• 【从俄罗斯图拉地区的监狱犯人中分离出的结核分枝杆菌中,耐多药的LAM和北京家族菌株占优势。】 复制标题 收藏 收藏
    DOI:10.1099/jmm.0.46575-0 复制DOI
    作者列表:Ignatova A,Dubiley S,Stepanshina V,Shemyakin I
    BACKGROUND & AIMS: :The genotypic characteristics and drug susceptibility profiles of clinical isolates of Mycobacterium tuberculosis recovered from prison hospital patients in the Tula region (central Russia) during 2001 and 2002 are reported. The emergence of multi-drug-resistant tuberculosis (TB) poses a major health risk to the population, with economic implications for TB control. Prisons serve as a continuous source of TB transmission. The results showed that members of the LAM and Beijing families are major contributors to the epidemiological picture of TB in the population studied. The two families of strains accounted for most of the drug-resistant TB in the population. The genotypic characteristics of the M. tuberculosis predominant LAM strain that was responsible for 31 % of TB cases in this setting are presented.
    背景与目标: :报告了2001和2002年从图拉地区(俄罗斯中部)的监狱医院患者中回收的结核分枝杆菌临床分离株的基因型特征和药物敏感性分布。耐多药结核病(TB)的出现给人们带来了重大的健康风险,对结核病控制产生了经济影响。监狱是结核病传播的持续来源。结果表明,LAM和北京家庭的成员是所研究人群中结核病流行病学特征的主要贡献者。菌株的两个家族占人口中大多数耐药结核病的比例。呈现了结核分枝杆菌占主导地位的LAM菌株的基因型特征,该菌株在这种情况下占31%的结核病病例。
  • 【药物见解:男性激素避孕的最新进展。】 复制标题 收藏 收藏
    DOI:10.1038/ncpendmet0069 复制DOI
    作者列表:Amory JK,Page ST,Bremner WJ
    BACKGROUND & AIMS: :As there are limitations to current methods of male contraception, research has been undertaken to develop hormonal contraceptives for men, analogous to the methods for women based on estrogen and progestogens. When testosterone is administered to a man, it functions as a contraceptive by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Since these hormones are the main stimulatory signals for spermatogenesis, low levels of LH and FSH markedly impair sperm production. After 3-4 months of testosterone treatment, 60-70% of men no longer have sperm in their ejaculate, and most other men exhibit markedly diminished sperm counts. Male hormonal contraception is well tolerated, free of serious adverse side effects, and 95% effective in the prevention of pregnancy. Importantly, male hormonal contraception is reversible, with sperm counts usually recovering within 4 months of the discontinuation of hormone treatment. Because exogenous testosterone administration alone does not completely suppress sperm production in all men, researchers have combined testosterone with second agents, such as progestogens or gonadotropin-releasing-hormone antagonists, to further suppress secretion of LH and FSH and improve suppression of spermatogenesis. Recent trials have used combinations of long-acting injectable or implantable forms of testosterone with progestogens, which can be administered orally, by injection or by a long-acting implant. Such combinations suppress spermatogenesis to zero without severe side effects in 80-90% of men, with near-complete suppression in the remainder of individuals. One of these testosterone and progestogen combination regimens might soon bring the promise of male hormonal contraception to fruition.
    背景与目标: :由于目前男性避孕方法的局限性,已经进行了研究以开发男性荷尔蒙避孕药,类似于基于雌激素和孕激素的女性避孕方法。当男人服用睾丸激素时,它通过抑制垂体促黄体生成激素(LH)和促卵泡激素(FSH)的分泌而起避孕作用。由于这些激素是精子发生的主要刺激信号,因此低水平的LH和FSH明显损害了精子的产生。经过3-4个月的睾丸激素治疗后,60-70%的男性不再有精子射精,其他大多数男性的精子数量也明显减少。男性荷尔蒙避孕药耐受性好,没有严重的不良副作用,并且95%的预防怀孕有效。重要的是,男性荷尔蒙避孕是可逆的,在停止激素治疗后的4个月内,精子数量通常会恢复。由于单独使用外源性睾丸激素并不能完全抑制所有男性的精子产生,因此研究人员已将睾丸激素与第二种药物(如孕激素或促性腺激素释放激素拮抗剂)联合使用,以进一步抑制LH和FSH的分泌并改善对精子发生的抑制作用。最近的试验已将长效可注射或可植入形式的睾丸激素与孕激素结合使用,可以口服,注射或长效植入物给药。这样的组合在80-90%的男性中将精子发生抑制为零而没有严重的副作用,而在其余个体中则几乎完全被抑制。这些睾丸激素和孕激素联合治疗方案之一可能很快会带来雄激素避孕的希望。
  • 【体外药物活性和药代动力学在预测抗分枝杆菌疗法有效性中的价值:一项重要综述。】 复制标题 收藏 收藏
    DOI:10.1097/00000441-199706000-00008 复制DOI
    作者列表:Burman WJ
    BACKGROUND & AIMS: Marked increases in case rates of drug-resistant tuberculosis and nontuberculous mycobacterial infections have brought renewed urgency to the development of new treatment regimens for mycobacterial infections. Preclinical data, such as in vitro measures of drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of drug-susceptible tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial therapy. In vitro measures of drug activity predict the potency of a drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a drug or the activity of drug combinations. In vitro measures of drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of drug activity but still do not predict sterilizing activity. In contrast, animal models of tuberculosis have predicted relative drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.

