Methods for site-specific drug conjugation to antibodies

Antibody drug conjugates (ADCs) are an emerging class of targeted therapeutics with the potential to improve therapeutic index over traditional chemotherapy. Drugs and linkers have been the current focus of ADC development, in addition to antibody and target selection. Recently, however, the importance of conjugate homogeneity has been realized. The current methods for drug attachment lead to a heterogeneous mixture, and some populations of that mixture have poor in vivo performance. New methods for site-specific drug attachment lead to more homogeneous conjugates and allow control of the site of drug attachment. These subtle improvements can have profound effects on in vivo efficacy and therapeutic index. This review examines current methods for site-specific drug conjugation to antibodies, and compares in vivo results with their non-specifically conjugated counterparts. The apparent improvement in pharmacokinetics and the reduced off target toxicity warrant further development of this site-specific modification approach for future ADC development.     

MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II

Background  

Autophagy plays a significant role in myocardial ischemia-reperfusion (IR) injury. So it is important to inhibit autophagy to protect cardiomyocytes besides anti-apoptosis. MiRNA has been demonstrated to protect cardiomyocytes against apoptosis during IR, while whether it has anti-autophagy effect has not been known. The aim of this study was to investigate whether miR-204 regulated autophagy by regulating LC3-II protein, which is the marker of autophagosome during myocardial IR injury.     

大白猪和通城猪全基因组选择性清扫分析

长期的人工选择使猪的生产性能得到显著提高,与选择相关的基因组区域也随之发生特定遗传变异表征(选择信号)。不同类型品种所受到选择强度不一,选择信号亦不相同,选择性清扫分析已逐渐成为选择信号的主要检测手段。文章基于商用型大白猪(n=45)和地方猪品种通城猪(n=45)的猪60K SNP芯片分型数据,借助遗传分化系数Fst法进行选择信号检测分析。利用gPLINK软件设定质控标准,共计34 304个SNPs被筛选出用于统计分析。使用Genepop软件包计算两个猪品种之间的遗传分化参数Fst,所得Fst平均值为0.3209。选取Fst>0.7036(即占总Fst值数目的 1%),共计344个SNPs被选择出来。SNP位置注释显示这些位点涉及到79个候选基因(Sus scrofa Build 9)。利用在线软件Ingenuity Pathway Analysis对候选基因的生物学通路进行网络分析,发现它们多与生长繁殖及免疫应答有关,如NCOA6、ERBB4、RUNX2和APOB等基因。研究结果为进行猪产肉、抗病等性状候选基因和致因突变深入挖掘提供了有益参考。     

Ⅱa型组蛋白脱乙酰基酶在心血管系统中的作用

组蛋白脱乙酰基酶(histone deacetylases, HDACs)具有转录抑制功能,近年来发现其参与心血管系统的分化发育,调控多种刺激诱发的心肌肥大及其相关基因表达.本文就有关Ⅱa型HDACs在心血管系统中作用的研究进展作一综述.     

Diallyl trisulfide induces apoptosis and inhibits proliferation of A549 cells in vitro and in vivo

Lung cancer is the leading cause of cancer-related mortality all over the world. In recent years, pulmonary adenocarcinoma has surpassed squamous cell carcinoma in frequency and is the predominant form of lung cancer in many countries. Epidemiological investigations have shown an inverse relationship between garlic (Allium sativum) consumption and death rate from many cancers. Diallyl trisulfide (DATS) is one of the garlic-derived compounds (also known as: organosulfer compounds, OSC). DATS can induce apoptosis and inhibit the growth of many cancer cell lines. Our study demonstrated that the apoptotic incidents induced by DATS were a mitochondria-dependent caspase cascade through a significant decrease of the anti-apoptotic Bcl-2 that resulted in up-regulation of the ratio of Bax/Bcl-2 and the activity of caspase-3, -8, and -9. Eventually, DATS induced the apoptosis and inhibited the proliferation in a concentration- and time-dependent manner. Furthermore, by establishing an animal model of female BALB/c nude mice with A549 xenografts, we found that oral gavage of DATS significantly retarded growth of A549 xenografts in nude mice without causing weight loss or any other side effects compared with the control group. All the evidence both in vitro and in vivo suggested that DATS could be an ideal anti-cancer drug.     

b-根瘤菌及特殊a-根瘤菌的研究概况

隶属于b-变形杆菌纲（proteobacteria）的根瘤菌,人们简称为b-根瘤菌。本文通过对分离自含羞草根瘤隶属于Burkhloderia 和Cupriavidus的b-根瘤菌及归于Blastobacter、Ochrobactrum和Phyllobacterium等特殊a-根瘤菌的研究总结,介绍了根瘤菌生物多样性研究的新进展。同时,简述了根瘤菌共生基因的进化研究,并对该研究领域存在的问题进行了分析,对未来相关研究方向做了展望。     

A combined approach for improving alkaline acetyl xylan esterase production in Pichia pastoris, and effects of glycosylation on enzyme secretion, activity and stability

High level expression of axe1, a gene previously cloned from Volvariella volvacea that encodes an acetyl xylan esterase with two potential N-linked glycosylation sites, has been achieved in Pichia pastoris using a codon-optimized axe1 synthesized by the primer extension PCR procedure. The GC content of the codon-optimized axe1 was 48.62% compared with 55.49% in the native gene. Using the codon-optimized construct, AXE1 expression in P. pastoris was increased from an undetectable level to 136.45U/ml six days after induction of yeast cultures grown in BMMY medium. A further increase (to 463U/ml) was achieved when conditions for yeast culture were optimized as follows: 2.8% methanol, 0.63% casamino acids, and pH 8.0. This latter value represented a 3.4-fold and 246-fold increase in the enzyme levels recorded in non-optimized P. pastoris cultures and in rice straw-grown cultures of V. volvacea, respectively. N-linked glycosylation played an essential role in AXE1 secretion but had only a slight effect on the catalytic activity and stability of the recombinant enzyme.