全文获取类型
收费全文 | 348篇 |
免费 | 26篇 |
国内免费 | 1篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 10篇 |
妇产科学 | 7篇 |
基础医学 | 97篇 |
口腔科学 | 6篇 |
临床医学 | 34篇 |
内科学 | 59篇 |
皮肤病学 | 2篇 |
神经病学 | 30篇 |
特种医学 | 6篇 |
外科学 | 12篇 |
综合类 | 2篇 |
预防医学 | 21篇 |
眼科学 | 1篇 |
药学 | 64篇 |
中国医学 | 2篇 |
肿瘤学 | 19篇 |
出版年
2024年 | 1篇 |
2023年 | 5篇 |
2022年 | 4篇 |
2021年 | 10篇 |
2020年 | 4篇 |
2019年 | 9篇 |
2018年 | 13篇 |
2017年 | 11篇 |
2016年 | 10篇 |
2015年 | 10篇 |
2014年 | 16篇 |
2013年 | 13篇 |
2012年 | 25篇 |
2011年 | 29篇 |
2010年 | 15篇 |
2009年 | 17篇 |
2008年 | 38篇 |
2007年 | 24篇 |
2006年 | 26篇 |
2005年 | 18篇 |
2004年 | 19篇 |
2003年 | 16篇 |
2002年 | 13篇 |
2001年 | 5篇 |
2000年 | 1篇 |
1999年 | 4篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1986年 | 1篇 |
1983年 | 2篇 |
1982年 | 2篇 |
1981年 | 3篇 |
1977年 | 1篇 |
排序方式: 共有375条查询结果,搜索用时 15 毫秒
41.
42.
Pavla Rejmanov Jií Labský Jindich Kope
ek 《Macromolecular chemistry and physics.》1977,178(8):2159-2168
4-Nitrophenyl esters of N-methacryloylamino acids and their copolymers with N-(2-hydroxypropyl)-methacrylamide were synthesized. The effect of the ester and amine structure and of the reaction medium on the rate constant of aminolysis was studied. 相似文献
43.
The oral anti-tumor activity of a novel platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand was evaluated and compared with another platinum(IV) complex satraplatin. The human carcinoma xenografts of colon HCT116, prostate PC3, and ovarian A2780 and A2780/cisR (resistant to cisplatin) were used to evaluate the in-vivo anti-tumor activity. The daily x 5 repeated dose regimen in equimolar doses of LA-12 and satraplatin, administered in 2 cycles, was selected for this evaluation. All doses of LA-12 and satraplatin were significantly effective in comparison with the control. The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin. The highest effect was reached with LA-12 at a dose of 60 mg/kg. The shapes of growth curves of ovarian carcinoma A2780 and its subline resistant to cisplatin after therapy with LA-12 were very similar. This shows that LA-12 is able to overcome resistance to cisplatin. 相似文献
44.
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-bound doxorubicin has showed greater potency than free doxorubicin in the treatment of ovarian cancer in vivo and in vitro. The promising activity of the conjugate demonstrated in clinical trials has generated considerable interest in understanding the mechanism of action of this macromolecular therapeutic. In this study, the involvement of the mitochondrial pathway in HPMA copolymer-bound doxorubicin-induced apoptosis in the human ovarian cancer cell line A2780 was investigated. Through a series of in vitro assays, including confocal microscopy, flow cytometry, and spectrofluorimetry, a significant decrease in mitochondrial membrane potential in A2780 cells treated with HPMA copolymer-bound doxorubicin was found. The most dramatic changes in mitochondrial membrane potential were observed between 2 and 12 h of continuous drug exposure. The potential of the mitochondrial membrane remained collapsed when drug treatment continued up to 24 h. For the first time, it was shown that HPMA copolymer-bound doxorubicin induces apoptosis in ovarian cancer cells by simultaneous activation of both caspase-dependent and caspase-independent pathways of DNA damage. This was determined by monitoring the translocation of the mitochondrial proteins cytochrome c and apoptosis-inducing factor to cytosol. The altered balance between anti-apoptotic and pro-apoptotic members of the Bcl-2 family of proteins was responsible for the mitochondrial function distraction. HPMA copolymer-bound doxorubicin induced a time-dependent decrease in the expression of the anti-apoptotic Bcl-2 and Bcl-xL proteins, which control cell survival. At the same time, the expression level of pro-apoptotic members (Bax, Bad) of the Bcl-2 family was increased under the chosen experimental conditions. Altogether, these results indicate that HPMA copolymer-bound doxorubicin induced apoptosis in ovarian cancer cells through the mitochondrial pathway. 相似文献
45.
Urdzíková L Jendelová P Glogarová K Burian M Hájek M Syková E 《Journal of neurotrauma》2006,23(9):1379-1391
Emerging clinical studies of treating brain and spinal cord injury (SCI) with autologous adult stem cells led us to compare the effect of an intravenous injection of mesenchymal stem cells (MSCs), an injection of a freshly prepared mononuclear fraction of bone marrow cells (BMCs) or bone marrow cell mobilization induced by granulocyte colony stimulating factor (G-CSF) in rats with a balloon- induced spinal cord compression lesion. MSCs were isolated from rat bone marrow by their adherence to plastic, labeled with iron-oxide nanoparticles and expanded in vitro. Seven days after injury, rats received an intravenous injection of MSCs or BMCs or a subcutaneous injection of GCSF (from day 7 to 11 post-injury). Functional status was assessed weekly for 5 weeks after SCI, using the Basso-Beattie-Bresnehan (BBB) locomotor rating score and the plantar test. Animals with SCI treated with MSCs, BMCs, or G-CSF had higher BBB scores and better recovery of hind limb sensitivity than controls injected with saline. Morphometric measurements showed an increase in the spared white matter. MR images of the spinal cords were taken ex vivo 5 weeks after SCI using a Bruker 4.7-T spectrometer. The lesions populated by grafted MSCs appeared as dark hypointense areas. Histology confirmed a large number of iron-containing and PKH 26-positive cells in the lesion site. We conclude that treatment with three different bone marrow cell populations had a positive effect on behavioral outcome and histopathological assessment after SCI, which was most pronounced after MSC injection. 相似文献
46.