    背景与目标: 耐药结核病和非结核分枝杆菌感染的病例率显着增加,这为开发针对分枝杆菌感染的新治疗方案带来了新的紧迫性。临床前数据,例如药物活性和药代动力学的体外测量,用于设计新的治疗方案。这篇综述调查了有关药物敏感性肺结核治疗的广泛发表的临床经验,以评估这些临床前措施在预测抗分枝杆菌治疗的临床结果中的应用。药物活性的体外量度可以预测药物对其他抗分枝杆菌药物产生抗药性的能力,但不能预测药物的灭菌活性或药物组合的活性。药物活性的体外测量不能可靠地预测应将生物体视为抗药性的水平。药物在组织中的渗透和针对细胞内细菌的活性的测定适度地增加了药物活性体外测量的预测价值,但仍不能预测灭菌活性。相反,结核病的动物模型预测了相对的药效(包括杀菌活性),多种药物疗法的疗效以及所需的治疗时间。尽管药代动力学参数表明每天需要多剂量,但每隔一周两次不频繁使用时,所有一线抗结核药物均具有活性。难以预测具有休眠能力的细胞内病原体的治疗效果。需要更好的体外模型,尤其是预测杀菌活性的模型。

  • 【血小板对ADP的反应先前存在变异的证据可解释为“氯吡格雷抵抗”。】 复制标题 收藏 收藏
    DOI:10.1111/j.1538-7836.2006.02234.x 复制DOI
    作者列表:Michelson AD,Linden MD,Furman MI,Li Y,Barnard MR,Fox ML,Lau WC,McLaughlin TJ,Frelinger AL
    BACKGROUND & AIMS: BACKGROUND:Clopidogrel is a widely used antithrombotic agent that inhibits the platelet P2Y(12) adenosine diphosphate (ADP) receptor. There is increasing interest in 'clopidogrel resistance'. OBJECTIVES:To determine whether 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP. METHODS:Platelet response to 20 microm ADP was analyzed by four independent whole blood flow cytometric assays: platelet surface activated GPIIb-IIIa, platelet surface P-selectin, monocyte-platelet aggregates and neutrophil-platelet aggregates. In 25 consecutive, non-aspirin-treated healthy subjects, we studied platelet response before and after clopidogrel administration. In addition, we studied the platelet response in 613 consecutive aspirinated patients with or without coronary artery disease (CAD, as determined by angiography) who had or had not been treated with clopidogrel. In these patients, we tested for homogeneity of variance across all durations of clopidogrel exposure and severity of CAD by estimating the 'goodness of fit' of two independent models. RESULTS:In the healthy subjects, pre-clopidogrel response to ADP predicted post-clopidogrel response to ADP. In the patients, clopidogrel, as expected, inhibited the platelet response to ADP. However, irrespective of the duration of clopidogrel administration, the severity of CAD, and the dose of aspirin, clopidogrel did not increase the variance in the platelet response to ADP in any of the four assays of platelet response. CONCLUSIONS:These studies provide evidence that 'clopidogrel resistance' is accounted for by a pre-existent variability in platelet response to ADP and this variability is not increased by clopidogrel administration.
