tbuckley/cabot-search huggingface dataset:
Abstract 432: Loss of Primary Cilia PertErbBs Ventricular Maturation in the Developing Heart
Authors: Lindsey A Fitzsimons, Sergey V Ryzhov, Kerry L Tucker
Journal: Circulation Research (2020)

The embryonic heart requires cardiac neural crest cells (CNCC), which elaborate the sensory organelle called the primary cilium and assist in the development of the cardiac valves, the interventricular septum, and the outflow tract. Our laboratory has modeled congenital heart defects (CHD) resulting from CNCC-specific ciliary loss, using a Wnt1:Cre-2, Ift88 -targeted conditional elimination of primary cilia. Ift88 -homozygous mutants (MUT) displayed a variety of predicted CNCC-associated CHDs, but also revealed a novel disorganization of the ventricular endocardium, pronounced noncompaction of the ventricular myocardium, and perinatal lethality. Neuregulin-1 / ErbB signaling is a well-known key modulator of myocardial development as well as the compaction process of the ventricular myocardium. Flow cytometric analysis of embryonic day 12.5 (E12.5) whole hearts revealed that loss of cilia in CNCC of MUT hearts led to a 43% reduction in cardiomyocytes (CM), defined as VCAM-1-positive/CD31-negative cells (p&lt;0.01), and a trend towards increased CD31-positive endocardial cell (EC) populations (34% increase; p = 0.09) when compared to control (CON) hearts. Analysis of cell surface expression of ErbB receptors revealed a slight decrease in ErbB2 and ErbB4 expression in VCAM-1-positive CM of MUT with no change in ErbB3 expression, and decreased ErbB4 expression in MUT EC. Immunofluorescence analysis of proliferation was quantified in various cardiac subpopulations, including cardiac Troponin-T-positive (cTnT+/CM) cells in the ventricular myocardium. While overall cell density at E12.5 did not differ between the MUT and CON (p=0.43), CM proliferation increased significantly in MUT (5.50%) when compared to CON (2.70%; p&lt;0.01). Taken together, decreased ErbB4 expression in the expanding MUT EC population, combined with decreased CM numbers, could serve as a novel mechanistic explanation for the pronounced hypertrabeculation and noncompaction of the MUT phenotype seen at E14.5. Our results indicate that loss of CNCC primary cilia leads to ventricular noncompaction, with a shift in the relative proportion and dynamics of both CM and EC subpopulations, which is potentially attributable to impaired ErbB signaling of the developing endocardium.
Unexpected Novel Findings That Caspase-1-KO Mice Are Poor Mobilizers and Engraft Poorly with Wild Type Bone Marrow Cells - Indicating a Presence of an Autocrine Feedback Loop Involving Interleukin 1b and Interleukin 18 Signaling That Potentiates Nlrp3 Inflammasome Activity, Both in HSPCs and in the BM Microenvironment for Optimal Stem Cell Trafficking
Authors: Arjun Thapa, Janina Ratajczak, Magdalena Kucia, Mariusz Z Ratajczak
Journal: Blood (2020)
DNA-Based Methods for Measurable Residual Disease Detection in <i>NPM1</i>-Mutated Acute Myeloid Leukemia; Establishment of Cut-Offs for qPCR, Digital Droplet PCR and Targeted Deep Sequencing
Authors: Louise Pettersson, Sofie Johansson Alm, Alvar Almstedt, Vladimir Lazarevic, Gustav Orrsjö, Giti Shah-Barkhordar, Linda Fogelstrand, Mats Ehinger
Journal: Blood (2020)
Abstract 427: A Patient-Specific 3D Bioprinted Platform for <i>in vitro</i> Disease Modeling and Treatment Planning in Pulmonary Vein Stenosis
Authors: Vahid Serpooshan, Martin L Tomov, Akaash Kumar, Bowen Jing, Sai Raviteja Bhamidipati, Nicki Panoskaltsis, Reza Avaz, Tim C SLESNICK, Athanasios MANTALARIS, Brooks Lindsey, Holly Bauser-Heaton
Journal: Circulation Research (2020)

Pulmonary vein stenosis (PVS) is an acute pediatric cardiovascular disease that is always lethal if not treated early. While current clinical interventions (stenting and angioplasties) have shown promising results in treating PVS, they require multiple re-interventions that can lead to re-stenosis and diminished long-term efficacy. Thus, there is an unmet need to develop functional in vitro models of PVS that can serve as a platform to study clinical interventions. Patient-inspired 3D bioprinted tissue models provide a unique model to recapitulate and analyze the complex tissue microenvironment impacted by PVS. Here, we developed perfusable in vitro models of healthy