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Nijaguna, Mamatha B., Vikas Patil, Alangar S. Hegde, Bangalore A. Chandramouli, Arimappamagan Arivazhagan, Vani Santosh, and Kumaravel Somasundaram. "An Eighteen Serum Cytokine Signature for Discriminating Glioma from Normal Healthy Individuals." PLOS ONE 10, no. 9 (September 21, 2015): e0137524. http://dx.doi.org/10.1371/journal.pone.0137524.
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Hel, Zdenek, Richard P. H. Huijbregts, Jun Xu, Jana Nechvatalova, Marcela Vlkova, and Jiri Litzman. "Altered Serum Cytokine Signature in Common Variable Immunodeficiency." Journal of Clinical Immunology 34, no. 8 (September 23, 2014): 971–78. http://dx.doi.org/10.1007/s10875-014-0099-z.
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Badros, Ashraf Z., Sunita Philip, Patricia Lesho, Dianna Weikel, Olga Goloubeva, Mariola Sadowska, Rena Lapidus, Lisa Hester, Todd Milliron, and Timothy Meiller. "Prospective Observational Study of 110 Multiple Myeloma (MM) Patients On Monthly Versus 3 Monthly Infusion of Zoledronic Acid." Blood 120, no. 21 (November 16, 2012): 4245. http://dx.doi.org/10.1182/blood.v120.21.4245.4245.
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Abstract Abstract 4245 Introduction: Osteonecrosis of the jaw (ONJ) is a recognized risk of bisphosphonate infusion; the incidence, etiology, risk factors and pathophysiology remains largely undefined. In this prospective study we evaluated patients on long-term zoledronic acid infusions; the aims of the study were to provide a comprehensive clinical, oral/dental assessment of patients prospectively and sequentially measure changes in zoledronic acid PKs, cytokines, microbial signatures and bone turnover markers in saliva and serum in correlation with 2 major clinical end points development of ONJ and myeloma relapse. Methods and patients: Over 6 months 110 patients were enrolled and followed for 18 months. Patients were on zoledronic acid infusions: monthly (n=75) for patients with significant bone disease (relapsed or newly diagnosed) or every 3 months (n=35) for those in stable remission > 3years. During the study follow up therapy was changed to pamidronate (n=4) due to renal insufficiency or denosumab (n=1). Patients had clinical and oral evaluations and saliva and blood samples collected at baseline and every 3 months up to 18 months; saliva samples were obtained before and after (5 and 15 minutes) zoledronic acid infusions. Results: Median time from MM diagnosis was 3.7 years (range: 1.5–13) for 100 patients; 10 newly diagnosed patients were enrolled as control with a median of 7 months (range: 1–9). Median age was 60 yrs (range: 32–82); 60 were Caucasians, 49 African American, one Asian; 68 were males. At study entry 79% of the patients were in remission: CR (n=35, 32%) of them 15 were in CR for > 7 years, PR (n=52, 47%) and PD (n=23, 21%). Twenty-four patients were not receiving any MM therapy; most were on maintenance with lenalidomide (n=52) or thalidomide (n=11) and the rest on other regimens (n=23). Fifty patients progressed during the 18 month study period; they continued the study with various salvage therapies that included: bortezomib (n=14), carfilzomib (n=14), lenalidomide (n=6) and clinical trails (n=16). Thirteen patients had died: 9 from complications of relapsed MM and 4 from other causes. Eighteen patients withdrew consent for sample collection and dental evaluations but were followed clinically. Most patients had prior-to-study entry dental procedures (extractions, n=80). The prevalent oral pathology detected on dental evaluations included: gingivitis (n=41), moderate/severe periodontal disease (n=35) and gross dental caries (n=15). During the 18 months of observation; 13 patients developed ONJ. Median time from MM diagnosis to ONJ was 5.7 years (range: 1.9–12 years). Risk factors for ONJ were relapsed disease (n=11), monthly zoledronic acid (n=8), dental extractions (n=8), severe periodontal disease (n=9), older age [median age was 62 yrs] and prior ONJ (n=3). ONJ treatment was conservative with antibiotics and holding BP therapy: 9 patients had complete healing of the site of ONJ and 4 had persistent non-healing ONJ lesions. Sequential saliva and serum samples were assessed for various cytokines involved in immune/inflammatory process (IL-1β, IL-6, IL-17, TNF-α, IFN-α, TGF-β, MIP-1 α β, MMP-9); bone turnover (Osteopontin, ostiocalcin, RANKL, Osteoprotregerin) and angiogenesis factors (VEGF and EGF) in 42 patients with ONJ (n=13), severe periodontal disease (n=10) and normal control (n=19), the later included 10 patients in remission and 9 with relapsed MM. In conclusion: In this longitudinal observational study, the ONJ incidence was 11%, 70% eventually healed. Our cytokine analysis suggest that saliva may accurately detect changes reflective of mucosal inflammation as well as bone turnover markers; data correlating these changes with ONJ and MM status will be presented. Disclosures: No relevant conflicts of interest to declare.
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Wang, Rui, Xiao Shao, Junying Zheng, Yuko Ishii, Irene Pak, Amit Roy, Akintunde Bello, et al. "Development of a baseline prognostic cytokine signature that correlates with nivolumab (NIVO) clearance (CL): Translational pharmacokinetic/pharmacodynamic (PK/PD) analysis in patients with renal cell carcinoma (RCC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 2544. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.2544.
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2544 Background: CL of checkpoint inhibitors has been identified as a predictive covariate of overall survival (OS) in several tumors. Determination of CL requires post-treatment samples, which negates its utility as a baseline prognostic biomarker. This study aims to identify a baseline composite cytokine signature that correlates with NIVO CL in patients with RCC using translational PK/PD analysis. Methods: Peripheral serum PK (NIVO CL) and serum biomarkers to assess PD (Myriad Rules-Based Medicine customized inflammatory cytokine panel) were analyzed from 985 patients with RCC enrolled in 3 clinical trials. CheckMate (CM) 009 (NCT01358721) and CM 025 (NCT01668784) of NIVO (n = 481) were used for model development (training dataset). CM 010 (NCT01354431) of NIVO and a cohort treated with everolimus in CM 025 were included in model application (test dataset; n = 504). PK/PD analyses were conducted using a machine learning algorithm with performance assessed by receiver operating characteristic (ROC) curve and accuracy by confusion matrix. Results: The model selected the top-10 baseline inflammatory cytokines to form a composite cytokine signature, which predicted NIVO CL (high vs low) that was significantly associated with OS (p < 0.001) across all 3 studies (training and test datasets). The same cytokine features were associated with OS of everolimus (p < 0.01), suggesting the potential prognostic nature of the composite signature. The PK/PD analysis provided a robust description of the association between selected cytokines and CL (ROC = 0.71). Identified cytokines (eg, serum C-reactive protein known to reflect immune cell modulation) have been shown individually to be associated with RCC prognosis. A multivariable approach resulting in tumor-specific composite signatures may provide more accurate prognostic value. Conclusions: The baseline composite cytokine signature could serve as a clinically useful biomarker for patients with RCC, pending further evaluation, as it may provide improved prognostic accuracy for long-term clinical outcome compared to individual cytokines.
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Nakamura, S., Y. Okamoto, Y. Katsumata, and M. Harigai. "POS0611 SHARED MONOCYTE CYTOKINE SIGNATURE INDUCED BY SERUM FROM PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS AND ANTI-MDA5 ANTIBODY-POSITIVE DERMATOMYOSITIS THROUGH TYPE I INTERFERON PATHWAY." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 577.2–578. http://dx.doi.org/10.1136/annrheumdis-2023-eular.844.
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BackgroundType I interferon (IFN) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and dermatomyositis (DM)/polymyositis (PM) as typically evidenced by upregulation of type I IFN-stimulated genes (ISGs) in peripheral immune cells [1]. In addition, a distinct monocyte cytokine signature, which was induced by plasma from pediatric SLE patients and abrogated by Janus kinase (JAK) inhibition, was reported [2]. However, contribution of serum factors to expression of ISGs was not fully elucidated.ObjectivesTo investigate the cytokine induction profile in multiple myeloid lineages by serum from patients with SLE or DM/PM using the whole blood stimulation system and identify the signaling pathway relavant to the monocyte cytokine signature.MethodsSerum was collected from newly diagnosed, untreated, and clinically active adult patients with SLE (SLE group), anti-MDA5 antibody-positive DM (MDA5 group), and anti-aminoacyl-tRNA synthetase (ARS) antibody-positive DM/PM (ARS group), and healthy controls (HCs) (n= 10 for each group). Heparinized whole blood from healthy donors was incubated with control serum (10 v/v%), patient serum (10 v/v%), or IFN-β in the presence of protein transport inhibitor cocktail for 6 hours. Red blood cells were lysed, and then leucocytes were fixed at a single step. Intracellular staining was performed and expression of 11 cytokines in CD14+monocytes, CD1c+dendritic cells (DCs), and CD123+DCs were analyzed using flow cytometry. A cut-off level was determined by 2% positivity of each cytokine in unstimulated condition. For transcriptomic analyses, sorted CD14+monocytes from healthy donors were incubated with serum (SLE, MDA5, ARS, or HCs), or IFN-β (n= 3 for each group) for 4 hours, and bulk RNA-sequencing was performed using the Illumina NextSeq 500 platform. RNA-seq raw sequence reads analysis and pathway analysis were performed using the Strand NGS software. To evaluate significance of JAK-signal transducer and activator of transcription (STAT) pathway, whole blood from healthy donors was pre-incubated with upadacitinib, a JAK1 inhibitor, stimulated with patient serum for 6 hours, and analyzed for cytokine expression as described above.ResultsSerum from SLE and MDA5 groups induced significantly higher monocyte chemoattractant protein-1 (MCP1) and interleukin-1 receptor antagonist (IL-1RA) expression in CD14+monocytes than serum from HCs (Figure 1). These monocyte cytokine signatures were closely resembled that induced by IFN-β stimulation. Serum from ARS group did not induce any significant cytokine expression in CD14+monocytes. No significant cytokine expression was observed in CD1c+DCs or CD123+DCs. RNA-seq demonstrated that 612 and 462 genes were upregulated (fold change >2 relative to control) following stimulation with serum from SLE and MDA5 groups, respectively. In these upregulated genes, 383 genes were commonly upregulated across SLE and MDA5 groups and IFN-β. Pathway analysis revealed similar transcriptional profiles in SLE and MDA5 groups: upregulated genes were most frequently involved in IFN-αβ signaling pathway including multiple ISGs and STAT1/2. Upadacitinib significantly abrogated the monocyte cytokine signature, and MCP1 and IL-1RA expression induced by serum from SLE and MDA5 groups in a dose-dependent manner (p< 0.001 in all analyses).ConclusionThese results suggest that serum factors in patients with active SLE and anti-MDA5 antibody-positive DM can induce shared monocyte cytokine signature through type I IFN pathway. CD14+monocytes ‘primed’ by serum might contribute to the pathogenesis of these diseases.References[1]Rheumatology (Oxford).2017;56:1662[2]J Autoimmun. 2017;81:74Figure 1.MCP1 (A) and IL-1RA (B) expression in CD14+monocytes induced by serum from SLE and anti-MDA5 antibody-positive DM.Horizontal bars represent median values.P-values were calculated using Kruskal-Wallis test followed by Dunn’s multiple comparisons test.Acknowledgements:NIL.Disclosure of InterestsShohei Nakamura: None declared, Yuko Okamoto: None declared, Yasuhiro Katsumata Speakers bureau: GlaxoSmithKline K.K., AstraZeneca K.K., Sanofi K.K., Pfizer Japan Inc., Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Asahi Kasei Pharma, Astellas Pharma Inc., Mitsubishi Tanabe Pharma Corporation, Masayoshi Harigai: None declared.
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Mahadevan, Daruka, Thomas Klinkhammer, Laurence Cooke, Christopher Riley, James Choi, Shripad Sinari, Thomas P. Miller, and Catherine Spier. "CLL Transcript and Serum Profiling Identifies Distinct Oncogenic Pathways in Rai Stage Progression." Blood 110, no. 11 (November 16, 2007): 4688. http://dx.doi.org/10.1182/blood.v110.11.4688.4688.
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Abstract Background: Chronic lymphocytic leukemia (CLL) is a common leukemia that is incurable. Survival curves for Rai stage 0/I and III/IV are distinct and a specific gene expression signature may be associated with stage progression (SP). However, distinct oncogenic pathways that differentiate stage progression are not well defined. Methods: Mononuclear cells from Rai stage 0/I (N=8) and III/IV (N=8) CLL patients were obtained through an IRB approved protocol and analyzed utilizing the HG-U133A 2.0 Affymetrix array after isolating and purifying total RNA (Qiagen, RNAeasy). Control RNA samples are from 4 normal volunteers’ peripheral blood (PB) B-cells (AllCell, CA) and a normal reactive lymph node. Statistical significance of individual genes and pathways was analyzed using ‘BioConductor’. Differential gene expression was analyzed using ‘Limma’. Pathways and cytogenetics regions were analyzed for enrichment using ‘Category’. Real time RT-PCR on specific genes was performed to validate the GEP based on stage. A serum cytokine profile (120 cytokines, RayBiotech) on 8 CLL patients (N=4 low risk; N=4 high risk) and 4 normal volunteers was evaluated to identify a signature for diagnosis and prognosis. Results: Data are presented as “robust” increases or decreases of relative gene expression common to 8 patients in the low or high risk stages. The Wnt/Ror-1 non-canonical, and TGFb pathways are over-expressed in Rai stage 0/I, implicating a program of cell survival and dysregulated migration. The Hedgehog, Proteasome, TNF/FAS/NF-kB, and MAPK pathways are over-expressed in Rai stage III/IV, suggestive of a tumor microenvironment driven program in SP. Genes located on chromosome 3q27.1 are also dysregulated in Rai stage III/IV. A distinct serum cytokine profile also differentiates low from high stage CLL. Conclusions: GEP of CLL with RT-PCR validation has identified distinct oncogenic pathways that distinguish Rai stage 0/I from III/IV. A serum cytokine profile also differentiates between low and high risk CLL. These data together provide a ‘molecular signature’ for SP in CLL.
