tbuckley/cabot-search huggingface dataset:
THU0066 Autoantigenic epitopes targeted by autoantibodies to rna helicase a in systemic lupus erythematosus
Authors: A Suwa, M Hirakata, T Nojima, S Satoh, T Nakajima, T Mimori
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> We have previously described new autoantibodies which recognise the 140 kDa polypeptide (p140) in a patient serum with SLE. Recently we have demonstrated that these antibodies are targeting RNA helicase A (RHA) which plays a pivotal role in nuclear events. <h3>Objectives</h3> To investigate the target epitopes recognised by autoantibodies to RHA. <h3>Methods</h3> Sera from 561 patients with systemic rheumatic disease (287 SLE, 71 SSc, 67 PM/DM, 58 RA, 54 MCTD/overlap, 18 Sjogren syndrome and 6 vasculitis syndrome), and 80 normal humans were screened by immunoprecipitation assay using [35S]-Met-labelled HeLa cell extracts as antigen. In some experiments, [32P]-labelled HeLa cells were used to analyse nucleic acid components. To determine the antigenic epitopes on RHA, restriction fragments of cDNA encoding D1 (amino acids 1–250) containing double-stranded RNA binding domain, D2 (230–650) containing a DEAH box motif, D3 (630–1,020), and D4 (1,000–1,279) containing a glycine-rich region were subcloned into pGEX-2TK vector and expressed in E. coli. The resulting fusion proteins (PD1, PD2, PD3, and PD4) were detected with patient sera. <h3>Results</h3> We have found 10 sera which immunoprecipitated a 140 kDa polypeptide from HeLa cell extracts in SLE patients with nephritis. When the precipitated polypeptides were used as antigen in immunoblotting, p140 was recognised by rabbit antisera against RHA. Thus, we have confirmed that all 10 sera contain autoantibodies to RHA. Moreover, it was noted that anti-RHA sera coprecipitated high molecular weight nucleic acids from [32P]-labelled HeLa cell extracts. When cell extracts were treated with RNase, these sera were unable to coprecipitate high molecular weight nucleic acids, indicating that nucleic acid components were RNAs. Under various salt conditions, anti-RHA antibodies were able to coprecipitate nucleic acid components at salt conditions lower than 0.35M NaCl. These results suggested that RHA is interacting with hn-RNA or mRNA. In immunoblotting using the fusion proteins (PD1, PD2, PD3, and PD4), all 10 anti-RHA positive sera strongly recognised PD4. Eight and 9 out of 10 sera recognised PD1 and PD3, respectively, but intensity of binding was variable among different sera. In contrast, none of sera reacted with PD2. <h3>Conclusion</h3> Autoantibodies to RHA were identified exclusively in patients with lupus nephritis. The universal epitope was present on the carboxyl-terminal domain of RHA. The reactive patterns of antibodies against multiple antigenic determinants detected here were consistent with the hypothesis that relatively native RHA molecules directly elicit autoantibodies in selected patients.
Abstract 387: Role of Aldehyde Dehydrogenase (aldh) 2 in Angiotensin II-induced Decrease in Angiogenesis of Coronary Endothelial Cells
Authors: Bipradas Roy, Suresh S Palaniyandi
Journal: Circulation Research (2020)

Diabetes-induced coronary endothelial cell (CEC) dysfunction following defective angiogenesis is reported in cardiovascular diseases (CVD). Angiotensin II (Ang II), a vasoactive molecule, is upregulated in diabetes. However, the underlying molecular mechanisms of Ang II-induced CEC dysfunction are not fully understood. Aldehyde dehydrogenase (ALDH) 2 is cytoprotective in diabetic CVD. Thus, we hypothesize that ALDH2 improves Ang II-mediated defective CEC angiogenesis. To test our hypothesis, we treated the cultured mouse CECs with Ang II (0.1, 1 and 10 μM) for 2 and 4 hours. Next, we treated CEC with Alda-1 (10 μM), an ALDH2 activator or disulfiram (2.5 μM), an ALDH2 inhibitor, before challenging MCECs with Ang II. We found that Ang II attenuated tube formation (P&lt;0.05 vs control) which indicates in vitro angiogenesis. Next, we found that Ang II have downregulated the mRNA expressions of vascular endothelial growth factor receptor VEGFR1 (p&lt;0.05) and upregulated angiotensin II type-2 receptor (AT2R) (P&lt;0.05) in cultured CECs compared to controls. ALDH2 inhibition with disulfiram potentiated Ang II-induced decrease in angiogenesis (P&lt;0.005) by decreasing the expressions of VEGFR1 (P&lt;0.0005) and increasing the expression of AT2R (p&lt;0.05) relative to Ang II alone. Additionally, activation of ALDH2 activity with Alda-1 rescued Ang II-induced decrease in angiogenesis (P&lt;0.05) by increasing the expression of VEGFR1 (P&lt;0.05) and decreasing the expression of AT2R (P&lt;0.05) relative to Ang II alone. Finally, we conclude that ALDH2 can be an important therapeutic target to improve coronary angiogenesis in diabetic CVD.
