tbuckley/cabot-search huggingface dataset:
Abstract 9424: Single versus Dual Antiplatelet Therapy for Stroke Prevention Following Left Atrial Appendage Occlusion in Patients With High Bleeding Risk
Authors: Mohammed Mhanna, Azizullah Beran, Ahmad Al-Abdouh, Hazem Ayesh, mahmoud Barbarawi, Omar Srour, Ziad Abuhelwa, Wasef Sayeh, Mahmoud Alsaiqali, Ehab A Eltahawy
Journal: Circulation (2021)

Introduction: The optimal antiplatelet therapy following Left atrial appendage occlusion (LAAO) in atrial fibrillation patients who are not candidates for long-term oral anticoagulation therapy (OAC) is subject to debate. Hypothesis: Is single antiplatelet therapy (SAPT) safe and effective when compared to dual antiplatelet therapy (DAPT) in patients with high bleeding risk? Methods: We conducted a comprehensive search for all studies that compared the use of SAPT with DAPT following LAAO for patients in whom OAC is deemed highly risky or contraindicated. The outcomes of our study were device-related thrombosis (DRT), stroke and systemic embolization (SSE), and major bleeding (MB). The risk ratio (RR) with 95% confidence intervals (CIs) are presented as summary statistics and were calculated using a random-effects model. Results: A total of 15 observational studies with 3231 patients (SAPT, n=1036; DAPT, n=2195; 64.5% men; median follow-up duration 12 months; mean age 74.7±8.5 years; CHA2DS2-VASc score 4.3±1.6; HASBLED score 3.2±1.2) were included. For DRT, data were available from 10 studies (2910 patients); there was no difference between SAPT and DAPT groups (2.6% vs. 2.3%; RR: 1.41; 95%CI: 0.77-2.59; P=0.26; I 2 :0%). For SSE (8 studies, 959 patients); although numerically more events were observed in the SAPT group, there was no statistical difference between the two groups in the pooled analysis (2.9% vs. 1.5%; RR: 5.43; 95%CI: 0.74-39.81; P=0.1; I 2 :78%). Finally, for MB (8 studies, 1818 patients); although numerically more events were observed in the DAPT group, there was no statistical difference between the two arms (2.3% vs. 3.2%; RR: 1.90; 95%CI: 0.46-7.87; P=0.37; I 2 :72%). Conclusions: Our study showed comparable safety and efficacy profiles for SAPT and DAPT after LAAO. Adequately powered randomized studies determining the optimal antithrombotic therapy in the first weeks after LAAO are warranted in patients at high risk for bleeding.
295 Tumor cell- intrinsic expression of FGFR3 drives anti-PDL-1 immunotherapy resistance in a murine bladder cancer model
Authors: Erica Fleming-Trujillo, Jeffrey Bloodworth, Anthony Fernald, Aubrianna Ramsland, Thomas Gajewski, Randy Sweis
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Immune checkpoint blockade therapy has recently shown efficacy in treating advanced urothelial bladder cancer and anti-PD-1/PD-L1 therapy is currently the standard of care. However, most patients do not respond to these drugs and resistance mechanisms remain elusive. The non-T cell-inflamed tumor microenvironment phenotype correlates with poor prognosis and immunotherapy resistance. We previously found that activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) were exclusive to non-T cell-inflamed bladder cancers. We investigated the impact of tumor cell-intrinsic FGFR3 activation on T cell infiltration and tumor responsiveness to anti-PD-1/PD-L1 in a murine model. Methods We developed a syngeneic transplantable murine bladder cancer model using the MB49 cell line engineered to express FGFR3 with either the activating G370C mutation (FGFR3-G370C), a kinase-dead mutation K508M (FGFR3-K508M), a truncating mutation resulting in a secreted receptor (FGFR3-sec), or control. Mice were injected subcutaneously into flank and size was measured every 3 days along with PD-L1 therapy (BioXcell clone 10F.9G2). Tumors, draining lymph nodes, and spleens were harvested at endpoint for flow cytometry. Results Tumors from mice inoculated with MB49-FGFR3-G370C cells showed diminished CD8+ T cell accumulation within the tumor and were resistant to anti-PD-L1 checkpoint blockade compared to MB49 controls. To determine if FGFR3-mediated immune resistance was dependent on FGFR3 kinase activity, MB49-FGFR3-K508M tumors were evaluated and unexpectedly found to be resistant to anti-PD-L1 treatment. Tumors with a secreted FGFR3 receptor (FGFR3-sec) retained responsiveness to anti-PD-L1 therapy. Conclusions In a murine bladder cancer model, FGFR3 activation led to relative T cell exclusion and resistance to immune checkpoint blockade. The mechanism of resistance was not dependent on receptor kinase activity. Further studies are ongoing to determine the biochemical mechanisms of FGFR3-mediated immunotherapy resistance in bladder cancer.
