tbuckley/cabot-search huggingface dataset:
Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration
Authors: Carola Ledderose, Kaifeng Liu, Yutaka Kondo, Christian J. Slubowski, Thomas Dertnig, Sara Denicoló, Mona Arbab, Johannes Hubner, Kirstin Konrad, Mahtab Fakhari, James A. Lederer, Simon C. Robson, Gary A. Visner, Wolfgang G. Junger
Journal: Journal of Clinical Investigation (2018)

T cells must migrate in order to encounter antigen-presenting cells (APCs) and to execute their varied functions in immune defense and inflammation. ATP release and autocrine signaling through purinergic receptors contribute to T cell activation at the immune synapse that T cells form with APCs. Here, we show that T cells also require ATP release and purinergic signaling for their migration to APCs. We found that the chemokine stromal-derived factor-1α (SDF-1α) triggered mitochondrial ATP production, rapid bursts of ATP release, and increased migration of primary human CD4+ T cells. This process depended on pannexin-1 ATP release channels and autocrine stimulation of P2X4 receptors. SDF-1α stimulation caused localized accumulation of mitochondria with P2X4 receptors near the front of cells, resulting in a feed-forward signaling mechanism that promotes cellular Ca2+ influx and sustains mitochondrial ATP synthesis at levels needed for pseudopod protrusion, T cell polarization, and cell migration. Inhibition of P2X4 receptors blocked the activation and migration of T cells in vitro. In a mouse lung transplant model, P2X4 receptor antagonist treatment prevented the recruitment of T cells into allograft tissue and the rejection of lung transplants. Our findings suggest that P2X4 receptors are therapeutic targets for immunomodulation in transplantation and inflammatory diseases.
Circulating Tumor Cells Undergoing EMT Provide a Metric for Diagnosis and Prognosis of Patients with Hepatocellular Carcinoma
Authors: Lu-Nan Qi, Bang-De Xiang, Fei-Xiang Wu, Jia-Zhou Ye, Jian-Hong Zhong, Yan-Yan Wang, Yuan-Yuan Chen, Zu-Shun Chen, Liang Ma, Jie Chen, Wen-Feng Gong, Ze-Guang Han, Yan Lu, Jin-Jie Shang, Le-Qun Li
Journal: Cancer Research (2018)

Abstract To clarify the significance of circulating tumor cells (CTC) undergoing epithelial–mesenchymal transition (EMT) in patients with hepatocellular carcinoma (HCC), we used an advanced CanPatrol CTC-enrichment technique and in situ hybridization to enrich and classify CTC from blood samples. One hundred and one of 112 (90.18%) patients with HCC were CTC positive, even with early-stage disease. CTCs were also detected in 2 of 12 patients with hepatitis B virus (HBV), both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal–CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g., cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggest that BCAT1 may trigger the EMT process. Overall, CTCs were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis. Significance: In liver cancer, CTC examination may represent an important “liquid biopsy” tool to detect both early disease and recurrent or metastatic disease, providing cues for early intervention or adjuvant therapy. Cancer Res; 78(16); 4731–44. ©2018 AACR.
AB1270 Achieving early disease control and reducing indirect cost – the crystal registry in hong kong rheumatoid arthritis patients
Authors: T.H. Cheng, M.C. Wan, L.S. Tam
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Rheumatoid arthritis is associated with irreversible joint erosion, jeopardising patients’ work ability and incurs substantial indirect cost to the society. While early treatment yield clinical efficacy, its economic outcome remains uncertain in Hong Kong. <h3>Objectives</h3> To ascertain the effect of early disease control in early RA subjects on indirect cost. <h3>Methods</h3> This was a multi-centre, prospective cohort study involved 13 hospitals in Hong Kong. Subjects underwent intensive treatment scheme aiming at remission. Early disease control was defined as achieving remission or low disease activity(LDA) at month 6 indicated by DAS-28 score. <h3>Results</h3> Seventy early RA patients [53 (75.7%)Female, mean age: 53±11 years, mean disease duration 30±11 months] were included in this analysis. Forty-two(60%) subjects achieved early disease control. Subjects with or without early disease control were comparable at