• 【外围定量计算机断层扫描(pQCT)可用于监测接受激素替代疗法的患者的骨矿物质密度。】 复制标题 收藏 收藏
    DOI:10.1016/j.maturitas.2006.08.006 复制DOI
    作者列表:Sawada K,Morishige K,Ohmichi M,Nishio Y,Yamamoto T,Hayakawa J,Mabuchi S,Isobe A,Sasaki H,Sakata M,Tasaka K,Murata Y
    BACKGROUND & AIMS: OBJECTIVE:A forearm fracture (Colles' fracture) is often the first sign of osteoporosis and should alert the patient and physician to the possibility of underlying skeletal fragility. Therefore, the establishment of a more accurate and reliable method for the measurement of bone mineral density (BMD) at the distal radius would be beneficial for the patients who suffer from osteoporosis. The objective of the present study was to evaluate the usefulness of peripheral quantitative computed tomography (pQCT) to assess the change of BMD at the distal radius in early postmenopausal women who receive hormone replacement therapy (HRT). METHODS:Twenty healthy early postmenopausal women who were diagnosed as osteoporosis or osteopenia were randomized to either HRT or placebo treatment. We analyzed BMD of the distal radius by pQCT, lumbar spine by dual-energy X-ray absorptiometry (DXA) and the biochemical markers of bone turn over (osteocalcin, deoxypyridinoline) every 6 months. RESULTS:The placebo group showed a significant decrease from the baseline in the trabecular BMD of the radius at 12 months (7.4+/-2.5%) (p<0.05), whereas the HRT group showed a slight increase (0.7+/-2.2%). The changes in the trabecular BMD of the radius between the HRT and placebo groups were statistically different at 12 months (p<0.05). On the other hand, in the cortical BMD of the radius, no significant differences were seen between the changes of bone densities in the HRT and control groups after 1 year of treatment. pQCT could detect a significant loss of BMD of the radius in early postmenopausal women after 1 year and HRT prevented its loss. CONCLUSION:Our preliminary clinical trial showed that pQCT might be useful for the early detection of bone loss in early postmenopausal women and for the monitoring BMD of the patients who receive HRT.
    背景与目标: 目的:前臂骨折(Colles骨折)通常是骨质疏松症的最初征兆,应提醒患者和医生潜在的骨骼脆弱性。因此,建立一种更准确和可靠的方法来测量远端radius骨的骨矿物质密度(BMD)对于患有骨质疏松症的患者将是有益的。本研究的目的是评估外围定量计算机体层摄影术(pQCT)的有效性,以评估接受激素替代疗法(HRT)的绝经后早期女性远端radius骨BMD的变化。
    方法:将20名被诊断为骨质疏松或骨质减少的健康早期绝经后妇女随机分为HRT或安慰剂治疗组。我们每6个月通过pQCT分析远端the骨的BMD,通过双能X线吸收法(DXA)分析腰椎,并分析骨翻倒的生化标志物(骨钙蛋白,脱氧吡啶并啉)。
    结果:安慰剂组在12个月时the骨小梁BMD较基线显着降低(7.4 /-2.5%)(p <0.05),而HRT组则略有增加(0.7 /-2.2%) 。 HRT组与安慰剂组之间的radius骨小梁BMD变化在12个月时有统计学差异(p <0.05)。另一方面,在治疗1年后,HRT和对照组的骨密度变化在B骨的BMD中没有显着差异。 pQCT可以检测到绝经后早期女性在1年后B骨BMD的显着减少,而HRT可以防止这种情况的发生。
    结论:我们的初步临床试验表明,pQCT可能对早期绝经后妇女的骨丢失早期检测以及监测接受HRT的患者的BMD有用。
  • 【患有严重左心室重构的心脏中的心肌肌钙蛋白I和T改变。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Ricchiuti V,Zhang J,Apple FS
    BACKGROUND & AIMS: Cardiac troponin T (cTnT) and troponin I (cTnI) have been suggested as new, more specific markers of myocardial cellular damage. The objective of this study was to examine how the distributions of cTnI and cTnT were affected in postinfarction left ventricular remodeled (LVR) myocardium. At 2 months postinfarct in a porcine heart failure model, both Western blot and biochemical assay analyses were performed on left ventricular myocardium remote from the infarct zone in ligation animals (n = 8). Results were compared with data from the left ventricular myocardium from similar sized healthy (control) pigs (n = 7). Autoradiograms from Western blot analysis showed that the protein mass for cTnI and cTnT in LVR hearts decreased 80% (P < 0.001) and 40% (P < 0.02), respectively, when compared with nondiseased tissue. Similarly, the concentrations for cTnI and cTnT in LVR hearts decreased 42% (P < 0.05) and 70% (P < 0.001), respectively, compared with nondiseased normal tissue. The clinical assumption is that the appearance of cTnI and cTnT in the blood is proportional to chronic loss of cTnI and cTnT from injured myocardium associated with left ventricular remodeling.

