tbuckley/cabot-search huggingface dataset:
Abstract 142: New Approach for Directly Reprogrammed Endothelial Cells
Authors: Sangho Lee, Dandan Chen, Young-sup Yoon
Journal: Circulation Research (2019)

Rationale: For therapeutic neovascularization through cell therapy to treat cardiovascular diseases, recently, we successfully generated reprogrammed ECs, directly from human dermal fibroblasts (HDF) with the ETV2 transcription factor. Although functional ECs were generated, ETV2 was delivered lentiviral vector, which is clinically unsuitable. Objective: In this study, we aimed to generate clinically compatible rECs, by employing an adenoviral vector to minimize genetic integration. Furthermore, to prolong the cell retention and improve cell survival, we applied synthetic biomaterial, polypeptide amphiphile (PA) nanomatrix gel and tested for experimental cell therapy in animal models. Methods and Results: After we transduced HDFs with Ad- ETV2 (Ad- ETV2 -HDF), EC gene expression was measured by qRT-PCR and flow cytometry. We found that Ad- ETV2- HDFs displayed a cobblestone-like morphology and showed notable induction of EC genes (CDH5, KDR, PECAM1). Flow cytometry analysis showed peak expression of CDH5 and KDR at D6 and continuous increase of PECAM1 over 9 days. Also, Ad- ETV2 -HDFs took up acetylated LDL and bound lectin, suggesting that these cells possess functional EC characteristics. To enrich cells showing EC characters, Ad- ETV 2-HDFs were sorted for KDR by FACS at day 6. qRT-PCR showed substantial enrichment of EC-specific gene expression in KDR + cells. Only KDR + cells (reprogrammed ECs, rECs) formed tube-like structures on Matrigel. In addition, immunostaining confirmed high expression of EC marker proteins in rECs. Next, we tested the functionality of rECs in hindlimb ischemia mouse model. At 4 weeks after injection of 4 x 10 5 rECs into the ischemic hindlimb, we observed rECs incorporated into host blood vessels or resided perivascular regions. Furthermore, we found more rECs in the tissues and were directly incorporated into the vessels when they were encapsulated in PA nanomatrix gel compared to bare rEC-injected mice. Conclusions: Together, these data strongly support the generation of Ad- ETV2 -induced rECs (Ad-rECs) and enhanced retention of rECs by PA nanomatrix gel in tissue. With this study, we can develop advanced concept and techniques for clinical application of rECs and establish a new platform for future cell therapy.
Generation and infusion of multi-antigen-specific T cells to prevent complications early after T-cell depleted allogeneic stem cell transplantation—a phase I/II study
Authors: Marthe C. J. Roex, Peter van Balen, Lothar Germeroth, Lois Hageman, Esther van Egmond, Sabrina A. J. Veld, Conny Hoogstraten, Ellis van Liempt, Jaap J. Zwaginga, Liesbeth C. de Wreede, Pauline Meij, Ann C. T. M. Vossen, Sophia Danhof, Hermann Einsele, M. Ron Schaafsma, Hendrik Veelken, Constantijn J. M. Halkes, Inge Jedema, J. H. Frederik Falkenburg
Journal: Leukemia (2019)
Abstract 258: Elucidating Sex Differences in Stress-related Atrial Remodeling and AF Risk in a Mouse Model of Atrial Dysfunction
Authors: Kamila M Bledzka, Iyad H Manaserh, Walter J Koch, Jessica Grondolsky, Sarah M Schumacher
Journal: Circulation Research (2019)

Atrial fibrillation (AF) is the most common arrhythmia and a major risk factor for cardiovascular mortality and stroke. Despite significant advances in AF diagnosis and management, major gender discrepancies in treatment and clinical outcomes remain. It is unclear if these are related to treatment disparities or to underlying differences in the structure and biochemical makeup of the female versus male heart. How lifestyle, diet, comorbidities and risk factors contribute to this clinical dimorphism are not well understood. My laboratory has recently developed a double-transgenic mouse line that recapitulates this gender dimorphism. These mice were generated by crossing lines with cardiac expression of an amino and carboxyl terminal fragment, βARKnt (residues 50-145) and βARKct (residues 495-689), of the prototypical G protein-coupled receptor (GPCR) kinase GRK2 (originally βARK1). This line was created to investigate the therapeutic potential of dual regulation of β-adrenergic receptor signaling independent of canonical GRK2 activity. Since preliminary data demonstrate atrial dysfunction in both genders, but structural remodeling in females only, this model presents a unique tool to investigate sex differences in the molecular and cellular mechanisms of atrial remodeling. Masson’s trichrome staining of 4-chamber paraffin sections demonstrated an increase in wall thickness in the βARKnt and βARKnt/βARKct mice in agreement with the increased heart weight. Interestingly, these data revealed a significant increase in left and right atrial size in the double transgenic female hearts only, with no apparent alteration in the male atria. Preliminary echo recordings demonstrated significant alterations in E/A ratio (ventricular relaxation/atrial contraction) in the βARKnt and even more pronounced in the βARKnt/βARKct male and female mice. These data suggest that although no remodeling is evident at baseline, the male βARKnt/βARKct mice have underlying atrial dysfunction that may be more susceptible to additional cardiovascular stress. A better understanding of gender differences in the underlying mechanisms of atrial susceptibility may facilitate the development of safer and more effective approaches for AF management and prevention.
