tbuckley/cabot-search huggingface dataset:
Abstract 17221: Stable Flow-Induced Expression of KLK10 Inhibits Endothelial Inflammation and Atherosclerosis
Authors: Darian Williams, Marwa Mahmoud, Hanjoong Jo
Journal: Circulation (2020)

Introduction: Atherosclerosis preferentially occurs in arterial regions exposed to disturbed blood flow ( d-flow ) while the straight regions exposed to stable flow ( s-flow ) are protected. The proatherogenic and atheroprotective effects of flow are mediated in large part by the global changes in endothelial cell gene expression, which regulate endothelial dysfunction and inflammation. Previously, we identified Kallikrein-Related Peptidase 10 (KLK10) as one of the most flow-sensitive genes in arterial endothelial cells using the partial carotid ligation model of d-flow -induced atherosclerosis. KLK10 is a secreted serine protease, but its role in endothelial function and atherosclerosis is unknown. Methods/Results: Here, we validated that KLK10 was upregulated under s-flow conditions and downregulated under d-flow conditions using the in vivo mouse models and in vitro studies using endothelial cells (ECs). Through in vitro functional studies using ECs, we found that KLK10 produced by s-flow protected against endothelial inflammation and permeability dysfunction. Furthermore, treatment with rKLK10 or overexpression of KLK10 plasmids in vivo decreased endothelial inflammation the mouse model. Further, rKLK10 injection or ultrasound-mediated transfection of KLK10 plasmids in the hind leg muscles led to inhibition of atherosclerosis in ApoE-/- mice with the partial carotid ligation surgery. Studies using the pharmacological inhibitors and siRNAs showed that the anti-inflammatory effects of KLK10 was mediated by the Protease Activated Receptors 1 and 2, but without directly cleaving them. Further studies show that KLK10’s anti-inflammatory effect was mediated by the NFκB and VCAM1 and ICAM1 expression pathway. In addition, immunostaining showed that KLK10 expression is significantly reduced in human coronary arterial sections with atherosclerotic plaques compared to the non-diseased controls. Conclusions: We found that KLK10 is a potent flow-sensitive secreted protein, which serve as a novel anti-inflammatory and anti-atherogenic factor. KLK10 may be a potential anti-atherogenic therapeutic.
THU0183 Significantly improved upper gastrointestinal (ugi) tolerability with celecoxib, a cox-2 specific inhibitor, compared with conventional nsaids. the success i trial
Authors: JL Goldstein, N Agrawal, G Eisen, W Stenson, AE Bello, JG Fort, SP Boots
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The Celecoxib Long-term Arthritis Safety Study (CLASS), a prospective outcomes study conducted in North America, demonstrated a significant reduction in UGI ulcer complications and improved tolerability. <h3>Objectives</h3> To extend our understanding of the UGI safety advantages of celecoxib over conventional nonsteroidal anti-inflammatory drugs (NSAIDs), in day-to-day practice, a naturalistic study was conducted worldwide. <h3>Methods</h3> SUCCESS I, a large, 12-week, multinational, double-blind, randomised trial in 13,274 osteoarthritis patients, was conducted in 39 countries. There were 6547 patients from Europe/Africa, 2756 from North America, 2889 from Latin America, and 1082 from Asia/Pacific. Celecoxib 200 mg/d (n = 4421) and 400 mg/d (n = 4429) was compared with naproxen 1000 mg/d (n = 914) and diclofenac 100 mg/d (n = 3510) with regard to GI tolerability. <h3>Results</h3> The frequency of all reported GI adverse events (AEs), the three most frequently reported UGI AEs, and withdrawals due to GI AEs are shown in the Table 1. <h3>Conclusion</h3> UGI symptoms, more commonly associated with NSAID use, were consistently and significantly lower with celecoxib. The percent reduction ranged from 18.6% to 29.4%. These data confirm the superior GI tolerability of celecoxib vs conventional NSAIDs and establish that this difference is clinically meaningful in terms of discontinuation of therapy for such symptoms. Sponsored by Pharmacia Corporation and Pfizer, Inc.
