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18 results on '"Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277"'

1. Novel PD-L1-Targeted Phenyl-Pyrazolone Derivatives with Antioxidant Properties

Author

Romain Regnault, Frédérique Klupsch, Hassiba El-Bouazzati, Romain Magnez, Raphaël Le Biannic, Natascha Leleu-Chavain, Hania Ahouari, Hervé Vezin, Régis Millet, Jean-François Goossens, Xavier Thuru, Christian Bailly, Université de Lille, CNRS, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)], Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 [LASIRE], Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], Lille Inflammation Research International Center - U 995 [LIRIC], Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 (LASIRE), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)

Subjects
antioxidant, pyrazolone, Organic Chemistry, Pharmaceutical Science, aldehyde reactivity, cancer, immune checkpoint, PD-L1 binding, Analytical Chemistry, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Chemistry (miscellaneous), Drug Discovery, Molecular Medicine, Physical and Theoretical Chemistry
Abstract

International audience; Orally-active anticancer small molecules targeting the PD-1/PD-L1 immune checkpoint are actively searched. Phenyl-pyrazolone derivatives with a high affinity for PD-L1 have been designed and characterized. In addition, the phenyl-pyrazolone unit acts as a scavenger of oxygen free radicals, providing antioxidant effects. The mechanism is known for the drug edaravone (1) which is also an aldehyde-reactive molecule. The present study reports the synthesis and functional characterization of new molecules (2–5) with an improved anti-PD-L1 activity. The leading fluorinated molecule 5 emerges as a potent checkpoint inhibitor, avidly binding to PD-L1, inducing its dimerization, blocking PD-1/PD-L1 signaling mediated by phosphatase SHP-2 and reactivating the proliferation of CTLL-2 cells in the presence of PD-L1. In parallel, the compound maintains a significant antioxidant activity, characterized using electron paramagnetic resonance (EPR)-based free radical scavenging assays with the probes DPPH and DMPO. The aldehyde reactivity of the molecules was investigated using 4-hydroxynonenal (4-HNE), which is a major lipid peroxidation product. The formation of drug-HNE adducts, monitored by high resolution mass spectrometry (HRMS), was clearly identified and compared for each compound. The study leads to the selection of compound 5 and the dichlorophenyl-pyrazolone unit as a scaffold for the design of small molecule PD-L1 inhibitors endowed with antioxidant properties.

Published
2023
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2. Direct interaction of TrkA/CD44v3 is essential for NGF-promoted aggressiveness of breast cancer cells

Author

Sarah Trouvilliez, Julien Cicero, Romain Lévêque, Léo Aubert, Cyril Corbet, Alexandre Van Outryve, Karolin Streule, Pierre-Olivier Angrand, Pamela Völkel, Romain Magnez, Guillaume Brysbaert, Caroline Mysiorek, Fabien Gosselet, Roland Bourette, Eric Adriaenssens, Xavier Thuru, Chann Lagadec, Jérôme de Ruyck, Véronique Orian-Rousseau, Xuefen Le Bourhis, Robert-Alain Toillon, Université de Lille, CNRS, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Plasticité Cellulaire et Cancer - U908 (CPAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Signalisation des facteurs de croissance dans le cancer du sein. Protéomique fonctionnelle, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lille, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, and UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique

Subjects
Life sciences, biology, Cancer Research, animal structures, [SDV]Life Sciences [q-bio], Breast Neoplasms, Mice, Hyaluronan Receptors, Oncology, nervous system, ddc:570, Nerve Growth Factor, Animals, Humans, Protein Isoforms, Female, Receptor, trkA
Abstract

Background CD44 is a multifunctional membrane glycoprotein. Through its heparan sulfate chain, CD44 presents growth factors to their receptors. We have shown that CD44 and Tropomyosin kinase A (TrkA) form a complex following nerve growth factor (NGF) induction. Our study aimed to understand how CD44 and TrkA interact and the consequences of inhibiting this interaction regarding the pro-tumoral effect of NGF in breast cancer. Methods After determining which CD44 isoforms (variants) are involved in forming the TrkA/CD44 complex using proximity ligation assays, we investigated the molecular determinants of this interaction. By molecular modeling, we isolated the amino acids involved and confirmed their involvement using mutations. A CD44v3 mimetic peptide was then synthesized to block the TrkA/CD44v3 interaction. The effects of this peptide on the growth, migration and invasion of xenografted triple-negative breast cancer cells were assessed. Finally, we investigated the correlations between the expression of the TrkA/CD44v3 complex in tumors and histo-pronostic parameters. Results We demonstrated that isoform v3 (CD44v3), but not v6, binds to TrkA in response to NGF stimulation. The final 10 amino acids of exon v3 and the TrkA H112 residue are necessary for the association of CD44v3 with TrkA. Functionally, the CD44v3 mimetic peptide impairs not only NGF-induced RhoA activation, clonogenicity, and migration/invasion of breast cancer cells in vitro but also tumor growth and metastasis in a xenograft mouse model. We also detected TrkA/CD44v3 only in cancerous cells, not in normal adjacent tissues. Conclusion Collectively, our results suggest that blocking the CD44v3/TrkA interaction can be a new therapeutic option for triple-negative breast cancers.

