tbuckley/cabot-search huggingface dataset:
Abstract 13947: Catheter-Induced Ectopy During Ventricular Electroanatomical Mapping: Simply Annoying or Potentially Useful?
Authors: Iwanari Kawamura, Vivek Y Reddy, Mohit Turagam, Daniel Musikantow, Edward Chu, Marc Miller, William Whang, Srinivas Dukkipati, jacob s Koruth
Journal: Circulation (2021)

Background: During ventricular catheter mapping to guide catheter ablation of scar-related ventricular tachycardia (VT), creating an electroanatomical map can be frustrated by catheter-induced ventricular ectopy. However, we observed anecdotally that catheter-induced ventricular ectopy may unmask local abnormal ventricular activities (LAVA). The aim of this study was to compare LAVA characteristics between catheter-induced ventricular ectopy and intrinsic ventricular conduction in post-infarction patients undergoing electroanatomic mapping. Methods: We performed a retrospective review of electroanatomical maps from 136 consecutive post-infarction VT patients who had undergone mapping using a contact force-sensing catheter (Thermocool STSF &amp; CARTO, Biosense Webster Inc). Patients who had any diagnostic catheters inside the ventricular were excluded. From 8 patients, 1154 discrete points were screened during sinus rhythm or right atrial pacing, and 443 points were identified to have ectopic and intrinsic beats - confirmed to be colocalized using show-catheter functionality. Results: Among 443 points, LAVA were identified in 151 points - either during catheter-induced ectopy or intrinsic rhythm. The interval from onset of QRS to ventricular electrogram (EGM) were measured: ectopy revealed negative values compared to intrinsic rhythm (-43.5 (-65.5, 0) vs 18.5 (0, 35.0), P&lt;0.001). Catheter-induced ectopy had significantly longer EGM duration (206.0ms (161.0, 285.0) vs 140.0 (123.8, 168.3), P&lt;0.001) and smaller EGM amplitude (0.59mV (0.34, 0.82) vs 0.66 (0.36, 1.06), P=0.003) compared to intrinsic rhythm. For 77 of 151 (51.0%) points, LAVA potentials were unmasked only during catheter-induced ectopy. Conclusions: During mapping of infarcted ventricles, catheter-induced ectopy offers potential insights into the underlying tissue, warranting further investigation as a guide to VT ablation.
MicroRNA-100-5p and microRNA-298-5p released from apoptotic cortical neurons are endogenous Toll-like receptor 7/8 ligands that contribute to neurodegeneration
Authors: Thomas Wallach, Zoé J. Mossmann, Michal Szczepek, Max Wetzel, Rui Machado, Martin Raden, Milad Miladi, Gunnar Kleinau, Christina Krüger, Paul Dembny, Drew Adler, Yuanyuan Zhai, Victor Kumbol, Omar Dzaye, Jutta Schüler, Matthias Futschik, Rolf Backofen, Patrick Scheerer, Seija Lehnardt
Journal: Molecular Neurodegeneration (2021)

