tbuckley/cabot-search huggingface dataset:
Unloading the Stenotic Path to Identifying Medical Therapy for Calcific Aortic Valve Disease
Authors: Brian R. Lindman, W. David Merryman
Journal: Circulation (2021)

alcific aortic valve disease (CAVD) represents an enormous public health problem in terms of adverse health consequences and economic burden.Approximately 5% to 10% of older adults have aortic stenosis (AS) and more than 25% have aortic sclerosis, the precursor to AS; clinically significant valve disease is anticipated to double by 2050. 1,2To date, there are no drugs approved to slow the progression of CAVD.Anticipation about statins turned into disappointment after several trials showed no benefit, which may have dampened enthusiasm for CAVD therapy.Although CAVD attracts comparatively less attention and is less mature than mechanistic research in atherosclerosis, numerous studies have elucidated the molecular biology underlying CAVD and point to several potentially promising drug targets (reviewed previously 3,4 ).For example, a causal role for lipoprotein(a) has been demonstrated, which, along with oxidized phospholipids, provides a potential link between atherosclerotic disease and CAVD and offers a rationale for testing drugs that lower lipoprotein(a) (eg, antisense oligonucleotides, PCSK9 inhibitors). 5However, despite numerous promising targets and drugs available directed at those targets, as of December 2, 2020, on clinicaltrials.gov,there are currently no actively enrolling clinical trials testing medical therapy to slow progression of CAVD; 1 trial testing both denosumab and bisphosphonates is completed and undergoing analysis.This dearth of active trials is sobering.We offer several potential reasons for this along with suggestions for addressing barriers (Figure).Unloading the Stenotic Path to Identifying Medical Therapy for Calcific Aortic Valve Disease Barriers and Opportunities PERSPECTIVE
Abstract 15701: Relationship Between Cardiac Biomarkers and Major Adverse Cardiovascular Events in DECLARE-TIMI 58
Authors: Thomas A Zelniker, David A Morrow, ofri Mosenzon, Erica Goodrich, Petr Jarolim, Avivit Cahn, Deepak L Bhatt, Lawrence A Leiter, Darren K McGuire, JOHN WILDING, Oleg V Averkov, Andrzej Budaj, Alexander Parkhomenko, Kausik K Ray, Ingrid A Gause-nilsson, Anna Maria Langkilde, Martin Fredriksson, Itamar RAZ, Marc S Sabatine, Stephen D Wiviott
Journal: Circulation (2020)

Introduction: Biomarkers of hemodynamic stress and myocardial injury are associated with the risk of CV death &amp; heart failure in patients with atherosclerotic vascular disease (ASCVD). Here we explore the association between cardiac biomarkers and ASCVD outcomes in patients with type 2 diabetes (T2DM). Methods: This was a nested biomarker study in DECLARETIMI 58, a randomized, blinded, placebo-controlled trial of dapagliflozin in T2DM and either multiple risk factors (MRF, ~60%) or established ASCVD (~40%). The relationship between baseline NT-proBNP and hsTnT levels (TIMI Biomarker Laboratory, n=14,565) and the composite of myocardial infarction, ischemic stroke, and CV death (MACE), was modeled within the placebo arm using Cox models adjusted for age, sex, race, smoking, baseline eGFR, BMI, T2DM duration, insulin use, history of CAD, MI, ischemic stroke, PAD, HF, dyslipidemia &amp; hypertension. Interaction testing was applied to assess the effect of dapagliflozin according to baseline biomarker value. Results: NT-proBNP and hsTnT were significantly associated with MACE (Adjusted hazard ratio (aHR) per 1-SD in log-transformed biomarker, NT-proBNP: aHR 1.62; hsTnT aHR 1.59). The magnitude of the relationship was similar in patients with ASCVD (NT-proBNP aHR 1.60; hsTnT aHR 1.62) and MRF (NT-proBNP aHR 1.62; hsTnT: aHR 1.51) [Fig A] . Moreover, both biomarkers remained independently associated with MACE when combined in the multivariable model (NT-proBNP aHR 1.46, hsTnT aHR 1.39). The risk of MACE by baseline biomarker level and stratified by treatment arm is shown in Fig B. Conclusions: In patients with T2DM both with and without ASCVD, higher baseline NT-proBNP or hsTnT levels identified patients at increased risk of MACE. The difference in MACE rates between dapagliflozin and placebo tended to be more pronounced in ASCVD patients with higher baseline or NT-proBNP or hsTnT levels.
Heterogeneity and temporal variation in the management of COVID-19: a multinational drug utilization study including 71,921 hospitalized patients from China, South Korea, Spain, and the United States of America
Authors: A Prats-Uribe, L Yin Hui Lai, Ahmed W-U-R., H Alghoul, O Alser, T M Alshammari, C Areia, W Carter, P Casajust, D Dawoud, A Golozar, J Jonnagaddala, P Mehta, G Menchung, Morales, F Nyberg, J D Posada, M Recalde, E Roel, K Shah, N Shah, L M Schilling, V Subbian, D Vizcaya, A Williams, L Zhang, Y Zhang, H Zhu, L Liu, P Rijnbeek, G Hripcsak, Lane Jce., E Burn, C Reich, M A Suchard, T Duarte-Salles, K Kostka, P B Ryan, D Prieto-Alhambra
Journal: BMJ (2020)
Spouse’s Diabetes Status and Incidence of Depression and Anxiety: An 18-Year Prospective Study
Authors: Jannie Nielsen, Solveig A. Cunningham, Mohammed K. Ali, Shivani A. Patel
Journal: Diabetes Care (2021)

