Journal articles: 'Inflammatory signature'

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Rigolet, Muriel, Cyrielle Hou, Yasmine Baba Amer, Jessie Aouizerate, Baptiste Periou, Romain K. Gherardi, Peggy Lafuste, and François Jérôme Authier. "Distinct interferon signatures stratify inflammatory and dysimmune myopathies." RMD Open 5, no. 1 (February 2019): e000811. http://dx.doi.org/10.1136/rmdopen-2018-000811.

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ObjectiveThe role of interferons (IFN) in the pathophysiology of primary inflammatory and dysimmune myopathies (IDM) is increasingly investigated, notably because specific neutralisation approaches may constitute promising therapeutic tracks. In present work we analysed the muscular expression of specific IFNα/β and IFNγ-stimulated genes in patients with various types of IDM.Methods39 patients with IDM with inclusion body myositis (IBM, n=9), dermatomyositis (DM, n=10), necrotising autoimmune myopathies (NAM, n=10) and antisynthetase myositis (ASM, n=10), and 10 controls were included. Quantification of expression levels of IFNγ, ISG15, an IFNα/β-inducible gene and of six IFNγ-inducible genes (GBP2, HLA-DOB, HLA-DPB, CIITA, HLA-DRB and HLA-DMB) was performed on muscle biopsy samples.ResultsDM usually associated with strong type I IFNα/β signature, IBM and ASM with prominent type II IFNγ signature and NAM with neither type I nor type II IFN signature. Immunofluorescence study in ASM and IBM showed myofibre expression of major histocompatibility class 2 (MHC-2) and CIITA, confirming the induction of the IFNγ pathway. Furthermore, MHC-2-positive myofibres were observed in close proximity to CD8+ T cells which produce high levels of IFNγ.ConclusionDistinct IFN signatures allow a more distinct segregation of IDMs and myofibre MHC-2 expression is a reliable biomarker of type II IFN signature.

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Wu, Zhong, Martin Schlumpberger, Sameen Raza, Jiaye Yu, John DiCarlo, Yexun Wang, and Vikram Devgan. "Pathway Signature PCR Array: a novel method for studying inflammatory responses (173.11)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 173.11. http://dx.doi.org/10.4049/jimmunol.188.supp.173.11.

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Abstract Signaling pathways play central roles in cellular physiology, and assessing the state of pathways helps clarify molecular mechanisms of disease and inflammatory responses. Gene expression signatures of pathway activation status enable reliable measurement of pathway activity. Our group developed Pathway Signature PCR Arrays to analyze gene expression and determine pathway activity within a single real-time PCR experiment. This study identified a set of genes that provide a gene signature for evaluating IL6/STAT3 pathway activity. A set of 88 signature genes were derived from microarray profiling on HepG2 and MCF10A cells treated with IL-6 protein and STAT3-specific siRNA. Genes were selected on the basis of statistically significant expression changes in response to IL-6 and reversion of altered expression upon treatment with STAT3 siRNA. These 88 IL-6/STAT3 response genes were further verified by real-time PCR, using a panel of 14 different cell lines stimulated with IL-6 or inhibited with STAT3 siRNA. Using a mathematical classifier method, a subset of genes was identified as a gene expression signature for assessing IL-6/STAT3 pathway activity. These signature genes, along with IL-6 pathway-related genes identified by literature mining, constitute the IL-6 Pathway Signature PCR Array. This array provides a useful tool for studying regulation of pathway activity via gene expression changes during inflammatory responses. Array is for molecular biology applications only.

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Li, Xinyu, Shuqiao Zhang, Shijun Zhang, Weihong Kuang, and Chunzhi Tang. "Inflammatory Response-Related Long Non-Coding RNA Signature Predicts the Prognosis of Hepatocellular Carcinoma." Journal of Oncology 2022 (March 17, 2022): 1–13. http://dx.doi.org/10.1155/2022/9917244.

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Background. Hepatocellular carcinoma (HCC) is a high mortality malignant tumor with genetic and phenotypic heterogeneity, making predicting prognosis challenging. Meanwhile, the inflammatory response is an indispensable player in the tumorigenesis process and regulates the tumor microenvironment, which can affect the prognosis of tumor patients. Methods. Using HCC samples in the TCGA-LIHC dataset, we explored lncRNA expression profiles associated with the inflammatory response. The inflammatory response-related lncRNA signature was constructed by univariate Cox regression, LASSO regression, and multivariate Cox regression methods based on inflammatory response-related differentially expressed lncRNAs in HCC. Results. Seven inflammatory response-related lncRNA signatures were identified in predicting HCC prognosis. Kaplan–Meier (K-M) survival analysis indicated that high-risk group HCC patients were associated with poor prognosis. The utility of the inflammatory response-related lncRNA signatures was proved by the AUC and DCA analysis. The nomogram further confirmed the accuracy of the novel signature in predicting HCC patients’ prognoses. In validation, our novel signature is more accurate than traditional clinicopathological performance for prognosis prediction of HCC patients. GSEA analysis further elucidated the underlying mechanisms and pathways of HCC progression in the low- and high-risk groups. Moreover, immune cells infiltration responses and immune function analyses revealed a significant difference between high- and low-risk groups in cytolytic activity, MHC class I, type I INF response, type II INF response, inflammation-promoting, and T cell coinhibition. Finally, HHLA2, NRP1, CD276, TNFRSF9, TNFSF4, CD80, and VTCN1 were expressed higher in high-risk groups in the immune checkpoint analysis. Conclusions. A novel inflammatory response-related lncRNA signature (AC145207.5, POLHAS1, AL928654.1, MKLN1AS, AL031985.3, PRRT3AS1, and AC023157.2) is capable of predicting the prognosis of HCC patients and providing new immune targeted therapies insight.

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Vasunilashorn, Sarinnapha, Long H. Ngo, Simon Dillon, Hasan Otu, Bridget Tripp, Sharon Inouye, Towia A. Libermann, and Edward R. Marcantonio. "AN INFLAMMATORY SIGNATURE OF POSTOPERATIVE DELIRIUM." Innovation in Aging 3, Supplement_1 (November 2019): S820—S821. http://dx.doi.org/10.1093/geroni/igz038.3027.

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Abstract Delirium is a common, morbid, and costly geriatric syndrome, yet its pathophysiology remains poorly understood. In a nested matched case-control study within the Successful Aging after Elective Surgery (SAGES) study, a cohort of adults age ≥70 without dementia undergoing major non-cardiac surgery, we previously identified inflammatory proteins to be associated with delirium. Using the entire SAGES cohort, the current study examines the independent associations of these inflammatory proteins with postoperative delirium. Plasma was collected preoperatively (PREOP) and on postoperative day 2 (POD2). Neuroinflammatory marker chitinase-3-like protein [CHI3l1 or YKL-40]; PREOP and POD2) and systemic inflammatory markers interleukin [IL]-6 (POD2 only) and C-reactive protein (CRP; PREOP and POD2) were measured using enzyme-linked immunosorbent assays. Generalized linear models were used to determine the independent (multivariable) associations between the inflammatory markers, measured in sample-based quartiles (Q). All models adjusted for age, sex, baseline cognition, surgery type, Charlson comorbidity index, and medical complications. Among the 555 patients (mean age 77 years, standard deviation, SD 5.2), 58% were female and 86% underwent orthopedic surgeries. Postoperative delirium occurred in 24%. High YKL-40 PREOP and IL-6 at POD2 (Q4 vs. Q1) were significantly associated with an increased risk of delirium: relative risk (RR) [95% confidence interval (CI)] 2.2[1.1-4.4] and 2.7[1.3-5.7], respectively. CRP (PREOP and POD2) was not significantly associated with delirium (p=0.37 and p=0.73, respectively). This work underscores the importance of inflammation (YKL-40 and IL-6) in the pathophysiology of postoperative delirium.

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Gallay, Laure, Guy Mouchiroud, and Bénédicte Chazaud. "Interferon-signature in idiopathic inflammatory myopathies." Current Opinion in Rheumatology 31, no. 6 (November 2019): 634–42. http://dx.doi.org/10.1097/bor.0000000000000653.

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Yang, Xiangchou, Yangyang Zhou, Linjing Huang, Shang Lin, Haihao Ye, and Yujuan Shan. "Fibroblast Common Serum Response Signature-Related Classification Affects the Tumour Microenvironment and Predicts Prognosis in Bladder Cancer." Oxidative Medicine and Cellular Longevity 2022 (October 19, 2022): 1–29. http://dx.doi.org/10.1155/2022/5645944.

