tbuckley/cabot-search huggingface dataset:
Mg2+ regulation of kinase signaling and immune function
Authors: Chryssa Kanellopoulou, Alex B. George, Evan Masutani, Jennifer L. Cannons, Juan C. Ravell, Tori N. Yamamoto, Margery G. Smelkinson, Ping Du Jiang, Mami Matsuda-Lennikov, Julie Reilley, Robin Handon, Ping-Hsien Lee, J. Richard Miller, Nicholas P. Restifo, Lixin Zheng, Pamela L. Schwartzberg, Matthew Young, Michael J. Lenardo
Journal: The Journal of Experimental Medicine (2019)

Mg2+ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg2+ reduced intracellular Mg2+ levels and impaired the Ca2+ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg2+ specifically impairs TCR signal transduction by IL-2–inducible T cell kinase (ITK) due to a requirement for a regulatory Mg2+ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg2+ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg2+ regulatory paradigm of kinase function. Finally, a reduced serum Mg2+ concentration in mice causes an impaired CD8+ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg2+ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg2+ concentration is important for antiviral immunity in otherwise healthy animals.
SP0137 CORE COMPETENCIES
Authors: Thea Vliet Vlieland
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> To maintain and optimize the quality of care provided by health professionals in rheumatology (HPRs), adequate educational offerings are needed. Ideally, these are based on defined core competences. <h3>Objectives:</h3> A task force (TF) aimed to develop evidence-based recommendations for the generic core competences of nurses, physical therapists (PTs) and occupational therapists (OTs) to serve as a basis for their postgraduate education. <h3>Methods:</h3> The EULAR standardised operating procedures for the development of recommendations were followed. A TF including rheumatologists, nurses, PTs, OTs, patient-representatives, an educationalist, methodologists and researchers from 12 countries met twice. In the first TF meeting, 13 research questions were defined to support a systematic literature review (SLR). In the second meeting, the SLR evidence was discussed and recommendations formulated. Subsequently, level of evidence and strength of recommendation were assigned and level of agreement (LoA) determined (0-10 rating scale). <h3>Results:</h3> Three overarching principles and 10 recommendations for the generic core competences of HPRs were developed supported by the SLR and expert opinion. The SLR included 79 full-text papers, 20 of which addressed the competences, knowledge, skills, attitudes or educational needs of HPRs from multiple professions. The average LoA for each recommendation ranged from 9.42 to 9.79. Consensus was reached on education and research agendas. <h3>Conclusion:</h3> Evidence and expert opinion informed a set of recommendations providing guidance on the generic core competences of nurses, PTs and OTs in rheumatology. Implementation of these recommendations in the postgraduate education of HPRs at the international and national level is advised, considering variation in health care systems and professional roles. <h3>Task Force Members:</h3> L.M. Edelaar, E. Nikiphorou, G.E. Fragoulis, A. Iagnocco, C. Haines, M. Bakkers, L. Barbosa, N. Cikes, M. Ndosi, J. Primdahl, Y. Prior, P. Pchelnikova, V. Ritschl, V.S. Schäfer, H. Smucrova, I. Storrønning, M. Testa, D. Wiek, T.P.M. Vliet Vlieland <h3>Reference:</h3> [1] Van der Heijde D, Aletaha D, Carmona L, et al. 2014 Update of the EULAR standardised operating procedures for EULAR-endorsed recommendations. Ann Rheum Dis. 2014;74:8-13. <h3>Disclosure of Interests:</h3> None declared
PF631 HEALTH‐RELATED QUALITY OF LIFE WITH POMALIDOMIDE + LOW‐DOSE DEXAMETHASONE + DARATUMUMAB IN PATIENTS WITH RELAPSED REFRACTORY MULTIPLE MYELOMA AFTER LENALIDOMIDE TREATMENT
Authors: D. Reece, N.J. Bahlis, C. Samaras, M. Sebag, J. Berdeja, S. Ganguly, J. Matous, K. Song, C.S. Seet, G. Talamo, M. Acosta‐Rivera, M. Bar, D. Quick, B. Anz, G. Fonseca, A. Agarwal, W. Chung, F. Zafar, D.S. Siegel
Journal: HemaSphere (2019)

