Interferon-inducible T-cell Alpha Chemoattractant Research Articles

Burning Mouth Syndrome Treated with Low-Level Laser and Clonazepam: A Randomized, Single-Blind Clinical Trial.

Burning mouth syndrome (BMS) is a chronic pain disorder characterized by intraoral burning or dysaesthetic sensation, with the absence of any identifiable lesions. Numerous treatments for BMS have been investigated, though without conclusive results. An analysis was conducted of the efficacy of treatment with a low-level diode laser and clonazepam in patients with BMS, and a study was carried out on the levels of different salivary biomarkers before and after treatment. A randomized, single-blind clinical trial was carried out involving 89 patients divided into the following groups: group 1 (laser, The Helbo® Theralite Laser 3D Pocket Probe + clonazepam) (n = 20), group 2 (sham laser placebo) (n = 19), group 3 (laser) (n = 21) and group 4 (clonazepam) (n = 18). Symptom intensity was scored based on a visual analogue scale (VAS). Sialometry was performed before and after treatment, and the Xerostomia Inventory, Oral Health Impact Profile-14 (OHIP-14) and Mini-Nutritional Assessment (MNA) questionnaires were administered. The following markers were measured in saliva samples: interleukins (IL2, IL4, IL5, IL6, IL7, IL8, IL1β, IL10, IL12, IL13, IL17, IL21 and IL23), proteins (MIP-3α, MIP-1α and MIP-1β), GM-CSF, interferon gamma (IFNγ), interferon-inducible T-cell alpha chemoattractant (ITAC), fractalkine and tumor necrosis factor α (TNFα). A significant decrease in the VAS scores was observed after treatment in group 1 (laser + clonazepam) (p = 0.029) and group 3 (laser) (p = 0.005). In turn, group 3 (laser) showed a decrease in the salivary concentration of fractalkine (p = 0.025); interleukins IL12 (p = 0.048), IL17 (p = 0.020), IL21 (p = 0.008), IL7 (p = 0.001) and IL8 (p = 0.007); proteins MIP1α (p = 0.048) and MIP1β (p = 0.047); and TNFα (p = 0.047) versus baseline. Following treatment, group 1 (laser + clonazepam) showed significant differences in IL21 (p = 0.045) and IL7 (p = 0.009) versus baseline, while group 4 (clonazepam) showed significant differences in IL13 (p = 0.036), IL2 (p = 0.020) and IL4 (p = 0.001). No significant differences were recorded in group 2 (sham laser placebo). The low-level diode laser is a good treatment option in BMS, resulting in a decrease in patient symptoms and in salivary biomarkers. However, standardization of the intervention protocols and laser intensity parameters is needed in order to draw more firm conclusions.

Immune Mediators Profiles in the Aqueous Humor of Patients with Simple Diabetic Retinopathy.

Various immune mediators identified to date are associated with the development of advanced forms of diabetic retinopathy (DR), such as proliferative DR and diabetic macular edema, although the exact pathophysiological mechanisms of early stages of DR such as simple DR remain unclear. We determined the immune mediator profile in the aqueous humor of eyes with simple DR. Fifteen eyes of fifteen patients with simple DR were studied. Twenty-two eyes of twenty-two patients with cataracts and no DR served as controls. Undiluted aqueous humor samples were collected, and a cytometric bead array was used to determine the aqueous humor concentrations of 32 immune mediators comprising 13 interleukins (IL), interferon-γ, interferon-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1α, MIP-1β, regulated on activation, normal T cell expressed and secreted (RANTES), monokine induced by interferon-γ, basic fibroblast growth factor (bFGF), Fas ligand, granzyme A, granzyme B, interferon-inducible T-cell alpha chemoattractant (ITAC), fractalkine, granulocyte macrophage colony-stimulating factor, granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF), angiogenin, tumor necrosis factor-α, and CD40 ligand. Among the 32 immune mediators, 10 immune mediators, including bFGF, CD40 ligand, fractalkine, G-CSF, IL-6, IL-8, MIP-α, MIP-1β, and VEGF, showed significantly higher aqueous humor concentrations and the Fas ligand had significantly lower concentration (p < 0.05) in eyes with simple DR compared with control eyes. Of these 10 cytokines with significant concentration alteration, protein-protein interaction analysis revealed that 8 established an intricate interaction network. Various immune mediators may contribute to the pathogenesis of simple DR. Attention should be given to the concentrations of immune mediators in ocular fluids even in simple DR. Large-scale studies are warranted to assess whether altered aqueous humor concentrations of these 10 immune mediators are associated with an increased risk of progression to advanced stages of DR.

Elevated serum levels of T-cell immunoglobulin and mucin-domain containing molecule 3 in patients with systemic inflammation following COVID-19 vaccination.

