Correction: Gene Expression Profiles Identify Inflammatory Signatures in Dendritic Cells
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PROVIDER: S-EPMC2886826 | biostudies-literature | 2010 Jan
REPOSITORIES: biostudies-literature
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Project description:Dendritic cells (DCs) constitute a heterogeneous group of antigen-presenting leukocytes important in activation of both innate and adaptive immunity. We studied the gene expression patterns of DCs incubated with reagents inducing their activation or inhibition. Total RNA was isolated from DCs and gene expression profiling was performed with oligonucleotide microarrays. Using a supervised learning algorithm based on Random Forest, we generated a molecular signature of inflammation from a training set of 77 samples. We then validated this molecular signature in a testing set of 38 samples. Supervised analysis identified a set of 44 genes that distinguished very accurately between inflammatory and non inflammatory samples. The diagnostic performance of the signature genes was assessed against an independent set of samples, by qRT-PCR. Our findings suggest that the gene expression signature of DCs can provide a molecular classification for use in the selection of anti-inflammatory or adjuvant molecules with specific effects on DC activity.
| S-EPMC2827557 | biostudies-literature
Project description:Respiratory infections caused by Bordetella pertussis are reemerging despite high pertussis vaccination coverage. Since the introduction of the acellular pertussis vaccine in the late twentieth century, circulating B. pertussis strains increasingly lack expression of the vaccine component pertactin (Prn). In some countries, up to 90% of the circulating B. pertussis strains are deficient in Prn. To better understand the resurgence of pertussis, we investigated the response of human monocyte-derived dendritic cells (moDCs) to naturally circulating Prn-expressing (Prn-Pos) and Prn-deficient (Prn-Neg) B. pertussis strains from 2016 in the Netherlands. Transcriptome analysis of moDC showed enriched IFNα response-associated gene expression after exposure to Prn-Pos B. pertussis strains, whereas the Prn-Neg strains induced enriched expression of interleukin- and TNF-signaling genes, as well as other genes involved in immune activation. Multiplex immune assays confirmed enhanced proinflammatory cytokine secretion by Prn-Neg stimulated moDC. Comparison of the proteomes from the Prn-Pos and Prn-Neg strains revealed, next to the difference in Prn, differential expression of a number of other proteins including several proteins involved in metabolic processes. Our findings indicate that Prn-deficient B. pertussis strains induce a distinct and stronger immune activation of moDCs than the Prn-Pos strains. These findings highlight the role of pathogen adaptation in the resurgence of pertussis as well as the effects that vaccine pressure can have on a bacterial population.
| S-EPMC8259873 | biostudies-literature
Project description:Using a focused glycan-gene microarray, we compared the glycosyltransferase (GT) and sulfotransferase gene expression profiles of human monocytes, dendritic cells (DCs) and macrophages (Mphis), isolated or differentiated from the same donors. Microarray analysis indicated that monocytes express transcripts for a full set of enzymes involved in the biosynthesis of multi-multiantennary branched N-glycans, potentially elongated by poly-N-acetyl-lactosamine chains, and of mucin-type Core 1 and Core 2 sialylated O-glycans. Monocytes also express genes involved in the biosynthesis and modification of glycosaminoglycans, but display a limited expression of GTs implicated in glycolipid synthesis. Among genes expressed in monocytes (90 out of 175), one third is significantly modulated in DCs and Mphi respectively, most of them being increased in both cell types relative to monocytes. These changes might potentially enforce the capacity of differentiated cells to synthesize branched N-glycans and mucin-type O-glycans and to remodel cell surface proteoglycans. Stimulation of DCs and Mphis with lipopolysaccharide caused a general decrease in gene expression, mainly affecting genes found to be positively modulated during the differentiation steps. Interestingly, although a similar set of enzymes are modulated in the same direction in mature DCs and Mphis, cell specific genes are also differentially regulated during maturation, a phenomenon that may sustain functional specificities. Validation of this analysis was provided by quantitative real-time PCR and flow cytometry of cell surface glycan antigens. Collectively, this study implies an important modification of the pattern of glycosylation in DCs and Mphis undergoing differentiation and maturation with potential biological consequences.
