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Background: There is limited research on cholesterol metabolism-related genes (CM-RGs) in non-alcoholic fatty liver disease (NAFLD), despite hypercholesterolemia being a recognized risk factor. The role of CM-RGs in NAFLD remains unclear. Methods: The differentially expressed genes (DEGs) between NAFLD and control were acquired by differential expression analysis. The differentially expressed genes associated with cholesterol metabolism (DE-CM-RGs) were identified and functional enrichment analyses were performed. Protein-protein interaction network analysis and a two-sample Mendelian randomization study were utilized for identifying hub genes. Nomogram model, competing endogenous RNA and messenger RNA-drug networks were established. In addition, immunoinfiltration analysis was performed. Results: We identified four hub genes (MVK, HMGCS1, TM7SF2, and FDPS) linked to NAFLD risk. MVK and TM7SF2 were protective factors, HMGCS1 and FDPS were risk factors for NAFLD. The area under the curve values of nomograms in GSE135251 and GSE126848 were 0.79 and 0.848, respectively. The gene set enrichment analysis indicated that hub genes participated in calcium signaling pathways and biosynthesis of unsaturated fatty acids. NAFLD patients showed increased CD56dim NK cells and Th17. Tretinoin, alendronate, zoledronic acid, and quercetin are potential target agents in NAFLD. Conclusion: Our study has linked cholesterol metabolism genes (MVK, HMGCS1, TM7SF2, and FDPS) to NAFLD, providing a promising diagnostic framework, identifying treatment targets, and offering novel perspectives into its mechanisms. [ABSTRACT FROM AUTHOR]

Ferroptosis has been observed to play an important role during erythrocyte differentiation (ED). However, the biological gene markers and ferroptosis mechanisms in ED remain unknown. We downloaded the datasets of ED in human umbilical cord blood-derived CD34+ cells from the Gene Expression Omnibus database. Using median differentiation time, the sample was categorized into long and short groups. The differentially expressed ferroptosis-related genes (DE-FRGs) were screened using differential expression analysis. The enrichment analyses and a protein-protein interaction (PPI) network were conducted. To predict the ED stage, a logistic regression model was constructed using the least absolute shrinkage and selection operator (LASSO). Overall, 22 DE-FRGs were identified. Ferroptosisrelated pathways were enriched using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Gene Set Enrichment Analysis and Gene Set Variation Analysis revealed the primary involvement of DE-FRGs in JAK-STAT, MAPK, PI3K-AKT-mTORC1, WNT, and NOTCH signaling pathways. Ten-hub DE-FRGs were obtained using PPI analysis. Furthermore, we constructed mRNA-microRNA (miRNA) and mRNA-transcription factor networks. Immune cell infiltration levels differed significantly during ED. LASSO regression analysis established a signature using six DE-FRGs (ATF3, CDH2, CHAC1, DDR2, DPP4, and GDF15) related to the ED stage. Bioinformatic analyses identified ferroptosis-associated genes during ED, which were further validated. Overall, we identified ferroptosis-related genes to predict their correlations in ED. Exploring the underlying mechanisms of ferroptosis may help us better understand pathophysiological changes in ED and provide new evidence for clinical transformation. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and limited treatment options. Although immune checkpoint inhibitors (ICIs) have been proven to improve outcomes in TNBC patients, the potential mechanisms and markers that determine the therapeutic response to ICIs remains uncertain. Revealing the relationship and interaction between cancer cells and tumor microenvironment (TME) could be helpful in predicting treatment efficacy and developing novel therapeutic agents. By analyzing single-cell RNA sequencing dataset, we comprehensively profiled cell types and subpopulations as well as identified their signatures in the TME of TNBC. We also proposed a method for quantitatively assessment of the TME immune profile and provided a framework for identifying cancer cell-intrinsic features associated with TME through integrated analysis. Using integrative analyses, RARRES1 was identified as a TME-associated gene, whose expression was positively correlated with prognosis and response to ICIs in TNBC. In conclusion, this study characterized the heterogeneity of cellular components in TME of TNBC patients, and brought new insights into the relationship between cancer cells and TME. In addition, RARRES1 was identified as a potential predictor of prognosis and response to ICIs in TNBC. [ABSTRACT FROM AUTHOR]

Ferroptosis has been observed to play an important role during erythrocyte differentiation (ED). However, the biological gene markers and ferroptosis mechanisms in ED remain unknown. We downloaded the datasets of ED in human umbilical cord blood-derived CD34+ cells from the Gene Expression Omnibus database. Using median differentiation time, the sample was categorized into long and short groups. The differentially expressed ferroptosis-related genes (DE-FRGs) were screened using differential expression analysis. The enrichment analyses and a protein–protein interaction (PPI) network were conducted. To predict the ED stage, a logistic regression model was constructed using the least absolute shrinkage and selection operator (LASSO). Overall, 22 DE-FRGs were identified. Ferroptosis-related pathways were enriched using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Gene Set Enrichment Analysis and Gene Set Variation Analysis revealed the primary involvement of DE-FRGs in JAK-STAT, MAPK, PI3K-AKT-mTORC1, WNT, and NOTCH signaling pathways. Ten-hub DE-FRGs were obtained using PPI analysis. Furthermore, we constructed mRNA-microRNA (miRNA) and mRNA-transcription factor networks. Immune cell infiltration levels differed significantly during ED. LASSO regression analysis established a signature using six DE-FRGs (ATF3, CDH2, CHAC1, DDR2, DPP4, and GDF15) related to the ED stage. Bioinformatic analyses identified ferroptosis-associated genes during ED, which were further validated. Overall, we identified ferroptosis-related genes to predict their correlations in ED. Exploring the underlying mechanisms of ferroptosis may help us better understand pathophysiological changes in ED and provide new evidence for clinical transformation.

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of dermatomyositis (DM), a rare autoimmune disease affecting the skin and muscles. However, the genetic basis underlying dysfunctional mitochondria and the development of DM remains incomplete. Methods: The datasets of DM muscle and skin tissues were retrieved from the Gene Expression Omnibus database. The mitochondrial related genes (MRGs) were retrieved from MitoCarta. DM-related modules in muscle and skin tissues were identified with the analysis of weighted gene co-expression network (WGCNA), and then compared with the MRGs to obtain the overlapping mitochondrial related module genes (mito-MGs). Subsequently, differential expression genes (DEGs) obtained from muscle and skin datasets were overlapped with MRGs to identify mitochondrial related DEGs (mito-DEGs). Next, functional enrichment analysis was applied to analyze possible relevant biological pathways. We used the Jvenn online tool to intersect mito-MGs with mito-DEGs to identify hub genes and validate them using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry staining. In addition, we evaluated immune infiltration in muscle and skin tissues of DM patients using the one-sample gene set enrichment analysis (ssGSEA) algorithm and predicted potential transcription factor (TF) -gene network by NetworkAnalyst. Results: The WGCNA analysis revealed 105 mito-MGs, while the DEG analysis identified 3 mito-DEGs. These genes showed functional enrichment for amino acid metabolism, energy metabolism and oxidative phosphorylation. Through the intersection analysis of the mito-MGs from the WGCNA analysis and the mito-DEGs from the DEG set, three DM mito-hub genes (IFI27, CMPK2, and LAP3) were identified and validated by RT-qPCR and immunohistochemistry analysis. Additionally, positive correlations were observed between hub genes and immune cell abundance. The TF-hub gene regulatory network revealed significant interactions involving ERG, VDR, and ZFX with CMPK2 and LAP3, as well as SOX2 with LAP3 and IFI27, and AR with IFI27 and CMPK2. Conclusion: The mito-hub genes (IFI27, CMPK2, and LAP3) are identified in both muscles and skin tissues from DM patients. These genes may be associated with immune infiltration in DM, providing a new entry point for the pathogenesis of DM. [ABSTRACT FROM AUTHOR]

Sarcopenia and osteoporosis, two degenerative diseases in older patients, have become severe health problems in aging societies. Muscles and bones, the most important components of the motor system, are derived from mesodermal and ectodermal mesenchymal stem cells. The adjacent anatomical relationship between them provides the basic conditions for mechanical and chemical signals, which may contribute to the co-occurrence of sarcopenia and osteoporosis. Identifying the potential common crosstalk genes between them may provide new insights for preventing and treating their development. In this study, DEG analysis, WGCNA, and machine learning algorithms were used to identify the key crosstalk genes of sarcopenia and osteoporosis; this was then validated using independent datasets and clinical samples. Finally, four crosstalk genes (ARHGEF10, PCDH7, CST6, and ROBO3) were identified, and mRNA expression and protein levels of PCDH7 in clinical samples from patients with sarcopenia, with osteoporosis, and with both sarcopenia and osteoporosis were found to be significantly higher than those from patients without sarcopenia or osteoporosis. PCDH7 seems to be a key gene related to the development of both sarcopenia and osteoporosis. [ABSTRACT FROM AUTHOR]

Topoisomerase II homologue 2 (PATL2) has been confirmed to be a key gene that contributes to oocyte maturation. However, the allele distribution and carrier frequency of these mutations remain uncharacterized. So a bioinformatics subcategory analysis of PATL2 mutations from outcome data and Single Nucleotide Polymorphism (SNP) databases was conducted. Altogether, the causative PATL2 mutation number detected in patients with oocyte maturation defects in the clinical studies and pathogenic PATL2 mutation sites predicted by software based on the database was approximately 53. The estimated carrier frequency of pathogenic mutation sites was at least 1.14 based on the gnomAD and ExAC database, which was approximately 1/877. The highest frequency of mutations detected in the independent patients was c.223-14_223-2del13. The carrier frequency of this mutation in the population was 0.25?, which may be a potential threat to fertility. Estimated allele and carrier frequency are relatively higher than those predicted previously based on clinical ascertainment. A review of PATL2 mutation lineage identified in 34 patients showed that 53.81%, 9.22% and 14.72% of the oocytes with PATL2 mutations were arrested at the germinal vesicle (GV) stage, metaphase I (MI) stage and first polar body stage, respectively. Oocytes that could develop to the first polar body stage were extremely rare to fertilise, and their ultimate fate was early embryonic arrest. Phenotypic variability is related to the function of the regions and degree of loss of function of PATL2 protein. A 3D protein structure changes predicted by online tools, AlphaFold, showed aberrations at the mutation sites, which may explain partially the function loss. When the mutated and wild-type proteins are not in the same amino acid category, the protein structure will be considerably unstable. The integration of additional mutation sites with phenotypes is helpful in drawing a complete picture of the disease. Bioinformatics analysis of PATL2 mutations will help reveal molecular epidemiological characteristics and provide an important reference for new mutation assessment, genetic counselling and drug research. [ABSTRACT FROM AUTHOR]