    背景与目标: 背景:氯吡格雷是一种广泛使用的抗血栓药,可抑制血小板P2Y(12)二磷酸腺苷(ADP)受体。人们对“氯吡格雷抵抗”的兴趣日益浓厚。
    目的:要确定“氯吡格雷抵抗”是否由血小板对ADP的反应中先前存在的变异性引起。
    方法:通过四个独立的全血流式细胞术分析血小板对20微米ADP的反应:血小板表面活化的GPIIb-IIIa,血小板表面P-选择素,单核细胞-血小板聚集体和中性白细胞-血小板聚集体。在连续25次非阿司匹林治疗的健康受试者中,我们研究了氯吡格雷给药前后的血小板反应。此外,我们研究了613名连续接受或未接受氯吡格雷治疗的有或没有冠状动脉疾病(CAD,通过血管造影术确定)的吸气患者的血小板反应。在这些患者中,我们通过评估两个独立模型的“拟合优度”,测试了氯吡格雷暴露的所有持续时间和CAD严重性的方差同质性。
    结果:在健康受试者中,氯吡格雷对ADP的反应可预测氯吡格雷对ADP的反应。如预期的那样,在患者中,氯吡格雷抑制了血小板对ADP的反应。但是,不管使用氯吡格雷的持续时间,CAD的严重程度以及阿司匹林的剂量如何,在四种血小板反应测定中,氯吡格雷均不会增加血小板对ADP的反应方差。
    结论:这些研究提供了证据,“氯吡格雷抵抗”是由血小板对ADP的反应中先前存在的变异性引起的,而使用氯吡格雷不会增加这种变异性。
  • 【抗菌药物的使用和肺炎链球菌青霉素耐药性:时间关系模型。】 复制标题 收藏 收藏
    DOI:10.1089/mdr.2006.12.158 复制DOI
    作者列表:Mera RM,Miller LA,White A
    BACKGROUND & AIMS: :The nature of the temporal relationship between antibacterial consumption and Streptococcus pneumoniae penicillin resistance is investigated using population level data across time. IMS Health Global Services provided national outpatient antibiotic prescription data for the years 1996-2003 from France, Spain, Italy, Germany, the United Kingdom, and the United States. Surveillance data consist of S. pneumoniae isolates obtained from a surveillance database in the same geographic regions from 1996 to 2003. A linear mixed model for repeated measures was used to analyze the association between resistance and several antibacterial classes through time. Changes in penicillin resistance through time in any country are better explained by the weighted cumulative antibacterial consumption with a 2-year lag. Narrow-spectrum penicillins are associated with lower resistance rates. Large reductions in consumption at the population level are needed to affect resistance. There is a peak level of penicillin resistance associated with cumulative exposure to a combination of antibiotic classes that is unique for every country.
    背景与目标: :使用跨时间的人口水平数据调查了抗菌药物消费与肺炎链球菌青霉素耐药性之间时间关系的性质。 IMS Health Global Services提供了1996-2003年法国,西班牙,意大利,德国,英国和美国的国家门诊抗生素处方数据。监测数据由1996年至2003年从同一地理区域的监测数据库中获得的肺炎链球菌分离株组成。采用线性混合模型进行重复测量,以分析耐药性与一段时间内几种抗菌剂类别之间的关联。在任何国家,青霉素耐药性随时间的变化都可以通过加权累积抗菌药消费量(滞后2年)来更好地说明。窄谱青霉素与较低的耐药率有关。需要在人口一级大幅度减少消费量以影响抵抗力。青霉素耐药性的峰值与每个国家所独有的抗生素类药物的累积接触有关。
  • 【进入三级医院内科病房的患者不良药物反应的直接费用和临床方面】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Tribiño G,Maldonado C,Segura O,Díaz J
    BACKGROUND & AIMS: INTRODUCTION:Adverse drug reactions (ADRs) occur frequently in hospitals and increase costs of health care; however, few studies have quantified the clinical and economic impact of ADRs in Colombia. OBJECTIVES:These impacts were evaluated by calculating costs associated with ADRs in patients hospitalized in the internal medicine ward of a Level 3 hospital located in Bogotá, Colombia. In addition, salient clinical features of ADRs were identified and characterized. MATERIAL AND METHODS:Intensive follow-ups for a cohort of patients were conducted for a five month period in order to detect ADRs; different ways to classify them, according to literature, were considered as well. Information was collected using the INVIMA reporting format, and causal probability was evaluated with the Naranjo algorithm. Direct costs were calculated from the perspective of payer, based on the following costs: additional hospital stay, medications, paraclinical tests, additional procedures, patient displacement to intermediate or intensive care units, and other costs. RESULTS:Of 836 patients admitted to the service, 268 adverse drug reactions were detected in 208 patients (incidence proportion 25.1%, occurence rate 0.32). About the ADRs found, 74.3% were classified as probable, 92.5% were type A, and 81.3% were moderate. The body system most often affected was the circulatory system (33.9%). Drugs acting on the blood were most frequently those ones associated with adverse reactions (37.6%). The costs resulting from medical care of adverse drug reactions varied from COL dollar 93,633,422 (USD dollar 35,014.92) to COL dollar 122,155,406 (USD dollar 45,680.94), according to insurance type, during the study period. CONCLUSIONS:Adverse drug reactions have a significant negative health and financial impact on patient welfare. Because of the substantial resources required for their medical care and the significant proportion of preventable adverse reactions, active programs of institutional pharmacovigilance are highly recommended.
