全文获取类型
收费全文 | 449篇 |
免费 | 31篇 |
国内免费 | 1篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 19篇 |
妇产科学 | 5篇 |
基础医学 | 89篇 |
口腔科学 | 1篇 |
临床医学 | 68篇 |
内科学 | 96篇 |
皮肤病学 | 8篇 |
神经病学 | 35篇 |
特种医学 | 4篇 |
外科学 | 44篇 |
综合类 | 2篇 |
预防医学 | 34篇 |
眼科学 | 2篇 |
药学 | 39篇 |
肿瘤学 | 34篇 |
出版年
2024年 | 1篇 |
2023年 | 1篇 |
2022年 | 7篇 |
2021年 | 10篇 |
2020年 | 8篇 |
2019年 | 7篇 |
2018年 | 12篇 |
2017年 | 20篇 |
2016年 | 14篇 |
2015年 | 12篇 |
2014年 | 13篇 |
2013年 | 20篇 |
2012年 | 22篇 |
2011年 | 29篇 |
2010年 | 10篇 |
2009年 | 15篇 |
2008年 | 27篇 |
2007年 | 25篇 |
2006年 | 37篇 |
2005年 | 25篇 |
2004年 | 34篇 |
2003年 | 31篇 |
2002年 | 25篇 |
2001年 | 4篇 |
2000年 | 4篇 |
1999年 | 6篇 |
1998年 | 3篇 |
1997年 | 11篇 |
1996年 | 3篇 |
1995年 | 2篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 5篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1982年 | 4篇 |
1981年 | 1篇 |
1980年 | 3篇 |
1976年 | 1篇 |
1975年 | 1篇 |
1970年 | 1篇 |
1949年 | 1篇 |
排序方式: 共有481条查询结果,搜索用时 31 毫秒
1.
Jean-Claude Painson Tibor Wenger Ginette Lagacé Nicole D. Masson Robert Collu 《Journal of neuroendocrinology》1994,6(4):447-455
Membrane-bound GTP-binding (G) proteins mediate signal transduction in a variety of cell systems. The exact mechanisms of G proteins action are still under investigation but they appear to involve effectors located in the plasma membrane as well as in other parts of the cell. With this study, we investigated the cellular and ultrastructural localization of G protein subunits, and particularly of Goa, in normal rat anterior pituitaries and in estrone-induced rat adenomatous lactotrophs. We also evaluated the effects of Goα cellular redistribution in rat adenomatous lactotrophs following short-term exposure to dopamine (DA). Using the Protein A-gold (PAG) methodology, Goα was found to be present in the cysternae of the endoplasmic reticulum of normal pituitary cells and of adenomatous lactotrophs. In the latter, Goα could be co-localized with prolactin (PRL). By immunoblots, using specific antisera, significant amounts of Goα and Gs42α, together with smaller amounts of Giα, Gs47α and Gβ were found to be present in the uncontaminated supernatant fraction of adenomatous lactotrophs. Unexpectedly, exposure of the cells to DA induced a rapid and short-lived decrease in the cytosolic fraction of Goα and Gβ associated with a decrease of PRL release. Since cytosolic Goα can be ADP-ribosylated by pertussis toxin (PT) and is therefore in a heterotrimeric form, our data suggest that the soluble Go protein may play a role during lactotrophs' exposure to an inhibitor of PRL release, perhaps through its relocalization after being internalized with the D2 receptor or by being used for interaction with intracellular and/or membrane-bound effectors. 相似文献
2.
3.
