tbuckley/cabot-search huggingface dataset:
Abstract 12880: Malnutrition Assessed by Geriatric Nutritional Risk Index Provides the Long-term Prognostic Information in Patients Admitted for Acute Decompensated Heart Failure, Regardless of Reduced or Preserved Left Ventricular Ejection Fraction; A Comparison With Prognostic Nutritional Index and CONUT Score
Authors: Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takumi Kondo, Masashi Ishimi, Hideyuki Hakui, Tatsuhisa Ozaki, Yoshihiro Satoh, Masahiro Seo, Iyo Ikeda, Eiji Fukuhara, Masatake Fukunami
Journal: Circulation (2015)

Backgrounds: Malnutrition is associated with increased mortality risk in patients (pts) with acute decompensated heart failure(ADHF). Nutritional status is assessed by several indices, such as Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), and Controlling Nutritional Status (CONUT) score. However, there is no information available on the comparison of prognostic significance of these indices in ADHF pts, relating to reduced or preserved left ventricular ejection fraction (HFrEF or HFpEF). Methods and Results: We studied 303 consecutive pts admitted for ADHF and discharged alive (HFrEF(LVEF&lt;50%);n=163, HFpEF(LVEF≥50%);n=140). Nutritional status was evaluated at the discharge by GNRI calculated as follows: 14.89 • serum albumin (g/dl) + 41.7 • BMI/22, PNI calculated as follows: 10 • serum albumin (g/dl) + 0.005 • total lymphocyte count (/ml) and CONUT score calculated by serum albumin, total cholesterol levels and lymphocyte count. During a follow-up period of 5.0±4.3 yrs, 75 pts had cardiovascular death (CVD). At multivariate Cox analysis, GNRI (p&lt;0.0001) was significantly associated with CVD, independently of systolic blood pressure, serum sodium level and eGFR, although PNI and CONUT score showed a significant association with CVD at univariate analysis. ROC analysis revealed that GNRI of 88 was a fair discriminator for CVD (AUC 0.70(95%CI 0.63-0.77), p&lt;0.0001). In group with HFrEF, CVD was significantly more frequently observed in pts with than without low GNRI &lt;88 (48% vs 25%, p&lt;0.0001, adjusted HR 3.5[1.8-6.6]). Furthermore, in group with HFpEF, pts with low GNRI had the significantly increased risk, compared to those with high GNRI&gt;88 (36% vs 10%, p&lt;0.0001, adjusted HR 3.8[1.4-10.2]). Conclusion: Malnutrition assessed by Geriatric Nutritional Index provides more valuable long-term prognostic information than PNI and CONUT score in pts admitted for ADHF, regardless of HFrEF or HFpEF.
PF397 IDENTIFICATION OF PROTEIN‐PROTEIN INTERACTIONS NECESSARY FOR MAINTENANCE OF BCR‐ABL CORE COMPLEX
Authors: T. Gregor, M.K. Bosakova, J. Rynes, S.F. Trantirkova, J. Mayer, L. Trantirek, P. Krejci
Journal: HemaSphere (2019)

Background: Approximately 50% of chronic myeloid leukemia (CML) patients in deep remission experience a return of clinical CML after withdrawal of tyrosine kinase inhibitors (TKIs), suggesting signaling of catalytically inactive BCR‐ABL. This allows for survival of cancer cells responsible for CML relapse after discontinuation of the TKI therapy. Elucidation of protein‐protein interactions within the BCR‐ABL signaling complex is crucial for understanding of the mechanism of residual signaling of TKI‐inhibited BCR‐ABL. Aims: This study aims on detailed characterization of BCR‐ABL interactions with members of its core complex, i.e. the signaling mediators Grb2, SOS1, SHC1, cCbl, CrkL, SHIP2, Sts1 and p85a. Methods: Peptide microarrays were used to map binding interfaces between BCR‐ABL and its interactors in high resolution. The microarray data were validated by in vivo co‐immunoprecipitation and proximity ligation assays carried out with BCR‐ABL deletion mutants and their respective interactors. Reporter assays were employed to analyze the downstream signaling of BCR‐ABL in cells. Results: We demonstrate that TKIs inhibit catalytic activity of BCR‐ABL, but do not completely abrogate its downstream signaling. Further, treatment with TKIs does not entirely dissolve the BCR‐ABL signaling complex consisting of Grb2, SOS1, SHC1, cCbl, CrkL and SHIP2. The interacting interfaces between BCR‐ABL and members of its core complex were mapped in high resolution. The data show that CrkL binds to proline‐rich regions located in C‐terminal, intrinsically disordered region of BCR‐ABL, that deletion of pleckstrin homology (PH) domain of BCR‐ABL diminishes interaction with SHC1, and that SHIP2 associates with the src‐homology (SH)3‐SH2‐tyrosine kinase (TK) domain of BCR‐ABL. We further demonstrate that BCR‐ABL sequence motif located in disordered region around phosphorylated tyrosine 177 mediates binding of at least three core complex members, the Grb2, SOS1 and cCbl. Introduction of Y177F substitution to BCR‐ABL blocks association with Grb2, SOS1 and cCbl, and reduces residual signaling of TKI‐inhibited BCR‐ABL. Summary/Conclusion: The protein‐protein interactions within the BCR‐ABL core complex were characterized in detail here. Our findings support the concept of targeting BCR‐ABL signaling in CML by inhibition of Y177 interaction interface.