Published
2022
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3. Protease-antiprotease imbalance in patients with severe COVID-19

Author

Brigitte Onraed, Boualem Sendid, Mercé Jourdain, Farid Zerimech, Licorne Study Groupa, Malika Balduyck, Marion Bouchecareilh, Pascal Pigny, Alain Duhamel, BOUCHECAREILH, Marion, CHU Lille, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Microbiologie [CHRU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, CNRS, Université de Lille, IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Recherche translationnelle sur le diabète (RTD) - U1190, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Bordeaux Research In Translational Oncology [Bordeaux] [BaRITOn], and METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694

Subjects
Adult, Male, ARDS, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clinical Biochemistry, Enzyme-Linked Immunosorbent Assay, Severity of Illness Index, alpha-1 antitrypsin, COVID-19, elastase, matrix metalloprotease-12 (MMP-12), 03 medical and health sciences, 0302 clinical medicine, Matrix Metalloproteinase 12, Severity of illness, medicine, Humans, In patient, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, 0303 health sciences, Protease, SARS-CoV-2, business.industry, Biochemistry (medical), Elastase, General Medicine, Middle Aged, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], Intensive Care Units, 030228 respiratory system, alpha 1-Antitrypsin, Immunology, Female, Leukocyte Elastase, business, Bronchoalveolar Lavage Fluid
Abstract

International audience; No abstract available

Published
2021
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4. Antioxidant Properties and Aldehyde Reactivity of PD-L1 Targeted Aryl-Pyrazolone Anticancer Agents

Author

Leleu, N. (Natascha), Regnault, R. (Romain), Ahouari, H. (Hania), Le Biannic, R. (Raphael), Kouach, M. (Mostafa), Klupsch, F. (Frederique), Magnez, R. (Romain), Vezin, H. (Herve), Thuru, X. (Xavier), Bailly, C. (Christian), Goossens, J-F. (Jean-Francois), MILLET, R. (Régis), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 (LASIRE), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Oncowitan [Wasquehal], Université de Lille, LillOA, Université de Lille, CNRS, Lille Inflammation Research International Center - U 995 [LIRIC], 495476|||Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Laboratoire Avancé de Spectroscopie pour les Intéractions la Réactivité et l'Environnement - UMR 8516 [LASIRE], Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], and Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Subjects
PD-L1, Aldehydes, antioxidant, edaravone, Programmed Cell Death 1 Receptor, Organic Chemistry, pyrazolone, Pharmaceutical Science, Antineoplastic Agents, Antioxidants, B7-H1 Antigen, Analytical Chemistry, aldehyde reactivity, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, drug adducts, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, Chemistry (miscellaneous), cancer, Drug Discovery, Molecular Medicine, Fluorouracil, Pyrazolones, Physical and Theoretical Chemistry
Abstract

International audience; Small molecules targeting the PD-1/PD-L1 checkpoint are actively searched to complement the anticancer arsenal. Different molecular scaffolds have been reported, including phenyl-pyrazolone derivatives which potently inhibit binding of PD-L1 to PD-1. These molecules are structurally close to antioxidant drug edaravone (EDA) used to treat amyotrophic lateral sclerosis. For this reason, we investigated the capacity of five PD-L1-binding phenyl-pyrazolone compounds (1–5) to scavenge the formation of oxygen free radicals using electron spin resonance spectroscopy with DPPH/DMPO probes. In addition, the reactivity of the compounds toward the oxidized base 5-formyluracil (5fU) was assessed using chromatography coupled to mass spectrometry and photodiode array detectors. The data revealed that the phenyl-pyrazolone derivatives display antioxidant properties and exhibit a variable reactivity toward 5fU. Compound 2 with a N-dichlorophenyl-pyrazolone moiety cumulates the three properties, being a potent PD-L1 binder, a robust antioxidant and an aldehyde-reactive compound. On the opposite, the adamantane derivative 5 is a potent PD-L1 binding with a reduced antioxidant potential and no aldehyde reactivity. The nature of the substituent on the phenyl-pyrazolone core modulates the antioxidant capacity and reactivity toward aromatic aldehydes. The molecular signature of the compound can be adapted at will, to confer additional properties to these PD-L1 binders.

Published
2022
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5. Preclinical Study of Radiation on Fat Flap Regeneration under Tissue-engineering Chamber: Potential Consequences for Breast Reconstruction

Author

Cleret, D. (Damien), Gradwohl, M. (Marion), Dekerle, L. (Lucie), Drucbert, A-S. (Anne-Sophie), Idziorek, T. (Thierry), Pasquier, D. (David), Blanchemain, N. (Nicolas), Payen, J. (Julien), Guerreschi, P. (Pierre), Marchetti, P. (Philippe), Université de Lille, Inserm, CHU Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Advanced Drug Delivery Systems (ADDS) - U1008, Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189, Médicaments et biomatériaux à libération contrôlée: mécanismes et optimisation - Advanced Drug Delivery Systems - U 1008 [MBLC - ADDS], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] [UNICANCER/ICL], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Médicaments et biomatériaux à libération contrôlée: mécanismes et optimisation - Advanced Drug Delivery Systems - U 1008 (MBLC - ADDS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Lattice Medical [Loos], Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
[SDV]Life Sciences [q-bio], Surgery
Abstract

International audience; Background: Use of a tissue-engineering chamber (TEC) for growth of fat flap is a promising approach for breast reconstruction. Here, we evaluated in a preclinical model the effects of radiation on adipose tissue growth either before or after 3D-printed bioresorbable TEC implantation. Methods: Twenty-eight female Wistar rats were distributed into three groups: TEC implantation as nonirradiated controls (G1), TEC insertion followed by irradiation 3 weeks later (G2), and irradiation 6 weeks before TEC insertion (G3). G2 and G3 received 33.3 Gy in nine sessions of 3.7 Gy. Growth of the fat flap was monitored via magnetic resonance imaging. At 6 months after implantation, fat flaps and TECs were harvested for analysis. Results: Irradiation did not alter the physicochemical features of poly(lactic-co-glycolic acid)-based TECs. Compared with G1, fat flap growth was significantly reduced by 1.6 times in irradiated G2 and G3 conditions. In G2 and G3, fat flaps consisted of mature viable adipocytes sustained by CD31+ vascular cells. However, 37% (3 of 8) of the G2 irradiated adipose tissues presented a disorganized architecture invaded by connective tissues with inflammatory CD68 + cells, and the presence of fibrosis was observed. Conclusions: Overall, this preclinical study does not reveal any major obstacle to the use of TEC in a radiotherapy context. Although irradiation reduces the growth of fat flap under the TEC by reducing adipogenesis and inducing inconsistent fibrosis, it does not impact flap survival and vascularization. These elements must be taken into account if radiotherapy is proposed before or after TEC-based breast reconstruction.

