tbuckley/cabot-search huggingface dataset:
SAT0108 Uveitis and its outcome in patients with juvenile idiopathic arthritis – long term study
Authors: K Jarosova, D Nemcova, J Vencovsky
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To determine the frequency of uveitis and its complications in patients with juvenile idiopathic arthritis (JIA). <h3>Methods</h3> A retrospective analysis of 185 patients with JIA diagnosed between 1980 ? 1995 followed in 2 paediatric rheumatology centres. Patients with chronic and acute uveitis were identified in subgroups of JIA. <h3>Results</h3> Uveitis was diagnosed in 24 (13.0%) patients. Sixteen (8.6%) patients had chronic and eight (4.3%) had acute uveitis. Twelve (75.0%) patients who developed chronic uveitis did so after the onset of arthritis, but only 8 within the first 7 years of JIA. There were four patients who developed chronic uveitis 9, 13, 14 and 17 years after JIA onset. Four patients who manifested arthritis after uveitis did so after 1, 3, 3 and 6 years. Chronic uveitis was associated with systemic arthritis (in 17.6%), persistent oligoarthritis (in 29.6%), extended oligoarthritis (in 4,5%), psoriatic arthritis (in 40%) and other arthritis (in 14.3%). Complications, such as synechiae, band keratopathy, cataract or glaucoma developed in 10 (62.5%) patients with chronic uveitis. As expected, these were found mainly in patients with ANA positivity (n = 8; 80.0%), in contrast to only 2 between ANA negative patients. Amaurosis was found in 7 patients; complete visual loss developed in one case. Acute uveitis was seen only among arthritis+enthesitis patients (n = 6; 10.7%) and in patients with other arthritis (n = 2; 14,3%). <h3>Conclusion</h3> Uveitis is relatively common in JIA. Chronic form may occur in several JIA subgroups, with persistent oligoarthritis patients and, surprisingly, with psoriatic arthritis patients being the most frequently affected. Acute uveitis is associated with HLA B27 associated disease forms. It is important to check for asymptomatic uveitis through the entire course of disease, as it may begin well after the onset of arthritis and may lead to severe complications. Supported by grant NE/4879–3 from IGA of the Czech Ministry of Health.
Cluster of Differentiation 20 Expression and Rituximab Use Do Not Improve Outcome of Classical Hodgkin Lymphoma Patients
Authors: Khadega A Abuelgasim, Raed Al Shammari, Saeed Alshieban, Bader Alahmari, Mohsen Alzahrani, Ayman Alhejazi, Ahmed Alaskar, Moussab Damlaj
Journal: Blood (2020)
Characteristics and Outcome of Myelofibrosis Patients on Long-Term Ruxolitinib Therapy (≥3 years)
Authors: Lucia Masarova, Prithviraj Bose, Naveen Pemmaraju, Lingsha Zhou, Sherry A. Pierce, Hagop M. Kantarjian, Zeev E. Estrov, Srdan Verstovsek
Journal: Blood (2020)
Ejection fraction and mortality: a nationwide register‐based cohort study of 499 153 women and men
Authors: Simon Stewart, David Playford, Gregory M. Scalia, Philip Currie, David S Celermajer, David Prior, Jim Codde, Geoff Strange
Journal: European Journal of Heart Failure (2020)

We investigated the sex-based risk of mortality across the spectrum of left ventricular ejection fraction (LVEF) in a large cohort of patients in Australia.Quantified levels of LVEF from 237 046 women (48.1%) and 256 109 men undergoing first-time, routine echocardiography (2000-2019) were linked to 119 232 deaths (median 5.6 years of follow-up). Overall, 17.6% of men vs. 8.3% of women had an LVEF <50%. An LVEF <40% was associated with the highest crude cardiovascular-related and all-cause mortality at 5 years (∼20-30% and ∼ 40-50%, respectively). Thereafter, actual cardiovascular-related and all-cause mortality at 5 years in both sexes steeply improved to a nadir LVEF of 65.0-69.9% (reference group). Below this LVEF level, the adjusted hazard ratio (HR) for cardiovascular-related mortality for a LVEF of 55.0-59.9% was 1.36 [95% confidence interval (CI) 1.16-1.59; P < 0.001] in women and 1.21 (95% CI 1.05-1.39; P = 0.008) in men. In women, an LVEF of 60.0-64.9% was also associated with a HR 1.33 (95% CI 1.16-1.52; P < 0.001) for cardiovascular-related mortality. These associations were most striking in women and men aged <65 years and were replicated in those with suspected heart failure (32 403 cases aged 65.2 ± 16.1 years, 57.0% women). For pre-existing heart failure (33 738 cases aged 67.6 ± 16.9 years, 46.5% women), the specific threshold of increased mortality was at and below 50.0-54.9%.Among patients investigated for suspected or established cardiovascular disease, we found clinically relevant sex-based differences in the distribution and mortality associated with an LVEF <65.0-69.9%. Specifically, they suggest a greater risk of mortality at higher LVEF levels among women.
