scholarly journals Dysregulation of the interleukin-17A pathway in endometrial tissue from women with unexplained infertility affects pregnancy outcome following assisted reproductive treatment

2020 ◽  
Vol 35 (8) ◽  
pp. 1875-1888
Author(s):  
D A Crosby ◽  
L E Glover ◽  
E P Brennan ◽  
P Kelly ◽  
P Cormican ◽  
...  
Keyword(s):  
Study Design ◽  
Enrichment Analysis ◽  
Unexplained Infertility ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Discovery Cohort ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Assisted Reproductive Treatment ◽  
Support Fund

Abstract STUDY QUESTION Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1β, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S) Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER NA.

scholarly journals Blood and Brain Transcriptome Analysis Reveals APOE Genotype-mediated and Immune-related Pathways Involved in Alzheimer Disease

2021 ◽  
Author(s):  
Rebecca Panitch ◽  
Junming Hu ◽  
Weiming Xia ◽  
David A Bennett ◽  
Thor D Stein ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Blood Brain Barrier ◽  
Vascular Injury ◽  
Apoe Genotype ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Brain Barrier ◽  
Gene Set Enrichment ◽  
Gene Set

Abstract Background: While Alzheimer disease (AD) is generally considered as a brain disorder, blood biomarkers may be useful for diagnosis and prediction of AD brain pathology. The APOE ε4 allele has shown cerebrovascular effects including acceleration of blood brain barrier breakdown. Methods: We evaluated differential expression of previously established AD genes in brains from 344 pathologically confirmed AD cases and 232 controls and in blood from 112 pathologically confirmed AD cases and 67 controls from the Religious Orders Study and Memory and Aging Project. Differential gene expression between AD cases and controls was analyzed in the blood and brain jointly using a multivariate approach in the total sample and within APOE genotype groups. Gene set enrichment analysis was performed within APOE genotype groups using the results from the combined blood and brain analyses to identify biologically important pathways. Gene co-expression networks in brain and blood samples were investigated using weighted correlation network analysis. Top ranked genes from networks and pathways were further evaluated with vascular injury traits. Results: We observed differentially expressed genes with P<0.05 in both brain and blood for established AD genes INPP5D (upregulated) and HLA-DQA1 (downregulated). PIGHP1 and FRAS1 were differentially expressed at the transcriptome-wide level (P<3.3x10 -6 ) within ε2/ε3 and ε3/ε4 groups, respectively. Gene-set enrichment analysis revealed 21 significant pathways (false discovery rate P<0.05) in at least one APOE genotype group. Ten pathways were significantly enriched in the ε3/ε4 group, and six of these were unique to these subjects. Four pathways were enriched for AD upregulated genes in the ε3/ε4 group and AD downregulated genes in ε4 lacking subjects. We identified a co-expressed gene network in brain that reproduced in blood and showed higher average expression in ε4 carriers. Twenty-three genes from pathway and network analyses were significantly associated at P<0.05 with at least one vascular injury trait. Conclusion: These results suggest that APOE genotype contributes to unique expression network profiles in both blood and brain. Several genes in these networks are associated with measures of vascular injury and potentially contribute to ε4’s effect on the blood brain barrier.

Gene expression in prostate tissue according to frequency of ejaculation.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 25-25
Author(s):  
Jennifer R. Rider ◽  
Jennifer A Sinnott ◽  
Lorelei A. Mucci
Keyword(s):  
Gene Expression ◽  
Normal Tissue ◽  
Tumor Tissue ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Adjacent Normal Tissue ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Ejaculation Frequency

