XRCC1基因多态与晚期胃癌化疗敏感性的关系

目的观察DNA修复酶XRCC1基因密码子399和194多态与晚期胃癌患者对5-氟尿嘧啶（5-FU）和铂类药物化敏感性的关系。方法 91例晚期胃癌患者给予5-FU和铂类药物方案治疗,化疗前检测XRCC1基因型。观察化疗疗效及其与XRCC1基因多态性的关系。结果本组化疗有效率为37.4%。XRCC1399和XRCC11943种基因型化疗有效率比较差异均无统计学意义（P〉0.05）。XRCC1399杂合子Arg/Gln基因型骨髓抑制发生率为25.7%低于纯合子基因型（Gln/Gln和Arg/Arg）的50.0%和47.8%;XRCC1399Gln等位基因携带型（Gln/Gln和Arg/Gln）呕吐反应发生率为30.0%和31.4%低于Arg/Arg基因型的54.4%;XRCC1194Trp/Trp基因型骨髓抑制发生率为0低于Arg等位基因携带型（Arg/Trp和Arg/Arg）的41.5%和45.2%,差异均有统计学意义（P〈0.05）。结论 XRCC1基因多态性与晚期胃癌患者对5-FU为基础的含铂类药物方案化疗疗效的关系不确切,但与晚期胃癌对5-FU和铂类药物化疗的Ⅱ度以上严重不良反应发生有关,检测XRCC1基因型可以为晚期胃癌化疗药物的选择、避免严重毒副反应的发生提供参考依据。     

亚甲基四氢叶酸还原酶C667T基因多态性与晚期胃癌患者对5-FU化疗疗效的相关性

目的 观察亚甲基四氢叶酸还原酶(MTHFR)C667T基因多态性与5-氟尿嘧啶(5-FU)为基础的化疗方案治疗晚期胃癌的疗效间的关系.方法 收集经病理学确诊的晚期胃癌59例.所有病例化疗前抽取外周静脉血,提取DNA,用连接酶检测反应技术(LDR)检测研究对象的MTHFR基因型.所有患者经5-FU为基础的联合化疗方案化疗.结果 59例晚期胃癌患者中,21例(35.59%)为MTHFR C/C基因型,22例(37.29%)为MTHFR C/T基因型,16例(27.12%)为MTHFR T/T基因型.其中,4例CR,14例PR,19例SD,22例PD,总有效率为30.51%(18/59).MTHFRT/T基因型患者的化疗有效率(68.75%)明显高于C/T基因型患者(18.18%)(P＜0.01),也明显高于C/C基因型(14.29%)(P＜0.01).结论 MTHFR基因型对预测以5-FU为基础化疗方案治疗晚期胃癌的疗效具有较好的临床意义.     

胸苷酸合成酶基因多态性与晚期胃癌化疗敏感性的关系

目的 研究胸苷酸合成酶(TS)基因5'端非编码区(UTR)多态性与晚期胃癌对氟尿嘧啶(5-FU)化疗敏感性的关系.方法 经病理学确诊的晚期胃癌56例,化疗前抽静脉血,提取白细胞DNA,用PCR技术检测TS5'-UTR基因型.所有患者均经5-FU为基础的化疗方案治疗.以实体瘤疗效评定标准和毒性评定标准评价疗效和毒性.结果 56例胃癌患者中,TS5'-UTR基因型分2R/2R、2R/3R、3R/3R,基因型频率分别为5.4%、42.8%和51.8%,化疗的总有效率为35.7%.2R/2R和2R/3R基因型组(27例)化疗的有效率为55.6%(15/27),明显高于3R/3R基因型组(29例)的17.2%(5/29)(P<0.01).2R/2R和2R/3R基因型组Ⅱ度以上毒副反应的发生率略高于3R/3R基因型组.结论 TS基因5'-UTR多态性与晚期胃癌对5-FU为基础的化疗敏感性相关.5'-UTR基因型检测有助于指导晚期胃癌的化疗.     

MDR1基因多态性与晚期胃癌化疗敏感性的关系

目的研究多药耐药(MDR1)基因C3435T多态性与晚期胃癌患者对5-氟尿嘧啶(5-FU)/奥沙利铂(OXA)为基础的方案化疗敏感性的关系。方法病理学确诊晚期胃癌患者82例,化疗前采集外周静脉血,提取DNA,采用RT-PCR技术检测MDR1C3435T基因型。分析基因型与化疗疗效的关系。结果 82例晚期胃癌患者中,35例(42.68%)为MDR1C3435TC/C基因型,34例(41.46%)为C/T基因型,13例(15.85%)为T/T基因型。其中,2例完全缓解(CR),30例部分缓解(PR),25例稳定(SD),25例进展(PD);总有效率为39.02%(32/82)。C/C基因型患者的化疗有效率57.14%,高于C/T基因型的26.47%和T/T基因型的23.08%(P<0.05)。结论 MDR1基因C3435T多态性与晚期胃癌患者对5-FU/OXA为基础方案的化疗敏感性相关。     