    背景与目标: 心肌肌钙蛋白T(cTnT)和肌钙蛋白I(cTnI)被认为是心肌细胞损伤的新的,更具体的标志物。这项研究的目的是检查梗死后左心室重构(LVR)心肌中cTnI和cTnT的分布如何受到影响。在猪心力衰竭模型中梗死后2个月,在结扎动物中,对远离梗死区的左心室心肌进行了Western blot和生化分析(n = 8)。将结果与来自类似大小的健康(对照)猪(n = 7)的左心室心肌的数据进行比较。 Western blot分析的放射自显影照片显示,与未患病的组织相比,LVR心脏中cTnI和cTnT的蛋白质质量分别降低了80%(P <0.001)和40%(P <0.02)。同样,与未患病的正常组织相比,LVR心脏中cTnI和cTnT的浓度分别降低了42%(P <0.05)和70%(P <0.001)。临床假设是血液中cTnI和cTnT的出现与左心室重构相关的心肌损伤导致cTnI和cTnT的慢性丧失成比例。

  • 【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。

  • 【肿瘤进展-差异治疗的目标。】 复制标题 收藏 收藏
    DOI:10.1002/jcp.20728 复制DOI
    作者列表:Pardee AB
    BACKGROUND & AIMS: :Differential killing of the patient's cancer cells versus normal cells is a necessity for chemotherapy. Advantage can be taken of close regulations of gene expression and of enzyme activity that are essential for normal cell functioning, and that are altered during tumor progression. Summarized here is our research on four such progression changes of cancer cells; some deregulate proliferation control and others decrease programmed death (apoptosis). These processes will be illustrated with examples of potential chemotherapies based on them. Methods for discovery of such changes include Differential Display and microarrays.
    背景与目标: :与正常细胞相比,不同程度地杀死患者的癌细胞是化疗的必要条件。可以利用基因表达和酶活性的紧密调节,这些调节对于正常的细胞功能是必不可少的,并且在肿瘤进展过程中会改变。这里总结了我们对癌细胞的四个这样的进展变化的研究。一些人放松了对增殖的控制,而另一些人减少了程序性死亡(细胞凋亡)。这些过程将以基于它们的潜在化学疗法为例进行说明。发现这种变化的方法包括差异显示和微阵列。
  • 【当代心肌梗塞溶栓治疗后出血的发生率和预测因素。闭塞性冠状动脉(GUSTO)I研究者的链激酶和组织纤溶酶原激活剂的全球利用。】 复制标题 收藏 收藏
    DOI:10.1161/01.cir.95.11.2508 复制DOI
    作者列表:Berkowitz SD,Granger CB,Pieper KS,Lee KL,Gore JM,Simoons M,Armstrong PW,Topol EJ,Califf RM
    BACKGROUND & AIMS: BACKGROUND:Although the benefit of thrombolytic therapy in reducing mortality in acute myocardial infarction is well established, the types of bleeding and risk factors for bleeding are less well described in large trials.

    METHODS AND RESULTS:We analyzed the baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment assignment among 41,021 patients in the GUSTO-I trial of thrombolysis for acute myocardial infarction. Of the 40,903 patients for whom there were complete data, 1.2% suffered severe bleeding and 11.4% experienced moderate hemorrhage at a variety of sites. The most common sources of bleeding were procedure related. The thrombolytic regimen was strongly related to the incidence of bleeding; comparatively more bleeding was seen with the therapies of streptokinase plus intravenous heparin and the streptokinase and tissue plasminogen activator plus intravenous heparin combination. In multivariate analysis, the four most powerful independent predictors of hemorrhage were older age, lighter body weight, female sex, and African ancestry; they remained the most important predictors of bleeding when multivariate analysis was performed on patients who did not undergo invasive procedures. The presence of serious hemorrhage was associated with other undesirable outcomes (recurrent events, left ventricular dysfunction, arrhythmia, or stroke).

    CONCLUSIONS:Important predictors of bleeding in this population are increased age, lighter weight, female sex, African ancestry, and experiencing invasive procedures. Other nonhemorrhagic adverse clinical outcomes were associated with moderate and severe bleeding, which was in turn associated with increased length of hospital stay and mortality at 30 days.

    背景与目标: 背景:尽管溶​​栓治疗在降低急性心肌梗死死亡率方面的益处已广为人知,但在大型试验中对出血的类型和出血的危险因素的描述却很少。

    < strong>方法和结果:我们在GUSTO-I急性心肌梗塞溶栓试验的GUSTO-I试验中,对41,021例患者的基线特征,结局和出血发生率,位置,严重程度和治疗方案进行了分析。在有完整数据的40,903名患者中,有1.2%出现严重出血,11.4%的患者在不同部位出现中度出血。最常见的出血来源与手术有关。溶栓方案与出血发生率密切相关。链激酶加静脉肝素,链激酶和组织纤溶酶原激活剂加肝素联合治疗的出血量相对较多。在多变量分析中,出血的四个最有力的独立预测因子是年龄大,体重轻,女性和非洲血统。当对未进行侵入性治疗的患者进行多变量分析时,它们仍然是出血的最重要预测指标。严重出血的存在与其他不良后果(复发事件,左心室功能障碍,心律不齐或中风)相关。

    结论:该人群出血的重要预测因素是年龄增加,体重减轻,女性性别,非洲血统和经历侵入性程序。其他非出血性不良临床预后与中度和重度出血有关,这又与住院天数的延长和30天病死率有关。

  • 【接受腹膜内光动力疗法的患者的肿瘤和正常组织中的光敏蛋白摄取。】 复制标题 收藏 收藏
    DOI:10.1158/1078-0432.CCR-06-0953 复制DOI
    作者列表:Hahn SM,Putt ME,Metz J,Shin DB,Rickter E,Menon C,Smith D,Glatstein E,Fraker DL,Busch TM
    BACKGROUND & AIMS: PURPOSE:A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues. EXPERIMENTAL DESIGN:Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models. RESULTS:Photofrin concentration was measured in 301 samples collected from 58 of 100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P<0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P=0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31 ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (
    背景与目标: 目的:Photofrin介导的i.p.的II期临床试验。先前报告中显示的光动力疗法疗效有限,且具有明显的急性毒性,但非慢性毒性。该试验和本报告主题的第二个目的是确定肿瘤和正常组织中的光敏蛋白摄取量。
    实验设计:患者在减容手术前48小时接受静脉注射2.5 mg / kg的Photofrin。通过分光光度法对从肿瘤和手术中切除的正常组织中提取的药物进行分光光度法分析来测量光蛋白的摄取。使用混合效应模型从统计学上考虑了这些组织之间的药物吸收差异。
    结果:在从该试验的100名患者中的58名患者中收集的301个样品中测量了光敏蛋白的浓度。在正常组织中,药物吸收显着不同(P <0.0001),是七种不同组织类型的函数。在肠道毒性限制组织中,全厚度大肠和小肠中基于模型的平均(SE)Photofrin水平分别为2.70 ng / mg(0.32 ng / mg)和3.42 ng / mg(0.24 ng / mg),分别。在肿瘤中,药物摄取随患者队列的不同而有显着差异(P = 0.0015):卵巢癌,胃癌或小肠癌患者中基于模型的平均Photofrin水平为3.32至5.31 ng / mg。肉瘤,阑尾或结肠癌患者中2.09至2.45 ng / mg;假性粘液瘤患者为0.93 ng / mg。与全厚度大肠和/或小肠相比,卵巢癌,胃癌和小肠癌的Photofrin摄取量明显更高。然而,肿瘤与肠道中平均药物水平的比率是中等的(<或= 2.31)。
    结论:在肿瘤与腹膜腔正常组织之间的光敏蛋白吸收中发现了一些选择性,但是相对于毒性受限的正常组织(肠)而言,药物吸收的绝对差异很小。先前已经报道过,药物选择性的这种狭窄差异可能导致治疗应用中的狭窄窗口。
  • 【在空肠弯曲杆菌感染的鸡中口服抗体预防和治疗。】 复制标题 收藏 收藏
    DOI:10.1046/j.1365-2249.1997.3901288.x 复制DOI
    作者列表:Tsubokura K,Berndtson E,Bogstedt A,Kaijser B,Kim M,Ozeki M,Hammarström L
    BACKGROUND & AIMS: :Passive immunity against gastrointestinal infections has recently been successfully applied as prophylaxis and therapy in patients in a variety of virally and bacterially induced infections. Campylobacter jejuni is frequently associated with acute diarrhoea in humans, and several species of animals have been shown to transmit the disease, although birds have been implicated as the main source of infection. We used bovine and chicken immunoglobulin preparations from the milk and eggs, respectively, of immunized animals for prophylactic and therapeutic treatment of chickens infected with C. jejuni. A marked prophylactic effect (a >99% decrease in the number of bacteria) was noted using either antibody preparation, whereas the therapeutic efficacy, i.e. when antibodies were given after the infection was established, was distinctly lower (80-95%) as judged by faecal bacterial counts. These observations may serve as a starting point for experiments aimed at elimination of the infection in an industrial or farm setting. It may also encourage future attempts to treat, prophylactically or therapeutically, patients with Campylobacter-induced diarrhoea.
    背景与目标: :最近,针对胃肠道感染的被动免疫已成功应用于各种病毒和细菌引起的感染的预防和治疗中。空肠弯曲菌经常与人类急性腹泻有关,尽管鸟类被认为是主要的感染源,但已显示出几种动物可传播这种疾病。我们分别使用免疫动物的牛奶和鸡蛋中的牛和鸡免疫球蛋白制剂对空肠弯曲杆菌感染的鸡进行预防和治疗。两种抗体制剂均具有显着的预防作用(细菌数量减少> 99%),而判断的治疗效果(即在感染确定后给予抗体)则明显较低(80-95%)通过粪便细菌计数。这些观察结果可作为旨在消除工业或农场感染的实验的起点。它还可能鼓励将来尝试预防性或治疗性弯曲杆菌引起的腹泻患者。
  • 【接受高活性抗逆转录病毒疗法治疗的替诺福韦富马酸二甲氧呋辛酯(TDF)暴露和TDF未暴露的HIV感染门诊患者的低血磷评估。】 复制标题 收藏 收藏
    DOI:10.1111/j.1468-1293.2006.00407.x 复制DOI
    作者列表:Buchacz K,Brooks JT,Tong T,Moorman AC,Baker RK,Holmberg SD,Greenberg A,HIV Outpatient Study (HOPS) Investigators.
    BACKGROUND & AIMS: OBJECTIVES:Cases of hypophosphataemia (often coincident with renal dysfunction) have been reported in HIV-infected patients taking tenofovir disoproxil fumarate (TDF), but randomized placebo-controlled trials of HIV-infected persons with normal baseline renal function have found a comparable incidence of hypophosphataemia in the TDF and placebo groups. We assessed the incidence of grade 2 and higher hypophosphataemia in the HIV Outpatient Study (HOPS). METHODS:We analysed a prospective cohort of patients who initiated either a TDF-containing highly active antiretroviral therapy (HAART) regimen [TDF-exposed (TDF+) group; n = 165] or a TDF-sparing HAART regimen [TDF-unexposed (TDF-) group; n = 90], and who had normal baseline phosphate and creatinine values. RESULTS:The TDF+ and TDF- groups had comparable median follow-up times (10.9 vs 8.8 months, respectively; P = 0.18) and number of phosphate measurements (median = 3 for both) and were similar on most clinical and demographic factors. During follow up, 12.7% of TDF+vs 6.7% of TDF-patients developed grade 2 hypophosphataemia (2.0-2.4 mg/dL), and 2.4% of TDF+ patients vs 0% of TDF-patients developed grade 3 hypophosphataemia (1.0-1.9 mg/dL); none developed grade 4 hypophosphataemia (<1.0 mg/dL). The incidence of grade 2 or higher hypophosphataemia was 16.7 per 100 person-years among TDF+ patients vs 8.0 per 100 person-years among TDF-patients (P = 0.11). CONCLUSIONS:The incidence of hypophosphataemia was somewhat elevated in HOPS patients who took TDF-containing HAART compared with those who took TDF-sparing HAART during the first 1 to 2 years of observation, but the difference was not statistically significant. Longer follow-up of a larger population is needed to determine if this trend towards an association achieves statistical significance and to evaluate the clinical consequences of hypophosphataemia.