and stenotic pulmonary vein by 3D reconstruction and bioprinting inspired by patient CT data ( Figure 1 ). Models were seeded with human endothelial (ECs) and smooth muscle cells (SMCs) to form a bilayer structure and perfused using a bioreactor to study cell response to stenotic geometry, and to the stent-based treatment. Flow hemodynamics through printed veins were quantified via Computational Fluid Dynamics (CFD) modeling, 4D MRI and 3D Ultrasound Particle Imaging Velocimetry (echo PIV). Cell growth and endothelialization were analyzed. Our work demonstrates the feasibility of bioprinting various cardiovascular cells, to create perfusable, patient-specific vascular constructs that mimic complex in vivo geometries. Deeper understanding of EC-SMC crosstalk mechanisms in in vitro biomimetic models that incorporate tissue-like geometrical, chemical, and biomechanical ques could offer substantial insights for prevention and treatment of PVS, as well as other cardiovascular disease.
Immunophenotypic Lineage Assessment By Multiparameter Flow Cytometry Provides More Precise MDS Prognosis
Authors: Ikenna Onyekwere, Julie Perilla Garcia, Kamal Menghrajani, Alexander Chan, Christopher Famulare, Minal A Patel, John Philip, Martin S. Tallman, Virginia M. Klimek, Ross L. Levine, Wenbin Xiao, Jacob L Glass
Journal: Blood (2020)
Dystrophin Gene-Editing Stability Is Dependent on Dystrophin Levels in Skeletal but Not Cardiac Muscles
Authors: Niclas E. Bengtsson, Hichem Tasfaout, Stephen D. Hauschka, Jeffrey S. Chamberlain
Journal: Molecular Therapy (2020)

Gene editing is often touted as a permanent method for correcting mutations, but its long-term benefits in Duchenne muscular dystrophy (DMD) may depend on sufficiently high editing efficiencies to halt muscle degeneration. Here, we explored the persistence of dystrophin expression following recombinant adeno-associated virus serotype 6 (rAAV6):CRISPR-Cas9-mediated multi-exon deletion/reframing in systemically injected 2- and 11-week-old dystrophic mice and show that induction of low dystrophin levels persists for several months in cardiomyocytes but not in skeletal muscles, where myofibers remain susceptible to necrosis and regeneration. Whereas gene-correction efficiency in both muscle types was enhanced with increased ratios of guide RNA (gRNA)-to-nuclease vectors, obtaining high dystrophin levels in skeletal muscles via multi-exon deletion remained challenging. In contrast, when AAV-microdystrophin was codelivered with editing components, long-term gene-edited dystrophins persisted in both muscle types. These results suggest that the high rate of necrosis and regeneration in skeletal muscles, compared with the relative stability of dystrophic cardiomyocytes, caused the rapid loss of edited genomes. Consequently, stable dystrophin expression in DMD skeletal muscles will require either highly efficient gene editing or the use of cotreatments that decrease skeletal muscle degeneration. Gene editing is often touted as a permanent method for correcting mutations, but its long-term benefits in Duchenne muscular dystrophy (DMD) may depend on sufficiently high editing efficiencies to halt muscle degeneration. Here, we explored the persistence of dystrophin expression following recombinant adeno-associated virus serotype 6 (rAAV6):CRISPR-Cas9-mediated multi-exon deletion/reframing in systemically injected 2- and 11-week-old dystrophic mice and show that induction of low dystrophin levels persists for several months in cardiomyocytes but not in skeletal muscles, where myofibers remain susceptible to necrosis and regeneration. Whereas gene-correction efficiency in both muscle types was enhanced with increased ratios of guide RNA (gRNA)-to-nuclease vectors, obtaining high dystrophin levels in skeletal muscles via multi-exon deletion remained challenging. In contrast, when AAV-microdystrophin was codelivered with editing components, long-term gene-edited dystrophins persisted in both muscle types. These results suggest that the high rate of necrosis and regeneration in skeletal muscles, compared with the relative stability of dystrophic cardiomyocytes, caused the rapid loss of edited genomes. Consequently, stable dystrophin expression in DMD skeletal muscles will require either highly efficient gene editing or the use of cotreatments that decrease skeletal muscle degeneration.