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Abbona, Andrea, Vincenzo Ricci, Matteo Paccagnella, Cristina Granetto, Fiorella Ruatta, Carolina Cauchi, Danilo Galizia, et al. "Baseline Cytokine Profile Identifies a Favorable Outcome in a Subgroup of Colorectal Cancer Patients Treated with Regorafenib." Vaccines 11, no. 2 (February 2, 2023): 335. http://dx.doi.org/10.3390/vaccines11020335.
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Metastatic colorectal cancer is frequently associated with poor clinical conditions that may limit therapeutic options. Regorafenib is a small molecule approved for the treatment of metastatic colorectal cancer, but it is hampered by significative toxicities. Moreover, only a relatively limited number of patients benefit from the treatment. Therefore, the identification of reliable markers for response is an unmet need. Eighteen cytokines, selected based on their prevalent Th1 or Th2 effects, were collected. Peripheral blood samples were gathered at baseline in 25 metastatic colorectal cancer patients treated with regorafenib. Data extracted have been linked to progression-free survival. ROC identified the best cytokines associated with outcome. The relative value of the selected cytokines was determined by PCA. Data analysis identified 8 cytokines (TGF-β, TNF-α, CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21), used to create a signature (TGF-β, TNF-α high; CCL-2, IL-6, IL-8, IL-10, IL-13 and IL-21 low) corresponding to patients with a significantly longer progression-free survival. This report suggests that the analysis of multiple cytokines might identify a cytokine signature related to a patient’s outcome that is able to recognize patients who will benefit from treatment. If confirmed, future studies, also based on different drugs, using this approach and including larger patient populations, might identify a signature allowing the a priori identification of patients to be treated.
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Montoya, Jose G., Tyson H. Holmes, Jill N. Anderson, Holden T. Maecker, Yael Rosenberg-Hasson, Ian J. Valencia, Lily Chu, Jarred W. Younger, Cristina M. Tato, and Mark M. Davis. "Cytokine signature associated with disease severity in chronic fatigue syndrome patients." Proceedings of the National Academy of Sciences 114, no. 34 (July 31, 2017): E7150—E7158. http://dx.doi.org/10.1073/pnas.1710519114.
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Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P= 0.0052) and resistin was lower (P= 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.
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Byers, L. A., J. V. Heymach, J. J. Lee, H. Lin, A. K. El-Naggar, V. Papadimitrakopoulou, S. M. Lippman, W. K. Hong, F. C. Holsinger, and M. S. Kies. "Association between human papillomavirus (HPV) status with serum cytokine and angiogenic factor (CAF) profile after induction chemotherapy in head and neck squamous cell carcinoma (HNSCC)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 6081. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.6081.
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6081 Background: Human papillomavirus has been implicated in the development of head and neck squamous cell carcinoma and is associated with a more favorable clinical outcome. Previously, we identified a serum hypoxia signature associated with HNSCC progression (Byers et al, Proc ASCO. 2008). We investigated the association between HPV status, serum biomarkers, and clinical outcome in patients treated with induction chemotherapy. Methods: 47 previously untreated patients with locally advanced nodal disease (T0–4, N2b/c/3, M0) received 6 weekly cycles of paclitaxel (135 mg/m2), carboplatin (AUC 2), and cetuximab (400 mg/m2 week 1; 250 mg/m2 weeks 2–6) followed by definitive local therapy. 46 (98%) patients had a complete or partial response to induction chemotherapy (Kies et al, Proc ASCO. 2006), and 6 have had tumor progression (PD) after a minimum follow-up of two years. Formalin fixed biopsies were available for HPV testing by in situ hybridization with non-radioisotopic chromogen for 25 patients (including 5/6 with PD). 38 CAFs were measured by multiplex bead assay before and during treatment. Results: 12/25 patients were HPV-positive, all male and six were never smokers; of the 13 HPV-negative patients, four were male and three were never smokers. Among those with available data, all 5 patients with PD were HPV-negative (p = 0.02). There were four study deaths, all in the HPV-negative group. Overall survival was superior in HPV-positive patients (p = 0.04). There was no significant association between HPV status and serum CAF markers. However, among HPV-negative patients, PD was associated with the CAF hypoxia signature (5/8 patients with the hypoxia signature progressed versus 0/5 signature-negative). Of the individual CAFs, osteopontin was significantly elevated in all HPV-negative patients with PD. Conclusions: HPV positivity was associated with a longer progression-free survival and overall survival. Among HPV-negative patients, only those with a serum hypoxia signature had disease progression. These data suggest that the combination of HPV status and CAF profiling may identify patients at risk for relapse after sequential therapy. No significant financial relationships to disclose.
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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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Cesati, Marco, Francesca Scatozza, Daniela D’Arcangelo, Gian Carlo Antonini-Cappellini, Stefania Rossi, Claudio Tabolacci, Maurizio Nudo, et al. "Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker." Cancers 12, no. 12 (December 8, 2020): 3680. http://dx.doi.org/10.3390/cancers12123680.
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The identification of reliable and quantitative melanoma biomarkers may help an early diagnosis and may directly affect melanoma mortality and morbidity. The aim of the present study was to identify effective biomarkers by investigating the expression of 27 cytokines/chemokines in melanoma compared to healthy controls, both in serum and in tissue samples. Serum samples were from 232 patients recruited at the IDI-IRCCS hospital. Expression was quantified by xMAP technology, on 27 cytokines/chemokines, compared to the control sera. RNA expression data of the same 27 molecules were obtained from 511 melanoma- and healthy-tissue samples, from the GENT2 database. Statistical analysis involved a 3-step approach: analysis of the single-molecules by Mann–Whitney analysis; analysis of paired-molecules by Pearson correlation; and profile analysis by the machine learning algorithm Support Vector Machine (SVM). Single-molecule analysis of serum expression identified IL-1b, IL-6, IP-10, PDGF-BB, and RANTES differently expressed in melanoma (p < 0.05). Expression of IL-8, GM-CSF, MCP-1, and TNF-α was found to be significantly correlated with Breslow thickness. Eotaxin and MCP-1 were found differentially expressed in male vs. female patients. Tissue expression analysis identified very effective marker/predictor genes, namely, IL-1Ra, IL-7, MIP-1a, and MIP-1b, with individual AUC values of 0.88, 0.86, 0.93, 0.87, respectively. SVM analysis of the tissue expression data identified the combination of these four molecules as the most effective signature to discriminate melanoma patients (AUC = 0.98). Validation, using the GEPIA2 database on an additional 1019 independent samples, fully confirmed these observations. The present study demonstrates, for the first time, that the IL-1Ra, IL-7, MIP-1a, and MIP-1b gene signature discriminates melanoma from control tissues with extremely high efficacy. We therefore propose this 4-molecule combination as an effective melanoma marker.
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Tsai, Susan, Laura McOlash, Shuang Jia, Jian Zhang, Pippa Simpson, Mary L. Kaldunski, Mohammed Aldakkak, et al. "A Serum-Induced Transcriptome and Serum Cytokine Signature Obtained at Diagnosis Correlates with the Development of Early Pancreatic Ductal Adenocarcinoma Metastasis." Cancer Epidemiology Biomarkers & Prevention 28, no. 4 (December 7, 2018): 680–89. http://dx.doi.org/10.1158/1055-9965.epi-18-0813.
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Choi, James, Harinder Garewal, Christopher Riley, Laurence Cooke, Thomas Klinkhammer, Sirisha Maddipati, Rohit Sud, Catherine Spier, and Daruka Mahadevan. "Transcriptosome and Serum Cytokine Profiling of B-CLL Identifies Oncogenic Pathways in Pathogenesis and Survival." Blood 108, no. 11 (November 16, 2006): 4953. http://dx.doi.org/10.1182/blood.v108.11.4953.4953.
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Abstract Background: B-cell chronic lymphocytic leukemia (B-CLL) the most common leukemia in the Western world accounts for 25% of all newly diagnosed leukemias. Despite new therapeutic advances, B-CLL is currently not curable. Potential oncogenic signaling pathways in B-CLL require elucidation. We identified ROR-1 receptor tyrosine kinase (RTK) in the WNT/Planar Cell Polarity non-canonical pathway as a possible mechanism of oncogenesis by gene expression profiling (GEP). Methods: Mononuclear cells from 8 low stage CLL patients were obtained through an IRB approved protocol and analyzed utilizing the HG-U133A 2.0 Affymetrix array (~18,400 transcripts, 22,000 probe sets) after isolating and purifying total RNA (Qiagen, RNAeasy). The control RNA samples were isolated from 8 normal volunteer peripheral blood (PB) B-cells (AllCell, CA) and a normal reactive lymph node. Tumor lineage was confirmed by immunohistochemistry (IHC). Quantitative real time RT-PCR was performed on 20 selected genes to validate the microarray GEP. Twenty one B-CLL patients (includes the 8 patients from the GEP) were evaluated by RT-PCR for several key components of oncogenic signaling pathways based on the GEP with gene specific probes. A serum cytokine profile (120 cytokines) on 12 CLL patients (8 for which GEP is available and 4 additional patients) and 4 normal volunteers were performed for identification of a signature for diagnostic and prognostic value. Results: Data are represented as “robust” increases or decreases of relative gene expression common to 8 patients. ROR-2, a close member of ROR-1, has been shown to bind Wnt-5A via the cysteine rich domain (CRD) and to activate the JNK signaling pathway. Our findings identify over-expression of members of the non-canonical WNT/PCP- ROR-1- signaling pathway genes that were validated by RT-PCR. A serum cytokine profile of 12 patients provides a signature that may be useful in CLL diagnosis and prognosis. Conclusions: GEP identified WNT/PCP-ROR-1 as key components of an autocrine pathway that helps B-CLL avoid apoptosis. Several serum cytokines are elevated and require validation as potential diagnostic and prognostic markers. GEP of B-CLL in combination with quantitative real time RT-PCR has identified several novel targets for therapy. The identification of ROR-1 RTK has led to the development of a molecular target for future therapeutic application. Several lead compounds have been identified and are being evaluated as potential therapies in B-CLL.
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Pratedrat, Pornpitra, Duangnapa Intharasongkroh, Jira Chansaenroj, Preeyaporn Vichaiwattana, Donchida Srimuan, Thaksaporn Thatsanatorn, Sirapa Klinfueng, et al. "Dynamics of Cytokine, SARS-CoV-2-Specific IgG, and Neutralizing Antibody Levels in COVID-19 Patients Treated with Convalescent Plasma." Diseases 11, no. 3 (August 30, 2023): 112. http://dx.doi.org/10.3390/diseases11030112.
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Coronavirus disease 2019 (COVID-19) is a contagious illness worldwide. While guidelines for the treatment of COVID-19 have been established, the understanding of the relationship among neutralizing antibodies, cytokines, and the combined use of antiviral medications, steroid drugs, and convalescent plasma therapy remains limited. Here, we investigated the connection between the immunological response and the efficacy of convalescent plasma therapy in COVID-19 patients with moderate-to-severe pneumonia. The study included a retrospective analysis of 49 patients aged 35 to 57. We conducted clinical assessments to determine antibody levels, biochemical markers, and cytokine levels. Among the patients, 48 (98%) were discharged, while one died. We observed significantly higher levels of anti-nucleocapsid, anti-spike, and neutralizing antibodies on days 3, 7, and 14 after the transfusion compared to before treatment. Serum CRP and D-dimer levels varied significantly across these four time points. Moreover, convalescent plasma therapy demonstrated an immunoregulatory effect on cytokine parameters, with significant differences in IFN-β, IL-6, IL-10, and IFN-α levels observed at different sampling times. Evaluating the cytokine signature, along with standard clinical and laboratory parameters, may help to identify the onset of a cytokine storm in COVID-19 patients and determine the appropriate indication for anti-cytokine treatment.
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Desai, Ankit A., Tong Zhou, Mehdi Nouraie, Victor R. Gordeuk, Joe GN Garcia, and Roberto F. Machado. "Genomic Assessment of Mortality in Sickle Cell Disease- A Novel Association with Cytokine Imbalance and T Cell Dysregulation." Blood 118, no. 21 (November 18, 2011): 1081. http://dx.doi.org/10.1182/blood.v118.21.1081.1081.