ChAdOx1 nCoV-19 vaccine has been widely used. Some unexpected adverse effects such as the development of systemic hyper inflammation with multiorgan involvement after vaccination, in rare cases, have been reported. However, its pathogenesis remains unclear. This study recruited two cases who suffered from systemic inflammation following ChAdOx1 nCoV-19 vaccine and two 30-year-old male volunteers without underlying disease who have received ChAdOx1 nCoV-19 vaccine as control group. Blood samples were collected from our patients and healthy subjects before and after treatment with anti-inflammatory agent such as glucocorticoid and tocilizumab. The immune profile from our patients and healthy controls were measured using a human XL cytokine Proteome Profiler array (ARY022b, R&D Systems). Biochemical parameters revealed leukocytosis with segmented neutrophil dominance and elevated serum levels of C-reactive protein (CRP), erythrocyte sedimentation rate, and ferritin in these two patients. The cytokine array revealed that mean levels of T cell immunoglobulin and mucin-domain containing-3 (TIM-3) (3640.3 vs 1580.5 pixels per inch [ppi]), B-cell activating factor (BAFF) (3036.8 vs 1471.0 ppi), urokinase plasminogen activator surface receptor (uPAR) (1043.1 vs 516.8 ppi), Resistin (1783.7 vs 711.3 ppi), platelet-derived growth factor (PDGF)-AB/BB (1980.7 vs 939.7 ppi), macrophage inflammatory protein-3-beta (MIP-3β) (911.9 vs 346.2 ppi), and interferon-inducible T-cell alpha chemoattractant (I-TAC) (1026.3 vs 419.7 ppi) were 2-fold higher in the patients than in normal subjects who received ChAdOx1 nCoV-19 vaccine. We demonstrated that systemic inflammation may occur in subjects who have received the ChAdOx1 nCoV-19 vaccination. Moreover, we proposed immune markers, which may be implicated in the pathogenesis of systemic inflammation following COVID-19 vaccination as potential diagnostic biomarkers.

Neonatal immune signatures differ by sex regardless of neurodevelopmental disorder status: Macrophage migration inhibitory factor (MIF) alone reveals a sex by diagnosis interaction effect

Immune dysregulation, including aberrant peripheral cytokine/chemokine levels, is implicated in neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD). While the diagnosis of ASD is more common in males compared to females, sex effects in immune dysregulation related to neurodevelopment remain understudied. The aim of this exploratory study was to determine whether there are sex-specific effects in neonatal immune dysregulation with respect to an ASD or delayed development (DD) diagnosis. We utilized the data from the Early Markers for Autism study, a population based case-control study of prenatal and neonatal biomarkers of ASD. The immune profile of newborns later diagnosed with ASD (n = 482, 91 females), DD (n = 140, 61 females) and sex-matched general population controls (GP; n = 378, 67 females) were analyzed using neonatal bloodspots (NBS) via 42-plex multiplex assay. Multiple linear regression analysis was performed to identify whether sex was associated with differences in cytokine/chemokine levels of children with ASD, DD, and GP. A sex by diagnosis interaction effect was observed only for the chemokine macrophage migration inhibitory factor (MIF), with males displaying higher levels of NBS MIF than females in the GP control group (p = 0.02), but not in ASD (p = 0.52) or DD (p = 0.29) groups. We found that regardless of child diagnosis, newborn bloodspot eluates from females had a significantly higher concentration than males with the same diagnosis of the chemokines granulocyte chemotactic protein 2 (GCP-2; p < 0.0001), macrophage inflammatory protein 2-alpha (GROβ; p = 0.002), interferon-inducible t-cell alpha chemoattractant (I-TAC; p < 0.0001), stromal cell-derived factor 1 alpha and beta (SDF-1α-β; p = 0.03), innate inflammatory chemokines interferon-gamma induced protein 10 (IP-10; p = 0.02), macrophage inflammatory protein 1-alpha (MIP-1α; p = 0.02), and Th1-related pro-inflammatory cytokine interleukin-12 active heterodimer (IL-12p70; p = 0.002). In contrast, males had a higher concentration than females of secondary lymphoid-tissue chemokine (6CKINE; p = 0.02), monocyte chemotactic protein 1 (MCP-1; p = 0.005) and myeloid progenitor inhibitory factor 1 (MPIF-1; p = 0.03). Results were similar when analyses were restricted to NBS from DD and ASD further classified as ASD with intellectual disability (ID), ASD without ID, and DD (GCP-2, p = 0.007; I-TAC, p = 0.001; IP-10, p = 0.005; IL-12p70, p = 0.03 higher in females; MPIF-1, p = 0.03 higher in male). This study is the first to examine sex differences in neonatal cytokine/chemokine concentrations, and whether these differences are associated with neurodevelopmental outcomes. Results highlight the importance of considering sex as a critical factor in understanding the immune system as it relates to child development.