25 Background: Long-term prospective data from within the Health Professionals Follow-up Study (HPFS) suggest more frequent ejaculation throughout adult life may be protective against future development of prostate cancer (PCa). Compared to men with an average monthly ejaculation frequency (EF) of 4-7 times/month during adulthood, men who ejaculated at least 21 times per month were 30% less likely to be diagnosed with PCa after adjustment for a number of potential confounders and PCa screening. We sought to explore mechanisms through which EF may influence PCa development utilizing gene expression data assessed on tumor and adjacent normal tissue. Methods: In 1992, 31,925 HPFS participants were questioned on their average monthly EF at ages 20-29, 40-49, and in the previous year; 3,839 of these men were later diagnosed with PCa. Expression of 20,254 genes was available from archival tumor tissue from 156 cases; 84 of these cases also had data from adjacent normal tissue. We regressed each gene expression value as a continuous outcome on EF, age at diagnosis, and year at diagnosis. We calculated the p value associated with the coefficient for the EF variable as a measure of the strength of the trend test. We then used t values for the coefficients to rank the genes, and ran a gene set enrichment analysis to identify pathways with genes associated with EF. Results: We observed that while there was not much signal in the tumor tissue, there was enrichment of smaller p values in the adjacent normal tissue. EF in the time period most proximal to diagnosis is most strongly associated with gene expression in normal tissue. Focusing on the association between gene expression in normal tissue and EF in the year prior to the questionnaire (1991), the top six differentially expressed genes were OR4K1, CCDC138, SERPINA9, TRMT61B, ZNF302, and ASB4. Gene set enrichment analysis revealed a substantial number of pathways differentially expressed at the FDR <0.05 threshold. Conclusions: Identifying changes in gene expression associated with EF in normal prostate tissue provides further support for a biological role of ejaculation frequency in the etiology of PCa. Notably, pathways downregulated with increasing ejaculation frequency were primarily immune related.

scholarly journals Prognostic Relevance of BRCA1 Expression in Survival of Patients With Cervical Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
E Sun Paik ◽  
Chi-Son Chang ◽  
Ye Lin Chae ◽  
So Young Oh ◽  
Sun-Ju Byeon ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Overall Survival ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Brca1 Expression ◽  
Gene Set Enrichment ◽  
Cox Regression Analysis ◽  
Gene Set ◽  
Prognostic Relevance

ObjectiveBRCA1 expression can be lost by a variety of mechanisms including germline or somatic mutation and promotor hypermethylation. Given the potential importance of BRCA1 loss as a predictive and prognostic biomarker in several cancers, the objective of this study was to investigate BRCA1 expression using immunohistochemistry (IHC) in cervical cancer and its possible prognostic relevance.MethodsSeventy patients with cervical cancer were enrolled in this study. Samples from each tumor were stained for BRCA1 and reviewed independently by gynecologic pathologists blinded to the BRCA status. Kaplan–Meier methods were used to estimate overall survival according to BRCA1 expression. Differentially expressed genes (DEGs) by BRCA1 expression were selected using GSE44001 dataset, which included 300 samples treated with radical hysterectomy. In addition, cox regression analysis with backward elimination was performed to select independent prognostic markers. Gene set enrichment analysis (GSEA) was done using these DEGs.ResultsBRCA1 IHC was positive in 62.9% (44/70) of cases. Patients with BRCA1 expression showed better overall survival (100% vs. 76.2%, HR 0.20, 95% CI 0.04 – 0.99, p = 0.028) than those without BRCA1 expression. Analysis of gene expression profiles according to BRCA1 expression identified 321 differentially expressed mRNAs. Gene set enrichment analysis results showed two dysregulated pathways (VEGF_A_UP.V1_DN and E2F1_UP.V1_UP). Of these DEGs, alterations of 20 gene signatures were found to be independently associated with survival outcomes of patients.ConclusionsBRCA1 expression in cervical cancer tissue is associated with survival. In addition, the identification of specific gene alterations associated with BRCA1 expression could help to provide individualized prediction in these patients.

scholarly journals Higher Acid-Base Imbalance Associated with Respiratory Failure Could Decrease the Survival of Patients with Scrub Typhus during Intensive Care Unit Stay: A Gene Set Enrichment Analysis

