Upregulation of ADAM12 Is Associated With a Poor Survival and Immune Cell Infiltration in Colon Adenocarcinoma

BackgroundA disintegrin and metalloprotease 12 (ADAM12) is a member of the multidomain protein family, but the mechanisms by which it affects prognosis and immune cell infiltration in patients with colon adenocarcinoma (COAD) remain unclear. Here, our study aimed to analyze the prognostic value of ADAM12 and investigate the correlation between ADAM12 expression and immune cell infiltration in patients with COAD.MethodsDifferential expression analyses were performed using the Oncomine and UALCAN databases, and prognostic analyses were conducted using PrognoScan, Gene Expression Profiling Interactive Analysis (GEPIA), and Kaplan–Meier Plotter. Then, the cBioPortal database was used to analyze alterations in the ADAM12 gene, and the STRING and Metascape websites were used to conduct Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Additionally, relationships between ADAM12 and the immune microenvironment were evaluated based on the TIMER, GEPIA, and TISIDB databases.ResultsADAM12 was overexpressed in COAD tissues, and higher ADAM12 expression correlated with a worse prognosis for patients with COAD. The gene regulatory network suggested that ADAM12 was mainly enriched in extracellular matrix (ECM) organization, ECM proteoglycans, skeletal system development, and ossification, among other pathways. Moreover, ADAM12 expression significantly correlated with the abundance of CD4+ T cells, B cells, CD8+ T cells, neutrophils, macrophages, dendritic cells, and their markers, as well as lymphocytes, immunomodulators, and chemokines.ConclusionsIn colorectal tumors, ADAM12 may play vital roles in regulating the ECM and the recruitment of immune cells, and we suggest that ADAM12 will become a reliable biomarker for determining response to immunotherapy and the prognosis of patients with COAD.

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SFTPA1 is a potential prognostic biomarker correlated with immune cell infiltration and response to immunotherapy in lung adenocarcinoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-021-02995-4 ◽

2021 ◽

Author(s):

Lu Yuan ◽

Xixi Wu ◽

Longshan Zhang ◽

Mi Yang ◽

Xiaoqing Wang ◽

...

Keyword(s):

Lung Cancer ◽

T Cells ◽

Lung Adenocarcinoma ◽

Expression Profile ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Regulatory Pathways ◽

Chronic Lung Diseases ◽

Potential Biomarker

AbstractPulmonary surfactant protein A1 (SFTPA1) is a member of the C-type lectin subfamily that plays a critical role in maintaining lung tissue homeostasis and the innate immune response. SFTPA1 disruption can cause several acute or chronic lung diseases, including lung cancer. However, little research has been performed to associate SFTPA1 with immune cell infiltration and the response to immunotherapy in lung cancer. The findings of our study describe the SFTPA1 expression profile in multiple databases and was validated in BALB/c mice, human tumor tissues, and paired normal tissues using an immunohistochemistry assay. High SFTPA1 mRNA expression was associated with a favorable prognosis through a survival analysis in lung adenocarcinoma (LUAD) samples from TCGA. Further GeneOntology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses showed that SFTPA1 was involved in the toll-like receptor signaling pathway. An immune infiltration analysis clarified that high SFTPA1 expression was associated with an increased number of M1 macrophages, CD8+ T cells, memory activated CD4+ T cells, regulatory T cells, as well as a reduced number of M2 macrophages. Our clinical data suggest that SFTPA1 may serve as a biomarker for predicting a favorable response to immunotherapy for patients with LUAD. Collectively, our study extends the expression profile and potential regulatory pathways of SFTPA1 and may provide a potential biomarker for establishing novel preventive and therapeutic strategies for lung adenocarcinoma.

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Enhanced CD4+ and CD8+ T cell infiltrate within convex hull defined pancreatic islet borders as autoimmune diabetes progresses

Scientific Reports ◽

10.1038/s41598-021-96327-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Alexander J. Dwyer ◽

Jacob M. Ritz ◽

Jason S. Mitchell ◽

Tijana Martinov ◽

Mohannad Alkhatib ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Convex Hull ◽

Pancreatic Islets ◽

Immune Cell ◽

Nod Mice ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Analytical Strategy ◽