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Abstract Abstract 1081 Rationale: Sickle cell disease (SCD) is characterized by systemic complications and significant clinical variability. While some patients never experience severe clinical events, others suffer lifelong morbidity and accelerated mortality. To address this variability, we prospectively followed patients with SCD at steady-state to assess outcomes and leveraged microarray analysis of RNA isolated from peripheral blood mononuclear cells (PBMCs) to identify novel gene expression patterns and signaling pathways that could be associated with survival in SCD. Methods: Forty-two adult patients with SCD at steady-state (no VOC or ACS episodes for >3 weeks) were followed for 5 years (median follow-up 1154 ± 317 days). At baseline enrollment, patients underwent phlebotomy for plasma and serum collection. The plasma was utilized to extract mRNA from PBMCs. The serum was used to assess targeted cytokine levels using high-sensitive cytokine kits. Microarray expression analysis of PBMC mRNA utilized an FDR<10% and a fold-change >1.2. Student t-tests were performed for statistical significance. Results: Five out of forty-two patients (∼12%) died over the course of the study (median follow-up 1093 ± 320 days for surviving patients vs 1246 ± 325 days for patients who died, p=0.42). Although there were trends towards older age, higher tricuspid regurgitation jet velocity, NT-pro-BNP levels, AST levels, and lifetime number of transfusions in the patients that died, there were no statistically significant differences between groups (Table 1). Patients who died (n=5) exhibited 278 differentially regulated genes in comparison to those who survived (n=37). Gene ontology analysis revealed significantly represented T-cell receptor and immune mediated pathways, comprising seven out of the top ten pathways (p<0.05). Using a fold-change of 1.5 threshold on the transcripts, we identified a 14 gene signature which discriminated the survival of patients with 100% accuracy. Multiple genes within this molecular signature for survival also included immune-mediate pathways including CD160, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (NFKBIA), tumor necrosis factor, alpha-induced protein 3 (TNFAIP3), interleukin 1, beta (Il1B), killer cell lectin-like receptor subfamily G, member 1 (KLRG1), CD3d molecule, delta (CD3D), and killer cell lectin-like receptor subfamily F, member 1 (KLRF1). Given this robust representation of immune-mediate pathways in the signature and ontology analysis, we measured targeted plasma cytokine levels (based on candidates known to be involved in SCD) in all patients. IL-6 (5.7 ± 4.8 vs 11.7 ± 4.8 pg/mL, p=0.006) and IL-8 levels (3.5 ± 2.3 vs 6.2 ± 2.3 pg/mL, p=0.009) were significantly higher during steady-state in patients who later died than in those who survived. Interestingly, the anti-inflammatory cytokine IL-10 (35.2 ± 109.6 vs 16.1 ± 15.6 pg/mL) trended higher in the survival group while tumor necrosis factor levels trended lower (38.2 ± 28.0 vs 48.8 ± 38.5 pg/mL) but this did not reach statistical significance. Conclusion: These preliminary data suggest that a PBMC genomic signature is a potential prognostic biomarker in SCD. Patients who subsequently died demonstrated a unique PBMC-gene expression profile with significant representation of specific T-cell and immune-mediated pathways. Concurrently, these at-risk patients also demonstrated higher serum IL-6 and IL-8 levels. Given that high circulating levels of these type 2 cytokines suppress both humoral and cell-mediated immune functions, we speculate that T-cells may play novel role in the variable morbidity and mortality observed in SCD. Disclosures: No relevant conflicts of interest to declare.
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Cutler, Antony J., Joao Oliveira, Ricardo C. Ferreira, Ben Challis, Neil M. Walker, Sarah Caddy, Jia Lu, et al. "Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial." Wellcome Open Research 2 (April 18, 2017): 28. http://dx.doi.org/10.12688/wellcomeopenres.11300.1.
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Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. Results: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4+ T cell (Treg), effector T cell (Teff) CD4+ and CD8+ subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69+ and Ki-67+ effector memory Teffs were followed by the emergence of memory CD8+ Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. Conclusions: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.
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Cutler, Antony J., Joao Oliveira, Ricardo C. Ferreira, Ben Challis, Neil M. Walker, Sarah Caddy, Jia Lu, et al. "Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial." Wellcome Open Research 2 (July 18, 2017): 28. http://dx.doi.org/10.12688/wellcomeopenres.11300.2.
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Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. Results: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4+ T cell (Treg), effector T cell (Teff) CD4+ and CD8+ subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69+ and Ki-67+ effector memory Teffs were followed by the emergence of memory CD8+ Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. Conclusions: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.
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Cutler, Antony J., Joao Oliveira, Ricardo C. Ferreira, Ben Challis, Neil M. Walker, Sarah Caddy, Jia Lu, et al. "Capturing the systemic immune signature of a norovirus infection: an n-of-1 case study within a clinical trial." Wellcome Open Research 2 (October 5, 2017): 28. http://dx.doi.org/10.12688/wellcomeopenres.11300.3.
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Background: The infection of a participant with norovirus during the adaptive study of interleukin-2 dose on regulatory T cells in type 1 diabetes (DILT1D) allowed a detailed insight into the cellular and cytokine immune responses to this prevalent gastrointestinal pathogen. Methods: Serial blood, serum and peripheral blood mononuclear cell (PBMC) samples were collected pre-, and post-development of the infection. To differentiate between the immune response to norovirus and to control for the administration of a single dose of aldesleukin (recombinant interleukin-2, rIL-2) alone, samples from five non-infected participants administered similar doses were analysed in parallel. Results: Norovirus infection was self-limited and resolved within 24 hours, with the subsequent development of anti-norovirus antibodies. Serum pro- and anti-inflammatory cytokine levels, including IL-10, peaked during the symptomatic period of infection, coincident with increased frequencies of monocytes and neutrophils. At the same time, the frequency of regulatory CD4+ T cell (Treg), effector T cell (Teff) CD4+ and CD8+ subsets were dynamically reduced, rebounding to baseline levels or above at the next sampling point 24 hours later. NK cells and NKT cells transiently increased CD69 expression and classical monocytes expressed increased levels of CD40, HLA-DR and SIGLEC-1, biomarkers of an interferon response. We also observed activation and mobilisation of Teffs, where increased frequencies of CD69+ and Ki-67+ effector memory Teffs were followed by the emergence of memory CD8+ Teff expressing the mucosal tissue homing markers CD103 and β7 integrin. Treg responses were coincident with the innate cell, Teff and cytokine response. Key Treg molecules FOXP3, CTLA-4, and CD25 were upregulated following infection, alongside an increase in frequency of Tregs with the capacity to home to tissues. Conclusions: The results illustrate the innate, adaptive and counter-regulatory immune responses to norovirus infection. Low-dose IL-2 administration induces many of the Treg responses observed during infection.
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Dörner, T., Y. Tanaka, M. A. Petri, J. S. Smolen, D. Wallace, B. Crowe, E. Dow, et al. "OP0045 DELINEATION OF A PROINFLAMMATORY CYTOKINE PROFILE TARGETED BY JAK1/2 INHIBITION USING BARICITINIB IN A PHASE 2 SLE TRIAL." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 29.2–30. http://dx.doi.org/10.1136/annrheumdis-2020-eular.846.
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Background:Given the unmet clinical needs in systemic lupus erythematosus (SLE), including poor disease control and drug toxicities, new therapies are needed. In a phase 2, randomized, placebo-controlled, double-blind study (JAHH), once-daily baricitinib (bari) resulted in significant clinical improvement in patients (pts) with active SLE versus PBO. Bari inhibits JAK1 and JAK2 signalling, and in turn may affect STAT1, STAT2, STAT4 pathways. Therefore, bari has the potential to simultaneously impact several pro-inflammatory immune cytokines implicated in the pathogenesis of SLE, including IFN-α, IFN-γ, IL-6, IL-12, and IL-23.Objectives:The objectives of the current study were: 1) to examine baseline serum cytokines in the JAHH phase 2 clinical trial for correlations with clinical or immunologic assessments; 2) to determine if changes in serum cytokine levels were associated with bari treatment.Methods:Pts enrolled in the JAHH phase 2 trial received daily treatment with PBO, bari 2 mg, or bari 4 mg through week 24. Serum samples were collected at baseline (week [wk] 0), wk 12, and wk 24) from SLE pts (n=270) and 50 sex- and age-matched controls. Samples were analyzed for: IL-2, IL-3, IL-5, IL-6, IL-10, IL-17A, IL-21, IL-12/23p40, IL-12p70, GM-CSF, IFN-α and IFN-γ using ultrasensitive quantitative assays. IFN gene signature, autoantibodies, C3 and C4 were measured as previously described [1].Results:At wk 0, serum IL-17A, IL-12/23p40, IL-6, IFN-γ and IFN-α were readily detectable. IL-12/23p40 was detectable in 100% of pts vs. 100% of controls, IFN-γ in 89% of pts vs. 66% of controls, IL-6 in 53% of pts vs. 12% of controls and in IFN-α 41% of pts vs. 2% of controls; detection of serum IL-2, GM-CSF, IL-5, IL-10 and IL-17A was variable (Fig 1). At baseline (wk 0), IL-12/23p40 was positively correlated with SLEDAI and IFN gene signature and negatively correlated with serum C4. IL-6 was positively correlated with joint swelling, joint tenderness, IFN-γ and C3. Serum IFN-α was positively correlated with serum IFN-γ, anti-Sm and anti-RNP, and the IFN gene signature (Fig 2). Treatment with bari 4 mg (Fig 1B) significantly decreased serum IL12/23p40 and IL-6 cytokine levels at wk 12 (p<0.05) but not serum IFN-α or IFN-γ levels (Fig 1B).Figure 1.* p = 0.015; ** p = 0.001; Abbreviations: LLOQ, Lower limit of quantification.Figure 2.Abbreviations: Anti-dsDNA, Anti-double stranded DNA; Anti-RNP, Anti-ribonucleoprotein; CLASI, Cutaneous lupus erythematosus disease area and severity index; SLEDAI, SLE disease activity index.Conclusion:Bari 4 mg treatment was associated with statistically significant decreases of serum IL-12/23p40 and IL-6 at week 12 which continued through week 24. Serum IFN-α or IFN-γ were not reduced with bari treatment. Thus, bari 4 mg simultaneously impacted multiple pro-inflammatory cytokines implicated in the pathogenesis of SLE.References:[1]Hoffman RW, et al.Arthritis Rheumatol.2017;69(3):643-654.Disclosure of Interests:Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Michelle A Petri Grant/research support from: GSK, Eli Lilly and Company, Consultant of: Eli Lilly and Company, Josef S. Smolen Grant/research support from: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Consultant of: AbbVie, AstraZeneca, Celgene, Celltrion, Chugai, Eli Lilly, Gilead, ILTOO, Janssen, Novartis-Sandoz, Pfizer Inc, Samsung, Sanofi, Daniel Wallace Consultant of: Amgen, Eli Lilly and Company, EMD Merck Serono, and Pfizer, Brenda Crowe Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ernst Dow Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Richard E Higgs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Guilherme Rocha Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Robert Benschop Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Maria Silk Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Stephanie de Bono Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Robert Hoffman Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Damiano Fantini Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company
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Sariol, Carlos A., Jorge L. Muñoz-Jordán, Kristina Abel, Lymarie C. Rosado, Petraleigh Pantoja, Luis Giavedoni, Idia Vanessa Rodriguez, et al. "Transcriptional Activation of Interferon-Stimulated Genes but Not of Cytokine Genes after Primary Infection of Rhesus Macaques with Dengue Virus Type 1." Clinical and Vaccine Immunology 14, no. 6 (April 11, 2007): 756–66. http://dx.doi.org/10.1128/cvi.00052-07.
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ABSTRACT Macaques are the only animal model used to test dengue virus (DENV) vaccine candidates. Nevertheless, the pathogenesis of DENV in macaques is not well understood. In this work, by using Affymetrix oligonucleotide microarrays, we studied the broad transcriptional modifications and cytokine expression profile after infecting rhesus macaques with DENV serotype 1. Five days after infection, these animals produced a potent, innate antiviral immune response by inducing the transcription of signature genes from the interferon (IFN) pathway with demonstrated antiviral activity, such as myxoprotein, 2′,5′-oligoadenylate synthetase, phospholipid scramblase 1, and viperin. Also, IFN regulatory element 7, IFN-stimulated gene 15, and protein ligases linked to the ISGylation process were up-regulated. Unexpectedly, no up-regulation of IFN-α, -β, or -γ genes was detected. Transcription of the genes of interleukin-10 (IL-10), IL-8, IL-6, and tumor necrosis factor alpha was neither up-regulated nor down-regulated. Results were confirmed by real-time PCR and by multiplex cytokine detection in serum samples.
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Hayman, Thomas, Peter Hickey, Daniela Amann-Zalcenstein, Cavan Bennett, Ricardo Ataide, Rahvia Alam Sthity, Afsana Mim Khandaker, et al. "Zinc Supplementation with or without Additional Micronutrients Does Not Affect Peripheral Blood Gene Expression or Serum Cytokine Level in Bangladeshi Children." Nutrients 13, no. 10 (October 7, 2021): 3516. http://dx.doi.org/10.3390/nu13103516.
