The prognostic and immunological role of MCM3 in pan-cancer and validation of prognosis in a clinical lower-grade glioma cohort.

Background: Previous studies have shown that MCM3 plays a key role in initiating DNA replication. However, the mechanism of MCM3 function in most cancers is still unknown. The aim of our study was to explore the expression, prognostic role, and immunological characteristics of MCM3 across cancers. Methods: We explored the expression pattern of MCM3 across cancers. We subsequently explored the prognostic value of MCM3 expression by using univariate Cox regression analysis. Spearman correlation analysis was performed to determine the correlations between MCM3 and immune-related characteristics, mismatching repair (MMR) signatures, RNA modulator genes, cancer stemness, programmed cell death (PCD) gene expression, tumour mutation burden (TMB), microsatellite instability (MSI), and neoantigen levels. The role of MCM3 in predicting the response to immune checkpoint blockade (ICB) therapy was further evaluated in four immunotherapy cohorts. Single-cell data from CancerSEA were analysed to assess the biological functions associated with MCM3 in 14 cancers. The clinical correlation and independent prognostic significance of MCM3 were further analysed in the TCGA and CGGA lower-grade glioma (LGG) cohorts, and a prognostic nomogram was constructed. Immunohistochemistry in a clinical cohort was utilized to validate the prognostic utility of MCM3 expression in LGG. Results: MCM3 expression was upregulated in most tumours and strongly associated with patient outcomes in many cancers. Correlation analyses demonstrated that MCM3 expression was closely linked to immune cell infiltration, immune checkpoints, MMR genes, RNA modulator genes, cancer stemness, PCD genes and the TMB in most tumours. There was an obvious difference in outcomes between patients with high MCM3 expression and those with low MCM3 expression in the 4 ICB treatment cohorts. Single-cell analysis indicated that MCM3 was mainly linked to the cell cycle, DNA damage and DNA repair. The expression of MCM3 was associated with the clinical features of LGG patients and was an independent prognostic indicator. Finally, the prognostic significance of MCM3 in LGG was validated in a clinical cohort. Conclusion: Our study suggested that MCM3 can be used as a potential prognostic marker for cancers and may be associated with tumour immunity. In addition, MCM3 is a promising predictor of immunotherapy responses.

Identification of prognostic risk score of disulfidptosis-related genes and molecular subtypes in glioma.

Background: Programmed cell death is closely related to glioma. As a novel kind of cell death, the mechanism of disulfidptosis in glioma remains unclear. Therefore, it is of great importance to study the role of disulfidptosis-related genes (DRGs) in glioma. Methods: We first investigated the genetic and transcriptional alterations of 15 DRGs. Two consensus cluster analyses were used to evaluate the association between DRGs and glioma subtypes. In addition, we constructed prognostic DRG risk scores to predict overall survival (OS) in glioma patients. Furthermore, we developed a nomogram to enhance the clinical utility of the DRG risk score. Finally, the expression levels of DRGs were verified by immunohistochemistry (IHC) staining. Results: Most DRGs (14/15) were dysregulated in gliomas. The 15 DRGs were rarely mutated in gliomas, and only 50 of 987 samples (5.07 %) showed gene mutations. However, most of them had copy number variation (CNV) deletions or amplifications. Two distinct molecular subtypes were identified by cluster analysis, and DRG alterations were found to be related to the clinical characteristics, prognosis, and tumor immune microenvironment (TIME). The DRG risk score model based on 12 genes was developed and showed good performance in predicting OS. The nomogram confirmed that the risk score had a particularly strong influence on the prognosis of glioma. Furthermore, we discovered that low DRG scores, low tumor mutation burden, and immunosuppression were features of patients with better prognoses. Conclusion: The DRG risk model can be used for the evaluation of clinical characteristics, prognosis prediction, and TIME estimation of glioma patients. These DRGs may be potential therapeutic targets in glioma.

