Diffuse cavernous hemangioma of the skull misdiagnosed as skull metastasis in breast cancer patient: one case report and literature review.

BACKGROUND: Primary intraosseous cavernous hemangiomas (PICHs) of the skull are extremely rare. To date, diffuse cranial hemangioma of skull has not been reported. In cancer patients, it is often misdiagnosed as metastasis. CASE PRESENTATION: Here, we presented a case of a 50-year-old female patient suffering from slightly headache who received breast cancer modified radical mastectomy in 2004, computed tomography and magnetic resonance imaging findings revealed abnormal lesions of diffuse skull which were misdiagnosed as skull metastasis, and the relevant literatures were also reviewed. CONCLUSIONS: Diffuse cavernous hemangioma of the skull is exceedingly rare, and imaging data are not typical. The condition is often misdiagnosed, and pathological evaluation is necessary and important. In cases where the mass cannot be completely removed by surgery, radiotherapy could be beneficial.

FAT10 Is Critical in Influenza A Virus Replication by Inhibiting Type I IFN.

The H5N1 avian influenza virus causes severe disease and high mortality, making it a major public health concern worldwide. The virus uses the host cellular machinery for several steps of its life cycle. In this report, we observed overexpression of the ubiquitin-like protein FAT10 following live H5N1 virus infection in BALB/c mice and in the human respiratory epithelial cell lines A549 and BEAS-2B. Further experiments demonstrated that FAT10 increased H5N1 virus replication and decreased the viability of infected cells. Total RNA extracted from H5N1 virus-infected cells, but not other H5N1 viral components, upregulated FAT10, and this process was mediated by the retinoic acid-induced protein I-NF-κB signaling pathway. FAT10 knockdown in A549 cells upregulated type I IFN mRNA expression and enhanced STAT1 phosphorylation during live H5N1 virus infection. Taken together, our data suggest that FAT10 was upregulated via retinoic acid-induced protein I and NF-κB during H5N1 avian influenza virus infection. And the upregulated FAT10 promoted H5N1 viral replication by inhibiting type I IFN.

Neuraminidase of Influenza A Virus Binds Lysosome-Associated Membrane Proteins Directly and Induces Lysosome Rupture.

UNLABELLED: As a recycling center, lysosomes are filled with numerous acid hydrolase enzymes that break down waste materials and invading pathogens. Recently, lysosomal cell death has been defined as "lysosomal membrane permeabilization and the consequent leakage of lysosome contents into cytosol." Here, we show that the neuraminidase (NA) of H5N1 influenza A virus markedly deglycosylates and degrades lysosome-associated membrane proteins (LAMPs; the most abundant membrane proteins of lysosome), which induces lysosomal rupture, and finally leads to cell death of alveolar epithelial carcinoma A549 cells and human tracheal epithelial cells. The NA inhibitors peramivir and zanamivir could effectively block the deglycosylation of LAMPs, inhibit the virus cell entry, and prevent cell death induced by the H5N1 influenza virus. The NA of seasonal H1N1 virus, however, does not share these characteristics. Our findings not only reveal a novel role of NA in the early stage of the H5N1 influenza virus life cycle but also elucidate the molecular mechanism of lysosomal rupture crucial for influenza virus induced cell death. IMPORTANCE: The integrity of lysosomes is vital for maintaining cell homeostasis, cellular defense and clearance of invading pathogens. This study shows that the H5N1 influenza virus could induce lysosomal rupture through deglycosylating lysosome-associated membrane proteins (LAMPs) mediated by the neuraminidase activity of NA protein. NA inhibitors such as peramivir and zanamivir could inhibit the deglycosylation of LAMPs and protect lysosomes, which also further interferes with the H5N1 influenza virus infection at early stage of life cycle. This work is significant because it presents new concepts for NA's function, as well as for influenza inhibitors' mechanism of action, and could partially explain the high mortality and high viral load after H5N1 virus infection in human beings and why NA inhibitors have more potent therapeutic effects for lethal avian influenza virus infections at early stage.

Complex roles of NRAGE on tumor.