Published
2022
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6. Comparison of the in vivo genotoxicity of electronic and conventional cigarettes aerosols after subacute, subchronic and chronic exposures

Author

Fabrice Nesslany, Romain Dusautoir, Gonzague Dourdin, Ludovic Huot, Sébastien Anthérieu, Anne Platel, Philippe Gosset, Smail Talahari, Anaïs Ollivier, Guillaume Garçon, Eulalie Gateau, Gwenola Kervoaze, Jérôme Kluza, William Laine, Jean-Marc Lo Guidice, Sophie Simar, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), CHU Lille, CNRS, Inserm, Université de Lille, Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS], IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483, Centre d'Infection et d'Immunité de Lille (CIIL) - U1019 - UMR 9017, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], and Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP]

Subjects
Environmental Engineering, Health, Toxicology and Mutagenesis, [SDV]Life Sciences [q-bio], Context (language use), Gene mutation, Pharmacology, Electronic Nicotine Delivery Systems, medicine.disease_cause, In vivo Pig-a gene mutation assay, In vivo micronucleus test, In vivo comet assay, E-cigs, Oxidative DNA damage, Mice, medicine, Environmental Chemistry, Animals, Waste Management and Disposal, Carcinogen, Aerosols, business.industry, Tobacco Products, Pollution, Comet assay, Micronucleus test, Toxicity, Electronics, business, Oxidative stress, Genotoxicity, DNA Damage
Abstract

International audience; Tobacco smoking is classified as a human carcinogen. A wide variety of new products, in particular electronic cigarettes (e-cigs), have recently appeared on the market as an alternative to smoking. Although the in vitro toxicity of e-cigs is relatively well known, there is currently a lack of data on their long-term health effects. In this context, the aim of our study was to compare, on a mouse model and using a nose-only exposure system, the in vivo genotoxic and mutagenic potential of e-cig aerosols tested at two power settings (18 W and 30 W) and conventional cigarette (3R4F) smoke. The standard comet assay, micronucleus test and Pig-a gene mutation assay were performed after subacute (4 days), subchronic (3 months) and chronic (6 months) exposure. The generation of oxidative stress was also assessed by measuring the 8-hydroxy-2'-deoxyguanosine and by using the hOGG1-modified comet assay. Our results show that only the high-power e-cig and the 3R4F cigarette induced oxidative DNA damage in the lung and the liver of exposed mice. In return, no significant increase in chromosomal aberrations or gene mutations were noted whatever the type of product. This study demonstrates that e-cigs, at high-power setting, should be considered, contrary to popular belief, as hazardous products in terms of genotoxicity in mouse model.

Published
2022
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7. Evaluation of the expression of fatty acid synthase and O‑GlcNAc transferase in patients with liver cancer by exploration of transcriptome databases and experimental approaches

Author

Sadia Raab, Ninon Very, Belinda Duchêne, Pierre Rybarczyk, Nicolas Jonckheere, Ikram El Yazidi‑belkoura, Tony Lefebvre, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, CHU Amiens-Picardie, Laboratoire de Physiologie Cellulaire et Moléculaire - UR UPJV 4667 (LPCM), Université de Picardie Jules Verne (UPJV), DESSAIVRE, Louise, Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Laboratoire de Physiologie Cellulaire et Moléculaire - UR UPJV 4667 [LPCM], Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, and Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Subjects
liver cancer, fatty acid synthase, Cancer Research, O-GlcNAcylation, mTOR pathway, O-GlcNAc transferase, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; Tumor occurrence and development are closely related to metabolism abnormalities. One of the metabolic networks that is dysregulated during carcinogenesis is the fatty acid synthesis pathway, which is mainly controlled by fatty acid synthase (FASN). We previously demonstrated in proliferating HepG2 liver cancer cells that FASN expression depends on the catalytic activity of O-GlcNAc transferase (OGT) and the activation of the mechanistic/mammalian target of rapamycin (mTOR) pathway. The aim of the present study was to go further in these investigations by analyzing datasets and tissues of patients with liver cancer. To that purpose, transcriptome databases were explored, and reverse transcription-quantitative PCR, western blotting and immunohistochemistry were used. Database analyses revealed that FASN and OGT gene expression was higher in certain cancer tissues, including liver hepatocellular carcinoma, compared with that in non-cancerous tissues. At the protein level, FASN expression was higher in the liver cancer-derived cell lines HepG2 and Hep3B compared with the immortalized human hepatocytes IHH cell line. However, neither the expression of OGT nor of its product O-GlcNAcylation showed any significant difference among the three hepatic cell lines. Subsequently, the expression of FASN and OGT at the protein and mRNA levels was evaluated in human liver cancer and non-tumoral tissues from the same patients with different liver lesions. The results from western blotting demonstrated a significant increase in OGT ands O-GlcNAcylation expression in liver cancer tissues independently of the type of lesion characterizing the non-tumoral counterpart. As previously reported for HepG2 proliferating cells, the protein level of FASN was positively correlated with the activation of mTOR and, although a rather upward trend, a high variability in its expression was monitored between patients. However, the results from immunohistochemistry showed no particular modification for OGT and O-GlcNAcylation expression and a significant increase in FASN expression in cancer tissues compared with that in adjacent non-tumoral tissues. Non-significant changes were observed for FASN and OGT mRNA levels between tumoral and non-tumoral samples, with a high variability between patients. Taken together, these results demonstrated that FASN expression was higher in hepatic cancer tissues in comparison with non-tumoral tissues. Furthermore, OGT expression and activity were shown to vary greatly between cell or cancer type, making any generalization difficult.

