tbuckley/cabot-search huggingface dataset:
Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins
Authors: Juan Mo, Corina Anastasaki, Zhiguo Chen, Tracey Shipman, Jason Papke, Kevin Yin, David H. Gutmann, Lu Q. Le
Journal: Journal of Clinical Investigation (2020)

Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulated their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation.
Abstract 298: Flavin Containing Monooxygenase 2 in Cardiac Fibrosis
Authors: Xinyang Hu, Cheng Ni
Journal: Circulation Research (2020)

Cardiac fibrosis is associated with clinical outcome in patients with heart failing. There is no information concerning whether flavin containing monooxygenase 2 (FMO2) is involved in the fibrotic response. Here, we demonstrate that FMO2 is consistently down-regulated after myocardial infarction (MI) in rats, non-human primates and patients with chronic MI. Furthermore, FMO2 knockdown or knockout results in significantly increased cardiac fibrosis accompanied with impaired heart function in rats. Compensation of non-myocyte FMO2 using the strategy of miR133a/1a TS aided lentivirus inhibits the cardiac fibrosis and restores the deteriorated cardiac function following MI in rats. In vitro studies showed FMO2 expression in neonatal rat cardiac fibroblasts (NRCFs) is dramatically decreased after treatment of TGF-β. FMO2 deficiency in CFs isolated from FMO2-/- rats induces augmented collagen deposition, fibroblast-myofibroblast transdifferentiation and increased phosphorylated SMAD2/3. However, overexpression of FMO2 in NRCFs or CFs from MI patients suppresses this exact process. Mechanistically, we demonstrate using mass spectrometry that FMO2 combines with cytochrome p450 superfamily 2J3 (CYP2J3) at the ubiquitination site of the latter one after TGF-β stimulation, and then blocks the CYP2J3 ubiquitination. The accumulated CYP2J3 expression induces the up-regulation and nuclear translocation of SMURF2, the E3 ubiquitin-protein ligase specifically degrades phosphorylated SMAD2/3, through a negative feedback as another substrate of SMURF2, in addition, FMO2 can competitively exploit CYP2J3 from SMURF2, thus in turn promotes nuclear translocation of SMURF2 to degrade phosphorylated SMAD2/3. Furthermore, in non-human primate MI model, delivery of non-myocyte FMO2 over-expression lentivirus significantly decreases the cardiac fibrosis and improves heart function. In summary, our study demonstrates for the first time that FMO2 is a critical determinant of cardiac fibrosis by interfering TGF-β/SMAD2/3 and provides a novel potential target for treating cardiac fibrosis.
Evolution of Outcome over Time for Relapsed Hodgkin Lymphoma after Autologous Stem Cell Transplant: Improved Survival for Early Relapse in Recent Years
Authors: Ali Bazarbachi, Ariane Boumendil, Hervé Finel, Irma Khvedelidze, Joanna Romejko-Jarosinska, Alina Daniela Tanase, Saad Akhtar, Tarek Ben Othman, Abdelghani Tbakhi, Boris Afanasyev, Javier Briones, Zafer Gülbas, Jean Elcheikh, Rose-Marie Hamladji, Tugrul Elverdi, Didier Blaise, Carmen Martinez, Eleonora Alma, Kazimierz Halaburda, Aida Botelho de Sousa, Bertram Glass, Stephen Robinson, Silvia Montoto, Anna Sureda Balari
Journal: Blood (2020)
BAY 94-9027 Provides Safe and Effective Long-Term Prophylaxis in Pediatric Patients: Results from the PROTECT VIII Kids Extension Study
Authors: Sanjay Ahuja, Kathelijn Fischer, Tina Biss, Monika Maas Enriquez, Maria-Elisa Mancuso, MacGregor Steele, Maria Wang, Gili Kenet
Journal: Blood (2020)
Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD
Authors: John T. Benjamin, Erin J. Plosa, Jennifer M.S. Sucre, Riet van der Meer, Shivangi Dave, Sergey Gutor, David S. Nichols, Peter M. Gulleman, Christopher S. Jetter, Wei Han, Matthew Xin, Peter C. Dinella, Ashley Catanzarite, Seunghyi Kook, Kalsang Dolma, Charitharth V. Lal, Amit Gaggar, J. Edwin Blalock, Dawn C. Newcomb, Bradley W. Richmond, Jonathan A. Kropski, Lisa R. Young, Susan H. Guttentag, Timothy S. Blackwell
Journal: Journal of Clinical Investigation (2020)

Emerging evidence indicates that early life events can increase the risk for developing chronic obstructive pulmonary disease (COPD). Using an inducible transgenic mouse model for NF-κB activation in the airway epithelium, we found that a brief period of inflammation during the saccular stage (P3–P5) but not alveolar stage (P10–P12) of lung development disrupted elastic fiber assembly, resulting in permanent reduction in lung function and development of a COPD-like lung phenotype that progressed through 24 months of age. Neutrophil depletion prevented disruption of elastic fiber assembly and restored normal lung development. Mechanistic studies uncovered a role for neutrophil elastase (NE) in downregulating expression of critical elastic fiber assembly components, particularly fibulin-5 and elastin. Further, purified human NE and NE-containing exosomes from tracheal aspirates of premature infants with lung inflammation downregulated elastin and fibulin-5 expression by saccular-stage mouse lung fibroblasts. Together, our studies define a critical developmental window for assembling the elastin scaffold in the distal lung, which is required to support lung structure and function throughout the lifespan. Although neutrophils play a well-recognized role in COPD development in adults, neutrophilic inflammation may also contribute to early-life predisposition to COPD.
SAT0159 ASSOCIATION BETWEEN JANUS KINASE INHIBITORS AND ALL-CAUSE MORTALITY IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: W. Xie, Z. Zhang
Journal: Annals of the Rheumatic Diseases (2020)

Background: According to preliminary analysis of study A3921133, tofacitinib10 mg twice daily was associated with increased occurrence of all-cause mortality and pulmonary embolism compared with anti-tumor necrosis factor (anti-TNF), whereas 5 mg tofacitinib twice daily exhibited similar safety profile with anti-TNF. Objectives: We aim to investigate the role of Janus kinase inhibitors (Jakinibs) in all-cause mortality among RA population via a meta-analysis of RCTs. Methods: PubMed, Embase and Cochrane Library were systemically searched for RCTs reporting adverse events in RA patients receiving Jakinibs, from inception to October 2018. Absolute risk differences (RD) and 95% confidence interval (CI) were used as an effect measure using the Mantel-Haenszel fixed-effect method. Results: A total of 31 RCTs randomizing 13,065 patients met the inclusion criteria. During the placebo-controlled phase, there were 16 and 6 deaths in Jakinibs and placebo respectively, accompanied by a numerically higher absolute incidence mortality rate in Jakinibs than in placebo (0.651 vs. 0.531 per 100 patient-years). In direct pairwise comparisons, 2,194 and 2,246 patient-years of exposure in lower and higher Jakinibs reported a total of 19 deaths (10 with lower dose [0.456 per 100 patient-years] and 9 with higher dose [0.401 per 100 patient-years]). Compared with placebo, no significant difference was observed in tofacitinib (RD,0.01 events/person-year; 