Abstract 298: Downregulation of Delta and Kappa Opioid Receptors in Post-heart Transplantation in Human and Rats
Authors: Mebratu A Gebrie, Alessio Rungatscher, Daniele Linardi, Anna Andrioli, Sajeela Ahmed, Naseer Ahmed, Mahmoud Ismail, Alberto Forni, Maddalena Tessari, Livio San Biagio, Alessandro Soave, Elizabetta Milani, Giulio Innamorati, Giovanni B Luciani, Giuseppe Faggian
Journal: Circulation Research (2019)

Over the past decade, multiple data regarding local opioid regulation of heart function have been demonstrated. However, opioid receptors (ORs) have not yet characterized in post-heart transplantation. Since a transplanted heart is devoid of innervations and autonomic innervations modulate ORs, we assessed the hypothesis that a possible down-regulation of k-OR and δ-OR in heart transplants. Endomyocardial biopsies were collected in 15 male patients at 30 days of orthotopic heart transplantation and in 15 control male patients during aortic valve surgery in human. Another study performed in 20 heterotopic heart transplants (HHT) and 20 naïve hearts of Sprague-Dawley male rats. The mRNA transcript encoding the Oprd1 and Oprk1, KOR and DOR proteins, distribution, and cellular localization were identified using RT-qPCR, Western blot, IHC, and IF, respectively. Transcripts of mRNA encoding the Oprd1 and Oprk1 were detected in hearts of human and rats. Expression of Oprd1 (p=0.036) and Oprk1 (p = 0.004) was significantly reduced in transplanted hearts. In Western blot analysis, KOR and DOR levels of expression were significantly lowered (p=0.03, KOR; p=0.01, DOR) in HHT compared to naïve hearts in rats. Immunohistochemistry analysis demonstrated a lighter labeling on the distribution of DOR and KOR in heart transplants` tissue in both rats and human. In both species, dual labeling myocardial isoforms (KOR and DOR) co-localized in cardiomyocytes of transplant and control hearts. These findings suggest that the down-regulation of DOR and KOR receptors in hearts transplant of both human and rats might have a possible increased susceptibility to ischemia-reperfusion injury.
Aceruloplasminemia and Paroxysmal Nocturnal Hemoglobinuria Uncover Differential Expressions of Ceruloplasmin and Ferroportin in Immune Cells
Authors: Marina Borges, Marina Dal'Bó Pelegrini Campioni, Dulcinéia Martins de Albuquerque, Carolina Lanaro, Fernando F. Costa, Kleber Yotsumoto Fertrin
Journal: Blood (2018)
Combined immunodeficiency caused by a loss-of-function mutation in DNA polymerase delta 1
Authors: Ye Cui, Sevgi Keles, Louis-Marie Charbonnier, Amélie M. Julé, Lauren Henderson, Seyma Celikbilek Celik, Ismail Reisli, Chen Shen, Wen Jun Xie, Klaus Schmitz-Abe, Hao Wu, Talal A. Chatila
Journal: Journal of Allergy and Clinical Immunology (2019)
A Potential Mechanism for the Antioxidant Compound Kushen Injection Targeting the ROS Signaling Pathway in Acute Myeloid Leukemia
Authors: Yanxia Jin, Qian Yang, Li Liang, Lu Ding, Yuxing Liang, Dongdong Zhang, Tian Yang, Mingfeng Zhao, Fuling Zhou
Journal: Blood (2018)
Abstract 241: Pharmacological Evaluation of Novel Anti-thrombospondin-1 Decoy Strategy for Prophylaxis of Atrial Fibrillation-associated Ischemic Stroke
Authors: Tamer Elbayoumi, Jalicia Sturdivant, Samayita Ganguly, Mingyi Yao
Journal: Circulation Research (2019)

Hemostatic abnormalities mainly decreased blood flow and increased stasis, and platelet hyper-aggregation increase thrombotic risk subsequent atrial fibrillation (AF) episodes. Excess elevation of extracellular glycoprotein thrombospondin 1 (TSP1) in circulation has emerged to predict prognosis of ischemic stroke. Moreover, TSP1 is found strongly associated with platelet hyper-aggregability and impaired nitric oxide response, through its cognate receptor CD47, thus exacerbating ischemic progression in AF patients. TSP1 arises as a prospective target of our candidate medicine. Our work provides “proof-of-concept” of a novel pharmacological strategy, relying on soluble recombinant human CD47 peptide (rh-CD47p) to serve as a decoy receptor to specifically bind TSP1, and consequently neutralize TSP1-impaired vasorelaxation. Our pilot studies