CNPY4 is a potential promising prognostic-related biomarker and correlated with immune infiltrates in gliomas.

Glioblastomas are classified into primary and secondary; primary glioblastomas develop rapidly and aggressively, whereas secondary glioblastomas are more common in grade II and III gliomas. Here, we aimed to demonstrate the role of the CNPY4 gene as a potential biomarker in immune infiltration in gliomas. Based on gene expression profile interaction analysis (GEPIA), we studied the survival model of CNPY4 and evaluated its effect on patients with glioma. The glioma dataset was downloaded from The Cancer Genome Atlas (TCGA) database. Logistic regression was used to analyze the relationship between clinical data and CNPY4 expression. Univariate and multivariate Cox proportional-hazards models were used to compare clinical features and patient survival. The relationship between CNPY4 and immune infiltration in glioma was studied using GEPIA and CIBERSORT online tools. TCGA data were analyzed using gene set enrichment analysis (GSEA). Finally, TIMER was used to analyze the expression and immune infiltration of CNPY4 in glioma to study the cumulative survival rate. Univariate logistic regression analysis showed that increased CNPY4 expression was associated with tumor age, grade, IDH status, and 1p/19q codeletion. Multivariate analysis showed that that downregulation of CNPY4 expression was an independent and satisfactory prognostic factor. CNPY4 expression was correlated with the infiltration level of dendritic cells in glioblastoma. In contrast, in low-grade gliomas, the infiltration level of B cells, dendritic cells, macrophages, neutrophils, and CD4+ T cells was significantly correlated with CNPY4 expression. The GSEA results showed that CNPY4 played an immunoregulatory role in immune-related phenotypic pathways between lymphoid and nonlymphoid cells. The intestinal immune networks for IgA production, rabbit thyroid disease, primary immunodeficiencies, and cancer immunotherapy were enriched by PD-1 blockade. High CNPY4 expression is a biomarker of glioma prognosis and is associated with the immune invasion of glioma.

Establishment and Validation of a Ferroptosis-Related lncRNA Signature for Prognosis Prediction in Lower-Grade Glioma.

Background: The prognosis of lower-grade glioma (LGG) is highly variable, and more accurate predictors are still needed. The aim of our study was to explore the prognostic value of ferroptosis-related long non-coding RNAs (lncRNAs) in LGG and to develop a novel risk signature for predicting survival with LGG. Methods: We first integrated multiple datasets to screen for prognostic ferroptosis-related lncRNAs in LGG. A least absolute shrinkage and selection operator (LASSO) analysis was then utilized to develop a risk signature for prognostic prediction. Based on the results of multivariate Cox analysis, a prognostic nomogram model for LGG was constructed. Finally, functional enrichment analysis, single-sample gene set enrichment analysis (ssGSEA), immunity, and m6A correlation analyses were conducted to explore the possible mechanisms by which these ferroptosis-related lncRNAs affect survival with LGG. Results: A total of 11 ferroptosis-related lncRNAs related to the prognosis of LGG were identified. Based on prognostic lncRNAs, a risk signature consisting of 8 lncRNAs was constructed and demonstrated good predictive performance in both the training and validation cohorts. Correlation analysis suggested that the risk signature was closely linked to clinical features. The nomogram model we constructed by combining the risk signature and clinical parameters proved to be more accurate in predicting the prognosis of LGG. In addition, there were differences in the levels of immune cell infiltration, immune-related functions, immune checkpoints, and m6A-related gene expression between the high- and low-risk groups. Conclusion: In summary, our ferroptosis-related lncRNA signature exhibits good performance in predicting the prognosis of LGG. This study may provide useful insight into the treatment of LGG.

A nomogram combining inflammatory markers and clinical factors predicts survival in patients with diffuse glioma.