Ginette Thomas Dominique Pépin Claude Loriette Michel Vidal Marcel Apparu Sabine Coornaert Jean Chambaz Gilbert Béréziat 《European journal of nuclear medicine and molecular imaging》1989,15(7):367-372
The metabolic fate of methyl-branched iodo fatty acids was studied in primary culture of rat hepatocytes. We compared 16-iodo-2-R,S-methyl palmitic acid (2-Me), which can be oxidized, with 16-iodo-3-R,S-methyl palmitic acid (3-Me) which can be oxidized only after an initial oxydation and with 16-iodo-2,2-dimethyl palmitic acid (2,2-Me2) and 16-iodo-3,3-dimethyl palmitic acid (3,3-Me2) which cannot be oxidized at all. The normal fate of natural fatty acids was given by comparative experiments with [1-14C] palmitic acid. Monomethyl-branched iodo fatty acids were taken up in the same range as palmitic acid but more than dimethyl-branched iodo fatty acids. After a 15-h incubation, acido-soluble products (ASP) accounted for 75% of the radioactivity taken up as 16-iodo-2-methyl palmitic acid, 50% as other methyl-branched iodo fatty acids and only 30% as palmitic acid, which indicated that all the methyl-branched iodo fatty acids underwent a strong deiodination process. Fatty acids were esterified in the following order: palmitic acid >16-iodo-3-R,S-methyl palmitic acid>16-iodo-2-R,S-methyl palmitic acid>16-iodo-2,2-dimethyl palmitic acid>16-iodo-3,3-dimethyl palmitic acid. Cultured hepatocytes, labelled for 3 h with the various fatty acids and reincubated for 12 h without fatty acid, secreted large amounts of free dimethylbranched iodo fatty acids as compared to the monomethyl ones and palmitic acid. Only hepatocytes prelabelled with 16-[125I]iodo-2,2-dimethyl palmitic acid exhibited an appreciable secretion of labeled triglycerides, but at a lower rate than with [1-14C] palmitic acid. Conversely, the 16-iodo-monomethyl palmitic acids remained chiefly in hepatocyte triglycerides. Minute amounts of 16-iodo-methyl-branched-palmitic acids were found in hepatocyte or secred phospholipids as compared with palmitic acid. This metabolic fate of methyl-branched iodo palmitic acids argues against their utilization as imaging probes to monitor in vivo the synthesis and the secretion of triglycerides by the liver. 相似文献
4.
Molecular alterations in atypical adenomatous hyperplasia occurring in benign and cancer-bearing lungs. 总被引:1,自引:0,他引:1
Joel F Gradowski Geeta S Mantha Jennifer L Hunt Sanja Dacic 《Diagnostic molecular pathology》2007,16(2):87-90
Atypical adenomatous hyperplasia (AAH) is considered to be a precursor lesion of the lung adenocarcinoma. Several genetic abnormalities have been reported in AAH associated with adenocarcinoma, but little is known about AAH associated with benign lung lesions. To address this we compared the molecular characteristics of AAH present in benign conditions to those coexisting with carcinoma. Seven cases of AAH from resected non-neoplastic lungs (AAH-B) and 12 cases from lungs resected for primary lung carcinoma (AAH-M) were analyzed for loss of heterozygosity (LOH) using 21 polymorphic microsatellite markers situated in proximity to known tumor suppressor genes on chromosomes 3p, 5q, 7p, 9p, 10q, and 17p. Direct DNA sequencing for K-ras mutation was also performed. There was a broad range of LOH in both groups. No LOH was identified in 3 cases (25%) of AAH-M, but all cases of AAH-B showed LOH (P=0.26). Six cases (50%) of AAH-M and 3 cases (43%) of AAH-B showed loss at 1 marker (P=0.99). LOH at 2 or more markers was identified in 3 (25%) cases of AAH-M and 4 (57%) cases of AAH-B (P=0.32). LOH was most frequently detected on chromosomes 3p and 10q in both groups. The difference in overall fractional allelic loss between the 2 groups did not reach statistical significance. K-ras mutations were not identified in either group. Our results showed a significant overlap in LOH patterns between AAH with or without coexistent lung malignancy. Therefore, AAH may represent a smoking induced low-grade neoplastic lesion that may be a precursor lesion of only a subset of invasive lung adenocarcinoma. 相似文献
5.