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Abnormal oncogenic signatures provide important clues regarding cancer prognosis and treatment. We analysed the variations in 189 oncogenic signature gene sets between normal and tumourous tissues from The Cancer Genome Atlas (TCGA) and found that the “CSR_LATE_UP” signature was the most upregulated oncogenic signature gene set in bladder cancer. Next, we developed a common serum response (CSR) risk score (CRS) model based on fibroblast CSR genes and systematically analysed the correlations of these genes or the CRSs with survival, previously reported molecular subtypes, clinicopathological features, cancer signalling pathways, chemotherapeutic responses, and the tumour microenvironment using TCGA and validation cohorts. The CRS could predict the malignant phenotype, chemotherapeutic efficacy, immune invasion, and disease prognosis. Inflammatory signalling pathways (e.g., inflammatory response, TNFA signalling via NFƘB, IFNα response, and IL2-STAT5 signalling) were markedly upregulated in patients with high CRS. Notably, the CSR-related gene ANLN was positively correlated with CD8+ immune cell infiltration, PD-L1 expression, and sensitivity to PD-L1 inhibitors and could thus provide guidance for clinical immunotherapy. This study highlights the crucial role of the CSR signature in bladder cancer and provides a CRS model for accurate predictions of the disease prognosis and chemotherapy and immunotherapy responses.

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Imami, Ali S., Sinead M. O’Donovan, Justin F. Creeden, Xiaojun Wu, Hunter Eby, Cheryl B. McCullumsmith, Kerstin Uvnäs-Moberg, Robert E. McCullumsmith, and Elissar Andari. "Oxytocin’s anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach." Physiological Genomics 52, no. 9 (September 1, 2020): 401–7. http://dx.doi.org/10.1152/physiolgenomics.00095.2020.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a worldwide pandemic, infecting over 16 million people worldwide with a significant mortality rate. However, there is no current Food and Drug Administration-approved drug that treats coronavirus disease 2019 (COVID-19). Damage to T lymphocytes along with the cytokine storm are important factors that lead to exacerbation of clinical cases. Here, we are proposing intravenous oxytocin (OXT) as a candidate for adjunctive therapy for COVID-19. OXT has anti-inflammatory and proimmune adaptive functions. Using the Library of Integrated Network-Based Cellular Signatures (LINCS), we used the transcriptomic signature for carbetocin, an OXT agonist, and compared it to gene knockdown signatures of inflammatory (such as interleukin IL-1β and IL-6) and proimmune markers (including T cell and macrophage cell markers like CD40 and ARG1). We found that carbetocin’s transcriptomic signature has a pattern of concordance with inflammation and immune marker knockdown signatures that are consistent with reduction of inflammation and promotion and sustaining of immune response. This suggests that carbetocin may have potent effects in modulating inflammation, attenuating T cell inhibition, and enhancing T cell activation. Our results also suggest that carbetocin is more effective at inducing immune cell responses than either lopinavir or hydroxychloroquine, both of which have been explored for the treatment of COVID-19.

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Luo, Yong, Xiaopeng Liu, Jingbo Lin, Weide Zhong, and Qingbiao Chen. "Development and validation of novel inflammatory response-related gene signature to predict prostate cancer recurrence and response to immune checkpoint therapy." Mathematical Biosciences and Engineering 19, no. 11 (2022): 11345–66. http://dx.doi.org/10.3934/mbe.2022528.

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<abstract> <p>The aim of this study is to construct an inflammatory response-related genes (IRRGs) signature to monitor biochemical recurrence (BCR) and treatment effects in prostate cancer patients (PCa). A gene signature for inflammatory responses was constructed on the basis of the data from the Cancer Genome Atlas (TCGA) database, and validated in external datasets. It was analyzed using receiver operating characteristic curve, BCR-free survival, Cox regression, and nomogram. Distribution analysis and external model comparison were utilized. Then, enrichment analysis, tumor mutation burden, tumor immune microenvironment, and immune cell infiltration signatures were investigated. The role of the signature in immunotherapy was evaluated. The expression patterns of core genes were verified by RNA sequencing. We identified an IRRGs signature in the TCGA-PRAD cohort and verified it well in two other independent external datasets. The signature was a robust and independent prognostic index for predicting the BCR of PCa. The high-risk group of our signature predicted a shortened BCR time and an aggressive disease progression. A nomogram was constructed to predict BCR-free time in clinical practices. Neutrophils and CD8+ T cells were in higher abundance among the low-risk individuals. Immune functions varied significantly between the two groups and immune checkpoint therapy worked better for the low-risk patients. The expression of four IRRGs showed significant differences between PCa and surrounding benign tissues, and were validated in BPH-1 and DU145 cell lines by RNA sequencing. Our signature served as a reliable and promising biomarker for predicting the prognosis and evaluating the efficacy of immunotherapy, facilitating a better outcome for PCa patients.</p> </abstract>

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Pachner, Andrew R., Krista DiSano, Darlene B. Royce, and Francesca Gilli. "Clinical utility of a molecular signature in inflammatory demyelinating disease." Neurology - Neuroimmunology Neuroinflammation 6, no. 1 (November 9, 2018): e520. http://dx.doi.org/10.1212/nxi.0000000000000520.

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ObjectiveWe sought to develop molecular biomarkers of intrathecal inflammation to assist neurologists in identifying patients most likely to benefit from a range of immune therapies.MethodsWe used Luminex technology and index determination to search for an inflammatory activity molecular signature (IAMS) in patients with inflammatory demyelinating disease (IDD), other neuroinflammatory diagnoses, and noninflammatory controls. We then followed the clinical characteristics of these patients to find how the presence of the signature might assist in diagnosis and prognosis.ResultsA CSF molecular signature consisting of elevated CXCL13, elevated immunoglobulins, normal albumin CSF/serum ratio (Qalbumin), and minimal elevation of cytokines other than CXCL13 provided diagnostic and prognostic value; absence of the signature in IDD predicted lack of subsequent inflammatory events. The signature outperformed oligoclonal bands, which were frequently false positive for active neuroinflammation.ConclusionsA CSF IAMS may prove useful in the diagnosis and management of patients with IDD and other neuroinflammatory syndromes.Classification of evidenceThis study provides Class IV evidence that a CSF IAMS identifies patients with IDD.

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Van Laere, S. J., I. Van der Auwera, G. G. Van den Eynden, X. Trinh, P. Van Hummelen, P. van Dam, E. A. Van Marck, P. B. Vermeulen, and L. Y. Dirix. "Confirmation of the distinct molecular phenotype of inflammatory breast cancer compared to non-inflammatory breast cancer using Affymetrix-based genome-wide gene expression analysis." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 21055. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21055.

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21055 Background: We have shown with cDNA microarrays that inflammatory breast cancer (IBC) and non-IBC are distinct biological entities. The purpose of this study was to confirm our previous results using Affymetrix chips. Methods: RNA was extracted from 19 IBC samples and 42 non-stage matched non-IBC samples. RNA was hybridized onto Affymetrix HG U133 Plus 2.0 chips. Gene expression data were normalized using GCRMA and genes with a gene expression of at least 250 in 50% of the cases were filtered in. Hierarchical clustering and principle component analysis was executed. Identification of the different cell-of-origin subtypes in our expression data set was done using the intrinsic gene list. A NFkB signature, a MAPK signature and our own IBC signature were tested by clustering analysis. Results: Clustering using 11341 genes resulted in the identification of two clusters: one containing 14/19 IBC samples and a second containing 32/42 non-IBC (Pearson χ2; p<0.0001). Principle component analysis separated IBC from non-IBC samples along the first principle component. Interestingly, IBC samples more closely resemble T1 - T2 tumours than T3 - T4 tumours. Application of the intrinsic gene set to our IBC/non-IBC data set resulted in the classification of 14/19 IBC samples as basal-like or ErbB2-overexpressing tumours compared to only 4/42 non-IBC tumours (Pearson χ2; p<0.0001). Our own IBC signature was confronted with the new data set and performed well in separating IBC specimens form non-IBC specimens. Clustering identified three clusters from which one cluster contained 18 samples, including 12 IBC specimens (p<0.0001). Using the NFkB and MAPK signatures, similar results were obtained. Conclusions: These results confirm our findings that IBC is a distinct biologic phenotype, characterized by activation of NFkB, possibly through activation of MAPK's. IBC tumours more often demonstrate characteristics from basal-like and ErbB2-overexpressing breast tumours. The fact that IBC tumours are rapidly developing tumours instead of longstanding tumourigenic processes might explain the close resemblance of the IBC gene expression profile to the gene expression profile of T1 and T2 tumours. No significant financial relationships to disclose.

