scholarly journals Expression And Clinical Significance of BIRC5 In Low-Grade Gliomas Based On Bioinformatics Analysis

2021 ◽  
Author(s):  
Xitong Yang
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Expression Level ◽  
Low Grade ◽  
Expression Screening ◽  
Immune Genes ◽  
Low Grade Gliomas ◽  
Normal Tissues ◽  
Immune Related Genes

Abstract Background: To screen target genes analyze the expression and mechanism of target genes in Low-grade Gliomas (LGG).Methods: LGG data were downloaded from TCGA database. Differentially expressed genes (DEGs) were screened by differential expression screening, protein–protein interaction (PPI) and enrichment analysis, and then the differentially immune related genes were obtained by analyzing DEGs and immune genes. The abundance of 22 leukocyte subtypes was calculated by CIBERSORT algorithm. The Hub gene constructed by PPI and the gene of prognosis model were analyzed to screen the LGG target gene. The correlation between target gene and LGG prognosis and clinical characteristics of LGG were analyzed. Results: After immunotherapy, the survival of high TMB group was significantly longer than that low TMB group, and the scores of TMB group were correlated with the age and grade of patients. PPI indicates that AURKA, BUB1, AURKB, CDC20, BIRC5, TTK, CCNB2, CDCA8, and CENPE are the hub genes of LGG. The expression level of BIRC5 in LGG tumor tissues was significantly higher than that in normal tissues. The expression level of BIRC5 was correlated with the age and grade of LGG patients. BIRC5 might participate in the occurrence and development of LGG through P53 pathway.Conclusion: BIRC5 can be used as LGG target gene, and its high expression in LGG indicates poor prognosis. BIRC5, as a therapeutic target of LGG, provides a new direction for immunotherapy of LGG.

scholarly journals A Novel Immune-Related Prognostic Biomarker and Target Associated With Malignant Progression of Glioma

2021 ◽  
Vol 11 ◽  
Author(s):  
Yu Zhang ◽  
Xin Yang ◽  
Xiao-Lin Zhu ◽  
Zhuang-Zhuang Wang ◽  
Hao Bai ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Immune Cell ◽  
Prognostic Biomarker ◽  
Roc Curves ◽  
High Grade Glioma ◽  
Low Grade ◽  
Normal Brain ◽  
Clinical Correlation ◽  
Immune Genes

BackgroundGlioma is one of the most common malignancies in the central nervous system and has limited effective therapeutic options. Therefore, we sought to identify a suitable target for immunotherapy.Materials and MethodsWe screened prognostic genes for glioma in the CGGA database and GSE43378 dataset using survival analysis, receiver operating characteristic (ROC) curves, independent prognostic analysis, and clinical correlation analysis. The results were intersected with immune genes from the ImmPort database through Venn diagrams to obtain likely target genes. The target genes were validated as prognostically relevant immune genes for glioma using survival, ROC curve, independent prognostic, and clinical correlation analyses in samples from the CGGA database and GSE43378 dataset, respectively. We also constructed a nomogram using statistically significant glioma prognostic factors in the CGGA samples and verified their sensitivity and specificity with ROC curves. The functions, pathways, and co-expression-related genes for the glioma target genes were assessed using PPI networks, enrichment analysis, and correlation analysis. The correlation between target gene expression and immune cell infiltration in glioma and the relationship with the survival of glioma patients were investigated using the TIMER database. Finally, target gene expression in normal brain, low-grade glioma, and high-grade glioma tissues was detected using immunohistochemical staining.ResultsWe identified TNFRSF12A as the target gene. Satisfactory results from survival, ROC curve, independent prognosis, and clinical correlation analyses in the CGGA and GSE43378 samples verified that TNFRSF12A was significantly associated with the prognosis of glioma patients. A nomogram was constructed using glioma prognostic correlates, including TNFRSF12A expression, primary-recurrent-secondary (PRS) type, grade, age, chemotherapy, IDH mutation, and 1p19q co-deletion in CGGA samples with an AUC value of 0.860, which illustrated the accuracy of the prognosis prediction. The results of the TIMER analysis validated the significant correlation of TNFRSF12A with immune cell infiltration and glioma survival. The immunohistochemical staining results verified the progressive up-regulation of TNFRSF12A expression in normal brain, low-grade glioma, and high-grade glioma tissues.ConclusionWe concluded that TNFRSF12A was a viable prognostic biomarker and a potential immunotherapeutic target for glioma.

scholarly journals Correlation of Prognostic Biomarker SLC25A1 with Immune Infiltrates in Low-Grade Gliomas

