scholarly journals Tumor ferroptosis status demonstrated vulnerability to chemotherapy and reflected immune-activation in colorectal cancer

2020 ◽  
Author(s):  
Yang Lv ◽  
QingYang Feng ◽  
ZhiYuan Zhang ◽  
Peng Zheng ◽  
DeXiang Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Enrichment Analysis ◽  
Progression Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
M1 Macrophage ◽  
Central Molecule ◽  
Ifn Γ ◽  
Cox Analysis

Abstract Background: Existing studies for ferroptosis and prognosis in colorectal cancer (CRC) were limited. In this study, we aim to investigate the prognostic role of ferroptosis markers in patients with CRC and exploration of its micro-environmental distributions. Methods: A total of 911 patients from 2008 to 2013 with CRC were enrolled. Immunohistochemical staining was performed for CRC patients’ tissue microarray. Selection and prognostic validation of markers were based on mRNA data from the cancer genome atlas (TCGA) database. Gene Set Enrichment Analysis (GSEA) was performed to indicate relative immune landmarks and hallmarks. Ferroptosis and immune contexture were examined by CIBERSORT. Survival outcomes were analyzed by Kaplan-meier analysis and cox analysis.Results: A panel of 42 genes was selected. Through mRNA expression difference and prognosis analysis, GPX4, NOX1 and ACSL4 were selected as candidate markers. By IHC, increased GPX4, decreased NOX1 and decreased FACL4 indicate poor prognosis and worse clinical characteristics. Ferroptosis score based on GPX4, NOX1 and ACSL4 was constructed and validated with high C-index. Low ferroptosis score can also demonstrate the better progression free survival and better adjuvant chemotherapy (ACT) responsiveness. Moreover, tumor with low ferroptosis score tend to be infiltrated with more CD4+ T cells, CD8+ T cells and less M1 macrophage. Finally, we found that IFN-γ was potentially the central molecule at the crossroad between ferroptosis and onco-immune response. Conclusion: Ferroptosis plays important role on CRC tumor progression, ACT response and prognosis. Ferroptosis contributes to immune-supportive responses and IFN-γ was the central molecule for this process.

scholarly journals NRAS Expression is Associated With Prognosis and Tumor Immune Microenvironment in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Yueren Yan ◽  
Zhendong Gao ◽  
Han Han ◽  
Yue Zhao ◽  
Yang Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Adenocarcinoma ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Level ◽  
Immune Microenvironment ◽  
Kaplan Meier ◽  
Tumor Immune Microenvironment ◽  
Cox Analysis

Abstract Purpose: NRAS plays a pivotal role in progression of various kinds of somatic malignancies; however, the correlation between NRAS and lung adenocarcinoma is less known. We aim to analyze the prognostic value of NRAS expression in lung adenocarcinoma, and explore the relationship between NRAS and tumor immune microenvironment. Methods: We obtained the transcriptome pofiles and clinical data of LUAD from The Cancer Genome Atlas database and three Genome Expression Omnibus datasets. Specimens from 325 patients with completely resected lung adenocarcinoma were collected for immunohistochemical assays of NRAS, PD-L1, PD-1 and TIM-3. Then we performed gene set enrichment analysis to investigate cancer-related and immune-related signaling pathways. TIMER algorithms were performed to evaluate tumor immune infiltrating cells and immune-related biomarkers.Results: Compared with adjacent non-tumor tissue, NRAS expression was significantly upregulated in LUAD tissue. NRAS expression was significantly correlated with more advanced stage and positive lymph nodes. Kaplan-Meier curves and Cox analysis suggested that high NRAS expression led to a poor prognosis, and could be an independent prognostic factor in LUAD patients. Besides, NRAS expression was positively correlated with CD8+ T cells, macrophages, and neutrophils, and negatively correlated with B cells and CD4+ T cells. The expression level of NRAS was positively correlated with PD-L1, PD-1, and TIM-3 both at RNA and protein level. Conclusions: To conclude, we found NRAS a novel prognostic biomarker in LUAD. Besides, the expression level of NRAS may influence the prognosis of LUAD via various kinds of cancer-related pathways and remodeling TIM.

scholarly journals Prognostic implications of metabolism-associated gene signatures in colorectal cancer

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9847
Author(s):  
Yandong Miao ◽  
Qiutian Li ◽  
Jiangtao Wang ◽  
Wuxia Quan ◽  
Chen Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Risk Score ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Clinicopathological Feature ◽  
Metabolic Genes ◽  
Cox Analysis

