BACKGROUND & AIMS: :As a model to investigate the mechanism of caspase activation we have analysed the processing of pro-caspase-7 by serine proteases with varied specificities. The caspase-7 zymogen was rapidly activated by granzyme B and more slowly by subtilisin and cathepsin G, generating active enzymes with similar kinetic properties. Significantly, cathepsin G activated the zymogen by cleaving at a Gln-Ala bond, indicating that the canonical cleavage specificity at aspartic acid is not required for activation.

背景与目标： ：作为研究caspase激活机制的模型，我们分析了具有不同特异性的丝氨酸蛋白酶对pro-caspase-7的加工。胱天蛋白酶7酶原被颗粒酶B迅速激活，而枯草杆菌蛋白酶和组织蛋白酶G则更慢，从而产生具有相似动力学特性的活性酶。重要的是，组织蛋白酶G通过在Gln-Ala键处裂解激活了酶原，表明激活不需要天冬氨酸的标准裂解特异性。

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： ：根据目前的联合化疗方案，根据国际预后指标（IPI），新诊断为侵袭性非霍奇金淋巴瘤（NHL）的患者的预后仍然不理想，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，甲基强的松龙，大剂量Ara-C，顺铂）联合使用的利妥昔单抗与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。

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（相对于其亲本株H69）的两倍。 Western blot分析表明，与H69相比，根瘤菌素显着抑制了H69 / VDS中的微管蛋白聚合，且呈浓度依赖性。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低15％，而H69 / VDS的外排量则略有提高。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，腹膜内三剂间断性的根瘤菌素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。

BACKGROUND & AIMS: PURPOSE:Consistent condom use is critical to efforts to prevent sexually transmitted infections among adolescents, but condom use may decline as relationships and contraceptive needs change. The purpose of this research is to assess changes in condom non-use longitudinally in the context of changes in relationship quality, coital frequency and hormonal contraceptive choice. METHODS:Participants were women (aged 14-17 years at enrollment) recruited from three urban adolescent medicine clinics. Data were collected at three-month intervals using a face-to-face structured interview. Participants were able to contribute up to 10 interviews, but on average contributed 4.2 interviews over the 27-month period. Independent variables assessed partner-specific relationship quality (five items; scale range 5-25; alpha = .92, e.g., this partner is a very important person to me); and, number of coital events with a specific partner. Additional items assessed experience with oral contraceptive pills (OCP) use and injected depo medroxy-progesterone acetate (DMPA). The outcome variable was number of coital events without condom use during the past three months. Analyses were conducted as a three-level hierarchical linear growth curve model using HLM 6. The Level 1 predictor was time, to test the hypothesis that condom non-use increases over time. Level 2 predictors assessed relationship quality and coital frequency across all partners to assess hypotheses that participants' condom non-use increases over time as a function of relationship quality and coital frequency. Level 3 predictors assessed the participant-level influence of OCP or DMPA experience on time-related changes in condom non-use. RESULTS:A total of 176 women reported 279 sex partners and contributed 478 visits. Both average coital frequency and average condom non-use linearly increased during the 27-month follow-up. At any given follow-up, about 35% reported recent OCP use, and 65% reported DMPA use. HLM analyses showed that condom non-use increased as a function of time (beta = .12; p = .03, Level 1 analysis). Increased condom non-use over time was primarily a function of increased coital frequency (beta = .01; p = .00), although higher levels of relationship quality were associated with increased condom non-use at enrollment (beta = .44; p = .00, Level 2 analysis). The temporal rise in condom non-use significantly increased among DMPA users (beta = .06; p = .00) but not OCP users (Level 3 analysis) (beta = -.04; p = .06). CONCLUSIONS:Developmentally, relationship characteristics and coital frequency appear to have increasing weight in decisions about condom use. Hormonal contraceptive methods are not equivalently associated with the overall temporal decline in condom use. Future research associated with dual contraceptive/condom use should address differential factors associated condom use in combination with different hormonal methods.

