A novel signaling pathway impact analysis

Tarca, Adi L.; Drăghici, Sorin; Khatri, Purvesh; Hassan, Sonia S.; Mittal, Pooja; Kim, Jung-Sun; Kim, Chong Jai; Kusanovic, Juan Pedro; Romero, Roberto

doi:10.1093/bioinformatics/btn577

Cited by 902 publications

(881 citation statements)

References 28 publications

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“…1, Table 1). An advantage of SPIA is that this analysis calculates which pathways are significantly up‐regulated, by combining the over‐representation of DE‐genes in a certain pathway with the effect of changes in the expression of these genes on the perturbation of the pathway, thereby incorporating pathway topology 23. In Great Danes relative to Miniature Poodles, there was activation of pathways associated with enhanced cell proliferation and matrix production by the different members of the cyclin protein family; activation of extracellular matrix–receptor interactions, with up‐regulation of many collagen, integrin, and laminin genes; activation of the tight‐junction pathway; and activation of the p53 pathway.…”

Section: Resultsmentioning

confidence: 99%

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Growth plate expression profiling: Large and small breed dogs provide new insights in endochondral bone formation

Teunissen

Riemers

Leenen

et al. 2017

Journal Orthopaedic Research

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The difference in the adult height of mammals, and hence in endochondral bone formation, is not yet fully understood and may serve to identify targets for bone and cartilage regeneration. In line with this hypothesis, the intra‐species disparity between the adult height of Great Danes and Miniature Poodles was investigated at a transcriptional level. Microarray analysis of the growth plate of five Great Danes and five Miniature Poodles revealed 2,981 unique genes that were differentially expressed, including many genes with an unknown role in skeletal development. A signaling pathway impact analysis indicated activation of the cell cycle, extracellular matrix receptor interaction and the tight junction pathway, and inhibition of pathways associated with inflammation and the complement cascade. In additional validation steps, the gene expression profile of the separate growth plate zones for both dog breeds were determined. Given that the BMP signaling is known for its crucial role in skeletal development and fracture healing, and BMP‐2 is used in orthopaedic and spine procedures for bone augmentation, further investigations concentrated on the BMP pathway.The canonical BMP‐2 and BMP‐6 signaling pathway was activated in the Great Danes compared to Miniature Poodles. In conclusion, investigating the differential expression of genes involved in endochondral bone formation in small and large breed dogs, could be a game changing strategy to provide new insights in growth plate development and identify new targets for bone and cartilage regeneration. © 2017 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:138–148, 2018.

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Section: Resultsmentioning

confidence: 99%

“…The canine Ensembl IDs were converted to their human homologue Entrez IDs and a SPIA was performed using R 2.15.2 23. The efficiency corrected

normalΔ

normalΔ

CT method was used to calculate relative gene expression 24.…”

Section: Methodsmentioning

confidence: 99%

Growth plate expression profiling: Large and small breed dogs provide new insights in endochondral bone formation

Teunissen

Riemers

Leenen

et al. 2017

Journal Orthopaedic Research

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“…Recently, several algorithms have tried to demonstrate the possibility of incorporating topological information in pathway graphs into gene set significance analysis, notably Pathway-Express [48], SPIA [49], SEPEA [50] and PWEA [51]. Pathway-Express defines a pathway score summarizing gene set over-representation probability and a gene "perturbation factor" accounting for both expression alteration and directional linkages, which is revised in SPIA by removing the mingling effects of expression changes in the "perturbation factor" [48,49].…”

Section: Discussionmentioning

confidence: 99%

A network-based gene-weighting approach for pathway analysis

Fang

Tian

2011

Cell Res

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Classical algorithms aiming at identifying biological pathways significantly related to studying conditions frequently reduced pathways to gene sets, with an obvious ignorance of the constitutive non-equivalence of various genes within a defined pathway. We here designed a network-based method to determine such non-equivalence in terms of gene weights. The gene weights determined are biologically consistent and robust to network perturbations. By integrating the gene weights into the classical gene set analysis, with a subsequent correction for the "over-counting" bias associated with multi-subunit proteins, we have developed a novel gene-weighed pathway analysis approach, as implemented in an R package called "Gene Associaqtion Network-based Pathway Analysis" (GANPA). Through analysis of several microarray datasets, including the p53 dataset, asthma dataset and three breast cancer datasets, we demonstrated that our approach is biologically reliable and reproducible, and therefore helpful for microarray data interpretation and hypothesis generation.

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“…The microarray data were annotated using custom CFD files (HGU133Plus2_Hs_ENTREZG.cdf ver 11.0.1) 27 and normalized using the RMA method. 28 Genes with fold-change at least 3 were considered as differentially expressed and analyzed for pathways using Signaling Pathway Impact Analysis (formerly known as Pathway-Express) 29,30 method. The data are deposited at http://www.ebi.ac.uk/microarray-as/aer/entry, accession number E-MEXP-2172.…”

Section: Microarray Analysismentioning

confidence: 99%

“…To further examine what pathways are affected by highly upregulated or downregulated genes, we analyzed pathways using PathwayExpress 29,30 (Supporting Information Table 2). Our results suggest that among the 3 most affected pathways that were inhibited were cell cycle, mTOR signaling pathway and MAPK signaling pathway.…”

Section: Gene Expression Profiles Of Radiated Cellsmentioning

confidence: 99%

Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

Rajecki

Hällström

Hakkarainen

et al. 2009

Intl Journal of Cancer

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New treatment approaches are needed for hormone refractory prostate cancer. Oncolytic adenoviruses are promising anti-cancer agents, and their efficacy can be improved by combining with conventional therapies such as ionizing radiation. The aim of this study was to determine the timing of oncolytic adenovirus treatment with regard to radiation and study the mechanisms of synergy in combination treatment. Prostate cancer cells were infected with oncolytic adenoviruses, irradiated and synergy mechanisms were assessed. In vivo models of combination treatment were tested. Radiation and oncolytic viruses were synergistic when viral infection was scheduled 24 hr after irradiation. Combination of oncolytic adenovirus with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone. Microarray analysis showed dysregulated pathways including cell cycle, mTOR and antigen processing pathways. Functional analysis showed that adenoviral infection was accompanied with degradation of proteins involved in DNA break repair. Mre11 was degraded for subsequent inactivation of Chk2-Thr68 in combination treated cells, while cH2AX-Ser139 was elevated implicating the persistence of DNA double strand breaks. Increased autophagocytosis was seen in combination treated cells. Combination treatment did not increase apoptosis or virus replication. The results provide evidence of the antitumor efficacy of combining oncolytic adenoviruses with irradiation as a therapeutic strategy for the treatment of prostate cancer. Further, these findings propose a molecular mechanism that may be important in radiation induced cell death, autophagy and viral cytopathic effect. ' 2009 UICC

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A novel signaling pathway impact analysis

Abstract: SPIA was implemented as an R package available at http://vortex.cs.wayne.edu/ontoexpress/

Cited by 902 publications

References 28 publications

Growth plate expression profiling: Large and small breed dogs provide new insights in endochondral bone formation

Growth plate expression profiling: Large and small breed dogs provide new insights in endochondral bone formation

A network-based gene-weighting approach for pathway analysis

Mre11 inhibition by oncolytic adenovirus associates with autophagy and underlies synergy with ionizing radiation

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