全文获取类型
收费全文 | 1134篇 |
免费 | 165篇 |
国内免费 | 25篇 |
专业分类
1324篇 |
出版年
2024年 | 3篇 |
2023年 | 45篇 |
2022年 | 33篇 |
2021年 | 40篇 |
2020年 | 69篇 |
2019年 | 109篇 |
2018年 | 69篇 |
2017年 | 46篇 |
2016年 | 54篇 |
2015年 | 65篇 |
2014年 | 94篇 |
2013年 | 128篇 |
2012年 | 62篇 |
2011年 | 71篇 |
2010年 | 53篇 |
2009年 | 44篇 |
2008年 | 44篇 |
2007年 | 24篇 |
2006年 | 28篇 |
2005年 | 19篇 |
2004年 | 26篇 |
2003年 | 9篇 |
2002年 | 23篇 |
2001年 | 19篇 |
2000年 | 12篇 |
1999年 | 12篇 |
1998年 | 12篇 |
1997年 | 6篇 |
1996年 | 10篇 |
1995年 | 7篇 |
1994年 | 14篇 |
1993年 | 14篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1989年 | 7篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1986年 | 1篇 |
1985年 | 4篇 |
1984年 | 1篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1980年 | 2篇 |
1979年 | 5篇 |
1976年 | 1篇 |
排序方式: 共有1324条查询结果,搜索用时 0 毫秒
991.
Mokkapati S Bechtel M Reibetanz M Miosge N Nischt R 《The journal of histochemistry and cytochemistry》2012,60(4):280-289
Nidogen 1 and 2 are ubiquitous basement membrane (BM) components. They show a divergent expression pattern in certain adult tissues with a prominent localization of nidogen 2 in blood vessel BMs. Deletion of either nidogen 1 or 2 in mice had no effect on BM formation, suggesting complementary functions. However, studies in these mice revealed isoform-specific functions with nidogen 1-deficient mice showing neurological abnormalities and wound-healing defects not seen in the absence of nidogen 2. To investigate this further nidogen 1- or 2-deficient mice were intravenously injected with B16 murine melanoma cells, and lung metastasis was analyzed. The authors could show that loss of nidogen 2, but not of nidogen 1, significantly promotes lung metastasis of melanoma cells. Histological and ultrastructural analysis of nidogen 1- and 2-deficient lungs did not reveal differences in morphology and ultrastructure of BMs, including vessel BMs. Furthermore, deposition and distribution of the major BM components were indistinguishable between the two mouse strains. Taken together, these results suggest that absence of nidogen 2 might result in subtle changes of endothelial BMs in the lung, which would allow faster passage of tumor cells through these BMs, leading to a higher metastasis rate and more larger tumors. 相似文献
992.
The peptide pVEC is a recently described cell-penetrating peptide, derived from the murine vascular endothelial-cadherin protein. In order to define which part of this 18-amino acid long peptide is important for the cellular translocation, we performed a structure-activity relationship study of pVEC. Together with the l-alanine substituted peptides, the retro-pVEC, D-pVEC and the scramble pVEC are studied for comparison. The peptide analogues are labeled with carboxyfluorescein at the N-terminus for monitoring the cellular uptake into human Bowes melanoma cells with different efficacy. We show that all the Fl-pVEC analogues internalize in live Bowes melanoma cells. l-Alanine substitution of the five respective N-terminal hydrophobic amino acids significantly decreases the translocation property, while replacing of Arg6, Arg8 or Ser17 by alanine enhances the uptake. The uptake of pVEC is significantly reduced by treatment with an endocytosis inhibitor wortmannin. Treatment with heparinase III, nystatin and EIPA had no effect on the peptide uptake. The data presented here show that the N-terminal hydrophobic part of pVEC is crucial for efficient cellular translocation. 相似文献
993.