baseline. Twenty-two(31.4%) subjects had non-zero indirect cost[median(IQR) indirect cost: USD162(76–317)]. Among them, early disease control non-achievers(n=11) had significantly higher indirect cost than achievers[median(IQR) indirect cost: USD317(133–934) vs USD95,<sup>48–163</sup> p=0.008](figure 1). Using multivariate linear regression, after adjusting for age, gender, baseline pain score, fatigue level, physical and mental condition, every 1-unit increase in DAS score at month 6 was associated with USD82 increase in indirect cost [95% CI: 12–151, p=0.022]. When disease activity was categorised, not achieving remission/LDA was associated with USD165 increase in indirect cost [95% CI: 21–310, p=0.025] (table 1). Model 1 – DAS score as continuous variable Model 2 – DAS score categorised as early disease control or not <h3>Conclusions</h3> Early intensive treatment with early disease control yield lower indirect cost. Health care system shall consider reallocating adequate resource for managing early arthritis patients to reduce indirect cost related to disease. <h3>Acknowledgements</h3> This is to acknowledge the Hong Kong Society of Rheumatology Education and Research Foundation for supporting this project. <h3>Disclosure of Interest</h3> None declared
Accuracy of Sensititre YeastOne echinocandins epidemiological cut-off values for identification of FKS mutant Candida albicans and Candida glabrata: a ten year national survey of the Fungal Infection Network of Switzerland (FUNGINOS)
Authors: A. Kritikos, D. Neofytos, N. Khanna, P.W. Schreiber, K. Boggian, J. Bille, J. Schrenzel, K. Mühlethaler, R. Zbinden, T. Bruderer, D. Goldenberger, G. Pfyffer, A. Conen, C. Van Delden, S. Zimmerli, D. Sanglard, D. Bachmann, O. Marchetti, F. Lamoth, T. Bregenzer, A. Conen, U. Flückiger, N. Khanna, C. Orasch, U. Heininger, M. Franciolli, L. Damonti, S. Zimmerli, M. Rothen, C. Zellweger, P. Tarr, F. Fleisch, C. Chuard, V. Erard, S. Emonet, J. Garbino, C. van Delden, D. Genne, P. Bochud, T. Calandra, F. Lamoth, O. Marchetti, J. Chave, P. Graber, R. Monotti, O. Regionale, E. Bernasconi, O. Civico, M. Rossi, M. Krause, R. Piso, F. Bally, N. Troillet, K. Boggian, G. Eich, J. Gubler, J. Fehr, A. Imhof, C. Ruef, C. Berger, H. Fankhauser, I. Heinzer, R. Frei, R. Hertel, M. Dolina, O. Petrini, O. Dubuis, K. Mühlethaler, S. Graf, M. Risch, E. Ritzler, D. Fracheboud, J. Schrenzel, P. Rohner, R. Lienhardt, J. Bille, C. Andreutti-Zaugg, A. Gallusser, G. Pfyffer, K. Herzog, U. Schibli, L. Tissière, T. Bruderer, D. Schultze, R. Zbinden
Journal: Clinical Microbiology and Infection (2018)
AB0865 Do asas, asdas and basdai therapy response evaluation translate the same information?
Authors: M. Eusébio, J.L. Gomes, M. Bernardes, P. Pinto, H. Santos, J. Tavares-Costa, J. Dias, S. Pimenta, L. Domingues, C. Crespo, S. Maia, F. Martins, J.C. Branco, F.M. Pimentel-Santos
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The ASAS-EULAR recommendations for the continuation of biological Disease-Modifying Anti-rheumatic Drugs (DMARD) suggest the evaluation of patients after at least 12 weeks of treatment by either the Ankylosing Spondylitis (AS) Disease Activity Score – C reactive protein (ASDAS-CRP) or by the Bath AS Disease Activity Index (BASDAI). For ASDAS-CRP, a Minimal Clinical Important Difference (MCID) ≥1.1 is necessary, while for the total BASDAI score a 50% reduction or a change of ≥2.0 points is considered clinically relevant. In clinical trials, the Assessment in Ankylosing Spondyloarthritis (ASAS) response criteria – ASAS 20, ASAS 40 and ASAS 70 – are still the most frequent primary outcome measures to evaluate improvement in treatment response. However, in clinical practice the BASDAI is still routinely used. <h3>Objectives</h3> The aim of this work was to assess the concordance/agreement between different therapeutic outcome measures, such as the ASAS response criteria, ΔASDAS-CRP and BASDAI 50. <h3>Methods</h3> Data from 54 patients who fulfilled the modified New York criteria for AS were collected at baseline, weeks 2 and 14 post-treatment with Adalimumab. Pearson's correlation (PCCs) and the Cohen's Kappa coefficients were calculated for the three scores. <h3>Results</h3> A strong correlation was found between the three scores throughout the visits: rho=−0.676 for ASDAS/ASAS, rho=−0.807 for ASAS/BASDAI, and rho=0.786 