全文获取类型
收费全文 | 888篇 |
免费 | 131篇 |
国内免费 | 55篇 |
专业分类
耳鼻咽喉 | 4篇 |
儿科学 | 12篇 |
妇产科学 | 6篇 |
基础医学 | 125篇 |
口腔科学 | 11篇 |
临床医学 | 56篇 |
内科学 | 191篇 |
皮肤病学 | 11篇 |
神经病学 | 78篇 |
特种医学 | 11篇 |
外国民族医学 | 1篇 |
外科学 | 31篇 |
综合类 | 87篇 |
预防医学 | 34篇 |
眼科学 | 4篇 |
药学 | 166篇 |
中国医学 | 12篇 |
肿瘤学 | 234篇 |
出版年
2024年 | 4篇 |
2023年 | 20篇 |
2022年 | 37篇 |
2021年 | 45篇 |
2020年 | 29篇 |
2019年 | 34篇 |
2018年 | 27篇 |
2017年 | 41篇 |
2016年 | 55篇 |
2015年 | 47篇 |
2014年 | 86篇 |
2013年 | 71篇 |
2012年 | 62篇 |
2011年 | 75篇 |
2010年 | 58篇 |
2009年 | 53篇 |
2008年 | 53篇 |
2007年 | 49篇 |
2006年 | 39篇 |
2005年 | 26篇 |
2004年 | 25篇 |
2003年 | 31篇 |
2002年 | 21篇 |
2001年 | 10篇 |
2000年 | 18篇 |
1999年 | 7篇 |
1998年 | 8篇 |
1997年 | 9篇 |
1996年 | 5篇 |
1995年 | 5篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1991年 | 2篇 |
1990年 | 5篇 |
1989年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
排序方式: 共有1074条查询结果,搜索用时 15 毫秒
1.
6-Mercaptopurine (6-MP) is commonly used for treatment of acute lymphoblastic leukemia (ALL). The incidence of hematotoxicity caused by this drug is quite high in Asians even using a standard low dosage regimen. The present study was aimed to elucidate the impact of thiopurine S-methyltransferase (TPMT), a nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), inosine triphosphatase (ITPA) and ATP Binding Cassette Subfamily C Member 4 (ABCC4) polymorphisms on hematotoxicity in pediatric patients who received a standard low starting dose of 6-MP. One hundred and sixty-nine pediatric patients were enrolled and their genotypes were determined. Patients who carried NUDT1513 and NUDT1512 genotypes were at a 10–15 fold higher risk of severe neutropenia than those of the wild-type during the early months of the maintenance phase. Risk of neutropenia was not significantly increased in patients with other NUDT15 variants as well as in patients with TPMT, ITPA or ABCC4 variants. These results suggest that NUDT15 polymorphisms particularly, NUDT1513 and NUDT1512, play major roles in 6-MP-induced severe hematotoxicity even when using a standard low dosage of 6-MP and genotyping of these variants is necessary in order to obtain precise tolerance doses and avoid severe hematotoxicity in pediatric patients. 相似文献
2.