    背景与目标: 目的:已经报道了接受替诺福韦二富马酸富马酸酯(TDF)感染HIV的患者发生低磷酸盐血症(通常与肾功能不全)的情况,但是对基线肾功能正常的HIV感染者进行的安慰剂对照随机试验发现TDF和安慰剂组的低磷血症。我们在HIV门诊研究(HOPS)中评估了2级和更高水平的低血磷的发生率。
    方法:我们分析了开始采用含TDF的高活性抗逆转录病毒疗法(HAART)方案[TDF暴露(TDF)组)的患者的前瞻性队列研究。 n = 165]或保留TDF的HAART方案[未暴露TDF(TDF-)的组; n = 90],并且基线磷酸盐和肌酐值正常。
    结果:TDF和TDF-组的中位随访时间(分别为10.9和8.8个月; P = 0.18)和磷酸盐测量次数(两者的中位数= 3)具有可比性,并且在大多数临床和人口统计学因素上相似。在随访期间,TDF的12.7%vs TDF的患者为6.7%发生了2级低血磷(2.0-2.4 mg / dL),TDF的2.4%vs TDF的患者为0%发生了3级低血磷(1.0-1.9 mg / dL);没有一个发生4级低血磷(<1.0 mg / dL)。 TDF患者中2级或更高水平低血磷的发生率为每100人年16.7人,而TDF患者为每100人年8.0人(P = 0.11)。
    结论:在观察的头1至2年中,与含TDF的HAART的HOPS患者相比,接受含TDF的HAART的HOPS患者的低磷酸盐血症发生率有所升高,但差异无统计学意义。需要对更大的人群进行更长时间的随访,以确定这种联系趋势是否达到统计学意义并评估低血磷的临床后果。
  • 【使用CT,EUS和FDG-PET进行新辅助治疗的反应监测。】 复制标题 收藏 收藏
    DOI:10.1016/j.bpg.2006.04.004 复制DOI
    作者列表:Sloof GW
    BACKGROUND & AIMS: :Neoadjuvant or adjuvant multimodality therapy in oesophageal cancer is introduced in an effort to improve prognosis. However, in a substantial fraction of patients there is no response to this non-surgical therapy. Non-invasive imaging modalities such as computed tomography (CT), endoscopic ultrasound (EUS) and 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) have been evaluated for assessing patient response to therapy, and these are described in this review. Currently, FDG-PET seems to be the best available tool for neoadjuvant therapy response assessment in oesophageal cancer.
    背景与目标: :在食管癌中引入新辅助或辅助多模治疗以改善预后。但是,在相当一部分患者中,对这种非手术疗法没有任何反应。已评估了计算机断层扫描(CT),内窥镜超声(EUS)和18F-2-氟-2-脱氧-d-葡萄糖正电子发射断层扫描(FDG-PET)等非侵入性成像方式,以评估患者对治疗的反应,并在这篇评论中对此进行了描述。目前,FDG-PET似乎是食管癌新辅助治疗反应评估的最佳可用工具。
  • 【利妥昔单抗-CHOP-ESHAP与CHOP-ESHAP-高剂量治疗与常规CHOP化疗治疗高中度和高风险的侵袭性非霍奇金淋巴瘤。】 复制标题 收藏 收藏
    DOI:10.1080/10428190500525656 复制DOI
    作者列表:Intragumtornchai T,Bunworasate U,Nakorn TN,Rojnuckarin P
    BACKGROUND & AIMS: :With currently available combination chemotherapy regimens, the outcome of the patients newly diagnosed with aggressive non-Hodgkin's lymphoma (NHL) identified as 'high' and 'high-intermediate' risk groups according to the international prognostic index (IPI) is still unsatisfactory and a more innovative therapy is urgently required to improve the survival of the patients. The purpose of this study was to compare the efficacy of rituximab given in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and ESHAP (etoposide, methylprednisolone, high-dose Ara-C, cisplatin) vs CHOP-ESHAP and upfront high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) vs standard CHOP in patients aged < or = 65 years old newly diagnosed with 'high' and 'high-intermediate' risk aggressive lymphoma enrolled onto two consecutive treatment trials at the institute. Between May 1995 - July 2002, 84 patients, aged 15 - 65 years old, with newly diagnosed aggressive NHL and an age-adjusted IPI of 2 or 3 were enrolled. The median age of the patients was 38 years (range 15 - 65). The baseline demographic features, in particular the major prognostic variables, were similar between the treatment groups. Patients treated with rituximab-CHOP-ESHAP received eight cycles of rituximab (375 mg m(-2) on day 1 of cycles 1 - 6 and days 21 and 28 of cycle 7) plus CHOP (day 3 of cycles 1, 3 and 5) and ESHAP (day 3 of cycles 2, 4 and 6 and day 1 of cycle 7) at 21-day intervals. Patients enrolled onto the CHOP-ESHAP-HDT arm (n = 23) were treated with three courses of CHOP and then switched to two or four cycles of ESHAP followed by HDT. Patients treated with CHOP alone (n = 25) were treated with the standard eight cycles of CHOP. The rate of complete remission was significantly improved with rituximab-CHOP-ESHAP compared with either CHOP-ESHAP-HDT or CHOP alone (67% compared with 44% and 36%, respectively; p = 0.043). With a median follow-up time of 53 months, the 5-year overall survival (OS) was improved by the addition of rituximab-61% with rituximab-CHOP-ESHAP, compared with 43% for CHOP-ESHAP-HDT and 24% for CHOP alone (p = 0.088). Significant increases in failure-free survival (FFS) and disease-free survival (DFS) (61% and 96%), compared with CHOP-ESHAP-HDT (34% and 90%) and CHOP (16% and 44%; p = 0.002 and p < 0.001, respectively) were observed. Compared to CHOP, rituximab-CHOP-ESHAP yielded significantly superior OS (p = 0.014), FFS (p < 0.001) and DFS (p < 0.001). The survivals, however, were not significantly different from patients treated with CHOP-ESHAP-HDT. It is concluded that rituximab-ESHAP-CHOP is superior over standard CHOP and fares comparably to upfront HDT/ASCT in previously untreated patients with aggressive lymphoma. A prospective randomized controlled trial is warranted to confirm these results.
