Identification and Validation of Gene Expression Pattern and Signature in Patients with Immune Thrombocytopenia

In the present study, we sought to define genes associated with immune thrombocytopenia (ITP). Microarray analysis revealed that of 1002 genes associated with ITP, 309 genes had downregulated expression and 693 genes had upregulated expression in patients with ITP. Gene set enrichment analysis revealed that 11 pathways were positively correlated to ITP, such as type I diabetes mellitus, intestinal immune network for IgA production, and oxidative phosphorylation. The messenger RNA expression levels of the indicated genes, including HLA-DRB5, IGHV3-66, IFI27, FAM212A, PLD5, tumor necrosis factor (TNF)–α, interferon-γ, interleukin (IL)–1β, and IL-4, were significantly increased in patients with ITP compared with healthy humans, while MMP8, SLC1A3, CRISP3, THBS1, FMN1, and IL-10 were decreased. In conclusion, the gene expression profile of patients with ITP has established a foundation to study the gene mechanism of ITP progression.

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Differential and longitudinal immune gene patterns associated with reprogrammed microenvironment and viral mimicry in response to neoadjuvant radiotherapy in rectal cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001717 ◽

2021 ◽

Vol 9 (3) ◽

pp. e001717

Author(s):

Anna Wilkins ◽

Elisa Fontana ◽

Gift Nyamundanda ◽

Chanthirika Ragulan ◽

Yatish Patil ◽

...

Keyword(s):

Gene Expression ◽

Rectal Cancer ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Poor Responders ◽

Type I ◽

Immune Gene ◽

Neoadjuvant Radiotherapy ◽

The Impact ◽

Crt Response

BackgroundRectal cancers show a highly varied response to neoadjuvant radiotherapy/chemoradiation (RT/CRT) and the impact of the tumor immune microenvironment on this response is poorly understood. Current clinical tumor regression grading systems attempt to measure radiotherapy response but are subject to interobserver variation. An unbiased and unique histopathological quantification method (change in tumor cell density (ΔTCD)) may improve classification of RT/CRT response. Furthermore, immune gene expression profiling (GEP) may identify differences in expression levels of genes relevant to different radiotherapy responses: (1) at baseline between poor and good responders, and (2) longitudinally from preradiotherapy to postradiotherapy samples. Overall, this may inform novel therapeutic RT/CRT combination strategies in rectal cancer.MethodsWe generated GEPs for 53 patients from biopsies taken prior to preoperative radiotherapy. TCD was used to assess rectal tumor response to neoadjuvant RT/CRT and ΔTCD was subjected to k-means clustering to classify patients into different response categories. Differential gene expression analysis was performed using statistical analysis of microarrays, pathway enrichment analysis and immune cell type analysis using single sample gene set enrichment analysis. Immunohistochemistry was performed to validate specific results. The results were validated using 220 pretreatment samples from publicly available datasets at metalevel of pathway and survival analyses.ResultsΔTCD scores ranged from 12.4% to −47.7% and stratified patients into three response categories. At baseline, 40 genes were significantly upregulated in poor (n=12) versus good responders (n=21), including myeloid and stromal cell genes. Of several pathways showing significant enrichment at baseline in poor responders, epithelial to mesenchymal transition, coagulation, complement activation and apical junction pathways were validated in external cohorts. Unlike poor responders, good responders showed longitudinal (preradiotherapy vs postradiotherapy samples) upregulation of 198 immune genes, reflecting an increased T-cell-inflamed GEP, type-I interferon and macrophage populations. Longitudinal pathway analysis suggested viral-like pathogen responses occurred in post-treatment resected samples compared with pretreatment biopsies in good responders.ConclusionThis study suggests potentially druggable immune targets in poor responders at baseline and indicates that tumors with a good RT/CRT response reprogrammed from immune “cold” towards an immunologically “hot” phenotype on treatment with radiotherapy.

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Identification of hub genes and construction of an mRNA-miRNA-lncRNA network of gastric carcinoma using integrated bioinformatics analysis

PLoS ONE ◽

10.1371/journal.pone.0261728 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261728

Author(s):

Gang Wei ◽

Youhong Dong ◽

Zhongshi He ◽

Hu Qiu ◽

Yong Wu ◽

...