Background: To analyze the lncRNA-mRNA differential expression and coexpression network of periosteal stem cells (PSCs) from congenital pseudarthrosis of the tibia (CPT) and normal patients, and to explore the role of key lncRNAs. Methods: Differentially expressed lncRNAs and mRNAs in PSCs were obtained by sequencing, and biological functions of differentially expressed mRNAs were detected by gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) pathway and protein -protein interaction (PPI) analysis. The co-expression network of lncRNA-mRNA was constructed by correlation analysis of differentially expressed lncRNAs and mRNAs, and the key lncRNAs were screened according to the connectivity degree. After that, the cis-regulated target genes of differential expressed lncRNAs and mRNAs were predicted. Results: A total of 194 differentially expressed lncRNAs were identified, including 73 upregulated and 121 downregulated genes. A total of 822 differentially expressed mRNAs were identified, including 311 upregulated and 511 downregulated genes. GO, KEGG and PPI enrichment analysis showed that the regulatory function of differentially expressed mRNAs were mainly gathered in skeletal system development and tissue morphogenesis. The co-expression network with 226 nodes and 3,390 edges was constructed based on correlation analysis. A total of 10 key lncRNAs, including FAM227B, POM121L9P, AF165147 and AC103702, were screened according to connectivity degree. Prediction of target genes indicated that FAM227B-FGF7 and AC103702-HOXB4/5/6 may play an important role in the pathogenesis of CPT. Conclusion: A total of 10 key lncRNAs, including FAM227B, POM121L9P, AF165147, and AC103702, occupy the core position in the co-expression network, suggesting that these lncRNAs and their target genes may play an important role in the pathogenesis of CPT. [ABSTRACT FROM AUTHOR]

Backgrounds: Given the roles of microRNA (miRNA) in human diseases and the high incidence of gestational diabetes mellitus (GDM), the aim of the study was to examine miRNA signatures and crucial pathways, as well as possible biomarkers for GDM diagnosis.Methods: We conducted a two-stage study to explore functional miRNA and those target genes. Twelve participants (6 GDM and 6 non-GDM) were first enrolled and performed RNA sequencing analysis. The overlapped candidate genes were further screened in combination with differentially expressed genes (DEGs) of GEO datasets (GSE87295, GSE49524 and GSE19649) and potential target genes of DEMs. Candidate genes, critical pathways, small molecular compounds and regulatory networks were identified using bioinformatic analysis. The potential candidate genes were then investigated using the GEO dataset (GSE103552) of 19 participants in the validation stage (11 GDM and 8 non-GDM women).Results: Briefly, blood samples were sequenced interrogating 50 miRNAs, including 20 upregulated and 30 downregulated differentially expressed microRNAs(DEMs) in our internal screening dataset. After screening GEO databases, 123 upregulated and 70 downregulated genes were overlapped through DEGs of GEO datasets and miRNA-target genes. MiR-29b-1-5p-TGFB2, miR-142-3p-TGFB2, miR-9-5p-FBN2, miR-212-5p-FBN2, miR-542-3p-FBN1, miR-9-5p-FBN1, miR-508-3p-FBN1, miR-493-5p-THBS1, miR-29b-3p-COL4A1, miR-432-5p-COL5A2, miR-9-5p-TGFBI, miR-486-3p-SLC7A5 and miR-6515-5p-SLC1A5 were revealed as thirteen possible regulating pathways by integrative analysis.Conclusion: Overall, thirteen candidate miRNA-target gene regulatory pathways representing potentially novel biomarkers of GDM diseases were revealed. Ten chemicals were identified as putative therapeutic agents for GDM. This study examined a series of DEGs that are associated with epigenetic alternations of miRNA through an integrated approach and gained insight into biological pathways in GDM. Precise diagnosis and therapeutic targets of GDM would be further explored through putative genes in the future.

Background: The molecular mechanisms underlying obstructive sleep apnea (OSA) and its comorbidities may involve mitochondrial dysfunction. However, very little is known about the relationships between mitochondrial dysfunctionrelated genes and OSA. Methods: Mitochondrial dysfunction-related differentially expressed genes (DEGs) between OSA and control adipose tissue samples were identified using data from the Gene Expression Omnibus database and information on mitochondrial dysfunction-related genes from the GeneCards database. A mitochondrial dysfunction-related signature of diagnostic model was established using least absolute shrinkage and selection operator Cox regression and then verified. Additionally, consensus clustering algorithms were used to conduct an unsupervised cluster analysis. A protein-protein interaction network of the DEGs between the mitochondrial dysfunctionrelated clusters was constructed using STRING database and the hub genes were identified. Functional analyses, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA), were conducted to explore the mechanisms involved in mitochondrial dysfunction in OSA. Immune cell infiltration analyses were conducted using CIBERSORT and single-sample GSEA (ssGSEA). Results: we established mitochondrial dysfunction related four-gene signature of diagnostic model consisted of NPR3, PDIA3, SLPI, ERAP2, and which could easily distinguish between OSA patients and controls. In addition, based on mitochondrial dysfunction-related gene expression, we identified two clusters among all the samples and three clusters among the OSA samples. A total of 10 hub genes were selected from the PPI network of DEGs between the two mitochondrial dysfunction-related clusters. There were correlations between the 10 hub genes and the 4 diagnostic genes. Enrichment analyses suggested that autophagy, inflammation pathways, and immune pathways are crucial in mitochondrial dysfunction in OSA. Plasma cells and M0 and M1 macrophages were significantly different between the OSA and control samples, while several immune cell types, especially T cells (γ/δ T cells, natural killer T cells, regulatory T cells, and type 17 T helper cells), were significantly different among mitochondrial dysfunction-related clusters of OSA samples. Conclusion: A novel mitochondrial dysfunction-related four-gen signature of diagnostic model was built. The genes are potential biomarkers for OSA and may play important roles in the development of OSA complications. [ABSTRACT FROM AUTHOR]

Slow-burning inflammation at the lesion rim is connected to the expansion of chronic multiple sclerosis (MS) lesions. However, the underlying processes causing expansion are not clearly realized. In this context, the current study used a bioinformatics approach to identify the expression profiles and related lncRNA-associated ceRNA regulatory axes in the periplaque region in MS patients. Expression data (GSE52139) from periplaque regions in the secondary progressive MS spinal cord and controls were downloaded from the Gene Expression Omnibus database (GEO), which has details on mRNAs and lncRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also found using the DIANA-LncBase, miRTarBase, and HMDD databases. The Pearson correlation coefficient was used to determine whether there were any positive correlations between DEmRNAs and DElncRNAs in the ceRNA network. Finally, lncRNA-associated ceRNA axes were created based on co-expression and connections between DElncRNA, miRNA, and DEmRNA. We used the Enrichr tool to enrich the biological process, molecular function, and pathways for DEmRNAs and DElncRNAs. A network of DEmRNAs' protein-protein interactions was developed, and the top five hub genes were found using Cytoscape and STRING. The current study indicates that 15 DEmRNAs, including FOS, GJA1, NTRK2, CTNND1, and SP3, are connected to the MS ceRNA network. Additionally, four DElncRNAs (such as TUG1, ASB16-AS1, and LINC01094) that regulated the aforementioned mRNAs by sponging 14 MS-related miRNAs (e.g., hsa-miR-145-5p, hsa-miR-200a-3p, hsa-miR-20a-5p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-27a-3p, hsamiR-29b-3p, hsa-miR-29c-3p, hsa-miR-34a-5p) were found. In addition, the analysis of pathway enrichment revealed that DEmRNAs were enriched in the pathways for the "MAPK signaling pathway", "Kaposi sarcoma-associated herpesvirus infection", "Human immunodeficiency virus one infection", "Lipid and atherosclerosis", and "Amphetamine addiction". Even though the function of these ceRNA axes needs to be investigated further, this study provides research targets for studying ceRNA-mediated molecular mechanisms related to periplaque demyelination in MS. [ABSTRACT FROM AUTHOR]

Background: There has been growing evidence that the aberrantly expressed Homeobox-C 4 (HOXC4) plays crucial roles in the development of some cancer types. However, it remains unclear as far as its expression patterns and prognostic significance are concerned, as is tumor immunity. Methods: To investigate the expression levels and prognostic implications of HOXC4, multiple data sources were used in conjunction with quantitative realtime polymerase chain reaction (qRT-PCR) verification. Afterward, diverse immunological-related analyses, along with anti-cancer drug sensitivity, were performed in a number of cancer types. A further exploration of the underlying mechanisms of HOXC4 in tumorigenesis and immunity was carried out using the Gene Set Enrichment Analysis (GSEA) and the Gene Set Variation Analysis (GSVA). Results: Based on extensive database mining, HOXC4 was ubiquitously expressed across 21 tumor cell lines and significantly higher than that of normal tissues in 21 tumor types. The outcome of survival analysis including overall survival (OS), disease-free interval (DFI), disease-specific survival (DSS) and progression-free interval (PFI) revealed that upregulation of HOXC4 expression in several cancers was associated with worse prognosis. Additionally, HOXC4 was observed to correlate closely with colon adenocarcinoma (COAD), head and neck squamous cell carcinoma (HNSC), lower grade glioma (LGG), liver hepatocellular carcinoma (LIHC), rectum adenocarcinoma (READ), and thyroid carcinoma (THCA) in terms of tumor immune cells infiltration. As a result of our comprehensive pan-cancer study, we have identified a significant link between the expression of HOXC4 and the efficacy of immunotherapy-related treatments, together with anti-cancer drug sensitivity. As a final note, HOXC4 was found to modulate multiple signaling pathways involved in tumorigenesis and immunity. Conclusion: HOXC4 has been implicated in our study for the first time as an oncogene in cancers with a poor prognosis, potentially laying the groundwork for promising clinical biomarkers and immunotherapy approaches. [ABSTRACT FROM AUTHOR]

