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81.
82.
IGF信号通路关键蛋白IGF1、IGF1R和AKT在原发性肺腺癌中的表达及意义 总被引:1,自引:0,他引:1
目的检测IGF信号通路关键蛋白IGF1,IGF1R和AKT在原发性肺腺癌中的表达,探讨其与临床病理学特征和生存时间的关系。方法采用免疫组化方法和免疫印迹技术检测IGF1,IGF1R和AKT在31例原发性肺腺癌及12例良性肺病变组织中的表达。结果IGF1、IGF1R和AKT在肺腺癌中的表达率分别为41.9%(13/31)、67.7%(21/31)和51.6%(16/31),显著高于良性肺组织(P值分别为0.0252、0.0016和0.0071)。IGF1和IGF1R及IGF1和AKT在肺腺癌中表达呈显著相关(P值分别为0.0344和0.0179)。晚期肺癌(Ⅲ+Ⅳ)IGF1和IGF1R表达显著高于早期(Ⅰ+Ⅱ)(P值分别为0.0109和0.0303)。IGF1、IGF1R和AKT在伴有淋巴结转移肺癌中的表达显著高于无淋巴结转移肺癌(P值分别为0.0468、0.0490和0.0443)。低分化肺癌中IGF1和IGF1R表达显著高于中或高分化肺癌(P值分别为0.0484和0.0291)。IGF1和IGF1R阳性患者的生存时间显著短于阴性者(IGF1:10比14个月,P=0.0103;IGF1R:13比26个月,P=0.0056)。IGF1和IGF1R是肺腺癌预后的影响因素,AKT无预后意义。结论IGF信号通路关键蛋白IGF1、IGF1R和AKT表达在肺腺癌的发生和发展中可能起重要作用,进一步的研究有望展示其在肺癌预后和治疗方面的意义。 相似文献
83.
丝/苏氨酸激酶通路在胶质瘤中的研究进展 总被引:1,自引:0,他引:1
丝/苏氨酸激酶(AKT)通路处于转导生长因子向细胞核内传递信号的中心环节,其功能涉及细胞周期调控、凋亡的启动、血管生成、端粒酶活性和细胞侵袭性等诸多方面。随着研究工作的不断深入,AKT通路在胶质瘤的研究中凸现出日益重要的作用。综述AKT功能调控、在胶质瘤研究中的研究进展以及在胶质瘤治疗中的潜在作用。 相似文献
84.
María Gabriela Muñoz-Cordero Fernando López Cristina García-Inclán Alejandro López-Hernández Sira Potes-Ares Laura Fernández-Vañes José Luis Llorente Mario Hermsen 《Acta otorrinolaringologica espanola》2019,70(1):16-24
Background and objectives
We have previously indicated that EGFR has a role in carcinogenesis in a subgroup of sinonasal squamous cell carcinomas (SNSCC). In addition, EGFR activates 2 of the most important intracellular signalling pathways: PI3K/pAKT/mTOR/pS6 and MAP pathway kinases. The objective of this study was to evaluate the involvement of the EGFR/PI3K/pAKT/mTOR/pS6 pathway and its relationship with clinical-pathological parameters and follow-up of sinonasal squamous cell carcinoma.Material and methods
The immunohistochemical expression of different components of the PI3K/AKT/mTOR/pS6 pathway and its relationship with various clinical-pathological parameters was studied in a series of 54 patients with SNSCC.Results
Loss of PTEN expression was observed in 33/54 cases (61%) and pAKT, mTOR and pS6 pre-expression was observed in 19/54 cases (35%), 8/54 cases (15%), and 47/54 cases (87%), respectively. Loss of PTEN expression was related to intracranial invasion and development of regional metastases (p=0.005). Overexpression of pS6 was associated with a decrease in survival (p=0.008), presence of local recurrences (p=0.055), and worsening of overall prognosis (p=0.007). No significant relationships were observed between pAKT and mTOR expression and the clinicopathological parameters studied.Conclusions
Alterations in the expression of EGFR/PI3K/pAKT/mTOR/pS6 pathway components are common in a subgroup of SNSCC. This study reveals that the absence of pS6 overexpression is associated with better clinical outcomes. Therefore, pS6 expression could be considered as an unfavourable prognostic marker. 相似文献85.