MicroRNA (miRNA) expression in the brain is altered in neurodegenerative diseases. Recent studies demonstrated that selected miRNAs conventionally regulating gene expression at the post-transcriptional level can act extracellularly as signaling molecules. The identity of miRNA species serving as membrane receptor ligands involved in neuronal apoptosis in the central nervous system (CNS), as well as the miRNAs' sequence and structure required for this mode of action remained largely unresolved.Using a microarray-based screening approach we analyzed apoptotic cortical neurons of C56BL/6 mice and their supernatant with respect to alterations in miRNA expression/presence. HEK-Blue Toll-like receptor (TLR) 7/8 reporter cells, primary microglia and macrophages derived from human and mouse were employed to test the potential of the identified miRNAs released from apoptotic neurons to serve as signaling molecules for the RNA-sensing receptors. Biophysical and bioinformatical approaches, as well as immunoassays and sequential microscopy were used to analyze the interaction between candidate miRNA and TLR. Immunocytochemical and -histochemical analyses of murine CNS cultures and adult mice intrathecally injected with miRNAs, respectively, were performed to evaluate the impact of miRNA-induced TLR activation on neuronal survival and microglial activation.We identified a specific pattern of miRNAs released from apoptotic cortical neurons that activate TLR7 and/or TLR8, depending on sequence and species. Exposure of microglia and macrophages to certain miRNA classes released from apoptotic neurons resulted in the sequence-specific production of distinct cytokines/chemokines and increased phagocytic activity. Out of those miRNAs miR-100-5p and miR-298-5p, which have consistently been linked to neurodegenerative diseases, entered microglia, located to their endosomes, and directly bound to human TLR8. The miRNA-TLR interaction required novel sequence features, but no specific structure formation of mature miRNA. As a consequence of miR-100-5p- and miR-298-5p-induced TLR activation, cortical neurons underwent cell-autonomous apoptosis. Presence of miR-100-5p and miR-298-5p in cerebrospinal fluid led to neurodegeneration and microglial accumulation in the murine cerebral cortex through TLR7 signaling.Our data demonstrate that specific miRNAs are released from apoptotic cortical neurons, serve as endogenous TLR7/8 ligands, and thereby trigger further neuronal apoptosis in the CNS. Our findings underline the recently discovered role of miRNAs as extracellular signaling molecules, particularly in the context of neurodegeneration.
Heart failure among patients with polymyositis/dermatomyositis: comment on the article by Lin et al
Authors: Renin Chang, Yao‐Min Hung, James Cheng‐Chung Wei
Journal: Arthritis & Rheumatology (2021)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Maneuvering the Complex Web of Treatment Options for Relapsed/Refractory Multiple Myeloma
Authors: Natalie S. Callander
Journal: Journal of the National Comprehensive Cancer Network (2021)

Numerous treatment options are available for patients with early relapsed multiple myeloma. Clinicians should consider using a monoclonal antibody for patients who have not yet received one, or changing either the immunomodulatory drug, the proteasome inhibitor, or both. Clinical trials are another option, or clinicians can refer transplant-naïve patients for autologous stem cell transplantation (ASCT). For patients with late relapse, a clinical trial is recommended, if possible, but many patients are ineligible due to poor blood cell counts or other factors. Additional treatment options include selinexor combinations, belantamab mafodotin-blmf, melflufen, or CAR T-cell therapy. Salvage ASCT should also be considered for this challenging population.
Abstract 13709: TRPV4 Enhances Ca2+Transients and Promotes Arrhythmic Ca2+ Signaling Following Hypoosmotic Stress and Ischemia-Reperfusion
Authors: Deborah Peana, Timothy Domeier
Journal: Circulation (2021)

Introduction: Transient Receptor Potential Vanilloid 4 (TRPV4) is an osmotically activated Ca2+ channel which enhances cardiomyocyte Ca2+ cycling and may contribute to arrhythmic Ca2+ signals in hy...
Evaluation of a Rapid Automated Next Generation Sequencing Assay for Precision Medicine in Acute Myeloid Leukemia
Authors: Georgia M. Andrew, Laura W. Dillon, Maria Saeed, Ting-Chia Chang, Srikrishna K. Narava, Erin M. Mosher, Marvin S. Majano, Anna Lee-Fong, John N. Zhang, Marina Sedova, Jiajie Huang, Vinay K. Mittal, Andrew G. Hatch, Jingwei Ni, Denis Kaznadzey, Seth Sadis, Jeffery M. Smith, Richard F. Little, Lyndsay Harris, James H. Doroshow, P. Mickey Williams, Shahanawaz Jiwani, Christopher S. Hourigan
Journal: Blood (2021)
DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs
Authors: Shao-bin Wang, Siddharth Narendran, Shuichiro Hirahara, Akhil Varshney, Felipe Pereira, Ivana Apicella, Meenakshi Ambati, Vidya L. Ambati, Praveen Yerramothu, Kameshwari Ambati, Yosuke Nagasaka, Dionne Argyle, Peirong Huang, Kirstie L. Baker, Kenneth M. Marion, Kartik Gupta, Bo Liu, David R. Hinton, Scott W. Canna, Tamer Sallam, Srinivas R. Sadda, Nagaraj Kerur, Bradley D. Gelfand, Jayakrishna Ambati
Journal: Science Immunology (2021)

