tbuckley/cabot-search huggingface dataset:
Abstract MP113: Protein Hyperacetylation Mediates Bradyarrhythmia in Mice With Mitochondrial Disease
Authors: Dao-Fu Dai, Yi Chu, Jin-Young Yoon
Journal: Circulation Research (2020)

Background: Mice with germline mutation of the mitochondrial respiratory complex I subunit Ndufs4 exhibit progressive neurodegenerative phenotypes resembling Leigh syndrome (LS). Cardiomyocyte-specific Ndufs4 -/- mice demonstrate protein hyperacetylation and accelerated heart failure in response to pressure overload. Methods and Results: LS mice developed bradyarrhythmia with heart rate &lt;400 bpm. EKG showed sick sinus syndrome (SSS) and high degree AV block. Supplementation of Nicotinamide Riboside (NR), which increased cellular NAD + , significantly reduced arrhythmia events and restored normal sinus rhythm, as shown by confocal scanning of sinoatrial nodal tissue dissected from LS mouse hearts. Immunoprecipitation and immunohistochemistry using antibody specific for K1479 of Nav 1.5 showed hyperacetylation of LS SA nodal tissue, which was attenuated by NR. HEK293-cells deficient in mitochondrial complex I subunit Ndufs2 had higher DCFDA (ROS) and lower TMRM intensity (mitochondrial membrane potential) compared with Ndufs4 knock-out cells. Ndufs2-knock-out HEK293 cells transfected with wild-type Nav 1.5 showed hyperacetylation of K1479 of Nav 1.5 . Patch clamp showed significantly reduced sodium current (I Na ) in Ndufs2 deficient HEK293 cells. NR prevented the decrease of I Na in Ndufs2 KO cells. HEK293 cells expressing mutant Nav 1.5 constructs mimicking deacetylation (K1479R) had increased I Na compared with HEK293 expressing WT Nav 1.5, suggesting that acetylation status affect Nav1.5 function. Arrythmia was noted in conduction tissue specific HCN4-Ndufs4 -/- mice, suggested a cell autonomous effect leading to arrhythmia. These findings indicate that mitochondrial complex I deficiency lead to hyperacetylation of Nav 1.5 , reduction of I Na , which subsequently cause bradyarrhythmia and this can be reversed by NR. Using echocardiography, we demonstrated significant diastolic dysfunction (decreased E’/A’, prolonged isovolemic relaxation time) in LS mice, which was ameliorated by NR. The calcium transient amplitude and decay rate, an indicator of ryanodine receptor and SERCA2 functions, was significantly decreased by ~15% in LS hearts and this was mitigated by NR, concomitant with reversal of SERCA2 hyperacetylation. Conclusions: Despite normal cardiac structure and systolic function, LS mice showed SSS, high degree AV block and diastolic dysfunction, which is mediated by hyperacetylation of Nav 1.5 and SERCA2, respectively. NR significantly reversed both arrhythmia and diastolic dysfunction. Our study demonstrates novel mechanistic link between mitochondrial complex I deficiency and the function of Nav 1.5 and SERCA2.
A High-Content Screen for Mucin-1-Reducing Compounds Identifies Fostamatinib as a Candidate for Rapid Repurposing for Acute Lung Injury
Authors: Maria Kost-Alimova, Eriene-Heidi Sidhom, Abhigyan Satyam, Brian T. Chamberlain, Moran Dvela-Levitt, Michelle Melanson, Seth L. Alper, Jean Santos, Juan Gutierrez, Ayshwarya Subramanian, Patrick J. Byrne, Elizabeth Grinkevich, Estefanía Reyes-Bricio, Choah Kim, Abbe R. Clark, Andrew J.B. Watts, Rebecca Thompson, Jamie Marshall, Juan Lorenzo Pablo, Juliana Coraor, Julie Roignot, Katherine A. Vernon, Keith Keller, Alissa Campbell, Maheswarareddy Emani, Matthew Racette, Silvana Bazua-Valenti, Valeria Padovano, Astrid Weins, Stephen P. McAdoo, Frederick W.K. Tam, Luciene Ronco, Florence Wagner, George C. Tsokos, Jillian L. Shaw, Anna Greka
Journal: Cell Reports Medicine (2020)

Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.