Clinical Characteristics and Outcomes of Patients with Large Granular Lymphocytic Leukemia Treated with Methotrexate, Cyclophosphamide or Cyclosporine. a Large Single Institutional Retrospective Analysis
Authors: Ankita Tandon, Ning Dong, Yumeng Zhang, Emilie Wang, Todd C. Knepper, Haipeng Shao, Ling Zhang, Leidy Isenalumhe, Rami Komrokji, Lubomir Sokol
Journal: Blood (2020)
Changes of Hepatitis B Immune Status after Allogeneic Hematopoietic Stem Cell Transplantation in HBsAg Negative/Anti-Hbc Positive Patients: A Single Center Observational Study
Authors: Jinhua Ren, Dabing Chen, Rong Zheng, Yu Zhang, Jingjing Xu, Xiaofeng Luo, Zhihong Zheng, Zhizhe Chen, Jianda Hu, Ting Yang
Journal: Blood (2020)
Abstract MP115: Transcriptional Patterning of the Ventricular Cardiac Conduction System
Authors: Ozanna Burnicka-Turek, Michael Broman, Jeffrey D Steimle, Bastiaan Boukens, Nataliya B Petrenko, Kohta Ikegami, Xinan H Yang, Marcelo A Nobrega, Michael J Rust, Vickas V Patel, Igor Efimov, Ivan P Moskowitz
Journal: Circulation Research (2020)

The heart beats 2 billion times over the average human lifespan and is the manifestation of a pattern of cardiomyocyte depolarization organized by a specialized network of cardiomyocytes, the cardiac conduction system (CCS). Patterning of the CCS into atrial node versus ventricular conduction system (VCS) components with distinct physiology is essential for the normal heartbeat and has been recognized for more than a century. However molecular basis of this regional patterning is not well understood. Using mouse genetics, we found that the ratio between T-box transcriptional activator, Tbx5 , and T-box transcriptional repressor, Tbx3 , determines the molecular and functional output of VCS myocytes. Adult VCS-specific removal of Tbx5 or overexpression of Tbx3 re-patterned the fast VCS into slow, nodal-like cells based on molecular, cellular and functional criteria. Specifically, the ventricular fast conduction gene expression network was lost whereas the slow conduction nodal gene expression network was retained. Action potentials (APs) of Tbx5 -deficient VCS myocytes adopted nodal-specific characteristics, including increased AP duration and cellular automaticity. Removal of Tbx5 in-vivo precipitated inappropriate depolarizations in the His-bundle that initiated lethal ventricular arrhythmias. A T-box rheostat mechanism for CCS patterning was confirmed by Tbx5/Tbx3 genetic interaction studies. TBX5 bound and directly activated cis -regulatory elements at fast conduction loci genome-wide, defining the identity of the adult VCS. Furthermore, TBX5 bound and activated cis-regulatory elements at Tbx5 itself, describing a multi-tiered T-box-dependent fast conduction gene regulatory network (GRN). The hierarchical GRN established a bi-stable network in mathematical modeling, with only high or low fast conduction gene expression states, suggesting a genomic mechanism for the establishment of VCS versus nodal states in-vivo . Thus, the CCS is patterned entirely as a slow, nodal ground state, with a T-box dependent, physiologically dominant, fast conduction network driven specifically in the VCS. Disruption of the fast VCS GRN allowed nodal physiology to emerge, providing a molecular mechanism for some lethal ventricular arrhythmias.