Background: Treatment of relapsed refractory multiple myeloma (RRMM) is complex and requires evaluation of disease and patient factors to maximize efficacy and minimize toxicity. As survival has improved with therapeutic advances, maintaining quality of life has become an important aspect of multiple myeloma treatment. Results from cohort B of the ongoing phase 2 MM‐014 trial (NCT01946477) have demonstrated that pomalidomide (POM) + low‐dose dexamethasone (LoDEX) + daratumumab (DARA) is safe and effective in patients with RRMM after first‐ or second‐line lenalidomide (LEN)‐based treatment. Aims: To evaluate the impact of POM+ LoDEX + DARA on health‐related quality of life (HRQoL) in patients with RRMM who received this regimen after first‐ or second‐line LEN. Methods: Patients with RRMM and 1 to 2 prior lines of treatment, LEN‐based treatment as their most recent regimen, and progressive disease during or after their last treatment line were eligible for inclusion in cohort B. In 28‐day cycles, patients received POM 4 mg/day on days 1–21 + LoDEX 40 mg/day (20 mg/day if aged &gt; 75 years) on days 1, 8, 15, and 22, and DARA 16 mg/kg IV on DEX dosing days of cycles 1 and 2, then on days 1 and 15 of cycles 3–6, and then on day 1 of cycle 7 and beyond. Thromboprophylaxis was mandatory. The primary endpoint was overall response rate. HRQoL, an exploratory endpoint for cohort B, was assessed via EQ‐5D. Results: As of 15 October 2018, 108 patients were evaluable for HRQoL. Baseline characteristics were similar to those of the ITT population (N = 112). EQ‐5D completion rates for each cycle (1–6) were ≥ 88%. Through 6 treatment cycles, mean change from baseline in the EQ‐5D index and VAS health score was stable. At cycle 6, minimum clinically important improvement in the EQ‐5D index (≥ 0.1) and VAS health score (≥ 6) was achieved by 28.8% and 39.0% of patients, respectively. EQ‐5D index values were stable; however, a trend toward improvement was observed in usual activities, pain/discomfort, and anxiety/depression (Figure). Summary/Conclusion: In patients with RRMM who received POM + LoDEX + DARA after first‐ or ‐second‐line LEN based treatment, HRQoL was maintained or trended toward improvement, despite the combination of 3 drugs with distinct toxicity profiles. In context with the previously reported safety and efficacy data from cohort B of MM‐014, the results of this HRQoL analysis further support the earlier use of POM‐based treatment in RRMM immediately following treatment with LEN. image
THU0588 CLINICAL PHENOTYPES OF IGG4-RELATED DISEASE IN SPAIN
Authors: María Toledano-Macías, Andreu Fernandez-Codina, Iago Carballo, Borja De Miguel-Campo, Luis Sáez-Comet, José Hernández-Rodríguez, Blanca Pinilla, Fernando Martínez-Valle
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Recently, several clinical phenotypes in IgG4-related disease have been described in a multinational and ethnically variate cohort<sup>1</sup>. <h3>Objectives</h3> To assess the clinical presentation of IgG4-related disease (IgG4-RD) in Spanish patients and assess the distribution among different clinical phenotypes. <h3>Methods</h3> Clinical data were obtained from the Spanish IgG4-RD registry (REERIGG4) from October 2013 to December 2018, including 9 centers. We reviewed demographic data and organ involvement. The assignation of clinical phenotypes was done by 2 experts, based on organ involvement and clinical manifestations, following Wallace et al.<sup>1</sup> subsets. The phenotypes were: pancreato-hepato-biliary (HBP), retroperitoneum and aorta (RA), head and neck limited (HNL) and Mikulicz and systemic (MS). A fifth group designated not defined (ND), included the patients that did not fit in the previous phenotypes. <h3>Results</h3> One-hundred patients were included. Thirty-four (34%) were females, median age at diagnosis was 54.8 years (IQR 20.7). The ethnicity of the participants was: Caucasian 83%, Hispanic 12% and North-African/Middle-East 5%. Ninety-two percent were diagnosed with a biopsy. Regarding the diagnostic criteria, 85% met consensus pathology criteria and 94% comprehensive criteria. Fifty-one patients (51%) had systemic IgG4-RD involving &gt;1 tissue. The most commonly involved tissues were: retroperitoneum (35%), lymph nodes (19%), orbit pseudotumor (18%), salivary glands (16%) and pancreas (14%). Forty-two patients (42%) had elevated serum