| S-EPMC2967374 | biostudies-literature
Project description:BackgroundThe majority of mammalian genes generate multiple transcript variants and protein isoforms through alternative transcription and/or alternative splicing, and the dynamic changes at the transcript/isoform level between non-oncogenic and cancer cells remain largely unexplored. We hypothesized that isoform level expression profiles would be better than gene level expression profiles at discriminating between non-oncogenic and cancer cellsgene level.MethodsWe analyzed 160 Affymetrix exon-array datasets, comprising cell lines of non-oncogenic or oncogenic tissue origins. We obtained the transcript-level and gene level expression estimates, and used unsupervised and supervised clustering algorithms to study the profile similarity between the samples at both gene and isoform levels.ResultsHierarchical clustering, based on isoform level expressions, effectively grouped the non-oncogenic and oncogenic cell lines with a virtually perfect homogeneity-grouping rate (97.5%), regardless of the tissue origin of the cell lines. However, gene levelthis rate was much lower, being 75% at best based on the gene level expressions. Statistical analyses of the difference between cancer and non-oncogenic samples identified the existence of numerous genes with differentially expressed isoforms, which otherwise were not significant at the gene level. We also found that canonical pathways of protein ubiquitination, purine metabolism, and breast-cancer regulation by stathmin1 were significantly enriched among genes thatshow differential expression at isoform level but not at gene level.ConclusionsIn summary, cancer cell lines, regardless of their tissue of origin, can be effectively discriminated from non-cancer cell lines at isoform level, but not at gene level. This study suggests the existence of an isoform signature, rather than a gene signature, which could be used to distinguish cancer cells from normal cells.
| S-EPMC3706752 | biostudies-literature
Project description:The traditional vaccine adjuvant research is mainly based on the trial and error method, and the mechanisms underlying the immune system stimulation remaining largely unknown. We previously demonstrated that heparan sulfate (HS), a TLR-4 ligand and endogenous danger signal, effectively enhanced humoral and cellular immune responses in mice immunized by HBsAg. This study aimed to evaluate whether HS induces better humoral immune responses against inactivated Hepatitis A or Rabies Vaccines, respectively, compared with traditional adjuvants (e.g. Alum and complete Freund's adjuvant). In order to investigate the molecular mechanisms of its adjuvanticity, the gene expression pattern of peripheral blood monocytes derived DCs (dendritic cells) stimulated with HS was analyzed at different times points. Total RNA was hybridized to Agilent SurePrint G3 Human Gene Expression 8×60 K one-color oligo-microarray. Through intersection analysis of the microarray results, we found that the Toll-like receptor signaling pathway was significantly activated, and NF-kB, TRAF3 and IRF7 were activated as early as 12 h, and MyD88 was activated at 48 h post-stimulation. Furthermore, the expression of the surface marker CD83 and the co-stimulatory molecules CD80 and CD86 was up-regulated as early as 24 h. Therefore, we speculated that HS-induced human monocyte-derived DC maturation may occur through both MyD88-independent and dependent pathways, but primarily through the former (TRIF pathway). These data provide an important basis for understanding the mechanisms underlying HS enhancement of the immune response.
| S-EPMC4514065 | biostudies-literature
Project description:BackgroundIn vitro, animal model and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.MethodsA cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients was used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as were two RNA-sequencing (seq) cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated to clarify stimulated from unstimulated immune responses.ResultsA discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Endotype A is characterised by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B has increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced cure rate. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.ConclusionThese findings provide evidence that metabolic and immune profiling could inform optimisation of endotype-specific host-directed therapies for tuberculosis.
| S-EPMC9474892 | biostudies-literature
Project description:In the last decade, many attempts have been made to use gene expression profiles to identify prognostic genes for various types of cancer. Previous studies evaluating the prognostic value of genes suffered by failing to solve the critical problem of classifying patients into different risk groups based on specific gene expression threshold levels. Here, we present a novel method, called iterative patient partitioning (IPP), which was inspired by the receiver operating characteristic (ROC) curve, is based on the log-rank test and overcomes the threshold decision problem. We applied IPP to analyze datasets pertaining to various subtypes of breast cancer. Using IPP, we discovered both novel and well-studied prognostic genes related to cell cycle/proliferation or the immune response. The novel genes were further analyzed using copy-number alteration and mutation data, and these results supported their relationship with prognosis.