PF404 TUMOR‐DERIVED EXOSOMES MAY BE USED AS NEW INFORMATIVE TOOL FOR THE DETECTION OF BONE MARROW RESIDUAL CML LEUKEMIC CELLS ACTIVITY
Authors: S. Bernardi, C. Foroni, C. Zanaglio, F. Re, N. Polverelli, A. Turra, E. Morello, M. Farina, F. Cattina, L. Gandolfi, T. Zollner, E. Accorsi Buttini, M. Malagola, D. Russo
Journal: HemaSphere (2019)

Background: Ph+ Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by BCR‐ABL1 fusion‐gene, derived from the t (9;22) translocation. Tyrosine Kinase Inhibitors (TKIs) target BCR‐ABL1 protein, induce molecular response in the most of patients, prolong the survival and allow the treatment free remission. Many studies have demonstrated the persistence of leukemic cells in the bone marrow (BM) niche, even after treatment. The conventional minimal residual disease monitoring for CML patients is based on the RT‐qPCR quantification of BCR‐ABL1 transcript in the peripheral blood (PB) cells. However, it is not able to appreciate the activity of residual CML leukemic cells in the BM, responsible of the molecular relapse in the patients undergoing TKIs discontinuation. Exosomes, carrying different information of the cell of origin, have garnered considerable attention in cancer research thanks to the discovery of their messenger role in cellular communication. Moreover, there are some evidences regarding the possibility to isolate the different exosomes sub‐populations targeting the antigens on their surface. Aims: In this study we aimed to explore the feasibility of the tumor‐derived exosomes fraction enrichment in CML patients in chronic phase (CP) and treated with TKIs. Ph‐ patients and healthy subjects served as controls. Methods: BCR‐ABL1 transcript was quantified following on PB cells both conventionally, according to the International Scale, and by dPCR, given the last published evidences of its accuracy and sensitivity. The exosomes enrichment was performed by a specific kit based on immuno‐selection for a pan‐cancer antigen. The quantification of BCR‐ABL1exosomal transcript was performed by dPCR. In addition, Y4 transctript, an exosomal housekeeper, was quantified in order to assess the exosomal RNA quantity. Results: The possibility of the tumor‐derived exosomes enrichmentwas confirmed by the quantification of Y4 and the immuno‐selection of the exosomes resulted specific thanks to the negative results obtained in healthy controls. In Ph‐controls and in CML patients we were able to isolate tumor exosomes (Y4 positive). Moreover, the presence of BCR‐ABL1 transcript in all CML exosomal samples highlighted, for the first time, the presence of active leukemic cells in CML patients in CP. Summary/Conclusion: These results suggest that tumor derived exosomes could be consider as a new toolfor the identification of active leukemic cells and for the assessment of an innovative monitoringfocused on the biological meaning of exosomes in CML. image
Abstract 35: Elevated MicroRNA-155 Targets HBP1 to Promote the Formation of Macrophage-Derived Foam Cell and This Can Be Effectively Suppressed by YY1/HDACs Complex
Authors: Qing Jing, Fu-Ju Tian, Qing Li, Jun Zou
Journal: Circulation Research (2012)

Aims: We aim to investigate the role of microRNAs in the formation of macrophage-derived foam cell. Methods and results: Using quantitative RT-PCR, we found that the level of microRNA-155 (miR-155), a macrophage-associated microRNA, was significantly increased both in plasma of atherosclerotic ApoE-/- mice and in macrophages isolated from this animal model. Indeed, oxLDL effectively induced expression and release of miR-155 in macrophages. We further identified that miR-155 was required to mediate oxLDL-induced lipid uptake and ROS production of macrophages. Importantly, ectopic overexpression and knockdown experiments identified that HMG box-containing protein 1(HBP1) is a novel target of miR-155. Knockdown of HBP1considerably enhanced lipid uptake and ROS production in oxLDL-induced macrophages, and overexpression of HBP1 effectively repressed these effects caused by miR-155 overexpression. Interestingly, bioinformatics analysis identified three YY1 binding sites in promoter region of pri-miR- 155. EMSA and ChIP analyses verified YY1 directly binding to its promoter region. Furthermore, quantitative RT-PCR analysis showed that YY1/HDAC2/4 complex negatively regulated the expression of miR-155 to suppress foam cell formation. Conclusions: In oxLDL-induced macrophages, elevated miR-155 directly targets HBP1 to promote lipid uptake and ROS production, and YY1/HDAC2/4 complex effectively inhibits foam cell formation mediated by miR-155. This study reveals a novel molecular mechanism in the atherosclerosis and suggests miR-155 is a potential therapeutic target.