Islet Mass

AbstractThe notion that T cell insulitis increases as type 1 diabetes (T1D) develops is unsurprising, however, the quantitative analysis of CD4+ and CD8+ T cells within the islet mass is complex and limited with standard approaches. Optical microscopy is an important and widely used method to evaluate immune cell infiltration into pancreatic islets of Langerhans for the study of disease progression or therapeutic efficacy in murine T1D. However, the accuracy of this approach is often limited by subjective and potentially biased qualitative assessment of immune cell subsets. In addition, attempts at quantitative measurements require significant time for manual analysis and often involve sophisticated and expensive imaging software. In this study, we developed and illustrate here a streamlined analytical strategy for the rapid, automated and unbiased investigation of islet area and immune cell infiltration within (insulitis) and around (peri-insulitis) pancreatic islets. To this end, we demonstrate swift and accurate detection of islet borders by modeling cross-sectional islet areas with convex polygons (convex hulls) surrounding islet-associated insulin-producing β cell and glucagon-producing α cell fluorescent signals. To accomplish this, we used a macro produced with the freeware software ImageJ equipped with the Fiji Is Just ImageJ (FIJI) image processing package. Our image analysis procedure allows for direct quantification and statistical determination of islet area and infiltration in a reproducible manner, with location-specific data that more accurately reflect islet areas as insulitis proceeds throughout T1D. Using this approach, we quantified the islet area infiltrated with CD4+ and CD8+ T cells allowing statistical comparison between different age groups of non-obese diabetic (NOD) mice progressing towards T1D. We found significantly more CD4+ and CD8+ T cells infiltrating the convex hull-defined islet mass of 13-week-old non-diabetic and 17-week-old diabetic NOD mice compared to 4-week-old NOD mice. We also determined a significant and measurable loss of islet mass in mice that developed T1D. This approach will be helpful for the location-dependent quantitative calculation of islet mass and cellular infiltration during T1D pathogenesis and can be combined with other markers of inflammation or activation in future studies.

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Development of an Immune-Related Gene Signature for Prognosis in Melanoma

Frontiers in Oncology ◽

10.3389/fonc.2020.602555 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jia-An Zhang ◽

Xu-Yue Zhou ◽

Dan Huang ◽

Chao Luan ◽

Heng Gu ◽

...

Keyword(s):

T Cells ◽

Immune Cell ◽

Treatment Method ◽

Gene Signature ◽

Cell Infiltration ◽

Venn Diagram ◽

Immune Cell Infiltration ◽

Tumor Purity ◽

New Treatment ◽

Immune Related Genes

Melanoma remains a potentially deadly malignant tumor. The incidence of melanoma continues to rise. Immunotherapy has become a new treatment method and is widely used in a variety of tumors. Original melanoma data were downloaded from TCGA. ssGSEA was performed to classify them. GSVA software and the "hclust" package were used to analyze the data. The ESTIMATE algorithm screened DEGs. The edgeR package and Venn diagram identified valid immune-related genes. Univariate, LASSO and multivariate analyses were used to explore the hub genes. The "rms" package established the nomogram and calibrated the curve. Immune infiltration data were obtained from the TIMER database. Compared with that of samples in the high immune cell infiltration cluster, we found that the tumor purity of samples in the low immune cell infiltration cluster was higher. The immune score, ESTIMATE score and stromal score in the low immune cell infiltration cluster were lower. In the high immune cell infiltration cluster, the immune components were more abundant, while the tumor purity was lower. The expression levels of TIGIT, PDCD1, LAG3, HAVCR2, CTLA4 and the HLA family were also higher in the high immune cell infiltration cluster. Survival analysis showed that patients in the high immune cell infiltration cluster had shorter OS than patients in the low immune cell infiltration cluster. IGHV1-18, CXCL11, LTF, and HLA-DQB1 were identified as immune cell infiltration-related DEGs. The prognosis of melanoma was significantly negatively correlated with the infiltration of CD4+ T cells, CD8+ T cells, dendritic cells, neutrophils and macrophages. In this study, we identified immune-related melanoma core genes and relevant immune cell subtypes, which may be used in targeted therapy and immunotherapy of melanoma.

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Immune Cell Infiltration in the Microenvironment of Liver Oligometastasis from Colorectal Cancer: Intratumoural CD8/CD3 Ratio Is a Valuable Prognostic Index for Patients Undergoing Liver Metastasectomy

Cancers ◽

10.3390/cancers11121922 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1922 ◽

Cited By ~ 2

Author(s):

Jianhong Peng ◽

Yongchun Wang ◽

Rongxin Zhang ◽

Yuxiang Deng ◽

Binyi Xiao ◽

...