    背景与目标: 简介:药物不良反应(ADR)在医院中经常发生,并增加了医疗保健费用;但是,很少有研究能够量化ADR在哥伦比亚的临床和经济影响。
    目的:通过计算在哥伦比亚波哥大三级医院内科病房住院的患者与ADR相关的费用来评估这些影响。此外,ADR的显着临床特征已得到鉴定和表征。
    材料与方法:对一组患者进行了为期五个月的强化随访,以检测ADR。根据文献,还考虑了不同的分类方法。使用INVIMA报告格式收集信息,并使用Naranjo算法评估因果概率。直接费用是根据以下费用从付款人的角度计算的:额外的住院时间,药物,辅助临床检查,其他程序,将患者转移到中级或重症监护室以及其他费用。
    结果:836例入院患者中,208例患者发生了268例药物不良反应(发生率25.1%,发生率0.32)。关于发现的ADR,有74.3%被归为可能,A型为92.5%,中度为81.3%。受影响最严重的身体系统是循环系统(33.9%)。作用于血液的药物最常见于那些与不良反应有关的药物(37.6%)。根据保险类型,在研究期间,药物不良反应的医疗费用从93,633,422美元(35,014.92美元)到122,155,406美元(45,680.94美元)不等。
    结论:药物不良反应会对患者的健康产生重大的负面健康和财务影响。由于其医疗服务所需的大量资源以及可预防的不良反应的比例很大,因此强烈建议积极进行机构药物警戒计划。
  • 【跳尾Orchesella cincta的气候抗逆性状的地理变异。】 复制标题 收藏 收藏
    DOI:10.1016/j.jinsphys.2006.06.005 复制DOI
    作者列表:Bahrndorff S,Holmstrup M,Petersen H,Loeschcke V
    BACKGROUND & AIMS: :Multiple traits of stress resistance were investigated in the epedaphic springtail Orchesella cincta. Second generation adults from five laboratory populations were compared with respect to resistance to extreme temperatures and desiccation, and traits relevant to climatic adaptation. Populations were collected along a 2000-km latitudinal gradient ranging from Denmark to southern Italy and reared under the same standard laboratory conditions. Traits investigated were resistance to high and low temperature, desiccation resistance, body size and water loss rate (WLR). Results showed genetically based differences in resistance to high and low temperature, desiccation, WLR, water pool and body size between populations. Individuals from the most northern population had the highest desiccation-and cold shock resistance, and the lowest heat shock resistance. Females were significantly more desiccation resistant than males. The results of cold shock resistance showed a positive increase with lowest environmental temperature recorded at the sites of population origin, whereas heat shock resistance showed a positive increase with highest recorded temperature at the sites of population origin. Desiccation resistance increased towards the most southern and northern population, suggesting that both low and high temperature extremes affect desiccation resistance. Body mass, water pool and WLR showed interpopulation as well as sex specific variation. This provides evidence for geographical variation in stress resistance of springtails related to climatic conditions.
    背景与目标: :研究了足立跳尾Orchesella cincta的多种抗逆性状。比较了来自五个实验室人群的第二代成年人对极端温度和干燥的抵抗力以及与气候适应有关的性状。从丹麦到意大利南部,沿着2000公里的纬度梯度收集种群,并在相同的标准实验室条件下进行饲养。研究的特征是对高温和低温的抗性,抗干燥性,体型和失水率(WLR)。结果显示,不同人群之间对高温和低温,干燥,WLR,水池和体重的遗传差异。来自最北部人口的个体具有最高的耐干燥性和抗冷震性,以及最低的抗热震性。女性的抗干燥能力明显高于男性。在种群起源点记录的最低环境温度下,抗冷震性结果呈正增长,而在种群起源点记录的最高温度下抗热震性呈正增长。大部分南部和北部人口的抗旱性增加,这表明低温和高温极端情况都会影响抗旱性。体重,水池和WLR表现出种群数量以及性别差异。这为与气候条件有关的跳尾抗逆性的地理变化提供了证据。
  • 【社区获得性耐甲氧西林金黄色葡萄球菌对奥沙西林耐药所需的VraS / VraR两组分调节系统。】 复制标题 收藏 收藏
    DOI:10.1111/j.1574-6968.2006.00384.x 复制DOI
    作者列表:Boyle-Vavra S,Yin S,Daum RS
    BACKGROUND & AIMS: :Methicillin/oxacillin (Oxa) resistance in Staphylococcus aureus is primarily mediated by the acquired penicillin-binding protein (PBP2a) encoded by mecA. PBP2a acts together with native PBP2 to mediate oxacillin resistance by contributing complementary transpeptidase and transglycosylase activities, respectively. The VraS/VraR two-component regulatory system is inducible by cell-wall antimicrobials (beta-lactams, glycopeptides) and controls transcriptional induction of many cell-wall genes including pbp2 and itself. We investigated the role of VraS/VraR in the phenotypic expression of oxacillin resistance by inactivating vraS in community-acquired MRSA clinical isolates that lack functional genes encoding the mecA regulatory sequences mecI and mecR1. Inactivation of vraS abrogated oxacillin resistance, and complementation with the vraS operon restored the resistance phenotype. mecA transcription increased in the vraS mutants; however, PBP2a abundance was similar to that of the wild type. Although pbp2 transcription decreased in the vraS mutants, overexpression of the pbp2 operon did not restore resistance. These data demonstrate that although expressions of mecA and pbp2 are required for oxacillin resistance, they are not sufficient. Therefore, the vraS/vraR regulatory system plays a crucial role in allowing MRSA to respond to beta-lactams by regulation of a gene target other than the known effectors of methicillin resistance.
