全文获取类型
收费全文 | 5157篇 |
免费 | 347篇 |
国内免费 | 452篇 |
专业分类
5956篇 |
出版年
2024年 | 26篇 |
2023年 | 125篇 |
2022年 | 182篇 |
2021年 | 243篇 |
2020年 | 192篇 |
2019年 | 310篇 |
2018年 | 225篇 |
2017年 | 157篇 |
2016年 | 152篇 |
2015年 | 203篇 |
2014年 | 388篇 |
2013年 | 534篇 |
2012年 | 280篇 |
2011年 | 343篇 |
2010年 | 184篇 |
2009年 | 192篇 |
2008年 | 211篇 |
2007年 | 208篇 |
2006年 | 183篇 |
2005年 | 191篇 |
2004年 | 141篇 |
2003年 | 131篇 |
2002年 | 134篇 |
2001年 | 105篇 |
2000年 | 79篇 |
1999年 | 78篇 |
1998年 | 67篇 |
1997年 | 68篇 |
1996年 | 56篇 |
1995年 | 45篇 |
1994年 | 66篇 |
1993年 | 57篇 |
1992年 | 43篇 |
1991年 | 56篇 |
1990年 | 21篇 |
1989年 | 33篇 |
1988年 | 21篇 |
1987年 | 33篇 |
1986年 | 15篇 |
1985年 | 19篇 |
1984年 | 24篇 |
1983年 | 24篇 |
1982年 | 23篇 |
1981年 | 24篇 |
1980年 | 14篇 |
1979年 | 23篇 |
1978年 | 8篇 |
1976年 | 7篇 |
1975年 | 4篇 |
1974年 | 4篇 |
排序方式: 共有5956条查询结果,搜索用时 0 毫秒
991.
Thanthrige Thiunuwan Priyathilaka Don Anushka Sandaruwan Elvitigala Ilson Whang Bong-Soo Lim Hyung-Bok Jeong Sang-Yeob Yeo Cheol Young Choi Jehee Lee 《Gene》2014
Toll-like receptors (TLRs) are a large family of pattern recognition receptors, which are involved in triggering host immune responses against various pathogens by detecting their evolutionarily conserved pathogen associated molecular patterns (PAMPs). TLR21 is a non-mammalian type TLR, which recognizes unmethylated CpG DNA, and is considered as a functional homolog of mammalian TLR9. In this study, we attempted to identify and characterize a novel TLR21 counterpart from rock bream (Oplegnathus fasciatus) designated as RbTLR21, at molecular level. The complete coding sequence of RbTLR21 was 2919 bp in length, which encodes a polypeptide of 973 amino acids with a predicted molecular mass of 112 kDa and a theoretical isoelectric point of 8.6. The structure of the deduced RbTLR21 protein is similar to that of the members of typical TLR family, and includes the ectodomain, which consists of 16 leucine rich repeats (LRRs), a transmembrane domain, and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain. According to the pairwise sequence analysis data, RbTLR21 was homologous to that of the orange-spotted grouper (Epinephelus coioides) with 76.9% amino acid identity. Furthermore, our phylogenetic analysis revealed that RbTLR21 is closely related to E. coioides TLR21. The RbTLR21 was ubiquitously expressed in all the tissues tested, but the highest expression was found in spleen. Additionally, upon stimulation with Streptococcus iniae, rock bream iridovirus (RBIV), and Edwardsiella tarda, RbTLR21 mRNA was significantly up-regulated in spleen tissues. Collectively, our findings suggest that RbTLR21 is indeed an ortholog of the TLR21 family and may be important in mounting host immune responses against pathogenic infections. 相似文献
992.
993.
CDK4 and CDK6 bound to D-type cyclins are master integrators of G1 phase cell cycle regulations by initiating the inactivating phosphorylation of the central oncosuppressor pRb. Because of their frequent deregulation in cancer, cyclin D-CDK4/6 complexes are emerging as especially promising therapeutic targets. The specific CDK4/6 inhibitor PD0332991 is currently tested in a growing number of phase II/III clinical trials against a variety of pRb-proficient chemotherapy-resistant cancers. We have previously shown that PD0332991 inhibits not only CDK4/6 activity but also the activation by phosphorylation of the bulk of cyclin D-CDK4 complexes stabilized by p21 binding. Here we show that PD0332991 has either a positive or a negative impact on the activation of cyclin D-CDK4/6 complexes, depending on their binding to p21. Indeed, whereas PD0332991 inhibits the phosphorylation and activity of p21-bound CDK4/6, it specifically stabilized activated cyclin D3-CDK4/6 complexes devoid of p21 and p27. After elimination of PD0332991, these activated cyclin D3-CDK4/6 complexes persisted for at least 24 h, resulting in paradoxical cell cycle entry in the absence of a mitogenic stimulation. This unsuspected positive effect of PD0332991 on cyclin D3-CDK4/6 activation should be carefully assessed in the clinical evaluation of PD0332991, which until now only involves discontinuous administration protocols. 相似文献
994.