Keyword(s):

Gene Expression ◽

Gastric Carcinoma ◽

Regulatory Network ◽

Messenger Rna ◽

Enrichment Analysis ◽

Bioinformatic Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Hub Genes ◽

Incidence And Mortality

Background Gastric carcinoma (GC) is one of the most common cancer globally. Despite its worldwide decline in incidence and mortality over the past decades, gastric cancer still has a poor prognosis. However, the key regulators driving this process and their exact mechanisms have not been thoroughly studied. This study aimed to identify hub genes to improve the prognostic prediction of GC and construct a messenger RNA-microRNA-long non-coding RNA(mRNA-miRNA-lncRNA) regulatory network. Methods The GSE66229 dataset, from the Gene Expression Omnibus (GEO) database, and The Cancer Genome Atlas (TCGA) database were used for the bioinformatic analysis. Differential gene expression analysis methods and Weighted Gene Co-expression Network Analysis (WGCNA) were used to identify a common set of differentially co-expressed genes in GC. The genes were validated using samples from TCGA database and further validation using the online tools GEPIA database and Kaplan-Meier(KM) plotter database. Gene set enrichment analysis(GSEA) was used to identify hub genes related to signaling pathways in GC. The RNAInter database and Cytoscape software were used to construct an mRNA-miRNA-lncRNA network. Results A total of 12 genes were identified as the common set of differentially co-expressed genes in GC. After verification of these genes, 3 hub genes, namely CTHRC1, FNDC1, and INHBA, were found to be upregulated in tumor and associated with poor GC patient survival. In addition, an mRNA-miRNA-lncRNA regulatory network was established, which included 12 lncRNAs, 5 miRNAs, and the 3 hub genes. Conclusions In summary, the identification of these hub genes and the establishment of the mRNA-miRNA-lncRNA regulatory network provide new insights into the underlying mechanisms of gastric carcinogenesis. In addition, the identified hub genes, CTHRC1, FNDC1, and INHBA, may serve as novel prognostic biomarkers and therapeutic targets.

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Innocuous IFNγ induced by adjuvant-free antigen restores normoglycemia in NOD mice through inhibition of IL-17 production

Journal of Experimental Medicine ◽

10.1084/jem.20071878 ◽

2008 ◽

Vol 205 (1) ◽

pp. 207-218 ◽

Cited By ~ 134

Author(s):

Renu Jain ◽

Danielle M. Tartar ◽

Randal K. Gregg ◽

Rohit D. Divekar ◽

J. Jeremiah Bell ◽

...

Keyword(s):

Th17 Cells ◽

Type I Diabetes ◽

Nod Mice ◽

Cell Receptor ◽

Interferon Γ ◽

Acid Decarboxylase ◽

Type I ◽

Pancreatic Cell ◽

Disease Stages ◽

Free Antigen

The role of Th17 cells in type I diabetes (TID) remains largely unknown. Glutamic acid decarboxylase (GAD) sequence 206–220 (designated GAD2) represents a late-stage epitope, but GAD2-specific T cell receptor transgenic T cells producing interferon γ (IFNγ) protect against passive TID. Because IFNγ is known to inhibit Th17 cells, effective presentation of GAD2 peptide under noninflammatory conditions may protect against TID at advanced disease stages. To test this premise, GAD2 was genetically incorporated into an immunoglobulin (Ig) molecule to magnify tolerance, and the resulting Ig-GAD2 was tested against TID at different stages of the disease. The findings indicated that Ig-GAD2 could not prevent TID at the preinsulitis phase, but delayed TID at the insulitis stage. More importantly, Ig-GAD2 sustained both clearance of pancreatic cell infiltration and β-cell division and restored normoglycemia when given to hyperglycemic mice at the prediabetic stage. This was dependent on the induction of splenic IFNγ that inhibited interleukin (IL)-17 production. In fact, neutralization of IFNγ led to a significant increase in the frequency of Th17 cells, and the treatment became nonprotective. Thus, IFNγ induced by an adjuvant free antigen, contrary to its usual inflammatory function, restores normoglycemia, most likely by localized bystander suppression of pathogenic IL-17–producing cells.

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LINC01018 and SMIM25 sponged miR-182-5p in endometriosis revealed by the ceRNA network construction

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738420976309 ◽

2020 ◽

Vol 34 ◽

pp. 205873842097630

Author(s):

Li Jiang ◽

Mengmeng Zhang ◽

Sixue Wang ◽

Yuzhen Xiao ◽

Jingni Wu ◽

...