Prognostic Significance of Genetic Alterations in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated with Hyper-CVAD Plus Dasatinib or Hyper-CVAD Plus Ponatinib
Authors: Yuya Sasaki, Hagop M. Kantarjian, Nicholas J. Short, Nitin Jain, Koji Sasaki, Farhad Ravandi, Marina Konopleva, Guillermo Garcia-Manero, Latasha Little, Curtis Gumbs, Li Zhao, P Andrew Futreal, Feng Wang, Ken Furudate, Rebecca Garris, Koichi Takahashi, Elias Jabbour
Journal: Blood (2020)
Birth and Infant Outcomes Following Laboratory-Confirmed SARS-CoV-2 Infection in Pregnancy — SET-NET, 16 Jurisdictions, March 29–October 14, 2020
Authors: Kate R. Woodworth, Emily O’Malley Olsen, Varsha Neelam, Elizabeth L. Lewis, Romeo R. Galang, Titilope Oduyebo, Kathryn Aveni, Mahsa M. Yazdy, Elizabeth Harvey, Nicole D. Longcore, Jerusha Barton, Chris Fussman, Samantha Siebman, Mamie Lush, Paul H. Patrick, Umme-Aiman Halai, Miguel Valencia-Prado, Lauren Orkis, Similoluwa Sowunmi, Levi Schlosser, Salma Khuwaja, Jennifer S. Read, Aron J. Hall, Dana Meaney-Delman, Sascha R. Ellington, Suzanne M. Gilboa, Van T. Tong, Augustina Delaney, Jason Hsia, Kellianne King, Mirna Perez, Megan Reynolds, Aspen Riser, Maria Rivera, Christina Sancken, John Sims, Ashley Smoots, Margaret Snead, Penelope Strid, Tineka Yowe-Conley, Laura Zambrano, Lauren Zapata, Susan Manning, Veronica Burkel, Amanda Akosa, Carolyne Bennett, Isabel Griffin, John Nahabedian, Suzanne Newton, Nicole M. Roth, Neha Shinde, Erin Whitehouse, Daniel Chang, Charise Fox, Yousra Mohamoud, Florence Whitehill
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Pregnant women with coronavirus disease 2019 (COVID-19) are at increased risk for severe illness and might be at risk for preterm birth (1-3). The full impact of infection with SARS-CoV-2, the virus that causes COVID-19, in pregnancy is unknown. Public health jurisdictions report information, including pregnancy status, on confirmed and probable COVID-19 cases to CDC through the National Notifiable Diseases Surveillance System.* Through the Surveillance for Emerging Threats to Mothers and Babies Network (SET-NET), 16 jurisdictions collected supplementary information on pregnancy and infant outcomes among 5,252 women with laboratory-confirmed SARS-CoV-2 infection reported during March 29-October 14, 2020. Among 3,912 live births with known gestational age, 12.9% were preterm (<37 weeks), higher than the reported 10.2% among the general U.S. population in 2019 (4). Among 610 infants (21.3%) with reported SARS-CoV-2 test results, perinatal infection was infrequent (2.6%) and occurred primarily among infants whose mother had SARS-CoV-2 infection identified within 1 week of delivery. Because the majority of pregnant women with COVID-19 reported thus far experienced infection in the third trimester, ongoing surveillance is needed to assess effects of infections in early pregnancy, as well the longer-term outcomes of exposed infants. These findings can inform neonatal testing recommendations, clinical practice, and public health action and can be used by health care providers to counsel pregnant women on the risks of SARS-CoV-2 infection, including preterm births. Pregnant women and their household members should follow recommended infection prevention measures, including wearing a mask, social distancing, and frequent handwashing when going out or interacting with others or if there is a person within the household who has had exposure to COVID-19.†.