NRAGE, also known as Dlxin-1or MAGE-D1, is a member of type II melanoma-associated antigen (MAGE) and plays an essential role in life activities, including differentiation, apoptosis, and cell cycle. Studies increasingly found that NRAGE is closely related to the tumor events, such as tumor occurrence, invasion, and metastasis. However, complex and contradictory functions of NRAGE in different circumstances are observed, suggesting that NRAGE is unique from other MAGE gene family members. This review summarizes recent findings concerning the structure and biological functions of NRAGE, which may provide a basis for a more comprehensive understanding of and further research on NRAGE.

Identification of novel NRAGE involved in the radioresistance of esophageal cancer cells.

Radiotherapy (RT) is one main method for the treatment of esophageal squamous cell carcinoma (ESCC), and the radioresistance is the predominant cause of patients with local recurrence. The previous results of gene microarray and subsequent verification showed that NRAGE might be involved in radiation resistance of ESCC cells. In this study, we reestablished human esophageal carcinoma radioresistant cell lines TE13R120 and ECA109R60 with gradient dose irradiation as previously reported, respectively. NRAGE expression was high in TE13R120 and ECA109R60 cells and was correlative with ionizing radiation (IR) resistance in clinic. However, the radiosensitivity of TE13R120 cells had a remarkable increase detected by colony formation assays after siRNA against NRAGE (siNRG) transfection into TE13R120 cells. Compared with TE13 cells, an increasing number of TE13R120 cells with NRAGE overexpression in S phase and a lower ratio in G2/M were observed by flow cytometry method (FCM). Intriguingly, the above changes were partially reversed in TE13R120 cells treated with siNRG. More importantly, the ectopic subcellular localization of NRAGE mediated nuclear translocation of ß-catenin which may be one reason of IR resistance of esophageal carcinoma cell. These data indicate that NRAGE extremely may be a pivotal factor involved in Wnt/ß-catenin signal pathway, mediating nuclear translocation of ß-catenin and then facilitating the formation of radioresistance of ESCC.

Identification of prognostic biomarkers in hepatitis B virus-related hepatocellular carcinoma and stratification by integrative multi-omics analysis.

BACKGROUND & AIMS: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy. METHODS: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patients with multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to contrast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174). RESULTS: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual-specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort. CONCLUSIONS: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

HMGB2 is a biomarker associated with poor prognosis promoting radioresistance in glioma by targeting base excision repair pathway.

BACKGROUND: High mobility group box 2 (HMGB2) is considered as a biomarker of poor prognosis in various cancers.This study aims to investigate the effect and mechanism of HMGB2 in gliomas. METHODS: With the glioma related on-line and our local hospital databases, the expression differences of HMGB2,Kaplan-Meier survival analysis and COX regression analysis were performed.The correlation analysis between the clinicopathological features and imaging parameters with the HMGB2 expression had been done. Then GSEA and PPI networks were carried out to find out the most significant pathway. The pathway inhibitor was applied to verify HMGB2's participation. CCK8,EDU assays,γ-H2AX immunofluorescence staining and colony formation assay were conducted to observe effects on glioma cells. RESULTS: Available datasets showed that HMGB2 was highly expressed in glioma and patients with high expression of HMGB2 had poorer prognosis and molecular characteristics. Protein level evidence of western blot and immunohistochemistry from our center supported the conclusions above. Analysis on imaging features suggested that HMGB2 expression level had an inverse association with ADCmean but positively with the thickness of enhancing margin. Results from GSEA and PPI network analysis exhibited that HMGB2 was involved in base excision repair (BER) signaling pathway. Experimental evidence demonstrated that the overexpression of HMGB2 promoted the proliferation of glioma cells and enhanced the radio-resistance. CONCLUSIONS: HMGB2 could promote glioma development and enhance the radioresistance of glioma cells, potentially related to the BER pathway, suggesting it may serve as an underlying biomarker for patients with glioma.

Identification of a novel immune landscape signature as effective diagnostic markers related to immune cell infiltration in diabetic nephropathy.

