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31.
Vanadocenes are potent apoptosis-inducing cytotoxic agents against human testicular cancer cells in vitro. The present study investigated the ability of four vanadocenes-vanadocene diazide (VDA), vanadocene dicyanate (VDCN), vanadocene dioxycyanate (VDOCN), and vanadocene monochloro oxycyanate (VDCO)-to induce male germ cell apoptosis in vivo in mouse testes by repetitive intratesticular injection of vanadocenes (7.5 mg/kg/testis) for 28 days. Germ cell loss in vivo was measured by epididymal sperm count, testes weights, and histologic evaluation of the testes. Repetitive intratesticular injection of vanadocenes led to decreased sperm counts and reduced testicular weights. Histopathological examination revealed seminiferous tubular atrophy, inhibition of spermatogenesis, and the preferential loss of maturing and elongated spermatids. In situ evaluation by the terminal deoxynucleotidyl transferase-mediated FITC-deoxyuridine triphosphate nick-end labeling (TUNEL) of seminiferous tubule cross sections and laser confocal microscopy showed characteristic apoptotic cells identified primarily as pachytene spermatocytes delineating the periphery of the seminiferous tubules. The ability of vanadocenes to induce germ cell apoptosis in vivo may have potential utility in the treatment of testicular seminomas in humans. 相似文献
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Bis-cyclopentadienyl complexes of vanadium(IV) or vanadocenes are rapid and potent inhibitors of human sperm motility with potential as a new class of contraceptive agents. In this study, groups of 10 B(6)C(3)F(1) and 20 CD-1 female mice were exposed intravaginally to a gel-microemulsion containing 0, 0.06, 0.12, or 0.25% of a representative vanadocene, vanadocene acetylacetonato monotriflate (VDACAC), five days per week for 13 consecutive weeks. The doses of VDACAC used were nearly 300- to 1250-fold higher than its in vitro spermicidal EC(50) value. After 13 weeks of intravaginal treatment, B(6)C(3)F(1) mice were evaluated for survival, body weight gain, absolute and relative organ weights, and systemic toxicity. Blood was analyzed for hematological and clinical chemistry profiles. Microscopic examination was performed on hematoxylin- and eosin-stained tissue sections from each study animal. Vanadium content in tissues was determined by atomic absorption spectroscopy. Gel-microemulsion (placebo) control and VDACAC dosed female CD-1 mice were mated with untreated males in order to evaluate if VDACAC has any adverse effects on the reproductive outcome. There were no treatment-related mortalities in either study. Mean body weight gain during the dosing period was not reduced by VDACAC treatment. Hemograms or clinical chemistry profiles did not reveal any toxicologically significant changes attributed to VDACAC treatment. No clinically significant dose-dependent changes in absolute and relative organ weights were noted in VDACAC dose groups. Extensive histopathological examination of tissues revealed no treatment-related abnormalities in any of the three VDACAC dose groups. Vanadium was not incorporated in mouse tissues at levels above 1 microg/g. Repeated intravaginal exposure of CD-1 mice to increasing concentrations of VDACAC for 13 weeks had no adverse effect on their subsequent reproductive capability (100% fertile), neonatal survival (>96%) or pup development. Collectively, these findings demonstrate that repetitive intravaginal administration of VDACAC to yield effective spermicidal concentrations (<0.1%) in the vagina was not associated with systemic toxicity and did not adversely affect the reproductive performance in mice. The spermicidal vanadocene-chelated complex, VDACAC, may be useful as a safe vaginal contraceptive. 相似文献