Keyword(s):

Messenger Rna ◽

Kegg Pathway ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Differentially Expressed ◽

Protein Protein Interaction ◽

Cerna Network ◽

Non Coding Rna ◽

Differentially Expressed Mirnas ◽

Long Non Coding Rna

The current study intended to explore the interaction of the long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) under the background of competitive endogenous RNA (ceRNA) network in endometriosis (EMs). The differentially expressed miRNAs (DEmiRs), differentially expressed lncRNA (DELs), and differentially expressed genes (DEGs) between EMs ectopic (EC) and eutopic (EU) endometrium based on three RNA-sequencing datasets (GSE105765, GSE121406, and GSE105764) were identified, which were used for the construction of ceRNA network. Then, DEGs in the ceRNA network were performed with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and protein-protein interaction (PPI) analysis. Besides, the DEmiRs in the ceRNA network were validated in GSE124010. And the target DELs and DEGs of verified DEmiRs were validated in GSE86534. The correlation of verified DEmiRs, DEGs, and DELs was explored. Moreover, gene set enrichment analysis (GSEA) was applied to investigate the function of verified DEmiRs, DEGs, and DELs. Overall, 1352 DEGs and 595 DELs from GSE105764, along with 27 overlapped DEmiRs between GSE105765 and GSE121406, were obtained. Subsequently, a ceRNA network, including 11 upregulated and 16 downregulated DEmiRs, 7 upregulated and 13 downregulated DELs, 48 upregulated and 46 downregulated DEGs, was constructed. The GO and KEGG pathway analysis showed that this ceRNA network probably was associated with inflammation-related pathways. Furthermore, hsa-miR-182-5p and its target DELs (LINC01018 and SMIM25) and DEGs (BNC2, CHL1, HMCN1, PRDM16) were successfully verified in the validation analysis. Besides, hsa-miR-182-5p was significantly negatively correlated with these target DELs and DEGs. The GSEA analysis implied that high expression of LINC01018, SMIM25, and CHL1, and low expression of hsa-miR-182-5p would activate inflammation-related pathways in endometriosis EU samples. LINC01018 and SMIM25 might sponge hsa-miR-182-5p to upregulate downstream genes such as CHL1 to promote the development of endometriosis.

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Identification of Potential Biomarkers and Biological Pathways in Juvenile Dermatomyositis Based on miRNA-mRNA Network

BioMed Research International ◽

10.1155/2019/7814287 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 1

Author(s):

Cheng-Cheng Qiu ◽

Qi-Sheng Su ◽

Shang-Yong Zhu ◽

Ruo-Chuan Liu

Keyword(s):

Regulatory Network ◽

Messenger Rna ◽

Target Genes ◽

Juvenile Dermatomyositis ◽

Type I Diabetes ◽

Differentially Expressed ◽

Pathway Enrichment Analysis ◽

Type I ◽

Ppi Network ◽

Potential Biomarkers

Objective. The aim of this study is to explore the potential pathogenesis of juvenile dermatomyositis by bioinformatics analysis of gene chips, which would screen the hub genes, identify potential biomarkers, and reveal the development mechanism of juvenile dermatomyositis. Material and Methods. We retrieved juvenile dermatomyositis’s original expression microarray data of message RNAs (mRNAs) and microRNAs (miRNAs) from NCBI’s Gene Expression Omnibus database (GEO, http://www.ncbi.nlm.nih.gov/geo/); through the R package of limma in Bioconductor, we can screen the differentially expressed miRNAs and mRNAs, and then we further analyzed the predicted target genes by the methods such as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and miRNA-mRNA regulatory network construction and protein-protein interaction (PPI) network using Cytoscape 3.6.1. Results. Compared with normal juvenile skin tissues, 6 upregulated microRNAs and 5 downregulated microRNAs were identified from 166 downregulated microRNAs and 58 upregulated microRNAs in juvenile dermatomyositis tissues. The enrichment pathways of differentially expressed microRNAs include cell adhesion molecules (CAMs), autoimmune thyroid disease, Type I diabetes mellitus, antigen and presentation, viral myocardium, graft-versus-host disease, and Kaposi sarcoma-associated herpes virus infection. By screening of microRNA-messenger RNA regulatory network and construction of PPI network map, three target miRNAs were identified, namely, miR-193b, miR-199b-5p, and miR-665. Conclusion. We identified mir-193b, mir-199b-5p, and mir-6653 target miRNAs by exploring the miRNA-mRNA regulation network mechanism related to the pathogenesis of juvenile dermatomyositis, which will be of great significance for further study on the pathogenesis and targeted therapy of juvenile dermatomyositis.

