tbuckley/cabot-search huggingface dataset:
PF687 RISK OF THROMBOSIS IN PATIENTS WITH POLYCYTHEMIA VERA AND ESSENTIAL THROMBOCYTHEMIA ACCORDING TO THE JAK2 V617F ALLELE BURDEN
Authors: S.H. Bae, J.Y. Nam, A.-J. Lee, J. Yun, S.-G. Kim, W.S. Lee
Journal: HemaSphere (2019)

Background: Thrombosis is one of the major causes of morbidity and mortality in patients with chronic phase myeloproliferative neoplasms (MPN) comprising polycythemia vera (PV) and essential thrombocythemia (ET). The JAK2 V617F mutation is the most common driver mutation in BCR-ABL1 negative MPNs and the presence of JAK2 V617F is an independent risk factor of thrombotic events in patients with ET. Aims: In this study, we analyzed whether the JAK2 V617F allele burden is associated with the incidence of thrombosis in JAK2 V617F-positive patients with PV or ET. Methods: This was a retrospective study that assessed the impact of JAK2 V617F allele burden on clinical and laboratory characteristics in JAK2 V617F-positive patients with PV or ET. Patients with a diagnosis of PV or ET according to the WHO criteria at Daegu Catholic University Hospital between 2008 and 2018 were included in this study. JAK2 V617F allele burden were measured by pyrosequencing. Results: A total of 127 patents, median age 68 years, with PV (n = 61) or ET (n = 66) were included in our analyses. The JAK2 V617F allele burden in the entire population of patients was 45.0 ± 25.9%. A higher V617F allele burden was associated with higher white blood cell counts, higher hemoglobin values, lower platelet counts and higher LDH level (p < 0.001, p < 0.001, p = 0.001, and p = 0.001, respectively). There was a statistically significant difference in the JAK2 V617F allele burden between PV and ET (p < 0.001). The median V617F allele burden in PV patients was 58%, and ET was 30%. Thrombotic events were observed in 27.8% and 51.5% in patients with PV and ET, respectively. Multivariate logistic regression analysis revealed that older age (odds ratio, 1.07; 95% CI 1.01–1.18) was associated with higher incidence of thrombosis in patients with PV. In patients with ET, multivariate logistic regression analysis revealed that older age (odds ratio, 1.36; 95% CI 1.14–1.72), higher hemoglobin (odds ratio, 1.26; 95% CI 1.09–1.54), and V617F allele burden≥30% (odds ratio, 1.03; 95% CI 1.00–1.08) was elucidated as risk factors for thrombotic complications. Summary/Conclusion: JAK2 V617F allele burden can represent the disease phenotype. The incidence of thrombotic complications in ET patients with high JAK2 V617F allele burden is significantly higher than patients with low JAK2 V617F allele burden. There was no significant difference of the rate of thrombosis in PV patients according to the JAK2 V617F allele burden.
