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981.
Haptoglobin-alpha subunit as potential serum biomarker in ovarian cancer: identification and characterization using proteomic profiling and mass spectrometry. 总被引:24,自引:0,他引:24
Bin Ye Daniel W Cramer Steven J Skates Steven P Gygi Vanessa Pratomo Lanfei Fu Nora K Horick Larry J Licklider John O Schorge Ross S Berkowitz Samuel C Mok 《Clinical cancer research》2003,9(8):2904-2911
PURPOSE: The objective of this study was to identify and characterize new serum biomarkers in ovarian cancer patients using mass spectrometric protein profiling and specific immunological assays. Experimental Design: Serum samples from 80 cancer patients and 91 healthy women were analyzed by surface enhanced laser desorption and ionization-mass spectrometry (MS) profiling. A candidate biomarker was purified by affinity chromatography, and its sequence was determined by liquid chromatography-tandem MS. An antibody was generated from the synthesized peptide for quantitative validation in the cases and controls. CA125 was determined and compared with the same set of specimens. RESULTS: Using surface enhanced laser desorption and ionization, we found a serum biomarker at approximately 11700 Da, which had peak intensity significantly higher in cases (1.366) compared with controls (0.208, P = 0.002), and subsequently identified this as the alpha chain of haptoglobin. ELISA indicated that Hp-alpha was =2-fold higher in cancer serum compared with normal, benign tumor, and other gynecological cancers (P < 0.05) and had 64% sensitivity at 90% specificity alone and 91% sensitivity and 95% specificity if combined with CA125. CONCLUSIONS: Haptoglobin-derived alpha subunit is a potential marker for ovarian cancer that is complementary to CA125. MS-based protein profiling is a valuable tool for screening protein markers and useful to detect post-translational modification of tumor-associated proteins or abnormal metabolic products. However, confirmation of protein identity with specific antibodies is crucial for clinical application and functional studies. 相似文献
982.
Everett E Vokes Kerstin Stenson Fred R Rosen Merrill S Kies Alfred W Rademaker Mary Ellyn Witt Bruce E Brockstein Marcy A List Bing Bing Fung Louis Portugal Bharat B Mittal Harold Pelzer Ralph R Weichselbaum Daniel J Haraf 《Journal of clinical oncology》2003,21(2):320-326
PURPOSE: The paclitaxel, fluorouracil, and hydroxyurea regimen of paclitaxel, infusional fluorouracil, hydroxyurea, and twice-daily radiation therapy (TFHX) administered every other week has resulted in 3-year survival rates of 60% of stage IV patients. Locoregional and distant failure rates were 13% and 23%, respectively. To reduce distant failure rates, we added a brief course of induction chemotherapy to TFHX. PATIENTS AND METHODS: Sixty-nine patients received six weekly doses of carboplatin (AUC2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX. RESULTS: Ninety-six percent had stage IV disease. Response to induction chemotherapy was partial response 52% and complete response (CR) 35%. Symptomatically, there was a significant reduction in mouth and throat pain. The most common grade 3 or 4 toxicity was neutropenia (36%). Best response following completion of TFHX was CR in 83%. Toxicities of TFHX consisted of grade 3 or 4 mucositis (74% and 2%) and dermatitis (47% and 14%). At a median follow-up of 28 months, locoregional or systemic disease progression were each noted in five patients. The overall 3-year progression-free survival was 80% (95% confidence interval [CI], 71% to 90%), and the 2- and 3-year overall survival rates were 77% (95% CI, 66% to 87%) and 70% (95% CI, 59% to 82%), respectively. At 12 months, five patients were completely feeding-tube dependent. CONCLUSION: Administration of carboplatin and paclitaxel before TFHX chemoradiotherapy results in high response activity and may decrease distant failure rates. Overall survival, progression, and organ preservation/functional outcome data support definitive evaluation of this approach. 相似文献
983.
Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia. 总被引:6,自引:0,他引:6
Charles T Miller Justin R Moy Lin Lin Matthew Schipper Daniel Normolle Dean E Brenner Mark D Iannettoni Mark B Orringer David G Beer 《Clinical cancer research》2003,9(13):4819-4825
PURPOSE: The purpose of this study was to determine the frequency and overall contribution of specific gene amplification events in the formation of Barrett's adenocarcinomas. The relationship of gene amplification to clinical-pathological variables and its potential usefulness as a marker for early cancer detection were also examined. EXPERIMENTAL DESIGN: We used quantitative PCR and Southern blot analysis to screen 87 cases of Barrett's adenocarcinoma for the presence or absence of 13 distinct gene amplification events. Gene amplification was then examined for correlation with other amplification events and clinical variables (survival, stage, nodal involvement, tumor invasion, smoking history, and gender). Additionally, 22 specimens of Barrett's with high-grade dysplasia (HGD) were examined for the presence of gene amplification. RESULTS: One or more amplification events were present in 50 of 87 (57%) adenocarcinomas. The ERBB2 gene was amplified in 19 of 87 (21.8%), CCNE1 in 11 of 87 (12.6%), GATA4 in 9 of 87 (10.3%), KRAS in 9 of 87 (10.3%), EGFR in 7 of 87 (8.0%), CCND1 in 6 of 87 (6.8%), HNF3alpha in 5 of 87 (5.7%), PIK3CA in 5 of 87 (5.7%), C-MYC in 4 of 87 (4.6%), DYRK2 in 2 of 87 (2.3%), and AIB1, AKT1, and IGF1R were amplified in 0 of 87 (0%) of the tumors. CCND1 amplification was found to correlate negatively with survival (P < 0.05). In addition, the ERBB2 amplicon positively correlated (P < 0.05) with GATA4 amplification. Increased copy number of the ERBB2 (1 of 22), GATA4 (1 of 22), KRAS (2 of 22), C-MYC (1 of 22), CCNE1 (2 of 22), and CCND1 (2 of 22) genes was also observed in one or more Barrett's adenocarcinomas with HGD. CONCLUSIONS: The high frequency of gene amplification in esophageal adenocarcinomas and HGD indicates the important role of these events in esophageal adenocarcinoma development. Additionally, these results underscore the possible usefulness of early detection approaches and chemotherapeutic strategies (ErbB2 and cyclin D1) targeted against amplified gene products. 相似文献
984.
Extravasations of oxaliplatin. 总被引:2,自引:0,他引:2
985.
Antineoplastic effects of partially HLA-matched irradiated blood mononuclear cells in patients with renal cell carcinoma. 总被引:11,自引:0,他引:11
Roger K Strair Dale Schaar Daniel Medina Mary B Todd Joseph Aisner Robert S DiPaola Jacqueline Manago Beth Knox Amanda Jenkinson Rachelle Senzon Christina Baker Dudek Liesel Marie Ciardella Mercy Kuriyan Arnold Rubin Edmund C Lattime 《Journal of clinical oncology》2003,21(20):3785-3791
PURPOSE: Vaccines, cytokines, and other biologic-based therapies are being developed as antineoplastic agents. Many of these agents are designed to induce an autologous immune response directed against the malignancy. In contrast, hematopoietic stem-cell transplantation is being developed as a form of allogeneic immunotherapy. This study tests the tolerance and antineoplastic activity of sequential infusions of partially HLA-matched allogeneic blood mononuclear cells (obtained from relatives) when administered outside of the context of a hematopoietic stem-cell transplantation. The cells are irradiated to prevent graft-versus-host disease. PATIENTS AND METHODS: Fifteen patients with relapsed or refractory malignancies for which no standard therapy was available were enrolled onto a clinical trial designed to assess the tolerability and antineoplastic effects of irradiated partially HLA-matched blood mononuclear cells obtained from relatives. RESULTS: There was disease regression in three patients with metastatic renal cell carcinoma during treatment. There was disease progression in six patients with metastatic renal cell carcinoma and two patients with metastatic melanoma during treatment. There was no change in disease state in several other patients. CONCLUSION: Irradiated allogeneic blood mononuclear cells administered outside the context of hematopoietic stem-cell transplantation may induce disease responses in patients with relapsed or refractory malignancies. Transfusion of irradiated allogeneic blood mononuclear cells should be developed further as a novel therapeutic antineoplastic approach. 相似文献
986.
Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation. 总被引:9,自引:0,他引:9
987.
Adjuvant immunization of HLA-A2-positive melanoma patients with a modified gp100 peptide induces peptide-specific CD8+ T-cell responses. 总被引:3,自引:0,他引:3
John W Smith Edwin B Walker Bernard A Fox Daniel Haley Ketura P Wisner Teri Doran Brenda Fisher Lisa Justice William Wood John Vetto Holden Maecker Annemiek Dols Sybren Meijer Hong-Ming Hu Pedro Romero W Gregory Alvord Walter J Urba 《Journal of clinical oncology》2003,21(8):1562-1573
PURPOSE: To measure the CD8+ T-cell response to a melanoma peptide vaccine and to compare an every-2-weeks with an every-3-weeks vaccination schedule. PATIENTS AND METHODS: Thirty HLA-A2-positive patients with resected stage I to III melanoma were randomly assigned to receive vaccinations every 2 weeks (13 vaccines) or every 3 weeks (nine vaccines) for 6 months. The synthetic, modified gp100 peptide, g209-2M, and a control peptide, HPV16 E7, were mixed in incomplete Freund's adjuvant and injected subcutaneously. Peripheral blood mononuclear cells obtained before and after vaccination by leukapheresis were analyzed using a fluorescence-based HLA/peptide-tetramer binding assay and cytokine flow cytometry. RESULTS: Vaccination induced an increase in peptide-specific T cells in 28 of 29 patients. The median frequency of CD8+ T cells specific for the g209-2M peptide increased markedly from 0.02% before to 0.34% after vaccination (P <.0001). Eight patients (28%) exhibited peptide-specific CD8+ T-cell frequencies greater than 1%, including two patients with frequencies of 4.96% and 8.86%, respectively. Interferon alfa-2b-treated patients also had significant increases in tetramer-binding cells (P <.0001). No difference was observed between the every-2-weeks and the every-3-weeks vaccination schedules (P =.59). CONCLUSION: Flow cytometric analysis of HLA/peptide-tetramer binding cells was a reliable means of quantifying the CD8+ T-cell response to peptide immunization. This assay may be suitable for use in future trials to optimize different vaccination strategies. Concurrent interferon treatment did not inhibit the development of a peptide-specific immune response and vaccination every 2 weeks, and every 3 weeks produced similar results. 相似文献
988.
Human milk oligosaccharides are resistant to enzymatic hydrolysis in the upper gastrointestinal tract 总被引:6,自引:0,他引:6
Engfer MB Stahl B Finke B Sawatzki G Daniel H 《The American journal of clinical nutrition》2000,71(6):1589-1596
BACKGROUND: Human milk oligosaccharides (HMOs) show a complexity and variety not found in milk of any other species. Although progress has been made in the past 3 decades with regard to identification and structural characterization of HMOs, not much is known about the physiologic functions of HMOs. OBJECTIVE: As a prerequisite for biological activity in infant metabolism, HMOs have to resist enzymatic hydrolysis in the gastrointestinal tract. To assess the extent to which selected HMOs are hydrolyzed, we carried out in vitro digestion studies using enzyme preparations of human and porcine pancreas and intestinal brush border membranes (BBMs). DESIGN: Fractions of HMOs, including structurally defined isolated oligosaccharides, were digested for up to 20 h with human pancreatic juice and BBMs prepared from human or porcine intestinal tissue samples. HMOs were incubated by using a porcine pancreatic homogenate and BBMs as enzyme sources. HMOs and digestion products were identified by mass spectrometry and anion-exchange chromatography. Additionally, free D-glucose, L-fucose, and N-acetylneuraminic acid were determined enzymatically. RESULTS: Whereas maltodextrin (control) was rapidly and completely hydrolyzed, neutral and acidic HMOs showed a profound resistance against pancreatic juice and BBM hydrolases. However, cleavage of most of the HMOs was achieved by using a pancreatic homogenate containing intracellular, including lysosomal, enzymes in addition to secreted enzymes. CONCLUSIONS: The results of this study strongly suggest that HMOs are not hydrolyzed by enzymes in the upper small intestine. Although intact HMOs may be absorbed, we postulate that a majority of HMOs reach the large intestine, where they serve as substrates for bacterial metabolism. Therefore, HMOs might be considered the soluble fiber fraction of human milk. 相似文献
989.
