Synthesis of 2-Aminofurans by Sequential [2+2] Cycloaddition-Nucleophilic Addition of 2-Propyn-1-ols with Tetracyanoethylene and Amine-Induced Transformation into 6-Aminopentafulvenes

Synthesis of 2-aminofuran derivatives with an azulene or N,N-dimethylanilino substituent was established by the formal [2+2] cycloaddition-retroelectrocyclization of 3-(1-azulenyl or N,N-dimethylanilino)-2-propyn-1-ols with tetracyanoethylene, followed by intramolecular nucleophilic addition to the initially formed tetracyanobutadiene moiety of the internal hydroxyl group that come from 2-propyn-1-ol. The reaction proceeds under mild conditions with short reaction period. The products of the reaction are readily available through a simple purification procedure. 2-Aminofuran derivatives obtained by this reaction could be converted into 6-aminofulvene derivatives upon reaction with various amines. The structures of 2-aminofuran and 6-aminopentafulvene with a N,N-dimethylanilino substituent were confirmed by single-crystal X-ray structural analysis.ArticleCHEMISTRY-A EUROPEAN JOURNAL. 23(21):5126-5136 (2017)journal articl

Sorafenib Prevents Escape from Host Immunity in Liver Cirrhosis Patients with Advanced Hepatocellular Carcinoma

Purpose. It has been reported that Th2 cytokines downregulate antitumor immunity, while activation of type T cells promotes antitumor immunity. The aim of this paper was to evaluate host immunity in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) receiving sorafenib therapy. Methods. Forty-five adult Japanese LC patients received sorafenib for aHCC between 2009 and 2011 at our hospital. Sorafenib was administered at a dose of 200–800 mg/day for 4 weeks. Blood samples were collected before and after treatment. Results. Eleven patients were treated with sorafenib at 200 mg/day (200 group), 27 patients received sorafenib at 400 mg/day (400 group), and 7 patients were given sorafenib at 800 mg/day (800 group). There was no significant change in the percentage of Th1 cells after treatment in any group. However, the percentages of Th2 cells and regulatory T cells were significantly decreased after treatment in the 400 group and 800 group compared with before treatment, although there was no significant change after treatment in the 200 group. Conclusions. These results indicate that treatment with sorafenib might induce Th1 dominance and prevent the escape of tumor cells from the host immune system in LC patients with aHCC

Interaksi Masyarakat Keturunan Arab dengan Masyarakat Setempat di Pekalongan

Dalam penelitian ini penulis mengeksplorasi interaksi antara masyarakat keturunan Arab dengan masyarakat setempat di Kelurahan Klego Kota Pekalongan serta mengetahui faktor pendorong dan penghambat terjadinya interaksi antara masyarakat keturunan Arab dengan masyarakat setempat. Penelitian ini menggunakan metode kualitatif. Teknik pengumpulan data melalui metode wawancara, observasi, dan dokumentasi. Hasil penelitian menunjukan bahwa terjadi interaksi antara masyarakat keturunan Arab dengan masyarakat setempat dengan intensitas dan kegiatan kebudayaan tertentu. Faktor pendukung terjadinya interaksi adalah adanya perkawinan campuran, terutama pada masyarakat keturunan Arab non-sayyid, dengan masyarakat setempat serta adanya kerjasama dalam bidang perdagangan. Sedangkan faktor penghambat terjadinya proses interaksi adalah adanya prasangka dan stereotip pada masyarakat keturunan Arab yang merasa masyarakat setempat kurang Islami, sebaliknya masyarakat setempat merasa masyarakat keturunan Arab itu sombong. Keturunan Arab yang tinggal di Kelurahan Klego terdiri dari golongan sayyid dan golongan non-sayyid. Keturunan Arab dari golongan non-sayyid sudah dapat berbaur dengan masyarakat setempat sedangkan keturunan Arab dari golongan sayyid belum berbaur dengan masyarakat non-Arab. Masyarakat keturunan Arab memiliki simbol-simbol seperti bahasa, pakaian, bangunan yang sangat mempengaruhi interaksi antara masyarakat keturunan Arab dengan masyarakat setempat. In this study, the author explores the interaction between people of Arab descent and the local people in the village of Klego Pekalongan city and also the factors that drive and inhibit the interaction between them. This study uses qualitative methods. The technique of collecting data are interviews, observation, and documentation. The results show that there is a pattern of interaction between people of Arab descent with the local people. Factors supporting the occurrence of interactions are the presence of mixed marriages, especially in the Arab non-sayyid descent, with the local community as well as the cooperation in the field of trade. While the factors inhibiting the interaction process is the existence of prejudice and stereotypes of people of Arab descent at a local community as less Islami. On the other hand, the local people feel that people of Arab descent are exclusive. The Arab descent living in the Village Klego consists of groups and classes of non-sayyid and sayyid. Arab descent from the class of non-sayyid are able to mingle with the local people, whereas Arab descent of sayyid cannot mingle with non-Arab communities. Society of Arab descent has symbols such as language, clothing, and building that strongly influence the interaction of people of Arab descent with the local community

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study-

The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). 1,037 treatment courses with bDMARDs from 2009 to 2016 [female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9%] were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.Ebina K., Hashimoto M., Yamamoto W., et al. (2018) Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study-. PLoS ONE 13(3): e0194130. doi: 10.1371/journal.pone.0194130

Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein

SummaryIn patients with poorly controlled type 2 diabetes mellitus (T2DM), hepatic insulin resistance and increased gluconeogenesis contribute to fasting and postprandial hyperglycemia. Since cAMP response element-binding protein (CREB) is a key regulator of gluconeogenic gene expression, we hypothesized that decreasing hepatic CREB expression would reduce fasting hyperglycemia in rodent models of T2DM. In order to test this hypothesis, we used a CREB-specific antisense oligonucleotide (ASO) to knock down CREB expression in liver. CREB ASO treatment dramatically reduced fasting plasma glucose concentrations in ZDF rats, ob/ob mice, and an STZ-treated, high-fat-fed rat model of T2DM. Surprisingly, CREB ASO treatment also decreased plasma cholesterol and triglyceride concentrations, as well as hepatic triglyceride content, due to decreases in hepatic lipogenesis. These results suggest that CREB is an attractive therapeutic target for correcting both hepatic insulin resistance and dyslipidemia associated with nonalcoholic fatty liver disease (NAFLD) and T2DM