全文获取类型
收费全文 | 615篇 |
免费 | 30篇 |
国内免费 | 13篇 |
专业分类
耳鼻咽喉 | 3篇 |
儿科学 | 13篇 |
妇产科学 | 5篇 |
基础医学 | 63篇 |
口腔科学 | 26篇 |
临床医学 | 69篇 |
内科学 | 139篇 |
皮肤病学 | 11篇 |
神经病学 | 8篇 |
特种医学 | 112篇 |
外科学 | 25篇 |
综合类 | 18篇 |
预防医学 | 18篇 |
眼科学 | 3篇 |
药学 | 22篇 |
中国医学 | 1篇 |
肿瘤学 | 122篇 |
出版年
2023年 | 4篇 |
2022年 | 4篇 |
2021年 | 5篇 |
2020年 | 8篇 |
2019年 | 7篇 |
2018年 | 8篇 |
2017年 | 7篇 |
2016年 | 12篇 |
2015年 | 10篇 |
2014年 | 14篇 |
2013年 | 23篇 |
2012年 | 12篇 |
2011年 | 22篇 |
2010年 | 30篇 |
2009年 | 34篇 |
2008年 | 20篇 |
2007年 | 34篇 |
2006年 | 15篇 |
2005年 | 16篇 |
2004年 | 23篇 |
2003年 | 11篇 |
2002年 | 14篇 |
2001年 | 16篇 |
2000年 | 18篇 |
1999年 | 11篇 |
1998年 | 35篇 |
1997年 | 42篇 |
1996年 | 31篇 |
1995年 | 25篇 |
1994年 | 17篇 |
1993年 | 21篇 |
1992年 | 10篇 |
1991年 | 4篇 |
1990年 | 14篇 |
1989年 | 14篇 |
1988年 | 15篇 |
1987年 | 18篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 5篇 |
1976年 | 3篇 |
1975年 | 3篇 |
排序方式: 共有658条查询结果,搜索用时 15 毫秒
651.
Busse A Asemissen AM Nonnenmacher A Braun F Ochsenreither S Stather D Fusi A Schmittel A Miller K Thiel E Keilholz U 《European journal of cancer (Oxford, England : 1990)》2011,47(5):690-696
Background
Tyrosine kinase inhibitors (TKI) such as sorafenib have substantially improved the prognosis of metastatic renal cell carcinoma (mRCC) patients, but long-term remissions have only been reached with immunotherapy. Sequencing or combining TKI treatment with immunotherapy may represent an attractive therapeutic concept. However, in vitro data have shown that TKI may not only affect tumour cells, but also inhibit signalling in immune effector cells. Therefore, we asked whether sorafenib had an influence on peripheral immune effector cells in a cohort of 35 mRCC patients receiving sorafenib treatment.Methods
Peripheral blood (pB) samples were analysed at baseline and after 8 weeks of treatment. IL-10 and TGF-ß mRNA levels were quantified by RT-PCR; regulatory T cell (Treg) counts and intracellular cytokine responses (TNF-α, IFN-γ, IL-10 and TGF-ß) of mononuclear cell subsets were determined by flow cytometry after in vitro stimulation with PMA/ionomycin.Results
Sorafenib did not alter the elevated TGF-ß and IL-10 mRNA levels or elevated frequencies of IL-10 and TGF-ß producing monocytes and had no influence on type 1 cytokine responses in pB. CD4+CD25high FOXP3+/CD3+ T cells, likely representing Treg cells, decreased during sorafenib therapy.Conclusions
In vivo, sorafenib treatment was associated with a decrease in frequency of Treg cells without influencing the function of peripheral immune effector cells. Therefore, although sorafenib did not convert the immunosuppressive phenotype associated with mRCC, it seemed to be a possible candidate for combination with immunotherapy. 相似文献652.
SL Able RL Fish H Bye L Booth YR Logan C Nathaniel P Hayter SD Katugampola 《British journal of pharmacology》2011,162(2):405-414
BACKGROUND AND PURPOSE
The P2X7 receptor is implicated in inflammation and pain and is therefore a potential target for therapeutic intervention. Here, the development of a native tissue radioligand binding, localization and ex vivo occupancy assay for centrally penetrant P2X7 receptor antagonists is described.EXPERIMENTAL APPROACH
Autoradiography studies using the P2X7 antagonist radioligand [3H]-A-804598 were carried out in rat brain and spinal cord. Subsequent in vitro binding and ex vivo occupancy assays were performed using rat cortex homogenate.KEY RESULTS
P2X7 expression was shown to be widespread throughout the rat brain, and in the grey matter of the spinal cord. In binding assays in rat cortex homogenate, ∼60% specific binding was achieved at equilibrium. In kinetic binding assays, kon and koff values of 0.0021·min−1·nM−1 and 0.0070·min−1 were determined, and the Kd derived from kinetic measurements was consistent with that derived from saturation analysis. Novel P2X7 antagonists inhibited the binding of [3H]-A-804598 to rat cortex P2X7 receptors with Ki values of <40 nM. In an ex vivo occupancy assay, a P2X7 antagonist dosed orally to rats caused a concentration-dependent inhibition of the specific binding of [3H]-A-804598 to rat cortex.CONCLUSIONS AND IMPLICATIONS
The present study describes the development of an assay that allows localization of P2X7 receptors, the measurement of the binding affinity of P2X7 receptor antagonists in native tissue, and provides a means of determining central P2X7 receptor occupancy. These assays could form an important part of a P2X7 drug discovery programme. 相似文献653.
