tbuckley/cabot-search huggingface dataset:
FRI0587 IGG4-RELATED DISEASE IN ITALY: RESULTS FROM A MONOCENTRIC COHORT OF 150 PATIENTS (2013–2018)
Authors: Marco Lanzillotta, Emanuel Della Torre, Corrado Campochiaro, Enrica Bozzolo, Lorenzo Dagna
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disease characterized by fibrotic lesions and elevated IgG4 serum level. Epidemiological and clinical data in our country have not been precisely assessed yet <h3>Objectives</h3> The aim of this work is to present the data from the largest monocentric Italian IgG4-RD cohort. <h3>Methods</h3> We conducted a retrospective analysis searching for IgG4-RD patients referred to our tertiary care centre between 2013 and 2018. Diagnosis were made according to the "Comprehensive Diagnostic Criteria 2011", and patients were clustered on the basis of a definite, probable and possible, diagnosis. Each patient underwent clinical, serological, and radiological evaluation according to the organ involvement. IgG4-RD activity was measured with IgG4-RD Responder Index (IgG4-RD RI). All the data are reported in median and interquartile range. <h3>Results</h3> 150 patients were included in this work (111 male, 39 female, M:F ratio 2.8:1). 75 cases received a definite IgG4-RD diagnosis, while 6 patients and 49 patients were diagnosed as <i>probable</i> and <i>possible</i> IgG4-RD, respectively. Median age at diagnosis was 60 (SD 13) years old. The most involved organ was the pancreas (66 cases; 44%), followed by lymph nodes (26 cases; 17%), biliary tree (25 cases; 17%), salivary glands (21 cases; 14%), aorta and retroperitoneum (12 cases; 8%), meninges (9 cases; 6%), nasal sinuses and nasal septum (5 cases; 3%). 18 patients (12%) had a positive history of malignancies that occurred ten years earlier or after IgG4-RD diagnosis. At baseline, IgG4 level was elevated in 92 patients (61%), while eosinophil count and IgE level were elevated in 35 (23%) and 52 (35%) patients, respectively. Circulating plasmablast were measured in 88 and elevated in 66 (1859 cell/mL, 600-3950). Median IgG4-RD RI at diagnosis was 6 (6-9). 55 patients were treated with glucocorticoids alone, whereas immunomodulator (Mycophenolate mofetil, azathioprine, cyclophosphamide) were associated in 31 cases. Rituximab was administered in 32 patients. 15 patients underwent surgical excision of the fibrotic lesion. 15 patients were candidate to a watchful waiting strategy, due to low disease burden. <h3>Conclusion</h3> Our study reports clinical and epidemiological data from the largest monocentric cohort of patients with IgG4-RD in Italy. Our data reflect those reported in other international cohorts of IgG4-RD patients. <h3>References</h3> [1] Della Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin exp Imm.2015 <h3>Disclosure of Interests</h3> Marco Lanzillotta: None declared, Emanuel Della Torre: None declared, Corrado Campochiaro Consultant for: Dr Corrado Campochiaro received consultation honoraria from Pfizer., Enrica Bozzolo: None declared, Lorenzo Dagna: None declared
AB1059 CLINICAL MANIFESTATIONS OF CHILDHOOD-ONSET SYSTEMIC LUPUS ERYTHEMATOSUS PRESENTING WITH CYTOPENIA
Authors: Woosuck Suh, Ki Hwan Kim, Jung Woo Rhim, Soo Young Lee, Seung Beom Han, Nack Gyun Chung, Dae Chul Jeong
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Childhood-onset Systemic Lupus Erythematosus is a rare disease, with more than 50% of patients presenting with cytopenia of a decrease in at least one cell line. <h3>Objectives</h3> The purpose of this study was to evaluate whether clinical characteristics differed according to hematologic manifestation. <h3>Methods</h3> We retrospectively reviewed the presenting clinical and laboratory manifestations for 40 pediatric SLE patients (mean age 13.4 years, range 0-18 years), with leukopenia (n=12) and thrombocytopenia (n=15). Variables including age, inflammatory markers (ESR and CRP), prothrombin time, complement system (C3, C4 and CH50), immunoglobulin (IgG, IgA and IgM), Lupus anticoagulant ratio, antinuclear antibody, anti-phospholipid antibody, anti-platelet antibodies, anti β2-glycoprotein antibody, anti-cardiolipin antibody, anti-smith antibody and anti-dsDNA antibody levels were compared according to grouping