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1.
Prostate cancer (PC) is the second most commonly occurring cancer in men. Conventional chemotherapy has wide variety of disadvantages such as high systemic toxicity and low selectivity. Targeted drug delivery is a promising approach to decrease side effects of therapy. Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer cells while low level of expression is observed in normal cells. In this study we describe the development of Glu-urea-Lys based PSMA-targeting conjugates with paclitaxel. A series of new PSMA targeting conjugates with paclitaxel was designed and synthesized. The cytotoxicity of conjugates was evaluated against prostate (LNCaP, 22Rv1 and PC-3) and non-prostate (Hek293T, VA13, A549 and MCF-7) cell lines. The most promising conjugate 21 was examined in vivo using 22Rv1 xenograft mice model. It demonstrated good efficiency comparable with paclitaxel, while reduced toxicity. 3D molecular docking study was also performed to understand underlying mechanism of binding and further optimization of the linker substructure and conjugates structure for improving the target affinity. These conjugates may be useful for further design of novel PSMA targeting delivery systems for PC.  相似文献   
2.
目的:探讨紫杉醇联合铂类方案对中晚期宫颈癌的临床疗效。方法:98例中晚期宫颈癌患者平均分为两组,观察组采用紫杉醇联合铂类方案治疗,对照组采用伊立替康联合铂类方案治疗。分别用电化学发光法、微粒子酶免疫分析法检测血清中人细胞角蛋白21-1片段(CYFRA21-1)、人鳞状细胞癌相关抗原(SCC-Ag)含量,对比两种治疗方案的临床疗效、生存质量、副反应。结果:观察组有效率73.5%显著高于对照组42.9%(P0.01)。治疗后两组血清CYFRA21-1、SCC-Ag较治疗前均有明显降低(均P0.05),且观察组较对照组降低更明显(P0.05)。治疗后,两组躯体功能(PF)、情绪功能(EF)、社会功能(SF)、疲乏(FA)、食欲减退(AP)、疼痛(PA)方面均改善,其中,除EF外,观察组改善均优于对照组(均P0.05)。观察组副反应总发生率显著低于对照组(P0.05)。结论:紫杉醇联合铂类方案对中晚期宫颈癌疗效显著,具有改善患者生存质量、减少副反应、降低血清CYFRA21-1、SCC-Ag水平的优点。  相似文献   
3.
Aneugenic compounds act on non-DNA targets to exert genotoxicity via an indirect mechanism. In contrast to DNA-binding agents, these compounds are expected to possess threshold levels of activity. Therefore, the risk for adverse effects following human exposure to an aneugen could be minimal, if the threshold of activity has been clearly determined in vivo and in vitro and providing the human exposure level is below this threshold. Thus, the development of a single-cell model to allow comparisons between in vitro and in vivo threshold values for aneugenic compounds is of importance.The in vivo micronucleus test is one of the main assays used in genetic toxicology, and is often performed in the mouse. Thus, an extensive database is available in the literature. However, there are only few data concerning the in vitro micronucleus assay using mouse cells, as the majority of in vitro micronucleus assays have been performed using human lymphocytes. In addition, there is a lack of data concerning thresholds for any compound using this model.First, we evaluated whether the use of mouse splenocytes would be an acceptable alternative to that of human lymphocytes to identify aneugens. To allow valid comparisons, the two protocols were first harmonized. Thus, phytohemagglutinin (PHA) and concanavalin A were used as specific mitogens for human lymphocytes and mouse splenocytes, respectively, in order to achieve similar cell-proliferation rates. To achieve similar and sufficient numbers of binucleated cells, cytochalasin B was added 44 and 56 h after culture initiation of the human and mouse cells, respectively.Second, we compared the sensitivity of the mouse protocol with that of the human protocol by exposing the cells to the aneugens nocodazole and paclitaxel.There was good reproducibility of the cytotoxic/genotoxic responses of the two cell models following exposure to the aneugens. The sensitivity of the mouse splenocytes to paclitaxel was higher than that of the human lymphocytes. The two cell types were equally sensitive to nocodazole.  相似文献   
4.
