scholarly journals Modulation of the immune system during postpartum uterine inflammation

2015 ◽  
Vol 47 (4) ◽  
pp. 89-101 ◽  
Author(s):  
Caroline G. Walker ◽  
Susanne Meier ◽  
Hassan Hussein ◽  
Scott McDougall ◽  
Chris R. Burke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Immune Response ◽  
Multiple Testing ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Immune Response Gene ◽  
Multiple Testing Correction ◽  
Uterine Inflammation ◽  
Subclinical Endometritis

Postpartum uterine inflammation (endometritis) in the dairy cow is associated with lower fertility at both the time of infection and after the inflammation has resolved. We hypothesized that aberrant DNA methylation may be involved in the subfertility associated with uterine inflammation. The objective of this study was to characterize genome-wide DNA methylation and gene expression in the endometrium of dairy cows with subclinical endometritis (SCE). Endometrial tissues were obtained at 29 days postpartum ( n = 12), and microarrays were used to characterize transcription and DNA methylation. Analyses revealed 1,856 probes differentially expressed in animals with SCE ( n = 6) compared with controls (CON, n = 6, P < 0.05, Storey Multiple testing correction) and 2,976 probes with significant correlation between gene expression and bacteriology score. No significant associations among DNA methylation and gene expression were detected. Analysis of transcription data using the Database for Annotation, Visualization, and Integrated Discovery and Gene Set Enrichment Analysis identified several pathways and processes enriched in SCE cows, with the majority related to the immune response. Furthermore, the top ontology terms enriched in genes that had expression data correlated to bacteriology score were: Defense response, inflammatory response, and innate immune response. Gene expression profiles in cows with subclinical endometritis in this study indicate that the immune response is activated, potentially resulting in a local proinflammatory environment in the uterus. If this period of inflammation is prolonged it could result in tissue damage or failure to complete involution of the uterus, which may create a suboptimal environment for future pregnancy.

scholarly journals Integrative DNA Methylation and Gene Expression Analysis Reveals Candidate Biomarkers Associated with Dichotomized Response to Chemoimmunotherapy in Diffuse Large B-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-22
Author(s):  
Ellen K. Kendall ◽  
Manishkumar S. Patel ◽  
Sarah Ondrejka ◽  
Agrima Mian ◽  
Yazeed Sawalha ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Research Funding ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Enrichment Analysis ◽  
B Cell Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Gene Sets

