全文获取类型
收费全文 | 1115篇 |
免费 | 161篇 |
国内免费 | 25篇 |
出版年
2024年 | 3篇 |
2023年 | 44篇 |
2022年 | 32篇 |
2021年 | 40篇 |
2020年 | 69篇 |
2019年 | 109篇 |
2018年 | 68篇 |
2017年 | 46篇 |
2016年 | 54篇 |
2015年 | 64篇 |
2014年 | 92篇 |
2013年 | 126篇 |
2012年 | 62篇 |
2011年 | 68篇 |
2010年 | 52篇 |
2009年 | 43篇 |
2008年 | 43篇 |
2007年 | 24篇 |
2006年 | 28篇 |
2005年 | 18篇 |
2004年 | 22篇 |
2003年 | 8篇 |
2002年 | 23篇 |
2001年 | 18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 | 4篇 |
1987年 | 5篇 |
1986年 | 1篇 |
1985年 | 4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1301条查询结果,搜索用时 15 毫秒
141.
Das A Pushparaj C Bahí N Sorolla A Herreros J Pamplona R Vilella R Matias-Guiu X Martí RM Cantí C 《Pigment cell & melanoma research》2012,25(2):200-212
The expression of voltage-gated calcium channels (VGCCs) has not been reported previously in melanoma cells in spite of increasing evidence of a role of VGCCs in tumorigenesis and tumour progression. To address this issue we have performed an extensive RT-PCR analysis of VGCC expression in human melanocytes and a range of melanoma cell lines and biopsies. In addition, we have tested the functional expression of these channels using Ca(2+) imaging techniques and examined their relevance for the viability and proliferation of the melanoma cells. Our results show that control melanocytes and melanoma cells express channel isoforms belonging to the Ca(v) 1 and Ca(v) 2 gene families. Importantly, the expression of low voltage-activated Ca(v) 3 (T-type) channels is restricted to melanoma. We have confirmed the function of T-type channels as mediators of constitutive Ca(2+) influx in melanoma cells. Finally, pharmacological and gene silencing approaches demonstrate a role for T-type channels in melanoma viability and proliferation. These results encourage the analysis of T-type VGCCs as targets for therapeutic intervention in melanoma tumorigenesis and/or tumour progression. 相似文献
142.
Yang XR Brown K Landi MT Ghiorzo P Badenas C Xu M Hayward NK Calista D Landi G Bruno W Bianchi-Scarrà G Aguilera P Puig S Goldstein AM Tucker MA 《Pigment cell & melanoma research》2012,25(2):243-247
Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity α) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggest that the alteration of CXC chemokine genes may confer susceptibility to melanoma. 相似文献
143.
B-RAF inhibitors (BRAFi) have been shown to improve rates of overall and progression-free survival in patients with stage IV metastatic melanoma positive for the BRAF V600E mutation. However, the main drawback is the development of verrucal keratosis (hyperkeratotic papules with verruca-like characteristics with benign histological findings) and cutaneous squamous cell carcinomas (cuSCC). We have found upstream mutations in RAS as well as PIK3CA in both verrucal keratosis and cuSCC. This suggests that verrucal keratosis is an early clinical presentation of cuSCC in patients on BRAFi. 相似文献
144.
Tumors create a unique immunosuppressive microenvironment (tumor microenvironment, TME) whereby leukocytes are recruited into the tumor by various chemokines and growth factors. However, once in the TME, these cells lose the ability to promote anti-tumor immunity and begin to support tumor growth and down-regulate anti-tumor immune responses. Studies on tumor-associated leukocytes have mainly focused on cells isolated from tumor-draining lymph nodes or spleen due to the inherent difficulties in obtaining sufficient cell numbers and purity from the primary tumor. While identifying the mechanisms of cell activation and trafficking through the lymphatic system of tumor bearing mice is important and may give insight to the kinetics of immune responses to cancer, in our experience, many leukocytes, including dendritic cells (DCs), in tumor-draining lymph nodes have a different phenotype than those that infiltrate tumors. Furthermore, we have previously demonstrated that adoptively-transferred T cells isolated from the tumor-draining lymph nodes are not tolerized and are capable of responding to secondary stimulation in vitro unlike T cells isolated from the TME, which are tolerized and incapable of proliferation or cytokine production. Interestingly, we have shown that changing the tumor microenvironment, such as providing CD4(+) T helper cells via adoptive transfer, promotes CD8(+) T cells to maintain pro-inflammatory effector functions. The results from each of the previously mentioned studies demonstrate the importance of measuring cellular responses from TME-infiltrating immune cells as opposed to cells that remain in the periphery. To study the function of immune cells which infiltrate tumors using the Miltenyi Biotech isolation system, we have modified and optimized this antibody-based isolation procedure to obtain highly enriched populations of antigen presenting cells and tumor antigen-specific cytotoxic T lymphocytes. The protocol includes a detailed dissection of murine prostate tissue from a spontaneous prostate tumor model (TRansgenic Adenocarcinoma of the Mouse Prostate -TRAMP) and a subcutaneous melanoma (B16) tumor model followed by subsequent purification of various leukocyte populations. 相似文献
145.
