全文获取类型
收费全文 | 4458篇 |
免费 | 557篇 |
国内免费 | 170篇 |
专业分类
耳鼻咽喉 | 12篇 |
儿科学 | 51篇 |
妇产科学 | 51篇 |
基础医学 | 715篇 |
口腔科学 | 54篇 |
临床医学 | 234篇 |
内科学 | 538篇 |
皮肤病学 | 67篇 |
神经病学 | 251篇 |
特种医学 | 34篇 |
外国民族医学 | 1篇 |
外科学 | 247篇 |
综合类 | 461篇 |
现状与发展 | 2篇 |
预防医学 | 101篇 |
眼科学 | 40篇 |
药学 | 1038篇 |
中国医学 | 390篇 |
肿瘤学 | 898篇 |
出版年
2024年 | 18篇 |
2023年 | 134篇 |
2022年 | 196篇 |
2021年 | 304篇 |
2020年 | 276篇 |
2019年 | 236篇 |
2018年 | 231篇 |
2017年 | 220篇 |
2016年 | 214篇 |
2015年 | 263篇 |
2014年 | 393篇 |
2013年 | 397篇 |
2012年 | 338篇 |
2011年 | 385篇 |
2010年 | 302篇 |
2009年 | 255篇 |
2008年 | 221篇 |
2007年 | 155篇 |
2006年 | 154篇 |
2005年 | 121篇 |
2004年 | 108篇 |
2003年 | 78篇 |
2002年 | 42篇 |
2001年 | 21篇 |
2000年 | 25篇 |
1999年 | 6篇 |
1998年 | 7篇 |
1997年 | 6篇 |
1996年 | 3篇 |
1995年 | 5篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1991年 | 5篇 |
1990年 | 1篇 |
1989年 | 3篇 |
1987年 | 2篇 |
1985年 | 9篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 7篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1979年 | 5篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1976年 | 3篇 |
1974年 | 1篇 |
排序方式: 共有5185条查询结果,搜索用时 15 毫秒
41.
ObjectiveExposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity.MethodsThree-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity.ResultsHigher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: βindirect −0.0234, 95% CI: −0.0573 to −0.0074; CTQ physical neglect: βindirect = −0.0316, 95% CI: −0.0741 to −0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (βindirect = −0.0618, 95% CI: −0.1523 to −0.285).ConclusionThis work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6′s association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted. 相似文献
42.
The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the most commonly deregulated pathways in human cancers. PI3K comprises a catalytic (p110α) and regulatory subunit (p85), and p110α is encoded by the PIK3CA gene. Here, we summarize the known genetic alterations, including amplifications and mutations, of the PIK3CA oncogene in oral cancer. We discuss in detail PIK3CA mutations and their mutual exclusivity with pathway genes in addition to the incidence of PIK3CA mutations in relation to ethnicity. We describe the constitutive activation of PI3K signaling, oncogenicity, and the genetic deregulation of the PIK3CA gene and its association with oral cancer disease stage. We emphasize the importance of therapeutically targeting the genetically deregulated PIK3CA oncogene and its signaling. We also discuss the implications of targeting Akt and/or mTOR, which are the downstream effectors of PI3K that may possibly pave the way for molecular therapeutic targets for PIK3CA-driven oral carcinogenesis. Furthermore, this critical review provides a complete picture of the PIK3CA oncogene and its deregulation in oral cancer, which may facilitate early diagnosis and improve prognosis through personalized molecular targeted therapy in oral cancer. 相似文献
43.
Tamoxifen (TAM) and fulvestrant (FUL) represent the major adjuvant therapy to estrogen receptor-alpha positive (ER+) breast cancer patients. However, endocrine resistance to TAM and FUL is a great impediment for successful treatment. We hypothesized that miR-21 might alter the sensitivity of breast cancer cells to TAM or FUL by regulating cell autophagy. Using the ER+ breast cancer cells, we knockdown miR-21.by transfection with miR-21 inhibitor, then the cells were exposed to TAM or FUL and the percentages of apoptosis and autophagy were determined. Knockdown of miR-21 significantly increased the TAM or FUL-induced apoptosis in ER+ breast cancer cells. Further, silencing of miR-21 in MCF-7 cells enhanced cell autophagy at both basal and TAM or FUL-induced level. The increase of autophagy in miR-21-knockdown MCF-7 cells was also indicated by increase of beclin-1, LC3-II and increased GFP-LC3 dots. Importantly, knockdown of miR-21 contributed to autophagic cell death, which is responsible for part of TAM induced cell death in miR-21 inhibitor-transfected cells. Further analysis suggested that miR-21 inhibitor enhance autophagic cell death through inhibition of PI3K-AKT-mTOR pathway. MiR-21 coordinated the function of autophagy and apoptosis by targeting Phosphatase and tensin homolog (PTEN) through inhibition of PI3K-AKT-mTOR pathway. In conclusion, silencing of miR-21 increased the sensitivity of ER+ breast cancer cells to TAM or FUL by increasing autophagic cell death. Targeting autophagy-related miRNAs is a potential strategy for overcoming endocrine resistance to TAM and FUL. 相似文献
44.
45.