背景与目标： 目的：持续使用避孕套对于预防青少年性传播感染至关重要，但是随着人际关系和避孕需求的变化，避孕套的使用可能会减少。这项研究的目的是在关系质量，性交频率和激素避孕选择的变化的背景下，纵向评估未使用安全套的变化。
方法：参与者是从三个城市青少年医学诊所招募的女性（入学年龄为14-17岁）。使用面对面的结构化访谈，每三个月收集一次数据。参加者最多可以贡献10个访谈，但在27个月内平均贡献了4.2个访谈。自变量评估了特定于伴侣的关系质量（五个项目；等级范围5-25；α= 0.92，例如，这个伴侣对我来说是非常重要的人）；以及与特定伴侣发生性行为的次数。其他项目评估了口服避孕药（OCP）的使用经验和注射醋酸去甲羟孕酮（DMPA）的经验。结果变量是在过去三个月中未使用安全套的性交事件的数量。使用HLM 6作为三级分层线性增长曲线模型进行了分析。1级预测因子是时间，以检验安全套不使用随时间增加的假设。 2级预测变量评估了所有伴侣之间的关系质量和性交频率，以评估以下假设：参与者不使用安全套会随着时间的推移而增加，这是关系质量和性交频率的函数。 3级预测变量评估了OCP或DMPA经验对安全套不使用时间相关变化的参与者水平影响。
结果：总共176名妇女报告了279个性伴侣，并贡献了478次探视。在27个月的随访期间，平均性交频率和平均不使用安全套均呈线性增加。在任何给定的随访中，约35％的患者报告了最近的OCP使用，而65％的患者报告了DMPA的使用。 HLM分析表明，不使用安全套的时间随时间增加（β= .12； p = .03，1级分析）。随着时间的推移，不使用安全套的增加主要是性交频率增加的函数（β= .01； p = .00），尽管较高的关系质量与入学时不使用安全套的增加有关（β= .44； p = .00，第2级分析）。在DMPA用户中，未使用安全套的时间增加显着增加（β= .06； p = .00），但在OCP用户中则没有（第三级分析）（β= -.04； p = .06）。
结论：在发展上，关系特征和性交频率似乎在有关使用安全套的决策中具有越来越大的重要性。激素避孕方法与使用避孕套的总体时间下降没有同等的联系。与双重避孕/避孕套使用相关的未来研究应解决与不同激素方法结合使用避孕套相关的差异因素。

BACKGROUND & AIMS: -2

背景与目标： -2

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，或者可能适于利用以改善治疗效果。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。虽然在肿瘤周围未照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。

BACKGROUND & AIMS: BACKGROUND:Previous studies revealed increased parietal late positive potentials (LPPs) in response to spider pictures in spider phobic individuals. This study searched for basic features of fear-relevant stimuli by investigating whether schematic spider images are sufficient to evoke differential behavioral as well as differential early and late ERP responses in spider phobic, social phobic (as a clinical control group), and non-phobic control participants. METHODS:Behavioral and electrophysiological correlates of the processing of schematic spider and flower images were investigated while participants performed a color (emotional Stroop) and an object identification task. Stimuli were schematic pictures of spiders and flowers matched with respect to constituting visual elements. RESULTS:Consistent with previous studies using photographic spider pictures, spider phobic persons showed enhanced LPPs when identifying schematic spiders compared to schematic flowers. In addition, spider phobic individuals showed generally faster responses than the control groups. This effect was interpreted as evidence for an increased general behavioral hypervigilance in this anxiety disorder group. Furthermore, both phobic groups showed enhanced P100 amplitudes compared to controls, which was interpreted as evidence for an increased (cortical) hypervigilance for incoming stimuli in phobic patients in general. Finally, all groups showed faster identification of and larger N170 amplitudes in response to schematic spider than flower pictures. This may reflect either a general advantage for fear-relevant compared to neutral stimuli, or might be due to a higher level of expertise in processing schematic spiders as compared to the more artificially looking flower stimuli. CONCLUSION:Results suggest that schematic spiders are sufficient to prompt differential responses in spider-fearful and spider-non-fearful persons in late ERP components. Early ERP components, on the other hand, seem to be modified by anxiety status per se, which is consistent with recent theories on general hypervigilance in the anxiety disorder spectrum.

