全文获取类型
收费全文 | 11812篇 |
免费 | 737篇 |
国内免费 | 26篇 |
专业分类
耳鼻咽喉 | 95篇 |
儿科学 | 225篇 |
妇产科学 | 220篇 |
基础医学 | 1591篇 |
口腔科学 | 258篇 |
临床医学 | 1503篇 |
内科学 | 2161篇 |
皮肤病学 | 75篇 |
神经病学 | 1089篇 |
特种医学 | 430篇 |
外科学 | 1511篇 |
综合类 | 124篇 |
一般理论 | 12篇 |
预防医学 | 1372篇 |
眼科学 | 217篇 |
药学 | 949篇 |
中国医学 | 13篇 |
肿瘤学 | 730篇 |
出版年
2023年 | 68篇 |
2022年 | 81篇 |
2021年 | 215篇 |
2020年 | 159篇 |
2019年 | 221篇 |
2018年 | 287篇 |
2017年 | 207篇 |
2016年 | 212篇 |
2015年 | 274篇 |
2014年 | 375篇 |
2013年 | 557篇 |
2012年 | 882篇 |
2011年 | 936篇 |
2010年 | 510篇 |
2009年 | 513篇 |
2008年 | 841篇 |
2007年 | 878篇 |
2006年 | 879篇 |
2005年 | 880篇 |
2004年 | 876篇 |
2003年 | 755篇 |
2002年 | 737篇 |
2001年 | 99篇 |
2000年 | 89篇 |
1999年 | 106篇 |
1998年 | 145篇 |
1997年 | 125篇 |
1996年 | 87篇 |
1995年 | 65篇 |
1994年 | 58篇 |
1993年 | 53篇 |
1992年 | 38篇 |
1991年 | 25篇 |
1990年 | 28篇 |
1989年 | 36篇 |
1988年 | 26篇 |
1987年 | 24篇 |
1986年 | 20篇 |
1985年 | 27篇 |
1984年 | 23篇 |
1983年 | 23篇 |
1982年 | 22篇 |
1981年 | 22篇 |
1980年 | 17篇 |
1979年 | 5篇 |
1978年 | 13篇 |
1977年 | 9篇 |
1976年 | 11篇 |
1975年 | 9篇 |
1972年 | 5篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
101.
David M. Vail Adnan A. Elfarra A. James Cooley David L. Panciera E. Gregory MacEwen Steve A. Soergel 《Cancer chemotherapy and pharmacology》1993,32(1):25-30
Dexniguldipine-HCl (DNIG) — a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MRD) — was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR), or mitoxantrone (MITO) in resistant F4-6RADR cells to the very levels observed in drug-sensitive F4-6 precursor cells. In parallel with the increase in DNR content (F4-6RADR, solvent: 303±27 pmol/mg protein; DNIG (3.3 mol/l): 1,067±174 pmol/mg protein; F4-6P, solvent: 948±110 pmol/mg protein;n=8–9, SEM), the amount of DNR tightly bound to the acid precipitate pellet obtained from F4-6RADR (i.e., protein, DNA, RNA) increased 3.9-times to the levels observed in sensitive F4-6 cells. The main pyridine metabolite of DNIG displayed similar activity. Concentration-response analysis revealed that DNIG and R,S-verapamil (VER) induced 100% reversal of the DNR accumulation shortage associated with the MDR phenotype but DNIG was 8 times more potent than VER (50% inhibitory concentration (IC50), 0.73 vs 5.4 mol/l). In keeping with the accumulation assay, DNIG was about 10 times more potent than VER in sensitizing F4-6RADR cells to the cytostatic and cytotoxic effects of DNR in proliferation assays. In conclusion, DNIG is a potent in vitro modulator, improving (a) the accumulation of anthracycline-like cytostatics, (B) drug access to cellular binding sites, and (c) the cytostatic action of DNR in F4-6RADR leukemia cells of the MDR phenotype.Abbreviations DOX
doxorubicin
- CSA
cyclosporin A
- DMSO
dimethylsulfoxide
- DNIG
dexniguldipine-HCl
- DNR
daunorubicin
- MDR
multidrug resistance
- MITO
mitoxantrone
- pgp170
permease glycoprotein 170
- VER
R.S.-verapamil
Dexniguldipine-HCl is the proposed INN for compound B859-35, the R-enantiomer of niguldipine. Segments of this work have been reported in the abstract form 相似文献
102.