Published
2022
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8. Thymidylate Synthase O-GlcNAcylation: a molecular mechanism of 5-FU sensitization in colorectal cancer

Author

Julie Kerr-Conte, Julien Thevenet, Adeline Page, Vanessa Dehennaut, Céline Schulz, Gérard Vergoten, Ninon Very, Tony Lefebvre, Ikram El Yazidi-Belkoura, Amélie Decourcelle, Madjid Djouina, Stéphan Hardivillé, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), SFR Biosciences, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lille, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), EL YAZIDI-BELKOURA, IKRAM, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Recherche translationnelle sur le diabète (RTD) - U1190, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Lille Inflammation Research International Center - U 995 (LIRIC), and Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP)

Subjects
Cancer Research, Gene knockdown, Colorectal cancer, [SDV]Life Sciences [q-bio], Thymidylate Synthase, Biology, medicine.disease, medicine.disease_cause, Thymidylate synthase, In vitro, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, In vivo, Tumor progression, Genetics, medicine, biology.protein, Cancer research, Carcinogenesis, Molecular Biology, Sensitization
Abstract

International audience; Alteration of O-GlcNAcylation, a dynamic post-translational modification, is associated with tumorigenesis and tumor progression. Its role in chemotherapy response is poorly investigated. Standard treatment for colorectal cancer (CRC), 5-fluorouracil (5-FU), mainly targets Thymidylate Synthase (TS). TS O-GlcNAcylation was reported but not investigated yet. We hypothesize that O-GlcNAcylation interferes with 5-FU CRC sensitivity by regulating TS. In vivo, we observed that combined 5-FU with Thiamet-G (O-GlcNAcase (OGA) inhibitor) treatment had a synergistic inhibitory effect on grade and tumor progression. 5-FU decreased O-GlcNAcylation and, reciprocally, elevation of O-GlcNAcylation was associated with TS increase. In vitro in non-cancerous and cancerous colon cells, we showed that 5-FU impacts O-GlcNAcylation by decreasing O-GlcNAc Transferase (OGT) expression both at mRNA and protein levels. Reciprocally, OGT knockdown decreased 5-FU-induced cancer cell apoptosis by reducing TS protein level and activity. Mass spectrometry, mutagenesis and structural studies mapped O-GlcNAcylated sites on T251 and T306 residues and deciphered their role in TS proteasomal degradation. We reveal a crosstalk between O-GlcNAcylation and 5-FU metabolism in vitro and in vivo that converges to 5-FU CRC sensitization by stabilizing TS. Overall, our data propose that combining 5-FU-based chemotherapy with Thiamet-G could be a new way to enhance CRC response to 5-FU.

Published
2021
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9. Robot-assisted spidermass for in vivo real-time topography mass spectrometry imaging

Author

Michel Salzet, Christian Duriez, Philippe Saudemont, Isabelle Fournier, Chann Lagadec, Nina Ogrinc, Alexandre Kruszewski, Paul Chaillou, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 [PRISM], Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 [CRIStAL], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], CNRS, Centrale Lille, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Deformable Robots Simulation Team (DEFROST ), Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Signalisation des facteurs de croissance dans le cancer du sein. Protéomique fonctionnelle, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Chaillou, Paul, Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Université de Lille-Centrale Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Centrale Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
0303 health sciences, Image fusion, [CHIM.ANAL] Chemical Sciences/Analytical chemistry, Computer science, [SDV]Life Sciences [q-bio], 010401 analytical chemistry, 01 natural sciences, Mass spectrometry imaging, [SPI.AUTO]Engineering Sciences [physics]/Automatic, 0104 chemical sciences, 03 medical and health sciences, Excision margins, [SPI.AUTO] Engineering Sciences [physics]/Automatic, Tissue sections, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, In vivo, Robot, Robotic arm, Ex vivo, 030304 developmental biology, Biomedical engineering
Abstract

Mass Spectrometry Imaging (MSI) has shown to bring invaluable information for biological and clinical applications. However, conventional MSI is generally performed ex vivo from tissue sections. Here, we develop a novel MS-based method for in vivo mass spectrometry imaging. By coupling the SpiderMass technology - that provides in vivo minimally invasive analysis – to a robotic arm of high accuracy, we demonstrate that images can be acquired from any surface by moving the laser probe above the surface. By equipping the robotic arm with a sensor, we are also able to both get the topography image of the sample surface and the molecular distribution, and then and plot back the molecular data, directly to the 3D topographical image without the need for image fusion. This is shown for the first time with the 3D topographic MS-Based whole-body imaging of a mouse. Enabling fast in vivo MSI bridged to topography pave the way for surgical applications to excision margins.