PD25-12 IDENTIFICATION OF INTRATUMOR PATHOGENS FROM SINGLE-CELL RNA SEQUENCING, CELLULAR DYSFUNCTION AND IMMUNE RESPONSE

You have accessJournal of UrologyCME1 Apr 2023PD25-12 IDENTIFICATION OF INTRATUMOR PATHOGENS FROM SINGLE-CELL RNA SEQUENCING, CELLULAR DYSFUNCTION AND IMMUNE RESPONSE Laura Bukavina, Mohit Sindhani, Henkel Valentine, Daniel Ranti, Kirtishri Mishra, Alexander Kutikov, Shilpa Gupta, John Sfakianos, Mahmoud Ghannoum, Mauricio Retuerto, Andres Correa, Robert Uzzo, and Philip Abbosh Laura BukavinaLaura Bukavina More articles by this author , Mohit SindhaniMohit Sindhani More articles by this author , Henkel ValentineHenkel Valentine More articles by this author , Daniel RantiDaniel Ranti More articles by this author , Kirtishri MishraKirtishri Mishra More articles by this author , Alexander KutikovAlexander Kutikov More articles by this author , Shilpa GuptaShilpa Gupta More articles by this author , John SfakianosJohn Sfakianos More articles by this author , Mahmoud GhannoumMahmoud Ghannoum More articles by this author , Mauricio RetuertoMauricio Retuerto More articles by this author , Andres CorreaAndres Correa More articles by this author , Robert UzzoRobert Uzzo More articles by this author , and Philip AbboshPhilip Abbosh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003303.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Pathogenic microbes can induce cellular dysfunction and alters immune response to therapy. Taking advantage of single-cell RNA-sequencing (scRNA-seq), we aim to assess the transcriptomic features of the single cell level to identify intracellular pathogens in patients with high grade bladder cancer. METHODS: CellRanger and Alevin were utilized to extract cell barcodes and unique molecular identifiers. Low complexity reads <20 was considered negative, and PCR duplicates were removed. Seuret Findmarkers, scIntegrate, and scDensity Plot were utilized to normalize the data, cluster the cells, and calculate markers in each cluster of differentially expressed genes between the two conditions. We focused our analysis on Pseudomonas aeruginosa due to high urogenital virulence, and immunomodulation capabilities by pattern recognition receptors and inflammasome. RESULTS: Patients with history of high-grade BC demonstrated increased presence of Aeromonas (175,473 reads, 54%), Pseudomonas (75,002 reads, 26.73%), and Bacillus (15,410 reads, 5.49%) in their tissue samples, not visualized in healthy controls (counts <10). Among 8,324 cells (across 7 patients), classical CD14+ monocyte subtype was most likely to be exposed to Pseudomonas species (4150 /5069, 81.8%), followed by non-classical CD16+ monocytes (722/1040, 69.4%), and CD8+ Tcells (348/680, 51.1%). (Figure 1A-C). Relative gene expression level between exposed and non-exposed monocytes demonstrated total 25 upregulated genes, with increased expression GNBL21 (aka: RACK1, log10 4.1), MALAT1(log10 3.7), TCEB2(log10 2.9) (increasing proliferation, migration, and reduction of cell autophagy) compared to non-infected, and normal controls. Pseudomonas involvement of non-monocyte cells (CD8+, CD4+Th17, CD4+ naïve) was associated with disease progression (2/5 patients), as well as increased expression of IFI6/27(interferon alpha inducible protein 6 & 27), ITAC (interferon inducible T cell alpha-chemoattractant). CONCLUSIONS: Altogether, our analysis depicted the distribution of intracellular bacteria not previously recognized within tumor microenvironment utilizing scRNAseq, and revealed overexpression of RACK1 in Pseudomonas positive cells, associated with apoptosis resistance. Source of Funding: Bladder Cancer Advocacy Network Young Investigator Award © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e734 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Laura Bukavina More articles by this author Mohit Sindhani More articles by this author Henkel Valentine More articles by this author Daniel Ranti More articles by this author Kirtishri Mishra More articles by this author Alexander Kutikov More articles by this author Shilpa Gupta More articles by this author John Sfakianos More articles by this author Mahmoud Ghannoum More articles by this author Mauricio Retuerto More articles by this author Andres Correa More articles by this author Robert Uzzo More articles by this author Philip Abbosh More articles by this author Expand All Advertisement PDF downloadLoading ...

The relationship between plasma cytokine levels and antidepressant response in patients with first-episode major depressive disorder

BackgroundCytokines are involved in the pathophysiology of major depressive disorder (MDD) and treatment response. Efforts have been made to identify inflammatory markers but results are often contradictory. The present study explored the plasma levels of multiple cytokines in first-episode MDD using a longitudinal design, with the aim to determine the involvement of cytokines in depression and identify the inflammatory markers. MethodFifty-four first-episode drug naïve MDD patients and 60 healthy controls (HCs) were enrolled in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered and blood samples were collected at baseline and four-week posttreatment in MDD group, while blood samples were only collected once in HC group. Plasma levels of nineteen cytokines were examined by a multiplexed flow cytometric assay. ResultsSixteen out of 19 cytokines levels in MDD group were significantly higher than those in HC group (all P < 0.05). After 4-week of antidepressant treatment, levels of the 14 cytokines elevated at baseline decreased to normal levels (all P < 0.05). Partial correlation showed that baseline level of interferon-inducible T cell alpha chemoattractant (ITAC) was negatively correlated with reduction in HAMD-17 score (r=−0.319, p=0.020), and multiple regression showed lower baseline ITAC level was associated with better treatment response (p = 0.020). LimitationThe sample size was relatively small. ConclusionA range of cytokines were abnormal in patients with first-episode drug naïve MDD and most of the cytokines could be normalized after antidepressant treatment. Furthermore, baseline ITAC level could be a predictive factor of antidepressant response.

