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61.
Soluble CD40 ligand plasma levels in lung cancer. 总被引:7,自引:0,他引:7
Mario Roselli Tommaso C Mineo Stefania Basili Francesca Martini Sabrina Mariotti Simona Aloe Girolamo Del Monte Vincenzo Ambrogi Antonella Spila Raffaele Palmirotta Roberta D'Alessandro Giovanni Davì Fiorella Guadagni Patrizia Ferroni 《Clinical cancer research》2004,10(2):610-614
PURPOSE: Tumor-induced platelet activation may cause the release of various cytokines, including CD40 ligand (CD40L). Activation of the CD40/CD40L pathway in human tumors may result in thrombin generation, which is known to be involved in angiogenesis. Thus, we investigated whether soluble (s)CD40L levels are increased in patients with lung cancer as a result of platelet and/or coagulation activation. EXPERIMENTAL DESIGN: Citrated plasma samples were obtained from 120 patients with different stages and histotypes of lung cancer and 60 age- and sex-matched control subjects. sCD40L, sP-selectin (marker of platelet activation), prothrombin fragment 1 + 2, and thrombin-antithrombin III complex levels (both markers of coagulative activation) were measured in all samples. RESULTS: Patients with lung cancer had median sCD40L levels higher than in control subjects (0.46 versus 0.13 ng/ml; P < 0.0001), although correlation with the stage of disease was not evident. Nonetheless, sCD40L levels were significantly higher in squamous cancer compared with adenocarcinoma (0.75 versus 0.27 ng/ml; P < 0.05). Moreover, median sCD40L levels were higher in stage IV compared with nonmetastatic squamous lung cancer (1.02 versus 0.61 ng/ml; P < 0.05). sCD40L levels significantly correlated with sP-selectin (P < 0.001), prothrombin fragment 1 + 2 (P < 0.001), or thrombin-antithrombin III complex (P < 0.05) in squamous lung cancer, but only sP-selectin (P = 0.011) was independently related to sCD40L. CONCLUSIONS: These findings indicate that elevated sCD40L levels can be preferentially found in patients with advanced squamous cancer and provide evidence that increased levels of this cytokine are associated to the occurrence of in vivo platelet activation. 相似文献
62.
63.
Wei Xin Ki J Yun Francesca Ricci Marianna Zahurak Wanglong Qiu Gloria H Su Charles J Yeo Ralph H Hruban Scott E Kern Christine A Iacobuzio-Donahue 《Clinical cancer research》2004,10(24):8516-8520
MKK4 (MAP2K4/SEK1) is a member of the mitogen-activated protein kinase family, originally identified as a kinase involved in the stress-activated protein kinase pathway by directly phosphorylating c-Jun NH2-terminal kinase. MKK4 genetic inactivation has been observed in a subset of pancreatic carcinomas, implicating deregulation of the stress-activated protein kinase pathway in pancreatic carcinogenesis. We evaluated Mkk4 protein expression patterns by immunohistochemical labeling in a series of 60 resected primary infiltrating pancreatic adenocarcinomas (24 cases with known MKK4 genetic status), and 14 different tissue arrays representing the primary carcinoma and all of the gross metastases from 26 patients that died of metastatic pancreatic cancer. Among the surgically resected carcinomas, focal or diffuse-positive immunolabeling for Mkk4 protein was found in 52 of 60 cases (86.7%). Among the eight carcinomas with negative Mkk4 immunolabeling, three harbored a homozygous deletion or intragenic mutation of the MKK4 gene, in contrast to none of the 52 cases with positive Mkk4 immunolabeling (P < 0.01). Loss of Mkk4 immunolabeling showed a trend toward shorter survival, with Mkk4-positive carcinomas having half the risk of death than Mkk4-negative carcinomas (P = 0.09). Mkk4 immunolabeling patterns were also evaluated among unresectable primary and metastatic cancer tissues from autopsy specimens, indicating intact Mkk4 immunolabeling in 88.8% of the unresectable primary carcinomas as compared with 63.3% of distant metastases (P < 0.001). Our data indicate that the loss of Mkk4 protein expression in pancreatic carcinomas may be more frequent than suggested by the rates of genetic inactivation alone and that MKK4 loss may contribute to disease progression. The correlation of MKK4 genetic status with immunolabeling patterns validate this approach for the evaluation of MKK4 status in routine histologic sections and may provide useful information regarding patient prognosis. 相似文献
64.