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Irwin, James R., Emma Ferguson, Lisa A. Simms, Katherine Hanigan, and Graham L. Radford-Smith. "Su1336 The Pre-Diagnosis Inflammatory Signature of Patients With Inflammatory Bowel Disease." Gastroenterology 148, no. 4 (April 2015): S—478. http://dx.doi.org/10.1016/s0016-5085(15)31607-3.

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Heim, Cortney E., Kelsey J. Yamada, Rachel Fallet, Jessica Odvody, Dana M. Schwarz, Elizabeth R. Lyden, Matthew J. Anderson, et al. "Orthopaedic Surgery Elicits a Systemic Anti-Inflammatory Signature." Journal of Clinical Medicine 9, no. 7 (July 6, 2020): 2123. http://dx.doi.org/10.3390/jcm9072123.

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Little information is available on the functional activity of leukocytes after arthroplasty or the expansion of populations with immune suppressive properties during the acute post-operative period. Synovial fluid and matched pre- and post-surgical blood samples were collected from total hip and knee arthroplasty patients (THA and TKA, respectively) to examine the impact of surgery on peripheral blood leukocyte frequency, bactericidal activity, and inflammatory mediator expression. For spinal surgeries, inflammatory mediator production by peripheral blood mononuclear cells (PBMCs) pre- and post-surgery was examined. An expansion of immune suppressive granulocytic myeloid-derived suppressor cells (G-MDSCs) was observed following arthroplasty, which correlated with significantly increased serum interleukin-10 (IL-10) levels. Analysis of synovial fluid from THA and TKAs revealed reduced granulocyte colony-stimulating factor (G-CSF) and soluble CD40 ligand (sCD40L) and increased interleukin-6 (IL-6), monocyte chemoattractant protein 2 (CCL2) and Fms-like tyrosine kinase 3 ligand (Flt-3L) compared to pre- and post-surgical serum. For the spinal surgery cohort, stimulation of PBMCs isolated post-surgery with bacterial antigens produced significantly less pro-inflammatory (IL-1α, IL-1β, interleukin-1 receptor antagonist (IL-1RA), IL-12p40, growth-related oncogene-α/GRO-α (CXCL1) and 6Ckine (CCL21)) and more anti-inflammatory/tissue repair mediators (IL-10, G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF)) compared to PBMCs recovered before surgery. The observed bias towards systemic anti-inflammatory changes without concomitant increases in pro-inflammatory responses may influence susceptibility to infection following orthopaedic surgery in the context of underlying co-morbidities or risk factors.

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Yau, Yunki, Sean S. Shin, Sonia Bustamante, Russell Pickford, Rupert W. Leong, and Valerie C. Wasinger. "Tryptophan Metabolome Signature Differences in Inflammatory Bowel Diseases." Gastroenterology 140, no. 5 (May 2011): S—840. http://dx.doi.org/10.1016/s0016-5085(11)63487-2.

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Ekmekcioglu, S., M. Shin-Sim, K. Tanese, V. G. Prieto, D. S. Hoon, and E. A. Grimm. "460 Molecular biomarkers of inflammatory signature in melanoma." European Journal of Cancer 50 (November 2014): 150. http://dx.doi.org/10.1016/s0959-8049(14)70586-6.

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Andrés, Germán, Daria Leali, Stefania Mitola, Daniela Coltrini, Maura Camozzi, Michela Corsini, Mirella Belleri, et al. "A pro-inflammatory signature mediates FGF2-induced angiogenesis." Journal of Cellular and Molecular Medicine 13, no. 8b (July 9, 2008): 2083–108. http://dx.doi.org/10.1111/j.1582-4934.2008.00415.x.

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Salihovic, S., N. Nyström, C. Bache-Wiig Mathisen, S. Andersen, C. Olbjørn, G. Perminow, R. Opheim, et al. "DOP14 Identification and validation of a lipidomic signature as a novel diagnostic biomarker of paediatric Inflammatory Bowel Disease." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i76—i77. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0054.

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Abstract Background Improved diagnostic biomarkers are an unmet clinical need for paediatric inflammatory bowel disease (IBD). We therefore aimed to identify a diagnostic lipidomic signature of IBD in blood. Methods We performed a non-targeted liquid chromatography-time of flight mass spectrometry-based lipidomics (UPLC-QTOFMS) analysis of plasma samples from 211 treatment-naïve children with suspected IBD (Table 1). Discovery cohort: the Uppsala Children’s Hospital cohort (n=94); Validation cohort: children from the population-based IBSEN III inception cohort (n=117). All children underwent diagnostic workup for IBD in accordance with the ESPGHAN/Porto criteria. Multivariable and supervised machine learning were used to identify a diagnostic lipidomic signature and its performance was compared to clinically established biomarkers i.e., high sensitivity C-reactive protein (hsCRP) and faecal Calprotectin. Results The discovery cohort comprised of 58 children with IBD and 36 symptomatic controls without any discernible evidence of IBD. In the validation cohort, the corresponding numbers were 80 and 37. In a multivariable analysis, using regularized regression and discovery cohort data, a lipidomic signature comprising 30 lipid species was identified as influential in distinguishing IBD from symptomatic controls (Figure 1). Further, while examining both individual lipidomic species and lipidomic signatures in the discovery cohort, the highest diagnostic accuracy was observed for a short lipidomic signature comprising of only two lipid species, LacCer(d18:1/16:0) and PC(18:0p/22:6). When applied to the validation cohort, the short signature improved the diagnostic prediction of paediatric IBD (AUC=0.87 [95%CI 0.79-0.95]) compared to high-sensitivity C-reactive protein (hsCRP) alone (AUC=0.73 [95%CI 0.63-0.82]), P-value=0.0004. Adding hsCRP to the diagnostic model did not improve its performance (AUC=0.86) (Figure 2). Only 77 (66%) children from the validation cohort provided a stool sample, and among these children, the diagnostic capacity of the short lipidomic signature (AUC=0.88 95%CI 0.80-0.95) and faecal Calprotectin (AUC=0.93 95%CI 0.87-0.99) did not differ (P-value=0.22). Conclusion This study has identified and validated a diagnostic lipidomic signature of pediatric IBD that was superior to hsCRP and did not differ from faecal Calprotectin. This signature could be developed into an accessible and scalable blood test for paediatric IBD, particularly among patients unwilling to provide stool samples.

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Haberman Ziv, Y., P. Minar, R. Karns, P. Dexheimer, S. Ghandikota, S. Tegge, D. Shapiro, et al. "DOP89 Pre-treatment mucosal inflammatory and wound healing gene programmes reveal mechanisms associated with future stricturing behaviour during 5-year follow-up in paediatric Crohn’s disease." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S127. http://dx.doi.org/10.1093/ecco-jcc/jjz203.128.

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Abstract Background Stricturing complications account for substantial morbidity in Crohn’s disease (CD). We aimed to define ileal gene programmes present at diagnosis in paediatric CD associated with future stricturing behaviour (B2), and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and ileal gene expression (RNASeq) were assessed at diagnosis in 249 CD patients enrolled in a 5-year inception cohort study. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing. Sirius Red immuno-histochemistry was utilised to determine the extent of collagen infiltration into the sub-cryptal space. A bioinformatics approach defined small molecules which may reverse the stricturing gene signature. Results Of 249 (8%) patients, 19 developed B2 behaviour during the 5-year follow-up, while 218 remained B1 inflammatory. We defined 518 genes that were differentially expressed in the ileum at diagnosis (FC≥1.5, FDR<0.05) in B1 patients who later developed B2 stricturing complications vs. those who remained B1 throughout. These were notable for baseline up-regulation of OSM implicated in anti-TNF non-response, NCF2 and CSF3R implicated in myeloid cell activation, TGFBI implicated in tissue fibrosis, and a panel of 17 collagen genes in patients who progressed to stricturing. Sirius red staining confirmed an increase in sub-cryptal type I/III collagen in B1 patients at diagnosis who progressed to B2 behaviour. Of these 518 genes, we highlighted an inflammatory OSM co-expression signature that was tightly associated with an extracellular matrix COL1A2 co-expression signature (Pearson r = 0.88, p < 0.0001). Network annotation analyses of those co-expression signatures showed that response to wounding, myeloid dendritic cells, and gp38+ stromal cells signatures are linked to both. Extracellular matrix (ECM) annotation, collagen binding, fibroblasts, and angiogenesis were more specific to the COL1A2 signature, and granulocytes and response to other organisms were more specific to the OSM co-expression signature. We further define small molecules targeting macrophage and fibroblast activation, and angiogenesis, which may reverse the stricturing gene signature including ephrin inhibitors, eicosatetraynoic acid (cyclooxygenase/lipoxygenase inhibitor), orantinib (PDGFR inhibitor), and PT-630 (fibroblast activation inhibitor). Our previous model containing serologies and a refined ECM gene set was significantly associated with stricturing development by year 5 (AUC:0.82) Conclusion An ileal gene program for macrophage and fibroblast activation is linked to future stricturing complications in treatment naïve paediatric CD, and may inform small-molecule therapeutic approaches.

