The comprehensive landscape of prognosis, immunity, and function of the GLI family by pan-cancer and single-cell analysis.

The Hedgehog (Hh) signaling pathway has been implicated in the pathogenesis of various cancers. However, the roles of the downstream GLI family (GLI1, GLI2, and GLI3) in tumorigenesis remain elusive. This study aimed to unravel the genetic alterations of GLI1/2/3 in cancer and their association with the immune microenvironment and related signaling pathways. Firstly, we evaluated the expression profiles of GLI1/2/3 in different cancer types, analyzed their prognostic and predictive values, and assessed their correlation with tumor-infiltrating immune cells. Secondly, we explored the relationships between GLI1/2/3 and genetic mutations, epigenetic modifications, and clinically relevant drugs. Finally, we performed enrichment analysis to decipher the underlying mechanisms of GLI1/2/3 in cancer initiation and progression. Our results revealed that the expression levels of GLI1/2/3 were positively correlated in most cancer tissues, suggesting a cooperative role of these factors in tumorigenesis. We also identified tissue-specific expression patterns of GLI1/2/3, which may reflect the distinct functions of these factors in different cell types. Furthermore, GLI1/2/3 expression displayed significant associations with poor prognosis in several cancers, indicating their potential as prognostic biomarkers and therapeutic targets. Importantly, we found that GLI1/2/3 modulated the immune microenvironment by regulating the recruitment, activation, and polarization of cancer-associated fibroblasts, endothelial cells, and macrophages. Additionally, functional enrichment analyses indicated that GLI1/2/3 are involved in the regulation of epithelial-mesenchymal transition (EMT). Together, our findings shed new light on the roles of GLI1/2/3 in tumorigenesis and provide a potential basis for the development of novel therapeutic strategies targeting GLI-mediated signaling pathways in cancer.

Characterizing hedgehog pathway features in senescence associated osteoarthritis through Integrative multi-omics and machine learning analysis.

Purpose: Osteoarthritis (OA) is a disease of senescence and inflammation. Hedgehog's role in OA mechanisms is unclear. This study combines Bulk RNA-seq and scRNA-seq to identify Hedgehog-associated genes in OA, investigating their impact on the pathogenesis of OA. Materials and methods: Download and merge eight bulk-RNA seq datasets from GEO, also obtain a scRNA-seq dataset for validation and analysis. Analyze Hedgehog pathway activity in OA using bulk-RNA seq datasets. Use ten machine learning algorithms to identify important Hedgehog-associated genes, validate predictive models. Perform GSEA to investigate functional implications of identified Hedgehog-associated genes. Assess immune infiltration in OA using Cibersort and MCP-counter algorithms. Utilize ConsensusClusterPlus package to identify Hedgehog-related subgroups. Conduct WGCNA to identify key modules enriched based on Hedgehog-related subgroups. Characterization of genes by methylation and GWAS analysis. Evaluate Hedgehog pathway activity, expression of hub genes, pseudotime, and cell communication, in OA chondrocytes using scRNA-seq dataset. Validate Hedgehog-associated gene expression levels through Real-time PCR analysis. Results: The activity of the Hedgehog pathway is significantly enhanced in OA. Additionally, nine important Hedgehog-associated genes have been identified, and the predictive models built using these genes demonstrate strong predictive capabilities. GSEA analysis indicates a significant positive correlation between all seven important Hedgehog-associated genes and lysosomes. Consensus clustering reveals the presence of two hedgehog-related subgroups. In Cluster 1, Hedgehog pathway activity is significantly upregulated and associated with inflammatory pathways. WGCNA identifies that genes in the blue module are most significantly correlated with Cluster 1 and Cluster 2, as well as being involved in extracellular matrix and collagen-related pathways. Single-cell analysis confirms the significant upregulation of the Hedgehog pathway in OA, along with expression changes observed in 5 genes during putative temporal progression. Cell communication analysis suggests an association between low-scoring chondrocytes and macrophages. Conclusion: The Hedgehog pathway is significantly activated in OA and is associated with the extracellular matrix and collagen proteins. It plays a role in regulating immune cells and immune responses.

Systematic analysis of the prognostic value and immunological function of LTBR in human cancer.

Lymphotoxin beta receptor (LTBR) is a positive T cell proliferation regulator gene. It is closely associated with the tumor immune microenvironment. However, its role in cancer and immunotherapy is unclear. Firstly, the expression level and prognostic value of LTBR were analyzed. Secondly, the expression of LTBR in clinical stages, immune subtypes, and molecular subtypes was analyzed. The correlation between LTBR and immune regulatory genes, immune checkpoint genes, and RNA modification genes was then analyzed. Correlations between LTBR and immune cells, scores, cancer-related functional status, tumor stemness index, mismatch repair (MMR) genes, and DNA methyltransferase were also analyzed. In addition, we analyzed the role of LTBR in DNA methylation, mutational status, tumor mutation burden (TMB), and microsatellite instability (MSI). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to explore the role of LTBR in pan-cancer. Finally, the drugs associated with LTBR were analyzed. The expression of LTBR was confirmed using quantitative real-time PCR and Western blot. LTBR is significantly overexpressed in most cancers and is associated with low patient survival. In addition, LTBR expression was strongly correlated with immune cells, score, cancer-related functional status, tumor stemness index, MMR genes, DNA methyltransferase, DNA methylation, mutational status, TMB, and MSI. Enrichment analysis revealed that LTBR was associated with apoptosis, necroptosis, and immune-related pathways. Finally, multiple drugs targeting LTBR were identified. LTBR is overexpressed in several tumors and is associated with a poor prognosis. It is related to immune-related genes and immune cell infiltration.

Corrigendum: Systematic pan-cancer analysis of the potential tumor diagnosis and prognosis biomarker P4HA3.

[This corrects the article DOI: 10.3389/fgene.2023.1045061.].

Transcranial magnetic stimulation-based closed-loop modality for activity of daily living gain in spinal cord injury: a retrospective study using propensity score matching analysis.

BACKGROUND: Although transcranial magnetic stimulation (TMS)-based closed-loop (TBCL) modality was seldom recommended for functional restoring following spinal cord injury (SCI), several studies recently came to a positive suggestion. AIM: To explore the independent factors which influence activity of daily living (ADL) gain, and systematically investigate the efficacy of TBCL for ADL gain. DESIGN: A retrospective observational study. SETTING: The First Affiliated Hospital of Guangxi Medical University. POPULATION: SCI patients with neurological dysfunction. METHODS: A total of 768 patients who received TBCL (N.=548) or sole rehabilitation (SR, N.=220) were enrolled. Analysis on propensity score matching was also performed. Finally, the cumulative inefficiencies between TBCL and SR within entire patient population, matched-patients as well as subgroup on per SCI clinical characteristics were performed. RESULTS: Multivariate analysis showed that thoracolumbar injury, single/double injury, incomplete injury, no neurogenic bladder, no neurogenic intestinal and no respiratory disorder, as well as TBCL strategy were independent positive factors for ADL gain. Meanwhile, TBCL strategy was the outstanding positive factor. TBCL caused a lower cumulative inefficiency over SR at 1, 90 and 180 days (83.2% vs. 86.8%, 54.0% vs. 63.6%, and 38.3% vs. 50.9%, respectively; all P<0.05). Propensity matching also found TBCL caused a lower cumulative inefficiency over SR after 1, 90 and 180 days (82.4% vs. 86.4%, 51.1% vs. 62.5%, and 33.5% vs. 49.4%, respectively; all P<0.05). Subgroup analysis showed that TBCL caused a greater ADL gain regardless of injured site, segments of injury and injured extent, as well as whether concurrent with neurogenic bladder, neurogenic intestinal and respiratory disorder (all P<0.05). Further, TBCL was more effective in 180-days overall ADL gain within each subgroup (all P<0.05), except the subgroup whether concurrent with respiratory disorder (P>0.05). CONCLUSIONS: Our study indicates that TBCL strategy was the most outstanding independent positive factors for ADL gain. Further, TBCL is a better choice than SR in ADL gain for SCI-relevant neurological dysfunctions in case of adequate stimuli distance and individual temperature, regardless of discrepancy of clinical feature. CLINICAL REHABILITATION IMPACT: This study helps to improve everyday management for rehabilitative intervention on SCI. For another thing, the present study may be good for neuromodulation practice on function restoring in SCI rehabilitation clinics.

Systematic pan-cancer analysis of the potential tumor diagnosis and prognosis biomarker P4HA3.

Purpose: Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) is implicated in several cancers' development. However, P4HA3 has not been reported in other cancers, and the exact mechanism of action is currently unknown. Materials and methods: First, the expression profile of P4HA3 was analyzed using a combination of the University of California Santa Cruz (UCSC) database, Cancer Cell Line Encyclopedia (CCLE) database, and Genotype-Tissue Expression (GTEx) database. UniCox and Kaplan-Meier were used to analyze the predictive value of P4HA3. The expression of P4HA3 was analyzed in clinical staging, immune subtypes, and Molecular subtypes. Secondly, the correlation of P4HA3 with immunomodulatory genes, immune checkpoint genes, RNA modification genes, immune cell infiltration, cancer-related functional status, tumor stemness index, DNA mismatch repair (MMR) genes and DNA Methyltransferase was examined. The role of P4HA3 in DNA methylation, copy number variation (CNV), mutational status, tumor mutational burden (TMB), and microsatellite instability (MSI) was also analyzed. In addition, gene set enrichment analysis (GSEA) was used to explore the potential functional mechanisms of P4HA3 in pan-cancer. Finally, P4HA3-related drugs were searched in CellMiner, Genomics of Drug Sensitivity in Cancer (GDSC), and Cancer Therapeutics Response Portal (CTRP) databases. Results: P4HA3 is significantly overexpressed in most cancers and is associated with poor prognosis. P4HA3 is strongly associated with clinical cancer stage, immune subtypes, molecular subtypes, immune regulatory genes, immune checkpoint genes, RNA modifier genes, immune cell infiltration, cancer-related functional status, tumor stemness index, MMR Gene, DNA Methyltransferase, DNA methylation, CNV, mutational status, TMB, and MSI are closely related. Available enrichment analysis revealed that P4HA3 is associated with the epithelial-mesenchymal transition and immune-related pathways. There are currently 20 drugs associated with P4HA3. Conclusion: In human pan-cancer, P4HA3 is associated with poor patient prognosis and multiple immune cells and may be a novel immunotherapeutic target. It may act on tumor progression through the epithelial-mesenchymal transition (EMT) pathway.

The Impact of COVID-19 on the Monitoring of Pregnancy and Delivery of Pregnant Women in the Dominican Republic.

Pregnancy monitoring is vital to guaranteeing that both the foetus and the mother are in optimal health conditions. WHO protocols recommend at least eight medical examinations during the pregnancy period. While the cancellation or reduction of appointments during pregnancy due to the pandemic may help reduce the risk of infection, it could also negatively influence perinatal outcomes and the birthing process. The aim of this research was to analyse the differences in perinatal outcomes and birth characteristics in two groups of pregnant women: women who gave birth before and during the pandemic, and whether these differences are due to changes in pregnancy monitoring because of the COVID-19 situation. A retrospective study was carried out from July 2018 to December 2021, at the Santo Domingo Hospital (Dominican Republic). A total of 1109 primiparous pregnant women were recruited for this study during the birthing process and perinatal visits. The results describe how women who gave birth before the pandemic had greater control and monitoring of their pregnancy, more doctor visits (p = 0.001), fewer caesarean sections (p = 0.006), and more skin-to-skin contact after birth (p = 0.02). During the COVID-19 pandemic, pregnant women's attendance at routine pregnancy monitoring, both doctor visits and ultrasound scans, has decreased, leading to an increase in the number of caesarean and instrumental deliveries. At the perinatal level, processes such as skin-to-skin contact after birth between mother and newborn or the introduction of early breastfeeding in the delivery room have also been reduced.

Bioinformatics analysis of genomic and immune infiltration patterns in autism spectrum disorder.

Background: Autism spectrum disorder (ASD) is a specific type of pervasive developmental disorder, and most studies suggest that the onset of autism may be related to genetic and immune factors. The etiology of autism and the underlying molecular events need to be further addressed. Methods: The ASD-related dataset GSE18123 was downloaded from the Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) was used to screen for Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that may be associated with autism. The top 5,000 genes with an absolute median difference were obtained, and a co-expression network was constructed using weighted correlation network analysis (WGCNA). In addition, GO and KEGG enrichment analyses were performed for genes in the modules most closely related to ASD. Hub genes were found in the significant modules, and the expression values and receiver operating characteristic (ROC) curves of the hub genes were analyzed and validated. Immune cell infiltration in ASD was calculated using the CIBERSORT algorithm, and the relationship between hub genes and immune cells was analyzed. Finally, GSEA was used to explore the potential pathways of hub genes affecting ASD. Results: The 5,000 DEGs were divided into eight significant modules by WGCNA. The green module was most significantly associated with ASD, and two hub genes [fatty acid-binding protein 2 (FABP2) and Janus kinase 2 (JAK2)] were found. Immune cell infiltration showed that resting dendritic cells and monocytes differed significantly in ASD and healthy individuals. FABP2 was significantly associated with memory B cells and CD8 T cells. JAK2 was significantly associated with monocytes, CD4 activated memory T cells, CD4 resting memory T cells, activated dendritic cells, gamma delta T cells, regulatory T cells (Tregs), CD8 T cells, and naïve CD4 T cells. FABP2 and JAK2 were found to affect multiple pathways of immunity. Conclusions: FABP2 and JAK2 may influence the immune microenvironment of ASD by regulating immune cells and immune-related pathways and are candidate molecular markers for the development of ASD.

Evaluation of Gonadal Alterations in a Population Environmentally Exposed to a Mixture of Endocrine Active Pesticides.

Although there are studies that show that some pesticides produce gonadal dysfunction and gonadal cancer in different animals, there are not many studiesregardinghumans. This study determined the prevalence and risk in humans of developing ovarian or testicular dysfunction or cancer in areas with distinct exposure to pesticides, which have endocrine disrupting properties. A population-based case-control study was carried out on humans living in ten health districts of Andalusia (Southern Spain) classified as areas of high or low environmental exposure to pesticides according to agronomic criteria. The study population included 5332 cases and 13,606 controls. Data were collected from computerized hospital records between 2000 and 2018.The risk of gonadal dysfunction or cancer was significantly higher in areas with higher use of pesticides in relation to those with lower use.

Analyzing the prognostic value of DKK1 expression in human cancers based on bioinformatics.

BACKGROUND: The Dickkopf1 (DKK1) gene encodes a protein that belongs to the Dickkopf family. The protein can inhibit the Wnt signaling pathway which plays a key role in the carcinogenesis and progression of various types of cancers. Based on this, we hypothesized that the differential expression of DKK1 may figure significantly in cancers by regulating Wnt signaling pathway transduction. In this study, we conducted bioinformatics analysis to evaluate the prognostic and therapeutic value of DKK1 expression level in human cancers. METHODS: The expression level was analyzed by using the Oncomine database and Gene Expression Profiling Interactive Analysis tool. The analysis of prognosis was conducted by using the UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA), and DriverDBv3 databases. We also investigated using DKK1 promoter methylation to define cancer types through the UALCAN database. Meanwhile, the related functional networks of DKK1 were analyzed by using the GeneMANIA interactive tool and Cytoscape software. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted using the Metascape online website, and we used the cBioPotartal database to explored DKK1 expression, aberrant information, and the co-expression genes in the subgroups of lung cancer. Finally, we performed the overall survival (OS) meta-analysis of the DKK1 expression in lung squamous cell carcinoma (LUSC) via the Lung Cancer Explorer (LCE). RESULTS: DKK1 was differentially expressed in different types of human cancers. DKK1 was overexpressed in human cancers including head and neck squamous cell carcinoma (HNSC), LUSC, and pancreatic adenocarcinoma (PAAD). Overexpression of DKK1 indicated adverse OS in bladder urothelial carcinoma (BLCA), HNSC, and PADD, but no difference in OS was found between the LUSC and healthy groups. The high expression of DKK1 was also associated with shorter disease-free survival (DFS) in HNSC, LUSC, and PAAD. Gene regulation network analysis indicated that DKK1 was mainly involved in Wnt signaling pathways and several other signaling pathways. CONCLUSIONS: Our findings showed that DKK1 is significantly expressed in various cancers and could be a biomarker for targeted therapy and a predictor for prognosis of these specific cancers. The bioinformatics analysis revealed a significant overexpression of DKK1 in HNSC, LUSC, and PAAD, with DKK1 overexpression being associated with adverse outcome in these patients, but how DKK1 expression levels relate to hematological malignancies and prognosis is still unclear. These new insights into the function of DKK1 may provide a basis for new targeted drug therapy and an avenue for further investigation into the mechanisms underlying carcinogenesis of DKK1 in different cancer types.

Expression and prognostic potential of GPX1 in human cancers based on data mining.

BACKGROUND: Glutathione peroxidase-1 (GPX1) is a member of the GPX family, which considered an enzyme that interacts with oxidative stress. GPX1 differential expression is closely correlated with carcinogenesis and disease progression. In this study, we used bioinformatics analysis to investigate GPX1 expression level and explore the prognostic information in different human cancers. METHODS: Expression was analyzed via the Oncomine database and Gene Expression Profiling Interactive Analysis tool, and potential prognostic analysis was evaluated using the UALCAN, GEPIA, and DriverDBv3 databases. Then, the UALCAN database was used to find the promoter methylation of GPX1 in defied cancer types. While GPX1 related functional networks were found within the GeneMANIA interactive tool and Cytoscape software. Moreover, Metascape online website was used to analyze Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways. RESULTS: We found that GPX1 was commonly overexpressed in most human cancers. High expression of GPX1 could lead to poor outcomes in Brain Lower Grade Glioma, while GPX1 over expression was correlated with better prognosis in Kidney renal papillary cell carcinoma (KIPP). High GPX1 expression was marginally associated with poor prognosis in acute myeloid leukemia (AML). Gene regulation network suggested that GPX1 mainly involved in pathways including the glutathione metabolism, ferroptosis, TP53 regulates metabolic genes, reactive oxygen species (ROS) metabolic process, and several other signaling pathways. CONCLUSIONS: Our findings revealed that GPX1 showed significant expression differences among cancers and served as a prognostic biomarker for defined cancer types. The data mining effectively revealed useful information about GPX1 expression, prognostic values, and potential functional networks in cancers, thus providing researchers with an available way to further explore the mechanism underlying carcinogenesis of genes of interest in different cancers.

miR-28-5p inhibits carcinogenesis in colon cancer cells and is necessary for erastin-induced ferroptosis.

BACKGROUND: Ferroptosis is a newly discovered type of regulated cell death, the underlying mechanisms of which need to be further illuminated. The regulatory activity of miR-28-5p in ferroptosis in colon cancer cells is currently unclear. This study set out to investigate the effect of miR-28-5p on ferroptosis in colon cancer cells and determine its underlying mechanism. METHODS: Biochemical Kits were used to measure iron concentration, malondialdehyde (MDA) concentration, glutathione (GSH) concentration and glutathione peroxidase (GPX) vitality. Cell counting kit 8 (CCK8) assays were conducted to evaluate cell viability. Flow cytometry was conducted to assess apoptosis. Transwell™ assays were used to measure the migratory and invasive abilities of HCT116 cells. Western blotting was used to measure the protein relative expression of NEDD4 binding protein 1 (N4BP1). Quantitative real-time polymerase chain reaction (RT-PCR) was used to measure the RNA relative expression of N4BP1 and miR-28-5p. RESULTS: Ferroptosis was induced in HCT116 cells by erastin in a dose- and time-dependent manner, which caused significant inhibition of proliferation, migration, and invasion in HCT116 cells; however, there was no obvious effect on apoptosis. miR-28-5p expression was decreased in colon cancer cells compared with the normal colon cells but was upregulated in erastin-treated HTC116 cells. Additionally, when overexpressed via the transfection of miR-28-5p mimics, miR-28-5p had an inhibitive effect on proliferation, migration, and invasion, while promoting apoptosis, in HCT116 cells. erastin-induced ferroptosis was also increased by miR-28-5p overexpression. Compared with normal colon cells, following erastin treatment, NEDD4 binding protein 1 (N4BP1) expression was increased in colon cancer cells and further decreased in HTC116 cells. miR-28-5p overexpression also inhibited N4BP1 mRNA and protein expression in HTC116 cells. CONCLUSIONS: miR-28-5p plays an important role in ferroptosis by targeting N4BP1 and could serve as a potential therapeutic approach for colon cancer.

LncRNA PCAT-1 plays an oncogenic role in epithelial ovarian cancer by modulating cyclinD1/CDK4 expression.

Epithelial ovarian cancer is one of the most common causes of gynecological cancer deaths. The knockdown of LncRNA PCAT-1 has been reported to suppress tumor growth in various kinds of cancers, including esophageal cancer, breast cancer, bladder cancer, and hepatocellular carcinoma. However, its function in epithelial ovarian cancer (EOC) is still unclear. In the present study, the expression of LncRNA PCAT-1 was investigated. The results indicate that the expression of LncRNA PCAT-1 is up-regulated in EOC tissues compared with non-cancer controls by reverse transcription-quantitative polymerase chain reaction analysis (RT-qPCR), and its higher expression is always associated with larger tumor sizes and advanced tumor grades in patients with EOC. In addition, silencing PCAT-1 in the EOC cell lines SKOV3 and OVCAR3 significantly inhibits cell proliferation, migration and invasion, which is also shown by cell cycle assays, as the proportion of cells in G0/G1 phase is dramatically increased after knocking down PCAT1. Finally, it is observed that PCAT-1's knockdown significantly decreased the levels of cyclin D1 and CDK4 protein expression. Taken together, LncRNA PCAT-1's oncogenic role in EOC by mediating cyclin D1/CDK4 is demonstrated, indicating it is a potential target for EOC treatment.

The SOX2OT/miR-194-5p axis regulates cell proliferation and mobility of gastric cancer through suppressing epithelial-mesenchymal transition.

Recent studies reported that long noncoding RNAs (LncRNAs) were involved in tumorigenesis of various human cancer types, including gastric cancer (GC) through targeting microRNAs (miRNAs/miRs). The present study investigated the biological functions of LncRNA SOX2 overlapping transcript (SOX2OT)/miR-194-5p axis and its underlying mechanism in the tumor progression of GC. The results showed that relative expression of LncRNA SOX2OT was highly upregulated while the expression of miR-194-5p was down-regulated in GC tissues and cell lines (MGC-803, SGC-7901, MKN-74). Knockdown of SOX2OT inhibited cell proliferation, invasion and migration of GC cells (MGC803, MKN-74) through reducing epithelial-mesenchymal transition (EMT). Moreover, miR-194-5p was predicted to be one of the targets of SOX2OT through bioinformatics analysis and was verified by luciferase reporter assay. miR-194-5p expression was negatively regulated by SOX2OT expression in GC cells and miR-194-5p inhibitor was found to counteract the inhibitory effects of SOX2OT short hairpin (sh)RNA on cell proliferation and mobility through enhancing EMT in GC cells. Taken together, the in vitro experiments revealed that knockdown of SOX2OT inhibited cell proliferation and mobility through suppressing EMT via targeting miR-194-5p in GC. In addition, results from in vivo experiments showed that knockdown of SOX2OT suppressed GC tumor growth and matrix metalloproteinase (MMP)-2 and MMP-9 expression through inhibiting EMT. Besides that, relative expression of miR-194-5p was increased in sh-SOX2OT group compared with sh-NC group. In summary, our study elucidated that the SOX2OT/miR-194-5p axis participated in the tumor progression of GC through regulation of EMT both in vitro and in vivo. Hence, targeting the SOX2OT/miR-194-5p axis may aid in establishing novel strategies for therapy of GC.