Surface‐expressed insulin receptors as well as IGF‐I receptors both contribute to the mitogenic effects of human insulin and its analogues

There is a medical need for new insulin analogues. Yet, molecular alterations to the insulin molecule can theoretically result in analogues with carcinogenic effects. Preclinical carcinogenicity risk assessment for insulin analogues rests to a large extent on mitogenicity assays in cell lines. We therefore optimized mitogenicity assay conditions for a panel of five cell lines. All cell lines expressed insulin receptors (IR), IGF‐I receptors (IGF‐IR) and hybrid receptors, and in all cell lines, insulin as well as the comparator compounds X10 and IGF‐I caused phosphorylation of the IR as well as IGF‐IR. Insulin exhibited mitogenicity EC₅₀ values in the single‐digit nanomolar to picomolar range. We observed correlations across cell types between (i) mitogenic potency of insulin and IGF‐IR/IR ratio, (ii) Akt phosphorylation and mitogenic potency and (iii) Akt phosphorylation and IR phosphorylation. Using siRNA‐mediated knockdown of IR and IGF‐IR, we observed that in HCT 116 cells the IR appeared dominant in driving the mitogenic response to insulin, whereas in MCF7 cells the IGF‐IR appeared dominant in driving the mitogenic response to insulin. Together, our results show that the IR as well as IGF‐IR may contribute to the mitogenic potency of insulin. While insulin was a more potent mitogen than IGF‐I in cells expressing more IR than IGF‐IR, the hyper‐mitogenic insulin analogue X10 was a more potent mitogen than insulin across all cell types, supporting that the hyper‐mitogenic effect of X10 involves the IR as well as the IGF‐IR. These results are relevant for preclinical safety assessment of developmental insulin analogues. Copyright © 2014 John Wiley & Sons, Ltd.     

Controlled self-assembly into diverse stimuli-responsive microstructures: from microspheres to branched cylindrical micelles and vesicles

A series of amphiphilic PDMAEMA–SS–PCL chains with variable ratios of hydrophilic poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) to hydrophobic poly(ε-caprolactone) (PCL) were prepared via ring-opening polymerization, in which the two different moieties were linked via a disulfide bond with reduction responsiveness. After cross-linking by the photodegradable o-nitrobenzyl linkage, the amphiphilic chains could self-assemble into microspheres, branched cylindrical micelles and vesicles, which were responsive to the reduction agent dl-dithiothreitol and UV light irradiation through different mechanisms.

A series of cross-linked amphiphilic PDMAEMA–SS–PCL were prepared, which could self-assemble into diverse microstructures with reduction and light responsiveness.     

The formation and growth of calcium sulfate crystals through oxidation of SO2 by O3 on size-resolved calcium carbonate

Calcium sulfate is a major constituent of atmospheric sulfate, with a typical rod-like morphology ranging from several hundred nanometers to approximately two micrometers observed in field studies. However, the chemical formation mechanism is still not well known. In this study, the kinetics and mechanism for the formation and growth of rod-like calcium sulfate crystals through oxidation of SO₂ by O₃ on size-resolved CaCO₃ at different relative humidity (RH) were investigated using diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and scanning electron microscopy (SEM). We found that the concentration and formation rate of sulfate decreased with the increasing diameter of CaCO₃ particles, and thus smaller particles could enhance the formation of sulfate due to more reactive sites on smaller particles. The rod-like calcium sulfate crystals were formed only at RH above 60% and in the presence of reactant gases through the heterogeneous pathway. The liquid-like water layer formed by promotion of high RH in the presence of reactant gases could facilitate the formation and aggregation of calcium sulfate hydrates and thus promote the formation and growth of rod-like calcium sulfate crystals. This study provides a possible mechanism for the formation and growth of rod-like calcium sulfate crystals existing in the atmosphere.

The heterogeneous formation pathway of rod-like calcium sulfate crystals in the atmosphere.     

湖南省永州市1993—2014年艾滋病疫情特点

目的分析永州市1993—2014年艾滋病疫情特点,为制定人免疫缺陷病毒(HIV)/获得性免疫缺陷综合征(AIDS)预防和控制策略提供科学依据。方法采用描述流行病学方法,对永州市1993—2014年艾滋病疫情进行统计分析。结果永州市1993—2014年累计报告HIV/AIDS病例2 917例,报告病例数逐年上升;男女比例为2.30∶1;20~49岁青壮年占52.04%,≥50岁者占46.76%,近年≥50岁人群所占比例上升明显;感染途径以性传播为主,占88.48%,其中男男同性传播占2.64%。结论永州市要进一步加大艾滋病知识宣传力度,切实落实高危人群行为干预各项措施;将端口下移,扩大检测范围,以有效防控艾滋病的传播与流行。     

2011—2013年北京某城区感染性腹泻患者致病菌检测分析

目的分析北京某城区2011—2013年感染性腹泻患者致病菌分布及脉冲场凝胶电泳(PFGE)图谱特征,为感染溯源提供依据。方法收集2011年1月—2013年12月该区域肠道门诊感染性腹泻患者粪便标本1 179份,对其培养分离的致病菌进行血清分型及PFGE分析。结果 1 179份标本,共培养肠道病原菌330株,其中检出居前4位的肠道致病菌依次为志贺菌属93株(28.18%)、沙门菌属69株(20.91%)、副溶血性弧菌44株(13.33%)及致泻性大肠埃希菌11株(3.33%)。18株宋内志贺菌PFGE分为8个型别,聚类相似度接近88%;69株沙门菌属细菌分为18个血清型,共41种PFGE型别,其中山夫登堡沙门菌和肠炎沙门菌具有明显的优势带型;23株副溶血性弧菌PFGE型别较为分散。结论 3年间感染性腹泻患者致病菌的血清型和PFGE带型分布较为广泛,应注意沙门菌属和志贺菌属细菌的PFGE优势菌型,警惕其引发的感染性腹泻暴发流行。     

