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81.
Prinz H Ishii Y Hirano T Stoiber T Camacho Gomez JA Schmidt P Düssmann H Burger AM Prehn JH Günther EG Unger E Umezawa K 《Journal of medicinal chemistry》2003,46(15):3382-3394
A novel series of 10-benzylidene-9(10H)-anthracenones and 10-(phenylmethyl)-9(10H)-anthracenones were synthesized and evaluated for antiproliferative activity in an assay based on K562 leukemia cells. The 3-hydroxy-4-methoxybenzylidene analogue 9h was found to be the most active compound (IC(50) K562: 20 nM). Structure-activity relationships are also considered. The highly active compound 9h and the 2,4-dimethoxy-3-hydroxybenzylidene analogue 9l were tested against five tumor cell lines using the XTT assay, including multidrug resistant phenotypes. Induction of cell death in a variety of tumor cell lines was determined in a monolayer assay using propidium iodide. Noteworthy, all compounds within the series induced elongations in K562 cells similar to vinblastine-treated cells. The effect of the lead compound 9h on K562 cell growth was associated with cell cycle arrest in G2/M. Concentrations for 50% KB/HeLa cells arrested in G2/M after treatment with 9h and 9l were determined and found to be in the range of 0.2 microM. Additionally, we monitored the dose dependent caspase-3-like protease activity in K562 cells and MCF-7/Casp-3 cells treated with 9h, indicating induction of apoptosis. Western blotting analysis demonstrated that 9h caused a shift in tubulin concentration from the polymerized state found in the cell pellet to the unpolymerized state found in the cell supernatant. Seven compounds strongly inhibited tubulin polymerization with activities higher or comparable to those of the reference compounds such as colchicine, podophyllotoxin, and nocodazole. In general, the antiproliferative activity correlated with inhibition of tubulin polymerization. The most active compounds strongly displaced [(3)H]colchicine from its binding site in the tubulin, yielding IC(50) values 3- to 4-fold lower than that of colchicine. The novel benzylidene-9(10H)-anthracenones described in the present study constitute an interesting group of highly active and easily accessible antimitotic agents that inhibit tubulin polymerization. 相似文献
82.
Korsch E Steinkuhle J Massin M Lyonnet S Touraine RL 《European journal of pediatrics》2001,160(1):68-69
The autonomic nervous system plays an important role in the generation of complex heart rate dynamics that enable an organism to adapt to stress. Little is known about genes influencing the development of this autonomic control of the heart. We suggest the SOX10 gene to be a candidate for this process. 相似文献
83.
84.
Transgenic pigs as models for translational biomedical research 总被引:1,自引:0,他引:1
Bernhard Aigner Simone Renner Barbara Kessler Nikolai Klymiuk Mayuko Kurome Annegret Wünsch Eckhard Wolf 《Journal of molecular medicine (Berlin, Germany)》2010,88(7):653-664
The translation of novel discoveries from basic research to clinical application is a long, often inefficient, and thus costly
process. Accordingly, the process of drug development requires optimization both for economic and for ethical reasons, in
order to provide patients with appropriate treatments in a reasonable time frame. Consequently, “Translational Medicine” became a top priority in national and international roadmaps of human health research. Appropriate animal models for the
evaluation of efficacy and safety of new drugs or therapeutic concepts are critical for the success of translational research.
In this context rodent models are most widely used. At present, transgenic pigs are increasingly being established as large
animal models for selected human diseases. The first pig whole genome sequence and many other genomic resources will be available
in the near future. Importantly, efficient and precise techniques for the genetic modification of pigs have been established,
facilitating the generation of tailored disease models. This article provides an overview of the current techniques for genetic
modification of pigs and the transgenic pig models established for neurodegenerative diseases, cardiovascular diseases, cystic
fibrosis, and diabetes mellitus. 相似文献
85.
86.
