• 【利妥昔单抗-CHOP-ESHAP与CHOP-ESHAP-高剂量疗法与常规CHOP化疗治疗高中和高风险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: : 根据目前可用的联合化疗方案,根据国际预后指数 (IPI),新诊断为侵袭性非霍奇金淋巴瘤 (NHL) 的患者的预后仍不令人满意,迫切需要一种更具创新性的疗法来改善患者的生存。本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,甲基强的松龙,大剂量Ara-C,顺铂与CHOP-ESHAP以及前期大剂量治疗 (HDT) 和自体干细胞移植 (ASCT) 与标准CHOP在新诊断为 “高” 和 “高中间” 风险侵袭性淋巴瘤的年龄 <或 = 65岁的患者中加入了该研究所的两项连续治疗试验。在1995年5月2002年7月之间,纳入了84例年龄在15-65岁之间的新诊断为侵袭性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岁)。治疗组之间的基线人口统计学特征,特别是主要预后变量相似。利妥昔单抗-CHOP-ESHAP治疗的患者接受8个周期的利妥昔单抗 (第1-6周期的第1天和第7周期的第21天和第28天的375 mg m(-2)) 加CHOP (第1、3和5周期的第3天) 和ESHAP (第2周期的第3天,第4和第6周期以及第7周期的第1天) 间隔21天。纳入CHOP-ESHAP-HDT臂 (n = 23) 的患者接受了三个疗程的CHOP治疗,然后切换到两个或四个周期的ESHAP,然后进行HDT。仅接受CHOP治疗的患者 (n = 25) 接受标准的8个CHOP周期治疗。与单独使用CHOP-ESHAP-HDT或单独使用CHOP相比,利妥昔单抗-CHOP-ESHAP显著提高了完全缓解率 (分别与44% 和36% 相比67%; p = 0.043)。中位随访时间为53个月,通过添加利妥昔单抗-CHOP-ESHAP的rituximab-61 %,改善了5年总生存率 (OS),而CHOP-ESHAP-HDT为43%,CHOP单独为24% (p = 0.088)。与CHOP-ESHAP-HDT (34% 和90%) 和CHOP (16% 和44%; 分别为p = 0.002和p <0.001) 相比,无失败生存率 (FFS) 和无病生存率 (DFS) 显著增加 (61% 和96%)。与CHOP相比,利妥昔单抗-CHOP-ESHAP产生显著优越的OS (p = 0.014) 、FFS (p < 0.001) 和DFS (p <0.001)。然而,生存率与接受CHOP-ESHAP-HDT治疗的患者没有显着差异。结论是,在先前未经治疗的侵袭性淋巴瘤患者中,利妥昔单抗-ESHAP-CHOP优于标准CHOP,与前期HDT/ASCT相比。需要进行前瞻性随机对照试验来证实这些结果。
  • 【甲状腺细针细胞学检查并发喉返神经麻痹和不必要的根治性手术。】 复制标题 收藏 收藏
    DOI:10.1017/S0022215106002453 复制DOI
    作者列表:Hulin SJ,Harris KP
    BACKGROUND & AIMS: :Fine needle aspiration cytology (FNAC) is an important tool in the investigation of thyroid nodules and has few reported complications. We present the first report of recurrent laryngeal nerve palsy arising as a complication of thyroid nodule FNAC. This complication led to inaccurate diagnosis and unnecessarily radical surgery, with consequent increased morbidity.