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R432 – Gene Expression of the Remodeling Rat Vocal Fold Wound

Otolaryngology ◽

10.1016/j.otohns.2008.05.587 ◽

2008 ◽

Vol 139 (2_suppl) ◽

pp. P189-P189

Author(s):

Tsunehisa Ohno ◽

Lesley C. French ◽

Bernard Rousseau

Keyword(s):

Gene Expression ◽

Extracellular Matrix ◽

Messenger Rna ◽

Vocal Fold ◽

Molecular Mechanisms ◽

Type I ◽

Post Injury ◽

Time Points ◽

Procollagen Type ◽

Procollagen Type I

Problem The authors investigated the expression of key extracellular matrix genes after vocal fold wounding in a rat model to better understand the reparative mechanisms of tissue repair during the remodeling phase of vocal fold injury. Methods Bilateral vocal fold wounds were created in 30 rats. Injured vocal fold specimens were harvested 1, 3, 7, 14, 28, and 56 days after wounding. 5 unwounded rats were used to establish baseline for polymerase chain reaction (PCR). The authors used real-time PCR to quantify messenger RNA expression of procollagen type I, III, interleukin-1 beta (IL-1 beta), decorin, and hyaluronan synthase (HAS) −1, −2, and −3. Analysis of variance was used to detect main effects for gene expression. Post-hoc tests were used to make comparisons between time points. Results Procollagen type I expression was decreased from baseline on post-injury day 1, 28, and 56. Procollagen type III was decreased on post-injury day 1 and 56, and increased from baseline on post-injury day 14. IL-1 beta expression was increased from baseline on post-injury day 1, 3, and 7. Decorin expression was decreased from baseline on post-injury day 1, 3, 7, and 56. HAS-1 expression was decreased from baseline at all post-injury time points. HAS-2 expression was increased from baseline on post-injury day 3, and decreased from baseline on post-injury day 14, 28, and 56. HAS-3 expression was decreased from baseline on post-injury day 1, 28, and 56. Conclusion Findings provide temporal changes in the expression of key extracellular matrix genes during a remodeling phase of vocal fold injury in a rat wound model. Significance Vocal fold wound models provide a means for investigating tissue reparative processes and molecular mechanisms controlling synthesis and degradation of the vocal fold extracellular matrix. Support Vanderbilt University Medical Center.

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Revealing Biological Pathways Implicated in Lung Cancer from TCGA Gene Expression Data Using Gene Set Enrichment Analysis

Cancer Informatics ◽

10.4137/cin.s13882 ◽

2014 ◽

Vol 13s1 ◽

pp. CIN.S13882 ◽

Cited By ~ 4

Author(s):

Binghuang Cai ◽

Xia Jiang

Keyword(s):

Gene Expression ◽

Lung Cancer ◽

Gene Expression Data ◽

Lung Squamous Cell Carcinoma ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Expression Data ◽

Gene Set Enrichment ◽

Gene Set ◽

Pathway Gene

Analyzing biological system abnormalities in cancer patients based on measures of biological entities, such as gene expression levels, is an important and challenging problem. This paper applies existing methods, Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis, to pathway abnormality analysis in lung cancer using microarray gene expression data. Gene expression data from studies of Lung Squamous Cell Carcinoma (LUSC) in The Cancer Genome Atlas project, and pathway gene set data from the Kyoto Encyclopedia of Genes and Genomes were used to analyze the relationship between pathways and phenotypes. Results, in the form of pathway rankings, indicate that some pathways may behave abnormally in LUSC. For example, both the cell cycle and viral carcinogenesis pathways ranked very high in LUSC. Furthermore, some pathways that are known to be associated with cancer, such as the p53 and the PI3K-Akt signal transduction pathways, were found to rank high in LUSC. Other pathways, such as bladder cancer and thyroid cancer pathways, were also ranked high in LUSC.

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Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14544 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14544-e14544

Author(s):

Eva Budinska ◽

Jenny Wilding ◽

Vlad Calin Popovici ◽

Edoardo Missiaglia ◽

Arnaud Roth ◽

...

Keyword(s):

Gene Expression ◽

Cell Line ◽

Clinical Significance ◽

Cell Lines ◽

Drug Response ◽

Drug Sensitivity ◽

Expression Profiles ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis

e14544 Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.

