tbuckley/cabot-search huggingface dataset:
Abstract 14301: Investigation of an Injection-Jet Self-Powered Fontan Circulation
Authors: Ray Prather, Arka Das, Michael Farias, Eduardo DIVO, Alain J Kassab, William M Decampli
Journal: Circulation (2021)

Introduction: The Fontan circulation is a fragile system in which imperfections at any one of multiple levels may compromise quality of life. Increased inferior vena caval (IVC) pressure itself may play some role in “Fontan failure”. The Fontan circulation is powered with a high speed injection jet shunt (IJS) drawing flow from the aortic arch, balanced by a fenestration to preserve the ratio of pulmonary flow (Qp) to systemic flow (Qs). The high-velocity jet causes flow entrainment, leading to a significant reduction of upstream pressure. We describe a tightly coupled multi-scale lumped parameter/computational fluids dynamics (LPM-CFD) model to validate this hypothesis. Methods: A synthetic 3D CAD model of the fenestrated total cavopulmonary connection (TCPC) was generated, with average dimensions matching those of a 2-4 yo patient. The prescribed cardiac output is of about 2.3L/min. The detailed 3D pulsatile hemodynamics in the fluid domain are modeled as unsteady, turbulent and incompressible. Blood is assumed to be non-Newtonian. Turbulence is approximated using a large eddy simulation (LES) approach. Potential optimal IJS configurations were determined by with a parametric sweep of several geometric design parameters such as TCPC morphology, shunt diameter and location, and fenestration diameter and location. The effects of the IJS implementation on IVC pressure with a fenestration and systemic oxygen saturation were calculated using a tightly coupled LPM-CFD. Results and Discussion: A set of baseline simulations representing a failing Fontan, with elevated IVC pressure (+17.8mmHg). Enlargement of the fenestration to 7 mm results in a 3 mm Hg IVC pressure drop but also significant reduction in systemic oxygen saturation (assuming a 96% pulmonary venous O2 saturation level). Addition of an IJS (2mm nozzle) to this model preserves the IVC pressure drop of 3.2mmHg but improves systemic oxygen saturation with only a small additional volume load to the ventricle (CO/Qs = 1.2). Conclusions: This study demonstrates the potential salutary effect of the IJS on the Fontan circulation. Further exploration of adjustable anatomic and parameters are needed to further reduce IVC pressure and improve systemic saturation.
Abstract MP208: A Shared Fog2 / Tbx5-dependent Gene Regulatory Network Identified By Transcription Factor-dependent Non-coding RNA Profiling Modulates Cardiac Rhythm
Authors: Linsin A Smith, Carlos Perez-Cervantes, Michael Broman, Rangarajan Nadadur, Jeff Steimle, Brigitte Laforest, Sonja Lazaveric, Stefan R Mazurek, Kohta Ikegami, Xinan Yang, William Pu, Christopher Weber, Elizabeth M McNally, Eric Svensson, Ivan Moskowitz
Journal: Circulation Research (2021)

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting over 33 million individuals throughout the world. AF is highly heritable and recent genome-wide association studies (GWAS) have cumulatively identified over 100 loci associated with AF risk. Genome-wide association studies (GWAS) often identify transcription factor (TF) loci in association with complex human diseases, implying that a significant transcriptional component underlies human disease risk and etiology. The transcription factors ZFPM2 (FOG2), GATA4, and TBX5 have all been implicated in human AF risk by genetic studies. We hypothesized that FOG2, GATA4, and TBX5 functionally interact to regulate a gene regulatory network essential for atrial rhythm control. We generated a novel mouse model of spontaneous AF based on FOG2 overexpression. FOG2 ChIP-seq identified FOG2 genomic localization at loci co-occupied by GATA4, a known FOG2 binding partner. However, we found that FOG2 OE caused gene expression alterations that correlated more highly with TBX5-dependent rather than GATA4-dependent gene expression, including a module of calcium handling genes required for atrial rhythm homeostasis. We applied TF-dependent non-coding transcriptional profiling to examine the FOG2 dependent atrial GRN, which identified 805 candidate regulatory regions with accessible chromatin and FOG2 dependent ncRNAs. TBX5 removal and FOG2 OE caused highly correlated dysregulation of ncRNA expression at open chromatin regions genome-wide, suggesting a functional interaction between TBX5 and FOG2. Furthermore, FOG2 OE only affected enhancer activity by altered ncRNA abundance at locations of TBX5 co-binding. The shared TBX5/FOG2 genomic interaction predicted a potential genetic interaction, and we found that cardiac rhythm abnormalities caused by Tbx5 haploinsufficiency were rescued by Fog2 haploinsufficiency. Taken together, TF-dependent ncRNA-profiling revealed an interconnected cardiac rhythm gene regulatory network (GRN) between FOG2, TBX5 and GATA4. These data nominate a specific model in which FOG2 is recruited by GATA4 to modulate a co-bound TBX5-dependent atrial gene regulatory network for calcium handling and atrial rhythm homeostasis.