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. While 60% of DLBCL patients achieve complete remission with frontline therapy, relapsed/refractory (R/R) DLBCL patients have a poor prognosis with median overall survival below one year, necessitating investigation into the biological principles that distinguish cured from R/R DLBCL. Recent analyses have identified unfavorable molecular signatures when accounting for gene expression, copy number alterations and mutational profiles in R/R DLBCL. However, an integrative analysis of the relationship between epigenetic and transcriptomic changes has yet to be described. In this study, we compared baseline methylation and gene expression profiles of DLBCL patients with dichotomized clinical outcomes. Methods: Diagnostic DLBCL biopsies were obtained from two patient cohorts: patients who relapsed or were refractory following chemoimmunotherapy ("R/R"), and patients who entered durable clinical remission following therapy ("cured"). The median age for R/R and cured cohorts were 62 (range 35-86) years vs. 64 (range 28-83) years (P= 0.27). High-intermediate or high IPI scores were present in 14 vs. 6 patients (P= 0.08) in the R/R and cured cohorts, respectively. All patients were treated with frontline R-CHOP or R-EPOCH. DNA and RNA were extracted simultaneously from formalin-fixed, paraffin embedded biopsy samples. An Illumina 850k Methylation Array was used to identify DNA methylation levels in 29 R/R patients and 20 cured patients. RNA sequencing was performed on 9 R/R patients and 7 cured patients at diagnosis using Illumina HiSeq4000. Differentially methylated probes were identified using the DMRcate package, and differentially expressed genes were identified using the DESeq2 package. Gene set enrichment analysis was performed using canonical pathway gene sets from MSigDB. Results: At the time of diagnosis, we found significant epigenetic and transcriptomic differences between cured and R/R patients. Comparing cured to R/R samples, there were 8,159 differentially methylated probes (FDR&lt;0.05). Differentially methylated regions between R/R and cured cohorts overlap with genes previously identified as mutation hotspots in DLBCL. Upon comparing transcriptomic profiles between R/R and cured, 267 genes were found to be differentially expressed (Log2FC&gt;|1| and FDR&lt;0.05). Gene set enrichment analysis revealed gene sets related to cell cycle, membrane trafficking, Rho and Rab family GTPase function, and transcriptional regulation were upregulated in the R/R samples. Gene sets related to innate immune signaling, Type I and II interferon signaling, fatty acid and carbohydrate metabolism were upregulated in the cured samples. To identify genes likely to be regulated by specific changes in methylation, we selected genes that were both differentially expressed and differentially methylated between the R/R and cured cohorts. In the R/R samples, 13 genes (ARMC5, ARRDC1, C12orf57, CCSER1, D2HGDH, DUOX2, FAM189B, FKBP2, KLF5, MFSD10, NEK8, NT5C, and WDR18) were significantly hypermethylated and underexpressed when compared to cured specimens, suggesting that epigenetic silencing of these genes is associated with lack of response to chemoimmunotherapy. In contrast, 12 genes (ATP2B1, C15orf41, FAM102B, FAM3C, FHOD3, FYTTD1, GPR180, KIAA1841, LRMP, MEF2A, RRAS2, and TPD52) were significantly hypermethylated and underexpressed in cured patients, suggesting that epigenetic silencing of these genes is favorable for treatment response. Many of these epigenetically modified genes have been previously implicated in cancer biology, including roles in NOTCH signaling, chromosomal instability, and biomarkers of prognosis. Conclusions: This is the first integrative epigenetic and transcriptomic analysis of diagnostic biopsies from cured and R/R DLBCL patients following chemoimmunotherapy. At the time of diagnosis, both the methylation and gene expression profiles significantly differ between patients that enter durable remission as opposed to those who are R/R to therapy. Soon, the hypomethylating agent CC-486 (i.e. oral azacitidine) will be explored in combination with mini-R-CHOP for older DLBCL patients in whom DNA methylation is likely increased. These data support the use of hypomethylating agents to potentially restore sensitivity of DLBCL to chemoimmunotherapy. Disclosures Hsi: Eli Lilly: Research Funding; Abbvie: Research Funding; Miltenyi: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; CytomX: Consultancy, Honoraria. Hill:Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding.

scholarly journals NIMG-44. NON-INVASIVE ADVANCED IMAGING METRICS PROVIDE POTENTIAL BIOMARKERS FOR GBM BIOLOGICAL HETEROGENEITY AND IMMUNE LANDSCAPE VARIANCE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi171-vi171
Author(s):  
Cymon Kersch ◽  
Leslie Muldoon ◽  
Rochelle Fu ◽  
Cheryl Claunch ◽  
Edward Neuwelt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Expression Profiles ◽  
Expression Patterns ◽  
Gene Set Enrichment Analysis ◽  
Immune Gene ◽  
Biological Processes ◽  
Non Invasive ◽  
Mri Features ◽  
Inflammatory Immune Response

Abstract BACKGROUND Treatment of glioblastoma multiforme (GBM) is complicated by extensive tumor heterogeneity. We hypothesize that transcriptomic analysis of brain tumor regions with different magnetic resonance imaging (MRI) characteristics will define specific biological processes, providing a non-invasive method for tumor characterization and stratification. METHODS Previously at the University of California San Francisco, treatment naïve GBM tissue from gadolinium contrast enhancing lesion (CEL) and non-enhancing lesion (NCEL) regions were stereotactically sampled; prior to resection, relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were determined. The tissue samples were characterized by immunohistochemistry and assessed for gene expression by microarray analysis. We correlated gene expression patterns in the CEL, NCEL, and non-tumor gliotic brain samples with multimodal physiological imaging metrics and immunohistochemical phenotypes. Gene expression networks were probed using Gene Set Enrichment Analysis. Key immunologic genes were examined individually. RESULTS Samples with differing MRI and histological phenotypes demonstrated transcriptomic variance reflecting distinct biological networks. We found significant differences in immune pathways, with immune gene signature prominent in CEL areas, moderate in NCEL and low in gliotic non-tumor brain. Within homogenously enhancing areas of CEL and NCEL there was underlying heterogeneity detectable by variable rCBV, ADC and histological phenotypes, which correlate with differing gene expression profiles indicative of biological and immunological tumor microenvironments. Increasing rCBV was correlated with an anti-inflammatory immune response in the CEL and a pro-inflammatory immune response in the NCEL. ADC was negatively correlated with cell cycle and immune networks in CEL, while NCEL ADC was positively correlated with immune processes. GBM samples with the mesenchymal molecular subtype had the greatest immune response. CONCLUSIONS Multimodal MRI features identify regionally diverse transcriptomic-based biological and immunological phenotypes in GBM. We propose that imaging genomics provides a technique for localizing biological processes and tumor immune microenvironments across space and time in GBM.

