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1. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties

Author

Mahrouf-Yorgov, Meriem, Augeul, Lionel, Da Silva, Claire Crola, Jourdan, Maud, Rigolet, Muriel, Manin, Sylvie, Ferrera, René, Ovize, Michel, Henry, Adeline, Guguin, Aurélie, Meningaud, Jean-Paul, Dubois-Randé, Jean-Luc, Motterlini, Roberto, Foresti, Roberta, Rodriguez, Anne-Marie, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Plateforme de Cytométrie en Flux, GHU A. Chenevier - Henri Mondor (Inserm U955, équipe 16), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), INSERM U955, équipe 10, Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Institut Mondor de Recherche Biomédicale (IMRB), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
Male, Original Paper, [SDV]Life Sciences [q-bio], Mitophagy, Myocardial Infarction, Apoptosis, Mesenchymal Stem Cells, Endosomes, Mesenchymal Stem Cell Transplantation, Coculture Techniques, Mitochondria, Mice, Inbred C57BL, Cytoprotection, Doxorubicin, Enzyme Induction, Human Umbilical Vein Endothelial Cells, Animals, Humans, Reactive Oxygen Species, Acids, ComputingMilieux_MISCELLANEOUS, Heme Oxygenase-1, Signal Transduction
Abstract

Mesenchymal stem cells (MSCs) protect tissues against cell death induced by ischemia/reperfusion insults. This therapeutic effect seems to be controlled by physiological cues released by the local microenvironment following injury. Recent lines of evidence indicate that MSC can communicate with their microenvironment through bidirectional exchanges of mitochondria. In particular, in vitro and in vivo studies report that MSCs rescue injured cells through delivery of their own mitochondria. However, the role of mitochondria conveyed from somatic cells to MSC remains unknown. By using a co-culture system consisting of MSC and distressed somatic cells such as cardiomyocytes or endothelial cells, we showed that mitochondria from suffering cells acted as danger-signaling organelles that triggered the anti-apoptotic function of MSC. We demonstrated that foreign somatic-derived mitochondria were engulfed and degraded by MSC, leading to induction of the cytoprotective enzyme heme oxygenase-1 (HO-1) and stimulation of mitochondrial biogenesis. As a result, the capacity of MSC to donate their mitochondria to injured cells to combat oxidative stress injury was enhanced. We found that similar mechanisms - activation of autophagy, HO-1 and mitochondrial biogenesis - occurred after exposure of MSC to exogenous mitochondria isolated from somatic cells, strengthening the idea that somatic mitochondria alert MSC of a danger situation and subsequently promote an adaptive reparative response. In addition, the cascade of events triggered by the transfer of somatic mitochondria into MSC was recapitulated in a model of myocardial infarction in vivo. Specifically, MSC engrafted into infarcted hearts of mice reduced damage, upregulated HO-1 and increased mitochondrial biogenesis, while inhibition of mitophagy or HO-1 failed to protect against cardiac apoptosis. In conclusion, our study reveals a new facet about the role of mitochondria released from dying cells as a key environmental cue that controls the cytoprotective function of MSC and opens novel avenues to improve the effectiveness of MSC-based therapies.

Published
2017
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2. Brain 18 F-FDG PET Metabolic Abnormalities in Patients with Long-Lasting Macrophagic Myofascitis

Author

François-Jérôme Authier, Mehdi Aoun Sebaiti, Anne-Ségolène Cottereau, Antoine Verger, Emmanuel Itti, Anne-Catherine Bachoud-Lévi, Sabrina Yara, Axel Van Der Gucht, Romain K. Gherardi, Julia Chalaye, Mukedaisi Abulizi, Eva Evangelista, Jessie Aouizerate, Eric Guedj, Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service Central de Biophysique et de Médecine Nucléaire, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de néphrologie [CHU Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Henri Mondor, Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de médecine nucléaire [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre de référence maladie de Huntington, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de médecine nucléaire [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de Médecine Nucléaire [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Trousseau [APHP], IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
030203 arthritis & rheumatology, medicine.medical_specialty, PET-CT, education.field_of_study, Neurology, medicine.diagnostic_test, business.industry, Papez circuit, Population, Neuropsychology, Statistical parametric mapping, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Neuroimaging, Internal medicine, medicine, Cardiology, Radiology, Nuclear Medicine and imaging, Neuropsychological assessment, business, education, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with 18F-FDG. Methods:18F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean ± SD], 45.9 ± 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all 18F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 ± 16 y; P = 0.87) and sex (73% women; P = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment (n = 42), those with frontal subcortical (FSC) dysfunction (n = 29), those with Papez circuit dysfunction (n = 22), and those with callosal disconnection (n = 7). Results: In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism (P < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Conclusion: Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction.

