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Modeling nonlinearity in dilution design microarray data

BIOINFORMATICS 2007年第11期23卷 1339-1347页

作者： Zheng, Xiuwen Huang, Hung-Chung Li, Wenyuan Liu, Peng Li, Quan-Zhen Liu, Ying Univ Texas Dept Math Sci Richardson TX 75083 USA Univ Texas Dept Comp Sci Richardson TX 75083 USA Univ Texas Dept Mol & Cell Biol Richardson TX 75083 USA Iowa State Univ Dept Stat Ames IA 50011 USA Univ Texas Med Ctr Microarray Core Facil Dallas TX 75390 USA

Motivation: Dilution design (Mixed tissue RNA) has been utilized by some researchers to evaluate and assess the performance of multiple microarray platforms. Current microarray data analysis approaches assume that the quantified signal intensities are linearly related to the expression of the corresponding genes in the sample. However, there are sources of nonlinearity in microarray expression measurements. Such nonlinearity study in the expressions of the RNA mixtures provides a new way to analyze gene expression data, and we argue that the nonlinearity can reveal novel information for microarray data analysis. Therefore, we proposed a statistical model, called proportion model, which is based on the linear regression analysis. To approximately quantify the nonlinearity in the dilution design, a new calibration, beta ratio (BR) was derived from the proportion model. Furthermore, a new adjusted fold change (adj-FC) was proposed to predict the true FC without nonlinearity, in particular for large FC. Results: We applied our method to one microarray dilution dataset. The experimental results indicated that, to some extent, there are global biases comparing with the linear assumption for the significant genes. Further analysis of those highly expressed genes with significant nonlinearity revealed some promising results, e.g. 'poison' effect was discovered for some genes in RNA mixtures. The adj-FCs of those genes with 'poison' effect, indicate that the nonlinearity can be also caused by the inherent feature of the genes besides signal noise and technical variation. Moreover, when percentage of overlapping genes (POG) was used as a cross-platform consistency measure, adj-FC outperformed simple fold change to show that Affymetrix and Illumina platforms are consistent.

关键词： .intensities microarray data utilized dilution calibration quantified data analysis microarray expression microarray platforms linearly Modeling nonlinearity sources of nonlinearity RNA mixtures beta ratio adj-FC

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The Influence of Salinomycin on the expression Profile of mRNAs Encoding Selected Caspases and MiRNAs Regulating their expression in Endometrial Cancer Cell Line

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CURRENT PHARMACEUTICAL BIOTECHNOLOGY 2020年第14期21卷 1505-1515页

作者： Januszyk, Krzysztof Januszyk, Piotr Grabarek, Beniamin O. Boron, Dariusz Oplawski, Marcin Publ Higher Med Profess Sch Opole Fac Hlth Sci Opole Poland Ludwik Rydygier Mem Specialized Hosp Dept Gynecol & Obstet Gynecol Oncol Krakow Poland Maria Sklodowska Curie Natl Res Inst Oncol Krakow Krakow Poland Univ Technol Fac Med Dept Histol Cytophysiol & Embryol Zabrze Poland

Background: Apoptosis could take place in the pathway dependent on death receptors or pathways dependent on mitochondria. In both, a key role is played by enzymes with protease activity, known as caspases. Aim: The aim of this study was to assess the variances in the expression pattern of caspase-dependent signaling pathways in the endometrial cancer cell line when treated with salinomycin. Additionally, the changes in the level of miRNA that potentially regulate these mRNAs were evaluated. Materials and Methods: Endometrial cancer cells were treated with 1 mu M of salinomycin for 12, 24 and 48 hours. Untreated cells made up the control culture. The molecular analysis consisted of screening mRNA and miRNA microarray expression profiles of caspases, and the evaluation of the expression of caspases 3,8 and 9 by RTqPCR, also on the protein level. Results and Discussion: It was observed that 5 of the 14 differentiating mRNAs were commonly found for all incubation times of the cells and they corresponded with CASP3, CASP8, and CASP9 genes. The highest impact probability was determined between CASP3(up-regulated) and hsa- miR-30d (FC -2.01), CASP8 (down-regulated) and hsa-miR-21 (FC +1.39) and between CASP9 (upregulated) and hsa-miR-1271 (FC +1.71). Conclusion: Salinomycin induces the apoptosis of endometrial cancer cells. The largest increase in activity was noted for caspases 3 and 9, while the expression of caspase 8 was decreased. Salinomycin causes a regulatory effect on the transcriptomes of mRNA and miRNA in in vitro endometrial cancer cells.