Although Wnt/beta-catenin/Tcf signaling pathway has been shown to be an important factor in the development of many malignancies including colorectal, ovarian, prostate, and many other cancers, little is known about its role in non-melanoma skin cancers. Here, we report the first evidence that beta-catenin/Tcf signaling pathway is constitutively activated in non-melanocytic skin tumors induced by two stage chemical carcinogenesis protocol. Mouse skin tumors showed cytoplasmic and nuclear accumulation of beta-catenin, and upregulation of beta-catenin/Tcf target genes (c-myc and c-jun). We found high levels of skin-expressed Wnt proteins (Wnt 3, 4, and 10b) in different parts of the tumors, likely representing key upstream events in beta-catenin/Tcf activation during mouse skin carcinogenesis. Inhibition of beta-catenin/Tcf signaling by ectopic expression of dominant negative Tcf4 resulted in significant inhibition of growth in squamous cell carcinoma cells. A role of the constitutive activation of beta-catenin/Tcf signaling in skin carcinogenesis is discussed. 相似文献
86.
Kirkegaard T Witton CJ McGlynn LM Tovey SM Dunne B Lyon A Bartlett JM 《The Journal of pathology》2005,207(2):139-146
Oestrogen receptor (ERalpha) expression is a strong predictor of response to endocrine therapy. The PI3K/AKT/mTOR signal transduction pathway has been implicated in endocrine resistance in vitro. The present study was carried out to test the hypothesis that AKT activation mediates tamoxifen resistance in clinical breast cancer. Immunohistochemistry (IHC) using AKT1-3, pan-AKT, pAKT (Thr-308), pAKT (Ser-473), pER (Ser-167), and pHER2 antibodies was performed on 402 ERalpha-positive breast carcinomas from patients treated with tamoxifen. High pAKT (Ser-473) activity (p = 0.0406) and low AKT2 expression (p = 0.0115) alone, or in combination [high pAKT (Ser-473)/low AKT2; 'high-risk' patient group] (p = 0.0014), predicted decreased overall survival in tamoxifen-treated patients with ERalpha-positive breast cancers. There was no significant association between tumour levels of AKT expression or activity and disease-free survival (DFS); however, the 'high-risk' patient group was significantly more likely to relapse (p = 0.0491). During tamoxifen treatment, neither AKT2 nor pAKT predicted DFS. Finally, activation of AKT, via phosphorylation, was linked to activation of both HER2 and ERalpha in this patient cohort. The data presented here show that the PI3K/AKT/mTOR pathway is associated with relapse and death in ERalpha-positive breast cancer patients treated with tamoxifen, supporting in vitro evidence that AKT mediates tamoxifen resistance. Patients with a 'high-risk' expression profile were at increased risk of death (hazard ratio 3.22, p = 0.002) relative to 'low-risk' patients, highlighting the potential that tumour profiling, with multiple IHC markers predictive of therapeutic response, may improve patient selection for endocrine therapies, eg tamoxifen or aromatase inhibitor-based treatments. 相似文献
87.
Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation 总被引:10,自引:0,他引:10
Pozo-Guisado E Lorenzo-Benayas MJ Fernández-Salguero PM 《International journal of cancer. Journal international du cancer》2004,109(2):167-173
Resveratrol (RES), a natural phytoalexin, has antiproliferative activity in human-derived cancer cells and in rodent models of tumor development. We have previously shown that RES induced apoptotic death in estrogen-responsive MCF-7 human breast cancer cells. Recent data have indicated that the estrogen receptor-alpha (ERalpha), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, nonnuclear function of the ERalpha potentially relevant in cell proliferation and apoptosis. In our study, using MCF-7, we have analyzed the ability of RES to modulate the ERalpha-dependent PI3K pathway. Immunoprecipitation and kinase activity assays showed that RES increased the ERalpha-associated PI3K activity with a maximum stimulatory effect at concentrations close to 10 microM; concentrations >50 microM decreased PI3K activity. Stimulation of PI3K activity by RES was ERalpha-dependent since it could be blocked by the antiestrogen ICI 182,780. RES did not affect p85 protein expression but induced the proteasome-dependent degradation of the ERalpha. Nevertheless, the amount of PI3K immunoprecipitated by the ERalpha remained unchanged in presence of RES, indicating that ERalpha availability was not limiting PI3K activity. Phosphoprotein kinase B (pPKB/AKT) followed the pattern of PI3K activity, whereas RES did not affect total PKB/AKT expression. PKB/AKT downstream target glycogen synthase kinase 3 (GSK3) also showed a phosphorylation pattern that followed PI3K activity. We propose a mechanism through which RES could inhibit survival and proliferation of estrogen-responsive cells by interfering with an ERalpha-associated PI3K pathway, following a process that could be independent of the nuclear functions of the ERalpha. 相似文献
88.