Keyword(s):

Colorectal Cancer ◽

Liver Metastases ◽

Immune Cell ◽

Cox Regression ◽

Simultaneous Detection ◽

Prognostic Index ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Prognostic Information ◽

Kaplan Meier

Background: A comprehensive investigation into immune cell infiltration provides more accurate and reliable prognostic information for patients with colorectal liver oligometastases (CLO) after liver metastasectomy. Methods: Simultaneous detection of the immune constituents CD3+, CD8+, Foxp3+ T, and α-SMA+ cells in the liver oligometastasis of 133 patients was conducted using a four-colour immunohistochemical multiplex technique. Immune cells were quantified, and tumour-infiltrating lymphocyte (TIL) ratios were subsequently calculated. Correlation analysis was performed using Pearson’s correlation. Recurrence-free survival (RFS) and overall survival (OS) for TIL ratios were analysed using the Kaplan–Meier method and Cox regression models. Results: Significantly fewer CD3+, CD8+, and Foxp3+ T cells were observed in the intratumoural region than in the peritumoural region of liver metastases. CD3+, CD8+, Foxp3+ T, and α-SMA+ cells showed significantly positive correlations with each other both in the intratumoural and peritumoural regions of liver metastases. Only the CD8/CD3 TIL ratio demonstrated a positive correlation between intratumoural and peritumoural regions of liver metastases (r = 0.541, p < 0.001). Patients with high intratumoural CD8/CD3 ratios had significantly longer 3-year RFS (59.0% vs. 47.4%, p = 0.035) and 3-year OS rates (83.3% vs. 65.8%, p = 0.007) than those with low intratumoural CD8/CD3 ratios. Multivariate analyses revealed that the intratumoural CD8/CD3 ratio was independently associated with RFS (HR = 0.593; 95% CI = 0.357–0.985; p = 0.043) and OS (HR = 0.391; 95% CI = 0.193–0.794; p = 0.009). Conclusion: These findings offer a better understanding of the prognostic value of immune cell infiltration on liver oligometastasis from colorectal cancer.

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Upregulated CCNE1 Correlates with Poor Prognosis, Tumor Immune Infiltration and Escape in Breast Cancer

10.21203/rs.3.rs-966772/v1 ◽

2021 ◽

Author(s):

Jiaxi Feng ◽

Yanan Hu ◽

Dan Liu ◽

Shanshan Wang ◽

Mengci Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Immune Cells ◽

Poor Prognosis ◽

Immune Cell ◽

High Expression ◽

Expression Level ◽

Immune Cell Infiltration ◽

Immune Infiltration ◽

Kaplan Meier ◽

Kaplan Meier Plotter

Abstract Background Breast cancer (BC) is the most common malignant tumor in women and widely known for its poor prognosis. More and more research has discovered that cyclin E1 (CCNE1) plays an important role in progression of various types of cancer. But its specific mechanism in BC progression still needs further research to explore.Methods At first, we determined the expression and prognostic value of CCNE1 through The Cancer Genome Atlas (TCGA) database and The Genotype-Tissue Expression (GTEx) data. Then, we predicted the upstream non-coding RNAs of CCNE1 through StarBase, GEPIA, and Kaplan-Meier plotter database. We further studied the correlation of CCNE1 expression with BC immune cell infiltration, biomarkers of immune cells and immune checkpoints expression through TIMER and GEPIA databases.Results The results suggested that CCNE1 was significantly upregulated in BC and its high expression was correlated with poor prognosis in BC patients. Next, we identified long noncoding RNA (lncRNA) LINC00511 / microRNA-195-5p (miR-195-5p) / CCNE1 axis as the most potential pathway that could regulate CCNE1 expression in BC through StarBase, GEPIA, and Kaplan-Meier plotter database. Furthermore, our in-depth research discovered that CCNE1 expression level was significantly correlated with tumor immune cell inﬁltration, biomarkers of immune cells, and immune checkpoint expression in BC. conclusions In summary, high expression level of CCNE1 was significantly correlated with poor prognosis, tumor immune infiltration and escape in BC.

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Identification of SHMT2 as a Potential Prognostic Biomarker and Correlating With Immune Infiltrates in Lung Adenocarcinoma

10.21203/rs.3.rs-105348/v1 ◽

2020 ◽

Author(s):

Lianxiang Luo ◽

Yushi Zheng ◽

Zhiping Lin ◽

Xiaodi Li ◽

Xiaoling Li ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Immune Cell ◽

Prognostic Biomarker ◽

Tumor Infiltrating Lymphocytes ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Kaplan Meier ◽

