FOXP4-AS1 promotes CD8+ T cell exhaustion and esophageal cancer immune escape through USP10-stabilized PD-L1.

Esophageal cancer (EC) is the 9th most frequently diagnosed malignancy globally with unfavorable prognosis. Immune escape is one of the principal factors leading to poor survival, however, the mechanism underlying immune escape remains largely uninvestigated. The xenograft mouse model and EC cell-CD8+ cytotoxic T lymphocytes (CTLs) co-culture system were established. Immunohistochemistry, qRT-PCR or western blot were employed to detect the levels of long non-coding RNA (lncRNA) FOXP4-AS1, PD-L1, USP10 and other molecules. The abundance of T cells, cytokine production and cell apoptosis were monitored by flow cytometry. The viability of CTLs was assessed by Trypan blue staining. The binding between FOXP4-AS1 and USP10 was validated by RNA pull-down assay, and the interaction between USP10 and PD-L1, as well as the ubiquitination of PD-L1, were detected by co-immunoprecipitation. The elevation of FOXP4-AS1 in EC was associated with decreased CTL abundance, and upregulated PD-L1 facilitated CTL apoptosis in EC. FOXP4-AS1 accelerated EC tumor growth by decreasing the abundance of tumor infiltrating CTLs in vivo. FOXP4-AS1 inhibited the viability of CTLs and facilitated the cytotoxicity and exhaustion of CTLs. In Kyse 450 cell-CTL co-culture system, FOXP4-AS1 suppressed the viability and abundance of CTLs, and inhibited EC cell apoptosis via PD-L1. Mechanistically, FOXP4-AS1 regulated the ubiquitination of PD-L1 through deubiquitinating enzyme USP10. FOXP4-AS1 promoted CTL exhaustion and EC immune escape through USP10-stabilized PD-L1. HIGHLIGHTS: PD-L1 facilitated CD8+ T cell apoptosis in EC. Upregulated FOXP4-AS1 promoted EC tumor growth by inhibiting the viability and facilitating the cytotoxicity and exhaustion of tumor infiltrating CD8+ T cells. FOXP4-AS1 suppressed the viability and abundance of CD8+ T cells through USP10-mediated deubiquitination of PD-L1.

High SNHG expression may predict a poor lung cancer prognosis based on a meta-analysis.

BACKGROUND: An increasing number of small nucleolar RNA host genes (SNHGs) have been revealed to be dysregulated in lung cancer tissues, and abnormal expression of SNHGs is significantly correlated with the prognosis of lung cancer. The purpose of this study was to conduct a meta-analysis to explore the correlation between the expression level of SNHGs and the prognosis of lung cancer. METHODS: A comprehensive search of six related databases was conducted to obtain relevant literature. Relevant information, such as overall survival (OS), progression-free survival (PFS), TNM stage, lymph node metastasis (LNM), and tumor size, was extracted. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled to evaluate the relationship between SNHG expression and the survival outcome of lung cancers. Sensitivity and publication bias analyses were performed to explore the stability and reliability of the overall results. RESULTS: Forty publications involving 2205 lung cancer patients were included in this meta-analysis. The pooled HR and 95% CI values indicated a significant positive association between high SNHG expression and poor OS (HR: 1.890, 95% CI: 1.595-2.185), disease-free survival (DFS) (HR: 2.31, 95% CI: 1.57-3.39) and progression-free survival (PFS) (HR: 2.01, 95% CI: 0.66-6.07). The pooled odds ratio (OR) and 95% CI values indicated that increased SNHG expression may be correlated with advanced TNM stage (OR: 1.509, 95% CI: 1.267-1.799), increase risk of distant lymph node metastasis (OR: 1.540, 95% CI: 1.298-1.828), and large tumor size (OR: 1.509, 95% CI: 1.245-1.829). Sensitivity analysis and publication bias results showed that each result had strong reliability and robustness, and there was no significant publication bias or other bias. CONCLUSION: Most SNHGs are upregulated in lung cancer tissues, and high expression of SNHGs predicts poor survival outcomes in lung cancer. SNHGs may be potential prognostic markers and promising therapeutic targets.

A Novel Autophagy-Related Marker for Improved Differential Diagnosis of Rheumatoid Arthritis and Osteoarthritis.