Asialoglycoprotein receptor (ASGP-R) is a promising biological target for drug delivery into hepatoma cells. Nevertheless, there are only few examples of small-molecule conjugates of ASGP-R selective ligand equipped by a therapeutic agent for the treatment of hepatocellular carcinoma (HCC). In the present work, we describe a convenient and versatile synthetic approach to novel mono- and multivalent drug-conjugates containing N-acetyl-2-deoxy-2-aminogalactopyranose and anticancer drug – paclitaxel (PTX). Several molecules have demonstrated high affinity towards ASGP-R and good stability under physiological conditions, significant in vitro anticancer activity comparable to PTX, as well as good internalization via ASGP-R-mediated endocytosis. Therefore, the conjugates with the highest potency can be regarded as a promising therapeutic option against HCC.  相似文献   
5.
Enucleated mammalian cells (cytoplasts) have been widely used for studying differential roles of the cytoplasm and nucleus in various cellular processes. Here, we reported an improved enucleation protocol, in which cells were seeded in extracellular matrix (ECM)-coated 24-wells and spun at 4600 g and 35 °C for 60 min in the presence of cytochalasin B and colchicine. When glass-bottom wells were used, cellular structures and organelles in cytoplasts could be examined directly by confocal microscopy. Nuclear envelope rupture did not occur probably due to mild centrifugation conditions used in this study. Addition of paclitaxel or doxorubicin completely blocked proliferation of residual nucleated cells; however, to our surprise, paclitaxel dramatically prolonged the survival of cytoplasts. Results from Annexin V and Propidium Iodide staining showed that cytoplasts died predominantly by apoptosis, which was partially inhibited by ECM and further by paclitaxel. Mitochondria were mostly rod-shaped and formed a connected network in paclitaxel-treated cytoplasts, indicating lack of fusion and fission dynamics. Moreover, paclitaxel increased mitochondrial membrane potential, suggesting that perturbation of mitochondria might be critical to the survival of cytoplasts. In conclusion, we had established an efficient and fast procedure for enucleation of adherent animal cells, which could facilitate the investigation of nucleocytoplasmic interaction.  相似文献   
6.
姜黄素和紫杉醇联用对前列腺癌PC3裸鼠移植瘤作用的研究   总被引:2,自引:0,他引:2  
目的:探讨姜黄素和半量紫杉醇联用对前列腺癌PC3裸鼠移植瘤生长增殖的影响及其机制。方法:构建人雄激素非依赖性前列腺癌细胞系PC3裸小鼠皮下移植瘤模型,随机分为溶酶对照组,姜黄素组,紫杉醇组和姜黄素+紫杉醇(半量)组(n=6)。姜黄素每隔2天腹腔注射100mg/kg,紫杉醇每3天腹腔注射10mg/kg,联合组紫杉醇减半,对照组注射药物溶剂。每6天测量计算移植瘤体积并绘制肿瘤生长曲线。药物注射30天后,取移植瘤组织标本分别进行免疫组化和定量RT-PCR,检测金属基质蛋白酶2(MMP2),增殖细胞核抗原(PCNA)蛋白及mRNA的表达。结果:移植瘤体积在24~30天时,姜黄素组和紫杉醇组肿瘤体积较对照组有不同程度的减小。姜黄素+紫杉醇(半量)组在第30天内肿瘤生长体积和紫杉醇组相近,30天后合用组肿瘤体积小于单纯紫杉醇组(P<0.05)。姜黄素和紫杉醇明显降低PC3移植瘤组织中PCNA和MMP2mRNA的表达(P<0.01)。姜黄素+紫杉醇(半量)组瘤组织中PCNA和MMP2的mRNA表达均低于紫杉醇组(P<0.05)。免疫组化染色显示PCNA和MMP2蛋白表达在治疗组均降低,和瘤组织中mRNA表达变化相一致。结论...  相似文献   
7.
