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991.
992.
Luigi Strizzi Katharine M Hardy Naira V Margaryan David W Hillman Elisabeth A Seftor Beiyun Chen Xochiquetzal J Geiger E Aubrey Thompson Wilma L Lingle Cathy A Andorfer Edith A Perez Mary JC Hendrix 《Breast cancer research : BCR》2012,14(3):R75-12
Introduction
The re-emergence of the tumour growth factor-beta (TGF-beta)-related embryonic morphogen Nodal has recently been reported in several different human cancers. In this study, we examined the expression of Nodal in a series of benign and malignant human breast tissues to determine the clinical significance of this expression and whether Nodal could represent a potential therapeutic target in breast cancer.Methods
Tissue sections from 431 therapeutically naive patients diagnosed with benign or malignant breast disease were stained for Nodal by immunohistochemistry and analysed in a blinded manner. The degree of Nodal staining was subsequently correlated with available clinical data, such as diagnoses and disease stage. These tissue findings were further explored in breast cancer cell lines MDA-MB-231 and MDA-MB-468 treated with a Nodal blocking antibody to determine biological effects for target validation.Results
A variable degree of Nodal staining was detected in all samples. The intensity of Nodal staining was significantly greater in undifferentiated, advanced stage, invasive breast cancer compared with benign breast disease or early stage breast cancer. Treatment of human breast cancer cells in vitro with Nodal blocking antibody significantly reduced proliferation and colony-forming ability in soft agar, concomitant with increased apoptosis.Conclusions
These data suggest a potential role for Nodal as a biomarker for disease progression and a promising target for anti-Nodal therapy in breast cancer. 相似文献993.
Tan WW Allred JB Salim M Flynn P Fishkin PA Stella PJ Wiesenfeld M Bernath AM Fitch TR Perez EA 《Clinical breast cancer》2012,12(2):81-86
BackgroundWe conducted a multiinstitutional phase II study of capecitabine in combination with vinorelbine and trastuzumab in patients eligible to receive first- or second-line treatment for human epidermal growth factor receptor type 2 (HER2)-positive (HER2+) metastatic breast cancer (MBC).Patients and MethodsThe study was designed to test that the true confirmed response rate (CRR) was at most 45% vs. a true CRR of at least 65%. Between March 2005 and June 2008, eligible patients received capecitabine 825 mg/m2 orally on days 1 to 14, vinorelbine 25 mg/m2 intravenously on days 1 and 8 every 3 weeks, and trastuzumab 8 mg/kg intravenously on day 1 week 1 and 6 mg/kg every 3 weeks. The main outcome measure was CRR.ResultsOf 47 women accrued, 45 were evaluable. This design required at least 25 confirmed responses in the 45 evaluable patients for the treatment to be considered promising. Thirty women (67%) achieved a confirmed response; 25 women (56%) had a confirmed partial response (PR); 5 women (11%) had confirmed complete responses (CRs). Median progression-free survival (PFS) was 11.3 months (95% confidence interval [CI], 8.4-16.7 months). Median overall survival was 28.5 months (95% CI, 24.8-36.4 months).ConclusionsThis triplet combination demonstrated promising activity in patients with HER2+ MBC. 相似文献
994.