Audio Interview: The Legal Basis for Covid-19 Restrictions and Mandates
Authors: Eric J. Rubin, Lindsey R. Baden, Michelle M. Mello, Stephen Morrissey
Journal: New England Journal of Medicine (2021)

The Legal Basis for Covid-19 Restrictions and Mandates In this audio interview conducted on November 16, 2021, the editors are joined by Stanford’s Michelle Mello to discuss the fundamentals of pub...
Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease
Authors: Malte Lenders, Eva Brand
Journal: Drugs (2021)

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A (AGAL/GLA) gene. The lysosomal accumulation of the substrates globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) results in progressive renal failure, cardiomyopathy associated with cardiac arrhythmia, and recurrent strokes, significantly limiting life expectancy in affected patients. Current treatment options for FD include recombinant enzyme-replacement therapies (ERTs) with intravenous agalsidase-α (0.2 mg/kg body weight) or agalsidase-β (1 mg/kg body weight) every 2 weeks, facilitating cellular Gb3 clearance and an overall improvement of disease burden. However, ERT can lead to infusion-associated reactions, as well as the formation of neutralizing anti-drug antibodies (ADAs) in ERT-treated males, leading to an attenuation of therapy efficacy and thus disease progression. In this narrative review, we provide a brief overview of the clinical picture of FD and diagnostic confirmation. The focus is on the biochemical and clinical significance of neutralizing ADAs as a humoral response to ERT. In addition, we provide an overview of different methods for ADA measurement and characterization, as well as potential therapeutic approaches to prevent or eliminate ADAs in affected patients, which is representative for other ERT-treated lysosomal storage diseases.
Level of Unique T-Cell Clonotypes Are Associated with Clonal Hematopoiesis and Survival in Patients with Lymphoma Intended for Autologous Stem Cell Transplant
Authors: Simon Husby, Gustav Ørting Jørgensen, Francesco Favero, Jakob Schmidt Jespersen, German G.R. Gonzalez, Christian Nielsen, Betina Sørensen, Lene Hyldahl Ebbesen, John Bæch, Eva Kannik Hastrup, Pär L. Josefsson, Michael Thorsgaard, Tarec Christoffer El-Galaly, Peter de Nully Brown, Thomas Stauffer Larsen, Joachim Weisenfeldt, Kirsten Grønbæk
Journal: Blood (2021)
Kidney VISTA prevents IFN-γ/IL-9 axis–mediated tubulointerstitial fibrosis after acute glomerular injury
Authors: Min-Gang Kim, Donghwan Yun, Chae Lin Kang, Minki Hong, Juhyeon Hwang, Kyung Chul Moon, Chang Wook Jeong, Cheol Kwak, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Dong-Sup Lee, Seung Seok Han
Journal: Journal of Clinical Investigation (2021)

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis that determines patient outcome, but the immunological molecules connecting these processes remain undetermined. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir-/-) kidney suffered more damage than those in WT kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased and the immunometabolic features of T cells changed to showing high oxidative phosphorylation and fatty acid metabolism and overproduction of IFN-γ. The Vsir-/- parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more IL-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against IFN-γ and IL-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., antineutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the IFN-γ/IL-9 axis after acute antibody-mediated glomerular injury.