Colorectal cancer (CRC) is one of the most common and deadly malignancies. Novel biomarkers for the diagnosis and prognosis of this disease must be identified. Besides, metabolism plays an essential role in the occurrence and development of CRC. This article aims to identify some critical prognosis-related metabolic genes (PRMGs) and construct a prognosis model of CRC patients for clinical use. We obtained the expression profiles of CRC from The Cancer Genome Atlas database (TCGA), then identified differentially expressed PRMGs by R and Perl software. Hub genes were filtered out by univariate Cox analysis and least absolute shrinkage and selection operator Cox analysis. We used functional enrichment analysis methods, such as Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis, to identify involved signaling pathways of PRMGs. The nomogram predicted overall survival (OS). Calibration traces were used to evaluate the consistency between the actual and the predicted survival rate. Finally, a prognostic model was constructed based on six metabolic genes (NAT2, XDH, GPX3, AKR1C4, SPHK1, and ADCY5), and the risk score was an independent prognostic prognosticator. Genetic expression and risk score were significantly correlated with clinicopathologic characteristics of CRC. A nomogram based on the clinicopathological feature of CRC and risk score accurately predicted the OS of individual CRC cancer patients. We also validated the results in the independent colorectal cancer cohorts GSE39582 and GSE87211. Our study demonstrates that the risk score is an independent prognostic biomarker and is closely correlated with the malignant clinicopathological characteristics of CRC patients. We also determined some metabolic genes associated with the survival and clinical stage of CRC as potential biomarkers for CRC diagnosis and treatment.

scholarly journals Analysis of Ferroptosis-Mediated Modification Patterns and Tumor Immune Microenvironment Characterization in Uveal Melanoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Yi Jin ◽  
Zhanwang Wang ◽  
Dong He ◽  
Yuxing Zhu ◽  
Lian Gong ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Enrichment Analysis ◽  
Progression Free Survival ◽  
Gene Set Enrichment Analysis ◽  
Consensus Clustering ◽  
Training Set ◽  
Poor Overall Survival ◽  
Competing Endogenous Rna Network ◽  
Underlying Mechanisms ◽  
Cox Analysis

Uveal melanoma (UVM) is an intraocular malignancy in adults in which approximately 50% of patients develop metastatic disease and have a poor prognosis. The need for immunotherapies has rapidly emerged, and recent research has yielded impressive results. Emerging evidence has implicated ferroptosis as a novel type of cell death that may mediate tumor-infiltrating immune cells to influence anticancer immunity. In this study, we first selected 11 ferroptosis regulators in UVM samples from the training set (TCGA and GSE84976 databases) by Cox analysis. We then divided these molecules into modules A and B based on the STRING database and used consensus clustering analysis to classify genes in both modules. According to the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), the results revealed that the clusters in module A were remarkably related to immune-related pathways. Next, we applied the ESTIMATE and CIBERSORT algorithms and found that these ferroptosis-related patterns may affect a proportion of TME infiltrating cells, thereby mediating the tumor immune environment. Additionally, to further develop the prognostic signatures based on the immune landscape, we established a six-gene-regulator prognostic model in the training set and successfully verified it in the validation set (GSE44295 and GSE27831). Subsequently, we identified the key molecules, including ABCC1, CHAC1, and GSS, which were associated with poor overall survival, progression-free survival, disease-specific survival, and progression-free interval. We constructed a competing endogenous RNA network to further elucidate the mechanisms, which consisted of 29 lncRNAs, 12 miRNAs, and 25 ferroptosis-related mRNAs. Our findings indicate that the ferroptosis-related genes may be suitable potential biomarkers to provide novel insights into UVM prognosis and decipher the underlying mechanisms in tumor microenvironment characterization.

scholarly journals Potential Mechanism of Immune Evasion Associated with the Master Regulator ASCL2 in Microsatellite Stability in Colorectal Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Qian Yang ◽  
Guowei Huang ◽  
Liyan Li ◽  
Enmin Li ◽  
Liyan Xu
Keyword(s):  
Colorectal Cancer ◽  
Immune Evasion ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Novel Treatments ◽  
T Cell Infiltration ◽  
Immune Resistance ◽  
Unbiased Gene ◽  
Ifn Γ ◽  
Microsatellite Stability