Technology is gaining increasing attention and competitive importance in the healthcare industry, but healthcare administrators need more than just talk to make effective technology investments. Andersen Consulting and the American College of Healthcare Executives have created Hospital of the FutureSM, in Dallas, Texas, as a dynamic, evolving research and demonstration forum that allows healthcare administrators and providers to see potential technology solutions in action—in healthcare settings specifically designed to look and feel like the real thing. This article discusses the functionality and technical structure of Hospital of the Future, as well as the integration issues among disparate healthcare systems addressed in developing the display. 相似文献
103.
104.
D. C. S. Roberts Rachel Phelan L. Mark Hodges Melinda M. Hodges Barbara Bennett Steve Childers Huw Davies 《Psychopharmacology》1999,144(4):389-397
Rationale: A novel scheme for the synthesis of cocaine analogs from vinylcarbenoid precursors has made available compounds that have
a diverse range of affinities for the DA and 5-HT transporters. These compounds were used to explore the relationship between
their biochemical properties and their reinforcing effects. Objectives: The objective was to assess the reinforcing efficacy of selected cocaine analogs and compare the results with their selectivity
in binding to DA and 5-HT transporters. Methods: Rats were prepared with chronically indwelling intravenous cannulae and trained to self-administer cocaine on a progressive
ratio (PR) schedule. A range of doses of seven cocaine analogs were substituted for cocaine in separate groups of animals. Results: The results demonstrate a wide range of reinforcing efficacies and potencies among the seven selected drugs. Four tropane
analogs (WF-11, WF-23, WF-24, WF-55) were found to support self-administration behavior on a PR schedule while three did not
(WF-31, WF-54 and WF-60). The DA/5-HT selectivity ratio was found to be a better predictor of self-administration behavior
than affinity at the DA transporter alone. Conclusion: These data suggest that drugs with a higher affinity for the DA versus the 5-HT transporter are more likely to be self-administered.
Received: 29 October 1998 / Final version: 5 February 1999 相似文献
105.
Adrian L. Harris Huatang Zhang Amir Moghaddam Steve Fox Prudence Scott Adam Pattison Kevin Gatter Ian Stratford Roy Bicknell 《Breast cancer research and treatment》1996,38(1):97-108
Summary Several groups have shown that quantitation of tumor angiogenesis by counting blood vessels in primary breast cancer gives an independent assessment of prognosis. Poor prognosis is associated with high blood vessel counts. We have shown that the rate of cell division in endothelial cells is much higher in breast tumours than in normal breast. Breast cancer cell lines and primary human breast tumours express a wide range of vascular growth factors, including VEGF, placenta growth factor, pleiotrophin, TGF1, acidic and basic FGF, and platelet-derived endothelial cell growth factor. Inhibiting angiogenesis by blocking vascular growth factors would be difficult with highly specific agents, but drugs with a broader spectrum of antagonism may be effective. We have developed several suramin analogues which are less toxic than suraminin vivo but more potent in inhibiting angiogenesis, and these have been developed for Phase I. A combination of anti-angiogenesis agents with drugs activated by hypoxia may also be useful, because anti-angiogenesis alone may not kill cells, whereas activation of hypoxic drugs could synergize.New endpoints may be necessary because inhibition of new blood vessel formation may not cause tumour regression. Thus, the endpoint of stable disease and biochemical assessment of inhibition of angiogenesis may be much more important in therapeutic studies and for drug development in the future. The prognostic importance of angiogenesis suggests that this should be a major new therapeutic target.Presented at the symposium "New Approaches in the Therapy of Breast Cancer", Georgetown University Medical Center, Washington DC, October 1994, generously supported by an education grant from Bristol-Myers Squibb. 相似文献
106.