Published
2017
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3. Cerebral 18F-FDG PET in macrophagic myofasciitis: An individual SVM-based approach

Author

Lionel Lerman, Mukedaisi Abulizi, Eric Guedj, Antoine Verger, Mehdi Aoun-Sebaiti, Paul Blanc-Durand, Axel Van Der Gucht, François-Jérôme Authier, Emmanuel Itti, Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Nancyclotep- Experimental Imaging Platform = Plate-forme d'imagerie moléculaire, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Lorraine (UL), Service Central de Biophysique et de Médecine Nucléaire, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Médecine Nucléaire [Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service de médecine nucléaire [Créteil], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
0301 basic medicine, Male, Pathology, Fibromyalgia, Support Vector Machine, lcsh:Medicine, Diagnostic Radiology, Machine Learning, Cortex (anatomy), Cerebellum, Medicine and Health Sciences, Medicine, Fasciitis, lcsh:Science, Tomography, ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, Multidisciplinary, Radiology and Imaging, Applied Mathematics, Simulation and Modeling, Macrophagic myofasciitis, Brain, Neuromuscular Diseases, Middle Aged, Temporal Lobe, medicine.anatomical_structure, Neurology, Predictive value of tests, Physical Sciences, Female, Occipital Lobe, Anatomy, Algorithms, Research Article, Adult, medicine.medical_specialty, Computer and Information Sciences, Imaging Techniques, Neuroimaging, Research and Analysis Methods, 18f fdg pet, 03 medical and health sciences, Machine Learning Algorithms, Text mining, Rheumatology, Artificial Intelligence, Diagnostic Medicine, Fluorodeoxyglucose F18, Predictive Value of Tests, Support Vector Machines, Humans, In patient, Myositis, business.industry, lcsh:R, Biology and Life Sciences, medicine.disease, Support vector machine, 030104 developmental biology, Positron-Emission Tomography, lcsh:Q, Radiopharmaceuticals, business, Positron Emission Tomography, Mathematics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Neuroscience
Abstract

Introduction Macrophagic myofasciitis (MMF) is an emerging condition with highly specific myopathological alterations. A peculiar spatial pattern of a cerebral glucose hypometabolism involving occipito-temporal cortex and cerebellum have been reported in patients with MMF; however, the full pattern is not systematically present in routine interpretation of scans, and with varying degrees of severity depending on the cognitive profile of patients. Aim was to generate and evaluate a support vector machine (SVM) procedure to classify patients between healthy or MMF 18F-FDG brain profiles. Methods 18F-FDG PET brain images of 119 patients with MMF and 64 healthy subjects were retrospectively analyzed. The whole-population was divided into two groups; a training set (100 MMF, 44 healthy subjects) and a testing set (19 MMF, 20 healthy subjects). Dimensionality reduction was performed using a t-map from statistical parametric mapping (SPM) and a SVM with a linear kernel was trained on the training set. To evaluate the performance of the SVM classifier, values of sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV) and accuracy (Acc) were calculated. Results The SPM12 analysis on the training set exhibited the already reported hypometabolism pattern involving occipito-temporal and fronto-parietal cortices, limbic system and cerebellum. The SVM procedure, based on the t-test mask generated from the training set, correctly classified MMF patients of the testing set with following Se, Sp, PPV, NPV and Acc: 89%, 85%, 85%, 89%, and 87%. Conclusion We developed an original and individual approach including a SVM to classify patients between healthy or MMF metabolic brain profiles using 18F-FDG-PET. Machine learning algorithms are promising for computer-aided diagnosis but will need further validation in prospective cohorts.

