Telomeres,telomerase and colorectal cancer

Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep process of genetic and epigenetic events.Besides heterogeneity in the molecular and biological features of CRC,chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation.Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential,and its dysfunction plays a key role in the oncogenetic process.The erosion of telomeres,mainly because of cell proliferation,may be accelerated by specific alterations in the genes involved in CRC,such as APC and MSH2.Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability,the prognostic role of telomere length in CRC is still under debate.The activation of telomerase reverse transcriptase(TERT),the catalytic component of the telomerase complex,allows cancer cells to grow indefinitely by maintaining the length of the telomeres,thus favouring tumour formation/progression.Several studies indicate that TERT increases with disease progression,and most studies suggest that telomerase is a useful prognostic factor.Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.

Scopadulciol对胸腺激酶依赖的丙氧鸟苷杀伤253J细胞的增效作用

目的观察Scopadulciol（SDC）在人端粒酶逆转录酶（hTERT）启动子调控腺病毒介导的单纯疱疹病毒胸腺激酶基因／丙氧鸟苷（HSV-tk／GCV）自杀基因系统对人膀胱癌细胞的体外杀伤作用中的增效作用。方法利用重组腺病毒Ad-hTERT-HSV-tk、GCV、SDC的不同组合作用于膀胱癌细胞253J和人成纤维细胞MRC-5，噻唑蓝（MTT）比色法观察细胞存活率；另外，利用携带Ad-hTERT-HSV-tk感染253J细胞和MRC-5细胞，加入不同组合和不同浓度的GCV和SDC，MTT法观察受染细胞的存活率。结果经重组腺病毒Ad-hTERT-HSV-tk感染的253J细胞，应用GCV处理后，253J细胞能被特异性地杀伤，而MRC-5细胞不被特异性杀伤，253J细胞存活率为25．7％（P〈0．01），联合应用SDC（0．1μmol）后，253J细胞的存活率又有明显降低，253J细胞存活率为2．3％（P〈0．01）；不同剂量SDC对不同配伍浓度的Ad-hTERT-HSV-tk／GCV作用于膀胱肿瘤细胞253J后，随着剂量和浓度的增加，253J细胞的存活率呈降低趋势（P〈0．05），当GCV浓度为1μmol／L，SDC剂量为0．04μmol时，253J细胞的存活率为45．7％，当GCV浓度为100μmol／L，SDC剂量为0．1μmol时，253J细胞的存活率仅为2．3％，并有旁观者效应。结论在胸腺激酶依赖的GCV可以靶向杀伤人膀胱癌细胞的基础上，联合应用SDC后，对膀胱癌细胞的杀伤作用具有明显增效作用。

Steered molecular dynamics simulations of protein-ligand interactions

Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dy- namics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be ac- cessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of bind- ing and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APAfrom HIV-1 reverse transcriptase.

Tankyrase1、TRF1及hTERT在肝细胞癌中的表达及意义

目的检测端锚聚合酶1（Tankyrose1）、端粒重复序列结合因子1（TRF1）及端粒酶逆转录酶（hTERT）mRNA在肝细胞癌（HCC）组织中的表达，探讨其在肝癌发生过程中的作用及其临床意义。方法应用RT—PCR技术对30例HCC及癌旁组织中Tankyrase1 、TRF1及hTERT mRNA的表达水平进行检测，分析其表达与HCC临床病理特征的关系。结果HCC组织中Tankyrose1及hTERT mRNA表达相对强度明显高于癌旁组织（P〈0．05）；TRF1在肝癌组织中的表达相对强度明显低于癌旁组织（P〈0．05）；HCC组织中Tankyrase1及TRF1表达与年龄、性别、肝硬化、HbsAg（＋）、肿瘤大小、肿瘤个数、术前Child-Pugh分级、TNM分期、Edmondson分级和血清AFP值均无显著相关（P〉0．05）；在HCC中Tankyrase1 mRNA和hTERT mRNA的表达呈正相关（r=0．519），Tankyrase1与TRF1 mRNA表达呈负相关（r=-0．395），TRF1 mRNA和hTERT mRNA表达呈负相关（r=-0．472）。结论HCC中Tankyrase1表达增加和TRF1表达下降可能是hTERT表达增加的原因之一，其对肝癌的发生可能起重要作用。