Published
2021
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10. 3‐phosphoinositide‐dependent protein kinase 1 (PDK1) mediates crosstalk between Src and Akt pathways in MET receptor signaling

Author

Katia Cailliau, Arlette Lescuyer, Ingrid Fliniaux, Caroline Molinaro, David Tulasne, Alain Martoriati, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003 (PHYCELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576, Physiologie Cellulaire (PHYCEL) - U1003, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290, Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - USR 3290 (MSAP), and Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Biophysics, G2/M transition, SH2 domain, hepatocyte growth factor receptor, Biochemistry, Receptor tyrosine kinase, 3-Phosphoinositide-Dependent Protein Kinases, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, MET signaling, Genetics, Humans, Akt, PDK1, Src, Xenopus oocyte, Phosphorylation, Protein kinase A, Molecular Biology, Protein kinase B, 030304 developmental biology, 0303 health sciences, biology, Cell Cycle, Cell Biology, Cell biology, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Crosstalk (biology), Hepatocyte Growth Factor Receptor, 030220 oncology & carcinogenesis, biology.protein, Signal transduction, Proto-Oncogene Proteins c-akt, Proto-oncogene tyrosine-protein kinase Src, Signal Transduction
Abstract

International audience; The high-affinity tyrosine kinase receptor MET plays a pivotal role in several facets of cell regulation. Although its mitogenic effect is well documented, some aspects of connection patterns between signaling pathways involved in cell cycle progression remain to be deciphered. We have used a tractable heterologous expression system, the Xenopus oocyte, to detect connections between distinct MET signaling cascades involved in G2/M progression. Our results reveal that Src acts as an adapter via its SH2 domain to recruit 3-phosphoinositide-dependent protein kinase 1 (PDK1) to the MET signaling complex leading to Akt phosphorylation. These data define an original crosstalk between Src and Akt signaling pathways that contributes to MET-induced entry into the M phase, and deserves further investigation in pathologies harboring deregulation of this receptor.

Published
2021
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11. Impact of Tacrolimus Daily Dose Limitation in Renal Transplant Recipients Expressing CYP3A5: A Retrospective Study

Author

Rémi Lenain, Romain Larrue, François Glowacki, Christelle Cauffiez, Franck Broly, Viviane Gnemmi, Aghilès Hamroun, Myriam Labalette, Mehdi Maanaoui, Cynthia Van der Hauwaert, Nicolas Pottier, Jean-Baptiste Gibier, Benjamin Hennart, Marc Hazzan, Sebastien Gomis, Service de Néphrologie et Transplantation rénale [CHRU-lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de pathologie [CHU Lille], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Lille Inflammation Research International Center - U 995 (LIRIC), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, CHU Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS], Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, and IMPact de l'Environnement Chimique sur la Santé humaine (IMPECS) - ULR 4483

Subjects
medicine.medical_specialty, therapeutic drug monitoring, [SDV]Life Sciences [q-bio], Urology, Medicine (miscellaneous), Renal function, chemical and pharmacologic phenomena, Article, polymorphism, Pharmacokinetics, medicine, tacrolimus, pharmacogenetics, integumentary system, medicine.diagnostic_test, business.industry, Incidence (epidemiology), food and beverages, Retrospective cohort study, renal transplantation, Tacrolimus, Transplantation, surgical procedures, operative, Therapeutic drug monitoring, Medicine, business, Pharmacogenetics
Abstract

The pharmacokinetic variability of tacrolimus can be partly explained by CYP3A5 activity. Our objective was to evaluate a tacrolimus sparing policy on renal graft outcome according to CYP3A5 6986A&gt, G genetic polymorphism. This retrospective study included 1114 recipients with a median follow-up of 6.3 years. Genotyping of the 6986A&gt, G allelic variant corresponding to CYP3A5*3 was systematically performed. One year after transplantation, tacrolimus blood trough concentration (C0) target range was 5–7 ng/mL. However, daily dose was capped to 0.10 mg/kg/day regardless of the CYP3A5 genotype. A total 208 CYP3A5*1/- patients were included. Despite a higher daily dose, CYP3A5*1/- recipients exhibited lower C0 during follow-up (p &lt, 0.01). Multivariate analysis did not show any significant influence of CYP3A5*1/- genotype (HR = 0.70, 0.46–1.07, p = 0.10) on patient-graft survival. Glomerular Filtration Rate (GFR) decline was significantly lower for the CYP3A5*1/- group (p = 0.02). The CYP3A5*1/- genotype did not significantly impact the risk of biopsy-proven acute rejection (BPAR) (HR = 1.01, 0.68–1.49, p = 0.97) despite significantly lower C0. Based on our experience, a strategy of tacrolimus capping is associated with a better GFR evolution in CYP3A5*1/- recipients without any significant increase of BPAR incidence. Our study raised some issues about specific therapeutic tacrolimus C0 targets for CYP3A5*1/- patients and suggests to set up randomized control studies in this specific population.

Published
2021
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12. Prevalence of Eosinophilic Esophagitis in Adolescents With Esophageal Atresia

Author

Julie Rebeuh, Laurent Michaud, Mihaela Onea, Emmanuelle Leteurtre, Florence Renaud, Emilie Lardenois, Anne Schneider, Frédéric Gottrand, Madeleine Gottrand-Aumar, CHU Lille, Inserm, Université de Lille, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Lille Inflammation Research International Center - U 995 [LIRIC], CHU Strasbourg, Lille Inflammation Research International Center (LIRIC) - U995, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), and Université de Lille-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Chest Pain, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Tracheoesophageal fistula, Chest pain, Gastroenterology, Endoscopy, Gastrointestinal, Leukocyte Count, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, Hypersensitivity, Prevalence, medicine, Humans, Prospective Studies, Esophagus, Eosinophilic esophagitis, Prospective cohort study, Esophageal Atresia, Ulcer, High-power field, business.industry, Case-control study, Proton Pump Inhibitors, Eosinophilic Esophagitis, medicine.disease, Eosinophils, medicine.anatomical_structure, Erythema, Case-Control Studies, Atresia, Pediatrics, Perinatology and Child Health, Female, 030211 gastroenterology & hepatology, medicine.symptom, business, Tracheoesophageal Fistula
Abstract

