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1.
Missense mutation in a von Willebrand factor type A domain of the alpha 3(VI) collagen gene (COL6A3) in a family with Bethlem myopathy 总被引:2,自引:0,他引:2
Pan TC; Zhang RZ; Pericak-Vance MA; Tandan R; Fries T; Stajich JM; Viles K; Vance JM; Chu ML; Speer MC 《Human molecular genetics》1998,7(5):807-812
The Bethlem myopathy is a rare autosomal dominant proximal myopathy
characterized by early childhood onset and joint contractures. Evidence for
linkage and genetic heterogeneity has been established, with the majority
of families linked to 21q22.3 and one large family linked to 2q37,
implicating the three type VI collagen subunit genes, COL6A1 (chromosome
21), COL6A2 (chromosome 21) and COL6A3 (chromosome 2) as candidate genes.
Mutations of the invariant glycine residues in the triple-helical
domain-coding region of COL6A1 and COL6A2 have been reported previously in
the chromosome 21-linked families. We report here the identification of a
G-->A mutation in the N-terminal globular domain-coding region of COL6A3
in a large American pedigree (19 affected, 12 unaffected), leading to the
substitution of glycine by glutamic acid in the N2 motif, which is
homologous to the type A domains of the von Willebrand factor. This
mutation segregated to all affected family members, to no unaffected family
members, and was not identified in 338 unrelated Caucasian control
chromosomes. Thus mutations in either the triple-helical domain or the
globular domain of type VI collagen appear to cause Bethlem myopathy.
相似文献
2.
Glenn Liu George Wilding Mary Jane Staab Dorthea Horvath Kelly Miller Amy Dresen Dona Alberti Rhoda Arzoomanian Rick Chappell Howard H Bailey 《Clinical cancer research》2003,9(11):4077-4083
PURPOSE: In this single institution Phase II trial, we evaluated the efficacy of the vitamin D analogue, 1alpha-OH-D(2), in patients with advanced hormone-refractory prostate cancer. Experimental Design: The patients initially received 1alpha-OH-D(2) at 12.5 micro g p.o. every day, which was dose adjusted for hypercalcemia. Given the cytostatic nature of the drug, the primary study end point was progression-free survival for a minimum of 6 months. The secondary end point was further characterization of drug toxicity. RESULTS: A total of 26 patients was enrolled. Using the intent-to-treat population, stable disease was seen for an average of 19.2 weeks (median 12 weeks, range 3-108 weeks). Twenty patients were evaluable for response. The one patient that achieved disease stabilization for >2 years elected to come off-study because of patient preference. His last disease evaluation showed no evidence of progression. No objective responses were seen. Previous and ongoing clinical observations strongly imply that PSA could be a misleading surrogate marker for clinical effect with this type of drug. Therefore, prostate-specific antigen was not used as a marker for disease response. Toxicity was as expected with mild hypercalcemia and associated symptoms like constipation and prerenal azotemia seen in some patients. Six (30%) evaluable patients experienced stable disease for >6 months, suggesting possible cytostatic activity. CONCLUSION: The results of this and other trials suggest further clinical investigation in this disease with vitamin D analogues alone or in combination with other agents, such as chemotherapy, should be pursued. 相似文献
3.
J. F. Cleary Rhoda Arzoomanian Donna Alberti Chris Feierabend Barry Storer Pauline Witt P. P. Carbone George Wilding 《Cancer chemotherapy and pharmacology》1997,39(4):300-306
Purpose: The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole
has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole
may provide additional benefit in the treatment of colon cancer. Methods: A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose
for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed. Results: A group of 38 patients with incurable etastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU
(375 mg/m2 per day) and leucovorin (200 mg/m2 per day) were administered intravenously (days 1–5). Levamisole was administered orally (days 1–3 and 15–17) at doses from
30 to 470 mg/m2 per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles.
All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia
and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m2 per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses
were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as
evidenced by release of neopterin from monocytes. Conclusion: With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m2. However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate
dose for further phase 11 studies.
Received: 20 October 1995 / Accepted: 16 June 1996 相似文献
4.
