TEAM
STEFANIA MILLEVOI

RNAreg :

RNA-Binding Proteins and Genotoxic Stress

THE SPECIFITIES

OF OUR RESEARCH AXIS

Our team has a long-standing interest in the regulation of cancer gene expression. In particular, we have been studying the post-transcriptional regulation of genes involved in key cellular processes underlying the response to genotoxic stress, which is associated with the emergence of resistance mechanisms to anti-cancer therapies such as chemo-/radiotherapy, but also immunotherapy. The development of this ambitious project relies on the combination of distinct but complementary expertise in the field of RNA, both coding (Anne Cammas, Hervé Prats, Stefania Millevoi) and non-coding (Estelle Espinos), and of the cellular response to DNA damage, including cell cycle, apoptosis and autophagy (Estelle Espinos and Stéphane Manenti).

Although our projects stem from fundamental questions on RNA regulation and the response to genotoxic stress, in particular autophagy, our ultimate ambition is to provide information on their clinical relevance in head and neck cancer (HNSCC), a prevalent and aggressive disease associated with high recurrence and mortality. Our team benefits from the expertise of Sébastien Vergez, otolaryngologist and cervico-facial surgeon, as well as from the synergy with IUCT-O, including the ORL committee and the biostatistic plateform (Thomas Filleron). The research program integrates bioinformatics analyses and experimental approaches, combining large-scale transcriptomic/proteomic analyses with more mechanistic studies on candidate genes, as well as analyses performed on primary patient samples. The knowledge generated through this project, linking the RNA molecule to the patient, will enlighten new concepts for the development of RNA-based therapeutic strategies targeting autophagy in HNSCC cancers.

Head and neck cancers (HNSCC)

