全文获取类型
收费全文 | 192篇 |
免费 | 10篇 |
国内免费 | 4篇 |
专业分类
儿科学 | 5篇 |
妇产科学 | 11篇 |
基础医学 | 52篇 |
临床医学 | 4篇 |
内科学 | 29篇 |
皮肤病学 | 2篇 |
神经病学 | 14篇 |
特种医学 | 4篇 |
外科学 | 4篇 |
综合类 | 8篇 |
预防医学 | 6篇 |
眼科学 | 1篇 |
药学 | 50篇 |
肿瘤学 | 16篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 3篇 |
2020年 | 4篇 |
2019年 | 10篇 |
2018年 | 4篇 |
2017年 | 3篇 |
2016年 | 5篇 |
2015年 | 9篇 |
2014年 | 6篇 |
2013年 | 17篇 |
2012年 | 11篇 |
2011年 | 8篇 |
2010年 | 9篇 |
2009年 | 12篇 |
2008年 | 10篇 |
2007年 | 9篇 |
2006年 | 6篇 |
2005年 | 4篇 |
2004年 | 7篇 |
2003年 | 12篇 |
2002年 | 3篇 |
2001年 | 1篇 |
2000年 | 5篇 |
1999年 | 2篇 |
1996年 | 1篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1986年 | 1篇 |
1985年 | 2篇 |
1984年 | 10篇 |
1983年 | 4篇 |
1982年 | 6篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1975年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有206条查询结果,搜索用时 15 毫秒
1.
Elena Schlapakow Viktoriya Peeva Gábor Zsurka Monika Jeub Bettina Wabbels Cornelia Kornblum Wolfram S. Kunz 《Neuromuscular disorders : NMD》2019,29(5):358-367
Chronic progressive external ophthalmoplegia (CPEO) is a frequent clinical manifestation of disorders caused by pathogenic mitochondrial DNA mutations. However, for diagnostic purposes skeletal muscle tissue is used, since extraocular muscle tissue is usually not available for work-up. In the present study we aimed to identify causative factors that are responsible for extraocular muscle to be primarily affected in CPEO. We performed comparative histochemical and molecular genetic analyses of extraocular muscle and skeletal muscle single fibers in a case of isolated CPEO caused by the heteroplasmic m.5667G>A mutation in the mitochondrial tRNAAsn gene (MT-TN). Histochemical analyses revealed higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle (41%) compared to skeletal muscle (10%). However, genetic analyses of single fibers revealed no significant difference either in the mutation loads between extraocular muscle and skeletal muscle cytochrome c oxidase deficient single fibers (extraocular muscle 86% ± 4.6%; skeletal muscle 87.8 %± 5.7%, p = 0.246) nor in the mutation threshold (extraocular muscle 74% ± 3%; skeletal muscle 74% ± 4%). We hypothesize that higher proportion of cytochrome c oxidase deficient fibers in extraocular muscle compared to skeletal muscle might be due to facilitated segregation of the m.5667G>A mutation into extraocular muscle, which may explain the preferential ocular manifestation and clinically isolated CPEO. 相似文献
2.
Synthesis and Evaluation of a CBZ‐AAN‐Dox Prodrug and its in vitro Effects on SiHa Cervical Cancer Cells Under Hypoxic Conditions 下载免费PDF全文
Hongyuan Chen Xiao Liu Eric S. Clayman Fangyuan Shao Manshan Xiao Xuyan Tian Wuyu Fu Caiyun Zhang Bibo Ruan Pengjun Zhou Zhong Liu Yifei Wang Wen Rui 《Chemical biology & drug design》2015,86(4):589-598
Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side‐effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N‐benzyloxycarbonyl‐Ala‐Ala‐Asn‐Doxorubicin (CBZ‐AAN‐Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain‐specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24 h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ‐AAN‐Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain. 相似文献
3.
