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The synthesis of indole skeleton by using Pd(II)-catalyzed cyclization of the urethane has been achieved. The urethanes with allylic alcohol were converted into vinyl indolines in good yield. The vinyl indoline was transformed into some intermediates of indole alkaloids.

Background: Mast cells are known to play a pivotal role in allergic diseases by releasing granules containing histamine and other preformed chemical mediators. Cross-linking of high-affinity receptors for IgE (FceRI) on mast cells results in rapid increases in intracellular free calcium concentration [Ca2+]i and consequent activation of many transcription factors, including NFAT, NF-κB, JNK and CREB. Ca2+ signaling is essential for many cellular activities such as proliferation, gene expression and degranulation in mast cells. In addition to Ca2+ signaling, previous reports have shown that IkappaB kinase 2 (IKK2 or IKKß), a central component of the IKK complex mediating NF-κB activation, also plays a crucial role in FceRI-mediated degranulation and cytokine production. Moreover, it has been demonstrated that activation of PKCß, a calcium-dependent PKC isoform, leads to IKK2 activation in many cell types. However, the roles of Ca2+ signaling and PKCß in the activation of IKK2 in mast cells remain largely unknown. Methods: We investigated the effect of PKC inhibitor Gö6976 on calcium ionophore A23187-induced activation of IKK2 in mast cells. We also examined the role of IKK2 in A23187-induced NF-κB-dependent gene induction, degranulation, proinflammatory cytokine production and extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation by using IKK2-deficient (IKK2-/-) fetal liver-derived mast cells (FLMCs). Results: A23187 activated IKK2 and NF-κB even in the presence of Gö6976 in mast cells. A23187-induced degranulation, cytokine production and activation of ERK1/2 were diminished in IKK2-/- FLMCs compared to those in wild-type FLMCs. Conclusions: Ca2+-IKK2 signaling is involved in the degranulation and cytokine production in activated mast cells by a mechanism independent of PKCß.

Pd-catalyzed cyclization of substrates (I) provides vinyl indolines, which are further transformed into intermediates of indole alkaloids such as (III) or (IV).

Objective This prospective study aimed to determine whether the comprehensive ultrasonographic assessment of synovial inflammation predicts relapse after discontinuation of treatment with a biologic agent in patients with rheumatoid arthritis (RA) in clinical remission. Methods RA patients in clinical remission (Disease Activity Score in 28 joints [DAS28]

Background Rheumatoid arthritis (RA) is a chronic inflammatory disease and proinflammatory cytokines such as TNFα and IL-6 play critical roles in the pathogenesis of RA. The blockade of IL-6 signaling by Tocilizumab (TCZ) has shown the clinical efficacy for patients with RA. To clarify the roles of IL-6 signaling in CD4+ T cells in the pathogenesis of RA, we previously compared gene expression profiles of CD4+ T cells by DNA microarray analysis before and after the treatment with TCZ in RA patients who exhibited good clinical responses to the treatment (1, 2), and identified that B cell leukemia/lymphoma 3 (Bcl3), an IκB family member, was down-regulated by TCZ therapy (1). However, the role of Bcl3 expressed in CD4+ T cells in the pathogenesis of RA remains unclear. Objectives The objective of this study is to examine the role of Bcl3 expressed in CD4+ T cells in the pathogenesis of RA. Methods We compared signal intensity of Bcl3 in CD4+ T cells between untreated RA patients and healthy controls by DNA microarray analysis. We examined the roles of IL-6-STAT3 signaling in Bcl3 induction. We also analyzed gene expression profiles of Bcl3-transduced CD4+ T cells by RNA-sequencing analysis. We examined the effect of enforced expression as well as gene silencing of Bcl3 on the development of T follicular helper (Tfh) cells. Finally, we examined a correlation between signal intensities of Bcl3 and Tfh cell-related genes in CD4+ T cells in untreated RA patients. Results Bcl3 levels were significantly higher in RA patients than those in healthy controls. IL-6 induced Bcl3 expression in CD4+ T cells in a STAT3-dependent manner. Transcriptome analysis revealed that the expression of Bcl6, a master regulator of Tfh cell differentiation, was significantly upregulated by the enforced Bcl3 expression ([Figure1][1]). The enforced Bcl3 expression increased but the Bcl3 silencing decreased IL-21-producing Tfh-like cells. Bcl3 levels were positively correlated with those of Tfh cell-related genes such as CXCR5, ICOS, and ASCL2 in CD4+ T cells in RA patients. ![Figure][2] Conclusions Bcl3 is involved in the development of Tfh cells and the pathogenesis of RA presumably by inducing IL-21 production. References 1. Saito Y, Kagami SI, Sanayama Y, Ikeda K, Suto A, Kashiwakuma D, et al. AT-rich interactive domain-containing protein 5a functions as a negative regulator of RORγt-induced Th17 cell differentiation. Arthritis Rheum. 2014;66(5):1185-94. 2. Sanayama Y, Ikeda K, Saito Y, Kagami S, Yamagata M, Furuta S, et al. Prediction of therapeutic responses to tocilizumab in patients with rheumatoid arthritis: biomarkers identified by analysis of gene expression in peripheral blood mononuclear cells using genome-wide DNA microarray. Arthritis Rheum. 2014;66(6):1241-31. Disclosure of Interest K. Meguro: None declared, K. Suzuki: None declared, J. Hosokawa: None declared, Y. Sanayama: None declared, S. Tanaka: None declared, S. Furuta: None declared, K. Ikeda: None declared, H. Takatori: None declared, A. Suto: None declared, O. Ohara: None declared, H. Nakajima Grant/research support from: Chugai Pharmaceutical Co., Ltd, Bristol-Myers Squibb, and Mitsubishi Tanabe Pharma Co. [1]: #F1 [2]: pending:yes