Vesatolimod, a Toll-like Receptor 7 Agonist, Induces Immune Activation in Virally Suppressed Adults Living With Human Immunodeficiency Virus–1

Treatment with vesatolimod, an investigational, oral, toll-like receptor 7 (TLR7) agonist, leads to sustained viral remission in some non-human primates when combined with anti-envelope antibodies or therapeutic vaccines. We report results of a Phase Ib study evaluating safety, pharmacokinetics, and pharmacodynamics of vesatolimod in adults living with human immunodeficiency virus (HIV)-1. In this double-blind, multicenter, placebo-controlled trial, participants on antiretroviral therapy with screening plasma HIV-1 RNA levels <50 copies/mL were randomized (6:2) to receive 6-10 doses of vesatolimod (1-12 mg) or matching placebo orally every other week in sequential dose-escalation cohorts. The primary study objectives included establishing the safety and virologic effects of vesatolimod (change from baseline in plasma HIV-1 RNA). Pharmacokinetics and pharmacodynamic/immunologic activity were assessed as secondary objectives. A total of 48 individuals were randomly assigned to vesatolimod (n = 36) or placebo (n = 12). Vesatolimod was generally well tolerated, with no study drug-related serious adverse events or adverse events leading to study drug discontinuation. There were no statistically significant changes from baseline in plasma HIV-1 RNA in the vesatolimod groups, compared to placebo.Vesatolimod plasma exposures increased dose proportionally; consistent responses in cytokines, interferon-stimulated gene expression, and lymphocyte activation were observed with increasing dose levels above 4 mg. Peak elevations 24 hours after receipt of a 6 mg dose were >3.9-fold higher for interferon gamma-induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RA), interferon-inducible T-cell alpha chemoattractant (ITAC) when compared to baseline values. Vesatolimod was well tolerated at doses ranging from 1 to 12 mg. Immune stimulation was observed at doses above 4 mg, providing rationale for future combination trials in people living with HIV. NCT02858401.

Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder

Increasing evidence has demonstrated that inflammatory cytokines play an important role in major depressive disorder (MDD) and are associated with treatment outcomes. Few studies have explored the trajectories of multiple inflammatory cytokines after repeated ketamine infusions in MDD. In this study, we conducted a secondary analysis to investigate the impact of ketamine on the modulation of the inflammatory pathway in depression and whether this pathway contributes to the antidepressant properties of ketamine. A total of 60 patients with depression received six ketamine infusions (0.5 mg/kg) during a 12-day period. The Montgomery–Asberg Scale (MADRS) was administered, and blood samples were collected at baseline and 24 h and 14 days after the sixth infusion (days 0, 13, and 26). Plasma levels of the 19 cytokines were measured using the Luminex assay. At baseline, inflammatory cytokines were associated with the severity of depression. The concentrations of pro- and anti-inflammatory factors, including granulocyte macrophage colony-stimulating factor (GM-CSF), fractalkine, interferon gamma (IFN-γ), interleukin (IL)-10, IL-12p70, IL-17A, IL-1β, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, and tumor necrosis factor alpha (TNF-α), were downregulated after repeated ketamine administration (all p < 0.05). In addition, alterations in the levels of IL-17A (r = −0.259, p = 0.046) and IL-6 (r = −0.262, p = 0.043) were correlated with symptom improvement. A lower level of interferon-inducible T cell alpha chemoattractant (ITAC) at baseline was predictive of ketamine treatment response on day 13 according to a stepwise linear regression analysis (β = −0.296, p = 0.040). Our results suggest that the inflammatory pathway may be involved in the antidepressant effects of ketamine, which may be conducive to future treatment strategy optimization.

Distinct inflammatory mediator patterns in young black and white adults: The African-predict study

ObjectiveInflammatory mediators have been implicated in the early stages of cardiovascular disease development, including hypertension. Since global reports reflect a higher hypertension prevalence in black than white populations, we hypothesise the involvement of specific inflammatory mediators. We therefore compared a detailed range of 22 inflammatory mediators between young black and white adults, and determined the relationship with blood pressure. Approach and resultsWe included 1197 adults (20–30 years; 50% black; 52% female) with detailed ambulatory blood pressures. Blood samples were analysed for 22 inflammatory mediators. For pro-inflammatory mediators, the black adults had higher C-reactive protein, interferon-inducible T-cell alpha chemoattractant, macrophage inflammatory protein 3 alpha (all p ≤ 0.008), but lower interferon-gamma, interleukin (IL)-1β, IL-8, IL-12, IL-17A, and tumour necrosis factor alpha (all p ≤ 0.048). For anti-inflammatory mediators the black group consistently had lower levels (IL-5, IL-10 and IL-13 (all p ≤ 0.012)), resulting in generally higher pro-to-anti-inflammatory ratios in black than white adults (p ≤ 0.001). In mediators with pro- and anti-inflammatory functions, the black group had lower granulocyte-macrophage colony-stimulating factor and IL-6 (both p ≤ 0.010). These patterns were confirmed after adjustment for age, sex and waist circumference, or when stratifying by hypertensive status, sex and socio-economic status. Multi-variable adjusted regression analyses and factor analysis yielded no relationship between inflammatory mediators and blood pressure in this young healthy population. ConclusionsBlack and white ethnic groups each consistently presented with unique inflammatory mediator patterns regardless of blood pressure, sex or social class. No association with blood pressure was seen in either of the groups.