by presence of leukopenia (&lt;4000/mm<sup>3</sup>) or thrombocytopenia (&lt;100,000/mm<sup>3</sup>). <h3>Results</h3> Patients with cytopenia showed younger age at diagnosis than without (mean 13.1 vs. 15.2 years, p=0.0031 for leukopenia and 12.8 vs. 15.2 years, p=0.014 for thrombocytopenia), although the onset of puberty might not contribute to cytopenia. Patients with leukopenia showed lower C3 level than without (mean 44.7 vs. 73.7, p=0.013). Patients with thrombocytopenia showed lower anti-dsDNA titer than without (mean 94.1 vs. 259.8, p=0.038), and was more often negative for anti-platelet antibody (Ib/IX). There were no statistical differences among other variables. Also, there was no significant difference in one cell line decrement compared with both. <h3>Conclusion</h3> Pediatric SLE patients with leukopenia and thrombocytopenia in our study may independently decrease the levels of C3 and anti-dsDNA/anti-platelet (Ib/IX) antibody, suggesting respective pathologic pathways that do not affect each other. <h3>Disclosure of Interests</h3> None declared
PF531 TRANSFORMING ACTIVITIES OF THE NUP98-KMT2A FUSION GENE ASSOCIATED WITH MYELODYSPLASIA AND ACUTE MYELOID LEUKEMIA
Authors: J.N. Fisher, A. Thanasopoulou, S. Juge, A. Tzankov, F.O. Bagger, M. Mendez, A.H. Peters, J. Schwaller
Journal: HemaSphere (2019)

Background: Inv (11)(p15q23) found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) was previously shown to lead to the expression of a fusion consisting of the N-terminal part of nucleoporin 98 (NUP98) and almost the entire open reading frame (ORF) of the lysine methyltransferase 2A (KMT2A, aka MLL1). Aims: To address the role of the NUP98-KMT2A fusion as a potential leukemogenic oncogene. Methods: To overcome the limitations related to the large size of the fusion ORF, we generated DOX-inducible transgenic iNUP98-KMT2A mice. We studied the effects of iNUP98-KMT2A expression in hematopoietic cells ex vivo in clonogenic assays; and in vivo by assessing blood counts, histology, and immunophenotyping as well as by competitive repopulation assays. In addition, we established primary mouse embryonic fibroblast (MEF) cultures to address the effects of iNUP98-KMT2A on cell cycle progression and cellular senescence. Results: In contrast to other KMT2A fusion such as MLL-AF9, induction of iNUP98-KMT2A did not alter differentiation but impaired growth of bone marrow (BM)-derived cells in vitro. Induction of iNUP98-KMT2A in vivo resulted in signs of disease after a highly variable latency of 13–106 weeks (median latency = 80 weeks, n = 22). Some symptomatic mice presented with increased white blood counts with morphological signs of dysplasia, reduced red blood cells, and increased apoptosis in the BM with signs of extramedullary hematopoiesis. In addition, we observed a 3-fold expansion of Lin−Sca-1+c-Kit+ (LSK) hematopoietic stem and progenitor cells (HSPC) in the BM of these mice. BM cells from symptomatic iNUP98-KMT2A mice had a competitive advantage in reconstitution assays. About 20% (5/22) of the mice on DOX presented with transplantable AML with elevated WBC counts and leukemic blasts in the peripheral blood with infiltration of multiple organs. Expression of iNUP98-KMT2A was associated with aberrant cell cycle progression in LSK cells from primary-induced mice. Similarly, iNUP98-KMT2A expression affected cell cycle progression and abrogated cellular senescence in MEF associated with aberrant expression of Sirt1, Tert, Rbl2, Twist1, Vim, and Prkcd that was also observed in BM cells. Notably, similar to patients with NUP98-KMT2A, and in contrast to other KMT2A fusions, primary AML cells from diseased iNUP98-KMT2A mice expressed very low levels of the Hox-A-B-C gene cluster. In addition, iNUP98-KMT2A leukemic blasts were resistant to the effects of pharmacological targeting of Menin/KMT2A interface or BET-family proteins. Summary/Conclusion: Our work shows that the NUP98-KMT2A fusion has oncogenic potential in mice leading to an MDS-like disease or AML. In contrast to other KMT2A fusions, NUP98-KMT2A does not primarily block differentiation and provide aberrant self-renewal potential, but alters cell cycle progression leading to dysplasia and impairs cellular senescence.