    背景与目标: :在目前可用的联合化疗方案下,根据国际预后指数(IPI)刚被诊断为侵袭性非霍奇金淋巴瘤(NHL)的患者的预后仍然不尽人意,并且迫切需要一种更具创新性的疗法来提高患者的生存率。这项研究的目的是比较利妥昔单抗与CHOP(环磷酰胺,阿霉素,长春新碱,泼尼松)和ESHAP(依托泊苷,甲基泼尼松龙,大剂量Ara-C,顺铂)联合使用时与CHOP-ESHAP和前期高剂量联合治疗的疗效在该研究所进行的两项连续治疗试验中,对新诊断为“高”和“高中度”风险性侵袭性淋巴瘤的年龄≤65岁的患者进行剂量治疗(HDT)和自体干细胞移植(ASCT)与标准CHOP对照。在1995年5月至2002年7月之间,纳入了84例年龄在15至65岁之间,新诊断为侵袭性NHL且年龄校正后的IPI为2或3的患者。患者的中位年龄为38岁(范围15-65)。治疗组之间的基线人口统计学特征,尤其是主要的预后变量相似。接受利妥昔单抗-CHOP-ESHAP治疗的患者接受了八个周期的利妥昔单抗(第1-6周期的第1天以及第7周期的第21和28天)(375 mg m(-2))加CHOP(第1、3和5周期的第3天) )和ESHAP(周期2、4和6的第3天和周期7的第1天),间隔为21天。入组CHOP-ESHAP-HDT组(n = 23)的患者接受了三个疗程的CHOP治疗,然后切换到ESSHAP的两个或四个周期,然后进行HDT。单独接受CHOP治疗的患者(n = 25)接受了标准的八个CHOP周期治疗。与单独使用CHOP-ESHAP-HDT或CHOP相比,利妥昔单抗-CHOP-ESHAP的完全缓解率显着提高(分别为67%,44%和36%; p = 0.043)。中位随访时间为53个月,利妥昔单抗-CHOP-ESHAP加利妥昔单抗-61%改善了5年总生存(OS),相比之下,CHOP-ESHAP-HDT和43%改善了5年总生存率仅适用于CHOP(p = 0.088)。与CHOP-ESHAP-HDT(34%和90%)和CHOP(16%和44%)相比,无失败生存率(FFS)和无病生存率(DFS)显着增加(61%和96%);分别观察到= 0.002和p​​ <0.001)。与CHOP相比,利妥昔单抗-CHOP-ESHAP产生显着优越的OS(p = 0.014),FFS(p <0.001)和DFS(p <0.001)。但是,其存活率与用CHOP-ESHAP-HDT治疗的患者无明显差异。结论是,对于以前未经治疗的侵袭性淋巴瘤患者,利妥昔单抗-ESHAP-CHOP优于标准CHOP,且其费用可与前期HDT / ASCT相提并论。必须进行前瞻性随机对照试验来证实这些结果。
  • 【白色念珠菌myristoylCoA的选择性肽和拟肽抑制剂:蛋白N-肉豆蔻酰基转移酶:一种抗真菌治疗的新方法。】 复制标题 收藏 收藏
    DOI:10.1002/(SICI)1097-0282(1997)43:1<43::AID-BIP5>3.0 复制DOI
    作者列表:Sikorski JA,Devadas B,Zupec ME,Freeman SK,Brown DL,Lu HF,Nagarajan S,Mehta PP,Wade AC,Kishore NS,Bryant ML,Getman DP,McWherter CA,Gordon JI
    BACKGROUND & AIMS: MyristoylCoA:protein N-myristoyltransferase (NMT) catalyzes the cotranslational covalent attachment of a rare cellular fatty acid, myristate, to the N-terminal Gly residue of a variety of eukaryotic proteins. The myristoyl moiety is often essential for expression of the biological functions for these proteins.