SP0095 EULAR POINTS TO CONSIDER ON BIG DATA
Authors: Joanna Kedra
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> There are tremendous opportunities for health research propelled by the recent expansion of big data and artificial intelligence. However, this is an emergent area where recommendations are needed. <h3>Objectives:</h3> The objective was to develop points to consider for the use of big data by computational modelling, machine learning and artificial intelligence in rheumatic and musculoskeletal disorders (RMDs). <h3>Methods:</h3> Based on a literature review of the current status of big data in RMDs and in other fields of medicine, on individual interviews of selected experts, and on the opinion of experts in a face-to-face meeting, points to consider were formulated, discussed and finalised by an international group of 14 experts from a range of disciplines including computer science and artificial intelligence. Levels of evidence and strengths of recommendations were allocated. <h3>Results:</h3> The document comprises 5 overarching principles and 9 points to consider. The overarching principles address the definition of big data and artificial intelligence, types of big data, and ethical and general principles for dealing with big data in RMDs. The points to consider cover aspects of data sources and data collection, discussing privacy by design, use of specific data platforms, and data sharing; data analyses in particular through artificial intelligence and machine-learning; they refer to big data as a moving field in need of correct reporting of methods used and of benchmarking; and data interpretation and implementation in clinical practice. <h3>Conclusion:</h3> These EULAR points to consider provide a framework for the use of big data in RMDs. <h3>Disclosure of Interests:</h3> None declared
Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury
Authors: Ephron S. Rosenzweig, Ernesto A. Salegio, Justine J. Liang, Janet L. Weber, Chase A. Weinholtz, John H. Brock, Rod Moseanko, Stephanie Hawbecker, Roger Pender, Christina L. Cruzen, Jennifer F. Iaci, Anthony O. Caggiano, Andrew R. Blight, Barbara Haenzi, J. Russell Huie, Leif A. Havton, Yvette S. Nout-Lomas, James W. Fawcett, Adam R. Ferguson, Michael S. Beattie, Jacqueline C. Bresnahan, Mark H. Tuszynski
Journal: Nature Neuroscience (2019)
PB1676 BONE MARROW NECROSIS IN A PATIENT FOLLOWING BLINATUMOMAB THERAPY
Authors: N. Yarali, M. Isık, O. Arman Bilir, Z. Guzelkucuk, A. Selcen Oguz
Journal: HemaSphere (2019)

Background: Bone marrow necrosis (BMN) is an extremely rare condition characterized by necrosis of the myeloid tissue and medullary stroma leaving an amorphous eosinophilic background and ill-defined necrotic cells in the hematopoietic bone marrow. Several conditions are associated with BMN, including sickle cell disease, metastatic carcinoma, hematological malignancies and the use of antineoplastic drugs, such as fludarabine, interferon alpha and imatinib. Aims: Here, we report a patient with acute lymphoblastic leukemia (ALL) developing BMN following blinatumomab therapy. Methods: To our knowledge, this is the first case report on BMN following blinatumomab treatment. Results: CASE: A 15-year-old patient was admitted for the treatment of relapse precursor B-cell ALL. He did not have a matched donor and resistant ALL BFM 2002 protocol was commenced. However, minimal residual disease (MRD) persisted with this protocol and FLAG-IDA protocol including fludarabine-cytarabine and idarabucine was