VEGF – Supplemented extracellular matrix is sufficient to induce endothelial differentiation of human iPSC
Authors: Imran Ullah, Raed Abu-Dawud, Jonas Felix Busch, Anja Rabien, Bettina Erguen, Iris Fischer, Petra Reinke, Andreas Kurtz
Journal: Biomaterials (2019)

Extracellular matrix (ECM) provides a scaffold for cells and tissues, but also supports organogenesis and tissue remodeling. The required instructive properties of the ECM to interact with cells depend on matrix architecture, structural proteins and functional matrix components such as growth factors, providing spatial, chemical and functional cues. Decellularized ECM (dECM) has been proposed as an instructive material that promotes tissue regeneration. We investigated the instructive ECM elements preserved in dECM and necessary to promote endothelial differentiation of human induced pluripotent stem cells (hiPSC). We show that detergent-decellularized human kidney ECM remains structurally intact and carries a number of heparin-binding growth factors, including FGF2, VEGF, BMP2, HGF, EGF, PDGF-BB and TGFβ, albeit at reduced levels compared to native tissues. Clearance of these heparin-binding factors, or heparan-sulfate proteoclycans from ECM resulted in massively reduced differentiation of hiPSC, suggesting that remaining structural dECM proteins such as laminin, collagen or fibronectin alone are not instructive. In contrast, replenishing dECM with VEGF replaced medium-supplemented VEGF and resulted in more efficient differentiation of hiPSC into endothelial cells, and even in the absence of other culture-supplemented differentiation factors dECM alone was superior to geltrex. In conclusion, conditioning of dECM with specific growth factors acting as functional cues may allow to generate functional niches by selective promotion of cell attachment, survival and differentiation.
Abstract 3756: The Fourth Heart Sound is Associated with Increased Left Ventricular End-Diastolic Elastance
Authors: Sanjiv J Shah, Gregory M Marcus, Ivor L Gerber, Barry H McKeown, Joshua C Vessey, Mark V Jordan, Michele Huddleston, Elyse Foster, Andrew D Michaels
Journal: Circulation (2006)

Background: The significance of the fourth heart sound (S4) is unclear. Although the S4 is thought to be associated with a stiff ventricle, prior studies have failed to consistently show an associa...
Abstract 17959: Is External Chest Compression Safe in Ventricular Assist Device Patients? A Case Series
Authors: BHASKAR ARORA, Joseph Radojevic, Konstadina Darsaklis, Jonathan Hammond, Nicole Huhn, Nicole Chomick, Tari Devoe, Thomas Ciesielski, David Underhill, Daniel Fusco, Jason Gluck
Journal: Circulation (2015)

Introduction: Current resuscitation guidelines do not address ventricular assist device (VAD) population. However, commonly adopted resuscitation algorithms discourage use of external chest compression (ECC). This deviation from convention is largely driven by the concern that ECC could dislodge the VAD inflow cannula. We present a case series of 4 patients with left ventricular assist device (LVAD) that underwent ECC during CPR without suffering any ill effects. One patient underwent targeted temperature therapy (TTT) after arrest and had successful neurological recovery. Hypothesis: 1. ECC may be safe and effective in patients with VAD. 2. End tidal CO2 (ETCO2), a surrogate for cardiac output, can guide initiation of ECC in this population. Methods: This case series was performed at a single North American tertiary medical center. Clinical data was gathered by review of hospital chart. Autopsy data was used to verify integrity of VAD after ECC. Baseline characteristics are described in Table 1. Results: Three out of these four patients underwent ECC. One had a VAD implant within 60 days of this event. Autopsy showed that VAD circuit was intact in all three including the fresh implant. The fourth patient with respiratory failure didn’t receive ECC because ETCO2 value was higher than 20 mm Hg. ROSC was established in two patients with ETCO2 greater than 10 mm Hg, none survived to hospital discharge. TTT was performed in one patient with improvement in neurological status.Results are described in table 2. Conclusions: ECC can be safely performed in VAD patients. ETCO2 less than 20 mm Hg can be used to initiate ECC. ETCO2 could predict survival in this population. TTT can be safely performed in VAD. More evidence is needed to consolidate these findings.