Increased Interleukin-8 (IL8)-CXCR2 Signaling Promotes Progression of Bone Marrow Fibrosis in Myeloproliferative Neoplasms
Authors: Andrew Dunbar, Min Lu, Mirko Farina, Young Park, Julie Yang, Dongjoo Kim, Abdul Karzai, Mohamed E Salama, Jenna Snyder, Aishwarya Krishnan, Richard P. Koche, Rong Fan, Ross L. Levine, Ronald Hoffman
Journal: Blood (2020)
Umbralisib Plus Ublituximab (U2) Is Superior to Obinutuzumab Plus Chlorambucil (O+Chl) in Patients with Treatment Naïve (TN) and Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): Results from the Phase 3 Unity-CLL Study
Authors: John G. Gribben, Wojciech Jurczak, Ryan W. Jacobs, Sebastian Grosicki, Krzysztof Giannopoulos, Tomasz Wrobel, Syed F. Zafar, Jennifer L. Cultrera, Suman Kambhampati, Alexey Danilov, John M. Burke, Jerome Goldschmidt, Douglas F. Beach, Scott F. Huntington, Javier Pinilla Ibarz, Jeff P Sharman, Tanya Siddiqi, Danielle M. Brander, John M. Pagel, Kathryn S. Kolibaba, Monika Dlugosz-Danecka, Nilanjan Ghosh, Peter Sportelli, Hari P. Miskin, Owen A. O'Connor, Michael S. Weiss, Ian W. Flinn
Journal: Blood (2020)
Immunologic Predictors for Clinical Responses in Patients with Myelodysplastic Syndromes Treated with Immune Checkpoint Blockade
Authors: Sung-Eun Lee, Feng Wang, Abel Trujillo-Ocampo, Wilfredo Ruiz Vazquez, Hyun-Woo Cho, Koichi Takahashi, Gheath Alatrash, Jeffrey J. Molldrem, Richard E. Champlin, Naval Daver, Hagop M. Kantarjian, P. Andrew Futreal, Guillermo Garcia-Manero, Jin S. Im
Journal: Blood (2020)
Clinical Response of CD19 CAR-T Cells (relmacabtagene autoleucel, relma-cel) in Adults with Heavily-Pre-Treated Relapsed/Refractory (r/r) Large B-Cell Lymphoma in China
Authors: Jun Zhu, Zhitao Ying, Yuqin Song, Haiyan Yang, Ye Guo, Wenyu Li, Dehui Zou, Daobin Zhou, Zhao Wang, Mingzhi Zhang, Jianqiu Wu, Hui Liu, Pian Zhang, Su Yang, Zisong Zhou, Hongxia Zheng
Journal: Blood (2020)
Abstract 531: Mechanistic and Functional Differences in Rna Binding and Processing Activities of the Muscle- and Non-muscle Rbfox2 Isoforms
Authors: Chaitali Misra, Ullas Valiya Chembazhi, Sarah Matatov, Sushant Bangru, Auinash Kalsotra
Journal: Circulation Research (2020)

Myotonic Dystrophy type 1 (DM1), the most prevalent form of adult onset muscular dystrophy, is caused by CTG trinucleotide repeat expansion in the 3’-UTR of DMPK gene. Over 80% of DM1 patients exhibit heart dysfunctions, which are the second leading cause for DM1-related deaths. Recently, we demonstrated that aberrant expression of a non-muscle splice isoform of RNA-binding protein RBFOX2 triggers cardiac conduction delay, atrioventricular heart blocks, and spontaneous arrhythmogenesis in DM1 heart. RBFOX2 is a master regulator of tissue-specific alternative splicing and a pair of mutually exclusive 43-nucleotide(nt) and 40-nt exons in its C-terminal domain encode the muscle (RBFOX2 43 ) and non-muscle (RBFOX2 40 ) isoforms. The RBFOX2 40 isoform is predominantly expressed in the fetal heart, and is replaced by the RBFOX2 43 isoform in development, specifically within the cardiomyocytes of adult hearts. To deconstruct the splicing regulatory networks of RBFOX2 43 and RBFOX2 40 isoforms, characterize their respective RNA binding landscapes, and determine the RBFOX2 40 -driven transcriptome alterations in DM1 heart tissue, we performed eCLIP and high-resolution RNA-sequencing studies on cardiomyocytes isolated from wild type (expressing the normal muscle-specific RBFOX2 43 isoform), Rbfox2 Δ43/Δ43 (expressing the non-muscle RBFOX2 40 isoform), and RBFOX2 40 overexpressing (OE) mice. By integrating genome-wide RNA binding and processing activities for the two RBFOX2 isoforms, we found that a switch from the muscle-specific (RBFOX2 43 ) to non-muscle (RBFOX2 40 ) isoform provokes DM1-like cardiac pathology by altering the mRNA abundance and splicing of genes encoding components of the conduction system and/or contractile apparatus. Further, through subnuclear fractionation and protein-protein interaction studies, we demonstrate that the higher-order assembly of LASR (large assembly of splicing regulators) complexes formed by the RBFOX2 40 isoform boost its splicing activity and promote the generation of pathogenic splice variants of voltage-gated ion channels and other components of the cardiac conduction system.