    Attachment of C14:0 alone provides barely enough hydrophobicity to allow stable association with membranes. The partitioning of N-myrisotylproteins is therefore often modulated by "switches" that function through additional covalent or noncovalent modifications. Candida albicans, the principal cause of systemic fungal infection in immunocompromised humans, contains a single NMT gene that is essential for its viability. The functional properties of the acylCoA binding site of human and C. albicans NMT are very similar. However, there are distinct differences in their peptide binding sites. An ADP ribosylation factor (Arf) is included among the few cellular protein substrates of the fungal enzyme. Alanine scanning mutagenesis of an octapeptide derived from an N-terminal Arf sequence (GLYASKLS-NH2) disclosed that Gly1, Ser5, and Lys6 play predominant roles in binding. ALYASKLS-NH2 is an inhibitor competitive for peptide [Ki(app) = 15.3 +/- 6.4 microM] and noncompetitive for myristoylCoA. Remarkably, replacement of the N-terminal tetrapeptide with an 11-aminoundecanoyl group results in a competitive inhibitor (11-aminoundecanoyl-SKLS-NH2) that is approximately 40-fold more potent [Ki(app) = 0.40 +/- 0.03 microM] than the starting octapeptide. Removal of Leu-Ser from the C-terminus generates a competitive dipeptide inhibitor (11-aminoundecanoyl-SK-NH2) with a Ki(app) of 11.7 +/- 0.4 microM, equivalent to that of the starting octapeptide. A derivative dipeptide inhibitor containing a C-terminal N-cyclohexylethyl lysinamide moiety has the advantage of being more potent (IC50 = 0.11 +/- 0.03 microM) and resistant to digestion by cellular carboxypeptidases. Rigidifying the flexible aminoundecanoyl chain results in very potent general NMT inhibitors (IC50 = 40-50 nM). Substituting a 2-methylimidazole for the N-terminal amine and adding a benzylic alpha-methyl group with R stereochemistry to the rigidifying element produces even more potent inhibitors (IC50 = 20-50 nM) that are up to 500-fold selective for the fungal compared to human enzyme. A related less potent member of this series of compounds is fungistatic. Its growth inhibitory effects are associated with a reduction in cellular protein N-myristoylation, judged using cellular Arf as a reporter. These studies establish that NMT is a new antifungal target.

    背景与目标: MyristoylCoA :蛋白N-肉豆蔻酰基转移酶(NMT)催化稀有细胞脂肪酸肉豆蔻酸酯与多种真核蛋白N-末端Gly残基的共翻译共价连接。肉豆蔻酰基部分通常对于表达这些蛋白质的生物学功能是必不可少的。

    仅C14 :0的附件仅提供了不足以使与膜稳定结合的疏水性。因此,N-肉豆蔻酰蛋白的分区通常由通过附加的共价或非共价修饰起作用的“开关”调节。白色念珠菌是免疫力低下的人体内全身真菌感染的主要原因,它包含一个对其生存能力至关重要的单个NMT基因。人和白色念珠菌NMT的酰基辅酶A结合位点的功能特性非常相似。但是,它们的肽结合位点存在明显差异。 ADP核糖基化因子(Arf)包括在真菌酶的几种细胞蛋白底物中。来自N末端Arf序列(GLYASKLS-NH2)的八肽的丙氨酸扫描诱变显示,Gly1,Ser5和Lys6在结合中起主要作用。 ALYASKLS-NH2是一种对肽[Ki(app)= 15.3 /-6.4 microM]具有竞争性的抑制剂,对肉豆蔻酰辅酶A不具有竞争性。值得注意的是,用11-氨基十一烷酰基取代N末端四肽会产生竞争性抑制剂(11-氨基十一烷酰基-SKLS-NH2),其效力比[Ki(app)= 0.40 /-0.03 microM]高40倍左右。起始八肽。从C末端去除Leu-Ser会产生竞争性的二肽抑制剂(11-氨基十一烷酰基-SK-NH2),Ki(app)为11.7 /-0.4 microM,与起始八肽相当。含有C-末端N-环己基乙基赖氨酰胺部分的衍生物二肽抑制剂具有更有效的优势(IC 50 = 0.11 /0.03μM),并且对细胞羧肽酶的消化具有抵抗力。刚性化柔性氨基十一烷酰基链会产生非常有效的常规NMT抑制剂(IC50 = 40-50 nM)。用2-甲基咪唑代替N端胺,并在刚性元素中添加具有R立体化学的苄基α-甲基,可产生更强效的抑制剂(IC50 = 20-50 nM),对真菌的选择性高达500倍与人类酶相比。该系列化合物的一个相关的效力较弱的成员是抑真菌的。使用细胞Arf作为报告基因判断,其生长抑制作用与细胞蛋白N-肉豆蔻酰化的减少有关。这些研究确定NMT是一种新的抗真菌靶标。

  • 【辐射诱发的旁观者和其他非靶向效应:癌症治疗中的新干预点?】 复制标题 收藏 收藏
    DOI:10.2174/156800906777723976 复制DOI
    作者列表:Mothersill C,Seymour C
    BACKGROUND & AIMS: :A major problem in the search for new cancer drug targets is that the drugs are often toxic to normal tissues and require high doses to kill tumor cells. Therefore cellular targets which appear to involve low dose responses to cancer therapy are especially interesting since they could selectively target normal tissues which are not targeted by the treatment and thus may be responsible for unpleasant side effects or may be amenable to exploitation in order to improve the therapeutic ratio. One such target, which is the subject of this review, is radiation-induced bystander effects [RIBE], which result in the observation of radiation like responses in cells which have not been irradiated. RIBE is a novel phenomenon which indicates that at low doses, cell signaling is more important than direct DNA damage. Historically, DNA has always been considered to be the target for radiation therapy. The growing realization that signaling is important opens up several important therapeutic strategies which will be discussed in this review. RIBE appears to be the result of a generalized stress response in tissues or cells which is expressed at the level of the tissue, organ or organism rather than at the level of the individual cell. The signals may be produced by all exposed cells, but the response may require a quorum of cells in order to be expressed. The major response involving low LET (x- or gamma-ray) radiation exposure discussed in the existing literature is a death response. This has many characteristics of apoptosis but may be detected in cell lines without p53 expression, although the death response is suppressed in many tumor cell lines. While a death response in unirradiated normal cells around a tumor might appear to be adverse, it can in fact be protective and remove damaged cells from the population. If harnessed correctly, it could lead to the development of new drugs aimed not at tissue destruction but at enabling homeostatic mechanisms to control tumor expansion. In this scenario, the level of harmful or beneficial response will be related to the background damage, carried by the cell population, and the genetic programme determining response to damage. This focus may be important when attempting to predict the consequences of mixed therapies involving radiation and other cytotoxic agents. In this review, our current knowledge of the mechanisms underlying the induction of bystander effects by ionizing radiation is reviewed, and the question of how bystander effects may be harnessed to produce a new generation of anti-cancer drugs aimed at stabilization of tissue homeostasis rather than tissue destruction is considered.