Re: Hwang et al.: Distinguishing highly asymmetric keratoconus eyes using combined Scheimpflug and spectral-domain OCT analysis (Ophthalmology. 2018;125:1862-1871)
Authors: Bernardo T. Lopes, Michael W. Belin, Fernando Faria-Correia, Marcella Q. Salomão, Renato Ambrósio
Journal: Ophthalmology (2019)
AB0781 ASSOCIATION OF MICA POLYMORPHISM AND SERUM LEVELS WITH PREDISPOSITION TO PSORIATIC ARTHRITIS
Authors: Renata Sokolik, Marta Dratwa, Joanna Wielinska, Milena Iwaszko, Monika Chaszczewska-Markowska, Piotr Wiland, Katarzyna Bogunia-Kubik
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Psoriatic arthritis (PsA) is a multifactorial chronic inflammatory disease manifested by joint inflammation and cutaneous psoriasis. The precise etiology of PsA remains unknown, however both genetic and environmental factors contribute to development of this immune-mediated disease. <h3>Objectives:</h3> This present study aimed to assess whether polymorphism within gene coding for major histocompatibility complex (MHC) class I chain-related a (MICA) proteins could be a prognostic factor of PsA. <h3>Methods:</h3> For this purpose 77 PsA patients and 234 controls were enrolled to the study on MICA polymorphic variants. Genotyping for MICA rs1051792 (Met/Val; G&gt;A) was performed using a LightSNiP assay. In addition the MICA serum levels were studied in 66 patients and 99 controls employing Luminex assay. <h3>Results:</h3> Interestingly, MICA polymorphism was found to affect the susceptibility to PsA. The presence of the a (Val) variant was found to increase the risk of PsA (OR= 1.932, p=0.022). No significant differences were detected between MICA serum levels in patients and controls. However, patients carrying this risk variant (A allele) characterized with lower MICA serum levels as compared GG homozygotes (p=0.018) <h3>Conclusion:</h3> These results imply that MICA polymorphism may constitute a risk factor of PsA and be associated with MICA serum levels in PsA patients. Supported by the National Science Centre (Poland) grant: 2016/21/B/NZ5/01901. <h3>Disclosure of interests:</h3> None declared
Abstract 13759: Impact of Intrauterine Insulin-like Growth Factor 1 Levels on Cardiovascular Structures and Function in Small for Gestational Age Infants
Authors: Yohei Akazawa, Noriko Motoki, Akira Hachiya
Journal: Circulation (2017)

Introduction: Small for gestational age (SGA) infants was identified as a relevant risk factor for adult onset cardiovascular disease by epidemiological studies. Although previous studies have demo...
Benefits of Stock Epinephrine Likely Misestimated—Reply
Authors: Marcus Shaker, Matthew Greenhawt
Journal: JAMA Pediatrics (2019)

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Abstract 19018: Histone 3 Lysine 4 Tri-Methylation is Necessary for Epicardial Epithelial-to-mesenchymal Transformation
Authors: Michael R Krainock, Omar Toubat, Soula Danopoulos, Kaho Keho, Denise Al Alam, Vaughn A Starnes, Richard W Kim
Journal: Circulation (2015)

Introduction: Recent whole exome sequencing carried out in patients with congenital heart disease revealed an over-representation of mutations in members of the Histone 3 Lysine 4 Methyltransferase Complex, indicating that the methylation of Histone 3 Lysine 4 (H3K4) is of particular importance during heart development. In the tri-methylated state (H3K4me3) this signature actively promotes gene transcription through the recruitment of the Pre-Initiation Complex to the promoter. There are currently no data regarding the role of the H3K4me3 modification in cardiogenesis. We investigated the hypothesis that the acquisition of H3K4me3 is necessary for Epicardial Epithelial-to-Mesenchymal Transformation (EMT). Methods: Global patterns of H3K4 tri-methylation were investigated in epicardial cells undergoing EMT in the embryonic quail heart in-vivo, via co-staining of H3K4me3 with the epicardial marker pan-cytokeratin, and the mesenchymal marker alpha-Smooth Muscle Actin. For the in-vitro investigation of H3K4me3 during Epicardial EMT, quail epicardial explants were induced to undergo mesenchymal transformation via treatment with Fetal Bovine Serum alone, and in the presence of an H3K4 methyltransferase inhibitor. Epicardial EMT was characterized by the induction of Snail expression, a loss of E-cadherin, the expression of alpha-Smooth Muscle Actin, and an increase in nuclear area. The acquisition of new H3K4me3 was investigated via Immunohistochemistry. Results: There is a global acquisiton of H3K4me3 in quail epicardial cells undergoing EMT in-vivo and in-vitro. Inhibition of H3K4 methyltransferase activity impaired Snail gene expression, rescued E-cadherin, prevented the expression of alpha-Smooth Muscle Actin, and prevented nuclear enlargement in epicardial cells in-vitro, while having no effect on cell proliferation. Conclusions: We conclude that the acquisition of tri-methylated H3K4 is featured in Epicardial EMT both in-vivo and in-vitro in embryonic quail epicardium. This acquisition is necessary for Epicardial Epithelial-to-Mesenchymal Transformation in-vitro. These data represent the first potential explanation as to how mutations in the H3K4 Methyltransferase Complex impair heart development.
