首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   1764873篇
  免费   130003篇
  国内免费   4380篇
耳鼻咽喉   24067篇
儿科学   59085篇
妇产科学   50337篇
基础医学   253261篇
口腔科学   49275篇
临床医学   155108篇
内科学   347698篇
皮肤病学   39003篇
神经病学   140507篇
特种医学   69505篇
外国民族医学   623篇
外科学   269832篇
综合类   40072篇
一般理论   620篇
预防医学   134149篇
眼科学   40494篇
药学   127409篇
  3篇
中国医学   3551篇
肿瘤学   94657篇
  2018年   18175篇
  2017年   14283篇
  2016年   15876篇
  2015年   17906篇
  2014年   24909篇
  2013年   38442篇
  2012年   50958篇
  2011年   54156篇
  2010年   32726篇
  2009年   30924篇
  2008年   51337篇
  2007年   54325篇
  2006年   54975篇
  2005年   53391篇
  2004年   51610篇
  2003年   49700篇
  2002年   48511篇
  2001年   80540篇
  2000年   82744篇
  1999年   70024篇
  1998年   19698篇
  1997年   17872篇
  1996年   17882篇
  1995年   16905篇
  1994年   15889篇
  1993年   14950篇
  1992年   55754篇
  1991年   53977篇
  1990年   53088篇
  1989年   51094篇
  1988年   46839篇
  1987年   46658篇
  1986年   44209篇
  1985年   42494篇
  1984年   31815篇
  1983年   27062篇
  1982年   16277篇
  1981年   14455篇
  1979年   29527篇
  1978年   21026篇
  1977年   17827篇
  1976年   16787篇
  1975年   18027篇
  1974年   21683篇
  1973年   20859篇
  1972年   19416篇
  1971年   18006篇
  1970年   17036篇
  1969年   15912篇
  1968年   14898篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
101.
Background Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10−6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma  相似文献   
102.
103.
104.
105.
106.
107.
108.
109.
Farnesyltransferase (FTase) is one of the prenyltransferase family enzymes that catalyse the transfer of 15-membered isoprenoid (farnesyl) moiety to the cysteine of CAAX motif-containing proteins including Rho and Ras family of G proteins. Inhibitors of FTase act as drugs for cancer, malaria, progeria and other diseases. In the present investigation, we have developed two structure-based pharmacophore models from protein–ligand complex (3E33 and 3E37) obtained from the protein data bank. Molecular dynamics (MD) simulations were performed on the complexes, and different conformers of the same complex were generated. These conformers were undergone protein–ligand interaction fingerprint (PLIF) analysis, and the fingerprint bits have been used for structure-based pharmacophore model development. The PLIF results showed that Lys164, Tyr166, TrpB106 and TyrB361 are the major interacting residues in both the complexes. The RMSD and RMSF analyses on the MD-simulated systems showed that the absence of FPP in the complex 3E37 has significant effect in the conformational changes of the ligands. During this conformational change, some interactions between the protein and the ligands are lost, but regained after some simulations (after 2 ns). The structure-based pharmacophore models showed that the hydrophobic and acceptor contours are predominantly present in the models. The pharmacophore models were validated using reference compounds, which significantly identified as HITs with smaller RMSD values. The developed structure-based pharmacophore models are significant, and the methodology used in this study is novel from the existing methods (the original X-ray crystallographic coordination of the ligands is used for the model building). In our study, along with the original coordination of the ligand, different conformers of the same complex (protein–ligand) are used. It concluded that the developed methodology is significant for the virtual screening of novel molecules on different targets.  相似文献   
110.
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号