关键词： Mitochondria-dependent independent apoptosis pathway salinomycin endometrial cancer miRNA mRNA microarray expression

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The growth inhibitory effect of gambogic acid on pancreatic cancer cells

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NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY 2018年第5期391卷 551-560页

作者： Youns, Mahmoud ElKhoely, Abeer Kamel, Rehab German Canc Res Ctr Dept Funct Genome Anal Neuenheimer Feld 580 D-69120 Heidelberg Germany Oman Pharm Inst Muscat Oman Helwan Univ Dept Biochem & Mol Biol Fac Pharm Cairo Egypt Helwan Univ Dept Pharmacol & Toxicol Fac Pharm Cairo Egypt

Pancreatic cancer, the fourth most common cause of cancer-related deaths, is one of the most aggressive and devastating human malignancies with increasing incidence worldwide. To date, surgical resection is the only potentially curative therapy available for pancreatic cancer patients. Early diagnosis of pancreatic tumors is difficult, and hence, nearly 80% of patients cannot receive surgical resection. Natural products have always been a vital source for novel compounds for cancer treatment. The naturally occurring prenylated xanthone, gambogic acid, has been previously shown to exert potent anticancer, anti-inflammatory, apoptotic, antiangiogenic, and antioxidant activities. However, to our knowledge, there have been no specific studies showing its effect on the whole-genome expression in pancreatic cancer cells. Here, the anticancer activity of gambogic acid toward a panel of pancreatic cancer cells with different differentiation stages has been evaluated. Additionally, a whole-genome transcription profiling study was performed in order to identify possible candidate players modulating the antitumor effect of gambogic acid on pancreatic cancer cells. expression analysis results showed that the pancreatic adenocarcinoma signaling pathway was specifically affected upon gambogic acid treatment. Moreover, the growth inhibitory effect of gambogic acid on pancreatic cancer cells was modulated through up-regulation of DDIT3, DUSP1, and DUSP5 and down-regulation of ALDOA, TOP2A, and ATG4B. The present work is a starting point for the generation of hypotheses on significantly regulated candidate key player genes and for a detailed dissection of the potential role of each individual gene for the activity of gambogic acid on pancreatic cancer.

关键词： Gambogic acid Pancreatic cancer ALDOA Topoisomerase 2A microarray expression

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Human microRNA target identification by RRSM

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JOURNAL OF THEORETICAL BIOLOGY 2011年第1期286卷 79-84页

作者： Hsieh, Wan J. Wang, Hsiuying Natl Chiao Tung Univ Inst Stat Hsinchu Taiwan

MicroRNAs (miRNAs) are small endogenously expressed non-coding RNAs that regulate target messenger RNAs in various biological processes. In recent years, there have been many studies concentrated on the discovery of new miRNAs and identification of their mRNA targets. Although researchers have identified many miRNAs, few miRNA targets have been identified by actual experimental methods. To expedite the identification of miRNA targets for experimental verification, in the literature approaches based on the sequence or microarray expression analysis have been established to discover the potential miRNA targets. In this study, we focus on the human miRNA target prediction and propose a generalized relative R-2 method (RRSM) to find many high-confidence targets. Many targets have been confirmed from previous studies. The targets for several miRNAs discovered by the HITS-CLIP method in a recent study have also been selected by our study. (C) 2011 Elsevier Ltd. All rights reserved.

关键词： microarray expression miRNA Relative R-2 method Regression model Correlation

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Valproic acid as epigenetic cancer drug: Preclinical, clinical and transcriptional effects on solid tumors

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CANCER TREATMENT REVIEWS 2008年第3期34卷 206-222页

作者： Duenas-Gonzalez, Alfonso Candelaria, Myrna Perez-Plascencia, Carlos Perez-Cardenas, Enrique de la Cruz-Hernandez, Erick Herrera, Luis A. Univ Nacl Autonoma Mexico Inst Invest Biomed Unidad Invest Biomed Canc INCan Mexico City 04510 DF Mexico Inst Nacl Cancerol Div Invest Clin Mexico City DF Mexico