Yu Wang Yingren Zhao Aiyun Zhang Juan Ma Zhenzhen Wang Xu Zhang 《International journal of clinical and experimental pathology》2015,8(10):12949-12954
Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, but with unclear mechanisms. Xeroderma pigmentosum gene D (XPD) is one important DNA damage repair gene and can be involved in protein mutation. Currently little has been known about XPD polymorphism and HCC susceptibility in Chinese people. This study used a meta-analysis approach to comprehensively investigate the correlation between XPD polymorphism and HCC susceptibility in Chinese population, based on previously published literatures. A computer retrieval system was used to collect all case-control studies about XPD Lys751Gln polymorphism and HCC susceptibility. Data in literatures were extracted for meta-analysis. After the primary screening, four independent studies, which were published in 3 English articles and one Chinese article, were recruited in this study. There were 1,717 samples included in all studies. Using Gln/Gln + Lys/Gln, Lys/Lys + Lys/Gln and Lys allels as the reference, HCC disease alleles including Lys/Lys, Gln/Gln and Gln had OR values (95% CI, I2) of 1.007 (0.657~4.672, 91%), 3.516 (0.220~20.661, 48%) and 3.225 (0.278~12.326, 84%), respectively. The polymorphism of XPD751 loci is closely correlated with primary HCC. Lys751Gln polymorphism of XPD gene can be used as one susceptibility factor for HCC. 相似文献
4.
Joanna Wzorek Marek Karpiński Ewa Wypasek Michał Michalski Andrzej Szczudlik Krzysztof Piotr Malinowski Anetta Undas 《Neurologia i neurochirurgia polska》2018,52(3):352-358
Objective
Genetic background of cryptogenic ischemic stroke (IS) and transient ischemic attack (TIA) remains uncertain. Alpha-2-antiplasmin (α2AP) Arg407Lys polymorphism has been shown to be less common in patients with abdominal aortic aneurysm (AAA) compared with healthy controls. We investigated associations of α2AP Arg407Lys polymorphism with cryptogenic IS and TIA.Methods
We studied 165 consecutive Caucasian patients who experienced cryptogenic IS (n = 123) or TIA (n = 42). Neurological outcomes were assessed using the modified Rankin Scale (mRS) in the acute phase of cerebral ischemia and 8 (6–12) months after the index episode. Patients were genotyped for α2AP Arg407Lys polymorphism (rs1057335) using real time PCR technique.Results
The allele frequency of Arg407Lys polymorphism was: 0.82/0.18. The 407Lys allele was more frequent in TIA patients compared to the IS group (0.29 vs. 0.14, p = 0.003). In the whole group, as well as in IS and TIA patients analyzed separately, possession of the 407Lys allele was associated with excellent outcome (mRS 0–1) during follow-up (p < 0.05) but not in the acute phase of ischemic events both in thrombolyzed and nonthrombolyzed IS patients.The multivariate logistic regression model showed that the excellent outcome (mRS 0–1) assessed after 8 (6–12) months since the index cerebral ischemia was predicted by the occurrence of Lys407 allele (OR 6.18, 95% CI, 2.01–18.98, p = 0.001).Conclusion
The presence of 407Lys allele is associated with better prognosis in cryptogenic cerebrovascular events. Our findings suggest that the α2AP Arg407Lys polymorphism could be involved in the pathogenesis of cerebral ischemia and its outcomes. 相似文献5.