Background: The study aimed to identify core biomarkers related to diagnosis and immune microenvironment regulation and explore the immune molecular mechanism of diabetic nephropathy (DN) through bioinformatics analysis. Methods: GSE30529, GSE99325, and GSE104954 were merged with removing batch effects, and different expression genes (DEGs) were screened at a criterion |log2FC| >0.5 and adjusted P <0.05. KEGG, GO, and GSEA analyses were performed. Hub genes were screened by conducting PPI networks and calculating node genes using five algorithms with CytoHubba, followed by LASSO and ROC analysis to accurately identify diagnostic biomarkers. In addition, two different GEO datasets, GSE175759 and GSE47184, and an experiment cohort with 30 controls and 40 DN patients detected by IHC, were used to validate the biomarkers. Moreover, ssGSEA was performed to analyze the immune microenvironment in DN. Wilcoxon test and LASSO regression were used to determine the core immune signatures. The correlation between biomarkers and crucial immune signatures was calculated by Spearman analysis. Finally, cMap was used to explore potential drugs treating renal tubule injury in DN patients. Results: A total of 509 DEGs, including 338 upregulated and 171 downregulated genes, were screened out. "chemokine signaling pathway" and "cell adhesion molecules" were enriched in both GSEA and KEGG analysis. CCR2, CX3CR1, and SELP, especially for the combination model of the three genes, were identified as core biomarkers with high diagnostic capabilities with striking AUC, sensitivity, and specificity in both merged and validated datasets and IHC validation. Immune infiltration analysis showed a notable infiltration advantage for APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. In addition, the correlation analysis showed that CCR2, CX3CR1, and SELP were strongly and positively correlated with checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation in the DN group. Finally, dilazep was screened out as an underlying compound for DN analyzed by CMap. Conclusions: CCR2, CX3CR1, and SELP are underlying diagnostic biomarkers for DN, especially in their combination. APC co-stimulation, CD8+ T cells, checkpoint, cytolytic activity, macrophages, MHC class I, and parainflammation may participate in the occurrence and development of DN. At last, dilazep may be a promising drug for treating DN.

The study of an anoikis-related signature to predict glioma prognosis and immune infiltration.

BACKGROUND: Gliomas are the most common highly aggressive primary malignant brain tumors in adults with different biological behaviors and clinically heterogeneous features. About the extremely poor prognosis of gliomas, the search for potential therapeutic modalities and targets is crucial. METHOD: We extracted the anoikis-related genes (ARG) from GeneCards and obtained differentially expressed genes in normal and glioma tissues from the GSE4290 dataset to obtain intersect differentially expressed ARG in gliomas by differential analysis. KEGG and GO analyses were used to evaluate the potential pathways and molecular processes of these genes. Based on The Cancer Genome Atlas (TCGA) training cohort, we performed the Least Absolute Shrinkage and Selection Operator (LASSO) regression and Cox regression to construct an ARG prognostic model and validated them in the TCGA testing cohort and the Chinese Glioma Genome Atlas (CGGA) validation cohort. Subsequently, we further explored the differences in clinical characteristics, tumor mutation burden (TMB), and the immune microenvironment in the high- and low-risk groups. Univariate and multifactorial regression analyses and nomogram construction were also performed. Moreover, we evaluated the expression levels of key genes via public databases, qPCR analysis and IHC staining, and further assessed the clinical prognostic value. RESULTS: The regulatory model based on quantitative ARG prognostic models showed that patients in the high-risk group were associated with poorer survival prognosis, poorer clinical characteristics, and higher TMB levels. Moreover, the high-risk group had high levels of immune infiltration and upregulated immune checkpoint gene expression. The ARG prognostic model and the Nomogram showed good predictive performance. Expression and survival analysis of five prognostic ARG signatures (ETV4, HMOX1, MYC, NFE2L2, and UBE2C) showed that these genes have potential prognostic value. CONCLUSION: Our constructed ARG prognostic risk model provides a potential therapeutic target and theoretical basis for predicting the prognosis of glioma patients and guiding individualized immunotherapy.

IDH1R132H mutation increases radiotherapy efficacy and a 4-gene radiotherapy-related signature of WHO grade 4 gliomas.