We investigated the risk of depression and anxiety in people whose spouse did or did not have diabetes. We also examined associations between depression and anxiety and severity of spouse's diabetes.
Covid-19: Pregnant women should be offered Pfizer or Moderna vaccine, says UK advisory committee
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Pregnant women should be offered Pfizer or Moderna vaccine, says UK advisory committee Elisabeth MahasePregnant women should be offered the Pfizer BioNTech or Moderna covid-19 vaccine at the same time as the rest of the population, with priority based on age and clinical risk group, the government's vaccine advisory committee has said.
Hyoid Bone Syndrome With Sympathetic Symptoms
Authors: Rongfei Wang, Huijuan Yuan, Zhao Dong
Journal: JAMA Neurology (2021)

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Cardiovascular Biomarkers in the Early Discrimination of Type 2 Myocardial Infarction
Authors: Thomas Nestelberger, Jasper Boeddinghaus, Pedro Lopez-Ayala, Thomas E. Kaier, Michael Marber, Vincent Gysin, Luca Koechlin, Ana Yufera Sanchez, Maria Rubini Giménez, Desiree Wussler, Joan Elias Walter, Ivo Strebel, Tobias Zimmermann, Noemi Glarner, Òscar Miró, F. Javier Martin-Sanchez, Tatjana Zehnder, Raphael Twerenbold, Dagmar I. Keller, Christian Mueller, Hadrien Schoepfer, Petra Hillinger, Paul David Ratmann, Danielle M. Gualandro, Tania Coscia, Valentina Troester, Juliane Gehrke, Velina Widmer, Alexandra Prepoudis, Katharina Rentsch, Patrick Badertscher, Karin Wildi, Christian Puelacher, Eliska Potlukova, Michael Freese, Eleni Michou, Arnold von Eckardstein, Damian Kawecki, Beata Morawiec, Piotr Muzyk, Franz Bürgler, Nicolas Geigy, Tobias Reichlin, Samyut Shrestha, Beatriz López, Helena Mañé Cruz, Carolina Isabel Fuenzalida Inostroza, Esther Rodgriguez Adrada, Miguel Angel García Briñón, Jiri Parenica, Andreas Buser
Journal: JAMA Cardiology (2021)

Rapid and accurate noninvasive discrimination of type 2 myocardial infarction (T2MI), which is because of a supply-demand mismatch, from type 1 myocardial infarction (T1MI), which arises via plaque rupture, is essential, because treatment differs substantially. Unfortunately, this is a major unmet clinical need, because even high-sensitivity cardiac troponin (hs-cTn) measurement provides only modest accuracy.
Accelerating Advances in Cancer Care Research: A Lookback at the 21st Century Cures Act in 2020
Authors: Leigh Gallo, Ronald S. Walters, Jeff Allen, Jenny Ahlstrom, Clay Alspach, Yelak Biru, Alyssa Schatz, Kara Martin, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2021)