Signal transduction of the protective effect of insulin like growth factor-1 on adriamycin-lnduced apoptosis in cardiac muscle cells 总被引:6,自引:0,他引:6
To determine whether Insulin-like growth factor (IGF-I) treatment represents a potential means of enhancing the survival of cardiac muscle cells from adriamycin (ADR)-induced cell death, the present study examined the ability of IGF-I to prevent cell death. The study was performed utilising the embryonic, rat, cardiac muscle cell line, H9C2. Incubating cardiac muscle cells in the presence of adriamycin increased cell death, as determined by MTT assay and annexin V-positive cell number. The addition of 100 ng/mL IGF-I, in the presence of adriamycin, decreased apoptosis. The effect of IGF-I on phosphorylation of PI, a substrate of phosphatidylinositol 3-kinase (PI 3-kinase) or protein kinase B (AKT), was also examined in H9C2 cardiac muscle cells. IGF-I increased the phosphorylation of ERK 1 and 2 and PKC zeta kinase. The use of inhibitors of PI 3-kinase (LY 294002), in the cell death assay, demonstrated partial abrogation of the protective effect of IGF-I. The MEK1 inhibitor-PD098059 and the PKC inhibitor-chelerythrine exhibited no effect on IGF-1-induced cell protection. In the regulatory subunit of PI3K-p85- dominant, negative plasmid-transfected cells, the IGF-1-induced protective effect was reversed. This data demonstrates that IGF-I protects cardiac muscle cells from ADR-induced cell death. Although IGF-I activates several signaling pathways that contribute to its protective effect in other cell types, only activation of PI 3-kinase contributes to this effect in H9C2 cardiac muscle cells. 相似文献
89.
Summary The reversing effect of wild-type PTEN gene on resistance of C13K cells to cisplatin and its inhibitory effect on the phosphorylation
of protein kinase B (AKT) were studied. The expression of PTEN mRNA and protein in OV2008 cells and C13K cells were semi-quantitatively
detected by using RT-PCR and Western blotting. Recombinant eukaryotic expression plasmid containing human wild-type PTEN gene
was transfected into C13K cells by lipofectamine2000. The expression of PTEN mRNA was monitored by RT-PCR and the expression
of PTEN, Akt, p-Akt protein were analyzed by Western blotting in PTEN-transfected and non-transfected C13K cells. Proliferation
and chemosensitivity of cells to DDP were measured by MTT, and cell apoptosis was detected by flow cytometry after treatment
with cisplatin. The expression of PTEN mRNA and protein in OV2008 cells were significantly higher than those in C13K cells.
After transfection with PTEN gene for 48 h, the expression of PTEN mRNA and protein in C13K cells were 2.04 ± 0.10, 0.94 ±
0.04 respectively and the expression of p-Akt protein (0.94 ± 0.07) was lower than those in control groups (1.68 ± 0.14, 1.66
± 0.10) (P < 0.05). The IC50 of DDP to C13K cells transfected with PTEN (7.2 ± 0.3 μmol/L) was obviously lower than those of empty-vector transfected
cells and non-transfected cells (12.7 ± 0.4 μmol/l, 13.0 ± 0.3 μmol/L) (P<0.05). The apopototis ratio of wild-type PTEN-transfected, empty vector transfected and non-transfected C13K cells were (41.65
± 0.87)%, (18.61 ± 0.70)% and (15.28 ± 0.80)% respectively, and the difference was statistically significant (P<0.05). PTEN gene plays an important role in ovarian cancer multidrug resistance. Transfection of PTEN could increase the
expression of PTEN and restore drug sensitivity to cisplatin in human ovarian cancer cell line C13K with multidrug-resistance
by decreasing the expression of p-Akt.
This project was supported by a grant from the National Natural Sciences Foundation of China (No. 30571950) and National Key
Basic Research Program Foundation (NO.2002CB513107). 相似文献
90.