Regulatory cytokines prescribe the outcome of the inflammation in the process of pseudoexfoliation production.

The purpose of this study is to reveal the participation of different regulatory cytokines within the process of pseudoexfoliation (PEX). Our study included 140 patients referred to cataract surgery with early and late stage of pseudoexfoliation syndrome (XFS) or pseudoexfoliation glaucoma (XFG). Humor and serum levels of cytokines: transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), IL-8 and interferon-inducible T cell alpha chemoattractant (ITAC) were measured in a sample using high sensitivity enzyme-linked immunoabsorbent assay (ELISA) kit. Our results indicate that profibrotic action induced by increasing TGF-β and PDGF locally activates fibrous tissue production in the early XFS with a prolonged effect of PDGF (late XFS) and finally (XFG stage) it is dominantly controlled by EGF and IGF. ITAC overrides angiogenetic effects of IL-8 in XFG. Based on our findings, local chronic inflammation in the eye is accompanied by the secretion of different profibrotic cytokines (TGF-β, PDGF, EGF, IGF, IL-8) without angiogenesis due to effects of ITAC.

Household coal combustion, indoor air pollutants, and circulating immunologic/inflammatory markers in rural China

ABSTRACTThe study aim was to investigate whether household bituminous (“smoky”) coal use and personal exposure to combustion emissions were associated with immunologic/inflammatory marker levels. A cross-sectional study of healthy never-smoking women from rural Xuanwei and Fuyuan, China was conducted, which included 80 smoky coal and 14 anthracite (“smokeless”) coal users. Personal exposure to fine particulate matter (PM2.5) and benzo[a]pyrene (BaP) was assessed using portable devices, while 67 circulating plasma immunologic/inflammatory markers were measured using multiplex bead-based assays. Multivariable linear regression models were employed to estimate associations between smoky coal versus smokeless coal use, indoor air pollutants, and immunologic/inflammatory markers. Six markers were altered among smoky coal users compared to smokeless coal, including significantly decreased interferon-inducible T-cell alpha chemoattractant (CXCL11/I-TAC), and increased serum amyloid P component (SAP). CXCL11/I-TAC was previously found to be reduced in workers exposed to high levels of diesel engine exhaust, which exhibits similar constituents as coal combustion emissions. Further, there was evidence that elevated PM2.5 and BaP exposure was associated with significantly diminished levels of the serum amyloid A (SAA); however, the false discovery rates (FDRs) were >0.2 after accounting for multiple comparisons. Inflammatory processes may thus mediate the carcinogenic effects attributed to smoky coal emissions.

Spinal cord hypometabolism associated with infection by human T-cell lymphotropic virus type 1(HTLV-1).

BackgroundHTLV-1 infection is endemic in Brazil. About 1 to 2% of the Brazilian population is estimated to be infected, but most infected HTLV-1 individuals do not know about their own infection, which favors the continuity of sexual and vertical virus transmission. In addition, HTLV-1 associated central nervous system diseases and their pathophysiologic mechanisms are not fully understood. This study aimed to evaluate the correlation of spinal cord metabolism, viral and inflammatory profiles with features of neurological presentation in HTLV-1 infected individuals.MethodologyThis is a cross-sectional study of a cohort including 48 HTLV-1 infected individuals clinically classified as asymptomatic-AG (N = 21), symptomatic-SG (N = 11) and HAM/TSP-HG (N = 16) and a nested case-control study with HTLV-1 infected individuals-HIG (N = 48) and HTLV-1 non infected controls-CG (N = 30) that had their spinal cord analysed by Positron Emission Tomography with 18F-Fluordeoxyglucose (18F-FDG PET/CT). HTLV-1 infected individuals had 18F-FDG PET/CT results analyzed with clinical and demographic data, proviral load, cytokines and chemokines in the blood and cerebrospinal fluid (CSF).Principal Findings18F-FDG PET/CT showed hypometabolism in the thoracic spinal cord in HTLV-1 infected individuals. The method had an accuracy of 94.4% to identify HAM/TSP. A greater involvement of the thoracic spinal cord was observed, although hypometabolism was also observed in the cervical spinal cord segment in HTLV-1 infected individuals. Individuals with HAM/TSP showed a pro-inflammatory profile in comparison to asymptomatic and symptomatic groups, with a higher level of Interferon-inducible T-cell alpha chemoattractant (ITAC/CXCL11), IL-6, IL-12p70 in the plasma; and ITAC, IL-4, IL-5, IL-8 (CXCL8) and TNF-alpha in the CSF. Using regression, thoracic spinal cord SUV (standardized uptake value) and CSF ITAC level were identified as the HAM/TSP predictors in the multivariate model.Conclusions18F-FDG PET/CT imaging showed spinal cord hypometabolism in most HTLV-1 infected individuals, even in the asymptomatic HTLV-1 group. Thoracic spinal cord hypometabolism and CSF-ITAC levels were identified predictors of HAM/TSP.SignificanceOur findings suggested that in most HTLV-1 infected individuals there was compromise of central nervous system (CNS) structures despite of the lack of clinical symptoms. To explain the found hypometabolism, the role of microcirculatory and metabolic factors in the pathogenesis of neurological diseases associated with HTLV-1 infection must be further investigated. It is paramount to evaluate the central nervous function and to compare the performance among HTLV-1 infected individuals considered asymptomatic to the uninfected controls.

