全文获取类型
收费全文 | 1622篇 |
免费 | 194篇 |
国内免费 | 41篇 |
出版年
2024年 | 4篇 |
2023年 | 57篇 |
2022年 | 47篇 |
2021年 | 71篇 |
2020年 | 104篇 |
2019年 | 161篇 |
2018年 | 97篇 |
2017年 | 58篇 |
2016年 | 68篇 |
2015年 | 92篇 |
2014年 | 123篇 |
2013年 | 165篇 |
2012年 | 84篇 |
2011年 | 83篇 |
2010年 | 70篇 |
2009年 | 55篇 |
2008年 | 69篇 |
2007年 | 48篇 |
2006年 | 49篇 |
2005年 | 29篇 |
2004年 | 45篇 |
2003年 | 19篇 |
2002年 | 35篇 |
2001年 | 26篇 |
2000年 | 17篇 |
1999年 | 18篇 |
1998年 | 17篇 |
1997年 | 11篇 |
1996年 | 16篇 |
1995年 | 11篇 |
1994年 | 18篇 |
1993年 | 16篇 |
1992年 | 11篇 |
1991年 | 9篇 |
1990年 | 5篇 |
1989年 | 9篇 |
1988年 | 5篇 |
1987年 | 9篇 |
1986年 | 2篇 |
1985年 | 6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1857条查询结果,搜索用时 15 毫秒
51.
《Cell cycle (Georgetown, Tex.)》2013,12(7):1071-1082
As DNA damage checkpoints are barriers to carcinogenesis, G2 checkpoint function was quantified to test for override of this checkpoint during melanomagenesis. Primary melanocytes displayed an effective G2 checkpoint response to ionizing radiation (IR)-induced DNA damage. Thirty-seven percent of melanoma cell lines displayed a significant defect in G2 checkpoint function. Checkpoint function was melanoma subtype-specific with “epithelial-like” melanoma lines, with wild type NRAS and BRAF displaying an effective checkpoint, while lines with mutant NRAS and BRAF displayed defective checkpoint function. Expression of oncogenic B-Raf in a checkpoint-effective melanoma attenuated G2 checkpoint function significantly but modestly. Other alterations must be needed to produce the severe attenuation of G2 checkpoint function seen in some BRAF-mutant melanoma lines. Quantitative trait analysis tools identified mRNA species whose expression was correlated with G2 checkpoint function in the melanoma lines. A 165 gene signature was identified with a high correlation with checkpoint function (p < 0.004) and low false discovery rate (≤ 0.077). The G2 checkpoint gene signature predicted G2 checkpoint function with 77–94% accuracy. The signature was enriched in lysosomal genes and contained numerous genes that are associated with regulation of chromatin structure and cell cycle progression. The core machinery of the cell cycle was not altered in checkpoint-defective lines but rather numerous mediators of core machinery function were. When applied to an independent series of primary melanomas, the predictive G2 checkpoint signature was prognostic of distant metastasis-free survival. These results emphasize the value of expression profiling of primary melanomas for understanding melanoma biology and disease prognosis. 相似文献
52.
《Cell Adhesion & Migration》2013,7(3):220-230
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that participate in the structural and functional maintenance of connective tissues under normal homeostasis. They also act as trophic mediators during tissue repair, generating bioactive molecules that help in tissue regeneration following injury. MSCs serve comparable roles in cases of malignancy and are becoming increasingly appreciated as critical components of the tumor microenvironment. MSCs home to developing tumors with great affinity, where they exacerbate cancer cell proliferation, motility, invasion and metastasis, foster angiogenesis, promote tumor desmoplasia and suppress anti-tumor immune responses. These multifaceted roles emerge as a product of reciprocal interactions occurring between MSCs and cancer cells and serve to alter the tumor milieu, setting into motion a dynamic co-evolution of both tumor and stromal tissues that favors tumor progression. Here, we summarize our current knowledge about the involvement of MSCs in cancer pathogenesis and review accumulating evidence that have placed them at the center of the pro-malignant tumor stroma. 相似文献
53.
