Significance of N6-methyladenosine RNA methylation regulators in diagnosis and subtype classification of primary Sjögren's syndrome.

The importance of N6-methyladenine (m6A) in mRNA metabolism, physiology, pathology and other life processes is well recognized. However, the exact role of m6A regulators in primary Sjögren's syndrome (PSS) remains unclear. In this study, we used bioinformatics and machine learning random forest approach to screen eight key m6A regulators from the Gene Expression Omnibus GSE7451, GSE40611 and GSE84844 datasets. An accurate nomogram model for predicting PSS risk was established based on these regulators. And using consensus clustering, patients diagnosed with PSS were classified into two different m6A patterns. We found that patients in group B had higher m6A scores compared to those in group A: furthermore, both groups were closely related to immunity and possibly to other diseases. These results emphasise the important role of m6A regulators in the pathogenesis of PSS. Our study of m6A patterns may inform future immunotherapy strategies for PSS.

Exploring the causal association between rheumatoid arthritis and the risk of cervical cancer: a two-sample Mendelian randomization study.

OBJECTIVE: Whether rheumatoid arthritis patients have an increased risk of cervical cancer remains controversial, and further research is needed on this clinical question. This study aims to investigate the association between rheumatoid arthritis and the susceptibility to cervical cancer by employing Mendelian randomization methodology, utilizing the extensive dataset from human genome-wide association data analysis. METHODS: The publicly accessible MR base database was utilized to obtain the complete genome, relevant research findings, and summarized data pertaining to rheumatoid arthritis and cervical cancer. Genetic tool variables, specifically single-nucleotide polymorphisms closely linked to rheumatoid arthritis, were chosen for analysis. Four methods, namely inverse variance weighted analysis, weighted median analysis, weighted mode, and MR-Egger regression, were employed. Statistical analysis was conducted to explore the potential association between rheumatoid arthritis and susceptibility to cervical cancer. RESULTS: The results of the inverse variance weighted analysis (OR = 1.096, 95% CI: 1.018-1.180, P = 0.015) indicate a significant causal relationship between rheumatoid arthritis and an increased risk of cervical cancer. Furthermore, the absence of horizontal pleiotropic effects (MR-Egger intercept = 0.00025, P = 0.574) and heterogeneity (QEgger = 2.239, I2Egger = 0.225, PEgger = 0.268, QIVW = 2.734, I2IVW = 0.220, PIVW = 0.999) suggests that the observed association is not influenced by confounding factors. Sensitivity analysis and other statistical methods also support the conclusion that genetic pleiotropy does not introduce bias to the findings. CONCLUSION: There is a causal relationship between rheumatoid arthritis and the occurrence of cervical cancer. People with rheumatoid arthritis is one of the high-risk groups for early screening of cervical cancer. The IL-18 may play a significant role in elevating the risk of cervical cancer among rheumatoid arthritis patients.

Identification of Immune-Related lncRNA Pairs and Construction and Validation of a New Prognostic Signature of Colon Cancer.

