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501.
Genetic or epigenetic inactivation of the pathway formed by the Fanconi Anemia (FA) proteins occurs in several cancer types, including head and neck squamous cell carcinomas (HNSCC), rendering the affected tumors potentially hypersensitive to DNA crosslinking agents. However, the cytotoxicity of other commonly used cancer therapeutics in cells with FA pathway defects remains to be defined. Here, we focused on the effects of cisplatin and oxaliplatin in a panel of HNSCC and fibroblast cell lines. We found that FANCC- and FANCD2-mutant cells were unexpectedly more sensitive to platinum drugs than FANCA-mutant cells, and mono-ubiquitination of FANCD2, which is mediated by the FANCA and FANCC containing FA core complex was not required for platinum resistance. Interestingly, platinum hypersensitivity could be dissociated from mitomycin C hypersensitivity suggesting different underlying mechanisms. FANCD2 or RAD51 subnuclear foci were not useful as biomarkers of platinum hypersensitivity of FANCC/FANCD2-mutant cells. Our data add to an emerging body of evidence indicating that the FA pathway is not linear and that several protein subcomplexes with different functions exist. It will be important to establish biomarkers that can predict the sensitivity of tumors with specific FA defects to chemotherapeutic agents.  相似文献   
502.
Neurotoxicity is a burdensome side effect of platinum‐based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA‐adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal‐regulated kinase 1/2, c‐Jun N‐terminal kinase/stress‐activated protein kinase, and p38 mitogen‐activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium‐sensitive voltage‐gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage‐gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance‐associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum‐induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum‐induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient‐oriented solution.  相似文献   
503.
ObjectiveThe concept of platinum sensitivity and cross-resistance among platinum agents are widely known in the management of recurrent ovarian cancer. The aim of this study was to evaluate two hypotheses regarding the validity of the concept of platinum sensitivity and non-cross-resistance of cisplatin analogue with cisplatin in recurrent cervical cancer.MethodsIn this retrospective study, the clinical data of patients with recurrent cervical cancer, who had a history of receiving cisplatin based chemotherapy (including concurrent chemoradiotherapy [CCRT] with cisplatin) and who received second-line chemotherapy at the time of recurrence between April 2004 and July 2012 were reviewed.ResultsIn total, 49 patients-34 squamous cell carcinomas (69.4%) and 15 non-squamous cell carcinomas (30.6%)-were enrolled. The median age was 53 years (range, 26 to 79 years). Univariate and multivariate analysis showed that a platinum free interval (PFI) of 12 months has a strong relationship with the response rate to second-line chemotherapy. Upon multivariate analysis of survival after second-line platinum-based chemotherapy, a PFI of 12 months significantly influenced both progression-free survival (hazard ratio [HR], 0.349; 95% confidence interval [CI], 0.140 to 0.871; p=0.024) and overall survival (HR, 0.322; 95% CI, 0.123 to 0.842; p=0.021). In patients with a PFI of less than 6 months, the difference of progression-free survival between patients with re-administration of cisplatin (3.0 months) and administration of cisplatin analogue (7.2 months) as second-line chemotherapy was statistically significant (p=0.049, log-rank test).ConclusionThe concept of platinum sensitivity could be applied to recurrent cervical cancer and there is a possibility of noncross-resistance of cisplatin analogue with cisplatin.  相似文献   
504.
BackgroundPlatinum drugs are the most powerful chemotherapeutic agents in the treatment of ovarian cancer. We demonstrated previously that unexpectedly ovarian cancer cells are sensitised to cisplatin (CDDP) by the hepatocyte growth factor (HGF), usually considered an anti-apoptotic factor.MethodsWe used quantitative polymerase chain reaction and Western blot analysis to evaluate gene and protein expression, immunofluorescence to evaluate protein localisation and functional assays to measure cell viability and apoptosis.ResultsIn ovarian cancer cells, CDDP induced the phosphorylation, i.e. the activation, of the p90RSK. Surprisingly, a 48-h-long cell pre-treatment with HGF reverted this activation. HGF pre-treatment also resulted in the increased expression of the integrin-linked kinase (ILK)-associated phosphatase (ILKAP) that dephosphorylated the p90RSK. Conversely, CDDP down-modulated ILKAP expression. This impaired CDDP efficacy, as ILKAP silencing protected cells from CDDP-induced death. In line, the biochemical inhibition of the p90RSK or the combined silencing of the most expressed RSK isoforms, namely RSK1 and RSK2, increased the efficacy of CDDP. However, p90RSK inhibition was not sufficient to revert cell protection from death after ILKAP suppression, because of the simultaneous increased activity of the anti-apoptotic kinases ILK and ILK substrate AKT, which were both dephosphorylated, i.e. negatively regulated, by ILKAP. Only the combined inhibition of p90RSK and ILK reverted the effect of ILKAP suppression.ConclusionsAs RSKs, ILK and AKT are vital kinases for ovarian cancer onset and progression, data suggest that ILKAP is a regulatory hub of ovarian cancer cell survival by controlling the activation of these kinases.  相似文献   
505.
