tbuckley/cabot-search huggingface dataset:
Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy
Authors: Panagiotis Efentakis, Aimilia Varela, Evangelia Chavdoula, Fragiska Sigala, Despina Sanoudou, Roxane Tenta, Katerina Gioti, Nikolaos Kostomitsopoulos, Andreas Papapetropoulos, Androniki Tasouli, Dimitrios Farmakis, Costantinos H Davos, Apostolos Klinakis, Thomas Suter, Dennis V Cokkinos, Efstathios K Iliodromitis, Philip Wenzel, Ioanna Andreadou
Journal: Cardiovascular Research (2019)

Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity.Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxide synthase (eNOS), and protein kinase-A and G (PKA/PKG) pathways emerged as contributors to the cardioprotection, converging onto phospholamban (PLN). To verify the contribution of PLN, phospholamban knockout (PLN-/-) mice were assigned to PLN-/-/Control (N/S-0.9%), PLN-/-/DXR (18 mg/kg), and PLN-/-/DXR+LEVO (ac) for 14 days. Furthermore, female breast cancer-bearing (BC) mice were divided into: Control (normal saline 0.9%, N/S 0.9%), DXR (18 mg/kg), LEVO, and DXR+LEVO (LEVO, 24 μg/kg-bolus) for 28 days. Echocardiography was performed in all protocols. To elucidate levosimendan's cardioprotective mechanism, primary cardiomyocytes were treated with doxorubicin or/and levosimendan and with N omega-nitro-L-arginine methyl ester (L-NAME), DT-2, and H-89 (eNOS, PKG, and PKA inhibitors, respectively); cardiomyocyte-toxicity was assessed. Single bolus administration of levosimendan abrogated DXR-induced cardiotoxicity and activated Akt/eNOS and cAMP-PKA/cGMP-PKG/PLN pathways but failed to exert cardioprotection in PLN-/- mice. Levosimendan's cardioprotection was also evident in the BC model. Finally, in vitro PKA inhibition abrogated levosimendan-mediated cardioprotection, indicating that its cardioprotection is cAMP-PKA dependent, while levosimendan preponderated over milrinone and dobutamine, by ameliorating calcium overload.Single dose levosimendan prevented doxorubicin cardiotoxicity through a cAMP-PKA-PLN pathway, highlighting the role of inotropy in doxorubicin cardiotoxicity.
Invasive DNA elements modify the nuclear architecture of their insertion site by KNOT-linked silencing in Arabidopsis thaliana
Authors: Stefan Grob, Ueli Grossniklaus
Journal: Genome biology (2019)

The three-dimensional (3D) organization of chromosomes is linked to epigenetic regulation and transcriptional activity. However, only few functional features of 3D chromatin architecture have been described to date. The KNOT is a 3D chromatin structure in Arabidopsis, comprising 10 interacting genomic regions termed KNOT ENGAGED ELEMENTs (KEEs). KEEs are enriched in transposable elements and associated small RNAs, suggesting a function in transposon biology.Here, we report the KNOT's involvement in regulating invasive DNA elements. Transgenes can specifically interact with the KNOT, leading to perturbations of 3D nuclear organization, which correlates with the transgene's expression: high KNOT interaction frequencies are associated with transgene silencing. KNOT-linked silencing (KLS) cannot readily be connected to canonical silencing mechanisms, such as RNA-directed DNA methylation and post-transcriptional gene silencing, as both cytosine methylation and small RNA abundance do not correlate with KLS. Furthermore, KLS exhibits paramutation-like behavior, as silenced transgenes can lead to the silencing of active transgenes in trans.Transgene silencing can be connected to a specific feature of Arabidopsis 3D nuclear organization, namely the KNOT. KLS likely acts either independent of or prior to canonical silencing mechanisms, such that its characterization not only contributes to our understanding of chromosome folding but also provides valuable insights into how genomes are defended against invasive DNA elements.
Abstract 1965: The Identification of Resident Endothelial Stem Cells in the Progression of Pulmonary Arterial Hypertension
Authors: Susan Majka, Jessica Martin, Karen Helm
Journal: Circulation (2008)

Proliferation of myofibroblasts in adult lung diseases such as pulmonary arterial hypertension (PAH) and fibrosis lead to vascular remodeling without functional tissue regeneration. A consequence o...
S1629 ERFE‐A260S ACCOUNTS FOR HEPATIC IRON METABOLISM IMPAIRMENT BY ACTING ON THE BMP‐SMAD PATHWAY
Authors: I. Andolfo, F. Manna, G. De Rosa, B.E. Rosato, R. Marra, A. Gambale, A. Iolascon, R. Russo
Journal: HemaSphere (2019)