    背景与目标: 金黄色葡萄球菌对甲氧西林/奥沙西林(Oxa)的耐药性主要由mecA编码的获得性青霉素结合蛋白(PBP2a)介导。 PBP2a与天然PBP2共同发挥作用,通过分别贡献互补的转肽酶和转糖基酶活性来介导奥沙西林抗性。 VraS / VraR两组分调节系统可通过细胞壁抗微生物剂(β-内酰胺,糖肽)诱导,并控制包括pbp2及其本身在内的许多细胞壁基因的转录诱导。我们通过灭活社区获得的MRSA临床分离株中的vraS而失活,研究了VraS / VraR在奥沙西林耐药性表型表达中的作用,该分离株缺乏编码mecA调控序列mecI和mecR1的功能基因。 vraS的失活消除了奥沙西林的耐药性,与vraS操纵子的互补恢复了耐药性表型。在vraS突变体中,mecA转录增加;但是,PBP2a的丰度与野生型相似。尽管在vraS突变体中pbp2转录降低,但是pbp2操纵子的过表达不能恢复抗性。这些数据表明,尽管抗mecA和pbp2的表达是奥沙西林耐药性所必需的,但它们还不够。因此,vraS / vraR调节系统在允许MRSA通过调节除已知的甲氧西林抗性效应子以外的基因靶标而对β-内酰胺作出响应中起着至关重要的作用。
  • 【吸毒规则:古代世界中的葡萄酒和罂粟衍生物。六。罂粟是食物和毒品的来源。】 复制标题 收藏 收藏
    DOI:10.3109/10826089709039375 复制DOI
    作者列表:Nencini P
    BACKGROUND & AIMS: :Poppies were widely used during antiquity as a source of food, therapeutics, and poisons. It is likely that the alimentary value of poppy seeds was known in the Neolithic age, and there is some evidence that the neuropsychopharmacological effects of poppy juice were exploited during the Minoan civilization in the eastern Mediterranean basin. The Minoan civilization dates the attribution to poppies of symbolic meanings connected with rites of agricultural fertility. The persistence throughout antiquity of this symbolism is testified by literary and iconographic evidence of the attribution of poppies to goddesses of fertility, such as Demeter, Aphrodite, and Ceres.
    背景与目标: :在古代,罂粟被广泛用作食物,治疗剂和毒药的来源。罂粟种子的营养价值很可能是在新石器时代就已经知道的,并且有一些证据表明,罂粟汁的神经心理药理作用是在地中海东部的米诺斯文明期间被利用的。米诺斯文明可追溯到象征意义的罂粟的归属,这些象征意义与农业生育的仪式有关。这种象征主义在整个上古时代的持久性通过文学和肖像学证据证明,罂粟归因于狄特耳特,阿芙罗狄蒂和谷神星等生育女神。
  • 【根瘤菌素在体外和体内对非P-糖蛋白介导的长春地辛抗性的调节。】 复制标题 收藏 收藏
    DOI:10.1007/BF01240315 复制DOI
    作者列表:Arioka H,Nishio K,Heike Y,Abe S,Saijo N
    BACKGROUND & AIMS: :Rhizoxin is an antineoplastic drug that inhibits tubulin polymerization. In this study, we demonstrated that rhizoxin was approximately twice as active in vitro against a human small-cell lung cancer cell line with non-P-glycoprotein-mediated resistance to vindesine, H69/VDS, as against its parental line, H69. Tubulin polymerization in H69/VDS, demonstrated by Western blot analysis, was inhibited markedly by rhizoxin compared with that in H69, in a concentration-dependent manner. A drug-accumulation study showed that the intracellular rhizoxin level in H69/VDS was 15% lower than that in H69, whereas efflux from H69/VDS was enhanced slightly. These results indicate that enhanced inhibition of tubulin polymerization rather than increased intracellular drug concentration accounted for the higher sensitivity of H69/VDS to rhizoxin. In an experiment using mice with severe combined immunodeficiency and inoculated subcutaneously with H69/VDS, in vivo tumor growth was reduced markedly by three intermittent intraperitoneal doses of rhizoxin compared with that in mice inoculated with H69. Three weeks after the last rhizoxin dose, the relative treated/untreated tumor volumes were 0.29 for H69, but only 0.06 for H69/VDS, indicating that H69/VDS regrowth was minimal even after a 3-week treatment-free period. In conclusion, rhizoxin conquers vindesine resistance of a human small-cell lung cancer cell line in vitro and in vivo.