Angela Poehlmann Kathrin Reissig Peter Schönfeld Diana Walluscheck Antje Schinlauer Roland Hartig Wiebke Lessel Thomas Guenther Andrew Silver Albert Roessner 《Journal of cellular and molecular medicine》2013,17(12):1619-1631
The production of hydrogen peroxide (H2O2) drives tumourigenesis in ulcerative colitis (UC). Recently, we showed that H2O2 activates DNA damage checkpoints in human colonic epithelial cells (HCEC) through c‐Jun N‐terminal Kinases (JNK) that induces p21WAF1. Moreover, caspases circumvented the G1/S and intra‐S checkpoints, and cells accumulated in G2/M. The latter observation raised the question of whether repeated H2O2 exposures alter JNK activation, thereby promoting a direct passage of cells from G2/M arrest to driven cell cycle progression. Here, we report that increased proliferation of repeatedly H2O2‐exposed HCEC cells (C‐cell cultures) was associated with (i) increased phospho‐p46 JNK, (ii) decreased total JNK and phospho‐p54 JNK and (iii) p21WAF1 down‐regulation. Altered JNK activation and p21WAF1 down‐regulation were accompanied by defects in maintaining G2/M and mitotic spindle checkpoints through adaptation, as well as by apoptosis resistance following H2O2 exposure. This may cause increased proliferation of C‐cell cultures, a defining initiating feature in the inflammation‐carcinoma pathway in UC. We further suggest that dysregulated JNK activation is attributed to a non‐apoptotic function of caspases, causing checkpoint adaptation in C‐cell cultures. Additionally, loss of cell‐contact inhibition and the overcoming of senescence, hallmarks of cancer, contributed to increased proliferation. Furthermore, there was evidence that p54 JNK inactivation is responsible for loss of cell‐contact inhibition. We present a cellular model of UC and suggest a sinusoidal pattern of proliferation, which is triggered by H2O2‐induced reactive oxygen species generation, involving an interplay between JNK activation/inactivation, p21WAF1, c‐Fos, c‐Jun/phospho‐c‐Jun, ATF2/phospho‐ATF2, β‐catenin/TCF4‐signalling, c‐Myc, CDK6 and Cyclin D2, leading to driven cell cycle progression. 相似文献
54.
Simona Cinta Pinzaru Alexandra Falamas Cristina Adriana Dehelean 《Journal of cellular and molecular medicine》2013,17(2):277-286
An interdisciplinary approach employing functionalized nanoparticles and ultrasensitive spectroscopic techniques is reported here to track the molecular changes in early stage of malignancy. Melanoma tissue tracking at molecular level using both labelled and unlabelled silver and gold nanoparticles has been achieved using surface enhanced Raman scattering (SERS) technique. We used skin tissue from ex vivo mice with induced melanoma. Raman and SERS molecular characterization of melanoma tissue is proposed here for the first time. Optical nanosensors based on Ag and Au nanoparticles with chemisorbed cresyl violet molecular species as labels revealed sensitive capability to tissues tagging and local molecular characterization. Sensitive information originating from surrounding native biological molecules is provided by the tissue SERS spectra obtained either with visible or NIR laser line. Labelled nanoparticles introduced systematic differences in tissue response compared with unlabelled ones, suggesting that the label functional groups tag specific tissue components revealed by proteins or nucleic acids bands. Vibrational data collected from tissue are presented in conjunction with the immunohistochemical analysis. The results obtained here open perspectives in applied plasmonic nanoparticles and SERS for the early cancer diagnostic based on the appropriate spectral databank. 相似文献
55.
Jing Li Rui Yang Haijie Yang Sujuan Chen Lei Wang Man Li Shaokui Yang Zhiwei Feng Jiajia Bi 《Journal of cellular biochemistry》2020,121(2):1192-1204
The neural cell adhesion molecule (NCAM) plays critical roles in multiple cellular processes in neural cells, mesenchymal stem cells, and various cancer cells. However, the effect and mechanism of NCAM in human melanoma cells are still unclear. In this study, we found that NCAM regulated the proliferation, apoptosis, autophagy, migration, and epithelial-to-mesenchymal transition of human melanoma cells by determining the biological behavior of NCAM knockdown A375 and M102 human melanoma cells. Further studies revealed that NCAM knockdown impaired the organization of actin cytoskeleton and reduced the phosphorylation of cofilin, an actin-cleaving protein. When cells were transfected with cofilin S3A (dephosphorylated cofilin), biological behavior similar to that of NCAM knockdown cells was observed. Research on the underlying molecular mechanism showed that NCAM knockdown suppressed activation of the Src/Akt/mTOR pathway. Specific inhibitors of Src and PI3K/Akt were employed to further verify the relationship between Src/Akt/mTOR signaling and cofilin, and the results showed that the phosphorylation level of cofilin decreased following inhibition of the Src/Akt/mTOR pathway. These results indicated that NCAM may regulate the proliferation, apoptosis, autophagy, migration, and epithelial-to-mesenchymal transition of human melanoma cells via the Src/Akt/mTOR/cofilin pathway-mediated dynamics of actin cytoskeleton. 相似文献
56.