The prognosis for the WHO grade 4 IDH-mutant astrocytoma is better than IDH-wildtype glioblastoma (GBM) patients. The purpose of this study is to explore the potential mechanism of how IDH1 mutation can increase the efficacy of radiotherapy and to establish a risk-score model to predict the efficacy of radiotherapy in WHO grade 4 gliomas. First, we conducted experimental study on the effect of IDH1R132H mutation on glioma cells in vitro. Radiosensitivity of glioma cells was detected by γ-H2AX after 5 Gy radiation. Cell proliferation, migration and invasion were determined respectively by CCK-8, EDU, monolayer cell migration scratch assay and Transwell assay. Then we analyzed IDH1 gene status and the survival of WHO grade 4 glioma patients received radiotherapy in our center and verified our results by analyzing CGGA and TCGA database. For the risk-score model, we use CGGA data to find genetic differences between WHO grade 4 IDH-mutant astrocytoma and IDH-wildtype GBM patients, and determined a 4-gene radiotherapy-related signature through survival analysis by R software. Evaluation and verification through different glioma validation sets and different statistical methods. For in vitro experiments, we established glioma cells stably overexpressing IDH1 wild-type and IDH1-mutant proteins. γ-H2AX assay showed that IDH1-mutant glioma cells had higher radiosensitivity than wild-type. CCK-8 and EDU assay showed that proliferation capacity of IDH1-mutant glioma cells declined. Transwell assay and monolayer cell migration scratch assay also showed that IDH1-mutant glioma cells reduced migration and invasion capabilities. Among the 83 WHO grade 4 glioma patients who received radiotherapy in our center, WHO grade 4 IDH-mutant astrocytoma patients had longer OS and PFS versus IDH-wildtype GBM (P = 0.0336, P = 0.0324, respectively). TCGA and CGGA database analysis had the similar results. Through complex analysis of CGGA and TCGA databases, we established a risk-model that can predict the efficacy of radiotherapy for WHO grade 4 glioma patients. The 4-gene radiotherapy-related signature including ADD3, GRHPR, RHBDL1 and SLC9A9. Patients in the high-risk group had worse OS compared to low-risk group (P = 0.0001). High- and low-risk groups of patients receiving radiotherapy have significant survival differences, while patients who did not receive radiotherapy have no survival difference both in CGGA and TCGA databases. WHO grade 4 IDH-mutant astrocytoma is more radiosensitive than IDH-wildtype GBM patients. Our 4-gene radiotherapy-related signature can predict the radiation efficacy of WHO grade 4 glioma patients, and it may provide some reference for clinical treatment options.

Integrated Analysis of Multiple Microarray Studies to Identify Core Gene-Expression Signatures Involved in Tubulointerstitial Injury in Diabetic Nephropathy.

Diabetic nephropathy is a leading cause of end-stage renal disease in both developed and developing countries. It is lack of specific diagnosis, and the pathogenesis remains unclarified in diabetic nephropathy, following the unsatisfactory effects of existing treatments. Therefore, it is very meaningful to find biomarkers with high specificity and potential targets. Two datasets, GSE30529 and GSE47184 from GEO based on diabetic nephropathy tubular samples, were downloaded and merged after batch effect removal. A total of 545 different expression genes screened with log2FC > 0.5 were weighted gene coexpression correlation network analysis, and green module and blue module were identified. The results of KEGG analyses both in green module and GSEA analysis showed the same two enriched pathway, focal adhesion and viral myocarditis. Based on the intersection among WGCNA focal adhesion/Viral myocarditis, GSEA focal adhesion/viral myocarditis, and PPI network, 17 core genes, ACTN1, CAV1, PRKCB, PDGFRA, COL1A2, COL6A3, RHOA, VWF, FN1, HLA-F, HLA-DPB1, ITGB2, HLA-DRA, HLA-DMA, HLA-DPA1, HLA-B, and HLA-DMB, were identified as potential biomarkers in diabetic tubulointerstitial injury and were further validated externally for expression at GSE99325 and GSE104954 and clinical feature at nephroseq V5 online platform. CMap analysis suggested that two compounds, LY-294002 and bufexamac, may be new insights for therapeutics of diabetic tubulointerstitial injury. Conclusively, it was raised that a series of core genes may be as potential biomarkers for diagnosis and two prospective compounds.

