全文获取类型
收费全文 | 4304篇 |
免费 | 1064篇 |
国内免费 | 475篇 |
专业分类
耳鼻咽喉 | 14篇 |
儿科学 | 27篇 |
妇产科学 | 59篇 |
基础医学 | 872篇 |
口腔科学 | 82篇 |
临床医学 | 457篇 |
内科学 | 468篇 |
皮肤病学 | 36篇 |
神经病学 | 146篇 |
特种医学 | 76篇 |
外国民族医学 | 1篇 |
外科学 | 234篇 |
综合类 | 895篇 |
预防医学 | 93篇 |
眼科学 | 97篇 |
药学 | 412篇 |
中国医学 | 75篇 |
肿瘤学 | 1799篇 |
出版年
2024年 | 48篇 |
2023年 | 295篇 |
2022年 | 603篇 |
2021年 | 800篇 |
2020年 | 689篇 |
2019年 | 438篇 |
2018年 | 300篇 |
2017年 | 330篇 |
2016年 | 363篇 |
2015年 | 597篇 |
2014年 | 469篇 |
2013年 | 297篇 |
2012年 | 201篇 |
2011年 | 193篇 |
2010年 | 104篇 |
2009年 | 59篇 |
2008年 | 24篇 |
2007年 | 7篇 |
2006年 | 1篇 |
2005年 | 3篇 |
2004年 | 1篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1995年 | 1篇 |
1993年 | 2篇 |
1991年 | 1篇 |
1989年 | 3篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 3篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1976年 | 2篇 |
1974年 | 1篇 |
排序方式: 共有5843条查询结果,搜索用时 15 毫秒
21.
Esmerina Tili Marcela Chiabai Dario Palmieri Melissa Brown Ri Cui Cecilia Fernandes Tim Richmond Taewan Kim Tyler Sheetz Hui-Lung Sun Alessandro Lagana Dario Veneziano Stefano Volinia Laura Rassenti Thomas Kipps Hamdy Awad Jean-Jacques Michaille Carlo M. Croce 《Oncotarget》2015,6(28):24599-24610
Quaking (QKI) is a tumor-suppressor gene encoding a conserved RNA-binding protein, whose expression is downregulated in several solid tumors. Here we report that QKI plays an important role in the immune response and suppression of leukemogenesis. We show that the expression of Qki is reduced in lipopolysaccharide (LPS)-challenged macrophages, suggesting that Qki is a key regulator of LPS signaling pathway. Furthermore, LPS-induced downregulation of Qki expression is miR-155-dependent. Qki overexpression impairs LPS-induced phosphorylation of JNK and particularly p38 MAPKs, in addition to increasing the production of anti-inflammatory cytokine IL-10. In contrast, Qki ablation decreases Fas expression and the rate of Caspase3/7 activity, while increasing the levels of IL-1α, IL-1β and IL-6, and p38 phosphorylation. Similarly, the p38 pathway is also a target of QKI activity in chronic lymphocytic leukemia (CLL)-derived MEC2 cells. Finally, B-CLL patients show lower levels of QKI expression compared with B cells from healthy donor, and Qki is similarily downregulated with the progression of leukemia in Eμ-miR-155 transgenic mice. Altogether, these data implicate QKI in the pathophysiology of inflammation and oncogenesis where miR-155 is involved. 相似文献
22.
23.
Malignant glioma is the most common and deadly primary brain tumor in adults. However, the mechanisms underlying the malignancy of glioma remain unclear. In the present study, we found that Fos-related antigen-2 (Fra-2) was overexpressed in most glioma cells, and knockdown of Fra-2 prevented cell proliferation, migration, and invasion. Mechanistically, Fra-2 silencing led to a significant reduction in cell-cycle drivers (Cyclin D1 and Cyclin E1), one invasion-associated gene (MMP9), the mesenchymal marker (Vimentin), and induction of the epithelial marker (E-cadherin). Further study confirmed that miR-124-3p decreased the expression of Fra-2 via directly targeting the 3′-UTR, and transfection with miR-124-3p in glioma cells inhibited expression of the above cell-cycle and EMT promoters. Phenotypic experiments also showed that overexpression of Fra-2 weakened the inhibitory effects of miR-124-3p on the proliferation, migration, and invasion of glioma cells. In addition, Fra-2 knockdown impaired the malignant phenotypes enhanced by miR-124-3p inhibition, which suggested a crucial role for the miR-124-3p/Fra-2 pathway in glioma development. Consistently, high expression of Fra-2 was closely associated with low miR-124-3p level and indicated a poor prognosis in patients with glioma. In conclusion, this study indicates the existence of an aberrant miR-124-3p/Fra-2 pathway that results in glioma aggressiveness, which suggests novel therapeutic opportunities for this fatal disease. 相似文献
24.
