scholarly journals Upregulation of IFNɣ-mediated chemokines dominate the immune transcriptome of muscle-invasive urothelial carcinoma

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Ekaterina Olkhov-Mitsel ◽  
Anjelica Hodgson ◽  
Stan K. Liu ◽  
Danny Vesprini ◽  
Jane Bayani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cellular Response ◽  
Antigen Processing ◽  
Leukocyte Adhesion ◽  
Expression Patterns ◽  
Lymphocyte Activation ◽  
Immune Gene ◽  
Mhc Molecules ◽  
Ifn Γ ◽  
Muscle Invasive

AbstractTumor inflammation is prognostically significant in high-grade muscle-invasive bladder cancer (MIBC). However, the underlying mechanisms remain elusive. To identify inflammation-associated immune gene expression patterns, we performed transcriptomic profiling of 40 MIBC archival tumors using the NanoString nCounter Human v.1.1 PanCancer Panel. Findings were validated using the TCGA MIBC dataset. Unsupervised and supervised clustering identified a distinctive immune-related gene expression profile for inflammation, characterized by significant upregulation of 149 genes, particularly chemokines, a subset of which also had potential prognostic utility. Some of the most enriched biological processes were lymphocyte activation and proliferation, leukocyte adhesion and migration, antigen processing and presentation and cellular response to IFN-γ. Upregulation of numerous IFN-γ-inducible chemokines, class II MHC molecules and immune checkpoint genes was detected as part of the complex immune response to MIBC. Further, B-cell markers linked to tertiary lymphoid structures were upregulated, which in turn is predictive of tumor response to immunotherapy and favorable outcome. Our findings of both an overall activated immune profıle and immunosuppressive microenvironment provide novel insights into the complex immune milieu of MIBC with inflammation and supports its clinical significance for predicting prognosis and immunotherapeutic responsiveness, which warrants further investigation. This may open novel opportunities to identify mechanisms for developing new immunotherapeutic strategies.

scholarly journals Early Response of CD8+ T Cells in COVID-19 Patients

2021 ◽  
Vol 11 (12) ◽  
pp. 1291
Author(s):  
Deni Ramljak ◽  
Martina Vukoja ◽  
Marina Curlin ◽  
Katarina Vukojevic ◽  
Maja Barbaric ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Mrna Expression ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Effector Memory ◽  
Healthy Controls ◽  
Ifn Γ

Healthy and controlled immune response in COVID-19 is crucial for mild forms of the disease. Although CD8+ T cells play important role in this response, there is still a lack of studies showing the gene expression profiles in those cells at the beginning of the disease as potential predictors of more severe forms after the first week. We investigated a proportion of different subpopulations of CD8+ T cells and their gene expression patterns for cytotoxic proteins (perforin-1 (PRF1), granulysin (GNLY), granzyme B (GZMB), granzyme A (GZMA), granzyme K (GZMK)), cytokine interferon-γ (IFN-γ), and apoptotic protein Fas ligand (FASL) in CD8+ T cells from peripheral blood in first weeks of SARS-CoV-2 infection. Sixteen COVID-19 patients and nine healthy controls were included. The absolute counts of total lymphocytes (p = 0.007), CD3+ (p = 0.05), and CD8+ T cells (p = 0.01) in COVID-19 patients were significantly decreased compared to healthy controls. In COVID-19 patients in CD8+ T cell compartment, we observed lower frequency effector memory 1 (EM1) (p = 0.06) and effector memory 4 (EM4) (p < 0.001) CD8+ T cells. Higher mRNA expression of PRF1 (p = 0.05) and lower mRNA expression of FASL (p = 0.05) at the fifth day of the disease were found in COVID-19 patients compared to healthy controls. mRNA expression of PRF1 (p < 0.001) and IFN-γ (p < 0.001) was significantly downregulated in the first week of disease in COVID-19 patients who progressed to moderate and severe forms after the first week, compared to patients with mild symptoms during the entire disease course. GZMK (p < 0.01) and FASL (p < 0.01) mRNA expression was downregulated in all COVID-19 patients compared to healthy controls. Our results can lead to a better understanding of the inappropriate immune response of CD8+ T cells in SARS-CoV2 with the faster progression of the disease.

scholarly journals RankerGUI: A Computational Framework to Compare Differential Gene Expression Profiles Using Rank Based Statistics