Background: Iron overload is a major clinical challenge in the management of hereditary ineffective erythropoiesis ‐related anemia (iron‐loading anemia). To coordinate iron metabolism with hemoglobin (Hb) synthesis, erythropoietin (EPO)‐stimulated erythroid precursors release erythroferrone (ERFE), a soluble protein that suppresses the expression of hepcidin. Hepcidin is a hormone that controls iron entry into the circulation by blocking the iron exporter ferroportin. Congenital dyserythropoietic anemia type II (CDAII) is a bone marrow failure anemia characterized by mono‐lineage cytopenia and morphological abnormalities of erythroid precursor cells. The marked clinical variability observed in CDAII patients is related to its major complication, the iron overload associated with reduced expression of hepatic hormone hepcidin. We recently analyzed ERFE expression in both CDAII patients and in vitro model, demonstrating that in CDAII patients ERFE is overexpressed and related to abnormal erythropoiesis. Aims: To study possible modifier genes affecting the iron overload phenotype in CDAII. Methods: t‐NGS custom panel; genotyping; cells culture and transfection assays; qRT‐PCR; immunoblotting. Results: We herein identified a recurrent low‐frequency variant, A260S, in ERFE gene in 12.5% of CDAII patients showing severe phenotype by our 81‐genes target custom panel for modifier genes. We demonstrated that ERFE‐A260S variant leads to an increased expression of ERFE. We further characterized the effect of ERFE‐A260S in an in vitro human hepatic model, HuH7 cells, showing a marked impairment of iron regulation pathways by inhibition of phosphorylation of SMAD1/5/8 and consequent downregulation of the expression of BMP/SMADs pathway target genes: HAMP, ID1, ATHO8 and SMAD6 . Summary/Conclusion: We herein described for the first time an ERFE polymorphism as modifier variant with a mild effect on disease expression under a multifactorial‐like model in a condition of iron‐loading anemia due to ineffective erythropoiesis. This is a novel paradigm that paves the ways to new investigations for evaluating the role of this ERFE variant as a modifier in many other related pathological conditions, as b‐thalassemia intermedia. Moreover, the discovery of the genetic basis of CDAII and its major complication, iron overload, will lead us to expand our understanding of the biology of ineffective erythropoiesis and to provide initiative for further investigation of new therapeutics. Indeed, ERFE is currently a candidate target for therapeutic inhibition, in iron loading anemia.
Comparative Analysis on the Anti-Tumor Activity of Venetoclax and Obinutuzumab (VO) Versus Venetoclax and Rituximab (VR) in Primary CLL Cells, Ex Vivo
Authors: Madiha Iqbal, Aarushi Sharma, Alak Manna, Sharoon Akhtar, Taimur Sher, Asher A. Chanan-Khan, Sikander Ailawadhi, Aneel Paulus
Journal: Blood (2018)
Abstract 19683: Radiation Exposure in Children With Congenital Heart Disease at a Single, Large Center.
Authors: Kristen N Stevens, Andrew Glatz, Amanda Klinger, Amanda R King, Jeffrey Hellinger, Stephen B Gruber, Peter J Gruber
Journal: Circulation (2010)

Introduction: Congenital heart disease (CHD) is a disease with life-long implications. Our objective is to characterize and quantify radiologic examinations in children requiring surgery for CHD on...
SP0138 WHAT WE ARE BRILLIANT AT; OT PERSPECTIVE
Authors: Ingvild Kjeken
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> The unique contribution of occupational therapy is its focus on occupation, which may be defined as <i>"groups of activities and tasks of everyday life, named, organized and given value and meaning by individuals and a culture. Occupation is everything people do to occupy themselves, including looking after themselves (self-care), enjoying life (leisure), and contributing to the social and economic fabric of their communities (productivity)".</i> Occupation is further being influenced by the environment, one"s social roles and one"s developmental level; being client-defined; and consisting of both a performance (objective) dimension and a satisfaction (subjective) dimension (1). Using the terminology of the International Classification of Functioning (ICF), occupational performance covers the domain of Activity and Participation in the ICF model. In clinical practice, occupational therapists use assessment and interventions to develop, recover, or maintain the meaningful occupations of individuals, groups, or communities. Lately, occupational therapists have also been increasingly concerned with occupational injustice, which relates to conditions wherein people are deprived, excluded or denied of occupations that are meaningful to them. Within rheumatology, the most frequently applied occupational therapy interventions are patient education concerning ergonomic principles and activity pacing, therapeutic exercise and activity programs, provision of orthoses and assistive technology, and environmental and task modifications. In the presentation, patient cases will be used to illustrate how occupational therapists may work to enhance occupation in individual clients with a rheumatic condition, and evidence for some of the core interventions will be discussed. <h3>Reference:</h3> [1] Townsend EA, Polatajko HJ. Enabling occupation II: advancing an occupational therapy vision for health, well-being, &amp; justice through occupation. Ottawa: Canadian Association of Occupational Therapists; 2007. <h3>Disclosure of Interests:</h3> None declared
PB2215 HOW TO PREDICT RESPONSE TO RUXOLITINIB IN PATIENTS WITH MYELOFIBROSIS
Authors: M.I. Montero, M. Reinoso, L. Pérez‐Ortega, F.J. Márquez, E. Rodríguez‐Arbolí, N. Rodríguez, J.F. Falantes, I. Espigado, J.A. Pérez‐Simón
Journal: HemaSphere (2019)