Prognostication, Survival and Treatment-Related Outcomes in HIV-Associated Burkitt Lymphoma (HIV-BL): A US and UK Collaborative Analysis
Authors: Juan Pablo Alderuccio, Adam J Olszewski, Andrew M. Evens, Graham P. Collins, Alexey Danilov, Mark Bower, Deepa Jagadeesh, Catherine Zhu, Amy Sperling, Seo-Hyun Kim, Ryan Vaca, Catherine Wei, Suchitra Sundaram, Nishitha Reddy, Alessia Dalla Pria, Christopher D'Angelo, Umar Farooq, David A. Bond, Stephanie Berg, Michael C. Churnetski, Amandeep Godara, Nadia Khan, Yun Kyong Choi, Shireen Kassam, Maryam Sarraf Yazdy, Emma Rabinovich, Frank Post, Gaurav Varma, Reem Karmali, Madelyn Burkart, Peter Martin, Albert Ren, Ayushi Chauhan, Catherine Diefenbach, Allandria Straker-Edwards, Andreas Klein, Kristie A. Blum, Kirsten M Boughan, Agrima Mian, Bradley Haverkos, Victor M. Orellana-Noia, Vaishalee P. Kenkre, Adam Zayac, Seth M Maliske, Narendranath Epperla, Paolo F Caimi, Scott E. Smith, Manali Kamdar, Parameswaran Venugopal, Tatyana A. Feldman, Daniel Rector, Stephen D. Smith, Andrzej Stadnik, Craig A. Portell, Yong Lin, Seema Naik, Silvia Montoto, Izidore S. Lossos, Kate Cwynarski
Journal: Blood (2020)
Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020)
Authors: Liling Huang, Shiyu Jiang, Yuankai Shi
Journal: Journal of Hematology & Oncology (2020)

Abstract Tyrosine kinases are implicated in tumorigenesis and progression, and have emerged as major targets for drug discovery. Tyrosine kinase inhibitors (TKIs) inhibit corresponding kinases from phosphorylating tyrosine residues of their substrates and then block the activation of downstream signaling pathways. Over the past 20 years, multiple robust and well-tolerated TKIs with single or multiple targets including EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT have been developed, contributing to the realization of precision cancer medicine based on individual patient’s genetic alteration features. TKIs have dramatically improved patients’ survival and quality of life, and shifted treatment paradigm of various solid tumors. In this article, we summarized the developing history of TKIs for treatment of solid tumors, aiming to provide up-to-date evidence for clinical decision-making and insight for future studies.
Levels of Osteopontin (<i>SPP1</i>), Osteonectin (<i>SPARC</i>) and Biglycan (<i>BGN</i>) in Acute Myeloid Leukemia Bone Marrow Biopsies Post-Induction Therapy Define the Status of Osteogenic Niche and Show Inverse Correlation with Therapeutic Response
Authors: Diana O Treaba, Dennis M Bonal, Anna D Chorzalska, Christoph Schorl, Kelsey Hopkins, John L Reagan, Peter Rintels, Peter J Quesenberry, Patrycja M Dubielecka
Journal: Blood (2020)
Theta-burst transcranial magnetic stimulation promotes stroke recovery by vascular protection and neovascularization
Authors: Xuemei Zong, Yuyu Li, Cui Liu, Wenxuan Qi, Dong Han, Lorelei Tucker, Yan Dong, Shuqun Hu, Xianliang Yan, Quanguang Zhang
Journal: Theranostics (2020)

Rationale: The integrity and function of the blood-brain barrier (BBB) is compromised after stroke. The current study was performed to examine potential beneficial effects and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) on angiogenesis and vascular protection, function, and repair following stroke, which are largely unknown. Methods: Using a rat photothrombotic (PT) stroke model, continuous theta-burst rTMS was administered once daily to the infarcted hemisphere for 5 min, beginning 3 h after PT stroke. This treatment was applied for 6 days. BBB integrity, blood flow, vascular associated proteins, angiogenesis, integrity of neuronal morphology and structure, and behavioral outcome were measured and analyzed at 6 and/or 22 days after PT stroke. Results: We report that rTMS significantly mitigated BBB permeabilization and preserved important BBB components ZO-1, claudin-5, occludin, and caveolin-1 from PT-induced degradation. Damage to vascular structure, morphology, and perfusion was ameliorated by rTMS, resulting in improved local tissue oxygenation. This was accompanied with robust protection of critical vascular components and upregulation of regulatory factors. A complex cytokine response was induced by PT, particularly at the late phase. Application of rTMS modulated this response, ameliorating levels of cytokines related to peripheral immune cell infiltration. Further investigation revealed that rTMS promoted and sustained post-ischemic angiogenesis long-term and reduced apoptosis of newborn and existing vascular endothelial cells. Application of rTMS also inhibited PT-induced excessive astrocyte-vasculature interactions and stimulated an A1 to A2 shift in vessel-associated astrocytes. Mechanistic studies revealed that rTMS dramatically increased levels of PDGFRβ associated with A2 astrocytes and their adjacent vasculature. As well, A2 astrocytes displayed marked amplification of the angiogenesis-related factors VEGF and TGFβ. PT induced a rise in vessel-associated expression of HIF-1α that was starkly intensified by rTMS treatment. Finally, rTMS preserved neuronal morphology, synaptic structure integrity and behavioral outcome. Conclusions: These results indicate that rTMS can exert powerful protective and restorative effects on the peri-infarct microvasculature after PT stroke by, in part, promoting HIF-1α signaling and shifting vessel-associated astrocytic polarization to the A2 phenotype. This study provides further support for the potent protective effects of rTMS in the context of ischemic stroke, and these findings implicate vascular repair and protection as an important underlying phenomenon.