2019 ◽  
Vol 20 (23) ◽  
pp. 6098 ◽  
Author(s):  
Amarinder Singh Thind ◽  
Kumar Parijat Tripathi ◽  
Mario Rosario Guarracino
Keyword(s):  
Gene Expression ◽  
Differential Expression ◽  
Differential Gene Expression ◽  
Web Application ◽  
Cellular Response ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Expression Profiles ◽  
Experimental Conditions ◽  
Differential Gene

The comparison of high throughput gene expression datasets obtained from different experimental conditions is a challenging task. It provides an opportunity to explore the cellular response to various biological events such as disease, environmental conditions, and drugs. There is a need for tools that allow the integration and analysis of such data. We developed the “RankerGUI pipeline”, a user-friendly web application for the biological community. It allows users to use various rank based statistical approaches for the comparison of full differential gene expression profiles between the same or different biological states obtained from different sources. The pipeline modules are an integration of various open-source packages, a few of which are modified for extended functionality. The main modules include rank rank hypergeometric overlap, enriched rank rank hypergeometric overlap and distance calculations. Additionally, preprocessing steps such as merging differential expression profiles of multiple independent studies can be added before running the main modules. Output plots show the strength, pattern, and trends among complete differential expression profiles. In this paper, we describe the various modules and functionalities of the developed pipeline. We also present a case study that demonstrates how the pipeline can be used for the comparison of differential expression profiles obtained from multiple platforms’ data of the Gene Expression Omnibus. Using these comparisons, we investigate gene expression patterns in kidney and lung cancers.

scholarly journals IFN-I Independent Antiviral Immune Response to Vesicular Stomatitis Virus Challenge in Mouse Brain

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 326
Author(s):  
Anurag R. Mishra ◽  
Siddappa N. Byrareddy ◽  
Debasis Nayak
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Vesicular Stomatitis Virus ◽  
Antiviral Response ◽  
Type I ◽  
Immune Gene ◽  
Antiviral Immune Response ◽  
Virus Challenge ◽  
Vesicular Stomatitis ◽  
Ifn Γ

Type I interferon (IFN-I) plays a pivotal role during viral infection response in the central nervous system (CNS). The IFN-I can orchestrate and regulate most of the innate immune gene expression and myeloid cell dynamics following a noncytopathic virus infection. However, the role of IFN-I in the CNS against viral encephalitis is not entirely clear. Here we have implemented the combination of global differential gene expression profiling followed by bioinformatics analysis to decipher the CNS immune response in the presence and absence of the IFN-I signaling. We observed that vesicular stomatitis virus (VSV) infection induced 281 gene changes in wild-type (WT) mice primarily associated with IFN-I signaling. This was accompanied by an increase in antiviral response through leukocyte vascular patrolling and leukocyte influx along with the expression of potent antiviral factors. Surprisingly, in the absence of the IFN-I signaling (IFNAR−/− mice), a significantly higher (1357) number of genes showed differential expression compared to the WT mice. Critical candidates such as IFN-γ, CCL5, CXCL10, and IRF1, which are responsible for the recruitment of the patrolling leukocytes, are also upregulated in the absence of IFN-I signaling. The computational network analysis suggests the presence of the IFN-I independent pathway that compensates for the lack of IFN-I signaling in the brain. The analysis shows that TNF-α is connected maximally to the networked candidates, thus emerging as a key regulator of gene expression and recruitment of myeloid cells to mount antiviral action. This pathway could potentiate IFN-γ release; thereby, synergistically activating IRF1-dependent ISG expression and antiviral response.

scholarly journals IFN-γ Mediates the Development of Systemic Lupus Erythematosus

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Wenping Liu ◽  
Mengdi Li ◽  
Ziye Wang ◽  
Jibo Wang
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Antigen Processing ◽  
Fiber Formation ◽  
The Body ◽  
Interferon Α ◽  
Systemic Lupus ◽  
Bioinformatics Analyses ◽  
Ifn Γ