Abstract 14101: A Correction Score for Comparison of Aortic Calcification in Post-contrast and Non-contrast Measurements From Computed Tomography Scans
Authors: Steven R Horbal, Edward Brown, Brian A Derstine, Peng Zhang, Andrea H Rossman, Aurelian Bidulescu, June A Sullivan, Brian E Ross, Grace L Su, Sven A Holcombe, Stewart C Wang
Journal: Circulation (2020)

Introduction: Aortic calcification can be utilized to assess cardiovascular risk. While contrast is useful for vascular enhancement in diagnostic imaging, enhancement creates heterogeneity between post and non-contrast scans and limits their direct comparability. Hypothesis: We hypothesized that post and non-contrast aortic calcification measures will correlate, and a correction score can be developed for statistical comparability. Methods: Retrospective CT-scans were obtained from the University of Michigan. Participants (N=330) received abdominal scans with and without contrast enhancement within 120 calendar days. Analytic Morphomics was used to obtain vertebral-indexed measurements of aortic calcium area, and aortic wall obfuscation percentage. Calcification was specifically identified as regions with a given morphology and pixel value five standard deviations above the defined central lumen zone. Pearson correlation and multiple linear regression were used to explain the relationship between aortic measurements with and without contrast. Regressions include calcification percent (Model 1), and area (Model 2). Independent variables were non-contrast measurements and dependent variables were contrast measurements, age, and sex. Results: Correlations of calcification percent ranged from 0.86 at T11 and 0.94 and L2. Correlations of calcification area ranged from 0.66 at T12 to 0.84 at L3. In Model 1, for every percent increase in post-contrast calcification, non-contrast calcification percent increased by 11% (β=1.11, p &lt;0.001, R2=0.85). In Model 2, for every mm2 increase in post-contrast calcification area, non-contrast calcification area increased by 0.45 mm2 (β=1.45, p &lt;0.001, R2=0.69). Variance inflation factor for Model 1 was 1.08 and 1.07 for Model 2. Conclusion: In conclusion, this research proposes a correction score for comparisons of abdominal aortic calcification measurements in post-contrast and non-contrast scans.
Distinct expression of SARS‐CoV‐2 receptor ACE2 correlates with endotypes of chronic rhinosinusitis with nasal polyps
Authors: Ming Wang, Xiangting Bu, Gaoli Fang, Ge Luan, Yanran Huang, Cezmi A. Akdis, Chengshuo Wang, Luo Zhang
Journal: Allergy (2020)

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) entry factors, ACE2 and TMPRSS2, are highly expressed in nasal epithelial cells. However, the association between SARS‐CoV‐2 and nasal inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been investigated. We thus investigated the expression of SARS‐CoV‐2 entry factors in nasal tissues of CRSwNP patients, and their associations with inflammatory endotypes of CRSwNP. Methods The expression of ACE2 and TMPRSS2 was assessed in nasal tissues of control subjects and eosinophilic CRSwNP (ECRSwNP) and nonECRSwNP patients. The correlations between ACE2/TMPRSS2 expression and inflammatory indices of CRSwNP endotypes were evaluated. Regulation of ACE2/TMPRSS2 expression by inflammatory cytokines and glucocorticoids was investigated. Results ACE2 expression was significantly increased in nasal tissues of nonECRSwNP patients compared to ECRSwNP patients and control subjects, and positively correlated with the expression of IFN‐γ, but negatively correlated with tissue infiltrated eosinophils, and expression of IL5 and IL13. IFN‐γ up‐regulated ACE2 expression while glucocorticoid attenuated this increase in cultured nasal epithelial cells. Genes co‐expressed with ACE2 were enriched in pathways relating to defence response to virus in nasal tissue. TMPRSS2 expression was decreased in nasal tissues of CRSwNP patients compared to control subjects and not correlated with the inflammatory endotypes of CRSwNP. Glucocorticoid treatment decreased ACE2 expression in nasal tissues of nonECRSwNP patients, but not in ECRSwNP patients, whereas TMPRSS2 expression was not affected. Conclusion These findings indicate that ACE2 expression, regulated by IFN‐γ, is increased in nasal tissues of nonECRSwNP patients and positively correlates with type 1 inflammation.