Ormsby T Schlecker E Ferdin J Tessarz AS Angelisová P Köprülü AD Borte M Warnatz K Schulze I Ellmeier W Horejsí V Cerwenka A 《Blood》2011,118(4):936-945
The triggering receptor expressed on myeloid cells 1 (TREM-1) has been implicated in the production of proinflammatory cytokines and chemokines during bacterial infection and sepsis. For downstream signal transduction, TREM-1 is coupled to the ITAM-containing adaptor DAP12. Here, we demonstrate that Bruton tyrosine kinase (Btk), a member of the Tec kinases, becomes phosphorylated upon TREM-1 triggering. In U937-derived cell lines, in which expression of Btk was diminished by shRNA-mediated knockdown, phosphorylation of Erk1/2 and PLCγ1 and Ca2? mobilization were reduced after TREM-1 stimulation. Importantly, TREM-1-induced production of the pro-inflammatory cytokines, TNF-α and IL-8, and up-regulation of activation/differentiation cell surface markers were impaired in Btk knockdown cells. Similar results were obtained upon TREM-1 stimulation of BMDCs of Btk(-/-) mice. The analysis of cells containing Btk mutants revealed that intact membrane localization and a functional kinase domain were required for TREM-1-mediated signaling. Finally, after TREM-1 engagement, TNF-α production by PBMCs was reduced in the majority of patients suffering from X-linked agammaglobulinemia (XLA), a rare hereditary disease caused by mutations in the BTK gene. In conclusion, our data identify Btk as a positive regulator in the ITAM-mediated TREM-1/DAP12 pathway and suggest its implication in inflammatory processes. 相似文献
47.
Receptor-binding peptides are suitable targeting moieties for macromolecular therapeutics. Binding several targeting peptides to one macromolecule may improve biorecognition due to the multivalency effect. On the other hand, the resulting amphipathic structure of such conjugates may result in the association of side-chains with a concomitant decrease in the accessibility of the side-chain-bound ligands. Using the one-bead one-compound combinatorial method, we have recently identified a heptapeptide (YILIHRN; HP) ligand for the CD21 receptor (Biomacromolecules 7, 3037, 2006). Here, we evaluated the relationship between structure and self-association of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-HP conjugates using fluorescence resonance energy transfer (FRET) to evaluate their conformation in solution. In addition to HP, HPMA copolymers containing side-chains terminating in tryptophan (energy donor) and dansyl (energy acceptor) were synthesized, and solutions were evaluated using an excitation wavelength of 295 nm (ratio of emission intensity 510 nm/370 nm indicated energy transfer efficiency). It was found that higher HP content correlated with higher FRET efficiency, indicating the formation of compact coils. Modification of the HPMA copolymer backbone by the incorporation of acrylic acid (AA) comonomer units resulted in decreased FRET efficiency, presumably due to the expansion of the polymer coils as a result of electrostatic repulsion. The dependence of FRET efficiency on pH was in agreement with the ionization profile of the AA residues. To determine the effect of HP content on enzymatic drug release kinetics, HPMA copolymer-HP conjugates containing GFLG side-chains terminating with doxorubicin (DOX) were incubated with papain and the release of free DOX monitored. When HP content increased above a particular threshold, the rate of DOX release decreased as a result of self-association of HPMA copolymer-GFLG-DOX-HP conjugates. The FRET data correlated well with hydrodynamic volumes determined by size exclusion chromatography (SEC), with molecular weights determined by light scattering, and with the kinetics of drug release. 相似文献
48.
Huaizhong Pan Pavla Kopečková Dong Wang Jiyuan Yang Scott Miller JindŘich Kopeček 《Journal of drug targeting》2013,21(6):425-435
A novel bone targeting, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer based, prostaglandin E1 (PGE1) delivery system was designed, synthesized and characterized. PGE1 was bound to the polymer backbone via a spacer, composed of a cathepsin K sensitive tetrapeptide (Gly-Gly-Pro-Nle) and a self-eliminating 4-aminobenzyl alcohol structure. The HPMA copolymer conjugates were prepared by photo–initiated free radical copolymerization of HPMA, PGE1-containing macromonomer, and optionally a comonomer containing a reactive p-nitrophenyl ester group. The latter group was used as attachment points for the d-aspartic acid octapeptide targeting moieties. Incubation of the PGE1-containing macromonomer and HPMA copolymer-PGE1 conjugates with cathepsin K resulted in release of unmodified PGE1. The rate of release depended on the composition of the conjugate. The higher the PGE1 content in the conjugate, the slower the PGE1 release. This appeared to be the result of association of hydrophobic side-chains in aqueous media, which rendered the formation of the enzyme substrate complex more difficult. The data seems to indicate that HPMA copolymer-PGE1 conjugates have a potential in the treatment of osteoporosis and other bone diseases. 相似文献
49.
50.