摘要：还记得那个古老的故事吗？从前，有一个农夫，他的一头老驴不小心掉进一口枯井里，农夫绞尽脑汁想办法想把它救出来，但耗费多时依然徒劳无功，驴子还在井里痛苦地哀嚎着。

摘要：本研究旨在比较不同实验设计下正态化预测分布误差(normalised prediction distribution errors,NPDE)和可视化预测检验(visual predictive check,VPC)对模型的评价效能。本研究通过仿真方法,分别在采血时间相同的单剂量、多剂量给药以及采血时间不同的多剂量给药3种条件下,比较考察NPDE和VPC对正确模型、参数群体典型值偏差或参数个体间变异(inter-individual variability)偏差造成的错误模型的评价能力。结果显示,VPC没有明确的判断标准并且会受到实验设计的影响,采血时间不同的多剂量给药实验设计下,VPC结果已很难辨别并且对模型的辨识能力也明显下降;而NPDE具有相应的统计学检验,其模型评价能力不受实验设计因素的影响。结果提示,临床研究中VPC不适用的数据及模型,NPDE依然可以进行合理的评价。

摘要：多靶点药物已成为一种有广阔前景的药物,特别是对抗肿瘤药物的研发.基于候选药物GSK2126458和上市药物Vorinostat的结构特点,设计并合成了一系列新型的磷脂酰肌醇3-激酶(PI3Ks)和组蛋白脱乙酰酶(HDACs)双重抑制剂.生物活性研究发现,化合物GYB-4对PI3Kα和HDAC1的IC50分别为1.0和4.2nmol/L;化合物GYB-5对PI3Kα和HDAC1的IC50分别为1.3和4.8nmol/L.对所有化合物在HCT116,PC3和A2780细胞株上进行了增殖抑制活性研究,相关的构效关系研究将为PI3K和HDAC双靶点抑制剂的进一步优化提供思路.

摘要：合成了2个系列的白杨素衍生物,采用噻唑蓝(MTT)法测试了所有化合物针对六种肿瘤细胞的体外抗增殖活性,包括MGC-803, BEL-7402, HepG2, HeLa, A549以及SGC-7901细胞.实验结果显示, 7-[1-(3-氟苯基)-1H-1,2,3-三唑-4-甲氧基]-白杨素(1c)与7-[1-(2-氯苯基)-1H-1,2,3-三唑-4-甲氧基]-白杨素(1g)针对MGC-803细胞的活性与先导化合物白杨素及阳性对照药5-氟尿嘧啶相比显著提高.因此,化合物1c与1g具有深入研究用以开发抗癌药物的潜能.

摘要：生物利用度研究中,对双交叉设计试验,已有成熟的等效性分析的统计方法,包括双单侧t检验法、可信区间法等。近年来,新药生物利用度研究中不时遇到采用多交叉设计的情形。为了判定试验制剂与参比制剂之间的等效性,双交叉设计中使用的方法难以满足要求,需借助专用于多交叉设计的生物等效性统计分析方法。本文将介绍一种适合于多交叉设计生物等效性分析的可信区间方法,结合一个实例详细给出不进行对数转换和进行对数转换时的不同处理技术,并提供了用SAS分析的程序代码。

摘要：目的分析国内开放性/单盲设计临床试验质量控制的现状,提出开放性/单盲设计临床试验中存在的问题及对策。方法通过检索1979—2009年中文期刊发表的有关开放性/单盲设计临床试验的文献,对文献中的质量控制现状进行分析。结果开放性/单盲设计的临床试验中存在的问题有:缺乏必要的质量控制措施,研究数据的质量得不到有效地保证。结论开放性/单盲设计临床试验的质量控制现状亟待进一步改进,以提高临床研究的质量。