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Suárez-Arriaga, Mayra Cecilia, Alfonso Méndez-Tenorio, Vadim Pérez-Koldenkova, and Ezequiel M. Fuentes-Pananá. "Claudin-Low Breast Cancer Inflammatory Signatures Support Polarization of M1-Like Macrophages with Protumoral Activity." Cancers 13, no. 9 (May 7, 2021): 2248. http://dx.doi.org/10.3390/cancers13092248.

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We previously reported that triple-negative breast cancer (BRCA) cells overexpress the cytokines GM-CSF, G-CSF, MCP-1, and RANTES, and when monocytes were 3-D co-cultured with them, M1-like macrophages were generated with the ability to induce aggressive features in luminal BRCA cell lines. These include upregulation of mesenchymal and stemness markers and invasion. In this study, we stimulated peripheral blood monocytes with the four cytokines and confirmed their capacity to generate protumoral M1-like macrophages. Using the METABRIC BRCA database, we observed that GM-CSF, MCP-1, and RANTES are associated with triple-negative BRCA and reduced overall survival, particularly in patients under 55 years of age. We propose an extended M1-like macrophage proinflammatory signature connected with these three cytokines. We found that the extended M1-like macrophage signature coexists with monocyte/macrophage, Th1 immune response, and immunosuppressive signatures, and all are enriched in claudin-low BRCA samples, and correlate with reduced patient overall survival. Furthermore, we observed that all these signatures are also present in mesenchymal carcinomas of the colon (COAD) and bladder (BLCA). The claudin-low tumor subtype has an adverse clinical outcome and remains poorly understood. This study places M1 macrophages as potential protumoral drivers in already established cancers, and as potential contributors to claudin-low aggressiveness and poor prognosis.

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Zhang, Jiahao, Yongchang Lai, Langjing Zhu, Zechao Lu, Chuxian Hu, Haobin Zhou, Zeguang Lu, Zhicheng Tang, Zhaohui He, and Fucai Tang. "A Novel Inflammation-Related Gene Signature for Overall Survival Prediction and Comprehensive Analysis in Pediatric Patients with Wilms Tumor." Disease Markers 2022 (May 7, 2022): 1–17. http://dx.doi.org/10.1155/2022/2651105.

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Wilms tumor (WT) is a common pediatric renal cancer, with a poor prognosis and high-risk recurrence in some patients. The inflammatory microenvironment is gradually gaining attention in WT. In this study, novel inflammation-related signatures and prognostic model were explored and integrated using bioinformatics analysis. The mRNA profile of pediatric patients with WT and inflammation-related genes (IRGs) were acquired from Therapeutically Available Research to Generate Effective Treatments (TARGET) and Gene Set Enrichment Analysis (GSEA) databases, respectively. Then, a novel prognostic model founded on 7-IRGs signature (BICC1, CSPP1, KRT8, MYCN, NELFA, NXN, and RNF113A) was established by the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression to stratify pediatric patients with WT into high- and low-risk groups successfully. And a stable performance of the prognostic risk model was verified in predicting overall survival (OS) by receiver-operating characteristic (ROC) curves, Kaplan-Meier (KM) curves, and independent prognostic analysis ( p < 0.05 ). In addition, a novel nomogram integrating risk scores with good robustness was developed and validated by C -index, ROC, and calibration plots. The potential function and pathway were explored via Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA, with mainly inflammation and immune-related biological processes. The higher-risk scores, the lower immune infiltration, as shown in the single-sample GSEA (ssGSEA) and tumor microenvironment (TME) analysis. The drug sensitivity analysis showed that regulating 7-IRGs signature has a significant correlation with the chemotherapy drugs of WT patients. In summary, this study defined a prognostic risk model and nomogram based on 7-IRGs signature, which may provide novel insights into clinical prognosis and inflammatory study in WT patients. Besides, enhancing immune infiltration based on inflammatory response and regulating 7-IRGs signature are beneficial to ameliorating the efficacy in WT patients.

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Zhou, Jieliang, Bernard Su Min Chern, Peter Barton-Smith, Jessie Wai Leng Phoon, Tse Yeun Tan, Veronique Viardot-Foucault, Chee Wai Ku, Heng Hao Tan, Jerry Kok Yen Chan, and Yie Hou Lee. "Peritoneal Fluid Cytokines Reveal New Insights of Endometriosis Subphenotypes." International Journal of Molecular Sciences 21, no. 10 (May 15, 2020): 3515. http://dx.doi.org/10.3390/ijms21103515.

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Endometriosis is a common inflammatory gynecological disorder which causes pelvic scarring, pain, and infertility, characterized by the implantation of endometrial-like lesions outside the uterus. The peritoneum, ovaries, and deep soft tissues are the commonly involved sites, and endometriotic lesions can be classified into three subphenotypes: superficial peritoneal endometriosis (PE), ovarian endometrioma (OE), and deep infiltrating endometriosis (DIE). In 132 women diagnosed laparoscopically with and without endometriosis (n = 73, 59 respectively), and stratified into PE, OE, and DIE, peritoneal fluids (PF) were characterized for 48 cytokines by using multiplex immunoassays. Partial-least-squares-regression analysis revealed distinct subphenotype cytokine signatures—a six-cytokine signature distinguishing PE from OE, a seven-cytokine signature distinguishing OE from DIE, and a six-cytokine-signature distinguishing PE from DIE—each associated with different patterns of biological processes, signaling events, and immunology. These signatures describe endometriosis better than disease stages (p < 0.0001). Pathway analysis revealed the association of ERK1 and 2, AKT, MAPK, and STAT4 linked to angiogenesis, cell proliferation, migration, and inflammation in the subphenotypes. These data shed new insights on the pathophysiology of endometriosis subphenotypes, with the potential to exploit the cytokine signatures to stratify endometriosis patients for targeted therapies and biomarker discovery.

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Makinde, Hadijat M., Elise V. MIke, Chaim Putterman, Deborah R. Winter, and Carla M. Cuda. "Expression of microglia-specific transcriptional signatures correlates with the severity of behavioral deficits in systemic lupus erythematosus." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 152.10. http://dx.doi.org/10.4049/jimmunol.204.supp.152.10.

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Abstract Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting multiple organs, including the brain. Though 50% of patients may experience neuropsychiatric symptoms (NPSLE), disease mechanisms remain largely unknown. Microglia are the resident innate immune cell of the brain and suggested to act as drivers of neurological conditions ranging from neurodevelopmental (autism) to neurodegenerative (Alzheimer’s disease) disorders. The majority of investigations into microglia, particularly the recently discovered disease-associated microglia (DAM) subset, have occurred in models of neurodegenerative disease. However, few studies have examined microglia, particularly DAM, in NPSLE. We performed RNA-seq on microglia isolated from two NPSLE-prone mouse strains to correlate gene signatures with behavioral deficits. Similar to patients, both NPSLE models exhibit cognitive impairment. Of the significantly upregulated genes found in NPSLE microglia compared to their respective controls, a common 18-gene ‘NPSLE signature’ is shared and enriched for genes associated with lipid metabolism, scavenger receptor activity and downregulating inflammatory responses and cell chemotaxis processes. NPSLE microglia are also enriched for DAM-associated genes and expression of ‘NPSLE’ and ‘DAM’ signatures significantly correlates with the severity of behavioral deficits. The discovery of our novel ‘NPSLE signature’ and enrichment of the ‘DAM signature’ represents the first to connect microglia-specific transcriptional signatures with clinical outcomes. In future studies, we will assess the penetrance of these signatures to further interrogate how defective microglial function may incite NPSLE.

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Galipeau, H. J., W. Turpin, A. Caminero Fernandez, A. Santiago, J. Libertucci, M. Bermudez-Brito, S. Armstrong, L. Bedrani, K. Croitoru, and E. Verdu. "A35 MICROBIAL PROTEOLYTIC SIGNATURE IN ULCERATIVE COLITIS INDUCES AN INFLAMMATORY SIGNATURE IN MICROBIOTA-HUMANIZED MICE." Journal of the Canadian Association of Gastroenterology 3, Supplement_1 (February 2020): 42–43. http://dx.doi.org/10.1093/jcag/gwz047.034.