Background: More and more evidence has shown that immune-related long noncoding ribonucleic acid (irlncRNAs) is a potential prognostic factor for colon cancer. The relevant gene pair pattern can improve the sensitivity of the prognostic model. Therefore, our present study aimed to identify irlncRNA Pairs and construct and validate a new prognostic signature in colon cancer. Methods: We downloaded the expression matrix of mRNA and lncRNA of patients with colon cancer and their clinical information from the public TCGA database. We obtained immune genes from the ImmPort database. Coexpression analysis was performed to identify irlncRNAs. We built an irlncRNA pair matrix by comparing the expression levels of each lncRNA pair in a cycle. Univariate Cox regression analysis, LASSO penalized regression analysis, and multivariate Cox regression analysis were performed to determine the final variables to construct the prognostic risk score model (a new signature). We draw the receiver operating characteristic (ROC) curves of the signature and clinical characteristics and determine the optimal cutoff value by the optimal Akaike Information Criterion (AIC) value. Based on the optimal cutoff value of the ROC curve of the signature, colon cancer patients were divided into the high- and low-risk groups. Then, the signature was evaluated by clinicopathological features, tumor-infiltrating immune cells, checkpoint-related biomarkers, targeted therapy, and chemotherapy. Results: We identified 8 lncRNA pairs including AC103740.1|LEF1-AS1, LINC02391|AC053503.5, WWC2-AS2|AL355916.2, AC104090.1|NEURL1-AS1, AC099524.1|AL161908.1, AC074011.1|AL078601.2, AL355916.2|LINC01723, and AP003392.4|LINC00598 from 71 differently expressed irlncRNAs. We constructed a prognostic risk score model (a new signature) using these optimal eight irlncRNA pairs. ROC curve analysis revealed that the highest AUC value of the signature was 0.776 at 1 year, with the optimal cutoff value of 1.283. Our present study also showed that the constructed signature could accurately identify adverse survival outcomes, prognostic clinicopathological features, and specify tumor invasion status. The expression of immune checkpoint-related genes and chemical drug sensitivity were related to different risk groups. Conclusion: In our present study, we constructed a new irlncRNA signature of colon cancer based on the irlncRNA pairs instead of the special expression level of lncRNA. We found this signature had not only good prognostic value but also certain clinical value, which might provide a new insight into the treatment and prognosis of colon cancer.

B7-H3, Negatively Regulated by miR-128, Promotes Colorectal Cancer Cell Proliferation and Migration.

BACKGROUND: B7 homolog 3 (B7-H3), a member of the immunoregulatory ligand B7 family, is pivotal in T-cell-mediated immune response. It is widely expressed in diverse human tumors and its high expression indicates the poor prognosis of the patients. Nonetheless, B7-H3's role in colorectal cancer (CRC) needs to be further explored. METHODS: Western blot and immunohistochemistry were employed for detecting B7-H3 protein expression in CRC tissues and cell lines, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for detecting B7-H3 mRNA and miR-128 expression levels. CRC cell lines SW620 and HT29 were used to construct B7-H3 overexpression or knockdown cell models, respectively. Cell counting kit-8 (CCK-8), 5-bromo-2'-deoxyuridine (BrdU), and scratch wound healing assays were employed for evaluating the effects of B7-H3 on CRC cell multiplication and migration. Besides, the regulatory relationship between miR-128 and B7-H3 was validated through dual-luciferase reporter gene assay, qRT-PCR, and western blotting. RESULTS: B7-H3 expression level was remarkably elevated in CRC tissues and cell lines, and its high expression level was associated with increased tumor size, positive lymph node metastasis, and increased T stage. In CRC cells, B7-H3 overexpression significantly facilitated the cell multiplication and migration, while B7-H3 knockdown worked oppositely. Moreover, B7-H3 was identified as a target of miR-128, and miR-128 negatively regulated B7-H3 expression in CRC cells. CONCLUSION: B7-H3 expression is upregulated in CRC tissues and cell lines, and B7-H3 participates in promoting the proliferation and migration of CRC cells. Besides, B7-H3 expression is negatively regulated by miR-128 in CRC.

Strategy for Extending the Nitrogen Chain: The Bis(1,2,3-triazole) Formation Reaction from Tosylhydrazones and N-Amino Azole.

A facile and versatile synthesis strategy for the bis(1,2,3-triazole) formation reaction was developed from tosylhydrazones and N-amino (N-NH2) azole instead of C-amino amine derivatives. The novel energetic compounds containing the bicycle catenated six-nitrogen chain (N6) and the first example of N7 neutral compounds were synthesized in a moderate or high yield. The possible mechanism of bis(1,2,3-triazole) formation reaction based on amino azole of N-NH2 was verified by the X-ray crystal structure of key intermediates. In addition, four energetic compounds 4aa, 4ba, 4ac, and 4ad containing N6 and N7 structures possess acceptable decomposition temperatures (150.1-201.6 °C) and moderate calculated detonation performances (6850-7727 m/s). Among them, 4aa (N6 structure) and 4ad (N7 structure) could be used as the melt-cast explosive candidate and the gas generation agent candidate, respectively. This type of nitrogen-nitrogen bonding formation opens a new method for discovery of novel high-nitrogen energetic compounds containing catenated multiple nitrogen atoms especially odd number nitrogen compounds.