Published
2017
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4. Low concentrations of aluminum hydroxide adjuvant, forming limited size aggregates, selectively induce cerebral aluminum increase and long-term neurotoxicity in mouse

Author

François-Jérôme Authier, Housam Eidi, Christopher Exley, Josette Cadusseau, Guillemette Crépeaux, Chris Shaw, Romain K. Gherardi, Bruno Giros, Marie-Odile David, INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Structure et activité des biomolécules normales et pathologiques (SABNP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Keele University [Keele], University of British Columbia (UBC), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), and École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB)

Subjects
medicine.medical_specialty, Vaccin, medicine.medical_treatment, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Chromosomal translocation, 010402 general chemistry, 01 natural sciences, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, Aluminium, Internal medicine, medicine, Adjuvant, Alum, Aluminium hydroxide, Neurotoxicity, Neurotoxicité, medicine.disease, 3. Good health, 0104 chemical sciences, Particule, Endocrinology, chemistry, Immunology, Hydroxide, Anatomy, 030217 neurology & neurosurgery
Abstract

Background Aluminium hydroxide (alum) has long been added as an adjuvant of vaccines. It consists of nanoparticles forming aggregates. Unexpectedly long-lasting biopersistence of alum aggregates were found within immune cells of patients with chronic fatigue, cognitive dysfunction, myalgias and dysimmunity [1] , [2] . We documented in mice slow translocation of alum aggregates captured by monocyte-lineage cells from the injected muscle to brain [3] , [4] , [5] . Herein, brain function and aluminium (Al) concentration were examined long after injections. Methods Alhydrogel® was injected in TA muscle in adult female CD1 mice at 3 doses ranging from 133 to 800 μg Al/kg. Eight validated tests were used to evaluate cognitive and motor performances 180 days after injection. Brains were collected for Al level determination and Iba-1 immunohistochemistry. Results A most unusual neuro-toxicological pattern limited to lower doses of alum was observed. Neurobehavioral changes, including decreased activity levels and altered anxiety-like behaviour, were documented in animals exposed to the two lowest doses (133 and 200 μg Al/kg) but not at the highest dose (800 μg Al/kg), compared to controls. Consistently, cerebral Al levels were increased in animals exposed to the lowest doses. Microglial cell increase was found in amygdala of the 200 μg Al/kg group. Interestingly, the injected suspensions corresponding to the two lowest doses contained much smaller aggregates (1.50–1.75 μm) compared to the highest dose (4.70 μm). Conclusion Alum particles injected in muscle may induce neurotoxic effects and Al cerebral accumulation six months after injection in mice. Neurotoxic effects are restricted to low concentration suspensions forming small particle aggregates. Such bacteria-sized aggregates are known to be selectively captured by monocyte-lineage cells. This study strongly suggests that, in contrast to “the dose makes the poison” paradigm of classical toxicology, alum toxicology obeys the specific rules of small particle toxicology, thus deserving in depth revaluation. (This study was supported by ANSM).

Published
2016
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5. Selective elevation of circulating CCL2/MCP1 levels in patients with longstanding post-vaccinal macrophagic myofasciitis and ASIA

Author

Mathieu Surenaud, François-Jérôme Authier, Josette Cadusseau, Sophie Hue, Romain K. Gherardi, Nilusha Ragunathan-Thangarajah, INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Service d'histologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de référence neuromusculaire (GNMH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre de référence neuromusculaire (GNMH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut Mondor de Recherche Biomédicale (IMRB), Région Ile-de- France through a programme PICRI (Partenariat Institutions-Citoyens pour la Recherche et l!Innovation) 'Recherche de polymorphismes dans les genes codant pour des facteurs inflammatoires (chimiokines) dans la myofasciite à macrophages'., IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Guellaen, Georges