Detection of microbial products by multiprotein complexes known as inflammasomes is pivotal to host defense against pathogens. Nucleotide-binding domain leucine-rich repeat (NLR) CARD domain containing 4 (NLRC4) forms an inflammasome in response to bacterial products; this requires their detection by NLR family apoptosis inhibitory proteins (NAIPs), with which NLRC4 physically associates. However, the mechanisms underlying sterile NLRC4 inflammasome activation, which is implicated in chronic noninfectious diseases, remain unknown. Here, we report that endogenous short interspersed nuclear element (SINE) RNAs, which promote atrophic macular degeneration (AMD) and systemic lupus erythematosus (SLE), induce NLRC4 inflammasome activation independent of NAIPs. We identify DDX17, a DExD/H box RNA helicase, as the sensor of SINE RNAs that licenses assembly of an inflammasome comprising NLRC4, NLR pyrin domain–containing protein 3, and apoptosis-associated speck-like protein–containing CARD and induces caspase-1 activation and cytokine release. Inhibiting DDX17-mediated NLRC4 inflammasome activation decreased interleukin-18 release in peripheral blood mononuclear cells of patients with SLE and prevented retinal degeneration in an animal model of AMD. Our findings uncover a previously unrecognized noncanonical NLRC4 inflammasome activated by endogenous retrotransposons and provide potential therapeutic targets for SINE RNA–driven diseases.
Impact of Transfusion Dependency on Health-Related Quality of Life Outcomes in Newly Diagnosed Patients with Myelodysplastic Syndromes (MDS). Analysis on 669 Patients By Disease Risk
Authors: Fabio Efficace, Pasquale Niscola, Gianluca Gaidano, Alessandra Ricco, Giovanni Caocci, Massimo Breccia, Giuseppe A Palumbo, Maria Teresa Voso, Daniele Vallisa, Bernardino Allione, Manuela Canicattì, Iris Okumura, Francesco Cottone, Rosangela Invernizzi, Micaela Bergamaschi, Lorenza Maria Borin, Anna Angela Di Tucci, Huiyong Zhang, Reinhard Stauder, Uwe Platzbecker, Mario Luppi, Duska Petranovic, Jo Caers, Nicola Cascavilla, Marco Vignetti, Franco Mandelli
Journal: Blood (2017)
Effects of Resistant Starch on Symptoms, Fecal Markers, and Gut Microbiota in Parkinson’s Disease — The RESISTA-PD Trial
Authors: Anouck Becker, Georges Pierre Schmartz, Laura Gröger, Nadja Grammes, Valentina Galata, Hannah Philippeit, Jacqueline Weiland, Nicole Ludwig, Eckart Meese, Sascha Tierling, Jörn Walter, Andreas Schwiertz, Jörg Spiegel, Gudrun Wagenpfeil, Klaus Faßbender, Andreas Keller, Marcus M. Unger
Journal: Genomics Proteomics & Bioinformatics (2021)