The 21st Century Cures Act (Cures Act), signed into law in 2016, was designed to advance new therapies by modernizing clinical trials, funding research initiatives, and accelerating the development and use of health information technology. To analyze the current issues in cancer care related to the implementation and impact of the Cures Act, NCCN convened a multistakeholder working group. Participants discussed the legislation's impact on the oncology community since enactment and identified the remaining gaps and challenges as experienced by stakeholders. In June 2020, the policy recommendations of the working group were presented at the virtual NCCN Policy Summit: Accelerating Advances in Cancer Care Research: A Lookback at the 21st Century Cures Act in 2020. The summit consisted of informative discussions and a multistakeholder panel to explore the recommendations and the future of the Cures Act. This article explores identified policy recommendations from the NCCN Working Group and the NCCN Policy Summit, and analyzes opportunities to advance innovative cancer care and patient access to data.
Abstract PO-023: Impact of a novel Ku-DNA binding inhibitor on the IR-induced DNA damage response
Authors: Pamela Mendoza-Munoz, Navnath S. Gavande, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Joseph R. Dynlacht, Joy Garrett, John J. Turchi
Journal: Clinical Cancer Research (2021)

Abstract The DNA-dependent protein kinase (DNA-PK) plays a critical role in the non-homologous end joining (NHEJ) double stand break (DSB) repair pathway and the DNA damage response (DDR). Consequently, blocking DNA-PK kinase activity is a novel anti-cancer therapeutic strategy in combination with ionizing radiation (IR). Towards developing a series of a new class of DNA-PK inhibitors, our laboratory has exploited the mechanism of DNA-PK activation which requires binding to DNA termini via the Ku 70/80 heterodimer. We recently reported the development of Ku-DNA binding inhibitors (Ku-DBi’s) that act via this novel mechanism of action to inhibit DNA-PK catalytic kinase activity. Ku-DBi’s display nanomolar activity in vitro, possess cellular DNA-PK and NHEJ inhibitory activity and sensitize non-small cell lung cancer (NSCLC) cells to chemotherapeutics bleomycin and etoposide. In this study, we demonstrate that pre-incubation of our novel Ku-DBi’s can potentiate the cellular effects of IR. We demonstrate that the increase in IR sensitivity is preceded by a decrease in DNA-PKcs autophosphorylation events at the S2056 (pS2056) cluster. Using a combination of Western blot and immunofluorescence assays in the NSCLC NCI-H460 cell line, Ku-DBi 245 treatment in combination with IR showed a significant reduction of phosphorylation of DNA-PKcs at S2056 compared to IR alone. Analysis of gH2A.X also showed an inhibition of the DDR as a function of 245 treatment, evidenced by reduction of S139 phosphorylation. These results demonstrate that Ku-DBi 245 blocks DNA-break dependent DNA-PKcs autophosphorylation, resulting in an increased in radiation sensitivity. These data are consistent with Ku-DBi’s possessing a novel mechanism of action that abrogates autophosphorylation of DNA-PKcs and DDR signaling as part of an anticancer therapeutic strategy in combination with IR. Citation Format: Pamela Mendoza-Munoz, Navnath S. Gavande, Pamela S. VanderVere-Carozza, Katherine S. Pawelczak, Joseph R. Dynlacht, Joy Garrett, John J. Turchi. Impact of a novel Ku-DNA binding inhibitor on the IR-induced DNA damage response [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-023.
Effects of wearing a cloth face mask on performance, physiological and perceptual responses during a graded treadmill running exercise test
Authors: Simon Driver, Megan Reynolds, Katelyn Brown, Jakob L Vingren, David W Hill, Monica Bennett, Taylor Gilliland, Evan McShan, Librada Callender, Erin Reynolds, Nate Borunda, John Mosolf, Casey Cates, Alan Jones
Journal: British Journal of Sports Medicine (2021)

