Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other ...inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Monocytes/macrophages are key players in all phases of physiological and pathological inflammation. To understanding the regulation of macrophage functional differentiation during inflammation, we ...designed an in vitro model that recapitulates the different phases of the reaction (recruitment, initiation, development, and resolution), based on human primary blood monocytes exposed to sequential changes in microenvironmental conditions. All reaction phases were profiled by transcriptomic microarray analysis. Distinct clusters of genes were identified that are differentially regulated through the different phases of inflammation. The gene sets defined by GSEA analysis revealed that the inflammatory phase was enriched in inflammatory pathways, while the resolution phase comprised pathways related to metabolism and gene rearrangement. By comparing gene clusters differentially expressed in monocytes vs. M1 and vs. M2 macrophages extracted from an in-house created meta-database, it was shown that cells in the model resemble M1 during the inflammatory phase and M2 during resolution. The validation of inflammatory and transcriptional factors by qPCR and ELISA confirmed the transcriptomic profiles in the different phases of inflammation. The accurate description of the development of the human inflammatory reaction provided by this in vitro kinetic model can help in identifying regulatory mechanisms in physiological conditions and during pathological derangements.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
By restraining T‐cell activation and promoting Treg‐cell expansion, myeloid‐derived suppressor cells (MDSCs) and tolerogenic DCs can control self‐reactive and antigraft effector T cells in ...autoimmunity and transplantation. Their therapeutic use and characterization, however, is limited by their scarce availability in the peripheral blood of tumor‐free donors. In the present study, we describe and characterize a novel population of human myeloid suppressor cells, named fibrocytic MDSC, which are differentiated from umbilical cord blood precursors by 4‐day culture with FDA‐approved cytokines (recombinant human‐GM‐CSF and recombinant human‐G‐CSF). This MDSC subset, characterized by the expression of MDSC‐, DC‐, and fibrocyte‐associated markers, promotes Treg‐cell expansion and induces normoglycemia in a xenogeneic mouse model of Type 1 diabetes. In order to exert their protolerogenic function, fibrocytic MDSCs require direct contact with activated T cells, which leads to the production and secretion of IDO. This new myeloid subset may have an important role in the in vitro and in vivo production of Treg cells for the treatment of autoimmune diseases, and in either the prevention or control of allograft rejection.
Objectif TEENs est la plus grande étude contemporaine, internationale, transversale, visant à identifier des approches d’optimisation du contrôle glycémique des jeunes patients DT1 (20 pays, n = 5 ...960). Nous rapportons ici les données de la cohorte européenne ( n = 2 943, 111 centres dans 11 pays, France comprise). Patients et méthodes Les données ont été recueillies lors des entretiens avec les patients, d’examens des dossiers médicaux et d’enquêtes patient/parents. Les patients ont été stratifiés en trois groupes d’âge: enfants (8-12 ans, n = 887), adolescents (13-18 ans, n = 1 451) et jeunes adultes (19-25 ans, n = 605). L’HbA1c a été mesurée avec l’A1CNow™ (Bayer ; plage de référence 4-6 %) . Valeurs cibles d’HbA1c < 7,5 % pour les patients ≤ 18 ans (ISPAD) et < 7 % pour les patients de 19-25 ans (ADA). Les patients âgés de ≥ 13 ans ont rempli le questionnaire PAID (Problem Areas In Diabetes) et leurs parents ont rempli la version révisée du PAID (scores de 0 à 100, 100 = maximum de sévérité). Résultats La durée médiane du DT1 était de 6,5 ans (intervalle interquartile de 3,7 à 9,9). Le taux d’HbA1c (± écart-type) était de 8,1 ± 1,6 %, dont 35 % des patients atteignant les valeurs cible d’HbA1c. Ces derniers (surtout les patients âgés de 8-18 ans) avaient tendance à recevoir un traitement plus intensif que ceux n’ayant pas atteint les valeurs cibles d’HbA1c (pompe à insuline 34-35 % vs 29-27 % des patients, autosurveillance glycémique 6,2-5,1 vs 5,5-4,4 fois/j). Les parents/tuteurs ont déclaré un fardeau de soins plus lourd que les adolescents (scores = 47,1 ± 20,5 vs 23,6 ± 18,0 respectivement). Conclusion Environ 1/3 des patients DT1 européens de 8-25 ans atteignent les valeurs cibles d’HbA1c. Ces patients ont tendance à bénéficier d’un traitement et d’une surveillance plus intensifs. Ainsi, il est nécessaire d’identifier des approches visant à intensifier le traitement, et à améliorer le contrôle glycémique chez les plus jeunes et réduire le fardeau du DT1 chez les jeunes patients européens. Déclaration d’intérêt Les auteurs déclarent avoir un intérêt avec un organisme privé, industriel ou commercial en relation avec le sujet présenté. Consultant scientifique Sanofi.