Abstract The composition of the gut microbiota is linked to multiple diseases, including Parkinson’s disease (PD). Abundance of bacteria producing short-chain fatty acids (SCFAs) and fecal SCFA concentrations are reduced in PD. SCFAs exert various beneficial functions in humans. In the interventional, monocentric, open-label clinical trial “Effects of Resistant Starch on Bowel Habits, Short Chain Fatty Acids and Gut Microbiota in Parkinson ’s Disease” (RESISTA-PD; ID: NCT02784145), we aimed at altering fecal SCFAs by an 8-week prebiotic intervention with resistant starch (RS). We enrolled 87 subjects in three study-arms: 32 PD patients received RS (PD + RS), 30 control subjects received RS, and 25 PD patients received solely dietary instructions. We performed paired-end 100 bp length metagenomic sequencing of fecal samples using the BGISEQ platform at an average of 9.9 GB. RS was well-tolerated. In the PD + RS group, fecal butyrate concentrations increased significantly, and fecal calprotectin concentrations dropped significantly after 8 weeks of RS intervention. Clinically, we observed a reduction in non-motor symptom load in the PD + RS group. The reference-based analysis of metagenomes highlighted stable alpha-diversity and beta-diversity across the three groups, including bacteria producing SCFAs. Reference-free analysis suggested punctual, yet pronounced differences in the metagenomic signature in the PD + RS group. RESISTA-PD highlights that a prebiotic treatment with RS is safe and well-tolerated in PD. The stable alpha-diversity and beta-diversity alongside altered fecal butyrate and calprotectin concentrations call for long-term studies, also investigating whether RS is able to modify the clinical course of PD.
Abstract 10853: Emergency Activations for Chest Pain and Ventricular Arrhythmias Related to Regional Covid-19 Across the US
Authors: Sidney Aung, Eric Vittinghoff, gregory nah, Anthony Lin, Sean Joyce, N. Clay Mann, Gregory M Marcus
Journal: Circulation (2021)

Introduction: Localized studies have reported a decline in myocardial infarctions during the coronavirus disease 2019 (COVID-19) pandemic. The mechanisms underlying these observations remain unknown, but evidence that patients may avoid healthcare facilities for fear of COVID-19 infection has heightened concern that true rates of myocardial infarctions have been under-ascertained and left untreated. Methods: We analyzed data from the National Emergency Medical Services Information System (NEMSIS) and incident COVID-19 infections across the United States between January 1, 2020 to April 30, 2020. Grouping events by US Census Division, multivariable adjusted negative binomial regression models were utilized to estimate the relationship between COVID-19 and EMS activations for chest pain, non-ST-elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI), cardiac arrests, and ventricular arrhythmias. Results: After multivariable adjustment, increasing rates of COVID-19 were associated with a reduction in EMS activations for chest pain (RR 0.67, 95% CI 0.63-0.70, p &lt; 0.001) and NSTEMIs (RR 0.16, 95% CI, 0.10-0.26; p &lt; 0.001). Simultaneously, increasing COVID-19 was associated with a significant increase in EMS activations for cardiac arrests (RR 1.51, 95% CI 1.36-1.68, p &lt; 0.001), ventricular fibrillation (RR 1.47, 95% CI 1.23-1.77, p &lt; 0.001), and ventricular tachycardia (VT) episodes (RR 1.34, 95% CI 1.16-1.56, p &lt; 0.001). These statistically significant relationships were consistently observed within each of the 9 US Census Divisions alone. Conclusions: Taken together, these data suggest that individuals are commonly delaying or avoiding care for myocardial infarction in areas with more COVID-19, leading to lethal consequences. Interventions aimed at reinforcing the need to seek appropriate care for suspected myocardial infarctions, even in the context of heightened infectious disease risks, should be pursued.
Abstract 10705: Association Between Clinical Outcomes and Bleeding Risk Factors in Very Elderly Patients with Atrial Fibrillation at High Bleeding Risk: The Fushimi Af Registry
Authors: Yuya Ide, Hisashi Ogawa, Kenjiro Ishigami, Syuhei Ikeda, KOSUKE DOI, Yasuhiro Hamatani, Takashi Yoshizawa, Akiko Fujino, MITSURU ISHII, Moritake Iguchi, Nobutoyo Masunaga, Masahiro Esato, Hikari Tsuji, Hiromichi Wada, Koji Hasegawa, Mitsuru Abe, Masaharu Akao
Journal: Circulation (2021)