Dietary supplementation exerts beneficial effects in reducing incidence of chronic neurodegenerative diseases. The purpose of this study was to examine protective effects of mussel (Mytilus edulis) oligopeptides supplementation on brain function in d-galactose induced aging mice. Sixty female 8-month-old mice were randomly divided into five groups: vehicle control, d-galactose, and d-galactose combined with 200, 500, 1000 mg/kg mussel oligopeptides. The results showed that mussel oligopeptides could improve cognitive learning and memory ability and protect the hippocampal neurons. In addition, GSH, SOD and GSH-pX activities were increased and MDA level was significantly decreased in mice fed with mussel oligopeptides. It was also found that mussel oligopeptides supplementation prevented d-galactose-induced elevations of iNOS activity and NO production and lactate acid levels in brain. Moreover, PI3K and Akt genes were up-regulated by mussel oligopeptides supplementation. These findings suggest that mussel oligopeptides are able to enhance exercise capacity and protect against oxidative damage caused by d-galactose in aging model mice through regulating oxidation metabolism and PI3K/Akt/NOS signal pathway. Therefore, mussel oligopeptides are good materials for future development of healthcare products to combat age-related brain dysfunction and to improve healthy life span. 相似文献
46.
《HIV clinical trials》2013,14(2):86-96
AbstractRecent data from clinical trials investigating the efficacy of enfuvirtide, a fusion inhibitor, in treatment-experienced patients have revealed that the addition of enfuvirtide (ENF) to an active boosted protease inhibitor regimen doubles the rate of virological response. At week 48 of the TORO studies, 55% of patients previously naive to and receiving lopinavir/ritonavir (LPV/r) with ENF achieved a viral load of <400 copies/mL compared with 24% of patients treated with LPV/r alone. At week 24 of the RESIST studies, 70% of previously ENF-naive patients who took both ENF and tipranavir/ritonavir (TPV/r) achieved a ≥1 log10 reduction in viral load compared with 37% of such patients treated with TPV/r alone. Similarly, concomitant use of TMC114/ritonavir (TMC114/r) with ENF, compared with TMC114/r alone, increased the number of patients with <50 copies/mL from 46% to 64% in a combined 24-week analysis from the POWER trials. Data from these trials suggest that combining one agent from a new class with a new agent from a previously exposed class offers a greater chance of achieving full virological control than either type of agent alone. Undetectable viraemia should be the primary objective for treatment-experienced patients requiring a switch in therapy, and the present data support the combination of an active boosted protease inhibitor with an agent from a new class (e.g., ENF) for triple-class-experienced patients. 相似文献
47.
Manojkumar Bupathi Ahmed Kaseb Funda Meric-Bernstam Aung Naing 《Molecular oncology》2015,9(8):1501-1509
Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor most commonly associated with underlying chronic liver disease, especially hepatitis. It is a growing problem in the United States and worldwide. There are two potential ways to prevent HCC. Primary prevention which is based on vaccination or secondary prevention involving agents that slow down carcinogenesis. Several pathways have been thought to play a role in the development of HCC; specifically, those involving vascular endothelial growth factor (VEGF)‐mediated angiogenesis, WNT, phosphatidylinositol 3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), AMP‐activated protein kinase (AMPK), and c‐MET. Currently, there are only a limited number of drugs which have been proven as effective treatment options for HCC and several clinical trials are testing drugs which target aberrations in the pathways mentioned above. In this review, we discuss currently approved therapies, monotherapies and combination therapy for the treatment of HCC. 相似文献
48.
49.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, metastatic disease with limited treatment options. Factors contributing to the metastatic predisposition and therapy resistance in pancreatic cancer are not well understood. Here, we used a mouse model of KRAS-driven pancreatic carcinogenesis to define distinct subtypes of PDAC metastasis: epithelial, mesenchymal and quasi-mesenchymal. We examined pro-survival signals in these cells and the therapeutic response differences between them. Our data indicate that the initiation and maintenance of the transformed state are separable, and that KRAS dependency is not a fundamental constant of KRAS-initiated tumors. Moreover, some cancer cells can shuttle between the KRAS dependent (drug-sensitive) and independent (drug-tolerant) states and thus escape extinction. We further demonstrate that inhibition of KRAS signaling alone via co-targeting the MAPK and PI3K pathways fails to induce extensive tumor cell death and, therefore, has limited efficacy against PDAC. However, the addition of histone deacetylase (HDAC) inhibitors greatly improves outcomes, reduces the self-renewal of cancer cells, and blocks cancer metastasis in vivo. Our results suggest that targeting HDACs in combination with KRAS or its effector pathways provides an effective strategy for the treatment of PDAC. 相似文献
50.
Temozolomide is a novel cytotoxic agent currently used as first-line chemotherapy for glioblastoma multiforme (GBM). Romidepsin (FK228), a histone deacetylase inhibitor, is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, combination of the two drugs in glioma remains largely unknown. In the present study, we evaluated the combinatory effects of FK228 with TMZ in glioma, and its molecular mechanisms responsible for these effects. Glioma cell lines were treated with TMZ, FK228 or the combination of drugs. The resistance effect including cytotoxicity and apoptosis was determined in glioma cells, respectively. We further evaluated the effects of FK228 in the PI3K/Akt-signaling pathway in vitro. Mice engrafted with 5 × 106 LN382 cells were treated with TMZ, FK228 or the combination of two drugs, and tumor weights and volumes were measured, respectively. FK228 enhanced the cytotoxic effects of TMZ in glioma cells compared to vehicle-treated controls or each drug alone. The combination of FK228 and TMZ-induced apoptosis was demonstrated by increased expression of cleaved-Caspase 3, Bax, cleaved-PARP, and decreased Bcl-2 expression. Furthermore, the expression of key components of the PI3K/Akt-signaling pathway showed that combination of FK228 and TMZ block PI3K/Akt pathways in vitro. This block effect was also confirmed in vivo in mice models. Mice treated with both FK228 and TMZ drugs showed significantly reduced tumor weights and volumes, compared to each drug alone. Our results suggested that FK228 augmented temozolomide sensitivity in human glioma cells partially by blocking PI3K/AKT/mTOR signal pathways. It thus may provide a promising target for improving the therapeutic outcome of TMZ-resistant gliomas, although further studies will be needed. 相似文献