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21.
Andrulis IL Anton-Culver H Beck J Bove B Boyd J Buys S Godwin AK Hopper JL Li F Neuhausen SL Ozcelik H Peel D Santella RM Southey MC van Orsouw NJ Venter DJ Vijg J Whittemore AS;Cooperative Family Registry for Breast Cancer studies 《Human mutation》2002,20(1):65-73
A number of methods are used for mutational analysis of BRCA1, a large multi-exon gene. A comparison was made of five methods to detect mutations generating premature stop codons that are predicted to result in synthesis of a truncated protein in BRCA1. These included four DNA-based methods: two-dimensional gene scanning (TDGS), denaturing high performance liquid chromatography (DHPLC), enzymatic mutation detection (EMD), and single strand conformation polymorphism analysis (SSCP) and an RNA/DNA-based protein truncation test (PTT) with and without complementary 5' sequencing. DNA and RNA samples isolated from 21 coded lymphoblastoid cell line samples were tested. These specimens had previously been analyzed by direct automated DNA sequencing, considered to be the optimum method for mutation detection. The set of 21 cell lines included 14 samples with 13 unique frameshift or nonsense mutations, three samples with two unique splice site mutations, and four samples without deleterious mutations. The present study focused on the detection of protein-truncating mutations, those that have been reported most often to be disease-causing alterations that segregate with cancer in families. PTT with complementary 5' sequencing correctly identified all 15 deleterious mutations. Not surprisingly, the DNA-based techniques did not detect a deletion of exon 22. EMD and DHPLC identified all of the mutations with the exception of the exon 22 deletion. Two mutations were initially missed by TDGS, but could be detected after slight changes in the test design, and five truncating mutations were missed by SSCP. It will continue to be important to use complementary methods for mutational analysis. 相似文献
22.
Wim J. Leijendekker Joachim W. Herzig 《Pflügers Archiv : European journal of physiology》1992,421(4):388-390
We have studied the effect of EMD 53998 (5-(1-(3, 4-dimethoxybenzoyl)-1,2,3,4-tetrahydrochinolin-6-yl)-6-methyl-3, 6-dihydro-2H-1,3,4-thiadiazin-2-one) on cross-bridge turnover rate at varying Ca2+ concentrations. Cross-bridge cycling rate was estimated both by adenosine triphosphatase measurements and determination of mechanical characteristics of constantly activated fibres, which is assumed to reflect cross-bridge kinetics. The results indicate that the turnover rate of myocardial cross-bridges was reduced in the presence of EMD 53998 at low Ca2+ concentrations (pCa6.25), but not at higher Ca2+ concentrations (pCa5.85). 相似文献
23.
胃的 探讨ATP敏感钾通道(KATP)开放剂EMD56431对清醒自发性高血压大鼠(SHR)和肾性高血压大鼠(RHR)血压的影响。方法 采用静脉注射和灌胃给药的方式,经颈总动脉插管,动态监测动脉收缩压(SAP),舒张压(DAP)及心串(HR)的变化。并测定小鼠灌胃给予EMD56431时的半数致死剂量(LD50)。结果 静注或灌胃给予EMD56431,25、50、100μg/kg均可使SHR血压产生剂量依赖性的下降,同时反射性加快HR。前者降压维持时间分别为45min、6h和6h以上,后者可分别维持45min、lh和6h以上。静注和灌胃EMD56431产生的效应相当。灌胃EMD5643l亦可使RHR血压产生剂量依赖性的下降,降压维持时间分别为30min、45min和6h以上。小鼠LD50为8.54mg/kg,95%可信区限为7.87—9.93mg/kg。结论 EMD56431对SHR和RHR有显著而持久的降压作用,安全有效,且该药生物利用度较高,具有广阔的临床开发前景。 相似文献
24.
EMD 28422 was compared to chlordiazepoxide for antianxiety activity in two behavioral tests known to predict the anxiolytic action of drugs. In the conflict test, male rats were trained to respond for food reinforcement in which some of the reinforced responses also resulted in the delivery of footshock. Treatment of these rats with chlordiazepoxide but not with EMD 28422 antagonized the foot-shock-induced suppression of responding. In the drug discrimination test, male hooded rats were trained to discriminate the anxiogenic action of pentylenetetrazol from saline by responding for food reinforcement on one of two levers after pentylenetetrazol treatment (subconvulsant dose) and on the other lever after saline injection. Pretreatment with chlordiazepoxide and not with EMD 28422 antagonized the pentylenetetrazol stimulus. Ineffectiveness of EMD 28422 in both tests sensitive to chlordiazepoxide action suggests lack of anxiolytic efficacy of this drug, despite its reported enhancement of benzodiazepine binding in the brain. 相似文献
25.