Access and benefit-sharing by the European Virus Archive in response to COVID-19
Authors: Scarlett Sett, Carolina dos Santos Ribeiro, Christine Prat, George Haringhuizen, Amber Hartman Scholz, Tatjana Avšič, Carrie Batten, Maria Serena Beato, Hervé Bourhy, Antonino Di Caro, Rémi Charrel, Bruno Coutard, Jan Felix Drexler, Christian Drosten, Anthony R. Fooks, Boris Klempa, Marion Koopmans, Thomas Klimkait, Stephan Günther, Jean-Claude Manuguerra, Ali Mirazimi, Thomas C. Mettenleiter, Florence Komurian-Pradel, Sven Reiche, Chantal Reusken, Jean-Louis Romette, Sylvie van der Werf, David Williams
Journal: The Lancet Microbe (2021)

SummaryBiobanking infrastructures, which are crucial for responding early to new viral outbreaks, share pathogen genetic resources in an affordable, safe, and impartial manner and can provide expertise to address access and benefit-sharing issues. The European Virus Archive has had a crucial role in the global response to the COVID-19 pandemic by distributing EU-subsidised (free of charge) viral resources to users worldwide, providing non-monetary benefit sharing, implementing access and benefit-sharing compliance, and raising access and benefit-sharing awareness among members and users. All currently available SARS-CoV-2 material in the European Virus Archive catalogue, including variants of concern, are not access and benefit-sharing cases per se, but multilateral benefit-sharing has nevertheless occurred. We propose and discuss how a multilateral system enabling access and benefit-sharing from pathogen genetic resources, based on the European Virus Archive operational model, could help bridge the discrepancies between the current bilateral legal framework for pathogen genetic resources and actual pandemic response practices.
A Role for Lipid Metabolism in Tyrosine Kinase Inhibitor (TKI) Resistance of Chronic Myeloid Leukemia (CML)
Authors: Mayra A. Gonzalez, Jose L. Lopez, Katherine Schenkel, Kelaiah Reffell, Christopher A. Eide, Sudip Bajpeyi, Anna M. Eiring
Journal: Blood (2021)
Abstract 112: Internal Consistency Between Cognitive Tests for Survivors of Cardiac Arrest
Authors: Katharyn L Flickinger, Melissa J Repine, Allison C Koller, John Faro, Elizabeth Skidmore, Clifton W Callaway, Jon C Rittenberger
Journal: Circulation (2018)

Introduction: Cardiac arrest survivors suffer cognitive impairment easily missed on a clinical examination. We evaluated a battery of cognitive tests including the Cerebral Performance Category Extended (CPC-E), Montreal Cognitive Assessment (MoCA), and the Computer Assessment of Cognitive Impairment (CAMCI) to evaluate these deficits. Hypothesis: The CPC-E, MoCA and CAMCI tests correlate with one another, but the internal consistency of each test differs. Methods: Chart review of 201 cardiac arrest survivors occurred between October 2010 and January 2018. Pearson’s correlation was used to assess between-test correlation while Cronbach’s alpha was used to assess internal consistency of each test. We evaluated both the overall measure score and individual items in the measure. Results: Complete assessments were available for 50 subjects, 75 completed both the MoCA and the CAMCI, 57 completed both the CPC-E and the CAMCI, and 76 completed the MoCA and the CPC-E. Internal consistencies existed within both the MoCA and the CPC-E (Cronbach alpha = 0.661, and 0.738, respectively), while only borderline internal consistency was found within the CAMCI (Cronbach alpha = 0.638). At the scale level moderate or limited correlation existed between tests (Figure). At the item level, the CAMCI had little to no correlation with items of the CPC-E or MoCA. Moderate correlations existed between item specific domains of visuospatial, attention and delayed recall items of the MoCA and domains of alert, logical thinking, attention, and short term memory of the CPC-E (r=0.3-0.5). Conclusions: Strong correlation between the CAMCI and MoCA suggests they evaluate similar domains of function. The MoCA is shorter, easily administered and inexpensive, arguing for its use over the CAMCI. The CPC-E’s strong internal consistency and moderate correlation with the MoCA suggests it may provide additional discrimination of cognitive function in the cardiac arrest population.