Identification of Pharmacogenomic Single Nucleotide Polymorphism Variants As Contributors to Toxicity Phenotype in the Treatment of Acute Childhood Leukemia
Authors: Trisha Larkin, Abdelrahman H Elsayed, Roya Rafiee, Natasha Emanuel, Beate Greer, Biljana N. Horn, Jatinder K Lamba
Journal: Blood (2020)
A Multicenter Prospective Study on Efficacy and Safety of Ponatinib in Patients with Chronic Myeloid Leukemia Resistant or Intolerant to Previous Therapy: A 3-Year Report
Authors: Tomasz Sacha, Elzbieta Szczepanek, Paulina Dumnicka, Joanna Gora-Tybor, Joanna Niesiobedzka-Krezel, Witold Prejzner, Ewa Wasilewska, Janusz Kloczko, Hanna Ciepluch, Wioletta Makowska, Elzbieta Patkowska, Joanna Wasilewska, Grazyna Bober, Malgorzata Kopera, Ryszard Wichary, Renata Kroll-Balcerzak, Tomasz Gromek, Malgorzata Wach, Anna Rudkowska-Kazanowska, Magdalena Swiniarska, Edyta Paczkowska, Ewa Medras, Monika Joks, Marta Oller, Renata Kasza, Aleksandra Kostyra, Justyna Gil, Olga Grzybowska-Izydorczyk
Journal: Blood (2020)
HMGB1 released from GSDME-mediated pyroptotic epithelial cells participates in the tumorigenesis of colitis-associated colorectal cancer through the ERK1/2 pathway
Authors: Gao Tan, Chongyang Huang, Jiaye Chen, Fachao Zhi
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Pyroptosis is a form of proinflammatory gasdermin-mediated programmed cell death. Abnormal mucosal inflammation in the intestine is a critical risk factor for colitis-associated colorectal cancer (CAC). However, it is unknown whether pyroptosis participates in the development of CAC. Methods To investigate the role of gasdermin E (GSDME)-mediated pyroptosis in the development of CAC, Gsdme −/− mice and their wild-type (WT) littermate controls were challenged with azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce a CAC model. Neutralizing antibodies against high-mobility group box protein 1 (HMGB1) were used to determine the role of HMGB1 in CAC. To identify the role of ERK1/2 in HMGB1-induced colon cancer cell proliferation, we performed western blotting and CCK8 assays using the ERK1/2-specific inhibitor U0126 in CT26 colon cancer cells. Results In the CAC model, Gsdme −/− mice exhibited reduced weight loss and colon shortening, attenuated rectal prolapse, and reduced tumor numbers and sizes compared to WT littermates. Furthermore, treatment with neutralizing anti-HMGB1 antibodies decreased the numbers and sizes of tumors, ERK1/2 activation and proliferating cell nuclear antigen (PCNA) expression in AOM/DSS-challenged WT mice. In addition, our in vitro experiments demonstrated that HMGB1 induced proliferation and PCNA expression in CT26 colon cancer cells through the ERK1/2 pathway. Conclusion GSDME-mediated pyroptosis promotes the development of CAC by releasing HMGB1, which induces tumor cell proliferation and PCNA expression through the ERK1/2 pathway. This finding reveals a previously unrecognized link between pyroptosis and CAC tumorigenesis and offers new insight into CAC pathogenesis.