HMGA1 protein overexpression in human breast carcinomas: correlation with ErbB2 expression. 总被引:6,自引:0,他引:6
Gennaro Chiappetta Gerardo Botti Mario Monaco Rosa Pasquinelli Francesca Pentimalli Maurizio Di Bonito Giuseppe D'Aiuto Monica Fedele Rodolfo Iuliano Emiliano A Palmieri Giovanna Maria Pierantoni Vincenzo Giancotti Alfredo Fusco 《Clinical cancer research》2004,10(22):7637-7644
We measured, by immunohistochemistry, HMGA1 protein expression in 212 breast tissue specimens: 6 normal samples, 28 hyperplastic lesions (13 with cellular atypia), 11 fibroadenomas, 10 in situ ductal carcinomas, 144 ductal carcinomas, and 13 lobular carcinomas. HMGA1 was not expressed in normal breast tissue; HMGA1 staining was intense in 40% of hyperplastic lesions with cellular atypia and in 60% of ductal carcinomas and weak in fibroadenomas and in hyperplastic lesions without cellular atypia. Because HMGA1 expression was similar among ductal breast carcinomas with different histologic grading, we evaluated the association between HMGA1 expression and that of other markers of breast carcinoma invasion (estrogen and progesterone receptors, Ki-67 antigen, and ErbB2) in 21 cases of grade 3 breast ductal carcinomas and 7 cases of breast lobular carcinomas. We found that HMGA1 expression tended to be associated only with c-erbB-2 expression (Spearman rho: 0.36; P=0.065). Taken together, these results suggest that HMGA1 expression might be a novel indicator for the diagnosis and prognosis of human breast cancer. 相似文献
65.
Francesca M Buffa S?ren M Bentzen Frances M Daley Stanley Dische Michele I Saunders Paul I Richman George D Wilson 《Clinical cancer research》2004,10(11):3745-3754
PURPOSE: Identification of factors that assist prediction of tumor response to radiotherapy may aid in refining treatment strategies and improving outcome. Possible association of molecular marker expression profiles with locoregional control of head and neck squamous cell carcinoma was investigated in a randomized trial of conventional versus continuous hyperfractionated accelerated radiotherapy (CHART). EXPERIMENTAL DESIGN: Tumor material was obtained from 402 patients. Immunohistochemistry was used to assess Ki-67, CD31, p53, Bcl-2, and cyclin D1 expression. A hierarchical clustering algorithm with a Bayesian information criterion was used to group tumors with similar marker expression; resulting expression profiles were then compared in terms of their difference in outcome after CHART and conventionally fractionated radiotherapy. RESULTS: Molecular marker profile was an independent prognostic factor for locoregional control. This was confirmed in multivariate analysis, including clinical variables such as tumor and nodal status, primary site, histological grade, age, and gender (P < 0.001 and P = 0.006 for local and nodal relapse, respectively). In particular, Bcl-2-positive tumors responded significantly better than average in both arms of the trial. Tumors negative for p53- and Bcl-2, with high and randomly patterned Ki-67 expression, responded worse than average with no benefit from CHART. Tumors with similarly negative p53 and Bcl-2, but low Ki-67 staining, with an organized pattern, benefit significantly from CHART schedule. CONCLUSIONS: This study demonstrates the potential of molecular profiles to predict radiotherapy response of head and neck squamous cell carcinoma and for treatment stratification. Distinct expression profiles correlate with three distinct clinical phenotypes, including good locoregional control, poor locoregional control, and an outcome strongly dependent upon fractionation schedule. 相似文献
66.
