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41.
Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. 总被引:11,自引:0,他引:11
Andre Goy Anas Younes Peter McLaughlin Barbara Pro Jorge E Romaguera Frederick Hagemeister Luis Fayad Nam H Dang Felipe Samaniego Michael Wang Kristine Broglio Barry Samuels Frederic Gilles Andreas H Sarris Susan Hart Elizabeth Trehu David Schenkein Fernando Cabanillas Alma M Rodriguez 《Journal of clinical oncology》2005,23(4):667-675
PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma. PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles. RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrom's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study. CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents. 相似文献
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West Nile encephalitis emerged in 1999 in the United States, then rapidly spread through the North American continent causing severe disease in human and horses. Since then, outbreaks appeared in Europe, and in 2012, the United States experienced a new severe outbreak reporting a total of 5,387 cases of West Nile virus (WNV) disease in humans, including 243 deaths. So far, no human vaccine is available to control new WNV outbreaks and to avoid worldwide spreading. In this review, we discuss the state-of-the-art of West Nile vaccine development and the potential of a novel safe and effective approach based on recombinant live attenuated measles virus (MV) vaccine. MV vaccine is a live attenuated negative-stranded RNA virus proven as one of the safest, most stable and effective human vaccines. We previously described a vector derived from the Schwarz MV vaccine strain that stably expresses antigens from emerging arboviruses, such as dengue, West Nile or chikungunya viruses, and is strongly immunogenic in animal models, even in the presence of MV pre-existing immunity. A single administration of a recombinant MV vaccine expressing the secreted form of WNV envelope glycoprotein elicited protective immunity in mice and non-human primates as early as two weeks after immunization, indicating its potential as a human vaccine. 相似文献
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Chinmayi Chandrasekhara Gireesha Mohannath Todd Blevins Frederic Pontvianne Craig S. Pikaard 《Genes & development》2016,30(2):177-190
In eukaryotes, scores of excess ribosomal RNA (rRNA) genes are silenced by repressive chromatin modifications. Given the near sequence identity of rRNA genes within a species, it is unclear how specific rRNA genes are reproducibly chosen for silencing. Using Arabidopsis thaliana ecotype (strain) Col-0, a systematic search identified sequence polymorphisms that differ between active and developmentally silenced rRNA gene subtypes. Recombinant inbred mapping populations derived from three different ecotype crosses were then used to map the chromosomal locations of silenced and active RNA gene subtypes. Importantly, silenced and active rRNA gene subtypes are not intermingled. All silenced rRNA gene subtypes mapped to the nucleolus organizer region (NOR) on chromosome 2 (NOR2). All active rRNA gene subtypes mapped to NOR4. Using an engineered A. thaliana line in which a portion of Col-0 chromosome 4 was replaced by sequences of another ecotype, we show that a major rRNA gene subtype silenced at NOR2 is active when introgressed into the genome at NOR4. Collectively, these results reveal that selective rRNA gene silencing is not regulated gene by gene based on mechanisms dependent on subtle gene sequence variation. Instead, we propose that a subchromosomal silencing mechanism operates on a multimegabase scale to inactivate NOR2. 相似文献
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Frederic Pontvianne Todd Blevins Chinmayi Chandrasekhara Iva Mozgová Christiane Hassel Olga M.F. Pontes Sarah Tucker Petr Mokro? Veronika Muchová Ji?í Fajkus Craig S. Pikaard 《Genes & development》2013,27(14):1545-1550
Eukaryotes can have thousands of 45S ribosomal RNA (rRNA) genes, many of which are silenced during development. Using fluorescence-activated sorting techniques, we show that active rRNA genes in Arabidopsis thaliana are present within sorted nucleoli, whereas silenced rRNA genes are excluded. DNA methyltransferase (met1), histone deacetylase (hda6), or chromatin assembly (caf1) mutants that disrupt silencing abrogate this nucleoplasmic–nucleolar partitioning. Bisulfite sequencing data indicate that active nucleolar rRNA genes are nearly completely demethylated at promoter CGs, whereas silenced genes are nearly fully methylated. Collectively, the data reveal that rRNA genes occupy distinct but changeable nuclear territories according to their epigenetic state. 相似文献
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George Kosmadakis Enrique Da Costa Correia Odette Carceles Frederic Somda Didier Aguilera 《Renal failure》2014,36(4):638-650
Despite the significant technical evolution of the blood purification methods, cardiovascular morbidity and mortality in dialysis patients is still several times higher than that observed in the general population. Vitamins are playing a crucial role in multiple key metabolic pathways. Due to multiple factors, dialysis patients present very often hypo- or hypervitaminosis for a broad range of vitamins. Dialysis in the context of renal replacement therapy is associated with a non-physiological potassium-sparing dietetic regime. Additionally, there is a non-selective intradialytic loss of micro- and macronutrients, deranged intracellular kinetics and gastrointestinal malabsorption due to uratemia. Frequent treatment with antibiotics due to infections associated with the acquired uremia-related immunosuppression may derange the vitamin-producing intestinal microflora. Certain agents prescribed in the context of renal failure or other conditions may reduce the absorption of vitamins from the gastrointestinal tract. These factors may deplete a dialysis patient from vitamins, especially the ones with antioxidant activity that may be associated with cardioprotective properties. In other cases, vitamins metabolized and excreted by the kidneys may be accumulated and exert toxic effects. The scope of this paper is to describe the main issues on vitamin therapy in dialysis patients in view of the ever contradictory opinions and practices. 相似文献
47.
Andrew R. Lavik Fei Zhong Ming-Jin Chang Edward Greenberg Yuvraj Choudhary Mitchell R. Smith Karen S. McColl John Pink Frederic J. Reu Shigemi Matsuyama Clark W. Distelhorst 《Oncotarget》2015,6(29):27388-27402
Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton’s tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction. 相似文献
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An international consensus report on a new algorithm for the management of infant diarrhoea
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Marc Benninga Ilse Broekaert Jackie Falconer Frederic Gottrand Carlos Lifschitz Paolo Lionetti Rok Orel Alexandra Papadopoulou Carmen Ribes‐Koninckx Silvia Salvatore Raanan Shamir Michela Schäppi Annamaria Staiano Hania Szajewska Nikhil Thapar Michael Wilschanski Alfredo Guarino 《Acta paediatrica (Oslo, Norway : 1992)》2016,105(8):e384-e389
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