6.
de Luis DA Gonzalez Sagrado M Aller R Izaola O Conde R 《Journal of diabetes and its complications》2008,22(3):199-204
BACKGROUND: Alterations of the normal leptin receptor (LEPR) gene may be involved in the development of obesity. Leptin has been shown to be able to modulate insulin secretion. Different polymorphisms in the LEPR gene have been studied, albeit with unclear results. The polymorphism on codon 656 produces a change in charge, making this change possibly functional. OBJECTIVE: The objective of this study was to investigate the influence of Lys656Asn polymorphism in the LEPR gene on serum insulin, glucose values, and insulin resistance in the fasted state among obese men and women without diabetes mellitus. DESIGN: Two hundred thirty-three (body mass index, >30 kg/m(2)) nondiabetic obese patients were analyzed. Indirect calorimetry, tetrapolar electrical bioimpedance, blood pressure determination, serial assessment of nutritional intake with 3-day written food records, and biochemical analysis were performed. Statistical analysis was performed for Lys656/Asn656 and Asn656/Asn656 jointly as a mutant allelic group and for Lys656/Lys656 as a wild allelic group. RESULTS: The subjects' (67 males and 166 females) mean age and mean body mass index were 43.6+/-16.6 years and 35.3+/-5.6 kg/m(2), respectively. One hundred forty-three patients (61.9%) had the genotype Lys656/Lys656 (wild group), whereas 88 (38.1%) had either the genotype Lys656/Asn656 (n=81; 30.7%) or the genotype Asn656/Asn656 (n=7; 7.4%) (mutant group). Age and sex distribution were similar in both groups. No difference was detected between the mutant and wild allelic groups in anthropometric parameters and dietary intakes. Homeostasis model assessment (HOMA; 2.8+/-1.7 vs. 5.6+/-4.8; P<.05) and insulin (18.1+/-10.7 vs. 32.1+/-25 mUI/ml; P<.05) levels were higher in males with the genotypes Lys656/Asn656 and Asn656/Asn656 than in males with the genotype Lys656/Lys656. Leptin levels were higher in males with a mutant genotype than in males with a wild genotype (39.3+/-23 vs. 63.5+/-28 ng/ml; P<.05). CONCLUSION: The novel findings of our study are those of the association of the Lys656/Asn656 and Asn656/Asn656 genotypes with higher levels of insulin, HOMA, and leptin in males and the lack of such an association in females. 相似文献
7.
LoAnn C. Peterson Clara D. Bloomfield R.Dorothy Sundberg K.J. Gajl-Peczalska Richard D. Brunning 《The American journal of medicine》1975,59(3):316-324
The morphology of lymphocytes in blood and bone marrow from patients with chronic lymphocytic leukemia was studied; blood lymphocyte morphology was related to survival. Three primary morphologic groups emerged. Group I was characterized by small to medium-sized lymphocytes with narrow rims of cytoplasm and coarsely clumped nuclear chromatin. In group II the predominant lymphocytes were large with abundant cytoplasm. Group III was characterized by a heterogeneous population of lymphocytes with characteristics of both groups I and II. Clinical features of the patients were studied, and B and T typing of the lymphocytes was done. The median survival in group I was 26+ months; In group II 46+ months; and in group III 50+ months. Our data are at variance with previous reports and suggest that survival in patients with large lymphocytes Is longer than in those with small lymphocytes. 相似文献
8.
Schwaab R Oldenburg J Kemball-Cook G Albert T Juhler C Hanfland P Ingerslev J 《British journal of haematology》2000,109(3):523-528
Factor VIII gene analysis in a large consanguinous Danish family comprising 24 affected males and four homozygously affected females revealed an Asn694Ile mutation within the A2 domain. The factor VIII gene mutation led to a mild haemophilia A phenotype with factor VIII function displaying discordance between one-stage clotting and chromogenic two-stage assays. In one-stage assays, values ranged from 0.05 to 0.30 IU/ml (males) and from 0.19 to 0.29 IU/ml (homozygous affected females), whereas the chromogenic two-stage assay produced values of around only 50% of the one-stage result [0. 02-0.12 IU/ml (males); 0.06-0.10 IU/ml (females)]. The differences are suggested to be caused by the effect of the mutation on the active cleaved form of the factor (F)VIII protein. As the original amino acid (Asn) is conserved in all known FVIII A2 sequences, but not in ceruloplasmin, we suggest that Asn694 is involved in an A2-specific functional role. Examination of a homology model of the A domains predicts that the Asn694Ile mutation (i) results in the loss of two potential hydrogen-bonding interactions and (ii) hampers the integration of the bulky side-chain of Ile into the A2 domain core, probably causing an altered stability and/or folding of the protein. Interestingly, the disease in this Danish family was originally proposed to be von Willebrand-Jürgens disease. However, the current study rules out the co-existence of either von Willebrand's disease or the presence of the Normandy variant of von Willebrand factor (type 2N). 相似文献
9.