To (1) determine if wearing a cloth face mask significantly affected exercise performance and associated physiological responses, and (2) describe perceptual measures of effort and participants' experiences while wearing a face mask during a maximal treadmill test.Randomised controlled trial of healthy adults aged 18-29 years. Participants completed two (with and without a cloth face mask) maximal cardiopulmonary exercise tests (CPETs) on a treadmill following the Bruce protocol. Blood pressure, heart rate, oxygen saturation, exertion and shortness of breath were measured. Descriptive data and physical activity history were collected pretrial; perceptions of wearing face masks and experiential data were gathered immediately following the masked trial.The final sample included 31 adults (age=23.2±3.1 years; 14 women/17 men). Data indicated that wearing a cloth face mask led to a significant reduction in exercise time (-01:39±01:19 min/sec, p<0.001), maximal oxygen consumption (VO2max) (-818±552 mL/min, p<0.001), minute ventilation (-45.2±20.3 L/min), maximal heart rate (-8.4±17.0 beats per minute, p<0.01) and increased dyspnoea (1.7±2.9, p<0.001). Our data also suggest that differences in SpO2 and rating of perceived exertion existed between the different stages of the CPET as participant's exercise intensity increased. No significant differences were found between conditions after the 7-minute recovery period.Cloth face masks led to a 14% reduction in exercise time and 29% decrease in VO2max, attributed to perceived discomfort associated with mask-wearing. Compared with no mask, participants reported feeling increasingly short of breath and claustrophobic at higher exercise intensities while wearing a cloth face mask. Coaches, trainers and athletes should consider modifying the frequency, intensity, time and type of exercise when wearing a cloth face mask.
Digital single-operator cholangioscope for endoscopic retrograde appendicitis therapy
Authors: Ling-Jian Kong, Dan Liu, Ji-Yu Zhang, Saif Ullah, Lixia Zhao, Deliang Li, Huiyu Yang, Bing-Rong Liu
Journal: Endoscopy (2021)

Abstract Background This study aimed to investigate the diagnostic and therapeutic value of a digital single-operator cholangioscope (SOC) system for endoscopic management of acute appendicitis. Methods 14 patients with acute uncomplicated simple or supportive appendicitis were evaluated between November 2018 and September 2020. The diagnosis of acute appendicitis was confirmed by direct colonoscopy imaging and cholangioscope. The success rate of digital SOC-assisted endoscopic retrograde appendicitis therapy (ERAT), the procedure time, postoperative length of hospital stay, complications, and recurrence rate were recorded. Results Technical success rate was 100 %, with high quality imaging of the appendiceal cavity achieved using SOC in all 14 patients. The mean procedure time was 37.8 (standard deviation [SD] 22) minutes. All patients experienced immediate relief from abdominal pain after the procedure. Mean postoperative hospitalization was 1.9 (SD 0.7) days. No recurrence occurred during 2–24 months of follow-up. Conclusion Digital SOC-assisted ERAT provided a feasible, safe, and effective alternative approach for diagnosis and management of acute uncomplicated appendicitis without the need for X-ray or ultrasonic guidance.
Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection
Authors: Alisha Chetty, Matthew G. Darby, Pia M. Vornewald, Mara Martín-Alonso, Anna Filz, Manuel Ritter, Henry J. McSorley, Lindi Masson, Katherine Smith, Frank Brombacher, Matthew K. O’Shea, Adam F. Cunningham, Bernhard Ryffel, Menno J. Oudhoff, Benjamin G. Dewals, Laura E. Layland, William G.C. Horsnell
Journal: Cell Host & Microbe (2021)

How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.
Myeloid cell–derived PROS1 inhibits tumor metastasis by regulating inflammatory and immune responses via IL-10
Authors: Avi Maimon, Victor Levi-Yahid, Kerem Ben-Meir, Amit Halpern, Ziv Talmi, Shivam Priya, Gabriel Mizraji, Shani Mistriel-Zerbib, Michael Berger, Michal Baniyash, Sonja Loges, Tal Burstyn-Cohen
Journal: Journal of Clinical Investigation (2021)