Objective. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect all organs in the body. It is characterized by overexpression of antibodies against autoantigen. Although previous bioinformatics analyses have identified several genetic factors underlying SLE, they did not discriminate between naive and individuals exposed to anti-SLE drugs. Here, we evaluated specific genes and pathways in active and recently diagnosed SLE population. Methods. GSE46907 matrix downloaded from Gene Expression Omnibus (GEO) was analyzed using R, Metascape, STRING, and Cytoscape to identify differentially expressed genes (DEGs), enrichment pathways, protein-protein interaction (PPI), and hub genes between naive SLE individuals and healthy controls. Results. A total of 134 DEGs were identified, in which 29 were downregulated, whereas 105 were upregulated in active and newly diagnosed SLE cases. GO term analysis revealed that transcriptional induction of the DEGs was particularly enhanced in response to secretion of interferon-γ and interferon-α and regulation of cytokine production innate immune responses among others. KEGG pathway analysis showed that the expression of DEGs was particularly enhanced in interferon signaling, IFN antiviral responses by activated genes, class I major histocompatibility complex (MHC-I) mediated antigen processing and presentation, and amyloid fiber formation. STAT1, IRF7, MX1, OASL, ISG15, IFIT3, IFIH1, IFIT1, OAS2, and GBP1 were the top 10 DEGs. Conclusions. Our findings suggest that interferon-related gene expression and pathways are common features for SLE pathogenesis, and IFN-γ and IFN-γ-inducible GBP1 gene in naive SLE were emphasized. Together, the identified genes and cellular pathways have expanded our understanding on the mechanism underlying development of SLE. They have also opened a new frontier on potential biomarkers for diagnosis, biotherapy, and prognosis for SLE.

Gene expression profiling in bladder cancer to identify potential therapeutic targets.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4518-4518
Author(s):  
Syed A. Hussain ◽  
Daniel H. Palmer ◽  
Wing Kin Syn ◽  
Joseph J Sacco ◽  
Bryony Lloyd ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Hierarchical Clustering ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Invasive Cancer ◽  
Classical Complement Pathway ◽  
Grade 3 ◽  
Muscle Invasive

4518 Background: Characterization of gene expression patterns in bladder cancer (BC) allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Methods: Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Results: Hierarchical clustering defined signatures, which differentiated between cancer and normal, muscle-invasive or non-muscle invasive cancer and normal, g1 and g3. Pathways associated with cell cycle and proliferations were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer as compared to normal tissue. Conclusions: This study contributes to a growing body of work on gene expression signatures in BC. The data support an important role for osteopontin in BC, and identify several pathways worthy of further investigation. [Table: see text]

Interferon α Has Varied Effects On CD34+ Cells From Patients With Polycythemia Vera

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2840-2840
Author(s):  
Min Lu ◽  
Seungyeul Yoo ◽  
Lijuan Xia ◽  
Xiaoli Wang ◽  
Yan Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Immune Response ◽  
Colony Formation ◽  
Cellular Response ◽  
P Value ◽  
Type I ◽  
Signature Genes ◽  
Cd34 Cells ◽  
Ifn Γ