Early Assessment of Treatment Response in Acute Myeloid Leukemia Using FLT PET/CT Imaging: A Trial of the ECOG-ACRIN Cancer Research Group (EAI141)
Authors: Robert Jeraj, Fenghai Duan, Ryan J. Mattison, Lale Kostakoglu, Daniel A. Arber, Elisabeth Paietta, Justin Romanoff, Jennifer Holter-Chakrabarty, Charles Arnold, Stephen A. Strickland, Jennifer Whisenant, Barry Alan Siegel, Geoffrey L Uy, Kebede H. Begna, Gregory Wiseman, Aric C. Hall, Scott Perlman, Mark Litzow, David Mankoff
Journal: Blood (2020)
Targeting and enhanced LAK cytolysis of EpiCAM-positive tumor cells by a chimeric antibody
Authors: Pak Kong, Yu-Feng Tseng, Chia-Rui Lee, Cherry T. R. Chang, Cheng-Keng Chuang, Shuen-Kuei Liao
Journal: Cancer Research (2004)

1281  EpiCAM (37-40 kDa) molecule is overexpressed on cell surface membranes of most human epithelial cancers and therefore may be a promising tumor-associated antigen for target-directed immunotherapy for most malignant diseases. In tumor cells, expression MHC class I is frequently down-regulated and tumor-specific cytotoxic lymphocytes are either not activated or in a status of anergy, thereby permitting tumors to grow progressively. Thus innovative modes of therapy which utilizes non-MHC-restricted lymphocytes in conjunction with chimeric/humanized antibodies are needed. In this study we characterized a mouse monoclonal antibody specific for an epitope on the EpiCAM molecule. This antibody was subsequently chimerized with the constant region of human IgG1, which was to bind to most cell lines and tissue specimens of a variety of epithelial tumor types as assessed by immuno-fluorescence/flow cytometric anaylsis and immunohistiochemistry. By 4-h 51Cr release cytotoxicity assays, this chimeric antibody (XO3) could induce enhanced antitumor cytolytic activity of ex vivo prepared IL2-activated human peripheral blood lymphocytes (LAK), biological response modifer (BRM)-activated killers (BAK, CD56+ cells including γδ T cells and NK, using IL2, anti-CD3, TNF-α), or perpheral blood mononuclear cells prepared from patients treated with IL2 (“in vivo LAK”). The targets used included HepG2 (HCC), HT-29 (colon) and BT-20 (breast) tumor cell lines. This enhancement of effector-mediated cytolysis induced by XO3 was demonstrated by comparison of their lytic units or percentages of specific cytolysis at a given effector: target ratio with those exhibited by the corresponding effector cells alone. The antitumor cytolytic effects were found to be further increased when IL2 was added (50-500 U/ml) to the mixture of target-effector cells during the cytotoxicity assay. The cytolytic mechanism was through antibody-dependent cell-mediated cytoxicity (ADCC), since the killing effect was not shown by use of this antibdoy without having the Fc portion. We conclude that the XO3 chimeric antibody is a suitable candidate for immunotherapy of EpiCAM-positive carcinomas, and that this antibody and the effector cell preparations used merits further investigation.