Subjects
Male, medicine.medical_treatment, MESH: Adjuvants, Immunologic, Biochemistry, Cohort Studies, 0302 clinical medicine, MESH: Fasciitis, MESH: Autoimmune Diseases, Drug Discovery, cytokinome, Fasciitis, MESH: Cohort Studies, Chemokine CCL2, Vaccines, 0303 health sciences, MESH: Middle Aged, Macrophagic myofasciitis, vaccine adjuvant, Middle Aged, macrophagic myofasciitis, MESH: Case-Control Studies, Pathophysiology, 3. Good health, Cytokine, Molecular Medicine, Female, inflammatory cytokine, CCL-2/MCP1, CCL3, CCL2, Article, Autoimmune Diseases, Proinflammatory cytokine, MESH: Myositis, 03 medical and health sciences, Immune system, Adjuvants, Immunologic, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Chemokine CCL2, 030304 developmental biology, Pharmacology, MESH: Humans, Myositis, business.industry, Organic Chemistry, Case-control study, medicine.disease, MESH: Male, MESH: Vaccines, alum, Case-Control Studies, Immunology, business, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; Several medical conditions sharing similar signs and symptoms may be related to immune adjuvants. These conditions described as ASIA (Autoimmune/inflammatory Syndrome Induced by Adjuvants), include a condition characterized by macrophagic myofasciitis (MMF) assessing long-term persistence of vaccine derived-alum adjuvants into macrophages at sites of previous immunization. Despite increasing data describing clinical manifestations of ASIA have been reported, biological markers are particularly lacking for their characterization and follow up. We report an extensive cytokine screening performed in serum from 44 MMF patients compared both to sex and age matched healthy controls and to patients with various types of inflammatory neuromuscular diseases. Thirty cytokines were quantified using combination of Luminex® technology and ELISA. There was significant mean increase of serum levels of the monocytechemoattractant protein 1 (CCL2/MCP-1) in MMF patients compared to healthy subjects. MMF patients showed no elevation of other cytokines. This contrasted with inflammatory patients in whom CCL2/MCP-1 serum levels were unchanged, whereas several other inflammatory cytokines were elevated (IL1β, IL5 and CCL3/MIP1α). These results suggest that CCL2 may represent a biological marker relevant to the pathophysiology of MMF rather than a non specific inflammatory marker and that it should be checked in the other syndromes constitutive of ASIA.

Published
2014

6. Dual Effects of Exercise in Dysferlinopathy

Author

Fabrice Chrétien, Nathalie Bourg, Isabelle Richard, Romain K. Gherardi, Alice Marchand, François-Jérôme Authier, Olivier Biondi, Marie Villemeur, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, and École pratique des hautes études (EPHE)

Subjects
Aging, MESH: Swimming, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Mice, Mutant Strains, MESH: Muscle Contraction, Muscle Fibers, Skeletal, Isometric exercise, MESH: Physical Conditioning, Animal, Quadriceps Muscle, Running, Dysferlin, Mice, 0302 clinical medicine, Eccentric, MESH: Aging, MESH: Animals, Muscular dystrophy, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Muscle Fibers, Skeletal, biology, MESH: Muscle Strength, Anatomy, MESH: Membrane Proteins, MESH: Quadriceps Muscle, medicine.symptom, Locomotion, Muscle Contraction, medicine.medical_specialty, Dysferlinopathy, MESH: Muscular Dystrophies, Limb-Girdle, MESH: Locomotion, MESH: Microscopy, Electron, Pathology and Forensic Medicine, Necrosis, 03 medical and health sciences, Physical Conditioning, Animal, Internal medicine, medicine, Animals, Muscle Strength, Muscle, Skeletal, Myopathy, MESH: Mice, Swimming, 030304 developmental biology, MESH: Necrosis, Sarcolemma, MESH: Dysferlin, Cell Membrane, MESH: Running, Membrane Proteins, Plasma membrane repair, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Mice, Mutant Strains, Microscopy, Electron, Endocrinology, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, 030217 neurology & neurosurgery, MESH: Cell Membrane
Abstract

International audience; Dysferlinopathy refers to a group of autosomal recessive muscular dystrophies due to mutations in the dysferlin gene causing deficiency of a membrane-bound protein crucially involved in plasma membrane repair. The condition is characterized by marked clinical heterogeneity, the different phenotypes/modes of presentation being unrelated to the genotype. For unknown reasons, patients are often remarkably active before the onset of symptoms. Dysferlin deficiency-related persistence of mechanically induced sarcolemma disruptions causes myofiber damage and necrosis. We postulate that limited myodamage may initially remain hidden with well-preserved resistance to physical strains. By subjecting dysferlin-deficient B6.A/J-Dysf(prmd) mice to long-term swimming exercise, we observed that concentric/isometric strain improved muscle strength and alleviated muscular dystrophy by limiting the accumulation of membrane lesions. By contrast, eccentric strain induced by long-term running in a wheel worsened the dystrophic process. Myofiber damage induced by eccentric strain increased with age, reflecting the accumulation of non-necrotic membrane lesions up to a critical threshold. This phenomenon was modulated by daily spontaneous activity. Transposed to humans, our results may suggest that the past activity profile shapes the clinical phenotype of the myopathy and that patients with dysferlinopathy should likely benefit from concentric exercise-based physiotherapy.