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Abstract Background Altered gut microbiota composition has been associated with inflammatory bowel diseases (IBD) including ulcerative colitis (UC), but causality and bacterially-driven mechanisms, are unclear. Proteases within the gastrointestinal tract play a critical role in maintaining homeostasis and are tightly regulated by anti-proteases. Host-derived proteolytic imbalances have been described in IBD, including UC, however, the role of intestinal microbiota as a source of proteases and anti-proteases has largely been ignored. Aims To study microbial proteolytic activity and intestinal microbiota profiles in a cohort of individuals at-risk for IBD, and in those individuals that develop UC at follow-up. Methods Fecal samples were collected from healthy individuals at-risk for IBD and who went on to develop UC (pre-UC; n=14) and again after UC diagnosis (post-UC, n=10). Fecal samples from matched at-risk individuals that did not develop UC were used as healthy controls (n=52). Overall fecal proteolytic and elastolytic activity was measured. We performed metagenomics sequencing in 4 UC subjects (pre and post) and 4 matched HC using Illumina Hi-Seq from stool DNA. To investigate bacterial origin and functional significance, pregnant germ-free (GF) mice were colonized with a fecal sample from a selected UC subject (pre and post) and a matched HC. Naturally colonized litters were followed for 12 weeks, after which proteolytic activities and signs of inflammation were measured. Results Fecal proteolytic and elastase activity was increased in pre- and post-UC samples compared to HCs. Metagenomics revealed over 20k genes were significantly different between HC and pre-UC samples, and of these, 440 related to proteases and peptidases. Increased fecal proteolytic activity, higher lipocalin levels, and increased colonic polymorphonuclear cells in colonic H&E sections was observed in pre- and post-UC colonized mice compared to HC colonized mice. Mice colonized with pre-UC microbiota showed increased mRNA expression of genes linked to immunological disease, antimicrobial and inflammatory responses (ie. Tlr2, Tlr5, Nod2, and Il1b) as compared to HC colonized mice. Conclusions These results suggest increased fecal proteolytic activity is observed prior to the onset and clinical diagnosis of UC in patients at-risk for IBD, and upon transfer to mice born from colonized GF dams, low-grade inflammation develops. These pathways could be developed as novel non-invasive biomarkers to monitor at-risk populations. Submitted on behalf of the CCC-GEM Project consortium. Supported by CCC GIA to EF Verdu Funding Agencies CCC

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Bai, Shuang, Ying-Bin Yan, Wei Chen, Ping Zhang, Tong-Mei Zhang, Yuan-Yuan Tian, and Hao Liu. "Bioinformatic Analysis Reveals an Immune/Inflammatory-Related Risk Signature for Oral Cavity Squamous Cell Carcinoma." Journal of Oncology 2019 (December 13, 2019): 1–10. http://dx.doi.org/10.1155/2019/3865279.

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High-throughput gene expression profiling has recently emerged as a promising technique that provides insight into cancer subtype classification and improved prediction of prognoses. Immune/inflammatory-related mRNAs may potentially enrich genes to allow researchers to better illustrate cancer microenvironments. Oral cavity squamous cell carcinoma (OC-SCC) exhibits high morbidity and poor prognosis compared to that of other types of head and neck squamous cell carcinoma (HNSCC), and these differences may be partially due to differences within the tumor microenvironments. Based on this, we designed an immune-related signature to improve the prognostic prediction of OC-SCC. A cohort of 314 OC-SCC samples possessing whole genome expression data that were sourced from The Cancer Genome Atlas (TCGA) database was included for discovery. The GSE41613 database was used for validation. A risk score was established using immune/inflammatory signatures acquired from the training dataset. Principal components analysis, GO analysis, and gene set enrichment analysis were used to explore the bioinformatic implications. When grouped by the dichotomized risk score based on the signature, this classifier could successfully discriminate patients with distinct prognoses within the training and validation cohorts (P<0.05 in both cohorts) and within different clinicopathological subgroups. Similar somatic mutation patterns were observed between high and low risk score groups, and different copy number variation patterns were also identified. Further bioinformatic analyses suggested that the lower risk score group was significantly correlated with immune/inflammatory-related biological processes, while the higher risk score group was highly associated with cell cycle-related processes. The analysis indicated that the risk score was a robust predictor of patient survival, and its functional annotation was well established. Therefore, this bioinformatic-based immune-related signature suggested that the microenvironment of OC-SCC could distinguish among patients with different underlying biological processes and clinical outcomes, and the use of this signature may shed light on future OC-SCC classification and therapeutic design.

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Montemari, Anna Lisa, Melania Manco, Alessandro Giovanni Fiocchi, Manuela Bartoli, Francesco Facchiano, Claudio Tabolacci, Maria Scatigna, et al. "An inflammatory Signature of Glucose Impairment in Cystic Fibrosis." Journal of Inflammation Research Volume 15 (October 2022): 5677–85. http://dx.doi.org/10.2147/jir.s365772.

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Cardoneanu, Anca, Alexandra Maria Burlui, and Elena Rezus. "The signature of intestinal dysbiosis in inflammatory rheumatic diseases." Romanian Journal of Rheumatology 28, no. 3 (September 30, 2019): 89–94. http://dx.doi.org/10.37897/rjr.2019.3.1.

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Schett, Georg, Iain B. McInnes, and Markus F. Neurath. "Reframing Immune-Mediated Inflammatory Diseases through Signature Cytokine Hubs." New England Journal of Medicine 385, no. 7 (August 12, 2021): 628–39. http://dx.doi.org/10.1056/nejmra1909094.

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McDonald, E., P. Wright, T. Zangerle-Murray, A. Bravo-Blas, J. Jung, E. Robertson, S. Siebert, et al. "P028 A distinct cellular signature of inflammatory bowel disease." Journal of Crohn's and Colitis 12, supplement_1 (January 16, 2018): S107—S108. http://dx.doi.org/10.1093/ecco-jcc/jjx180.155.

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Hayes, Lindsay N., Emily G. Severance, Jeffrey T. Leek, Kristin L. Gressitt, Cathrin Rohleder, Jennifer M. Coughlin, F. Markus Leweke, Robert H. Yolken, and Akira Sawa. "Inflammatory Molecular Signature Associated With Infectious Agents in Psychosis." Schizophrenia Bulletin 40, no. 5 (April 17, 2014): 963–72. http://dx.doi.org/10.1093/schbul/sbu052.

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Boersma, Brenda J., Mark Reimers, Ming Yi, Joseph A. Ludwig, Brian T. Luke, Robert M. Stephens, Harry G. Yfantis, Dong H. Lee, John N. Weinstein, and Stefan Ambs. "A stromal gene signature associated with inflammatory breast cancer." International Journal of Cancer 122, no. 6 (November 12, 2007): 1324–32. http://dx.doi.org/10.1002/ijc.23237.

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Haroon, E., X. Chen, Z. Li, X. P. Hu, J. C. Felger, and A. H. Miller. "Multimodal neural signature of inflammatory response in mood disorders." Brain, Behavior, and Immunity 66 (November 2017): e38-e39. http://dx.doi.org/10.1016/j.bbi.2017.07.140.

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Cuadros, Marta, Sandeep S. Dave, Elaine S. Jaffe, Emiliano Honrado, Roger Milne, Javier Alves, Jose Rodríguez, et al. "Identification of a Proliferation Signature Related to Survival in Nodal Peripheral T-Cell Lymphomas." Journal of Clinical Oncology 25, no. 22 (August 1, 2007): 3321–29. http://dx.doi.org/10.1200/jco.2006.09.4474.

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Purpose Nodal peripheral T-cell lymphomas (PTCLs) constitute a heterogeneous group of neoplasms, suggesting the existence of molecular differences contributing to their histologic and clinical variability. Initial expression profiling studies of T-cell lymphomas have been inconclusive in yielding clinically relevant insights. We applied DNA microarrays to gain insight into the molecular signatures associated with prognosis. Materials and Methods We analyzed the expression profiles of 35 nodal PTCLs (23 PTCLs unspecified and 12 angioimmunoblastic) using two different microarray platforms, the cDNA microarray developed at the Spanish National Cancer Centre and an oligonucleotide microarray. Results We identified five clusters of genes, the expression of which varied significantly among the samples. Genes in these clusters seemed to be functionally related to different cellular processes such as proliferation, inflammatory response, and T-cell or B-cell lineages. Regardless of the microarray platform used, overexpression of genes in the proliferation signature was associated significantly with shorter survival of patients. This proliferation signature included genes commonly associated with the cell cycle, such as CCNA, CCNB, TOP2A, and PCNA. Moreover the PTCL proliferation signature showed a statistically significant inverse correlation with clusters of the inflammatory response (P < .0001), as well as with the percentage of CD68+ cells. Conclusion Our findings indicate that proliferation could be an important factor in evaluating nodal PTCL outcome and may help to define a more aggressive phenotype.