Clinical Benefit and Tolerability of Crenolanib in Children with Relapsed Acute Myeloid Leukemia Harboring Treatment Resistant FLT3 ITD and Variant FLT3 TKD Mutations Treated on Compassionate Access
Authors: Katherine Tarlock, Soheil Meshinchi, Jeffrey E. Rubnitz, Seth E. Karol, Barbara Spitzer, Amit J. Sabnis, Asif Pathan, Boo Messahel
Journal: Blood (2020)
Core Binding Factor Leukemias Utilize a Physiologic Sense/Antisense Promoter Switch Employed By T-Cells
Authors: Emiel van der Kouwe, Gerwin Heller, Akos Czibere, Lucio H. Castilla, Ruud Delwel, Annalisa Di Ruscio, Alexander Ebralidze, Maurizio Forte, Lukas Kazianka, Christoph Kornauth, Trang Le, Karin Lind, Ines Barbosa, Alexander Pichler, John Pulikkan, Ann-Sofie Schmolke, Heinz Sill, Wolfgang R. Sperr, Andreas Spittler, Bon Q. Trinh, Peter Valent, Katrina Vanura, Robert Welner, Johannes Zuber, Daniel G. Tenen, Philipp B. Staber
Journal: Blood (2020)
Outcomes of Front-Line Therapy for Adult T Cell Leukemia/Lymphoma: A Pooled Analysis of Two Institutions
Authors: Jose Sandoval-Sus, Franco Castillo Tokumori, Ning Dong, Stephanie Boisclair, Amanda Brahim, Damaal Walker, Sanjay Bridgelall, Ling Zhang, Hayder Saeed, Lubomir Sokol
Journal: Blood (2020)
Influence of COVID-19 pandemic on decisions for the management of people with inflammatory rheumatic and musculoskeletal diseases: a survey among EULAR countries
Authors: Christian Dejaco, Alessia Alunno, Johannes WJ Bijlsma, Annelies Boonen, Bernard Combe, Axel Finckh, Pedro M Machado, Ivan Padjen, Francisca Sivera, Tanja A Stamm, Frank Buttgereit
Journal: Annals of the Rheumatic Diseases (2020)

Objectives To investigate how the first wave of COVID-19 pandemic influenced decisions of rheumatologists and health professionals in rheumatology regarding the management of patients with inflammatory rheumatic and musculoskeletal diseases (RMDs). Methods An English-language questionnaire was developed by a EULAR working group and distributed via national rheumatology societies of EULAR countries, EMEUNET and individual working group members. Responses were collected using an online survey tool. Descriptive statistics were calculated. Results We analysed 1286 responses from 35/45 EULAR countries. Due to containment measures, 82% of respondents indicated cancellation/postponement of face-to-face visits of new patients (84% of them offering remote consultation) and 91% of follow-up visits (96% with remote consultation). The majority of respondents (58%) perceived that the interval between symptom onset and first rheumatological consultations was longer during containment restrictions than before. Treatment decisions were frequently postponed (34%), and the majority (74%) of respondents stated that it was less likely to start a biological disease modifying anti-rheumatic drug (DMARD)/targeted synthetic DMARD during the pandemic, mainly because of patients’ fear, limited availability of screening procedures and decreased availability of rheumatological services. Use of (hydroxy)chloroquine (HCQ) and tocilizumab (TCZ) for the COVID-19 indication was reported by 47% and 42% of respondents, respectively, leading to a shortage of these drugs for RMDs indications according to 49% and 14% of respondents, respectively. Conclusion Measures related to containment of COVID-19 pandemic led to a perceived delay between symptom onset and a first rheumatological visit, postponement of treatment decisions, and shortage of HCQ and TCZ, thereby negatively impacting early treatment and treat-to-target strategies.