Published
2013
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7. Macrophagic myofasciitis: characterization and pathophysiology

Author

François-Jérôme Authier, Romain K. Gherardi, IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), and Guellaen, Georges

Subjects
myalgia, Pathology, medicine.medical_specialty, medicine.medical_treatment, Spleen, MESH: Adjuvants, Immunologic, MESH: Phagocytes, Article, MESH: Myositis, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Immune system, MESH: Nanostructures, Adjuvants, Immunologic, Rheumatology, MESH: Fasciitis, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Medicine, MESH: Animals, MESH: Syndrome, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Fasciitis, Autoimmune/inflammatory syndrome induced by adjuvants, 030304 developmental biology, Phagocytes, 0303 health sciences, MESH: Humans, Myositis, business.industry, Alum, Macrophagic myofasciitis, Syndrome, medicine.disease, Nanostructures, 3. Good health, medicine.anatomical_structure, chemistry, Immunization, Immunology, Alum Compounds, medicine.symptom, MESH: Alum Compounds, business, Adjuvant, 030217 neurology & neurosurgery
Abstract

International audience; Aluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated 'autoimmune/inflammatory syndrome induced by adjuvants' (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain.

Published
2012
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8. Clinical relevance of tumor cells with stem-like properties in pediatric brain tumors

Author

Thirant, Cécile, Bessette, Barbara, Varlet, Pascale, Puget, Stéphanie, Cadusseau, Josette, Dos Reis Tavares, Silvina, Studler, Jeanne-Marie, Silvestre, David Carlos, Susini, Aurélie, Villa, Chiara, Miquel, Catherine, Bogeas, Alexandra, Surena, Anne-Laure, Dias-Morais, Amélia, Léonard, Nadine, Pflumio, Françoise, Bièche, Ivan, Boussin, François D, Sainte-Rose, Christian, Grill, Jacques, Daumas-Duport, Catherine, Chneiweiss, Hervé, Junier, Marie-Pierre, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of neuropathology, Hôpial Sainte-Anne, Service de neurochirurgie pédiatrique [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Collège de France (CdF (institution)), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Genetique Moleculaire des Cancers d'Origine Epitheliale, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]

Subjects
MESH: Adolescent, MESH: Neural Stem Cells, child, MESH: Humans, MESH: Immunophenotyping, MESH: Child, Preschool, MESH: Flow Cytometry, medulloblastoma, MESH: Infant, MESH: Neoplastic Stem Cells, MESH: Cell Separation, MESH: Male, MESH: Glioma, glioma, MESH: Survival Analysis, MESH: Child, MESH: Brain Neoplasms, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, TP53, pilocytic astrocytoma, MESH: Female, ganglioglioma
Abstract

International audience; BACKGROUND: Primitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting. CONCLUSIONS/SIGNIFICANCE: In brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

Published
2011
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9. Clinical relevance of tumor cells with stem-like properties in pediatric brain tumors. : Tumor stem-like cells in pediatric brain tumors

Author

Stéphanie Puget, Marie-Pierre Junier, Pascale Varlet, Silvina Dos Reis Tavares, Aurélie Susini, David C. Silvestre, Nadine Leonard, Cécile Thirant, François D. Boussin, Jacques Grill, Ivan Bièche, Alexandra Bogeas, Anne-Laure Surena, Françoise Pflumio, Hervé Chneiweiss, Amélia Dias-Morais, Josette Cadusseau, Christian Sainte-Rose, Catherine Miquel, Chiara Villa, Barbara Bessette, J. M. Studler, Catherine Daumas-Duport, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of neuropathology, Hôpial Sainte-Anne, Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vectorologie et thérapeutiques anti-cancéreuses [Villejuif] (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Collège de France (CdF (institution)), Stabilité génétique, Cellules Souches et Radiations (SCSR (U_967)), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Genetique Moleculaire des Cancers d'Origine Epitheliale, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Psychiatrie et Neurosciences (CPN - U894), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP] - Assistance publique - Hôpitaux de Paris (AP-HP), Université Paris-Sud - Paris 11 (UP11) - Institut Gustave Roussy (IGR) - Centre National de la Recherche Scientifique (CNRS), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12) - Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR10 - Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12) - Institut National de la Santé et de la Recherche Médicale (INSERM) - IFR10, Collège de France (CDF), Collège de France (CdF), Cellules Souches et Radiations (SCSR - U 967), Université Paris-Sud - Paris 11 (UP11) - Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Université Paris Diderot - Paris 7 (UPD7) - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM) - INSTITUT CURIE, and Centre de Psychiatrie et Neurosciences (U894)