were initially conducted with isolated mouse thoracic aorta. A pre-treatment with rh-CD47p (added 15 min prior to TSP1 incubation) showed a significant amelioration of TSP1-impaired endothelium-dependent vasodilation ( p &lt;0.0001, rh-CD47p+TSP1 vs. TSP1, n=6), indicating a prophylactic effect by rh-CD47p against vasoconstriction enhanced by excess TSP1. A post-treatment set-up, where TSP1 incubation was started 15 min prior to rh-CD47p addition to mimic pre-existing high level of TSP1 in ischemic stroke, exhibited a marked reversal of TSP1-inhibited vasodilation back to the same level as controls ( p &lt;0.0001, rh-CD47p+TSP1 vs. TSP1, n=4). Dose titration of rh-CD47p in molar ratios to TSP1 in both set-ups identified the dose range of rh-CD47p for prevention/recovery from TSP1-induced vascular dysfunction. Binding of rh-CD47p and TSP1 was first verified as the primary mechanism via Western Blot, and further quantified with a modified ELISA assay. A linear correlation was found between % of rh-CD47p bound to TSP1 and dose of rh-CD47p added (r 2 =0.8). Current results established the ground of rh-CD47p as a unique pharmacologic moiety for drug development to limit vasoconstriction and improve vasodilation against TSP1 in excess, thus showing great potential for proposed novel decoy CD47-coated formulation to abrogate/mitigate TSP1-associated cardiovascular complications in AF patients.
Interlaboratory Precision in the Monitoring of Unfractionated Heparin Using the Anti-Factor Xa-Correlated Activated Partial Thromboplastin Time
Authors: Adam Cuker, Beverly Ptashkin, Barbara A. Konkle, Steven W. Pipe, Herbert C. Whinna, X. Long Zheng, Douglas B. Cines, Eleanor Pollak
Journal: Blood (2008)
Abstract 256: Cardiac Fibroblast-derived Exosomes Mediate Endothelial Dysfunction and Heart Failure
Authors: Prabhat Ranjan, Rajesh Kumari, Prasanna Krishnamurthy, Raj Kishore, Suresh K Verma
Journal: Circulation Research (2019)

Objective: Endothelial cells (ECs) play critical role to maintain the normal heart function. Others and we have previously shown that stress-induced chronic inflammation mediates ECs dysfunction and restoration of IL10 (an anti-inflammatory cytokine) preserve ECs function, but, its mechanism is not clearly known. Here we hypothesized that activated cardiac fibroblasts-derived exosomes (FB-Exo) mediates cardiac ECs dysfunction and leads for cardiac pathology and IL10 treatment negatively regulates the FB-Exo contents and thus improve ECs function and biology. Methods: Human aortic endothelial cells (HAECs), human umbilical endothelial cells (HUVEC) and cardiac endothelial cells were cultured in EC growth media. Cells were treated with TGFβ/IL10/FB-exo. Exosomes were isolated from fibroblast condition media by ultracentrifugation and characterized by nanosight &amp; electron microscopy. Results: TGFβ treatment significantly induced ECs dysfunction as shown by Matrigel assay, real-time Q-PCR and immunostaining data. IL10 treatment significantly restored TGFβ-induced endothelial dysfunction as evident by immunostaining and western blot (CD31, Smad2/3 and αSMA) data. Furthermore, exosomes were isolated from saline/AngII treated neonatal heart fibroblast conditioned media by ultracentrifugation and characterized. We found that exosomes-derived from Ang II/TGF treated fibroblast were enriched with TGFβ and collagen-1α. Matrigel tube formation and quantitative PCR results suggest that activated fibroblasts secrete factors which triggered endothelial dysfunction (Matrigel/qPCR). Intriguingly, Ang II treated fibroblast-derived exosomes strongly promote endothelial cell differentiation to fibroblasts like cells. Conclusions: Taken together, this study demonstrates that Ang II/TGFb treated fibroblasts-derived exosomes are enriched in pro-fibrotic factors and can lead to endothelial dysfunction and promotes cardiac fibrosis in PO myocardium. Ongoing investigations using molecular approaches will provide a better understanding on the mechanistic and therapeutic aspects of IL10 and modification of fibroblast-derived exosomal content on endothelial function and cardiac fibrosis failing heart.
