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71.
Ciusani E Perego P Carenini N Corna E Facchinetti F Boiardi A Salmaggi A Zunino F 《Biochemical pharmacology》2002,63(5):881-887
The expression of the death receptor Fas/CD95 is cell type-specific and can be modulated by different cytotoxic treatments. In spite of a frequent expression of Fas/CD95 in high-grade gliomas, these tumours are typically refractory to conventional therapy. Using a human glioblastoma cell line (GBM), we explored the possibility of modulating susceptibility to Fas/CD95-mediated apoptosis following cytotoxic treatment. GBM cells were sensitive to the antiproliferative effects of topoisomerase I inhibitors (topotecan and a novel lipophilic analog CPT83) and taxol, less sensitive to cisplatin and, in any case, rather resistant to drug-induced apoptosis. This pattern of cellular response was consistent with p53 mutation. GBM cells expressed low levels of Fas/CD95, which was associated with low susceptibility to antibody-stimulated Fas/CD95-mediated apoptosis. A significant up-regulation of Fas/CD95 expression was detected after exposure to topotecan and CPT83, whereas cisplatin induced a low increase and taxol did not modify Fas/CD95 expression. In addition, after treatment with topoisomerase I inhibitors, the up-regulation of Fas/CD95 resulted in an increased susceptibility of GBM cells to antibody-stimulated Fas/CD95-mediated apoptosis, while no synergistic effects were detected after treatment with cisplatin or taxol. Our data suggest that Fas/CD95 up-regulation can be a common response to DNA damage, whereas sensitisation to Fas/CD95-mediated apoptosis appears to be dependent on the type of DNA damage and on the pathway of cellular response. The observed effects might have important therapeutic implications for the design of novel therapeutic strategies in the treatment of malignant gliomas. 相似文献
72.
Treatment of the hormone refractory prostate cancer cell line DU 145 with sublethal concentrations of chemotherapeutic drugs has been reported to sensitise these cells to Fas mediated apoptosis. However, the mechanism by which this occurs has not been determined. Our group has shown that inhibition of JNK activity completely abrogates the effects of chemotherapeutic drugs. Using anisomycin, a potent JNK agonist, we have demonstrated a role for JNK in Fas mediated apoptosis in DU 145 cells. Inhibition of Caspase 8 and Caspase 9 completely inhibits this process which suggests that DU 145 cells require mitochondrial amplification of the Fas apoptotic signal. Furthermore, we have shown that inhibition of Fas mediated apoptosis is an early event in DU 145 cells, occurring upstream of Caspase 8 cleavage. It is hoped that identifying the target of JNK will allow novel therapies to be developed for the treatment of hormone refractory prostate cancer. Such therapies are especially important because no single or combined treatment to date has significantly prolonged survival in patients with hormone refractory prostate cancer. 相似文献
73.
74.
Christer von Bahr Belisario P. Lisboa Sten Orrenius 《Naunyn-Schmiedeberg's archives of pharmacology》1969,264(4):420-426
Summary The metabolism of 4-androstene-3,17-dione has been studied in rat liver microsomes. Treatment of the animals with repeated doses of phenobarbitalin vivo caused an enhanced rate of formation of 5-androstane-3,17-dione and of polar metabolites from this steroid. On the other hand, no significant increase was found in the 5-reductase activity present in the soluble cytoplasm after phenobarbital administration to the rats. Carbon monoxide and oxidized cytochrome c abolished the formation of polar metabolites from 4-androstene-3,17-dione but did not inhibit the 5-reductase activity. The present findings indicate that the hydroxylation and 5-reduction reactions, although both stimulated by phenobarbital treatment of the animals, do not involve common enzyme components.Supported by grants from the Swedisch Cancer Society, Swedish Medical Research Council (Project no. 13X-2525) and from Caroline Andriette Nobel's foundations for experimental medical research. 相似文献
75.