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Preventive zinc supplementation provided as a stand-alone dispersible tablet, or via home fortification as multiple micronutrient powders (MNPs), has been considered a potential strategy to prevent zinc deficiency and improve health (including immune) outcomes among children in low- and middle-income countries. However, the impact of zinc supplementation on immune profiles has not been well characterized. We sought to define the effect of zinc supplementation on peripheral blood gene expression and cytokine levels among young children in Dhaka, Bangladesh. In a sub-study of a large randomized, controlled, community-based efficacy trial where children 9–11 months of age received one of the following interventions on a daily basis for 24 weeks: (1) MNPs containing 10 mg of zinc; (2) dispersible tablet containing 10 mg zinc; or (3) placebo powder, we used RNA sequencing to profile the peripheral blood gene expression, as well as highly sensitive multiplex assays to detect cytokine profiles. We profiled samples from 100 children enrolled in the parent trial (zinc MNPs 28, zinc tablets 39, placebo 33). We did not detect an effect from either zinc intervention on differential peripheral blood gene expression at the end of the intervention, or an effect from the intervention on changes in gene expression from baseline. We also did not detect an effect from either intervention on cytokine concentrations. Exploratory analysis did not identify an association between undernutrition (defined as stunting, underweight or wasting) and peripheral blood gene expression. Zinc interventions in children did not produce a gene expression or cytokine signature in the peripheral blood. However, this study demonstrates a proof of principle that sensitive multi-omic techniques can be applied to samples collected in field studies.
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Pierson, Sheila K., and David C. Fajgenbaum. "Characterizing Serum Cytokine Levels in Idiopathic Multicentric Castleman Disease Reveals Increased Chemokines and a Potential Signature Compared to Related Diseases." Blood 138, Supplement 1 (November 5, 2021): 2693. http://dx.doi.org/10.1182/blood-2021-153893.
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Abstract Idiopathic multicentric Castleman disease (iMCD) is a heterogeneous and life-threatening hematologic disorder with unknown etiology. It involves extensive lymphadenopathy with characteristic histopathology, inflammatory symptoms, and life-threatening cytokine-driven multi-organ failure, if inadequately treatment. Diagnosis requires the presence of histopathological, clinical, laboratory, and radiologic findings as well as exclusion of other related diseases including infectious, autoimmune, and lymphoproliferative disorders. Despite these guidelines, definitive diagnosis remains challenging as histopathological changes, clinical features, and laboratory abnormalities are non-specific. Given that iMCD can be aggressive and life-threatening, timely diagnosis is crucial, and specific diagnostic biomarkers are needed. Interleukin-6 (IL-6) is a known disease driver in a portion of patients, but it is not consistently elevated at diagnosis and characterization of other cytokines has not been systematically performed. Previously, a plasma proteomics study identified upregulation of multiple cytokines, including several chemokines, such as C-X-C Motif Chemokine Ligand 13 (CXCL13) and C-C motif ligand 21 (CCL21), during disease flare in a small cohort. We sought to investigate whether these findings would be replicated in a larger cohort and to identify cytokines that could help to improve diagnosis of iMCD. Herein, we analyzed serum samples from 88 iMCD patients, 42 healthy donors, and 20 patients each with rheumatoid arthritis (RA), Hodgkin lymphoma (HL), and a subtype of multicentric Castleman disease caused by infection with human herpes virus 8 (HHV8+MCD). 1300 analytes were quantified by SomaLogic SOMASCAN; Uniprot database was used to select the 159 quantified cytokines for analysis. Data were log2 normalized and capped at the 2.5 th and 97.5 th percentiles. Linear models were used to identify significant differences among disease groups, with p values adjusted by Benjamini & Hochberg. Hierarchical clustering was performed using complete linkage. Of the 159 cytokines quantified, 54 (34%) were identified as significantly different between iMCD and healthy donors. The most upregulated cytokine was CXCL13 with a log2 fold-change (FC) of 1.7 (p<0.0001). The chemokines CCL21 (FC: 1.3, p<0.0001) and CCL23 (FC: 0.87, p<0.0001) were also noted among the top 10 most upregulated cytokines, consistent with the earlier plasma proteomic study. Of note, IL-6 (FC: 0.35, p=0.039) was also found, but it ranked 31 out of 54 in log2 FC magnitude. We next sought to compare cytokine elevation in iMCD to related disorders. Hierarchical clustering of all 159 cytokines appeared to differentiate iMCD from RA, HL, and HHV8+MCD (Figure 1), revealing a cluster with 72/88 (82%) iMCD and 4/60 (6%) related disease patients versus another with 16/88 (18%) iMCD and 56/60 (93%) related disease patients. Given this, we used linear models to test for significant differences in protein expression between iMCD and related diseases. We identified 12 cytokines that were significantly different between iMCD and each comparator disease (Table 1). Of these, 10 cytokines all trended in the positive direction in iMCD versus each comparator disease. CCL21 was again noted among this group and had the highest average FC for all three groups. Herein we validate earlier findings that cytokines, particularly chemokines are significantly upregulated in iMCD. While previous results compared disease flare to disease remission in a small pilot cohort, our patient sample is >10 times larger, represents a broader spectrum of disease severity, and is compared to a set of healthy donors and related diseases. Unbiased hierarchical clustering was able to separate iMCD from other diseases, and linear models identified specific cytokines that are significantly different in iMCD compared to each RA, HL, and HHV8+MCD. Further validation is need to assess whether a cytokine panel can differentiate iMCD from other related diseases, which would be crucial for timely diagnosis and treatment. Of note, CXCL13 and CCL21 are primarily produced by follicular dendritic cells and fibroblastic reticular cells, stromal cells responsible for coordinating B cell and T cell trafficking in the lymph node, respectively. Dysregulation of these cells may contribute to the dysmorphic appearance of lymph nodes and pathogenesis in iMCD. Figure 1 Figure 1. Disclosures Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'.
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Hillyer, Lyn M., Harry E. Maliwichi, and Bill Woodward. "Blood serum interferon-γ bioactivity is low in weanling mice subjected to acute deficits of energy or both protein and energy." British Journal of Nutrition 97, no. 3 (March 2007): 528–34. http://dx.doi.org/10.1017/s0007114507352409.
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The main objective of the present study was to determine the influence of acute deficits of protein and energy on the blood serum level of interferon-γ, a signature type 1 polarising inflammatory cytokine. In two 14 d experiments, male and female C57BL/6J mice, initial age 19 d, consumed a complete purified diet ad libitum or in restricted daily quantities, or had free access to an isoenergetic purified low-protein diet. A zero-time control group (age 19 d) was included in the second experiment. Serum interferon-γ was assessed in both experiments by sandwich ELISA and, in the second experiment, also by a bioassay based on inhibition of proliferation by WEHI-279 B lymphoma cells. The immunoassay detected interferon-γ inconsistently in all groups (range 0–14 pg/ml; detection limits 1·5 and 0·7 pg/ml in experiments 1 and 2, respectively). By contrast, interferon-γ bioactivity was found in all animals of each group (means 339, 499, 124 and 200 pg/ml in zero-time controls, age-matched controls, low-protein and restricted intake groups, respectively; detection limit, 12 pg/ml), and the mean serum bioactivity of each malnourished group was low compared with the age-matched control (P ≤ 0·05). The present study defines the physiological serum interferon-γ bioactivity of the adolescent mouse. Moreover, to the extent achievable by way of the blood, the results reflect the influence of metabolically diverse forms of acute malnutrition on the polarising type 1 cytokine profile within lymphoid microenvironments wherein immune responses arise. Therefore, the results suggest a mechanism underlying the cell-mediated inflammatory incompetence that characterises acute, prepubescent malnutrition.
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Kainonen, Essi, Samuli Rautava, and Erika Isolauri. "Immunological programming by breast milk creates an anti-inflammatory cytokine milieu in breast-fed infants compared to formula-fed infants." British Journal of Nutrition 109, no. 11 (October 30, 2012): 1962–70. http://dx.doi.org/10.1017/s0007114512004229.
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Breast milk provides important maturational stimuli to an infant's developing immune system. However, data concerning the role of breast-feeding in reducing the risk of allergic disease remain contradictory. Previous studies have centred on comparative analyses of breast milk and formula compositions. We chose a slightly different angle, whereby we focused on the effects of the chosen diet on the infant himself, comparing the immune development of formula-fed and breast-fed children. The objective of the present study was to determine how the mode of feeding affects infant immunology. Altogether, eighteen formula-fed infants with limited breast-feeding for < 3 months and twenty-nine infants who were exclusively breast-fed for >3 months were included in the study. Concentrations of interferon γ, TNF-α IL-10, IL-5, IL-4 and IL-2 were measured simultaneously from the same serum sample through use of a multiplexed flow cytometric assay at the ages of 1, 3, 6 and 12 months. Transforming growth factor β2 (TGF-β2) was measured using ELISA at the same time points. Serum TNF-α and IL-2 concentrations were significantly higher in formula-fed than in breast-fed infants during the first year of life (ANOVA, P= 0·002). The serum concentrations of TGF-β were significantly lower in formula-fed than in breast-fed infants throughout the first year of life (ANOVA, P≤ 0·0001). Exclusive breast-feeding promotes an anti-inflammatory cytokine milieu, which is maintained throughout infancy. Such an immunological environment limits hyper-responsiveness and promotes tolerisation, possibly prohibiting the onset of allergic disease.
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Noto, Alessandra, Victor Joo, Antonio Mancarella, Madeleine Suffiotti, Celine Pellaton, Craig Fenwick, Matthieu Perreau, and Giuseppe Pantaleo. "CXCL12 and CXCL13 Cytokine Serum Levels Are Associated with the Magnitude and the Quality of SARS-CoV-2 Humoral Responses." Viruses 14, no. 12 (November 28, 2022): 2665. http://dx.doi.org/10.3390/v14122665.
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A better understanding of the immunological markers associated with long-lasting immune responses to SARS-CoV-2 infection is of paramount importance. In the present study, we characterized SARS-CoV-2-specific humoral responses in hospitalized (ICU and non-ICU) and non-hospitalized individuals at six months post-onset of symptoms (POS) (N = 95). We showed that the proportion of individuals with detectable anti-SARS-CoV-2 IgG or neutralizing (NAb) responses and the titers of antibodies were significantly reduced in non-hospitalized individuals, compared to ICU- or non-ICU-hospitalized individuals at 6 months POS. Interestingly, SARS-CoV-2-specific memory B cells persist at 6 months POS in both ICU and non-ICU patients and were enriched in cells harboring an activated and/or exhausted phenotype. The frequency/phenotype of SARS-CoV-2-specific memory B cells and the magnitude of IgG or NAb responses at 6 months POS correlated with the serum immune signature detected at patient admission. In particular, the serum levels of CXCL13, IL-1RA, and G-CSF directly correlated with the frequency of Spike-specific B cells and the magnitude of Spike-specific IgG or NAb, while the serum levels of CXCL12 showed an antagonizing effect. Our results indicate that the balance between CXCL12 and CXCL13 is an early marker associated with the magnitude and the quality of the SARS-CoV-2 humoral memory.
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Harding, James J., Raymond Yeh, Yan Nikhamin, Mark Frattini, Nicole Lamanna, Joseph G. Jurcic, Mark Heaney, and Renier Brentjens. "Characteristic Proinflammatory Serum Cytokine Profiles In Patients with B-Cell Chronic Lymphocytic Leukemia." Blood 116, no. 21 (November 19, 2010): 3595. http://dx.doi.org/10.1182/blood.v116.21.3595.3595.
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Abstract Abstract 3595 Background: Cytokines are posited to play a critical regulatory role on the survival of the B-cell neoplastic clone in Chronic Lymphocytic Leukemia (CLL). AIM: The primary goals of this study were 1) to define additional relevant cytokines, growth factors and chemokines in CLL pathophysiology and 2) to correlate abnormal cytokine levels with disease stage, relevant hematological data and multiple prognostic factors. METHODS: A novel bead-based protein array system was employed to simultaneously measure 38 proinflammatory cytokines in the sera of CLL patients (N=116) and healthy age and sex matched controls (N=30). These results were correlated with Rai stage, β2-microglobulin level, LDH, CD38 expression and cytogenetic abnormalities. RESULTS: We first confirmed previous observations that TNFα, IL-1α, IL-1RA, IL-10, sIL-2Rα, VEGF and sCD40 ligand are significantly elevated in patients with CLL as compared with healthy controls. Expanding on the current literature, we demonstrated perturbations in an additional 15 serum cytokines in affected individuals. Compared to healthy controls, CLL patients had an increase in serum levels of IL-3 (p=0.002), IL-7 (p=0.008), INF-2α (p<0.0001), MCP-1 (p<0.0001), MIP-1β (p=0.002), MDC (p<0.0001), Fractakine (p<0.0001), EGF (p<0.0001), FGF-2 (p<0.0001), GRO (p<0.0001), Eotaxin (p<0.0001) and FLT-3 ligand (p<0.0001). Patients with CLL also exhibited significantly lower levels of INF-γ (p<0.01), IL-6 (p<0.005) and IL-8 (p<0.002) when compared to healthy individuals. Advanced Rai stage and high risk chromosomal abnormalities (del 11q and del 17p) strongly correlated with higher serum levels of TNFα, soluble IL-2Rα, IL-10, MCP-1, MIP-1α, MIP-1β and IP-10. Finally, serum levels of TNFα, MIP-1α and MIP-1β correlated with other adverse prognostic markers, including total white blood cell count, serum β2-microglobulin and LDH levels as well as CD38 expression. CONCLUSION: We have demonstrated numerous previously unrecognized cytokine abnormalities in patients with CLL and described a unique cytokine signature associated with advanced disease. Supported by the current understanding of cytokine biology and CLL pathophysiology, our observations suggest an important regulatory role for hematopoietic cytokines, such as IL-3 and IL-7, in promulgating survival of the aberrant B-cell clone. Likewise, the profoundly high levels of chemokines (i.e. MCP-1, MIP-1α, MIP-1β, IP-10) and their association with high risk prognostic factors argue for their role in sustaining the neoplastic microenvironment. Finally, the altered levels of IL-10, IL-6 and INF-γ observed in patients with CLL likely contribute to the immunosuppressive phenotype of the disease state. Disclosures: No relevant conflicts of interest to declare.