IgG4. The representation of each clinical phenotype was: HBP 14%, RA 25%, HNL 26%, MS 20%, ND 15%. Patients were equally distributed from the perspective of ethnicity. Men were predominant in all groups (71, 84, 70, 73%) except in HNL (61% for women). Systemic disease was present in all the MS patients, but in 1/3 of the other groups. Serum IgG4 was elevated in 86% of the cases in HBP, 28% in RA, 19% in HNL, 60% in MS and 40% in ND. <h3>Conclusion</h3> The Spanish IgG4-RD population was mainly ethnically Caucasian. Few patients had serum IgG4 elevation. The most frequent phenotype was HNL, followed by RA. The HBP phenotype was less frequent than in previous reports. The influence of race could modify the clinical expression of IgG4-RD. Knowing the regional phenotypes of IgG4-RD may help clinicians improve disease management. <h3>References</h3> [1] Wallace ZS, Zhang Y, Perugino CA, et al. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis. doi: 10.1136/annrheumdis-2018-214603 <h3>Disclosure of Interests</h3> None declared
PB1709 TET 2 POLYMORPHISM AND MIRNA 22 EXPRESSION AMONG EGYPTIAN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Authors: E. Dammag, N. Hamed, N. El Halawany, H. Kassem, M. Ayad
Journal: HemaSphere (2019)

Background: Acute myelogenous leukemia (AML) is a heterogeneous group of disease characterized by uncontrolled proliferation of myeloid progenitor cells. It is clear that TET2 polymorphisms are common among Egyptian AML patients and larger scale studies are needed to iinvestigate the role of this in both modulating treatment and prognostic impact of the disease. TET2 mutations are established poor prognostic molecular risk factors yet TET2 polymorphism status are not thoroughly studied. Role of miRNA22 and its impact on TET2 expression needs to be further studied to improve risk stratification of AML. Aims: The aim of this study is to evaluate the incidence of the TET2 single nucleotide polymorphism (SNP) (rs2454206, rs34402524, rs61744960) and its correlation to miRNA22 gene expression in Egyptian Adult Acute Myeloid Leukemia patients. Methods: Cases were selected from Alexandria Main University Hospital Internal Medicine Department (Hematology Unit) from March 2017‐December 2017; 52 patients diagnosed as AML and 30 healthy subjects matched for age and sex to determine SNPs genotype frequency among patients. DNA extraction by Invitrogen purelink genomic DNA minikit (Cat No. k1820‐01, Lot No 1510617) and real time PCR for TET2 SNP polymorphism using Taqman primers and probes of TET2 polymorphism (rs2454206, rs34402524, rs61744960) using an ABI Prism GeneAmp 7500 using peripheral or bone marrow blood. Micro RNA 22 Taqman quantitative Assay using real time PCR (Thermal Fisher Biosystems Taqman miRNA22 Cat. no. 4427975) and control miRNA was U6. Micro RNA extraction was done using Qiagen extraction kits (Cat No./ID: 217004). Written Informed consent was taken from every patient and approval of the Ethical committee (IRB No. 00008699, FWA No.00015712) was provided. Results: 35 AML patients (14 females, 21 males) had mean age of 43.42 ± 14.0yrs are the subject of the study. SNP RS 34402524 ranged from heterozygous (23/52 46%) to homozygous (27/52 54%) in AML group but was mainly homozygous (24/30 80%) among the control group (p&gt;0.05). As for RS 6843141, most AML patients had wild pattern (31/52 62%) and control group were homozygous (20/30 60%) (p &lt; 0.0001). RS 2454206, and RS 61744960 showed no statistical significance between cases and controls (p &gt; 0.05). miRNA22 were under‐expressed among AML most patients. This was of statistical significance compared to controls p &lt; 0.0001. As for miRNA 22 and TET2 polymorphism, there was no statistical significance between the status of SNPs and miRNA22 expression p &gt; 0.05. Summary/Conclusion: miRNA22 is markedly underexpressed in AML patients and may participate in hypermethylation and leukomogenesis. Confirmation of this finding could open a new therapeutic approach in AML and even in bone marrow transplant candidates. image
Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy
Authors: Christina Claus, Claudia Ferrara, Wei Xu, Johannes Sam, Sabine Lang, Franziska Uhlenbrock, Rosmarie Albrecht, Sylvia Herter, Ramona Schlenker, Tamara Hüsser, Sarah Diggelmann, John Challier, Ekkehard Mössner, Ralf J. Hosse, Thomas Hofer, Peter Brünker, Catherine Joseph, Jörg Benz, Philippe Ringler, Henning Stahlberg, Matthias Lauer, Mario Perro, Stanford Chen, Christine Küttel, Preethi L. Bhavani Mohan, Valeria Nicolini, Martina Carola Birk, Amandine Ongaro, Christophe Prince, Reto Gianotti, Gregory Dugan, Christopher T. Whitlow, Kiran Kumar Solingapuram Sai, David L. Caudell, Armando G. Burgos-Rodriguez, J. Mark Cline, Michael Hettich, Maurizio Ceppi, Anna Maria Giusti, Flavio Crameri, Wouter Driessen, Peter N. Morcos, Anne Freimoser-Grundschober, Victor Levitsky, Maria Amann, Sandra Grau-Richards, Thomas von Hirschheydt, Stella Tournaviti, Michael Mølhøj, Tanja Fauti, Viola Heinzelmann-Schwarz, Volker Teichgräber, Sara Colombetti, Marina Bacac, Alfred Zippelius, Christian Klein, Pablo Umaña
Journal: Science Translational Medicine (2019)

Endogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti-4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcγ receptor-mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP-4-1BBL (RG7826) and CD19-4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen-mediated hyperclustering without systemic activation by FcγR binding. We could show targeting of FAP-4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer-bearing rhesus monkey. Combination of FAP-4-1BBL with tumor antigen-targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-γ and granzyme B secretion. Further, combination of FAP- or CD19-4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8+ T cells. FAP- and CD19-4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies.
SAT0411 COMORBIDITY PATTERNS IN GOUT USING THE US GENERAL POPULATION – CLUSTER ANALYSIS OF THE NATIONAL HEALTH AND NUTRITION EXAMINATION SURVEY 2007-2016
Authors: Chio Yokose, Leo Lu, Michael Chen-Xu, Yuqing Zhang, Hyon Choi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Gout is associated with many metabolic and cardiorenal comorbidities. Several previous studies investigated the comorbidity patterns by cluster analysis; however, no such study has been based on the entire general population. As such, the generalizability, which is essential to these pattern analyses, remains unknown. <h3>Objectives:</h3> We used cluster analysis on a large, representative general population sample of the United States to identify discrete phenotype patterns comorbidities observed in gout patients. <h3>Methods:</h3> We used data from 8,607,137 participants in the 2007-2016 National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of adults in the United States. Diagnosis of gout was based on survey of physician- or health professional-diagnosed gout. We used cluster analysis to identify subgroups among participants with gout with distinct comorbidity subgroups based on 9 variables: obesity, hypertension, diabetes, hypercholesterolemia, hypertriglyceridemia, coronary heart disease (CHD), heart failure (HF), chronic kidney disease (CKD), and liver disease. <h3>Results:</h3> Cluster analysis identified 5 different subgroups (C1-C5) (Table 2). C1 had the highest proportion of patients with CKD (97%). C2 consisted of patients with gout but few other comorbidities. All patients in C3 had diabetes, but no HF, CHD, or CKD. C4 consisted primarily of patients with liver disease (85%), with high prevalences of lipid abnormalities and obesity. C5 had the highest proportion of patients with CHD and HF. <h3>Conclusion:</h3> These findings from a nationally representative data of US adults indicate that gout comorbidities have 5 distinctive phenotypic patterns. These subgroups may have implications in pathogenesis of gout and/or for personalized care in the management of gout and comorbidities. <h3>Disclosure of Interests:</h3> None declared
PS1079 CLINICAL OUTCOME OF INTENSIFIED CHEMO‐TARGETED THERAPY IN ACTIVATED B CELL NON HODGKIN LYMPHOMA
Authors: A. Sohaib, T. Hashim, M. Abouelfetouh, E. Elkhouly, A. Alhanafy, R. Samaka
Journal: HemaSphere (2019)