2019 ◽  
Vol 8 (10) ◽  
pp. 1580 ◽  
Author(s):  
Kyoung Min Moon ◽  
Kyueng-Whan Min ◽  
Mi-Hye Kim ◽  
Dong-Hoon Kim ◽  
Byoung Kwan Son ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Respiratory Failure ◽  
Scrub Typhus ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Acid Base ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Gene Sets

Ninety percent of patients with scrub typhus (SC) with vasculitis-like syndrome recover after mild symptoms; however, 10% can suffer serious complications, such as acute respiratory failure (ARF) and admission to the intensive care unit (ICU). Predictors for the progression of SC have not yet been established, and conventional scoring systems for ICU patients are insufficient to predict severity. We aimed to identify simple and robust indicators to predict aggressive behaviors of SC. We evaluated 91 patients with SC and 81 non-SC patients who were admitted to the ICU, and 32 cases from the public functional genomics data repository for gene expression analysis. We analyzed the relationships between several predictors and clinicopathological characteristics in patients with SC. We performed gene set enrichment analysis (GSEA) to identify SC-specific gene sets. The acid-base imbalance (ABI), measured 24 h before serious complications, was higher in patients with SC than in non-SC patients. A high ABI was associated with an increased incidence of ARF, leading to mechanical ventilation and worse survival. GSEA revealed that SC correlated to gene sets reflecting inflammation/apoptotic response and airway inflammation. ABI can be used to indicate ARF in patients with SC and assist with early detection.

scholarly journals Transcriptional survey of alveolar macrophages in a murine model of chronic granulomatous inflammation reveals common themes with human sarcoidosis

2018 ◽  
Vol 314 (4) ◽  
pp. L617-L625 ◽  
Author(s):  
Arjun Mohan ◽  
Anagha Malur ◽  
Matthew McPeek ◽  
Barbara P. Barna ◽  
Lynn M. Schnapp ◽  
...  
Keyword(s):  
Differentially Expressed Genes ◽  
Murine Model ◽  
Alveolar Macrophages ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Multiwall Carbon Nanotube ◽  
Gene Set Enrichment ◽  
Integrated Network ◽  
Gene Set ◽  
Gene Sets

To advance our understanding of the pathobiology of sarcoidosis, we developed a multiwall carbon nanotube (MWCNT)-based murine model that shows marked histological and inflammatory signal similarities to this disease. In this study, we compared the alveolar macrophage transcriptional signatures of our animal model with human sarcoidosis to identify overlapping molecular programs. Whole genome microarrays were used to assess gene expression of alveolar macrophages in six MWCNT-exposed and six control animals. The results were compared with the transcriptional profiles of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate activated pathways, integrated network and gene set enrichment analysis (GSEA) was performed. We identified over 1,000 differentially expressed between control and MWCNT mice. Gene ontology functional analysis showed overrepresentation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling, and oxidative phosphorylation. Differences in gene set enrichment between MWCNT mice and sarcoidosis patients were also observed. We applied network analysis to differentially expressed genes common between the MWCNT model and sarcoidosis to identify key drivers of disease. In conclusion, an integrated network and transcriptomics approach revealed substantial functional similarities between a murine model and human sarcoidosis particularly with respect to activation of immune-specific pathways.

scholarly journals Drug perturbation gene set enrichment analysis (dpGSEA): a new transcriptomic drug screening approach

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mike Fang ◽  
Brian Richardson ◽  
Cheryl M. Cameron ◽  
Jean-Eudes Dazard ◽  
Mark J. Cameron
Keyword(s):  
Drug Targets ◽  
T Regulatory Cells ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Regulatory Cells ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Gene Sets ◽  
Gastroenteropancreatic Neuroendocrine Tumor ◽  
Public Datasets