《Process Biochemistry》2014,49(8):1370-1376
This study investigated changing the methanol/water ratio during fractional precipitation of paclitaxel, and adding all the distilled water at room temperature, followed mixing for an additional 10 min. When the methanol/water ratio was 50:50, 40:60, and 30:70 (v/v), the paclitaxel yield was 42.0%, 84.3%, and 92.0%, respectively. When using a methanol/water ratio of 50:50 (v/v), a similar high purity and yield of paclitaxel to the case of storing at a low temperature was achieved when adding all the distilled water at room temperature, followed by additional mixing for 10 min and further mixing at room temperature during fractional precipitation. Thus, additional mixing after adding all the distilled water is confirmed as important during fractional precipitation. Furthermore, the present results show that a high yield of high-purity paclitaxel is possible with additional mixing at room temperature after adding all the distilled water, which is significantly more economical than the existing method of storing at a low temperature for a long time after adding all the distilled water during fractional precipitation.  相似文献   
8.
紫杉醇虽被证明在多种肿瘤治疗中均具有良好的效果,但其有一个严重的缺陷:水溶性低。临床使用中需使用聚氧乙烯蓖麻油(CremphorEL)或无水乙醇作为溶剂,但其在体内降解时能释放组胺,导致严重的过敏反应以及肾毒性和神经毒性等不良反应,此外还存在患者耐受性差、血药浓度低、靶向性差等不足。在乳腺癌的诊断和治疗中,纳米技术改变了紫杉醇制剂的特征参数而使药物表现出缓释、控释性及靶向性等优势,解决了传统紫杉醇制剂水溶性差的缺点,提高了药物的生物利用度,并明显降低了紫杉醇的毒性和副作用,给紫杉醇药物在体内运输提供了新途径。  相似文献   
9.
RNA interference (RNAi) is an intrinsic cellular mechanism for the regulation of gene expression. Harnessing the innate power of this system enables us to knockdown gene expression levels in loss of gene function studies.There are two main methods for performing RNAi. The first is the use of small interfering RNAs (siRNAs) that are chemically synthesized, and the second utilizes short-hairpin RNAs (shRNAs) encoded within plasmids 1. The latter can be transfected into cells directly or packaged into replication incompetent lentiviral particles. The main advantages of using lentiviral shRNAs is the ease of introduction into a wide variety of cell types, their ability to stably integrate into the genome for long term gene knockdown and selection, and their efficacy in conducting high-throughput loss of function screens. To facilitate this we have created the LentiPlex pooled shRNA library.The MISSION LentiPlex Human shRNA Pooled Library is a genome-wide lentiviral pool produced using a proprietary process. The library consists of over 75,000 shRNA constructs from the TRC collection targeting 15,000+ human genes 2. Each library is tested for shRNA representation before product release to ensure robust library coverage. The library is provided in a ready-to-use lentiviral format at titers of at least 5 x 108 TU/ml via p24 assay and is pre-divided into ten subpools of approximately 8,000 shRNA constructs each. Amplification and sequencing primers are also provided for downstream target identification.Previous studies established a synergistic antitumor activity of TRAIL when combined with Paclitaxel in A549 cells, a human lung carcinoma cell line 3, 4. In this study we demonstrate the application of a pooled LentiPlex shRNA library to rapidly conduct a positive selection screen for genes involved in the cytotoxicity of A549 cells when exposed to TRAIL and Paclitaxel. One barrier often encountered with high-throughput screens is the cost and difficulty in deconvolution; we also detail a cost-effective polyclonal approach utilizing traditional sequencing.  相似文献   
10.
Paclitaxel (also known as Taxol) is a well-known anticancer agent that blocks cell mitosis and kills tumor cells, and is often used in clinic to treat cancers. Despite the success of Paclitaxel, the development of drug resistance prevents its clinical applicability. Here, we screened an siRNA library against the entire human genomes using HeLa cells, and have find that lack of USP15 (ubiquitin-specific protease 15) causes Paclitaxel resistance. We also observed the decreased expression of USP15 in Paclitaxel-resistant human ovarian cancer samples. In addition, we have demonstrated that USP15 plays an essential role for stability and activity of caspase-3 during Paclitaxel-induced apoptosis. Thus, USP15 may be a candidate diagnostic marker and therapeutic target for Paclitaxel-resistant cancers.  相似文献   
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