Sterz
Journal: Circulation (2014)

Purpose: Sudden out-of-hospital cardiac arrest (OHCA) is one of the leading causes of death worldwide. In Vienna, roughly 1,000 people are affected every year. Survival is strongly influenced by by...
SP0105 REGULATION OF AUTOANTIBODY ACTIVITY BY T CELL SUBSETS
Authors: Gerhard Krönke
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Our recent data show that the IL-23–T<sub>H</sub>17 axis controls the intrinsic inflammatory activity of autoantibodies and thereby triggers the clinical onset of autoimmune arthritis in mice and humans suffering from rheumatoid arthritis. TH17 cells regulate expression of sialyltransferases in newly differentiating antibody-producing cells and determine the glycosylation profile and activity of immunoglobulin G (IgG) that is produced by the consecutively emerging plasma cells. <h3>Disclosure of Interests:</h3> Gerhard Krönke Grant/research support from: Lilly, Pfizer, Speakers bureau: Novartis
Linkage disequilibrium–dependent architecture of human complex traits shows action of negative selection
Authors: Steven Gazal, Hilary K Finucane, Nicholas A Furlotte, Po-Ru Loh, Pier Francesco Palamara, Xuanyao Liu, Armin Schoech, Brendan Bulik-Sullivan, Benjamin M Neale, Alexander Gusev, Alkes L Price
Journal: Nature Genetics (2017)
Abstract 17188: Aortic Cusp Ventricular Tachycardias in Patients With Prior Myocardial Infarction
Authors: Konstantinos Siontis, Mario Njeim, Miki Yokokawa, Rakesh Latchamsetty, Fred Morady, Frank Bogun
Journal: Circulation (2017)

Introduction: Ventricular tachycardia (VT) originating from the aortic cusps has been previously described in patients with non-ischemic cardiomyopathy. However, it is unclear whether the aortic cu...
De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial
Authors: Richard E Clark, Fotios Polydoros, Jane F Apperley, Dragana Milojkovic, Katherine Rothwell, Christopher Pocock, Jennifer Byrne, Hugues de Lavallade, Wendy Osborne, Lisa Robinson, Stephen G O'Brien, Lucy Read, Letizia Foroni, Mhairi Copland
Journal: The Lancet Haematology (2019)
FRI0616 ANAKINRA TREATMENT IN RECURRENT PERICARDITIS: SINGLE CENTER EXPERIENCE
Authors: Zeynep Toker Dincer, Osman Corbali, Serdal Ugurlu, Huri Ozdogan
Journal: Annals of the Rheumatic Diseases (2019)

Background: Familial Mediterranean Fever (FMF) is an autoinflammatory disease requiring long-term treatment.Increasing the compatibility with colchicine treatment in patients with FMF is the first step for preventing amyloidosis.Patients' beliefs about medicines and treatment may affect treatment adherence and treatment success.Objectives: The aim of this study was to determine adherence to colchicine treatment and related factors in FMF patients.In addition, patients' beliefs about colchicine, which are one of the important factors affecting the treatment adherence of patients, were evaluated.Methods: Total of 179 patients with FMF was included in this study.The demographic and clinical features and MEFV gene mutations were recorded.The treatment adherence of the patients was assessed using by Compliance Questionnaire on Rheumatology (CQR).The Beliefs About Medicines Questionnaire (BMQ-T) was used to assess patient's beliefs about colchicine.The relationship between compliance of treatment and clinical characteristics of patients were assessed.Results: One hundred thirteen (63.1%) of the patients were male.The mean age of patients was 34.5 ± 12.7 years and mean delay in diagnosis was 6.7 ± 8.4 years.The mean dose of colchicine was 1.37 ± 0.43 mg/day and, the percentage of patients using colchicine regularly was 66.5%.Adherence to treatment was higher in patients with concomitant diseases than those without comorbidities (p = 0.028).In addition, treatment compliance was higher in married patients compared to single patients (p = 0.013).The colchicine dose used in compatible patients was higher than in non-compatible patients (p = 0.033) (Table 1).We also found that as the BMQ-T Specific Necessity scores increased, compliance with treatment increased.On the other hand, as the BMQ-T General Overuse and General Harm scores increased, non-compliance with treatment increased (Table 2).
Corrigendum to “Cancer stem cells-emanated therapy resistance: Implications for liposomal drug delivery systems”. [Journal of Controlled Release 288 (2018) 62–83]
Authors: Hassan Dianat-Moghadam, Maryam Heidarifard, Rana Jahanban-Esfahlan, Yunes Panahi, Hamed Hamishehkar, Farhad Pouremamali, Reza Rahbarghazi, Mohammad Nouri
Journal: Journal of Controlled Release (2019)