Gianni Sava Sonia Zorzet Claudia Turrin Francesca Vita MariaRosa Soranzo Giuliano Zabucchi Moreno Cocchietto Alberta Bergamo Stefano DiGiovine Gabriella Pezzoni Luigi Sartor Spiridione Garbisa 《Clinical cancer research》2003,9(5):1898-1905
NAMI-A is a ruthenium complex endowed with a selective effect on lung metastases of solid metastasizing tumors. The aim of this study is to provide evidence that NAMI-A's effect is based on the selective sensitivity of the metastasis cell, as compared with other tumor cells, and to show that lungs represent a privileged site for the antimetastatic effects. The transplantation of Lewis lung carcinoma cells, harvested from the primary tumor of mice treated with 35 mg/kg/day NAMI-A for six consecutive days, a dose active on metastases, shows no change in primary tumor take and growth but a significant reduction in formation of spontaneous lung metastases. Transmission electron microscopy examination of lungs and kidney shows NAMI-A to selectively bind collagen of the lung extracellular matrix and also type IV collagen of the basement membrane of kidney glomeruli. The half lifetime of NAMI-A elimination from the lungs is longer than for liver, kidney, and primary tumor. NAMI-A bound to collagen is active on tumor cells as shown in vitro by an invasion test, using a modified Boyden chamber and Matrigel, and it inhibits the matrix metallo-proteinases MMP-2 and MMP-9 at micromolar concentrations, as shown in vitro by a zimography test. These data show NAMI-A to significantly affect tumor cells with metastatic ability. Binding to collagen allows NAMI-A to exert its selective activity on metastatic cells during dissemination and particularly in the lungs. These data also stress the wide spectrum of daily doses and treatment schedules at which NAMI-A is active against metastases. 相似文献
67.
Giancarlo Colombo Carla Lobina Paola Maccioni M Francesca Mascia Alessandro Orrù Gian Luigi Gessa Mauro A M Carai 《Alcohol》2005,35(1):35-41
In the current study, we investigated the effect of the concurrent presentation of saccharin on the maintenance of alcohol-drinking behavior in selectively bred Sardinian alcohol-preferring (sP) rats. Rats were initially given access to alcohol [10% (volume/volume) in water] and water under the home cage, two-bottle, free-choice regimen, with unlimited access for 24 h/day for eight consecutive weeks. Next, a third bottle, containing saccharin [0%, 0.01%, 0.1%, 1%, or 3% (weight/volume) in water], was concomitantly offered for an additional 10 consecutive days. Intake of saccharin solution resulted as an inverted-U function of saccharin concentration, with the 0.1% saccharin solution being the highest accepted. Alcohol intake was a U function of saccharin concentration, being reduced by 65%-95% in the group of rats exposed to the 0.1% saccharin solution. These results indicate that (1) the concurrent presentation of highly palatable solutions of saccharin markedly reduced alcohol intake in alcohol-experienced sP rats and (2) the reducing effect of saccharin solutions on the alcohol intake in sP rats was positively related to their degree of acceptability. We hypothesized that saccharin solutions may have functioned as a reinforcer, partially substituting for alcohol reinforcement and rendering alcohol drinking less urgent. 相似文献
68.
Serio G 《Chirurgia italiana》2000,52(1):1-9
Technological progress and the evolution of biological knowledge lead us to expect major developments in the fields of organ replacement, minimally invasive surgery and tumour therapy in the coming decades. It is widely believed that xenotransplantation may offer a possible solution to the problem of the current chronic shortage of donors, though their use at present encounters formidable immunological obstacles, particularly as regards discordant transplants. Genetic engineering and the realisation of transgenic donors as well as new strategies aimed at modifying the immune status of the donor may well be the key to new developments in this sector. Selective culturing of tissues and the production of totally implantable artificial organs are additional lines of research which may provide useful means of meeting the increasing demand for organs. The enormous advances made in the field of high-tech solutions applied to the biomedical disciplines are destined to open up new frontiers in diagnostics, operating technique and the permanent training of surgeons. In particular, we are about to witness an extension of the use of computer technology and robotics, embracing the simulation and reproduction of virtual reality, telemedicine (teleconsulting and telesurgery) and the creation of experimental models. Minimally invasive surgery will unquestionably benefit from this progress with the possibility of extending its range of indications to procedures in which human limitations are more evident owing to difficulties of access and the size of the target, at the same time guaranteeing high-precision manoeuvres. In the oncological field, high expectations accompany the advances in our knowledge of molecular biology with the genetic mapping of tumours which may pave the way for screening programs and gene therapy. Alongside the scientific and technological development of the surgery of the future, we can expect to see the increasing emergence of: a) economic problems related to the progressive increase in healthcare costs, amongst other things as a result of the powerful impact of high-tech solutions; b) social problems in terms of the inevitable conflict between cost-containment policies and the right to healthcare; c) moral and bioethical problems relating to the possible establishment of genetic registries and to the different patient-care provider relationship which is likely to come about as the result of the interference of machines or robots. The surgeon's persona may undergo profound changes, not merely from the technical and professional training standpoint, but also with regard to his or her effective role, which may no longer be that of a central, dominant figure, but may be scaled down in a context of multidisciplinary co-operation. 相似文献
69.