Evidence from both experimental carcinogenesis and studies in human cirrhotic liver suggest that defective repair of the
promutagenic DNA base lesion, O
6-methylguanine, is a factor in the multistep process of hepatocellular carcinogenesis. Ubiquitous environmental alkylating
agents such as N-nitroso compounds can produce O
6-methylguanine in cellular DNA. Unrepaired, O
6-methylguanine can lead to the formation of G ? A transition mutations, a known mechanism of human oncogene activation and
tumour suppressor gene inactivation. Combined treatment of rodents with an agent producing O
6-methylguanine in DNA, and an agent promoting cell proliferation, leads to development of hepatic nodules and hepatocellular
carcinoma (HCC), cell division, hence DNA replication, being required for the propagation of tumorigenic mutation(s) in hepatocyte
DNA. The paramount importance of O
6-methylguanine in hepatocellular carcinogenesis is indicated by the observation that transgenic mice engineered to have increased
hepatic levels of repair enzyme O
6-methylguanine-DNA methyltransferase (MGMT) are significantly less prone to hepatocellular carcinogenesis following alkylating
agent treatment. Cirrhosis is a universal risk factor for development of human HCC, and a condition that is characterized
by increased hepatocyte proliferation as a result of tissue regeneration. Levels of the human repairing enzyme for O
6-methylguanine were found to be significantly lower in cirrhotic liver than in normal tissue. In accord with findings from
animal models, this suggested a mechanism in which persistence of O
6-methylguanine due to defective DNA repair by MGMT, together with increased hepatocyte proliferation, might lead to specific
gene mutation(s) and hepatocellular carcinogenesis. Screening for the presence and persistence of O
6-methylguanine in human DNA presently involves formidable technical difficulty. Indications are that such limitations might
be overcome by the use of an ultrasensitive method such as immuno-polymerase chain reaction (PCR). This approach should allow
parallel measurement of DNA adduct and repair enzyme in routine liver biopsy samples. It might also enable investigation of
O
6-methylguanine in human genes specifically associated with hepatocellular carcinogenesis. Given the wide variation in human
MGMT levels observed between individuals, tissues, and cells, this technology should be adapted to permit the ultrasensitive
localisation and measurement of adducts and repairing enzyme in liver biopsy tissue sections. Ability to ultrasensitively
measure O
6-methylguanine, and its repair enzyme, should prove valuable in the risk assessment of cirrhotic patients for developing hepatocellular
carcinoma.
Received for publication on July 6, 1998; accepted on Aug. 12, 1998 相似文献
3.
Xiao B Jing C Kelly G Walker PA Muskett FW Frenkiel TA Martin SR Sarma K Reinberg D Gamblin SJ Wilson JR 《Genes & development》2005,19(12):1444-1454
Methylation of lysine residues of histones is an important epigenetic mark that correlates with functionally distinct regions of chromatin. We present here the crystal structure of a ternary complex of the enzyme Pr-Set7 (also known as Set8) that methylates Lys 20 of histone H4 (H4-K20). We show that the enzyme is exclusively a mono-methylase and is therefore responsible for a signaling role quite distinct from that established by other enzymes that target this histone residue. We provide evidence from NMR for the C-flanking domains of SET proteins becoming ordered upon addition of AdoMet cofactor and develop a model for the catalytic cycle of these enzymes. The crystal structure reveals the basis of the specificity of the enzyme for H4-K20 because a histidine residue within the substrate, close to the target lysine, is required for completion of the active site. We also show how a highly variable component of the SET domain is responsible for many of the enzymes' interactions with its target histone peptide and probably also how this part of the structure ensures that Pr-Set7 is nucleosome specific. 相似文献
4.
卵巢癌组织中MGMT表达意义 总被引:1,自引:0,他引:1
目的探讨6-氧-甲基鸟嘌呤-DNA甲基转移酶(MGMT)在卵巢癌中的表达及临床意义.方法应用免疫组化(SP)法对60例卵巢癌及癌旁正常组织中MGMT的表达进行检测.结果60例卵巢癌组织中MGMT的表达率为46.7%,癌旁正常组织MGMT的表达率为100%(P<0.05).MGMT的表达与卵巢癌的组织学类型和临床分期无关(P>0.05),但与卵巢癌的病理分级有关(P<0.05).结论卵巢癌组织中存在MGMT的表达缺失,MGMT的功能失活可能是卵巢癌发生的重要机制之一. 相似文献
5.
6.
目的 观察5-氮杂-2’-脱氧胞苷(5-aza-2-deoxycytidine,5-Aza-CdR)对体外培养人涎腺腺样囊性癌(salivary adenoid cystic carcinoma,SACC)细胞系细胞O6-甲基鸟嘌呤-DNA甲基转移酶(O6-methylguanine-DNA methyhransferase,MGMT)和人类mutL同源物1(homo sapiens mutL homolog 1,hMLH1)基因表达的影响,探讨DNA甲基转移酶抑制剂应用于SACC治疗的可行性及机制.方法 用不同浓度5-Aza-CdR分别处理体外培养SACC-83和SACC-LM细胞作为药物处理组,以药物处理浓度0 μmol/L为对照组.甲基噻唑基四唑法确定5-Aza-CdR的半数抑制浓度(half maximal inhibitory concentration of a substance,IC50);实时聚合酶链反应和反转录聚合酶链反应检测用药后细胞中MGMT和hMLH1 mRNA表达水平.结果 药物处理细胞24 h后细胞形态发生变化,并且随时间延长变化愈加显著.5-Aza-CdR对SACC-83和SACC-LM细胞的IC50分别为(11.816±0.023)、(5.751± 0.049) μmol/L.经5-Aza-CdR处理后,SACC-83和SACC-LM细胞中MGMT和hMLH1 mRNA表达增高1~5倍,MGMT和hMLH1在药物处理组与对照组之间的表达差异有统计学意义(P<0.01).结论 5-Aza-CdR可改变细胞形态,上调MGMT和hMLH1 mRNA的表达,其机制可能与5-Aza-CdR反转MGMT、hMLH1基因DNA启动子区高甲基化状态有关. 相似文献
7.
