全文获取类型
收费全文 | 7257篇 |
免费 | 762篇 |
国内免费 | 351篇 |
出版年
2024年 | 37篇 |
2023年 | 195篇 |
2022年 | 310篇 |
2021年 | 435篇 |
2020年 | 409篇 |
2019年 | 673篇 |
2018年 | 402篇 |
2017年 | 229篇 |
2016年 | 241篇 |
2015年 | 245篇 |
2014年 | 497篇 |
2013年 | 566篇 |
2012年 | 332篇 |
2011年 | 419篇 |
2010年 | 254篇 |
2009年 | 272篇 |
2008年 | 270篇 |
2007年 | 284篇 |
2006年 | 267篇 |
2005年 | 190篇 |
2004年 | 180篇 |
2003年 | 153篇 |
2002年 | 142篇 |
2001年 | 127篇 |
2000年 | 120篇 |
1999年 | 93篇 |
1998年 | 79篇 |
1997年 | 72篇 |
1996年 | 75篇 |
1995年 | 78篇 |
1994年 | 76篇 |
1993年 | 66篇 |
1992年 | 63篇 |
1991年 | 52篇 |
1990年 | 55篇 |
1989年 | 43篇 |
1988年 | 41篇 |
1987年 | 28篇 |
1986年 | 26篇 |
1985年 | 33篇 |
1984年 | 53篇 |
1983年 | 32篇 |
1982年 | 46篇 |
1981年 | 23篇 |
1980年 | 20篇 |
1979年 | 24篇 |
1978年 | 13篇 |
1977年 | 8篇 |
1976年 | 6篇 |
1974年 | 6篇 |
排序方式: 共有8370条查询结果,搜索用时 15 毫秒
991.
Ugur Sahin Sylvia Kraft-Bauer Sascha Ohnesorge M. Pfreundschuh Christoph Renner 《Cancer immunology, immunotherapy : CII》1996,42(1):9-14
The combination of CD16/CD30 bispecific monoclonal antibodies (bi-mAb) and unstimulated human resting natural killer (NK)
cells can cure about 50% of mice with severe combined immunodeficiency (SCID) bearing subcutaneously growing established Hodgkin’s
lymphoma. As interleukin-2 (IL-2) and IL-12 have been shown to increase NK cell activity, we tested the capacity of these
cytokines to increase bi-mAb-mediated NK cell cytotoxicity against two types of human tumors (Hodgkin’s disease and colorectal
carcinoma). Unstimulated NK cells needed a three- to five-times higher antibody concentration than cytokine-stimulated NK
cells to exert similar levels of bi-mAb-mediated cytotoxicity. The augmented tumor cell lysis was achieved with IL-12 at considerably
lower concentrations than with IL-2 and was associated with a significantly increased bi-mAb-mediated intracellular Ca2+ mobilization. The efficiency of IL-12 in this setting together with its low toxicity make it the ideal candidate for a combination
therapy with NK-cell-activating bi-mAb in human tumors that are resistant to standard treatment.
Received: 26 July 1995 / Accepted: 16 November 1995 相似文献
992.
There are conflicting data about the effect of the epidermal growth factor (EGF) on protein kinase C (PKC) enzyme activity. The aim of our study was to find out which type of phospholipids [phosphatidylinositol 4,5-bisphosphate P14,5P2 or the other phospholipids-phosphatidylcholine (PC) or phosphatidic acid (PA)] could be the source of 1,2-diacylglycerol (1,2-DAG) in PKC activation. In colon carcinoma cells (HT29) we observed a more than 2-fold increase in the PC pool and at the same time decreased tyrosine kinase activity (50%). With increasing incubation time EGF affects the pools of both phosphatidylinositols and other phospholipids parallel with the activation of the tyrosine kinase activity. EGF increases the activity of PKC in the HT29 cell line and PC could be the source of 1,2-DAG which may stimulate PKC activity. 相似文献
993.