Eldering E Mackus WJ Derks IA Evers LM Beuling E Teeling P Lens SM van Oers MH van Lier RA 《European journal of immunology》2004,34(7):1950-1960
Various routes to apoptosis can be active during B cell development. In a model system of mature B cells, differences in caspase-3 processing have suggested that antigen receptor (BCR)-mediated apoptosis may involve a zVAD-insensitive initiator protease(s). In search of the events leading to caspase-3 activation, we now establish that both CD95- and BCR-mediated apoptosis depend on Bax activation and cytochrome C (cytC) release. Nevertheless, the timing and caspase-dependence of mitochondrial membrane depolarization differed considerably after CD95- or BCR-triggering. To delineate events subsequent to cytC release, we compared apoptosis induced via BCR triggering and via direct mitochondrial depolarization by CCCP. In both cases, partial processing of caspase-3 was observed in the presence of zVAD. By expression in 293 cells we addressed the potential of candidate initiator caspases to function in the presence of zVAD, and found that caspase-9 efficiently processed caspase-3, while caspase-2 or -8 were inactive. Finally, retroviral expression of dominant-negative caspase-9 inhibited both CD95- and BCR-mediated apoptosis. In conclusion, we obtained no evidence for involvement of a BCR-specific protease. Instead, our data show for the first time that the BCR-signal causes Bax translocation, followed by mitochondrial depolarization, and cytC release. Subsequent caspase-9 activation can solely account for events further downstream. 相似文献
76.
Arsenic trioxide sensitizes CD95/Fas-induced apoptosis through ROS-mediated upregulation of CD95/Fas by NF-kappaB activation 总被引:8,自引:0,他引:8
Woo SH Park IC Park MJ An S Lee HC Jin HO Park SA Cho H Lee SJ Gwak HS Hong YJ Hong SI Rhee CH 《International journal of cancer. Journal international du cancer》2004,112(4):596-606
CD95/Fas is a cell surface protein that belongs to the tumor necrosis factor receptor family. Signals through CD95/Fas are able to induce apoptosis in sensitive cells. Therefore, modalities to regulate the CD95/Fas expression level in tumor cells are called for. In the present study, we show that sublethal doses of arsenic trioxide (As2O3) sensitized CD95/Fas-induced apoptosis in human cervical cancer cells, and the sensitizing effects resulted from As2O3-mediated increase in the expression of the CD95/Fas. N-acetyl-L-cysteine, a specific scavenger of reactive oxygen species, abrogated As2O3-induced upregulation of CD95/Fas and enhancement of CD95/Fas-mediated apoptosis. Furthermore, inhibition of NF-kappaB by transient transfection of IkappaBalpha supersurppessor blocked the increase of CD95/Fas expression following As2O2 treatment. Antisense oligonucleotide of CD95/Fas and ZB4, an antibody that blocks the binding of CD95/Fas ligand to CD95/Fas, reduced the amount of As2O3-sensitized CD95/Fas-induced apoptosis, demonstrating the specificity of CD95/Fas-binding ligands in the As2O3-sensitized CD95/Fas-induced apoptosis. These findings demonstrate that sensitization of human cervical cancer cells to CD95/Fas-mediated apoptosis by As2O3 can be partly due to induction of ROS and subsequent upregulation of CD95/Fas gene expression by NF-kappaB activation. 相似文献
77.
78.
The induction of immunologic tolerance to solid organ allografts is a subject of intense investigation because of the morbidity
and mortality associated with standard immunosuppressive therapy. One method that is currently in clinical and preclinical
testing involves the transient ablation of recipient T cells using polyclonal antithymocyte sera or monoclonal anti-CD4/CD8
antibody treatment, followed by the posttransplant administration of donor bone marrow cells or of donor peripheral lymphoid
populations. Recent studies in our laboratory have shown that the molecular and cellular basis of the prolongation of graft
survival by donor cell administration depends on the cellular compartment from which the donor cells were derived. We provide
here a brief review of these data followed by new data suggesting that the mode of peripheral and central selection is also
dependent on the source from which the donor cells were derived. 相似文献
79.