Molecular Features of Cancers Exhibiting Exceptional Responses to Treatment
Authors: David A. Wheeler, Naoko Takebe, Toshinori Hinoue, Katherine A. Hoadley, Maria F. Cardenas, Alina M. Hamilton, Peter W. Laird, Linghua Wang, Adrienne Johnson, Ninad Dewal, Vincent Miller, David Piñeyro, Manuel Castro de Moura, Manel Esteller, Hui Shen, Jean Claude Zenklusen, Roy Tarnuzzer, Lisa M. McShane, James V. Tricoli, Paul M. Williams, Irina Lubensky, Geraldine O'Sullivan-Coyne, Elise C. Kohn, Richard F. Little, Jeffrey White, Shakun Malik, Lyndsay Harris, Carol Weil, Alice P. Chen, Chris Karlovich, Brian Rodgers, Lalitha Shankar, Paula Jacobs, Tracy Nolan, Jianhong Hu, Donna M. Muzny, Harshavardhan Doddapaneni, Viktoriya Korchina, Julie Gastier-Foster, Jay Bowen, Kristen Leraas, Elijah F. Edmondson, James H. Doroshow, Barbara A. Conley, S. Percy Ivy, Louis M. Staudt
Journal: Cancer Cell (2020)
Abstract 13930: Sex and Race/Ethnic Differences in Primary Prevention of Atherosclerotic Cardiovascular Disease Among Patients Diagnosed With Hypertension
Authors: Nicole E Glowacki, Julie Lauffenburger, Alvia Siddiqi, Rasha Khatib
Journal: Circulation (2020)

Introduction: Randomized controlled trials evidence indicates that atherosclerotic cardiovascular disease (ASCVD) can be prevented in patients with hypertension if risk factors such as high blood pressure, high cholesterol, elevated glucose levels, and smoking are controlled. While it is known that sex and race/ethnic disparities persist for ASCVD, disparities in risk factor control have not been well-described in primary care. Methods: Hypertensive adult patients free of ASCVD were included in a retrospective analysis of electronic health record data from a large US integrated healthcare system from 2018. Patients were categorized based on achieving clinical practice guideline targets from their last available measurement including blood pressure &lt;130/80 mm Hg; statin therapy among patients with indication (LDL-C &gt;190, diabetic between ages 40-70, or with 10-year ASCVD score ≥7.5%), HbA1c of &lt;7%, and not smoking. Multivariable Poisson regressions were developed to explore associations between achieving three targets (A1c reported separately among patients with value) and sex and race/ethnicity. Results are presented as relative risk (RR) and 95% confidence intervals (95%CI) and adjusted for age, obesity, years since hypertension diagnosis, and insurance, sex, insurance, preferred language. Results: Among women, African Americans were 11% more likely to fail to achieve the three targets (RR:1.11; 95%CI: 1.01-1.21). Among men, African Americans were 19% more likely to fail to achieve the three targets compared to Caucasian men (RR: 1.19; 95%CI: 1.05-1.35). The risk of failing to achieve the three targets was not statistically significantly different between Hispanic/Latino groups and Caucasians but trended to be smaller. Hispanic/Latino women (47.2%) and men (50.9%) had the highest proportions of failing to achieve HbA1c targets. Conclusions: Disparities were observed in control of ASCVD risk factors among hypertensive patients in primary care and were not fully explained by measured demographic or clinical characteristics. Monitoring of changes in disparities across sex, racial, and ethnic groups is important to ensure equity effectiveness as interventions to prevent ASCVD in primary care are developed, tested, and implemented.
Abstract 15873: Novel Contributions of Neutrophil-derived Myeloperoxidase and Hypochlorous Acid to 20-hydroxyeicosatetraenoic Acid Production That Drives Post-ischemic Angiogenesis
Authors: Juan A Azcona, Samantha Tang, Thomas M Jeitner, Michal Schwartzman, Austin M Guo
Journal: Circulation (2020)

Introduction: Compensatory angiogenic response to ischemia is often insufficient in maintaining adequate tissue perfusion resulting in critical limb ischemia and amputation. Identifying a novel mechanism by which angiogenesis occurs in these conditions is clinically relevant. We recently uncovered that an increase in 20-HETE, an arachidonic acid metabolite of CYP4A/F ω-hydroxylases, regulates post-ischemic angiogenesis. However, the underlying mechanism resulting in this increase is unknown. Hypothesis: Neutrophil-derived myeloperoxidase (MPO) and hypochlorous acid (HOCl) critically contribute to post-ischemic 20-HETE increases that drive angiogenesis. Methods: Hindlimb ischemia was established in mice depleted of neutrophils, macrophages, and MPO (MPO -/- ). Angiogenesis was assessed by laser doppler perfusion imaging and micro-vessel density quantitation in the hindlimb gracilis muscles. MPO and HOCl were detected in these tissues using immunohistochemistry and a HOCl-specific fluorophore. We also determined the effects of MPO and HOCl on 20-HETE production, the expression of 20-HETE synthase CYP4A11, and hypoxia inducible factor-1α in cultured endothelial cells (EC) using LC/MS/MS, real time-PCR and western blot analysis, respectively. Results: We found that ischemia failed to increase 20-HETE production in mice depleted of neutrophils and MPO (13 ± 1.5 vs 35 ± 5 and ~2 ± .25 vs 35 ± 5 pg/mg of protein, respectively), accompanied with a decreased post-ischemic angiogenic phenotype. We also detected the formation of MPO and HOCl in post-ischemic gracilis muscles. MPO and HOCl also significantly stimulate CYP4A11 expression and 20-HETE production (40±12 vs 8±5 pg/mg of protein) in EC. Furthermore, HOCl quickly induces CYP4A11 mRNA/protein expression (2-fold,) and the protein expression of HIF-1α (2-fold) in as little as 15 min. Conclusion: Our studies establish for the first time that neutrophil-derived MPO and HOCl are responsible for promoting 20-HETE increases that critically drive angiogenesis post ischemia. Thus, identifying these novel mediators can further future therapeutic strategies to balance angiogenic responses during ischemia as well as treating diseases that are associated with abnormal angiogenesis.