Abstract 223: Yap and Its Homolog Wwtr1 Are Regulators of Myofibroblast Activation Following Ischemic Injury
Authors: Michael A Flinn, Victor Alencar, Michaela Patterson, Caitlin Omeara
Journal: Circulation Research (2020)

Introduction: Following ischemic injury in adult mammals, cardiac fibroblasts differentiate into myofibroblasts and promote secretion of matrix fibers. Myofibroblast activation is critical for initial scar formation and preventing heart rupture, however, extended activity can lead to heart failure progression. Thus, there is a need to identify the mechanisms mediating persistent activation of myofibroblasts to prevent excessive fibrosis and adverse cardiac remodeling. Here we demonstrate that Hippo-Yap pathway offers a target for modulating myofibroblast activation and thus the fibrotic response. Methods and Results: We tested the hypothesis that Yap and its homolog Wwtr1 (known as ‘Taz’) are regulators of myofibroblast activation following ischemic injury. We implemented a Cre-lox system whereby Yap alone or both Yap and Wwrt1 were depleted using an inducible Cre expressed under a myofibroblast specific promoter ( Postn MCM ). Following permeant ligation of the left anterior descending artery in adult mice, we found that myofibroblast depletion of Yap alone resulted in a significant reduction in left ventricular dilation 28 days post injury (dpi) and decreased proliferation of scar associated cells. Strikingly, myofibroblast specific depletion of Yap and one copy of Wwrt1 resulted in further attenuation of left ventricular dilation as well as improved fractional shortening and ejection fraction at 28 and 60 dpi. Histological assessment revealed that depletion of both Yap and Wwrt1 resulted in greater than 50% reduction in scar size (by midline) at 60 dpi. RNAseq of whole hearts collected at 4 dpi suggested that Hippo-Yap pathway expression specifically in myofibroblasts facilitates immune cell recruitment in the heart. Collectively These data illustrate a role for Hippo-Yap signaling mediating myofibroblast activity and immune cell coordination following injury and therefore cardiac fibrosis and remodeling. Conclusions: Our data demonstrate that endogenous Yap and Wwrt1 deletion in myofibroblasts suppresses the fibrotic response, mediates inflammation, and improves cardiac function after ischemic injury. These results therefore offer a regulatory pathway that can be targeted therapeutically to prevent progressive heart failure.
Abstract 339: Runx1 Knock-down by Adeno Associated Viral Mediated-delivery of Short Hairpin RNA Preserves Cardiac Contractility Following Myocardial Infarction
Authors: Tamara P Martin, Ewan Cameron, Stuart Nicklin, Christopher M Loughrey
Journal: Circulation Research (2020)

Myocardial infarction (MI) is a leading cause of heart failure (HF) and mortality worldwide. Preservation of contractile function and prevention of adverse cardiac remodelling following MI are essential to limit progression to HF. Expression of the Runx1 transcription factor in border zone cardiomyocytes is increased within 24 hours after MI. Genetically modified mice with Runx1 deficiency demonstrate an absence of cardiac dilation and preservation of left ventricular (LV) contractility following MI without a change of infarct size. Here, we investigate if adeno-associated viral (AAV)-mediated gene transfer to knock-down Runx1 expression post-MI attenuates adverse cardiac remodelling in mice. Male C57BL/6J mice underwent LAD ligation followed by intravenous injection of AAV-Runx1-shRNA or control AAV-scramble-shRNA (1x10 11 viral genomes). LV contractility (% fractional shortening, FS) was assessed by M-mode echocardiography. RNAscope assessed Runx1 expression in border zone cardiomyocytes and infarct size was histologically quantified using Picro sirius red stain. Runx1 expression within border zone cardiomyocytes was reduced by 30% in AAV-Runx1-shRNA treated mice (37.8±4.5 vs. 53.9±6.4% of cardiomyocytes; AAV-Runx1-shRNA vs. control). LV contractile function was significantly preserved as early as 1 day post-MI (%FS, day 1; 37.7±1.4 vs . 27.6±1.4, day 7; 37.2 ±1.2 vs .28.2±1.4; LV internal dimension during systole day 1; 2.9±0.2 vs . 2.4±0.1, day 7; 3.1±0.2 vs . 2.5±0.1mm; AAV-Runx1-shRNA vs. control, P &lt;0.05). Interestingly, infarct size was reduced with AAV-Runx1-shRNA (31.7±2.0 vs . 40.4±1.4% of LV; AAV-Runx1-shRNA vs . control, P &lt;0.05). In conclusion, a therapeutic approach utilising AAV-mediated knock-down of Runx1 preserved LV contractility and reduced infarct size following MI. These data further highlight Runx1 as a key driver of adverse cardiac remodelling and a therapeutic target with translational potential to prevent adverse cardiac remodelling following MI.