Stimulation of TAM (TYRO3, AXL, and MERTK) receptor tyrosine kinases promotes tumor progression through numerous cellular mechanisms. TAM cognate ligands GAS6 and PROS1 (for TYRO3 and MERTK) are secreted by host immune cells, an interaction which may support tumor progression. Here, we revealed an unexpected antimetastatic role for myeloid-derived PROS1: suppressing metastatic potential in lung and breast tumor models. Pros1 deletion in myeloid cells led to increased lung metastasis, independent of primary tumor infiltration. PROS1-cKO bone marrow–derived macrophages (BMDMs) led to elevated TNF-α, IL-6, Nos2, and IL-10 via modulation of the Socs3/NF-κB pathway. Conditioned medium from cKO BMDMs enhanced EMT, ERK, AKT, and STAT3 activation within tumor cells and promoted IL-10–dependent invasion and survival. Macrophages isolated from metastatic lungs modulated T cell proliferation and function, as well as expression of costimulatory molecules on DCs in a PROS1-dependent manner. Inhibition of MERTK kinase activity blocked PROS1-mediated suppression of TNF-α and IL-6 but not IL-10. Overall, using lung and breast cancer models, we identified the PROS1/MERTK axis within BMDMs as a potent regulator of adaptive immune responses with a potential to suppress metastatic seeding and revealed IL-10 regulation by PROS1 to deviate from that of TNF-α and IL-6.
META-ANALYSIS OF SAFETY AND EFFICACY OF RENIN ANGIOTENSIN ALDOSTERONE SYSTEM INHIBITORS IN COVID-19 POPULATION
Authors: Yasar Sattar, Pradeeksha Mukuntharaj, Hassan Attique, Waqas Ullah, Muhammad Khawar Sana, Nathan Zaher, Abdul-Rahman M. Suleiman, Maham Mehmood, Ankur Panchal, Tanveer Mir, Muhammad Nadeem, Mohamed Zghouzi, Bachar Ahmad, Zaher Hakim, Delair Gardi, Omar E. Ali, Ghaith Alhatemi, Mohamad Mohamed, Islam Elgendy, Mamas Mamas, M. Chadi Alraies
Journal: Journal of the American College of Cardiology (2021)
CAR-T cells and BiTEs in solid tumors: challenges and perspectives
Authors: Julien Edeline, Roch Houot, Aurélien Marabelle, Marion Alcantara
Journal: Journal of Hematology & Oncology (2021)

Abstract Chimeric antigen receptor (CAR)-modified T cells and BiTEs are both immunotherapies which redirect T cell specificity against a tumor-specific antigen through the use of antibody fragments. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Nonetheless, the use of such new drugs to treat solid tumors is not straightforward. So far, the results from early phase clinical trials are not as impressive as expected but many improvements are under way. In this review we present an overview of the clinical development of CAR-T cells and BiTEs targeting the main antigens expressed by solid tumors. We emphasize the most frequent hurdles encountered by either CAR-T cells or BiTEs, or both, and summarize the strategies that have been proposed to overcome these obstacles.
Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis
Authors: Heng Li, Yao Zhang, Moting Liu, Chen Fan, Chunlan Feng, Qiukai Lu, Caigui Xiang, Huimin Lu, Xiaoqian Yang, Bing Wu, Duowu Zou, Wei Tang
Journal: Acta Pharmaceutica Sinica B (2021)

Phosphodiesterase-4 (PDE4) functions as a catalyzing enzyme targeting hydrolyzation of intracellular cyclic adenosine monophosphate (cAMP) and inhibition of PDE4 has been proven to be a competitive strategy for dermatological and pulmonary inflammation. However, the pathological role of PDE4 and the therapeutic feasibility of PDE4 inhibitors in chronic ulcerative colitis (UC) are less clearly understood. This study introduced apremilast, a breakthrough in discovery of PDE4 inhibitors, to explore the therapeutic capacity in dextran sulfate sodium (DSS)-induced experimental murine chronic UC. In the inflamed tissues, overexpression of PDE4 isoforms and defective cAMP-mediating pathway were firstly identified in chronic UC patients. Therapeutically, inhibition of PDE4 by apremilast modulated cAMP-predominant protein kinase A (PKA)-cAMP-response element binding protein (CREB) signaling and ameliorated the clinical symptoms of chronic UC, as evidenced by improvements on mucosal ulcerations, tissue fibrosis, and inflammatory infiltrations. Consequently, apremilast maintained a normal intestinal physical and chemical barrier function and rebuilt the mucosal homeostasis by interfering with the cross-talk between human epithelial cells and immune cells. Furthermore, we found that apremilast could remap the landscape of gut microbiota and exert regulatory effects on antimicrobial responses and the function of mucus in the gut microenvironment. Taken together, the present study revealed that intervene of PDE4 provided an infusive therapeutic strategy for patients with chronic and relapsing UC.