Background: The PITX gene family, comprising PITX1, PITX2, and PITX3, is critical in organogenesis and has been evolutionary conserved in animals. PITX genes are associated with the advanced progression and poor prognosis of multiple cancers. However, the relationship between the PITX genes and head and neck squamous cell carcinoma (HNSC) has not been reported. Methods: We used data from The Cancer Genome Atlas (TCGA) to analyze the association between PITX mRNA expression and clinicopathological parameters of patients with HNSC. The prognostic value of PITX genes was evaluated using the Kaplan-Meier plotter. Multivariate Cox analysis was used to screen out prognosis-associated genes to identify better prognostic indicators. The potential roles of PITX1 and PITX2 in HNSC prognosis were investigated using the protein-protein interaction (PPI) network, Gene Ontology (GO) analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The correlation between PITX1 and PITX2 expression or methylation and immune cell infiltration was evaluated using the tumor-immune system interaction database (TISIDB). MethSurv was used to identify DNA methylation and its effect on HNSC prognosis. Results: PITX genes expression was correlated with different cancers. PITX1 and PITX2 expression was lower in the patients with HNSC. In HNSC, PITX1 expression was significantly related to the clinical stage, histologic grade, and N stage, while PITX2 expression was only significantly related to the histologic grade. The high expression of PITX3 was significantly related to the histologic grade, T stage, and N stage. Survival analysis revealed that PITX genes had prognostic value in HNSC, which was supported by multivariate Cox analysis. PPI network and enrichment analysis showed that the genes interacting with PITX1 and PITX2 belonged predominantly to signaling pathways associated with DNA binding and transcription. Of the CpG DNA methylation sites in PITX1 and PITX2, 28 and 22 were related to the prognosis of HNSC, respectively. Additionally, PITX1 and PITX2 expression and methylation was associated with tumor-infiltrating lymphocytes (TILs). Conclusion: The PITX genes were differentially expressed in patients with HNSC, highlighting their essential role in DNA methylation and tumorinfiltrating immune cell regulation, as well as overall prognostic value in HNSC. [ABSTRACT FROM AUTHOR]

Background: There is limited research on cholesterol metabolism-related genes (CM-RGs) in non-alcoholic fatty liver disease (NAFLD), despite hypercholesterolemia being a recognized risk factor. The role of CM-RGs in NAFLD remains unclear., Methods: The differentially expressed genes (DEGs) between NAFLD and control were acquired by differential expression analysis. The differentially expressed genes associated with cholesterol metabolism (DE-CM-RGs) were identified and functional enrichment analyses were performed. Protein-protein interaction network analysis and a two-sample Mendelian randomization study were utilized for identifying hub genes. Nomogram model, competing endogenous RNA and messenger RNA-drug networks were established. In addition, immunoinfiltration analysis was performed., Results: We identified four hub genes (MVK, HMGCS1, TM7SF2, and FDPS) linked to NAFLD risk. MVK and TM7SF2 were protective factors, HMGCS1 and FDPS were risk factors for NAFLD. The area under the curve values of nomograms in GSE135251 and GSE126848 were 0.79 and 0.848, respectively. The gene set enrichment analysis indicated that hub genes participated in calcium signaling pathways and biosynthesis of unsaturated fatty acids. NAFLD patients showed increased CD56 dim NK cells and Th17. Tretinoin, alendronate, zoledronic acid, and quercetin are potential target agents in NAFLD., Conclusion: Our study has linked cholesterol metabolism genes (MVK, HMGCS1, TM7SF2, and FDPS) to NAFLD, providing a promising diagnostic framework, identifying treatment targets, and offering novel perspectives into its mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Rao and Zheng.)

Slow-burning inflammation at the lesion rim is connected to the expansion of chronic multiple sclerosis (MS) lesions. However, the underlying processes causing expansion are not clearly realized. In this context, the current study used a bioinformatics approach to identify the expression profiles and related lncRNA-associated ceRNA regulatory axes in the periplaque region in MS patients. Expression data (GSE52139) from periplaque regions in the secondary progressive MS spinal cord and controls were downloaded from the Gene Expression Omnibus database (GEO), which has details on mRNAs and lncRNAs. Using the R software’s limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also found using the DIANA-LncBase, miRTarBase, and HMDD databases. The Pearson correlation coefficient was used to determine whether there were any positive correlations between DEmRNAs and DElncRNAs in the ceRNA network. Finally, lncRNA-associated ceRNA axes were created based on co-expression and connections between DElncRNA, miRNA, and DEmRNA. We used the Enrichr tool to enrich the biological process, molecular function, and pathways for DEmRNAs and DElncRNAs. A network of DEmRNAs’ protein-protein interactions was developed, and the top five hub genes were found using Cytoscape and STRING. The current study indicates that 15 DEmRNAs, including FOS, GJA1, NTRK2, CTNND1, and SP3, are connected to the MS ceRNA network. Additionally, four DElncRNAs (such as TUG1, ASB16-AS1, and LINC01094) that regulated the aforementioned mRNAs by sponging 14 MS-related miRNAs (e.g., hsa-miR-145-5p, hsa-miR-200a-3p, hsa-miR-20a-5p, hsa-miR-22-3p, hsa-miR-23a-3p, hsa-miR-27a-3p, hsa-miR-29b-3p, hsa-miR-29c-3p, hsa-miR-34a-5p) were found. In addition, the analysis of pathway enrichment revealed that DEmRNAs were enriched in the pathways for the “MAPK signaling pathway”, “Kaposi sarcoma-associated herpesvirus infection”, “Human immunodeficiency virus one infection”, “Lipid and atherosclerosis”, and “Amphetamine addiction”. Even though the function of these ceRNA axes needs to be investigated further, this study provides research targets for studying ceRNA-mediated molecular mechanisms related to periplaque demyelination in MS.

Vascular dementia (VaD) is the second most common cause of dementia. At present, precise molecular processes of VaD are unclear. We attempted to discover the VaD relevant candidate genes, enrichment biological processes and pathways, key targets, and the underlying mechanism by microarray bioinformatic analysis. We selected GSE122063 related to the autopsy samples of VaD for analysis. We first took use of Weighted Gene Co-expression Network Analysis (WGCNA) to achieve modules related to VaD and hub genes. Second, we filtered out significant differentially expressed genes (DEGs). Third, significant DEGs then went through Geno Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Fourth, Gene Set Enrichment Analysis (GSEA) was performed. At last, we constructed the protein-protein interaction (PPI) network. The results showed that the yellow module had the strongest correlation with VaD, and we finally identified 21 hub genes. Toll-like receptor 2 (TLR2) was the top hub gene and was strongly correlated with other possible candidate genes. In total, 456 significant DEGs were filtered out and these genes were found to be enriched in the Toll receptor signaling pathway and several other immune-related pathways. In addition, Gene Set Enrichment Analysis results showed that similar pathways were significantly over-represented in TLR2-high samples. In the PPI network, TLR2 was still an important node with high weight and combined scores. We concluded that the TLR2 acts as a key target in neuroinflammation which may participate in the pathophysiological process of VaD. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most malignant childhood tumor. The outcome of neuroblastoma is hard to predict due to the limitation of prognostic markers. In our study, we constructed a 16-miRNA prognostic model to predict the overall survival of neuroblastoma patients for early diagnosis. A total of 205 DE miRNAs were screened using RNA sequencing data from GSE121513. Lasso Cox regression analysis generated a 16-miRNA signature consisting of hsa-let-7c, hsa-miR-135a, hsa-miR-137, hsa-miR-146a, hsa-miR-149, hsa-miR-15a, hsa-miR-195, hsa-miR-197, hsa-miR-200c, hsa-miR-204, hsa-miR-302a, hsa-miR-331, hsa-miR-345, hsa-miR-383, hsa-miR-93, and hsa-miR-9star. The concordance index of multivariate Cox regression analysis was 0.9, and the area under the curve (AUC) values of 3-year and 5-year survival were 0.92 and 0.943, respectively. The mechanism was further investigated using the TCGA and GSE90689 datasets. Two miRNA–gene interaction networks were constructed among DEGs from two datasets. Functional analysis revealed that immune-related processes were involved in the initiation and metastasis of neuroblastoma. CIBERSORT and survival analysis suggested that lower CD8 T-cell proportion and higher SPTA1 expressions were related to a better prognosis. Our study demonstrated that the miRNA signature may be useful in prognosis prediction and management improvement. [ABSTRACT FROM AUTHOR]

Recent studies have well demonstrated that 5-methylcytosine (m5C) regulators play pivotal roles in pathological conditions, including cancer. This study first tried to identify potential 5-methylcytosine (m5C) regulators in breast cancer by combination of expression, diagnosis, and survival analyses, and then established an ncRNA–mRNA network accounting for m5C regulators' roles in breast cancer. Among 13 m5C regulators, DNMT3B and ALYREF were significantly upregulated in breast cancer and their high expression indicated unfavorable prognosis. Both DNMT3B and ALYREF possessed the statistical abilities to distinguish breast cancer from normal breast samples. Moreover, five potential upstream miRNAs (let-7b-5p, miR-195-5p, miR-29a-3p, miR-26a-5p, and miR-26b-5p) of m5C regulators could not only serve as independent prognostic predictors but also together made up a promising miRNA prognostic signature in breast cancer. Next, upstream potential lncRNAs of the five miRNAs were predicted and analyzed. Pathway enrichment analysis revealed that the target genes of these miRNAs were markedly enriched in some cancer-related pathways, and further investigation indicated VEGFA and EZH2 were found to be the most potential target genes in the m5C regulators-related ncRNA–mRNA network in breast cancer. These findings comprehensively provided key clues for developing m5C regulators-related effective therapeutic targets and promising diagnostic biomarkers in breast cancer. [ABSTRACT FROM AUTHOR]