Background: The ELDERCARE-AF trial demonstrated that low-dose edoxaban (15 mg once-daily) prevented stroke or systemic embolism (SE) in very elderly Japanese patients with nonvalvular atrial fibrillation (NVAF) who were inappropriate for standard oral anticoagulant therapy due to high bleeding risk. The association between clinical outcomes and bleeding risks in such patients in routine clinical practice are unclear. Methods: From the Fushimi AF registry, we obtained ELDERCARE-eligible patients with NVAF who aged ≥80 years, had CHADS 2 score ≥2, and had one or more bleeding risks as shown in the ELDERCARE-AF trial: low creatinine clearance (15 to 30 ml/min), a history of bleeding from a critical organ, low body weight (≤45 kg), or regular use of antiplatelet drugs. The association of the four bleeding risk factors with the outcomes was evaluated in eligible patients. Results: We obtained 549 ELDERCARE-eligible patients (12.8% of entire cohort, 52.8% of ≥80 years and CHADS 2 score ≥2). The median follow-up period was 1,823 (interquartile range: 809-2,900) days. The incidences (% per patient-year) of stroke/SE, major bleeding, all-cause mortality, and cardiovascular death were significantly higher in eligible patients than in non-eligible patients (stroke/SE: 4.6% vs. 2.0%, major bleeding: 3.5% vs. 1.8%, all-cause mortality: 15.5% vs. 3.9%, cardiovascular death: 2.9% vs. 0.6%, all log-rank P&lt;0.001). Among the four bleeding risk factors, low body weight and low creatinine clearance were significantly associated with the incidence of all-cause mortality (adjusted hazard ratio [95% confidence interval], low body weight: 1.56 [1.16-2.10], P=0.003, low creatinine clearance: 1.70 [1.23-2.25], P&lt;0.001). Low creatinine clearance was also significantly associated with the incidence of cardiovascular death (2.55 [1.35-4.81], P=0.004). However, none of the four bleeding risk factors had associations with the incidences of stroke/SE or major bleeding after multivariate adjustment. Conclusion: Patients with NVAF who met the inclusion criteria of the ELDERCARE-AF trial had poor clinical outcomes, and low creatinine clearance was associated with the incidences of both all-cause and cardiovascular mortality.
Validation of the Copenhagen Hip and Groin Outcome Score (HAGOS) using modern test theory across different cultures and languages: a cross-sectional study of 452 male athletes with groin pain
Authors: Karl Bang Christensen, Mikkel Bek Clausen, Enda King, Andrew Franklyn-Miller, Joar Harøy, Thor Einar Andersen, Per Hölmich, Kristian Thorborg
Journal: British Journal of Sports Medicine (2021)

No studies have tested the validity of the Copenhagen Hip and Groin Outcome Score (HAGOS) using modern test theory, across different cultures and languages.To validate the Danish, English and Norwegian versions of HAGOS and its six subscales (Symptoms (S, Item 1-7), Pain (P, Item 1-10), activities of daily living (Item 1-5), Sport and recreation (Sport/rec, Item 1-8), Participation in physical activity (item 1-2) and quality of life (item 1-5)) by evaluating differential item functioning (DIF) and measurement invariance across the three language versions in male multidirectional team athletes with groin pain. Second, to modify subscales depending on goodness-of-fit to the item response theory models and calculate conversion tables if language DIF was observed.We included individual responses to the Danish (n=157), English (n=146) and Norwegian (n=149) language versions of HAGOS from 452 athletes (median age 24 years old, range 20-28) with groin pain. Overall fit, model fit, individual item fit, local response dependence and measurement invariance was examined using confirmatory factor analysis and graphical Rasch models.The removal of seven misfitting items (S2, P1, P2, A4, SP1, SP5, Q3) resulted in 6 HAGOS subscales with acceptable psychometric properties. For the Symptoms, Pain and Sports subscales evidence of DIF was disclosed between the three different language-versions of HAGOS and conversion tables were created.A revised HAGOS derived using modern test theory provides valid measurements for male multidirectional athletes with groin pain across different cultures and languages. Conversion tables must be applied to compare HAGOS scores from Danish, Norwegian and English language versions.
Author Correction: Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance
Authors: Donnele Daley, Vishnu R. Mani, Navyatha Mohan, Neha Akkad, Atsuo Ochi, Daniel W. Heindel, Ki Buom Lee, Constantinos P. Zambirinis, Gautam S. D. Balasubramania Pandian, Shivraj Savadkar, Alejandro Torres-Hernandez, Shruti Nayak, Ding Wang, Mautin Hundeyin, Brian Diskin, Berk Aykut, Gregor Werba, Rocky M. Barilla, Robert Rodriguez, Steven Chang, Lawrence Gardner, Lara K. Mahal, Beatrix Ueberheide, George Miller
Journal: Nature Medicine (2021)
Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device
Authors: A M James Shapiro, David Thompson, Thomas W Donner, Melena D Bellin, Willa Hsueh, Jeremy Pettus, Jon Wilensky, Mark Daniels, Richard M Wang, Eugene P Brandon, Manasi S Jaiman, Evert J Kroon, Kevin A D'Amour, Howard L Foyt
Journal: Cell Reports Medicine (2021)