Abstract Prolonged therapy with pegylated interferon a (Peg-IFNα 2a) leads to hematological and complete molecular remissions in 70% and 17% of patients with polycythemia vera (PV) , respectively (Quintas-Cardama et al, Blood 2013). We have previously shown that PV CD34+ cells are more responsive to Peg-IFNα 2a than normal CD34+ cell. The type I IFN receptor 1 and 2 were shown to be expressed by a greater number of by PV CD34+ cells than normal(N) CD34+ cells (p=0.01 and p=0.002, respectively). The effects of Peg-IFNα 2a on PV hematopoietic stem cells(HSCs) was next evaluated by incubating PV CD34+ cell for 7 days with Peg-IFNα 2a (200ng/ml) followed by their transplantation into NSG mice. The degree of human cell chimerism following the transplantation of MPN CD 34+ cells was reduced by 50 -90% and the JAK2V617F allele burden by 40 -80%. Treatment of N CD34+ cells with Peg-IFNα 2a reduced donor chimerism by only 20%. We next examined the effects of increasing doses of Peg-IFNα 2a on CD34+ cells from 11 PV patients and 5 N controls. In 4 out of 10 PV cases the IC50 of Peg-IFNα 2a was less than 200ng/ml while in the remainder of cases the IC50 was greater. Low doses of IFNa were capable of eliminating JAK2V617F+ hematopoietic colonies in these IFNα sensitive patients while higher doses of IFNα were required to achieve the same effect in the other patients. PV and N CD34+ cells were then profiled using Illumina Gene expression arrays. In total, 32 intensity data files were generated, each containing 47,231 features, corresponding to 12,388 unique genes. At p-value <0.05 386 genes were down-regulated in PV; these genes were enriched for biological processes related to immune response including the IFN-γ-mediated signaling pathway (p=0.0002), the response to IFN-gamma (p=0.004), and the cellular response to IFN-γ (p=0.0004). The 715 up-regulated genes in PV were enriched for pathways involving glycolysis (p=9.4×10-05), cellular response to stress (p=0.006), and catabolic processes. The gene expression patterns of CD34+ cells incubated with and without INFα were next analyzed. At pairwise t-test p-value <0.001, 315 genes were differentially expressed (223 up-regulated and 92 down-regulated by INFα). Up-regulated genes were enriched for INFα functions and immune response including: response to type I IFN (p=9.0×10-49), innate immune response (2.6×10-45), response to virus (7.5×10-40). Among the 223 up-regulated genes, half were previously known as IFN regulated genes (IRGs). The individual response (IR) of genes to IFN was then defined as: IRi=log (exp ressioni @IFN/exp ressioni@control) IR patterns were remarkably consistent within N samples while large inter-patient variations were observed within the PV samples. Significantly positive IRs were observed for 75 genes and negative IRs for 117 genes within PV as compared to N samples (p value<0.01). The 75 positively responsive genes to IFNa overlapped with 16 down-regulated PV signature genes (p=1.1×10-10) while the negatively responsive of genes overlapped with 41 up-regulated PV signature genes (p=2.2×10-24).These data indicate that the action of IFNa is associated with the alteration of the expression of specific PV signature genes. The varied inhibitory effect of Peg-IFNα 2a on PV colony formation was then correlated with the IR of individual genes. The IRs of OAS2 and RPS24 showed particularly high variance and were related to colony formation. OAS2 (2'-5'-oligoadenylate synthetase 2) is an INF-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response but also influences apoptosis, cell growth, differentiation and gene regulation. The IR of this gene was directly related to the inhibitory actions of IFNa (p=0.0011). By contrast, the IR of RPS24 (40S ribosomal protein S24), was inversely correlated to the IFNα response (p=0.0038). Mutations in RPS24 are associated with Diamond-Blackfan anemia. The strong correlation between the IR of these 2 genes with the inhibitory effects of IFNα suggests that their response ratio might be useful as therapeutic biomarker. These data indicate that the IFNα receptor is up-regulated in PV CD34+ cells and that IFNα treatment eliminates PV stem cells and its sensitivity against individual patient PV HSC/HPC varies. The patterns of differentially expressed genes following IFNα treatment may prove useful in determining its mechanism of action and predicting IFNα patient response. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genomic Expression Responses to DNA-damaging Agents and the Regulatory Role of the Yeast ATR Homolog Mec1p

2001 ◽  
Vol 12 (10) ◽  
pp. 2987-3003 ◽  
Author(s):  
Audrey P. Gasch ◽  
Mingxia Huang ◽  
Sandra Metzner ◽  
David Botstein ◽  
Stephen J. Elledge ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Cellular Response ◽  
Expression Patterns ◽  
Wild Type ◽  
Data Set ◽  
Genomic Expression ◽  
Dna Damaging Agents

Eukaryotic cells respond to DNA damage by arresting the cell cycle and modulating gene expression to ensure efficient DNA repair. The human ATR kinase and its homolog in yeast, MEC1, play central roles in transducing the damage signal. To characterize the role of the Mec1 pathway in modulating the cellular response to DNA damage, we used DNA microarrays to observe genomic expression inSaccharomyces cerevisiae responding to two different DNA-damaging agents. We compared the genome-wide expression patterns of wild-type cells and mutants defective in Mec1 signaling, includingmec1, dun1, and crt1 mutants, under normal growth conditions and in response to the methylating-agent methylmethane sulfonate (MMS) and ionizing radiation. Here, we present a comparative analysis of wild-type and mutant cells responding to these DNA-damaging agents, and identify specific features of the gene expression responses that are dependent on the Mec1 pathway. Among the hundreds of genes whose expression was affected by Mec1p, one set of genes appears to represent an MEC1-dependent expression signature of DNA damage. Other aspects of the genomic responses were independent of Mec1p, and likely independent of DNA damage, suggesting the pleiotropic effects of MMS and ionizing radiation. The complete data set as well as supplemental materials is available at http://www-genome.stanford.edu/mec1 .

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