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71.
为了寻找毒性低、增敏作用强的乏氧细胞放射增敏剂,设计并合成了一系列5-溴-,5-甲基-,和5-未取代的3-硝基-1,2,4-三唑-1-乙酰胺类化合物,用HeLaS3细胞进行了体外试验。结果表明5-溴取代衍生物的增敏作用强于相应的5-甲基-或5-未取代的硝基三唑衍生物,但是它们的毒性亦增大。修饰1位乙酰胺侧链也可以改变化合物的增敏作用和亲脂性。在所测定的化合物中TA-101[2-(3-硝基-1-三唑基)乙酰胺]由于有高的增敏作用和低亲脂性,可能是一个有希望的放射增敏剂。 相似文献
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S H Northrup M R Pear C Y Lee J A McCammon M Karplus 《Proceedings of the National Academy of Sciences of the United States of America》1982,79(13):4035-4039
A method is described for calculating the reaction rate in globular proteins of activated processes such as ligand binding or enzymatic catalysis. The method is based on the determination of the probability that the system is in the transition state and of the magnitude of the reactive flux for transition-state systems. An "umbrella sampling" simulation procedure is outlined for evaluating the transition-state probability. The reactive flux is obtained from an approach described previously for calculating the dynamics of transition-state trajectories. An application to the rotational isomerization of an aromatic ring in the bovine pancreatic trypsin inhibitor is presented. The results demonstrate the feasibility of calculating rate constants for reactions in proteins and point to the importance of solvent effects for reactions that occur near the protein surface. 相似文献
76.
目的:分析非亲缘异基因外周血干细胞移植治疗幼儿急性非淋巴性白血病的可行性。方法:患儿,男,3岁,于2005-07-18为行造血干细胞移植入本院血液科骨髓移植病房,入院诊断为急性非淋巴细胞性白血病-M5b。经抗肿瘤药物治疗病情获得完全缓解。患儿首先接受清髓性预处理,然后接受同性别非亲缘异基因外周血造血干细胞移植。①移植预处理包括马利兰、阿糖胞苷和环磷酰胺。移植前依次用药为马利兰3.2mg/(kg·d)×4d,口服,于移植前6,7,8,9d给药;阿糖胞苷3.2g/(m2·d)×2d,于移植前4,5d给药;环磷酰胺54mg/(kg·d),于移植前2,3d给药。②急性移植物抗宿主病的预防用药包括环孢菌素A和氨甲蝶呤、抗胸腺细胞球蛋白及吗替麦考酚酯。供者接受粒细胞集落刺激因子动员4d后采集外周血造血干细胞,供、受者间HLA全相合,患者血型A,供者血型B,主次要均不合。结果:①患儿移植后早期获得造血重建,中性粒细胞>0.5×109L-1和血小板>50×109L-1的天数分别是12d和11d。②移植后1个月经DNA短串联重复序列多态性分析证明为供者型完全植入,移植后3个月查骨髓象正常。③移植后3,6个月定期行淋巴细胞亚群检查表明除CD19 ,CD4 细胞未恢复外,自然杀伤细胞在移植后3个月恢复正常,T淋巴细胞CD3 与CD8 、体液免疫球蛋白在移植后6个月中均获得重建。④整个移植过程顺利,未出现明显感染和重度急性移植物抗宿主病。移植后96d时出现Ⅰ度皮肤移植物抗宿主病,经加用激素治疗,皮疹消失。移植术后已随访观察12个月,患儿正常生活。结论:如果患儿有HLA完全相合的供者,非亲缘异基因外周血干细胞移植治疗儿童高危白血病是一种有效和安全的方法,对国内独生子女家庭拓宽供者来源有重要的实用价值。 相似文献
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P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy 总被引:3,自引:3,他引:3
Grogan TM; Spier CM; Salmon SE; Matzner M; Rybski J; Weinstein RS; Scheper RJ; Dalton WS 《Blood》1993,81(2):490-495
Multidrug-resistant (MDR) myeloma patients failing chemotherapy may express P-glycoprotein (PGP), which serves as an efflux pump protecting the neoplastic cells. Unknown is whether PGP expression might relate to prior cytotoxic drug exposure. To address this question, we studied 106 consecutive bone marrow samples from 104 myeloma patients with samples studied either before or after therapy and at the time of relapse. We performed an established immunocytochemical assay of PGP using an MDR-1- specific monoclonal antibody and correlated PGP status with prior chemotherapy dosage. Myeloma patients with no prior therapy had a low incidence of PGP expression (6%, 3/47), whereas those receiving chemotherapy had a significantly higher incidence (43%, 21/49) (P < .0001). A substantially higher incidence of PGP expression (50%, 83%, respectively) occurred when the total vincristine dose exceeded 20 mg and when doxorubicin exceeded 340 mg. In the 11 patients who received both high vincristine and doxorubicin dosages (> 20 mg, > 340 mg total dose) there was 100% incidence of PGP expression in the tumor cells. These data provided the basis for a predictive mathematical model from which dose-related PGP expression normograms were generated. Time with myeloma for PGP-negative patients (mean 33 months) had overlapping confidence limits with PGP-positive patients (mean 42 months), suggesting that disease duration was not a significant variable. PGP expression did not correlate with other clinical factors or immunophenotypic factors. Our findings indicate a strong correlation between PGP expression in myeloma and past chemotherapy in myeloma, in particular, related to prior exposure to the natural product agents vincristine and doxorubicin. Additionally, the proportion of PGP- positive plasma cells was significantly higher in the doxorubicin- treated patients than the nondoxorubicin-treated patients (87.7% v 65.17%; P = .013). Combined high vincristine and doxorubicin total dosage appear highly predictive of PGP expression. 相似文献
78.