The role of beta-carotene, alpha-tocopherol, and vitamin C in the prevention of cardiovascular diseases (CVD) is controversial. Prospective studies on gamma-tocopherol and carotenoids other than beta-carotene are sparse. We assessed relations between the intake of different carotenoids, alpha- and gamma-tocopherol, and vitamin C with 15-y CVD mortality in elderly men who participated in the Zutphen Elderly Study. Information on diet and potential confounding factors was collected in 1985, 1990, and 1995. In 1985, 559 men (mean age approximately 72 y) free of chronic diseases were included in the current analysis. After 15 y of follow-up, comprising 5744 person-years, 197 men had died from CVD. After adjustment for age, smoking, and other potential lifestyle and dietary confounders, relative risks (RR) (95% CI) of CVD death for a 1-SD increase in intake were 0.81 (0.66-0.99) for alpha-carotene and 0.80 (0.66-0.97) for beta-carotene. Carrots were the primary source of alpha- and beta-carotene and their consumption was related to a lower risk of death from CVD (adjusted RR, 0.83; 95% CI = 0.68-1.00). Intakes of carotenoids other than alpha- and beta-carotene were not associated with CVD mortality, nor were vitamin C and alpha- and gamma tocopherol. In conclusion, dietary intakes of alpha-carotene and beta-carotene are inversely associated with CVD mortality in elderly men. This study does not indicate an important role for other carotenoids, tocopherols, or vitamin C in lowering the risk of CVD death. 相似文献
995.
996.
This study has the aim of verifying the morphologic alterations in the hepatic tissue of Rhamdia quelen juveniles when exposed to 0.01 mL/L of Folidol 600. Techniques of light microscopy and transmission electronic microscopy were used. The liver was target for the Folidol 600 action after 4 h of contamination. Loss of cellular contour, picnotic nucleus and decharacterization of the endothelium and of the rough endoplasmic reticulum were observed. Focuses of necrosis increased significantly when compared to the control sample at the exposure times of 48 and 72 h to the organophosphate. The density of hepatocytes increased significantly in every experimental time when compared to the control sample. The number of hepatocytes with biliary pigment increased significantly in the first 72 h of exposure when compared to the control. Folidol 600 was responsible for serious alterations in the hepatic tissue of the Rhamdia quelen. 相似文献
997.
Stacy Moulder Hailun Li Molin Wang William J. Gradishar Edith A. Perez Joseph A. Sparano Michael Pins Ximing Yang George W. Sledge 《Breast cancer research and treatment》2010,119(3):663-671
The epothilone B analogue, ixabepilone, binds to β-tubulin, is effective for taxane-refractory metastatic breast cancer (MBC),
and may be given every 3 weeks or weekly. We evaluated the efficacy of weekly ixabepilone (I) plus trastuzumab (T) and carboplatin
(C) as first line therapy in HER2 + MBC. Patients with HER2+ (3+ by IHC or FISH amplified) MBC received I (15 mg/m2 IV) and C (area under the curve, AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of 6 cycles, plus weekly
T (4 mg/kg loading dose then 2 mg/kg IV) during chemotherapy then every 3 weeks (6 mg/kg IV) until disease progression. The
primary objective was to determine whether the combination was associated with a response rate (RR) of at least 75%. Fifty-nine
patients were treated, and 39 had HER2 overexpression confirmed in a central lab (cHER2+). For all treated patients, objective
response occurred in 26 patients (44%; 95% CI 31–58%), median time to progression was 8.2 months (95% CI 6.3–9.9), and median
overall survival was 34.7 months (95% CI 25.7 to [not reached]). Results were comparable for cHer2+ cancers. Grade 3–4 adverse
events included neutropenia (49%), thrombocytopenia (14%), fatigue (12%), nausea (7%), diarrhea (7%), and neuropathy (7%).
One patient died from treatment complications during cycle 1. Weekly ixabepilone and carboplatin plus trastuzumab have an
acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable
to paclitaxel, carboplatin, and trastuzumab. 相似文献
998.