Noninfectious Virus-Like Particle Antigen for Detection of Swine Vesicular Disease Virus Antibodies in Pigs by Enzyme-Linked Immunosorbent Assay
下载免费PDF全文
![点击此处可从《Clinical and Vaccine Immunology : CVI》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Young-Joon Ko Kang-Seuk Choi Jin-Ju Nah David J. Paton Jae-Ku Oem Ginette Wilsden Shien-Young Kang Nam-In Jo Joo-Ho Lee Jae-Hong Kim Hee-Woo Lee Jong-Myeong Park 《Clinical and Vaccine Immunology : CVI》2005,12(8):922-929
An inactivated SVDV antigen is used in current enzyme-linked immunosorbent assays (ELISAs) for the detection of antibodies to swine vesicular disease virus (SVDV). To develop a noninfectious recombinant alternative, we produced SVDV-like particles (VLPs) morphologically and antigenically resembling authentic SVDV particles by using a dual baculovirus recombinant, which expresses simultaneously the P1 and 3CD protein genes of SVDV under different promoters. Antigenic differences between recombinant VLPs and SVDV particles were not statistically significant in results obtained with a 5B7-ELISA kit, indicating that the VLPs could be used in the place of SVDV antigen in ELISA kits. We developed a blocking ELISA using the VLPs and SVDV-specific neutralizing monoclonal antibody 3H10 (VLP-ELISA) for detection of SVDV serum antibodies in pigs. The VLP-ELISA showed a high specificity of 99.9% when tested with pig sera that are negative for SVDV neutralization (n = 1,041). When tested using sera (n = 186) collected periodically from pigs (n = 19) with experimental infection with each of three different strains of SVDV, the VLP-ELISA detected SVDV serum antibodies as early as 3 days postinfection and continued to detect the antibodies from all infected pigs until termination of the experiments (up to 121 days postinfection). This test performance was similar to that of the gold standard virus neutralization test and indicates that the VLP-ELISA is a highly specific and sensitive method for the detection of SVDV serum antibodies in pigs. This is the first report of the production and diagnostic application of recombinant VLPs of SVDV. Further potential uses of the VLPs are discussed. 相似文献
6.
Selection by phage display of llama conventional V(H) fragments with heavy chain antibody V(H)H properties 总被引:4,自引:0,他引:4
Tanha J Dubuc G Hirama T Narang SA MacKenzie CR 《Journal of immunological methods》2002,263(1-2):97-109
A llama single domain antibody (dAb) library designed and constructed to contain only heavy chain antibody variable domains (V(H)Hs) also contained a substantial number of typical conventional antibody heavy chain variable sequences (V(H)s). Panning the library against two carbohydrate-specific antibodies yielded anti-idiotypic dAbs and enriched solely for sequences from the V(H) subpopulation of the library. The conventional antibody origin of these V(H)s was confirmed by using oligonucleotide probes, specific for the enriched V(H)s, to identify the parental sequences in the message employed in library construction. Surprisingly, these V(H) dAbs, which are produced in high yield in Escherichia coli, are highly soluble, have excellent temperature stability profiles and do not display any aggregation tendencies. The very close similarity of these molecules to human V(H)s makes them potentially very useful as therapeutic dAbs. 相似文献
7.
Compliance with consensus recommendations for systemic therapy is associated with improved survival of women with node-negative breast cancer. 总被引:3,自引:0,他引:3
Nicole Hébert-Croteau Jacques Brisson Jean Latreille Michèle Rivard Nadia Abdelaziz Ginette Martin 《Journal of clinical oncology》2004,22(18):3685-3693
PURPOSE: The impact of consensus recommendations for systemic therapy on outcome of disease is unclear. We evaluated if compliance with guidelines for systemic adjuvant treatment is associated with improved survival of women with node-negative breast cancer. PATIENTS AND METHODS: The study population included women diagnosed with invasive node-negative breast cancer in Québec, Canada, in 1988 to 1989, 1991 to 1992, and 1993 to 1994. Information was collected by chart review, linkage with administrative databases, and queries to attending physicians. Guidelines from the 1992 St Gallen conference were used as standard of care. Survival was estimated by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Among 1,541 women, 358 died before December 1999. Median follow-up was 6.8 years. Seven-year event-free and overall survivals were 66% and 81%, respectively. Survival was 88%, 84%, and 74% in women at minimal, moderate, or high risk of recurrence. Virtually all women at minimal risk were treated according to the consensus (98.4% of 370). In comparison, adjusted hazard ratios of death were 1.0 (95% CI, 0.6 to 1.7) and 2.3 (95% CI, 1.3 to 4.0) among women at moderate risk treated according to the consensus or not, respectively. Among women at high risk, adjusted hazard ratios of death were 2.0 (95% CI, 1.4 to 2.8) and 2.7 (95% CI, 1.9 to 3.9), respectively. Both risk category (P <.0005) and compliance with guidelines (P <.0005) were independent significant predictors of survival. CONCLUSION: Treatment according to consensus recommendations is associated with improved survival of women with breast cancer in the community. Promoting the adoption of guidelines for treatment is an effective strategy for disease control. 相似文献
8.