A Sister Lineage of Sampled Retroviruses Corroborates the Complex Evolution of Retroviruses
Authors: Jianhua Wang, Guan-Zhu Han
Journal: Molecular Biology and Evolution (2020)

The origin and deep history of retroviruses remain mysterious and contentious, largely because the diversity of retroviruses is incompletely understood. Here, we report the discovery of lokiretroviruses, a novel major lineage of retroviruses, within the genomes of a wide range of vertebrates (at least 137 species), including lampreys, ray-finned fishes, lobe-finned fishes, amphibians, and reptiles. Lokiretroviruses share a similar genome architecture with known retroviruses, but display some unique features. Interestingly, lokiretrovirus Env proteins share detectable similarity with fusion glycoproteins of viruses within the Mononegavirales order, blurring the boundary between retroviruses and negative sense single-stranded RNA viruses. Phylogenetic analyses based on reverse transcriptase demonstrate that lokiretroviruses are sister to all the retroviruses sampled to date, providing a crucial nexus for studying the deep history of retroviruses. Comparing congruence between host and virus phylogenies suggests lokiretroviruses mainly underwent cross-species transmission. Moreover, we find that retroviruses replaced their ribonuclease H and integrase domains multiple times during their evolutionary course, revealing the importance of domain shuffling in the evolution of retroviruses. Overall, our findings greatly expand our views of the diversity of retroviruses, and provide novel insights into the origin and complex evolutionary history of retroviruses.
Updated Follow-up of the Alta Study, a Phase 1/2 Study of Giroctocogene Fitelparvovec (SB-525) Gene Therapy in Adults with Severe Hemophilia a
Authors: Andrew D. Leavitt, Barbara A. Konkle, Kimo Stine, Nathan Visweshwar, Thomas J. Harrington, Adam Giermasz, Steven Arkin, Annie Fang, Frank Plonski, Lynne Smith, Li-Jung Tseng, Gregory Di Russo, Bettina M Cockroft, Jeremy Rupon, Didier Rouy
Journal: Blood (2020)
Oral Nanatinostat (Nstat) and Valganciclovir (VGCV) in Patients with Recurrent Epstein-Barr Virus (EBV)-Positive Lymphomas: Initial Phase 2 Results
Authors: Pierluigi Porcu, Bradley Haverkos, Onder Alpdogan, Robert Baiocchi, Jonathan E Brammer, Tatyana A. Feldman, Marcelo Capra, Elizabeth A Brem, Phillip Scheinberg, Juliana Pereira, Leyla Shune, Afton Katkov, Robert McRae, Lisa Rojkjaer, Ivor Royston, Douglas V. Faller
Journal: Blood (2020)
The Italian Medicines Agency Prospective Registry of Bortezomib-Based Treatment in AL Amyloidosis
Authors: Giovanni Palladini, Paolo Milani, Simone Celant, Valentina Summa, Giovanni Affronti, Pier Paolo Olimpieri, Sandra Petraglia, Andrea Foli, Mario Nuvolone, Giampaolo Merlini, Pierluigi Russo
Journal: Blood (2020)
Outcomes of COVID-19 Infection in Patients with Hematologic Malignancies
Authors: Elizabeth Behrens, Anne Timmermann, Alexander Yerkan, Deborah A. Katz, Agne Paner, Melissa C. Larson, Seo-Hyun Kim, Shivi Jain, Sefer Gezer, Parameswaran Venugopal, Irene Dehghan-Paz, Yoona Rhee, Celalettin Ustun, Ankur Varma, Jamile M. Shammo