    背景与目标: :Rhizoxin是一种抑制微管蛋白聚合的抗肿瘤药。在这项研究中,我们证明了根霉毒素在体外对人小细胞肺癌细胞株的活性约为非亲本糖蛋白对长春地辛H69 / VDS的抗性的P糖蛋白介导的,比其亲本株H69的活性高出两倍。 Western blot分析表明,与H69中的相比,根瘤菌素显着抑制了H69 / VDS中的微管蛋白聚合,并呈浓度依赖性。一项药物蓄积研究表明,H69 / VDS中的细胞内根瘤菌素水平比H69中的低15%,而H69 / VDS中的流出量则略有提高。这些结果表明,增强的对微管蛋白聚合的抑制而不是增加的细胞内药物浓度,说明了H69 / VDS对根瘤菌素的敏感性更高。在一项使用严重联合免疫缺陷小鼠并皮下接种H69 / VDS的小鼠进行的实验中,与接种H69的小鼠相比,腹膜内给予3种间断剂量的硫唑嗪显着降低了体内肿瘤的生长。最后一次根瘤菌素给药后三周,H69的相对治疗/未治疗肿瘤体积为0.29,而H69 / VDS仅为0.06,表明即使经过3周的无治疗期,H69 / VDS的再生长也很小。总之,根瘤菌素可在体外和体内克服人类小细胞肺癌细胞株的长春地辛耐药性。
  • 【与人类神经胶质瘤细胞系SNB-19中获得性替莫唑胺抗性相关的遗传改变。】 复制标题 收藏 收藏
    DOI:10.1158/1535-7163.MCT-05-0428 复制DOI
    作者列表:Auger N,Thillet J,Wanherdrick K,Idbaih A,Legrier ME,Dutrillaux B,Sanson M,Poupon MF
    BACKGROUND & AIMS: :Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.
    背景与目标: :胶质瘤是高度致死性的肿瘤,目前尚无法治愈。替莫唑胺是最近引入的烷基化剂,已在治疗高级神经胶质瘤中产生了显着的益处。然而,从头或获得性化学抗性经常发生,并且归因于O6-甲基鸟嘌呤-DNA甲基转移酶水平的增加或失配修复能力的丧失。但是,极少的神经胶质瘤过表达O6-甲基鸟嘌呤-DNA甲基转移酶或错配修复缺陷,提示其他机制可能与对替莫唑胺的抗性有关。本研究的目的是从人类神经胶质瘤细胞系(SNB-19)产生抗替莫唑胺的变体,并使用大规模的基因组和转录分析来研究获得的替莫唑胺抗性的分子基础。两个独立获得的替莫唑胺抗性变体对其他烷基化剂[1,3-双(2-氯乙基)-1-亚硝基脲和卡铂]无交叉抗性,并且共有遗传变异,例如2p区域丢失和扩增丢失染色体4和16q区域。核型改变与亲本SNB-19细胞系中先前存在的抗性细胞的克隆选择相容。基因芯片分析显示,在17,000个基因中,有78个在亲代细胞和两种替莫唑胺耐药变体之间差异表达。没有人参与已知的抗性机制,例如DNA修复,而有趣的是,参与分化的几个基因被下调。数据表明,在该模型中获得对替莫唑胺的抗药性是由于在亲本肿瘤中选择了分化程度较低的抗药性细胞而引起的。
  • 【耐药细胞提取物中癌基因依赖性细胞凋亡。】 复制标题 收藏 收藏
    DOI:10.1101/gad.11.10.1266 复制DOI
    作者列表:Fearnhead HO,McCurrach ME,O'Neill J,Zhang K,Lowe SW,Lazebnik YA
    BACKGROUND & AIMS: Many genotoxic agents kill tumor cells by inducing apoptosis; hence, mutations that suppress apoptosis produce resistance to chemotherapy. Although directly activating the apoptotic machinery may bypass these mutations, how to achieve this activation in cancer cells selectively is not clear. In this study, we show that the drug-resistant 293 cell line is unable to activate components of the apoptotic machinery-the ICE-like proteases (caspases)-following treatment with an anticancer drug. Remarkably, extracts from untreated cells spontaneously activate caspases and induce apoptosis in a cell-free system, indicating that drug-resistant cells have not only the apoptotic machinery but also its activator. Comparing extracts from cells with defined genetic differences, we show that this activator is generated by the adenovirus E1A oncogene and is absent from normal cells. We provide preliminary characterization of this oncogene generated activity (OGA) and show that partially purified OGA activates caspases when added to extracts from untransformed cells. We suggest that agents that link OGA to caspases in cells would kill tumor cells otherwise resistant to conventional cancer therapy. As this killing relies on an activity generated by an oncogene, the effect of these agents should be selective for transformed cells.