背景与目标： 背景：以前的研究表明，在恐惧蜘蛛的个体中，对蜘蛛图片的顶壁晚期正电位（LPPs）增加。这项研究通过调查示意性蜘蛛图像是否足以引起蜘蛛恐惧症，社交恐惧症（作为临床对照组）和非恐惧症中的差异行为以及差异化的早期和晚期ERP反应，从而寻找与恐惧相关的刺激的基本特征。控制参与者。
方法：在参与者执行颜色（情绪化的Stroop）和对象识别任务的过程中，研究了示意性蜘蛛和花朵图像处理的行为和电生理相关性。刺激是与构成视觉元素相匹配的蜘蛛和花朵的示意图。
结果：与以前使用摄影蜘蛛图片进行的研究一致，与原理图花朵相比，畏惧蜘蛛的人在识别原理图蜘蛛时显示出增强的LPP。另外，蜘蛛恐惧症个体通常显示出比对照组更快的反应。该效应被解释为该焦虑症组中一般行为过度警觉性增加的证据。此外，与对照组相比，两个恐惧组均显示出增强的P100振幅，这可以解释为总体而言，恐惧患者传入刺激的（皮质）超警觉性增加的证据。最后，所有组均显示出对蜘蛛网的响应比花卉图片更快地识别N170振幅，并具有更大的N170振幅。与中性刺激相比，这可能反映与恐惧相关的一般优势，或者可能是由于与较人为看似的花刺激相比，在处理示意性蜘蛛上的专业知识水平更高。
结论：结果表明，原理图蜘蛛足以在ERP后期的恐惧蜘蛛和非恐惧蜘蛛患者中引起差异反应。另一方面，早期的ERP组件似乎已被焦虑状态本身所改变，这与最近关于焦虑症谱系的一般超警觉的理论相一致。

BACKGROUND & AIMS: :The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors that have potential value in the treatment of HIV/AIDS. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties. A series of novel ADAMs were therefore designed and synthesized in order to replace the metabolically labile methyl ester moieties of the existing ADAM lead compounds with hydrolytically stable, fused isoxazolone, isoxazole, oxazolone, or cyano substituents on the aromatic rings. The methyl ester and methoxy substituents on both of the aromatic rings in the parent compound 1 were successfully replaced with metabolically stable moieties with retention of anti-HIV activity and a general decrease in cytotoxicity.

背景与目标： ：烯基二芳基甲烷（ADAM）是一类独特的非核苷类逆转录酶抑制剂，在治疗HIV / AIDS中具有潜在价值。然而，ADAM的潜在用途受到代谢不稳定的甲基酯部分的存在的限制。因此，设计并合成了一系列新颖的ADAM，以在芳香环上用水解稳定的稠合异恶唑酮，异恶唑，恶唑酮或氰基取代基取代现有ADAM铅化合物的代谢不稳定的甲基部分。母体化合物1的两个芳香环上的甲酯和甲氧基取代基均成功地被代谢稳定的部分所取代，并保留了抗HIV活性并普遍降低了细胞毒性。

BACKGROUND & AIMS: Etoposide produces reversible inhibition of topoisomerase II, leading to cleavage of DNA, and thereby has an antitumor effect. This mechanism suggests that the longer treatment is continued, the greater the antitumor effect will be. In the present study, both therapeutic and adverse effects of long-term treatment with low-dose oral etoposide were studied in 29 patients aged > or = 65 years with non-Hodgkin's lymphoma (NHL) for whom standard chemotherapy was not effective or refractory. These patients received etoposide at a dose of 50 mg/d for as long as possible. Treatment was continued until white blood cell count decreased to < or = 2,000/microL or the platelet count decreased to < or = 5 x 10(4)/microL. According to the World Health Organization (WHO) criteria of therapeutic effects, 6 (20.7%) of the 29 patients achieved complete remission and 13 patients (44.8%) had partial remission, for a response rate of 65.5%. Adverse effects of > or = grade 3 included leukopenia in 24 patients (82.8%) and anemia in 7 (24.1%). Granulocyte colony-stimulating factor (G-CSF) was given in combination with etoposide to eight patients because of leukopenia (granulocyte count < or = 1,000/microL). In view of the excellent subjective tolerance, low incidence of serious adverse effects, and good activity, single agent oral etoposide given continuously over prolonged periods represents a useful treatment for elderly patients with NHL.