Abstract 14350: Cost Effectiveness Analysis of the HEART Pathway as a Clinical Decision Support Tool for Chest Pain in Emergency Department
Authors: Olivia N Gilbert, Simon A Mahler, Sara Machado, Amresh Hanchate, Cedric Lefebvre
Journal: Circulation (2021)

Background: The History Electrocardiogram Age Risk factor Troponin (HEART) Pathway clinical decision support tool was designed to assist emergency department providers with chest pain risk stratification. Prior studies have demonstrated its safety and ability to reduce hospitalizations. However, cost effectiveness data is lacking. We performed a cost effectiveness analysis of the HEART Pathway compared with Standard Care. Hypothesis: The value of the HEART Pathway exceeds that of Standard Care as measured by cost effectiveness. Methods: A pre-planned economic analysis of the HEART Pathway Implementation Study was conducted. This prospective interrupted time-series accrued adults with possible acute coronary syndrome from 3 sites (11/2013-1/2016). The construct for the current analysis was a 1000-member Cohort (Deterministic) Markov model with two different time periods - one with a cycle length of 30 days run over the course of 1 year and one with a cycle length of 1 year run over the course of 10 years. Transition probabilities were obtained from patient encounter data from the original trial. A smaller subset of patients had direct costs available from the hospital perspective, including resources consumed and professional fees. Results: The HEART pathway and Standard Care cohorts included 3713 and 4761 patients with costing data respectively available for 140 and 139 patients. In both the 1-year and 10-year models, the HEART pathway had reduced costs and increased quality adjusted life years (QALYs) compared to Standard Care, making the HEART pathway strongly dominant in terms of cost effectiveness. Accordingly, an incremental cost effectiveness ratio is not defined. From the Markov models, mean cost per patient was projected to be lower for the HEART Pathway compared to Standard Care at 1 year ($6,225.31 versus $8,138.06) and at 10 years ($11,107.00 versus $13,322.76). Also, QALYs for the HEART Pathway were superior to Standard Care at 1 year (10.43 versus 10.20) and 10 years (7.73 versus 7.40). Conclusions: Compared to Standard Care, the HEART pathway was strongly dominant in terms of cost effectiveness using Markov modeling with 1-year and 10-year termination points.
The promise of microRNA-based therapies in Alzheimer’s disease: challenges and perspectives
Authors: Hannah Walgrave, Lujia Zhou, Bart De Strooper, Evgenia Salta
Journal: Molecular Neurodegeneration (2021)

Abstract Multi-pathway approaches for the treatment of complex polygenic disorders are emerging as alternatives to classical monotarget therapies and microRNAs are of particular interest in that regard. MicroRNA research has come a long way from their initial discovery to the cumulative appreciation of their regulatory potential in healthy and diseased brain. However, systematic interrogation of putative therapeutic or toxic effects of microRNAs in (models of) Alzheimer’s disease is currently missing and fundamental research findings are yet to be translated into clinical applications. Here, we review the literature to summarize the knowledge on microRNA regulation in Alzheimer’s pathophysiology and to critically discuss whether and to what extent these increasing insights can be exploited for the development of microRNA-based therapeutics in the clinic.