    背景与目标: : 细针穿刺细胞学检查 (FNAC) 是检查甲状腺结节的重要工具,几乎没有并发症的报道。我们提出了作为甲状腺结节FNAC并发症引起的喉返神经麻痹的第一份报告。这种并发症导致不准确的诊断和不必要的根治性手术,从而增加了发病率。
  • 【白色念珠菌肉豆蔻酶a的选择性肽和拟肽抑制剂: 蛋白N-肉豆蔻酶转移酶: 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: 肉豆蔻酰辅酶a : 蛋白质N-肉豆蔻酰转移酶 (NMT) 催化稀有细胞脂肪酸肉豆蔻酸酯与多种真核蛋白质的N末端Gly残基的共翻译共价连接。肉豆蔻酰部分对于表达这些蛋白质的生物学功能通常是必不可少的。
    C14的附着 :0仅提供了足够的疏水性,无法与膜稳定结合。因此,N-肉豆蔻基蛋白的分配通常由 “开关” 调节,该开关通过其他共价或非共价修饰起作用。白色念珠菌是免疫功能低下的人体全身性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NMT基因。人与白色念珠菌NMT的酰基辅酶a结合位点的功能特性非常相似。然而,它们的肽结合位点存在明显差异。真菌酶的少数细胞蛋白底物中包括ADP核糖基化因子 (Arf)。衍生自N-末端Arf序列 (GLYASKLS-NH2) 的八肽的丙氨酸扫描诱变揭示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] 有竞争力的抑制剂,对肉豆蔻酰辅酶a无竞争力。值得注意的是,用11-氨基十一酰取代N-末端四肽导致竞争性抑制剂 (11-氨基十一酰-skls-nh2) 的效力比起始八肽高约40倍 [Ki(app) = 0.40 +/- 0.03微米]。从C末端去除Leu-Ser会产生竞争性二肽抑制剂 (11-氨基十一酰-sk-nh2),Ki(app) 为11.7 +/- 0.4微米,相当于起始八肽。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 (IC50 = 0.11 +/- 0.03微米) 和对细胞羧肽酶消化的抗性的优点。硬化柔性氨基十一酰链会产生非常有效的通用NMT抑制剂 (IC50 = 40-50nm)。用2-甲基咪唑代替N-末端胺并将具有R立体化学的苄基 α-甲基添加到硬化元件中,产生甚至更有效的抑制剂 (IC50 = 20-50nm),其对真菌的选择性与人酶相比高达500倍。该系列化合物中一个相关的效力较低的成员是真菌抑制剂。使用细胞Arf作为报告基因,其生长抑制作用与细胞蛋白N-肉豆蔻酰化的减少有关。这些研究表明,NMT是一种新的抗真菌靶标。
  • 【辐射诱导的旁观者和其他非靶向效应: 癌症治疗的新干预要点?】 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一个主要问题是,这些药物通常对正常组织有毒,需要高剂量才能杀死肿瘤细胞。因此,似乎涉及对癌症治疗的低剂量反应的细胞靶标是特别令人感兴趣的,因为它们可以选择性地靶向不被治疗靶向的正常组织,并且因此可能导致令人不快的副作用或可能易于利用以提高治疗比率。作为本综述主题的一个这样的目标是辐射诱导的旁观者效应 [RIBE],该效应导致在未辐照的细胞中观察到类似辐射的反应。RIBE是一种新现象,表明在低剂量下,细胞信号传导比直接DNA损伤更重要。从历史上看,DNA一直被认为是放射治疗的目标。越来越多的意识到信号很重要,这开辟了一些重要的治疗策略,这些策略将在本文中进行讨论。RIBE似乎是组织或细胞中普遍应激反应的结果,该应激反应在组织,器官或生物体的水平而不是单个细胞的水平上表达。信号可能由所有暴露的细胞产生,但是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射线或伽马射线) 辐射暴露的主要反应是死亡反应。这具有许多凋亡特征,但可以在没有p53表达的细胞系中检测到,尽管在许多肿瘤细胞系中死亡反应受到抑制。虽然肿瘤周围未照射的正常细胞的死亡反应似乎是不利的,但实际上它可以起到保护作用并从人群中清除受损的细胞。如果正确使用,它可能会导致新药的开发,其目的不是组织破坏,而是使稳态机制能够控制肿瘤的扩张。在这种情况下,有害或有益反应的水平将与细胞群体携带的背景损害以及确定对损害反应的遗传程序有关。在尝试预测涉及辐射和其他细胞毒性药物的混合疗法的后果时,此重点可能很重要。在这篇综述中,我们对电离辐射诱导旁观者效应的潜在机制的当前知识进行了综述,并讨论了如何利用旁观者效应来生产旨在稳定组织稳态而不是组织破坏的新一代抗癌药物的问题。
  • 【肌营养不良症的遗传修饰因子: 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,对肌肉营养不良的遗传认识有了很大的进步。现在已知超过25个不同的单个基因会产生肌营养不良,并且已经针对每个单个肌营养不良基因描述了许多不同的 “私人” 突变。对于更常见的肌营养不良症,表型变异可以用精确的突变来解释。但是,对于许多基因突变,相同突变的存在与明显的表型范围有关,该表型范围会影响肌肉功能以及心脏功能。现在才探索对肌营养不良症表型变异的解释。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。由于遗传背景而改变的表型变异认为存在可以改善或增强营养不良表型的遗传修饰位点。通过对肌营养不良的基因工程小鼠模型的研究,许多单个基因被认为是肌营养不良的调节剂。这些基因和产物的价值在于,通过这些实验确定的途径可以用于治疗。
  • 【睡眠剥夺与连续睡眠阶段提前相结合作为抑郁症的一种快速治疗方法: 一项在药物治疗和非药物治疗患者中的公开试点试验。】 复制标题 收藏 收藏
    DOI:10.1176/ajp.154.6.870 复制DOI
    作者列表:Berger M,Vollmann J,Hohagen F,König A,Lohner H,Voderholzer U,Riemann D
    BACKGROUND & AIMS: OBJECTIVE:The authors' goal was to test the hypothesis that the antidepressant effect of total sleep deprivation can be maintained by initially avoiding sleep during a supposedly "critical" time period in the early morning.