Diagnostic Accuracy of the Tina-Quant D-Dimer Gen.2 Assay with Age-Adjusted Cut-Off Ranges for Evaluation of Patients with Suspected Deep Vein Thrombosis or Pulmonary Embolism
Authors: Thomas Bertsch, Wilhelm Behringer, Sabine Blaschke, Richard Body, Simon Davidson, Anna Rieger, Daniel Horner, Ulrich Sonner, Yuli Sun, Lucia Turnes, Michael Hoffman
Journal: Blood (2020)
The Role of Structural Violence in Acute Myeloid Leukemia Outcomes
Authors: Ivy Abraham, Garth Rauscher, Anand Ashwin Patel, William B Pearse, Priya Rajakumar, Stephanie Berg, Ahmed Aleem, Ami Dave, Sushma Bharadwaj, Koosha Paydary, Maria Acevedo-Mendez, Richard Gomez, Kylie Carlson, Stephanie B. Tsai, Jessica K. Altman, Wendy Stock, John G. Quigley, Maryam Zia, Melissa C. Larson, Irum Khan
Journal: Blood (2020)
Assessment of Changes in Rural and Urban Primary Care Workforce in the United States From 2009 to 2017
Authors: Donglan Zhang, Heejung Son, Ye Shen, Zhuo Chen, Janani Rajbhandari-Thapa, Yan Li, Heesun Eom, Daniel Bu, Lan Mu, Gang Li, José A. Pagán
Journal: JAMA Network Open (2020)

Access to primary care clinicians, including primary care physicians and nonphysician clinicians (nurse practitioners and physician assistants) is necessary to improving population health. However, rural-urban trends in primary care access in the US are not well studied.To assess the rural-urban trends in the primary care workforce from 2009 to 2017 across all counties in the US.In this cross-sectional study of US counties, county rural-urban status was defined according to the national rural-urban classification scheme for counties used by the National Center for Health Statistics at the Centers for Disease Control and Prevention. Trends in the county-level distribution of primary care clinicians from 2009 to 2017 were examined. Data were analyzed from November 12, 2019, to February 10, 2020.Density of primary care clinicians measured as the number of primary care physicians, nurse practitioners, and physician assistants per 3500 population in each county. The average annual percentage change (APC) of the means of the density of primary care clinicians over time was calculated, and generalized estimating equations were used to adjust for county-level sociodemographic variables obtained from the American Community Survey.The study included data from 3143 US counties (1167 [37%] urban and 1976 [63%] rural). The number of primary care clinicians per 3500 people increased significantly in rural counties (2009 median density: 2.04; interquartile range [IQR], 1.43-2.76; and 2017 median density: 2.29; IQR, 1.57-3.23; P < .001) and urban counties (2009 median density: 2.26; IQR. 1.52-3.23; and 2017 median density: 2.66; IQR, 1.72-4.02; P < .001). The APC of the mean density of primary care physicians in rural counties was 1.70% (95% CI, 0.84%-2.57%), nurse practitioners was 8.37% (95% CI, 7.11%-9.63%), and physician assistants was 5.14% (95% CI, 3.91%-6.37%); the APC of the mean density of primary care physicians in urban counties was 2.40% (95% CI, 1.19%-3.61%), nurse practitioners was 8.64% (95% CI, 7.72%-9.55%), and physician assistants was 6.42% (95% CI, 5.34%-7.50%). Results from the generalized estimating equations model showed that the density of primary care clinicians in urban counties increased faster than in rural counties (β = 0.04; 95% CI, 0.03 to 0.05; P < .001).Although the density of primary care clinicians increased in both rural and urban counties during the 2009-2017 period, the increase was more pronounced in urban than in rural counties. Closing rural-urban gaps in access to primary care clinicians may require increasingly intensive efforts targeting rural areas.