2021 ◽  
Author(s):  
Li Qian ◽  
Shu-min Lu ◽  
Xin He ◽  
Hua Huang ◽  
Jianguo Zhang
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Clinical Information ◽  
Expression Level ◽  
Cell Infiltration ◽  
Receptor Interaction ◽  
Low Grade ◽  
Immune Cell Infiltration ◽  
Normal Tissues

Abstract Background: Glioma is the most common primary malignant tumor of the central nervous system (CNS), and low-grade glioma (LGG) is an important pathological type of glioma. Immune infiltration of tumor microenvironment is an independent predictor of survival and prognosis in LGG patients. SLC25A1 is a gene that has not been reported in LGG. We used the TCGA database to study the expression level of SLC25A1 in LGG tissues and its relationship with the prognosis of LGG patients and tumor immune cell infiltration.Methods: Download gene expression profile data and clinical information of LGG patients from the TCGA database. The expression level of SLC25A1 gene in LGG tissues and normal tissues was compared. The expression level of SLC25A1 gene in LGG tissue samples with different WHO grades and its relationship with the prognosis of patients were analyzed. The correlation between clinical information and SLC25A1 expression was analyzed by Logistic regression. The effect of SLC25A1 on survival of LGG patients was evaluated by survival module. The correlation between SLC25A1 gene expression and tumor immune cell infiltration in LGG and the effect of immune cell infiltration on the prognosis of patients were analyzed by using the relevant modules of GEPIA. The gene groups related to SLC25A1 expression were analyzed by KEGG pathway enrichment analysis. In addition, TCGA dataset was used for gene set enrichment analysis (GSEA).Result: The expression level of SLC25A1 gene in LGG tissues was higher than that in normal tissues. The expression of SLC25A1 in WHO Ⅱ LGG tissues was higher than that in WHO Ⅲ tissues. Multivariate analysis showed that the up-regulated expression of SLC25A1 was an independent prognostic factor for good prognosis in patients with LGG. There was a correlation between the expression level of SLC25A1 and the level of immune cell infiltration of LGG, and the latter affects the prognosis of patients with LGG. In addition, GSEA also found that Neuroactive ligand receptor interaction, cell adhesion molecules cams and so on were differentially enriched in the phenotypic pathway of high expression of SLC25A1. In the Kyoto Encyclopedia of Genome and Genome (KEGG), Neuroactive ligand-receptor interaction, Morphine addiction et al have been identified as differential enrichment pathways.Conclusion: SLC25A1 is the prognosis of LGG related to immune cell infiltration, and may become a biomarker of LGG grade diagnosis, immunotherapy and prognosis.

scholarly journals Comprehensive Analysis of ESRRA in Endometrial Cancer

2021 ◽  
Vol 20 ◽  
pp. 153303382199208
Author(s):  
Shufang Wang ◽  
Xinlong Huo
Keyword(s):  
Endometrial Cancer ◽  
Protein Expression ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Operating Characteristics ◽  
Protein Expression Level ◽  
Normal Tissues

Background: Estrogen-related receptor alpha (ESRRA) was reported to play an important role in multiple biological processes of neoplastic diseases. The roles of ESRRA in endometrial cancer have not been fully investigated yet. Methods: Expression data and clinicopathological data of patients with uteri corpus endometrial carcinoma (UCEC) were obtained from The Cancer Genome Atlas (TCGA). Comprehensive bioinformatics analysis was performed, including receiver operating characteristics (ROC) curve analysis, Kaplan-Meier survival analysis, gene ontology (GO) enrichment analysis, and Gene Set Enrichment Analysis (GSEA). Immunohistochemistry was used to detect the protein expression level of ESRRA and CCK-8 assay was performed to evaluate the effect of ESRRA on the proliferation ability. Results: A total of 552 UCEC tissues and 35 normal tissues were obtained from the TCGA database. The mRNA and protein expression level of ESRRA was highly elevated in UCEC compared with normal tissues, and was closely associated with poor prognosis. ROC analysis indicated a very high diagnostic value of ESRRA for patients with UCEC. GO and GSEA functional analysis showed that ESRRA might be mainly involved in cellular metabolism processes, in turn, tumorigenesis and progression of UCEC. Knockdown of ESRRA inhibited the proliferation of UCEC cells in vitro. Further immune cell infiltration demonstrated that ESRRA enhanced the infiltration level of neutrophil cell and reduced that of T cell (CD4+ naïve), NK cell, and cancer associated fibroblast (CAF). The alteration of immune microenvironment will greatly help in developing immune checkpoint therapy for UCEC. Conclusions: Our study comprehensively analyzed the expression level, clinical value, and possible mechanisms of action of ESRRA in UCEC. These findings showed that ESRRA might be a potential diagnostic and therapeutic target.