Background Clinical information does not accurately predict relapse after discontinuation of biological agents in patients with rheumatoid arthritis (RA). Although ultrasound is a sensitive tool to detect sub-clinical synovial inflammation in RA patients with low disease activity, the ultrasound findings on the unilateral hand did not discriminate between patients who relapsed and who did not after discontinuation of TNF antagonists in the previous report 1 . Objectives This pilot, single-blinded, prospective study aimed to determine whether the comprehensive ultrasound scan on 40 joints is informative in the prediction of relapse after discontinuation of biological agents. Methods RA patients in remission states (DAS28 ≤ 2.6) receiving biological agents who agreed to discontinue the biological agent were recruited. Patients underwent a comprehensive ultrasound scan on 40 joints (DAS28 joints + ankles + MTP joints) and were prospectively followed up for 26 weeks. The physicians who evaluated the patients during the study period were blinded to the ultrasound findings at baseline. Results Thirty patients receiving either TNF antagonists (n = 24), or tocilizumab (n = 6) were enrolled. The disease activity was very low (median DAS28 1.64 [IQR 1.2-2.3]) before the biological agent was discontinued. Eleven patients had relapse which was defined as DAS28 > 3.2 and restarted receiving the same biological agent within 26 weeks. Total ultrasound scores provided with larger areas under the ROC curves for the prediction of relapse than DAS28 did. Using the optimal cut-off values determined by the ROC analysis, the PPV and NPV of total GS score ≥ 12 to predict flare were 88% and 82%, respectively. On the other hand, the PPV and NPV of total PD score ≥ 3 were 100% and 79%, respectively. Image/graph Conclusions In RA patients with very low disease activity receiving biological agents, a comprehensive ultrasound scan provides good diagnostic values to predict relapse after discontinuation of the biological agent. References Saleem B, Keen H, Goeb V, Parmar R, Nizam S, Hensor EM, et al. Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 2010;69(9):1636-42. Disclosure of Interest T. Iwamoto: None Declared, K. Ikeda Grant/research support from: Mitsubishi-Tanabe Pharma Corporation, Abbott Japan Co., Ltd, Consultant for: Mitsubishi-Tanabe Pharma Corporation, Abbott Japan Co., Ltd, J. Hosokawa: None Declared, M. Yamagata: None Declared, S. Tanaka: None Declared, Y. Sanayama: None Declared, D. Nakagomi: None Declared, A. Okubo: None Declared, K. Takahashi: None Declared, K. Hirose: None Declared, M. Sueishi: None Declared, H. Nakajima Grant/research support from: Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd, Consultant for: Mitsubishi-Tanabe Pharma Corporation, Chugai Pharmaceutical Co., Ltd