Pluripotent stem cell-derived CAR-macrophage cells with antigen-dependent anti-cancer cell functions
Authors: Li Zhang, Lin Tian, Xiaoyang Dai, Hua Yu, Jiajia Wang, Anhua Lei, Mengmeng Zhu, Jianpo Xu, Wei Zhao, Yuqing Zhu, Zhen Sun, Hao Zhang, Yongxian Hu, Yanlin Wang, Yuming Xu, George M. Church, He Huang, Qinjie Weng, Jin Zhang
Journal: Journal of Hematology & Oncology (2020)

The Chimera antigen receptor (CAR)-T cell therapy has gained great success in the clinic. However, there are still major challenges for its wider applications in a variety of cancer types including lack of effectiveness due to the highly complex tumor microenvironment, and the forbiddingly high cost due to the personalized manufacturing procedures. In order to overcome these hurdles, numerous efforts have been spent focusing on optimizing Chimera antigen receptors, engineering and improving T cell capacity, exploiting features of subsets of T cell or NK cells, or making off-the-shelf universal cells. Here, we developed induced pluripotent stem cells (iPSCs)-derived, CAR-expressing macrophage cells (CAR-iMac). CAR expression confers antigen-dependent macrophage functions such as expression and secretion of cytokines, polarization toward the pro-inflammatory/anti-tumor state, enhanced phagocytosis of tumor cells, and in vivo anticancer cell activity. This technology platform for the first time provides an unlimited source of iPSC-derived engineered CAR-macrophage cells which could be utilized to eliminate cancer cells.
Abstract 17232: Cardiopulmonary Exercise Testing in Diabetic Chronic Heart Failure Patients With Microalbuminuria
Authors: Thida tabucanon, Timothy Engelman, Sanjeeb S Bhattacharya, J Emanuel Finet, Wai Hong W Tang
Journal: Circulation (2020)

Introduction: Microalbuminuria can be a presentation of microvascular complication in diabetes mellitus (DM). Hypothesis: Microalbuminuria is associated with impaired exercise performance in chronic HF with DM patients. Methods: We retrospectively analyzed a cardiopulmonary exercise testing (CPET) database in 255 chronic HF patients with DM that had urine microalbumin test between December 2012 and September 2019. Demographic data and CPET parameters were compared between the patients who had and had not microalbuminuria which was defined by microalbumin/creatinine ratio ≥ 30 mg/g. Peak oxygen consumption (peak VO 2 ) ≤ 14 ml/kg/min and ≤ 12 ml/kg/min if had history of beta-blocker uses were classified as low peak VO 2 and used in multivariable analysis. Results: There were a total 92 patients (36.1%) that had microalbuminuria. Mean age was not significant different between the patients with and without microalbuminuria (57.7 vs 59.4 years, p = 0.26). The patients with microalbuminuria had lower body mass index (BMI; 30.8 vs. 32.7 kg/m 2 , p = 0.014) and had more history of beta-blocker (BB) uses (81.5% vs. 69.3%, p = 0.038), no significant different in other medication uses. Left ventricular ejection fraction (LVEF) was significant lower in patients with microalbuminuria (35.8% vs. 41.5%, p = 0.028). The patients with microalbuminuria had significant higher prevalence of low peak VO 2 (45.7% vs. 30.1%, p = 0.015) and lower peak stroke work (VO 2 /HR; 11.5 vs. 12.8 ml/ beat, p = 0.008). No significant different in ventricular efficiency slope (VE/VCO 2 ; 37.1 vs. 35.4, p = 0.094), Multivariable analysis showed that proteinuria was independently associated with low peak VO 2 after adjusted for age, sex, BMI LVEF, history of BB uses, VE/VCO 2 and HR at peak VO 2 , (odds ratio = 3.83, p &lt; 0.001). Conclusions: Microalbuminuria was independently associated with low peak oxygen consumption in chronic HF with DM patients.