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Fan, X. G., W. E. Liu, C. Z. Li, Z. C. Wang, L. X. Luo, D. M. Tan, G. L. Hu, and Z. Zhang. "Circulating Th1 and Th2 cytokines in patients with hepatitis C virus infection." Mediators of Inflammation 7, no. 4 (1998): 295–97. http://dx.doi.org/10.1080/09629359890992.
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The imbalance of T-helper (Th) lymphocyte cytokine production may play an important role in immunopathogenes is of persistent hepatitis C virus (HCV) infection. To know whether an imbalance between Th1 and Th2 cytokines is present in chronic HCV infection, serum levels of Th1 cytokines , interferon gamma (IFN-γ ) and interleukin (IL)-2, and Th2 cytokines, IL-4 and IL-10, were measured using enzyme - linked immunosorbent as say in this study. Eighteen individuals with chronic HCV infection, 11 healthy subjects as normal controls and 10 chronic HBV infected patients as disease controls were observed. The results showed that the leve ls of Th2 cytokines (IL-4 and IL-10) were significantly increased inchronic HCV infected patients compared with normal controls (IL-4: 30.49 ± 17.55 vs . 14.94 ± 13.73, pg/ml,p<0.025; IL-10: 50.30 ± 19.59 vs. 17.87 ± 9.49, pg/ml,p<0.001). Similarly, the levels of Th1 cytokine, IL-2, was also elevated in individuals with chronic HCV infection when compared with normal controls (IL-2: 118.53 ± 95.23 vs . 61.57 ± 28.70, pg/ml,p<0.05). However, Th1 cytokine IFN-γ level was not significantly changed during HCV infection (IFN-γ: 28.09 ± 15.65 vs . 24.10 ± 15.61, pg/ml,p>0.05). Further more, the elevated levels of Th2 cytokines are greater than Th1 cytokines in HCV infection. Thus , the study indicates that an enhanced Th2 responses are present during chronic HCV infection, which may partly be responsible for the persistence of HCV infection.
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Mikulski, Damian, Paweł Robak, Ewelina Perdas, Edyta Węgłowska, Aleksandra Łosiewicz, Izabela Dróżdż, Dariusz Jarych, et al. "Pretreatment Serum Levels of IL-1 Receptor Antagonist and IL-4 Are Predictors of Overall Survival in Multiple Myeloma Patients Treated with Bortezomib." Journal of Clinical Medicine 11, no. 1 (December 26, 2021): 112. http://dx.doi.org/10.3390/jcm11010112.
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Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The present study examines the influence on progression-free survival (PFS) and overall survival (OS) by the serum levels of 27 selected cytokines in 61 newly diagnosed MM patients receiving first-line therapy with bortezomib-based regimens. The measurements were performed using a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay and a MAGPIX Multiplex Reader, based on the Bio-Plex® 200 System (Bio-Rad). The following levels were determined: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. Most patients received a VCD chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone). In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240–0.8291, p = 0.0302) and ASCT (HR 0.3722, 95% CI: 0.1826–0.7585, p = 0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046–0.438, p = 0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471–9.949, p = 0.0059), and two cytokine levels—IL-1Ra (HR 1.017, 95% CI: 1.004–1.030, p = 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037–0.698, p = 0.0147)—were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.
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Aravindraja, Chairmandurai, Krishna Mukesh Vekariya, Ruben Botello-Escalante, Shaik O. Rahaman, Edward K. L. Chan, and Lakshmyya Kesavalu. "Specific microRNA Signature Kinetics in Porphyromonas gingivalis-Induced Periodontitis." International Journal of Molecular Sciences 24, no. 3 (January 24, 2023): 2327. http://dx.doi.org/10.3390/ijms24032327.
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Porphyromonas gingivalis is one of the major bacteria constituting the subgingival pathogenic polymicrobial milieu during periodontitis. Our objective is to determine the global microRNA (miRNA, miR) expression kinetics in 8- and 16-weeks duration of P. gingivalis infection in C57BL/6J mice and to identify the miRNA signatures at specific time-points in mice. We evaluated differential expression (DE) miRNAs in mandibles (n = 10) using high-throughput NanoString nCounter® miRNA expression panels. The bacterial colonization, alveolar bone resorption (ABR), serum immunoglobulin G (IgG) antibodies, and bacterial dissemination were confirmed. In addition, all the infected mice showed bacterial colonization on the gingival surface, significant increases in ABR (p < 0.0001), and specific IgG antibody responses (p < 0.05–0.001). The miRNA profiling showed 26 upregulated miRNAs (e.g., miR-804, miR-690) and 14 downregulated miRNAs (e.g., miR-1902, miR-1937a) during an 8-weeks infection, whereas 7 upregulated miRNAs (e.g., miR-145, miR-195) and one downregulated miR-302b were identified during a 16-weeks infection. Both miR-103 and miR-30d were commonly upregulated at both time-points, and all the DE miRNAs were unique to the specific time-points. However, miR-31, miR-125b, miR-15a, and miR-195 observed in P. gingivalis-infected mouse mandibles were also identified in the gingival tissues of periodontitis patients. None of the previously identified miRNAs reported in in vitro studies using cell lines (periodontal ligament cells, gingival epithelial cells, human leukemia monocytic cell line (THP-1), and B cells) exposed to P. gingivalis lipopolysaccharide were observed in the in vivo study. Most of the pathways (endocytosis, bacterial invasion, and FcR-mediated phagocytosis) targeted by the DE miRNAs were linked with bacterial pathogen recognition and clearance. Further, eighteen miRNAs were closely associated with the bacterial invasion of epithelial cells. This study highlights the altered expression of miRNA in gingiva, and their expression depends on the time-points of infection. This is the first in vivo study that identified specific signature miRNAs (miR-103 and miR-30d) in P. gingivalis invasion of epithelial cells, establishes a link between miRNA and development of periodontitis and helping to better understand the pathobiology of periodontitis.
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Mardiak, Jozef, Dana Cholujova, Igor Jurisica, Paulina Gronesova, Vera Miskovska, Jana Obertova, Patrik Palacka, et al. "A cytokine and angiogenic factor (CAF) analysis in plasma in testicular germ cell tumor patients (TGCTs)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e15599-e15599. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e15599.
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e15599 Background: We investigated cytokines and angiogenic factors (CAFs) in patients with testicular germ cell tumors (TGCTs). We aimed to link the CAF profile to type of response to chemotherapy and select candidate prognostic and predictive markers for further study. Methods: In the presented study, plasma from 99 patients (pt) with TGCTs treated with first line (95 pt) or salvage (4 pt) chemotherapy was collected. The concentrations of 51 plasma CAFs were measured pre-treatment (n = 80) and on day 22 (n = 60) using multiplex bead arrays (Human Group I and II cytokine panels and TGF beta by Bio-Plex 200 system (Bio-Rad Laboratories, Hercules, CA). We used unsupervised clustering with self-organizing map (SOM) and k-means clustering to analyze CAF expression profiles. Results: Unsupervised clustering with self-organizing maps and k-means identified characteristic plasma cytokine profiles in different subgroups of patients according to response to chemotherapy and other clinical variables. Several cytokines were differentially expressed in patients with favourable and unfavorable response in serum before chemotherapy including IL-1b, IL-15, M-CSF, IL-4, IL-5, b-NGF, IL-10, MCP-3, FGF basic, IL-6, MIP-1a, GM-CSF, IL-17, IL-13, MIP1b, IL-8, SCF, IFN alfa, SCGFb, IL-2RA, IP-10, IL-16, TGFb-3. Similarly, following cytokines were differentially expressed in serum after 1st cycle of chemotherapy IL-1b, TGFb-3, LIF, TGFb-2, IL-16, IL-18, IL-2RA, MCP-3, IFN alfa, HGF, IL1a, MIF, SCF, IL-3, SCGFb, b-NGF, MIG, CTACK. Conclusions: CAF profiling with unsupervised clustering revealed clinically relevant differences in subgroups of TGCTs patients. We suggest that this platform may provide valuable insights into TGCTs biology, and could help to identify plasma cytokine signature for predicting treatment resistance.
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Vantaggiato, Lorenza, Enxhi Shaba, Paolo Cameli, Laura Bergantini, Miriana d’Alessandro, Alfonso Carleo, Giusy Montuori, Luca Bini, Elena Bargagli, and Claudia Landi. "BAL Proteomic Signature of Lung Adenocarcinoma in IPF Patients and Its Transposition in Serum Samples for Less Invasive Diagnostic Procedures." International Journal of Molecular Sciences 24, no. 2 (January 4, 2023): 925. http://dx.doi.org/10.3390/ijms24020925.
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Idiopathic pulmonary fibrosis (IPF) is a form of chronic and irreversible fibrosing interstitial pneumonia of unknown etiology. Although antifibrotic treatments have shown a reduction of lung function decline and a slow disease progression, IPF is characterize by a very high mortality. Emerging evidence suggests that IPF increases the risk of lung carcinogenesis. Both diseases show similarities in terms of risk factors, such as history of smoking, concomitant emphysema, and viral infections, besides sharing similar pathogenic pathways. Lung cancer (LC) diagnosis is often difficult in IPF patients because of the diffuse lung injuries and abnormalities due to the underlying fibrosis. This is reflected in the lack of optimal therapeutic strategies for patients with both diseases. For this purpose, we performed a proteomic study on bronchoalveolar lavage fluid (BALF) samples from IPF, LC associated with IPF (LC-IPF) patients, and healthy controls (CTRL). Molecular pathways involved in inflammation, immune response, lipid metabolism, and cell adhesion were found for the dysregulated proteins in LC-IPF, such as TTHY, APOA1, S10A9, RET4, GDIR1, and PROF1. The correlation test revealed a relationship between inflammation- and lipid metabolism-related proteins. PROF1 and S10A9, related to inflammation, were up-regulated in LC-IPF BAL and serum, while APOA1 and APOE linked to lipid metabolism, were highly abundant in IPF BAL and low abundant in IPF serum. Given the properties of cytokine/adipokine of the nicotinamide phosphoribosyltransferase, we also evaluated its serum abundance, highlighting its down-regulation in LC-IPF. Our retrospective analyses of BAL samples extrapolated some potential biomarkers of LC-IPF useful to improve the management of these contemporary pathologies. Their differential abundance in serum samples permits the measurement of these potential biomarkers with a less invasive procedure.
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Ogłodek, Ewa. "Changes in the Serum Levels of Cytokines: IL-1β, IL-4, IL-8 and IL-10 in Depression with and without Posttraumatic Stress Disorder." Brain Sciences 12, no. 3 (March 14, 2022): 387. http://dx.doi.org/10.3390/brainsci12030387.
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Background: Both depressive disorders (DD) and post-traumatic stress disorders (PTSD) are caused by immune system dysfunction. Affected individuals show increased proinflammatory cytokine concentration levels. Also, it has been hypothesized that DD and PTSD might be associated with a generalized proinflammatory cytokine signature. The study assessed the concentration of IL-1β, IL-4, IL-8 and IL-10 in depression alone and with PTSD. Methods: The study involved 460 participants. Out of them, 420 subjects comprised a study group and 40 subjects comprised a control group. Each study group consisted of 60 patients with mild depression (MD), moderate depression (MOD), severe depression (SeD), MD and PTSD (MD + PTSD), MOD and PTSD (MOD + PTSD), SeD and PTSD (SeD + PTSD), and with PTSD alone. All patients had serum concentration of IL-1β, IL-4, IL-8 and IL-10 measured with ELISA. Results: DD and PTSD are reflected in IL-1β, IL-4, IL-8 and IL-10 concentration levels. It was reported that mean levels of IL-1β, IL-4, IL-8 increase as depression became more severe. A regular decrease in IL-10 concentration levels was noted with the onset and exacerbation of depressive symptoms. Conclusion: The findings might be useful when considering chronic inflammation as a potential target or biomarker in depression and PTSD treatment.
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Vera Aguilera, Jesus, Courtney L. Erskine, Vera J. Suman, Jonas Paludo, Robert R. McWilliams, Lisa A. Kottschade, Yiyi Yan, et al. "IL-12p40 and MIP3a to predict clinical responses to anti-PD-1 therapy in patients with metastatic melanoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 9535. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9535.