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Differential gene expression in prostate tissue according to vasectomy.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.298 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 298-298

Author(s):

Kathryn M Wilson ◽

Travis Gerke ◽

Ericka Ebot ◽

Jennifer A Sinnott ◽

Jennifer R. Rider ◽

...

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Cancer Diagnosis ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Prostate Tissue ◽

Gene Set Enrichment ◽

Normal Prostate ◽

Gene Sets ◽

Normal Prostate Tissue

298 Background: We previously found that vasectomy was associated with an increased risk of prostate cancer, and particularly, risk of lethal prostate cancer in the Health Professionals Follow-up Study (HPFS). However, the possible biological basis for this finding is unclear. In this study, we explored possible biological mechanisms by assessing differences in gene expression in the prostate tissue of men with and without a history of vasectomy prostate cancer diagnosis. Methods: Within the HPFS, vasectomy data and gene expression data (20,254 genes) was available from archival tumor tissue from 263 cases, 124 of whom also had data for adjacent normal tissue. To relate expression of individual genes to vasectomy we used linear regression adjusting for age and year at diagnosis. We ran gene set enrichment analysis to identify pathways of genes associated with vasectomy. Results: Among 263 cases, 67 (25%) reported a vasectomy prior to cancer diagnosis. Mean age at diagnosis was 66 years among men without and 65 years among men with vasectomy. Median time between vasectomy and prostate cancer diagnosis was 25 years. Gene expression in tumor tissue was not associated with vasectomy status. In adjacent normal tissue, three individual genes were associated with vasectomy with Bonferroni-corrected p-values of < 0.10: RAPGEF6, OR4C3, and SLC35F4. Gene set enrichment analysis found five pathways upregulated and seven pathways downregulated in men with vasectomy compared to those without in normal prostate tissue with a FDR < 0.05. Upregulated pathways included several immune-related gene sets and G-protein-coupled receptor gene sets. Conclusions: We identified significant differences in gene expression profiles in normal prostate tissue according to vasectomy status among men treated for prostate cancer. The fact that such differences existed several decades after vasectomy provides support for the idea that vasectomy may play a role in the etiology of prostate cancer.

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RNA profiling of neuroendocrine tumors (NETs) to define new targets and mechanisms of progression.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.302 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 302-302

Author(s):

Namrata Vijayvergia ◽

Suraj Peri ◽

Karthik Devarajan ◽

Jianming Pei ◽

Yulan Gong ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Drug Targets ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Enrichment Score ◽

Rna Profiling ◽

Histone Lysine Methyltransferase ◽

Canonical Pathways ◽

Lysine Methyltransferase

302 Background: NETs lack mutations in the “classical” signaling pathways but share mutations in regulators of gene expression (Jiao; 2011). We compared gene expression in PD & WD NETs to identify novel targets and biomarkers of differentiation. Methods: High quality RNA, extracted from paraffin blocks of deidentified NETs under an IRB-approved protocol, was profiled using a 770 gene panel (nCounter PanCancer pathway, Nanostring Technologies). The resulting data was used to identify the differentially expressed genes between PD and WD NETs using limma software (Ritchie; 2015). Gene Set Enrichment Analysis (Subramanian; 2005) identified differential pathway enrichment by calculating a Normalized Enrichment Score (NES). Results: Analysis of 16 PD and 23 WD NET samples identified 154 genes as extreme outliers ( > 2 fold up/downregulation between the subtypes). Compared to WD NETS, drug targets of interest overexpressed in PD NETs were histone lysine methyltransferase EZH2, and a cell cycle regulator CHEK1 (6.5x and 8.1x, respectively, p < 0.001). In contrast, serine/threonine protein kinase PAK 3 was upregulated in WD (10.6x, p < 0.001). These and other biomarkers will be further validated by immunolabeling of tissue sections. We also found differential enrichment of canonical pathways in PD versus WD NETs (table). Conclusions: Extreme outlier transcripts identified in PD & WD NETs support investigation of inhibitors of EZH2 (e.g. EPZ6438) and CHEK1 (e.g. LY2606368) in PD and PAK3(e.g. FRAX597) in WD NETs. Genes involved in cell cycle regulation and DNA repair in PD NETs and calcium / G protein coupled receptor signaling in WD NET account for biological differences between the 2 molecular subtypes and warrant future investigation as classifiers for NETs. Our findings provide mechanistic insights into the biology of NET and targets for therapy with direct clinical implications.[Table: see text]

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