Background: Myelofibrosis (MF) is a classical myeloproliferative neoplasm characterized both in its primary and secondary form by splenomegaly, constitutional and disease‐related symptoms as well as by cytopenias. Aberrant constitutive activation of the JAK‐STAT pathway is core to its pathogenesis and the inhibitors of this pathway such as ruxolitinib, approved for MF treatment seven years ago, have been proven effective in a majority of patients. Aims: To describe ruxolitinib response and median survival in a group of patients diagnosed with MF in a single center and correlate it with the molecular profile, hematimetric data and previous myeloproliferative neoplasm (polycythemia vera (PV) or essential thrombocytosis (ET)). Methods: Of a total of one‐hundred twenty four patients diagnosed with MF in our center, thirty eight patients were treated with ruxolitinib between April 2012 and September 2018. Diagnosis of myelofibrosis was made based on bone marrow examination and according to the updated WHO criteria. Molecular study was carried out in peripheral blood for the mutation JAK2V617F as well as allele‐specific PCR for mutations type 1 and type 2 of exon 9 of calreticulin (CALR) gene, and exon 10 of myeloproliferative leukemia virus (MPL) gene. The prognostic risk stratification was carried out according to the International Prognostic Index (IPSS). All patients treated with ruxolitinib belonged to the intermediate group‐2 or were classified as high risk. Statistical analyses were performed in SPSS 15.0. Results: Average age of the group was 63 years (range 36‐88). 58% were males and 42% female. Average leukocyte, haemoglobin and platelet counts at diagnosis were 9,8x10e9/l (1.9‐62), 10.3 g/dl (6‐15.7) and 236x10e9/L (52‐789), respectively. 47% of patients had a previous diagnosis of another MPN (50% PV and 50% ET). JAK2V617F mutation was present in 70.3%, and CARL and MPL mutation in 12.5% and 2.6%, respectively. All patients responded to ruxolitinib although 39% finally lost this response, with a 13% evolution to acute leukemia, 40% of this group being subjected to allogeneic SCT. Currently, 73% of patients are alive. Six‐year overall survival of patients with JAK2V617F mutation was 80% compared to 60% of those with wild‐type mutational status, statistical significance not being reached. Patients with previous MPN also had greater six‐year overall survival (70%) than those with idiopathic MF (56%). Summary/Conclusion: Patients with MF with JAK2V617F mutation and previous MPN present a greater duration of response to ruxolitinib than others, probably due to greater inhibition of the preponderant pathogenetic mechanism and the more effective action of the drug on a more differentiated progenitor than in idiopathic MF, although broader studies are required to confirm these results.
OMSV enables accurate and comprehensive identification of large structural variations from nanochannel-based single-molecule optical maps
Authors: Le Li, Alden King-Yung Leung, Tsz-Piu Kwok, Yvonne Y. Y. Lai, Iris K. Pang, Grace Tin-Yun Chung, Angel C. Y. Mak, Annie Poon, Catherine Chu, Menglu Li, Jacob J. K. Wu, Ernest T. Lam, Han Cao, Chin Lin, Justin Sibert, Siu-Ming Yiu, Ming Xiao, Kwok-Wai Lo, Pui-Yan Kwok, Ting-Fung Chan, Kevin Y. Yip
Journal: Genome biology (2017)