Assessment of Treatment Response By Ife, Next Generation Flow Cytometry and Mass Spectrometry Coupled with Liquid Chromatography in the GEM2012MENOS65 Clinical Trial
Authors: Noemi Puig, Teresa Contreras Sanfeliciano, Bruno Paiva, María Teresa Cedena, Laura Rosinol, Ramón Garcia-Sanz, Joaquín Martínez-López, Albert Oriol, María Jesús Blanchard, Rafael Rios, Jesus Martin, Anna Sureda, Miguel Hernández, Javier De La Rubia, Isabel Krsnik, Jose Maria Moraleda, Belén Iñigo, Luis Palomera, Cristina Agulló, Joan Bargay, Joan Bladé Creixenti, Jesús San-Miguel, Juan-José Lahuerta, Maria-Victoria Mateos
Journal: Blood (2021)
BET Inhibition As a Targeted Epigenetic Approach to Reverse T Cell Dysfunction in Chronic Lymphocytic Leukemia
Authors: Audrey L Smith, Alexandria P Eiken, Sydney A Skupa, Dalia Y Moore, Avyakta Kallam, Christopher D'Angelo, Gregory R Bociek, Matthew A. Lunning, Julie M. Vose, Ben Powell, Gideon Bollag, Dalia ElGamal
Journal: Blood (2021)
Renal AT <sub>2</sub> Receptors Mediate Natriuresis via Protein Phosphatase PP2A
Authors: Brandon A. Kemp, Nancy L. Howell, John J. Gildea, Susanna R. Keller, David L. Brautigan, Robert M. Carey
Journal: Circulation Research (2021)

How signals from activated angiotensin type-2 receptors (AT2R) mediate inhibition of sodium ion (Na+) reabsorption in renal proximal tubule cells is currently unknown. Protein phosphatases including PP2A (protein phosphatase 2A) have been implicated in AT2R signaling in tissues other than kidney. We investigated whether inhibition of protein phosphatase PP2A reduced AT2R-mediated natriuresis and evaluated changes in PP2A activity and localization after renal AT2R activation in normal 4- and 10-week-old control Wistar-Kyoto rats and 4-week-old prehypertensive and 10-week-old hypertensive spontaneously hypertensive rats.In Wistar-Kyoto rats, direct renal interstitial administration of selective AT2R nonpeptide agonist Compound-21 (C-21) increased renal interstitial cyclic GMP (cGMP) levels, urine Na+ excretion, and simultaneously increased PP2A activity ≈2-fold in homogenates of renal cortical tubules. The cyclic GMP and natriuretic responses were abolished by concurrent renal interstitial administration of protein phosphatase inhibitor calyculin A. In renal proximal tubule cells in response to C-21, PP2A subunits A, B55α and C, but not B56γ, were recruited to apical plasma membranes together with AT2Rs. Calyculin A treatment abolished C-21-induced translocation of both AT2R and PP2A regulatory subunit B55α to apical plasma membranes. Immunoprecipitation of AT2R solubilized from renal cortical homogenates demonstrated physical association of AT2R with PP2A A, B55α, and C but not B56γ subunits. In contrast, in spontaneously hypertensive rats, administration of C-21 did not alter urine Na+ excretion or PP2A activity and failed to translocate AT2Rs and PP2A subunits to apical plasma membranes.In renal proximal tubule cells of Wistar-Kyoto rats, PP2A is activated and PP2A subunits AB55αC are recruited to C-21-activated AT2Rs during induction of natriuresis. This response is defective in prehypertensive and hypertensive spontaneously hypertensive rats, presenting a potential novel therapeutic target for treating renal Na+ retention and hypertension.