Abstract 243: Myocardial-associated B Cells Modulate the Composition of Cardiac Resident Macrophages
Authors: Cibele Rocha Resende, Luigi Adamo
Journal: Circulation Research (2020)

Background: The murine myocardium contains distinct subsets of macrophages with disparate roles that can be defined by expression levels of CCR2 and MHC-II. The factors that modulate the composition of the myocardial macrophage pool in the naïve heart are not completely known. B cells have been recently shown to modulate the prevalence of T cells in the heart but the relationship between B cells and myocardial macrophage subsets remains unknown. Objective: To test the hypothesis that myocardial-associated B cells modulate the composition of the myocardial macrophage pool. Methods and Results: Hearts from B cell deficient (μMT) or B cell depleted (treated with Anti-CD20 antibody) mice and age/sex matched controls were analyzed via flow cytometry at post-natal day 14 and soon after weaning. Absence of B cells was consistently associated with a decrease in the prevalence of CCR2 - MHC-II high resident macrophages. Immunofluorescence analysis of the heart showed that the myocardial-associated B cells were frequently in close proximity of CD68+ myocardial macrophages. In vitro co-culture of myocardial-derived CD64+ macrophages with B cells or with B cell-conditioned media showed that B cells fostered an increase in the prevalence of CCR2 - MHC-II high macrophages through a direct paracrine effect. In vivo 10X single cells sequencing and flow cytometric analysis together with in vitro ELISA and antibody mediate blocking suggested that the paracrine effect of B cells on myocardial macrophages is mediated, at least in part, by IL-16 secretion. Conclusion: Myocardial-associated B cells modulate the phenotype of myocardial resident macrophages. This is likely the result of a direct paracrine effect mediated, at least in part, by IL-16. These findings describe for the first time a relationship between circulating naïve B cells and tissue resident macrophages and unveil a previously unappreciated relationship between lymphoid and myeloid myocardial cells.
Masks and Face Coverings for the Lay Public
Authors: Thomas Czypionka, Trisha Greenhalgh, Dirk Bassler, Manuel B. Bryant
Journal: Annals of Internal Medicine (2020)

Whether and when to mandate the wearing of facemasks in the community to prevent the spread of coronavirus disease 2019 remains controversial. Published literature across disciplines about the role of masks in mitigating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is summarized. Growing evidence that SARS-CoV-2 is airborne indicates that infection control interventions must go beyond contact and droplet measures (such as handwashing and cleaning surfaces) and attend to masking and ventilation. Observational evidence suggests that masks work mainly by source control (preventing infected persons from transmitting the virus to others), but laboratory studies of mask filtration properties suggest that they could also provide some protection to wearers (protective effect). Even small reductions in individual transmission could lead to substantial reductions in population spread. To date, only 1 randomized controlled trial has examined a community mask recommendation. This trial did not identify a significant protective effect and was not designed to evaluate source control. Filtration properties and comfort vary widely across mask types. Masks may cause discomfort and communication difficulties. However, there is no evidence that masks result in significant physiologic decompensation or that risk compensation and fomite transmission are associated with mask wearing. The psychological effects of masks are culturally shaped; they may include threats to autonomy, social relatedness, and competence. Evidence suggests that the potential benefits of wearing masks likely outweigh the potential harms when SARS-CoV-2 is spreading in a community. However, mask mandates involve a tradeoff with personal freedom, so such policies should be pursued only if the threat is substantial and mitigation of spread cannot be achieved through other means.