Online Databases ◽

Cox Proportional Hazard Regression

Abstract Background: The role of Serine hydroxymethyltransferase2 (SHMT2) in diverse cancers has attracted increasing attention. However, the prognostic role of SHMT2 in lung adenocarcinoma (LUAD) and its relationship with immune cell infiltration is yet to be studied.Methods: The data of mRNA and clinic in LUAD were respectively downloaded from the GEO and TCGA database. We conducted a biological analysis to select the signature gene SHMT2. Online databases including Oncomine, GEPIA, TISIDB, TIMER, and HPA were applied to analyze the characterization of SHMT2 expression, prognosis and the correlation with immune infiltrates in LUAD.Results: The mRNA expression and protein expression of SHMT2 in LUAD were higher than normal tissue. A Kaplan-Meier analysis showed the lower expression level of SHMT2 had a better overall survival rate. Multivariate analysis and the Cox proportional hazard regression model revealed that SHMT2 expression was an independent prognostic factor for patients with LUAD. Meanwhile, the gene SHMT2 was highly associated with tumor-infiltrating lymphocytes in LUAD.Conclusions: These results suggest that the SHMT2 gene is a promising candidate as a potential prognostic biomarker and highly associated with different types of phenotypes of immune cell infiltration in LUAD.

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Comprehensive Analysis of YTH Domain Family in Lung Adenocarcinoma: Expression Profile, Association with Prognostic Value, and Immune Infiltration

Disease Markers ◽

10.1155/2021/2789481 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Kuan Hu ◽

Lei Yao ◽

Yuanliang Yan ◽

Lei Zhou ◽

Juanni Li

Keyword(s):

T Cells ◽

Lung Adenocarcinoma ◽

Prognostic Value ◽

Immune Cell ◽

Expression Profiles ◽

Family Members ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Domain Family ◽

Yth Domain

Background. All YTH domain family members are m6A reader proteins accounting for the methylation modulation involved in the process of tumorgenesis and tumor progression. However, the expression profiles and roles of the YTH domain family in lung adenocarcinoma (LUAD) remain to be further illustrated. Methods. GEPIA2 and TNMplot databases were used to generate the expression profiles of the YTH family. Kaplan-Meier plotter database was employed to analysis the prognostic value of the YTH family. Coexpression profiles and genetic alterations analysis of the YTH family were undertaken using the cBioPortal database. YTH family protein-associated protein-protein interaction (PPI) network was identified by using STRING. Functional enrichment analysis was performed with the help of the WebGestalt database. The correlation analysis between the YTH family and immune cell infiltration in LUAD was administrated by using the TIMER2.0 database. Results. mRNA expression of YTHDC1 and YTHDC2 was significantly lower in LUAD, whereas YTHDF1, YTHDF2, and YTHDF3 with apparently higher expression. YTHDF2 expression was observed to be the highest in the nonsmoker subgroup, and its expression gradually decreased with the increased severity of smoking habit. LUAD patients with low expression of YTHDC2, YTHDF1, and YTHDF2 were correlated with a better overall survival (OS) time. The YTHDF1 genetic alteration rate was 26%, which was the highest in the YTH family. The major cancer-associated functions of YTH family pointed in the direction of immunomodulation, especially antigen processing and presentation. Most of the YTH family members were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, indicating the deep involvement of the YTH domain family in the immune cell infiltration in LUAD. Conclusion. The molecular and expression profiles of the YTH family were dysregulated in LUAD. YTH family members (especially YTHDC2) were promising biomarkers and potential therapeutic targets that may bring benefit for the patients with LUAD.

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Identification of new biomarkers and pathways associated with treatment and prognosis in melanoma patients

10.21203/rs.2.23305/v1 ◽

2020 ◽

Author(s):

Biao Huang ◽

Wei Han ◽

Zu-Feng Sheng ◽

Guo-Liang Shen

Keyword(s):

Gene Expression ◽

T Cells ◽

Tumor Microenvironment ◽

Prognostic Value ◽

Immune Cell ◽

Gene Interaction ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Strong Positive Correlation ◽