AB1008 AGE DEPENDENT SAFETY AND EFFICACY OF COLCHICINE TREATMENT FOR FAMILIAL MEDITERRANEAN FEVER IN CHILDREN
Authors: Yoel Levinsky, Ori Goldberg, Orit Peled, Gideon Koren, Liora Harel, Gil Amarilyo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Colchicine has been found to be highly effective for the treatment of familial Mediterranean fever (FMF). However, it is FDA-approved only for children older than 4 years owing to the lack of studies in younger children. <h3>Objectives</h3> Our tertiary pediatric rheumatology department routinely uses colchicine even in very young children with FMF. The aim of the study was to evaluate its safety and efficacy in children with FMF &lt;4 years old. <h3>Methods</h3> The departmental database was searched for all children diagnosed with FMF between 2010-2018. Those who started treatment with colchicine before age 4 years were identified and matched by MEFV variant to children who started treatment at age 4-8 years. Drug efficacy was assessed by the improvement in the frequency and duration of attacks. Adverse events were assessed according to the Rheumatology Common Toxicity Criteria ver. 2.0. <h3>Results</h3> The cohort included 89 patients with FMF: 41 first treated before age 4 years, and 48 first treated at age 4-8 years. Rates of complete response to colchicine were 61% in the younger group and 60.4% in the older group. Corresponding rates of partial remission were 24.4% and 29.2% (<i>p</i>=0.77). The most frequent adverse event was diarrhea, with a prevalence of 24.4% in the younger group and22. 9% in the older group (p=0.87). There were no significant between-group differences in other adverse events. <h3>Conclusion</h3> Colchicine is equally effective and safe for use in patients with FMF under 4 years old, with no difference in response from older pediatric patients. IQR-interquartile range Values are n(%) unless otherwise indicated. AEs – adverse events * RCTC- Rheumatology Common Toxicity Criteria, version 2.0 for AE severity:0-no, 1-- mild, 2 – moderate, 3 – severe, 4 – life-threatening Values are n (%) unless otherwise indicated. <sup>§</sup> Due to statistical limitations, Statistic analysis (Fisher's exact test) was performed between No AEs &amp; RCTC score 1 and RCTC score 2-4 in the respected age groups. <sup>†</sup>Data available for 34 patients. <sup>‡</sup>Data available for 43 patients. <h3>Disclosure of Interests</h3> None declared
Androgen receptor (AR), E-cadherin, and Ki-67 as prognostic markers in triple-negative breast cancer (TNBC).
Authors: Giuseppina R. R. Ricciardi, Barbara Adamo, Giuseppa Ferraro, Tindara Franchina, Mariangela Zanghì, Carmelo Buda, Giuseppe Trimarchi, Roberta Cardia, Giovanni Tuccari, Vincenzo Adamo
Journal: Journal of Clinical Oncology (2013)

1062 Background: TNBC is an aggressive subset of breast cancer (BC) with central nervous system and visceral metastatic involvement and it represents a molecular subtype without specific target therapy. Methods: This observational, retrospectivestudy included 45 TNBC. The aim of this study was to evaluate the expression of some molecular determinants such as the AR, E-cadherin and Ki-67 in relation to histological type, time to relapse and overall survival.Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients (pts) defined TNBC, since ER and PgR were 0% and HER2 negative (IHC score 0/1 or FISH not amplified). Results: Median age was 58.8 years (range 39-77). The main histological type was ductal in 35 pts (77.7%), lobular in 7 (15.5%), medullary in 3(6.6%). 29 pts (64.4%) had a G3 tumor. Tumor stage was: I 6/45 (13.3%), IIA 21/45 (46.6%), IIIA 11/45 (24.4%), IIIB 3/45 (6.6%) and IV 4/45 (8.8%). All patients received treatments; the most frequently used regimens were anthracycline and taxanes. The androgen receptor was positive (IHC &gt;10%) in 12/45 (26.6%). E-cadherin expression was semi-quantitatively analyzed according to the percentage of cells showing membrane positivity: 0 (0 to 10%); 1+ (10 to 30%); 2+ (30 to 70%); 3+ (&gt; 70%). E-cadherin expression was considered positive if the score was ≥ 2, and negative when score was ≤ 1. This expression was negative in 24/45 (53.3%) cases. The Ki-67 index was ≥ 25% in 17/45(37.7%). The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with the ductal histotype and G3 tumors (p &lt; 0.001). Multivariate analysis showed that the patients with AR and E-cadherin negative but Ki-67 positive expression showed significantly (p &lt; 0.001) worse overall survival time than those with either AR and E-cadherin positive but Ki-67 negative expression. Conclusions: Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC.
MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia
Authors: Fiona C. Brown, Eric Still, Richard P. Koche, Christina Y. Yim, Sumiko Takao, Paolo Cifani, Casie Reed, Shehana Gunasekera, Scott B. Ficarro, Peter Romanienko, Willie Mark, Craig McCarthy, Elisa de Stanchina, Mithat Gonen, Venkatraman Seshan, Patrick Bhola, Conor O'Donnell, Barbara Spitzer, Crystal Stutzke, Vincent-Philippe Lavallée, Josée Hébert, Andrei V. Krivtsov, Ari Melnick, Elisabeth M. Paietta, Martin S. Tallman, Anthony Letai, Guy Sauvageau, Gayle Pouliot, Ross Levine, Jarrod A Marto, Scott A. Armstrong, Alex Kentsis
Journal: Cancer Discovery (2018)

Abstract In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL–AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease. Significance: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. Cancer Discov; 8(4); 478–97. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 371
β Cell–intrinsic β-arrestin 1 signaling enhances sulfonylurea-induced insulin secretion
Authors: Luiz F. Barella, Mario Rossi, Lu Zhu, Yinghong Cui, Fang C. Mei, Xiaodong Cheng, Wei Chen, Vsevolod V. Gurevich, Jürgen Wess
Journal: Journal of Clinical Investigation (2019)

β-Arrestin 1 and 2 (Barr1 and Barr2, respectively) are intracellular signaling molecules that regulate many important metabolic functions. We previously demonstrated that mice lacking Barr2 selectively in pancreatic β cells showed pronounced metabolic impairments. Here we investigated whether Barr1 plays a similar role in regulating β cell function and whole-body glucose homeostasis. Initially, we inactivated the Barr1 gene in β cells of adult mice (β-barr1-KO mice). β-barr1-KO mice did not display any obvious phenotypes in a series of in vivo and in vitro metabolic tests. However, glibenclamide and tolbutamide, 2 widely used antidiabetic drugs of the sulfonylurea (SU) family, showed greatly reduced efficacy in stimulating insulin secretion in the KO mice in vivo and in perifused KO islets in vitro. Additional in vivo and in vitro studies demonstrated that Barr1 enhanced SU-stimulated insulin secretion by promoting SU-mediated activation of Epac2. Pull-down and coimmunoprecipitation experiments showed that Barr1 can directly interact with Epac2 and that SUs such as glibenclamide promote Barr1/Epac2 complex formation, triggering enhanced Rap1 signaling and insulin secretion. These findings suggest that strategies aimed at promoting Barr1 signaling in β cells may prove useful for the development of efficacious antidiabetic drugs.
FRI0243 RECOVERY OF RENAL FUNCTION IN PATIENTS WITH LUPUS NEPHRITIS AND REDUCED RENAL FUNCTION
Authors: Jung Sun Lee, Wook Jang Seo, Ji Seon Oh, Seokchan Hong, Yong-Gil Kim, Chang-Keun Lee, Bin Yoo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Reduced renal function is associated with worse renal outcome in patients with lupus nephritis (LN). However, there is insufficient knowledge regarding renal function recovery in patients with LN with reduced baseline renal function. <h3>Objectives</h3> The present study aimed to investigate renal function recovery and related factors in patients with reduced baseline renal function. <h3>Methods</h3> The present retrospective longitudinal cohort study included patients with LN and reduced renal function. Reduced renal function was defined as an estimated glomerular filtration rate (eGFR) &lt;60 mL/min/1.73 m<sup>2</sup>. Recovery of renal function was determined by eGFR &gt;60 mL/min/1.73 m<sup>2</sup> at 6 months after baseline, and factors associated with it were evaluated using logistic regression analysis. <h3>Results</h3> We included 90 patients with LN, with a mean eGFR value of 37.2 (± 13.9) mL/min/1.73 m<sup>2</sup>. Forty-six patients (51.1%) recovered their renal function after 6 months. On multivariate analysis, hydroxychloroquine use (OR: 3.891, 95% CI: 1.196–12.653, p = 0.024), prolonged LN (OR: 0.926, 95% CI: 0.874–0.981, p = 0.009), and high-grade tubular atrophy (OR: 0.451, 95% CI: 0.208–0.829, p = 0.013) were associated with renal function recovery. During follow up, 25 patients were on end stage renal disease (ESRD). Kaplan-Meier analysis revealed that renal function recovery after 6 months and lower probability of ESRD are associated. <h3>Conclusion</h3> In patients with LN and reduced renal function, renal function recovery at 6 months was associated with use of hydroxychloroquine and inversely related to longer duration of LN and higher grade of tubular atrophy. <h3> Disclosure of Interests</h3> None declared
S100a8/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocyte Death in Response to Ischemic/Reperfusion Injury