    METHOD:They studied 33 inpatients with major depression, melancholic type, all of whom responded positively to total sleep deprivation. Twelve of the patients were men and 21 were women; their mean age was 46.7 years (SD = 13.7). After total sleep deprivation, the patients started a sleep schedule from 5:00 p.m. to 12:00 midnight, which then was shifted back by 1 hour each day until a sleep time of 11:00 p.m. to 6:00 a.m. was reached.

    RESULTS:Twenty (61%) of the 33 patients who responded to total sleep deprivation with an improved state of mood maintained this improvement during sleep phase advance therapy. Drug-free and medicated patients did not differ from each other.

    CONCLUSIONS:The rapid amelioration of mood observed with total sleep deprivation can be preserved with a succeeding phase shift of the sleep period.

    背景与目标: 目的 : 作者的目标是检验以下假设: 完全睡眠剥夺的抗抑郁作用可以通过最初在清晨的一个所谓的 “关键” 时期避免睡眠来维持。
    方法 : 他们研究了33名患有抑郁症,忧郁型的住院患者,他们都对完全睡眠不足有积极的反应。12名患者为男性,21名患者为女性; 他们的平均年龄为46.7岁 (SD = 13.7)。完全睡眠剥夺后,患者开始从下午5:00到午夜12:00的睡眠计划,然后每天向后转移1小时,直到达到下午11:00上午6:00的睡眠时间。
    结果 : 33名对完全睡眠剥夺有改善的情绪状态有反应的患者中有20名 (61% 名) 在睡眠阶段提前治疗期间保持了这种改善。无药物和药物治疗的患者彼此之间没有差异。
    结论 : 完全睡眠剥夺所观察到的情绪迅速改善可以通过睡眠期的后续相移来保持。
  • 【阵发性心房颤动患者CHADS2评分与抗心律失常药物治疗疗效的关系.】 复制标题 收藏 收藏
    DOI:10.1253/circj.cj-12-0854 复制DOI
    作者列表:Komatsu T,Sato Y,Ozawa M,Kunugita F,Ueda H,Tachibana H,Morino Y,Nakamura M
    BACKGROUND & AIMS: BACKGROUND:The Cardiac failure, Hypertension, Age, Diabetes, Stroke [Doubled] (CHADS(2)) score is a useful scheme for risk stratification of thromboembolism patients, but there is little information about its usefulness for the evaluation of antiarrhythmic drug (AAD) therapy. METHODS AND RESULTS:This study included 459 paroxysmal atrial fibrillation (AF) patients (309 men, mean age 66 ± 12 years, mean follow-up 50 ± 35 months) and prophylactic efficacy was analyzed on the basis of CHADS(2) score. (1) Survival rates free from AF recurrence at 1, 6, 12 and 24 months were, respectively, 89%, 74%, 63% and 47% in score-0 group (n=152); 92%, 68%, 59% and 48% in score-1 group (n=158); 86%, 64%, 56% and 46% in score-2 group (n=84); 81%, 65%, 51% and 35% in score-3 group (n=43); and 68%, 50%, 36% and 18% in ≥ score-4 group (n=22) (P<0.05; score-0, score-1 or score-2 vs. ≥ score-4 group). (2) Survival rates free from progression to chronic AF at 12, 36, 60 and 90 months were, respectively, 95%, 93%, 91% and 89% in score-0 group; 97%, 91%, 89% and 88% in score-1 group; 96%, 93%, 88% and 83% in score-2 group; 91%, 74%, 67% and 60% in score-3 group; and 91%, 82%, 68% and 55% in ≥ score-4 group (P<0.01; score-0, score-1 or score-2 vs. ≥ score-4 group). (3) In multivariate logistic regression analysis adjusted for potentially confounding variables, CHADS(2) score was associated with AF recurrence (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.16-1.81, P<0.001), and progression to chronic AF during AAD therapy (OR 1.64, 95% CI 1.04-2.69, P<0.001). CONCLUSIONS:When using a rhythm control strategy, the CHADS(2) score is a useful scheme for predicting the outcome of AAD treatment of patients with paroxysmal AF.  