Reply to Lindenauer <i>et al.</i>: Apparent Increase in Chronic Obstructive Pulmonary Disease Mortality Is Likely an Artifact of Changes in Documentation and Coding
Authors: Daniel A. Puebla Neira, En Shuo Hsu, Yong-Fang Kuo, Kenneth J. Ottenbacher, Gulshan Sharma
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Abstract 15096: Electrocardiographic QRS Amplitude Predicts Mortality in Hospitalized Patients With CoViD-19
Authors: Joshua Lampert, Jonathan Halperin, Gennaro Giustino, Connor Oates, Kyle Nelson, Jason Feinman, Matthew Pulaski, Daniel Musikantow, Mohit Turagam, Michael Miller, marie-noelle langan, jacob s Koruth, Srinivas Dukkipati, Marc Miller, William Whang, Martin Goldman, Valentin Fuster, Vivek Y Reddy
Journal: Circulation (2020)

Introduction: In a variety of cardiovascular diseases, low QRS voltage amplitude on the 12-lead ECG is associated with poor prognosis. We studied the relative frequency and importance of this phenomenon in hospitalized patients with SARS-coronavirus 2019 (CoViD-19) - a condition associated with myocardial injury in ~1/3 of patients. Methods: We performed a retrospective analysis of 800 consecutive patients with laboratory-confirmed CoViD-19 hospitalized from Mar 7 and Apr 12, 2020. Patients without a final disposition or telemetry data were excluded, resulting in 140 patients. On 12-lead ECG, low amplitude was defined as QRS amplitude &lt;5mm in II/III/aVF, &lt;10 mm in V1-V6, or a ≥50% decrease in amplitude on follow-up ECG during hospitalization, relative to the baseline/admission ECG. The association of 14 clinical variables to mortality was tested in multivariable logistic regression models. Results: Among 140 patients, 33 (23.6%) met criteria for low QRS amplitude. Compared to patients without low amplitude, these patients had a higher risk of in-hospital mortality (72.7% vs 26.2%; p&lt;0.0001) and mechanical ventilation (63.3% vs 32.4%; p=0.002). In multivariable models, there were only 3 independent predictors of in-hospital death: age (OR=1.1, 95% CI 1.0-1.1, p&lt;0.001), BMI (OR=1.1, 95% CI 1.1-1.2, p0.001), and the strongest predictor, low amplitude (OR=7.2; 95% CI 2.3-23.0). Low amplitudes in either the limb or precordial leads both predicted death (Table). Conclusions: A reduction in electrocardiographic QRS amplitude in patients with CoViD-19 is the strongest clinical predictor of death, and may be useful for risk stratification during hospitalization. Further study is needed to elucidate the mechanisms underlying changes in QRS amplitude, and their relationship to disease severity.
Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs
Authors: Jay W. Schneider, Saji Oommen, Muhammad Y. Qureshi, Sean C. Goetsch, David R. Pease, Rhianna S. Sundsbak, Wei Guo, Mingming Sun, Han Sun, Hidehito Kuroyanagi, Dennis A. Webster, Alexander W. Coutts, Kimberly A. Holst, Brooks S. Edwards, Nikolas Newville, Matthew A. Hathcock, Tamene Melkamu, Francesca Briganti, Wu Wei, Maria G. Romanelli, Scott C. Fahrenkrug, Doug E. Frantz, Timothy M. Olson, Lars M. Steinmetz, Daniel F. Carlson, Timothy J. Nelson, Susana Cantero Peral, Sarah Edgerton, Joan Wobig, Boyd Rasmussen, Jodi A. Scholz, Frank Cetta, Scott H. Suddendorf, Joanne M. Pedersen, Steve Krage, Craig S. Frisk, Chelsea L. Reece, Angela R. Miller, Sara E. Martineau, Rebecca K. Johnson, Amanda L. Breuer, Janell K. Fox
Journal: Nature Medicine (2020)