Jennifer E. Hauser Ana Luisa Kadekaro Renny J. Kavanagh Kazumasa Wakamatsu Silva Terzieva Sandy Schwemberger George Babcock M. B. Rao Shosuke Ito Zalfa A. Abdel‐Malek 《Pigment cell & melanoma research》2006,19(4):303-314
Malignant transformation of melanocytes leads to melanoma, the most fatal form of skin cancer. Ultraviolet radiation (UVR)‐induced DNA photoproducts play an important role in melanomagenesis. Cutaneous melanin content represents a major photoprotective mechanism against UVR‐induced DNA damage, and generally correlates inversely with the risk of skin cancer, including melanoma. Melanoma risk is also determined by susceptibility genes, one of which is the melanocortin 1 receptor (MC1R) gene. Certain MC1R alleles are strongly associated with melanoma. We hereby present experimental evidence for the role of two melanoma risk factors, constitutive pigmentation, as assessed by total melanin, eumelanin and pheomelanin contents, and MC1R genotype and function, in determining the induction and repair of DNA photoproducts in cultured human melanocytes after irradiation with increasing doses of UVR. We found that total melanin and eumelanin contents (MC and EC) correlated inversely with the extent of UVR‐induced growth arrest, apoptosis and induction of cyclobutane pyrimidine dimers (CPD), but not with hydrogen peroxide release in melanocytes expressing functional MC1R. In comparison, melanocytes with loss‐of‐function MC1R, regardless of their MC or EC, sustained more UVR‐induced apoptosis and CPD, and exhibited reduced CPD repair. Therefore, MC, mainly EC, and MC1R function are independent determinants of UVR‐induced DNA damage in melanocytes. 相似文献
994.
Vaccination of melanoma patients using dendritic cells loaded with an allogeneic tumor cell lysate 总被引:2,自引:0,他引:2
Salcedo M Bercovici N Taylor R Vereecken P Massicard S Duriau D Vernel-Pauillac F Boyer A Baron-Bodo V Mallard E Bartholeyns J Goxe B Latour N Leroy S Prigent D Martiat P Sales F Laporte M Bruyns C Romet-Lemonne JL Abastado JP Lehmann F Velu T 《Cancer immunology, immunotherapy : CII》2006,55(7):819-829
The aim of the present phase I/II study was to evaluate the safety, immune responses and clinical activity of a vaccine based
on autologous dendritic cells (DC) loaded with an allogeneic tumor cell lysate in advanced melanoma patients. DC derived from
monocytes were generated in serum-free medium containing GM-CSF and IL-13 according to Good Manufacturing Practices. Fifteen
patients with metastatic melanoma (stage III or IV) received four subcutaneous, intradermal, and intranodal vaccinations of
both DC loaded with tumor cell lysate and DC loaded with hepatitis B surface protein (HBs) and/or tetanus toxoid (TT). No
grade 3 or 4 adverse events related to the vaccination were observed. Enhanced immunity to the allogeneic tumor cell lysate
and to TAA-derived peptides were documented, as well as immune responses to HBs/TT antigens. Four out of nine patients who
received the full treatment survived for more than 20 months. Two patients showed signs of clinical response and received
3 additional doses of vaccine: one patient showed regression of in-transit metastases leading to complete remission. Eighteen
months later, the patient was still free of disease. The second patient experienced stabilization of lung metastases for approximately
10 months. Overall, our results show that vaccination with DC loaded with an allogeneic melanoma cell lysate was feasible
in large-scale and well-tolerated in this group of advanced melanoma patients. Immune responses to tumor-related antigens
documented in some treated patients support further investigations to optimize the vaccine formulation.
Margarita Salcedo and Nadège Bercovici both contributed equally to this work 相似文献
995.
为探讨新狼毒素A抑制人黑色素瘤A375细胞增殖及诱导凋亡的作用。本实验采用噻唑蓝(MTT)法检测新狼毒素A对人黑色素瘤A375细胞增殖的影响,Hoechst33258法观察细胞形态,流式细胞仪检测细胞凋亡率和线粒体膜电位,Westernblot检测凋亡相关蛋白表达。结果显示新狼毒素A以时间剂量依赖性的方式显著抑制A375细胞的增殖;不同浓度新狼毒素A(0、15、30、45μmol/L)作用于A375细胞48h后细胞出现显著凋亡特征,新狼毒素A增加A375细胞的凋亡率且降低了线粒体膜电位,上调Bax、caspase-3和细胞色素C(CytochromeC)蛋白的表达,下调Bcl-2蛋白的表达。以上结果说明新狼毒素A抑制A375细胞增殖,诱导细胞凋亡,其机制可能与诱导线粒体途径的凋亡有关。 相似文献
996.
997.