Journal: Blood (2020)
An Essential Role for the RNA Editor-Exonuclease Axis in Terminal Erythroid Differentiation
Authors: Areum Han, Alena V. Yermalovich, Vanessa Lundin, Daniel S. Pearson, Mariam Hachimi, Patricia Sousa, Brianna Hilton, Michael Morse, John Atwater, Yosra Zhang, Pheobe Hunter, Vivian Morris, Jihan K. Osborne, Jenna M. Frame, Ran Jing, Yu Chung Huang, Caroline Kubaczka, Trista E. North, Thorsten Schlaeger, George Q. Daley
Journal: Blood (2020)
Abstract 371: Cardiac Fibrosis is Associated With Increased Gut Barrier Leakage and Circulating Peptidoglycan in Type 2 Diabetic Mice With Ace2 Deficiency
Authors: Ram Prasad, Prabhat Ranjan, Suresh K Verma, Maria Grant
Journal: Circulation Research (2020)

Purpose: Cardiac fibrosis is linked with hyperglycemia and increases the risk of cardiovascular complications and heart failure. Despite several advancements, the molecular mechanisms responsible for cardiac fibrosis in diabetes remain unclear. The renin-angiotensin system (RAS) is activated and plays an essential role in diabetes-induced cardiac dysfunctions through activation of Ang II. However, angiotensin converting enzyme 2 (ACE2), the protective arm of RAS, opposes the classical RAS functions mediated by ACE. Previously, we have reported that ACE2 deficient exacerbates hyperglycemia-induced gut dysbiosis, increased gut barrier permeability, and facilities translocation of gut microbial peptides (GMPs) into system circulation in type 1 diabetic mice. Here, we sought to determine whether dysbiosis induced by type 2 diabetes and ACE2 deficiency contributes to cardiac fibrosis. Methods: Toll-like receptor- (TLR-2) associated inflammatory signaling and cardiac fibrosis were studied in WT, db/db, and ACE2 -/y -db/db mice with 4-months of diabetes. The levels of peptidoglycan (PGN), a TLR-2 ligand, were measured by ELISA assay. The markers of gut barriers and inflammatory cytokines were assessed by immunohistochemistry and qRT-PCR. To measure cardiac fibrosis, Masson’s trichrome staining was used to stain collagen fibers. Results: ACE2 -/y -db/db mice exhibited increased myocardial fibrosis as compared with db/db and WT mice. In the myocardium, TLR-2 expression (4 folds, p&lt;0.005) and pro-inflammatory cytokines IL-1β (p&lt;0.001), IL-6 (p&lt;0.0001), and TNF-α (p&lt;0.01 were significantly up-regulated in ACE2 -/y -db/db mice compared with db/db and WT mice. Increased gut barrier permeability as detected by a reduction in expression of tight junction molecules (ZO-1, p120-catenin, and VE-cadherin) and a 2- fold increase in circulating PGN was observed in ACE2 -/y -db/db mice when compared to db/db. Conclusions: These data suggest that PGN and other circulating gut microbial particles may have a deleterious impact on cardiac health by promoting inflammation-mediated fibrosis. In addition to controlling hyperglycemia, strategies aimed at restoring gut barrier integrity may prevent diabetic cardiovascular complications.