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9535 Background: A broad understanding of baseline immunity is needed in order to predict responses to PD-1 blockade. We previously reported in a preclinical model that elevated Th1 signature cytokines are present after successful therapy with PD-1 blockade. In this study we evaluated serum cytokines as biomarkers of response in a cohort of patients with metastatic melanoma undergoing anti-PD1 therapy. Methods: 27 pts diagnosed with metastatic melanoma (MM) received anti-PD-1 therapy and had peripheral blood collected prior to anti-PD-1 therapy start and 12 weeks after; 55 proinflammatory-related serum cytokines were analyzed at both times using the Meso Scale Discovery (MSD) assay. At week 12, we identified 15 pts who had radiographic complete or partial response (TR) and 12 had progressive disease (PD) using RECIST criteria. Spearman rank correlation coefficients (rho) were used to assess association between pre-treatment serum cytokine levels. For each cytokine, differences in pretreatment serum levels and the ratio of the 12 week to pre-treatment serum levels between TR and PD groups were assessed using Wilcoxon rank sum tests. Results: Pretreatment serum IL-12p40 and MIP3a (CCL20) were moderately correlated (rho=0.3944). Pretreatment IL-12p40 and was found to be significantly higher (p=0.0025) in the TR group (median=48.5; 25th to 75th percentile [IQR]:25.3-63.8) relative to the PD group (median=17.3; IQR: 8.6-30.3). Pretreatment MIP3a was also found to be significantly higher (p=0.0359) in the TR group (median=1.72; IQR: 1.41-2.65) relative to the PD group (median=1.33; IQR: 1.09-1.98). The 12th week pretreatment IL-12p40 ratio (median=1.98; IQR: 1.4-11.3) in the TR group was greater than that (median=0.64; IQR: 0.23-1.61) in the PD group (p=0.0029); we identified that baseline serum levels >15pg/ml of IL12p40 prior to immunotherapy were associated with significantly prolonged event free survival (p=0.001). Conclusions: Measurements of IL-12p40 and MIP-3a levels before immunotherapy may help to select patients who are likely to benefit from anti-PD1 therapy. Additionally, exploration of combination therapies that increase IL-12P40 and MIP3 prior or during immunotherapy should be undertaken.
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Salim, Saad Y., Nour AlMalki, Kimberly F. Macala, Alyssa Wiedemeyer, Thomas F. Mueller, Thomas A. Churchill, Stephane L. Bourque, and Rachel G. Khadaroo. "Oncostatin M Receptor Type II Knockout Mitigates Inflammation and Improves Survival from Sepsis in Mice." Biomedicines 11, no. 2 (February 8, 2023): 483. http://dx.doi.org/10.3390/biomedicines11020483.
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Sepsis remains one of the leading causes of death worldwide. Oncostatin M (OSM), an interleukin (IL)-6 family cytokine, can be found at high levels in septic patients. However, little is known about its role in sepsis. This study aimed to determine if the genetic knockout of OSM receptor (OSMR) type II signaling would improve survival in a murine model of sepsis. Aged (>50 weeks) OSMR type II knockout (KO) mice and wild-type (WT) littermates received an intraperitoneal injection of fecal slurry (FS) or vehicle. The KO mice had better survival 48 h after the injection of FS than the WT mice (p = 0.005). Eighteen hours post-FS injection, the KO mice had reduced peritoneal, serum, and tissue cytokine levels (including IL-1β, IL-6, TNFα, KG/GRO, and IL-10) compared to the WT mice (p < 0.001 for all). Flow cytometry revealed decreased recruitment of CD11b+ F4/80+ Ly6chigh+ macrophages in the peritoneum of KO mice compared to WT mice (34 ± 6 vs. 4 ± 3%, PInt = 0.005). Isolated peritoneal macrophages from aged KO mice had better live E. coli killing capacity than those from WT mice (p < 0.001). Peritoneal lavage revealed greater bacterial counts in KO mice than in WT mice (KO: 305 ± 22 vs. 116 ± 6 CFU (×109)/mL; p < 0.001). In summary, deficiency in OSMR type II receptor signaling provided a survival benefit in the progression of sepsis. This coincided with reduced serum levels of pro-inflammatory (IL-1β, TNFα, and KC/GRO) and anti-inflammatory markers (IL-10), increased bacterial killing ability of macrophages, and reduced macrophage infiltration into to site of infection.
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Beckman, Micaela F., Elizabeth J. Brennan, Chika K. Igba, Michael T. Brennan, Farah B. Mougeot, and Jean-Luc C. Mougeot. "A Computational Text Mining-Guided Meta-Analysis Approach to Identify Potential Xerostomia Drug Targets." Journal of Clinical Medicine 11, no. 5 (March 5, 2022): 1442. http://dx.doi.org/10.3390/jcm11051442.
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Xerostomia (subjective complaint of dry mouth) is commonly associated with salivary gland hypofunction. Molecular mechanisms associated with xerostomia pathobiology are poorly understood, thus hampering drug development. Our objectives were to (i) use text-mining tools to investigate xerostomia and dry mouth concepts, (ii) identify associated molecular interactions involving genes as candidate drug targets, and (iii) determine how drugs currently used in clinical trials may impact these genes and associated pathways. PubMed and PubMed Central were used to identify search terms associated with xerostomia and/or dry mouth. Search terms were queried in pubmed2ensembl. Protein–protein interaction (PPI) networks were determined using the gene/protein network visualization program search tool for recurring instances of neighboring genes (STRING). A similar program, Cytoscape, was used to determine PPIs of overlapping gene sets. The drug–gene interaction database (DGIdb) and the clinicaltrials.gov database were used to identify potential drug targets from the xerostomia/dry mouth PPI gene set. We identified 64 search terms in common between xerostomia and dry mouth. STRING confirmed PPIs between identified genes (CL = 0.90). Cytoscape analysis determined 58 shared genes, with cytokine–cytokine receptor interaction representing the most significant pathway (p = 1.29 × 10−23) found in the Kyoto encyclopedia of genes and genomes (KEGG). Fifty-four genes in common had drug interactions, per DGIdb analysis. Eighteen drugs, targeting the xerostomia/dry mouth PPI network, have been evaluated for xerostomia, head and neck cancer oral complications, and Sjögren’s Syndrome. The PPI network genes IL6R, EGFR, NFKB1, MPO, and TNFSF13B constitute a possible biomarker signature of xerostomia. Validation of the candidate biomarkers is necessary to better stratify patients at the genetic and molecular levels to facilitate drug development or to monitor response to treatment.
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Tomaszewska, Katarzyna, Magdalena Kozłowska, Andrzej Kaszuba, Aleksandra Lesiak, Joanna Narbutt, and Anna Zalewska-Janowska. "Increased Serum Levels of IFN-γ, IL-1β, and IL-6 in Patients with Alopecia Areata and Nonsegmental Vitiligo." Oxidative Medicine and Cellular Longevity 2020 (August 3, 2020): 1–5. http://dx.doi.org/10.1155/2020/5693572.
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Alopecia areata (AA) and vitiligo are both common skin diseases of autoimmune origin. Both alopecia areata and vitiligo have shown to be affected by oxidative stress. The present work is aimed at evaluating and comparing the serum proinflammatory cytokine levels in AA and nonsegmental vitiligo (NSV). A cross-sectional study was conducted of 33 patients with AA, 30 patients with NSV, and 30 healthy controls. Serum levels of interferon γ (IFN-γ), interleukin- (IL-) 1β, and IL-6 were determined quantitatively by ELISA method. Our analysis identified a signature of oxidative stress associated with AA and NSV, characterized by elevated levels of IFN-γ (AA: p=0.007283; NSV: p=0.038467), IL-1β (AA; NSV: p≤0.001), and IL-6 (AA; NSV: p≤0.001). IL-6 was also significantly increased in NSV patients in comparison with AA patients (p=0.004485). Our results supported the hypothesis that oxidative stress may play a significant role in promoting and amplifying the inflammatory process both in AA and vitiligo. The complex understanding of both disease etiopathogenesis involves interrelationships between oxidative stress and autoimmunity. The clinical study registration number is RNN/266/16/KE.
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Kim, Do-Kyun, Young-Eun Cho, Hirsh D. Komarow, Geethani Bandara, Byoung-Joon Song, Ana Olivera, and Dean D. Metcalfe. "Mastocytosis-derived extracellular vesicles exhibit a mast cell signature, transfer KIT to stellate cells, and promote their activation." Proceedings of the National Academy of Sciences 115, no. 45 (October 23, 2018): E10692—E10701. http://dx.doi.org/10.1073/pnas.1809938115.
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Extracellular vesicles (EVs) have been implicated in the development and progression of hematological malignancies. We thus examined serum samples from patients with systemic mastocytosis (SM) and found EVs with a mast cell signature including the presence of tryptase, FcεRI, MRGX2, and KIT. The concentration of these EVs correlated with parameters of disease including levels of serum tryptase, IL-6, and alkaline phosphatase and physical findings including hepatosplenomegaly. Given reports that EVs from one cell type may influence another cell’s behavior, we asked whether SM-EVs might affect hepatic stellate cells (HSCs), based on the abnormal liver pathology associated with mastocytosis. We found that KIT was transferred from SM-EVs into an HSC line eliciting proliferation, cytokine production, and differentiation, processes that have been associated with liver pathology. These effects were reduced by KIT inhibition or neutralization and recapitulated by enforced expression of KIT or constitutively active D816V-KIT, a gain-of-function variant associated with SM. Furthermore, HSCs in liver from mice injected with SM-EVs had increased expression of α-SMA and human KIT, particularly around portal areas, compared with mice injected with EVs from normal individuals, suggesting that SM-EVs can also initiate HSC activation in vivo. Our data are thus consistent with the conclusion that SM-EVs have the potential to influence cells outside the hematological compartment and that therapeutic approaches for treatment of SM may be effective in part through inhibition of effects of EVs on target tissues, findings important both to understanding complex disease pathology and in developing interventional agents for the treatment of hematologic diseases.
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Zuñiga, Joaquín, José Alberto Choreño-Parra, Luis Jiménez-Alvarez, Alfredo Cruz-Lagunas, José Eduardo Márquez-García, Gustavo Ramírez-Martínez, Aminadab Goodina, et al. "A unique immune signature of serum cytokine and chemokine dynamics in patients with Zika virus infection from a tropical region in Southern Mexico." International Journal of Infectious Diseases 94 (May 2020): 4–11. http://dx.doi.org/10.1016/j.ijid.2020.02.014.
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Amin, Jay, Delphine Boche, Zoe Clough, Jessica Teeling, Anthony Williams, Yifang Gao, Lindsey Chudley, et al. "Peripheral immunophenotype in dementia with Lewy bodies and Alzheimer’s disease: an observational clinical study." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 11 (September 23, 2020): 1219–26. http://dx.doi.org/10.1136/jnnp-2020-323603.
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BackgroundInflammation plays a key role in the aetiology and progression of Alzheimer’s disease (AD). However, the immunophenotype of the second most common neurodegenerative cause of dementia, dementia with Lewy bodies (DLB), remains unclear. To date there have been no studies examining peripheral inflammation in DLB using multiplex immunoassay and flow cytometry concomitantly. We hypothesised that, using blood biomarkers, DLB would show an increased proinflammatory profile compared with controls, and that there would be a distinct profile compared with AD.Methods93 participants (31 with DLB, 31 with AD and 31 healthy older controls) completed a single study visit for neuropsychiatric testing and phlebotomy. Peripheral blood mononuclear cells were quantified for T and B cell subsets using flow cytometry, and serum cytokine concentrations were measured using multiplex immunoassay.ResultsWe detected reduced relative numbers of helper T cells and reduced activation of B cells in DLB compared with AD. Additionally, interleukin (IL)-1β was detected more frequently in DLB and the serum concentration of IL-6 was increased compared with controls.ConclusionsPeripheral inflammation is altered in DLB compared with AD, with T cell subset analysis supporting a possible shift towards senescence of the adaptive immune system in DLB. Furthermore, there is a proinflammatory signature of serum cytokines in DLB. Identification of this unique peripheral immunophenotype in DLB could guide development of an immune-based biomarker and direct future work exploring potential immune modulation as a novel treatment.
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Zhang, Xin, Shikha Singla, Jerry Pound, Jerald Zakem, Kismet Collin, Tamika Webb-Detiege, William Davis, and Robert Quinet. "Identification of follicular helper T cells as a novel cell population potentially involved in the pathogenesis of Rheumatoid Arthritis (HUM3P.251)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 121.11. http://dx.doi.org/10.4049/jimmunol.194.supp.121.11.
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Abstract Background. RA is an autoimmune disease characterized by chronic inflammation of the synovium, causing progressive joint destruction. The treatment for RA is largely based on the clinic manifestations, which are remote from the fundamental pathophysiologic defects. Identification of cellular subsets or biomarkers is a necessary first step toward more accurate prognosis and better therapeutic decisions. Here, we identified a novel T cell subset, follicular helper T cells (Tfh) in RA patients, and examined the hypothesis that Tfh cells may account for RA pathogenesis by providing a fostering environment for self-reactive B cells, resulting in autoantibody production. Methods. Peripheral blood was collected from 26 RA patients and healthy donors. Synovial fluid from actively inflamed joints of RA patients was also collected. Clinical disease activity (DAS-28) and serum laboratory results were obtained. Tfh cells were defined by their signature surface markers via flow cytometry. IL-21 expression and plasmablasts were measured by intracellular staining. Results. A novel T cell subset with Tfh cell signature molecule and cytokine was expanded in the peripheral blood of active RA patients. The percentage of Tfh cells correlated positively with the level of pathogenic auto-antibody (anti-CCP) and disease activity. Conclusions. Circulating Tfh cells may serve as a biomarker of pathogenesis in RA patients. Targeting RA-Tfh cells may provide earlier and precise treatment strategies.
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Arnaud, Laurent, Guy Gorochov, Frédéric Charlotte, Virginie Lvovschi, Christophe Parizot, Martin Larsen, Pascale Ghillani-Dalbin, et al. "Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients." Blood 117, no. 10 (March 10, 2011): 2783–90. http://dx.doi.org/10.1182/blood-2010-10-313510.