Acute respiratory distress syndrome (ARDS) is a leading cause of death in critically ill patients due to hypoxemic respiratory failure. The specific pathogenesis underlying ARDS has not been fully elucidated. In this study, we constructed a triple regulatory network involving competing endogenous RNA (ceRNA) to investigate the potential mechanism of ARDS and evaluated the immune cell infiltration patterns in ARDS patients. Overall, we downloaded three microarray datasets that included 60 patients with sepsis-induced ARDS and 79 patients with sepsis alone from the public Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs, including 9 DElncRNAs, 9 DEmiRNAs, and 269 DEmRNAs) by R software. The DEGs were subjected to the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional enrichment analysis, and a protein–protein interaction (PPI) network was generated for uncovering interactive relationships among DEmRNAs. Then, a ceRNA network that contained 5 DElncRNAs, 7 DEmiRNAs, and 71 DEmRNAs was established according to the overlapping genes in both DEGs and predicted genes by public databases. Finally, we identified the TUG1/miR-140-5p/NFE2L2 pathway as the hub pathway in the whole network through Cytoscape. In addition, we evaluated the distribution of 22 subtypes of immune cells and recognized three differentially expressed immune cells in patients with sepsis-induced ARDS by "Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT)" algorithm, namely, naive B cells, regulatory T cells, and eosinophils. Correlations between differentially expressed immune cells and hub genes in the ceRNA network were also performed. In conclusion, we demonstrated a new potential regulatory mechanism underlying ARDS (the TUG1/miR-140-5p/NFE2L2 ceRNA regulatory pathway), which may help in further exploring the pathogenesis of ARDS. [ABSTRACT FROM AUTHOR]

Recent studies have well demonstrated that 5-methylcytosine (m5C) regulators play pivotal roles in pathological conditions, including cancer. This study first tried to identify potential 5-methylcytosine (m5C) regulators in breast cancer by combination of expression, diagnosis, and survival analyses, and then established an ncRNA–mRNA network accounting for m5C regulators’ roles in breast cancer. Among 13 m5C regulators, DNMT3B and ALYREF were significantly upregulated in breast cancer and their high expression indicated unfavorable prognosis. Both DNMT3B and ALYREF possessed the statistical abilities to distinguish breast cancer from normal breast samples. Moreover, five potential upstream miRNAs (let-7b-5p, miR-195-5p, miR-29a-3p, miR-26a-5p, and miR-26b-5p) of m5C regulators could not only serve as independent prognostic predictors but also together made up a promising miRNA prognostic signature in breast cancer. Next, upstream potential lncRNAs of the five miRNAs were predicted and analyzed. Pathway enrichment analysis revealed that the target genes of these miRNAs were markedly enriched in some cancer-related pathways, and further investigation indicated VEGFA and EZH2 were found to be the most potential target genes in the m5C regulators-related ncRNA–mRNA network in breast cancer. These findings comprehensively provided key clues for developing m5C regulators-related effective therapeutic targets and promising diagnostic biomarkers in breast cancer.

Acute respiratory distress syndrome (ARDS) is a leading cause of death in critically ill patients due to hypoxemic respiratory failure. The specific pathogenesis underlying ARDS has not been fully elucidated. In this study, we constructed a triple regulatory network involving competing endogenous RNA (ceRNA) to investigate the potential mechanism of ARDS and evaluated the immune cell infiltration patterns in ARDS patients. Overall, we downloaded three microarray datasets that included 60 patients with sepsis-induced ARDS and 79 patients with sepsis alone from the public Gene Expression Omnibus (GEO) database and identified differentially expressed genes (DEGs, including 9 DElncRNAs, 9 DEmiRNAs, and 269 DEmRNAs) by R software. The DEGs were subjected to the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional enrichment analysis, and a protein–protein interaction (PPI) network was generated for uncovering interactive relationships among DEmRNAs. Then, a ceRNA network that contained 5 DElncRNAs, 7 DEmiRNAs, and 71 DEmRNAs was established according to the overlapping genes in both DEGs and predicted genes by public databases. Finally, we identified the TUG1/miR-140-5p/NFE2L2 pathway as the hub pathway in the whole network through Cytoscape. In addition, we evaluated the distribution of 22 subtypes of immune cells and recognized three differentially expressed immune cells in patients with sepsis-induced ARDS by “Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT)” algorithm, namely, naive B cells, regulatory T cells, and eosinophils. Correlations between differentially expressed immune cells and hub genes in the ceRNA network were also performed. In conclusion, we demonstrated a new potential regulatory mechanism underlying ARDS (the TUG1/miR-140-5p/NFE2L2 ceRNA regulatory pathway), which may help in further exploring the pathogenesis of ARDS.

Neuroblastoma is the most malignant childhood tumor. The outcome of neuroblastoma is hard to predict due to the limitation of prognostic markers. In our study, we constructed a 16-miRNA prognostic model to predict the overall survival of neuroblastoma patients for early diagnosis. A total of 205 DE miRNAs were screened using RNA sequencing data from GSE121513. Lasso Cox regression analysis generated a 16-miRNA signature consisting of hsa-let-7c, hsa-miR-135a, hsa-miR-137, hsa-miR-146a, hsa-miR-149, hsa-miR-15a, hsa-miR-195, hsa-miR-197, hsa-miR-200c, hsa-miR-204, hsa-miR-302a, hsa-miR-331, hsa-miR-345, hsa-miR-383, hsa-miR-93, and hsa-miR-9star. The concordance index of multivariate Cox regression analysis was 0.9, and the area under the curve (AUC) values of 3-year and 5-year survival were 0.92 and 0.943, respectively. The mechanism was further investigated using the TCGA and GSE90689 datasets. Two miRNA–gene interaction networks were constructed among DEGs from two datasets. Functional analysis revealed that immune-related processes were involved in the initiation and metastasis of neuroblastoma. CIBERSORT and survival analysis suggested that lower CD8 T-cell proportion and higher SPTA1 expressions were related to a better prognosis. Our study demonstrated that the miRNA signature may be useful in prognosis prediction and management improvement.

A high proportion of critically ill patients with coronavirus disease 2019 (COVID-19) experience thrombosis, and there is a strong correlation between anticoagulant therapy and the COVID-19 survival rate, indicating that common COVID-19 and thrombosis targets have potential therapeutic value for severe COVID-19.Gene expression profiling data were downloaded from Gene Expression Omnibus (GEO), and common differentially expressed genes (co-DEGs) were identified. The potential biological functions of these co-DEGs were explored by functional enrichment analysis, and protein–protein interaction (PPI) networks were constructed to elucidate the molecular mechanisms of the co-DEGs. Finally, hub genes in the co-DEG network were identified, and correlation analysis was performed.We identified 8320 upregulated genes and 7651 downregulated genes from blood samples of COVID-19 patients and 368 upregulated genes and 240 downregulated genes from blood samples of thrombosis patients. The enriched cellular component terms were mainly related to cytosolic ribosomes and ribosomal subunits. The enriched molecular function terms were mainly related to structural constituents of ribosomes and electron transfer activity. Construction of the PPI network and identification of hub genes ultimately confirmed that RPS7, IGF1R, DICER1, ERH, MCTS1, and TNPO1 were jointly upregulated hub genes, and FLNA and PXN were jointly downregulated hub genes.The identification of novel potential biomarkers provides new options for treating COVID-19-related thrombosis and reducing the rate of severe COVID-19. [ABSTRACT FROM AUTHOR]

Objective: The commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments of IgA nephropathy (IgAN) remains largely undetermined. We aim to perform bioinformatic analysis for providing a comprehensive insight into the characteristics of immune cells and associated molecular mechanisms in IgAN. Materials and Methods: We performed integrated bioinformatic analyses by using IgAN-related datasets from the Gene Expression Omnibus database. First, the differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Then, CIBERSORT was employed to determine the landscape of infiltrating immune cells in both glomerular and tubulointerstitial compartments of IgAN patients, followed by Pearson's correlation analysis and principal component analysis (PCA). Finally, commonly shared DEGs between glomerular and tubulointerstitial entities were recognized, followed by correlation analyses to identify the dominant commonly shared DEGs associated with immune cell infiltration in IgAN. Results: GO and KEGG enrichment analyses showed apparently distinct biological processes in the glomerular and tubulointerstitial compartments of IgAN. In addition, CIBERSORT analyses revealed a clear trend of increasing proportions of M1 macrophage and M2 macrophage in the glomerular compartment while noticeably higher proportions of resting CD4+ memory T cells and M2 macrophages in the tubulointerstitial compartments. The PCA analyses showed that the varying composition of immune cells in both glomerular and tubulointerstitial entities was compelling to distinguish IgAN patients from healthy living controls. In addition, 21 commonly shared DEGs between glomerular and tubulointerstitial entities were recognized as key regulators in the pathogenesis of IgAN, among which the enhanced hemoglobin subunit beta (HBB) gene expression was found to be positively associated with M2 macrophage in the glomerular compartment and resting CD4+ memory T cells in the tubulointerstitial compartment. Most importantly, FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene deficiency was recognized as the dominant alteration in promoting M2 macrophage infiltration in the glomerular compartment of IgAN. Conclusion: The findings from our current study for the first time reveal commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments, as well as decode the essential role of M2 macrophages and associated molecular patterns within the microenvironments of IgAN. [ABSTRACT FROM AUTHOR]