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The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 exhibited favorable pharmacokinetics in CD-1 mice, BALB/c mice, rats, and dogs. The intraperitoneal bioavailability was estimated to be -100%, while the oral bioavailability was -30%. LFM-A13 enters, but does not bind to multiple tissues followed by a rapid elimination from most of the tissues. Limited distribution of LFM-A13 to extravascular tissues and its corresponding low volume of distribution could be attributed to its plasma protein binding. LFM-A13 was not toxic to mice, rats, or dogs at daily dose levels as high as 100 mg/kg. LFM-A13 formulated as a suspension and hard gelatin capsules for oral administration showed a rapid absorption and favorable pharmacokinetic features. These preclinical research studies provide the basis for future pre-IND studies and clinicaldevelopment of LFM-A13 as an intravenously or orally administered new anti-leukemia agent targeting BTK. 相似文献
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Fatih M. Uckun Mildred Hanson Lisa Tuel-ahlgren Ilker Dibirdik Mridula Chandan-langlie Dean Discher Vedat Obuz Gary L. Schieven Jeffrey A. Ledbetter 《Leukemia & lymphoma》1992,6(2):117-132
The purposes of this study were to elucidate the biologic effects of recombinant human interleukin 3 (rhIL-3) on leukemia T-cell precursors and fetal thymocytes corresponding to discrete and sequential developmental stages of human T-cell ontogeny, and to examine the biochemical nature of the IL-3 receptor linked transmembrane signal in human T-cell precursor populations. The specific binding of biosynthetically labeled 35S-rhIL-3 to leukemic T-cell precursors from T-lineage ALL patients was initially investigated. In 5 of 9 cases, the binding of 35S-rhIL-3 was significantly blocked by excess cold rhIL-3, and the percentage of inhibitable binding ranged from 40% to 64% (mean ± SE = 53 ± 4%). In these cases, 5-13 femtomols (mean + SE = 7.0 ± 1.5 fms) of 35S-rhIL-3/107 cells were specifically bound. rhIL-3 stimulated in a dose dependent fashion the in vitro clonal proliferation of leukemic T-cell precursors with composite immunophenotypes corresponding to the developmental stages of prothymocytes/double negative immature thymocytes (3 of 5 cases) and corticothymocytes/double positive CD4+CD8+ immature thymocytes (4 of 4 cases). By contrast, leukemic T-cell precursors from 2 T-lineage ALL cases with a composite immunophenotype of medullary thymocytes/single positive CD4+CD8-/CD4-CD8+ mature thymocytes did not show an enhanced proliferative activity after stimulation with increasing concentrations of rhIL-3. All of the 5 cases with significant 35S-rhIL-3 binding and none of the 4 cases with no 35S-rhIL-3 binding showed a proliferative response to rhIL-3. Thus, there was a high correlation between 35S-rhIL-3 binding and proliferative response of leukemic T-cell precursors in colony assays, indicating that functional IL-3 receptors were detected in ligand binding assays. rhIL-3 also stimulated the proliferation of immature double positive CD4+CD8+ thymocytes from 9 of 10 fetal thymuses without inducing differentiation and with no selective advantage for the development of CD4+CD8- or CD4- or CD4-CD8+ single positive thymocytes. The observed differences in IL-3 responsiveness among T-cell precursor populations at distinct developmental stages indicates that IL-3 receptors may be expressed only during the early stages of human T-cell ontogeny preceding the negative or positive selection events within the thymic microenvironment. Stimulation of fetal thymocytes with rhIL-3 resulted in enhanced tyrosine phosphorylation of 8 distinct cellular substrates with molecular weights of 44 kDa, 55 kDa, 60 kDa, 69 kDa, 98 kDa, 123 kDa, 150 kDa and 190 kDa, but it did not result in stimulation of phosphoinositide turnover and increased Ins-1,4,5-P3 production. The induction of tyrosine phosphorylation by rhIL-3 was augmented by further crosslinking surface bound IL-3 molecules with an anti-IL-3 antibody and it was abrogated by the tyrosine kinase inhibitor genistein. The ligation of the CD45 protein tyrosine phosphatase markedly suppressed the tyrosine phosphorylation of specific substrates induced by IL-3 stimulation. Thus, the mitogenic transmembrane signal triggered by the engagement of the IL-3 R on human T-cell precursors is linked to a functional protein tyrosine kinase (PTK)/protein tyrosine phosphatase (PTP) regulatory pathway. Taken together, these results indicate that IL-3 may have an important growth regulatory role in early stages of human T-cell ontogeny. 相似文献