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Abstract Immunopathogenesis of Erdheim-Chester disease (ECD), a rare non–Langerhans cell histiocytosis, is poorly known. In previous studies, various cytokines were detected in ECD lesions, presumably orchestrating lesional histiocyte recruitment. Because ECD lesions are frequently associated with systemic symptoms, we postulated that underlying global immune perturbations might also be revealed. We quantitatively analyzed 23 cytokines in serum samples obtained from a large single-center cohort of 37 patients with ECD, and studied the impact of treatment on cytokine production. IL-6, IL-12, interferon-α (IFN-α), and monocyte chemotactic protein-1 (MCP-1) levels were significantly higher in untreated patients than in controls, whereas interferon-γ (IFN-γ) inducible protein 10, IL-12, MCP-1, and IL-1 receptor antagonist were found significantly increased in IFN-α–treated patients. A biomathematical approach was used to rationalize multiparameter data, to generate new hypotheses, and identify global control pathways. Interestingly, cytokine profiles proved to be particularly stable at the individual level, and an “ECD signature” further distinguished patients from controls, based on their production of IFN-α, IL-12, MCP-1, IL-4, and IL-7. Altogether, our data underline the systemic immune Th-1–oriented perturbation associated with this condition and provide clues for the choice of more focused therapeutic agents in this rare disease with noncodified therapeutic management.
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O'Gorman, William, Huang Huang, Yu-Ling Wei, Kara Davis, Michael Leipold, Sean Bendall, Brian Kidd, et al. "The split-virus influenza vaccine activates Fcγ receptors instead of Toll-like receptors (VAC2P.930)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 72.8. http://dx.doi.org/10.4049/jimmunol.192.supp.72.8.
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Abstract Seasonal influenza vaccination is the most common medical procedure targeting the immune system and yet the extent to which influenza vaccination activates innate immunity in humans is not fully understood. Currently, the most prevalent formulations of the vaccine consist of degraded or “split” viral particles often prepared without any adjuvants. We sought to determine whether the unadjuvanted split influenza vaccine activates innate immune receptors—specifically Toll-like receptors. A mass-cytometry (CyTOF) based proteomic profiling platform was developed and used to compare signaling pathway activation and cytokine production between the split influenza vaccine and a prototypical TLR response in human whole-blood (ex vivo). This analysis revealed that the split vaccine rapidly and potently activates multiple immune cell types but yields a proteomic signature distinct from TLR activation. Importantly, vaccine induced activity was dependent upon the presence of human sera indicating that a serum factor was necessary for vaccine-dependent immune activation. We found this serum factor to be human antibodies specific for influenza proteins and therefore immediate immune activation by the split vaccine is immune-complex dependent. These studies demonstrate that influenza vaccine splitting inactivates any microbial adjuvants endogenous to influenza but potentially elicits a potent immune modulator by facilitating the rapid formation of immune complexes.
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Mato, Anthony R., James Greenberg, Mary E. Putt, K. Stephen Suh, Yvonne Remache, Tania Zielonka, Kathryn Waksmundzki, et al. "Baseline Serum Cytokines Profiles in Mantle Cell Lymphoma Correlates with Outcome." Blood 120, no. 21 (November 16, 2012): 1579. http://dx.doi.org/10.1182/blood.v120.21.1579.1579.
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Abstract Abstract 1579 Background: There is a growing awareness of the biological heterogeneity of MCL, which likely translates into differences in outcomes. Cytokines play an important role in the pathogenesis of lymphoma. Recent reports suggest that cytokine profiles can identify DLBCL (ASH 2010: Abstract 991) and HL pt (ASH 2011: Abstract 429) subsets with inferior outcomes. A distinct cytokine profile for MCL has not yet been defined. We therefore examined serum cytokines levels in MCL pts to gain insight into which may have biological relevance and their association with clinical outcomes. Methods: Serum samples from MCL pts (57% newly diagnosed, 43% relapsed) were prospectively collected and linked to relevant clinical data from our MCL outcomes database. Cytokine levels were determined quantitatively utilizing a commercially available protein array system. We first used Wilcoxan tests to identify relevant cytokines by comparing the distribution of 507 serum cytokines levels in MCL cases (n=97) to serum cytokines levels from normal controls (n=20). For cytokines that showed significant differences, we report the ratio of median values (cases vs. controls). To maintain a type I error rate of.05 we adjusted for multiple comparisons (Hochberg's method). Using Cox regression model and adjusting for multiplicity, we next examined the association between serum cytokines levels and outcome (PFS) in a MCL cohort uniformly treated with R-HyperCVAD (R-HCVAD). Results: 214 pts with MCL were identified of which 97 pts had available serum samples. Clinical characteristics were as follows: med age 62 yr, med MIPI score of 4, med Ki67 25% (range 5–95%) and median follow up of 35 months. Our analysis identified 22 cytokines with statistically significantly distinct levels in MCL pts (vs. normal serum controls) including (p<.05): angiopoietin-1, angiostatin, endothelin, FGFR3, FGF18, GDF3, APJ, 6Ckine, CXCR4, BDNF, Glut1, Inf γ, IL2, IL3Rα, IL4R, IL10, IL15, IL17C, Gro.a, LeptinR, MCP1 and NrCAM. In univariate analysis, we were able to identify 6 cytokines (analyzed as continuous variables) that at baseline correlated with outcome (PFS) in a cohort (n=42) of uniformly treated MCL pts with R-HCVAD in the front-line setting (p<.05). These cytokines were as follows: Activin receptor type 1, Macrophage inflammatory protein 1 β (CCL4), Neutrophil collagenase (MMP8), Neurturin, Serum amyloid A protein and Ubiquitin (Table). Conclusions: Our results are the first to demonstrate a serum cytokines signature associated with MCL and additionally suggest an association between serum cytokines levels and outcome in MCL patients treated with R-HCVAD. These results may provide new insight into the biology of MCL and add to the known heterogeneity of MCL biology. An elevated pretreatment baseline serum cytokines subset, (mostly related to tumor and inflammatory processes) was found to be associated with an increased likelihood of disease relapse and an inferior outcome in patients with MCL treated with R-HCVAD and may predict pts at higher risk of relapse in that setting. Disclosures: Mato: Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Feldman:Merck: Speakers Bureau; Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Allos: Speakers Bureau. Goy:Milennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; J & J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.
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Karapetyan, Lilit, Hassan Mohammed Abushukair, Aofei Li, Andrew David Knight, Ayah N. Al-Bzour, Ian Macfawn, Zachary Thompson, et al. "Expression of lymphoid structure-associated cytokine/chemokine gene transcripts in tumor and protein in serum: Outcomes for patients with melanoma." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 9565. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.9565.
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9565 Background: Proinflammatory chemokines/cytokines support development and maturation of tertiary lymphoid structures (TLS) within the tumor immune microenvironment (TIME). In the current study, we sought to investigate the prognostic value of TLS-associated chemokine/cytokine (TLS-kine) expression levels in melanoma patients (MEL PTs) by performing serum protein and tissue transcriptomic analyses, and to then correlate these data with PT tumor clinicopathological and TIME characteristics. Methods: Levels of TLS-kines in PT sera were quantitated using a custom Luminex Multiplex Assay. The Cancer Genomic Atlas MEL cohort (TCGA-SKCM) and a Moffitt MEL cohort were used for tissue transcriptomic analyses. Associations between target analytes and survival outcomes, clinicopathological variables, and correlations between TLS-kines were statistically analyzed. Results: Serum of 95 PTs with MEL were evaluated; 48 (50%) female, median age of 63, IQR 51-70 years. Serum levels of APRIL/TNFSF13 were positively correlated with levels of both CXCL10 and CXCL13. Tumors with brisk/non-brisk tumor-infiltrating lymphocytes (TIL) vs. absence of TIL exhibited significantly higher levels of APRIL/TNFSF13 (p = 0.01), CCL19 (p = 0.01) and CXCL13 (p = 0.01). In multivariate analyses, high levels of serum APRIL/TNFSF13 were associated with improved event-free survival after adjusting for age and stage (HR = 0.64, 95% CI 0.43-0.95; p = 0.03). High expression of APRIL/TNFSF13 transcripts was significantly associated with improved OS in TCGA-SKCM[n = 448](HR = 0.69, 95% CI 0.52-0.93; p = 0.01) and in Moffitt MEL PTs [n = 134] (HR = 0.51, 95% CI: 0.32-0.82; p = 0.006). Further incorporation of CXCL10 and CXCL13 transcript levels in a 3-gene index revealed that high APRIL/CXCL10/CXCL13 expression was associated with improved OS in the TCGA SKCM cohort (HR = 0.42, 95% CI 0.19-0.94; p = 0.035). High coordinate expression of the TNFSF13/CXCL10/CXCL13 transcripts in MEL was correlated with an increased presence of naïve B cells, plasma B cells, CD8+ T cells, and M1 macrophages and decreased levels of M2 macrophages and mast cells as well as a reduced neural network gene signature. Conclusions: Serum protein and tumor transcript levels of APRIL/TNFSF13 are associated with improved survival outcomes. PTs exhibiting high coordinate expression of APRIL/CXCL10/CXCL13 transcripts in their tumors displayed superior OS. MEL differentially expressed genes positively associated with high coordinate APRIL/CXCL10/CXCL13 expression were linked to tumor infiltration by a diverse array of proinflammatory immune cell types. Further investigation of TLS-kine expression profiles related to clinical outcomes is warranted.
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Shaw, Joanne, Brandon Ballard, Xiaohui Yi, Aditya Malankar, Matthew R. Collinson-Pautz, Carlos Roberto Becerra, Joseph Paul Woodard, and Aaron E. Foster. "Tumor infiltration and cytokine biomarkers of prostate stem cell antigen (PSCA)-directed GOCAR-T cells in patients with advanced pancreatic tumors." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 734. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.734.
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734 Background: PSCA is a cell surface protein overexpressed in approximately 60% of pancreatic cancers. BPX-601 is an autologous GOCAR-T cell therapy engineered to express a PSCA-CD3ζ CAR and the MyD88/CD40 (iMC) costimulatory domain activated by rimiducid (Rim), designed to boost CAR-T performance in solid tumors. The safety and activity of BPX-601 activated with Rim in PSCA+ metastatic pancreatic cancer is being assessed in a Phase 1/2 clinical trial, BP-012 (NCT02744287). Methods: Phase 1 of BP-012 is a 3+3 dose escalation of BPX-601 (1.25-5 x106/kg) administered on Day 0 with a single, fixed-dose of Rim (0.4 mg/kg) on Day 7 in subjects with previously treated PSCA+ metastatic pancreatic cancer. All 5 subjects in cohort 5B received Flu/Cy lymphodepletion followed by BPX-601 (5 x106/kg) and Rim. BPX-601 kinetics, PBMC phenotype, and serum cytokines were assayed by qPCR, flow cytometry, and cytokine multiplex, respectively. Baseline and on-treatment biopsies were evaluated by RNAscope in situ hybridization. Results: BPX-601 cells expanded in all subjects and persisted up to 9 months (median 42 days). Transient reduction in BPX-601 vector copy number and total T cell count concurrent with Rim infusion, supports margination of activated BPX-601 cells. Increased serum cytokines, such as IFN-γ and GM-CSF, were observed following BPX-601 infusion with further elevation after Rim activation. All subjects with evaluable on-treatment biopsies had infiltration of BPX-601 cells (n = 3) proximal to tumor cells 7-15 days after Rim, but not in an end of treatment biopsy > 200 days after Rim (n = 1). Stratification by best response (RECIST 1.1) revealed stable disease in 3 subjects and progressive disease in 2 subjects was potentially associated with distinct cytokine signatures. Conclusions: BPX-601 GOCAR-T cells expand and persist in patients with PSCA+ metastatic pancreatic cancer and infiltrate metastatic lesions. A peripheral cytokine signature was observed following BPX-601 infusion. Select cytokines were enhanced after GOCAR-T cell activation and may correlate with clinical response. A cohort of subjects exploring serial administration of Rim is open for enrollment. Clinical trial information: NCT02744287.
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Bongenaar, M., H. T. Smeele, E. Lubberts, and R. Dolhain. "AB0052 INFLAMMATORY PROTEOMIC SIGNATURE RELATED TO DECREASED FERTILITY IN WOMEN WITH RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1058. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2063.