95% CI, -0.01 to 0.02; P =0.52); barictinib (RD,-0.00 events/person-year; 95% CI, -0.01to 0.01; P =0.59); upadacitinib (RD,0.00 events/person-year; 95% CI, -0.02to 0.03; P =0.71); perficitinib (RD,0.00 events/person-year; 95% CI, -0.05 to 0.06; P =0.86); decernotinib (RD,0.02 events/person-year; 95% CI, -0.03 to 0.06; P =0.44); fligotinib (RD,0.00 events/person-year; 95% CI, -0.05 to 0.06; P=0.85). In pairwise comparisons, no dose-dependent impact of Jakinibs on all-cause mortality was not observed in tofacitinib (5mg vs. 10mg, bid), baricitinib (2mg vs. 4mg, qd) upadacitinib (15mg vs. 30mg, qd). Conclusion: Compared with placebo, there was no significant difference in the all-cause mortality rate observed in patients receiving Jakinibs treatments, but post-marketing data in real-life setting are sorely needed to ascertain their safety in general population. Large, prospective, well-designed studies are needed to explore the effects of such drugs on diabetes development in the RA patients with high-risk diabetes. Disclosure of Interests: None declared
Abstract MP151: Cardiomyocyte HIPK2 is a Critical Regulator of Purinergic Signaling Regulated Myocardial Inflammation
Authors: Tousif Sultan, Anand P Singh, Prachi Umbarkar, QinKun Zhang, Hind Lal
Journal: Circulation Research (2020)

Objective: Heart failure (HF) is a major and growing public health problem worldwide. Recently our lab has identified HIPK2 as an essential kinase to maintain basal cardiac function. However, the role of cardiomyocytes specific HIPK2 (CM-HIPK2) in myocardial inflammation is unknown. Methods: α-MHC promoter-driven, Cre mice were crossed with HIPK2 fl/fl mice to generate CM-HIPK2 KO. Echocardiography was performed to assess cardiac function. Immunoblotting assays were performed to determine the expression of HIPK2, CD39, CD73, and other signaling pathway . Flow cytometry and ELISA were performed to study the dynamics of inflammation. Results: Consistent with our previous report , echocardiography confirmed an impaired cardiac function in 3 months old CM-HIPK2 KO as compared to their littermate controls. Importantly, cardiac function in the KOs starts to deteriorate at ~2.5 months of age, thus, at two months of age, the cardiac function of KO and littermate control was comparable. Comprehensive immune profiling of CM-HIPK2 KO and littermate control hearts were performed at two months of age. We observed an increased frequency of infiltrated CD45 + leukocytes, CCR2 + pro-inflammatory macrophages, Th17 + , Th9 + , CD45 + TNFα + , CD45 + IL1β + , CD45 + Ki67 + cells but diminished frequency of Myeloid-derived suppressor cells (MDSCs), TCRαβ + CTLA-4 + and TCRαβ + PD-1 + in the CM-HIPK2 KO hearts. Mechanistically, we observed a significantly reduced expression of CD39 and CD73 over HIPK2 deleted cardiomyocytes. Indeed, CD39 and CD73 are the key players of purinergic signaling regulated inflammation response. In-vitro studies with neonatal rat ventricular cardiomyocytes (NRVMs) corroborated the in-vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 significantly increased CD39 expression. Consistently, Ad-shRNA-HIPK2 expression suppressed the CD39 expression. Taken together, our findings suggest a critical role of CM-HIPK2 in purinergic signaling mediated myocardial inflammation. Conclusions: CM-HIPK2 maintains basal cardiac function by controlling purinergic signaling regulated myocardial inflammation. Future work will explore the underlying mechanism of HIPK2 mediated regulation of CD39 and CD73.