T-Cell Depleted (TCD) Hematopoietic Stem Cell Transplantation (HCT) For Adult Patients With Acute Myelogenous Leukemia (AML) In First and Second Remission: Long-Term Disease Free Survival(DFS) With a Significantly Reduced Risk Of Graft-Versus-Host Disease(GvHD)
Authors: Izaskun Ceberio, Patrick Hilden, Sean M. Devlin, Molly Maloy, Jenna D Goldberg, Miguel A Perales, Juliet N Barker, Hugo Castro-Malaspina, Guenther Koehne, Doris M Ponce, Craig S. Sauter, Marcel R.M. van den Brink, James W. Young, Richard J. O'Reilly, Sergio Giralt, Ann A. Jakubowski, Esperanza B Papadopoulos
Journal: Blood (2013)
The cancer care network clinical trials program: Rising from the camp fire ashes.
Authors: Ofilio Ramon Vigil, Dana Ann Little, Kristin J. Mensonides, Richard J. Bold
Journal: Journal of Clinical Oncology (2019)

168 Background: The UC Davis Health Cancer Care Network (CCN) in Sacramento improves quality through partnerships with community cancer centers and the UC Davis Comprehensive Cancer Center (UCDCCC). The UCDCCC, as an NCI Lead Academic Participating Site (LAPS) grant recipient, lists Adventist Health Rideout Cancer Center (RCC) in Marysville (42 miles north of Sacramento) as a component. The Adventist Health Feather River Cancer Center (FRCC) and the town of Paradise were devastated by the 2018 Camp Fire, forcing FRCC’s relocation to the city of Chico (49 miles north of Marysville). FRCC was forced to disband its local IRB and unable to continue clinical trials research operations during the aftermath of this natural disaster. The CCN established an affiliation with the FRCC in April 2019. Future plans include establishing an IRB agreement and adding FRCC as a LAPS component. The CCN identified strategies to facilitate the participation of FRCC patients in clinical trials. Methods: The CCN identified 13 NCTN clinical trials with 34 enrolled patients that were in need of appropriate research oversight. Four of these trials were previously never activated at the UCDCCC or its affiliates. CCN staff engaged leaders at the various institutions involved: Quality Assurance (QA) Managers at each NCTN research base, the CIRB, the local IRB, the CTSU, and other leaders within UC Davis and Adventist Health. Results: Stakeholders acknowledged the unusual and urgent nature of our requests and questions, while contributing to the development of a plan allowing patients to continue clinical trial participation. QA managers approved a plan transferring patients to the RCC, allowing research staff to collect and submit data while patients continue receiving care closer to home. Together we developed a notification letter to inform patients of this plan. Conclusions: The relocation of facilities and patients brought rare challenges while conducting clinical research in rural communities. We learned that the cooperation and flexibility of all parties involved was crucial in supporting the continued care for FRCC's clinical trial patients and research contributions.