George V Thomas Steve Horvath Bradley L Smith Katherine Crosby Lori A Lebel Matthew Schrage Jonathan Said Jean De Kernion Robert E Reiter Charles L Sawyers 《Clinical cancer research》2004,10(24):8351-8356
PURPOSE: As kinase inhibitors transition from the laboratory to patients, it is imperative to develop biomarkers that can be used in the clinic. The primary objectives are to identify patients most likely to benefit from molecularly targeted therapies and to document modulation of the drug target. Constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway and its downstream effectors, as a result of PTEN loss or by other mechanisms, occurs in a high proportion of prostate cancers, making it an ideal template for the design of clinical trials involving PI3K pathway inhibitors. Prostate cancers also present unique organ-specific challenges, in that tumors are heterogeneous and diagnostic tissue is extremely limited. EXPERIMENTAL DESIGN: Working within these limitations, we have developed a set of immunohistochemical assays that define activation of the PI3K pathway in clinical samples. Results and CONCLUSIONS: Using both univariate and multivariate analyses, we show that loss of PTEN is highly correlated with the activation of AKT, and this, in turn, is associated with the phosphorylation of S6, one of its main effectors. These three antibodies are potentially able to define a molecular signature of PTEN loss and/or AKT pathway activation in prostate cancer. 相似文献
107.
108.
Ravi Salgia Thomas Lynch Arthur Skarin Joan Lucca Cathleen Lynch Ken Jung F Stephen Hodi Michael Jaklitsch Steve Mentzer Scott Swanson Jean Lukanich Raphael Bueno John Wain Douglas Mathisen Cameron Wright Panos Fidias Dean Donahue Shirley Clift Steve Hardy Donna Neuberg Richard Mulligan Iain Webb David Sugarbaker Martin Mihm Glenn Dranoff 《Journal of clinical oncology》2003,21(4):624-630
PURPOSE: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC. 相似文献
109.
Judit Anido Pablo Matar Joan Albanell Marta Guzmán Federico Rojo Joaquin Arribas Steve Averbuch Jose Baselga 《Clinical cancer research》2003,9(4):1274-1283
PURPOSE: ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that has shown clinical activity against EGFR-expressing tumors. Our aim was to explore the effects of ZD1839 in breast cancer cell lines expressing different levels of EGFR and the closely related HER2 receptor. EXPERIMENTAL DESIGN: We studied the growth-inhibitory effects of ZD1839 in a series of breast carcinoma cell lines. In HER2-overexpressing BT-474 breast cancer cells, we studied the effects of ZD1839 on cell growth and heterodimerization of receptors under basal and ligand-stimulated conditions. RESULTS: ZD1839 was an equally potent inhibitor of growth in breast cancer cells expressing high levels of EGFR and HER2. In BT-474 breast cancer cells, ZD1839 abolished EGF- and heregulin-induced activation of ErbB receptors and downstream signaling molecules. Because ZD1839 does not inhibit the HER2 tyrosine kinase in vitro, and because heregulin is a ligand that activates HER2 by binding to HER3 and HER4 but does not bind to the EGFR, our findings suggested that ZD1839 interfered with HER2 function in intact cells. Searching for mechanisms, we report that ZD1839 induces the formation of inactive unphosphorylated EGFR/HER2 and EGFR/HER3 heterodimers. Furthermore, ZD1839 completely abolishes basal and heregulin-induced formation of active phosphorylated HER2/HER3 heterodimers. CONCLUSIONS: ZD1839 inhibits the growth of HER2-overexpressing breast cancer cells, possibly by sequestration of HER2 and HER3 receptors in an inactive heterodimer configuration with the EGFR. Our findings suggest that there is a strong rationale to conduct clinical trials of ZD1839 in patients with HER2-overexpressing breast tumors. 相似文献
110.
This study examined the implementation of a model of managing aggressive and harmful behaviour in an adolescent in-patient psychiatric unit. This model, Positive Behaviour Management, replaced a previous model, Control and Restraint, which was considered unsuitable. Both models included the use of physical interventions, and the research into such techniques is considered. The aims of the study were to evaluate the effects of three training courses on staff confidence in managing aggressive behaviour, knowledge about good practice and staff satisfaction with the new model. A multiple baseline design was used to examine change before, during and after the training period, and at one-year follow-up. The study found that staff confidence increased significantly following training but had returned to baseline levels by the time of follow-up. Staff knowledge significantly increased during the study periods but did not appear to be directly linked to the training courses, and was maintained at one-year follow-up. Staff reported significantly higher levels of satisfaction with the new model than with the previous model, which were maintained at follow-up. The findings of the study and the difficulties encountered are discussed in relation to similar findings elsewhere. 相似文献