Colorectal cancer (CRC) has two major subtypes, microsatellite instability (MSI) and microsatellite stability (MSS) based on the genomic instability. In this study, using computational programs, we identified 9 master transcription factors (TFs) based on epigenomic profiling in MSS CRC samples. Notably, unbiased gene set enrichment analysis (GSEA) showed that several master TFs were strongly associated with immune-related functions in TCGA MSS CRC tissues, such as interferon gamma (IFN-γ) and interferon alpha (IFN-α) responses. Focusing to the top candidate, ASCL2, we found that CD8+ T cell infiltration was low in ASCL2 overexpressed MSS CRC samples. Compared with other gastrointestinal (GI) cancers (gastric cancer, MSI CRC, and esophageal cancer), ASCL2 is specifically upregulated in MSS CRC. Moreover, we identified 28 candidate genes in IFN-γ and IFN-α response pathways which were negatively correlated with ASCL2. Together, these results link transcriptional dysregulation with the immune evasion in MSS CRC, which may advance the understanding of immune resistance and contribute to developing novel treatments of MSS CRC.

scholarly journals FABP4 Might be an Indicator of the Status of Tumor Microenvironment in Colorectal Cancer

2021 ◽  
Author(s):  
Lijun Ning ◽  
Yuqing Yan ◽  
Tianying Tong ◽  
Ziyun Gao ◽  
Zhe Cui ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cox Regression ◽  
Nk Cell ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Fatty Acid Binding ◽  
Cox Regression Analysis ◽  
The Status

Abstract Background: As tumor microenvironment (TME) play an indispensable role in tumorigenesis of colorectal cancer, this study performs a bunch of bioinformatics analysis to identify the indicator of the status of TME in Colorectal cancer (CRC). Results: In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal components in 444 COAD-READ cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein–protein interaction (PPI) network construction. Then, fatty acid-binding protein four ( FABP4 ) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that FABP4 expression was positively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and negatively correlated with the survival of CRC patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression FABP4 group were mainly enriched in immune-related activities. In the low-expression FABP4 group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that NK cell, CD4 + T cells and CD8 + T cells were negatively correlated with FABP4 expression, suggesting that FABP4 might be a potential prognostic factor of CRC patients. Conclusion: Our study has developed a new biomarker (FABP4) that can predict the status of tumor microenvironment in Colorectal cancer. Keywords: FABP4, tumor microenvironment, ESTIMATE, CIBERSORT, colorectal cancer

scholarly journals Comprehensive analysis of ceRNA networks reveals prognostic lncRNAs related to immune infiltration in colorectal cancer

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Jingyi Chen ◽  
Yuxuan Song ◽  
Mei Li ◽  
Yu Zhang ◽  
Tingru Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Target Genes ◽  
Immune Cell ◽  
Pearson Correlation ◽  
Enrichment Analysis ◽  
Cell Types ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cerna Network

Abstract Background Competing endogenous RNA (ceRNA) represents a class of RNAs (e.g., long noncoding RNAs [lncRNAs]) with microRNA (miRNA) binding sites, which can competitively bind miRNA and inhibit its regulation of target genes. Increasing evidence has underscored the involvement of dysregulated ceRNA networks in the occurrence and progression of colorectal cancer (CRC). The purpose of this study was to construct a ceRNA network related to the prognosis of CRC and further explore the potential mechanisms that affect this prognosis. Methods RNA-Seq and miRNA-Seq data from The Cancer Genome Atlas (TCGA) were used to identify differentially expressed lncRNAs (DElncRNAs), microRNAs (DEmiRNAs), and mRNAs (DEmRNAs), and a prognosis-related ceRNA network was constructed based on DElncRNA survival analysis. Subsequently, pathway enrichment, Pearson correlation, and Gene Set Enrichment Analysis (GSEA) were performed to determine the function of the genes in the ceRNA network. Gene Expression Profiling Interactive Analysis (GEPIA) and immunohistochemistry (IHC) were also used to validate differential gene expression. Finally, the correlation between lncRNA and immune cell infiltration in the tumor microenvironment was evaluated based on the CIBERSORT algorithm. Results A prognostic ceRNA network was constructed with eleven key survival-related DElncRNAs (MIR4435-2HG, NKILA, AFAP1-AS1, ELFN1-AS1, AC005520.2, AC245884.8, AL354836.1, AL355987.4, AL591845.1, LINC02038, and AC104823.1), 54 DEmiRNAs, and 308 DEmRNAs. The MIR4435-2HG- and ELFN1-AS1-associated ceRNA subnetworks affected and regulated the expression of the COL5A2, LOX, OSBPL3, PLAU, VCAN, SRM, and E2F1 target genes and were found to be related to prognosis and tumor-infiltrating immune cell types. Conclusions MIR4435-2HG and ELFN1-AS1 are associated with prognosis and tumor-infiltrating immune cell types and could represent potential prognostic biomarkers or therapeutic targets in colorectal carcinoma.