ABSTRACT: In this study, we aimed to investigate the prognostic value of neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), and platelet/lymphocyte ratio (PLR) in diffuse glioma, and to establish a prognostic nomogram accordingly.The hematologic and clinicopathological data of 162 patients with primary diffuse glioma who received surgical treatment from January 2012 to December 2018 were retrospectively analyzed. Receiver operator characteristic (ROC) curve was carried out to determine the optimal cut-off values for NLR, MLR, PLR, age, and Ki-67 index, respectively. Kaplan-Meier method was used to investigate the correlation between inflammatory indicators and prognosis of glioma patients. Univariate and multivariate Cox regression were performed to evaluate the independent prognostic value of each parameter in glioma. Then, a nomogram was developed to predict 1-, 3-, and 5-year postoperative survival in diffuse glioma patients based on independent prognostic factors. Subsequent time-dependent ROC curve, calibration curve, decision curve analysis (DCA), and concordance index (C-index) were performed to assess the predictive performance of the nomogram.The Kaplan-Meier curve indicated that patients with high levels of NLR, MLR, and PLR had a poor prognosis. In addition, we found that NLR level was associated with World Health Organization (WHO) grade and IDH status of glioma. The multivariate Cox analysis indicated that resection extent, WHO grade, and NLR level were independent prognostic factors, and we established a nomogram that included these three parameters. The evaluation of the nomogram indicated that the nomogram had a good predictive performance, and the addition of NLR could improve the accuracy.NLR, MLR, and PLR were prognostic factors of diffuse glioma. In addition, the nomogram including NLR was reliable for predicting survival of diffuse glioma patients.

Use of Genome-Scale Integrated Analysis to Identify Key Genes and Potential Molecular Mechanisms in Recurrence of Lower-Grade Brain Glioma.

BACKGROUND The aim of this study was to identify gene signals for lower-grade glioma (LGG) and to assess their potential as recurrence biomarkers. MATERIAL AND METHODS An LGG-related mRNA sequencing dataset was downloaded from The Cancer Genome Atlas (TCGA) Informix. Multiple bioinformatics analysis methods were used to identify key genes and potential molecular mechanisms in recurrence of LGG. RESULTS A total of 326 differentially-expressed genes (DEGs), were identified from 511 primary LGG tumor and 18 recurrent samples. Gene ontology (GO) analysis revealed that the DEGs were implicated in cell differentiation, neuron differentiation, negative regulation of neuron differentiation, and cell proliferation in the forebrain. The Kyoto Encyclopedia of Genes and Genomes (KEGG) database suggests that DEGs are associated with proteoglycans in cancer, the Wnt signaling pathway, ECM-receptor interaction, the PI3K-Akt signaling pathway, transcriptional deregulation in cancer, and the Hippo signaling pathway. The hub DEGs in the protein-protein interaction network are apolipoprotein A2 (APOA2), collagen type III alpha 1 chain (COL3A1), collagen type I alpha 1 chain (COL1A1), tyrosinase (TYR), collagen type I alpha 2 chain (COL1A2), neurotensin (NTS), collagen type V alpha 1 chain (COL5A1), poly(A) polymerase beta (PAPOLB), insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), and anomalous homeobox (ANHX). GSEA revealed that the following biological processes may associated with LGG recurrence: cell cycle, DNA replication and repair, regulation of apoptosis, neuronal differentiation, and Wnt signaling pathway. CONCLUSIONS Our study demonstrated that hub DEGs may assist in the molecular understanding of LGG recurrence. These findings still need further molecular studies to identify the assignment of DEGs in LGG.

[Investigation of the site of origin to develop micro-focal nasopharyngeal carcinoma].

