计算机模拟药物筛选在新药设计与开发中的应用

过去十几年中，研制新药的环境和条件发生了巨大变化，使得传统的药物开发途径步履艰难。传统的药物开发模式 (见图1) 往往需花费数亿美元、十数年的时间，从上万个化合物中才能发掘出一个有应用价值的新药［1］。由于这种方法周期长、耗费巨大，有很大的随机性和盲目性，人们在寻找新的药物发现的新方法。

分子生物学新技术与新方法的临床应用

20世纪90年代起,分子生物学进入临床检测.短短的几年中,以聚合酶链反应(PCR)为核心的分子生物学技术深入到临床多个领域.在临床检验中,我国分子生物学在遗传病诊断及产前筛查、肿瘤诊断与疗效预后判断、微生物耐药机理的研究等方面取得较突出的成绩[1-4].

AIM To study the clonality of the esophageal carcinosarcoma by using molecular approaches.METHODS Two esophageal carcinosarcomas were included in the study. Tumor area from dysplasticlesion, squamout cell carcinoma, basaloid cell carcinoma and spindle cell elements were microdissectedseparately. Each element was analyzed with 14 microsatellite markers and direct sequenced for p53 gene andras gene mutation.RESULTS Both tumors displayed a typical histologic feature of carcinosarcoma. Both cases showed thedivergent differentiation by immunohistochemistry study. In case 1 the identical LOH at p53 and hMLH1 lociwas detected. The heterogenous LOH was detected only in carcinosarcoma at RB1 and BRCA1 loci, whilethe LOH at ACTC locus was seen only in sarcoma. The same mutation of the splice site of exon 6-intron 6displayed in the two tumor elements. In case 2, a coordinate LOH at RB locus was demonstrated in threetypes of tumor elements: sqamous carcinoma, basaloid carcinoma and spindle cell element. A heterogenousLOH was seen only in spindle cells at TAP1 locus. No mutation in exon 5-8 of p53 gene has been found incase 2. No mutation of K-ras gene was found.CONCLUSION Although the different differentiation, the two elements of esophageal carcinosarcoma mayhave a single clonality. The p53 gene mutation occurred before the two differentiation directions switched.The distinct molecular genotype can be determined through molecular biological analysis. The microsatelliteprofiling can serve as an approach to find out which genetic alteration occurs before or after thedifferentiation is determines.

Advances in molecular biology made possible the discovery of the virus that causes hepatitis C. However,little is known about the fundamental aspects of hepatitis C virus (HCV) replication, primarily because arobust cell culture has not been established. As a result, the currently available drugs for the treatment ofhepatitis C are not specifically directed against HCV. Based on what is known about the molecular biology ofHCV, however, drugs can now be developed against specific viral and cellular targets. The next generationof drugs for the treatment of hepatitis C will likely be directed against non-structural HCV proteins withknown enzymatic activities, such as the proteases, RNA helicase and RNA polymerase. Others agentstargeted against the viral RNA, core protein that assembles into the virion capsid and putative cellular“receptors” that bind HCV envelope proteins are also being developed. These drugs should have fewer sideeffects than those currently available and be much more effective for the treatment of chronic hepatitis C.

分子生物学技术在膀胱癌诊断中的研究现状与存在的问题

膀胱癌是我国泌尿外科领域常见的恶性肿瘤,多系移行上皮来源的肿瘤,具有多发和容易复发的特点.膀胱癌的诊断和术后复发的监测,长期以来一直是泌尿外科领域研究的重点.膀胱肿瘤90%以上均以无痛性肉眼血尿作为首发症状,没有明显的体征.目前,膀胱镜检查仍是诊断膀胱肿瘤的主要方法.而尿液脱落细胞学检查尽管不能定位,但由于方法简捷方便,并属于非侵袭性检查,已是临床上膀胱癌诊断和术后随访的重要方法.尿细胞学检查对G3级肿瘤具有很高的敏感性,达到80%～95%,但对G1和G2级肿瘤诊断敏感性则明显下降,仅为30%,而且结果常常受到检查者水平与临床经验的限制.

Molecular Biology based on the DNA Double-helix structure has made great progress in 20 century.After Human Genome Project (HGP) completed, Molecular Biology is faced upon more and more challenges, andtake changes from protion concept to integration concept, from linear thinking to complicated thinking. so post-genomics, including functional genomics, proteomics, is gradually established. Among them, System Biology is themost prominent. It is becoming to tend to integration, and infiltrate to each other for the two thinking of genomeand TCM in studying life science, which reflect the inevitablility and importance of integration of TCM and West-ern Medicine. The priority of TCM in treatment as a whole, and regulating functional gene and functional networkmay take greater achievement in post - genomic time.