Triple MAPK Inhibition Salvaged a Relapsed Post BCMA CAR-T Cell Therapy in Multiple Myeloma Patient with BRAF V600E Dominant Clone
Authors: Muhammad Elnaggar, David T. Melnekoff, Sarita Agte, Christos Adamopoulos, Mark M. Stevens, Violetta Leshchenko, Katerina Kappes, Daniel Verina, Poulikos I. Poulikakos, Sundar Jagannath, Samir Parekh
Journal: Blood (2021)
Abstract 12532: Extracellular Vesicles Released by Cardiosphere-Derived Cells Dampen the Pro-Inflammatory Monocyte Response Through Repression of C-C Chemokine Receptor Type 2 (CCR2)
Authors: Kyle I Mentkowski, Rohan Pandey, Paul J Schiffmacher, Lisa A Eagler, Jessica L Reynolds, Jennifer K Lang
Journal: Circulation (2021)

Background: Following a myocardial infarction (MI), CCR2+ monocytes migrate toward the injury site along a CCL2 concentration gradient and play an integral role in removing debris and facilitating repair. Although required to orchestrate the pro-inflammatory response, prolonged activation of CCR2+ monocytes can lead to adverse outcomes. Extracellular vesicles (EVs) derived from cardiosphere-derived cells (CDCs) have been suggested to mediate cardioprotection in part via immunomodulation. We hypothesized that CDC-EVs influence CCR2+ monocyte recruitment and function. Methods: Blood samples were obtained from healthy human donors under approved institutional IRBs. Human monocytes were isolated from peripheral blood using density gradient centrifugation (Ficoll) followed by magnetic activated cell sorting (MACS). EVs were isolated from CDCs, normal human dermal fibroblasts (NHDFs, an inert population in models of ischemia), and CDCs transfected with a miR-146a antagomir. EVs were characterized according to established guidelines for size, morphology and protein expression. Monocytes were incubated with PBS, NHDF-EVs, CDC-EVs, or miR-146a deficient CDC-EVs and analyzed for CCR2 protein expression by flow cytometry and western blot and migration along a CCL2/MCP-1 gradient by in vitro chemotaxis assays. Results: CDC-EVs significantly reduced CD14 hi CD16 - monocyte surface expression of CCR2 by 50% as quantified by flow cytometry when compared with PBS and NHDF-EVs (p&lt;0.05, one-way ANOVA, n=4). This appeared to be mediated by miR-146a as monocytes treated with CDC-EVs deficient in miR-146a had no significant difference in CCR2 levels compared with cells treated with PBS and NHDF-EV controls. Importantly, reduced levels of monocyte CCR2 expression following CDC-EV treatment led to a greater than 35% functional reduction in monocyte migration towards CCL2 compared to PBS control (42.8 ± 3.2% vs. 68.3 ± 4.9%, p&lt;0.05, t-test, n=4). CCR2 expression remained suppressed for 8-12 hours and could be maintained with repeated doses. Conclusions: CDC-EVs modulate classical monocyte expression of CCR2 and migration towards CCL2/MCP-1 via miR-146a, elucidating a novel mechanism of CDC-EV immunomodulation.