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Szabo, Peter M., Zhenhao Qi, Kim Zerba, Scott Ely, Robin Edwards, James Lu, James Cooley, Marian Navratil, Gillian L. Dalgliesh, and Neeraj Adya. "Association of an inflammatory gene signature with CD8 expression by immunohistochemistry (IHC) in multiple tumor types." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2593. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2593.

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2593 Background: A multiparameter tumor inflammation assay based on gene expression profiling (TIA-GEP) can extend the utility of IHC to interrogate the tumor microenvironment (TME). Using CD8 expression assessed by IHC (CD8-IHC) as a surrogate for inflammation, statistical modelling was used to develop a specific gene signature on the TIA-GEP panel to predict CD8-IHC. The correlation between TIA-GEP and CD8-IHC and the prevalence of inflammation were explored across multiple tumor types. Methods: Levels of inflammation were measured by CD8-IHC and TIA-GEP on 1778 procured samples across 12 tumor types. Quality control metrics involved sample input quality, technical errors, and inter-run variability. Generalized linear models were used to identify an inflammation score that predicts the CD8-IHC score in melanoma and SCCHN tissue. The predictive accuracy of this signature was also examined in 10 additional tumor types. Results: Assessment of TME inflammation by CD8-IHC was consistent with that observed by TIA-GEP in multiple tumor types. The range of inflammation varied across different tumor types, with relatively lower inflammation range and scores in SCLC, ovarian, and prostate cancers, and higher values in NSCLC, melanoma, SCCHN, and gastric cancers. R2 x 100 values reflecting percent variation in CD8-IHC associated with TIA-GEP ranged from 62.4% to 79.2% ( P < 0.0001) for all tumor types except prostate cancer (32.5%). Low correlation in prostate cancer may be a result of low prevalence of inflammation by CD8-IHC. Estimated linear regression slopes between CD8-IHC and TIA-GEP ranged from 0.74 in SCLC to 1.27 in gastric cancer. Conclusions: The results suggest that the inflammation signature is a robust potential diagnostic tool predicting inflammation in the TME. The inflammation signature not only correlates with CD8-IHC for multiple tumor types, but also leverages the alternative benefits associated with TIA-GEP, which include information related to tumor inflammation-associated biomarkers and flexibility in exploring the value of other genomic signatures.

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Murugesan, S., M. Kumar, M. Saadaoui, D. A. Elhag, M. A. Hendaus, N. Ibrahim, F. Al-Mudhaka, et al. "P322 Mycobiome signature in pediatric patients with Inflammatory Bowel Disease." Journal of Crohn's and Colitis 17, Supplement_1 (January 30, 2023): i462. http://dx.doi.org/10.1093/ecco-jcc/jjac190.0452.

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Abstract Background Inflammatory bowel disease (IBD) encompasses dysregulation of mucosal immunity involving multiple factors including diet, medication, family history, and the gut microbiome. The symptoms of Pediatric IBD are different from an adult-onset disease. Based on the clinical conditions, IBD can be classified into three categories: Crohn’s disease (CD), Ulcerative colitis (UC), and IBD-unclassified (IBDU). The gut bacteriome alteration is widely reported in IBD. But the gut mycobiome link to the disease remains sparse. This study compared mycobiome profile changes in pediatric patients with IBD and healthy controls. Methods Stool samples were collected from patients with CD (n = 110), UC (n=64), IBDU (n=23), and healthy control subjects (n = 42). ITS-2 (Internal Transcribed Spacer) libraries were sequenced and analyzed using the QIIME pipeline to assess the gut mycobiome composition. Lefse analysis was performed to identify the signature members among the study groups. Results Ascomycota and Basidiomycota were the most common phyla among the study groups. Saccharomyces cerevisiae and Candida albicans were the most abundant species in the gut. Patients with IBDU and CD had significantly lower alpha and beta diversities compared to the controls. Conclusion Pediatric IBD is associated with reduced alpha and beta gut fungal microbiome diversity. Specific Candida taxa were found to be increased in abundance in the IBD samples. These results emphasize the potential importance of fungal microbiota signatures as biomarkers of pediatric IBD, supporting their possible role in disease pathogenesis.

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Zhang, Feng, Yan Deng, Dong Wang, and Shuai Wang. "Construction and Verification of the Molecular Subtype and a Novel Prognostic Signature Based on Inflammatory Response-Related Genes in Uveal Melanoma." Journal of Clinical Medicine 12, no. 3 (January 21, 2023): 861. http://dx.doi.org/10.3390/jcm12030861.

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The significance of inflammation in tumorigenesis and progression has become prominent. This study aimed to construct and validate the molecular subtype and a novel prognostic signature based on inflammatory response-related genes in uveal melanoma (UM). Patients from the TCGA, GSE84976, and GSE22138 UM cohorts were enrolled. According to the consensus cluster analysis, patients were divided into two molecular subtypes, namely IC1 and IC2. Survival curves showed that patients in IC1 had a better prognosis. The IC2 subgroup had higher levels of immune cell infiltration and more enriched immunological pathways. There were statistical differences in the immune-inflammation microenvironment, immune checkpoint genes expression, and drug sensitivity. The prognostic signature constructed based on inflammatory response-related genes exhibited a stable predictive power. Multivariate analysis confirmed that the signature was a prognostic factor independent of clinical characteristics. Functional analyses showed that the high-risk group was associated with immunological response, inflammatory cell activation, and tumor-related signal pathways. The riskscore had a negative relationship with tumor purity and was positively correlated with immune and stromal scores. Furthermore, the prognostic signature could sensitively predict the response to drug treatments. In conclusion, the prognostic signature might aid in stratifying patients at risk premised on the prognosis and immunotherapy sensitivity.

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Carsuzaa, Florent, Émilie Béquignon, Xavier Dufour, Guillaume de Bonnecaze, Jean-Claude Lecron, and Laure Favot. "Cytokine Signature and Involvement in Chronic Rhinosinusitis with Nasal Polyps." International Journal of Molecular Sciences 23, no. 1 (December 30, 2021): 417. http://dx.doi.org/10.3390/ijms23010417.

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Cytokines are well known to play a central role in chronic rhinosinusitis with nasal polyps (CRSwNP), particularly in maintenance of the inflammatory response and the recruitment of eosinophils. The pathophysiological concepts concerning the involvement of inflammatory cytokines in CRSwNP have gradually evolved. Although the Th2 cytokines environment associated with an eosinophilic infiltration has retained a central role in the genesis of polyps, the role of other cytokine subpopulations has also and more recently been detailed, leading to a specific and complex signature in CRSwNP. The purpose of this review is to summarize the current state of knowledge about the cytokine signature in CRSwNP, the role of cytokines in the pathogenesis of this disease and in the intercellular dialog between epithelial cells, fibroblasts and inflammatory cells. Knowledge of this precise cytokine signature in CRSwNP is fundamental in the perspective of potential targeting biotherapies.

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Haberman Ziv, Y., N. Loberman-Nachum, S. Katya, A. Di Segni, G. Efroni, T. Braun, M. BenShoshan, et al. "OP06 Comparison between Crohn and coeliac diseases small intestine transcriptomics and microbial data define similarities and divergent pathways linked to pathogenesis." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S006. http://dx.doi.org/10.1093/ecco-jcc/jjz203.005.