Niche-like Ex Vivo High Throughput (NEXT) Drug Screening Platform in Acute Myeloid Leukemia
Authors: Reinaldo Dal Bello Figueiras, Justine Pasanisi, Romane Joudinaud, Matthieu Duchmann, Gaetano Sodaro, Clementine Chauvel, Loic Vasseur, Bryann Pardieu, Frank Ling, Kim Pacchiardi, Camille Vaganay, Lionel Faivre, Chaïma Benaksas, Claude Preudhomme, Emmanuel Raffoux, Emmanuelle Clappier, Lionel Ades, Alexandre Puissant, Raphael Itzykson
Journal: Blood (2020)
Transcriptome Analysis of Severe Congenital Neutropenia Associated Leukemia with Different Types of <i>RUNX1</i> Mutations in an iPSC-Based Model
Authors: Benjamin Dannenmann, Benedikt Oswald, Malte U Ritter, Masoud Nasri, Regine Bernhard, Cornelia Zeidler, Karl Welte, Julia Skokowa, Maksim Klimiankou
Journal: Blood (2020)
Air pollution and health: recent advances in air pollution epidemiology to inform the European Green Deal: a joint workshop report of ERS, WHO, ISEE and HEI
Authors: Barbara Hoffmann, Nathalie Roebbel, Sophie Gumy, Francesco Forastiere, Bert Brunekreef, Dorota Jarosinska, Katherine D. Walker, Annemoon M. van Erp, Robert O'Keefe, Dan Greenbaum, Martin Williams, Michal Krzyzanowski, Frank J. Kelly, Michael Brauer, Hans Bruyninckx, Hanna Boogaard
Journal: European Respiratory Journal (2020)

<b>Current European air pollution levels, which are in most places well below air quality limit values, still have deleterious health effects. The report discusses ways to move forward with air quality legislation to improve public health.</b>https://bit.ly/3kFRHHf
SP0051 Hsp reactive T cells as inflammation regulators
Authors: W Van Eden, L Paul, U Wendling, P Van Kooten, J Bos-de Ruijter, R Van der Zee, B Prakken
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Immunisation with heat shock proteins has protective effects in models of induced arthritis. Analysis has shown a reduced synovial inflammation in such protected animals. Adoptive transfer and immunisation with selected T cell epitopes (synthetic peptides) have indicated the protection to be mediated by T cells directed to conserved hsp epitopes. This was shown first for mycobacterial hsp60<sup>1</sup> and later for mycobacterial hsp70.<sup>2,3</sup> Fine specificity analysis showed that such T cells were cross-reactive with the homologous self hsp. Therefore protection by microbial hsp reactive T cells can be by cross-recognition of self hsp overexpressed in the inflamed tissue. Preimmunisation with hsp leads to a relative expansion of such self hsp cross-responsive T cells. The regulatory nature of such T cells may originate from mucosal tolerance maintained by commensal flora derived hsp or from partial activation through recognition of self hsp as a partial agonist (Altered Peptide Ligand) or in the absence of proper costimulation. Recently, we reported the selective upregulation of B7.2 on microbial hsp60 specific T cells in response to self hsp60.<sup>4</sup> Through a preferred interaction with CTLA-4 on proinflammatory T cells this may constitute an effector mechanism of regulation. Also, regulatory T cells produced IL10. <h3>References</h3> Anderton SM, van der Zee R, Prakken B, Noordzij A, van Eden W. Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J Exp Med. 1995;181:943–52 Tanaka S, Kimura Y, Mitani A, Yamamoto G, Nishimura H, Spallek R, Singh M, Noguchi T, Yoshikai Y. Activation of T cells recognizing an epitope of heat-shock protein 70 can protect against rat adjuvant arthritis. J Immunol. 1999;163:5560–65 Wendling U, Paul L, van der Zee R, Prakken B, Singh M, van Eden W. A conserved mycobacterial heat shock protein (hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10-producing T cells that cross-react with the mammalian self-hsp70 homologue. J Immunol. 2000;164:2711–17 Paul AG, van Der Zee R, Taams LS, van Eden W. A self-hsp60 peptide acts as a partial agonist inducing expression of B7-2 on mycobacterial hsp60-specific T cells: a possible mechanism for inhibitory T cell regulation of adjuvant arthritis? Int Immunol. 2000;12:1041–50