scholarly journals MUC1-C integrates activation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer

2021 ◽  
Vol 9 (1) ◽  
pp. e002115
Author(s):  
Nami Yamashita ◽  
Mark Long ◽  
Atsushi Fushimi ◽  
Masaaki Yamamoto ◽  
Tsuyoshi Hata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
T Cells ◽  
Cd8 T Cells ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Molecular Taxonomy ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Ifn Γ

BackgroundImmune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness of TNBCs to ICIs is a lack of functional tumor-infiltrating lymphocytes (TILs) in ‘non-inflamed’ or ‘cold’ tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C in a mouse transgenic TNBC tumor model increases cytotoxic tumor-infiltrating CD8+ T cells (CTLs), supporting a role for MUC1-C in immune evasion. The basis for these findings and whether they extend to human TNBCs are not known.MethodsHuman TNBC cells silenced for MUC1-C using short hairpin RNAs (shRNAs) were analyzed for the effects of MUC1-C on global transcriptional profiles. Differential expression and rank order analysis was used for gene set enrichment analysis (GSEA). Gene expression was confirmed by quantitative reverse-transcription PCR and immunoblotting. The The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets were analyzed for effects of MUC1 on GSEA, cell-type enrichment, and tumor immune dysfunction and exclusion. Single-cell scRNA-seq datasets of TNBC samples were analyzed for normalized expression associations between MUC1 and selected genes within tumor cells.ResultsOur results demonstrate that MUC1-C is a master regulator of the TNBC transcriptome and that MUC1-C-induced gene expression is driven by STAT1 and IRF1. We found that MUC1-C activates the inflammatory interferon (IFN)-γ-driven JAK1→STAT1→IRF1 pathway and induces the IDO1 and COX2/PTGS2 effectors, which play key roles in immunosuppression. Involvement of MUC1-C in activating the immunosuppressive IFN-γ pathway was extended by analysis of human bulk and scRNA-seq datasets. We further demonstrate that MUC1 associates with the depletion and dysfunction of CD8+ T cells in the TNBC TIME.ConclusionsThese findings demonstrate that MUC1-C integrates activation of the immunosuppressive IFN-γ pathway with depletion of TILs in the TNBC TIME and provide support for MUC1-C as a potential target for improving TNBC treatment alone and in combination with ICIs. Of translational significance, MUC1-C is a druggable target with chimeric antigen receptor (CAR) T cells, antibody-drug conjugates (ADCs) and a functional inhibitor that are under clinical development.

scholarly journals Expression Profile and Prognostic Value of CXCR Family Members in Head and Neck Squamous Cell Carcinoma

2021 ◽  
Author(s):  
Yiming Shen ◽  
Chongchang Zhou ◽  
Yujie Cao ◽  
Qun Li ◽  
Hongxia Deng ◽  
...  
Keyword(s):  
Head And Neck ◽  
Expression Profile ◽  
Prognostic Value ◽  
Inflammatory Responses ◽  
Receptor Gene ◽  
Family Members ◽  
Enrichment Analysis ◽  
Progression Free Survival ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas

Abstract Background: CXC chemokine receptor gene family consists of seven well-established members which are broadly involved in biological functions of various cancers. Currently, limited studies have shed light on the expression profile of CXCR family members (CXCRs), as well as their prognostic value, in head and neck squamous cells carcinoma (HNSCC). Methods: The data for this study were retrieved from the Cancer Genome Atlas database and other publicly available databases, including gene expression, methylation profiles, clinical information, immunological features and prognoses. The expression pattern and prognostic values of CXCRs were identified, and the potential mechanism underlying CXCRs function in HNSCC was investigated by gene set enrichment analysis (GSEA). Results: CXCRs were differentially expressed in HNSCC. As shown by Kaplan Meier analysis, high CXCR3-6 expression was significantly associated with better prognostic outcomes of HNSCC patients, including overall survival and progression-free survival. According to the results of univariate and multivariate Cox proportional risk regression analysis, it was demonstrated that upregulation of CXCR3-6 was an independent factor for better prognosis, while the two other clinical features, age and stage, were factors for worse prognosis. A significant positive correlation between CXCR3-6 and tumor-infiltrated immune cells was revealed by results from Tumor Immune Estimation Resource and CIBERSORT analysis database. The main involvement of CXCRs in immune and inflammatory responses was further confirmed by GSEA. Conclusions: Overall, this study provided a rationale for targeting CXCRs as a promising therapeutic strategy of HNSCC.

A Mutational Signature that Predicts Prognosis and Benefit of Immune Checkpoint Blockade in Colorectal Cancer

2020 ◽  
Author(s):  
Liang Xu ◽  
Yanyun Lin ◽  
Xijie Chen ◽  
Lisheng Zheng ◽  
Yufeng Cheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Immune Checkpoint Blockade ◽  
Low Risk ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cancer Center ◽  
Prognostic Information ◽  
Mutational Signature

Abstract Background: Colorectal cancer (CRC) is characterized by broad genomic and transcriptional heterogeneity. However, the genomic basis of this variability remains poorly understood. Our pilot study identified mutated genes were associated with immune infiltration. This study aims to explore a novel mutational signature (MS) in tumor microenvironment (TME) of CRC.Methods: We integrated single nucleotide variation and transcriptome data and collected corresponding clinicopathologic information from 1,133 and 588 CRC patients of Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases, respectively. Single sample gene set enrichment analysis (ssGSEA) was used to identify the subtypes of CRC based on the immune genomes of 29 immune signatures. CIBERSORT was used to analyze the infiltration of 22 immune cell types in the TME and immune-related gene expression CRC tissues. Results: In the training cohort, we identified a novel MS consisting of 27 genes and generated a prognostic model that classifies patients into high- and low-risk groups. The low-risk group was associated with better survival and more tumor mutational burden, microsatellite instability, and mismatch repair deficiency. The data were all verified in the validation set. Further analysis revealed that the MS was associated with tumor immunogenicity and immunocyte infiltration, and the determined risk score (RS) could be an index for the immunity level.Conclusion: We identified a MS that could assist clinicians to select immunotherapy responsive patients and the combination of RS and TNM stage could provide comprehensive prognostic information for CRC.

scholarly journals Upregulated NLGN1 predicts poor survival in colorectal cancer

2021 ◽  
Author(s):  
Qian Yu ◽  
Xiaojie Wang ◽  
Yinghong Yang ◽  
Pan Chi ◽  
Jianping Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Hedgehog Signaling ◽  
Enrichment Analysis ◽  
Multivariate Regression Analysis ◽  
Repair Process ◽  
Gene Expression Omnibus ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Clinical Value ◽  
Poor Prognostic Factor

Abstract Background: Neuroligin1 (NLGN1) is a main component of excitatory glutamatergic synapses complex and is important for synapse assembly and function. The clinical value of NLGN1 in colorectal cancer (CRC) is not clear. Methods: We obtained the expression data of 1143 CRC patients from 3 independent Gene Expression Omnibus (GEO) datasets (GSE32323, GSE24551, GSE39582) and The Cancer Genome Atlas (TCGA) to make the comparison of the NLGN1 expression level between CRC tissues and matched noncancerous tissues, and to evaluate its value in predicting survival of CRC patients. At the protein level, these results were further confirmed by immunohistochemical staining of 52 CRC samples in our own centre. Finally, the function of NLGN1 was explored by gene set enrichment analysis (GSEA). Results: Increased mRNA and protein levels of NLGN1 expression were associated with worse overall survival or recurrence-free survival in CRC patients from 2 GEO datasets, the TCGA database, and our cohort. In addition, multivariate regression analysis showed that NLGN1 was an independent poor prognostic factor of survival in patients with CRC in TCGA database (OR = 2.524, P = 0.010). Functional analysis revealed that NLGN1 was correlated with function involving the Hedgehog signaling pathway, mismatch repair process, and some material metabolism processes. Conclusions: This study is the first to implicate and verify NLGN1 as a new poor prognostic marker for CRC.

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