铂类抗肿瘤药的进展与临床评价   总被引:2,自引:0,他引:2  
目的:探讨铂类抗肿瘤药的临床特点及其研究进展,为临床应用提供参考。方法:通过查阅国内外相关文献,系统地了解铂类抗肿瘤药的临床作用及相关不良反应;并检索近年上市、未获批准及正在进行临床研究的铂类药物,以分析其临床发展趋势。结果与结论:在过去的10年间,药物研发转向注重药物运输靶向介质,这些新药在保留传统铂类化合物的活性的同时,在很大程度上减少了传统铂类药物的不良反应。  相似文献   
506.
507.
目的 探讨以铂类为基础治疗非小细胞肺癌的疗效及其与亚甲基四氢叶酸还原酶(MTHFR)C677T基因多态性的相关性.方法 选取经病理确诊行手术切除后接受以铂类为基础化疗方案的NSCLC患者180例为研究组,另选择同期体检的健康人100名作为健康对照组.通过血液学标本提取的DNA进行MTHFR C677T基因分型.比较MT...  相似文献   
508.
509.
目的 分析血清耐药相关的差异表达蛋白质在诊断卵巢上皮性癌铂类耐药患者中的价值,为非手术卵巢上皮性癌患者化疗药物方案的制定提供参考.方法 选择川北医学院附属医院妇产科2015年3月至2016年3月收治的经铂类药物治疗无效的卵巢癌患者40例设为观察组,选择同期收治的经铂类药物治疗获得改善的卵巢癌患者40例作为对照组,采集两组受试者静脉血,采用酶联免疫法(ELISA)检测并比较两组患者的血清耐药相关蛋白(SERPINA1、FN1、ORM1、annexinA3、destrin、IDHl))的表达情况,所有患者均行病理穿刺,获取病理组织,采用逆转录一聚合酶链反应(RT-PCR)检测方法对病理组织中的上述耐药相关蛋白进行检测.分析血清标本检测结果和病理组织检测的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl结果之间的差异性和相关性.结果 观察组患者血清中的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl水平分别为(753.6±138.6)μg/μL、(223.5±51.5)μg/μL、(72.2±40.9)μg/μL、(331.5±21.8)μg/μL、(344.2±40.6)μg/μL、(44.5±21.3)μg/μL,病理组织中上述指标分别为(38.69±6.7)%、(32.32±6.6)%、(35.48±6.1)%、(29.44±5.4)%、(26.63±4.8)%、(11.37±1.5)%,对照组患者血清中的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl水平分别为(512.6±113.4)μg/μL、(125.5±41.4)μg/μL、(64.6±41.4)μg/μL、(215.7±21.1)μg/μL、(23.42±5.3)μg/μL、(115.5±21.3)μg/μL,病理组织中上述指标分别为(27.49±5.7)%、(21.38±5.4)%、(23.41±5.2)%、(23.41±5.2)%、(21.22±4.6)%、(29.43±2.3)%.观察组患者血清中SERPINA1、FN1、ORM1、destrin、annexinA3均明显高于对照组,但血清中IDHl水平明显低于对照组,差异均有统计学意义(P<0.05);观察组患者卵巢癌病理组织中的SERPINA1、FN1、ORM1、destrin、annexinA3水平均明显高于对照组,但IDHl水平明显低于对照组,差异均有统计学意义(P<0.05);血清中检测的SERPINA1、FN1、ORM1、destrin、annexinA3、IDHl水平与病理组织中检测的结果的spearman相关性系数分别为0.734、0.683、0.702、0.682、0.593、0.618,均呈正相关(P<0.05).结论 血清中耐药相关的差异表达蛋白质检测结果与病理组织中的检测结果密切相关,对于无法行手术探查或者治疗的患者,采用血清样本检测耐药相关差异蛋白质可为化疗药物方案的制定提供重要的参考,具有较高的临床价值.  相似文献   
510.
目的设计与合成具有高水溶性的铂类抗肿瘤药物。方法通过在丙二酸铂结构中偶联糖分子设计出目标化合物并合成取得水溶性抗肿瘤药物。结果得到了迄今水溶性最好的金属铂类抗肿瘤化合物,其动物模型抗肿瘤活性和安全性均优于顺铂和卡铂。结论通过糖分子偶联设计取得的新型铂类抗肿瘤药物能够解决一般铂类药物的低水溶性问题,经初步动物模型抗肿瘤药效实验证明该类药物具有理想的抗肿瘤效果。  相似文献   
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