全文获取类型
收费全文 | 2088篇 |
免费 | 81篇 |
国内免费 | 39篇 |
专业分类
2208篇 |
出版年
2024年 | 2篇 |
2023年 | 25篇 |
2022年 | 34篇 |
2021年 | 45篇 |
2020年 | 51篇 |
2019年 | 106篇 |
2018年 | 98篇 |
2017年 | 43篇 |
2016年 | 53篇 |
2015年 | 64篇 |
2014年 | 142篇 |
2013年 | 167篇 |
2012年 | 79篇 |
2011年 | 198篇 |
2010年 | 155篇 |
2009年 | 172篇 |
2008年 | 113篇 |
2007年 | 133篇 |
2006年 | 120篇 |
2005年 | 113篇 |
2004年 | 98篇 |
2003年 | 21篇 |
2002年 | 43篇 |
2001年 | 9篇 |
2000年 | 16篇 |
1999年 | 10篇 |
1998年 | 20篇 |
1997年 | 10篇 |
1996年 | 4篇 |
1995年 | 11篇 |
1994年 | 6篇 |
1993年 | 11篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 2篇 |
1989年 | 7篇 |
1986年 | 2篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 2篇 |
排序方式: 共有2208条查询结果,搜索用时 15 毫秒
11.
12.
A possible strategy against head and neck cancer: in silico investigation of three-in-one inhibitors
Yung-An Tsou Kuan-Chung Chen Su-Sen Chang Yeong-Ray Wen 《Journal of biomolecular structure & dynamics》2013,31(12):1358-1369
Overexpression of epidermal growth factor receptor (EGFR), Her2, and uroporphyrinogen decarboxylase (UROD) occurs in a variety of malignant tumor tissues. UROD has potential to modulate tumor response of radiotherapy for head and neck cancer, and EGFR and Her2 are common drug targets for the treatment of head and neck cancer. This study attempts to find a possible lead compound backbone from TCM Database@Taiwan (http://tcm.cmu.edu.tw/) for EGFR, Her2, and UROD proteins against head and neck cancer using computational techniques. Possible traditional Chinese medicine (TCM) lead compounds had potential binding affinities with EGFR, Her2, and UROD proteins. The candidates formed stable interactions with residues Arg803, Thr854 in EGFR, residues Thr862, Asp863 in Her2 protein, and residues Arg37, Arg41 in UROD protein, which are key residues in the binding or catalytic domain of EGFR, Her2, and UROD proteins. Thus, the TCM candidates indicated a possible molecule backbone for evolving potential inhibitors for three drug target proteins against head and neck cancer.An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:35 相似文献
13.
Xiao Fu Guanghui Cui Shuaishuai Liu Song Zhao 《Journal of cellular and molecular medicine》2020,24(2):1670-1675
This study aimed to explore the underlying mechanism of linc01014 in oesophagus cancer gefitinib resistance. Gefitinib‐resistant oesophagus squamous cell carcinoma (ESCC gefitinibR) cell lines were constructed by using different gefitinib treatment in FLO‐1, KYAE‐1, TE‐8 and TE‐5 cell lines and confirmed by MTS50 and proliferation assays. Expression of linc01014 was overexpressed/silenced in FLO‐1 cells followed by gefitinib treatment, and then, the apoptosis‐associated markers Bax and Bcl‐2, and PI3KCA in PI3K signalling pathway were determined using Western blotting. MST50 and morphology analyses showed that ESCC gefitinibR cell lines presented obvious gefitinib resistance than their parental ESCC cell lines. ESCC gefitinibR cell lines showed significantly higher proliferation abilities than their parental ESCC cell lines after treating with gefitinib. Overexpression of linc01014 significantly inhibited the apoptosis of FLO‐1 cells induced by gefitinib and silencing linc01014 obviously promoted the apoptosis of FLO‐1 cells induced by gefitinib. Silencing linc01014 could significantly increase the gefitinib chemotherapy sensitivity of oesophagus cancer via PI3K‐AKT‐mTOR signalling pathway. 相似文献
14.
Sergey S. Karlov Anastasia A. Selina Yuri F. Oprunenko Victor A. Tafeenko Judith A.K. Howard 《Inorganica chimica acta》2007,360(2):563-578
A new series of mono- and diphenylsubstituted silatranes and boratranes N(CH2CH2O)2(CHR3CR1R2O)MZ (M = Si, Z = CH2Cl, CCPh, H, OMenth, R1, R2, R3 = H, Ph; M = B, Z = nothing, R1, R2, R3 = H, Ph) have been synthesized. Both transalkoxylation and stepwise modification of a preformed metallatrane skeleton were used. The chloromethyl derivatives N(CH2CH2O)2(CHRCHRO)SiCH2Cl (R = H, Ph) react with tert-BuOK under intramolecular cycle expansion to give 1-tert-butoxy-2-carba-3-oxahomosilatranes N(CH2CH2O)(CH2CH2OCH2)(CHRCHRO)SiOtBu (R = H, Ph). The treatment of boratranes N(CH2CH2O)2(CH2CR1R2O)B (R1,R2 = H, Ph) with triflic acid and trimethylsilyl triflate results in the products of electrophilic attack at the nitrogen atom. The molecular structures of four silatranes and one boratrane bearing phenyl groups in the atrane skeleton were determined by the X-ray structure analysis. 相似文献
15.