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Abstract Background Crohn disease and coeliac disease are two inflammatory conditions known to cause small intestine inflammation. Using high throughput transcriptomics, microbial, and bioinformatics approaches we aimed to capture differences and similarities linked to the pathogenesis and to future potential interventions for those chronic manifestations. Methods We performed high throughput transcriptomics and 16S microbial characterisation of 55 paediatric new-onset coeliac patients and controls using clinical pathology specimens, and compared those signatures to our previously reported 248 RISK Crohn’s disease newly diagnosed cohort. ToppGene/ToppCluster and ClueGO platforms were used for functional annotation enrichment analyses, and MaAsLin for microbial differential abundance. Results A substantial number (>90%) of genes passed the expression filtering criteria in both studies enabling the comparison. Of the 354 coeliac down-regulated genes, 59% (209/354) overlapped with the reduced Crohn signature. Shared reduced signatures and functions included a decrease in epithelial lipid metabolism, oxidoreductase activity, and brush border transport signatures. In contrast, a significantly smaller proportion [19% (97/427, Chi-squares p < 0.001] of the coeliac disease 524 up-regulated genes overlapped with the induced Crohn disease signature. We noted shared enriched signatures for adaptive immune-related pathways and interferon-γ in both coeliac and Crohn diseases. However, the Crohn disease signature exhibited more specific enrichments for signatures associated with innate immune pathways and with a strong signal for granulocytes, an extracellular matrix signature, and CXCR chemokines signalling, while the coeliac up-regulated signature showed unique enrichment for cell cycle and mitosis. As opposed to the robust dysbiosis previously characterised in Crohn disease, we were only able to identify significant enrichment for Bacteroidetes taxa in coeliac patients in comparison to controls. Conclusion We highlight important biologic differences between Crohn and coeliac diseases emphasising an intensified innate granulocytes activation signature in Crohn disease and a specific epithelial proliferative signal in coeliac disease. Unlike the robust dysbiosis linked to Crohn disease, the coeliac patient showed only modest enrichment for several Bacteroidetes taxa in comparison to controls. It is possible that microbial alteration in Crohn disease triggers granulocytes activation, and that this signal inhibits epithelial proliferation/renewal, eventually leading the epithelial damage seen in Crohn but not coeliac disease. Inhibiting innate immune activation or reverting Crohn dysbiosis may be a beneficial future therapy for Crohn disease.

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Mecatti, Giovana Colozza, Salvador Sánchez-Vinces, Anna Maria A. P. Fernandes, Marcia C. F. Messias, Gabrielle K. D. de Santis, Andreia M. Porcari, Fernando A. L. Marson, and Patrícia de Oliveira Carvalho. "Potential Lipid Signatures for Diagnosis and Prognosis of Sepsis and Systemic Inflammatory Response Syndrome." Metabolites 10, no. 9 (September 1, 2020): 359. http://dx.doi.org/10.3390/metabo10090359.

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Systemic inflammatory response syndrome (SIRS) and sepsis are two conditions which are difficult to differentiate clinically and which are strongly impacted for prompt intervention. This study identified potential lipid signatures that are able to differentiate SIRS from sepsis and to predict prognosis. Forty-two patients, including 21 patients with sepsis and 21 patients with SIRS, were involved in the study. Liquid chromatography coupled to mass spectrometry and multivariate statistical methods were used to determine lipids present in patient plasma. The obtained lipid signatures revealed 355 features for the negative ion mode and 297 for the positive ion mode, which were relevant for differential diagnosis of sepsis and SIRS. These lipids were also tested as prognosis predictors. Lastly, L-octanoylcarnitine was found to be the most promising lipid signature for both the diagnosis and prognosis of critically ill patients, with accuracies of 75% for both purposes. In short, we presented the determination of lipid signatures as a potential tool for differential diagnosis of sepsis and SIRS and prognosis of these patients.

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Zheng, Mingzhu, and Jinfang Zhu. "Innate Lymphoid Cells and Intestinal Inflammatory Disorders." International Journal of Molecular Sciences 23, no. 3 (February 6, 2022): 1856. http://dx.doi.org/10.3390/ijms23031856.

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Innate lymphoid cells (ILCs) are a population of lymphoid cells that do not express T cell or B cell antigen-specific receptors. They are largely tissue-resident and enriched at mucosal sites to play a protective role against pathogens. ILCs mimic the functions of CD4 T helper (Th) subsets. Type 1 innate lymphoid cells (ILC1s) are defined by the expression of signature cytokine IFN-γ and the master transcription factor T-bet, involving in the type 1 immune response; ILC2s are characterized by the expression of signature cytokine IL-5/IL-13 and the master transcription factor GATA3, participating in the type 2 immune response; ILC3s are RORγt-expressing cells and are capable of producing IL-22 and IL-17 to maintain intestinal homeostasis. The discovery and investigation of ILCs over the past decades extends our knowledge beyond classical adaptive and innate immunology. In this review, we will focus on the roles of ILCs in intestinal inflammation and related disorders.

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Da, Bin-Bin, Shuai Luo, Ming Huang, Fei Song, Rong Ding, Yao Xiao, Yang Fu, Yin-Shan Yang, and Hai-Lei Wang. "Prediction of Hepatocellular Carcinoma Prognosis and Immune Cell Infiltration Using Gene Signature Associated with Inflammatory Response." Computational and Mathematical Methods in Medicine 2022 (January 7, 2022): 1–24. http://dx.doi.org/10.1155/2022/2415129.

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It has been demonstrated that the inflammatory response influences cancer development and can be used as a prognostic biomarker in various tumors. However, the relevance of genes associated with inflammatory responses in hepatocellular carcinoma (HCC) remains unknown. The Cancer Genome Atlas (TCGA) database was analyzed using weighted gene coexpression network analysis (WGCNA) and differential analysis to discover essential inflammatory response-related genes (IFRGs). Cox regression studies, both univariate and multivariate, were employed to develop a prognostic IFRGs signature. Additionally, Gene Set Enrichment Analysis (GSEA) was used to deduce the biological function of the IFRGs signature. Finally, we estimated immune cell infiltration using a single sample GSEA (ssGSEA) and x-cell. Our results revealed that, among the major HCC IFRGs, two (DNASE1L3 and KLKB1) were employed to create a predictive IFRG signature. The IFRG signature could correctly predict overall survival (O.S) as per Kaplan-Meier time-dependent roc curves analysis. It was also linked to pathological tumor stage and T stage and might be used as a prognostic predictor in HCC. GSEA analysis concluded that the IFRG signature might influence the immune response in HCC. Immunological cell infiltration and immune checkpoint molecule expression differed in the high-risk and low-risk groups. As a result of our findings, DNASILE may play a role in the tumor microenvironment. However, more research is necessary to confirm the role of DNASE1L3 and KLKB1.

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Lin, Howard, Brooks P. Scull, Baruch R. Goldberg, Harshal A. Abhyankar, Olive E. Eckstein, Daniel J. Zinn, Joseph Lubega, et al. "IFN-γ signature in the plasma proteome distinguishes pediatric hemophagocytic lymphohistiocytosis from sepsis and SIRS." Blood Advances 5, no. 17 (August 30, 2021): 3457–67. http://dx.doi.org/10.1182/bloodadvances.2021004287.

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Abstract Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by pathologic immune activation in which prompt recognition and initiation of immune suppression is essential for survival. Children with HLH have many overlapping clinical features with critically ill children with sepsis and systemic inflammatory response syndrome (SIRS) in whom alternative therapies are indicated. To determine whether plasma biomarkers could differentiate HLH from other inflammatory conditions and to better define a core inflammatory signature of HLH, concentrations of inflammatory plasma proteins were compared in 40 patients with HLH to 47 pediatric patients with severe sepsis or SIRS. Fifteen of 135 analytes were significantly different in HLH plasma compared with SIRS/sepsis, including increased interferon-γ (IFN-γ)–regulated chemokines CXCL9, CXCL10, and CXCL11. Furthermore, a 2-analyte plasma protein classifier including CXCL9 and interleukin-6 was able to differentiate HLH from SIRS/sepsis. Gene expression in CD8+ T cells and activated monocytes from blood were also enriched for IFN-γ pathway signatures in peripheral blood cells from patients with HLH compared with SIRS/sepsis. This study identifies differential expression of inflammatory proteins as a diagnostic strategy to identify critically ill children with HLH, and comprehensive unbiased analysis of inflammatory plasma proteins and global gene expression demonstrates that IFN-γ signaling is uniquely elevated in HLH. In addition to demonstrating the ability of diagnostic criteria for HLH and sepsis or SIRS to identify groups with distinct inflammatory patterns, results from this study support the potential for prospective evaluation of inflammatory biomarkers to aid in diagnosis of and optimizing therapeutic strategies for children with distinctive hyperinflammatory syndromes.

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Galozzi, Paola, Ola Negm, Sara Bindoli, Patrick Tighe, Paolo Sfriso, and Leonardo Punzi. "A Pro-Inflammatory Signature Constitutively Activated in Monogenic Autoinflammatory Diseases." International Journal of Molecular Sciences 23, no. 3 (February 5, 2022): 1828. http://dx.doi.org/10.3390/ijms23031828.