scholarly journals A prospective study revealing the role of an immune-related eRNA, WAKMAR2, in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linbang Wang ◽  
Jingkun Liu ◽  
Jiaojiao Tai ◽  
Nian Zhou ◽  
Tianji Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Target Genes ◽  
Pearson Correlation ◽  
Tumour Microenvironment ◽  
The Cancer Genome Atlas ◽  
Mcf7 Cells ◽  
Tumour Immunity ◽  
Immune Genes ◽  
Normal Tissues

AbstractEnhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer.

scholarly journals 3131 ONCOSTREAMS: NOVEL DYNAMICS PATHOLOGICAL MULTICELLULAR STRUCTURES INVOLVED IN GLIOBLATOMA GROWTH AND INVASION

2019 ◽  
Vol 3 (s1) ◽  
pp. 111-111 ◽  
Author(s):  
Andrea Comba ◽  
Patrick Dunn ◽  
Anna E Argento ◽  
Padma Kadiyala ◽  
Sebastien Motsch ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Target Genes ◽  
Collective Motion ◽  
Malignant Tumors ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Genetically Engineered ◽  
Functional Enrichment ◽  
Low Grade ◽  
Normal Brain

OBJECTIVES/SPECIFIC AIMS: Oncostreams represent a novel growth pattern of GBM. In this study we uncovered the cellular and molecular mechanism that regulates the oncostreams function in GBM growth and invasion. METHODS/STUDY POPULATION: We studied oncostreams organization and function using genetically engineered mouse gliomas models (GEMM), mouse primary patient derived GBM model and human glioma biopsies. We evaluated the molecular landscape of oncostreams by laser capture microdissection (LCM) followed by RNA-Sequencing and bioinformatics analysis. RESULTS/ANTICIPATED RESULTS: Oncostreams are multicellular structures of 10-20 cells wide and 2-400 μm long. They are distributed throughout the tumors in mouse and human GBM. Oncostreams are heterogeneous structures positive for GFAP, Nestin, Olig2 and Iba1 cells and negative for Neurofilament. Using GEMM we found a negative correlation between oncostream density and animal survival. Moreover, examination of patient’s glioma biopsies evidenced that oncostreams are present in high grade but no in low grade gliomas. This suggests that oncostreams may play a role in tumor malignancy. Our data also indicated that oncostreams aid local invasion of normal brain. Transcriptome analysis of oncostreams revealed 43 differentially expressed (DE) genes. Functional enrichment analysis of DE genes showed that “collagen catabolic processes”, “positive regulation of cell migration”, and “extracellular matrix organization” were the most over-represented GO biological process. Network analysis indicated that Col1a1, ACTA2, MMP9 and MMP10 are primary target genes. These genes were also overexpressed in more malignant tumors (WT-IDH) compared to the less malignant (IDH1- R132H) tumors. Confocal time lapse imagining of 3D tumor slices demonstrated that oncostreams display a collective motion pattern within gliomas that has not been seen before. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, oncostreams are anatomically and molecularly distinctive, regulate glioma growth and invasion, display collective motion and are regulated by the extracellular matrix. We propose oncostreams as novel pathological markers valuable for diagnosis, prognosis and designing therapeutics for GBM patients.

scholarly journals Identification, Verification and Pathway Enrichment Analysis of Prognosis-Related Immune Genes in Patients With Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhipeng Zhu ◽  
Mengyu Song ◽  
Wenhao Li ◽  
Mengying Li ◽  
Sihan Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Regression Analysis ◽  
Risk Score ◽  
Prognostic Model ◽  
Cox Regression ◽  
Enrichment Analysis ◽  
Expression Data ◽  
Cox Regression Analysis ◽  
Immune Genes ◽  
Immune Related Genes