Rheumatoid arthritis (RA) and osteoarthritis (OA) are two most common rheumatic diseases in the world. Although there are standard methods for the diagnosis of both RA and OA, the differentials in some cases are poor. With deepening research, the role of autophagy in maintaining cell homeostasis and thus enabling cells adapt to external environments has become increasingly prominent. Both RA and OA, two diseases with inherent differences in pathogenesis, gradually show differences in autophagy levels. Our study therefore aims to further understand differences in pathogenesis of RA and OA through in-depth studies of autophagy in RA and OA. We also define appropriate autophagy-related markers as recognition indicators. Differences in autophagy levels between RA and OA were found based on analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) and single-sample gene set enrichment (ssGSEA). These differences were mainly caused by 134 differentially expressed genes (DEGs). In two autophagy-related genes, CXCR4 and SERPINA1, there existed significant statistical difference between RA and OA. An autophagy related index (ARI) was thus successfully constructed based on CXCR4 and SERPINA by binary logistic regression of the generalized linear regression (GLR) algorithm. Pearson analysis indicated that the expression of CXCR4, SERPINA1, and ARI were closely correlated with autophagy scores and immune infiltration. Moreover, ARI showed high disease identification through receiver operating characteristic (ROC) analysis (AUCtesting cohort = 0.956, AUCtraining cohort = 0.867). These results were then verified in GSE12021 independent cohort. In conclusion, ARI associated with autophagy and immune infiltration was successfully constructed for accurately identifying OA and RA. The index, thus, has great potential in clinical applications.

Development of an immune-related gene pairs index for the prognosis analysis of metastatic melanoma.

Melanoma is a skin cancer with great metastatic potential, which is responsible for the major deaths in skin cancer. Although the prognosis of melanoma patients has been improved with the comprehensive treatment, for patients with metastasis, the complexity and heterogeneity of diffuse diseases make prognosis prediction and systematic treatment difficult and ineffective. Therefore, we established a novel personalized immune-related gene pairs index (IRGPI) to predict the prognosis of patients with metastatic melanoma, which was conducive to provide new insights into clinical decision-making and prognostic monitoring for metastatic melanoma. Through complex analysis and filtering, we identified 24 immune-related gene pairs to build the model and obtained the optimal cut-off value from receiver operating characteristic curves, which divided the patients into high and low immune-risk groups. Meantime, the Kaplan-Meier analysis, Cox regression analysis and subgroup analysis showed that IRGPI had excellent prognostic value. Furthermore, IRGPI was shown that was closely associated with immune system in the subsequent tumor microenvironment analysis and gene set enrichment analysis. In addition, we broken through the data processing limitations of traditional researches in different platforms through the application of gene pairs, which would provide great credibility for our model. We believe that our research would provide a new perspective for clinical decision-making and prognostic monitoring in metastatic melanoma.

OGDHL closely associates with tumor microenvironment and can serve as a prognostic biomarker for papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common type of thyroid cancer. However, due to the lack of reliable prognostic biomarkers for PTC, overtreatment has been on the rise. Therefore, our research aims to identify new and promising prognostic biomarkers and provide fresh perspectives for clinical decision making. METHODS: The RNA-seq data and clinical data of PTC samples were obtained from The Cancer Genome Atlas data portal. GSE64912 and GSE83520 datasets were downloaded through the GEOquery R package. The difference in the expression of oxoglutarate dehydrogenase like (OGDHL) between PTC and normal tissues was explored by the Wilcoxon test. Kaplan-Meier (KM) and Cox regression analyses were used to further explore the prognostic value of OGDHL. The tumor microenvironments of PTC patients were explored based on ssGSEA and Tumor Immune Estimation Resource online database. Gene Set Enrichment Analysis (GSEA) was performed to explore the biological processes associated with OGDHL. RESULTS: The expression level of OGDHL in PTC was significantly altered compared to that in normal tissues (p < 0.05). Various biological processes associated with OGDHL were also explored through GSEA. KM analysis suggested that the low-OGDHL group had a better overall survival [OS, p = 3.49e-03, hazard ratio (HR) = 4.567]. The receiver operating characteristic curve also indicated the favorable prognostic potential of OGDHL. Moreover, OGDHL was proved to be an independent prognostic indicator in Cox analysis (p = 1.33e-02, HR = 0.152). In the analysis of the tumor microenvironment, the low-OGDHL group showed a lower immune score and stromal score, while tumor purity was higher. The expression of OGDHL was also closely correlated with the infiltration of immune cells. CONCLUSION: Our study elucidated the influence of OGDHL on the prognosis of PTC and demonstrated its potential as a novel biomarker, which would provide new insights into the prognosis monitoring and clinical decision making in PTC patients.