Utilizing Cancer - Functional Gene Set - Compound Networks to Identify Putative Drugs for Breast Cancer

2018 ◽  
Vol 21 (2) ◽  
pp. 74-83
Author(s):  
Tzu-Hung Hsiao ◽  
Yu-Chiao Chiu ◽  
Yu-Heng Chen ◽  
Yu-Ching Hsu ◽  
Hung-I Harry Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Cancer Survival ◽  
Expression Profiles ◽  
Functional Gene ◽  
Gene Set Enrichment Analysis ◽  
Gene Set ◽  
Gene Sets

Aim and Objective: The number of anticancer drugs available currently is limited, and some of them have low treatment response rates. Moreover, developing a new drug for cancer therapy is labor intensive and sometimes cost prohibitive. Therefore, “repositioning” of known cancer treatment compounds can speed up the development time and potentially increase the response rate of cancer therapy. This study proposes a systems biology method for identifying new compound candidates for cancer treatment in two separate procedures. Materials and Methods: First, a “gene set–compound” network was constructed by conducting gene set enrichment analysis on the expression profile of responses to a compound. Second, survival analyses were applied to gene expression profiles derived from four breast cancer patient cohorts to identify gene sets that are associated with cancer survival. A “cancer–functional gene set– compound” network was constructed, and candidate anticancer compounds were identified. Through the use of breast cancer as an example, 162 breast cancer survival-associated gene sets and 172 putative compounds were obtained. Results: We demonstrated how to utilize the clinical relevance of previous studies through gene sets and then connect it to candidate compounds by using gene expression data from the Connectivity Map. Specifically, we chose a gene set derived from a stem cell study to demonstrate its association with breast cancer prognosis and discussed six new compounds that can increase the expression of the gene set after the treatment. Conclusion: Our method can effectively identify compounds with a potential to be “repositioned” for cancer treatment according to their active mechanisms and their association with patients’ survival time.

scholarly journals Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients

2021 ◽  
Vol 14 (1) ◽  
pp. 41
Author(s):  
Hana Votavova ◽  
Zuzana Urbanova ◽  
David Kundrat ◽  
Michaela Dostalova Merkerova ◽  
Martin Vostry ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Blood Cell ◽  
Myelodysplastic Syndrome ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Adaptive Immune Response ◽  
Gene Expression Profiles ◽  
Iron Chelator ◽  
Multiple Cancer

Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.

scholarly journals Age-related differences in monocyte DNA methylation and immune function in healthy Kenyan adults and children

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Katherine R. Dobbs ◽  
Paula Embury ◽  
Emmily Koech ◽  
Sidney Ogolla ◽  
Stephen Munga ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Young Adults ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Innate Immune ◽  
Inflammatory Gene Expression ◽  
Cpg Sites ◽  
Age Related ◽  
Adults And Children

Abstract Background Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profiles in monocytes from young adults and children from western Kenya. Results We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles. Conclusions These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

scholarly journals Peripheral Blood Gene Expression and IgG Glycosylation Profiles as Markers of Tocilizumab Treatment in Rheumatoid Arthritis

2012 ◽  
Vol 39 (5) ◽  
pp. 916-928 ◽  
Author(s):  
BERTALAN MESKO ◽  
SZILARD POLISKA ◽  
SZILVIA SZAMOSI ◽  
ZOLTAN SZEKANECZ ◽  
JANOS PODANI ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Peripheral Blood ◽  
Multiple Testing ◽  
Mononuclear Cells ◽  
Expression Profiles ◽  
Quantitative Polymerase Chain Reaction ◽  
Response To Treatment ◽  
Peripheral Blood Mononuclear ◽  
Gene Sets