Identification of FABP7 as a Potential Biomarker for Predicting Prognosis and Antiangiogenic Drug Efficacy of Glioma.

Objective: Glioma is a common malignant tumor of the central nervous system with extremely poor prognosis. An efficient molecular marker for diagnosis and treatment is urgently needed. Fatty acid binding protein 7(FABP7), which regulates intracellular lipid metabolism, is highly expressed in nervous system tumors, but its prognostic value remains undetermined. The present study investigated the relationship between FABP7 expression and prognosis in glioma patients by bioinformatics analysis, as well as immunohistochemically evaluating the effect of FABP7 expression on the efficacy of antiangiogenic drugs. Methods: Gene expression and clinical data on patients with glioma were collected from the China Glioma Genome Atlas (CGGA) database, The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases. Levels of FABP7 expression and their association with the clinicopathologic characteristics of glioma patients were analyzed in the CGGA database. The relationships between FABP7 expression and clinical findings, such as survival and prognostic, were determined and used for nomogram construction. Mechanisms of action of FABP7 were assessed using GSEA software. FABP7 expression in the tissues of glioma patients treated with apatinib was evaluated immunohistochemically. Results: FABP7 was highly expressed in glioma samples, with higher FABP7 expression associated with poorer patient prognosis and more advanced clinicopathological features. Bioinformatics analysis, including survival, receiver operating characteristic curve, and univariate and multivariate Cox analyses, showed that FABP7 was independently prognostic of outcomes in glioma patients. GSEA analysis showed that FABP7 was associated with angiogenesis, with FABP7 having correlation coefficients > 0.4 with seven factors in the angiogenic pathway, POSTN, TIMP1, PDGFA, FGFR1, S100A4, COL5A2, and STC1, and the expression of these factors related to patient prognosis. Immunohistochemistry showed that FABP7 expression was higher in glioma patients with poor survival after apatinib treatment. Conclusions: High FABP7 expression is associated with poor prognosis in glioma patients. FABP7, which is important for glioma angiogenesis, may serve as an independent prognostic predictor in glioma patients.

MELK is a prognostic biomarker and correlated with immune infiltration in glioma.

Objective: Glioma accounts for the vast majority of primary brain tumors with inevitable recurrence and poor prognosis. Maternal embryonic leucine zipper kinase (MELK) is overexpressed in multiple human tumors and could activate a variety of oncogenic-associated signal pathways. However, its role in the glioma microenvironment is still largely unknown. Methods: We collected the RNA sequence data and clinical information of gliomas from the Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and the Gene Expression Omnibus (GEO) databases, and investigated MELK expression and its correlation with clinicopathologic features and prognosis in glioma. Moreover, the relationship between MELK expression and immune cell infiltration in the tumor microenvironment of gliomas was explored through single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. In addition, gene set enrichment analysis (GSEA) and Metascape online analysis were performed to find out signaling pathways enriched by differentially expressed genes (DEGs) between high- and low-MELK expression groups. Finally, immunohistochemistry was performed to validate our findings. Results: Data analysis of CGGA and GEO datasets showed that MELK was significantly upregulated in gliomas than in normal brain tissues, and MELK expression was obviously correlated with clinicopathologic features, including age, WHO grade, histological subtype, IDH mutant status, 1p19q codeletion status, and PRS type. Stratified analysis, Cox regression analysis, and nomogram model revealed that high expression of MELK predicted poor survival; hence, MELK could serve as an independent prognostic biomarker for glioma. Moreover, results from enrichment pathway analysis indicated that the immune system process, angiogenesis, apoptosis, cell cycle, and other oncogenic-related signal pathways were significantly enriched between high- and low-MELK expression groups. Immune infiltration analysis demonstrated that increased MELK expression was significantly correlated with higher immune scores, higher fractions of immunocytes (T cells, NK cells resting, macrophages, resting mast cells, and neutrophils), and higher expression levels of immune checkpoints (B7-H3, CTLA4, LAG3, PD-1, PD-L1, and TIM3). Finally, immunohistochemistry analysis validated our findings that high expression of MELK relates to increased malignancy and poor prognosis of glioma. Conclusion: Our findings identified that MELK could act as an independent prognostic indicator and potential immunotherapy target for glioma. In conclusion, these findings suggested that DDOST mediated the immunosuppressive microenvironment of gliomas and could be an important biomarker in diagnosing and treating gliomas.

