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。     

Cynomolgus macaque model for pneumonic plague

A recombinant vaccine (rF1V) is currently being developed for protection against pneumonic plague. An essential component in evaluating efficacy of the rF1V vaccine is the development of a well-understood animal model that shows similarity to human disease. The objective of this study was to determine the inhaled median lethal dose (LD₅₀), evaluate the pathophysiology of disease and identify appropriate study endpoints in a cynomolgus macaque (CM) model of pneumonic plague. Eighteen CMs were challenged by head-only aerosol exposure with seven dosages of Yersinia pestis CO92. An LD₅₀ of 24 colony forming units was estimated using Probit analysis. Disease pathology was evaluated by blood culture, clinical pathology, histopathology and telemetry. CMs that died became febrile following challenge and died 34–92 h after onset of fever. Bacteremia, increased respiration and heart rate, decreased blood pressure and loss of diurnal rhythm were also observed in conjunction with onset of fever. Histopathological examinations revealed significant findings in the lungs (intra-alveolar neutrophils and fibrinous pleuritis) consistent with pneumonic plague. These data indicate that the disease pathology observed in CMs following aerosol exposure to Y. pestis CO92 is similar to that of pneumonic plague in humans. Thus, the CM is an appropriate model to evaluate efficacy of a recombinant F1V vaccine candidate.     

Greenberg dysplasia (hydrops–ectopic calcification–moth‐eaten skeletal dysplasia): Prenatal ultrasound diagnosis and review of literature

A second pregnancy of young, nonconsanguineous parents of Macedonian ethnic origin was examined by ultrasound. Polyhydramnios and hydrops fetalis were found as well as severe short limb, short stature, and cystic hygroma of the neck. An artificial abortion was performed at the age of 23 weeks. The radiological features included moth‐eaten severely shortened long bones and ectopic calcifications of long bones, vertebral column, ribs, pelvis, larynx, trachea. In addition, the fetus had large head with depressed nasal bridge, severe platyspondyly, and short barrel‐shaped trunk. Light microscopy demonstrated lack of chondrocyte columns and disorganization of the cartilaginous architecture. This is the seventh reported case of this rare form of lethal skeletal dysplasia. © 2002 Wiley‐Liss, Inc.     

炭疽杆菌致死因子LF253的制备及活性分析

目的 :制备具有生物学活性的重组致死因子253(lethal factor 253,LF253)抗原,获得纯化的目的蛋白,检测其与全分子致死因子(lethal focfor,LF)蛋白竞争性结合保护性抗原(protective antigen,PA)的能力。方法:PCR扩增致死因子LF253片段的DNA,将目的基因插入p ET-28a(+)表达载体中,利用大肠杆菌BL21(DE3)作为宿主菌,IPTG诱导重组蛋白表达,通过His标签亲和层析柱获得目的蛋白,Western blot和ELISA法检测蛋白抗原性,Biacore T-100测定重组蛋白与保护性抗原PA结合的亲和力,细胞毒性实验检测其生物学活性。结果:成功构建原核表达载体p ET-28a/LF253,诱导获得重组蛋白s LF253的表达。Western blot和ELISA检测结果证实,该重组蛋白具有良好抗原特异性;细胞毒实验结果表明,重组蛋白可在体内外中和致死毒素引起的生物学效应。结论:本研究制备的融合蛋白s LF253能够与保护性抗原PA结合,可竞争性抑制LF全分子蛋白与PA的聚合,阻断炭疽毒素的致死作用,为今后炭疽疫苗等药物的研发奠定了基础。     

胎肝细胞骨髓内注射对受致死量照射小鼠的疗效

本文报告了用骨髓内注射法对8.5Gy照射的昆明种小鼠进行同种胎肝移植的结果,并与静脉内注射组进行比较。结果表明,骨髓内注射组的疗效比静脉内注射组好。这一研究结果说明,直接注入骨髓腔内的胎肝细胞,能在骨髓腔内定居、增殖,实验结果还提示,用骨髓内注射法进行造血细胞移植时,注入骨髓腔内的细胞悬液量不宜太多。     

大蒜素对甲基磺酸甲酯和环磷酰胺诱发果蝇伴性隐性致死的影响

用果蝇伴性隐性致死试验进行大蒜素的抗诱变性研究。大蒜素与甲基磺酸甲酯(MMS)同时喂饲果蝇,未能抑制MMS诱导的伴性隐性致死效应。而在先给MMS 24h后再给大蒜素则有抑制效应。大蒜素与环磷酰胺(Cy)同时给药有一定的抑制作用。提示大蒜素有一定抗诱变作用。     

External and Skeletal Observations on a New Lethal Mutant of the Rat: Congenital Osteochondrodysplasia with Systemic Subcutaneous Edema

Abstract Malformed rat newborns showing severe subcutaneous edema were frequently found dead in our Wistar-Imamichi rat colony. Their family record suggested that this malformation would be an inherited disorder. Experimental crosses of the phenotypically normal litter-mates revealed that this malformation was a new lethal mutant of the rat, following a single autosomal recessive inheritance. External features and skeletal anomalies of the mutant were carefully checked and compared to those of the phenotypically normal litter-mates. The comparison revealed that (1) this mutant has a characteristic external appearance that includes shortening of the head, trunk, tail and extremities, systemic subcutaneous edema, protruding of the tongue and cleft palate, (2) the axial bones and appendices are shortened and deformed severely and (3) ossification status of the newborn is delayed in digital bones and advanced in the vertebral centra and arches, stemebrae, choracoid process and talus. Observation of the parturition showed that this mutant is born alive but die shortly after birth because of breathing insufficiency. Based on these observations, this mutant was diagnosed as congenital osteochondrodysplasia with systemic subcutaneous edema (ocd for the gene symbol). The mode of inheritance and the similarities to some genetical disorders of other species, including human, are discussed.     

苦参乙醇提取物体外抗贾第虫药物作用的观察

对苦参乙醇提取物体外抗贾第虫药物作用做了观察。实验结果表明，将此药物与贾第虫滋养体共同培养５ｈ后，导致９９％虫体致死的浓度为５ｇ／Ｌ，随着药物浓度的降低，致死率相应减少；该药的半数致死浓度为１．５ｇ／Ｌ，在此浓度的最短作用时间为３ｈ。对照试验结果显示，在相同时间作用下，阿苯哒唑导致９３．８％虫体致死的浓度为０．２ｇ／Ｌ。     

三硝基甲苯的遗传毒性研究

用果蝇伴性隐性致死（ＳＬＲＬ）实验和非整倍体检测实验，对三硝基甲苯（ＴＮＴ）的遗传毒性进行了研究。结果表明：雄性果蝇在５４．０ｍｇ、２７．０ｍｇ、１３．５ｍｇ／１００ｍｌ培养基浓度下喂饲２４小时，在ＳＬＲＬ实验中，可引起生殖细胞隐性致死率明显增加，并有明显的剂量反应关系；在非整倍体检测实验中，Ｘ或Ｙ染色体丢失率明显增加，也有明显的剂量反应关系。说明ＴＮＴ对果蝇生殖细胞具有明显的致突变作用。分阶段（２，３，３天）实验表明，ＴＮＴ对果蝇各阶段生殖细胞具有相同的致突变作用。