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961.
The Hedgehog (Hh) signaling pathway is of central importance during embryo development in metazoans and governs a diverse array of processes including cell proliferation, differentiation, and tissue patterning. In normal adult physiology, the pathway is implicated in stem cell maintenance, tissue repair and regeneration. However, the pathway's darker side is its involvement in several types of human cancer, to which it confers growth promoting and/or survival capabilities to the cancer cell to varying degrees, and by different mechanisms. The Hh pathway is firmly linked to the etiology of basal cell carcinoma and to at least a subset of medulloblastoma. There is increasing evidence that other sporadic cancers, including those in pancreas, prostate, lung, and breast, could also be dependent on Hh pathway activity. In this review, we provide an overview of the pathway's role in various tumor types, where much of the framework for Hh-dependent malignancies has been elucidated in experimental mouse models. We discuss three different signal transduction models for the pathway's involvement in cancer: i) ligand-independent signaling, ii) ligand-dependent autocrine/juxtacrine signaling, and iii) ligand-dependent paracrine signaling. These different modes of signaling may have implications for future therapeutic interventions aimed at inhibiting the pathway during disease. In addition, crosstalk with other pathways, and indications of non-canonical Hh signaling in cancer cells may further cause complications, or perhaps possibilities, in the treatment regimen. Finally, we review the rapid progress and promising results in the development of small-molecule inhibitors of the Hh pathway. 相似文献
962.
Metastasis is considered the obvious mark for most aggressive cancers. However, little is known about the molecular mechanism of the regulation of cancer metastasis. Recent evidence increasingly suggests that the interaction between chemokines and chemokine receptors is pivotal in the process of metastasis. The chemokine receptor CXCR4 and its ligand CXCL12, for example, have been reported to play a vital role in cancer metastasis. Another chemokine and chemokine receptor pair, the CXCL16/CXCR6 axis, has been studied by several independent research groups. Here, we summarize recent advances in our knowledge of the function of CXC chemokine receptor CXCR6 and its ligand CXCL16 in regulating metastasis and invasion of cancer. CXCR6 and CXCL16 are up-regulated in multiple cancer tissue types and cancer cell lines relative to normal tissues and cell lines. In addition, both CXCR6 and CXCL16 levels increase as tumor malignancy increases. Trans-membranous CXCL16 chemokine reduces proliferation while soluble CXCL16 chemokine enhances proliferation and migration. TM-CXCL16 functions as an inducer for lymphocyte build-up around tumor sites. High trans-membranous CXCL16 expression correlates with a good prognosis. Moreover, the Akt/mTOR signal pathway is involved in activating the CXCR6/CXCL16 axis. These findings suggest multiple opportunities for blocking the CXCR6/CXCL16 axis and the Akt/mTOR signal pathway in novel cancer therapies. 相似文献
963.
Søndergaard H Frederiksen KS Thygesen P Galsgaard ED Skak K Kristjansen PE Odum N Kragh M 《Cancer immunology, immunotherapy : CII》2007,56(9):1417-1428
Interleukin (IL)-21 is a recently discovered cytokine in early clinical development, which has shown anti-tumor activity in
various animal models. In the present study, we examine the anti-tumor activity of IL-21 protein therapy in two syngeneic
tumor models and its effect on the density of tumor infiltrating T cells. We treated mice bearing established subcutaneous
B16 melanomas or RenCa renal cell carcinomas with intraperitoneal (i.p.) or subcutaneous (s.c.) IL-21 protein therapy and
subsequently scored the densities of tumor infiltrating CD4+ and CD8+ T cells by immunohistochemistry. Whereas both routes of IL-21 administration significantly inhibited growth of small, established
RenCa and B16 tumors, only s.c. therapy significantly inhibited the growth of large, established tumors. We found a greater
bioavailability and significant drainage of IL-21 to regional lymph nodes following s.c. administration, which could account
for the apparent increase in anti-tumor activity. Specific depletion of CD8+ T cells with monoclonal antibodies completely abrogated the anti-tumor activity, whereas NK1.1+ cell depletion did not affect tumor growth. In accordance, both routes of IL-21 administration significantly increased the
density of tumor infiltrating CD8+ T cells in both B16 and RenCa tumors; and in the RenCa model s.c. administration of IL-21 led to a significantly higher density
of tumor infiltrating CD8+ T cells compared to i.p. administration. The densities of CD4+ T cells were unchanged following IL-21 treatments. Taken together, these data demonstrate that IL-21 protein has anti-tumor
activity in established syngeneic tumors, and we show that IL-21 therapy markedly increases the density of tumor infiltrating
CD8+ T cells. 相似文献
964.
目的:探讨LMP1对鼻咽癌中转录因子c-Jun和Etsl表达的影响,以及对Etsl和AP-1间相互作用的调控,为LMP1的致瘤机制提供新的依据。方法:选用可调控表达LMP1的鼻咽癌细胞系pTet-on-LMP1 HNE2(L7细胞),通过针对c-Jun、Ets1的硫代反义寡核苷酸进行阻断,观察LMP1对c-Jun、Ets1表达的影响及其相互作用,蛋白质印迹法检测Ets-1、c-Jun蛋白质表达。免疫共沉淀(IP)结合Western blot研究c-Jun和Ets1相互结合的情况。结果:在不同浓度Dox诱导24 h后,Dox为0.6μg/mL时的c-Jun和Ets1表达均最强。随着Dox诱导时间的延长,L7细胞中c-Jun和Ets1的表达上调,至4 h达到最高。阻断c-Jun表达后,Ets1表达显著降低;阻断Ets1表达后,c-Jun表达显著降低。在Dox诱导的L7细胞总蛋白中,在IP沉淀的Ets1中存在c-Jun表达,并且在Dox 0.6μ/mL时最强;在IP沉淀的c-Jun中存在Ets1表达,同样在Dox 0.6μg/mL时最强。结论:EBV-LMP1可以调控转录因子c-Jun和Ets1表达,且在调控过程中可能存在c-Jun和Ets1间的相互作用。 相似文献
965.