Case Fatality Rates for Patients with COVID-19 Requiring Invasive Mechanical Ventilation. A Meta-analysis
Authors: Zheng Jie Lim, Ashwin Subramaniam, Mallikarjuna Ponnapa Reddy, Gabriel Blecher, Umesh Kadam, Afsana Afroz, Baki Billah, Sushma Ashwin, Mark Kubicki, Federico Bilotta, J. Randall Curtis, Francesca Rubulotta
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Initial reports of case fatality rates (CFRs) among adults with coronavirus disease (COVID-19) receiving invasive mechanical ventilation (IMV) are highly variable.
AVAIL-T: A Phase 2a Trial of Avelumab, and Anti-PD-L1 Antibody, in Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL)
Authors: Matthew J Ahearne, Charlotte Gaskell, Aimee E Jackson, Clare Morland, Louise Hopkins, Nadia Nawaz, Matthew A Timmins, Christopher P Fox, Graham P. Collins, Andrew Davies, David John Lewis, Kate Cwynarski, Kim Linton, Pam McKay, Rod Johnson, Simon D. Wagner
Journal: Blood (2020)
The Genomic Landscape of Myeloid Neoplasms Evolved from AA/PNH
Authors: Carmelo Gurnari, Simona Pagliuca, Bhumika J. Patel, Hassan Awada, Cassandra M Kerr, Wenyi Shen, Sunisa Kongkiatkamon, Laila Terkawi, Misam Zawit, Jibran Durrani, Valeria Visconte, Seth J. Corey, Maria Teresa Voso, Hetty E. Carraway, Jaroslaw P. Maciejewski
Journal: Blood (2020)
Pharmacotherapy for Hospitalized Patients with COVID-19: Treatment Patterns by Disease Severity
Authors: Kueiyu Joshua Lin, Sebastian Schneeweiss, Helen Tesfaye, Elvira D’Andrea, Jun Liu, Joyce Lii, Shawn N. Murphy, Joshua J. Gagne
Journal: Drugs (2020)

Treatment decisions for Coronavirus Disease 2019 (COVID-19) depend on disease severity, but the prescribing pattern by severity and drivers of therapeutic choices remain unclear. The objectives of the study were to evaluate pharmacological treatment patterns by COVID-19 severity and identify the determinants of prescribing for COVID-19. Using electronic health record data from a large Massachusetts-based healthcare system, we identified all patients aged ≥ 18 years hospitalized with laboratory-confirmed COVID-19 from 1 March to 24 May, 2020. We defined five levels of COVID-19 severity at hospital admission: (1) hospitalized but not requiring supplemental oxygen; (2–4) hospitalized and requiring oxygen ≤ 2, 3–4, and ≥ 5 L per minute, respectively; and (5) intubated or admitted to an intensive care unit. We assessed the medications used to treat COVID-19 or as supportive care during hospitalization. Among 2821 patients hospitalized for COVID-19, we found inpatient mortality increased by severity from 5% for level 1 to 23% for level 5. As compared to patients with severity level 1, those with severity level 5 were 3.53 times (95% confidence interval 2.73–4.57) more likely to receive a medication used to treat COVID-19. Other predictors of treatment were fever, low oxygen saturation, presence of co-morbidities, and elevated inflammatory biomarkers. The use of most COVID-19 relevant medications has dropped substantially while the use of remdesivir and therapeutic anticoagulants has increased over the study period. Careful consideration of disease severity and other determinants of COVID-19 drug use is necessary for appropriate conduct and interpretation of non-randomized studies evaluating outcomes of COVID-19 treatments.