Response to DNA damage 

Molecular mechanisms of therapeutic resistance 

Autophagy

Post-transcriptional regulations 

Epitranscriptomics

Translation of mRNAs

RNA binding proteins 

G-quadruplex RNA structures 

“Omics” approaches

Bioinformatics

RESEARCH PROJECTS

SCIENTIFIC PRODUCTIONS

PUBLICATIONS 2022
Cammas, Anne, Pauline Herviou, Leïla Dumas, and Stefania Millevoi. “Analysis of MRNA Translation by Polysome Profiling.” Methods in Molecular Biology (Clifton, N.J.) 2404 (2022): 69–81. https://doi.org/10.1007/978-1-0716-1851-6_4.
PUBLICATIONS 2021
Baudu, Timothée, Chloé Parratte, Valérie Perez, Marie Ancion, Stefania Millevoi, Eric Hervouet, Anne Peigney, et al. “The NMD Pathway Regulates GABARAPL1 MRNA during the EMT.” Biomedicines 9, no. 10 (September 23, 2021): 1302. https://doi.org/10.3390/biomedicines9101302.
Espinos, Estelle, Raymond Lai, and Sylvie Giuriato. “The Dual Role of Autophagy in Crizotinib-Treated ALK+ ALCL: From the Lymphoma Cells Drug Resistance to Their Demise.” Cells 10, no. 10 (September 23, 2021): 2517. https://doi.org/10.3390/cells10102517.
Milliet, Florent, Alexandre Bozec, Renaud Schiappa, Julien Viotti, Anouchka Modesto, Olivier Dassonville, Gilles Poissonnet, et al. “Metachronous Second Primary Neoplasia in Oropharyngeal Cancer Patients: Impact of Tumor HPV Status. A GETTEC Multicentric Study.” Oral Oncology 122 (September 6, 2021): 105503. https://doi.org/10.1016/j.oraloncology.2021.105503.
Vendramin, Roberto, Vicky Katopodi, Sonia Cinque, Angelina Konnova, Zorica Knezevic, Sara Adnane, Yvessa Verheyden, et al. “Activation of the Integrated Stress Response Confers Vulnerability to Mitoribosome-Targeting Antibiotics in Melanoma.” The Journal of Experimental Medicine 218, no. 9 (September 6, 2021): e20210571. https://doi.org/10.1084/jem.20210571.
Nowosad, Ada, Pauline Jeannot, Caroline Callot, Justine Creff, Renaud Thierry Perchey, Carine Joffre, Patrice Codogno, Stephane Manenti, and Arnaud Besson. “Publisher Correction: P27 Controls Ragulator and MTOR Activity in Amino Acid-Deprived Cells to Regulate the Autophagy-Lysosomal Pathway and Coordinate Cell Cycle and Cell Growth.” Nature Cell Biology 23, no. 9 (September 2021): 1048. https://doi.org/10.1038/s41556-021-00741-7.
Dahan, Laurie Saloner, Roch Giorgi, Sébastien Vergez, Ludovic Le Taillandier de Gabory, Valérie Costes-Martineau, Philippe Herman, Gilles Poissonnet, et al. “Mucoepidermoid Carcinoma of Salivary Glands: A French Network of Rare Head and Neck Tumors (REFCOR) Prospective Study of 292 Cases.” European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47, no. 6 (June 2021): 1376–83. https://doi.org/10.1016/j.ejso.2020.11.123.
Culié, Dorian, Renaud Schiappa, Anouchka Modesto, Julien Viotti, Emmanuel Chamorey, Olivier Dassonville, Gilles Poissonnet, et al. “Upfront Surgery or Definitive Radiotherapy for P16+ Oropharyngeal Cancer. A GETTEC Multicentric Study.” European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47, no. 6 (June 2021): 1389–97. https://doi.org/10.1016/j.ejso.2020.12.011.
Nowosad, Ada, Justine Creff, Pauline Jeannot, Raphael Culerrier, Patrice Codogno, Stephane Manenti, Laurent Nguyen, and Arnaud Besson. “P27 Controls Autophagic Vesicle Trafficking in Glucose-Deprived Cells via the Regulation of ATAT1-Mediated Microtubule Acetylation.” Cell Death & Disease 12, no. 5 (May 13, 2021): 481. https://doi.org/10.1038/s41419-021-03759-9.
Chabrillac, Emilien, Gaël Espinasse, Benoît Lepage, Emmanuelle Uro-Coste, Agnès Dupret-Bories, Guillaume De Bonnecaze, and Sébastien Vergez. “Contribution of Narrow Band Imaging in Delineation of Laryngopharyngeal Superficial Cancer Spread: A Prospective Study.” European Archives of Oto-Rhino-Laryngology: Official Journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS): Affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 278, no. 5 (May 2021): 1491–97. https://doi.org/10.1007/s00405-020-06499-2.
Modesto, Anouchka, Aurore Siegfried, Amelie Lusque, Sébastien Vergez, Jerome Sarini, Laurent Brouchet, Emmanuelle Uro-Coste, Pierre Graff-Cailleaud, and Jean Pierre Delord. “Distinct Outcomes of Oropharyngeal Squamous Cell Carcinoma Patients after Distant Failure According to P16 Status: Implication in Therapeutic Options.” Current Oncology (Toronto, Ont.) 28, no. 3 (April 29, 2021): 1673–80. https://doi.org/10.3390/curroncol28030156.
