The combined 2D- and 3D-QSAR studies suggest that the moderate-size, hydrophilic and electron-withdrawing group at R1 position, the bulky and hydrophobic group at R2 position, and the minor, hydrophobic, H-bond donor and electron-donating group at R3 position would enhance the anticancer activities. These obtained results help to insight into the action mechanism, and will serve as a basis for the design of new potent anticancer agents.
表皮生长因子受体(EGFR)基因突变的非小细胞肺癌(non-small cell lung cancer,NSCLC)是一类具有独特病理和临床特征的恶性肿瘤。目前由于针对EGFR基因突变阳性NSCLC治疗中TKIs的应用,患者的生存期已超过三年,所以此类患者从诊断到治疗应进行全程管理。首先要进行分子检测,发现EGFR基因突变NSCLC,以避免失去EGFR-TKIs的治疗机会。研究证明,EGFR基因突变NSCLC任何线接受第一代抑制剂治疗,患者疗效及生存获益且耐受性良好。一代EGFR-TKIs耐药后根据失败模式选择后续局部或全身治疗,或根据耐药失败分子机制给予新的分子靶向治疗。对EGFR基因突变NSCLC应实施科学、有序的全程管理。
目的:观察佐剂关节炎大鼠滑膜PTEN/PI3K/AKT通路及缺氧诱导因子(HIF-1α)、血管内皮细胞生长因子(VEGF)表达,探讨类风湿关节炎血管新生的机制。方法:30只大鼠随机分成正常对照组和模型对照组,模型对照组采用弗氏完全佐剂建立佐剂关节炎大鼠模型。造模成功后第19天,采用酶联免疫吸附法检测大鼠HIF-1α、VEGF、微血管密度(MVD)的表达,采用Western

因为 Blotting检测滑膜PTEN、PI3K、AKT蛋白表达。结果:与正常对照组比较,模型对照组大鼠足跖肿胀度、关节炎指数升高,血清MVD、VEGF、HIF-1α表达及滑膜PI3K、AKT升高,PTEN降低。相关性分析显示,PI3K、HIF-1α与MVD呈正相关,VEGF、AKT与足趾肿胀度呈正相关,PTEN与关节炎指数呈负相关。HIF-1α与VEGF呈正相关,PI3K与AKT呈正相关,PTEN与PI3K、AKT、VEGF呈负相关。结论:佐剂关节炎大鼠滑膜PTEN/PI3K/AKT通路表达失调是引起滑膜血管新生的机制之一。
The phosphatidylinositol 3 kinase(PI3K) pathway is frequently altered in cancer, including ovarian cancer(OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of Cilengitide订单 rapamycin(m DNA Methyltransferase inhibitor TOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective m TOR complex-1(m TORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents

are being investigated, including dual m TORC1/m TORC2, Akt, and PI3 K inhibitors. Although it is likely that inhibition of the PI3K/Akt/m TOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha(PIK3CA) and/or phosphatase and tensin homolog(PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3 K signaling network, PI3 K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3 K pathway in OC and provide an up-to-date review of clinical trials of novel PI3 K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.