摘要：Cholangiocarcinoma(CCA)is characterized by heterogeneous mutations and a refractory ***,the development of a model for effective drug screening is urgently *** the established therapeutic testing models for CCA are often ineffective,we fabricated an enabling three-dimensional(3D)-bioprinted CCA-on-a-chip model that to a good extent resembled the multicellular microenvironment and the anatomical microstructure of the hepato-vascular-biliary system to perform high-content antitumor drug ***,cholangiocytes,hepatocytes,and vascular endotheliocytes were employed for 3D bioprinting of the models,allowing for a high degree of spatial and tube-like microstructural ***,it was possible to observe CCA cells attached to the surfaces of the gelatin methacryloyl(GelMA)hydrogelembedded microchannels and overgrown in a thickening manner,generating bile duct stenosis,which was expected to be analogous to the in vivo *** 4000 differentially expressed genes were detected in the CCA cells in our 3D coculture model compared to the traditional two-dimensional(2D)*** screening revealed that the CCA cells grown in the 3D traditional model were more sensitive to the antitumoral prodrug than those in the 2D monoculture due to drug biotransformation by the neighboring functional *** study provides proof-of-concept validation of our bioprinted CCA-on-a-chip as a promising drug screening model for CCA treatment and paves the way for potential personalized medicine strategies for CCA patients in the future.

摘要：Traditional two-dimensional(2D)cell cultures lack the extracellular matrix(ECM)-like structure or dynamic fluidic microenvironment for cells to maintain in vivo ***-dimensional(3D)tissue scaffolds,on the other hand,could provide the ECM-like microenvironment for cells to reformulate into tissue or organoids that are highly useful for in vitro drug *** this study,a high-throughput two-chamber 3D microscale tissue model platform is *** scaffolds are selectively foamed on a commercially available compact disk using *** of cell culture medium is achieved with centrifugal force-driven diffusion by disk *** studies were conducted on the fabrication process under various gas saturation and laser power *** cultures were performed with two types of human cell lines:M059K and *** is shown that the structure of microscale porous scaffolds can be controlled with laser foaming parameters and that coating with polydopamine these scaffolds are inducive for cell attachment and aggregation,forming a 3D *** many such two-chamber models fabricated on a single CD and perfusion driven by the centrifugal force from rotation,the proposed platform provides a simple solution to the high-cost and lengthy drug development process with a high-throughput and physiologically more relevant tissue model system.

摘要：酪氨酸磷酸酶PTP1B已被公认为治疗II型糖尿病药物的理想靶标蛋白.通过重组表达制备PTP1B蛋白及其蛋白质晶体,并尝试将其与768种小分子片段进行以结构为基础的筛选,得到了数个与PTP1B结合的小分子片段及其化学结构.在此基础上利用计算机辅助药物设计方法设计与优化出一种新型PTP1B抑制剂,并经13步反应合成了该目标分子.体外药理活性和毒性的初步评价的结果表明,其对体外重组人源PTP1B的酪氨酸磷酸酶活性半数抑制浓度IC50值达到(3.4±1.2)μmol/L,优于阳性对照;在Hep G2细胞胰岛素抵抗模型中,该化合物能有效改善胰岛素抵抗细胞对葡萄糖的利用能力,其改善效果与阳性药匹格列酮相当.初步的斑马鱼毒性检测表明,目标该化合物在浓度为500μmol/L时未对幼鱼产生明显毒性.新化合物的发现为新型PTP1B抑制剂的后续开发开辟了新基础.

摘要：新药临床试验设计中存在的问题涉及指导思想、科研设计、质量控制、统计分析等临床试验研究过程中的关键环节。本文揭示了新药临床试验设计中存在的8大问题,并提供具有可操作性的防范措施。新药临床试验研究是一个非常复杂的系统工程,在新药Ⅰ、Ⅱ、Ⅲ、Ⅳ期临床试验研究过程中,特别是在新药临床试验研究方案和临床病例报告表的研制和实施过程中,必须严格参照国家相关部门制定的政策、法规、标准和操作规程。忽视临床试验设计与数据分析的科学性与严谨性,必将导致临床试验研究的失败。