Agnieszka K Witkiewicz Abhijit Dasgupta Sara Sammons Ozlem Er Magdalena B Potoczek Fran Guiles Federica Sotgia Jonathan R Brody Edith P Mitchell Michael P Lisanti 《Cancer biology & therapy》2010,10(2):135-143
Here, we investigated the possible predictive value of stromal caveolin-1 (Cav-1) as a candidate biomarker for clinical outcome in triple negative (TN) breast cancer patients. A cohort of 85 TN breast cancer patients was available, with the necessary annotation and nearly 12 years of follow-up data. Our primary outcome of interest in this study was overall survival. Interestingly, TN patients with high-levels of stromal Cav-1 had a good clinical outcome, with >50% of the patients remaining alive during the follow-up period. In contrast, the median survival for TN patients with moderate stromal Cav-1 staining was 33.5 months. Similarly, the median survival for TN patients with absent stromal Cav-1 staining was 25.7 months. A comparison of 5-year survival rates yields a similar pattern. TN patients with high stromal Cav-1 had a good 5-year survival rate, with 75.5% of the patients remaining alive. In contrast, TN patients with moderate or absent stromal Cav-1 levels had progressively worse 5-year survival rates, with 40 and 9.4% of the patients remaining alive. In contrast, in a parallel analysis, the levels of tumor epithelial Cav-1 had no prognostic significance. As such, the prognostic value of Cav-1 immunostaining in TN breast cancer patients is compartment-specific, and selective for an absence of Cav-1 staining in the stromal fibroblast compartment. A recursive-partitioning algorithm was used to assess which factors are most predictive of overall survival in TN breast cancer patients. In this analysis, we included tumor size, histologic grade, whether the patient received surgery, radiotherapy or chemotherapy, CK5/6, EGFR, p53 and Ki67 status, as well as the stromal Cav-1 score. This analysis indicated that stromal loss of Cav-1 expression was the most important prognostic factor for overall survival in TN breast cancer. Virtually identical results were obtained with CK5/6 (+) and/or EGFR (+) TN breast cancer cases, demonstrating that a loss of stromal Cav-1 is also a strong prognostic factor for basal-like breast cancers. Our current findings may have important implications for the close monitoring and treatment stratification of TN and basal-like breast cancer patients.Key words: caveolin-1, mammary tumor stroma, stromal biomarkers, cancer survival, cancer-associated fibroblasts 相似文献
999.
J Spencer Liles Juan Pablo Arnoletti Ching-Wei D Tzeng J Harrison Howard Andrew V Kossenkov Peter Kulesza Martin J Heslin Andrey Frolov 《Cancer biology & therapy》2010,10(6):555-563
Historically, ErbB3 has been overlooked within the ErbB receptor family due to its perceived lack of tyrosine kinase activity. We have previously demonstrated that in pancreatic cancer ErbB3 is the preferred dimerization partner of EGFR, ErbB3 protein expression level directly correlates with the anti-proliferative effect of erlotinib (an EGFR-specific tyrosine kinase inhibitor), and transient knockdown of ErbB3 expression results in acquired resistance to EGFR-targeted therapy. In this study, we develop a stable isogenic model of ErbB3 expression in an attempt to decipher ErbB3''s true contribution to pancreatic cancer tumorigenesis and to examine how this receptor affects cellular sensitivity to EGFR-targeted therapy. Analysis of the EGFR-ErbB3 heterodimer demonstrates that ligand-induced PI3K-AKT signaling is limited to ErbB3-expressing cells and that this signaling cascade can be partially abrogated by inhibiting EGFR function with erlotinib. Using our model of exogenous ErbB3 expression we showed a direct relationship between ErbB3 protein levels and increased pancreatic cancer cell proliferation in vitro. In vivo, ErbB3+PANC-1 xenografts had a significantly larger tumor volume than PANC-1 control xenografts (ErbB3-PANC-1) and displayed increased sensitivity to EGFR-targeted therapy. In pancreatic cancer, ErbB3 appears to be critically involved in EGFR signaling as evidenced by its profound effect on cellular proliferation and its ability to influence response to EGFR-targeted therapy.Key words: ErbB3, EGFR, pancreatic cancer, EGFR-targeted therapy, tumorigenesis 相似文献
1000.
von Gruenigen V Frasure H Kavanagh MB Janata J Waggoner S Rose P Lerner E Courneya KS 《Gynecologic oncology》2012,125(3):699-704