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991.
Mutation of plasma membrane Ca2+ ATPase isoform 3 in a family with X-linked congenital cerebellar ataxia impairs Ca2+ homeostasis 总被引:1,自引:0,他引:1
G Zanni T Calì VM Kalscheuer D Ottolini S Barresi N Lebrun L Montecchi-Palazzi H Hu J Chelly E Bertini M Brini E Carafoli 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(36):14514-14519
Ca(2+) in neurons is vital to processes such as neurotransmission, neurotoxicity, synaptic development, and gene expression. Disruption of Ca(2+) homeostasis occurs in brain aging and in neurodegenerative disorders. Membrane transporters, among them the calmodulin (CaM)-activated plasma membrane Ca(2+) ATPases (PMCAs) that extrude Ca(2+) from the cell, play a key role in neuronal Ca(2+) homeostasis. Using X-exome sequencing we have identified a missense mutation (G1107D) in the CaM-binding domain of isoform 3 of the PMCAs in a family with X-linked congenital cerebellar ataxia. PMCA3 is highly expressed in the cerebellum, particularly in the presynaptic terminals of parallel fibers-Purkinje neurons. To study the effects of the mutation on Ca(2+) extrusion by the pump, model cells (HeLa) were cotransfected with expression plasmids encoding its mutant or wild-type (wt) variants and with the Ca(2+)-sensing probe aequorin. The mutation reduced the ability of the PMCA3 pump to control the cellular homeostasis of Ca(2+). It significantly slowed the return to baseline of the Ca(2+) transient induced by an inositol-trisphosphate (InsP(3))-linked plasma membrane agonist. It also compromised the ability of the pump to oppose the influx of Ca(2+) through the plasma membrane capacitative channels. 相似文献
992.
Schelotto F Hernández E González S Del Monte A Ifran S Flores K Pardo L Parada D Filippini M Balseiro V Geymonat JP Varela G 《Revista do Instituto de Medicina Tropical de S?o Paulo》2012,54(2):69-75
Leptospira spp. are delicate bacteria that cannot be studied by usual microbiological methods. They cause leptospirosis, a zoonotic disease transmitted to humans through infected urine of wild or domestic animals. We studied the incidence of this disease in the Uruguayan population, its epidemiologic and clinical features, and compared diagnostic techniques. After examining 6,778 suspect cases, we estimated that about 15 infections/100,000 inhabitants occurred yearly, affecting mainly young male rural workers. Awareness about leptospirosis has grown among health professionals, and its lethality has consequently decreased. Bovine infections were probably the principal source of human disease. Rainfall volumes and floods were major factors of varying incidence. Most patients had fever, asthenia, myalgias or cephalalgia, with at least one additional abnormal clinical feature. 30-40% of confirmed cases presented abdominal signs and symptoms, conjunctival suffusion and altered renal or urinary function. Jaundice was more frequent in patients aged > 40 years. Clinical infections followed an acute pattern and their usual outcome was complete recovery. Laboratory diagnosis was based on indirect micro-agglutination standard technique (MAT). Second serum samples were difficult to obtain, often impairing completion of diagnosis. Immunofluorescence was useful as a screening test and for early detection of probable infections. 相似文献
993.
Beatriz Lara Inocencia Fornet María Goya Francisco López José Ramón De Miguel María Molina Pilar Morales Esther Quintana Sabina Salicrú Elena Suárez Piedad Usetti Felipe Zurbano 《Archivos de bronconeumología》2012
Three percent of rare diseases are pneumopathies. Improvements in survival and quality of life have led to a new situation where patients with rare respiratory diseases want to plan their reproductive lives. The intention of this review is to present the experience accumulated in the field of the reproductive health of these women. 相似文献
994.