Hepatocellular carcinoma is a common malignant tumor with poor prognosis, poor treatment effect, and lack of effective biomarkers. In this study, bioinformatics analysis of immune-related genes of hepatocellular carcinoma was used to construct a multi-gene combined marker that can predict the prognosis of patients. The RNA expression data of hepatocellular carcinoma were downloaded from The Cancer Genome Atlas (TCGA) database, and immune-related genes were obtained from the IMMPORT database. Differential analysis was performed by Wilcox test to obtain differentially expressed genes. Univariate Cox regression analysis, lasso regression analysis and multivariate Cox regression analysis were performed to establish a prognostic model of immune genes, a total of 5 genes (HDAC1, BIRC5, SPP1, STC2, NR6A1) were identified to construct the models. The expression levels of 5 genes in HCC tissues were significantly different from those in paracancerous tissues. The Kaplan-Meier survival curve showed that the risk score calculated according to the prognostic model was significantly related to the overall survival (OS) of HCC. The receiver operating characteristic (ROC) curve confirmed that the prognostic model had high accuracy. Independent prognostic analysis was performed to prove that the risk value can be used as an independent prognostic factor. Then, the gene expression data of hepatocellular carcinoma in the ICGC database was used as a validation data set for the verification of the above steps. In addition, we used the CIBERSORT software and TIMER database to conduct immune infiltration research, and the results showed that the five genes of the model and the risk score have a certain correlation with the content of immune cells. Moreover, through Gene Set Enrichment Analysis (GSEA) and the construction of protein interaction networks, we found that the p53-mediated signal transduction pathway is a potentially important signal pathway for hepatocellular carcinoma and is positively regulated by certain genes in the prognostic model. In conclusion, this study provides potential targets for predicting the prognosis and treatment of hepatocellular carcinoma patients, and also provides new ideas about the correlation between immune genes and potential pathways of hepatocellular carcinoma.

scholarly journals High Expression of H2BC12 Predicts Poor Survival Outcome of Low-Grade Gliomas: A Study Based on TCGA Data

2021 ◽  
Author(s):  
Yilei Xiao ◽  
Zhaoquan Xing ◽  
Mengyou Li ◽  
Xin Li ◽  
Ding Wang ◽  
...  
Keyword(s):  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Survival Outcomes ◽  
Low Grade ◽  
Primary Therapy ◽  
Poor Survival ◽  
Gene Set Enrichment ◽  
Data Set ◽  
Gene Set ◽  
Low Grade Gliomas

Abstract Purpose Low-grade gliomas (LGG) have highly variable clinical behaviors, with a high incidence of disease progression as 70% within ten years. Regardless of treatment combining surgery and radiotherapy or chemotherapy, LGG is still associated with adverse survival outcomes. Therefore, our study was performed to satisfy the increasing demand of novel sensitive biomarkers and therapeutic targets in treatment and diagnosis of LGG. Methods The TCGA data set was used to examine the relationship between H2BC12 expression and clinical pathologic characteristics. The significance of H2BC12 expression in prognosis was also investigated. In addition, H2BC12 expression-related pathways were enriched by gene set enrichment analysis (GSEA). Association analysis of H2BC12 gene expression and immune infiltration was performed by single sample gene set enrichment analysis (ssGSEA). Results Significantly up-regulated expression of H2BC12 mRNA was found in LGG tissue when compared to normal tissue and was proven to be diagnostic (have diagnostic significance) for LGG. In the meantime, high H2BC12 levels were associated with WHO grade, IDH status, 1p/19q codeletion, primary therapy outcome and histological type of LGG, and additionally, prognostic for adverse survival outcomes. In the multivariate analysis, high H2BC12 levels were identified to be an independent predictor for poor survival outcomes of LGG patients. Pathways in cancer, signaling by Wnt or PI3K-AKT signaling pathway, DNA repair, cellular senescence and DNA double strand break repair were differentially activated in the phenotype that positively associated with H2BC12. Conclusion H2BC12 is a promising biomarker for the diagnosis and prognosis of LGG.

scholarly journals Systematic Investigation of the Effect of Powerful Tianma Eucommia Capsule on Ischemic Stroke Using Network Pharmacology

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Pengcheng Feng ◽  
Guixia Li ◽  
Yan Huang ◽  
Jinhong Pei
Keyword(s):  
Ischemic Stroke ◽  
Amino Acid ◽  
Molecular Mechanism ◽  
Gene Network ◽  
Target Gene ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Receptor Activity ◽  
Signal Pathways ◽  
Therapeutic Effects