Efficacy of Isatuximab on Surrogate Endpoints in Multiple Myeloma; A Systematic Review
Authors: Mohammad Ammad Ud Din, Syed Ather Hussain, Hizra Farrukh, Fajar Pasha, Syed Maaz Abdullah, Imtisaal Waris, Ebad Rehman, Alireza Setarehaseman, Asmat Ullah, Faiz Anwer
Journal: Blood (2020)
Machine Learning (ML) Can Successfully Support Microscopic Differential Counts of Peripheral Blood Smears in a High Throughput Hematology Laboratory
Authors: Christian Pohlkamp, Kapil Jhalani, Niroshan Nadarajah, Inseok Heo, William Wetton, Rudolf Drescher, Siegfried Hänselmann, Thomas Lörch, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach
Journal: Blood (2020)
Results of Venetoclax and Azacitidine Combination in Chemotherapy Ineligible Untreated Patients with Acute Myeloid Leukemia with <i>FLT3</i> Mutations
Authors: Marina Konopleva, Michael Thirman, Keith W. Pratz, Anthony G. Letai, Christian Recher, Vinod A. Pullarkat, Hagop M. Kantarjian, Monique Dail, Yinghui Duan, Brenda J. Chyla, Jalaja Potluri, Catherine Miller, Courtney D. Dinardo, Andrew H. Wei
Journal: Blood (2020)
Streamline - Retrospective Cohort Study of Relapsed or Refractory (R/R) <i>FLT3</i>-Mutated Acute Myeloid Leukemia (AML): Real-World Treatment, Testing Patterns, and Outcomes
Authors: Amer M. Zeidan, Adrienne M. Gilligan, Santosh Gautam, David L. Grinblatt, Dina Elsouda, Loretta Sullivan, Bhavik J. Pandya
Journal: Blood (2020)
In vivo evaluation of CD38 and CD138 as targets for nanoparticle-based drug delivery in multiple myeloma
Authors: David T. Omstead, Franklin Mejia, Jenna Sjoerdsma, Baksun Kim, Jaeho Shin, Sabrina Khan, Junmin Wu, Tanyel Kiziltepe, Laurie E. Littlepage, Basar Bilgicer
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Drug-loaded nanoparticles have established their benefits in the fight against multiple myeloma; however, ligand-targeted nanomedicine has yet to successfully translate to the clinic due to insufficient efficacies reported in preclinical studies. Methods In this study, liposomal nanoparticles targeting multiple myeloma via CD38 or CD138 receptors are prepared from pre-synthesized, purified constituents to ensure increased consistency over standard synthetic methods. These nanoparticles are then tested both in vitro for uptake to cancer cells and in vivo for accumulation at the tumor site and uptake to tumor cells. Finally, drug-loaded nanoparticles are tested for long-term efficacy in a month-long in vivo study by tracking tumor size and mouse health. Results The targeted nanoparticles are first optimized in vitro and show increased uptake and cytotoxicity over nontargeted nanoparticles, with CD138-targeting showing superior enhancement over CD38-targeted nanoparticles. However, biodistribution and tumor suppression studies established CD38-targeted nanoparticles to have significantly increased in vivo tumor accumulation, tumor cell uptake, and tumor suppression over both nontargeted and CD138-targeted nanoparticles due to the latter’s poor selectivity. Conclusion These results both highlight a promising cancer treatment option in CD38-targeted nanoparticles and emphasize that targeting success in vitro does not necessarily translate to success in vivo.
