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71.
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
72.
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73.
The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity
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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
74.
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
75.
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
76.
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
77.
Linda Pilgaard Joachim Høg Mortensen Michael Henriksen Pia Olesen Preben Sørensen Rene Laursen Mogens Vyberg Ralf Agger Vladimir Zachar Torben Moos Meg Duroux 《Brain pathology (Zurich, Switzerland)》2014,24(4):360-370
Human glioblastoma multiforme (GBM) is an aggressive cancer with a very poor prognosis. Cripto‐1 (CR‐1) has a key regulatory role in embryogenesis, while in adult tissue re‐expression of CR‐1 has been correlated to malignant progression in solid cancers of non‐neuronal origin. As CR‐1 expression has yet to be described in cerebral cancer and CR‐1 is regulated by signaling pathways dysregulated in GBM, we aimed to investigate CR‐1 in the context of expression in GBM. The study was performed using enzyme‐linked immunosorbent assay (ELISA), Western blotting, polymerase chain reaction (PCR) and immunohistochemistry to analyze the blood and tissue from 28 GBM and 4 low‐grade glioma patients. Within the patient cohort, we found high CR‐1 protein levels in blood plasma to significantly correlate with a shorter overall survival. We identified CR‐1 in different areas of GBM tissue, including perivascular tumor cells, and in endothelial cells. Collectively, our data suggest that CR‐1 could be a prognostic biomarker for GBM with the potential of being a therapeutic target. 相似文献
78.
Antonio Eduardo Monteiro de Almeida Ricardo Stein Miguel Gus Jo?o Agnaldo Nascimento Karlyse Claudino Belli Jorge Rene Garcia Arévalo Flávio Dani Fuchs Jorge Pinto Ribeiro 《Arquivos brasileiros de cardiologia》2014,103(4):338-347
Background
The importance of measuring blood pressure before morning micturition and in the afternoon, while working, is yet to be established in relation to the accuracy of home blood pressure monitoring (HBPM). Objective: To compare two HBPM protocols, considering 24-hour ambulatory blood pressure monitoring (wakefulness ABPM) as gold-standard and measurements taken before morning micturition (BM) and in the afternoon (AM), for the best diagnosis of systemic arterial hypertension (SAH), and their association with prognostic markers.Methods
After undergoing 24-hour wakefulness ABPM, 158 participants (84 women) were randomized for 3- or 5-day HBPM. Two variations of the 3-day protocol were considered: with measurements taken before morning micturition and in the afternoon (BM+AM); and with post-morning-micturition and evening measurements (PM+EM). All patients underwent echocardiography (for left ventricular hypertrophy - LVH) and urinary albumin measurement (for microalbuminuria - MAU).Result
Kappa statistic for the diagnosis of SAH between wakefulness-ABPM and standard 3-day HBPM, 3-day HBPM (BM+AM) and (PM+EM), and 5-day HBPM were 0.660, 0.638, 0.348 and 0.387, respectively. The values of sensitivity of (BM+AM) versus (PM+EM) were 82.6% × 71%, respectively, and of specificity, 84.8% × 74%, respectively. The positive and negative predictive values were 69.1% × 40% and 92.2% × 91.2%, respectively. The comparisons of intraclass correlations for the diagnosis of LVH and MAU between (BM+AM) and (PM+EM) were 0.782 × 0.474 and 0.511 × 0.276, respectively.Conclusions
The 3 day-HBPM protocol including measurements taken before morning micturition and during work in the afternoon showed the best agreement with SAH diagnosis and the best association with prognostic markers. 相似文献79.
80.
BM Meehan AD Baughn R Gallegos MH Malamy 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(30):12153-12158
Bacteroides fragilis can replicate in atmospheres containing ≤0.05% oxygen, but higher concentrations arrest growth by an unknown mechanism. Here we show that inactivation of a single gene, oxe (i.e., oxygen enabled) in B. fragilis allows for growth in concentrations as high as 2% oxygen while increasing the tolerance of this organism to room air. Known components of the oxidative stress response including the ahpC, kat, batA-E, and tpx genes were not individually important for microaerobic growth. However, a Δoxe strain scavenged H(2)O(2) at a faster rate than WT, indicating that reactive oxygen species may play a critical role in limiting growth of this organism to low-oxygen environments. Clinical isolates of B. fragilis displayed a greater capacity for growth under microaerobic conditions than fecal isolates, with some encoding polymorphisms in oxe. Additionally, isolation of oxygen-enabled mutants of Bacteroides thetaiotaomicron suggests that Oxe may mediate growth arrest of other anaerobes in oxygenated environments. 相似文献