David A Gewirtz 《Autophagy》2014,10(3):391-392
Multiple papers have been published that have identified and/or characterized the cytoprotective function of autophagy, primarily in tumor cells exposed to chemotherapy or radiation. These studies have relied on pharmacological and/or genetic interference with autophagy to establish its protective function, often primarily by demonstrating that cells in which autophagy has been suppressed undergo increased apoptosis. The purpose of this Editor’s Corner is to emphasize that these approaches, while absolutely necessary, are of themselves insufficient to support the conclusion that autophagy is cytoprotective in a given experimental tumor line exposed to a particular agent; complementary studies are required that demonstrate that autophagy inhibition sensitizes the tumor cell to the autophagy-inducing treatment. Otherwise, autophagy may be responsible for the growth arrest and/or cell death that is observed with the drug or radiation treatment alone, and autophagy inhibition may simply be converting one form of growth inhibition/cell death to an alternative pathway that achieves the same end result in terms of sensitivity to the treatment. 相似文献
995.
Vera Kloten Michael Rose Sophie Kaspar Saskia von Stillfried Ruth Knüchel Edgar Dahl 《Epigenetics》2014,9(9):1290-1301
Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is supposed to be involved in extracellular matrix stability and thus may play a key role in the inhibition of tumor progression. The current study is the first to analyze in depth ITIH5 expression as well as its potential clinical and functional impact in colon cancer. Based on 30 tumor and 30 adjacent normal tissues we examined ITIH5 mRNA expression and promoter methylation, whose significance was further validated by independent data sets from The Cancer Genome Atlas (TCGA) platform. In addition, ITIH5 protein expression was evaluated using immunohistochemistry. ITIH5 mRNA expression loss was significantly associated (P < 0.001) with hypermethylation of the ITIH5 promoter in primary colon tumors. In addition, treatment of tumor cell lines with demethylating (DAC) and histone acetylating (TSA) agents induced ITIH5 expression. In line, independent TCGA data revealed a significant expression loss of ITIH5, particularly in the MSI-high and CIMP-positive phenotype concordant with an increased ITIH5 hypermethylation in CIMP-positive colon tumors (P < 0.001). In proximal, i.e., right-sided tumors, abundant ITIH5 expression was associated with longer overall survival (OS, P = 0.049) and the CIMP-positive (P = 0.032) subgroup. Functionally, ITIH5 re-expression mediated a reduced proliferation in HCT116 and CaCo2 cells. In conclusion, our results indicate that ITIH5 is a novel putative tumor suppressor gene in colon cancer with a potential impact in the CIMP-related pathway. ITIH5 may serve as a novel epigenetic-based diagnostic biomarker with further clinical impact for risk stratification of CIMP-positive colon cancer patients. 相似文献
996.
Advances in functional genomics have led to discovery of a large group of previous uncharacterized long non-coding RNAs (IncRNAs). Emerging evidence indicates that IncRNAs may serve as master gene regulators through various mechanisms. Dysregulation of IncRNAs is often associated with a variety of human diseases including cancer. Of significant interest, recent studies suggest that IncRNAs participate in the p53 tumor suppressor regulatory network. In this review, we discuss how IncRNAs serve as p53 regulators or p53 effectors. Further characterization of these p53-associated IncRNAs in cancer will provide a better understanding of lncRNA- mediated gene regulation in the p53 pathway. As a result, IncRNAs may prove to be valuable biomarkers for cancer diagnosis or poten- tial targets for cancer therapy. 相似文献
997.
目的:探讨腹腔镜辅助探查并治疗腹部恶性肿瘤术后肠梗阻患者的可行性及安全性。方法:应用腹腔镜技术对我院42例腹部恶性肿瘤术后患者行手术治疗,其中包括良性粘连性肠梗阻14例、肿瘤复发16例、原发性结肠癌1例、恶性肠粘连11例。结果:42例患者均在腹腔镜下明确诊断,其中18例患者在完全腹腔镜下手术治疗,13例患者在腹腔镜辅助下行手术治疗,6例患者腹腔严重粘连中转开腹手术治疗,5例患者腹腔广泛转移行保守治疗。腹腔镜手术时间为35~290min,平均住院日9.2±1.7d。患者术后疼痛较轻、下床活动时间及肠道功能恢复时间短、术后并发症少。结论:恶性肿瘤术后肠梗阻患者仍需手术治疗,在严格掌握手术适应症下,应用腹腔镜技术对恶性肿瘤术后肠梗阻病人的治疗是安全、可行的。 相似文献
998.
