期刊文献+
共找到4篇文章
< 1 >
每页显示 20 50 100
Improved potency of F10 relative to 5-fluorouracil in colorectal cancer cells with p53 mutations 被引量:2
1
作者 Anthony Dominijanni William H.Gmeiner 《Cancer Drug Resistance》 2018年第1期48-58,共11页
Aim:Resistance to fluoropyrimidine drugs(FPs)is a major cause of mortality in colorectal cancer(CRC).We assessed the potency advantage of the polymeric FP F10 relative to 5-fluorouracil(5-FU)in four human CRC cell lin... Aim:Resistance to fluoropyrimidine drugs(FPs)is a major cause of mortality in colorectal cancer(CRC).We assessed the potency advantage of the polymeric FP F10 relative to 5-fluorouracil(5-FU)in four human CRC cell lines that differ only in TP53 mutational status to determine how p53 mutations affect drug response and whether F10 is likely to improve outcomes.Methods:HCT-116 human CRC cells(p53^(+/+))and three isogenic variants(p53^(-/-),R248W/+,R248W/-)were assessed for drug response.Resistance factors were derived from cell viability data and used to establish the relative potency advantage for F10.Rescue studies with exogenous uridine/thymidine determined if cytotoxicity resulted from DNA-directed processes.Results:Significant resistance to 5-FU resulted from p53-loss or from gain-of-function(GOF)mutation(R248W)and was greatest when GOF mutation was coupled with loss of wild-type p53.F10 is much more potent than 5-FU(137-314-fold depending on TP53 mutational status).F10 and 5-FU induce apoptosis by DNA-and RNA-directed mechanisms,respectively,and only F10 shows a modest enhancement in cytotoxicity upon co-treatment with leucovorin.Conclusion:TP53 mutational status affects inherent sensitivity to FPs,with p53 GOF mutations most deleterious.F10 is much more effective than 5-FU regardless of TP53 mutations and has potential to be effective to CRC that is resistant to 5-FU due,in part,to TP53 mutations. 展开更多
关键词 FLUOROPYRIMIDINE colorectal cancer P53 drug resistance
原文传递
scLM:Automatic Detection of Consensus Gene Clusters Across Multiple Single-cell Datasets 被引量:2
2
作者 Qianqian Song Jing Su +1 位作者 Lance D.Miller Wei Zhang 《Genomics, Proteomics & Bioinformatics》 SCIE CAS CSCD 2021年第2期330-341,共12页
In gene expression profiling studies,including single-cell RNA sequencing(scRNA-seq)analyses,the identification and characterization of co-expressed genes provides critical information on cell identity and function.Ge... In gene expression profiling studies,including single-cell RNA sequencing(scRNA-seq)analyses,the identification and characterization of co-expressed genes provides critical information on cell identity and function.Gene co-expression clustering in scRNA-seq data presents certain challenges.We show that commonly used methods for single-cell data are not capable of identifying co-expressed genes accurately,and produce results that substantially limit biological expectations of co-expressed genes.Herein,we present single-cell Latent-variable Model(scLM),a gene coclustering algorithm tailored to single-cell data that performs well at detecting gene clusters with significant biologic context.Importantly,scLM can simultaneously cluster multiple single-cell datasets,i.e.,consensus clustering,enabling users to leverage single-cell data from multiple sources for novel comparative analysis.scLM takes raw count data as input and preserves biological variation without being influenced by batch effects from multiple datasets.Results from both simulation data and experimental data demonstrate that scLM outperforms the existing methods with considerably improved accuracy.To illustrate the biological insights of scLM,we apply it to our in-house and public experimental scRNA-seq datasets.scLM identifies novel functional gene modules and refines cell states,which facilitates mechanism discovery and understanding of complex biosystems such as cancers.A user-friendly R package with all the key features of the scLM method is available at https://github.com/QSong-github/scLM. 展开更多
关键词 Single-cell RNA sequencing Consensus clustering Latent space Markov Chain Monte Carlo Maximum likelihood approach
原文传递
Entrapment of DNA topoisomerase-DNA complexes by nucleotide/nucleoside analogs 被引量:1
3
作者 William H.Gmeiner 《Cancer Drug Resistance》 2019年第4期994-1001,共8页
Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1(Top1)is the sole target of the camptothecin(CPT)class of anticancer drugs.Over the last 20 years,multiple studies have shown To... Topoisomerases are well-validated targets for cancer chemotherapy and DNA topoisomerase 1(Top1)is the sole target of the camptothecin(CPT)class of anticancer drugs.Over the last 20 years,multiple studies have shown Top1 activity is modulated by non-native DNA structures and this can lead to trapping of Top1 cleavage complexes(Top1cc)and conversion to DNA double strand breaks.Among the perturbations to DNA structure that generate Top1cc are nucleoside analogs that are incorporated into genomic DNA during replication including cytarabine,gemcitabine,and 5-fluoro-2’-deoxyuridine(FdU).We review the literature summarizing the role of Top1cc in mediating the DNA damaging and cytotoxic activities of nucleoside analogs.We also summarize studies demonstrating distinct differences between Top1cc induced by nucleoside analogs and CPTs,particularly with regard to DNA repair.Collectively,these studies demonstrate that,while Top1 is a common target for both Top1 poisons such as CPT and nucleoside analogs such as FdU,these agents are not redundant.In recent years,studies have shown that Top1 poisons and nucleoside analogs together with other anti-cancer drugs such as cisplatin cause replication stress and the DNA repair pathways that modulate the cytotoxic activities of these compounds are being elucidated.We present an overview of this evolving literature,which has implications for how targeting of Top1 with nucleoside analogs can be used more effectively for cancer treatment. 展开更多
关键词 DNA topoisomerase 1 cancer chemotherapy CYTARABINE GEMCITABINE FLUOROPYRIMIDINE
原文传递
Targeting DNA topoisomerases: past & future
4
作者 William H.Gmeiner Robert C.A.Mvan Waardenburg 《Cancer Drug Resistance》 2021年第4期758-761,共4页
Aggressive malignancies are characterized by relatively uncontrolled cell proliferation making them especially reliant on topoisomerase enzymes to enable high rates of DNA replication and transcription.DNA topoisomera... Aggressive malignancies are characterized by relatively uncontrolled cell proliferation making them especially reliant on topoisomerase enzymes to enable high rates of DNA replication and transcription.DNA topoisomerases resolve topological problems associated with DNA replication and other essential cellular processes involving DNA,such as transcription and recombination^([1]).As such,they are important targets for anti-cancer therapeutics.Further,understanding of topoisomerase biology is important for unraveling the mechanistic basis for resistance to many widely used anti-cancer drugs,such as doxorubicin,etoposide,and topotecan,for which DNA topoisomerases are established targets.Interestingly,several drugs that are not considered to directly target topoisomerase enzymes,such as the nucleoside analogs 5-FU and AraC,and those in development such as the polymeric fluoropyrimidine CF10^([2]),also affect the function of topoisomerases. 展开更多
关键词 ANALOGS TOPOLOGICAL enable
原文传递
上一页 1 下一页 到第
使用帮助 返回顶部