牙龈间充质干细胞递送支架载体的研究进展

组织工程技术通过利用支架材料、种子细胞、生长因子以达到修复或再生组织器官的目的。支架材料的作用是为种子细胞提供机械支撑并且保护细胞免受体内有害微环境的影响。因此,选择或制备适当的支架材料是组织工程中的关键一步。近年来,将支架材料和牙龈间充质干细胞(gingival mesenchymal stem cells,GMSCs)联合应用于组织工程的研究逐渐走向成熟。本文就组织工程中牙龈间充质干细胞递送支架载体的研究现状进行综述,以期为GMSCs组织工程递送支架载体材料的开发和选择提供思路。     

High-performance multiplex drug-gated CAR circuits

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双环[1.1.1]戊烷衍生物的合成研究进展

双环[1.1.1]戊烷（BCP）是一种具有三维立体结构的桥环骨架，其作为苯环、叔丁基和炔烃的生物电子等排体，已经在药物化学领域得到广泛的应用。随着BCP应用范围的扩大，BCP及其衍生物的合成日益成为研究的热点。本文对BCP衍生物的主要合成策略和方法进行总结，旨在为新药研发人员提供参考。     

替米沙坦关键中间体的新合成路线

本研究设计了替米沙坦关键中间体2-正丙基-4-甲基-6-(1-甲基苯并咪唑-2-基)苯并咪唑(1)的新合成路线。正丁腈(2)与甲醇或乙醇在氯化氢作用下反应得到正丁基亚胺酯(3)的盐酸盐,经碱化得到游离的3,再与4-氨基-3-甲基苯甲酸(4)反应得到4-丁脒基-3-甲基苯甲酸(5)。5与次氯酸钠反应生成中间过渡产物,然后直接在氢氧化钠作用下关环生成2-正丙基-4-甲基苯并咪唑-6-羧酸(6)。6与N-甲基邻苯二胺盐酸盐(7)脱水缩合生成1。该路线采用了2次叠缩工艺,简化了生产操作,总收率高达79%(以4计)。     

Rucaparib in the landscape of PARP inhibition in ovarian cancer

Introduction: The landscape of poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer is rapidly evolving and becoming increasingly complex. Ovarian cancer is leading therapeutic innovation by providing the proof of concept for DNA repair as a target. Three different PARP inhibitors have now received approvals in the US and Europe in different indications. Subtle but crucial differences can be found among the licensed indications for each PARP inhibitor in terms of histology, type of BRCA mutation (germline and/or somatic), number of prior lines of chemotherapy and whether the indication is in the treatment or maintenance settings.

Areas covered: We review the latest clinical data regarding the PARP inhibitor rucaparib in ovarian cancer, provide an update on the evolving landscape of PARP inhibition in ovarian cancer, and summarize avenues of ongoing and future research.

Expert opinion: All eligible patients should be offered a PARP inhibitor. SOLO1 trial results demonstrated an unprecedented benefit maintenance with PARP inhibitors in first line. Results from trials evaluating PARP inhibitors as maintenance in first line regardless of BRCA status and from trials evaluating combinatorial strategies are eagerly awaited.     

Endurance Behavior of Cemented Tibial Tray Fixation Under Anterior Shear and Internal-External Torsional Shear Testing: A New Methodological Approach

BackgroundEarly total knee arthroplasty failures continue to surface in the literature. Cementation technique and implant design are two of the most important scenarios that can affect implant survivorship. Our objectives were to develop a more suitable preclinical test to evaluate the endurance of the implant-cement-bone interface under anterior shear and internal-external (I/E) torsional shear testing condition in a biomechanical sawbones.MethodsImplants tested included the AS VEGA System PS and the AS Columbus CR/PS (Aesculap AG, Germany), with zirconium nitride (ZrN) coating. Tibial implants were evaluated under anterior shear and I/E torsional shear conditions with 6 samples in 4 test groups. For the evaluation of the I/E torsional shear endurance behavior, a test setup was created allowing for clinically relevant I/E rotation with simultaneous high axial/tibio-femoral load. The test was performed with an I/E displacement of ±17.2°, for 1 million cycles with an axial preload of 3,000 N.ResultsAfter the anterior shear test an implant-cement-bone fixation strength for the AS VEGA System tibial tray of 2,674 ± 754 N and for the AS Columbus CR/PS tibial tray of 2,177 ± 429 N was determined (P = .191). After I/E rotational shear testing an implant-cement-bone fixation strength for the AS VEGA System PS tray of 2,561 ± 519 N and for the AS Columbus CR/PS tray of 2,824 ± 515 N was resulted (P = .39).ConclusionBoth methods had varying degrees of failure modes from debonding to failure of the sawbones foam. These two intense biomechanical loading tests are more strenuous and more representative of clinical activity.     

Biological properties of the native and synthetic lipid A of Porphyromonas gingivalis lipopolysaccharide

INTRODUCTION AND METHODS: A pentaacyl and diphosphoryl lipid A molecule found in the lipid A isolated from Porphyromonas gingivalis lipopolysaccharide (LPS) was chemically synthesized, and its characteristics were evaluated to reconfirm its interesting bioactivities including low endotoxicity and activity against LPS-unresponsive C3H/HeJ mouse cells. RESULTS: The synthesized P. gingivalis lipid A (synthetic Pg-LA) exhibited strong activities almost equivalent to those of Escherichia coli-type synthetic lipid A (compound 506) in all assays on LPS-responsive mice, and cells. LPS and native lipid A of P. gingivalis displayed overall endotoxic activities, but its potency was reduced in comparison to the synthetic analogs. In the assays using C3H/HeJ mouse cells, the LPS and native lipid A significantly stimulated splenocytes to cause mitosis, and peritoneal macrophages to induce tumor necrosis factor-alpha and interleukin-6 production. However, synthetic Pg-LA and compound 506 showed no activity on the LPS-unresponsive cells. Inhibition assays using some inhibitors including anti-human Toll-like receptor 2 (TLR2) and TLR4/MD-2 complex monoclonal antibodies showed that the biological activity of synthetic Pg-LA was mediated only through the TLR4 signaling pathway, which might act as a receptor for LPS, whereas TLR2, possibly together with CD14, was associated with the signaling cascade for LPS and native lipid A of P. gingivalis, in addition to the TLR4 pathway. CONCLUSION: These results suggested that the moderated and reduced biological activity of P. gingivalis LPS and native lipid A, including their activity on C3H/HeJ mouse cells via the TLR2-mediated pathway, may be mediated by bioactive contaminants or low acylated molecules present in the native preparations having multiple lipid A moieties.     

微卫星不稳定性恶性肿瘤合成致死新靶点WRN的研究进展

微卫星不稳定性（microsatellite instability,MSI）是一种肿瘤细胞中由错配修复受损或缺陷导致而出现新的微卫星等位基因的现象。MSI可以导致肿瘤细胞基因组进一步紊乱和突变,从而促进恶性肿瘤的发生发展,是公认的重要致癌途径之一。Werner syndrome protein （WRN）解旋酶是属于RecQ家族的DNA解旋酶,该酶在DNA修复和维持基因组稳定性中发挥着重要的作用。近年来研究发现,MSI恶性肿瘤的生长高度依赖WRN解旋酶,提示WRN是潜在的MSI恶性肿瘤合成致死新靶点。文章系统综述了WRN解旋酶的结构和生物学功能,总结该蛋白作为合成致死新靶点的最新进展,以及WRN解旋酶抑制剂的研究进展,以期为MSI恶性肿瘤的治疗和WRN抑制剂研发提供参考。