BackgroundNon-small cell lung cancer (NSCLC) chemoresistance usually limits the clinical efficacy of chemotherapeutic approaches. However, few reports have revealed the regulation of miR-135b and Frizzled-1 (FZD1) involved in NSCLC chemoresistance.MethodsTo identify the mechanism of miR-135b and FZD1 in NSCLC chemoresistance and to observe their biological functions, we detected the expression levels of miR-135b and FZD1 by conducting quantitative real-time polymerase chain reaction (RT-qPCR) and modified the expressions of miR-135b and FZD1 by transiently transfecting cells with miR-135b mimics or FZD1-siRNA. The 3′-untranslated region (3′-UTR) of FZD1 combined with miR-135b was verified through dual-luciferase reporter assay.ResultsCompared with that in A549 parental cell lines, the miR-135b expression in drug-resistant lung cancer cell lines (A549/DDP) was decreased and their FZD1 expression was increased. The increased miR-135b expression and silenced FZD1 expression enhanced the sensitivity of resistant cells to cisplatin treatment. The high expression of miR-135b in A549/DDP cells remarkably decreased the mRNA levels of FZD1. FZD1 was further identified as the functional downstream target of miR-135b by directly targeting the 3′-UTR of FZD1.ConclusionThe amplification of miR-135b suppressed NSCLC chemoresistance by directly mediating the FZD1 downregulation. 相似文献
25.
目的探讨miR-155对人大肠癌细胞侵袭能力的影响。方法大肠癌Lovo细胞分为3组:脂质体介导反义miR-155(AS-miR-155)组、无义寡脱氧核苷酸(ODN)组和对照组。测定荧光素酶活性验证3组细胞中miR-155的表达,采用Matrigel基质生长试验检测细胞生长情况,以Transwe Ⅱ方法检测细胞的侵袭力,结果与对照组和无义ODN组比较,转染AS-miR-155组Lovo细胞miR-2l表达水平降低;Matrigel基质生长试验显示,转染AS-miR-155组Lovo细胞体外培养克隆平均直径较小,Transwe Ⅱ细胞侵袭试验显示转染AS-miR-155组穿膜细胞数较少。结论 miR-2l高表达可促进Lovo大肠癌细胞侵袭生长,提示miR-155可以作为基因治疗大肠癌的候选靶点。 相似文献
26.
27.
Nerea Matamala Beatriz Lara Gema Gómez-Mariano Selene Martínez Irene Vázquez-Domínguez Álvaro Otero-Sobrino Antonio Muñoz-Callejas Elena Sánchez Cristina Esquinas Ana Bustamante Sergio Cadenas Sergio Curi Lourdes Lázaro María Teresa Martínez Esther Rodríguez Marc Miravitlles María Torres-Duran Inés Herrero Beatriz Martínez-Delgado 《Archivos de bronconeumologia》2021,57(7):457-463
IntroductionAlpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting in lung and liver disease with a great clinical variability. MicroRNAs have been identified as disease modifiers; therefore miRNA deregulation could play an important role in disease heterogeneity. Members of miR-320 family are involved in regulating of multiple processes including inflammation, and have potential specific binding sites in the 3′UTR region of SERPINA1 gene. In this study we explore the involvement of miR-320c, a member of this family, in this disease.MethodsFirstly in vitro studies were carried out to demonstrate regulation of SERPINA1 gene by miR-320. Furthermore, the expression of miR-320c was analyzed in the blood of 98 individuals with different AAT serum levels by using quantitative PCR and expression was correlated to clinical parameters of the patients. Finally, HL60 cells were used to analyze induction of miR-320c in inflammatory conditions.ResultsOverexpression of miR-320 members in human HepG2 cells led to inhibition of SERPINA1 expression. Analysis of miR-320c expression in patient's samples revealed significantly increased expression of miR-320c in individuals with pulmonary disease. Additionally, HL60 cells treated with the pro-inflammatory factor lipopolysaccharide (LPS) showed increase in miR-320c expression, suggesting that miR-320c responds to inflammation.ConclusionOur findings demonstrate that miR-320c inhibits SERPINA1 expression in a hepatic cell line and its levels in blood are associated with lung disease in a cohort of patients with different AAT serum levels. These results suggest that miR-320c can play a role in AAT regulation and could be a biomarker of inflammatory processes in pulmonary diseases. 相似文献
28.