The Inflammatory CXC Chemokines, GROαhigh, IP-10low, and MIGlow, in Tumor Microenvironment Can Be Used as New Indicators for Non-small Cell Lung Cancer Progression

ABSTRACTAims: To investigate the clinical significance of tumor tissue-infiltrating chemokines expression in non-small cell lung cancer (NSCLC) microenvironment.Materials and methods: Fresh tissue samples were acquired from 50 patients with NSCLC after operation. Then, we quantified the total protein with the BCA Protein Assay Kit and tested 13 chemotactic factors in paired samples including tumor tissues, tumor adjacent tissues, and normal tissues with the CBA Kit.Results: We found that the chemokine CC subfamily of MCP-1, MIP-1α, MIP-1β, and MIP-3α and the chemokine CXC subfamily of IL-8, GROα, IP-10, and MIG expressions in tumor tissues were significantly higher than those in tumor-adjacent tissues and normal tissues. However, regulated upon activation normal T cell expressed and secreted (RANTES), human thymus activation regulated chemokine (TARC), chemokine (C-C motif) ligand 11 (CCL11), interferon-inducible T cell alpha chemoattractant (I-TAC), and ENA-78 expressions did not show significant difference. Analyzing the influence of chemokine expression level in tumor tissues on disease progression, we found the median progression-free survival (mPFS) of patients with GROαhigh was significantly lower than those with GROαlow; mPFS of patients with IP-10low was significantly lower than those with IP-10high; and mPFS of patients with MIGlow was significantly lower than those with MIGhigh. However, MCP-1, MIP-1α, MIP-1β, MIP-3α, and IL-8 had no significant value to elevate the mPFS of patients with NSCLC.Conclusion: In summary, tumor tissue-infiltrating CXC chemokines, GROαhigh, IP-10low, and MIGlow in the tumor microenvironment can be used as potential indicators for the progression of NSCLC.

Lemongrass (Cymbopogon flexuosus) essential oil demonstrated anti-inflammatory effect in pre-inflamed human dermal fibroblasts

Lemongrass (Cymbopogon flexuosus) essential oil (LEO), which has citral as its main component, has exhibited anti-inflammatory effect in both animal and human cells. In this study, we evaluated the anti-inflammatory activity of a commercially available LEO in pre-inflamed human dermal fibroblasts. We first studied the impact of LEO on 17 protein biomarkers that are critically associated with inflammation and tissue remodeling. LEO significantly inhibited production of the inflammatory biomarkers vascular cell adhesion molecule 1 (VCAM-1), interferon gamma-induced protein 10 (IP-10), interferon-inducible T-cell alpha chemoattractant (I-TAC), and monokine induced by gamma interferon (MIG); decreased levels of the tissue remodeling biomarkers collagen-I and III, epidermal growth factor receptor (EGFR), and plasminogen activator inhibitor (PAI-1); and inhibited the immunomodulatory biomarker macrophage colony-stimulating factor (M-CSF). Furthermore, we studied the impact of LEO on genome-wide gene expression profiles. LEO significantly modulated global gene expression and robustly impacted signaling pathways, many of which are critical for inflammation and tissue remodeling processes. This study provides the first evidence of the anti-inflammatory activity of LEO in human skin cells and indicates that it is a good therapeutic candidate for treating inflammatory conditions of the skin.

Anti-inflammatory, tissue remodeling, immunomodulatory, and anticancer activities of oregano (Origanum vulgare) essential oil in a human skin disease model

The use of oregano (Origanum vulgare) essential oil (OEO) has become popular in skin care products. However, scientific research regarding its effects on human skin cells is scarce. In this study, we investigated the biological activity of a commercially available OEO, which is high in carvacrol content, in a human skin cell disease model. OEO induced marked antiproliferative effects and significantly inhibited several inflammatory biomarkers, including monocyte chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), intracellular cell adhesion molecule 1 (ICAM-1), interferon gamma-induced protein 10 (IP-10), interferon-inducible T-cell alpha chemoattractant (I-TAC), and monokine induced by gamma interferon (MIG). OEO also significantly inhibited tissue remodeling biomarkers, namely collagen I, collagen III, epidermal growth factor receptor (EGFR), matrix metalloproteinase 1 (MMP-1), plasminogen activator inhibitor 1 (PAI-1), tissue inhibitor of metalloproteinase (TIMP) 1 and 2. An immunomodulatory biomarker, macrophage colony-stimulating factor (M-CSF), was also strongly inhibited by OEO treatment. In addition, OEO significantly modulated global gene expression and altered signaling pathways, many of which are critical in inflammation, tissue remodeling, and cancer signaling processes. These findings along with existing studies largely support the anti-inflammatory, tissue remodeling, immunomodulatory, and anticancer activities of OEO. In conclusion, this study provides the first evidence of the biological activity of OEO in human dermal fibroblasts. We suggest that OEO, with carvacrol as the major active component, is a promising candidate for use in skin care products with anti-inflammatory and anticancer properties.