Hub Genes

Abstract Background Skin cutaneous melanoma (SKCM) is known as the most malignancy and treatment-resistant in human tumor, causing about 72% of deaths in skin carcinoma. However, the potential mechanism and new effective targets remain to be further elucidated. Available datasets such as Gene Expression Omnibus (GEO) can be utilized to search for novel therapeutic targets and prognostic biomarkers. Methods Three data sets were downloaded from GEO database . The differentially expressed genes (DEGs) were identified via Venn software. Protein‐protein interaction network of DEGs was developed and the module hub genes analysis was constructed by Cytoscape. Subsequently, multiple online tools and Kaplan-Meier survival curves were analyzed to detect underlying signaling pathways, gene expression, drug-gene interaction and prognostic value of hub genes. In addition, we explored the correlation between hub genes and immune cell infiltration. At last, the related miRNA, lncRNA networks were constructed by R software. Results A total of 308 DEGs and 12 hub genes were identified. Function and pathway enrichment results demonstrated a correlation between DEGs and the tumor microenvironment, immune response and melanoma tumorigenesis. Subsequently, we focused on assessing potential value of 12 hub genes. Seven hub genes ( CCL4, CCL5, NMU, GAL, CXCL9, CXCL10, CXCL13 ) were identified with significant overall survival for prognosis. What’s more, five of these seven hub genes were found to be related to clinical stages (P values<0.05). In addition, the most important pathways of hub genes include interleukin-10 signaling, peptide ligand-binding receptors, which play important roles in tumor microenvironment for immune activation or immunosuppressive by regulating the infiltration of immune cells. Our results revealed a strong positive correlation between gene expression (CCL4, CCL5, CXCL9, CXCL10 and CXCL13) and immune cell infiltration (B-cell, CD8+ T cells, CD4+ T cells, macrophages, Neutrophils, Dendritic cells). Interestingly, 8 of 12 hub genes (CXCL10, CCL4, CCL5, IL6, CXCL2, PTGER3, GAL, NPY1R) were also found in the predicted drug-gene interaction. The related miRNA, lncRNA for diagnosis and prognosis were found in networks. Conclusion In conclusion, CCL4, CCL5, NMU, GAL, CXCL9, CXCL10, CXCL13 were of high prognostic value and may be potential targets for the diagnosis and therapy of patients with melanoma.

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Tumor-derived GDF-15 to suppress t-lymphocyte recruitment to the tumor microenvironment resulting in resistance to ANTI-PD-1 treatment.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14532 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14532-e14532

Author(s):

Joerg Wischhusen ◽

Markus Haake ◽

Neha Vashist ◽

Sabrina Genßler ◽

Kilian Wistuba-Hamprecht ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Cell ◽

Serum Levels ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

T Cell Infiltration ◽

Melanoma Patients

e14532 Background: Growth and differentiation factor 15 (GDF-15) is a divergent member of the TGF-β superfamily with low to absent expression in healthy tissue. GDF-15 has been linked to feto-maternal immune tolerance, to prevention of excessive immune cell infiltration during tissue damage, and to anorexia. Various major tumor types secrete high levels of GDF-15. In cancer patients, elevated GDF-15 serum levels correlate with poor prognosis and reduced overall survival (OS). Methods: Impact of a proprietary GDF-15 neutralizing antibody (CTL-002) regarding T cell trafficking was analyzed by whole blood adhesion assays, a HV18-MK melanoma-bearing humanized mouse model and a GDF-15-transgenic MC38 model. Additionally, patient GDF-15 serum levels were correlated with clinical response and overall survival in oropharyngeal squamous cell carcinoma (OPSCC) and melanoma brain metastases. Results: In whole blood cell adhesion assays GDF-15 impairs adhesion of T and NK cells to activated endothelial cells. Neutralization of GDF-15 by CTL-002 rescued T cell adhesion. In HV18-MK-bearing humanized mice CTL-002 induced a strong increase in TIL numbers. Subset analysis revealed an overproportional enrichment of T cells, in particular CD8+ T cells. As immune cell exclusion is detrimental for checkpoint inhibitor (CPI) therapy, a GDF-15-transgenic MC38 model was tested for anti-PD-1 therapy efficacy. In GDF-15 overexpressing MC38 tumors response to anti PD-1 therapy was reduced by 90% compared to wtMC38 tumors. Combining aPD-1 with CTL-002 resulted in 50% of the mice rejecting their GDF-15 overexpressing tumors. Clinically, inverse correlations of GDF-15 levels with CD8+ T cell infiltration were shown for HPV+ OPSCC and for melanoma brain metastases. GDF-15 serum levels were significantly higher in HPV- than in HPV+ OPSCC patient (p < 0.0001). Low GDF-15 levels corresponded to longer OS in both HPV- and HPV+ OPSCC. In two independent melanoma patient cohorts treated with nivolumab or pembrolizumab low baseline serum GDF-15 levels were predictive for clinical response to anti-PD1 treatment and superior OS. Bivariate analysis including LDH indicates that GDF-15 independently predicts poor survival in aPD-1 treated melanoma patients. Conclusions: Taken together our in vitro and in vivo data show that elevated GDF-15 levels block T-cell infiltration into tumor tissues. Neutralizing GDF-15 with CTL-002 restores the ability of T cells to extravasate blood vessels and enter tumor tissue both in vitro and in vivo. In melanoma, patients with higher GDF-15 levels have significantly shorter survival and are less likely to respond to anti-PD1 therapy. GDF-15 may thus serve as a new predictive biomarker for anti-PD1 response, but most importantly also represents a novel target for cancer immunotherapy to improve tumor immune cell infiltration and response to anti-PD1 therapy.

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