A horizon scan of global biological conservation issues for 2022
Authors: William J. Sutherland, Philip W. Atkinson, Stuart H.M. Butchart, Marcela Capaja, Lynn V. Dicks, Erica Fleishman, Kevin J. Gaston, Rosemary S. Hails, Alice C. Hughes, Becky Le Anstey, Xavier Le Roux, Fiona A. Lickorish, Luke Maggs, Noor Noor, Thomasina E.E. Oldfield, James E. Palardy, Lloyd S. Peck, Nathalie Pettorelli, Jules Pretty, Mark D. Spalding, Femke H. Tonneijck, Gemma Truelove, James E.M. Watson, Jonathan Wentworth, Jeremy D. Wilson, Ann Thornton
Journal: Trends in Ecology & Evolution (2021)
An Unexplained Hyperphosphatemia in an Hispanic Woman , a Diagnosis Challenge
Authors: Jorge Cuervo sierra, Juan Esteban Arteaga Silva, Luis Eduardo Buitrago-Naranjo, William Castellanos-Olarte, Ruben amorocho-Perez, Eduardo Argote-Bravo, Juan Antonio Flores-Jimenez
Journal: Blood (2021)
Abstract P372: Serum From Pediatric Dilated Cardiomyopathy Patients Promotes Dysregulation Of Cardiolipin Biosynthesis And Mitochondrial Dysfunction In Primary Cardiomyocytes
Authors: Julie Pires da Silva, Anastacia M Garcia, Carissa A Miyano, Genevieve C Sparagna, Raleigh L Jonscher, Hanan B Elajaili, Carmen C Sucharov
Journal: Circulation Research (2021)

Pediatric dilated cardiomyopathy (DCM) is a devastating and poorly understood disease with most clinical treatment paradigms extrapolated from the adult population. Our studies have demonstrated that aspects of metabolism and mitochondrial function are dysregulated in pediatric DCM hearts. Cardiolipin (CL), a unique phospholipid in the inner mitochondrial membrane, is essential for optimal mitochondrial function and was shown to be dysregulated in both the failing adult and pediatric human heart. The objective of this study is to investigate if serum circulating factors from pediatric DCM patients can remodel CL resulting in mitochondrial dysfunction in vitro , similar to what is observed in the failing pediatric heart. Using a novel in vitro model that consists of treating neonatal rat ventricular myocytes (NRVMs) with serum from pediatric DCM patients or from non-failing (NF) healthy controls, mitochondrial respiration was assessed using the Agilent Seahorse, and reactive oxygen species (ROS) was assessed using Electron Paramagnetic Resonance Spectroscopy. Relative mitochondrial DNA (mtDNA) copy number was determined by qPCR and expression of enzymes involved in CL biosynthesis and remodeling were analyzed using RT-qPCR. Mass-spectrometry was used to quantitate total and specific CL species and to investigate the metabolite composition of NRVMs treated with NF or DCM serum. While mitochondrial ROS and mtDNA copy number were not significantly altered, we show that DCM serum decreases mitochondrial function, which is associated with alterations in CL content and composition and the downregulation of enzymes implicated in CL biosynthesis and remodeling. Analysis of metabolite content showed an alteration of pathways involved in fatty acid metabolism, mitochondrial biogenesis and regulation of β-oxidation by the transcription factor PPARα. In conclusion, pediatric DCM serum circulating factors can promote CL remodeling resulting mitochondrial dysfunction in primary cardiomyocytes. These findings suggest that CL could be a novel therapeutic target for this particular population.