乐脉颗粒促进鸡胚绒毛尿囊膜血管的生成 总被引:1,自引:1,他引:1
目的:乐脉颗粒在缺血性心脑血管病的治疗中具有较好的效果,其是否通过促进血管生成而发挥作用还不清楚。观察乐脉颗粒对鸡胚绒毛尿囊膜血管生成的影响。方法:实验于2005-03/08在江西省重点实验室南昌大学第二附属医院分子中心完成。①实验材料:新西兰大白兔8只,体质量2~2.5kg;新鲜白皮种蛋70只,质量50~60g。②实验方法:种蛋在(37.5±0.5)℃条件下孵育,种蛋受精率90%以上。第7天开窗暴露鸡胚绒毛尿囊膜建立鸡胚绒毛尿囊膜模型。将60枚存活鸡胚随机分为生理盐水组、正常血清组、乐脉血清组、内膜损伤血清组、内膜损伤乐脉治疗组以及血管内皮生长因子(20mg/L)组,每组10枚鸡胚。新西兰大白兔腹主动脉用球囊导管损伤建立血管内膜损伤模型,乐脉血清组及内膜损伤乐脉治疗组给予乐脉颗粒25mg/(kg·d)喂饲,各组7d后取血清。第8天,在鸡胚绒毛尿囊膜上放一直径为5mm的滤膜作为载体,分别加样5μL,1次/d,连续3d,③实验评估:第11天取鸡胚绒毛尿囊膜,数码相机拍照后平铺于载玻片上,计数载体周围血管数目及滤膜周围0.5cm范围内的血管分支点数并进行比较。结果:纳入大白兔8只,存活鸡胚60枚,均进入结果分析,无脱落。与正常血清组相比较,乐脉血清组鸡胚绒毛尿囊膜周围血管总数明显增多,血管以载体为中心呈辐辏状生长,差异具有显著性意义(P<0.05);与正常血清组相比较,内膜损伤血清组血清载体周围血管数量明显增多,差异具有极显著性意义(P<0.01);与内膜损伤乐脉治疗组相比较,血管总数差异无显著性。结论:①兔乐脉颗粒血清能够明显促进鸡胚绒毛尿囊膜上血管生成。②血管内膜损伤7d后的血清能够促进鸡胚绒毛尿囊膜上血管生成。 相似文献
5.
Joseph Merchant Kendra Tutsch Amy Dresen Rhoda Arzoomanian Dona Alberti Chris Feierabend Kim Binger Rebecca Marnoccha James Thomas Jim Cleary George Wilding 《Clinical cancer research》2002,8(7):2193-2201
PURPOSE: NSC 655649 was given in both single- and multiple-dose formats, to characterize maximum tolerated dose (MTD), toxicity, and pharmacokinetic profile. Experimental Design: Patients with advanced malignancies were treated with escalating doses of NSC 655649 in either a single-dose format (step 1) or a multiple-dose format (step 2). In step 1, NSC 655649 was given as a 30-60 min infusion. In step 2, the NSC 655649 dose was divided into three consecutive daily doses. Plasma and urine were sampled to assess the pharmacokinetic and excretory characteristics of NSC 655649. A total of 12 patients were enrolled at the MTD for the purpose of gender equity. RESULTS: Forty-three patients were treated with NSC 655649 for a total of 108 cycles in step 1, and 26 patients were treated for a total of 41 cycles in step 2. The MTD for both steps 1 and 2 was determined to be 572 mg/m(2). Myelosuppression was the dose-limiting toxicity. Local venous irritation was generally grade 1-2 in severity but could only be adequately prevented by administration of study drug through central i.v. access. One patient with adenocarcinoma of unknown primary experienced a partial response on step 1. Four patients experienced stable disease of >100 days duration. CONCLUSIONS: NSC 655649 may be safely given at an MTD of 572 mg/m(2) in both single-dose and multiple-dose formats. Optimally, this drug should be administered through central i.v. access. 相似文献
6.
Bailey HH Wilding G Tutsch KD Arzoomanian RZ Alberti D Feierabend C Simon K Marnocha R Holstein SA Stewart J Lewis KA Hohl RJ 《Cancer chemotherapy and pharmacology》2004,54(4):368-376
Purpose Perillyl alcohol (POH) has been shown to have both chemopreventative and chemotherapeutic activities in preclinical studies. The underlying mechanism(s) of action of POH have yet to be delineated but may involve effects on the transforming growth factor (TGF) and/or the Ras signaling pathways. A phase I study of POH for 14 days out of every 28 days in subjects with advanced malignancies was performed to evaluate dose escalation, toxicity, pharmacokinetics, and effects on TGF and Ras.Methods POH was administered orally (500 mg capsules containing 250 mg POH) to 20 patients four times a day on a continuous basis for 14 days followed by a 14-day rest period, for up to three courses. The starting dose was 1200 mg/m2 per dose. A minimum of three patients were treated and evaluated at each escalating POH dose. Pharmacokinetic analysis was performed on days 1 and 14 of course 1 and day 1 of selected later courses. Plasma TGF levels were measured on days 1 and 14. Peripheral blood lymphocyte (PBLs) Ras levels were assayed on days 1 and 2 of the first course.Results The 20 patients, of whom 15 were evaluable, received doses between 1200 and 2000 mg/m2 per dose for a total of 43 courses. The most common observed toxicities were nausea, gastrointestinal distress, and fatigue. Other toxicities included diarrhea or constipation, hypokalemia, and one incidence of acute pancreatitis. Due to these toxicities, four of the patients declined further treatment either during or after the second course. While POH was not detected in plasma, perillic acid (PA) and dihydroperillic acid (DHPA) were detected in plasma, and the peak levels at 2000 mg/m2 per dose were approximately 600 M (PA) and 50 M (DHPA). There was some evidence for linearity in the peak plasma levels and area under the concentration–time curve of the metabolites from the starting dose to the highest dose. Metabolite pharmacokinetics were not significantly affected by ingestion in the fed or fasting state, or repeated exposure to POH. No evidence for an effect of POH on plasma TGF or PBL Ras protein was observed. No objective responses were observed.Conclusions In adults with advanced malignancies, an interrupted administration schedule of POH did not reveal significant advantages over continuous dosing schedules. 相似文献
7.