Subjects
Male, MESH: Neural Stem Cells, Pathology, MESH: Flow Cytometry, Cell Separation, Developmental and Pediatric Neurology, Pediatrics, MESH: Glioma, 0302 clinical medicine, Immunophenotyping, Neural Stem Cells, glioma, MESH: Child, Molecular Cell Biology, Basic Cancer Research, TP53, pilocytic astrocytoma, Neurological Tumors, ganglioglioma, 0303 health sciences, child, Multidisciplinary, Pilocytic astrocytoma, Brain Neoplasms, Stem Cells, Astrocytoma, Flow Cytometry, MESH: Infant, Neural stem cell, 3. Good health, Neurology, Oncology, 030220 oncology & carcinogenesis, Child, Preschool, MESH: Survival Analysis, MESH: Brain Neoplasms, Neoplastic Stem Cells, Medicine, Female, Cellular Types, Research Article, medicine.medical_specialty, Adolescent, MESH: Immunophenotyping, Science, Biology, medulloblastoma, MESH: Cell Separation, 03 medical and health sciences, Cancer stem cell, Glioma, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, 030304 developmental biology, Medulloblastoma, MESH: Adolescent, MESH: Humans, MESH: Child, Preschool, Cancers and Neoplasms, Infant, medicine.disease, Survival Analysis, MESH: Neoplastic Stem Cells, MESH: Male, Pediatric Oncology, MESH: Female, Developmental Biology, Neuroscience
Abstract

International audience; BACKGROUND: Primitive brain tumors are the leading cause of cancer-related death in children. Tumor cells with stem-like properties (TSCs), thought to account for tumorigenesis and therapeutic resistance, have been isolated from high-grade gliomas in adults. Whether TSCs are a common component of pediatric brain tumors and are of clinical relevance remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: Tumor cells with self-renewal properties were isolated with cell biology techniques from a majority of 55 pediatric brain tumors samples, regardless of their histopathologies and grades of malignancy (57% of embryonal tumors, 57% of low-grade gliomas and neuro-glial tumors, 70% of ependymomas, 91% of high-grade gliomas). Most high-grade glioma-derived oncospheres (10/12) sustained long-term self-renewal akin to neural stem cells (>7 self-renewals), whereas cells with limited renewing abilities akin to neural progenitors dominated in all other tumors. Regardless of tumor entities, the young age group was associated with self-renewal properties akin to neural stem cells (P = 0.05, chi-square test). Survival analysis of the cohort showed an association between isolation of cells with long-term self-renewal abilities and a higher patient mortality rate (P = 0.013, log-rank test). Sampling of low- and high-grade glioma cultures showed that self-renewing cells forming oncospheres shared a molecular profile comprising embryonic and neural stem cell markers. Further characterization performed on subsets of high-grade gliomas and one low-grade glioma culture showed combination of this profile with mesenchymal markers, the radio-chemoresistance of the cells and the formation of aggressive tumors after intracerebral grafting. CONCLUSIONS/SIGNIFICANCE: In brain tumors affecting adult patients, TSCs have been isolated only from high-grade gliomas. In contrast, our data show that tumor cells with stem cell-like or progenitor-like properties can be isolated from a wide range of histological sub-types and grades of pediatric brain tumors. They suggest that cellular mechanisms fueling tumor development differ between adult and pediatric brain tumors.