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Background:Fertility issues are common in women with rheumatoid arthritis (RA). Decreased fertility in these patients is associated with high disease activity and the use of certain medication [1]. However, immunological mechanisms behind this phenomenon remain unresolved.Objectives:This study aims to identify inflammation-related proteins associated with decreased fertility in women with rheumatoid arthritis and a wish to conceive.Methods:Patients were derived from the PARA-study, a prospective cohort on RA and pregnancy. High-multiplex immunoassay technology with qPCR readout (Olink Proteomics, Uppsala, Sweden) was used to assess 92 inflammation-related proteins in serum obtained before pregnancy of 186 women with RA and a wish to conceive. Measured protein levels were imputed into multivariable cox regression models with time to pregnancy (TTP) as dependent variable. This model was corrected for known confounders age, nulliparity, NSAID use, prednisone use and past methotrexate use [2].Results:Our analyses show prolonged TTP to be associated with increased expression of pro-inflammatory cytokines (TNF, IL-6, IL-18), chemokines (CCL23, CCL19, CXCL10, MCP-3, CXCL9) and T cell stimulating factors (TNFRSF9, CDCP-1). Furthermore, increased factors associated with angiogenesis (VEGF-A) and bone and collagen damage (RANKL, MMP-1) were found. Lastly, decreased fertility is associated with increased immune regulatory factors (IL-10, IL10RB, PD-L1). After false discovery rate (FDR) correction for multiple testing, IL-10, CCL23, MCP-3 and CDCP-1 remained statistically significant (adjusted P<0.05). Results are depicted in table 1.Conclusion:This study shows a pro-inflammatory proteomic signature, including a counterbalance of increased immune regulatory proteins, to be associated with prolonged TTP. These findings provide more insight into the immunological pathways involved in fertility in RA patients.References:[1]Smeele HTW, Dolhain R. Current perspectives on fertility, pregnancy and childbirth in patients with Rheumatoid Arthritis. Semin Arthritis Rheum. 2019;49(3S):S32-S5.[2]Brouwer J, Hazes JM, Laven JS, Dolhain RJ. Fertility in women with rheumatoid arthritis: influence of disease activity and medication. Ann Rheum Dis. 2015;74(10):1836-41.Table 1.Significant multivariable cox regression results with time to pregnancy as dependent variable, corrected for age, nulliparity, NSAID use, prednisone use and past MTX use. HR = hazard ratio, FDR = false discovery rate.ProteinHRPP FDR adjustedFunctionIL-100,640,0010,026Immune regulatoryCCL230,510,0010,026T cell/monocyte migrationMCP-30,740,0010,026Monocyte migrationCDCP10,560,0020,039T cell migrationCCL190,770,0050,077DC/T cell/B cell migrationTNFRSF90,630,0070,090T cell costimulatorVEGF-A0,70,0140,154AngiogenesisCXCL100,820,0210,185T cell/monocyte/NK/DC migrationRANKL0,760,0220,185Osteoclast activation, DC survivalIL-60,880,0240,185Pro-inflammatory cytokine, stimulation of acute phase responsePD-L10,550,0270,189Immune suppressionIL-180,70,0350,193Type 1 response activatorIL-70,690,0380,208Lymphocyte maturationIL-10RB0,480,0390,208IL-10 receptorMMP-10,730,0450,208Collagen breakdownTNF0,440,0480,208Pro-inflammatory cytokine, necrosisCXCL90,260,0490,208Th1 polarizationAcknowledgements:The authors are grateful to all patients who participated in the PARA study. Additionally, they thank Yaël de Man, Fleur van de Geijn, Esther Gasthuis, Florentien de Steenwinkel, Jenny Brouwer and all laboratory workers and research assistants for their contribution to the data collection.Disclosure of Interests:Margot Bongenaar: None declared, Hieronymus TW Smeele: None declared, Erik Lubberts Grant/research support from: CHDR, Galapagos, Radboud Dolhain Speakers bureau: Yes, for UCB, Roche, Abbvie, Genzyme, Novartis, Consultant of: Yes, Galapagos, Grant/research support from: Yes, UCB
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Colt, Susannah, Blanca Jarilla, Palmera Baltazar, Veronica Tallo, Luz P. Acosta, Hannah W. Wu, Christopher V. Barry, et al. "Effect of maternal praziquantel treatment for Schistosoma japonicum infection on the offspring susceptibility and immunologic response to infection at age six, a cohort study." PLOS Neglected Tropical Diseases 15, no. 4 (April 16, 2021): e0009328. http://dx.doi.org/10.1371/journal.pntd.0009328.
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In areas endemic to schistosomiasis, fetal exposure to schistosome antigens prime the offspring before potential natural infection. Praziquantel (PZQ) treatment for Schistosoma japonicum infection in pregnant women has been demonstrated to be safe and effective. Our objectives were to evaluate whether maternal PZQ treatment modifies the process of in utero sensitization to schistosome antigens potentially impacting later risk of infection, as well as immune response to S. japonicum. We enrolled 295 children at age six, born to mothers with S. japonicum infection who participated in a randomized control trial of PZQ versus placebo given at 12–16 weeks gestation in Leyte, The Philippines. At enrollment, we assessed and treated current S. japonicum infection and measured serum cytokines. During a follow-up visit four weeks later, we assessed peripheral blood mononuclear cell (PBMC) cytokine production in response to soluble worm antigen preparation (SWAP) or soluble egg antigen (SEA). Associations between maternal treatment group and the child’s S. japonicum infection status and immunologic responses were determined using multivariate linear regression analysis. PZQ treatment during pregnancy did not impact the prevalence (P = 0.12) or intensity (P = 0.59) of natural S. japonicum infection among children at age six. Among children with infection at enrollment (12.5%) there were no significant serum cytokine concentration differences between maternal treatment groups. Among children with infection at enrollment, IL-1 production by PBMCs stimulated with SEA was higher (P = 0.03) in the maternal PZQ group compared to placebo. Among children without infection, PBMCs stimulated with SEA produced greater IL-12 (P = 0.03) and with SWAP produced less IL-4 (P = 0.01) in the maternal PZQ group compared to placebo. Several cytokines produced by PBMCs in response to SWAP and SEA were significantly higher in children with S. japonicum infection irrespective of maternal treatment: IL-4, IL-5, IL-10, and IL-13. We report that maternal PZQ treatment for S. japonicum shifted the PBMC immune response to a more inflammatory signature but had no impact on their offspring’s likelihood of infection or serum cytokines at age six, further supporting the safe use of PZQ in pregnant women. Trial Registration: ClinicalTrials.gov NCT00486863.
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Padron, Eric, Jeffrey S. Painter, Adam W. Mailloux, Jessica M. McDaniel, Christopher Bebbington, Mark Baer, Rami S. Komrokji, Alan F. List, and Pearlie K. Epling-Burnette. "GM-CSF Signaling Abnormalities in Chronic Myelomonocytic Leukemia." Blood 118, no. 21 (November 18, 2011): 1713. http://dx.doi.org/10.1182/blood.v118.21.1713.1713.
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Abstract Abstract 1713 Background: Chronic Myelomonocytic Leukemia (CMML) and Juvenile Myelomonocytic leukemia (JMML) are classified as MDS/MPN in the WHO classification system. Despite sharing clinical and histological features, CMML is characterized by a heterogeneous collection of molecular lesions while JMML is defined by well-established molecular aberrations clustered along the RAS pathway leading directly to GM-CSF hypersensitivity; a pathognomonic characteristic of JMML. Here we test whether a molecular signature for GM-CSF hypersensitivity in JMML, determined by the pSTAT5 activation assay, is also present in CMML and whether this signature clusters within a specific CMML subgroup. Methods: Cryopreserved bone marrow aspirates from 24 patients with newly diagnosed or relapsed CMML were obtained from the Moffitt Cancer Center Tissue Repository. Cells were thawed and rested in Stem Span H3000 with 10% FBS for 2 hours and then either starved for one hour in serum-free media, serum free group (n=12), or rested in Stem Span for an additional hour, serum group (n=12), prior to stimulation with G-CSF, IL-3, or GM-CSF for 15 minutes and then fixed and permeabilized with formaldehyde and methanol, as previously described. Samples were stained with an anti-pSTAT5(Y-694) antibody and analyzed by flow cytometry (Kotecha, Cancer Cell. 2009). Cells stained with isotype-control antibody were used to establish the threshold for basal STAT5 phosphorylation. Because STAT5 was constitutively phosphorylated in serum, and to a lesser extent in serum-free conditions, inducible cytokine activation was defined as the percentage of pSTAT5 positive cells above untreated samples in both CMML and healthy controls. A retrospective chart review was performed to obtain clinical variables including age, sex, WHO classification, Dusseldorf scoring system, MD Anderson scoring system, WBC, peripheral monocyte count, blast percentage, anemia, platelet count, splenomegaly, and metaphase cytogenetics. Results: The percentage of pSTAT5 responsive cells after G-CSF stimulation with doses up to 10 ng/ml was similar in cases and normal BM controls (p=0.14), whereas, a statistically significant increase in the percentage of inducible pSTAT5 positive cells was observed with GM-CSF 0.1 ng/ml (p=0.04), GM-CSF 1 ng/ml (p=0.02), and GM-CSF 10 ng/ml (p=0.01) in CMML BM cells compared to healthy donor BM cells, as shown in Figure 1. Using one standard deviation below the mean as a cut point, only 5 patients failed to show GM-CSF hypersensitivity in the serum (n=3) and serum-free groups (n=2), respectively. IL-3 and GM-CSF play similar roles in hematopoietic growth through the activation of JAK2/STAT5 and share a common beta-chain required for signaling. Signaling mediated by GM-CSF and IL3 converge to activate RAS and other downstream intermediates that regulate DNA synthesis, cell-cycle progression and suppression of apoptosis. The concentration of IL3 required to induce STAT5 phosphorylation was 10-fold greater than GM-CSF in CMML cells, but the percentage of cells responsive to IL3 was greater in CMML cases compared to controls at 10 ng/ml (p=0.02). Analysis of the percentage of GM-CSF hypersensitive cells and clinical parameters revealed no associations with age at onset, WHO classification, Dusseldorf scoring system, MD Anderson scoring system, blast percentage, anemia, platelet count, splenomegaly, or karyotype. The percentage of pSTAT5 positive cells with GM-CSF 0.1 ng/ml positively correlated with the total leukocyte (p=0.03) and total monocyte (p=0.02) count indicating that the JAK2/STAT5 signaling response is indicative of disease burden. Conclusions: Based on the threshold for cytokine stimulation and percentage of cells that display pSTAT5 induction, CMML appears to preferentially utilize GM-CSF for survival and/or expansion. Although RAS mutations were not assessed, CMML cells were preferentially sensitive to GM-CSF in newly diagnosed cases independent of cytogenetic abnormalities suggesting that JMML and CMML share biological features of GM-CSF hypersensitivity. Disclosures: Padron: KaloBios Pharmaceuticals, Inc.: Research Funding. Bebbington:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership. Baer:KaloBios Pharmaceuticals, Inc.: Employment, Equity Ownership.
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Mahmoud, Sara Bahaa, Marwa Kadry Anwar, Olfat Gamil Shaker, and Dina Ahmed El Sharkawy. "Possible Relation between Vitamin D and Interleukin-17 in the Pathogenesis of Lichen Planus." Dermatology 237, no. 6 (October 22, 2020): 896–901. http://dx.doi.org/10.1159/000510539.
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<b><i>Background:</i></b> Lichen planus (LP) is a chronic autoimmune inflammatory mucocutaneous disease. Interleukin (IL)-17 is the signature cytokine of T-helper 17 cells, involved in the aetiology of many autoimmune and inflammatory disorders. Vitamin D has an immune-regulatory role and suppresses IL-17 production via direct transcriptional inhibition of IL-17 gene expression. <b><i>Objective:</i></b> To explore the relationship of IL-17 and vitamin D levels with LP, and the possible inter-relationship between IL-17 and vitamin D. <b><i>Methods:</i></b> The study enrolled 30 patients with LP and 30 healthy controls. Blood samples and skin biopsies were taken from all participants for evaluation of serum vitamin D, and serum and tissue IL-17 levels using enzyme-linked immunosorbent assay (ELISA). <b><i>Results:</i></b> Patients had significantly higher serum and tissue IL-17 (<i>p</i> < 0.001 for both), as well as significantly lower serum vitamin D levels and more deficient patterns of vitamin D status than controls (<i>p</i> < 0.001 for both). In the patient group, there was a statistically significant positive correlation between extent of the disease and serum IL-17. There was no direct statistical correlation between IL-17 levels and serum vitamin D in either patients or controls. <b><i>Conclusion:</i></b> This study confirms a previously suggested role of IL-17 in the pathogenesis of LP and suggests its relation to the extent and severity of the disease. We also found an association between vitamin D deficiency and LP. However, a direct relationship between IL-17 and vitamin D deficiency could not be clarified.
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Adu-Agyeiwaah, Yvonne, Maria B. Grant, and Alexander G. Obukhov. "The Potential Role of Osteopontin and Furin in Worsening Disease Outcomes in COVID-19 Patients with Pre-Existing Diabetes." Cells 9, no. 11 (November 23, 2020): 2528. http://dx.doi.org/10.3390/cells9112528.
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The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing coronavirus disease 2019 (COVID-19) pandemic, with more than 50 million cases reported globally. Findings have consistently identified an increased severity of SARS-CoV-2 infection in individuals with diabetes. Osteopontin, a cytokine-like matrix-associated phosphoglycoprotein, is elevated in diabetes and drives the expression of furin, a proprotein convertase implicated in the proteolytic processing and activation of several precursors, including chemokines, growth factors, hormones, adhesion molecules, and receptors. Elevated serum furin is a signature of diabetes mellitus progression and is associated with a dysmetabolic phenotype and increased risk of diabetes-linked premature mortality. Additionally, furin plays an important role in enhancing the infectivity of SARS-CoV-2 by promoting its entry and replication in the host cell. Here, we hypothesize that diabetes-induced osteopontin and furin protein upregulation results in worse outcomes in diabetic patients with SARS-CoV-2 infection owing to the roles of these protein in promoting viral infection and increasing metabolic dysfunction. Thus, targeting the osteopontin-furin axis may be a plausible strategy for reducing mortality in SARS-CoV-2 patients with diabetes.