The granulin-epithelin precursor/PC-cell-derived growth factor is a growth factor for epithelial ovarian cancer. 总被引:6,自引:0,他引:6
9.
In this era of medical technology assessment and evidence-based medicine, evaluating new methods to measure physiologic variables is facilitated by standardization of reporting results. It has been proposed that assessing repeatability be followed by assessing agreement with an established technique. If the "limits of agreement" (mean bias +/- 2SD) are not clinically important, then one could use two measurements interchangeably. Generalizability to larger populations is facilitated by reporting confidence intervals. We identified 44 studies that compared methods of clinical measurement published during 1996 to 1998 in seven anesthesia journals. Although 42 of 44 (95.4%) used the limits of agreement methodology for analysis, several inadequacies and inconsistencies in reporting the results were noted. Limits of agreement were defined a priori in 7.1%, repeatability was evaluated in 21.4%, and relationship (pattern) between difference and average was evaluated in 7.1%. Only one of the articles reported confidence intervals. A computer macro for the Minitab statistical package (State College, PA) is described to facilitate reporting of Bland and Altman analysis with confidence intervals. We propose standardization of nomenclature in clinical measurement comparison studies. IMPLICATIONS: A literature review of anesthesia journals revealed several inadequacies and inconsistencies in statistical reports of results of comparison studies with regard to interchangeability of measurement methods. We encourage journal editors to evaluate submissions on this subject carefully to ensure that their readers can draw valid conclusions about the value of new technologies. 相似文献
10.
Targeting the mevalonate pathway inhibits the function of the epidermal growth factor receptor. 总被引:3,自引:0,他引:3
Angela J Mantha Jennifer E L Hanson Glenwood Goss Alain E Lagarde Ian A Lorimer Jim Dimitroulakos 《Clinical cancer research》2005,11(6):2398-2407
PURPOSE: The epidermal growth factor receptor (EGFR) is a key regulator of growth, differentiation, and survival of epithelial cancers. In a small subset of tumors, the presence of activating mutations within the ATP binding site confers increased susceptibility to gefitinib, a potent tyrosine kinase inhibitor of EGFR. Agents that can inhibit EGFR function through different mechanisms may enhance gefitinib activity in patients lacking these mutations. Mevalonate metabolites play significant roles in the function of the EGFR; therefore, mevalonate pathway inhibitors may potentiate EGFR-targeted therapies. EXPERIMENTAL DESIGN: In this study, we evaluated the effect of lovastatin on EGFR function and on gefitinib activity. Effects on EGFR function were analyzed by Western blot analysis using phosphospecific antibodies to EGFR, AKT, and extracellular signal-regulated kinase. Cytotoxic effects of lovastatin and/or gefitinib were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and flow cytometry. RESULTS: Lovastatin treatment inhibited EGF-induced EGFR autophosphorylation by 24 hours that was reversed by the coadministration of mevalonate. Combining lovastatin and gefitinib treatments showed enhanced inhibition of AKT activation by EGF in SCC9 cells. The combination of 10 mumol/L lovastatin and 10 mumol/L gefitinib treatments showed cooperative cytotoxicity in all 8 squamous cell carcinomas, 4 of 4 non-small cell lung carcinoma and 4 of 4 colon carcinoma cell lines tested. Isobologram and flow cytometric analyses of three representative cell lines with wild-type EGFR ATP binding sites confirmed that this combination was synergistic inducing a potent apoptotic response. CONCLUSIONS: Taken together, these results show that targeting the mevalonate pathway can inhibit EGFR function. They also suggest the potential utility of combining these clinically relevant therapeutic approaches. 相似文献