Abstract 9096: Young Adults With Early-Onset Cardiovascular Risk Factors Demonstrate Subclinical Alterations in Cardiac Morphology and Function
Authors: Gert Snel, Maaike van den Boomen, Riemer Slart, Christopher Nguyen, David Sosnovik, Vincent van Deursen, Rudi Dierckx, Birgitta Velthuis, Ronald Borra, Niek Prakken
Journal: Circulation (2021)

Background: Overweight, hypertension and type 2 diabetes (risk factors) are associated with subclinical alterations in cardiac morphology and function in asymptomatic mature adults (age &gt;40 years). However, the time and extent of these cardiac alterations is unknown in the young adult (age 21-40 years) population with increasing early-onset risk factors, possibly overlapping findings in cardiomyopathy. Hypothesis: Risk factors already cause subclinical cardiac alterations in asymptomatic young adults. Methods: Non-smoking nonathletic adults aged 21-40 years without cardiac history underwent MRI for assessment of cardiac morphology and function. Multivariate linear regression analysis was performed to investigate the independent association of risk factor related parameters with cardiac outcomes. Results: In total, 279 subjects (49% male, mean age 31±6 years) were included. After adjustment for age, gender and height, all risk factors had significant impact on cardiac outcomes (Table+Figure). Most importantly, higher body mass index was associated with increases in left ventricular (LV) mass (ß=1.30), end-diastolic volumes (EDV) (LV, ß=1.82) and stroke volume (ß=1.04). Further, systolic blood pressure was positively associated with LV mass (ß=0.52), mass-volume ratio (ß=0.0024), stroke volume (ß=0.26) and LV ejection fraction (ß=0.073), and HbA1c with LV mass (ß=0.30) and right ventricular EDV (ß=0.43). Conclusions: In aysmptomatic young adults without cardiovascular disease, risk factors are associated with subclinical cardiac alterations. These alterations should be considered when evaluating clinical scans in young adults to avoid misdiagnosis.
PET-CT for Assessment of Multiple Myeloma Disease Burden and Metabolic Response before and after Carfilzomib-Based Induction, Consolidation and Carfilzomib Maintenance Therapy: Data from the UK NCRI Cardamon Study
Authors: Ceri A Bygrave, Manil Subesinghe, William Wilson, Rakesh Popat, Karthik Ramasamy, Gavin Pang, Richard Jenner, Sumaiya Kamora, Tushhar Dadaga, Lucy Pike, Matthew Streetly, Marquita Camilleri, Roger G Owen, James Cavenagh, Jonathan Sive, Michael Chapman, Elizabeth H Phillips, Selina J Chavda, Maria del Mar Cuadrado, Reuben Benjamin, Lydia Eccersley, Sally Moore, Lalita Banerjee, Laura Clifton-Hadley, Sally F Barrington, Kwee Yong
Journal: Blood (2021)
Gvhd Targets Organoid-Forming Biliary Epithelial Stem Cells Via a TGF-β-Dependent Manner
Authors: Yuta Hasegawa, Daigo Hashimoto, Ryo Kikuchi, Zixuan Zhang, Hajime Senjo, Tomoko Sekiguchi, Eiko Hayase, Takahiro Tateno, Emi Yokoyama, Shuichiro Takahashi, Xuanzhong Chen, Kazuki Yoneda, Hiroyuki Ohigashi, Takahide Ara, Takanori Teshima
Journal: Blood (2021)
Publisher Correction: Comprehensive genomic characterization of gene therapy-induced T-cell acute lymphoblastic leukemia
Authors: Peter Horak, Sebastian Uhrig, Maximilian Witzel, Irene Gil-Farina, Barbara Hutter, Tim Rath, Laura Gieldon, Gnana Prakash Balasubramanian, Xavier Pastor, Christoph E. Heilig, Daniela Richter, Evelin Schröck, Claudia R. Ball, Benedikt Brors, Christian J. Braun, Michael H. Albert, Claudia Scholl, Christof von Kalle, Manfred Schmidt, Stefan Fröhling, Christoph Klein, Hanno Glimm
Journal: Leukemia (2021)
Allogeneic CAR-T PBCAR0191 with Intensified Lymphodepletion Is Highly Active in Patients with Relapsed/Refractory B-Cell Malignancies
Authors: Bijal D. Shah, Caron Jacobson, Scott R. Solomon, Nitin Jain, Mark C. Johnson, Monika Vainorius, Lou Yu, Christopher R. Heery, Alan F. List, Fiona He, Ran Reshef, Luke P. Akard, Craig S. Sauter, Adam J. Olszewski, Abhinav Deol, Koen van Besien
Journal: Blood (2021)