A Model for Predicting Clinical Prognosis in Patients with WHO Grade 2 Glioma.

Objectives: Although patients with grade 2 glioma have a relatively better prognosis and longer survival than those with high-grade glioma, there are still a number of patients with disappointing outcomes. In order to accurately predict the prognosis of patients, relevant risk factors were included in the analysis to establish a clinical prediction model so as to provide a basis for clinically individualized treatment. Methods: A retrospective study was conducted in patients diagnosed with grade 2 glioma. Data including clinical features, pathological type, molecular classification, neuroimaging examination, treatment, and survival were collected. The data sets were randomly assigned, with 80% of the data used for model building and 20% for validation. Cox proportional hazard regression analysis was used to construct the model using important risk factors and present it in the form of a nomogram. The nomogram was evaluated a using C-index and calibration chart. Results: A total of 160 patients were enrolled in this analysis, including 128 in the training group and 32 in the validation group. In the training group, eight important risk factors including preoperative KPS, the first presenting symptom, the extent of resection, the gross tumor size, 1p19q, IDH, radiotherapy, and chemotherapy were identified to construct the model. The C-index of the training group and the validation group was 0.832 and 0.801, respectively, indicating that the model had good prediction ability. The calibration charts of the two groups were drawn respectively, which showed that the calibration line and the standard line had a good consistency, which suggested that the model-predicted risk had a good consistency with the actual risk. Conclusions: Based on the data of our center, a nomogram prediction model with eight variables has been established as an off-the-rack tool and verified its accuracy, which can guide clinical work and provide consultation for patients.

TOP2A correlates with poor prognosis and affects radioresistance of medulloblastoma.

Radiotherapy remains the standard treatment for medulloblastoma (MB), and the radioresistance contributes to tumor recurrence and poor clinical outcomes. Nuclear DNA topoisomerase II-alpha (TOP2A) is a key catalytic enzyme that initiates DNA replication, and studies have shown that TOP2A is closely related to the therapeutic effects of radiation. In this study, we found that TOP2A was significantly upregulated in MB, and high expression of TOP2A related to poor prognosis of MB patients. Knockdown of TOP2A inhibited MB cell proliferation, migration, and invasion, whereas overexpression of TOP2A enhanced the proliferative and invasive ability of MB cells. Moreover, si-TOP2A transfection in combination with irradiation (IR) significantly reduced the tumorigenicity of MB cells, compared with those transfected with si-TOP2A alone. Cell survival curve analysis revealed that the survival fraction of MB cells was significantly reduced upon TOP2A downregulation and that si-TOP2A-transfected cells had decreased D0, Dq, and SF2 values, indicating that TOP2A knockdown suppresses the resistance to radiotherapy in MB cells. In addition, western blot analysis demonstrated that the activity of Wnt/ß-catenin signaling pathway was inhibited after TOP2A downregulation alone or in combination with IR treatment, whereas overexpression of TOP2A exhibited the opposite effects. Gene set enrichment analysis also revealed that Wnt/ß-catenin signaling pathway is enriched in TOP2A high-expression phenotypes. Collectively, these data indicate that high expression of TOP2A leads to poor prognosis of MB, and downregulation of TOP2A inhibits the malignant behaviour as well as the radioresistance of MB cells. The Wnt/ß-catenin signaling pathway may be involved in the molecular mechanisms of TOP2A mediated reduced tumorigenicity and radioresistance of MB cells.

Meta of classical chemotherapy compared with high-dose chemotherapy and autologous stem cell rescue in newly diagnosed medulloblastoma after radiotherapy.