for BASDAI/ASDAS (all PCCs with p&lt;0.001). Additionally, when the categorization in different disease activity states and response levels was performed, PCCs revealed significant concordance/agreement between the three scores' cut-offs (see table 1). The individuals categorised as responders, by eitheir BASDAI50 or ΔASDAS ≥1.1, have shown similar clinical characteristics (Erythrocyte Sedimentation Rate, CRP, AS Quality of Life Scale and Bath AS Functional Index). Importantly, when more stringent measures of ASAS response criteria and ASDAS were used (i.e. ASAS 70 and ASDAS≥2.1) the agreement with BASDAI values decreased. <h3>Conclusions</h3> Our results suggest that the ASAS response criteria, ΔASDAS-CRP and BASDAI 50 report the same clinical information. Hence, the clinician's decision should still be consistent independently of the score adopted. However, this study also highlights the importance of establishing a new and more stringent BASDAI cut-off, in alignment with ASDAS-CRP'≥2.1 and ASAS 70. <h3>Disclosure of Interest</h3> None declared
AB0032 B-cell subpopulations in newly diagnosed eora and yora patients
Authors: K. Thorarinsdottir, A. Camponeschi, L. Jacobsson, I.-L. Mårtensson, I. Gjertsson
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> B-cells are thought to have an important role in rheumatoid arthritis (RA). This is demonstrated by the success of B-cell depleting therapy as well as the negative prognostic value of anti-citrullinated protein antibodies (ACPA)<sup>1</sup>. However, the pathogenesis of the disease is unclear. Studies have suggested that there are differences in disease characteristics between elderly-onset RA patients (EORA, defined by disease onset at ≥60 years of age) and younger-onset RA patients (YORA, with disease onset &lt;60 years of age).<sup>2</sup> <h3>Objectives</h3> Our aim was to study the B-cell subpopulations in newly diagnosed EORA and YORA patients. We investigated whether there were differences in B-cell subpopulations between the groups and whether there was a correlation between B-cell subpopulations and disease activity, autoantibody profile and inflammatory parameters in these two RA patient groups. <h3>Methods</h3> Treatment-naive EORA (n=29) and Yora (n=31) patients with newly diagnosed RA were included at their first visit to the Rheumatology clinic. The patients' clinical response (DAS28), autoantibodies and B-cells were assessed. Flow cytometry was used for the analysis of cellular surface markers on leukocytes in peripheral blood: CD19, CD27, CD24, CD27, CD38, PD-1, PD-L1, IgG, IgD and IgM. Non-parametric tests were used for comparing groups and Spearman's test was used for correlation. <h3>Results</h3> We found a correlation between the ACPA titers and the frequency of the CD27<sup>+</sup> and CD27<sup>-</sup> memory B cell populations in EORA patients but not in YORA patients. This was further supported by a correlation of the ACPA titer and IgG<sup>+</sup> B cells in the EORA patients (r=0.7, p=0.003) and not in the YORA patients. There was neither a correlation between age and ACPA titer nor between age and memory B cell populations. We did not find any significant difference between the B cell subpopulations in the two patient groups. <h3>Conclusions</h3> Our results suggest that the memory B cell compartment in peripheral blood in EORA patients reflects the ACPA titer. This was not seen in the YORA patients. The mechanisms behind these findings need to be further elucidated. <h3>References</h3> [1] Bugatti S, Vitolo B, Caporali R, Montecucco C, Manzo A. B cells in rheumatoid arthritis: from pathogenic players to disease biomarkers. Biomed Res Int2014;2014:681678. [2] Kobak S, Bes C. An autumn tale: geriatric rheumatoid arthritis. Ther Adv Musculoskelet Dis2018;10:3–11. <h3>Disclosure of Interest</h3> None declared
miR-210 Enhances the Therapeutic Potential of Bone-Marrow-Derived Circulating Proangiogenic Cells in the Setting of Limb Ischemia
Authors: Marie Besnier, Stefano Gasparino, Rosa Vono, Elena Sangalli, Amanda Facoetti, Valentina Bollati, Laura Cantone, Germana Zaccagnini, Biagina Maimone, Paola Fuschi, Daniel Da Silva, Michele Schiavulli, Sezin Aday, Massimo Caputo, Paolo Madeddu, Costanza Emanueli, Fabio Martelli, Gaia Spinetti
Journal: Molecular Therapy (2018)