966.
Huang EJ Wu CC Huang HP Liu JY Lin CS Chang YZ Lin JA Lin JG Chen LM Lee SD Kuo WW Huang CY 《Molecular and cellular biochemistry》2006,290(1-2):1-7
Since there is evidence for estrogen and estrogen-like compounds to have beneficial effect on the pathogenesis of hepatocellular
carcinoma (HCC), this study was designed to investigative the apoptotic and anti-proliferative effects of these compounds
on the human hepatoma Hep3B cell line. The Hep3B cells were treated with 17β-estradiol (E2), diethylstilbestrol (DES), tamoxifen,
and genistein. After treatments of these compounds at the concentration of 10-6 or 10-8 M, the Hep3B cells were demonstrated to have significant DNA fragmentation, nucleus condensation, cytochrome-c leaking from
the mitochondria and caspase-3 activation by DAPI and Western blotting. The cells were also observed to have declined proliferative
potential by MTT assay, arrested cell cycle by flow-cytometry measurements. However, the cytochrome-c leaking from the mitochondria
induced by E2 and E2-like compounds was blocked totally by ICI 182,780 treatment. These finding suggest that estrogen and
the estrogen-like compounds may induce anti-proliferative and apoptotic effects in Hep3B cells, and the E2 and the E2-like
compounds mediated apoptotic effect was estrogen receptor dependent. Among the drugs tested, E2, E2 agonists (DES and genistein)
and partial antagonist (tamoxifen), all showed the stronger anti-tumor potential.
The last two authors, Wei-Wen Kuo and Chih-Yang Huang, share equal contribution. 相似文献
967.
Characterization of human islet-like structures generated from pancreatic precursor cells in culture 总被引:2,自引:0,他引:2
Bodnar CA Sen A Kallos MS Behie LA Petropavlovskaia M Rosenberg L 《Biotechnology and bioengineering》2006,93(5):980-988
This study addresses the characterization of human islet-like structures generated from a newly discovered sparse population of precursor cells (Petropavlovskaia and Rosenberg, 2002) in the human pancreas. These cells may be progenitor cells capable of producing pancreatic cells suitable for the treatment of type 1 diabetes. The cells were cultured successfully in non-adherent stationary cultures and yielded, as an important first step, a 1.9-fold expansion in a serum-free medium developed specifically for this cell type. This expanded population grew as pancreatic cell aggregates, which were analyzed for islet-like characteristics. Specifically, through RT-PCR analyses and functionality assays, we show that cells within the population expressed all four of the endocrine hormone genes and proteins (insulin, glucagon, somatostatin, pancreatic polypeptide). As well, the expanded pancreatic precursor cell population exhibited glucose responsiveness although the produced cells appeared to be still primitive in nature. 相似文献
968.
The contribution of drug metabolites to cyproheptadine (CPH)-induced alterations in endocrine pancreatic -cells was investigated by examining the inhibitory activity of CPH and its biotransformation products, desmethylcyproheptadine (DMCPH), CPH-epoxide and DMCPH-epoxide, on hormone biosynthesis and secretion in pancreatic islets isolated from 50-day-old rats. Measurement of (pro)insulin (proinsulin and insulin) synthesis using incorporation of 3H-leucine showed that DMCPH-epoxide, DMCPH and CPH-epoxide were 22, 10 and 4 times, respectively, more potent than CPH in inhibiting hormone synthesis. The biosynthesis of (pro)insulin was also inhibited by CPH and DMCPH-epoxide in islets isolated from 21-day-old rat fetuses. The inhibitory action of CPH and its metabolites was apparently specific for (pro)insulin, and the synthesis of other islet proteins was not affected. Other experiments showed the metabolites of CPH were active in inhibiting glucose-stimulated insulin secretion but were less potent than the parent drug in producing this effect. CPH and its structurally related metabolites, therefore, have differential inhibitory activities on insulin synthesis and release. The observation that CPH metabolites have higher potency than CPH to inhibit (pro)insulin synthesis, when considered with published reports on the disposition of the drug in rats, indicate that CPH metabolites, particularly DMCPH-epoxide, are primarily responsible for the insulin depletion observed when the parent compound is given to fetal and adult animals.Abbreviations CPH
cyproheptadine
- CPH-epoxide
cyproheptadine-10-11-epoxide
- DMCPH
desmethylcyproheptadine
- DMCPH-epoxide
desmethylcyproheptadine-10,11-epoxide
- HPLC
high-performance liquid chromatography
- KBB
Krebs biocarbonate buffer
Recipient of a Society of Toxicology Predoctoral Research Fellowship.Present address: Department of Biochemistry, The University of Hong Kong, Hong Kong. 相似文献
969.
970.