Nonclinical Efficacy and Toxicity and Selection of a Safe Clinical Starting Dose for an NMT Inhibitor in Development for Hematological Malignancies
Authors: Michael J. Weickert, John Dillberger, Caren Brown, Francis Phaneuf, John R. Mackey, Randeep Sangha, Luc G. Berthiaume
Journal: Blood (2020)
Integration of Hi-C and Nanopore Sequencing for Structural Variant Analysis in AML with a Complex Karyotype: (Chromothripsis)²
Authors: Marius-Konstantin Klever, Eric Sträng, Julius Jungnitsch, Uirá Souto Melo, Sara Hetzel, Anna Dolnik, Robert Schöpflin, Jens F. Schrezenmeier, Olga Blau, Jörg Westermann, Konstanze Döhner, Hubert Schrezenmeier, Malte Spielmann, Alexander Meissner, Stefan Mundlos, Lars Bullinger
Journal: Blood (2020)
Predicting Immune Pathology after Hematopoietic Stem Cell Transplant with Transcriptomics: Naïve CD4 T Cell Expansion at Day 100 Predicts Patients with De Novo Chronic Gvhd
Authors: Ben Watkins, James Kaminski, Muna Qayed, Kayla Betz, Yvonne Suessmuth, Brandi Bratrude, Alison Yu, Victor Tkachev, Kathryn Pellegrini, Steven Bosinger, Bruce R. Blazar, John T. Horan, Amelia Langston, Leslie Kean
Journal: Blood (2020)
Characterization of Rare Germline Variants in Familial Multiple Myeloma
Authors: Calogerina Catalano, Joanna Blocka, Stefanie Huhn, Nagarajan Paramasivam, Matthias Schlesner, Niels Weinhold, Rolf Sijmons, Christian Langer, Klaus Preuss, Brian G.M. Durie, Björn Nilsson, Hartmut Goldschmidt, Obul Reddy Bandapalli, Kari Hemminki, Asta Försti
Journal: Blood (2020)
Abstract 441: Neurofibromin 2 Regulates Metabolism in the Heart
Authors: Yu Zhang, Wataru Mizushima, Shinichi Oka, Zhi Yang, Peiyong Zhai, Maha Abdellatif, Dominic Del Re
Journal: Circulation Research (2020)

Background: Neurofibromin 2 (NF2) is a tumor suppressor and signaling platform that can engage the Hippo pathway to modulate cell proliferation and survival. We previously demonstrated that NF2 mediates injury caused by acute myocardial infarction (MI) through inhibition of the Hippo target YAP. However, NF2 function in the heart remains largely uncharacterized. This study sought to determine whether NF2 contributes to cardiac remodeling, dysfunction, and heart failure resulting from chronic stress. Methods and Results: We used a transverse aortic constriction (TAC) model to generate pressure overload (PO), which elicits cardiac hypertrophy, remodeling and heart failure. We found that NF2 is transiently upregulated in WT C57Bl/6J myocardium in response to PO. To investigate if increased NF2 contributes to pathology, we used cardiomyocyte-specific (αMHC-Cre) NF2 knockout (CKO) mice. At baseline, adult NF2 CKO mice had normal cardiac morphology and function. However, following TAC, NF2 CKO hearts unexpectedly showed worsened cardiac function compared to littermate controls. No differences in the extent of TAC-induced hypertrophy or apoptosis were observed between genotypes. RNAseq analysis indicated downregulation of several metabolic pathways including oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) in unstressed NF2 CKO hearts. RNAseq identified, and qPCR confirmed, downregulation of ERRβ and ERRγ expression and function in NF2 CKO hearts, as well as ATP content. Critical ETC genes were also suppressed in NF2 CKO hearts after 3 days PO. Experiments in neonatal rat cardiomyocytes (NRCM) confirmed that altered ERRβ and ERRγ expression and function, as well as ATP content, by NF2 is cell autonomous. Mechanistically, we discovered that nuclear NF2 is enriched following TAC, and that NF2 associates with the proximal promoter regions of ERRβ and ERRγ using DNA pulldown assay. We also found that NF2 activates transcription in NRCMs using the Gal4-UAS system. Future studies will identify transcription factors important for mediating this response. Conclusion: Myocardial NF2 is transiently upregulated and may be compensatory during PO through preservation of metabolic gene expression and energy content in the heart.
