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Roguin A Zviman MM Meininger GR Rodrigues ER Dickfeld TM Bluemke DA Lardo A Berger RD Calkins H Halperin HR 《Circulation》2004,110(5):475-482
65.
Dupuis L Pehar M Cassina P Rene F Castellanos R Rouaux C Gandelman M Dimou L Schwab ME Loeffler JP Barbeito L Gonzalez de Aguilar JL 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(2):740-745
The Nogo-66 receptor (NgR) plays a critical role in restricting axon regeneration in the central nervous system. This inhibitory action is in part mediated by a neuronal receptor complex containing p75NTR, a multifunctional receptor also well known to trigger cell death upon binding to neurotrophins such as NGF. In the present study, we show that Pep4 and NEP1-40, which are two peptides derived from the Nogo-66 sequence that modulate NgR-mediated neurite outgrowth inhibition, prevent NGF-stimulated p75NTR-dependent death of cultured embryonic motor neurons. They also confer protection on spinal cord motor neurons after neonatal sciatic nerve axotomy. These findings demonstrate an as-yet-unknown function of NgR in maintaining neuronal survival that may be relevant for motor neuron development and degeneration. 相似文献
66.
Nastassja Köhn Johannes Maubach Rene Warschkow Catherine Tsai Daniel P. Nussbaum Daniel Candinas Beat Gloor Bruno M. Schmied Dan G. Blazer Mathias Worni 《HPB : the official journal of the International Hepato Pancreato Biliary Association》2018,20(11):1073-1081
Background
Current consensus guidelines suggest that gallbladder cancer (GBC) patients with resected T1a disease can be observed while patients with T1b or greater lesions should undergo lymphadenectomy (LNE). The primary aim of this study was to critically explore the impact of LNE in early-stage GBC on overall survival (OS) on a population-based level.Method
The 2004–2014 National Cancer Database was reviewed to identify non-metastatic GBC patients with T1a, T1b, or T2 disease and grouped whether a dedicated LNE was performed. OS and relative survival were assessed using Cox proportional hazard regression analyses before and after propensity score adjustments.Results
4015 patients were included, 246 (6%) had T1a, 654 (16%) T1b, and 3115 (78%) T2 GBC. The rate of positive lymph nodes was 13%, 12%, and 40% for T1a, T1b, and T2 tumors, respectively. Even after propensity score adjustment, no OS benefit was found if LNE was performed for T1a disease (HR:0.63, 95%CI:0.35–1.13) while OS was improved for T1b (HR:0.65, 95%CI:0.49–0.87) and T2 tumors (HR:0.65, 95%CI:0.57–0.73).Conclusion
Despite a higher rate of nodal positivity among patients with T1a disease compared to previous reports, there was no impact on survival and current treatment guidelines appear appropriate for the management of T1a disease. 相似文献67.
The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity 下载免费PDF全文
Cortellino S Turner D Masciullo V Schepis F Albino D Daniel R Skalka AM Meropol NJ Alberti C Larue L Bellacosa A 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(25):15071-15076
Cytotoxicity of methylating agents is caused mostly by methylation of the O6 position of guanine in DNA to form O6-methylguanine (O6-meG). O6-meG can direct misincorporation of thymine during replication, generating O6-meG:T mismatches. Recognition of these mispairs by the mismatch repair (MMR) system leads to cell cycle arrest and apoptosis. MMR also modulates sensitivity to other antitumor drugs. The base excision repair (BER) enzyme MED1 (also known as MBD4) interacts with the MMR protein MLH1. MED1 was found to exhibit thymine glycosylase activity on O6-meG:T mismatches. To examine the biological significance of this activity, we generated mice with targeted inactivation of the Med1 gene and prepared mouse embryonic fibroblasts (MEF) with different Med1 genotype. Unlike wild-type and heterozygous cultures, Med1-/- MEF failed to undergo G2-M cell cycle arrest and apoptosis upon treatment with the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Similar results were obtained with platinum compounds' 5-fluorouracil and irinotecan. As is the case with MMR-defective cells, resistance of Med1-/- MEF to MNNG was due to a tolerance mechanism because DNA damage accumulated but did not elicit checkpoint activation. Interestingly, steady state amounts of several MMR proteins are reduced in Med1-/- MEF, in comparison with Med1+/+ and Med1+/- MEF. We conclude that MED1 has an additional role in DNA damage response to antitumor agents and is associated with integrity of the MMR system. MED1 defects (much like MMR defects) may impair cell cycle arrest and apoptosis induced by DNA damage. 相似文献
68.