    背景与目标:
  • 【放射性碘125种子定位在新辅助化疗后保乳治疗中的作用。】 复制标题 收藏 收藏
    DOI:10.1093/annonc/mds475 复制DOI
    作者列表:Gobardhan PD,de Wall LL,van der Laan L,ten Tije AJ,van der Meer DC,Tetteroo E,Poortmans PM,Luiten EJ
    BACKGROUND & AIMS: BACKGROUND:Neoadjuvant chemotherapy (NAC) is increasingly used in the framework of breast-conserving therapy (BCT). Localization of the initial tumor is essential to guide surgical resection after NAC. This study describes the results obtained with I-125 seed localization in BCT including NAC. PATIENTS AND METHODS:Between January 2009 and December 2010, 85 patients treated with NAC and BCT after I-125 seed localization were included. Radiological and pathological response and resection margins were retrospectively evaluated. RESULTS:BCT was carried out in 85 patients without secondary local excisions. Nineteen patients with unifocal tumors and seven patients with multifocal tumors showed a complete pathological response (P = 0.18). Tumor-free resection margins were obtained in 78 patients (50 patients with unifocal and 28 patients with multifocal tumors, P = 0.27). Focally involved margins were found in four patients (two patients with a unifocal and two patients with a multifocal tumor, P = 0.27). A subsequent mastectomy was carried out in three patients (two patients with multifocal tumors, P = 0.29). CONCLUSIONS:BCT after NAC can be carried out successfully after initial localization with I-125 seeds in both unifocal and multifocal breast tumors with complete resection rates of >90%.
    背景与目标:
  • 【基因疗法可减少色素失禁模型的癫痫发作。】 复制标题 收藏 收藏
    DOI:10.1002/ana.24981 复制DOI
    作者列表:Dogbevia GK,Töllner K,Körbelin J,Bröer S,Ridder DA,Grasshoff H,Brandt C,Wenzel J,Straub BK,Trepel M,Löscher W,Schwaninger M
    BACKGROUND & AIMS: OBJECTIVE:Incontinentia pigmenti (IP) is a genetic disease leading to severe neurological symptoms, such as epileptic seizures, but no specific treatment is available. IP is caused by pathogenic variants that inactivate the Nemo gene. Replacing Nemo through gene therapy might provide therapeutic benefits. METHODS:In a mouse model of IP, we administered a single intravenous dose of the adeno-associated virus (AAV) vector, AAV-BR1-CAG-NEMO, delivering the Nemo gene to the brain endothelium. Spontaneous epileptic seizures and the integrity of the blood-brain barrier (BBB) were monitored. RESULTS:The endothelium-targeted gene therapy improved the integrity of the BBB. In parallel, it reduced the incidence of seizures and delayed their occurrence. Neonate mice intravenously injected with the AAV-BR1-CAG-NEMO vector developed no hepatocellular carcinoma or other major adverse effects 11 months after vector injection, demonstrating that the vector has a favorable safety profile. INTERPRETATION:The data show that the BBB is a target of antiepileptic treatment and, more specifically, provide evidence for the therapeutic benefit of a brain endothelial-targeted gene therapy in IP. Ann Neurol 2017;82:93-104.