Hematopoietic Progenitor Cell Mobilization and Collection for Autologous Hematopoietic Cell Transplantation in AL Amyloidosis: A Single Center Experience
Authors: Anne K Hubben, Lisa Rybicki, Kristin Ricci, Navneet S. Majhail, Matt Kalaycio, Betty K. Hamilton, Brian T. Hill, Allison M. Winter, Brad Pohlman, Deepa Jagadeesh, Faiz Anwer, Robert M. Dean, Ronald Sobecks, Chakra P Chaulagain, Hien D. Liu, Jack Khouri
Journal: Blood (2020)
CAR19 iPSC-Derived NK Cells Utilize the Innate Functional Potential Mediated through NKG2A-Driven Education and Override the HLA-E Check Point to Effectively Target B Cell Lymphoma
Authors: Minoru Kanaya, Camille Philippon, Artur Cieslar-Pobuda, Frank Cichocki, Michelle Saetersmoen, Sajid Mahmood, Quirin Hammer, Marianna Vincenti, Merete Thune Wiiger, Hanna Julie Hoel, Lise Kveberg, Svetlana Gaidarova, Ryan Bjordahl, Hui-yi Chu, Brian Groff, Matthew Denholtz, Jeffrey S. Miller, Tom Lee, Dan S Kaufman, Jode P Goodridge, Bahram Valamehr, Karl-Johan Malmberg
Journal: Blood (2020)
Clonal Hematopoiesis and COVID-19 Severity in Cancer Patients
Authors: Kelly L. Bolton, Michael Foote, Justin Jee, Anton Safonov, Ryan Ptashkin, Sean Devlin, Erika Gedvilaite, Teng Gao, Elli Papaemmanuil, Melissa S. Pessin, Mini Kamboj, Joseph Vijai, Kenneth Offit, Phillip Awadalla, Pradeep Nataranjan, Michael F. Berger, Larry Norton, Ross L. Levine, Ahmet Zehir
Journal: Blood (2020)
Impact of Cytogenetic Abnormalities (CA) on Outcome of Patients (Pts) with Relapsed/Refractory (R-R) Acute Lymphoblastic Leukemia (ALL) Treated with Inotuzumab Ozogamicin (INO) in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab: Results from a Phase 2 Study
Authors: Hind Rafei, Hagop M. Kantarjian, Koji Sasaki, Nicholas J. Short, Farhad Ravandi, Xuelin Huang, Joseph D. Khoury, Sa A Wang, Jeffrey L. Jorgensen, C. Cameron Yin, Issa F. Khouri, Partow Kebriaei, Nitin Jain, Koichi Takahashi, Bouthaina S. Dabaja, Srdan Verstovsek, Tapan M. Kadia, Shilpa Paul, Caitlin R. Rausch, Guillermo Garcia-Manero, William G. Wierda, Courtney D. DiNardo, Naval Daver, Guillermo Montalban-Bravo, Musa Yilmaz, Patrice Nasnas, Rita Khouri, Monica Kwari, Jovitta Jacob, Meagan Rostykus, Rebecca Garris, Marina Konopleva, Susan M. O'Brien, Elias Jabbour
Journal: Blood (2020)
Waldenström's Macroglobulinaemia in the Modern Era: Real World Outcomes and Prognostication across 35 Chinese Academic Hospitals
Authors: Xin-xin Cao, Shuhua Yi, Zhongxing Jiang, Jingsong He, Wei Yang, Juan Du, Chunyan Sun, Yu Wu, Chen Wenming, Xiao-jun Liu, Bingzong Li, Chunrui Li, Wei Sang, Qin-hua Liu, Xiaoxia Chu, Li Fei, Ou Bai, Min Mao, Rong Fu, Wei WANG, Lihong Liu, Luqun Wang, Yujun Dong, Jun Luo, Zhenling Li, Yongqiang Wei, Qi-ke Zhang, Jing Liu, Kaiyang Ding, Liang Zou, Bi-yun Chen, Luoming Hua, Hongmei Jing, Juan He, Liang Wang, Lugui Qiu, Jian Li
Journal: Blood (2020)
Biological Effects of Abdominal Irradiation on Intestinal Barrier Breakdown Identified By Second-Generation Probiotic, LR-IL-22
Authors: Alexis Marie Espinal, Michael Epperly, Amitava Mukherjee, Donna Shields, Wen Hou, Renee Fisher, Jan-Peter van Pijkeren, Ravi Patel, Naveed Islam, Joel S Greenberger
Journal: Blood (2020)