皮肤癌细胞株p53基因及其表达蛋白质的分析

目的：检测皮肤癌细胞株p53基因特性，为今后的p53基因治疗及生物治疗研究提供实验材料。方法：采用聚合酶链反应．单链构象多态性分析，DNA序列分析结合Western blot方法，对4个皮肤癌细胞株的p53基因突变及p53基因的亚型进行研究。结果：3个细胞株中检出了基因突变，即在KUMA3细胞株密码子176的砼基T被A置换，密码子281的砼基G被A置换；在KUMA4细胞株密码子241的砼基CC被TT置换；在KUMA6细胞株密码子266的砼基G被T置换。第72位密码子的多态性分析结果KUMA3和KUMA4细胞株是Arg/Pro杂合型，KUMA5细胞株是Arg/Arg纯合型，KUMA6细胞株是Pro／Pro纯含型。结论：KUMA3，KUMA4和KUMA6细胞株p53基因有突变，而KUMA5细胞株p53基因无突变；KUMA3和KUMA4细胞株是p53-72Arg／Pro基因型，KUMA5细胞株是p53-72Arg／Arg基因型，KUMA6细胞株是p53-72Pro／Pro基因型。     

p53基因第72位密码子基因多态性与HPV16相关宫颈癌

目的探讨湖北地区汉族女性人群中p53基因第72位密码子基因多态性与HPV16相关宫颈癌发生的关系。方法随机选取经PCR检测证实HPV16阳性的宫颈病变病例228例。其中病理证实为宫颈浸润癌的156例作为宫颈癌组,宫颈上皮内瘤变或宫颈炎72例为对照组。用直接PCR法检测新鲜组织标本中p53基因第72位密码子的基因型在宫颈癌组与对照组的分布情况,分析p53codon72基因多态性与HPV16阳性宫颈癌之间的相关性。结果所有样本均成功检测出p53codon72基因型。Pro／Pro、Arg／Pro、Arg／Arg在HPV阳性宫颈癌样本中所占比例分别为22．2％、47．2％、30．6％;在对照组中的比例分别为32．7％、53．2％、14．1％。两组总构成比差异有统计学意义（P=0．010）。与其他两种基因型相比,p53codon72Arg／Arg基因型在HPV16阳性宫颈癌样本检出率明显高于在HPV16阳性宫颈上皮内瘤变及宫颈炎组中的检出率（P=0．004,OR=2．680）。结论p53codon72Arg／Arg基因型是湖北地区汉族女性发生HPV16相关宫颈癌的遗传易感因素。     

缓释型5-氟尿嘧啶术中使用对进展期胃癌的疗效

胃癌是消化道肿瘤中发病率最高的恶性肿瘤,到目前为止,胃癌患者术后5年生存率仅为30%左右,死亡的主要原因是腹腔复发和肝转移.为探讨进展期胃癌术中使用缓释型5-氟尿嘧啶(5-FU)对防止复发转移的疗效,2005～2006年,本院给予69例进展期胃癌患者术中使用缓释型5-FU腹腔化疗,另53例术中未用药患者作为对照组,比较两组的存活率、复发转移率的差异,现报道如下.     

Tp53单核苷酸多态与晚期NSCLC对铂类药物化疗敏感性关系

目的 探讨Tp53基因单核苷酸多态性(SNP)与非小细胞型肺癌(NSCLC)患者对铂类药物为主的化疗方案敏感性的关系.方法 用新型三维DNA微阵列检测芯片进行基因分型,测序法验证该芯片结果,比较不同基闪型对化疗敏感性的影响.结果 携带杂合基因型和突变纯合型对化疗敏感性的影响趋势不同;但多种因素校正、分析差异无统计学意义.结论 Tp53 Pro72Arg位点基因状态可能对NSCLC患者化疗敏感性有影响.     

Ⅲ期胃癌术前新辅助化疗85例临床分析

目的探讨新辅助化疗对Ⅲ期胃癌预后的影响。方法回顾性分析我科2005年1月至2008年12月Ⅲ期胃癌85例行新辅助化疗＋手术与70例常规手术治疗患者的预后。结果化疗的有效率为55.3%。新辅助化疗＋手术组3年、5年生存率分别为53%、41%,常规手术组3年、5年生存率分别为42%、17.6%,两组生存率差异具有统计学意义。结论Ⅲ期胃癌术前先行新辅助化疗预后好。     

术中区域淋巴结化疗治疗胃癌的疗效观察

目的:观察术中用5-氟尿嘧啶(5-FU)行区域淋巴结封闭治疗胃癌的远期疗效和不良反应.方法:63例Ⅱ、ⅢA期胃癌患者随机分为术中区域淋巴结化疗组和全身化疗组进行对照观察.结果:两组仅见Ⅰ、Ⅱ级不良反应,未见Ⅲ～Ⅳ级不良反应发生.实验组1、3、5年的生存率分别为93.8%、68.9%、46.9%,对照组分别为90.3%、45.2%、22.6%.两组比较3、5年生存率差异有显著性(P＜0.05).结论:术中加用5-FU行区域淋巴结封闭治疗胃癌,无严重并发症,可提高患者的生存率和生存质量.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.