Enhanced Efficacy of Simultaneous PD-1 and PD-L1 Immune Checkpoint Blockade in High-Grade Serous Ovarian Cancer
Authors: Changxin Wan, Matthew P. Keany, Han Dong, Linah F. Al-Alem, Unnati M. Pandya, Suzan Lazo, Karsten Boehnke, Katherine N. Lynch, Rui Xu, Dominique T. Zarrella, Shengqing Gu, Paloma Cejas, Klothilda Lim, Henry W. Long, Kevin M. Elias, Neil S. Horowitz, Colleen M. Feltmate, Michael G. Muto, Michael J. Worley, Ross S. Berkowitz, Ursula A. Matulonis, Marisa R. Nucci, Christopher P. Crum, Bo R. Rueda, Myles Brown, Xiaole Shirley Liu, Sarah J. Hill
Journal: Cancer Research (2020)

Immune therapies have had limited efficacy in high-grade serous ovarian cancer (HGSC), as the cellular targets and mechanism(s) of action of these agents in HGSC are unknown. Here we performed immune functional and single-cell RNA sequencing transcriptional profiling on novel HGSC organoid/immune cell co-cultures treated with a unique bispecific anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibody compared with monospecific anti-PD-1 or anti-PD-L1 controls. Comparing the functions of these agents across all immune cell types in real time identified key immune checkpoint blockade (ICB) targets that have eluded currently available monospecific therapies. The bispecific antibody induced superior cellular state changes in both T and natural killer (NK) cells. It uniquely induced NK cells to transition from inert to more active and cytotoxic phenotypes, implicating NK cells as a key missing component of the current ICB-induced immune response in HGSC. It also induced a subset of CD8 T cells to transition from naïve to more active and cytotoxic progenitor-exhausted phenotypes post-treatment, revealing the small, previously uncharacterized population of CD8 T cells responding to ICB in HGSC. These state changes were driven partially through bispecific antibody-induced downregulation of the bromodomain-containing protein BRD1. Small-molecule inhibition of BRD1 induced similar state changes in vitro and demonstrated efficacy in vivo, validating the co-culture results. Our results demonstrate that state changes in both NK and a subset of T cells may be critical in inducing an effective anti-tumor immune response and suggest that immune therapies able to induce such cellular state changes, such as BRD1 inhibitors, may have increased efficacy in HGSC. SIGNIFICANCE: This study indicates that increased efficacy of immune therapies in ovarian cancer is driven by state changes of NK and small subsets of CD8 T cells into active and cytotoxic states.