    背景与目标: 许多遗传毒性剂通过诱导细胞凋亡杀死肿瘤细胞。因此,抑制细胞凋亡的突变产生了对化学疗法的抗性。尽管直接激活凋亡机制可能绕过这些突变,但是如何在癌细胞中选择性地实现这种激活尚不清楚。在这项研究中,我们显示了抗药性293细胞系无法激活凋亡机制的成分(如ICE样蛋白酶(胱天蛋白酶)),随后进行了抗癌药物治疗。值得注意的是,未经处理的细胞提取物会自发激活胱天蛋白酶并在无细胞系统中诱导凋亡,这表明耐药细胞不仅具有凋亡机制,还具有其激活剂。比较具有确定的遗传差异的细胞提取物,我们表明该激活剂是由腺病毒E1A癌基因产生的,而正常细胞中却不存在。我们提供了此致癌基因产生的活性(OGA)的初步表征,并表明当添加到未转化细胞的提取物中时,部分纯化的OGA会激活胱天蛋白酶。我们建议将OGA与细胞中的半胱氨酸蛋白酶连接的药剂会杀死肿瘤细胞,否则它们会对常规癌症治疗产生抵抗力。由于这种杀伤作用依赖于癌基因产生的活性,因此这些药剂对转化细胞的作用应该是选择性的。

  • 【腺病毒对细胞蛋白质合成的抑制作用被药物2-氨基嘌呤阻止。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.87.18.7115 复制DOI
    作者列表:Huang JT,Schneider RJ
    BACKGROUND & AIMS: :Adenovirus infection results in the suppression of cellular protein synthesis, but the mechanism has not been established. In this report we demonstrate that the shut-off of cellular protein synthesis by adenovirus is prevented in cells by treatment with the drug 2-aminopurine. Treatment with 2-aminopurine is shown to prevent suppression of cellular translation without disrupting the normal viral block in the transport of cellular mRNAs from the nucleus to the cytoplasm. We show that viral suppression of cellular protein synthesis occurs concomitant with activation of the interferon-induced double-stranded RNA-activated inhibitor (DAI), a protein kinase, and phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2 alpha), but that prevention of host cell shut-off by 2-aminopurine occurs without a decrease in kinase activity or a dephosphorylation of eIF-2 alpha. Results are presented that indicate that activation of DAI kinase and phosphorylation of eIF-2 alpha may be required but are not sufficient to achieve inhibition of cellular protein synthesis during adenovirus infection. We suggest that other events, in particular the modification of additional initiation factors, are likely involved in viral inhibition of cellular translation.