Global estimates of viral suppression in children and adolescents and adults on antiretroviral therapy adjusted for missing viral load measurements: a multiregional, retrospective cohort study in 31 countries
Authors: Win Min Han, Matthew G Law, Matthias Egger, Kara Wools-Kaloustian, Richard Moore, Catherine McGowan, Nagalingesawaran Kumarasamy, Sophie Desmonde, Andrew Edmonds, Mary-Ann Davies, Constantin Yiannoutsos, Keri N Althoff, Claudia P Cortes, Thahira Jamal Mohamed, Antoine Jaquet, Kathryn Anastos, Jonathan Euvrard, Barbara Castelnuovo, Kate Salters, Lara Esteves Coelho, Didier K Ekouevi, Brian Eley, Lameck Diero, Elizabeth Zaniewski, Nathan Ford, Annette H Sohn, Azar Kariminia
Journal: The Lancet HIV (2021)
Prognostic Factors of Idiopathic Hypereosinophilic Syndrome: A Nationwide Survey in Japan
Authors: Akira Honda, Kazuhiro Toyama, Yu Oyama, Kensuke Matsuda, Hideaki Mizuno, Akiko M Saito, Yoshio Katayama, Norio Komatsu, Mineo Kurokawa
Journal: Blood (2021)
Abstract 12679: Clinical Applications and Comparison of the Oscar 2 and Spacelabs 90207 Ambulatory Blood Pressure Monitors (ABPMs) Using a Novel Dual Monitor Field Protocol
Authors: Vincent P Lombardi, Patrick C Reichhold, Jennifer L Cramer, Hannah P Harkness, Natalie J DeBell, Nicholas R Dietz, Donald L Pate
Journal: Circulation (2021)

Background: Our novel Dual Monitor Protocol and postural lab testing in 15 normotensives,15 hypertensives and 11 alcohol-dependents demonstrated that auscultatory ABPMs had problems assessing diastolic (DBP) and systolic pressures (SBP) with postural changes and misclassified up to 90% of DBPs and 20% of SBPs. Our lab studies of 11 normotensives and 4 hypertensives determined the oscillometric Oscar 2 and Spacelabs 90207 ABPMs overestimated SBP by ≥ 5 mm Hg for 87% (13/15) and 60% (9/15) of cases, respectively. GOAL . To apply our Dual Monitor Protocol in the field to compare values obtained by the Oscar 2 and Spacelabs 90207 ABPMs. Hypothesis: ABPMs will differ statistically and clinically depending upon the posture. Methods: A total of 9 field tests were conducted in 6 subjects either with 1 or 2 ABPMs. For dual monitor tests, ABPM clocks were synchronized and cuffs switched every 3 - 4 hr. Correction factors for each subject, specific to each ABPM and posture were used to adjust BPs from field tests. Results: All values = X ± SE, mm Hg . For 56 BPs over 24-hr in a normotensive, the Oscar overestimated observer-corrected SBPs by 8.7 ± 1.2 (135.5 ± 2.2 vs 126.8 ± 1.8, P &lt; 0.001). For 101 simultaneous opposite arm BPs over 24 hr in a 66-yr old hypertensive, the Oscar was statistically (all P &lt; 0.001) and clinically &gt; Spacelabs for SBP (156.8 ± 1.2 vs 144.3 ± 0.9, Δ = 12.5 ± 1.0), MAP (118.8 ± 0.9 vs 110.7 ± 0.8, Δ = 8.1 ± 0.6) and DBP (99.8 ± 0.9 vs 95.2 ± 0.8, Δ = 4.6 ± 0.7). The Oscar overestimated (all P ≤ 0.001) the Spacelabs supine SBP (11.0 ± 1.7) and DBP (6.0 ± 0.7), seated SBP (10.8 ± 1.2) and DBP (3.5 ± 0.9) and standing SBP 16.4 ± 2.1) and DBP (5.5 ± 1.5). R was weakest for supine SBP (0.19, NS) and standing SBP (0.38, P &lt; 0.05) and DBP (0.42, P &lt; 0.05). Conclusions: These results are alarming despite our limited number of subjects. Oscar and Spacelabs ABPMs differ clinically and statistically and unlike auscultatory ABPMs are prone to significant SBP overestimation. To avoid SBP hypertensive bias and to obtain a more accurate representation of 24-hr BPs, values must be corrected for ABPM and Hg column lab postural Δs and converted to the phlebostatic axis. ABPM accuracy and reliability cannot be trusted until National and International validation protocols are revised to require multiple postural testing.