PSD-95 binds to and co-localizes with NMDA receptors at postsynaptic sites. Their co-expression in COS7 cells induces the formation of aggregates containing both proteins. These findings have lead to the hypothesis that PSD-95 helps to cluster NMDA receptors at postsynaptic sites. In addition, PSD-95 binds various regulatory proteins including Src, Pyk2, SynGAP, and nNOS and may recruit signaling proteins to NMDA receptors. We tested whether synaptic transmission or plasticity was affected by acute dissociation of the PSD-95-NMDA receptor interaction with various peptides that bound to the first two PDZ domains of PSD-95 and its homologs and with antibodies directed against the very C-terminus of the NR2A and NR2B subunits of the NMDA receptor. Membrane-impermeable peptides injected via whole cell patch electrodes distributed within minutes throughout dendritic branches into spines in acute hippocampal slices and membrane-permeable peptides containing 11 arginine residues effectively accumulated in neurites in slices and primary hippocampal cultures. Neither peptides nor antibodies showed any effect on basal synaptic transmission or induction of long-term potentiation (LTP) in hippocampal slices. Pharmacologically isolated NMDA receptor activity was also not affected. However, the membrane-permeable peptide disrupted the NMDA receptor-PSD-95 interaction in slices as tested by immunoprecipitation and subsequent immunoblotting. These findings suggest that acute dissociation of PSD-95 and its homologs from the NMDA receptor and likely from other protein complexes does not result in any easily detectable physiological effects in hippocampal slices. However, we cannot exclude a role of PSD-95 in early events that lead to clustering of NMDA receptors or of other proteins including stargazin and AMPA receptors at postsynaptic sites nor do these experiments address the possibility of long-term changes in the slices. In fact, incubation of primary hippocampal cultures with the membrane-permeable peptide lead to a moderate decrease in the number of dendritic clusters of PSD-95 and NMDA receptors and their colocalization by 20-30%, suggesting some role of PSD-95 and its homologs in NMDA receptor clustering. 相似文献
80.
Reissig D Rassoul F Salvetter J Wagner O Richter V 《European journal of nutrition》2003,42(4):224-227
Summary.Background: With respect
to linoleic acid both beneficial
and proatherogenic effects
have been described. However, the
effect on expression of cell adhesion
molecules on human coronary
artery endothelial cells (HCAEC) is
not yet established. The aim of the
experiments was to evaluate the influence
of linoleic acid in comparison
with palmitic acid regarding
the cytokine-induced expression of
endothelial leukocyte adhesion
molecules (intercellular cell adhesion
molecule-1 ICAM-1, vascular
cell adhesion molecule-1 VCAM-1,
E-selectin).Methods: HCAEC were
cultured in microvascular endothelial
cell growth medium. In the experiments,
the cells were preincubated
with linoleic acid and
palmitic acid, respectively
(10 µmol/l, 2 days) or under control
conditions, after which interleukin-
1 (IL-1, 10 ng/ml in the test
medium) was added for 1 day. The
monoclonal antibodies used were
fluorescein isothiocyanate (FITC)-
labeled anti-ICAM-1, FITC-labeled
anti-VCAM-1, and FITC-labeled
anti-E-selectin. Expression was analyzed
by flow cytofluorimetry.
Next, to examine the effects of fatty
acids on adhesion of monocytes to
endothelial cells, adhesion experiments
with the monocytic U 937
cell line were performed.Results and conclusions: IL-1 increased
ICAM-1,VCAM-1, and E-selectin
expression compared to controls.
Incubation with IL-1 together
with linoleic acid reduced the expression
of ICAM-1 and VCAM-1
in contrast to palmitic acid. Furthermore,
in the presence of
linoleic acid a tendency of diminished
adhesion of monocytes is
seen.The results indicate that a reduced
expression of cell adhesion
molecules may be relevant to the
antiatherogenic effects of linoleic
acid. This is in contrast to the properties
of palmitic acid. 相似文献