Andreas Straub Daniela Schiebold Hans Peter Wendel Carole Hamilton Thomas Wagner Eckhard Schmid Klaus Dietz Gerhard Ziemer 《European journal of cardio-thoracic surgery》2008,34(3):641-647
Objective: Cardiac surgery employing cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) can induce coagulation disturbances and bleeding complications that may be especially severe in infants. A better understanding of the coagulopathy and a quick method for its evaluation would be helpful in the management of patients exposed to CPB and DHCA. This study aimed to monitor coagulation defects in congenital heart surgery using rotational thromboelastometry (ROTEM((R))), standard coagulation tests and platelet flow cytometry. Methods: The study comprised 10 infants undergoing surgery for congenital heart disease on CPB and DHCA. Blood was sampled at skin incision, after heparinisation during CPB (directly pre- and directly post-DHCA) and after protamine administration post-CPB. ROTEM((R)) using different reagents including a heparinase-containing assay to evaluate coagulation during heparinisation, APTT and INR, and flow cytometry to evaluate platelet activation were performed. Results: During CPB, the ROTEM((R)) indicated CPB-induced clotting factor depletion and platelet dysfunction that persisted after CPB and heparin neutralisation. ROTEM((R)) results were available within 15min and therefore much faster than standard tests. ROTEM((R))-guided specific blood product treatment resulted in satisfactory coagulatory function. The highest degree of platelet activation was found directly after DHCA. Conclusions: A major benefit of ROTEM((R)) is the quick detection of a developing coagulopathy already during CPB. ROTEM((R)) guides quick and specific blood product treatment after CPB, which may decrease bleeding complications in cardiac surgery. The finding of maximal platelet activation directly after DHCA suggests that not only CPB but also hypothermia activates platelets in vivo, thereby contributing to platelet dysfunction. 相似文献
87.
Sebastian Ochsenreither Alberto Fusi Susanne Wojtke Antonia Busse Natascha C Nüssler Eckhard Thiel Ulrich Keilholz Dirk Nagorsen 《Journal of translational medicine》2010,8(1):35
Several immunotherapeutic approaches rely on antigen-specific T-cells. Restrictions in the T-cell receptor (TCR) repertoire
were reported as indicator of anti-tumor cytotoxic T-lymphocyte (CTL) response in various tumor entities. It is unclear yet
whether a TCR restriction in peripheral blood mirrors the tumor compartment. We compared the expression of TCR Vβ-families for the quantification of TCR repertoire alterations in blood and tissue samples from patients with colorectal carcinoma.
Blood samples from patients with colorectal carcinoma and healthy volunteers and tissue samples of normal colonic mucosa and
colorectal carcinoma were analyzed. Relative Vβ-family quantification was performed based on quantitative reverse transcribed PCR. Standard deviation and average mean of
the single families were determined. Two variables describing the degree of Vβ-repertoire restriction were defined. Forty-eight blood samples and 37 tissue samples were analyzed. TCR repertoire restriction
was higher in blood of tumor patients than in blood of healthy controls (p < 0.05). No difference in the degree of TCR repertoire restriction was found between carcinoma and unaffected colon tissue.
We found no corresponding elevated TCR families among the different compartments blood, normal colon, and carcinoma tissue
of the same patient. In conclusion, we observed a repertoire restriction in peripheral blood as well as in tumor tissue of
cancer patients. However, in tumor tissue, repertoire alterations were comparable to normal mucosa, suggesting compartment-specific
TCR distribution rather than alterations due to tumor-T-cell interaction questioning the presence of highly restricted clonal
T-cell expansions in colorectal cancer as they have been described in other, assumingly more immunogenic tumor entities. 相似文献
88.
Immunolocalization of dipeptidyl aminopeptidase (DAP IV) in the developing human brain 总被引:1,自引:0,他引:1
Hans-Gert Bernstein Eckhard Schn Siegfried Ansorge Ingeborg Rse Alfred Dorn 《International journal of developmental neuroscience》1987,5(3):237-242
By means of immunohistochemical techniques we have investigated the presence of dipeptidyl aminopeptidase IV immunoreactivity in brain material derived from human fetuses, newborns and aged persons. It was revealed that the enzyme protein is abundantly present in the immature human CNS. On the contrary the adult human brain contains much less dipeptidyl aminopeptidase immunoreactivity. It is speculated that the enzyme might play an important role in neuronal proliferation and/or differentiation especially with regard to its possible action on certain neuronotrophic peptides (IGF II, growth hormone). 相似文献
89.
90.