SP0157 PRO SESSION: IMPUTATION IS A POWERFUL ANALYTICAL TOOL, WHEN APPROPRIATELY USED
Authors: Loreto Carmona
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Analysing a study with missing data very likely will yield biased results. Of course, the first principle is to avoid missing data by designing the study and the data collection very thoughtfully. If the study is already done and data collected, then one needs to study how important, and what type of missingness is affecting our data. Simple <i>ad hoc</i> methods, such as LOCF, or imputing the mean or other value are generally invalid. Multiple imputations need additional work and expertise, but generally yield better results, closer to reality. Many statistical programmes have macros available for imputing missing values and analysing imputed data. We will review how these work. Understanding what multiple imputations do will make the decision clearer. <h3>Disclosure of Interests:</h3> Loreto Carmona Grant/research support from: Abbvie, Actelion, Astellas, BMS, Eisay, Gebro Pharma, Grünenthal, Leo Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis and UCB Pharma, Paid instructor for: Novartis
SP0046 CAN IMAGING MONITOR/DEMONSTRATE TREATMENT RESPONSE IN OA?
Authors: Felix Eckstein
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Treatment for osteoarthritis (OA) should ideally not be limited to ameliorating symptoms, but should include the modification of synovial joint structures that are involved in the disease process (disease modification). Imaging, particularly MRI, has unparalleled ability to evaluate joint structures qualitatively or quantitatively. <h3>Objectives:</h3> To discuss 1) Why one should care about structure (and its modification) in OA, 2) Which joint structures may be most relevant to modify, 3) Why quantification of tissue structure is beneficial, 4) To what extent tissue structure in OA can currently be modified by intervention, and 5) Whether translation of structure modification to clinical benefits is realistic? <h3>Methods:</h3> Narrative literature review. <h3>Results:</h3> A public meeting for the FDA, organized by the Arthritis Foundation in March 2017, concluded that "most importantly, patients want therapies which stop progression whilst alleviating pain and improving function, yet stopping disease progression is their utmost concern and desire for new therapies". Despite other notions, there is good evidence that structural damage of synovial tissues is related to joint pain. Quantification of synovial tissue from serial MRIs can detect longitudinal changes that are too small to be detected by the naked eye. There exist surgical (e.g. joint distraction<sup>1</sup> and high tibial osteotomy), and pharmacological approaches are in development (e.g. FGF 18 or sprifermin<sup>2</sup>), to modify joint structure. Finally, structural change of joint tissues has been shown to be related to knee replacement (KR) as a hard clinical outcome<sup>3</sup>. <h3>Conclusion:</h3> Quantitative imaging has become a powerful tool for demonstrating structure modification (treatment response) in OA. This may hopefully lead to regulatory approval of disease modifying therapy for OA in the not too distant future. <h3>References:</h3> [1] van der Woude JAD, et al. Cartilage 2017: 263 [2] Hochberg M, et al. Osteoarthritis and Cartilage 2018; 26, S26-S27 [abstract] [3] Eckstein et al. European Radiology 2016: 1942 <h3>Disclosure of Interests:</h3> Felix Eckstein Shareholder of: Shareholder of Chondrometrics GmbH, Consultant for: Consulting fees from Merck KGaA, Samumed LLC, Abbvie, Bioclinica, TissueGene, Servier, and Roche, Employee of: Employee of Chondrometrics GmbH