Background. Ischemic stroke (IS) is a serious disease with a high rate of death and disability, and a growing number of people are becoming victims. Existing drugs not only have limited therapeutic effects but also have obvious side effects. Most importantly, drug resistance due to long-term or improper use of drugs is detrimental to patients. Therefore, it is urgent to find some alternative or supplementary medicines to alleviate the current embarrassment. Powerful Tianma Eucommia Capsule (PTEC) is mainly used to treat IS in China for thousands of years; however, the molecular mechanism is not clear. Methods. Pharmacology ingredients and target genes were filtered and downloaded from websites. A pharmacology ingredient-target gene network was constructed to predict the molecular interactions between ingredients and target genes. Enrichment analysis was performed to explore the possible signal pathways. LeDock was used to simulate the interaction form between proteins and main active ingredients and to deduce key amino acid positions. Results. Two hundred eighty-nine target genes and seventy-four pharmacological ingredients were obtained from public databases. Several key ingredients (quercetin, kaempferol, and stigmasterol) and primary core target genes (PTGS1, NCOA2, and PRSS1) were detected through ingredient-target gene network analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated that ingredients affect networks mainly in nuclear receptor activity and G protein-coupled amine receptor activity; besides, fluid shear stress and atherosclerosis, human cytomegalovirus infection, and hepatitis B signaling pathways might be the principal therapy ways. A series of presumed key amino acid sites (189ASP, 190SER, 192GLN, 57HIS, and 99TYE) were calculated in PRSS1. Six of the target genes were differentially expressed between male and female patients. Conclusions. Seven new putative target genes (ACHE, ADRA1A, AR, CHRM3, F7, GABRA1, and PRSS1) were observed in this work. Based on the result of GO and KEGG analysis, this work will be helpful to further demonstrate the molecular mechanism of PTEC treatment of IS.

Novel RAF Fusions in Pediatric Low-Grade Gliomas Demonstrate MAPK Pathway Activation

2021 ◽  
Author(s):  
Katherine T Lind ◽  
Hannah V Chatwin ◽  
John DeSisto ◽  
Philip Coleman ◽  
Bridget Sanford ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Immunofluorescent Staining ◽  
Low Grade ◽  
Normal Brain ◽  
Mapk Activation ◽  
Low Grade Gliomas ◽  
Pathway Activation ◽  
Mitogen Activated Protein

Abstract Brain tumors are the most common solid tumor in children, and low-grade gliomas (LGGs) are the most common childhood brain tumor. Here, we report on 3 patients with LGG harboring previously unreported or rarely reported RAF fusions: FYCO1-RAF1, CTTNBP2-BRAF, and SLC44A1-BRAF. We hypothesized that these tumors would show molecular similarity to the canonical KIAA1549-BRAF fusion that is the most widely seen alteration in pilocytic astrocytoma (PA), the most common pediatric LGG variant, and that this similarity would include mitogen-activated protein kinase (MAPK) pathway activation. To test our hypothesis, we utilized immunofluorescent imaging and RNA-sequencing in normal brain, KIAA1549-BRAF-harboring tumors, and our 3 tumors with novel fusions. We performed immunofluorescent staining of ERK and phosphorylated ERK (p-ERK), identifying increased p-ERK expression in KIAA1549-BRAF fused PA and the novel fusion samples, indicative of MAPK pathway activation. Geneset enrichment analysis further confirmed upregulated downstream MAPK activation. These results suggest that MAPK activation is the oncogenic mechanism in noncanonical RAF fusion-driven LGG. Similarity in the oncogenic mechanism suggests that LGGs with noncanonical RAF fusions are likely to respond to MEK inhibitors.

scholarly journals EnhancerAtlas 2.0: an updated resource with enhancer annotation in 586 tissue/cell types across nine species

2019 ◽  
Author(s):  
Tianshun Gao ◽  
Jiang Qian
Keyword(s):  
Large Scale ◽  
Target Gene ◽  
Target Genes ◽  
Cell Types ◽  
Regulatory Elements ◽  
Tissue Cell ◽  
Normal Tissues ◽  
Genome Wide ◽  
Wide Range ◽  
User Friendly

Abstract Enhancers are distal cis-regulatory elements that activate the transcription of their target genes. They regulate a wide range of important biological functions and processes, including embryogenesis, development, and homeostasis. As more and more large-scale technologies were developed for enhancer identification, a comprehensive database is highly desirable for enhancer annotation based on various genome-wide profiling datasets across different species. Here, we present an updated database EnhancerAtlas 2.0 (http://www.enhanceratlas.org/indexv2.php), covering 586 tissue/cell types that include a large number of normal tissues, cancer cell lines, and cells at different development stages across nine species. Overall, the database contains 13 494 603 enhancers, which were obtained from 16 055 datasets using 12 high-throughput experiment methods (e.g. H3K4me1/H3K27ac, DNase-seq/ATAC-seq, P300, POLR2A, CAGE, ChIA-PET, GRO-seq, STARR-seq and MPRA). The updated version is a huge expansion of the first version, which only contains the enhancers in human cells. In addition, we predicted enhancer–target gene relationships in human, mouse and fly. Finally, the users can search enhancers and enhancer–target gene relationships through five user-friendly, interactive modules. We believe the new annotation of enhancers in EnhancerAtlas 2.0 will facilitate users to perform useful functional analysis of enhancers in various genomes.

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