P Skolnick S Paul J Crawley E Lewin A Lippa D Clody K Irmscher O Saiko K O Minck 《European journal of pharmacology》1983,88(4):319-327
The imidazopyridines EMD 35993 and EMD 41717 antagonized the anticonflict actions of diazepam and chlordiazepoxide in rodent models which are predictive for anxiolytic action in man. In contrast to other described benzodiazepine antagonists, these compounds did not antagonize either the anticonvulsant or muscle relaxant properties of either benzodiazepine. Both EMD 39593 and EMD 41717 competitively inhibit the binding of [3H]diazepam to brain membranes, but do not exhibit regional differences in potency. These observations suggest that both EMD 39593 and EMD 41717 display some selectivity in antagonizing the anxiolytic properties of benzodiazepines, and as such may be useful tools in identifying neuronal substrates of anxiety. 相似文献
26.
27.
While serotonin 5HT2-receptors have been implicated in the etiology and pharmacological treatment of a number of neuropsychiatric conditions, there are few potent and specific agents available for use in human clinical studies. EMD 281014 is a highly specific 5HT2-receptor antagonist that is currently under development. To find optimal doses for early clinical studies, we conducted a PET study using [18F]setoperone in nine healthy subjects scanned at baseline and following the administration of 1, 3, and 7 mg EMD 281014. The study drug was well tolerated by all study participants, and all doses resulted in 70% occupancy at frontal 5HT2-receptors 3 h after drug administration. The data suggest that daily dosing of 3 mg EMD 281014 should be sufficient to provide sustained high levels of 5HT2-receptor occupancy in future clinical trials. 相似文献
28.
Hilbert-黄变换方法分析压力脉搏波信号 总被引:1,自引:0,他引:1
目的:将Hilbert-黄变换方法用于压力脉搏波信号的分析,以获得脉搏波信号的时域特征和频率-能量分布。方法:通过经验模态分解(EMD)将脉搏波分解为一组内在模态函数(IMF),对每个IMF进行Hilbert变换,获得脉搏波信号幅度和频率的时间分布;由HH谱得到边际谱,反映信号的能量一频率分布;对典型正常个体的脉搏波信号和该个体脉滑变时的脉搏波信号进行处理,比较两种状态下脉搏波信号时一频分布情况。结果:用于实验的两例信号的分析结果显示,脉平信号的HH边际谱与脉滑信号的HH边际谱所表现的能量-频率分布有明显区别,这种区别能被脉平和脉滑变时的心血管活动状态所解释。结论:EMD算法和HHT能较好地用于脉搏波的分析,并且在医学信号处理领域将会有广阔的应用前景。 相似文献
29.
目的:研究ATP敏感钾通道开放剂EMD56431对麻醉开胸犬血流动力学的作用.方法:采用静注(i.v.)给药方式,动态监测麻醉开胸犬左心室收缩压(LVSP)、左室压上升和下降速率(±dp/dtmax),左室舒张末期压(LVEDP)、收缩压(SAP)、舒张压(DAP)、平均动脉压(MAP)、ECG等指标,并计算出心率(HR)、心脏指数(CI)和外周阻力(TPR).结果:静注EMD56431在一定范围内可使麻醉开胸犬呈时间和剂量依赖性的血压降低,尤以DAP下降为甚,在降压的同时,可见HR减慢.除大剂量EMD56431外,其余各剂量对心脏泵功能、血流量、ECG均无明显影响.结论:EMMD56431可显著降低血压,改善心脏供血. 相似文献
30.
Timo L.M. ten Hagen Ann L.B. Seynhaeve Gisela aan de Wiel‐Ambagtsheer Ernst A. de Bruijn Sandra T. van Tiel Curzio Ruegg Michael Meyring Matthias Grell Simon L. Goodman Alexander M.M. Eggermont 《International journal of cancer. Journal international du cancer》2013,132(11):2694-2704
Isolated limb perfusion (ILP) with melphalan and tumor necrosis factor (TNF)‐α is used to treat bulky, locally advanced melanoma and sarcoma. However, TNF toxicity suggests a need for better‐tolerated drugs. Cilengitide (EMD 121974), a novel cyclic inhibitor of alpha‐V integrins, has both anti‐angiogenic and direct anti‐tumor effects and is a possible alternative to TNF in ILP. In this study, rats bearing a hind limb soft tissue sarcoma underwent ILP using different combinations of melphalan, TNF and cilengitide in the perfusate. Further groups had intra‐peritoneal (i.p.) injections of cilengitide or saline 2 hr before and 3 hr after ILP. A 77% response rate (RR) was seen in animals treated i.p. with cilengitide and perfused with melphalan plus cilengitide. The RR was 85% in animals treated i.p. with cilengitide and ILP using melphalan plus both TNF and cilengitide. Both RRs were significantly greater than those seen with melphalan or cilengitide alone. Histopathology showed that high RRs were accompanied by disruption of tumor vascular endothelium and tumor necrosis. Compared with ILP using melphalan alone, the addition of cilengitide resulted in a three to sevenfold increase in melphalan concentration in tumor but not in muscle in the perfused limb. Supportive in vitro studies indicate that cilengitide both inhibits tumor cell attachment and increases endothelial permeability. Since cilengitide has low toxicity, these data suggest the agent is a good alternative to TNF in the ILP setting. 相似文献