Two microbiota subtypes identified in irritable bowel syndrome with distinct responses to the low FODMAP diet
Authors: Kevin Vervier, Stephen Moss, Nitin Kumar, Anne Adoum, Meg Barne, Hilary Browne, Arthur Kaser, Christopher J Kiely, B Anne Neville, Nina Powell, Tim Raine, Mark D Stares, Ana Zhu, Juan De La Revilla Negro, Trevor D Lawley, Miles Parkes
Journal: Gut (2021)

Reducing FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) can be clinically beneficial in IBS but the mechanism is incompletely understood. We aimed to detect microbial signatures that might predict response to the low FODMAP diet and assess whether microbiota compositional and functional shifts could provide insights into its mode of action.
Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors
Authors: François Doz, Cornelis M van Tilburg, Birgit Geoerger, Martin Højgaard, Ingrid Øra, Valentina Boni, Michael Capra, Julia Chisholm, Hyun Cheol Chung, Steven G DuBois, Soledad Gallego-Melcon, Nicolas U Gerber, Hiroaki Goto, Juneko E Grilley-Olson, Jordan R Hansford, David S Hong, Antoine Italiano, Hyoung Jin Kang, Karsten Nysom, Anne Thorwarth, Joanna Stefanowicz, Makoto Tahara, David S Ziegler, Igor T Gavrilovic, Ricarda Norenberg, Laura Dima, Esther De La Cuesta, Theodore W Laetsch, Alexander Drilon, Sebastien Perreault
Journal: Neuro-Oncology (2021)

Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors.Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR).As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified.In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.
Phase 1b/2 Study of Cirmtuzumab and Ibrutinib in Mantle Cell Lymphoma (MCL) or Chronic Lymphocytic Leukemia (CLL)
Authors: Hun Ju Lee, Michael Choi, Tanya Siddiqi, Jacqueline Barrientos, William G. Wierda, Iris Isufi, Joseph Tuscano, Nicole Lamanna, Suki Subbiah, Jean L. Koff, Lori A. Leslie, Alec Goldenberg, Gina G Chung, James B. Breitmeyer, Salim Yazji, Yao Wang, Michael Wang, Catriona Jamieson, Thomas J. Kipps
Journal: Blood (2021)
Abstract 12798: Somatic Mosaicism in Blood Cells is a Risk Factor for Incident Heart Failure in 200,628 UK Biobank Participants
Authors: Benjamin A Satterfield, Seyedmohammad Saadatagah, Ozan Dikilitas, Iftikhar J Kullo
Journal: Circulation (2021)

Introduction: Somatic mutations accrue in hematopoietic stem cells with age and can lead to selective clonal expansion, a process termed Clonal Hematopoiesis of Indeterminate Potential (CHIP). CHIP has been associated with increased risk of coronary heart disease (CHD) and myocardial infarction (MI). Whether CHIP is a risk factor for incident heart failure is unclear. Methods: The presence of CHIP was assessed in exome sequence data from 200,628 UKB participants using the Genome Analysis Toolkit pipeline and filtering somatic mutations from a pre-specified list within DNMT3A , TET2 , and ASXL1 . CHIP was defined as somatic mutations in these 3 genes with variant allele fraction (VAF) &gt;10%. We ascertained incident heart failure (overall, ischemic, and non-ischemic), death, cardiovascular death, and coronary heart disease (CHD defined as of MI and/or coronary revascularization) as determined by UKB algorithms, self-report, and diagnosis/procedure codes. Cox proportional hazard models adjusted for age, sex, self-reported race/ethnicity, diabetes, hypertension, smoking, and BMI were used to assess whether CHIP was associated with incident adverse events. Results: We identified 3,885 participants with CHIP in DNMT3A , TET2 , and ASXL1 at a VAF of &gt;10%. Over a median follow-up of 9 years, 2,055 participants developed incident heart failure. CHIP was associated with both ischemic and non-ischemic heart failure. We replicated previously reported associations of CHIP with death and incident CHD ( Table ). Conclusions: CHIP was associated with increased risk of both ischemic and non-ischemic heart failure. The association with ischemic subtype is likely mediated by the increased risk of CHD. The basis for the increased hazard of non-ischemic heart failure is unclear but may be due to an inflammatory milieu in CHIP carriers.