蛋白激酶C的分子生物学特征及研究进展

本文对蛋白激酶C(PKC)的分子生物学特征,特别是其结构与功能的关系进行了简要综述.鉴于PKC的γ亚单位在脊髓背角浅层痛信号传递和调控过程中的作用愈来愈受到关注,故本文还对PKC γ亚单位在痛模型中的作用及其它递质共存等方面进行了简要回顾.

Hepatocarcinoma is a disease that threatens human health. To date,the known etiology of hepatocarcinomahas not been narrowed down to just one factor. It is possible that there are their own causes in different areas.Thus, there are no absolute, but relative therapy to cure all kinds of hepatocarcinoma. Presently,there exists other treatment for the hepatocarcinoma which cannot be operated by surgery, such as cryosurgery,photodynamic therapy,immunotherapy,interventional radiotherapy and targeting therapy.With the development of molecular biology ,gene therapy offers new possibilities in the treatment of genetic diseases,tumors,AIDS and other gene defect disease.

OBJECTIVE To study the structural and preliminary functional characterization of the hepatitis B virus(HBV) enhancer Ⅰ in patients with chronic hepatitis B treated with interferon (IFN). METHODS The characteristics of the HBV enhancer Ⅰ in 12chronic carrier who were treated with alpha interferon was detected by the methods of molecular biology including PCR, cloning of PCR products, sequencing and cell culture.RESULTS Four of 6 patients cleared viral DNA; all 6 in this group also seroconverted from e antigen to antibody. Prior to therapy, the HBV enhancer Ⅰ region demonstrated many point mutations in all 6 patients who became nonresponders, compared to patients who responded to interferon. The mutated sequences, many of which were within regions of transcription factor binding, were significantly more active than the corresponding wild type sequences in reporter gene assays. CONCLUSION These results imply that the mutations found in nonresponders appear to render the virus less sensitive to interferon.

Molecular biology is an exciting, rapidly expanding field, which has enabled enormously greater understanding of the biology of diseases and malfunctions in many fields. It chiefly concerns itself with understanding the interactions between the various systems of a cell, including the interrelationship of DNA, RNA and protein synthesis and how these interactions are regulated. Since the introduction of molecular biology into modern science, numerous other fields have been enabled to go "molecular". Advanced molecular biological techniques showed us new avenue towards finding answers to the questions asked for decades. The first part of this article described the history of molecular biology.It started as a joined discipline of other areas of biology, i.e. genetics and biochemistry in the 1930s and 1940s, and enjoyed its classical period and became institutionalized in the 1950s and 1960s. Major molecular techniques manipulating proteins, DNA and RNA were introduced and their mechanisms were concisely illustrated. The current knowledge of molecular biology and their applications in orthodontic and oral and maxillofacial surgery, i.e. osteoclast differentiation and function, regulation of tooth movement, mechanotransduction/cell-signalling, bone fracture healing, oral cancer as well as craniofacial/dental anomalies and distraction osteogenesis were discussed. Although the problems of introducing molecular technologies are still substantial, it is anticipated that the future of medicine/dentistry will be "molecular": molecular prevention, molecular diagnosis and molecular therapy.

The current World Health Organization classification system of primary brain tumors is solely based on morphologic criteria. However, there is accumulating evidence that tumors with similar histology have distinct molecular signatures that significantly impact treatment response and survival. Recent practice-changing clinical trials have defined a role for routine assessment of O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients, especially in the elderly, and 1p and 19q codeletions in patients with anaplastic glial tumors. Recently discovered molecular alterations including mutations in IDH-1/2, epidermal growth factor receptor (EGFR), and BRAF also have the potential to become targets for future drug development. This article aims to summarize current knowledge on the molecular biology of high-grade gliomas relevant to daily practice.

医学分子生物学教学模式改革初探

医学分子生物学(medical molecular biology)是一门理论知识和实验技术并重的医学基础课,该学科已经迅速渗透到生命科学的各个领域,越来越成为生命科学的共同语言[1].但这门课程理论性强,模型假说多,难懂难记.

1 IntroductionRecent progress in molecular biology has enabled us to better understand the molecular mechanism underlying pathogenesis of human malignancy including lung cancer. Sequencing of human genome has identified many oncogenes and tumor suppressor genes,giving us a better understanding of the molecular events leading to the formation, progression, metastasis, and the development of drug resistance in human lung cancer. In addition, many signal transduction pathways have been discovered that play important roles in lung cancer. Novel strategy of anti-cancer drug development now involves the identification and development of targeted therapy that interrupts one or more than one pathways or cross-talk among different signal transduction pathways. In addition, efforts are underway that combine the traditional cytotoxic (non-targeted) agents with the biological (targeted) therapy to increase the response rate and survival in patients with lung cancer, especially advanced non-small cell lung cancer (NSCLC).