146.
147.
148.
Vijay Alla Bhavani S. Kowtharapu David Engelmann Stephan Emmrich Ulf Schmitz Marc Steder Brigitte M. Pützer 《Cell cycle (Georgetown, Tex.)》2012,11(16):3067-3078
Resistance to anti-neoplastic agents is the major cause of therapy failure, leading to disease recurrence and metastasis. E2F1 is a strong inducer of apoptosis in response to DNA damage through its capacity to activate p53/p73 death pathways. Recent evidence, however, showed that E2F1, which is aberrantly expressed in advanced malignant melanomas together with antagonistic p73 family members, drives cancer progression. Investigating mechanisms responsible for dysregulated E2F1 losing its apoptotic function, we searched for genomic signatures in primary and late clinical tumor stages to allow the prediction of downstream effectors associated with apoptosis resistance and survival of aggressive melanoma cells. We identified miR-205 as specific target of p73 and found that upon genotoxic stress, its expression is sufficiently abrogated by endogenous DNp73. Significantly, metastatic cells can be rescued from drug resistance by selective knockdown of DNp73 or overexpression of miR-205 in p73-depleted cells, leading to increased apoptosis and the reduction of tumor growth in vivo. Our data delineate an autoregulatory circuit, involving high levels of E2F1 and DNp73 to downregulate miR-205, which, in turn, controls E2F1 accumulation. Finally, drug resistance associated to this genetic signature is mediated by removing the inhibitory effect of miR-205 on the expression of Bcl-2 and the ATP-binding cassette transporters A2 (ABCA2) and A5 (ABCA5) related to multi-drug resistance and malignant progression. These results define the E2F1-p73/DNp73-miR-205 axis as a crucial mechanism for chemoresistance and, thus, as a target for metastasis prevention. 相似文献
149.
Yingbin GE Rikka AZUMA Bethsebah GEKONGE Alfonso LOPEZ-CORAL Min XIAO Gao ZHANG Xiaowei XU Luis J. MONTANER Zhi WEI Meenhard HERLYN Tao WANG Russel E. KAUFMAN 《生物学前沿》2012,7(4):359-367
Tumor-associated macrophages (TAMs) play a critical role in melanoma growth and metastasis.Infiltration of TAMs correlates with the poor prognosis of melanoma.TAMs are differentiated from monocytes in ... 相似文献
150.
Pshenichnaya I Schouwey K Armaro M Larue L Knoepfler PS Eisenman RN Trumpp A Delmas V Beermann F 《Pigment cell & melanoma research》2012,25(3):312-325
c-Myc is involved in the control of diverse cellular processes and implicated in the maintenance of different tissues including the neural crest. Here, we report that c-Myc is particularly important for pigment cell development and homeostasis. Targeting c-Myc specifically in the melanocyte lineage using the floxed allele of c-Myc and Tyr::Cre transgenic mice results in a congenital gray hair phenotype. The gray coat color is associated with a reduced number of functional melanocytes in the hair bulb and melanocyte stem cells in the hair bulge. Importantly, the gray phenotype does not progress with time, suggesting that maintenance of the melanocyte through the hair cycle does not involve c-Myc function. In embryos, at E13.5, c-Myc-deficient melanocyte precursors are affected in proliferation in concordance with a reduction in numbers, showing that c-Myc is required for the proper melanocyte development. Interestingly, melanocytes from c-Myc-deficient mice display elevated levels of the c-Myc paralog N-Myc. Double deletion of c-Myc and N-Myc results in nearly complete loss of the residual pigmentation, indicating that N-Myc is capable of compensating for c-Myc loss of function in melanocytes. 相似文献