International audience; OBJECTIVE: Eosinophilic esophagitis (EoE) is an increasingly recognized childhood disease. Esophageal atresia (EA) is the most frequent congenital malformation of the esophagus. Recently, cases of EoE occurring in patients with EA have been reported, although the exact prevalence of EoE in EA remains unknown. The aim is to investigate the prevalence of EoE among EA in adolescents and to describe these patients' characteristics.METHODS: Systematic upper gastrointestinal endoscopies with multistage esophageal biopsies were prospectively performed in 63 adolescents with EA. A standardized form was used to collect clinical and endoscopic data. Diagnosis of EoE was made as ≥15 intraepithelial eosinophils/high power field, whatever the response on proton pump inhibitors therapy.RESULTS: Six patients (9.5%) presented an EoE (17-100 eosinophils/high power field). An atopic condition was reported more frequently in the eosinophil ≥15 group than in patients with no EoE (66% vs 16%; P = 0.014). Except for chest pain, symptoms and endoscopic features were similar in patients with EoE and patients with no EoE.CONCLUSIONS: In our series of 63 patients born with EA, mainly distal tracheoesophageal fistula, the prevalence of EoE is increased, and therefore should be considered in adolescents with EA.

Published
2019
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13. Addition of Regular Insulin to Ternary Parenteral Nutrition: A Stability Study

Author

Pascal Pigny, Thierry Dine, Pascal Odou, Héloïse Henry, David Seguy, Patrice Maboudou, Damien Lannoy, CHU Lille, CNRS, Inserm, Université de Lille, Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 (GRITA), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Université de Lille, LillOA

Subjects
medicine.medical_specialty, 030309 nutrition & dietetics, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Serum albumin, Pharmaceutical Science, chemistry.chemical_element, lcsh:RS1-441, 030209 endocrinology & metabolism, Parenteral Nutrition Solutions, Zinc, Article, lcsh:Pharmacy and materia medica, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Glycation, Internal medicine, regular insulin, parenteral nutrition solutions, medicine, immunoassay, 0303 health sciences, biology, Insulin, Ethylene-vinyl acetate, stability, [SDV] Life Sciences [q-bio], Endocrinology, Parenteral nutrition, chemistry, Regular insulin, biology.protein
Abstract

Background: Parenteral nutrition (PN) is a complex medium in which added insulin can become unstable. The aim of this study is, therefore, to evaluate the stability of insulin in PN and to identify influencing factors. Methods: A total of 20 IU/L of regular insulin was added to PN in either glass or Ethylene Vinyl Acetate (EVA) containers. A 24 h stability study was performed via an electrochemiluminescence immunoassay in different media: A ternary PN admixture, separate compartments of the PN bag and a binary admixture. This study was repeated in the absence of zinc, with the addition of serum albumin or tween and with pH adjustment (3.6 or 6.3). Insulin concentration at t time was expressed as a percentage of the initial insulin concentration. Analysis of covariance (ANCOVA) was applied to determine the factors that influence insulin stability. Results: In all PN admixtures, the insulin concentration ratio decreased, stabilising at a 60% and then plateauing after 6 h. At pH 3.6, the ratio was above 90%, while at pH 6.3 it decreased, except in the amino acid solution. ANCOVA (r2 = 0.68, p = 0.01) identified dextrose and pH as significant factors influencing insulin stability. Conclusion: A low pH level seems to stabilise insulin in PN admixtures. The influence of dextrose content suggests that insulin glycation may influence stability.

Published
2021
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14. Systemic Pulmonary Events Associated with Myelodysplastic Syndromes: A Retrospective Multicentre Study

Author

Anne-Laure Lejeune, Louis Terriou, D. Launay, Lidwine Stervinou-Wemeau, Quentin Scanvion, Arsène Mekinian, Laurent Pascal, Valérie Deken, Bruno Quesnel, Eric Hachulla, Thierno Sy, CHU Lille, CNRS, Inserm, Université de Lille, Université Lille Nord (France), METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286, Hôpital Saint Vincent de Paul de Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Service de Pneumologie et Immuno-Allergologie [CHU LIlle], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Miniaturisation pour la Synthèse, l'Analyse et la Protéomique (MSAP) - USR 3290, and CHU Saint-Antoine [AP-HP]

Subjects
medicine.medical_specialty, pulmonary alveolar proteinosis, Population, lcsh:Medicine, Context (language use), [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, pulmonary hypertension, medicine, pneumonia, 10. No inequality, education, 030304 developmental biology, interstitial lung disease, 0303 health sciences, education.field_of_study, Lung, business.industry, lcsh:R, Interstitial lung disease, Retrospective cohort study, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, medicine.disease, Pulmonary hypertension, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, iatrogenic effects, pleuritic effusion, business, Pulmonary alveolar proteinosis
Abstract