Anti-inflammatory activity of Juniper (Juniperus communis) berry essential oil in human dermal fibroblasts

Although juniper (Juniperus communis) berry essential oil (JEO) has been used in skin care products, research on its biological activity in human skin cells is scarce. In the current study, we explored the biological activity of JEO (with alpha-pinene as the major active component) in pre-inflamed human dermal fibroblasts, which were designed to mimic the disease biology of chronic inflammation and fibrosis. We analyzed the levels of 17 important protein biomarkers pertinent to inflammation and tissue remodeling. JEO exhibited robust antiproliferative activity and significantly inhibited the increased production of the proinflammatory chemokines interferon gamma-induced protein 10 (IP-10) and interferon-inducible T-cell alpha chemoattractant (I-TAC). Additionally, JEO significantly inhibited tissue remodeling biomarkers, namely collagen I, collagen III, and plasminogen activator inhibitor 1 (PAI-I). Macrophage colony-stimulating factor (M-CSF), an immunomodulatory protein molecule, was also significantly downregulated by JEO. Moreover, we found that JEO robustly modulated global gene expression. Ingenuity Pathway Analysis also showed that JEO affected many important signaling pathways that are closely related to metabolism, inflammation, immune response, wound healing, and cancer biology. This study provides the first evidence of the biological activity of JEO in human dermal fibroblasts. Thus, JEO is a promising therapeutic candidate for inflammatory conditions in the skin.

Interferon‐inducible T‐cell alpha chemoattractant (ITAC) induces the melanocytic migration and hypopigmentation through destabilizing p53 via histone deacetylase 5: a possible role of ITAC in pigment‐related disorders

Cell migration plays a major role in the immune response and in tumorigenesis. Interferon-inducible T-cell alpha chemoattractant (ITAC) elicits a strong chemotactic response from immune cells. To examine the effect of ITAC on melanocyte migration and pigmentation and its involvement in related disorders, and to investigate potential key players in these processes. Human melanocytes or melanoma cells were treated with ITAC and a migration assay was carried out. Global gene expression analysis was performed to find genes regulated by ITAC treatment. The function of key players involved in ITAC-induced cellular processes was addressed using knockdown or overexpression experiments in combination with ITAC treatment. ITAC expression in the inflammation-associated hypopigmentary disorder, vitiligo, was examined. Among CXCR3 ligands, only ITAC induced melanocyte migration. ITAC treatment upregulated the expression of histone deacetylase 5 (HDAC5) and downregulated that of p53, a known target of HDAC5. Through knockdown or overexpression of HDAC5 and p53, we confirmed that HDAC5 mediates ITAC-induced migration by decreasing levels of p53 via deacetylation. In addition, ITAC treatment could decrease pigmentation in a p53- and HDAC5-dependent manner. Finally, the increased migration of human melanoma cells by ITAC treatment and the increased ITAC expression in the epidermis of vitiligo skin were verified. This study provides in vitro evidence for the migratory and hypopigmentation effects of ITAC on melanocytic cells, gives translational insights into the roles of ITAC in pathological conditions, and suggests that HDAC5 and its substrate p53 are potent targets for regulating ITAC-induced cellular processes.

Microglia-Derived Cytokines/Chemokines Are Involved in the Enhancement of LPS-Induced Loss of Nigrostriatal Dopaminergic Neurons in DJ-1 Knockout Mice.

Mutation of DJ-1 (PARK7) has been linked to the development of early-onset Parkinson’s disease (PD). However, the underlying molecular mechanism is still unclear. This study is aimed to compare the sensitivity of nigrostriatal dopaminergic neurons to lipopolysaccharide (LPS) challenge between DJ-1 knockout (KO) and wild-type (WT) mice, and explore the underlying cellular and molecular mechanisms. Our results found that the basal levels of interferon (IFN)-γ (the hub cytokine) and interferon-inducible T-cell alpha chemoattractant (I-TAC) (a downstream mediator) were elevated in the substantia nigra of DJ-1 KO mice and in microglia cells with DJ-1 deficiency, and the release of cytokine/chemokine was greatly enhanced following LPS administration in the DJ-1 deficient conditions. In addition, direct intranigral LPS challenge caused a greater loss of nigrostriatal dopaminergic neurons and striatal dopamine content in DJ-1 KO mice than in WT mice. Furthermore, the sensitization of microglia cells to LPS challenge to release IFN-γ and I-TAC was via the enhancement of NF-κB signaling, which was antagonized by NF-κB inhibitors. LPS-induced increase in neuronal death in the neuron-glia co-culture was enhanced by DJ-1 deficiency in microglia, which was antagonized by the neutralizing antibodies against IFN-γ or I-TAC. These results indicate that DJ-1 deficiency sensitizes microglia cells to release IFN-γ and I-TAC and causes inflammatory damage to dopaminergic neurons. The interaction between the genetic defect (i.e. DJ-1) and inflammatory factors (e.g. LPS) may contribute to the development of PD.