Naibijiang Maolakuerban Baihetiya Azhati Hamulati Tusong Asimujiang Abula Anniwaer Yasheng 《Cancer biology & therapy》2018,19(4):282-291
In this study, we investigated the mechanism of miR-200c-3p and SLC6A1 in regulating cell activity of clear cell renal cell carcinoma (CCRCC). The mRNA and miRNA expressions of tissue specimens were analyzed by CapitalBio Corporation (Beijing, China). The expression of SLC6A1 in CCRCC cells was examined through qRT-PCR and western blot. The migration and invasion ability of 786-O cells was testified by transwell assay after transfected. 786-O cell proliferation ability was detected by MTT assay. Dual luciferase reporter assay verified the association between SLC6A1 and miR-200c-3p. SLC6A1 was high expressed and miR-200c-3p was low expressed in CCRCC tissues and cells. Besides, lower SLC6A1 expression indicated longer survival time and higher survival rate. MiR-200c-3p could directly target at SLC6A1 and reduce its expression. MiR-200c-3p inhibited the proliferation, migration and invasion in 786-O cells by down-regulating SLC6A1 expression. The results suggested that the miR-200c-3p served as a suppressor for CCRCC via down-regulating SLC6A1. 相似文献
29.
Amit Kumar Pandey Yanzhou Zhang Siting Zhang Ying Li Greg Tucker-Kellogg Henry Yang Sudhakar Jha 《Oncotarget》2015,6(38):41290-41306
MicroRNAs (miRNAs) are 22- to 24-nucleotide, small, non-coding RNAs that bind to the 3′UTR of target genes to control gene expression. Consequently, their dysregulation contributes to many diseases, including diabetes and cancer. miR-22 is up-regulated in numerous metastatic cancers and recent studies have suggested a role for miR-22 in promoting stemness and metastasis. TIP60 is a lysine acetyl-transferase reported to be down-regulated in cancer but the molecular mechanism of this reduction is still unclear. In this study, we identify TIP60 as a target of miR-22. We show a negative correlation in the expression of TIP60 and miR-22 in breast cancer patients, and show that low levels of TIP60 and high levels of miR-22 are associated with poor overall survival. Furthermore, pathway analysis using high miR-22/low TIP60 and low miR-22/high TIP60 breast cancer patient datasets suggests association of TIP60/miR-22 with epithelial-mesenchymal transition (EMT), a key alteration in progression of cancer cells. We show that blocking endogenous miR-22 can restore TIP60 levels, which in turn decreases the migration and invasion capacity of metastatic breast cancer cell line. These results provide mechanistic insight into TIP60 regulation and evidence for the utility of the combination of TIP60 and miR-22 as prognostic indicator of breast cancer progression. 相似文献
30.
MicroRNAs (miRNAs) regulate gene expression and are involved in cervical cancer. But the molecular mechanism is still unclear. Here, miRNA profile of cervical cancer was performed and demonstrated that miR-486-3p decreased in specimens of cervical cancer patients. In addition, our clinical data show that decreased miR-486-3p was associated with metastasis in cervical cancer patients. ECM1 was predicted and velified as a target gene of miR-486-3p. Overexpression of miR-486-3p inhibited cell growth and metastasis by targeting ECM1. In a conclusion, these findings suggest that miR-486-3p is a tumor suppressor miRNA and induction of miR-486-3p is a potential strategy to inhibit cervical cancer progression. 相似文献