S100a9 might act as a modulator of the Toll-like receptor 4 transduction pathway in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyp (CRSwNP) is a highly prevalent disorder characterized by persistent nasal and sinus mucosa inflammation. Despite significant morbidity and decreased quality of life, there are limited effective treatment options for such a disease. Therefore, identifying causal genes and dysregulated pathways paves the way for novel therapeutic interventions. In the current study, a three-way interaction approach was used to detect dynamic co-expression interactions involved in CRSwNP. In this approach, the internal evolution of the co-expression relation between a pair of genes (X, Y) was captured under a change in the expression profile of a third gene (Z), named the switch gene. Subsequently, the biological relevancy of the statistically significant triplets was confirmed using both gene set enrichment analysis and gene regulatory network reconstruction. Finally, the importance of identified switch genes was confirmed using a random forest model. The results suggested four dysregulated pathways in CRSwNP, including "positive regulation of intracellular signal transduction", "arachidonic acid metabolic process", "spermatogenesis" and "negative regulation of cellular protein metabolic process". Additionally, the S100a9 as a switch gene together with the gene pair {Cd14, Tpd52l1} form a biologically relevant triplet. More specifically, we suggested that S100a9 might act as a potential upstream modulator in toll-like receptor 4 transduction pathway in the major CRSwNP pathologies.

RT-DOb, a switch gene for the gene pair {Csf1r, Milr1}, can influence the onset of Alzheimer's disease by regulating communication between mast cell and microglia.

In biology, homeostasis is a central cellular phenomenon that plays a crucial role in survival. The central nervous system (CNS) is controlled by exquisitely sensitive homeostatic mechanisms when facing inflammatory or pathological insults. Mast cells and microglia play a crucial role in CNS homeostasis by eliminating damaged or unnecessary neurons and synapses. Therefore, decoding molecular circuits that regulate CNS homeostasis may lead to more effective therapeutic strategies that specifically target particular subsets for better therapy of Alzheimer's disease (AD). Based on a computational analysis of a microarray dataset related to AD, the H2-Ob gene was previously identified as a potential modulator of the homeostatic balance between mast cells and microglia. Specifically, it plays such a role in the presence of a three-way gene interaction in which the H2-Ob gene acts as a switch in the co-expression relationship of two genes, Csf1r and Milr1. Therefore, the importance of the H2-Ob gene as a potential therapeutic target for AD has led us to experimentally validate this relationship using the quantitative real-time PCR technique. In the experimental investigation, we confirmed that a change in the expression levels of the RT1-DOb gene (the rat ortholog of murine H2-Ob) can switch the co-expression relationship between Csf1r and Milr1. Furthermore, since the RT1-DOb gene is up-regulated in AD, the mentioned triplets might be related to triggering AD.

Novel insight into pancreatic adenocarcinoma pathogenesis using liquid association analysis.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy associated with a poor prognosis. High-throughput disease-related-gene expression data provide valuable information on gene interaction, which consequently lead to deeper insight about pathogenesis. The co-expression analysis is a common approach that is used to investigate gene interaction. However, such an approach solely is inadequate to reveal the complexity of the gene interaction. The three-way interaction model is known as a novel approach applied to decode the complex relationship between genes. METHODS: In the current study, the liquid association method was used to capture the statistically significant triplets involved in the PDAC pathogenesis. Subsequently, gene set enrichment and gene regulatory network analyses were performed to trace the biological relevance of the statistically significant triplets. RESULTS: The results of the current study suggest that "response to estradiol" and "Regulation of T-cell proliferation" are two critical biological processes that may be associated with the PDAC pathogenesis. Additionally, we introduced six switch genes, namely Lamc2, Klk1, Nqo1, Aox1, Tspan1, and Cxcl12, which might be involved in PDAC triggering. CONCLUSION: In the current study, for the first time, the critical genes and pathways involved in the PDAC pathogenesis were investigated using the three-way interaction approach. As a result, two critical biological processes, as well as six potential biomarkers, were suggested that might be involved in the PDAC triggering. Surprisingly, strong evidence for the biological relevance of our results can be found in the literature.

Nkx3-1 and Fech genes might be switch genes involved in pituitary non-functioning adenoma invasiveness.