Circulating and tumor-based biomarkers predict clinical activity in cancer patients treated with the engineered anti-PD-L1 antibody MPDL3280A

PD-L1 expressed in the tumor microenvironment regulates Th1 immune responses and mediates cancer immune evasion through interactions with PD-1 or B7.1 receptors on activated T cells. MPDL3280A, an engineered human monoclonal antibody, targets PD-L1 and inhibits its function. To identify immunologic predictive and pharmacodynamic biomarkers of MPDL3280A treatment, we performed a comprehensive analysis of tumors and blood samples collected at baseline and/or on treatment from ≈280 patients with locally advanced or metastatic solid tumors, including NSCLC, RCC, melanoma and bladder cancer. Regardless of tumor type, clinical responses were characterized by PD-L1 expression, the presence of markers of T cell activation (Th1 gene signature and CTLA4), and the absence of fractalkine at baseline in the tumor microenvironment. Elevated baseline expression of IFN-γ and IFN-γ-inducible genes (e.g., IDO1 and CXCL9) was associated with MPDL3280A response in melanoma but not NSCLC or RCC. On treatment, responding tumors showed increased infiltration of Th1-dominant immune infiltrate and evidence of adaptive PD-L1 up-regulation. In contrast, progressing tumors displayed the following patterns of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression: (1) few/no TILs and absent PD-L1 expression (immunologic ignorance), (2) TILs present with minimal/no PD-L1 expression (non-functional immune responses), or (3) TILs residing solely around the tumor cell mass outer edge (excluded infiltrate), suggesting that resistance to MPDL3280A may be associated with impaired T cell trafficking and/or function. Profiling of ≈180 circulating biomarkers revealed that plasma concentrations of IL-18 and interferon-inducible T cell alpha chemoattractant (ITAC) increased in all patients following MPDL3280A treatment, representing a pharmacodynamic measurement of PD-L1 inhibition. In addition, analysis of PBMC showed an increase in T cell activation, as measured by IFN-γ and granzymes A and B gene expression in responders following MPDL3280A treatment, consistent with the observations in responding tumors. Baseline soluble PD-L1 was not associated with response. Some indication-specific biomarkers, such as plasma VEGF, decreased in responders with RCC but not with other indications. In NSCLC, a decrease in tumor burden markers, CA-125 and CEA, was associated with response. Similarly, IL-6 and IL-8 were differentially expressed on treatment in responders vs non-responders. Additionally, responders exhibited a decrease in circulating tumor DNA (ctDNA) in plasma, suggesting that ctDNA may be used to monitor MPDL3280A clinical activity in NSCLC. In conclusion, these data provide general and indication-specific mechanistic insights into immune checkpoint inhibition, potential mechanisms of response and resistance, as well as identification of potential predictive and pharmacodynamic biomarkers of anti-PD-L1/PD-1 clinical activity across multiple tumor types.

Impact of the Controlled Release of a Connexin 43 Peptide on Corneal Wound Closure in an STZ Model of Type I Diabetes

The alpha-carboxy terminus 1 (αCT1) peptide is a synthetically produced mimetic modified from the DDLEI C-terminus sequence of connexin 43 (Cx43). Previous research using various wound healing models have found promising therapeutic effects when applying the drug, resulting in increased wound healing rates and reduced scarring. Previous data suggested a rapid metabolism rate in vitro, creating an interest in long term release. Using a streptozotocin (STZ) type I diabetic rat model with a surgically induced corneal injury, we delivered αCT1 both directly, in a pluronic gel solution, and in a sustained system, using polymeric alginate-poly-l-ornithine (A-PLO) microcapsules (MC). Fluorescent staining of wound area over a 5 day period indicated a significant increase in wound closure rates for both αCT1 and αCT1 MC treated groups, withαCT1 MC groups showing the most rapid wound closure overall. Analysis of inflammatory reaction to the treatment groups indicated significantly lower levels of both Interferon Inducible T-Cell Alpha Chemoattractant (ITAC) and Tumor Necrosis Factor Alpha (TNFα) markers using confocal quantification and ELISA assays. Additional analysis examining genes selected from the EMT pathway using RT-PCR and Western blotting suggested αCT1 modification of Transforming Growth Factor Beta 2 (TGFβ2), Keratin 8 (Krt8), Estrogen Receptor 1 (Esr1), and Glucose Transporter 4 (Glut4) over a 14 day period. Combined, this data indicated a possible suppression of the inflammatory response by αCT1, leading to increased wound healing rates.