Hunt RH Xiao SD Megraud F Leon-Barua R Bazzoli F van der Merwe S Vaz Coelho LG Fock M Fedail S Cohen H Malfertheiner P Vakil N Hamid S Goh KL Wong BCY Krabshuis J Le Mair A 杜颖 戴宁 《胃肠病学》2011,16(7):423-428
世界上有一半人口感染幽门螺杆菌(H.pylori),其感染率因地理位置、种族、年龄和社会经济状况不同而存在很大差异.在发展中国家较高.发达国家较低。但总体而言,近年世界许多地区的H.pylori感染率均呈下降趋势。 相似文献
654.
Human malignant melanoma is highly resistant to chemotherapy and current immunotherapeutic approaches induce long term remission only in the minority of patients. The transforming growth factor-β (TGF-β) has attracted much attention as a therapeutic target because it plays an important and pleiotropic role in melanoma progression. TGF-β is a multifunctional cytokine involved in the regulation of many cellular processes including cell proliferation, differentiation and survival. Resistance to the growth inhibitory effects of TGF-β without alterations of TGF-β signaling molecules is characteristic of cutaneous melanoma. Melanoma produces increasing amounts of TGF-β with disease progression, inhibiting immune responses and providing an optimal microenvironment for undisturbed tumor growth. In addition, TGF-β exerts its tumor promoting functions via direct effects on tumor cell motility and invasiveness and indirectly by modulating tumor stroma and extracellular matrix, supporting angiogenesis and inhibiting immune surveillance. TGF-β acts through multiple intracellular signaling pathways and the outcome of TGF-β signaling is context-dependent. Defining the impact of the different TGF-β signaling pathways on melanoma progression will help to identify suitable therapeutic targets. Here we review the current knowledge of TGF-β in melanoma and discuss recent therapeutic approaches targeting the TGF-β pathway. 相似文献
655.
Keilholz U 《Journal of immunotherapy (Hagerstown, Md. : 1997)》2008,31(5):431-439
A novel approach for cancer immunotherapy is to augment T-cell-mediated immunity by blocking inhibitory signals that suppress T-cell function. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T-cell activation. CTLA-4 blockade using anti-CTLA-4 monoclonal antibodies (mAbs) potentiates the T-cell response against tumors, and preliminary data on these agents demonstrate good efficacy and tolerability in the treatment of patients with metastatic melanoma and other cancers. This paper will review data from studies with anti-CTLA-4 mAbs to date, discuss some of the key clinical considerations emerging from early clinical trials with this therapeutic strategy, and provide an overview of ongoing and planned clinical trials for anti-CTLA-4 mAb therapy in metastatic melanoma and other cancers. 相似文献
656.
普通变异型免疫缺陷病(common variable immunodeficiency,CVID)是一组病因小明的疾病,表现为各种免疫球蛋白合成障碍。CVID的发病率为1:10000,其典型表现为外周血液中免疫球蛋白水平低下甚至缺失,但是B淋巴细胞数目和表现型正常。本病男性和女性发病概率相似,没有明确已知的遗传模式。 相似文献
657.
658.
Identification of tumor-associated MHC class I ligands by a novel T cell-independent approach 总被引:9,自引:0,他引:9
Schirle M Keilholz W Weber B Gouttefangeas C Dumrese T Becker HD Stevanović S Rammensee HG 《European journal of immunology》2000,30(8):2216-2225
Specific immunotherapy of cancer utilizes tumor-directed cytotoxic T lymphocytes (CTL) that lyse tumor cells presenting MHC class I-associated peptides derived from tumor-associated proteins. Many tumor-associated gene products are known, but corresponding T cell epitopes are only known for relatively few of these. The most commonly used approaches to identify such antigens require pre-existing CTL lines or clones. By using a CTL-independent high performance liquid chromatography mass spectrometry (HPLC MS)-based approach we identified HLA-A2-presented peptides from carcinoembryonic antigen and wild-type p53 with a copy number as low as eight molecules per cell. Potential epitopes were predicted from the sequences of known tumor antigens and the corresponding synthetic peptides were analyzed by nanocapillary HPLC MS. In parallel, peptides were extracted from fresh, solid tumor tissue or tumor cell lines and analyzed in the same way. Upon co-elution of a natural peptide with a predicted peptide of the same mass, the peptide sequence was confirmed by on-line tandem MS. This approach allows rapid screening of large numbers of tumor-associated gene products for naturally processed peptides presented by different MHC class I molecules as a prerequisite for efficient epitope identification and rapid transfer to therapeutic vaccine trials. 相似文献