《Epigenetics》2013,8(4):579-586
The Na,K-ATPase or sodium pump carries out the coupled extrusion of Na+ and uptake of K+ across the plasma membranes of cells of most higher eukaryotes. We have shown earlier that Na,K-ATPase-β1 (NaK-β) protein levels are highly reduced in poorly differentiated kidney carcinoma cells in culture and in patients' tumor samples. The mechanism(s) regulating the expression of NaK-β in tumor tissues has yet to be explored. We hypothesized that DNA methylation plays a role in silencing the NaK-β gene (ATP1B1) expression in kidney cancers. In this study, to the best of our knowledge we provide the first evidence that ATP1B1 is epigenetically silenced by promoter methylation in both renal cell carcinoma (RCC) patients’ tissues and cell lines. We also show that knockdown of the von Hippel-Lindau (VHL) tumor suppressor gene in RCC cell lines results in enhanced ATP1B1 promoter AT hypermethylation, which is accompanied by reduced expression of NaK-β. Furthermore, treatment with 5-Aza-2′-deoxycytidine rescued the expression of ATP1B1 mRNA as well as NaK-β protein in these cells. These data demonstrate that promoter hypermethylation is associated with reduced NaK-β expression, which might contribute to RCC initiation and/or disease progression. 相似文献
994.
995.
Julie A. McEarchern David G. Besselsen Emmanuel T. Akporiaye 《Cancer immunology, immunotherapy : CII》1999,48(2-3):63-70
Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that contributes to the immunological escape of tumor
cells. In a previous study we demonstrated that inhibition of TGFβ production by EMT6 murine mammary tumor cells expressing
an antisense TGF-β transgene reduces their tumorigenicity. On the basis of this observation we hypothesized that down-regulation
of TGFβ production coupled with interferon γ (IFNγ) stimulation would induce an immune response superior to that generated
by either strategy alone. In this study, EMT6 tumor cells expressing antisense TGFβ were transduced with the murine IFNγ gene.
Tumor cells expressing either or both transgenes grew more slowly than mock-transduced tumors. Dual-transgene-expressing tumor
cells were more immunogenic than tumor cells expressing either transgene alone. Studies in mice depleted of T cell subsets
indicated that CD8+ T cells are the primary effectors of the antitumor activity observed. These results suggest that down-regulation of immunosuppression
combined with cytokine-mediated immune augmentation is a useful strategy to improve antitumor immunity.
Received: 6 October 1998 / Accepted: 15 January 1999 相似文献
996.
Bassam M. Ayoub Yasmeen M. Attia 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):858-866
Chemical entities with structural diversity were introduced as candidates targeting adenosine receptor with different clinical activities, containing 3,7-dihydro-1H-purine-2,6-dione, especially adenosine 3 receptors (ADORA3). Our initial approach started with pharmacophore screening of ADORA3 modulators; to choose linagliptin (LIN), approved anti-diabetic drug as Dipeptidyl peptidase-4 inhibitors, to be studied for its modulating effect towards ADORA3. This was followed by generation, purification, analytical method development, and structural elucidation of oxidative degraded product (DEG). Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a downregulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7?nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted. 相似文献
997.
998.
Long noncoding RNA HOX antisense intergenic RNA (HOTAIR) is overexpressed in many types of cancers, and substantial evidence has suggested a link between cancers and HOTAIR. In the present study, we reviewed the structure and the corresponding biologic function of HOTAIR to clarify its molecular mechanism in cancer progression. HOTAIR promotes proliferation, invasion, and migration, and inhibits apoptosis in cancer cells. HOTAIR also participates in the pathogenesis and progression of cancer by regulating inflammation and immune signaling. These findings suggested that HOTAIR is a novel biomarker in human cancers. 相似文献
999.
1000.
《Molecular & cellular proteomics : MCP》2022,21(11):100422
Cellular biomolecular complexes including protein–protein, protein–RNA, and protein–DNA interactions regulate and execute most biological functions. In particular in brain, protein–protein interactions (PPIs) mediate or regulate virtually all nerve cell functions, such as neurotransmission, cell–cell communication, neurogenesis, synaptogenesis, and synaptic plasticity. Perturbations of PPIs in specific subsets of neurons and glia are thought to underly a majority of neurobiological disorders. Therefore, understanding biological functions at a cellular level requires a reasonably complete catalog of all physical interactions between proteins. An enzyme-catalyzed method to biotinylate proximal interacting proteins within 10 to 300 nm of each other is being increasingly used to characterize the spatiotemporal features of complex PPIs in brain. Thus, proximity labeling has emerged recently as a powerful tool to identify proteomes in distinct cell types in brain as well as proteomes and PPIs in structures difficult to isolate, such as the synaptic cleft, axonal projections, or astrocyte–neuron junctions. In this review, we summarize recent advances in proximity labeling methods and their application to neurobiology. 相似文献