背景与目标： 依托泊苷产生对拓扑异构酶II的可逆抑制，导致DNA裂解，因此具有抗肿瘤作用。该机制表明持续的治疗时间越长，抗肿瘤作用越大。在本研究中，对29岁年龄≥65岁的非霍奇金淋巴瘤（NHL）患者进行了长期低剂量口服依托泊苷的治疗，并对其不良反应进行了研究，这些患者对于标准化疗均无效或难治。这些患者尽可能长时间接受依托泊苷50 mg / d的剂量。继续治疗直至白细胞计数降低至<或= 2,000 / microL或血小板计数降低至<或= 5 x 10（4）/ microL。根据世界卫生组织（WHO）的疗效标准，在29例患者中有6例（20.7％）完全缓解，13例（44.8％）部分缓解，缓解率为65.5％。 ≥3级的不良反应包括24例白细胞减少症（82.8％）和7例贫血（24.1％）。由于白细胞减少症（粒细胞计数<或= 1,000 / microL），与依托泊苷联合给予了粒细胞集落刺激因子（G-CSF）与依托泊苷。鉴于出色的主观耐受性，严重不良反应的发生率低和良好的活动性，长时间连续给予单剂口服依托泊苷代表了对老年NHL患者的一种有效治疗方法。

BACKGROUND & AIMS: BACKGROUND:Brain metastasis (BM) is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC). Recent studies demonstrated that microRNA-330-3p (miR-330-3p) was involved in NSCLC brain metastasis (BM). However, the exact parts played by miR-330-3p in BM of NSCLC remain unknown. Discovery and development of biomarkers and elucidation of the mechanism underlying BM in NSCLC is critical for effective prophylactic interventions. Here, we evaluated the expression and biological effects of miR-330-3p in NSCLC cells and explored the underlying mechanism of miR-330-3p in promoting cell migration and invasion in NSCLC. METHODS:Stable over-expression and knockdown of miR-330-3p in NSCLC cells was constructed with lentivirus. Expression levels of miR-330-3p in NSCLC cells were quantified by quantitive real-time PCR (qRT-PCR). The effects of miR-330-3p on NSCLC cells were investigated using assays of cell viability, migration, invasion, cell cycle, apoptosis, western blotting, immunohistochemical, and immunofluorescence staining. A xenograft nude mouse model and in situ brain metastasis model were used to observe tumor growth and brain metastasis. The potential target of miR-330-3p in NSCLC cells was explored using the luciferase reporter assay, qRT-PCR, and western blotting. The miR-330-3p targets were identified using bioinformatics analysis and verified by luciferase reporter assay. The correlation between GRIA3 and DNA methyltransferase (DNMT) 1 and DNMT3A was tested by RT-PCR, western blotting, and co-immunoprecipitation (IP). RESULTS:miR-330-3p was significantly up-regulated in NSCLC cell lines. MTT assay, transwell migration, and invasion assays showed that miR-330-3p promoted the growth, migration, and invasion of NSCLC cells in vitro and induced tumor growth and metastasis in vivo. Luciferase reporter assays showed that GRIA3 was a target of miR-330-3p. qRT-PCR and western blotting exhibited that miR-330-3p promoted the growth, invasion, and migration of NSCLC cells by activating mitogen-activated protein kinase (MAPK)/extracellular-regulated protein kinases (ERK) signaling pathway. Furthermore, miR-330-3p up-regulated the total DNA methylation in NSCLC cells, and co-IP-demonstrated GRIA3 was directly related with DNMT1 and DNMT3A. CONCLUSIONS:miR-330-3p promoted the progression of NSCLC and might be a potential target for the further research of NSCLC brain metastasis.