We present a new method, OMSV, for accurately and comprehensively identifying structural variations (SVs) from optical maps. OMSV detects both homozygous and heterozygous SVs, SVs of various types and sizes, and SVs with or without creating or destroying restriction sites. We show that OMSV has high sensitivity and specificity, with clear performance gains over the latest method. Applying OMSV to a human cell line, we identified hundreds of SVs >2 kbp, with 68 % of them missed by sequencing-based callers. Independent experimental validation confirmed the high accuracy of these SVs. The OMSV software is available at http://yiplab.cse.cuhk.edu.hk/omsv/ .
AB0996 APPLICATION OF YAMAGUCHI CRITERIA FOR CLASSIFICATION OF SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS
Authors: Kwang Nam Kim, Jong Gyun Ahn, Young Dae Kim
Journal: Annals of the Rheumatic Diseases (2019)

which 88% had onset of JIA before the age of 6 (all girls).Complete remission of uveitis was achieved in two patients treated with topical corticosteroids, with non-steroid anti-inflammatory medication and methotrexate used in one of the patients.Inactive uveitis was most frequently achieved with a combined therapy which included biologics.A patient suffering from uveitis and JIA was found to be significantly more likely to suffer from oligoarthritic subtype (64.5%, CI 45.4-80.8%,p<0.001).We determined that a positive ANA titer occurred statistically significantly more frequent in females (OR inf., p=0.001).No significant statistical difference in ANA titer was found between groups of patients who were diagnosed with rheumatologic or ocular disease before and after the age of 6 (OR 1.85, CI 0.12-29.57,p=0.6111) nor between different subtypes of JIA.There was no difference in time passed between the occurrence of rheumatologic and ocular manifestations (median difference =1.75 years, W=131, p=0.2597), nor between ANA titer (OR 0.57, CI 0.09-3.12,p=0.4775) between groups with and without ocular complications.Patients who first presented with ocular manifestations did not have a greater likelihood to develop ocular complications (OR 5.59, p=0.175).Conclusion: A group of female patients suffering from RF negative subtypes of JIA and uveitis, with onset occurring before the age of 6 and positive ANA was prominent.These patients were traditionally classified as different subtypes of JIA, but together, they are best described as "early onset ANA positive JIA", concurring the need for reclassification of JIA.Limited by a small number of patients, this was partly confirmed with significant statistical findings, a recurrent positive ANA titer in females with JIA and uveitis and a more frequent occurrence of uveitis in oligoarthritis.The occurrence of ocular complications was not dependent upon ANA titer, nor upon the time difference between rheumatic and ocular symptoms or their order of appearance.
AB0806 EFFICACY MANAGEMENT AND ADHERENCE EVALUATION OF DICLOFENAC IN THE TREATMENT OF KNEE OSTEOARTHRITIS PAIN
Authors: Yudian Qiu, Jianhao Lin, Hu LI, Yunfei Hou
Journal: Annals of the Rheumatic Diseases (2019)

result.The effectiveness of treatment was less in patients >65 years (OR 0.418; p<0.001),OA stage 2 by Kelgren-Lawrence (OR 0.556; 95% CI 0.298-0.738,p<0.001), with rest pain (OR 0.690; 95% CI 0.596 -0.800, p<0.001), synovitis (OR 0.780; 95% CI 0.673-0.900,p=0.001), and sensory symptoms such as burning, pain cold, electric shocks (OR 0.530; 95% CI 0.458-0.613,p<0.001).Conclusion: the ASU and KLS combination allows to achieve successful pain control in OA.A number of factors: age >65 years, OA stage 2 by Kelgren-Lawrence, rest pain, synovitis, and sensory symptoms are associated with the worst result of treatment.
Abstract P227: Circulating and Dietary Linoleic Acid and Prevalent Diabetes in Post-Myocardial Infarction Patients
Authors: Kamalita Pertiwi, Anne J Wanders, Peter L Zock, Marjolein C Harbers, Johanna M Geleijnse
Journal: Circulation (2018)