| S-EPMC5717170 | biostudies-literature
Project description:IntroductionMeningiomas are the most common brain tumor, with prevalence of approximately 3%. Histological grading has a major role in determining treatment choice and predicting outcome. While indolent grade 1 and aggressive grade 3 meningiomas exhibit relatively homogeneous clinical behavior, grade 2 meningiomas are far more heterogeneous, making outcome prediction challenging. We hypothesized two subgroups of grade 2 meningiomas which biologically resemble either World Health Organization (WHO) grade 1 or WHO grade 3. Our aim was to establish gene expression signatures that separate grade 2 meningiomas into two homogeneous subgroups: a more indolent subtype genetically resembling grade 1 and a more aggressive subtype resembling grade 3.MethodsWe carried out an observational meta-analysis on 212 meningiomas from six distinct studies retrieved from the open-access platform Gene Expression Omnibus. Microarray data was analyzed with systems-level gene co-expression network analysis. Fuzzy C-means clustering was employed to reclassify 34 of the 46 grade 2 meningiomas (74%) into a benign "grade 1-like" (13/46), and malignant "grade 3-like" (21/46) subgroup based on transcriptomic profiles. We verified shared biology between matching subgroups based on meta-gene expression and recurrence rates. These results were validated further using an independent RNA-seq dataset with 160 meningiomas, with similar results.ResultsRecurrence rates of "grade 1-like" and "grade 3- like" tumors were 0 and 75%, respectively, statistically similar to recurrence rates of grade 1 (17%) and 3 (85%). We also found overlapping biological processes of new subgroups with their adjacent grades 1 and 3.ConclusionThese results underpin molecular signatures as complements to histological grading systems. They may help reshape prediction, follow-up planning, treatment decisions and recruitment protocols for future and ongoing clinical trials.
| S-EPMC7674612 | biostudies-literature
Project description:PurposePancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed.Experimental designTissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1).ResultsA total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds.ConclusionsWe employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs.
| S-EPMC7165057 | biostudies-literature
Project description:BACKGROUND With the development of research on cancer genomics and microenvironment, a new era of oncology focusing on the complicated gene regulation of pan-cancer research and cancer immunotherapy is emerging. This study aimed to identify the common gene expression characteristics of multiple cancers - lung cancer, liver cancer, kidney cancer, cervical cancer, and breast cancer - and the potential therapeutic targets in public databases. MATERIAL AND METHODS Gene expression analysis of GSE42568, GSE19188, GSE121248, GSE63514, and GSE66272 in the GEO database of multitype cancers revealed differentially expressed genes (DEGs). Then, GO analysis, KEGG function, and path enrichment analyses were performed. Hub-genes were identified by using the degree of association of protein interaction networks. Moreover, the expression of hub-genes in cancers was verified, and hub-gene-related survival analysis was conducted. Finally, infiltration levels of tumor immune cells with related genes were explored. RESULTS We found 12 cross DEGs in the 5 databases (screening conditions: "adj p<0.05" and "logFC>2 or logFC<-2"). The biological processes of DEGs were mainly concentrated in cell division, regulation of chromosome segregation, nuclear division, cell cycle checkpoint, and mitotic nuclear division. Furthermore, 10 hub-genes were obtained using Cytoscape: TOP2A, ECT2, RRM2, ANLN, NEK2, ASPM, BUB1B, CDK1, DTL, and PRC1. The high expression levels of the 10 genes were associated with the poor survival of these multiple cancers, as well as ASPM, may be associated with immune cell infiltration. CONCLUSIONS Analysis of the common DEGs of multiple cancers showed that 10 hub-genes, especially ASPM and CDK1, can become potential therapeutic targets. This study can serve as a reference to understand the characteristics of different cancers, design basket clinical trials, and create personalized treatments.
| S-EPMC7027371 | biostudies-literature