Hayashi C Rittling S Hayata T Amagasa T Denhardt D Ezura Y Nakashima K Noda M 《Journal of cellular biochemistry》2007,101(4):979-986
Tumor malignancy is associated with several features such as proliferation ability and frequency of metastasis. Since tumor metastasis shortens patients' lifetime, establishment of therapy for anti-metastasis is very important. Osteopontin (OPN), which abundantly expressed in bone matrix, is involved in cell adhesion, migration, extracellular matrix (ECM) invasion and cell proliferation via interaction with its receptor, that is, alphavbeta3 integrin. OPN is believed to be a positive regulator of tumor metastasis in vivo. However, how OPN regulates metastasis is largely unknown. Here, we explore the role of OPN in cell migration. Serum from wild-type mice induced cell migration of B16 melanoma cells, while serum from OPN-deficient mouse suppressed this event. The presence of recombinant OPN significantly enhanced cell migration compared to albumin containing medium. OPN-induced cell migration was suppressed by inhibiting the ERK/MAPK pathway indicating that OPN-induced cell migration depends on this pathway. Overexpression of OPN in these cancer cells per se promoted cell proliferation and tended to increase B16 cell migration suggesting that OPN promotes bone metastasis by playing dual roles both in host microenvironment and in tumor cell itself. In conclusion, the elevated OPN expression in host tissue and tumor cell itself promotes tumor cell migration reading to tumor metastasis, suggesting that neutralization of OPN-induced signal might be effective in suppression of tumor metastasis. 相似文献
998.
Hua Tang Xiaopeng Xu Weirong Xiao Yangying Liao Xiao Xiao Lan Li Ke Li Xiaomin Jia Hao Feng 《Journal of cellular biochemistry》2019,120(8):13262-13274
Melanoma is considered as an aggressive neoplastic transformation and featured with high metastatic potential. Although some studies have provided targets for novel therapeutic interventions, clinical development of targeted drugs for melanoma still remains obscure. Therefore, this study aims to identify the role of microRNA-27a (miR-27a) in autophagy and apoptosis of melanoma cells in regulating spleen tyrosine kinase (SYK)-mediated the mammalian target of rapamycin (mTOR) signaling pathway. A microarray-based analysis was made to screen differentially expressed genes and predict target miRNA. Melanoma specimens were collected with pigmented nevus as a control. Melanoma cell line Mel-RM was treated with miR-27a inhibitor or pcDNA-SYK to prove their effects on autophagy and apoptosis of melanoma cells. The volume change and tumor mass of nude mice in each group were detected by the tumorigenesis assay. Microarray-based analysis results showed that SYK was lowly expressed in melanoma cells and may be regulated by miR-27a. Besides, miR-27a expression was increased whereas SYK expression was decreased in melanoma tissues. Meanwhile, miR-27a was positively correlated with tumor stage and lymph node metastasis of melanoma tissues. Furthermore, miR-27a targeted SYK and silencing of miR-27a or overexpression of SYK cells promoted autophagy and apoptosis of melanoma cells and reduced their tumorigenic ability in vivo. In conclusion, this study proves that silencing of miR-27a facilitates autophagy and apoptosis of melanoma cells by upregulating SYK expression and activating the mTOR signaling pathway. The finding offers new ideas for the clinical development of melanoma. 相似文献
999.
Mohanalaxmi Indramohan Christian Stehlik Andrea Dorfleutner 《Journal of molecular biology》2018,430(2):153-173
Sensing and responding to pathogens and tissue damage is a core mechanism of innate immune host defense, and inflammasomes represent a central cytosolic pattern recognition receptor pathway leading to the generation of the pro-inflammatory cytokines interleukin-1β and interleukin-18 and pyroptotic cell death that causes the subsequent release of danger signals to propagate and perpetuate inflammatory responses. While inflammasome activation is essential for host defense, deregulated inflammasome responses and excessive release of inflammatory cytokines and danger signals are linked to an increasing spectrum of inflammatory diseases. In this review, we will discuss recent developments in elucidating the role of PYRIN domain-only proteins (POPs) and the related CARD-only proteins (COPs) in regulating inflammasome responses and their impact on inflammatory disease. 相似文献
1000.
Mechanisms of MAVS Regulation at the Mitochondrial Membrane 总被引:1,自引:0,他引:1
Mitochondria have emerged as critical platforms for antiviral innate immune signaling. This is due in large part to the mitochondrial localization of the innate immune signaling adaptor MAVS (mitochondrial antiviral signaling protein), which coordinates signals received from two independent cytosolic pathogen recognition receptors (PRRs) to induce antiviral genes. The existence of a shared adaptor for two central PRRs presents an ideal target by which the host cell can prevent cellular damage induced by uncontrolled inflammation through alteration of MAVS expression and/or signaling. In this review, we focus on the MAVS regulome and review the cellular factors that regulate MAVS by (1) protein–protein interactions, (2) alterations in mitochondrial dynamics, and/or (3) post-translational modifications. 相似文献