Among many anticancer drugs collectively named "targeted or molecular therapies" epigenetic drugs are clearly promising. Differently from other agents targeting a single gene product, epigenetic drugs have chromatin as their target through inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) therefore, yet unspecific, they may act upon most or all tumor types, as deregulation of the methylation and deacetylation machinery are a common hallmark of neoplasia. In the last years, valproic acid (VPA) as emerged as a promising drug for cancer treatment. VPA has shown potent antitumor effects in a variety of in vitro and in vivo systems, and encouraging results in early clinical. trials either atone or in combination with demethylating and/or cytotoxic agents. In addition, whole genome expression by microarray analysis from the primary tumors of patients treated with VPA show significant up-regulation of hundred of genes belonging to multiple pathways including ribosomal proteins, oxidative phosphorylation, MAPK signaling;focal adhesion, cell cycle, antigen processing and presentation, proteasome, apoptosis, PI3K, Wnt signaling, calcium signaling, TGF-beta signaling, and ubiquitin-mediated proteolysis among others. Despite in general, industry is not particularly interested in funding the clinical development of VPA, -at least in comparison to novel HDAC inhibitors-, existing preclinical and preliminary clinical data strongly suggest that VPA could be a drug that eventually will be used in combination therapies, either with classical cytotoxics, other molecular-targeted drugs or radiation in a number of solid tumors. (c) 2007 Elsevier Ltd. All rights reserved.

关键词： valproic acid epigenetic therapy solid tumors microarray expression

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Utilizing logical relationships in genomic data to decipher cellular processes

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FEBS JOURNAL 2005年第20期272卷 5110-5118页

作者： Bowers, PM O'Connor, BD Cokus, SJ Sprinzak, E Yeates, TO Eisenberg, D Univ Calif Los Angeles Howard Hughes Med Inst Los Angeles CA 90095 USA Univ Calif Los Angeles Inst Genom & Proteom Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Chem & Biochem Los Angeles CA 90095 USA Univ Calif Los Angeles Dept Math Los Angeles CA 90095 USA

The wealth of available genomic data has spawned a corresponding interest in computational methods that can impart biological meaning and context to these experiments. Traditional computational methods have drawn relationships between pairs of proteins or genes based on notions of equality or similarity between their patterns of occurrence or behavior. For example, two genes displaying similar variation in expression, over a number of experiments, may be predicted to be functionally related. We have introduced a natural extension of these approaches, instead identifying logical relationships involving triplets of proteins. Triplets provide for various discrete kinds of logic relationships, leading to detailed inferences about biological associations. For instance, a protein C might be encoded within an organism if, and only if, two other proteins A and B are also both encoded within the organism, thus suggesting that gene C is functionally related to genes A and B. The method has been applied fruitfully to both phylogenetic and microarray expression data, and has been used to associate logical combinations of protein activity with disease state phenotypes, revealing previously unknown ternary relationships among proteins, and illustrating the inherent complexities that arise in biological data.

关键词： genomic data logic analysis microarray expression phylogenetic profile

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White Blood Cell Differentials Enrich Whole Blood expression Data in the Context of Acute Cardiac Allograft Rejection

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BIOINFORMATICS AND BIOLOGY INSIGHTS 2012年第6期6卷 49-61页

作者： Shannon, Casey P. Hollander, Zsuzsanna Wilson-McManus, Janet Balshaw, Robert Ng, Raymond T. McMaster, Robert McManus, Bruce M. Keown, Paul A. Tebbutt, Scott J. NCE CECR PROOF Ctr Excellence Vancouver BC Canada Univ British Columbia Dept Stat Vancouver BC Canada Univ British Columbia Dept Comp Sci Vancouver BC Canada Univ British Columbia Dept Med Genet Vancouver BC Canada Univ British Columbia Dept Med Div Nephrol Vancouver BC Canada Univ British Columbia Dept Med Div Resp Med Vancouver BC Canada UBC James Hogg Res Ctr Vancouver BC Canada Inst Heart Lung Hlth Vancouver BC Canada

Acute cardiac allograft rejection is a serious complication of heart transplantation. Investigating molecular processes in whole blood via microarrays is a promising avenue of research in transplantation, particularly due to the non-invasive nature of blood sampling. However, whole blood is a complex tissue and the consequent heterogeneity in composition amongst samples is ignored in traditional microarray analysis. This complicates the biological interpretation of microarray data. Here we have applied a statistical deconvolution approach, cell-specific significance analysis of microarrays (csSAM), to whole blood samples from subjects either undergoing acute heart allograft rejection (AR) or not (NR). We identified eight differentially expressed probe-sets significantly correlated to monocytes (mapping to 6 genes, all down-regulated in ARs versus NRs) at a false discovery rate (FDR) <= 15%. None of the genes identified are present in a biomarker panel of acute heart rejection previously published by our group and discovered in the same data.