Everolimus Plus Itacitinib in Relapsed/Refractory Classical Hodgkin Lymphoma: Results of a Phase I/II Investigator Initiated Trial (EVITA Study)
Authors: Jakub Svoboda, Stefan K. Barta, Daniel J. Landsburg, Sunita Dwivedy Nasta, Wei-Ting Hwang, Grace Delp, Brittany Amundsen, Hatcher J. Ballard, James N. Gerson, Elise A. Chong, Mitchell E. Hughes, Steven A. Emanuel, Marco Ruella, Stephen J. Schuster
Journal: Blood (2020)
Effects of a Tailored Text Messaging Intervention Among Diverse Adults With Type 2 Diabetes: Evidence From the 15-Month REACH Randomized Controlled Trial
Authors: Lyndsay A. Nelson, Robert A. Greevy, Andrew Spieker, Kenneth A. Wallston, Tom A. Elasy, Sunil Kripalani, Chad Gentry, Erin M. Bergner, Lauren M. LeStourgeon, Sarah E. Williamson, Lindsay S. Mayberry
Journal: Diabetes Care (2020)

OBJECTIVE Text messaging interventions have high potential for scalability and for reductions in health disparities. However, more rigorous, long-term trials are needed. We examined the long-term efficacy and mechanisms of a tailored text messaging intervention. RESEARCH DESIGN AND METHODS Adults with type 2 diabetes participated in a parallel-groups, 15-month randomized controlled trial and were assigned to receive Rapid Education/Encouragement and Communications for Health (REACH) for 12 months or control. REACH included interactive texts and tailored texts addressing medication adherence and nontailored texts supporting other self-care behaviors. Outcomes included hemoglobin A1c (HbA1c), diabetes medication adherence, self-care, and self-efficacy. RESULTS Participants (N = 506) were approximately half racial/ethnic minorities, and half were underinsured, had annual household incomes &amp;lt;$35,000, and had a high school education or less; 11% were homeless. Average baseline HbA1c was 8.6% ± 1.8%; 70.0 ± 19.7 mmol/mol) with n = 219 having HbA1c ≥8.5% (69 mmol/mol). Half were prescribed insulin. Retention was over 90%. Median response rate to interactive texts was 91% (interquartile range 75%, 97%). The treatment effect on HbA1c at 6 months (−0.31%; 95% CI −0.61%, −0.02%) was greater among those with baseline HbA1c ≥8.5% (−0.74%; 95% CI −1.26%, −0.23%), and there was no evidence of effect modification by race/ethnicity or socioeconomic disadvantage. REACH improved medication adherence and diet through 12 months and self-efficacy through 6 months. Treatment effects were not significant for any outcome at 15 months. REACH reduced barriers to adherence, but barrier reduction did not mediate outcome improvements. CONCLUSIONS REACH engaged at-risk patients in diabetes self-management and improved short-term HbA1c. More than texts alone may be needed to sustain the effects.