    背景与目标:
  • 【贝伐单抗和厄洛替尼靶向治疗适合复发性胶质母细胞瘤患者的分子特征.初步经验。】 复制标题 收藏 收藏
    DOI:10.1007/s00701-012-1536-5 复制DOI
    作者列表:D'Alessandris QG,Montano N,Cenci T,Martini M,Lauretti L,Bianchi F,Larocca LM,Maira G,Fernandez E,Pallini R
    BACKGROUND & AIMS: BACKGROUND:Advances in comprehension of molecular biology of glioblastoma (GBM) have led to the development of targeted therapies. The aim of the present study was to evaluate the efficacy and safety of a targeted therapeutic approach in which administration of bevacizumab and erlotinib was tailored on the molecular profile of recurrent GBM. METHODS:We prospectively enrolled ten adult patients suffering from recurrent GBM who had undergone surgical resection and standard chemo-radiotherapy. Tumor tissue was assessed for the expression of EGFRvIII and MGMT promoter methylation by RT-PCR, and for PTEN and VEGF expression by immunohistochemistry. Normal PTEN status was required for inclusion. Patients with VEGF overexpressing tumors (10/10) were treated with bevacizumab (10 mg/kg iv every 2 weeks in 6-week cycles); patients whose tumor expressed EGFRvIII (4/10) added erlotinib (150 mg/day orally; 300 mg/day if on enzyme-inducing antiepileptic drugs). Therapy was continued until disease progression or unacceptable toxicity. Primary endpoints of the study were response rate (RR), 6-month progression-free survival (PFS-6), and safety profile. RESULTS:The RR and PFS-6 were 100 % (4/4) and 50 % (3/6) in patients treated with bevacizumab+erlotinib (n = 4) and bevacizumab (n = 6), respectively. In the whole cohort (n = 10), RR and PFS-6 were both 70 % (7/10); median PFS and overall survival (OS) were 8.0 (3.0-31.0) and 9.5 (5.0-31.0) months, respectively. No grade 3/4 adverse events were observed; three patients treated with bevacizumab+erlotinib displayed grade 1/2 rash not requiring dose reduction; one patient treated with bevacizumab developed intratumoral hemorrhage requiring treatment discontinuation. CONCLUSION:To our knowledge, this is the first study on recurrent GBM in which administration of bevacizumab and erlotinib was tailored on the molecular profile of the patient's tumor. Although we treated a limited number of patients, we obtained significantly higher RR and PFS-6 than those reported in a previous trial lacking molecular tumor analysis.
    背景与目标:
  • 【睡眠障碍负担及其相关危险因素: 中国HIV感染者抗逆转录病毒治疗的横断面调查。】 复制标题 收藏 收藏
    DOI:10.1038/s41598-017-03968-3 复制DOI
    作者列表:Huang X,Li H,Meyers K,Xia W,Meng Z,Li C,Bai J,He S,Cai W,Huang C,Liu S,Wang H,Ling X,Ma P,Tan D,Wang F,Ruan L,Zhao H,Wei H,Liu Y,Yu J,Lu H,Wang M,Zhang T,Chen H,Wu H
    BACKGROUND & AIMS: :This study evaluated the prevalence and factors associated with sleep disturbance in a large cohort of HIV-infected patients across China. A cross-sectional study was conducted among HIV-infected patients on antiretroviral therapy at 20 AIDS clinics. The Pittsburgh Sleep Quality Index was self-administered by subjects. Socio-demographic characteristics, medical history and HIV-related clinical data were collected. 4103 patients had complete data for analysis. Sleep disturbances were observed in 43.1% of patients. Associated factors in multivariable analysis included psychological factors: anxiety (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.44-4.00; P < 0.001), depression (OR, 2.09; 95% CI, 1.70-2.57; P < 0.001), and both anxiety and depression (OR, 5.90; 95% CI, 4.86-7.16; P < 0.001); sociodemographic factors: MSM (OR, 1.26; 95% CI, 1.04-1.52; P = 0.018), being single (OR, 1.45; 95%CI 1.21-1.74; P < 0.001), higher education (OR, 1.25; 95% CI, 1.03-1.53; P = 0.025); and clinical factors: suboptimal adherence (OR,1.51; 95% CI,1.23-1.85; P < 0.001), regimen-switching (OR, 1.94; 95% CI, 1.12-3.35; P = 0.018), and antidepressant use (OR, 1.98; 95% CI, 1.47-2.67; P = 0.044). Prevalence of sleep disturbance is high in this large Chinese cohort. Associated factors appear related to psychological and social-demographic factors. Health workers may consider routinely assessing sleep disturbances among HIV-infected patients, especially in the first three months after HIV diagnosis, and referring for mental health services, which may positively impact adherence to treatment.
