Nicotine and hippocampus-dependent learning

Addiction is a complex disorder because many factors contribute to the development and maintenance of addiction. One factor is learning. For example, drug-context associations that develop during drug use could facilitate drug craving upon re-exposure to contexts previously associated with drugs. Additionally, deficits in cognitive processes associated with withdrawal could precipitate relapse in attempts to ameliorate those deficits. Because addiction and learning involve common neural areas and cell signaling cascades, addiction-related changes in processes underlying plasticity may contribute to addiction. This article examines similarities between addiction and learning at the behavioral, neural, and cellular levels, with emphasis on the neural substrates underlying the effects of acute nicotine, chronic nicotine, and withdrawal from chronic nicotine on hippocampus-dependent contextual, learning.     

Prevalent mutations in prostate cancer

Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer.     

Viral Transduction of Cocaine Hydrolase in Brain Reward Centers

1. Site-directed mutagenesis of human plasma butyrylcholinesterase has led to novel hydrolases that rapidly destroy cocaine. We are investigating whether viral gene transfer of such enzymes might reduce addiction liability by blocking cocaine from its sites of action.2. As groundwork for a possible gene therapy, we previously studied adenoviral transduction of cocaine hydrolases in the rat. Systemically injected vectors raised plasma cocaine hydrolase activity greatly, reduced pressor responses to cocaine, and lowered cocaine's tissue burden.3. In the present study, to reduce cocaine's brain access still further, vectors were injected directly into the nucleus accumbens. Six days later, medium sized neurons gained dramatic butyrylcholinesterase activity. Species-selective immunohistochemistry proved that the transgene accounted for this activity.4. Since the transgene product is so efficient with cocaine as a substrate, it is now reasonable to begin testing gene therapy in rodent models of cocaine addiction.     

Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions

In normal human somatic cells, telomere dysfunction causes cellular senescence, a stable proliferative arrest with tumour suppressing properties. Whether telomere dysfunction-induced senescence (TDIS) suppresses cancer growth in humans, however, is unknown. Here, we demonstrate that multiple and distinct human cancer precursor lesions, but not corresponding malignant cancers, are comprised of cells that display hallmarks of TDIS. Furthermore, we demonstrate that oncogenic signalling, frequently associated with initiating cancer growth in humans, dramatically affected telomere structure and function by causing telomeric replication stress, rapid and stochastic telomere attrition, and consequently telomere dysfunction in cells that lack hTERT activity. DNA replication stress induced by drugs also resulted in telomere dysfunction and cellular senescence in normal human cells, demonstrating that telomeric repeats indeed are hypersensitive to DNA replication stress. Our data reveal that TDIS, accelerated by oncogene-induced DNA replication stress, is a biological response of cells in human cancer precursor lesions and provide strong evidence that TDIS is a critical tumour suppressing mechanism in humans.     

Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation

Smyd3 is a lysine methyltransferase implicated in chromatin and cancer regulation. Here we show that Smyd3 catalyzes histone H4 methylation at lysine 5 (H4K5me). This novel histone methylation mark is detected in diverse cell types and its formation is attenuated by depletion of Smyd3 protein. Further, Smyd3-driven cancer cell phenotypes require its enzymatic activity. Thus, Smyd3, via H4K5 methylation, provides a potential new link between chromatin dynamics and neoplastic disease.     

电化学发光PCR方法检测结肠癌中K-ras癌基因点突变

发展了一种可用于快速检测K-ras癌基因点突变的电化学发光PCR(ECL-PCR)分析方法,该法采用三联吡啶钌标记的上游引物和生物素标记的下游引物对目的片段进行PCR扩增;随后,采用限制性内切酶MvaI对扩增产物进行酶切,由于突变导致酶切位点的丢失,所以只有野生型样品能被切断;通过生物素与链霉亲和素包被的磁珠连接,将生物素标记的DNA片段收集到反应池中进行电化学发光检测。采用该法对20例结肠癌组织中的K-ras癌基因第12位密码子进行点突变分析,得出其中有9例存在点突变,点突变率为45%。该方法操作简便、安全、快速、灵敏,可用于快速检测K-ras癌基因点突变。     

癌症发生机理的研究进展

根据近年的研究进展,从癌基因与抑癌基因的突变及环境因素的影响等方面综述了癌症的发生机理。     

应用双色FISH技术检测肝癌中HER—2的定量扩增及其临床意义

为探讨原发性肝细胞癌(HCC)中原癌基因HER-2的扩增激活情况及其与临床病理特征和预后的关系,应用双色荧光原位杂交(dualFISH)技术检测42例原发性肝癌间期细胞核中HER-2的扩增和17号染色体的数目及其比值,并用统计学分析HER-2的扩增与临床病理特征及预后的相关性.结果在42例肝癌中有9例HER-2扩增(amplification),占21.4%,其中高拷贝扩增(HC)有4例(9.5%),低拷贝扩增(LC)有5例(11.9%),HER-2的扩增与性别、年龄、AFP水平、HBV感染、术后复发及临床分期无关(P＞0.05),而与术后2年生存期相关(P=0.046)且HER-2扩增病人的肿瘤有比无扩增病人的肿瘤增大的倾向(P=0.085);同时,在42例肝癌中有3l例为HER-2拷贝数增加(gain),占73.8%,其中9例(21.4%)为扩增所致,22例(52.4%)为17号染色体多倍体或异倍体(polysomy17/aneusomy17)所致,HER-2拷贝数增加与性别、临床分期、肿瘤大小、术后复发及术后2年生存期无关(P＞0.05),但与年龄、AFP水平和HBV感染有关(P＜0.05).以上结果提示原发性肝癌中存在较低频的HER-2癌基因扩增激活及较高频的17号染色体异倍体/多倍体;HER-2癌基因的扩增激活可能与部分肝癌的发生发展有关,是肝癌术后生存期短的有价值独立预后因子.