    背景与目标: :寻找新的癌症药物靶标的主要问题是该药物通常对正常组织有毒性,需要高剂量才能杀死肿瘤细胞。因此,细胞靶标似乎涉及对癌症治疗的低剂量反应,因此特别令人感兴趣,因为它们可以选择性地靶向未被治疗靶标的正常组织,因此可能引起令人不快的副作用,或者可能适合于剥削以改善治疗效果。治疗比率。辐射诱导的旁观者效应[RIBE]是本综述的主题之一,该效应导致在未辐射的细胞中观察到辐射样反应。 RIBE是一种新现象,表明在低剂量时,细胞信号传导比直接DNA损伤更为重要。从历史上看,DNA一直被认为是放射治疗的目标。人们日益认识到信号转导很重要,这开启了几种重要的治疗策略,本文将对此进行讨论。 RIBE似乎是组织或细胞中普遍的应激反应的结果,这种应激反应是在组织,器官或生物体的水平而不是单个细胞的水平表达的。信号可能由所有暴露的细胞产生,但响应可能需要一定数量的细胞才能表达。现有文献中讨论的涉及低LET(X射线或γ射线)辐射暴露的主要反应是死亡反应。这具有许多细胞凋亡特征,但尽管在许多肿瘤细胞系中死亡反应受到抑制,但在没有p53表达的细胞系中可能检测到。虽然在肿瘤周围未辐射的正常细胞中的死亡反应似乎是不利的,但实际上可以起到保护作用,并从群体中清除受损的细胞。如果利用得当,它可能会导致开发新药物,其目的不是破坏组织,而是使稳态机制能够控制肿瘤的扩展。在这种情况下,有害或有益反应的水平将与细胞群体所携带的背景损伤以及决定对损伤的反应的遗传程序有关。当试图预测涉及放射线和其他细胞毒剂的混合疗法的后果时,这一重点可能很重要。在这篇综述中,我们对电离辐射诱发旁观者效应的潜在机制的现有知识进行了综述,并探讨了如何利用旁观者效应来生产旨在稳定组织稳态而不是稳定组织的新一代抗癌药物的问题。考虑组织破坏。
  • 【肌营养不良症的遗传修饰因子:对治疗的意义。】 复制标题 收藏 收藏
    DOI:10.1016/j.bbadis.2006.06.013 复制DOI
    作者列表:Heydemann A,Doherty KR,McNally EM
    BACKGROUND & AIMS: :The genetic understanding of the muscular dystrophies has advanced considerably in the last two decades. Over 25 different individual genes are now known to produce muscular dystrophy, and many different "private" mutations have been described for each individual muscular dystrophy gene. For the more common forms of muscular dystrophy, phenotypic variability can be explained by precise mutations. However, for many genetic mutations, the presence of the identical mutation is associated with marked phenotypic range that affects muscle function as well as cardiac function. The explanation for phenotype variability in the muscular dystrophies is only now being explored. The availability of genetically engineered animal models has allowed the generation of single mutations on the background of highly inbred strain. Phenotypic variation that is altered by genetic background argues for the presence of genetic modifier loci that can ameliorate or enhance aspects of the dystrophic phenotype. A number of individual genes have been implicated as modifiers of muscular dystrophy by studies in genetically engineered mouse models of muscular dystrophy. The value of these genes and products is that the pathways identified through these experiments may be exploited for therapy.