Characterization of Philadelphia-Negative Myeloproliferative Neoplasms By the Bone Marrow Immune Microenvironment
Authors: Sung-Eun Lee, Seowon Choi, Gi June Min, Sung-Soo Park, Silvia Park, Jae-Ho Yoon, Byung-Sik Cho, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Hee-Je Kim, Seok-Goo Cho, Jong Wook Lee
Journal: Blood (2021)
Abstract 13054: Longitudinal Strain-Derived Myocardial Work to Reflect the Systolic Performance of Athlete’s Heart
Authors: Marton Tokodi, Attila Oláh, Alexandra Fabian, Balint K Lakatos, István Hizoh, Mihály Ruppert, Alex A Sayour, Balint A Barta, Orsolya Kiss, Nóra Sydó, Emese Csulak, Zsuzsanna Ladanyi, Béla Merkely, Attila Kovacs, Tamás Radovits
Journal: Circulation (2021)

Introduction: In athletes, the exercise training-induced enhancement of myocardial contractility is challenging to be captured using conventional echocardiographic parameters due to their load-dependency. Hypothesis: As speckle-tracking echocardiography (STE)-derived myocardial work (MW) is considered to be less dependent on loading conditions than global longitudinal strain (GLS), we hypothesized that it reflects cardiac contractility more reliably, and thus, it represents a robust resting marker of the athlete's heart. Accordingly, we investigated whether MW can capture the supernormal LV systolic performance of swim-trained rats and elite human swimmers even during resting conditions. Methods: Sixteen rats underwent a 12-week swim training program and were compared to controls (n=16). STE was performed to assess GLS, which was followed by invasive pressure-volume (P-V) analysis to measure contractility (slope of end-systolic P-V relationship [ESPVR]). Global MW index (GMWI) was calculated from GLS curves and LV pressure recordings. In the human investigations, 20 elite swimmers and 20 healthy sedentary controls were enrolled. GMWI was calculated through the simultaneous evaluation of GLS and non-invasively approximated LV pressure curves at rest. All subjects underwent cardiopulmonary exercise testing to determine peak oxygen uptake (VO 2 /kg). Results: Exercised rats exhibited higher values of GLS, GMWI, and ESPVR than controls (-20.9±1.7 vs. -17.6±1.9 %, 2745±280 vs. 2119±272 mmHg·%, 3.72±0.72 vs. 2.61±0.40 mmHg/μL, all p&lt;0.001). Ordinary least squares modeling revealed that GLS was predominantly determined by sex and afterload, whereas the major determinants of GMWI were contractility and exercise. In humans, regular exercise training was associated with decreased GLS (-17.6±1.5 vs. -18.8±0.9 %, p=0.002) but increased GMWI at rest (1899±136 vs. 1755±234 mmHg·%, p=0.025). GMWI correlated positively with VO 2 /kg (r=0.53, p&lt;0.001). Conclusions: GMWI precisely reflected LV contractility in a rat model of exercise-induced LV hypertrophy and captured the supernormal systolic performance in human athletes even at rest. Our findings endorse the utilization of MW analysis in the evaluation of the athlete's heart.