The impact of physiological loading on immune cell infiltration and myocardial function evaluated by cardiac MRI: a comparison between non-working heart and working heart transplant models

Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 (ERAP2) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti–PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy.

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Analyzing the Impact of ATF3 in Tumorigenesis and Immune Cell Infiltration of Ovarian Tumor: A Bioinformatics Study

10.21203/rs.3.rs-471861/v1 ◽

2021 ◽

Author(s):

Xiujuan wu

Keyword(s):

Ovarian Tumor ◽

Immune Cell ◽

Interaction Network ◽

Critical Factor ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Transcription Activator ◽

Critical Pathways ◽

The Impact

Abstract ATF3 is an essential transcription activator in regulating cancer-related genetic expression. To identify the role of ATF3 in ovarian, we investigated the correlation between ATF3 expression and the clinicopathological properties using multiple database. The cBioPortal and GEPIA database displayed the clinical information of ovarian patients harboring or without harboring ATF3 mutation. Furthermore, we assessed the relationship between survival and ATF3 expression level using Kaplan-Meier plotter, which reveals that the ovarian patients with higher expression of ATF3 suffered the worse overall survival and progression-free survival. The differentially expressed genes were analyzed using Gene Ontology, protein-protein interaction network and gene set enrichment analysis to identify the hub gene and critical pathways, significantly affecting the tumorigenesis of ovarian tumor. Finally, we assessed the correlation between ATF3 and immune cell infiltration using Tumor Immunoassay Resource (TIMER) database. The results demonstrated that higher expression is positive correlation with macrophage infiltration, expression for M1 and M2 type macrophages. Our study suggests that ATF3 can regulate the cell cycle and heme-related oxidative phosphorylation process, and it may be a critical factor to regulate the macrophage cell to be infiltrated into ovarian cancer. ATF3 can be as a biomarker for diagnosis and therapy of ovarian.

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Detection of acute TLR-7 agonist-induced hemorrhagic myocarditis in mice by refined multi-parametric quantitative cardiac MRI

10.1101/502237 ◽

2018 ◽

Author(s):

Nicoleta Baxan ◽

Angelos Papanikolaou ◽

Isabelle Salles-Crawley ◽

Amrit Lota ◽

Rasheda Chowdhury ◽

...

Keyword(s):

Viral Infection ◽

Systemic Inflammation ◽

Cardiac Mri ◽

Immune Cell ◽

Relaxation Times ◽

Iron Deposition ◽

Cell Infiltration ◽

Severe Thrombocytopenia ◽

Immune Cell Infiltration ◽

Tissue Iron

AbstractBACKGROUNDHemorrhagic myocarditis is a potentially fatal complication of excessive levels of systemic inflammation. It has been reported in viral infection, but is also possible in systemic autoimmunity. Cardiac magnetic resonance (CMR) imaging is the current gold standard for non-invasive detection of suspected inflammatory damage to the heart and changes in T1 and T2 relaxation times are commonly used to detect edema associated with immune cell infiltration and fibrosis. These measurements also form the basis of the Lake Louise Criteria, which define a framework for the CMR-based diagnosis of myocarditis. However, they do not take into account the possibility of hemorrhage leading to tissue iron deposition which strongly influences T1 and T2 measurements and may complicate interpretation based on these two parameters only.METHODSSystemic inflammation was induced in CFN mice by application of the TLR-7 agonist Resiquimod. Histopathology was performed on heart sections to assess immune cell infiltration (Hematoxylin & Eosin), fibrosis (PicoSirius Red) and tissue iron deposition (Perl’s Prussian Blue). A multi-parametric cardiac MRI tissue mapping approach measuring T1, T2, and T2* relaxation times was established to non-invasively identify these parameters in this small rodent model.RESULTSResiquimod-treated mice developed severe thrombocytopenia and hemorrhagic myocarditis. We identified patches of cardiac hemorrhage based on the presence of two major MRI phenotypes. Increased T2 with normal T1 and T2* values correlated with infiltration/edema only, while decreased T1, T2, and T2* values identify areas with infiltration/edema in the presence of iron indicating hemorrhagic myocarditis.CONCLUSIONWe show that over-activation of the TLR-7 pathway by Resiquimod treatment of CFN mice induces an early immune response reminiscent of excessive systemic inflammation due to viral infection. This causes internal bleeding which manifests most prominently as severe hemorrhagic myocarditis. We optimized a comprehensive noninvasive in vivo MRI approach based on quantitative measurement of T1, T2 and T2* to demonstrate the presence of diffuse myocardial edema, infiltration and iron deposition without the need of contrast agent administration. We propose that adding quantitative T2* mapping to CMR protocols for detection of myocarditis will improve diagnostic sensitivity and interpretation of disease mechanisms.