Lorenzo Fornaro Gianna Musettini Paola Orlandi Irene Pecora Caterina Vivaldi Marta Banchi Francesca Salani Elisabetta Fini Valentina Massa Silvia Catanese Federico Cucchiara Monica Lencioni Gianluca Masi Enrico Vasile Guido Bocci 《American journal of cancer research》2022,12(7):3347
Ramucirumab plus paclitaxel is considered the standard of care in the second-line treatment of gastric carcinoma (GC). The aim of this study was to evaluate plasma vascular endothelial growth factor-A (VEGF-A), VEGF-D, and circulating soluble VEGF receptor-2 (sVEGFR-2) as possible markers of resistance or response to ramucirumab administered with paclitaxel in pretreated metastatic GC patients. Plasma samples were collected at different time points (on days 1 and 15 of the first 3 cycles, at best radiologic response and at disease progression). VEGF-A, VEGF-D and sVEGFR-2 were analysed by ELISA. Correlations of biomarker baseline levels or dynamic changes with outcome measures were assessed. Progression-free survival (PFS) was the primary endpoint of the study. Forty-one patients were enrolled. VEGF-A and VEGF-D, but not sVEGFR-2, values significantly increased during treatment compared to baseline (P < 0.001). A positive correlation between VEGF-A and sVEGFR-2 at cycle 2 was found (P=0.045). At univariate analysis, higher baseline levels of VEGF-A were associated with worse OS (P=0.015). Early increase of sVEGFR-2 levels after the first treatment cycle was the only factor associated with longer PFS (6.6 vs. 3.6 months, P=0.049) and OS (18.6 vs. 5.2 months, P=0.008). Significance of sVEGFR-2 early increase was retained at multivariate analysis for OS (HR 0.32; 95% CI 0.12-0.91; P=0.032). The reported results confirmed the prognostic role of baseline VEGF-A and, with the limitations of the limited sample size and the lack of a control arm, suggested that the early increase of sVEGFR-2 after 1 cycle of treatment could be a potential predictive biomarker of benefit from second-line ramucirumab plus paclitaxel in GC. 相似文献
70.
Identification
of RAD51–BRCA2 Inhibitors Using N-Acylhydrazone-Based
Dynamic Combinatorial Chemistry
Greta Bagnolini Beatrice Balboni Fabrizio Schipani Dario Gioia Marina Veronesi Francesca De Franco Cansu Kaya Ravindra P. Jumde Jose Antonio Ortega Stefania Girotto Anna K. H. Hirsch Marinella Roberti Andrea Cavalli 《ACS medicinal chemistry letters》2022,13(8):1262
RAD51 is an ATP-dependent recombinase, recruited by BRCA2 to mediate DNA double-strand breaks repair through homologous recombination and represents an attractive cancer drug target. Herein, we applied for the first-time protein-templated dynamic combinatorial chemistry on RAD51 as a hit identification strategy. Upon design of N-acylhydrazone-based dynamic combinatorial libraries, RAD51 showed a clear templating effect, amplifying 19 N-acylhydrazones. Screening against the RAD51–BRCA2 protein–protein interaction via ELISA assay afforded 10 inhibitors in the micromolar range. Further 19F NMR experiments revealed that 7 could bind RAD51 and be displaced by BRC4, suggesting an interaction in the same binding pocket of BRCA2. These results proved not only that ptDCC could be successfully applied on full-length oligomeric RAD51, but also that it could address the need of alternative strategies toward the identification of small-molecule PPI inhibitors. 相似文献