    背景与目标: :腺病毒感染导致细胞蛋白质合成受到抑制,但该机制尚未建立。在本报告中,我们证明了通过用2-氨基嘌呤药物治疗可防止腺病毒关闭细胞蛋白质合成。已显示用2-氨基嘌呤处理可防止细胞翻译受到抑制,而不会破坏细胞mRNA从细胞核到细胞质的运输过程中的正常病毒阻滞。我们显示病毒抑制细胞蛋白质合成的发生与干扰素诱导的双链RNA激活的抑制剂(DAI),蛋白激酶和真核生物起始因子2(eIF-2 alpha)的α亚基的磷酸化的激活同时发生。 ,但可以防止2-氨基嘌呤阻止宿主细胞的关闭,而不会降低激酶活性或eIF-2α的去磷酸化。结果表明,可能需要DAI激酶的激活和eIF-2α的磷酸化,但不足以抑制腺病毒感染期间细胞蛋白质合成。我们建议其他事件,特别是其他起始因子的修饰,可能与细胞翻译的病毒抑制有关。
  • 【保留,遵守和依从性:针对老年人的基于家庭和团体的抵抗训练计划的重要考虑因素。】 复制标题 收藏 收藏
    DOI:10.1016/j.jsams.2006.06.020 复制DOI
    作者列表:Cyarto EV,Brown WJ,Marshall AL
    BACKGROUND & AIMS: :Reports on the efficacy of physical activity intervention trials usually only include discussion of the primary outcomes. However, assessing factors such as participant retention, adherence and compliance can assist in the accurate interpretation of the overall impact of a program in terms of reach and appeal. A quasi-randomised trial was carried out to assess and compare retention and adherence rates, and compliance with, a twice weekly resistance training program provided either individually at home or in a group format. Retirement villages (n=6) were assigned to either 'Have A Try' (HAT, home-based) or 'Come Have A Try' (CHAT, group-based); both programs included nine strength and two balance exercises. The program involved a 20-week Intervention Phase a 24-week Maintenance Phase and a 20-week On-going Maintenance Phase. One hundred and nineteen participants (mean age 80+/-6 years) were recruited (HAT=38, CHAT=81). There was no difference in retention rates at the end of the Intervention Phase, but significantly more HAT than CHAT participants had dropped out of the study (p<0.01) after the Maintenance Phase and the On-going Maintenance Phase. During the Intervention Phase, over half the HAT and CHAT participants completed > or =75% of the prescribed activity sessions, but adherence was significantly greater in CHAT than HAT during the Maintenance Phase (p<0.01). Participants in CHAT were significantly more compliant than HAT participants (p<0.05). Both home- and group-based formats were successful over the short-term, but, in retirement villages, the group program had better adherence and compliance in the longer-term.
    背景与目标: :有关体育锻炼干预试验功效的报告通常仅包括对主要结局的讨论。但是,评估参与者的保留,遵守和遵守等因素可以帮助准确地解释计划在影响力和吸引力方面的总体影响。进行了一项半随机试验,以评估和比较保留率和依从率,以及是否遵守每周两次的在家中或以小组形式提供的每周两次阻力训练计划。退休村(n = 6)被分配为“尝试一下”(HAT,基于家庭)或“来一下尝试”(CHAT,基于组);这两个程序都包括九项力量和两项平衡练习。该计划包括20周的干预阶段,24周的维护阶段和20周的持续维护阶段。招募了119名参与者(平均年龄80 / -6岁)(HAT = 38,CHAT = 81)。在干预阶段结束时,保留率没有差异,但是在维护阶段和正在进行的维护阶段之后,HAT的退出人数比CHAT参与者退出研究的次数多(p <0.01)。在干预阶段,超过一半的HAT和CHAT参与者完成了规定活动的>或= 75%,但是在维持阶段,CHAT中的依从性明显高​​于HAT(p <0.01)。与CHAT参与者相比,CHAT参与者的依从性更高(p <0.05)。以家庭为基础和以团体为基础的形式在短期内都是成功的,但是在退休村,从长期来看,团体计划具有更好的遵守性和合规性。
  • 【胆囊体积的改变不会影响胆囊管阻力。】 复制标题 收藏 收藏
    DOI:10.1001/archsurg.1990.01410160046010 复制DOI
    作者列表:Sharp KW,Ross CB,Tillman VN,Williams LF Jr
    BACKGROUND & AIMS: :To our knowledge, the relationship between gallbladder volume and cystic duct function has not been studied. We hypothesized that changes in gallbladder volume would influence cystic duct resistance. The effect of gallbladder volume changes on cystic duct resistance to both prograde (emptying) and retrograde (filling) steady-state flow was tested in 12 dogs under basal cholecystokinin-stimulated conditions utilizing a multiport catheter with a highly compliant balloon placed within the gallbladder fundus. Gallbladder volume was regulated by varying balloon volume from empty to just beyond physiologic distention. Cystic duct resistance was not affected by balloon volume under basal or stimulated conditions or by the direction of perfusate flow. This study demonstrated no relationship between gallbladder volume and cystic duct resistance and did not demonstrate a cystic duct sphincter mechanism at physiologic gallbladder volumes.
    背景与目标: :据我们所知,尚未研究胆囊体积与胆囊管功能之间的关系。我们假设胆囊体积的变化会影响胆囊管阻力。胆囊体积变化对胆囊管抵抗顺行(空)和逆行(充盈)稳态血流的影响在12条经基础胆囊收缩素刺激的狗中使用多端口导管,并在胆囊内放置高度顺应性球囊进行了测试。胆囊体积的调节是通过将气囊体积从空变到生理上的变化来进行的。囊性导管阻力不受基础或刺激条件下的球囊容积或灌注液流向的影响。这项研究表明胆囊体积和胆囊管阻力之间没有关系,并且在生理胆囊体积上也没有证明胆囊括约肌的机制。

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