A near-vision chart for children aged 3-5 years old: new designs and clinical applications.

AIM: To introduce a new near-vision chart for children aged 3-5 years old and its clinical applications. METHODS: The new near-vision chart which combined the Bailey-Lovie layout with a newly devised set of symmetry symbols was designed based on Weber-Fechner law. It consists of 15 rows of symmetry symbols, corresponding to a visual acuity range from 1.3 to 0.1 logMAR. The optotypes were red against a white background and were specially shaped four basic geometric symbols: circle, square, triangle, and cross, which matched the preschool children's cognitive level. A regular geometric progression of the optotype sizes and distribution was employed to arrange in 15 lines. The progression rate of the optotype size between two lines was 1.2589 and two smaller groups of optotypes ranging from 0.7 to -0.1 logMAR were included for repetitive testing. A near visual acuity was recorded in logMAR or decimal, and the testing distance was 25 cm. RESULTS: This new near-vision chart with pediatric acuity test optotypes which consists of 4 different symbols (triangle, square, cross, and circle) met the national and international eye chart design guidelines. When performing the near visual acuity assessment in preschoolers (3-5 years old). It overcame an inability to recognize the letters of the alphabet and difficulties in designating the direction of black abstract symbols such as the tumbling 'E' or Landolt 'C', which the subjects were prone to lose interest in. Near vision may be recorded in different notations: decimal acuity and logMAR. These two notations can be easily converted each other in the new near-vision chart. The measurements of this new chart not only showed a significant correlation and a good consistency with the Chinese national standard logarithmic near-vision chart (r=0.932, P<0.01), but also indicated good test-retest reliability (89% of retest scores were within 0.1 logMAR units of the initial test score) and a high response rate. CONCLUSION: The results of this study support the validity and reliability of near visual acuity measurements using the new near-vision chart in children aged 3-5y over a wide range of visual acuities, and the new eye chart was especially suitable for the detection of amblyopia risk factors and low vision examination in children (3-5y of age). It can be applied in routine clinical practice.

A new specialized visual acuity chart for amblyopic children aged 3-5 years old: development and its clinical applications.

AIM: To introduce a new specialized visual acuity chart for amblyopic children aged 3-5 years old and its clinical applications. METHODS: The new visual acuity chart and notations were designed based on Weber-Fechner law. The optotypes were red against a white background and were specially shaped four basic geometric symbols: circle, square, triangle, and cross. A regular geometric progression of the optotype sizes and distribution was employed to arrange in 14 lines. The progression rate of the optotype size between two lines was 1.2589 and the testing distance was 3m. Visual acuity score could be recorded as logMAR notation or decimal notation. Age-stratified diagnostic criteria for amblyopia established by consensus statement on diagnosis of amblyopia (2011) among members of the Strabismus and Pediatric Ophthalmology Group, Ophthalmology Society, Chinese Medical Association (SPOGOSCMA) were illustrated in the new visual acuity chart. RESULTS: When assessing visual acuity in children aged 3-5 years old, this new visual acuity chart that consists of four symmetrical shapes (triangle, square, cross, and circle) overcame an inability to recognize the letters of the alphabet and difficulties in designating the direction of black abstract symbols such as the tumbling 'E' or Landolt 'C', which the subjects were prone to lose interest in. The visual acuity score may be recorded in different notations: decimal acuity and logMAR. These two notations can be easily converted each other in the new eye chart. The measurements of this new chart not only showed a significant correlation and a good consistency with the international standard logarithmic visual acuity chart (r=0.932, P<0.01), but also indicated a high test-retest reliability (89% of retest scores were within 0.1logMAR units of the initial test score). CONCLUSION: The results of this study support the validity and reliability of distance visual acuity measurements using the new eye chart in children aged 3 to 5 years over a wide range of visual acuities, and the new eye chart is great for early detection of amblyopia. It can be applied in various clinical settings.