调节p53途径—提高癌症治疗效率

p53肿瘤抑制蛋白,也被称为基因组监控因子,是一种保护细胞免受一系列生理逆境(例如致癌基因活化、辐射、有丝分裂压力、核糖体压力和化学损害)的转录控制因子.这些生理逆境会导致依赖于p53激活的信号产生,并通过复杂的相互作用网络定位到细胞核,起始转录或抑制许多基因的表达,这些基因与诱导生长停滞、修复、细胞凋亡、衰老或者改变新陈代谢有关.由于p53途径对于调控疾病有如此重要的作用,使得针对该途径的药物干预日益成为人们关注的焦点.本文对调节p53功能的最新研究进展进行综述,并对有关p53基因的癌症治疗前景进行展望.     

CYP2F1 genetic polymorphism: Identification of interethnic variations

Since human cytochrome P450 2F1 (CYP2F1) is predominantly expressed in lung tissue and is involved in the metabolism of various pneumotoxicants with potential carcinogenic effects, variations in the nucleotidic sequence of its gene may contribute to interindividual and interethnic differences in the susceptibility to lung tumorigenesis. The aim of the current study was to compare the frequency of a previously reported frameshift mutation, namely c.14_15insC, responsible for the synthesis of a severely truncated protein, between several populations of different ethnic origins. The frequencies of this polymorphism were 26.1, 51.6, 42.7 and 22.9% in French, Gabonese, Senegalese, and Tunisian population samples, respectively, thereby representing a substantial inter ethnic variation in the CYP2F1 gene. These findings provide data for further studies that investigate the potential association of CYP2F1 haplotypes with an incidence of lung cancer genesis in respect of ethnicity.     

Serotonin (5-hydroxytryptamine) glucuronidation in vitro : assay development,human liver microsome activities and species differences

1. The main purpose was to develop a high-performance liquid chromatography (HPLC)-based method to assay serotonin glucuronidation activity using liver microsomal fractions. Application of this method was then demonstrated by determining serotonin UDP-glucuronosyltransferase (UGT) enzyme kinetics using human liver microsomes and recombinant human UGT1A6. Interspecies differences were also evaluated using liver microsomes from 10 different mammalian species. 2. Incubation of liver microsomes with serotonin, UDP-glucuronic acid and magnesium resulted in the formation of a single product peak using HPLC with fluorescence and ultraviolet absorbance detection. This peak was confirmed as serotonin glucuronide based on sensitivity to β-glucuronidase and by obtaining the expected mass of 352 with positive-ion mass spectrometry. 3. Following a preparative HPLC isolation, the structure of this metabolite was established as serotonin-5- O -glucuronide by 1 H-NMR spectroscopy. 4. Enzyme kinetic studies showed apparent K m and V max of 8.8 ±0.3 mM and 43.4 ±0.4 nmoles min <1 mg <1 protein, respectively, for human liver microsomes, and 5.9 ±0.2 mM and 15.8 ±0.2 nmoles min <1 mg <1, respectively, for recombinant UGT1A6. 5. The order of serotonin-UGT activities in animal liver microsomes was rat > mouse > human > cow > pig > horse > dog > rabbit > monkey > ferret. Cat livers showed no serotonin-UGT activity. Heterozygous and homozygous mutant Gunn rat livers had 40 and 13%, respectively, of the activity of the normal Wistar rat, indicating a significant contribution by a rat UGT1A isoform to serotonin glucuronidation. 6. This assay provides a novel sensitive and specific technique for the measurement of serotonin-UGT activity in vitro.     

TP53 mutations predict decitabine‐induced complete responses in patients with myelodysplastic syndromes

To identify the molecular signatures that predict responses to decitabine (DAC ), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome (MDS ) patients at diagnosis. We determined that TP 53 mutations predicted complete response (CR ), as 10 of 15 patients (66·7%) who possessed TP 53 mutations achieved a CR . Univariate and multivariate analyses showed that TP 53 mutations are the only molecular signatures predictive of a CR to DAC in MDS . Among the ten patients with TP 53 mutations who achieved a CR , nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP 53 mutations were associated with a higher frequency of CR s, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR . Post‐DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR . It seems that suppression of these gene mutations was facilitated by DAC , resulting in a CR . In summary, TP 53 mutations might predict decitabine‐induced complete responses in patients with MDS . DAC ‐induced responses may result from partial suppression of malignant clones containing mutated TP 53 genes.     

P2Y2受体激动剂治疗干眼的研究进展

干眼是一类累及眼表和泪膜的多因素疾病.临床上治疗干眼的传统方法主要是被动性增加泪液,如人工泪液点眼、泪小点栓塞等,但新的关于干眼发病机制的研究表明,理想的干眼治疗方法是促进泪腺分泌泪液.研究已经证实,P2Y2受体激动剂具有促进水分及黏蛋白分泌的作用,可以促进泪腺主动分泌泪液.目前研制了多种人工合成的P2Y2受体激动剂并用于干眼的治疗,临床研究证实,P2Y2受体激动剂能够明显增加水性泪液的分泌和黏蛋白的分泌,改善临床症状,且Ⅰ期临床试验证实其具有较好的安全性.就近年来P2Y2受体激动剂在干眼治疗方面的作用机制、临床疗效和研究进展进行综述.     

精神发育迟滞儿童的事件相关电位P300的特征

目的探讨精神发育迟滞（MR）儿童的事件相关电位P300的特征。方法对30名精神发育迟滞儿童（精神发育迟滞组）和30名正常儿童（正常对照组）分别进行事件相关电位P300测定，取P300的潜伏期和波幅，将所得结果进行统计学分析。结果与正常对照组相比，精神发育迟滞组儿童事件相关电位视觉P300波的潜伏期延长，波幅降低，差异显著（P〈0．05）。结论事件相关电位P300的潜伏期和波幅可客观地反映精神发育迟滞儿童的认知功能的变化，具有协助诊断的意义，可作为评价精神发育迟滞患儿的认知功能的客观指标之一。