Interim Phase 2 Clinical Trial Results for LCL161, an Oral Smac Mimetic, in Patients with Intermediate or High Risk Myelofibrosis
Authors: Naveen Pemmaraju, Bing Z Carter, Hagop M. Kantarjian, Prithviraj Bose, Tapan Kadia, Elias J. Jabbour, Courtney D. DiNardo, Naval Daver, Zeev Estrov, Jorge E. Cortes, Guillermo Garcia-Manero, Lingsha Zhou, Po Yee Mak, Karina Salinas, Carla Kay Tuttle, Sherry Pierce, Uday Popat, Srdan Verstovsek
Journal: Blood (2017)
Abstract 423: Cardiomyocyte Maturation and Multinucleation in Postnatal Swine
Authors: Nivedhitha Velayutham, Christina M Alfieri, Emma J Agnew, Kyle W Riggs, Richard S Baker, Farhan Zafar, Katherine E Yutzey
Journal: Circulation Research (2019)

Objectives: Cardiomyocyte (CM) cell cycle arrest and decline of mononucleated diploid CMs have been implicated in loss of regenerative potential in postnatal mouse hearts. Sarcomeric and extracellular matrix (ECM) maturation also occur concurrently in mice, influencing CM proliferative arrest. Recent studies show a 3-day neonatal period of cardiac regeneration in pigs similar to mice, but the dynamics of postnatal pig CM growth are unknown. Our objective is to explore cardiac cell cycling, growth and maturation in postnatal pigs to understand the events guiding loss of cardiac regenerative capacity in large mammals. Methods &amp; Results: Left-ventricular tissue from farm pigs (White Yorkshire-Landrace) at Postnatal day (P)0, P7, P15, P30, 2 months (2mo) and 6mo were utilized. CM dissociations revealed predominant CM mononucleation at birth in swine, with persistence of ~50% (1186/2537 cells, n=5) mononucleated CMs at P15, and ~10% (227/1785 cells, n=4) at 2mo. By 6mo, pig CMs are entirely multinucleated, exhibiting 4-16 nuclei per cell. Assessing hypertrophic growth in dissociated pig CMs revealed longitudinal CM growth relative to increased nucleation at all ages. However, onset of diametric hypertrophy only occurs beyond 2mo. When nuclear pHH3 and mRNA expression of cell cycle genes was assessed, pig hearts show robust cell-cycling up to 2mo. Also, fetal TNNI1 and MYH6 are active up to 2mo in pig hearts. Ongoing studies on collagen remodeling indicate ECM remodeling in swine occurs beyond P7. Future studies are designed to identify nuclear ploidy in postnatal pig CMs and measure cytokinesis. Conclusions: Cardiac maturational events are staggered over a 2-6 month postnatal window in pigs, with older pig hearts exhibiting extensive CM multinucleation and differences in longitudinal versus diametric CM growth. These fundamental variations in CM growth characteristics are important to consider when designing preclinical trials for cardiac regenerative strategies in pigs. Also, despite a similar period of regenerative capacity as mice, pig hearts do not undergo loss of CM cell cycling and mononucleation until 2mo after birth. Utilizing pigs may thus offer unique opportunities to study aspects of heart regeneration unavailable in other animal models.
Abstract 340: Myosin Regulatory Light Chain: A Major Player in Defining the ‘OFF’ State of Cardiac Myosin
Authors: Na Sa, Ivan Tomasic, Sampath Gollapudi, Suman Nag
Journal: Circulation Research (2019)

Myosin regulatory light chain (RLC) is a regulatory subunit of the myosin molecule, which plays a major role in stabilizing the Interacting Head Motif (IHM) of myosin in non-striated muscle. However, in striated muscle, its purpose is less well defined, and it is only in the past decade that researchers have started unraveling the function of RLC and its phosphorylation in muscle contraction. In this study, we report the role of human cardiac RLC in forming the Super-Relaxed State (SRX) of myosin in reconstituted full-length cardiac myosin thick filaments and show that removal of RLC destabilizes the ability of myosin to form the SRX state. Phosphorylation of the RLC with MLCK has the same effect, which renders the myosin to the ‘OFF’ state as confirmed by its ATPase activity. Interestingly we found that Ca 2+ and not Mg 2+ binding to synthetic myosin filaments had differential effects on the population of the myosin SRX state. At systolic Ca 2+ myosin exhibits lower SRX state than at diastolic Ca 2+ . This effect is obliterated in RLC-lacking myosin constructs such as sS1, or RLC stripped myosin filaments suggesting that Ca 2+ binding to RLC can activate the myosin from the ‘OFF’ state to a more active state. Naturally occurring cardiomyopathy-causing RLC mutants R58Q, K104E and D94A did not alter this property, but two of them, K104E and D94A abolished the phosphorylation regulation of the SRX state of myosin. Altogether, these observations demonstrate that either RLC phosphorylation or binding of systolic Ca 2+ can reduce the number of accessible myosin heads for contraction and could form the basis of the Ca 2+ -mediated activation of the sarcomeric thick filament and mutations in RLC can alter these abilities differentially.
Clinical Outcomes of Matched Unrelated Allogeneic Stem Cell Transplant Patients: Low Dose ATG Vs. No ATG
Authors: Luke Mountjoy, Katie L. Kunze, Tania Jain, James L. Slack, Nandita Khera, Jose F. Leis, Pierre Noel, Lisa Z. Sproat, Jeanne Palmer
Journal: Blood (2018)