    背景与目标: : 这项研究评估了中国大量HIV感染患者的患病率和与睡眠障碍相关的因素。在20个艾滋病诊所对接受抗逆转录病毒治疗的HIV感染患者进行了横断面研究。匹兹堡睡眠质量指数由受试者自行管理。收集了社会人口统计学特征,病史和与HIV相关的临床数据。4103患者有完整的数据进行分析。在43.1% 患者中观察到睡眠障碍。多变量分析的相关因素包括心理因素: 焦虑 (优势比 [OR],3.13; 95% 置信区间 [CI],2.44-4.00; P  <  0.001),抑郁 (OR,2.09; 95% CI,1.70-2.57; P  <  0.001),焦虑和抑郁 (OR,5.90; 95% CI,4.86-7.16; P  <  0.001); 社会人口统计学因素: MSM (OR,1.26; 95% CI,1.04-1.52; P   =   0.018),单身 (OR,1.45; 95% CI 1.21-1.74; P  <  0.001),高等教育 (OR, 1.25; 95% CI,1.03-1.53; P   =   0.025); 和临床因素: 次优依从性 (OR,1.51; 95% CI,1.23-1.85; P <  0.001),方案转换 (OR,1.94; 95% CI,1.12-3.35; P   =   0.018) 和抗抑郁药的使用 (或,1.98; 95% CI,1.47-2.67; P   =   0.044)。在这个庞大的中国人群中,睡眠障碍的患病率很高。相关因素似乎与心理和社会人口因素有关。卫生工作者可以考虑定期评估HIV感染患者的睡眠障碍,尤其是在HIV诊断后的前三个月,并推荐精神卫生服务,这可能会对治疗依从性产生积极影响。
  • 【低水平激光治疗对链脲佐菌素诱导的糖尿病大鼠骨缺损愈合的影响: 组织学和形态计量学评估。】 复制标题 收藏 收藏
    DOI:10.1080/14764172.2017.1341048 复制DOI
    作者列表:Yildirimturk S,Sirin Y,Soluk Tekkesin M,Gurler G,Firat D
    BACKGROUND & AIMS: BACKGROUND:The aim of the present study was to evaluate the effects of low-level laser therapy (LLLT) on the healing of bone defects in rats with streptozotocin (STZ)-induced DM. METHODS:28 male Sprague-Dawley rats were used in this study. 14 animals received a single dose of STZ intraperitoneally (65 mg/kg) to induce Type I DM, whereas others were injected only with sterile saline solution. Four weeks later, standard bone defects were created in the tibiae of rats. Surgical wounds in one group from each of the diabetic and non-diabetic animals were irradiated with diode laser for every other day for 4 weeks and they were described as DM + LLLT and CONT + LLLT groups, respectively. Remaining two groups received no laser treatment. New bone formation, osteoblast and blood vessel counts were calculated in histologic sections. RESULTS:DM group had significantly smaller bone area and lower blood vessel count when compared to DM + LLLT, CONT and CONT + LLLT groups (p < 0.05 for each). CONT and CONT + LLLT groups had significantly larger bone area than DM + LLLT group (p < 0.05 for both). CONCLUSIONS:LLLT application promoted vascularization and new bone formation in animals with DM to a limited extent, since it was unable to support the healing process up to the level of non-diabetic animals.