Abstract 457: Outer Membrane Vesicle From Pseudomonas Aeruginosa Causes Inflammation and Cardiac Dysfunction
Authors: Naresh Kumar, Matthew Pestrak, Qian Wu, Sheri dellos-nolan, Lianbo Yu, William Lafuse, Latha Ganesan, Daniel Wozniak, Murugesan Rajaram
Journal: Circulation Research (2020)

Rationale: P. aeruginosa ( P.a ) infection causes severe pneumonia in ICU patients that lead to cardiac inflammation, eventual tissue remodeling, fibrosis, and cardiac complication. Growing evidence indicates that cardiac resident CCR2 - , MHC-II low macrophages function as important regulators of cardiac inflammation and steady-state heart function. After tissue injury or infection, inflammatory monocytes are recruited to the heart and differentiate into inflammatory macrophages, which contribute to cardiac inflammation and dysfunction. Our preliminary result showed P.a. infection causes cardiac inflammation, fibrosis, and cardiac dysfunction without disseminating into the heart tissue. Also, the gram-negative bacteria can release toxins or outer membrane vesicles (OMVs) that target host cells and induces apoptosis. Thus we hypothesize that the cardiac damage caused by P.a infection is mainly due to the release of bacterial toxins and OMVs or inflammatory mediators released by immune cells. Understanding the molecular mechanism of cardiac inflammation and dysfunction is critical for the development of host-directed therapy. Objective: To identify the mechanism of P.a induced inflammation and cardiac dysfunction to develop therapies to prevent cardiac damage during infection. Methods and Results: To investigate the role of OMVs in cardiac inflammation and cardiac dysfunction, we have isolated OMVs from P. aeruginosa culture supernatant and purified using ultracentrifugation followed by gradient centrifugation. We quantified OMVs and used to stimulate the MDMs, BMDMs and hiPSC cardiomyocytes. Our in vitro study showed that OMVs activates Akt and MAPK signaling pathways and induces the production of inflammatory cytokines from macrophages. Additionally, we found that OMVs incubation significantly reduced the hiPSC myocyte contraction. Conclusion: These studies demonstrated that OMVs from P.a induced inflammatory cytokine production and subsequent myocyte contractile dysfunction. Studies are ongoing to determine the role of OMVs on the action potential of hiPSC-CMs. In future, we will determine the impact of OMVs in cardiac dysfunction in mouse model.
Abstract 372: Misoprostol Attenuates Hypoxia-induced Cardiomyocyte Proliferation Through Bnip3 and Perinuclear Calcium Signaling
Authors: Matthew D Martens, Jared T Field, Nivedita Seshadri, Chelsea Day, Christine Doucette, Adrian R West, Tammy L Ivanco, Joseph W Gordon
Journal: Circulation Research (2020)

Systemic hypoxia resulting from preterm birth, altered lung development, and cyanotic congenital heart disease is known to impede the regulatory and developmental pathways in the neonatal heart. While the molecular mechanisms are still unknown, hypoxia induces aberrant cardiomyocyte proliferation, which may be initially adaptive, but can ultimately program the heart to fail in early life. Recent evidence suggests that the prostaglandin E1 analogue, misoprostol, is cytoprotective in the hypoxia-exposed neonatal heart by impacting alternative splicing of the Bcl-2 family member Bnip3, resulting in the generation of a variant lacking the third exon (Bnip3 Δ Exon3 or small Nip; sNip). Using a rodent model of neonatal hypoxia, in combination with rat primary neonatal cardiomyocytes (PVNC’s) and H9c2 cells, we sought to determine if misoprostol can prevent cardiomyocyte proliferation and what the key molecular mechanisms might be in this pathway. In PVNC’s, exposure to 10% oxygen induced myocyte proliferation concurrent with molecular markers of cell-cycle progression, such as Cyclin-D1, which were prevented by misoprostol treatment. Furthermore, we describe a critical role for sNip in opposing cardiomyocyte proliferation through several mechanisms, including reduced expression of the proliferative MEF2C-myocardin-BMP10 pathway, promoting nuclear calcium accumulation leading to NFATc3 activation, and increased expression of the cardiac maturation factor BMP2. Intriguingly, misoprostol and sNip inhibited a hypoxia-induced glycolytic flux, which directly influenced myocyte proliferation. These observations were further supported by knockdown studies, where hypoxia-induced cardiomyocyte proliferation is restored in misoprostol-treated cells by an siRNA targeting sNip. Finally, in postnatal day (PND)-10 rat pups exposed to hypoxia, we observed histological evidence of increased nuclei number and increased PPH3 staining, without fibrosis which were completely attenuated by misoprostol treatment. Collectively, this data demonstrates how neonatal cardiomyocyte proliferation can be pharmacologically modulated by misoprostol treatment, which may have important implications for both neonatal and regenerative medicine.