17-BI-1206-02 Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to Fcgriib, in Combination with Rituximab in Subjects with Indolent B-Cell Non-Hodgkin Lymphoma That Has Relapsed or Is Refractory to Rituximab
Authors: Mats Jerkeman, Andres McAllister, Carl Roos, Marie Lindell Andersson, Ingrid Karlsson, Marie Borggren, Pau Abrisqueta, Ana Carneiro, Raul Cordoba, Hans Hagberg, Santiago Mercadal, Ingrid Teige, Björn Frendéus
Journal: Blood (2020)
Lower Risk of Graft Versus Host Disease after Exposure to Checkpoint Inhibitors with the Use of Post-Transplant Cyclophosphamide Prophylaxis
Authors: Chantal Saberian, Noha Abdel-Wahab, Ala Abudayyeh, Hind Rafei, Jacinth Joseph, May Daher, Stephen K. Gruschkus, Cristina Knape, Laura Whited, Alison Gulbis, Megan Marcotulli, Gabriela Rondon, Uday R. Popat, Rohtesh S. Mehta, Marina Konopleva, Betul Oran, Maro Ohanian, Farhad Ravandi, Guillermo Garcia-Manero, Amin M. Alousi, Naval Daver, Richard E. Champlin, Adi Diab, Gheath Alatrash
Journal: Blood (2020)
Efficacy and Safety of Loncastuximab Tesirine (ADCT-402) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Paolo F Caimi, Weiyun Z. Ai, Juan Pablo Alderuccio, Kirit M. Ardeshna, Mehdi Hamadani, Brian T. Hess, Brad S. Kahl, John A. Radford, Melhem Solh, Anastasios Stathis, Pier Luigi Zinzani, Jay Feingold, David Ungar, Yajuan Qin, Shui He, Carmelo Carlo-Stella
Journal: Blood (2020)
CXCR5-CXCL13 expression regulates cellular mechanisms involved in prostate cancer cell invasion and correlates with prostate cancer progression
Authors: Shailesh Singh, Rajesh Singh, Udai P. Singh, Sean K. Kimbro, Carlton R. Cooper, Leland W K Chung, Milton W. Datta, Peter J. Didier, William E. Grizzle, James W. Lillard
Journal: Cancer Research (2006)

289  Chemokine-chemokine receptor interactions play significant roles in prostate cancer metastasis. Here we show that CXCR5 is functionally expressed by prostate cancer cell lines (LNCaP and PC3). Correspondingly, the ligand for CXCR5, CXCL13, was secreted by bone marrow (endothelial, osteoblast, and osteoclast) cells due to the host response following prostatic neoplasia and is elevated in patients with prostate cancer, compared to those with PIN or hyperplasia. Both LNCaP and PC3 cell lines express higher levels of CXCR5 than normal prostatic epithelial cells (PrEC). After CXCL13-engagement, prostate cancer cells displayed a higher migration and invasive potential in vitro, which was significantly reduced by CXCR5 blockade. CXCL13 also increased collagenases (MMP-1 and -13), stromelysins (MMP-3 and -10), and gelatinases (MMP-2 and -9) expression by both LNCaP and PC3 cell lines. Our data also suggest that CXCL13-induced motility, invasion, and firm (bone endothelial) cell adhesion by prostate cancer cells is only partially sensitive to pertussis toxin and PI3K inhibition, resulting in predominant Src kinase, moderate PI3K and FAK, but not NFkB, activation. These data suggest that the expression of CXCR5 by prostate carcinomas and CXCL13 by bone marrow cells affects migration, invasion and MMP expression for prostate cancer progression. In addition, the ability to detect CXCL13 in patient serum may represent a new method for monitoring prostate cancers progression. [Supported in part by National Institutes of Health grants MD000525, CA092078, CA098912 and RR03034]
Developing a Novel Anti-CD19/CD20 Bi-Specific Chimeric Antigen Receptor T (CAR-T) Cell Therapy for Relapsed/Refractory (r/r) B-Cell NHL
Authors: Lili Zhou, Jiaqi Huang, Shigui Zhu, Xin Yao, Shiguang Ye, Judy Zhu, Chengxiao Zheng, Shiyi Chen, Yanfeng Li, Liping Lan, Shicheng Chen, Lin Guo, Qingsong Zhang, Jiangqin Zheng, Rirfei Wang, Yi Hong, Jiaqiang Ren, Li Zhang, Wenjun Zhang, Xiaochen Tang, Junbang Wang, Jie Liu, Michael Humphries, Ping Li, Yihong Yao, Aibin Liang
Journal: Blood (2020)