MHC-I Antigen Presentation Role in Immune Escape of Acute Myeloid Leukemia with High Burden of Genomic Aberration
Authors: Giovanni Marconi, Maria Chiara Fontana, Eugenio Fonzi, Cristina Papayannidis, Mariachiara Abbenante, Emanuela Ottaviani, Nicoletta Testoni, Giorgia Simonetti, Antonella Padella, Chiara Sartor, Carmen Baldazzi, Nanni Jacopo, Luca Bertamini, Andrea Ghelli Luserna Di Rorà, Valentina Robustelli, Martina Pazzaglia, Elena Tenti, Sarah Parisi, Giovanni Martinelli
Journal: Blood (2017)
Nicotinamide Phosphoribosyltransferase Inhibitors Induce Apoptosis of AML Stem Cells through Dysregulation of Lipid Metabolism
Authors: Amit Subedi, Qiang Liu, David Sharon, Severine Cathelin, Gary D Bader, Changjiang Xu, Veronique Voisin, Angelo D'Alessandro, Eric R Lechman, John E. Dick, Mark D. Minden, Jean C.Y. Wang, Steven M Chan
Journal: Blood (2020)
Preclinical and Translational Data Support Development of Iberdomide in Combination with CD38- and SLAMF7-Directed Monoclonal Antibodies: Evidence for Rational Combinations
Authors: Michael Amatangelo, Chad Bjorklund, Peilin Ma, Krista Wollerman, William Pierceall, Sagar Lonial, Niels W.C.J. van de Donk, Rakesh Popat, Sundar Jagannath, Jeffrey Zonder, Monique C. Minnema, Albert Oriol, Jeremy Larsen, Ashraf Z. Badros, Paula Rodriguez-Otero, Pieter Sonneveld, Tuong Vi Nguyen, Kevin Hong, April Sorrell, Anjan Thakurta
Journal: Blood (2020)
Abstract MP145: Potential Functions of the Nuclear Basket Associated With Dilated Cardiomyopathy
Authors: Claudia C Preston, Ryan D Burdine, Emily C Storm, Claudia S Preston
Journal: Circulation Research (2020)

Objectives: NUP153 overexpression is clinically correlated with cardiomyopathies, specifically dilated cardiomyopathy (DCM). In combination with the nuclear pore complex (NPC) proteins TPR and NUP50, all three form the basket structure of the NPC that sits within the nuclear envelope. The nuclear basket regulates chromatin dynamics and nuclear export, yet its potential role in cardiopathological development and progression remains unknown. This study was thus carried out to elucidate possible functional roles for nuclear basket nucleoporins in cardiac biology. Methods: Human induced pluripotent stem cells (hiPSCs) with endogenous mEGFP tagged NUP153 were differentiated into cardiomyocytes (hiPSC-CMs) via direct differentiation. Beating started ~ Day 10 and contractile areas were analyzed for contraction velocity and magnitude. NUP153 mobility in hiPSCs and hiPSC-CMs was determined by iFRAP experiments. Bioinformatic analysis of a clinical dilated cardiomyopathy dataset (GSE29819) returned a focused ‘nuclear envelope’ gene list that was uploaded to Ingenuity Pathways Analysis for network analysis. Results: Within hiPSC-CM beating foci (A), NUP153 mobility decreased and went from a biphasic to a monophasic decay curve (B). Bioinformatic analysis of a DCM dataset (C) revealed expression changes in TPR and NUP50 , with no significant changes in NUP153 (D). Conclusions: A switch to monophasic decay kinetics of NUP153 in hiPSC-CMs suggests prioritization of stable slow pools that may reflect changes in global transcriptome regulation. In DCM, differential nucleoporin gene expression changes implicate discrete functional disruptions within the nuclear basket.
Acalabrutinib Plus RICE Followed By Autologous Hematopoietic Cell Transplantation and/or Acalabrutinib Maintenance Therapy for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Neil Bailey, Tenzin Tsomo, Jennie Szeto, William I Bensinger, Daniel Egan, Livia Hegerova, Raya Mawad, Ami Batchelder, Joanna Fesler, Heather Holdread, Sonia Glennie, Judson Hall, Joey Ferry, Megumi Bailey, David Kane, John M. Pagel, Krish Patel
Journal: Blood (2020)