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Autoinflammatory diseases (AIDs) are disorders characterised by recurrent inflammatory episodes in charge of different organs with no apparent involvement of autoantibodies or antigen-specific T lymphocytes. Few common clinical features have been identified among all monogenic AIDs (mAIDs), while the search for a common molecular pattern is still ongoing. The aim of this study was to increase knowledge on the inflammatory pathways in the development of mAIDs in order to identify possible predictive or diagnostic biomarkers for each disease and to develop future preventive and therapeutic strategies. Using protein array-based systems, we evaluated two signalling pathways known to be involved in inflammation and a wide range of inflammatory mediators (pro-inflammatory cytokines and chemokines) in a cohort of 23 patients affected by different mAIDs, as FMF, TRAPS, MKD, Blau syndrome (BS), and NLRP12D. Overall, we observed upregulation of multiple signalling pathway intermediates at protein levels in mAIDs patients’ PBMCs, compared with healthy controls, with significant differences also between patients. FMF, TRAPS, and BS presented also peculiar activations of inflammatory pathways that can distinguish them. MAPK pathway activation, however, seems to be a common feature. The serum level of cytokines and chemokines produced clear differences between patients with distinct diseases, which can help distinguish each autoinflammatory disease. The FMF cytokine production profile appears broader than that of TRAPS, which, in turn, has higher cytokine levels than BS. Our findings suggest an ongoing subclinical inflammation related to the abnormal and constitutive signalling pathways and define an elevated inflammatory cytokine signature. Moreover, the upregulation of Th17-related cytokines emphasises the important role for Th17 and/or Th17-like cells also in monogenic AIDs.

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Ferris, Stephen T., Pavel N. Zakharov, Xiaoxiao Wan, Boris Calderon, Maxim N. Artyomov, Emil R. Unanue, and Javier A. Carrero. "The islet-resident macrophage is in an inflammatory state and senses microbial products in blood." Journal of Experimental Medicine 214, no. 8 (June 19, 2017): 2369–85. http://dx.doi.org/10.1084/jem.20170074.

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We examined the transcriptional profiles of macrophages that reside in the islets of Langerhans of 3-wk-old non-obese diabetic (NOD), NOD.Rag1−/−, and B6.g7 mice. Islet macrophages expressed an activation signature with high expression of Tnf, Il1b, and MHC-II at both the transcript and protein levels. These features are common with barrier macrophages of the lung and gastrointestinal tract. Moreover, injection of lipopolysaccharide induced rapid inflammatory gene expression, indicating that blood stimulants are accessible to the macrophages and that these macrophages can sense them. In NOD mice, the autoimmune process imparted an increased inflammatory signature, including elevated expression of chemokines and chemokine receptors and an oxidative response. The elevated inflammatory signature indicates that the autoimmune program was active at the time of weaning. Thus, the macrophages of the islets of Langerhans are poised to mount an immune response even at steady state, while the presence of the adaptive immune system elevates their activation state.

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de Gonzalo-Calvo, David, Alberto Dávalos, Ana Montero, Ángela García-González, Iryna Tyshkovska, Antonio González-Medina, Sara M. A. Soares, et al. "Circulating inflammatory miRNA signature in response to different doses of aerobic exercise." Journal of Applied Physiology 119, no. 2 (July 15, 2015): 124–34. http://dx.doi.org/10.1152/japplphysiol.00077.2015.

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While moderate acute exercise has been associated with strong anti-inflammatory mechanisms, strenuous exercise has been linked to deleterious inflammatory perturbations. It is therefore fundamental to elucidate the mechanisms that regulate the exercise-induced inflammatory cascade. Information on novel regulators such as circulating inflammatory microRNAs (c-inflammamiRs) is incomplete. In this study, we evaluated the response of a panel of c-inflammamiRs to different doses of acute aerobic exercise. We first studied the exercise-induced inflammatory cascade in serum samples of nine active middle-aged males immediately before and after (0 h, 24 h, 72 h) 10-km, half-marathon, and marathon races. Next, we analyzed the circulating profile of 106 specific c-inflammamiRs immediately before) and after (0 h, 24 h) 10-km (low inflammatory response) and marathon (high inflammatory response) races. Analysis of classical inflammatory parameters revealed a dose-dependent effect of aerobic exercise on systemic inflammation, with higher levels detected after marathon. We observed an increase in miR-150-5p immediately after the 10-km race. Levels of 12 c-inflammamiRs were increased immediately after the marathon (let-7d-3p, let-7f-2-3p, miR-125b-5p, miR-132-3p, miR-143-3p, miR-148a-3p, miR-223-3p, miR-223-5p, miR-29a-3p, miR-34a-5p, miR-424-3p, and miR-424-5p). c-inflammamiRs returned to basal levels after 24 h. Correlation and in silico analyses supported a close association between the observed c-inflammamiR pattern and regulation of the inflammatory process. In conclusion, we found that different doses of acute aerobic exercise induced a distinct and specific c-inflammamiR response, which may be associated with control of the exercise-induced inflammatory cascade. Our findings point to c-inflammamiRs as potential biomarkers of exercise-induced inflammation, and hence, exercise dose.

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Misko, Albert L., Laura D. Weinstock, Sitara B. Sankar, Amanda Furness, Yulia Grishchuk, and Levi B. Wood. "Peripheral Inflammatory Cytokine Signature Mirrors Motor Deficits in Mucolipidosis IV." Cells 11, no. 3 (February 4, 2022): 546. http://dx.doi.org/10.3390/cells11030546.

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Background: Mucolipidosis IV (MLIV) is an autosomal recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by a loss of function of the lysosomal channel transient receptor potential mucolipin-1 and is associated with an early pro-inflammatory brain phenotype, including increased cytokine expression. The goal of the current study was to determine whether blood cytokines are linked to motor dysfunction in patients with MLIV and reflect brain inflammatory changes observed in an MLIV mouse model. Methods: To determine the relationship between blood cytokines and motor function, we collected plasma from MLIV patients and parental controls concomitantly with assessment of motor function using the Brief Assessment of Motor Function and Modified Ashworth scales. We then compared these profiles with cytokine profiles in brain and plasma samples collected from the Mcoln1−/− mouse model of MLIV. Results: We found that MLIV patients had prominently increased cytokine levels compared to familial controls and identified profiles of cytokines correlated with motor dysfunction, including IFN-γ, IFN-α2, and IP-10. We found that IP-10 was a key differentiating factor separating MLIV cases from controls based on data from human plasma, mouse plasma, and mouse brain. Conclusions: Our data indicate that MLIV is characterized by increased blood cytokines, which are strongly related to underlying neurological and functional deficits in MLIV patients. Moreover, our data identify the interferon pro-inflammatory axis in both human and mouse signatures, suggesting that interferon signaling is an important aspect of MLIV pathology.

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Jablonski, Kyle A., Andrew D. Gaudet, Stephanie A. Amici, Phillip G. Popovich, and Mireia Guerau-de-Arellano. "Control of the Inflammatory Macrophage Transcriptional Signature by miR-155." PLOS ONE 11, no. 7 (July 22, 2016): e0159724. http://dx.doi.org/10.1371/journal.pone.0159724.

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Del Valle, Diane Marie, Seunghee Kim-Schulze, Hsin-Hui Huang, Noam D. Beckmann, Sharon Nirenberg, Bo Wang, Yonit Lavin, et al. "An inflammatory cytokine signature predicts COVID-19 severity and survival." Nature Medicine 26, no. 10 (August 24, 2020): 1636–43. http://dx.doi.org/10.1038/s41591-020-1051-9.

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Allison, Susan J. "A signature of inflammatory proteins associated with ESRD in diabetes." Nature Reviews Nephrology 15, no. 7 (May 3, 2019): 387. http://dx.doi.org/10.1038/s41581-019-0157-0.

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Okahara, S., Y. Arimura, T. Yabana, K. Kobayashi, A. Gotoh, S. Motoya, A. Imamura, T. Endo, and K. Imai. "Inflammatory gene signature in ulcerative colitis with cDNA macroarray analysis." Alimentary Pharmacology and Therapeutics 21, no. 9 (May 2005): 1091–97. http://dx.doi.org/10.1111/j.1365-2036.2005.02443.x.

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Johnston, A., X. Xing, L. Wolterink, Z. Yin, L. Reingold, J. M. Kahlenberg, P. W. Harms, and J. E. Gudjonsson. "459 Pustular inflammatory skin diseases have a common molecular signature." Journal of Investigative Dermatology 136, no. 5 (May 2016): S81. http://dx.doi.org/10.1016/j.jid.2016.02.495.

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Charafe-Jauffret, Emmanuelle, Carole Tarpin, Valérie-Jeanne Bardou, François Bertucci, Christophe Ginestier, Anne-Chantal Braud, Brigitte Puig, et al. "Immunophenotypic analysis of inflammatory breast cancers: identification of an‘inflammatory signature’." Journal of Pathology 202, no. 3 (February 24, 2004): 265–73. http://dx.doi.org/10.1002/path.1515.

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Journal articles on the topic 'Inflammatory signature'

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