Published
2011
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10. Slow CCL2-dependent translocation of biopersistent particles from muscle to brain

Author

Meriem Mahrouf-Yorgov, Christophe Combadière, Olivier Tillement, Zakir Khan, Josette Cadusseau, François Lux, Valerie Itier, Xavier Decrouy, Philippe Moretto, Romain K. Gherardi, Christopher Exley, François-Jérôme Authier, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Immunologie [CHU Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunité et Infection, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR113-Université Pierre et Marie Curie - Paris 6 (UPMC), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire d'Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre d'Etudes Nucléaires de Bordeaux Gradignan (CENBG), Université Sciences et Technologies - Bordeaux 1-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physico-Chimie des Matériaux Luminescents (LPCML), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Lumière Matière [Villeurbanne] (ILM), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), The Birchall Centre, Keele University-Lennard-Jones Laboratories, Service d'Histologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Centre de Référence Neuromusculaire GNMH, This work has benefited from research funding from two patients associations: E3M (Entraide aux Malades de Myofasciite à Macrophages) 'Neurodélivrance des particules injectées par voie intra musculaire et sécurité des adjuvants aluminiques' , AFM (Association Française contre les Myopathies) 'Etude des mécanismes de la myofasciite à macrophages' and Dwoskin Foundation (Nano in brain), from Région Ile-de-France through a programme PICRI (Partenariat Institutions-Citoyens pour la Recherche et l'Innovation) 'Recherche de polymorphismes dans les gènes codant pour des facteurs inflammatoires (chimiokines) dans la myofasciite à macrophages', and through two post-doctoral positions from NeRF (Neuropole de Recherche Francilien) on the topic 'The macrophage as a Trojan horse for brain delivery' and 'Brain delivery of i.m. injected nanoparticles: relevance to safety of aluminum-containing adjuvants of vaccines', European Project, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'immunologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR113-Université Pierre et Marie Curie - Paris 6 ( UPMC ), INSERM U955, équipe 10, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Centre de Référence Neuromusculaire GNMH-Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Centre de Référence Neuromusculaire GNMH-Institut Mondor de Recherche Biomédicale ( IMRB ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre d'Etudes Nucléaires de Bordeaux Gradignan ( CENBG ), Université Sciences et Technologies - Bordeaux 1-Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Physico-Chimie des Matériaux Luminescents ( LPCML ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier-Centre de Référence Neuromusculaire GNMH, Team 10 'Interactions cellulaires dans le système neuromusculaire', Faculté de Médecine-Institut Mondor de Recherche Biomédicale (IMRB)-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), BMC, Ed., European Community's Seventh Framework Programme in the project ENDOSTEM 'Activation of vasculature - INCOMING, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, Pathology, Nanomaterial neurodelivery, medicine.medical_treatment, Nanomaterial biodistribution, Monocytes, Mice, 0302 clinical medicine, Cell Movement, Tissue Distribution, Alum, Chemokine CCL2, Medicine(all), Vaccines, 0303 health sciences, education.field_of_study, Microglia, Muscles, Single nucleotide polymorphisms (SNPs), Brain, General Medicine, 3. Good health, medicine.anatomical_structure, Macrophagic myofasciitis, Blood-Brain Barrier, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Alum Compounds, Lymph, Adjuvant, Research Article, medicine.medical_specialty, Biodistribution, Asia, Population, Spleen, Blood–brain barrier, Injections, Intramuscular, Vaccine adjuvant, 03 medical and health sciences, Adjuvants, Immunologic, CCL-2, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, education, 030304 developmental biology, business.industry, Monocyte, Macrophages, Virion, Mice, Inbred C57BL, Nanoparticles, Immunization, Vaccine adverse effect, business, 030217 neurology & neurosurgery
Abstract