Authors: Yulin Li, Boya Chen, Xinying Yang, Congcong Zhang, Yao Jiao, Ping Li, Yan Liu, Zhenya Li, Bokang Qiao, Wayne Bond Lau, Xin-liang Ma, Jie Du
Journal: Circulation (2019)

Background: Myocardial ischemia-reperfusion (MI/R) injury is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key MI/R mediators to initiate MI/R injury. Methods: We used a dynamic transcriptome analysis of mouse heart exposed to various MI/R periods to identify S100a8/a9 as an early mediator. Using loss/gain-of-function approaches to understand the role of S100a8/a9 in MI/R injury, we explored the mechanisms through transcriptome and functional experiment. Dynamic serum S100a8/a9 levels were measured in patients with acute myocardial infarction before and after percutaneous coronary intervention. Patients were prospectively followed for the occurrence of major adverse cardiovascular events. Results: S100a8/a9 was identified as the most significantly upregulated gene during the early reperfusion stage. Knockout of S100a9 markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of S100a9 exacerbated MI/R injury. Transcriptome/functional studies revealed that S100a8/a9 caused mitochondrial respiratory dysfunction in cardiomyocytes. Mechanistically, S100a8/a9 downregulated NDUF gene expression with subsequent mitochondrial complex I inhibition via Toll-like receptor 4/Erk–mediated Pparg coactivator 1 alpha/nuclear respiratory factor 1 signaling suppression. Administration of S100a9 neutralizing antibody significantly reduced MI/R injury and improved cardiac function. Finally, we demonstrated that serum S100a8/a9 levels were significantly increased 1 day after percutaneous coronary intervention in patients with acute myocardial infarction, and elevated S100a8/a9 levels were associated with the incidence of major adverse cardiovascular events. Conclusions: Our study identified S100a8/a9 as a master regulator causing cardiomyocyte death in the early stage of MI/R injury via the suppression of mitochondrial function. Targeting S100a8/a9-intiated signaling may represent a novel therapeutic intervention against MI/R injury. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03752515
Abstract 17129: Differences in Work Activities and Compensation of Male and Female Cardiologists in Community Practice in 2013
Authors: Reshma Jagsi, Cathie Biga, Athena Poppas, George P Rodgers, Mary N Walsh, Patrick J White, Colleen McKendry, Joseph Sasson, Philip J Schulte, Pamela Douglas
Journal: Circulation (2015)

Background: Despite laudable efforts to increase gender diversity in cardiology, much remains unknown about the experiences - including working activities and pay - of those women who have joined this still predominantly male specialty. Hypothesis: We hypothesized that a gender difference in compensation would exist on unadjusted analyses and that this could be explained by differences in the many personal, job, and practice characteristics measured in our dataset. Methods: Using the 2013 annual practice survey of MedAxiom, a subscription-based service provider for cardiology practices, we described personal, job, and practice characteristics of cardiologists from 161 practices and their salary by gender. Multivariable linear regression analysis and the Peters-Belson technique of labor economics were applied to evaluate gender differences. Results: Of 2679 subjects, 229 (8.5%) were female and 2450 male. Women were more likely to have specialized in general/non-invasive cardiology (53.1% vs 28.2%), and a lower proportion (11.4% vs 39.3%) reported an interventional subspecialty compared to men. Numerous job characteristics differed by gender, including the proportion working full-time (79.9% of women vs 90.9% of men, p&lt;0.001), number of half-days worked (median 422 for women vs 433 for men, p=0.001), and wRVUs generated (median 7430 for women vs 9301 for men, p&lt;0.001). Median salary was $394,586 (IQR: $256,064; $518,277) among women and $502,251 ($381,417; $621,306) among men. Peters-Belson analysis revealed that the women in this sample would have been expected to have a mean salary of $432,631, based on their productivity and other characteristics, had they been male, but the actual observed mean salary among women was $400,882 (unexplained difference=$31,749, 95% CI $16,303 - $48,028). Multivariable linear regression analysis yielded significant results similar in direction and magnitude. Conclusions: This study provides novel information about the diverse jobs held by men and women practicing cardiology in the US today. The observed gender difference in compensation, which remained substantial and significant even after adjusting for differences in multiple measures of productivity and job activity, merits attention.