Siyao Wang Xin Zhang Chunlu Yang Shun Xu 《Clinical and experimental pharmacology & physiology》2019,46(10):955-967
MicroRNA‐198‐5p (miR‐198‐5p) displays crucial roles in various cancers including non‐small cell lung cancer (NSCLC), but the underlying molecular mechanisms remain unclear. Fucosyltransferase 8 (FUT8) is associated with tumour metastasis and prognosis. In this study, we explored the expression of miR‐198‐5p and FUT8 in NSCLC patients. Results showed that miR‐198‐5p was under‐expressed in NSCLC tissues and was negatively correlated with tumour size, lymph node metastasis and tumour‐node‐metastasis stage, while FUT8 expression was highly upregulated. Next, we altered miR‐198‐5p expression using the mimic or inhibitor in the functional study. Results showed that miR‐198‐5p overexpression could inhibit the migration, invasion and epithelial‐to‐mesenchymal transition (EMT) of NSCLC cells; reversely, suppression of miR‐198‐5p enhanced cell migration, invasion and EMT. In vivo, miR‐198‐5p overexpression inhibited the formation of mouse lung and liver metastasis. Luciferase reporter, real‐time PCR and western blot assays showed that miR‐198‐5p could directly target FUT8 and regulate FUT8 expression. Further, FUT8 overexpression reversed the effect of miR‐198‐5p overexpression on the migration, invasion and EMT of NSCLC cells. Taken together, miR‐198‐5p functions as a tumour suppressor by targeting FUT8 in NSCLC. MiR‐198‐5p may be developed as a new diagnostic biomarker and therapeutic target for lung cancer. 相似文献
10.
Daniela de Oliveira ToyamaEduardo Britto dos Santos Diz Filho Benildo Sousa CavadaBruno Anderson Matias da Rocha Simone Cristina Buzzo de Oliveira Camila Aparecida Cotrim Veronica Cristina Gomes Soares Plínio DelatorreSérgio Marangoni Marcos Hikari Toyama 《Toxicon》2011,57(6):851-860
In this paper was demonstrated that umbelliferone induces changes in structure and pharmacological activities of Bn IV, a lysine 49 secretory phospholipase A2 (sPLA2) from Bothrops neuwiedi. Incubation of Bn IV with umbelliferone virtually abolished platelet aggregation, edema, and myotoxicity induced by native Bn IV. The amino acid sequence of Bn IV showed high sequence similarities with other Lys49 sPLA2s from B. jararacussu (BthTx-I), B. pirajai (PrTx-I), and B. neuwiedi pauloensis (Bn SP6 and Bn SP7). This sPLA2 also has a highly conserved C-terminal amino acid sequence, which has been shown as important for the pharmacological activities of Lys49 sPLA2. Sequencing of Bn IV previously treated with umbelliferone revealed modification of S(1) and S(20). Fluorescent spectral analysis and circular dichroism (CD) studies showed that umbelliferone modified the secondary structure of this protein. Moreover, the pharmacological activity of Bn IV is driven by synergism of the C-terminal region with the α-helix motifs, which are involved in substrate binding of the Asp49 and Lys49 residues of sPLA2 and have a direct effect on the Ca2+-independent membrane damage of some secretory snake venom PLA2. For Bn IV, these interactions are potentially important for triggering the pharmacological activity of this sPLA2. 相似文献