Background Long-term biodistribution of nanomaterials used in medicine is largely unknown. This is the case for alum, the most widely used vaccine adjuvant, which is a nanocrystalline compound spontaneously forming micron/submicron-sized agglomerates. Although generally well tolerated, alum is occasionally detected within monocyte-lineage cells long after immunization in presumably susceptible individuals with systemic/neurologic manifestations or autoimmune (inflammatory) syndrome induced by adjuvants (ASIA). Methods On the grounds of preliminary investigations in 252 patients with alum-associated ASIA showing both a selective increase of circulating CCL2, the major monocyte chemoattractant, and a variation in the CCL2 gene, we designed mouse experiments to assess biodistribution of vaccine-derived aluminum and of alum-particle fluorescent surrogates injected in muscle. Aluminum was detected in tissues by Morin stain and particle induced X-ray emission) (PIXE) Both 500 nm fluorescent latex beads and vaccine alum agglomerates-sized nanohybrids (Al-Rho) were used. Results Intramuscular injection of alum-containing vaccine was associated with the appearance of aluminum deposits in distant organs, such as spleen and brain where they were still detected one year after injection. Both fluorescent materials injected into muscle translocated to draining lymph nodes (DLNs) and thereafter were detected associated with phagocytes in blood and spleen. Particles linearly accumulated in the brain up to the six-month endpoint; they were first found in perivascular CD11b+ cells and then in microglia and other neural cells. DLN ablation dramatically reduced the biodistribution. Cerebral translocation was not observed after direct intravenous injection, but significantly increased in mice with chronically altered blood-brain-barrier. Loss/gain-of-function experiments consistently implicated CCL2 in systemic diffusion of Al-Rho particles captured by monocyte-lineage cells and in their subsequent neurodelivery. Stereotactic particle injection pointed out brain retention as a factor of progressive particle accumulation. Conclusion Nanomaterials can be transported by monocyte-lineage cells to DLNs, blood and spleen, and, similarly to HIV, may use CCL2-dependent mechanisms to penetrate the brain. This occurs at a very low rate in normal conditions explaining good overall tolerance of alum despite its strong neurotoxic potential. However, continuously escalating doses of this poorly biodegradable adjuvant in the population may become insidiously unsafe, especially in the case of overimmunization or immature/altered blood brain barrier or high constitutive CCL-2 production.

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11. Fluorescent nanodiamonds as a relevant tag for the assessment of alum adjuvant particle biodisposition

Author

Eidi, Housam, David, Marie-Odile, Crépeaux, Guillemette, Henry, Laetitia, Joshi, Vandana, Berger, Marie-Hélène, Sennour, Mohamed, Cadusseau, Josette, Gherardi, Romain, Curmi, Patrick, Structure et activité des biomolécules normales et pathologiques (SABNP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre des Matériaux (CDM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), INSERM U955, équipe 10, Institut Mondor de Recherche Biomédicale (IMRB), Centre des Matériaux (MAT), MINES ParisTech - École nationale supérieure des mines de Paris, and UMR7633, Bibliothèque

Subjects
Medicine(all), alum, [PHYS.COND.CM-MS]Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci], fluorescent nanodiamonds, vaccine adjuvant, biodisposition, complex mixtures, [PHYS.COND.CM-MS] Physics [physics]/Condensed Matter [cond-mat]/Materials Science [cond-mat.mtrl-sci]
Abstract

International audience; Aluminum oxyhydroxide (alum) is a crystalline compound widely used as an immunologic adjuvant of vaccines. Concerns linked to alum particles have emerged following recognition of their causative role in the so-called macrophagic myofasciitis (MMF) lesion in patients with myalgic encephalomyelitis, revealing an unexpectedly long-lasting biopersistence of alum within immune cells and a fundamental misconception of its biodisposition. Evidence that aluminum-coated particles phagocytozed in the injected muscle and its draining lymph nodes can disseminate within phagocytes throughout the body and slowly accumulate in the brain further suggested that alum safety should be evaluated in the long term. However, lack of specific staining makes difficult the assessment of low quantities of bona fide alum adjuvant particles in tissues. Methods: We explored the feasibility of using fluorescent functionalized nanodiamonds (mfNDs) as a permanent label of alum (Alhydrogel ®). mfNDs have a specific and perfectly photostable fluorescence based on the presence within the diamond lattice of nitrogen-vacancy centers (NV centers). As the NV center does not bleach, it allows the microspectrometric detection of mfNDs at very low levels and in the long-term. We thus developed fluorescent nanodiamonds functionalized by hyperbranched polyglycerol (mfNDs) allowing good coupling and stability of alum:mfNDs (AluDia) complexes. Specificities of AluDia complexes were comparable to the whole reference vaccine (anti-hepatitis B vaccine) in terms of particle size and zeta potential. Results: In vivo, AluDia injection was followed by prompt phagocytosis and AluDia particles remained easily detectable by the specific signal of the fND particles in the injected muscle, draining lymph nodes, spleen, liver and brain. In vitro, mfNDs had low toxicity on THP-1 cells and AluDia showed cell toxicity similar to alum alone. Expectedly, AluDia elicited autophagy, and allowed highly specific detection of small amounts of alum in autophagosomes.

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