Purpose: Mitochondrial dysfunction refers to cancer immune evasion. A novel 7-gene prognostic signature related to the mitochondrial DNA copy number was utilized to evaluate the immunocyte infiltration in colon cancer according to the risk scores and to predict the survival for colon cancer. Experimental design: We performed an integrated bioinformatic analysis to analyze transcriptome profiling of the EB-treated mitochondrial DNA–defected NCM460 cell line with differentially expressed genes between tumor and normal tissues of COAD in TCGA. The LASSO analysis was utilized to establish a prognostic signature. ESTIMATE and CIBERSORT validated the differences of immunocyte infiltration between colon cancer patients with high- and low-risk scores. Results: Our study identified a 7-gene prognostic signature (LRRN2 , ANKLE1 , GPRASP1 , PRAME , TCF7L1 , RAB6B , and CALB2). Patients with colon cancer were split into the high- and low-risk group by the risk scores in TCGA (training cohort: HR = 2.50 p < 0.0001) and GSE39582 (validation cohort: HR = 1.43 p < 0.05). ESTIMATE and CIBERSORT revealed diverseness of immune infiltration in the two groups, especially downregulated T-cell infiltration in the patients with high-risk scores. Finally, we validated the colon patients with a low expression of the mitochondrial number biomarker TFAM had less CD3+ and CD8+ T-cell infiltration in clinical specimens. Conclusion: An mtDNA copy number-related 7-gene prognostic signature was investigated and evaluated, which may help to predict the prognosis of colon cancer patients and to guide clinical immunotherapy via immunocyte infiltration evaluation. [ABSTRACT FROM AUTHOR]

Objective: The commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments of IgA nephropathy (IgAN) remains largely undetermined. We aim to perform bioinformatic analysis for providing a comprehensive insight into the characteristics of immune cells and associated molecular mechanisms in IgAN.Materials and Methods: We performed integrated bioinformatic analyses by using IgAN-related datasets from the Gene Expression Omnibus database. First, the differentially expressed genes (DEGs) were identified and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Then, CIBERSORT was employed to determine the landscape of infiltrating immune cells in both glomerular and tubulointerstitial compartments of IgAN patients, followed by Pearson’s correlation analysis and principal component analysis (PCA). Finally, commonly shared DEGs between glomerular and tubulointerstitial entities were recognized, followed by correlation analyses to identify the dominant commonly shared DEGs associated with immune cell infiltration in IgAN.Results: GO and KEGG enrichment analyses showed apparently distinct biological processes in the glomerular and tubulointerstitial compartments of IgAN. In addition, CIBERSORT analyses revealed a clear trend of increasing proportions of M1 macrophage and M2 macrophage in the glomerular compartment while noticeably higher proportions of resting CD4+ memory T cells and M2 macrophages in the tubulointerstitial compartments. The PCA analyses showed that the varying composition of immune cells in both glomerular and tubulointerstitial entities was compelling to distinguish IgAN patients from healthy living controls. In addition, 21 commonly shared DEGs between glomerular and tubulointerstitial entities were recognized as key regulators in the pathogenesis of IgAN, among which the enhanced hemoglobin subunit beta (HBB) gene expression was found to be positively associated with M2 macrophage in the glomerular compartment and resting CD4+ memory T cells in the tubulointerstitial compartment. Most importantly, FBJ murine osteosarcoma viral oncogene homolog B (FOSB) gene deficiency was recognized as the dominant alteration in promoting M2 macrophage infiltration in the glomerular compartment of IgAN.Conclusion: The findings from our current study for the first time reveal commonalities and differences regarding immune states between glomerular and tubulointerstitial compartments, as well as decode the essential role of M2 macrophages and associated molecular patterns within the microenvironments of IgAN.

A high proportion of critically ill patients with coronavirus disease 2019 (COVID-19) experience thrombosis, and there is a strong correlation between anticoagulant therapy and the COVID-19 survival rate, indicating that common COVID-19 and thrombosis targets have potential therapeutic value for severe COVID-19.Gene expression profiling data were downloaded from Gene Expression Omnibus (GEO), and common differentially expressed genes (co-DEGs) were identified. The potential biological functions of these co-DEGs were explored by functional enrichment analysis, and protein–protein interaction (PPI) networks were constructed to elucidate the molecular mechanisms of the co-DEGs. Finally, hub genes in the co-DEG network were identified, and correlation analysis was performed.We identified 8320 upregulated genes and 7651 downregulated genes from blood samples of COVID-19 patients and 368 upregulated genes and 240 downregulated genes from blood samples of thrombosis patients. The enriched cellular component terms were mainly related to cytosolic ribosomes and ribosomal subunits. The enriched molecular function terms were mainly related to structural constituents of ribosomes and electron transfer activity. Construction of the PPI network and identification of hub genes ultimately confirmed that RPS7, IGF1R, DICER1, ERH, MCTS1, and TNPO1 were jointly upregulated hub genes, and FLNA and PXN were jointly downregulated hub genes.The identification of novel potential biomarkers provides new options for treating COVID-19-related thrombosis and reducing the rate of severe COVID-19.

Purpose: Mitochondrial dysfunction refers to cancer immune evasion. A novel 7-gene prognostic signature related to the mitochondrial DNA copy number was utilized to evaluate the immunocyte infiltration in colon cancer according to the risk scores and to predict the survival for colon cancer.Experimental design: We performed an integrated bioinformatic analysis to analyze transcriptome profiling of the EB-treated mitochondrial DNA–defected NCM460 cell line with differentially expressed genes between tumor and normal tissues of COAD in TCGA. The LASSO analysis was utilized to establish a prognostic signature. ESTIMATE and CIBERSORT validated the differences of immunocyte infiltration between colon cancer patients with high- and low-risk scores.Results: Our study identified a 7-gene prognostic signature (LRRN2, ANKLE1, GPRASP1, PRAME, TCF7L1, RAB6B, and CALB2). Patients with colon cancer were split into the high- and low-risk group by the risk scores in TCGA (training cohort: HR = 2.50 p < 0.0001) and GSE39582 (validation cohort: HR = 1.43 p < 0.05). ESTIMATE and CIBERSORT revealed diverseness of immune infiltration in the two groups, especially downregulated T-cell infiltration in the patients with high-risk scores. Finally, we validated the colon patients with a low expression of the mitochondrial number biomarker TFAM had less CD3+ and CD8+ T-cell infiltration in clinical specimens.Conclusion: An mtDNA copy number-related 7-gene prognostic signature was investigated and evaluated, which may help to predict the prognosis of colon cancer patients and to guide clinical immunotherapy via immunocyte infiltration evaluation.

Spinal cord injury (SCI) and ankylosing spondylitis (AS) are common inflammatory diseases in spine surgery. However, it is a project where the relationship between the two diseases is ambiguous and the efficiency of drug discovery is limited. Therefore, the study aimed to investigate new drug therapies for SCI and AS. First, text mining was used to obtain the interacting genes related to SCI and AS, and then, the functional analysis was conducted. Protein–protein interaction (PPI) networks were constructed by STRING online and Cytoscape software to identify hub genes. Last, hub genes and potential drugs were performed after undergoing drug–gene interaction analysis, and MicroRNA and transcription factors regulatory networks were also analyzed. Two hundred five genes common to "SCI" and "AS" identified by text mining were enriched in inflammatory responses. PPI network analysis showed that 30 genes constructed two significant modules. Ultimately, nine (SST , VWF , IL1B , IL6 , CXCR4 , VEGFA , SERPINE1 , FN1 , and PROS1) out of 30 genes could be targetable by a total of 13 drugs. In conclusion, the novel core genes contribute to a novel insight for latent functional mechanisms and present potential prognostic indicators and therapeutic targets in SCI and AS. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) and ankylosing spondylitis (AS) are common inflammatory diseases in spine surgery. However, it is a project where the relationship between the two diseases is ambiguous and the efficiency of drug discovery is limited. Therefore, the study aimed to investigate new drug therapies for SCI and AS. First, text mining was used to obtain the interacting genes related to SCI and AS, and then, the functional analysis was conducted. Protein–protein interaction (PPI) networks were constructed by STRING online and Cytoscape software to identify hub genes. Last, hub genes and potential drugs were performed after undergoing drug–gene interaction analysis, and MicroRNA and transcription factors regulatory networks were also analyzed. Two hundred five genes common to “SCI” and “AS” identified by text mining were enriched in inflammatory responses. PPI network analysis showed that 30 genes constructed two significant modules. Ultimately, nine (SST, VWF, IL1B, IL6, CXCR4, VEGFA, SERPINE1, FN1, and PROS1) out of 30 genes could be targetable by a total of 13 drugs. In conclusion, the novel core genes contribute to a novel insight for latent functional mechanisms and present potential prognostic indicators and therapeutic targets in SCI and AS.

Ferroptosis has been observed to play an important role during erythrocyte differentiation (ED). However, the biological gene markers and ferroptosis mechanisms in ED remain unknown. We downloaded the datasets of ED in human umbilical cord blood-derived CD34 + cells from the Gene Expression Omnibus database. Using median differentiation time, the sample was categorized into long and short groups. The differentially expressed ferroptosis-related genes (DE-FRGs) were screened using differential expression analysis. The enrichment analyses and a protein-protein interaction (PPI) network were conducted. To predict the ED stage, a logistic regression model was constructed using the least absolute shrinkage and selection operator (LASSO). Overall, 22 DE-FRGs were identified. Ferroptosis-related pathways were enriched using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. Gene Set Enrichment Analysis and Gene Set Variation Analysis revealed the primary involvement of DE-FRGs in JAK-STAT, MAPK, PI3K-AKT-mTORC1, WNT, and NOTCH signaling pathways. Ten-hub DE-FRGs were obtained using PPI analysis. Furthermore, we constructed mRNA-microRNA (miRNA) and mRNA-transcription factor networks. Immune cell infiltration levels differed significantly during ED. LASSO regression analysis established a signature using six DE-FRGs ( ATF3, CDH2, CHAC1, DDR2, DPP4, and GDF15 ) related to the ED stage. Bioinformatic analyses identified ferroptosis-associated genes during ED, which were further validated. Overall, we identified ferroptosis-related genes to predict their correlations in ED. Exploring the underlying mechanisms of ferroptosis may help us better understand pathophysiological changes in ED and provide new evidence for clinical transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Lin, Yue, Wu, Li, Huang, Fang, Zhang and Hao.)

Background: Hepatocellular carcinoma (HCC) is the most frequent fatal malignancy, and it has a poor prognosis. Apolipoprotein 1 (APOA-1), the main protein component of high-density lipoproteins, is involved in numerous biological processes. Thus, this study was performed to detect the clinical significance of APOA-1 mRNA, APOA-1 expression, and APOA-1DNA methylation in patients with HCC. Methods: Data mining was performed using clinical and survival data from the Cancer Genome Atlas (TCGA) and Oncomine databases. The serum concentration of APOA-1 was measured in 316 patients with HCC and 100 healthy individuals at Renmin Hospital of Wuhan University, and the intact clinical information was reviewed and determined using univariate and multivariate Cox hazard models. Results: Bioinformatic analysis revealed that APOA-1 mRNA was present at lower levels in the serum of patients with HCC than in that of healthy individuals, and there was a strong negative correlation between levels of APOA-1 mRNA and APOA-1 DNA methylation. High expression of APOA-1 transcription correlated with better overall survival (p = 0.003), and APOA-1 hypermethylation correlated with progress-free survival (p = 0.045) in HCC sufferers. Next, the clinical data analysis demonstrated that APOA-1 protein levels in the serum were significantly lower in patients with HCC than in healthy controls. Furthermore, the expression of APOA-1 was significantly associated with some significant clinical indexes, and elevated APOA-1 expression was significantly associated with favorable (OS; HR:1.693, 95% CI: 1.194–2.401, p = 0.003) and better progression-free survival (PFS; HR = 1.33, 95% CI = 1.194–2.401, p = 0.045). Finally, enrichment analysis suggested that co-expressed genes of APOA-1 were involved in lipoprotein metabolism and FOXA2/3 transcription factor networks. Conclusion: APOA-1 mRNA expression is negatively regulated by DNA methylation in HCC. Low expression of APOA-1 might be a potential risk biomarker to predict survival in patients with HCC. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma (LUAD) was the first one all over the world. RAB11FIP1 was found to be expressed differently in a critical way among different cancers. However, the prognostic value and immune infiltration of RAB11FIP1 expression in LUAD are unclear. In this study, the expression of RAB11FIP1 in LUAD was investigated in the Oncomine, TCGA, GEO, and UALCAN databases. Kaplan-Meier analysis was chosen to compare the association between RAB11FIP1 expression and overall survival (OS) in LUAD patients. The dataset of TCGA was used to analyze the pertinence between RAB11FIP1 and clinicpathological factors. GO, KEGG, and network analysis of protein-protein interactions (PPI) were conducted to investigate the potential mechanism of RAB11FIP1. In the end, the relevance of RAB11FIP1 to cancer-immune infiltrates was investigated. RAB11FIP1 was found to be down-regulated by tumors compared with adjacent normal tissue in multiple LUAD cohorts. RAB11FIP1 is an independent prognostic factor in lung adenocarcinoma. There was a high correlation between low RAB11FIP1 in tumors and worse OS in LUAD. Functional network analysis suggested that RAB11FIP1 was associated with multiple pathways. Besides, the expression of RAB11FIP1 was closely related to the infiltration levels of B cell, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. RAB11FIP1 expression in LUAD occurred with a variety of immune markers. Our findings suggest that RAB11FIP1 is related to prognosis and immune infiltrates in LUAD. [ABSTRACT FROM AUTHOR]

Juvenile-onset diabetes may occur in the context of a rare syndromic presentation, suggesting a monogenic etiology rather than a common multifactorial diabetes. In the present study, we report the case of a young diabetic Tunisian patient presenting learning problems, speech deficits, short stature, brachydactyly, and a normal weight. Whole exome sequencing analysis revealed five heterozygous genetic variants in BBS1, BBS4, BBS8, MKS1 , and CEP290. These genes are involved in the regulation of cilium biogenesis and function. We analyzed variant combinations pathogenicity using the recently developed ORVAL tool, and we hypothesized that cumulative synergetic effects of these variants could explain the syndromic phenotype observed in our patient. Therefore, our investigation suggested a genetic diagnosis of Bardet–Biedl syndrome with an oligogenic inheritance pattern rather than a monogenic diabetes. Although there is no curative therapy for this ciliopathy at the moment, a genetic diagnosis may offer other supportive care options, including the prevention of other possible clinical manifestations of this syndrome, mainly renal abnormalities, obesity, liver fibrosis, and hypertension, as well as the genetic counseling for family members. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is the most frequent fatal malignancy, and it has a poor prognosis. Apolipoprotein 1 (APOA-1), the main protein component of high-density lipoproteins, is involved in numerous biological processes. Thus, this study was performed to detect the clinical significance of APOA-1 mRNA, APOA-1 expression, and APOA-1DNA methylation in patients with HCC.Methods: Data mining was performed using clinical and survival data from the Cancer Genome Atlas (TCGA) and Oncomine databases. The serum concentration of APOA-1 was measured in 316 patients with HCC and 100 healthy individuals at Renmin Hospital of Wuhan University, and the intact clinical information was reviewed and determined using univariate and multivariate Cox hazard models.Results: Bioinformatic analysis revealed that APOA-1 mRNA was present at lower levels in the serum of patients with HCC than in that of healthy individuals, and there was a strong negative correlation between levels of APOA-1 mRNA and APOA-1 DNA methylation. High expression of APOA-1 transcription correlated with better overall survival (p = 0.003), and APOA-1 hypermethylation correlated with progress-free survival (p = 0.045) in HCC sufferers. Next, the clinical data analysis demonstrated that APOA-1 protein levels in the serum were significantly lower in patients with HCC than in healthy controls. Furthermore, the expression of APOA-1 was significantly associated with some significant clinical indexes, and elevated APOA-1 expression was significantly associated with favorable (OS; HR:1.693, 95% CI: 1.194–2.401, p = 0.003) and better progression-free survival (PFS; HR = 1.33, 95% CI = 1.194–2.401, p = 0.045). Finally, enrichment analysis suggested that co-expressed genes of APOA-1 were involved in lipoprotein metabolism and FOXA2/3 transcription factor networks.Conclusion: APOA-1 mRNA expression is negatively regulated by DNA methylation in HCC. Low expression of APOA-1 might be a potential risk biomarker to predict survival in patients with HCC.

Juvenile-onset diabetes may occur in the context of a rare syndromic presentation, suggesting a monogenic etiology rather than a common multifactorial diabetes. In the present study, we report the case of a young diabetic Tunisian patient presenting learning problems, speech deficits, short stature, brachydactyly, and a normal weight. Whole exome sequencing analysis revealed five heterozygous genetic variants in BBS1, BBS4, BBS8, MKS1, and CEP290. These genes are involved in the regulation of cilium biogenesis and function. We analyzed variant combinations pathogenicity using the recently developed ORVAL tool, and we hypothesized that cumulative synergetic effects of these variants could explain the syndromic phenotype observed in our patient. Therefore, our investigation suggested a genetic diagnosis of Bardet–Biedl syndrome with an oligogenic inheritance pattern rather than a monogenic diabetes. Although there is no curative therapy for this ciliopathy at the moment, a genetic diagnosis may offer other supportive care options, including the prevention of other possible clinical manifestations of this syndrome, mainly renal abnormalities, obesity, liver fibrosis, and hypertension, as well as the genetic counseling for family members.

Lung adenocarcinoma (LUAD) was the first one all over the world. RAB11FIP1 was found to be expressed differently in a critical way among different cancers. However, the prognostic value and immune infiltration of RAB11FIP1 expression in LUAD are unclear. In this study, the expression of RAB11FIP1 in LUAD was investigated in the Oncomine, TCGA, GEO, and UALCAN databases. Kaplan-Meier analysis was chosen to compare the association between RAB11FIP1 expression and overall survival (OS) in LUAD patients. The dataset of TCGA was used to analyze the pertinence between RAB11FIP1 and clinicpathological factors. GO, KEGG, and network analysis of protein-protein interactions (PPI) were conducted to investigate the potential mechanism of RAB11FIP1. In the end, the relevance of RAB11FIP1 to cancer-immune infiltrates was investigated. RAB11FIP1 was found to be down-regulated by tumors compared with adjacent normal tissue in multiple LUAD cohorts. RAB11FIP1 is an independent prognostic factor in lung adenocarcinoma. There was a high correlation between low RAB11FIP1 in tumors and worse OS in LUAD. Functional network analysis suggested that RAB11FIP1 was associated with multiple pathways. Besides, the expression of RAB11FIP1 was closely related to the infiltration levels of B cell, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. RAB11FIP1 expression in LUAD occurred with a variety of immune markers. Our findings suggest that RAB11FIP1 is related to prognosis and immune infiltrates in LUAD.

Dysregulation of autophagy-related genes (ARGs) is related to the prognosis of cancers. However, the aberrant expression of ARGs signature in the prognosis of hepatocellular carcinoma (HCC) remain unclear. Using The Cancer Genome Atlas and the International Cancer Genome Consortium database, 188 common autophagy-related gene pairs (ARGPs) were identified. Through univariate, least absolute shrinkage and selection operator analysis, and multivariate Cox regression analysis, a prognostic signature of the training set was constructed on the basis of 6 ARGPs. Further analysis revealed that the ARGP based signature performed more accurately in overall survival (OS) prediction compared to other published gene signatures. In addition, a high risk of HCC was closely related to CTLA4 upregulation, LC3 downregulation, low-response to axitinib, rapamycin, temsirolimus, docetaxel, metformin, and high-response to bleomycin. Univariate Cox and multivariate Cox analysis revealed that the risk score was an independent prognostic factor for HCC. These results were internally validated in the test and TCGA sets and externally validated in the ICGC set. A nomogram, consisting of the risk score and the TNM stage, performed well when compared to an ideal nomogram. In conclusion, a 6-ARGP-based prognostic signature was identified and validated as an effective predictor of OS of patients with HCC. Furthermore, we recognized six small-molecule drugs, which may be potentially effective in treating HCC.

Cation gradients in plant cellular compartments are maintained by the synergistic actions of various ion exchangers, pumps, and channels. Cation/Ca2+ exchanger (CCX) is one of the clades of the Ca2+/cation antiporter super family. Here, five SlCCX genes were identified in tomato. Sequence analysis indicated that SlCCXs have the conserved motifs as the CCX domain. Analysis of the expression level of each member of tomato CCX gene family under cation (Mg2+, Mn2+, Na+, and Ca2+) treatment was determined by qRT-PCR. Tomato CCX demonstrated different degrees of responding to cation treatment. Changes in SlCCX1-LIKE expression was induced by Mg2+ and Mn2+ treatment. Analysis of the expression of SlCCX genes in different tissues demonstrated that constitutive high expression of a few genes, including SlCCX1-LIKE and SlCCX5, indicated their role in tomato organ growth and development. Overexpression of SlCCX1-LIKE dramatically induced leaf senescence. Transcriptome analysis showed that genes related to ROS and several IAA signaling pathways were significantly downregulated, whereas ETH and ABA signaling pathway-related genes were upregulated in overexpression of SlCCX1-LIKE (OE-SlCCX1-LIKE) plants, compared with the wild type (WT). Moreover, overexpression of SlCCX1-LIKE plants accumulated more ROS content but less Mg2+ content. Collectively, the findings of this study provide insights into the base mechanism through which CCXs regulate leaf senescence in tomato.

Dysregulation of autophagy-related genes (ARGs) is related to the prognosis of cancers. However, the aberrant expression of ARGs signature in the prognosis of hepatocellular carcinoma (HCC) remain unclear. Using The Cancer Genome Atlas and the International Cancer Genome Consortium database, 188 common autophagy-related gene pairs (ARGPs) were identified. Through univariate, least absolute shrinkage and selection operator analysis, and multivariate Cox regression analysis, a prognostic signature of the training set was constructed on the basis of 6 ARGPs. Further analysis revealed that the ARGP based signature performed more accurately in overall survival (OS) prediction compared to other published gene signatures. In addition, a high risk of HCC was closely related to CTLA4 upregulation, LC3 downregulation, low-response to axitinib, rapamycin, temsirolimus, docetaxel, metformin, and high-response to bleomycin. Univariate Cox and multivariate Cox analysis revealed that the risk score was an independent prognostic factor for HCC. These results were internally validated in the test and TCGA sets and externally validated in the ICGC set. A nomogram, consisting of the risk score and the TNM stage, performed well when compared to an ideal nomogram. In conclusion, a 6-ARGP-based prognostic signature was identified and validated as an effective predictor of OS of patients with HCC. Furthermore, we recognized six small-molecule drugs, which may be potentially effective in treating HCC. [ABSTRACT FROM AUTHOR]

Cation gradients in plant cellular compartments are maintained by the synergistic actions of various ion exchangers, pumps, and channels. Cation/Ca2+ exchanger (CCX) is one of the clades of the Ca2+/cation antiporter super family. Here, five SlCCX genes were identified in tomato. Sequence analysis indicated that SlCCXs have the conserved motifs as the CCX domain. Analysis of the expression level of each member of tomato CCX gene family under cation (Mg2+, Mn2+, Na+, and Ca2+) treatment was determined by qRT-PCR. Tomato CCX demonstrated different degrees of responding to cation treatment. Changes in SlCCX1-LIKE expression was induced by Mg2+ and Mn2+ treatment. Analysis of the expression of SlCCX genes in different tissues demonstrated that constitutive high expression of a few genes, including SlCCX1-LIKE and SlCCX5 , indicated their role in tomato organ growth and development. Overexpression of SlCCX1-LIKE dramatically induced leaf senescence. Transcriptome analysis showed that genes related to ROS and several IAA signaling pathways were significantly downregulated, whereas ETH and ABA signaling pathway-related genes were upregulated in overexpression of SlCCX1-LIKE (OE-SlCCX1-LIKE) plants, compared with the wild type (WT). Moreover, overexpression of SlCCX1-LIKE plants accumulated more ROS content but less Mg2+ content. Collectively, the findings of this study provide insights into the base mechanism through which CCXs regulate leaf senescence in tomato. [ABSTRACT FROM AUTHOR]

Background: The majority of chronic liver disease is caused by non-alcoholic fatty liver disease (NAFLD), which is one of the highly prevalent diseases worldwide. The current studies have found that non-coding RNA (ncRNA) plays an important role in the NAFLD, but few studies on circRNA. In this study, genes, microRNA (miRNA), and circular RNA (circRNA) associated with NAFLD were found by bioinformatic methods, bringing a novel perspective for the prevention and treatment of NAFLD.Methods: Expression data of GSE63067 was acquired from Gene Expression Omnibus (GEO) database. The liver samples were collected from the people diagnosed with NAFLD or not. Differentially expressed genes (DEGs) were obtained from the steatosis vs. the control group and non-alcoholic steatohepatitis (NASH) vs. the control group using the GEO2R online tool. The overlapping genes remained for further functional enrichment analysis and protein-protein interaction network analysis. MiRNAs and circRNAs targeting these overlapping DEGs were predicted from the databases. Finally, the GSE134146 dataset was used to verify the expression of circRNA.Results: In summary, 228 upregulated and 63 downregulated differential genes were selected. The top 10 biological processes and relative signaling pathways of the upregulated differential genes were obtained. Also, ten hub genes were performed in the Protein-protein interaction (PPI) network. One hundred thirty-nine miRNAs and 902 circRNAs were forecast for the differential genes by the database. Ultimately, the crosstalk between hsa_circ_0000313, miR-6512-3p, and PEG10 was constructed.Conclusion: The crosstalk of hsa_circ_0000313-hsa-miR-6512-3p-PEG10 and some related non-coding RNAs may take part in NAFLD’s pathogenesis, which could be the potential biomarkers of NAFLD in the future.

BackgroundChaperonin-containing TCP-1 (TRiC or CCT) was demonstrated to be involved in oncogenesis of cancers carcinogenesis and development of various malignancies. Increasing experimental evidence indicated that dysregulation of TRiC was implicated in the tumor progression of breast cancer (BCa). However, few definitive studies have addressed the diverse expression patterns and prognostic values of eight TRiC subunits. Thus, we aimed to investigate the clinical significance of TRiC subunit expression and prognostic values for their possible implications in diagnosis and treatment of BCa.MethodsBased on updated public resources and comprehensive bioinformatics analysis, we used some online databases (e.g., UALCAN, GEPIA, cBioPortal, TIMER, BC-GenExMiner, metascape, and GeneMANIA) to comprehensively explore the expression levels and the prognostic effects of eight TRiC subunits in patients with BCa.ResultsThe transcriptional levels of most subunits of the Chaperonin TRiC (CCT2, CCT3, CCT4, CCT5, CCT6A, and CCT7) were significantly elevated compared with normal breast tissues, whereas TCP1, CCT4, and CCT6B were lower in BCa tissues than in normal tissues. Besides, copy-number alterations (CNA) of eight TRiC subunits positively regulated their mRNA expressions. Furthermore, high mRNA expression of TCP1/CCT2/CCT4/CCT5/CCT6A/CCT7/CCT8 was significantly associated with poor overall survival (OS) in BCa patients. The eight subunits of the chaperonin TRiC was related to tumor purity and immune infiltration levels of BCa. Co-expression analysis showed CCT6B was negatively associated with other subunits of TRiC and other subunits of TRiC were positively correlated with each other. Additionally, TRiC and their interactive proteins were correlated with positive regulation of biological process, localization, and biological regulation.ConclusionThis study systematically illustrated the expression profiles and distinct prognostic values of chaperonin TRiC in BCa, providing insights for further investigation of subunits of the chaperonin TRiC as novel therapeutic targets and potential prognostic biomarkers in BCa.

Background: The majority of chronic liver disease is caused by non-alcoholic fatty liver disease (NAFLD), which is one of the highly prevalent diseases worldwide. The current studies have found that non-coding RNA (ncRNA) plays an important role in the NAFLD, but few studies on circRNA. In this study, genes, microRNA (miRNA), and circular RNA (circRNA) associated with NAFLD were found by bioinformatic methods, bringing a novel perspective for the prevention and treatment of NAFLD. Methods: Expression data of GSE63067 was acquired from Gene Expression Omnibus (GEO) database. The liver samples were collected from the people diagnosed with NAFLD or not. Differentially expressed genes (DEGs) were obtained from the steatosis vs. the control group and non-alcoholic steatohepatitis (NASH) vs. the control group using the GEO2R online tool. The overlapping genes remained for further functional enrichment analysis and protein-protein interaction network analysis. MiRNAs and circRNAs targeting these overlapping DEGs were predicted from the databases. Finally, the GSE134146 dataset was used to verify the expression of circRNA. Results: In summary, 228 upregulated and 63 downregulated differential genes were selected. The top 10 biological processes and relative signaling pathways of the upregulated differential genes were obtained. Also, ten hub genes were performed in the Protein-protein interaction (PPI) network. One hundred thirty-nine miRNAs and 902 circRNAs were forecast for the differential genes by the database. Ultimately, the crosstalk between hsa_circ_0000313, miR-6512-3p, and PEG10 was constructed. Conclusion: The crosstalk of hsa_circ_0000313-hsa-miR-6512-3p- PEG10 and some related non-coding RNAs may take part in NAFLD's pathogenesis, which could be the potential biomarkers of NAFLD in the future. [ABSTRACT FROM AUTHOR]

Background: Chaperonin-containing TCP-1 (TRiC or CCT) was demonstrated to be involved in oncogenesis of cancers carcinogenesis and development of various malignancies. Increasing experimental evidence indicated that dysregulation of TRiC was implicated in the tumor progression of breast cancer (BCa). However, few definitive studies have addressed the diverse expression patterns and prognostic values of eight TRiC subunits. Thus, we aimed to investigate the clinical significance of TRiC subunit expression and prognostic values for their possible implications in diagnosis and treatment of BCa. Methods: Based on updated public resources and comprehensive bioinformatics analysis, we used some online databases (e.g., UALCAN, GEPIA, cBioPortal, TIMER, BC-GenExMiner, metascape, and GeneMANIA) to comprehensively explore the expression levels and the prognostic effects of eight TRiC subunits in patients with BCa. Results: The transcriptional levels of most subunits of the Chaperonin TRiC (CCT2, CCT3, CCT4, CCT5, CCT6A, and CCT7) were significantly elevated compared with normal breast tissues, whereas TCP1, CCT4, and CCT6B were lower in BCa tissues than in normal tissues. Besides, copy-number alterations (CNA) of eight TRiC subunits positively regulated their mRNA expressions. Furthermore, high mRNA expression of TCP1/CCT2/CCT4/CCT5/CCT6A/CCT7/CCT8 was significantly associated with poor overall survival (OS) in BCa patients. The eight subunits of the chaperonin TRiC was related to tumor purity and immune infiltration levels of BCa. Co-expression analysis showed CCT6B was negatively associated with other subunits of TRiC and other subunits of TRiC were positively correlated with each other. Additionally, TRiC and their interactive proteins were correlated with positive regulation of biological process, localization, and biological regulation. Conclusion: This study systematically illustrated the expression profiles and distinct prognostic values of chaperonin TRiC in BCa, providing insights for further investigation of subunits of the chaperonin TRiC as novel therapeutic targets and potential prognostic biomarkers in BCa. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and limited treatment options. Although immune checkpoint inhibitors (ICIs) have been proven to improve outcomes in TNBC patients, the potential mechanisms and markers that determine the therapeutic response to ICIs remains uncertain. Revealing the relationship and interaction between cancer cells and tumor microenvironment (TME) could be helpful in predicting treatment efficacy and developing novel therapeutic agents. By analyzing single-cell RNA sequencing dataset, we comprehensively profiled cell types and subpopulations as well as identified their signatures in the TME of TNBC. We also proposed a method for quantitatively assessment of the TME immune profile and provided a framework for identifying cancer cell-intrinsic features associated with TME through integrated analysis. Using integrative analyses, RARRES1 was identified as a TME-associated gene, whose expression was positively correlated with prognosis and response to ICIs in TNBC. In conclusion, this study characterized the heterogeneity of cellular components in TME of TNBC patients, and brought new insights into the relationship between cancer cells and TME. In addition, RARRES1 was identified as a potential predictor of prognosis and response to ICIs in TNBC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Liu, Ye, Liu, Xin, Liu, Cheng, Yin and Xu.)

Colorectal cancer (CRC) is one of the most malignant cancers with high morbidity and mortality. MicroRNAs (miRNAs) are small non-coding RNAs that affect biological processes by binding to mRNAs and regulating their expression, and epigenetic alterations including miRNA dysregulation are significantly involved in CRC development. Determining the effect of the miRNA-mRNA network on CRC could be helpful for developing novel therapeutic targets and prognostic biomarkers, and even improving survival. In this study, microarray assays were used to screen differentially expressed miRNAs (DE miRNAs) and mRNAs (DE mRNAs) in CRC and the adjacent normal tissues. Among the detected genes, 42 miRNAs and 142 mRNAs were significantly upregulated in CRC, while 23 miRNAs and 279 mRNAs were significantly downregulated. Through overlapping of predicted targets of DE miRNAs and anti-expressed DE mRNAs, networks of DE miRNAs and DE mRNAs in CRC were established. Additionally, the formation of a protein-protein interaction network of DE mRNAs possibly targeted by DE miRNAs, functional annotation and pathway analysis, stable subnetwork mining, and determination of hub genes provided the probable mechanism used by DE miRNAs and DE mRNAs to regulate CRC growth. Finally, validation of expression and prognostic potential of hub genes provided further support for the results above and indicated that CCL-28, GPR15, PNOC, NUSAP1, and their interacted miRNAs may be a potential signature for prognosis of CRC patients. In sum, we successfully established miRNA-mRNA regulatory networks based on microarray results targeting CRC, and these findings may elucidate the mechanisms used for CRC growth and identify miRNA-related signatures for prognosis and treatment of CRC.

Single nucleotide polymorphisms (SNPs) in the IL1RL1–IL18R1 region are associated with various immune-mediated diseases. This study was carried out to investigate the causal variant for ocular Behçet’s disease (BD) and elucidate its target genes in the IL1RL1–IL18R1 region. Nine candidate functional SNPs were prioritized with bioinformatics analysis, followed by a two-stage association study in 694 ocular BD patients and 1,458 unaffected controls. Functional studies were performed in the peripheral blood mononuclear cells (PBMCs) of 45 healthy men and 16 active male BD patients. Genotyping was performed using the MassARRAY System. The mRNA expressions of IL1RL1, IL18R1, IL18RAP, and SLC9A4 were assayed by real-time PCR and secretion of cytokines was examined by ELISA. Significantly lower frequencies of the rs12987977 GG genotype/G allele (Pc = 8.93 × 10–7, OR = 0.39; Pc = 2.60 × 10–3, OR = 0.77, respectively), rs12999364 TT genotype/T allele (Pc = 3.15 × 10–4, OR = 0.51; Pc = 1.13 × 10–2, OR = 0.80, respectively), and rs4851569 AA genotype/A allele (Pc = 3.29 × 10–4, OR = 0.52; Pc = 9.72 × 10–3, OR = 0.80, respectively) were observed in BD patients compared with the controls. Functional experiments revealed a downregulation of IL1RL1, IL18R1, and SLC9A4 and a decreased secretion of IFN-γ in the anti-CD3/CD28 antibody-treated PBMCs as well as a decreased production of TNF-α in the lipopolysaccharide (LPS)-stimulated PBMCs in carriers of the protective homozygous rs12987977/GG genotype compared with the TT genotype. Our findings show that functional SNPs—rs12987977, rs12999364, and rs4851569—in the IL1RL1–IL18R1 region confer susceptibility to ocular BD in a Chinese Han population. And IL1RL1, IL18R1, and SLC9A4 may be the target genes of rs12987977.

Studies have shown that long non-coding RNA (lncRNA) may act as the carcinogenic factor or tumor suppressor of laryngeal squamous cell carcinoma (LSCC). This study aims to identify the prognostic value and potential target protein-coding genes (PCGs) of lncRNAs in LSCC. The LSCC datasets were collected from The Cancer Genome Atlas (TCGA). Statistical and bioinformatic methods were used to establish and evaluate the prognostic model, identify the correlation between lncRNAs and clinical characteristics, and screen for PCGs co-expressed with lncRNAs. Weighted gene co-expression network analysis (WGCNA) identified PCG modules associated with clinical characteristics. The expression of lncRNAs and PCGs was analyzed using our LSCC patients by RT-qPCR. LINC02154, LINC00528, SPRY4-AS1, TTTY14, LNCSRLR, and KLHL7-DT were selected to establish the prognostic model. The overall survival (OS) of low-risk patients forecasted by the model was significantly better than high-risk patients. Receiver operating characteristic (ROC) curve and concordance index (C-index) validated the accuracy of the prognostic model. Chi-square test showed that six lncRNAs were associated with one of the clinical characteristics, i.e., gender, clinical stage, T and N stage, respectively. WGCNA identified PCG modules associated with gender, clinical stage, T and N stage. We took the intersection of the PCG modules of WGCNA, the differentially expressed PCGs between LSCC and normal samples, and the PCGs co-expressed with six lncRNAs. The intersection PCGs survival analysis showed that four PCGs, i.e., STC2, TSPAN9, SMS, and TCEA3 affected the OS of LSCC. More importantly, the differential expression of six lncRNAs and four PCGs between LSCC and normal samples was verified by our LSCC patients. In conclusion, we successfully established a prognostic model based on six-lncRNA RiskScore and initially screened the potential target PCGs of six lncRNAs for further basic and clinical research.

Colorectal cancer (CRC) is one of the most malignant cancers with high morbidity and mortality. MicroRNAs (miRNAs) are small non-coding RNAs that affect biological processes by binding to mRNAs and regulating their expression, and epigenetic alterations including miRNA dysregulation are significantly involved in CRC development. Determining the effect of the miRNA-mRNA network on CRC could be helpful for developing novel therapeutic targets and prognostic biomarkers, and even improving survival. In this study, microarray assays were used to screen differentially expressed miRNAs (DE miRNAs) and mRNAs (DE mRNAs) in CRC and the adjacent normal tissues. Among the detected genes, 42 miRNAs and 142 mRNAs were significantly upregulated in CRC, while 23 miRNAs and 279 mRNAs were significantly downregulated. Through overlapping of predicted targets of DE miRNAs and anti-expressed DE mRNAs, networks of DE miRNAs and DE mRNAs in CRC were established. Additionally, the formation of a protein-protein interaction network of DE mRNAs possibly targeted by DE miRNAs, functional annotation and pathway analysis, stable subnetwork mining, and determination of hub genes provided the probable mechanism used by DE miRNAs and DE mRNAs to regulate CRC growth. Finally, validation of expression and prognostic potential of hub genes provided further support for the results above and indicated that CCL-28, GPR15, PNOC, NUSAP1, and their interacted miRNAs may be a potential signature for prognosis of CRC patients. In sum, we successfully established miRNA-mRNA regulatory networks based on microarray results targeting CRC, and these findings may elucidate the mechanisms used for CRC growth and identify miRNA-related signatures for prognosis and treatment of CRC. [ABSTRACT FROM AUTHOR]