Although pulmonary events are considered to be frequently associated with malignant haemopathies, they have been sparsely studied in the specific context of myelodysplastic syndromes (MDS). We aimed to describe their different types, their relative proportions and their relative effects on overall survival (OS). We conducted a multicentre retrospective cohort study. Patients with MDS (diagnosed according to the 2016 WHO classification) and pulmonary events were included. The inclusion period was 1 January 2007 to 31 December 2017 and patients were monitored until August 2019. Fifty-five hospitalized patients were included in the analysis. They had 113 separate pulmonary events. Thirteen patients (23.6%) had a systemic autoimmune disease associated with MDS. Median age at diagnosis of MDS was 77 years. Median time to onset of pulmonary events was 13 months. Pulmonary events comprised: 70 infectious diseases (62%), 27 interstitial lung diseases (23.9%), including 13 non-specific interstitial pneumonias and seven secondary organizing pneumonias or respiratory bronchiolitis–interstitial lung diseases, 10 pleural effusions (8.8%), including four cases of chronic organizing pleuritis with exudative effusion, and six pulmonary hypertensions (5.3%). The median OS of the cohort was 29 months after MDS diagnosis but OS was only 10 months after a pulmonary event. The OS was similar to that of the general myelodysplastic population. However, the occurrence of a pulmonary event appeared to be either an accelerating factor of death or an indicator for the worsening of the underlying MDS in our study. More than a third of pulmonary events were non-infectious and could be systemic manifestations of MDS.

Published
2021
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15. Effects of Two Melt Extrusion Based Additive Manufacturing Technologies and Common Sterilization Methods on the Properties of a Medical Grade PLGA Copolymer

Author

Nicolas Blanchemain, Feng Chai, P. Guerreschi, Philippe Marchetti, Marion Gradwohl, Julien Payen, Médicaments et biomatériaux à libération contrôlée: mécanismes et optimisation - Advanced Drug Delivery Systems - U 1008 [MBLC - ADDS], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], Médicaments et biomatériaux à libération contrôlée: mécanismes et optimisation - Advanced Drug Delivery Systems - U 1008 (MBLC - ADDS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Lattice Medical [Loos], Université de Lille, LillOA, CNRS, Inserm, Université de Lille, Advanced Drug Delivery Systems (ADDS) - U1008, and Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277

Subjects
[CHIM.POLY] Chemical Sciences/Polymers, Materials science, sterilization, medical devices, polymer, bioabsorbable, additive manufacturing, Polymers and Plastics, [SPI.GPROC] Engineering Sciences [physics]/Chemical and Process Engineering, Fused filament fabrication, Article, Gel permeation chromatography, lcsh:QD241-441, chemistry.chemical_compound, Differential scanning calorimetry, lcsh:Organic chemistry, Copolymer, [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, chemistry.chemical_classification, Ethylene oxide, technology, industry, and agriculture, General Chemistry, Polymer, Sterilization (microbiology), [SDV.IB.BIO] Life Sciences [q-bio]/Bioengineering/Biomaterials, PLGA, [CHIM.POLY]Chemical Sciences/Polymers, chemistry, Biomedical engineering
Abstract

Although bioabsorbable polymers have garnered increasing attention because of their potential in tissue engineering applications, to our knowledge there are only a few bioabsorbable 3D printed medical devices on the market thus far. In this study, we assessed the processability of medical grade Poly(lactic-co-glycolic) Acid (PLGA)85:15 via two additive manufacturing technologies: Fused Filament Fabrication (FFF) and Direct Pellet Printing (DPP) to highlight the least destructive technology towards PLGA. To quantify PLGA degradation, its molecular weight (gel permeation chromatography (GPC)) as well as its thermal properties (differential scanning calorimetry (DSC)) were evaluated at each processing step, including sterilization with conventional methods (ethylene oxide, gamma, and beta irradiation). Results show that 3D printing of PLGA on a DPP printer significantly decreased the number-average molecular weight (Mn) to the greatest extent (26% Mn loss, p &lt, 0.0001) as it applies a longer residence time and higher shear stress compared to classic FFF (19% Mn loss, p &lt, 0.0001). Among all sterilization methods tested, ethylene oxide seems to be the most appropriate, as it leads to no significant changes in PLGA properties. After sterilization, all samples were considered to be non-toxic, as cell viability was above 70% compared to the control, indicating that this manufacturing route could be used for the development of bioabsorbable medical devices. Based on our observations, we recommend using FFF printing and ethylene oxide sterilization to produce PLGA medical devices.

Published
2021
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16. Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network

Author

Anne Moreau, Francois Collin, Anne Gomez-Brouchet, Jean François Emile, Marie Karanian-Philippe, François Gouin, Myriam Jean-Denis, Resos, Nicolas Ortonne, Emilie Angot, Céline Bazille, Laurent Doucet, Maxime Battistella, Antoine Italiano, Jean-Pierre Ghnassia, Gonzague de Pinieux, Marick Laé, Nouria Mesli, Isabelle Quintin-Rouet, Françoise Ducimetière, Sabrina Croce, Anne de Muret, Nathalie Stock, Repps, Isabelle Birtwisle-Peyrottes, Bruno Chetaille, Philippe Terrier, Jean-Baptiste Courrèges, Agnès Neuville, Yves-Marie Robin, Lenaig Mescam-Mancini, Juliane Berchoud, Philippe Rochaix, French Sarcoma Group-Groupe d’Etude des Tumeurs Osseuses, Nicolas Penel, Nicolas Macagno, Marie-Christine Chateau, Jean-Michel Coindre, Sophie Le Guellec, Corinne Bouvier, Isabelle Pommepuy, Frédérique Larousserie, Dominique Ranchère-Vince, Yohan Fayet, Sébastien Aubert, Sylvie Chabaud, Axel Le Cesne, Jean-Yves Blay, Céline Charon-Barra, Nicolas Weinbreck, Christophe Delfour, Florence Mishellany, Agnes Leroux, François Le Loarer, Isabelle Valo, Maud Toulmonde, Claire Chemin-Airiau, CHU Lille, CNRS, ENSCL, INRA, INSERM, Université de Lille, Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192, Institut de Pathologie [CHU Lille], Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), ANR-17-CONV-0002,PLASCAN,Institut François Rabelais pour la recherche multidisciplinaire sur le cancer(2017), and ANR-18-RHUS-0009,DEPGYN,Clinical proof of concept of dependence receptor targeting in gynecological Oncology(2018)