慢性戊型肝炎相关研究进展

戊型肝炎散发于世界各地,多为急性自限性疾病,但近年来不断有文献报道在HIV感染者、器官移植和放化疗患者等免疫力低下人群中发现基因3型戊型肝炎病毒感染导致的戊型肝炎慢性化疾病,其临床表现类似急性戊型肝炎,但症状及肝功能损伤均较轻.目前研究发现,人群感染戊型肝炎病毒后肝炎慢性化的机制主要包括宿主因素和病毒因素.此文就慢性戊型肝炎的定义、临床表现、患者特征、感染慢性化的病毒因素及治疗等方面的进展进行综述.     

Applications of mass spectrometry in drug metabolism: 50 years of progress

Abstract

Mass spectrometry plays a pivotal role in drug metabolism studies, which are an integral part of drug discovery and development nowadays. Metabolite identification has become critical to understanding the metabolic fate of drug candidates and to aid lead optimization with improved metabolic stability, toxicology and efficacy profiles. Ever since the introduction of atmospheric ionization techniques in the early 1990s, liquid chromatography coupled with mass spectrometry (LC/MS) has secured a central role as the predominant analytical platform for metabolite identification as LC and MS technologies continually advanced. In this review, we discuss the evolution of both MS technology and its applications over the past 50 years to meet the increasing demand of drug metabolism studies. These advances include ionization sources, mass analyzers, a wide range of MS acquisition strategies and data mining tools that have substantially accelerated the metabolite identification process and changed the overall drug metabolism landscape. Exemplary applications for characterization and identification of both small-molecule xenobiotics and biological macromolecules are described. In addition, this review discusses novel MS technologies and applications, including xenobiotic metabolomics that hold additional promise for advancing drug metabolism research, and offers thoughts on remaining challenges in studying the metabolism and disposition of drugs and other xenobiotics.     

非小细胞肺癌患者外周血与组织中K-ras基因突变的研究

目的检测非小细胞肺癌患者外周血与肿瘤组织K-ras基因突变率及两者的一致性,探讨外周血K-ras基因突变的临床应用价值。方法应用实时荧光定量PCR方法检测257例非小细胞肺癌组织,318例非小细胞肺癌外周血,其中185例外周血标本和组织标本配对,检测其中K-ras基因突变,比较外周血和组织标本突变一致性,分析K-ras基因突变和患者临床特征相关性。结果外周血标本中检测出37例突变(11.64%),组织标本中29例突变(11.28%),两种标本一致性为76.19%,差异有统计学意义(Kappa=0.671,P=0.000)。结论非小细胞肺癌患者外周血与组织K-ras基因突变一致性较高,在无法获得组织学标本时可以检测外周血K-ras基因状态,为非小细胞肺癌的临床诊疗提供帮助。     

药学服务对眼科改进围术期抗菌药物利用的作用

目的:评价临床药师对眼科抗菌药物合理使用干预的效果。方法:派驻临床药师进入眼科开展临床药学服务,参与主任查房,开展临床抗菌药物使用监测评价、对医务人员和患者进行抗菌药物知识培训和宣教,调查临床药师开展药学服务工作前后眼科及其亚专业科室的出院人数和抗菌药物临床使用指标,据其评价临床药师的工作效果。结果:临床药师开展药学服务工作前后眼科月均出院人数由321人次增加至492人次(P<0.05);抗菌药物使用率由83.39%下降为39.63%(P<0.05),抗菌药物使用强度由14.99下降为11.55(P<0.05),抗菌药物使用金额占药品使用金额比例由17.38%下降为9.27%(P<0.05),使用抗菌药物病例的微生物标本送检率由0上升为6.15%(P<0.05)。各亚专业科室相关指标也呈现类似变化,尤以白内障和斜视小儿眼科改善效果明显。结论:临床药师在眼科开展药学服务工作可以规范临床抗菌药物使用,促进医务人员提高合理使用抗菌药物的意识。     

VanC型肠球菌与屎肠球菌对常用抗菌药的耐药状况研究

目的：比较VanC型肠球菌及屎肠球菌对常用抗菌药物的敏感性。方法针对56株VanC型肠球菌及299株屎肠球菌,用琼脂二倍稀释法进行药物敏感性分析;检测高水平耐万古霉素屎肠球菌的万古霉素耐药基因型。结果VanC型肠球菌万古霉素最低抑菌浓度（ MIC）众数为4 mg? L－1,未发现对氨苄西林、万古霉素、替考拉宁及利奈唑胺耐药的VanC型肠球菌。屎肠球菌对氨苄西林、左氧氟沙星、红霉素及利福平的耐药率均达85％以上;对万古霉素和替考拉宁的耐药率分别为1．7％和0．7％;未发现对利奈唑胺和替加环素耐药的屎肠球菌。屎肠球菌万古霉素MIC众数为0．5 mg? L－1。5株万古霉素屎肠球菌万古霉素耐药基因均为vanA型。结论屎肠球菌对万古霉素尚保持较高敏感性,万古霉素对VanC型肠球菌最低抑菌浓度较屎肠球菌高。