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        Dual-Responsive Cross-Linked Micelles from Amphiphilic Four-Arm Star Copolymers with Different Block Ratios for Triggering DOX Release

        Yunwei Huang,Yanzhe Li,Zilun Tang,Qiuping Su,Tingting Liao,Yuxin Gu,Xiaofeng Lin,Xihong Zu,Wenjing Lin,Guobin Yi 한국고분자학회 2020 Macromolecular Research Vol.28 No.8

        The four-arm star copolymers poly(methacrylic acid)-poly(2-hydroxyethyl methacrylate-disulfide~)-poly(poly(ethylene glycol) methyl ether methacrylate) (4AS-PMAAx-(PHEMA-SS~)y-PPEGMAz) with four different block ratios were synthesized and could self-assembled into cross-linked polymer micelles for the exploration of the structure-property relationship. The cross-linked polymer micelles in aqueous solution had low critical micelle concentration (CMC) values (1.9-4.6 mg/L), which exhibited better stability than non-cross-linked micelles. The CMC value decreased with the increase of the length of inner PMAA core and hydrophobic PHEMA cross-linked middle layer. The blank and doxorubicin (DOX)- loaded micelles with different block ratios were prepared by dialysis with the particle sizes of 120-240 nm. The longer inner PMAA core and cross-linked middle layer enhanced the drug loading content (DLC) results and led to relatively bigger particle sizes of polymer micelles. The in vitro DOX release data revealed that DOX-loaded micelles had low DOX cumulative release percentages of 18-37% after 110 h at pH 7.4, but up to 83-90% when introducing reductant GSH at pH 5.0. The 4AS-PMAA21.2-(PHEMASS~) 13.1-PPEGMA5.1 micelles with the longest PMAA core had the largest cumulative release of 90.1%. The DOX release process and mechanism of the micelles at different conditions fitted well with the semi-empirical equation. Overall, the results demonstrated that the block ratios and pH/redox-responsiveness of these four-arm star copolymers could be well-controlled and their self-assembled cross-linked micelles as anticancer drug carrier system could be improved by optimizing the different ratios.

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        Alternative splicing of PSMD13 mediated by genetic variants is significantly associated with endometrial cancer risk

        Sisi He,Rong Cao,Yan Mao,Na Li,Yanzhe Wang,Hu Ma,Kunming Tian 대한부인종양학회 2023 Journal of Gynecologic Oncology Vol.34 No.3

        Objective: Accumulating evidence has shown that aberrant alternative splicing events are closely associated with the onset and development of cancer. However, whether genetic variants-associated alternative splicing is linked to risk of endometrial cancer remains largely uncertain. Methods: We identified single nucleotide polymorphisms (SNPs) locates in the splicing number trait locus (sQTL) of endometrial cancer using the CancerSplicing QTL database. In parallel with bioinformatics analysis, we conducted a case-control study comprising 2,000 cases and 2,013 controls to assess the association between identified SNP which possesses mRNA splicing function and endometrial cancer susceptibility. Furthermore, we used the Kaplan-Meier Plotter, The Human Protein Atlas, SPNR, and Spliceman2 databases for sQTL and differential gene expression analyses to identify the genetic variant which most potentially influence the risk of endometrial cancer through alternative splicing to reveal the potential mechanism by which candidate SNPs regulate the risk of endometrial cancer. Results: The results indicated that SNP rs7128029 A<G was significantly associated with an increased risk of endometrial cancer (odds ratio=1.384; 95% confidence interval=1.038–1.964). Moreover, the carcinogenic effect of SNP rs7128029 A<G was consistently revealed by propensity matching analysis, an additive model, and a dominant model. Importantly, sQTL analysis showed that SNP rs7128029 could affect the transcriptional modification of PSMD13 via regulating the exon skipping of PSMD13. When the rs7128029 allele was mutated from A to G, the expression of exon 2 of PSMD13 was markedly lower (p<0.001). Furthermore, compared with participants who had higher PSMD13 expression, those who had lower PSMD13 expression had shorter survival times. Conclusion: These findings suggest that SNP rs7128029-mediated alternative splicing events in PSMD13 are associated with endometrial cancer risk and may be a potential early screening biomarker for endometrial cancer-susceptible populations.

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