激光小角光散射仪(LALLS)由于采用了激光光源,具有光强度高、单色性强、准直性好等特点,可以在微量样品池及很低浓度的溶液中进行小角度(3°~7°)散射光强的测量,溶质的瑞利系数与其分子量有如下关系: 相似文献
8.
目的:验证雪灵芝是否具有抑制大鼠肝癌的功效。方法:实验于2003—09/2004—08在广西疾病预防控制中心SPF级动物实验室完成。选用健康成年SD大鼠160只。按体质量分层随机分为5组:空白对照组、模型组、雪灵芝高剂量组、雪灵芝中剂量组和雪灵芝低剂量组,每组32只。雪灵芝高、中、低剂量组大鼠分别灌胃2.500,1.250,0.625mL/kg雪灵芝溶液,阴性对照组和模型组灌胃等量蒸馏水,1次/d,连续60d。第61天开始雪灵芝高、中、低剂量组和模型组灌胃二乙基亚硝胺溶液,对照组灌胃等量的生理盐水。于停止灌胃90d后各组处死一半受试大鼠(雌雄各半),检测血常规及血清主要生化指标,观察各脏器大体形态改变、脏器的癌变程度。1周后给剩余大鼠灌胃雪灵芝溶液(不含二乙基亚硝胺)。7周后处死余下的一半雄性大鼠,进行相同操作。8周后处死余下的全部大鼠,操作及检测方法同前。结果:纳入的160只SD大鼠,145只进入结果分析,15只脱落。①病理切片检查结果:除阴性对照组,其他各组大鼠肝组织均发生癌变或癌前病变。雪灵芝高、中、低剂量组的癌前病变发生率与模型组相近(P〉0.05);癌变的发生率均低于模型组,差异有显著性意义(P〈0.05,0.01)。②大体标本检查结果:阴性对照组大鼠肝脏的大体标本均无异常改变,其他各组大鼠的肝脏有些可见表面粗糙等病理改变。模型组大体标本病理改变的阳性率高于雪灵芝高、中、低剂量组,差异有显著性意义(P〈0.05)。肉眼观模型组癌变发生率高于其他各组。③其他脏器检查结果:模型组2只大鼠有肝癌肺转移。结论:以较大剂量的二乙基亚硝胺连续灌胃30d可以复制大鼠肝癌模型;雪灵芝对二乙基亚硝胺诱导的大鼠肝癌具有预防和抑制的作用。 相似文献
9.
Adverse events and treatment completion for latent tuberculosis in jail inmates and homeless persons 总被引:1,自引:0,他引:1
BACKGROUND: Recently, a short-course treatment using 60 daily doses of rifampin and pyrazinamide was recommended for latent tuberculosis (TB) infection (LTBI). STUDY OBJECTIVES: To determine the acceptability, tolerability, and completion of treatment. DESIGN: Observational cohort study. SETTING: Five county jails and TB outreach clinics for homeless populations in three cities. PATIENTS: Study staff enrolled 1,211 patients (844 inmates and 367 homeless persons). INTERVENTIONS: Sites used 60 daily doses of rifampin and pyrazinamide, an approved treatment regimen for LTBI. MEASUREMENTS: Types and frequency of drug-related adverse events and outcomes of treatment. RESULTS: Prior to treatment, 25 of 1,178 patients (2.1%) had a serum aminotransferase measurement at least 2.5 times the upper limit of normal. Patients who reported excess alcohol use in the past 12 months were more likely than other patients to have an elevated pretreatment serum aminotransferase level (odds ratio, 2.1; 95% confidence interval, 1.1 to 6.1; p = 0.03). Treatment was stopped in 66 of 162 patients (13.4%) who had a drug-related adverse event. Among 715 patients who had serum aminotransferase measured during treatment, 43 patients (6.0%) had an elevation > 5 times the upper limits of normal, including one patient who died of liver failure attributed to treatment. In multivariate analyses, increasing age, an abnormal baseline aspartate aminotransferase level, and unemployment within the past 24 months were independent risk factors for hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%). CONCLUSIONS: This study detected the first treatment-associated fatality with the rifampin and pyrazinamide regimen, prompting surveillance that detected unacceptable levels of hepatotoxicity and retraction of recommendations for its routine use. Completion rates for LTBI treatment using a short-course regimen exceeds historical rates using isoniazid. Efforts to identify an effective short-course treatment for LTBI should be given a high priority. 相似文献
10.