Therapies based on circulating proangiogenic cells (PACs) have shown promise in ischemic disease models but require further optimization to reach the bedside. Ischemia-associated hypoxia robustly increases microRNA-210 (miR-210) expression in several cell types, including endothelial cells (ECs). In ECs, miR-210 represses EphrinA3 (EFNA3), inducing proangiogenic responses. This study provides new mechanistic evidences for a role of miR-210 in PACs. PACs were obtained from either adult peripheral blood or cord blood. miR-210 expression was modulated with either an inhibitory complementary oligonucleotide (anti-miR-210) or a miRNA mimic (pre-miR-210). Scramble and absence of transfection served as controls. As expected, hypoxia increased miR-210 in PACs. In vivo, migration toward and adhesion to the ischemic endothelium facilitate the proangiogenic actions of transplanted PACs. In vitro, PAC migration toward SDF-1α/CXCL12 was impaired by anti-miR-210 and enhanced by pre-miR-210. Moreover, pre-miR-210 increased PAC adhesion to ECs and supported angiogenic responses in co-cultured ECs. These responses were not associated with changes in extracellular miR-210 and were abrogated by lentivirus-mediated EFNA3 overexpression. Finally, ex-vivo pre-miR-210 transfection predisposed PACs to induce post-ischemic therapeutic neovascularization and blood flow recovery in an immunodeficient mouse limb ischemia model. In conclusion, miR-210 modulates PAC functions and improves their therapeutic potential in limb ischemia.
Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality
Authors: Ewa Gogola, Alexandra A. Duarte, Julian R. de Ruiter, Wouter W. Wiegant, Jonas A. Schmid, Roebi de Bruijn, Dominic I. James, Sergi Guerrero Llobet, Daniel J. Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J. Ogilvie, Marcel van Vugt, Lodewyk F.A. Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg
Journal: Cancer Cell (2018)
AB0652 Pet/mr in large-vessel vasculitis: clinical value for the diagnosis and assessment of disease activity
Authors: C. Laurent, L. Ricard, I. Buvat, O. Fain, A. Mekinian, M. Soussan
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> The diagnosis and the activity determination could be challenging in large-vessel vasculitis (LVV). <h3>Objectives</h3> The aim of this study was to analyze the value of hybrid PET/MR in LVV. <h3>Methods</h3> All consecutive patients with LVV who underwent PET/MR were included. PET/MR patterns were defined as inflammatory in the case of positive PET (grade=3) and abnormal MR (stenosis and/or wall thickening) and fibrous in the case of negative PET (grade 1 or 2) and abnormal MR. <h3>Results</h3> Thirteen patients with median age at 67 years (23–87 years) and 10 (77%) females were included, and underwent 18 PET/MR scans. Eleven PET/MR performed at diagnosis (n=4) or relapse (n=7) and 7 in patients in remission. 8/18 (44%) had PET/MR inflammatory pattern and 3/18 (17%) had fibrous pattern. PET/MR were normal in 2/10 (20%) cases of TA versus 5/8 (62%) cases of GCA (p=0.3). The median SUVmax was 3.0 [1.8–8.6] without significative difference between GCA and TA: 3.4 (2.1–8.6) versus 2.6 (1.8–7.1) (p=0.4), respectively. Eleven PET (61%) were performed under treatment, which consisted of steroids with a median dose at 30 mg/day [3–240]. Among 11 patients with active disease, 8 had inflammatory patterns and 3 had normal PET/MR, i.e a sensibility of 73%, and the sensibility increased to 100% in patients with active TA disease. Median SUVmax were 4.7 [2.1–8.6] in patients with active disease versus 2 [1.8–2.6] in patients with remission (p=0.003). <h3>Conclusions</h3> PET/MR is a new hybrid modality of imaging which is interesting for the diagnosis and the follow-up of large-vessel vasculitis. <h3>References</h3> [1] Soussan M, Nicolas P, Schramm C, Katsahian S, Pop G, Fain O, Mekinian A. Management of large-vessel vasculitis with FDG-PET: a systematic literature review and meta-analysis. Medicine (Baltimore). 2015 Apr;94(14):e 622. [2] Einspieler I, Thürmel K, Pyka T, Eiber M, Wolfram S, Moog P, Reeps C, Essler M. Imaging large vessel vasculitis with fully integrated PET/MR: a pilot study. Eur J Nucl Med Mol Imaging 2015;42:1012–24. [3] Desai MY, Stone JH, Foo TK, Hellmann DB, Lima JA, Bluemke DA. Delayed contrast-enhanced MRI of the aortic wall in Takayasu9s arteritis: initial experience. AJR Am J Roentgenol. 2005 May;184(5):1427–31. [4] Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [18F]- fluorodeoxyglucose positron emission tomography. Circulation 2002;105:2708–11. [5] Baldursson O, Steinsson K, Björnsson J, Lie JT. Giant cell arteritis in Iceland. An epidemiologic and histopathologic analysis. Arthritis Rheum. 1994 Jul;37(7):1007–12. [6] Gonzalez-Gay MA, Garcia-Porrua C, Llorca J, Gonzalez-Louzao C, Rodriguez-Ledo P. Biopsy-negative giant cell arteritis: clinical spectrum and predictive factors for positive temporal artery biopsy. Semin Arthritis Rheum. 2001 Feb;30(4):249–56. <h3>Disclosure of Interest</h3> None declared