    背景与目标: 在过去的二十年中,人们对肌肉营养不良的遗传学认识有了很大的提高。现在已知产生肌营养不良症的超过25个不同的个体基因,并且对于每个个体肌营养不良症基因已经描述了许多不同的“私人”突变。对于更常见的肌肉营养不良形式,表型变异性可以通过精确的突变来解释。然而,对于许多遗传突变,相同突变的存在与影响肌肉功能以及心脏功能的显着表型范围有关。肌肉营养不良症的表型变异性的解释目前才被探索。基因工程动物模型的可用性允许在高度近交系的背景下产生单个突变。由遗传背景改变的表型变异主张存在可以改善或增强营养不良表型方面的遗传修饰基因座。通过对肌营养不良症的基因工程小鼠模型的研究,许多个体基因被认为是肌营养不良症的修饰因子。这些基因和产物的价值在于通过这些实验确定的途径可用于治疗。
  • 【多达三分之一的心脏病患者的干预后生活质量下降。】 复制标题 收藏 收藏
    DOI:10.1080/14017430600784343 复制DOI
    作者列表:Hawkes AL,Mortensen OS
    BACKGROUND & AIMS: OBJECTIVE:To investigate clinically relevant intra-individual and mean changes in health-related quality of life (HRQoL) with the Short Form-36 Health Survey (SF-36) need to acknowledge that SF-36 is trademarked ie: SF-36(R) following cardiac intervention for Australian and Danish patients. DESIGN:Prospective observational study in tertiary cardiac centres in Townsville, Queensland, Australia and Copenhagen, Denmark. Two hundred coronary artery bypass graft surgery (CABG) patients of two Townsville hospitals, and 47 CABG or percutaneous coronary intervention (PCI) patients of a Copenhagen hospital. The main outcome measures are eight SF-36 health subscales at baseline and six months post-intervention. RESULTS:Australian and Danish patients experienced similar HRQoL pre-intervention. By six months post-intervention, patients experienced a significant mean improvement in all subscales of the SF-36 survey (p < or = 0.05), although up to 27% of patients had a clinically significant decline in HRQoL from baseline. CONCLUSIONS:These results demonstrate that it is necessary to investigate intra-individual changes in HRQoL as well as group mean changes as they produce different conclusions. In addition, establishing clinically significant intra-individual change standards may assist researchers and clinicians in determining whether an individual may benefit from therapy or intervention.
    背景与目标: 目的:要通过36型健康调查(SF-36)调查与健康相关的生活质量(HRQoL)的临床相关个人和平均变化,需要承认SF-36是商标,即:SF-36( R)对澳大利亚和丹麦患者进行心脏干预后。
    设计:在澳大利亚昆士兰州汤斯维尔和丹麦哥本哈根的三级心脏中心进行前瞻性观察研究。两家汤斯维尔医院的200例冠状动脉搭桥术(CABG)患者,以及哥本哈根医院的47例CABG或经皮冠状动脉介入治疗(PCI)患者。主要结果指标是基线时和干预后六个月的八个SF-36健康子量表。
    结果:澳大利亚和丹麦患者经历了类似的HRQoL干预前。干预后六个月,患者在SF-36调查的所有子量表中均经历了显着的平均改善(p <或= 0.05),尽管高达27%的患者的HRQoL与基线相比有临床上的显着下降。
    结论:这些结果表明,有必要研究HRQoL的个体内部变化以及群体均值变化,因为它们会产生不同的结论。此外,建立具有临床意义的个体内部变更标准可能有助于研究人员和临床医生确定个人是否可以从治疗或干预中受益。
  • 【麻醉师术前评估心输出量储备和输血可能性的差异:一项前瞻性研究。】 复制标题 收藏 收藏
    DOI:10.1177/0310057X0603400407 复制DOI
    作者列表:Harrison MJ
    BACKGROUND & AIMS: :The aim of this pilot study was to investigate anaesthetists' assessment of the ability of patients to increase cardiac output over a range of clinical scenarios and of their perceived 'likelihood of transfusion' in these scenarios. Specialist anaesthetists were given a questionnaire with clinical cues in the form of diagnoses about theoretical patients. They were asked to use 100 mm visual analogue scales (VAS) for their assessments of each patient's cardiac reserve and their 'likelihood of transfusion' of these patients; the endpoints of the VAS being 'Very low' (0 mm) to 'High' (100 mm), and 'Do not transfuse' (0 mm) to 'Transfuse' (100 mm) respectively. The assessment of patients' cardiac output reserve by anaesthetists (n = 54) showed great variation; for example, a patient with severe aortic stenosis was perceived overall to have a limited ability to increase cardiac output (mean VAS 16 mm) but there was considerable variation between anaesthetists (25-75 percentiles 10 mm to 21 mm). Assessment of 'likelihood of transfusion' (n = 42) also had great variation; as an example a patient with 'angina' with a haemoglobin of 95 g l(-1) was perceived overall to have an average likelihood of transfusion of 50 mm, but the 25-75 percentiles ranged from 33 mm to 71 mm. This study suggests that inter-anaesthetist variability in the assessment of a patient's 'cardiac output reserve' and his 'likelihood of transfusion' is large.
    背景与目标: :这项初步研究的目的是调查麻醉师对患者在一系列临床情况下增加心输出量的能力以及他们在这些情况下感知的“输血可能性”的评估。专家麻醉师接受了有关临床线索的问卷调查,形式是对理论患者的诊断。他们被要求使用100 mm视觉模拟量表(VAS)评估每个患者的心脏储备和这些患者的“输血可能性”。 VAS的端点分别为“非常低”(0毫米)至“高”(100毫米)和“请勿输液”(0毫米)至“输液”(100毫米)。麻醉师对患者心输出量储备的评估(n = 54)显示出很大的差异。例如,总的来说,严重的主动脉瓣狭窄患者的心输出量增加能力有限(平均VAS 16毫米),但是麻醉师之间的差异很大(10毫米至21毫米为25-75%)。对“输血可能性”的评估(n = 42)也有很大差异。例如,患有“心绞痛”且血红蛋白为95 g l(-1)的患者总体上被认为平均输血的可能性为50 mm,但25-75%的范围为33 mm至71 mm。这项研究表明,麻醉师之间在评估患者的“心输出量储备”和“输血可能性”方面存在很大差异。

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