The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl 总被引:3,自引:6,他引:3
The bcr/abl fusion in chronic myelogenous leukemia (CML) creates a chimeric tyrosine kinase with dramatically different properties than intact c-abl. In P210 bcr/abl, the bcr portion includes a coiled-coil oligomerization domain (amino acids 1-63) and a grb2-binding site at tyrosine 177 (Tyr177) that are critical for fibroblast transformation, but give variable results in other cell lines. To investigate the role of the coiled-coil domain and Tyr177 in promoting CML, 4 P210 bcr/abl-derived mutants containing different bcr domains fused to abl were constructed. All 4 mutants, Delta(1-63) bcr/abl, (1-63) bcr/abl, Tyr177Phe bcr/abl, and (1-210) bcr/abl exhibited elevated tyrosine kinase activity and conferred factor-independent growth in cell lines. In contrast, differences in the transforming potential of the 4 mutants occurred in our mouse model, in which all mice receiving P210 bcr/abl-expressing bone marrow cells exclusively develop a myeloproliferative disease (MPD) resembling human CML. Of the 4 mutants assayed, only 1-210 bcr/abl, containing both the coiled-coil domain and Tyr177, induced MPD. Unlike full-length P210, this mutant also caused a simultaneous B-cell acute lymphocytic leukemia (ALL). The other 3 mutants, (1-63) bcr/abl, Tyr177Phe bcr/abl, and Delta(1-63) bcr/abl, failed to induce an MPD but instead caused T-cell ALL. These results show that both the bcr coiled-coil domain and Tyr177 are required for MPD induction by bcr/abl and provide the basis for investigating downstream signaling pathways that lead to CML. 相似文献
79.
Hematopoietic reconstitution of SLP-76 corrects hemostasis and platelet signaling through alpha IIb beta 3 and collagen receptors
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Judd BA Myung PS Leng L Obergfell A Pear WS Shattil SJ Koretzky GA 《Proceedings of the National Academy of Sciences of the United States of America》2000,97(22):12056-12061
Mice deficient in the hematopoietic cell-specific adapter protein SLP-76 demonstrate a failure of T cell development and fetal hemorrhage. Although SLP-76-deficient platelets manifest defective collagen receptor signaling, this alone may not explain the observed bleeding diathesis. Because alpha IIb beta 3, the platelet fibrinogen receptor, is required for normal hemostasis, we explored a potential role for SLP-76 in alpha IIb beta 3 signaling. Interaction of soluble or immobilized fibrinogen with normal human or murine platelets triggers rapid tyrosine phosphorylation of SLP-76. Moreover, platelet adhesion to fibrinogen stimulates actin rearrangements, filopodial and lamellipodial extension, and localization of tyrosine phosphorylated proteins to the cell periphery. In contrast, SLP-76-deficient murine platelets bind fibrinogen normally, but spread poorly and exhibit reduced levels of phosphotyrosine. The in vivo bleeding diathesis as well as the defects in platelet responses to fibrinogen and collagen are reversed by retroviral transduction of SLP-76 into bone marrow derived from SLP-76-deficient mice. These studies establish that SLP-76 functions downstream of alpha IIb beta 3 and collagen receptors in platelets. Furthermore, expression of SLP-76 in hematopoietic cells, including platelets, plays a necessary role in hemostasis. 相似文献
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