目的:探讨aAd-p53注射液靶向灌注治疗癌性胸腹水的临床疗效和安全性。方法:选择2012年5月-2014年2月在我院接受治疗的癌性胸腹水患者80例,根据治疗方法的不同,将患者随机分为研究组和对照组,每组40例。研究组患者采用腔内灌注rAd-p53治疗,对照组患者采用表阿霉素灌注治疗,观察并比较两组患者的治疗总有效率、不良反应的发生率及KPS功能评分的变化情况。结果:所有患者均顺利完成灌注治疗,病情获得好转,生存质量得到改善。研究组和对照组的治疗总有效率分别为70%、67.5%,两组比较无显著性差异(P0.05)。两组治疗后KPS评分均显著高于治疗前,且研究组高于对照组,差异具有统计学意义(P0.05)。研究组和对照组不良反应的发生率分别为20%和25%,研究组低于对照组,但两组差异并无统计学意义(P0.05)。结论:rAd-p53注射液靶向灌注治疗是一种治疗癌性胸腹水安全有效的方法,值得临床推广。 相似文献
999.
摘要 目的:探讨建立稳定的荷人膀胱癌 SCID 鼠人化复合型的方法,为在人免疫重建荷人膀胱肿瘤 SCID 鼠型检测重组
BCG 的免疫刺激和免疫保护中打下基础。方法: 经 SCID 鼠腹腔内注射人 PBL、 皮下接种 RT4 膀胱癌细胞, 于接种后 4 周检测
SCID 鼠体内人免疫细咆水平(IgG 和 CD
3+
、 CD
4+
、 CD
8+
T 细胞)及脾脏重量, 观察皮下成瘤潜伏期及成瘤率。结果: 型组 100% 成
瘤,病理类型为移行细胞癌; 检测 SCID 鼠血中人 IgG 均一定水平存在, 与对照组间差异有统计学意义(P<0.01); 人 CD
3+
、 CD
4+
、
CD
8+
T 细胞在鼠血及脾中均有表达, 而对照组均未检出(P<0.05); 4 周鼠脾重平均(178.9± 45.2)mg。较对照组(40.6± 14.8)mg 差异
有统计学意义(P<0.01)。结论: 采用腹腔注射人 PBL、 皮下接种 RT4 膀胱癌细胞的方法可以有效地建立人化荷人膀胱癌 SCID 鼠
型, 较好地拟人浸润性膀胱癌体内生物学特性,是膀胱癌免疫基因治疗的较理想型。 相似文献
1000.
Satoshi Serada Atsushi Tanemura Fei Yang Shintaro Nomura Akira Kudo Kenji Izuhara Hiroyuki Murota Minoru Fujimoto Ichiro Katayama Tetsuji Naka 《Pigment cell & melanoma research》2014,27(4):630-639
Given no reliable therapy for advanced malignant melanoma, it is important to elucidate the molecular mechanisms underlying the disease progression. Using a quantitative proteomics approach, the ‘isobaric tags for relative and absolute quantitation (iTRAQ)’ method, we identified that the extracellular matrix protein, periostin (POSTN), was highly expressed in invasive melanoma compared with normal skin. An immunohistochemical analysis showed that POSTN was expressed in all invasive melanoma (n = 20) and metastatic lymph node (n = 5) tissue samples, notably restricted in their stroma. In terms of the intercellular regulation of POSTN, we found that there was upregulation of POSTN when melanoma cells and normal human dermal fibroblasts (NHDFs) were cocultured, with restricted expression of TGF‐β1 and TGF‐β3. In a functional analyses, recombinant and NHDF‐derived POSTN significantly accelerated melanoma cell proliferation via the integrin/mitogen‐activated protein kinase (MAPK) signaling pathway in vitro. The size of implanted melanoma tumors was significantly suppressed in POSTN/Rag2 double knockout mice compared with Rag2 knock‐out mice. These results indicate that NHDF‐derived POSTN accelerates melanoma progression and might be a promising therapeutic target for malignant melanoma. 相似文献