Fausto Calderazzo Author Vitae Author Vitae Guido Pampaloni Author Vitae 《Inorganica chimica acta》2009,362(12):4291-4297
Redox processes consisting of disproportionation and syn-proportionation are reviewed with special attention to metal complexes containing carbon-based ligands, i.e. carbon monoxide or unsaturated hydrocarbons. An introduction and a survey of reactions aimed to show the large applicability of syn-proportionation reactions in the field of coordination chemistry, is followed by examples of the use of these redox processes for the preparation of catalytic precursors. The latter studies derive from the idea that if a syn-proportionation reaction can be carried out between two complexes containing different metals in different oxidation states, inter-metallic systems could be formed which may act as active catalysts, e.g. for polymerization reactions. 相似文献
16.
Lambertucci C Cristalli G Dal Ben D Kachare DD Bolcato C Klotz KN Spalluto G Volpini R 《Purinergic signalling》2007,3(4):339-346
A new series of 2,6,9-trisubstituted adenines (5–14) have been prepared and evaluated in radioligand binding studies for their affinity at the human A1, A2A and A3 adenosine receptors and in adenylyl cyclase experiments for their potency at the human A2B subtype. From this preliminary study the conclusion can be drawn that introduction of bulky chains at the N
6 position of 9-propyladenine significantly increased binding affinity at the human A1 and A3 adenosine receptors, while the presence of a chlorine atom at the 2 position resulted in a not univocal effect, depending
on the receptor subtype and/or on the substituent present in the N
6 position. However, in all cases, the presence in the 2 position of a chlorine atom favoured the interaction with the A2A subtype. These results demonstrated that, although the synthesized compounds were found to be quite inactive at the human
A2B subtype, adenine is a useful template for further development of simplified adenosine receptor antagonists with distinct
receptor selectivity profiles. 相似文献
17.
18.
Shehnaz Fatima 《Journal of receptor and signal transduction research》2013,33(3):243-252
AbstractSimultaneous inhibition of EGFR and HER2 by dual-targeting inhibitors is an established anti-cancer strategy. Therefore, a recent trend in drug discovery involves understanding the features of such dual inhibitors. In this study, three different G-QSAR models were developed corresponding to individual EGFR, HER2 and the dual-model for both receptors. The dual-model provided site-specific information wherein (i) increasing electronegative character and higher index of saturated carbon at R4 position; (ii) presence of chlorine atom at R2 position; (iii) decreasing alpha modified shape index at R1 and R3 positions; and (iv) less electronegativity at R2 position; were found important for enhancing the dual activity. Also, comparison of dual-model with the EGFR/HER2 individual models revealed that it incorporates the properties of both models and, thus, represents a combination of EGFR/HER2. Further, fragment analysis revealed that R2 and R4 are important for imparting high potency while specificity is decided by R1/R3 fragment. We also checked the predictive ability of the dual-model by determining applicability domain using William’s plot. Also, analysis of active molecules showed they show favorable substitutions that agree with the constructed dual-model. Thus, we have been successful in developing a single dual-response QSAR model to get an insight into various structural features influencing EGFR/HER2 activity. 相似文献
19.
目的:研究三氧化二砷(As2O3)对人口腔鳞癌A431细胞生长的抑制作用,探讨其抗肿瘤的机制。方法:合成特异性靶向到肿瘤细胞表面表皮生长因子受体(EGFR)的近红外荧光分子对比剂EGF-Cy5.5,验证试剂合成的靶向特异性。口腔鳞状细胞癌A431细胞系暴露于浓度分别为0μM,0.5μM,2.5μM和5.0μM的三氧化二砷溶液中0,24 h,48 h和72 h。共聚焦显微镜、流式细胞仪及免疫组化证实EGFR的表达水平,上述实验均测量三次,结果取平均值。结果:EGF-Cy5.5靶向荧光对比剂的标记率为68%~70%。对比对照组,越高浓度的三氧化二砷处理的肿瘤细胞其获得的细胞荧光信号强度越小,这与药物浓度越高细胞表面表达EGFR的量越少相一致。流式细胞仪显示,在72小时,作用于细胞的三氧化二砷药物浓度分别为0.5μM,2.5μM,和5.0μM,其相对应获得的细胞EGFR表达量分别为57.28±3.2%(P〈0.05),29.91±2.2%(P〈0.01)和10.73±2.4%(P〈0.01),明显低于对照组的细胞EGFR表达量74.42±1.8%,(P〈0.05)。结论:本研究应用近红外荧光分子成像的方法体外检测口腔鳞状细胞癌A431的EGFR表达水平,实验证明三氧化二砷对其EGFR具有明显的抑制作用,且抑制作用具有时间-剂量依赖性。 相似文献
20.
Jeong JH Jeong YJ Cho HJ Shin JM Kang JH Park KK Park YY Chung IK Chang HW Magae J 《Journal of cellular biochemistry》2012,113(4):1302-1313
Ascochlorin, a non-toxic prenylphenol compound derived from the fungus Ascochyta viciae, has been shown recently to have anti-cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti-cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)-induced HIF-1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF-1α expression in response to EGF stimulation, but not in response to hypoxia (1% O(2)) or treatment with a transition metal (CoCl(2)). Second, ascochlorin inhibited EGF-induced ERK-1/2 activation but not AKT activation, both of which play essential roles in EGF-induced HIF-1α protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR-specific small interfering RNA (siRNA) diminished HIF-1α expression, which suggested that ascochlorin inhibits HIF-1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF-mediated induction of HIF-1α expression in CaSki cells, providing a potentially new avenue of development of anti-cancer drugs that target tumor angiogenesis. 相似文献