Katherine A VandenHeuvel Rami N Al-Rohil Michael E Stevenson Jiang Qian Naina L Gross Rene McNall-Knapp Shibo Li Eric P Wartchow Gary W Mierau Kar-Ming Fung 《International journal of clinical and experimental pathology》2015,8(1):260-274
Pediatric primary “small round blue cell” tumors in the CNS represent several entities, some more common than others. Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) is rare and must be distinguished from other tumors such as medulloblastoma [1, 2], atypical rhabdoid/teratoid tumor, ependymomal tumors, metastatic sarcomas, hematologic malignancies, and other mimics. Although therapy for ES/pPNET is effective, it brings severe side effects, including cardiac toxicity, making correct recognition important [3]. As small blue cell tumors look similar, diagnosis often depends on special stains, immunohistochemistry, and molecular techniques. While the combination of membranous immunohistochemical reactivity for CD99 with cytoplasmic glycogen provides effective screening, demonstration of characteristic translocations of EWSR1 (chromosome 22) or FUS (chromosome 16) by fluorescent in situ hybridization (FISH) can confirm the diagnosis. We are reporting three primary ES/pPNET of the CNS, two of which occurred in children. While the adult case demonstrates the classic histopathology, the two pediatric cases have histopathology that significantly deviates from the usual. One is suggestive of a primary sarcoma, and the other mimics an ependymoma, but all three cases are confirmed with FISH. These observations suggest that primary ES in the CNS may have histology different from the classic morphology and a high index of suspicion should be maintained in order to make the correct diagnosis. A search of the literature suggests that these tumors are most frequently seen in children and young adults. Imaging often shows a supratentorial enhancing mass that touches the leptomeninges. Survival over three years is good but long term prognosis is unknown [3, 4]. 相似文献
69.
Emma Sprooten Cota Navin Gupta Emma E.M. Knowles D. Reese McKay Samuel R. Mathias Joanne E. Curran Jack W. Kent Jr Melanie A. Carless Marcio A. Almeida Thomas D. Dyer Harald H.H. Göring Rene L. Olvera Peter Kochunov Peter T. Fox Ravi Duggirala Laura Almasy Vince D. Calhoun John Blangero Jessica A. Turner David C. Glahn 《American journal of medical genetics. Part B, Neuropsychiatric genetics》2015,168(8):678-686
70.
Alice W. Tsai Colleen F. McNeil Joshua R. Leeman Hamilton B. Bennett Kwame Nti-Addae Cassey Huang Ursula A. Germann Randal A. Byrn Francoise Berlioz-Seux Rene Rijnbrand Michael P. Clark Paul S. Charifson Steven M. Jones 《Antimicrobial agents and chemotherapy》2015,59(10):6007-6016
Through antigenic drift and shifts, influenza virus infections continue to be an annual cause of morbidity in healthy populations and of death among elderly and at-risk patients. The emergence of highly pathogenic avian influenza viruses such as H5N1 and H7N9 and the rapid spread of the swine-origin H1N1 influenza virus in 2009 demonstrate the continued need for effective therapeutic agents for influenza. While several neuraminidase inhibitors have been developed for the treatment of influenza virus infections, these have shown a limited window for treatment initiation, and resistant variants have been noted in the population. In addition, an older class of antiviral drugs for influenza, the adamantanes, are no longer recommended for treatment due to widespread resistance. There remains a need for new influenza therapeutic agents with improved efficacy as well as an expanded window for the initiation of treatment. Azaindole compounds targeting the influenza A virus PB2 protein and demonstrating excellent in vitro and in vivo properties have been identified. To evaluate the in vivo efficacy of these PB2 inhibitors, we utilized a mouse influenza A virus infection model. In addition to traditional endpoints, i.e., death, morbidity, and body weight loss, we measured lung function using whole-body plethysmography, and we used these data to develop a composite efficacy score that takes compound exposure into account. This model allowed the rapid identification and ranking of molecules relative to each other and to oseltamivir. The ability to identify compounds with enhanced preclinical properties provides an opportunity to develop more-effective treatments for influenza in patients. 相似文献