These preliminary data from an ongoing first-in-human phase 1/2, open-label study provide proof-of-concept that pluripotent stem cell-derived pancreatic endoderm cells (PEC-01) engrafted in type 1 diabetes patients become islet cells releasing insulin in a physiologically regulated fashion. In this study of 17 subjects aged 22-57 with type 1 diabetes, PEC-01 cells were implanted subcutaneously in VC-02 macroencapsulation devices, allowing for direct vascularization of the cells. Engraftment and insulin expression were observed in 63% of VC-02 units explanted from subjects at 3-12 months post-implant. Six of 17 subjects (35.3%) demonstrated positive C-peptide as early as 6 months post-implant. Most reported adverse events were related to surgical implant or explant procedures (27.9%) or to side-effects of immunosuppression (33.7%). Initial data suggest that pluripotent stem cells, which can be propagated to the desired biomass and differentiated into pancreatic islet-like tissue, may offer a scalable, renewable alternative to pancreatic islet transplants.
CTIM-27. LOCOREGIONAL B7-H3-SPECIFIC CAR T CELLS FOR CHILDREN AND YOUNG ADULTS WITH DIPG: INTERIM REPORT OF BRAINCHILD-03 ARM C
Authors: Nicholas Vitanza, Ashley Wilson, Jason Yokoyama, Adam Johnson, Jule Gust, Wenjun Huang, Catherine Albert, Navin Pinto, Jessica Foster, Rimas Orentas, Amanda Paulovich, Michael Berens, Rebecca Gardner, Michael Jensen, Julie Park
Journal: Neuro-Oncology (2021)

Abstract Following preclinical optimization of B7-H3-specific CAR T cells against pediatric brain tumor models, we opened BrainChild-03 (NCT04185038), a phase 1 clinical trial of repeatedly dosed, outpatient, locoregional B7-H3-specific CAR T cells for children with recurrent/refractory central nervous system (CNS) tumors or diffuse intrinsic pontine glioma (DIPG). Here, we report the interim findings from patients enrolled on Arm C, dedicated to DIPG. The primary endpoints are feasibility and safety, with secondary endpoints of disease response. We utilize second-generation CAR T cells with a 4-1BB costimulatory domain and a methotrexate-resistant human DHFR mutein (huDHFRFS; L22F,F31S), allowing for methotrexate selection. We do not deliver conditioning chemotherapy. The first three evaluable patients with DIPG all met feasibility for generating a balanced CD4:CD8 CAR T cell product, with 3.85x109 CAR T cells generated for S005, 4.29x109 for S008, and 2.45x109 for S012, allowing for greater than 6 months of biweekly dosing for each patient. All subjects were treated at Dose Level 1 (1x107 CAR T cells). S005 received 10 doses before clinical progression greater than 2 years from diagnosis, S008 has received 10 doses and continues on therapy with decreased tumor volume, and S012 has received 5 doses and continues on study with stable disease. There have been no dose limiting toxicities (DLT). 3/3 patients exhibited post infusion fever, headache, and elevated serum CRP but no evidence of cytokine release syndrome (CRS) or systemic CAR T cells. 0/3 patients required PICU admissions. In the cerebrospinal fluid (CSF), 2/3 patients have had elevations of cytokines such as CXCL10 and CCL2, as well as circulating CSF CAR T cells. Advanced serial patient CSF proteomic and transcriptomic profiling are underway. Ultimately, this report provides preliminary evidence that outpatient locoregional B7-H3 CAR T cells for children with DIPG may be feasible and tolerable.