Background: Circulating linoleic acid 18:2n-6 (LA) has been considered to reflect LA intake, but its utility as a dietary biomarker could be affected by metabolism. Objective: To study the associations of plasma and dietary LA with T2D prevalence in drug-treated patients with a history of myocardial infarction (MI). Methods: Cross-sectional analysis of baseline data in 4,072 Dutch post-MI patients of the Alpha Omega Cohort. Circulating LA (as % of total fatty acids) was assessed in plasma cholesterol esters (CE) in the total cohort and in plasma phospholipids (PL) in a random subset of 833 patients. LA intake was assessed by a 203-item validated food frequency questionnaire. Prevalence ratios of T2D and associations with metabolic parameters were estimated in plasma and dietary LA quintiles using multivariable generalized linear models adjusted for demographic, lifestyle and dietary factors. Results: Patients were on average 69 years old, 79% was male and 77% were overweight or obese. Most patients used statins (86%), antihypertensive drugs (90%) and antiplatelet drugs (84%). A total of 813 patients (20%) had T2D. Mean LA intake (±SD) was 5.7±2.2 energy%, and circulating LA was 49.9±5.0% in CE and 18.7±3.0% in PL. Spearman’s correlations of dietary LA with circulating LA in CE and PL were 0.16 and 0.10, respectively. Higher plasma LA, but not dietary LA, was significantly associated with a lower diabetes prevalence (Table 1). BMI (β= -0.07, p&lt;0.001), log non-fasting triglycerides (β= -0.01, p&lt;0.001), log non-fasting glucose (β= -0.01, p&lt;0.001), and log alcohol intake (β= -0.03, p&lt;0.001) were significantly associated with circulating LA in plasma CE. Similar associations were found for LA in plasma PL. Dietary LA was not significantly associated with T2D prevalence and metabolic parameters (all p&gt;0.05). Conclusions: Circulating LA may reflect both LA intake and metabolic state in drug-treated post-MI patients. This bears restrictions for its use as a biomarker of dietary LA intake in epidemiological studies.
SAT0348 HOW FREQUENT IS NEUROPATHIC PAIN COMPONENT IN PATIENTS WITH SPONDYLOARTHRITIS?
Authors: leila rouached, Saoussen Miladi, Alia Fazaa, Lilia Nacef, Kmar Ouenniche, Leila Souabni, Salma Kassab, Selma Chekili, Zakraoui Leith, Kawther Ben Abdelghani, Ahmed Laatar
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Criteria to define inflammatory back pain in Spondyloarthritis (SA) are multiple. Although neuropathic pain component was known to be part of disease symptoms, it has been rarely assessed. <h3>Objectives:</h3> The aim of this study was to determine the prevalence of the neuropathic pain component in SA patients and secondarily, to detect correlation with the disease duration, activity scores and functional impairment. <h3>Methods:</h3> A cross-sectional study including patients with radiographic axial SA defined by ASAS criteria was conducted. Patients were questioned about their neuropathic pain using painDETECT questionnaire and Douleur Neuropathique en 4 Questions (DN4) interview. Further information about disease characteristics, activity (BASDAI, ASDAS<sub>CRP</sub>) and functional (BASFI) scores were assessed the same day. Statistical analysis, was performed by Khi<sup>2</sup>-test for qualitative variables and Student-test for quantitative variables. A p value ≤0.05 was considered significant. <h3>Results:</h3> Forty patients were included. The average age was about 41 years old (±12.9) and the sex ratio was 12.3 (H/F). The mean disease duration was 10.7±6.9 years. Most of patients suffered from back pain and the visual analogic scale pain scale was about 3.78±2.5. The mean BASDAI score was 2.75±2.3 and the mean ASDAS<sub>CRP</sub> was 2.24±1.07. The average BASFI score was 2.57±2.5. Neuropathic pain component was noted only in 7.5% of patients by DN4 interview (≥4/10) and in 10% of patients by pain DETECT questionnaire. As expected, patients with DN4≥4 were correlated to the visual analogic scale pain (p=0.04) and female gender (p=0.07). But no relation was found with the type of SA or the disease activity or the functional scores. <h3>Conclusion:</h3> Neuropathic pain component was noted only in 10% of SA in our work. Positive correlation was found with visual analogic scale pain and female gender. Larger studies are needed to assess this type of pain since therapeutic strategy may be affected. <h3>Disclosure of Interests:</h3> None declared
Helen Salisbury: Doctors’ duties in a fractured welfare state
Authors: Helen Salisbury
Journal: BMJ (2019)

Like many other GPs around the country, I’m spending more and more time writing medical reports to appeal on behalf of patients who have been refused welfare benefit payments. Welfare is a right: we have a welfare state we all pay into through taxation, and we rely on it when we are sick or become unable to work. It’s a mark of a humane society that we look after each other in this way.

The main grounds for refusing incapacity benefit is that the person has been found fit to work by someone at an outsourced assessment company. Many of my …
FRI0112 INCREASED RISK OF SEVERE INFECTION RECURRENCE IN PATIENTS WHO DEVELOPED SEVERE INFECTIONS DURING BDMARDS THERAPY: A STUDY OF THE MIRAI COHORT
Authors: Eri Oguro, Yuji Yoshida, Kentaro Kuzuya, Yasutaka Okita, Hidetoshi Matsuoka, Satoru Teshigawara, Maiko Yoshimura, Kentaro Isoda, Yoshinori Harada, Shiro Ohshima, Jun Hashimoto, Yukihiko Saeki
Journal: Annals of the Rheumatic Diseases (2019)

Conclusion: Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients.