Implications of ZNF334 gene in lymph node metastasis of lung SCC: potential bypassing of cellular senescence.

BACKGROUND: The primary goal of this work is to identify biomarkers associated with lung squamous cell carcinoma and assess their potential for early detection of lymph node metastasis. METHODS: This study investigated gene expression in lymph node metastasis of lung squamous cell carcinoma using data from the Cancer Genome Atlas and R software. Protein-protein interaction networks, hub genes, and enriched pathways were analyzed. ZNF334 and TINAGL1, two less explored genes, were further examined through in vitro, ex vivo, and in vivo experiments to validate the findings from bioinformatics analyses. The role of ZNF334 and TINAGL1 in senescence induction was assessed after H2O2 and UV induced senescence phenotype determined using ß-galactosidase activity and cell cycle status assay. RESULTS: We identified a total of 611 up- and 339 down-regulated lung squamous cell carcinoma lymph node metastasis-associated genes (FDR < 0.05). Pathway enrichment analysis highlighted the central respiratory pathway within mitochondria for the subnet genes and the nuclear DNA-directed RNA polymerases for the hub genes. Significantly down regulation of ZNF334 gene was associated with malignancy lymph node progression and senescence induction has significantly altered ZNF334 expression (with consistency in bioinformatics, in vitro, ex vivo, and in vivo results). Deregulation of TINAGL1 expression with inconsistency in bioinformatics, in vitro (different types of lung squamous cancer cell lines), ex vivo, and in vivo results, was also associated with malignancy lymph node progression and altered in senescence phenotype. CONCLUSIONS: ZNF334 is a highly generalizable gene to lymph node metastasis of lung squamous cell carcinoma and its expression alter certainly under senescence conditions.

Congenital myasthenic syndromes in two male siblings born to healthy consanguineous parents: a case report.

PURPOSE: Congenital myasthenic syndromes include a wide range of early-onset genetic neuromuscular transmission disorders. Mutations in any one of genes coding for proteins related to the neuromuscular junction synaptic transmission function, can lead to such rare recessive inherited disorders. CASE PRESENTATION: We present a report on recurrence of congenital myasthenic syndromes in two consecutive male siblings who were diagnosed on the basis of clinical findings. CONCLUSION: To minimize risks for having affected child/children with autosomal recessive disorders, consanguineous couples must undergo genetic risk assessment, counseling, and screening.

Highlighting allelic variations at the interleukin-19 locus in term of preeclampsia predisposing factors and access to an accurate diagnostic/screening option.

BACKGROUND: Preeclampsia is the main cause of preterm parturition and maternal-fetal complications. T helper 1 and T helper 2 cytokines balance is a requirement in normal pregnancy and aberrant in this immunologic balance, play an important role in the pathology of preeclampsia. In previous studies single nucleotide polymorphisms have been associated with the alteration of serum cytokine levels. OBJECTIVE: This study was aimed to discover association between interleukin-13 (rs20541, and rs56035208) and interleukin-19 (rs1028181 (T/C) and rs2243191(T/C)) polymorphisms with susceptibility to preeclampsia. METHODS: In this case-control study 300 women with and without preeclampsia (n = 150/each) who referred to Zeynabieh Hospital- Shiraz, Iran, from February 2021 to April 2022 were enrolled. For genotyping the interleukin-13 and interleukin-19 polymorphisms, the Allele-specific polymerase chain reaction and direct sequencing method was carried out. RESULTS: Our statistical results revealed no significant differences in allele and genotype frequencies for interleukin-13 polymorphisms compared to controls. We found that the interleukin-13 polymorphisms are significantly associated with vulnerability to edema at rs20541 position and maternal drinking at rs56035208 position. But it was interesting to note that the differences of both the allele and genotype frequencies of interleukin-19 polymorphisms and their contribution to the risk of preeclampsia susceptibility were significant. CONCLUSIONS: No risk of preeclampsia was found in all comparisons for interleukin-13 polymorphisms. However, the interleukin-19 polymorphisms were found to confer the risk of preeclampsia in our population.

Spontaneous miscarriage driven by maternal genetic mutation at position of PAI-1-844G/A: shed light on a race-specific genetic polymorphism.

OBJECTIVE: Association between a genetic polymorphism and disease, either positively or negatively, within a population may not necessarily predict association in other race-ethnic populations. The aim of this study was to genotype well recognized thrombophilia associated polymorphisms as common risk factors for miscarriage and investigate their benefit to use as risk factors in southwest region of Iran females (Khuzestan) in the Arabs ethnic minority group with spontaneous miscarriage. We developed a Reverse Dot Blot Assay for the genotyping of four polymorphisms. RESULTS: There were significant differences in the genotype distribution and allelic frequencies of the MTHFR 1298 A > C, MTHFR 677 C > T, Factor V Leiden 1691 G > A, PAI-1-844G > A polymorphisms between the case and control groups. The MTHFR 1298 A > C, MTHFR 677 C > T and Factor V Leiden 1691 G > A polymorphisms were significantly associated with spontaneous miscarriage risk. Unlike some other race-ethnic populations, PAI-1-844G > A polymorphism was associated with risk of developing unplanned miscarriage in Iranian Arabs ethnic minority group females.

Crucial Role of Foxp3 Gene Expression and Mutation in Systemic Lupus Erythematosus, Inferred from Computational and Experimental Approaches.

The impaired suppressive function of regulatory T cells is well-understood in systemic lupus erythematosus. This is likely due to changes in Foxp3 expression that are crucial for regulatory T-cell stability and function. There are a few reports on the correlation between the Foxp3 altered expression level and single-nucleotide polymorphisms within the Foxp3 locus. Moreover, some studies showed the importance of Foxp3 expression in the same diseases. Therefore, to explore the possible effects of single-nucleotide polymorphisms, here, we evaluated the association of IVS9+459/rs2280883 (T>C) and -2383/rs3761549 (C>T) Foxp3 polymorphisms with systemic lupus erythematosus. Moreover, through machine-learning and deep-learning methods, we assessed the connection of the expression level of the gene with the disease. Single-nucleotide polymorphisms of Foxp3 (IVS9+459/rs2280883 (T>C) and -2383/rs3761549 (C>T)) were, respectively, genotyped using allele-specific PCR and direct sequencing and polymerase chain reaction-restriction fragment length polymorphism, in 199 systemic lupus erythematosus patients and 206 healthy age- and sex-matched controls. The Statistical Package for the Social Sciences version 19 and Fisher's exact and chi-square tests were used to analyze the data. Moreover, six machine-learning models and two sequential deep-learning models were designed to classify patients from normal people in the E-MTAB-11191 dataset through the expression level of Foxp3 and its correlated genes. The allele and genotype frequencies of both polymorphisms in question were found to be significantly associated with an increased risk of systemic lupus erythematosus. Furthermore, both of the two single-nucleotide polymorphisms were associated with some systemic-lupus-erythematosus-related risk factors. Three SVM models and the logistic regression model showed an 81% accuracy in classification problems. In addition, the first deep-learning model showed an 83% and 89% accuracy for the training and validation data, respectively, while the second model had an 85% and 79% accuracy for the training and validation datasets. In this study, we are prompted to represent the predisposing loci for systemic lupus erythematosus pathogenesis and strived to provide evidence-based support to the application of machine learning for the identification of systemic lupus erythematosus. It is predicted that the recruiting of machine-learning algorithms with the simultaneous measurement of the applied single nucleotide polymorphisms will increased the diagnostic accuracy of systemic lupus erythematosus, which will be very helpful in providing sufficient predictive value about individual subjects with systemic lupus erythematosus.

Preeclampsia Susceptibility Assessment Based on Deep Learning Modeling and Single Nucleotide Polymorphism Analysis.

The early diagnosis of preeclampsia, a key outlook in improving pregnancy outcomes, still remains elusive. The present study aimed to examine the interleukin-13 and interleukin-4 pathway potential in the early detection of preeclampsia as well as the relationship between interleukin-13 rs2069740(T/A) and rs34255686(C/A) polymorphisms and preeclampsia risk to present a combined model. This study utilized raw data from the GSE149440 microarray dataset, and an expression matrix was constructed using the RMA method and affy package. The genes related to the interleukin-13 and interleukin-4 pathway were extracted from the GSEA, and their expression levels were applied to design multilayer perceptron and PPI graph convolutional neural network models. Moreover, genotyping for the rs2069740(T/A) and rs34255686(C/A) polymorphisms of the interleukin-13 gene were tested using the amplification refractory mutation system PCR method. The outcomes revealed that the expression levels of interleukin-4 and interleukin-13 pathway genes could significantly differentiate early preeclampsia from normal pregnancy. Moreover, the present study's data suggested significant differences in the genotype distribution, the allelic frequencies and some of the risk markers of the study, in the position of rs34255686 and rs2069740 polymorphisms between the case and control groups. A combined test of two single nucleotide polymorphisms and an expression-based deep learning model could be designed for future preeclampsia diagnostic purposes.