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INHBA is A Novel Prognostic Biomarker And Correlated With Immune Infiltrates In Gastric Cancer

10.21203/rs.3.rs-877929/v1 ◽

2021 ◽

Author(s):

Weifeng Yu ◽

Zishao Zhong ◽

Guihua He ◽

Wang Zhang ◽

Zhenhao Ye ◽

...

Keyword(s):

Gastric Cancer ◽

Extracellular Matrix ◽

Immune Cell ◽

Prognostic Biomarker ◽

Curve Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Collagen Formation ◽

Matrix Organization ◽

The Impact

Abstract Background: Inhibin subunit beta A (INHBA) is reportedly a potential prognostic biomarker for a variety of cancers. However, its role in gastric cancer (GC) remains elusive. Methods: The expression of INHBA in GC and healthy tissues based on the data obtained from the UCSC Xena database. Logistic regression and Cox regression was performed to explore the correlation between clinical indicators and INHBA expression. Kaplan–Meier curve analysis was performed to assess the impact of INHBA expression on overall survival(OS). In addition, Received operating characteristic curve analysis was implied to clarify the diagnostic role of INHBA in GC. Functional analyses were conducted to explain the potential functions and enrichment pathways for INHBA. TIMER and GEPIA databases were used to calculate the confidence between INHBA and immune cell infiltration in GC. Results: INHBA was upregulated in GC(P < 0.001) and associated with a poor prognosis(P = 0.037). INHBA expression was an independent risk factor for OS(P = 0.004). Additionally, INHBA was a potential diagnostic marker in GC(AUC=0.961) and it was associated with extracellular matrix organization, response to growth factor, and cell-substrate adhesion. Tumor-associated signaling pathways, such as Wnt, Hippo, and p53, were associated with INHBA. Reactome pathways, such as collagen formation and extracellular matrix organization, were significantly enriched. Moreover, high INHBA expression displayed a strong correlation with immune cell infiltration, especially with macrophage infiltration in GC.Conclusions: INHBA could be a potential prognostic biomarker for GC and may drive the abnormal activity of critical cancer-associated pathways, potentially contributing to immune cell infiltration to promote GC development and becoming a new drug target for targeted GC therapies.

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TAMI-17. RELATIONSHIP BETWEEN IRON METABOLISM, IMMUNE CELL INFILTRATION AND SEX-BASED SURVIVAL DIFFERENCES IN GLIOMAS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.906 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii216-ii216

Author(s):

Darya Nesterova ◽

Sang Lee ◽

Brad Zacharia ◽

Elizabeth Proctor ◽

Justin Lathia ◽

...

Keyword(s):

Gene Expression ◽

Immune Cell ◽

Iron Regulation ◽

Cell Infiltration ◽

Low Grade ◽

Immune Cell Infiltration ◽

Male And Female ◽

Mitochondrial Aconitase ◽

Survival Differences ◽

The Impact

Abstract Iron plays a central role in cellular metabolism, both in normal cellular functioning and in tumorigenesis. Recent evidence has shown sex-based survival differences in glioblastoma (GBM) may be related to differential expression of metabolism genes. We previously reported the iron regulating gene, HFE, was shown to have a sex-based survival impact in both low-grade gliomas and GBM. We additionally found that females with low HFE expressing tumors have significantly higher survival than males in GBM. To evaluate the relationship between iron gene expression and sex-based survival differences in GBM, we analyzed TCGA GBM gene expression and clinical data. We first analyzed the impact of iron genes on sex-based survival. In addition to HFE, FTL, TFRC, TF, and SLC39A8 (ZIP8), also showed sex-based survival differences. We then compared correlations of HFE and other iron genes to identify whether male and female GBMs differ in iron regulation and metabolism. HFE expression is significantly positively correlated with HMOX1, SLC25A28, SLC11A2, FTH1, HAMP, and TFR2 only in females. Alternatively, HFE expression is negatively correlated with ACO2 (mitochondrial aconitase) in males and ACO1 (cytoplasmic aconitase) in females. We noted that the expression of certain iron genes was highly associated with immune cell infiltration based on sex. TFR2, LRP1, and XIST expression were negatively correlated with low immune cell infiltration in females, but not males. Alternatively, in males, SLC11A2, ACO2, FOXO1, HIF1a, and HAMP genes were negatively correlated with immune infiltration. This suggests that differences in iron regulation between males and females may be contributing to differences in immune function and subsequent survival in GBM. These data suggest that the iron signature of a tumor reflects and possibly drives the metabolic and immune landscape of the tumor microenvironment thereby directly impacting survival differences between male and female GBMs.