Xin Liao Wei Zhan Jiandong Zhang Zhongsheng Cheng Lianghe Li Tian Tian Lei Yu Rui Li 《Journal of cellular biochemistry》2020,121(10):4295-4309
Colorectal cancer is one of the most common and leading malignancies globally. Long noncoding RNAs (lncRNAs) function as potentially critical regulator in colorectal cancer. LINC01234, a novel lncRNA in tumor biology, regulates the progression of various tumors. However, the tumorigenic mechanism of LINC01234 in colorectal cancer is still unclear. This study was performed with the aim to prospectively investigate clinical significance, effect, and mechanism of lncRNA LINC01234 in colorectal cancer. First, we found that LINC01234, localized in the cytoplasm, was increased in both colorectal cancer cell lines and tissues. Subsequent functional assays suggested LINC01234 knockdown suppressed cell proliferation, migration, and invasion of colorectal cancer cells, while blocked cell cycle and induced cell apoptosis. Moreover, we identified that miR-1284 was target of LINC01234, we further demonstrated a negative correlation with LINC01234 in colorectal cancer tissues and cells. Furthermore, miR-1284 targeted and suppressed tumor necrosis factor receptor–associated factor 6 (TRAF6). Loss-of-function assay revealed that LINC01234 silencing suppressed colorectal cancer progression through inhibition of miR-1284. In vivo subcutaneous xenotransplanted tumor model indicated LINC01234 knockdown inhibited in vivo tumorigenic ability of colorectal cancer via downregulation of TRAF6. Collectively, this study clarified the biological significance of LINC01234/miR-1284/TRAF6 axis in colorectal cancer progression, providing insights into LINC01234 as novel potential therapeutic target for colorectal cancer therapeutic from bench to clinic. 相似文献
57.
Yu Yang Fangyi Zhang Hang Huang Zhiyue Xie Weiping Huang Hui Xie Feng Wang 《Journal of cellular physiology》2020,235(4):3768-3775
Growing reports indicate that long noncoding RNA (lncRNA) are involved in the regulation of various biological processes of cancer cells. LINC00319 is an ill investigated lncRNA and has been shown to regulate lung cancer, nasopharyngeal carcinoma and ovarian cancer. Nevertheless, its roles in bladder cancer (BCa) remain unclear. In our research, LINC00319 was shown to be an upregulated lncRNA in BCa tissues. LINC00319 expression is negatively correlated with the patient's prognosis. Silencing of LINC00319 suppressed BCa proliferation and invasiveness. In addition, the data indicated LINC00319 was a sponge for miR-4492 and miR-4492 suppressed ROMO1 expression in BCa. Furthermore, our results illustrated miR-4492/ROMO1 axis regulates proliferation, migration, and invasion and LINC00319 exerts oncogenic roles through modulating miR-4492/ROMO1 axis. In sum, this study suggested that LINC00319 acts as oncogenic roles in BCa progression. 相似文献
58.
59.
Fadwa Chaabane Aline Pinon Alain Simon Kamel Ghedira Leila Chekir-Ghedira 《Cell biochemistry and function》2013,31(6):460-467
In this study, we have investigated inhibitory capacity of ethyl acetate, total oligomer flavonoid (TOF), aqueous extracts and beta amyrin acetate, a triterpene isolated from ethyl acetate extract obtained from leaves of Daphne gnidium, on mouse melanoma (B16-F0 and B16-F10 cells) proliferation. Influence of these products on percentage cell distribution in cycle phases and melanogenesis was also studied. Cell viability was determined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and flow cytometry was used to analyse effects of tested compounds on progression through the cell cycle. In addition, amounts of melanin and tyrosinase were measured spectrophotometrically at 475 nm. Ethyl acetate, TOF and aqueous extracts exhibited significant anti-proliferative activity after incubation with the two types of tumour skin cells B16-F0 and B16-F10. Furthermore, cell cycle analysis revealed that cells treated with ethyl acetate and TOF extracts were arrested predominantly in G2-M phase. Ethyl acetate extract has also the ability to enhance melanogenesis and tyrosinase activity of B16-F0 melanoma cells. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
60.
4-Hydroxynonenal (HNE) is the most studied end product of the lipoperoxidation process, by virtue of its relevant biological activity. The antiproliferative and proapoptotic effects of HNE have been widely demonstrated in a great variety of tumor cell types in vitro. Thus, it might represent a promising new molecule in anticancer therapy strategies. However, the extreme reactivity of this aldehyde, as well as its insolubility in water, a limiting factor for drug bioavailability, and its rapid degradation by specific enzymes represent major obstacles to its possible in vivo application. Various strategies can used to overcome these problems. One of the most attractive strategies is the use of nanovehicles, because loading drugs into nanosized structures enhances their stability and solubility, thus improving their bioavailability and their antitumoral effectiveness. Several natural or synthetic polymers have been used to synthesize nanosized structures and, among them, β-cyclodextrin (βCD) polymers are playing a very important role in drug formulation by virtue of the ability of βCD to form inclusion compounds with a wide range of solid and liquid molecules by molecular complexation. Moreover, several βCD derivatives have been designed to improve their physicochemical properties and inclusion capacities. Here we report that the inclusion complex of HNE with a derivative of βCD, the βCD–poly(4-acryloylmorpholine) conjugate (PACM-βCD), enhances the aldehyde stability. Moreover, the inclusion of HNE in PACM-βCD potentiates its antitumor effects in several tumor cell lines and in a more complex system, such as a human reconstructed skin carrying melanoma tumor cells. 相似文献