Genes whose expressions in the primary lung squamous cell carcinoma are able to accurately predict the progression of metastasis through lymphatic system, inferred from a bioinformatics analyses.

Lymph node metastasis is the most important prognostic factor in patients with lung squamous cell carcinoma. The current findings show that lymph node metastatic tumor cells can arise by programming metastasis in primary tumor cells. Thereby, the genetic alterations responsible for the metastasis could be detected in the primary tumors. This bioinformatic study aimed to determine novel potential prognostic biomarkers shared between primary lung squamous cell tumors (without lymph node metastasis) and lymphatic metastasis, using the Cancer Genome Atlas database. Differentially expressed genes were screened by limma statistical package in R environment. Gene ontology and biological pathways analyses were performed using Enrichr for up-regulated and down-regulated genes. Also, we selected lymph node metastasis related genes among DEGs using correlation analysis between DEGs and suitable references genes for metastasis. Receiver operating characteristic curves was applied using pROC and R package ggplot2 to evaluate diagnostic value of differentially expressed genes. In addition, survival and drug resistance analyses were performed for differentially expressed genes. The miRNA-mRNA interaction networks were predicted by miRwalk and TargetScan databases and expression levels analysis of the miRNAs which were mainly targeting mRNAs was performed using UALCAN database. Protein-protein interaction network analysis and hub genes identification were performed using FunRich and Cytoscape plugin cytoHubba. In this study, a total of 397 genes were differentially expressed not only with a significant difference between N + vs. normal and N0 vs. normal but also with significant difference between N + vs. N0. Identified GO terms and biological pathways were consistent with DEGs role in the lung squamous cell carcinoma and lymph node metastasis. A significant correlation between 56 genes out of 397 differentially expressed genes with reference genes prompted them being considered for identifying lymph node metastasis of lung squamous cell carcinoma. In addition, SLC46A2, ZNF367, AC107214.1 and NCBP1 genes were identified as survival-related genes of patients with lung squamous cell carcinoma. Moreover, NEDD9, MRPL21, SNRPF, and SCLT1 genes were identified to be involved in lung squamous cell carcinoma drug sensitivity/resistance. We have identified several numbers of miRNAs and their related target genes which could emerge as potential diagnostic biomarkers. Finally, CDK1, PLK1, PCNA, ZWINT and NDC80 identified as hub genes for underlying molecular mechanisms of lung squamous cell carcinoma and lymphatic metastasis. Our study highlights new target genes according to their relation to lymph node metastasis, whose expressions in the primary lung squamous cell carcinoma are able to accurately assess the presence of lymphatic metastasis.

Predisposition to Myocardial Infarction Influenced by Interleukin 13 Gene Polymorphisms: A Case-Control Study.

BACKGROUND: Additional inflammatory responses and subsequent damage-arising from enhance transcriptional activity or forming the more active protein due to existence of polymorphic sites in the pro-inflammatory cytokines gene loci-give rise to myocardial infarction susceptibility. OBJECTIVES: The aim of our study was to explore whether two interleukin-13 gene polymorphisms (-1512A/C and +2044G/A) could serve as underpins genetic susceptibility of myocardial infarction. METHODS: The Iranian population that belong to the Parsis ethnic group was involved in the present study. A total 250 patients with definite myocardial infarction-meeting hypertension, hypercholesterolemia, hyperglycemia, and coronary artery disease requirements-were recruited from the Shiraz urban hospitals. 250 age- and sex-matched healthy individuals without a history of cardiovascular disease and heart disease related risk factors constituted the control group. PCR-restriction fragment length polymorphism technique applied to genotyping at -1512A/C and +2044G/A loci. Hardy-Weinberg equilibrium test was performed (combined cases and controls). The differences of the genotype frequencies in cases and controls were analyzed using a chi-square test. Logistic regression analysis was performed to assess the association between the genotypes and most important risk factors for myocardial infarction. All statistical analyses were performed in SPSS Version 22.0. p-values below 0.05 were hailed as statistically significant. RESULTS: Deviation from Hardy-Weinberg equilibrium was not significant in the -1512A/C locus. Statistically significant difference between our study groups was found in genotype frequency of the -1512A/C. This variant was found in associated with myocardial infarction risk factors. The +2044G/A polymorphism was not in Hardy-Weinberg equilibrium and no significant difference observed in the distribution of +2044G/A genotype frequency among cases and controls. However, further analysis revealed that this genotype associated with an increased susceptibility to myocardial infarction risk factors. CONCLUSIONS: The presence of interleukin-13 -1512A/C and +2044G/A gene polymorphisms underpin myocardial infarction predisposition in the ethnic Parsis of the Iranian population.