BACKGROUND: High-dose chemotherapy combined with autologous stem cell rescue (HDCT + ASCR) has been used to treat newly diagnosed medulloblastoma, but there was no high-level evidence to support its efficacy. METHODS: Databases were retrieved, and patients were divided into 2 groups: group A was radiotherapy combined with HCDT + ASCR, and group B was classical radiotherapy and chemotherapy. The clinical benefit rate, progression-free survival (PFS), overall survival (OS) and toxicities data were extracted. RESULTS: 22 clinical trials met the inclusion criteria, 416 in group A and 2331 in group B. There was no difference in CBR between 2 groups (80.0% vs 71.5%, P.262). The 3-year PFS (3-y PFS) of group A was significantly better than group B (79.0% vs 69.5%, P = .004). The analysis found that there was no difference between the 2 groups of the standard risk group or the high-risk group. In the standard risk group, the 5-y PFS of group A was significantly better than group B (83.6% vs75.6%, P = .004). Comparison of 3-y OS and 5-y OS between 2 groups of all MB patients showed no difference (P = .086; P = .507), stratified analysis was the same result. The gastrointestinal toxicity in group A was significantly higher than that in group B (P = .016), and the level 3/4 ototoxicity in high-risk group A was higher than that in group B (P = .001). CONCLUSIONS: HDCT + ASCR can prolong 3-year PFS significantly, and prolong 5-y PFS significantly in the standard risk group, but increase gastrointestinal toxicity significantly for newly diagnosed medulloblastoma.

Blocking REDD1/TXNIP Complex Ameliorates HG-Induced Renal Tubular Epithelial Cell Apoptosis and EMT through Repressing Oxidative Stress.

Diabetic nephropathy (DN) has become the most common secondary kidney disease causing end-stage renal disease (ESRD). Nevertheless, the underlying mechanisms responsible for DN remain largely unknown. Regulated in development and DNA damage response 1 (REDD1) is a prooxidative molecule known to contribute to diabetes mellitus and its complications. However, it has not been previously examined whether and how REDD1 can further drive renal tubular epithelial cell (RTEC) apoptosis and epithelial-to-mesenchymal transition in DN. The expression of REDD1 was elevated in the kidneys of DN patients and diabetic mice in this study. By generating the DN model in REDD1 knockout mice, we demonstrated that REDD1 deficiency significantly improved apoptosis and EMT in diabetic mice. In vitro experiments showed that REDD1 generation was induced by high glucose (HG) in HK-2 cells. Similarly, the transfection of REDD1 siRNA plasmid also suppressed HG-induced apoptosis and EMT. Furthermore, we discovered that the inhibition of REDD1 suppressed the expression of Nox4-induced HG and reactive oxygen species (ROS) synthesis in HK-2 cells. In addition, HG could induce endogenous REDD1 and TXNIP to form a powerful complex. In summary, our findings demonstrate that blocking the REDD1/TXNIP complex can prevent HG-induced apoptosis and EMT by inhibiting ROS production, highlighting REDD1 as a valuable therapeutic priority site for DN.

NRAGE Confers Radiation Resistance in 2D and 3D Cell Culture and Poor Outcome in Patients With Esophageal Squamous Cell Carcinoma.

Objective: The purpose of the study is to explore the mechanism of NRAGE enhancing radioresistance of esophageal squamous cell carcinoma (ESCC) in 2D and 3D levels. Methods: Stably NRAGE-overexpressed ESCC cells and 3D-printing models for ESCC cells were established. Then, cellular malignancy indexes, such as cell morphology, proliferation, radioresistance, motility, apoptosis, cell cycle, and proteins of the Wnt/ß-catenin pathway, were compared between radioresistant and its parental cells in 2D and 3D levels. Additionally, 44 paraffin ESCC specimens with radical radiotherapy were selected to examine NRAGE and ß-catenin protein expression and analyze the clinical correlation. Results: Experiments in 2D culture showed that morphology of the Eca109/NRAGE cells was more irregular, elongated spindle-shaped and disappeared polarity. It obtained faster growth ability, stronger resistance to irradiation, enhanced motility, reduced apoptosis ratio and cell cycle rearrangement. Moreover, Western blot results showed ß-catenin, p-Gsk-3ß and CyclinD1 expressions were induced, while p-ß-catenin and Gsk-3ß expressions decreased in Eca109/NRAGE cells. Experiments in the 3D-printing model showed Eca109/NRAGE cell-laden 3D scaffolds had the advantage on growth and spheroiding according to the brightfield observation, scanning electron microscopy and Ki-67 IHC staining, and higher expression at the ß-catenin protein. Clinical analysis showed that NRAGE expression was higher in tumor tissues than in control tissues of ESCC patients from the Public DataBase. Compared with radiotherapy effective group, both NRAGE total and nuclear and ß-catenin nuclear expressions were significantly upregulated from ESCC specimens in invalid group. Further analysis showed a positive and linear correlation between NRAGE nuclear and ß-catenin nuclear expressions. Additionally, results from univariate and multivariate analyses revealed NRAGE nuclear expression could serve as a risk factor for ESCC patients receiving radical radiotherapy. Conclusion: ESCC cells with NRAGE nuclear accumulation demonstrated greater radioresistance, which may be related to the activation of the Wnt/ß-catenin signaling pathway. It indicated that NRAGE nuclear expression was a potential biomarker for monitoring radiotherapeutic response.