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miR-130-3p Promotes MTX-Induced Immune Killing of Hepatocellular Carcinoma Cells by Targeting EPHB4

Journal of Healthcare Engineering ◽

10.1155/2021/4650794 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Liangtian Shao ◽

Qing Ye ◽

Moyang Jia

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Target Gene ◽

Immune Cell ◽

Cell Infiltration ◽

Block Type ◽

Immunogenic Cell Death ◽

Immune Cell Infiltration ◽

Drug Induced ◽

The Impact

The vast majority of primary hepatocellular cancer is hepatocellular carcinomas (HCCs). Currently, HCC is one of the more common cancers in humans, and it has a high mortality and disability rate. Mitoxantrone (MTX) is an antitumor drug that can block type II topoisomerase. It has been reported that immunogenic cell death evoked by MTX can induce the discharge of damage associated with molecular patterns (DAMPs) and subsequently influence immune cell infiltration in the tumor microenvironment. High mobilities aggregation box 1 (HMGB1) is the prototypical extracellular DAMP. Many cellular processes have been reported to involve EPHB4 receptor tyrosine kinases, but the relation of DAMP and EPHB4 is uncertain. In this research, we assessed the impact of miR-130-3p by Edu incorporation test on cell proliferation, and we have proven its impact on HCC cell migration through Transwell and wound healing tests. Flow cytometry was applied to study its influence on apoptosis. Luciferase report test was integrated in detecting the miR-130-3p target gene. The influence of miR-130-3p on the manifestation of classical DAMPs was studied, such as HMGB1, ATP, and Calreticulin. A coculture experiment was carried out to further confirm its effects on immune cell infiltration. The result displayed that miR-130-3p overexpression considerably facilitates apoptosis and suppresses the migration or proliferation of HCC cells. EPHB4 was confirmed as the target gene of miR-130-3p. Overexpression of this target gene promotes emission of Calreticulin, ATP, and HMGB1 and subsequently promotes DCs maturation and proliferation of CD4+ T cells. In summary, our results demonstrated that miR-130-3p inhibits HCC cell proliferation and migration by targeting EPHB4 and promotes drug-induced immunogenic cell death.

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Analyzing the impact of ATF3 in tumorigenesis and immune cell infiltration of ovarian tumor: a bioinformatics study

Medical Oncology ◽

10.1007/s12032-021-01541-7 ◽

2021 ◽

Vol 38 (8) ◽

Author(s):

Xiaoliu Li ◽

Panpan Liu ◽

Xiaona Sun ◽

Runhong Ma ◽

Ting Cui ◽

...

Keyword(s):

Ovarian Tumor ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Bioinformatics Study ◽

The Impact

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Bioinformatics Analysis of C3 in Brain Low Grade Gliomas as Potential Therapeutic Target and Promoting Immune Cell Infiltration

10.21203/rs.3.rs-1040002/v1 ◽

2021 ◽

Author(s):

Xiujuan wu ◽

Siyi Wu ◽

Kaiting Miao ◽

Lijing Wang ◽

Yuanyuan Ma

Keyword(s):

Cell Cycle ◽

Immune Cell ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Low Grade ◽

Immune Cell Infiltration ◽

Mesenchymal Transition ◽

Low Grade Gliomas ◽

Regulation Of Cell Cycle ◽

The Impact

Abstract Background Low grade gliomas is the malignant nervous tumor with distinct biological and clinical characteristics. Despite advances in diagnostic and therapeutic methods, how to significantly elongate the survival of low grade gliomas is still the challenge. Complement 3, as the critical component in the innate immune system, play an essential role in local immune response and participated into the regulation of the epithelial-mesenchymal transition and tumor microenvironment. Methods In this study, we systematically determined the expression levels of C3 in low grade gliomas using various public databases. Then, we further identified the impact of C3 expression on immune cell infiltration compared to normal tissue, indicating the effect of cellular microenvironment on overall survival of LGG patients. Results We obtained transcriptional and survival of C3 in LGG from GEPIA and cBioportal database, and the differentially expressed genes were obtained. By performing the analysis of GO and protein-protein interaction network, we have identified the top-ranked 10 hub genes, which are highly associated with regulation of cell cycle. The gene set enrichment analysis demonstrated that overexpression of C3 in LGG patient is positively correlated with regulation of cell cycle. Finally, the immune cell infiltration of C3 in LGG patients was employed and clearly showed that higher neutrophil infiltration can worsen the survival of LGG patients with higher C3 expression. These results were confirmed by the Human Protein Atlas database, in which expression level of C3 protein in gliomas patients always higher. Conclusions This investigation implied that C3 can be as the potential targets of precise therapy for patient with low grade gliomas.

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