Richard B. Lock Bruce S. Thompson Daniel M. Sullivan Lolita Stribinskiene 《Cancer chemotherapy and pharmacology》1997,39(5):399-409
Protein kinase inhibitors have demonstrated potential for use in the therapy of human cancers, in particular leukemia. Staurosporine,
a protein kinase inhibitor with broad specificity, enhances the cytotoxic effects of various antitumor agents with different
modes of action. The topoisomerase II inhibitor, etoposide, has shown clinical activity against a wide range of tumor types.
Purpose: The purpose of this study was to assess the effects of staurosporine on etoposide-induced cell death processes in a human
tumor of epithelial origin. Methods: Modulation of etoposide-induced apoptosis by staurosporine in HeLa cells was assessed by cell morphology, extraction of
low molecular weight DNA, quantitation of DNA-protein complexes, and measurements of rates of DNA synthesis. The effects on
cellular genes implicated in apoptosis were determined by Northern and Western blotting, along with assays of cyclin-dependent
kinase activities. Results: Stauro- sporine exhibited a two- to three-fold potentiation of apoptosis caused by etoposide in HeLa cells when ap- plied
concurrently, or immediately following etoposide removal, but did not alter the quantity of DNA-protein complexes produced
by etoposide. Etoposide-induced apoptosis, and its potentiation by staurosporine, were associated with reduced c-myc expression, and a moderate increase in p21WAF1/CIP1 mRNA and protein levels. Inhibitors of cyclic AMP-dependent protein kinase and protein kinase C, which exhibit greater specificity
than staurosporine, were without effect on apoptosis caused by etoposide, whereas use of the tyrosine phosphatase inhibitor,
vanadate, resulted in its abrogation. The potentiation of etoposide-induced apoptosis by staurosporine was associated with
a significant increase in cyclin A-dependent kinase activity. In addition, etoposide caused substantial inhibition of DNA
synthesis. Conclusion: These results indicate that staurosporine potentiates apoptosis through events which occur downstream of DNA damage, and
implicate unscheduled activation of cyclin A-dependent kinase during inhibition of DNA synthesis as a possible cause.
Received: 28 November 1995/Accepted: 8 July 1996 相似文献
990.
Disentangling the Overlap between Tourette's Disorder and ADHD 总被引:11,自引:0,他引:11
Thomas Spencer Joseph Biederman Margaret Harding Deborah O'Donnell Timothy Wilens Stephen Faraone Barbara Coffey & Daniel Geller 《Journal of child psychology and psychiatry, and allied disciplines》1998,39(7):1037-1044
Objective : To identify similarities and differences in neuropsychiatric correlates in children with Tourette's syndrome (TS) and those with ADHD. Method : The sample consisted of children with Tourette's syndrome with ADHD( N = 79), children with Tourette's syndrome without ADHD ( N = 18), children with ADHD ( N = 563), psychiatrically referred children ( N = 212), and healthy controls ( N = 140). Results: Disorders specifically associated with Tourette's syndrome were obsessive compulsive disorder (OCD) and simple phobias. Rates of other disorders, including other disruptive behavioral, mood, and anxiety disorders, neuropsychologic correlates, and social and school functioning were indistinguishable in children with Tourette's and ADHD. However, children with Tourette's syndrome plus ADHD had more additional comorbid disorders overall and lower psychosocial function than children with ADHD. Conclusions: These findings confirm previously noted associations between Tourette's syndrome and OCD but suggest that disruptive behavioral, mood, and anxiety disorders as well as cognitive dysfunctions may be accounted for by comorbidity with ADHD. However, Tourette's syndrome plus ADHD appears to be a more severe condition than ADHD alone. 相似文献