背景与目标： 背景：脑转移（BM）与非小细胞肺癌（NSCLC）患者预后差有关。最近的研究表明，microRNA-330-3p（miR-330-3p）参与了NSCLC脑转移（BM）。但是，miR-330-3p在NSCLC的BM中所起的确切作用仍然未知。发现和开发生物标志物以及阐明NSCLC中BM的潜在机制对于有效的预防性干预至关重要。在这里，我们评估了miR-330-3p在NSCLC细胞中的表达和生物学效应，并探讨了miR-330-3p在促进NSCLC细胞迁移和侵袭中的潜在机制。
方法：用慢病毒构建稳定表达miR-330-3p的NSCLC细胞。通过定量实时PCR（qRT-PCR）定量检测NSCLC细胞中miR-330-3p的表达水平。使用细胞活力，迁移，侵袭，细胞周期，凋亡，蛋白质印迹，免疫组织化学和免疫荧光染色的方法研究了miR-330-3p对NSCLC细胞的影响。用异种移植裸鼠模型和原位脑转移模型观察肿瘤的生长和脑转移。使用荧光素酶报告基因检测，qRT-PCR和Western印迹探索了NSCLC细胞中miR-330-3p的潜在靶标。使用生物信息学分析鉴定了miR-330-3p靶标，并通过萤光素酶报告基因检测法对其进行了验证。通过RT-PCR，蛋白质印迹和免疫共沉淀（IP）测试了GRIA3与DNA甲基转移酶（DNMT）1和DNMT3A之间的相关性。
结果：miR-330-3p在NSCLC细胞系中显着上调。 MTT测定，穿孔迁移和侵袭测定显示，miR-330-3p在体外促进NSCLC细胞的生长，迁移和侵袭，并在体内诱导肿瘤生长和转移。萤光素酶报告基因检测表明GRIA3是miR-330-3p的靶标。 qRT-PCR和western blotting显示，miR-330-3p通过激活有丝分裂原激活的蛋白激酶（MAPK）/细胞外调节的蛋白激酶（ERK）信号通路，促进了NSCLC细胞的生长，侵袭和迁移。此外，miR-330-3p上调了NSCLC细胞中的总DNA甲基化，并且共同IP展示的GRIA3与DNMT1和DNMT3A直接相关。
结论：miR-330-3p促进了非小细胞肺癌的发展，可能是进一步研究非小细胞肺癌脑转移的潜在靶标。

BACKGROUND & AIMS: :Objective To evaluate the etiologies for dense vitreous hemorrhage in adults with non-traumatic and reveal management of early vitrectomy for the disease. Methods Study included 105 eyes from 105 patients. Outcome measures were etiologies of vitreous hemorrhage, formation of retinal and/or disk neovascular membrane (NVM), incidence of retinal tear and detachment, visual acuity (VA) and postoperative complications. Results Mean time between presentation and surgery was 7.1 days. The most common etiologies were retinal vein occlusion (RVO) (58.1%), retinal tear (22.9%) and retinal vasculitis (10.4%). Most RVO (77.0%) and retinal vasculitis (72.7%) eyes were associated with retinal and/or disk NVM. Retinal tear and retinal detachment was found in 24 and 48 eyes, respectively. VA improved significantly from 1/70 to 0.6 following vitrectomy. The most common postoperative complication was cataract (28.6%). Conclusion RVO, retinal tear and retinal vasculitis were the most common causes of dense vitreous hemorrhage. Early vitrectomy has a good outcome with acceptable complication rates in this setting.

背景与目标： ：目的评估非创伤成人玻璃体大出血的病因，并揭示该疾病的早期玻璃体切除术的治疗方法。方法研究包括来自105名患者的105只眼睛。结果的措施是玻璃体出血，视网膜和/或盘状新血管膜（NVM）形成，视网膜撕裂和脱离的发生率，视力（VA）和术后并发症的病因。结果从就诊到手术的平均时间为7.1天。最常见的病因是视网膜静脉阻塞（RVO）（58.1％），视网膜撕裂（22.9％）和视网膜血管炎（10.4％）。大多数RVO（77.0％）和视网膜血管炎（72.7％）眼睛与视网膜和/或椎间盘NVM相关。分别在24和48只眼中发现了视网膜撕裂和视网膜脱离。玻璃体切除术后VA从1/70显着提高至0.6。最常见的术后并发症是白内障（28.6％）。结论RVO，视网膜撕裂和视网膜血管炎是玻璃体致密性出血的最常见原因。在这种情况下，早期玻璃体切除术的结果良好，并发症发生率可以接受。