Abstract 17501: Incremental Value of Combined Left Ventricular Volume and Matrix Metalloproteinase-2 for Risk Stratification of Patients with Non-Ischemic Dilated Cardiomyopathy
Authors: Dong Heon Yang, Sun Hee Park, Kyun Hee Kim
Journal: Circulation (2011)

Background: Extracellular matrix remodeling and apoptosis are known to play important roles in the progression of heart failure (HF). The aim of this study was to evaluate the prognostic value of serum levels of matrix metalloproteinase(MMP)-2, MMP-3, soluble Fas (sFas) and soluble Fas ligand (sFasL) in patients with non-ischemic dilated cardiomyopathy (DCM). Methods: Serum samples were obtained from 70 patients with DCM and analyzed for MMP-2, MMP-3, sFas and sFasL. Patients were followed up for the occurrence of either mortality or hospitalizations due to HF. Results: Cardiac events were occurred at 21(30%) patients (death: 10, hospitalization due to HF: 11). LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) were higher and mitral Ea was lower in cardiac event group. Serum level of MMP-2 was significantly higher in cardiac event group (287.2±99.3 vs 221.0±68.9 ng/mL, p=0.01). However, serum levels of MMP-3, sFas and sFasL were not different between two groups. Kaplan-Meier event free survival curve stratified into 4 groups according to combinations of LVEDV and MMP-2 showed significantly different event rates (Fig 1). Cox proportional hazards analysis demonstrated that MMP-2 added significant incremental prognostic information (Fig 2). Conclusion: Serum level of MMP-2, but not MMP-3, sFas or sFasL is an independent prognostic factor and combined LVV and MMP-2 have incremental value to predict cardiac events in patients with DCM.
Next-generation sequencing of immunoglobulin gene rearrangements for clonality assessment: a technical feasibility study by EuroClonality-NGS
Authors: Blanca Scheijen, Ruud W. J. Meijers, Jos Rijntjes, Michèle Y. van der Klift, Markus Möbs, Julia Steinhilber, Tomas Reigl, Michiel van den Brand, Michaela Kotrová, Julia-Marie Ritter, Mark A. Catherwood, Kostas Stamatopoulos, Monika Brüggemann, Frédéric Davi, Nikos Darzentas, Christiane Pott, Falko Fend, Michael Hummel, Anton W. Langerak, Patricia J. T. A. Groenen
Journal: Leukemia (2019)

One of the hallmarks of B lymphoid malignancies is a B cell clone characterized by a unique footprint of clonal immunoglobulin (IG) gene rearrangements that serves as a diagnostic marker for clonality assessment. The EuroClonality/BIOMED-2 assay is currently the gold standard for analyzing IG heavy chain (IGH) and κ light chain (IGK) gene rearrangements of suspected B cell lymphomas. Here, the EuroClonality-NGS Working Group presents a multicentre technical feasibility study of a novel approach involving next-generation sequencing (NGS) of IGH and IGK loci rearrangements that is highly suitable for detecting IG gene rearrangements in frozen and formalin-fixed paraffin-embedded tissue specimens. By employing gene-specific primers for IGH and IGK amplifying smaller amplicon sizes in combination with deep sequencing technology, this NGS-based IG clonality analysis showed robust performance, even in DNA samples of suboptimal DNA integrity, and a high clinical sensitivity for the detection of clonal rearrangements. Bioinformatics analyses of the high-throughput sequencing data with ARResT/Interrogate, a platform developed within the EuroClonality-NGS Working Group, allowed accurate identification of clonotypes in both polyclonal cell populations and monoclonal lymphoproliferative disorders. This multicentre feasibility study is an important step towards implementation of NGS-based clonality assessment in clinical practice, which will eventually improve lymphoma diagnostics.