Background: Diffuse large B cell lymphoma (DLBCL) accounts for approximately a third of all NHL and is the most common lymphoma subtype in all parts of the world. Advances in DNA array has resulted in further subclassification of DLCBL into germinal center type and activated B cell type (ABC). Activated B cell type has a worse prognosis than germinal center type Aims: To assess the role of intensified chemotherapy for patients with activated B cell type of DLBCL if it would result in better outcome. Primary end point is response rate and secondary end points are PFS and toxicity, OS Methods: This is a randomized phase II study done on 82 patients. Cases are randomized into two arms. Control arm received R‐CHOP (47 patients) and test arm received R‐CHEOP (35 patients). All cases are tested for BCL‐6, MUM‐1 and CD10 to confirm being of ABC type according to Hans algorithm. GCSF was used for prophylaxis in the test arm in the form of daily 1 vial of neupogen for 3 days after the cycle. Evaluation is done by Cheson et. al. criteria. Toxicity was described according to CTCAE V4 Results: Both groups were comparable as regard age, gender, performance status, stage and LDH. Median age was 52 years for the control arm and 46 years for the test arm. Results are analyzed at a median follow up of 15 months. Complete remission at end of treatment was 70.2% for the control arm and 91.4% for the test arm (p = 0.019) while interim assessment showed 58% median tumor shrinkage for the control arm and 79% for the test arm ( p &lt; 0.001). Median PFS was 25 months for the control arm and not reached for the test arm (p = 0.022) while median overall survival was 28 months for the control group and not reached for the test arm (p = 0.145). At one year of follow up, overall survival was 74.46% for the control arm and 91.4% for the test arm. Toxicity was comparable in both groups regarding neutropenia (p = 0.356), oral mucositis (p = 0.419), diarrhea (p = 0.54), vomiting (p = 0.504), thrombocytopenia (p = 0.308), anemia (p = 0.453), neuropathy (p = 1) Summary/Conclusion: R‐CHEOP showed more tumor shrinkage than R‐CHOP in activated B cell lymphoma with comparable toxicity. PFS was better in the first year of follow up but more time is needed to calculate mature survival data image
PB1740 PROGNOSTIC SIGNIFICANCE OF JAK-II GENE EXPRESSION IN ACUTE MYELOID LEUKEMIA PATIENTS
Authors: M. El Gammal, L. Fathalla, N. Hassan, O. ElGebaly, B. Elgamal
Journal: HemaSphere (2019)

Background: AML is a heterogenous disease with multiple established prognostic factors including molecular genetic markers, and also many genetic changes with yet little or unknown role. Mutation of JAK2 tyrosine kinase has been detected in myeloproliferative disorder that can evolve into AML, but yet its prognostic role in AML not established. Aims: to study JAK-II gene expression pattern in AML patients and its relation with other established prognostic variables and outcome parameters Methods: Prospective study on 175 AML patients treated at medical oncology department. Jak2 gene expression was evaluated by quantitative real time PCR using taqman primer probe assay. All patients received current standard of care treatment for AML at NCI, Cairo University, Egypt. Results: the median age was 31 year with male to female ratio of 53.1/46.9. The most common FAB subtypes were M2 followed by M4. The median OS of the whole group is 4 months, and significantly higher for APL than AML (29.8 v 2.8 month, p = 0.005), for favorable risk cytogenetic patients than other patients (29.8 v 1.8 month, p < 0.001), and lower for poor risk group than other groups (1.2 v 4.2 month, p = 0.019). Patients with JAK-II expression fold change ≤0.5 had better OS than those with >0.5 (median 17.5 v2.4 month, p = 0.011). The median DFS for patients who achieved complete remission (CR) was 11.8 months. APL patients had better DFS than AML (median 28.8 v 8.7 month, p = 0.007). DFS according to risk grouping, low risk group had significantly better DFS than either intermediate or poor risk (p = 0.019 and p = 0.029). On multivariate analysis, combined (cytogenetic and molecular genetic)risk status (low v high) and cytogenetic catgorization were independent factors for survival (p = 0.048 & 0.005 respectively), JAK-II expression fold change remained an independent factor for OS.Summary/Conclusion: JAK-II gene expression is associated with decreased overall survival and disease free survival in AML patients