    背景与目标:
  • 【3个治疗靶点多沙唑嗪对映体的手性识别以及动物实验中的药物不良反应。】 复制标题 收藏 收藏
    DOI:10.1139/y2012-129 复制DOI
    作者列表:Zhao D,Duan LH,Wang FY,Wang M,Lu HG,Wu ZG,Wang X,Ren LM
    BACKGROUND & AIMS: :Doxazosin used in benign prostatic hyperplasia has the side effects of causing hypotension and the risk of heart failure. The 3 targets of α(1A)-adrenoceptors (in the prostate), α(1D)-adrenoceptors (in the aorta), and an unknown mechanism (in the heart) are involved, respectively. We hypothesized that there is a chiral recognition of doxazosin enantiomers in the 3 targets. Using isolated rat aorta (α(1D)-adrenoceptors) and rabbit prostate (α(1A)-adrenoceptors), we examined pA(2) and pK(B) values of doxazosin enantiomers. We observed chronotropic and inotropic effects of doxazosin enantiomers in isolated rat and rabbit heart tissues. (-)Doxazosin and (+)doxazosin produced a shift to the right of concentration-contraction curves for noradrenalin (aorta) and phenylephrine (prostate smooth muscle). The pA(2) value of (-)doxazosin (8.625 ± 0.053) was smaller than (+)doxazosin (9.503 ± 0.051) in rat aorta, but their pK(B) values in rabbit prostate were the same. In rat and rabbit heart tissues, (+)doxazosin (3-30 µmol·L(-1)) significantly decreased atrial rate, and produced negative inotropic effects; however, (-)doxazosin did not affect the atrial rate, and produced positive inotropic effects in the atria. Thus, the chiral carbon atom of doxazosin does not affect its activity at the therapeutic target of α(1A)-adrenoceptors in the prostate, but significantly changes its blocking activity against α(1D)-adrenoceptors in the aorta, and produces opposite inotropic effects in the atria via an α(1)-adrenoceptor-independent mechanism.
    背景与目标: : 多沙唑嗪用于良性前列腺增生具有引起低血压和心力衰竭风险的副作用。分别涉及 α(1A)-肾上腺素受体 (在前列腺中),α(1D)-肾上腺素受体 (在主动脉中) 和未知机制 (在心脏中) 的3个目标。我们假设在3个靶标中存在多沙唑嗪对映体的手性识别。使用分离的大鼠主动脉 (α(1D)-肾上腺素受体) 和兔前列腺 (α(1A)-肾上腺素受体),我们检查了多沙唑嗪对映体的pA(2) 和pK(B) 值。我们观察到多沙唑嗪对映体在分离的大鼠和兔心脏组织中的变时性和正性肌力作用。(-) 多沙唑嗪和 () 多沙唑嗪使去甲肾上腺素 (主动脉) 和去氧肾上腺素 (前列腺平滑肌) 的浓度-收缩曲线向右移动。在大鼠主动脉中 (-) 多沙唑嗪 (8.625 ± 0.053) 的pA(2) 值小于 () 多沙唑嗪 (9.503 ± 0.051),但它们在兔前列腺中的pK(B) 值相同。在大鼠和兔心脏组织中,() 多沙唑嗪 (3-30 µ mol·L(-1)) 显着降低了心房速率,并产生了负性肌力作用; 但是,(-) 多沙唑嗪不影响心房速率,并在心房中产生了正性肌力作用。因此,多沙唑嗪的手性碳原子不会影响其在前列腺中 α(1A)-肾上腺素受体的治疗靶标上的活性,但会显着改变其对主动脉中 α(1D)-肾上腺素受体的阻断活性,并通过不依赖 α(1)-肾上腺素受体的机制在心房中产生相反的正性肌力作用。
  • 【接受辅助生殖技术的不良反应者的拮抗剂方案中的辅助生长激素治疗。】 复制标题 收藏 收藏
    DOI:10.1007/s00404-012-2655-1 复制DOI
    作者列表:Eftekhar M,Aflatoonian A,Mohammadian F,Eftekhar T
    BACKGROUND & AIMS: PURPOSE:The incidence of poor ovarian response in controlled ovarian stimulation (COH) has been reported in 9-24 % of IVF-ET cycles. Growth hormone augments the effect of gonadotropin on granulosa and theca cells, and plays an essential role in ovarian function, including follicular development, estrogen synthesis and oocyte maturation. The aim of this study was to assess IVF-ET cycle outcome after the addition of growth hormone in antagonist protocol in poor responders. MATERIALS AND METHODS:Eighty-two poor responder patients selected for ART enrolled the study and were randomly divided into two groups. Group I (GH/HMG/GnRHant group, n = 40) received growth hormone/gonadotropin/GnRH antagonist protocol and group II (HMG/GnRHant group, n = 42) received gonadotropin/GnRH antagonist protocol. RESULTS:The number of retrieved oocytes was significantly higher in GH/HMG/GnRHant group than HMG/GnRHant group, 6.10 ± 2.90 vs. 4.80 ± 2.40 (p = 0.035) and the number of obtained embryos was also significantly higher in GH/HMG/GnRHant group than HMG/GnRHant group, 3.7 ± 2.89 as compared to 2.7 ± 1.29 (p = 0.018). There were no significant differences between groups regarding implantation, and chemical and clinical pregnancy rates. CONCLUSION:Our study showed that co-treatment with growth hormone in antagonist protocol in patients with a history of poor response in previous IVF-ET cycles did not increase pregnancy rates.