BACKGROUND & AIMS: :We recently showed that non-small cell lung carcinomas (NSCLCs) are of dismal prognosis when encompassing accelerated autophagic activity. The regulation of this abnormally functioning degradation system and its association with hypoxia and apoptosis in lung carcinoma patients is unexplored. In this study we used 115 NSCLC tissues to examine the immunohistochemical expression of four distinct molecules - the major regulator of autophagy Beclin 1, the anti-apoptotic and anti-autophagic protein Bcl-2, the pro-apoptotic and pro-autophagic protein BNIP3, and a marker of hypoxia and glucolysis, the glucose transporter Glut 1. Most cases showed reduced reactivity for Beclin 1 (62%) and Bcl-2 (82%) proteins, almost half of our sample revealed strong BNIP3 expression (57%), whereas most of the carcinomas strongly expressed Glut 1 antigen (71%). Beclin 1 expression showed no association with survival. Bcl-2 positivity was a marker of good prognosis (p = 0.04), whereas BNIP3 (p = 0.0004) and Glut 1 (p = 0.03) expression correlated with poor outcome in Stage I disease. Autophagic status was negatively associated with Bcl-2 (p = 0.0006), but positively with Glut 1 expression (p = 0.001). In conclusion, the accelerated autophagic status in NSCLC is unrelated to Beclin 1 and BNIP3 expression, but does show significant association with Bcl-2 reactivity. Furthermore, we showed important correlations between glucolysis and autophagy, guiding new pathways in future lung carcinoma research.

背景与目标： ：我们最近发现，非小细胞肺癌（NSCLC）包含加速自噬活性时预后不良。肺癌患者中这种功能异常的降解系统的调节及其与缺氧和细胞凋亡的关系尚待探索。在这项研究中，我们使用了115个非小细胞肺癌组织来检查四种不同分子的免疫组织化学表达-自噬Beclin 1的主要调节剂，抗凋亡和抗自噬蛋白Bcl-2，促凋亡和自噬蛋白BNIP3，葡萄糖转运蛋白Glut 1是缺氧和糖酵解的标志。大多数病例显示Beclin 1（62％）和Bcl-2（82％）蛋白的反应性降低，几乎一半的样本显示BNIP3表达强（57％），而大多数癌症强烈表达Glut 1抗原（71％）。 Beclin 1的表达与存活率无关。 Bcl-2阳性是预后良好的标志（p = 0.04），而BNIP3（p = 0.0004）和Glut 1（p = 0.03）的表达与I期疾病的不良预后相关。自噬状态与Bcl-2呈负相关（p = 0.0006），但与Glut 1表达呈正相关（p = 0.001）。总之，NSCLC中自噬状态的加速与Beclin 1和BNIP3的表达无关，但确实与Bcl-2的反应性显着相关。此外，我们显示了糖酵解与自噬之间的重要关联，为未来肺癌研究的新途径提供了指导。

BACKGROUND & AIMS: :The sensorimotor cortical system undergoes structural and functional changes across its lifespan. Some of these changes are physiological and parallel the normal aging process, while others might represent pathophysiological mechanisms underlying neurodegenerative disorders. In the last years, the study of possible age-related modifications in brain sensorimotor functional characteristics has been the focus of several research projects. Here we have used the transcranial magnetic stimulation (TMS)-electroencephalography (EEG) navigated co-registration to investigate the influence of physiological aging on the excitability and connectivity of the human sensorimotor cortical system. To this end, we compared the TMS-evoked EEG potentials (TEPs) collected after stimulating the dominant primary motor cortex (M1) in healthy young subjects (mean age 24.5years) with those collected in healthy older adults (mean age 67.6years). We have shown that, after stimulation of the left motor cortex, TEPs are significantly affected by physiological aging. This phenomenon has a clear spatio-temporal specificity and we speculate that normal aging per se leads to some changes in the excitability of specific cortical neural assemblies whereas other alterations could reflect compensatory mechanisms to such changes.

背景与目标： ：感觉运动皮质系统在其整个生命周期中都会发生结构和功能的变化。这些变化中的一些是生理上的并且与正常衰老过程平行，而其他一些则可能代表了神经退行性疾病的病理生理机制。近年来，对大脑感觉运动功能特征可能与年龄有关的修饰的研究一直是数个研究项目的重点。在这里，我们已使用经颅磁刺激（TMS）-脑电图（EEG）导航的共同注册，以研究生理老化对人类感觉运动皮层系统的兴奋性和连通性的影响。为此，我们比较了健康年轻受试者（平均年龄24.5岁）和健康老年人（平均年龄67.6岁）在刺激主要运动皮层（M1）后所采集的TMS诱发的脑电势（TEP）。我们已经表明，刺激左运动皮层后，TEP受生理老化的影响很大。这种现象具有明显的时空特异性，我们推测正常衰老本身会导致特定皮层神经组件兴奋性发生某些变化，而其他变化可能反映出这种变化的补偿机制。