initiated. Remission was achieved however second bone marrow relapse developed one-year later. Both mini-FLAG protocol and vincristine, dexamethasone, bortezomib, PEG-asparaginase and doxorubicine therapies did not achieve remission. Five months after the 2nd bone marrow relapse, blinatumomab was commenced. At the 4th day of blinatumomab treatment, fever, peripheral edema, pleural effusion, mild ascites and severe bone pain developed. Blinatumomab was withheld for 9 days and following dexamethasone, wide spectrum antibiotics and antifungal treatment along with appropriate fluid and albumin supplementation,his fever and effusions regressed. Blinatumomab was restarted and it was completed without any severe complication except persistent severe bone pain. Control bone marrow aspiration displayed an eosinophilic background with ill-defined cells and biopsy revealed massive necrotic cells that could not be differentiated compatible with bone marrow necrosis. His cytopenia did not resolve and he, unfortunately, died one month after the end of first cycle due to sepsis and multiple organ failures. Summary/Conclusion: The exact physiopathology of BMN is not known. Hypoxic injury to the marrow, microvascular obstruction and/or thrombosis as a consequence of disseminated intravascular coagulation have been proposed to play a role in the development of this condition. It may also develop with chemotherapy use secondary to direct toxic effect on bone marrow cells or indirect effect via cytokines, toxic or vasoactive substances secreted from the damaged cells. In our case, we speculate that high blast load with severe cytokine release syndrome resulted in capillary leak triggering the development of BMN. We conclude that BMN should be considered in the differential diagnosis of patients with persistent bone pain and cytopenia during blinatumomab therapy
A Comprehensive Map of Genetic Variation in the World’s Largest Ethnic Group—Han Chinese
Authors: Charleston W K Chiang, Serghei Mangul, Christopher Robles, Sriram Sankararaman
Journal: Molecular Biology and Evolution (2018)

As are most non-European populations, the Han Chinese are relatively understudied in population and medical genetics studies. From low-coverage whole-genome sequencing of 11,670 Han Chinese women we present a catalog of 25,057,223 variants, including 548,401 novel variants that are seen at least 10 times in our data set. Individuals from this data set came from 24 out of 33 administrative divisions across China (including 19 provinces, 4 municipalities, and 1 autonomous region), thus allowing us to study population structure, genetic ancestry, and local adaptation in Han Chinese. We identified previously unrecognized population structure along the East-West axis of China, demonstrated a general pattern of isolation-by-distance among Han Chinese, and reported unique regional signals of admixture, such as European influences among the Northwestern provinces of China. Furthermore, we identified a number of highly differentiated, putatively adaptive, loci (e.g., MTHFR, ADH7, and FADS, among others) that may be driven by immune response, climate, and diet in the Han Chinese. Finally, we have made available allele frequency estimates stratified by administrative divisions across China in the Geography of Genetic Variant browser for the broader community. By leveraging the largest currently available genetic data set for Han Chinese, we have gained insights into the history and population structure of the world's largest ethnic group.