    背景与目标:
  • 【直肠癌的新辅助短期或长期放射 (化疗) 治疗: 如何以及应由谁治疗?】 复制标题 收藏 收藏
    DOI:10.1159/000342038 复制DOI
    作者列表:Rödel C,Trojan J,Bechstein WO,Woeste G
    BACKGROUND & AIMS: :There are two general approaches to preoperative radiotherapy (RT) in rectal cancer: short-course (25 Gy in 5 fractions) radiation with immediate surgery and long-course 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT; 50.4 Gy in 28 fractions) with surgery scheduled 6-8 weeks thereafter. While it is clear that downsizing and downstaging effects are more pronounced with long-course CRT and delayed surgery, a Polish randomized trial and, more recently, an Australian phase III trial demonstrated no significant differences in long-term oncologic outcomes and late toxicity rates between either preoperative concept. Ongoing studies currently address short-course preoperative RT with a longer interval to surgery (Stockholm III trial), and short-course RT with sequential combination chemotherapy in patients with synchronous distant metastasis. With respect to the long-course CRT approach, newer-generation chemotherapeutics as well as molecularly targeted agents have been tested within phase I-III studies, both as induction/adjuvant chemotherapy as well as during concomitant CRT. Evidently, the monolithic approaches to either apply the same schedule of preoperative 5-FU-based CRT to all patients with TNM stage II/III rectal cancer or to give preoperative short-course RT for all patients with resectable rectal cancer irrespective of tumor stage and location need to be questioned. The inclusion of different multimodal treatments into the surgical oncological concept, adapted to tumor location, stage, and individual patient risk factors and preferences is upcoming. Clearly, future developments will aim at identifying and selecting patients for ideal treatment alternatives.
    背景与目标: : 直肠癌术前放疗 (RT) 有两种常规方法: 短期 (25 Gy,5个部分) 立即手术放疗和基于5-氟尿嘧啶 (5-FU) 的长期放化疗 (CRT; 50.4 Gy,28个部分),术后6-8周进行手术。尽管很明显,长期CRT和延迟手术的缩小和缩小分期效果更为明显,但波兰的一项随机试验以及最近的一项澳大利亚III期试验均显示,两种术前概念之间的长期肿瘤学结局和晚期毒性率均无显着差异。目前正在进行的研究针对具有较长手术间隔的短期术前放疗 (Stockholm III试验),以及同步远处转移患者的短期放疗和序贯联合化疗。关于长期CRT方法,已在i-iii期研究中测试了新一代化学疗法以及分子靶向药物,包括诱导/辅助化疗以及伴随CRT期间。显然,对于所有TNM II/III期直肠癌患者,采用相同的术前基于5-fu的CRT时间表,或者对所有可切除直肠癌患者进行术前短期RT,无论肿瘤分期和位置如何都需要质疑。即将将不同的多模式治疗纳入外科肿瘤学概念,以适应肿瘤的位置,阶段和个体患者的风险因素和偏好。显然,未来的发展将旨在识别和选择理想治疗方案的患者。

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