Effectiveness of 13-valent pneumococcal conjugate vaccination for protection against acute otitis media caused by Streptococcus pneumoniae in healthy young children: a prospective observational study
Authors: Michael Pichichero, Ravinder Kaur, Daniel A Scott, William C Gruber, James Trammel, Anthony Almudevar, Kimberly J Center
Journal: The Lancet Child & Adolescent Health (2018)
SAT0103 Three-monthly ultrasound monitoring of rheumatoid arthritis patients tapering their medication has limited value in predicting disease relapse
Authors: M. van der Ven, M. Kuijper, A. Gerards, I. Tchetverikov, A. Weel, D. van Zeben, C. Bijkerk, Y. de Man, M. Hazes, J. Luime
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Prognostic factors that may guide tapering decisions for DMARDs and TNFi on individual patient level are not available. To improve successful tapering subclinical synovitis may play a role in maintaining the remission state. Studies using ultrasound suggest that the presence of subclinical synovitis may elicit early disease relapse in remission. <h3>Objectives</h3> Our aim is to determine if ultrasound synovitis precedes disease relapse while tapering synthetic DMARD (sDMARD) or TNFi in patients with RA who achieved clinical remission on sDMARD and TNFi. <h3>Methods</h3> We included 125 RA patients (aged&gt;17 years) treated with an sDMARD and a TNF-inhibitor who were in remission (DAS44≤2.4 &amp; SJC≤1). Demographic characteristics, swollen and tender joints, laboratory variables and ultrasound synovitis (MCP2-5; PIP2-5; wrists; MTP2-5) were recorded at each visit (every three months) during one year follow-up. Patients were randomised to two tapering strategies: i) tapering sDMARD; ii) tapering TNFi. Disease relapse was defined as DAS44&gt;2.4 or SJC&gt;1. Ultrasound synovitis was defined as GS≤1 and/or PD≤0. To estimate whether ultrasound is able to identify patients who will have a disease relapse within three months follow-up a Cox proportional regression model for time to event data was used. <h3>Results:</h3> Ultrasound synovitis was found in 58% of RA patients in clinical remission. After one year follow-up 36% of RA patients had a disease relapse of whom 60% had ultrasound synovitis at baseline. table 1 shows the distribution of relapse en ultrasound synovitis for every three months. In the multivariate Cox model increasing number of joints with ultrasound synovitis was not significantly associated with disease relapse within three months follow-up (HR 1.21; 95%CI: 0.97-1.51) [table 2]. <h3>Conclusions</h3> Monitoring RA patients who started tapering their medication every three months showed limited value for ultrasound to identify patients who will have a disease relapse. <h3>Disclosure of Interest:</h3> None declared
Corrigendum: Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine (vol 48, pg 856, 2016)
Authors: Padhraig Gormley, Verneri Anttila, Bendik S. Winsvold, Priit Palta, Tonu Esko, Tune H. Pers, Kai-How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A. Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M. Terwindt, Mikko Kallela, Tobias M. Freilinger, Caroline Ran, Scott G. Gordon, Anine H. Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H. H. Adams, Terho Lehtimaki, Antti-Pekka Sarin, Juho Wedenoja, David A. Hinds, Julie E. Buring, Markus Schurks, Paul M. Ridker, Maria Gudlaug Hrafnsdottir, Hreinn Stefansson, Susan M. Ring, Jouke-Jan Hottenga, Brenda W. J. H. Penninx, Markus Farkkila, Ville Artto, Mari Kaunisto, Salli Vepsalainen, Rainer Malik, Andrew C. Heath, Pamela A. F. Madden, Nicholas G. Martin, Grant W. Montgomery, Mitja I. Kurki, Mart Kals, Lude Franke, Jie Huang
Journal: Nature Genetics (2016)