8.
背景与目的血管平滑肌细胞(VSMC)凋亡在许多血管钙化疾病的病理过程中起关键作用。近期研究表明,赖氨酸甲基转移酶SET8参与调节细胞增殖、凋亡过程。文章旨在探寻SET8是否通过调节VSMC增殖、凋亡而影响血管钙化。方法体外培养原代大鼠VSMC,将VSMC随机分为正常对照组、空质粒组和SET8-shRNA组。以脂质体Lipofectamine~(TM)2000为载体,转染VSMC。采用茜素红染色法和钙含量测定法判断细胞钙化程度;采用MTT法检测三组细胞的增殖能力;实时荧光定量PCR、Western blot法检测三组细胞中增殖基因Survivin和凋亡基因Caspase-3的表达水平,分析干扰SET8对VSMC增殖、凋亡及其相关基因和蛋白表达的影响。结果 (1)干扰SET8可成功抑制VSMC中SET8蛋白的表达(P0.05)。(2)转染VSMC后,与正常对照组和空质粒组比较,SET8-shRNA组钙含量明显升高(P0.05)。(3)MTT结果显示,在第12 h、24 h、36 h、48 h,SET8-shRNA组VSMC的增殖能力较正常对照组和空质粒组明显降低(P0.05)。(4)实时荧光定量PCR和Western blot结果显示SET8-shRNA组Survivin的mRNA和蛋白表达较正常对照组和空质粒组明显下降,而Caspase-3的mRNA和蛋白表达则相反(P0.05)。结论干扰SET8能够增加促凋亡基因表达,抑制增殖基因表达,SET8有可能参与调节大鼠血管钙化。 相似文献
9.
10.
Neuroblastoma is predominantly characterised by chromosomal rearrangements. Next to V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma Derived Homolog (MYCN) amplification, chromosome 7 and 17q gains are frequently observed. We identified a neuroblastoma patient with a regional 7q36 gain, encompassing the enhancer of zeste homologue 2 (EZH2) gene. EZH2 is the histone methyltransferase of lysine 27 of histone H3 (H3K27me3) that forms the catalytic subunit of the polycomb repressive complex 2. H3K27me3 is commonly associated with the silencing of genes involved in cellular processes such as cell cycle regulation, cellular differentiation and cancer. High EZH2 expression correlated with poor prognosis and overall survival independent of MYCN amplification status. Unexpectedly, treatment of 3 EZH2-high expressing neuroblastoma cell lines (IMR32, CHP134 and NMB), with EZH2-specific inhibitors (GSK126 and EPZ6438) resulted in only a slight G1 arrest, despite maximum histone methyltransferase activity inhibition. Furthermore, colony formation in cell lines treated with the inhibitors was reduced only at concentrations much higher than necessary for complete inhibition of EZH2 histone methyltransferase activity. Knockdown of the complete protein with three independent shRNAs resulted in a strong apoptotic response and decreased cyclin D1 levels. This apoptotic response could be rescued by overexpressing EZH2ΔSET, a truncated form of wild-type EZH2 lacking the SET transactivation domain necessary for histone methyltransferase activity. Our findings suggest that high EZH2 expression, at least in neuroblastoma, has a survival function independent of its methyltransferase activity. This important finding highlights the need for studies on EZH2 beyond its methyltransferase function and the requirement for compounds that will target EZH2 as a complete protein. 相似文献