ANXA1: An Important Independent Prognostic Factor and Molecular Target in Glioma.

Objective: The expression, prognosis, and related mechanisms of ANXA1 are investigated in glioma, with the objective to find potential therapeutic molecular targets for glioma. Methods: We analyzed the gene expression of ANXA1 using glioma-related databases, including the Chinese Glioma Genome Atlas (CGGA) database, The Cancer Genome Atlas (TCGA) database, and the Gene Expression Omnibus (GEO) database. Moreover, we collected the sample tissues and corresponding paracancerous tissues of 23 glioma patients and then conducted a Western blot experiment to verify the expression and correlate survival of ANXA1. Moreover, we generated survival ROC curves, performing univariate and multivariate Cox analyses and the construction of the nomogram. Differential expression analysis was conducted by high and low grouping based on the median of the ANXA1 gene expression values. We conducted Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis and Gene Set Enrichment Analysis (GSEA) to explore possible mechanisms, and gene co-expression analysis was also performed. Results: The results showed that the ANXA1 expression level was higher in gliomas than in normal tissues, and a high expression level of ANXA1 in gliomas was associated with poorer prognosis. The independent prognosis analysis showed that the ANXA1 gene was an independent prognostic factor of glioma. In the analysis of KEGG and Gene Set Enrichment Analysis (GSEA), it is shown that ANXA1 may play an important role in glioma patients by affecting extracellular matrix (ECM)-receptor interaction and the focal adhesion signal pathway. The core genes, including COL1A1, COL1A2, FN1, ITGA1, and ITGB1, were screened for gene correlation and prognosis analysis. The expression level of the five genes was verified by qPCR in glioma. We concluded that these five core genes and ANXA1 could play a synergistic role in gliomas. Conclusion: The results indicated that a high expression level of ANXA1 leads to worse prognosis and ANXA1 is an independent prognostic factor and a potentially important target for the treatment of gliomas.

Circular RNA: A novel type of biomarker for glioma (Review).

With the rapid development of sequencing technologies, the characteristics and functions of circular RNAs (circRNAs) in different tissues, and their underlying pathophysiological mechanisms, have been identified. circRNAs are significantly enriched in the brain and are continually expressed from the embryonic stage to the adult stage in rats. Previous studies have reported that certain circRNAs are differentially expressed in glioma and regulate a number of biological processes, such as cell proliferation, metastasis and oncogenesis of glioma. Furthermore, certain circRNAs have been associated with tumor size, World Health Organization tumor grade and poor prognosis in patients with glioma. It has been hypothesized that circRNAs may be involved in the onset and progression of glioma through transcriptional regulation, protein translation and binding to microRNAs. These properties and functions suggest the potential of circRNAs as prognostic biomarkers and therapeutic targets for glioma. For the present review, published studies were examined from PubMed, Embase, Cochrane Central and the reference lists of the retrieved articles. The aim of the present review was to summarize the progress of circRNA research in glioma, discuss the potential diagnostic and prognostic values, and the roles of circRNAs in glioma, and provide a novel theoretical basis and research concepts for the prediction, diagnosis and treatment of glioma.