关键词： microarray expression cell-specific expression deconvolution heart transplantation

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Autocrine loops

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Genome Biology 2001年第1期2.0卷 1-2页

作者： Weitzman, Jonathan B.

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Identification of putative miRNA biomarkers in early rheumatoid arthritis by genome-wide microarray profiling: A pilot study

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GENE 2019年 720卷 144081-000页

作者： Romo-Garcia, M. F. Bastian, Y. Zapata-Zuniga, M. Macias-Segura, N. Castillo-Ortiz, J. D. Lara-Ramirez, E. E. Fernandez-Ruiz, J. C. Berlanga-Taylor, A. J. Gonzalez-Amaro, R. Ramos-Remus, C. Enciso-Moreno, J. A. Castaneda-Delgado, J. E. IMSS Unidad Invest Biomed Zacatecas Zacatecas Mexico Catedras CONACyT Unidad Invest Biomed Zacatecas I Zacatecas Mexico IMSS Hosp Rural 51 Villanueva Zacatecas Mexico Unidad Invest Enfermedades Cren Degenerat Guadalajara Jalisco Mexico Univ Autonoma Guadalajara Guadalajara Jalisco Mexico Imperial Coll London Fac Med MRC PHE Ctr Environm & Hlth Dept Epidemiol & BiostatSch Publ Hlth St Marys CampusNorfolk Pl London England Univ Autonoma San Luis Potosi Fac Med Dept Inmunol San Luis Potosi San Luis Potosi Mexico Univ Autonoma Zacatecas Fac Med Humana & Ciencias Salud Zacatecas Mexico Univ Autonoma Aguascalientes Ctr Ciencias Basicas Dept Fisiol & Farmacol Lab Neuroinmunoendocrinol Aguascalientes Aguascalientes Mexico

Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in' early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA. When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR 361-5p, identifying this miRNA as a potential biomarker of disease. We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use.

关键词： Early rheumatoid arthritis Biomarker miRNA CCP microarray expression

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Construction and comprehensive analysis of a ceRNA network to reveal potential prognostic biomarkers for lung adenocarcinoma

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BMC CANCER 2021年第1期21卷 849-849页

作者： Gao, Lei Zhang, Ling Anhui Med Univ Dept Resp & Crit Care Med Hosp 2 Econ & Technol Dev Zone 678 Furong Rd Hefei 230601 Anhui Peoples R China Anhui Med Univ Affiliated Hosp 1 Dept Crit Care Med 218 Jixi Rd Hefei 230022 Anhui Peoples R China

Background More and more studies have proven that circular RNAs (circRNAs) play vital roles in cancer development via sponging miRNAs. However, the expression pattern of competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD) remains largely unclear. The current study explored functional roles and the regulatory mechanisms of circRNA as ceRNAs in LUAD and their potential impact on LUAD patient prognosis. Methods In this study, we systematically screened differential expression circRNAs (DEcircRNAs), miRNAs (DEmiRNAs) and mRNAs (DEGs) associated with LUAD. Then, DEcircRNAs, DEmiRNAs and DEGs were selected to construct a circRNA-miRNA-mRNA prognosis-related regulatory network based on interaction information from the ENCORI database. Subsequently, the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed on the genes in the network to predict the potential underlying mechanisms and functions of circRNAs in LUAD. In addition, Kaplan-Meier survival analysis was performed to evaluate clinical outcomes of LUAD patients, and drug sensitivity analysis was used to screen potential biomarkers for drug treatment of patients with LUAD. Results As a result, 10 circRNAs were aberrantly expressed in LUAD tissues. The ceRNA network was built, which included 3 DEcircRNAs, 6 DEmiRNAs and 157 DEGs. The DEGs in the ceRNA network of hsa_circ_0049271 enriched in biological processes of cell proliferation and the Jak-STAT signaling pathway. We also detected 7 mRNAs in the ceRNA network of hsa_circ_0049271 that were significantly associated with the overall survival of LUAD patients (P < 0.05). Importantly, four genes (PDGFB, CCND2, CTF1, IL7R) identified were strongly associated with STAT3 activation and drugs sensitivity in GDSC. Conclusions In summary, a ceRNA network of hsa_circ_0049271 was successfully constructed, which including one circRNA, two miRNAs, and seven mRNAs. Seven mRNAs (PDGFB, TNFRSF19, CCND2, CTF1, IL11R

关键词： Circular RNA Lung adenocarcinoma microarray expression Competing endogenous RNA Overall survival Prognostic biomarker Drug sensitivity

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