AB0227 EXTENSIVE IMMUNOPHENOTYPIC ANALYSIS OF CO-INHIBITORY AND CO-STIMULATORY MOLECULES IN JUVENILE IDIOPATHIC ARTHRITIS (JIA) PERIPHERAL LYMPHOCYTES
Authors: Estefanía Quesada-Masachs, Daniel álvarez de la Sierra, Antonio Julià, Mónica Martínez-Gallo, María Moreno-Cortés, Ricardo Pujol-Borrell, Consuelo Modesto, Sara Marsal
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> In a previous in-depth phenotypic analysis of PBLs in JIA, we detected differences in cell subpopulations dependent on the age and also some cellular changes that could be often associated with an exhausted phenotype. <h3>Objectives</h3> To analyze the expression of co-inhibitory and co-stimulatory molecules in different cellular subpopulations in Oligoarticular JIA patients stratified by age and treatment. <h3>Methods</h3> Exploratory cross-sectional study. 53 patients fulfilling Oligoarticular JIA (ILAR) criteria and 22 controls were included. All of them were children or young adults (2 to 35 years of age). JIA patients were either not treated (n=14) or treated with MTX (n=14), anti-TNF (n=8), or a combination of both (n=16). JIA disease activity was clinically and biologically assessed. Four flow cytometry panels were designed for the analysis of co-stimulatory/co-inhibitory markers, some typical of "exhausted" cells (PD1, TIM 3, TIGIT, CD226, CD137, HVEM, LIGHT, BTLA), assessed in memory, effector and naïve CD4+ and CD8+ T lymphocytes, and also in B lymphocytes and NK cells. Statistical analysis was performed, and FDR correction was applied for p values. <h3>Results</h3> No correlation was found among the different exhaustion/activation markers and age neither in JIA nor in controls. Interestingly, age-related differential trends were observed in the CD8+ compartment in controls, while in JIA patients were detected in the B cell compartment. We didn't observe, after correcting for treatment, any significant difference in lymphocyte subpopulations defined by the above co-inhibitory and co-stimulatory markers in JIA patients in relation to indexes of disease activity. However, there was a tendency towards a higher expression of CD137 in several CD8+ subpopulations of active patients as compared to inactive. <h3>Conclusion</h3> No clear differences were found in PBL subpopulations of oligoarticular-JIA patients regarding co-stimulatory/co-inhibitory molecules. This finding could be explained, at least in part, by the good therapeutic control achieved in this patient population, or by the particular characteristics of this group of patients, in which prevails a more localized expression of the disease. It could be of interest to carry out complementary analysis to further define the differential tendencies observed. <h3>Acknowledgement</h3> Instituto de Salud Carlos III (ISCIII), Sociedad Española Reumatología (SER) <h3>Disclosure of Interests</h3> None declared
THU0496 RESULTS OF AN EARLY INTERVENTION PROGRAM ON THE VARIATIONS IN THE LENGTH OF MUSCULOSKELETAL TEMPORARY WORK DISABILITIES
Authors: Ana Lois-Iglesias, Clara Ventin-Rodriguez, Maria Caeiro-Aguado, Alvaro Seijas-Lopez, Rodrigo Aguirre-del-Pino, Francisco Javier de-Toro-Santos
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Musculoskeletal disorders cause in Spain 23% of temporary work disability (TD). They are the first cause of permanent work disability (PD). A study of early intervention by a rheumatologist reduced TD days reduced PD. Using the "Fit for Work" European coalition led by AbbVie, the program was implemented nationwide. <h3>Objectives:</h3> To analyze the variation in the duration of sick leaves in patients referred to an early intervention program in relation to the delay on the referral from primary care and from the Occupational Health service of our hospital. <h3>Methods:</h3> Cross-sectional observational study of a hospital cohort of patients referred for 34 consecutive months to the Rheumatology Early Intervention program due to TDdue to musculoskeletal pathologies. Patients whoseTD had a traumatic or surgical origin, or with incomplete information were excluded from the analysis. We created 4 groups of patients according to the time elapsed from the start of the TD until the referral to our office: 0 to 15 days, 15 to 30 days, 30-60 days or&gt; 90 days. We compared the patients referred from primary care with those referred from occupational health. <h3>Results:</h3> For the analysis we included 394 patients, 63.3% women, with a mean age (±D.E.) of 48.5 (±9.8) years. We analyzed the most frequent pathologies: back pain (33.5%), shoulder pain (19.8%) and neck pain (8.4%). 85.8% came from primary care, 10.2% from occupational health and 4.1% from other units. The median time between referral and 1st consultation was 6 days. We found statistically significant differences in the total duration of TD among the patients referred to consultation in the first 30 days compared to those sent later in the 3 pathologies (decreasing the duration of TD between 50 and 100 days in low back pain, between 44 and 54 days in shoulder pain and between 13 and 20 days in neck pain). In back pain we found statistically significant differences in the duration of the TD after the 1st consultation, obtaining an average decrease in the duration of the TD between 42 and 52 days. In shoulder pain and neck pain an important decrease is observed without reaching statistical significance, probably related to the sample size. Regarding the patients referred from occupational health, the median time between TD and referral was 2.5 days. The pathology most frequently evaluated was low back pain (60% of cases), finding statistically significant differences in the total duration of TD, with a mean decrease in the duration of TD of 59 days compared to the general population. <h3>Conclusion:</h3> Early intervention by rheumatologists in patients with TD due to musculoskeletal disorders reduces the duration of the processes, saving costs to the health system. <h3>Disclosure of Interests:</h3> None declared