Non-functioning pituitary adenomas (NFPAs) are typical pituitary macroadenomas in adults associated with increased mortality and morbidity. Although pituitary adenomas are commonly considered slow-growing benign brain tumors, numerous of them possess an invasive nature. Such tumors destroy sella turcica and invade the adjacent tissues such as the cavernous sinus and sphenoid sinus. In these cases, the most critical obstacle for complete surgical removal is the high risk of damaging adjacent vital structures. Therefore, the development of novel therapeutic strategies for either early diagnosis through biomarkers or medical therapies to reduce the recurrence rate of NFPAs is imperative. Identification of gene interactions has paved the way for decoding complex molecular mechanisms, including disease-related pathways, and identifying the most momentous genes involved in a specific disease. Currently, our knowledge of the invasion of the pituitary adenoma at the molecular level is not sufficient. The current study aimed to identify critical biomarkers and biological pathways associated with invasiveness in the NFPAs using a three-way interaction model for the first time. In the current study, the Liquid association method was applied to capture the statistically significant triplets involved in NFPAs invasiveness. Subsequently, Random Forest analysis was applied to select the most important switch genes. Finally, gene set enrichment (GSE) and gene regulatory network (GRN) analyses were applied to trace the biological relevance of the statistically significant triplets. The results of this study suggest that "mRNA processing" and "spindle organization" biological processes are important in NFAPs invasiveness. Specifically, our results suggest Nkx3-1 and Fech as two switch genes in NFAPs invasiveness that may be potential biomarkers or target genes in this pathology.

Characterization of pathways involved in colorectal cancer using real-time RT-PCR gene expression data.

AIM: Efforts to explore biomarkers and biological pathways involved in the disease are needed to improve colorectal cancer (CRC) diagnosis and alternative treatments. BACKGROUND: The fourth common malignancy in the world is colorectal cancer. The over-all burden is predicted to rise by 2030. METHODS: In the current study, nine genes were selected. Previously, a panel of genes by Agendia, a classifier of robust gene expression (ColoPrint), was determined to significantly improve the prognostic accuracy of pathologic factors in stage II and III colorectal cancer patients. Five genes, including Ppara, Mctp1, Pyroxd1, Il2r, and Cyfip2, from this panel and four other genes which were not in this panel but were cited abundantly in the literature were selected. Then, expression levels of the selected genes in CRC tissue were compared with levels in adjacent normal tissue. To identify the pathways involved in CRC, gene set enrichment analysis was subsequently performed. Furthermore, to illustrate the relationship between genes in this disease, the cross-shaped co-expression pattern and gene regulatory network were determined using computational methods. RESULTS: This research found that the pairs of genes: {IL2R, CYFIP2}, {FOXM1, PPARA}, {MCTP1, CTSC}, and {PYROXD1, CYF1P2} are functionally related. Furthermore, two differentially expressed gene pairs ({FOXM1, PPARA} and {IL2R, CYFIP2}) are involved in the vascular endothelial growth factor receptor signaling pathway and the purine ribonucleoside diphosphate metabolic process, respectively. CONCLUSION: This research found that the combination of computational analysis and laboratory data provided the opportunity to better characterize the relation between central colorectal cancer genes as well as possible pathways involved in the colorectal cancer.

Rps27a might act as a controller of microglia activation in triggering neurodegenerative diseases.

Neurodegenerative diseases (NDDs) are increasing serious menaces to human health in the recent years. Despite exhibiting different clinical phenotypes and selective neuronal loss, there are certain common features in these disorders, suggesting the presence of commonly dysregulated pathways. Identifying causal genes and dysregulated pathways can be helpful in providing effective treatment in these diseases. Interestingly, in spite of the considerable researches on NDDs, to the best of our knowledge, no dysregulated genes and/or pathways were reported in common across all the major NDDs so far. In this study, for the first time, we have applied the three-way interaction model, as an approach to unravel sophisticated gene interactions, to trace switch genes and significant pathways that are involved in six major NDDs. Subsequently, a gene regulatory network was constructed to investigate the regulatory communication of statistically significant triplets. Finally, KEGG pathway enrichment analysis was applied to find possible common pathways. Because of the central role of neuroinflammation and immune system responses in both pathogenic and protective mechanisms in the NDDs, we focused on immune genes in this study. Our results suggest that "cytokine-cytokine receptor interaction" pathway is enriched in all of the studied NDDs, while "osteoclast differentiation" and "natural killer cell mediated cytotoxicity" pathways are enriched in five of the NDDs each. The results of this study indicate that three pathways that include "osteoclast differentiation", "natural killer cell mediated cytotoxicity" and "cytokine-cytokine receptor interaction" are common in five, five and six NDDs, respectively. Additionally, our analysis showed that Rps27a as a switch gene, together with the gene pair {Il-18, Cx3cl1} form a statistically significant and biologically relevant triplet in the major NDDs. More specifically, we suggested that Cx3cl1 might act as a potential upstream regulator of Il-18 in microglia activation, and in turn, might be controlled with Rps27a in triggering NDDs.

Three-way interaction model with switching mechanism as an effective strategy for tracing functionally-related genes.

Introduction: Identification of functionally-related genes is an important step in understanding biological systems. The most popular strategy to infer functional dependence is to study pairwise correlations between gene expression levels. However, certain functionally-related genes may have a low expression correlation due to their nonlinear interactions. The use of a three-way interaction (3WI) model with switching mechanism (SM) is a relatively new strategy to trace functionally-related genes. The 3WI model traces the dynamic and nonlinear nature of the co-expression relationship of two genes by introducing their link to the expression level of a third gene. Areas covered: In this paper, we reviewed a variety of existing methods for tracing the 3WIs. Furthermore, we provide a comprehensive review of the previous biological studies based on 3WI models. Expert commentary: Comparison of features of these methods indicates that the modified liquid association algorithm has the best efficiency for tracing 3WI between others. The limited number of biological studies based on the 3WI suggests that high computational demand of the available algorithms is a major challenge to apply this approach for analyzing high-throughput omics data.

Three-way interaction model to trace the mechanisms involved in Alzheimer's disease transgenic mice.

Alzheimer's disease (AD) is the most common cause for dementia in human. Currently, more than 46 million people in the world suffer from AD and it is estimated that by 2050 this number increases to more than 131 million. AD is considered as a complex disease. Therefore, understanding the mechanism of AD is a universal challenge. Nowadays, a huge number of disease-related high-throughput "omics" datasets are freely available. Such datasets contain valuable information about disease-related pathways and their corresponding gene interactions. In the present work, a three-way interaction model is used as a novel approach to understand AD-related mechanisms. This model can trace the dynamic nature of co-expression relationship between two genes by introducing their link to a third gene. Apparently, such relationships cannot be traced by the classical two-way interaction model. Liquid association method was applied to capture the statistically significant triplets which are involved in three-way interaction. Subsequently, gene set enrichment analysis (GSEA) and gene regulatory network (GRN) inference were applied to analyze the biological relevance of the statistically significant triplets. The results of this study suggest that the innate immunity processes are important in AD. Specifically, our results suggest that H2-Ob as the switching gene and the gene pair {Csf1r, Milr1} form a statistically significant and biologically relevant triplet, which may play an important role in AD. We propose that the homeostasis-related link between mast cells and microglia is presumably controlled with H2-Ob expression levels as a switching gene.

Oral squamous cell cancer protein-protein interaction network interpretation in comparison to esophageal adenocarcinoma.

AIM: The aim of this study is to present the oral Squamous Cell Cancer protein-protein interaction network interpretation in comparison to esophageal adenocarcinoma. BACKGROUND: Oral squamous cell cancer (OSCC) is a common disease worldwide, with poor prognosis and limited treatment. Thus, introducing molecular markers through network analysis can be helpful. METHODS: STRING database (DB) was applied for network construction through Cytoscape 3.4.0. Clue GO handled the gene annotation for the retrieved clusters. Eight proteins were indicated to be differential in the network constitution. RESULTS: The centrality and clustering analysis indicate that TP53 plays an over-significant role in network integrity among eight most central proteins including TP53, AKT1, EGFR, MYC, JUN, CDH1, CCND1, and CTNNB1. The suggested biomarker set is very similar to the related biomarker panel of esophageal adenocarcinoma. CONCLUSION: The ontology analysis implies that the prominent proteins are involved in regulation of smooth muscle cell proliferation, regulation of fibroblast proliferation, and response to UV-A processes. In conclusion, these proteins and their associated biological processes may be more critical compared to other reported biomarkers for OSCC. Nevertheless, validation studies are required for confirming the pivotal role of potential candidates. Similar biomarker panel of this disease and esophagus adenocarcinoma is corresponded to the origin of the two malignancies.