Del Giudice I Rossi D Chiaretti S Marinelli M Tavolaro S Gabrielli S Laurenti L Marasca R Rasi S Fangazio M Guarini A Gaidano G Foà R 《Haematologica》2012,97(3):437-441
Trisomy 12, the third most frequent chromosomal aberration in chronic lymphocytic leukemia (CLL), confers an intermediate prognosis. In our cohort of 104 untreated patients carrying +12, NOTCH1 mutations occurred in 24% of cases and were associated to unmutated IGHV genes (P=0.003) and +12 as a sole cytogenetic abnormality (P=0.008). NOTCH1 mutations in +12 CLL associated with an approximately 2.4 fold increase in the risk of death, a significant shortening of survival (P<0.01) and proved to be an independent predictor of survival in multivariate analysis. Analogous to +12 CLL with TP53 disruption or del(11q), NOTCH1 mutations in +12 CLL conferred a significantly worse survival compared to that of +12 CLL with del(13q) or +12 only. The overrepresentation of cell cycle/proliferation related genes of +12 CLL with NOTCH1 mutations suggests the biological contribution of NOTCH1 mutations to determine a poor outcome. NOTCH1 mutations refine the intermediate prognosis of +12 CLL. 相似文献
995.
Guarini A Marinelli M Tavolaro S Bellacchio E Magliozzi M Chiaretti S De Propris MS Peragine N Santangelo S Paoloni F Nanni M Del Giudice I Mauro FR Torrente I Foà R 《Haematologica》2012,97(1):47-55
Background
The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease.Design and Methods
Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval.Results
Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations.Conclusions
ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval. 相似文献996.
First‐in‐Human Proof‐of‐Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist,to Melanoma Skin Metastases
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Jasper Wouters Robert E. Hunger Terence Garrod Benoit Dubuis Thomas Hunziker Joost J. van den Oord Ronit Lahav‐le Coutre 《The oncologist》2015,20(10):1121-1122
Lessons Learned
- Local tolerance of intralesional treatment of melanoma skin metastases with BQ788 is excellent.
- Hints of efficacy are observed, consisting of both direct effects (decreased expression of endothelin receptor B [EDNRB] and of survival factors, reduced proliferation) and indirect effects (enhanced immune cell infiltration and angiogenesis).
- Patients in future trials should be screened for EDNRB expression level prior to treatment because only patients with high EDNRB-expressing melanomas (four of five) responded to BQ788.
- Future studies should be performed for at least 2 weeks because reduced lesion growth was observed in the only patient that was treated for longer than 1 week.
Background.
This first-in-human proof-of-concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients.Methods.
Three patients received a single intralesional BQ788 application of 3 mg. After 3–7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0–3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate-buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings.Results.
No statistical evaluation was possible because of the number of patients (n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788- and PBS-treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788-treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement.Conclusion.
The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells. 相似文献997.
Young investigator challenge: Application of cytologic techniques to circulating tumor cell specimens: Detecting activation of the oncogenic transcription factor STAT3
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998.
999.
Sabina Low Mark J. Van Ryzin Eric C. Brown Brian H. Smith Kevin P. Haggerty 《Prevention science》2014,15(2):165-176
Steps to Respect: A Bullying Prevention Program (STR) relies on a social–ecological model of prevention to increase school staff awareness and responsiveness, foster socially responsible beliefs among students, and teach social–emotional skills to students to reduce bullying behavior. As part of a school-randomized controlled trial of STR, we examined predictors and outcomes associated with classroom curriculum implementation in intervention schools. Data on classroom implementation (adherence and engagement) were collected from a sample of teachers using a weekly on-line Teacher Implementation Checklist system. Pre-post data related to school bullying-related outcomes were collected from 1,424 students and archival school demographic data were obtained from the National Center for Education Statistics. Results of multilevel analyses indicated that higher levels of program engagement were influenced by school-level percentage of students receiving free/reduced lunch, as well as classroom-level climate indicators. Results also suggest that higher levels of program engagement were related to lower levels of school bullying problems, enhanced school climate and attitudes less supportive of bullying. Predictors and outcomes related to program fidelity (i.e., adherence) were largely nonsignificant. Results suggest that student engagement is a key element of program impact, though implementation is influenced by both school-level demographics and classroom contexts. 相似文献
1000.
Eduardo Santos da Silva Sara Huber Neuza Maria Alcantara-Neves Claudia Asam Elisânia Fontes Silveira Emília Maria Medeiros de Andrade Belitardo Lorenz Aglas Michael Wallner Gabriele Gadermaier Peter Briza Ingrid Karner Rogério Tanan Torres Juan Ricardo Urrego Alvarez Sabina Wuenschmann Martin Chapman Fatima Ferreira Carina Silva Pinheiro 《Allergy》2020,75(6):1503-1507