OBJECTIVE: To investigate the prevalent area where the nasopharyngeal carcinoma (NPC) initially would develop most frequently in the nasopharynx. METHODS: From March, 1994 to June, 2003, the data of original micro-focus of 32 pathologically confirmed NPC were retrospectively reviewed, All cases were shown by CT to have stages T(0) or T(1) lesions. RESULTS: On clinical examination, only 3 cases (9.4%) were found to have original micro-tumor in the recess, the other 29 cases (90.6%) had developed from the other regions including 20 (69.0%) from the roof and 9 cases (31.0%) from the posterior wall, all with the mucosa in the recess smooth and symmetrical. However, CT images showed that membrane of all the nasopharyngeal walls, including the recess, were normal in 24 cases (75.0%); except the micro-foci were observed on one side of the posterior wall in 5 cases (15.6%) but still with the recess normal, One lateral wall and/or the recess were involved with abnormal appearance in 3 cases (9.4%) who were clinically found to have NPC focus originated from the recess. CONCLUSION: Our data suggest that the roof of nasopharyngeal cavity may be the area likely to develop the original NPC micro-focus, followed in frequency by the posterior wall, with the recess the least likely. The recess involvement observed in advanced lesions may be the extension of the NPC focus from the original site on the roof or the posterior wall of nasopharynx.

[The management of thyroid well-differentiated carcinoma invading the upper aerodigestive tract].

OBJECTIVE: To investigate the management and prognosis of thyroid well-differentiated carcinoma invading the upper aerodigestive tract. METHODS: A retrospective analysis of the management was performed done 62 patients with thyroid well-differentiated carcinoma invading the upper aerodigestive tract. The main method of surgery was shaving excision, and the other means including partial thyrochondrectomy, total laryngectomy, sleeve tracheal resection, sternocleidomastoid myoperiosteal flap and myodermal flap reconstruction, or simply palliative excision. Some patients received postoperative radioactive isotope therapy and radiotherapy. All patients were followed-up for 2 to 15 years with an average of 6.5 years. RESULTS: The best curative effect was proved in the patients with local invasion, with the lumen uninvolved and their locoregional control rate was 100.0% (17/17). And the second choice was in patients with more extensive involvement of the upper aerodigestive tract structures. For them, extensive surgical management was done attempting to remove all gross disease followed by reconstruction, their locoregional control rate was 87.5% (7/8). And the third place was designated to patients with local invasion for which shaving excision was performed even though minor residual disease was left, their locoregional control rate was 55.6% (5/9). The poorest result went to simple palliative excision. For 17 patients with minor residual tumor, the locoregional control rate of those who were given postoperative radioactive isotope therapy was significantly higher than those without. CONCLUSION: According to the limits and degree of invasion in the upper aerodigestive tract by thyroid well-differentiated carcinoma, different ways of surgery is indicated. For patients with residual disease, radioactive isotope therapy should be used to improve the result and life quality. Advanced lesions should be given postoperative radio therapy.

[Significance of detecting serum tumor supplied group of factors in differential diagnosis of neck masses].

BACKGROUND & OBJECTIVE: It was reported that serum tumor supplied group of factors (TSGF) were useful in differential diagnosis of various benign and malignant tumor. However, there was little report involving the differential diagnosis of neck masses. This study was designed to evaluate the significance of serum TSGF in differential diagnosis of neck masses. METHOD: Serum TSGFs on the samples from 128 patients with neck masses were detected by immunohistochemistry. Forty seven non-tumor patients served as control. RESULTS: Serum TSGF level and positive rate in various malignant group (including nasopharyngeal carcinoma, non-Hodgkin's disease, and metastatic carcinoma which primary lesion remained unknown) were higher than that in benign mass group (including cervical lymphoadenitis, or reactive hyperplasia, and neck lymphoid tuberculosis without general active tuberculosis), with very significant difference (all P < 0.01). There was no significant difference between two benign masses or neck benjgn masses or neck benign masses and non tumor patients (all P > 0.05). The differential diagnosis parameters of positive serum TSGF for neck malignant masses were: sensitivity 78.16%, specificity 75.61%, efficiency 77.34%, positive predictive value [PV(+)] 87.18%, negative predictive value [PV(-)] 62.00%. CONCLUSION: Determination of serum TSGF was useful in differential diagnosis of neck masses.