Background
It is still unclear whether D2 lymphadenectomy improves the survival of patients with gastric cancer and should therefore be performed routinely or selectively. The aim of this multicentre ...randomized trial was to compare D2 and D1 lymphadenectomy in the treatment of gastric cancer.
Methods
Between June 1998 and December 2006, patients with gastric adenocarcinoma were assigned randomly to either D1 or D2 gastrectomy. Intraoperative randomization was implemented centrally by telephone. Primary outcome was overall survival; secondary endpoints were disease‐specific survival, morbidity and postoperative mortality.
Results
A total of 267 eligible patients were allocated to either D1 (133 patients) or D2 (134) resection. Morbidity (12·0 versus 17·9 per cent respectively; P = 0·183) and operative mortality (3·0 versus 2·2 per cent; P = 0·725) rates did not differ significantly between the groups. Median follow‐up was 8·8 (range 4·5–13·1) years for surviving patients and 2·4 (0·2–11·9) years for those who died, and was not different in the two treatment arms. There was no difference in the overall 5‐year survival rate (66·5 versus 64·2 per cent for D1 and D2 lymphadenectomy respectively; P = 0·695). Subgroup analyses showed a 5‐year disease‐specific survival benefit for patients with pathological tumour (pT) 1 disease in the D1 group (98 per cent versus 83 per cent for the D2 group; P = 0·015), and for patients with pT2–4 status and positive lymph nodes in the D2 group (59 per cent versus 38 per cent for the D1 group; P = 0·055).
Conclusion
No difference was found in overall 5‐year survival between D1 and D2 resection. Subgroup analyses suggest that D2 lymphadenectomy may be a better choice in patients with advanced disease and lymph node metastases. Registration number: ISRCTN11154654 (http://www.controlled‐trials.com).
No difference
Objective: The quantification of the way an individual walks is key to the understanding of diseases affecting the neuromuscular system. More specifically, to improve diagnostics and treatment plans, ...there is a continuous interest in quantifying gait consistency, allowing clinicians to distinguish natural variability of the gait patterns from disease progression or treatment effects. To this end, the current article presents a novel objective method for assessing the consistency of an individual's gait, consisting of two major components. Methods: Firstly, inertial sensor accelerometer data from both shanks and the lower back is used to fit an AutoRegressive with eXogenous input model. The model residuals are then used as a key feature for gait consistency monitoring. Secondly, the non-parametric maximum mean discrepancy hypothesis test is introduced to measure differences in the distributions of the residuals as a measure of gait consistency. As a paradigmatic case, gait consistency was evaluated both in a single walking test and between tests at different time points in healthy individuals and those affected by multiple sclerosis (MS). Results: It was found that MS patients experienced difficulties maintaining a consistent gait, even when the retest was performed one-hour apart and all external factors were controlled. When the retest was performed one-week apart, both healthy and MS individuals displayed inconsistent gait patterns. Conclusion: Gait consistency has been successfully quantified for both healthy and MS individuals. Significance: This newly proposed approach revealed the detrimental effects of varying assessment conditions on gait pattern consistency, indicating potential masking effects at follow-up assessments.
Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit ...from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8
T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8
T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8
population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first step in the kynurenine pathway of tryptophan (Trp) degradation that produces several biologically active Trp metabolites. L-kynurenine (Kyn), ...the first byproduct by IDO1, promotes immunoregulatory effects via activation of the Aryl hydrocarbon Receptor (AhR) in dendritic cells (DCs) and T lymphocytes. We here identified the nuclear coactivator 7 (NCOA7) as a molecular target of 3-hydroxyanthranilic acid (3-HAA), a Trp metabolite produced downstream of Kyn along the kynurenine pathway. In cells overexpressing NCOA7 and AhR, the presence of 3-HAA increased the association of the two molecules and enhanced Kyn-driven, AhR-dependent gene transcription. Physiologically, conventional (cDCs) but not plasmacytoid DCs or other immune cells expressed high levels of NCOA7. In cocultures of CD4
T cells with cDCs, the co-addition of Kyn and 3-HAA significantly increased the induction of Foxp3
regulatory T cells and the production of immunosuppressive transforming growth factor β in an NCOA7-dependent fashion. Thus, the co-presence of NCOA7 and the Trp metabolite 3-HAA can selectively enhance the activation of ubiquitary AhR in cDCs and consequent immunoregulatory effects. Because NCOA7 is often overexpressed and/or mutated in tumor microenvironments, our current data may provide evidence for a new immune check-point mechanism based on Trp metabolism and AhR.
Walking/gait speed is a key measure for daily mobility characterization. To date, various studies have attempted to design algorithms to estimate walking speed using an inertial sensor worn on the ...lower back, which is considered as a proper location for activity monitoring in daily life. However, these algorithms were rarely compared and validated on the same datasets, including people with different preferred walking speed. This study implemented several original, improved, and new algorithms for estimating cadence, step length and eventually speed. We designed comprehensive cross-validation to compare the algorithms for walking slow, normal, fast, and using walking aids. We used two datasets, including reference data for algorithm validation from an instrumented mat (40 subjects) and shanks-worn inertial sensors (88 subjects), with normal and impaired walking patterns. The results showed up to 50% performance improvements. Training of algorithms on data from people with different preferred speeds led to better performance. For the slow walkers, an average RMSE of 2.5 steps/min, 0.04 m, and 0.10 m/s were respectively achieved for cadence, step length, and speed estimation. For normal walkers, the errors were 3.5 steps/min, 0.08 m, and 0.12 m/s. An average RMSE of 1.3 steps/min, 0.05 m, and 0.10 m/s were also observed on fast walkers. For people using walking aids, the error significantly increased up to an RMSE of 14 steps/min, 0.18 m, and 0.27 m/s. The results demonstrated the robustness of the proposed combined speed estimation approach for different speed ranges. It achieved an RMSE of 0.10, 0.18, 0.15, and 0.32 m/s for slow, normal, fast, and using walking aids, respectively.
Aim: To investigate the prevalence of reticular pseudodrusen (RPD) in eyes of patients presenting with newly diagnosed choroidal neovascularisation (CNV) in age-related macular degeneration (AMD), ...and to analyse the association between RPD, age-related maculopathy (ARM) and AMD. Method: Two observational consecutive prospective series. In series 1, patients with AMD with newly diagnosed CNV were sampled to determine the incidence of RPD. Eyes with and without RPD were compared by the Mann–Whitney non-parametric test and Fisher’s exact test for age, sex of patients, the eye involved and type of CNV. Series 2 comprised 100 patients referred for fundus photography, fluorescein and/or indocyanine green angiography, for whom pictures showed RPD. This second cohort was then selected from a larger group of patients. Results: Patients with newly diagnosed CNV in series 1 comprised 67 women and 33 men, aged 57–96 years (mean 79.5). CNV was “classic” (32 eyes), “occult” (41) or exhibited vascularised pigment epithelial detachment (PED, 11), retinal angiomatous proliferation (RAP) with or without PED (13), or haemorrhagic or fibrovascular scarring (3). In all, 24 (24%) eyes had RPD. The prevalence of RAP was significantly higher in eyes with RPD than in those without (p = 0.0128), despite the small number of patients with RAP. In series 2, 100 patients with RPD were enrolled in 3 months, and corresponded to 8% of the overall cases referred to our centre (Centre Ophtalmologique d’Imagerie et de Laser, Paris, France). There were 77 women and 23 men, aged 54–93 years (mean 79.2). Eyes with RPD (n = 155) usually exhibited signs of ARM or AMD, including soft drusen (101 eyes) and/or retinal pigment epithelium abnormalities (70), geographical atrophy (27) and/or CNV (61). In both studies, examination of blue-light fundus pictures was extremely helpful in diagnosing RPD. Conclusion: RPD have a high prevalence among patients with AMD with newly diagnosed CNV (24% of cases). RPD were commonly associated with ARM or AMD. This study suggests that eyes with RPD could be classified as a phenotype of ARM.
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