Subjects
Male, Skin Neoplasms, Epidemiology, [SDV]Life Sciences [q-bio], 0302 clinical medicine, Epidemiology of cancer, Gastrointestinal Cancers, Medicine and Health Sciences, Angiosarcoma, Medicine, 030212 general & internal medicine, Prospective Studies, Neurological Tumors, Skin Tumors, 0303 health sciences, Multidisciplinary, GiST, Incidence (epidemiology), Incidence, Sarcoma, Middle Aged, 3. Good health, medicine.anatomical_structure, Oncology, Neurology, 030220 oncology & carcinogenesis, Female, France, Cancer Epidemiology, Research Article, Adult, medicine.medical_specialty, Adolescent, Metastatic tumors, Cancer epidemiology, Neurological tumors, Skin tumors, Gastrointestinal cancers, Malignant tumors, Science, Connective tissue, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Gastroenterology and Hepatology, Liposarcoma, Malignancy, World Health Organization, 03 medical and health sciences, Young Adult, Malignant Tumors, Humans, 030304 developmental biology, Aged, business.industry, Cancers and Neoplasms, Histology, medicine.disease, Clinical trial, Metastatic Tumors, Neoplasm Grading, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France. Methods The nationwide incidence of sarcoma or TIM (2013–2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed. Results Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1–0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p−6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per. Conclusions This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (16/year) are less likely to be included in clinical trials.

Published
2021
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17. Measurement of Protein-Protein Interactions through Microscale Thermophoresis (MST)

Author

Magnez Romain, Bryan Thiroux, Xavier Thuru, Morgane Tardy, Bruno Quesnel, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), This work was supported by Inserm, CNRS, IRCL (Institut pour la Recherche sur le Cancer de Lille), SIRIC ONCOLille (Grant INCaDGOS-Inserm 6041) and a grant from 'Contrat de Plan Etat Région Hauts de France' CPER Cancer 2014-2019., Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Lille Neurosciences & Cognition - U 1172 [LilNCog], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], and Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - UMR 1277 [CANTHER]

Subjects
PD-L1, Purification-free protocol, [SDV]Life Sciences [q-bio], Strategy and Management, Microscale thermophoresis, Immune escape, PD-1, Protein-protein interaction (PPI), Screening, Cell lysate, Industrial and Manufacturing Engineering, Protein–protein interaction, Methods Article, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Surface plasmon resonance, ComputingMilieux_MISCELLANEOUS, Mechanical Engineering, Metals and Alloys, Isothermal titration calorimetry, Ligand (biochemistry), Small molecule, Dissociation constant, Biophysics, Target protein
Abstract

The binding interactions of PD-1 and PD-L1 have been studied by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) over the past few years, but these investigations resulted in controversy regarding the values of the dissociation constant (Kd) (Freeman et al., 2000). MST is a powerful new method for the quantitative analysis of protein-protein interactions (PPIs) with low sample consumption. The technique is based on the movement of molecules along microscopic temperature gradients, and it detects changes in their hydration shell, charge or size. One binding partner is fluorescently labeled, while the other binding partner remains label-free. We used a protocol that allows the determination of the binding affinity by MST without purification of the target protein from the cell lysate. The application of this MST method to PD-1-eGFP and PD-L1-eGFP expressed in CHO-K1 cells allowed us, for the first time, to determine the affinity of the complex formed between PD-1 and its ligand PD-L1 during tumor escape. The protocol has a variety of potential applications for studying the interactions of proteins with small molecules. 10;7

Published
2020
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18. Erratum. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care 2019;42:2042-2049

Author

Eric Van Belle, François Machuron, Marc Hazzan, Marie-Christine Vantyghem, Christian Noel, Thomas Hubert, Robert Caiazzo, Stéphanie Espiard, Julie Kerr-Conte, Arnaud Jannin, Violeta Raverdy, Pascal Pigny, François Pattou, Nathalie Delalleau, Valery Gmyr, Kristell Le Mapihan, Marie Frimat, Mikael Chetboun, Université de Lille, LillOA, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 (MSAP), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - USR 3290 (MSAP), Institut de Chimie du CNRS (INC)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Inserm, CHU Lille, Recherche translationnelle sur le diabète (RTD) - U1190, Cancer Heterogeneity, Plasticity and Resistance to Therapies (CANTHER) - UMR 9020 - UMR 1277, Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (EGID) - U1011, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Miniaturisation pour la Synthèse, l’Analyse et la Protéomique - UAR 3290 [MSAP], Lille Inflammation Research International Center - U 995 [LIRIC], and Recherche translationnelle sur le diabète - U 1190 [RTD]

Subjects
Advanced and Specialized Nursing, Type 1 diabetes, medicine.medical_specialty, geography, geography.geographical_feature_category, business.industry, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], MEDLINE, 030209 endocrinology & metabolism, medicine.disease, Islet, 3. Good health, Islet after kidney, Transplantation, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, 030212 general & internal medicine, business, Cohort study
Abstract

The names of the working groups that collaborated in the study reported in this article were inadvertently omitted from the byline. The corrected byline should … 2019;42

Published
2020
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