Abstract Background In this study, we demonstrate that our modified Gene Set Enrichment Analysis (GSEA) method, drug perturbation GSEA (dpGSEA), can detect phenotypically relevant drug targets through a unique transcriptomic enrichment that emphasizes biological directionality of drug-derived gene sets. Results We detail our dpGSEA method and show its effectiveness in detecting specific perturbation of drugs in independent public datasets by confirming fluvastatin, paclitaxel, and rosiglitazone perturbation in gastroenteropancreatic neuroendocrine tumor cells. In drug discovery experiments, we found that dpGSEA was able to detect phenotypically relevant drug targets in previously published differentially expressed genes of CD4+T regulatory cells from immune responders and non-responders to antiviral therapy in HIV-infected individuals, such as those involved with virion replication, cell cycle dysfunction, and mitochondrial dysfunction. dpGSEA is publicly available at https://github.com/sxf296/drug_targeting. Conclusions dpGSEA is an approach that uniquely enriches on drug-defined gene sets while considering directionality of gene modulation. We recommend dpGSEA as an exploratory tool to screen for possible drug targeting molecules.

scholarly journals Key pathways involved in prostate cancer based on gene set enrichment analysis and meta analysis

2011 ◽  
Vol 10 (4) ◽  
pp. 3856-3887 ◽  
Author(s):  
Q.Y. Ning ◽  
J.Z. Wu ◽  
N. Zang ◽  
J. Liang ◽  
Y.L. Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Meta Analysis ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Key Pathways

scholarly journals A Novel Prognostic Model Based On Cytosolic DNA Sensing-Related Gene Signature for Pancreatic Cancer

2021 ◽  
Author(s):  
Chuan-Qi Xu ◽  
Kui-Sheng Yang ◽  
Shu-Xian Zhao ◽  
Jian Lv
Keyword(s):  
Pancreatic Cancer ◽  
Prognostic Factor ◽  
Prognostic Model ◽  
Risk Group ◽  
Enrichment Analysis ◽  
Independent Prognostic Factor ◽  
Gene Set Enrichment Analysis ◽  
Dna Sensing ◽  
Gene Set Enrichment ◽  
Gene Set

Abstract Objective: Pancreatic cancer (PC) is one of the most malignant tumors. Cytosolic DNA sensing have been found to play an essential role in tumor. In this study, a cytosolic DNA sensing-related genes (CDSRGs) signature was constructed and the potential mechanisms also been discussed.Methods: The RNA expression and clinical data of PC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Subsequently, univariate (UCR) and multivariate Cox regression (MCR) analyses were conducted to establish a prognostic model in the TCGA patients, which was verified by GEO patients. Cancer immune infiltrates were investigated via single sample gene set enrichment analysis (ssGSEA) and Tumor Immune Estimation Resource (TIMER). Finally, Gene Set Enrichment Analysis (GSEA) was used to investigate the related signaling pathways.Results: A prognostic model comprising four genes (POLR2E,IL18, MAVS, and FADD) was established. The survival rate of patients in the low-risk group was significantly higher than that of patients in the high-risk group. In addition, CDSRGs-risk score was proved as an independent prognostic factor in PC. Immune infiltrates and drug sensitivity are associated with POLR2E,IL18, MAVS, and FADD expression.Conclusions: In summary, we present and validated a CDSRGs risk model that is an independent prognostic factor and indicates the immune characteristics of PC. This prognostic model may facilitate the personalized treatment and monitoring.

scholarly journals Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma

2021 ◽  
Vol 4 (5) ◽  
pp. e201900332
Author(s):  
Elena A Afanasyeva ◽  
Moritz Gartlgruber ◽  
Tatsiana Ryl ◽  
Bieke Decaesteker ◽  
Geertrui Denecker ◽  
...  
Keyword(s):  
Enrichment Analysis ◽  
Time Lapse ◽  
Dna Methyltransferases ◽  
Gene Set Enrichment Analysis ◽  
Gene Set Enrichment ◽  
Gene Set ◽  
Risk Characteristics ◽  
Weak Points ◽  
Treatment Research ◽  
Time Lapse Imaging

The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin–GEF1–suppressed ADRN-type cells are a batch of AU-rich element–containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis–based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin–GEF1–suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.

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