Objective.Tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has recently been approved as a biological therapy for rheumatoid arthritis (RA) and other diseases. It is not known if there are characteristic changes in gene expression and immunoglobulin G glycosylation during therapy or in response to treatment.Methods.Global gene expression profiles from peripheral blood mononuclear cells of 13 patients with RA and active disease at Week 0 (baseline) and Week 4 following treatment were obtained together with clinical measures, serum cytokine levels using ELISA, and the degree of galactosylation of the IgG N-glycan chains. Gene sets separating responders and nonresponders were tested using canonical variates analysis. This approach also revealed important gene groups and pathways that differentiate responders from nonresponders.Results.Fifty-nine genes showed significant differences between baseline and Week 4 and thus correlated with treatment. Significantly, 4 genes determined responders after correction for multiple testing. Ten of the 12 genes with the most significant changes were validated using real-time quantitative polymerase chain reaction. An increase in the terminal galactose content of N-linked glycans of IgG was observed in responders versus nonresponders, as well as in treated samples versus samples obtained at baseline.Conclusion.As a preliminary report, gene expression changes as a result of tocilizumab therapy in RA were examined, and gene sets discriminating between responders and nonresponders were found and validated. A significant increase in the degree of galactosylation of IgG N-glycans in patients with RA treated with tocilizumab was documented.

Abstract 16564: Analysis of the Mechanisms of Intravenous Immunoglobulin-Resistant Kawasaki Disease Using iPS Cell Technology

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kazuyuki Ikeda ◽  
Tomonaga Ameku ◽  
Yui Nomiya ◽  
Masahiro Nakamura ◽  
Satoshi Matsui ◽  
...  
Keyword(s):  
Gene Expression ◽  
Kawasaki Disease ◽  
Intravenous Immunoglobulin ◽  
Expression Profiles ◽  
Systemic Vasculitis ◽  
Dermal Fibroblasts ◽  
Gene Set Enrichment Analysis ◽  
Recurrent Fever ◽  
Ips Cell ◽  
Ivig Resistance

Introduction: Kawasaki disease (KD) is a systemic vasculitis of unknown origin. Although the treatment of intravenous immunoglobulin (IVIG) significantly resolves inflammation, 10-20% of KD patients have persistent or recurrent fever after the administration of IVIG, and IVIG-resistant patients have a particularly high risk of developing coronary artery abnormalities. Hypothesis: The mechanisms of IVIG-resistant KD have been analyzed using the patients’ leukocyte samples. However, vascular endothelial cells (ECs), closely related to the vasculitis of KD, have not been examined in the previous reports. We propose a hypothesis that ECs are mainly involved in the etiology of IVIG-resistance. Methods: The purpose of this study is to establish new in vitro disease models of vasculitis using induced pluripotent stem cell (iPSC) technology, and clarify the mechanisms of IVIG-resistance in KD. Dermal fibroblasts or T cells from 2 IVIG-resistant and 2 IVIG-responsive KD patients were reprogrammed by episomal vectors encoding Oct3/4, Sox2, Klf4, L-Myc, LIN28, and p53 shRNA. The iPSC lines were then differentiated into ECs by using a previously-reported differentiation method, and the EC samples were subjected to the microarray analyses. Results: The KD patient-derived iPSCs could be differentiated into ECs. The gene expression profiles were compared between iPS-derived ECs (iPS-ECs) generated from IVIG-resistant and IVIG-responsive KD patients. We found that 107 genes were at least two fold up-regulated and 101 genes were at least two fold down-regulated in iPS-ECs from IVIG-resistant KD patients compared with those from IVIG-responsive patients. The Principle Component Analysis (PCA) was performed, but the gene expression levels showed no significant differences between the groups. The Gene Set Enrichment Analysis (GSEA) revealed that the gene sets related to IL-6, NRAS (a member of the RAS oncogene family) and breast cancer were up-regulated in iPS-ECs from IVIG-resistant KD patients. Conclusions: Taking into account that the concentration of IL-6 has been reported to be elevated in acute phase of IVIG-resistant KD, our results suggest that the up-regulation of IL-6 related genes in ECs might be involved in the pathogenesis of IVIG-resistant KD.

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