Dumas, Leïla, Pauline Herviou, Erik Dassi, Anne Cammas, and Stefania Millevoi. “G-Quadruplexes in RNA Biology: Recent Advances and Future Directions.” Trends in Biochemical Sciences 46, no. 4 (April 2021): 270–83. https://doi.org/10.1016/j.tibs.2020.11.001.
Gomez-Roca, Carlos, Jean-Pierre Delord, Caroline Even, Neus Basté, Stephane Temam, Christophe Le Tourneau, Caroline Hoffmann, et al. “Exploratory Window-of-Opportunity Trial to Investigate the Tumor Pharmacokinetcs/Pharmacodynamics of the IAP Antagonist Debio 1143 in Patients with Head and Neck Cancer.” Clinical and Translational Science, March 20, 2021. https://doi.org/10.1111/cts.13002.
Culié, Dorian, Julien Viotti, Anouchka Modesto, Renaud Schiappa, Emmanuel Chamorey, Olivier Dassonville, Gilles Poissonnet, et al. “Upfront Surgery or Definitive Radiotherapy for Patients with P16-Negative Oropharyngeal Squamous Cell Carcinoma. A GETTEC Multicentric Study.” European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 47, no. 2 (February 2021): 367–74. https://doi.org/10.1016/j.ejso.2020.07.034.
Cartel, Maëlle, Pierre-Luc Mouchel, Mathilde Gotanègre, Laure David, Sarah Bertoli, Véronique Mansat-De Mas, Arnaud Besson, Jean-Emmanuel Sarry, Stéphane Manenti, and Christine Didier. “Inhibition of Ubiquitin-Specific Protease 7 Sensitizes Acute Myeloid Leukemia to Chemotherapy.” Leukemia 35, no. 2 (February 2021): 417–32. https://doi.org/10.1038/s41375-020-0878-x.
Culié, Dorian, Quentin Lisan, Charlotte Leroy, Anouchka Modesto, Renaud Schiappa, Emmanuel Chamorey, Olivier Dassonville, et al. “Oropharyngeal Cancer: First Relapse Description and Prognostic Factor of Salvage Treatment According to P16 Status, a GETTEC Multicentric Study.” European Journal of Cancer (Oxford, England: 1990) 143 (January 2021): 168–77. https://doi.org/10.1016/j.ejca.2020.10.034.
PUBLICATIONS 2020
Fierens, Sylvestre, Antoine Moya‐Plana, Sebastien Vergez, Antoine Bénard, Romain Gallard, Sandrine Molinier‐Blossier, Claire Castain, et al. “Do Practitioners Assess Sinonasal Adenocarcinoma Extension Similarly? Interdisciplinary Concordance in 21 Cases.” Clinical Otolaryngology, December 29, 2020, coa.13708. https://doi.org/10.1111/coa.13708.
Balança, Camille-Charlotte, Anna Salvioni, Clara-Maria Scarlata, Marie Michelas, Carlos Martinez-Gomez, Carlos Gomez-Roca, Victor Sarradin, et al. “PD-1 Blockade Restores Helper Activity of Tumor-Infiltrating Exhausted PD-1hiCD39+ CD4 T Cells.” JCI Insight, December 17, 2020. https://doi.org/10.1172/jci.insight.142513.
Bier-Laning, Carol, John D. Cramer, Soham Roy, Patrick A. Palmieri, Ayman Amin, José Manuel Añon, Cesar A. Bonilla-Asalde, et al. “Tracheostomy During the COVID-19 Pandemic: Comparison of International Perioperative Care Protocols and Practices in 26 Countries.” Otolaryngology–Head and Neck Surgery, November 3, 2020, 019459982096198. https://doi.org/10.1177/0194599820961985.
Garrel, Renaud, Gilles Poissonnet, Antoine Moyà Plana, Nicolas Fakhry, Gilles Dolivet, Benjamin Lallemant, Jérôme Sarini, et al. “Equivalence Randomized Trial to Compare Treatment on the Basis of Sentinel Node Biopsy Versus Neck Node Dissection in Operable T1-T2N0 Oral and Oropharyngeal Cancer.” Journal of Clinical Oncology, October 14, 2020, JCO.20.01661. https://doi.org/10.1200/JCO.20.01661.
Sorrentino, Domenico, Julie Frentzel, Géraldine Mitou, Rafael B. Blasco, Avédis Torossian, Coralie Hoareau-Aveilla, Chiara Pighi, et al. “High Levels of MiR-7-5p Potentiate Crizotinib-Induced Cytokilling and Autophagic Flux by Targeting RAF1 in NPM-ALK Positive Lymphoma Cells.” Cancers 12, no. 10 (October 13, 2020): 2951. https://doi.org/10.3390/cancers12102951.
Bertorello, Juliette, Julie Sesen, Julia Gilhodes, Solène Evrard, Monique Courtade-Saïdi, Meera Augustus, Emmanuelle Uro-Coste, et al. “Translation Reprogramming by EIF3 Linked to Glioblastoma Resistance.” NAR Cancer 2, no. 3 (September 2020): zcaa020. https://doi.org/10.1093/narcan/zcaa020.
Nowosad, Ada, Pauline Jeannot, Caroline Callot, Justine Creff, Renaud Thierry Perchey, Carine Joffre, Patrice Codogno, Stephane Manenti, and Arnaud Besson. “P27 Controls Ragulator and MTOR Activity in Amino Acid-Deprived Cells to Regulate the Autophagy-Lysosomal Pathway and Coordinate Cell Cycle and Cell Growth.” Nature Cell Biology, August 17, 2020. https://doi.org/10.1038/s41556-020-0554-4.
Saloner Dahan, Laurie, Roch Giorgi, Renaud Garrel, Ludovic Le Taillandier de Gabory, Valérie Costes‐Martineau, Philippe Herman, Gilles Poissonnet, et al. “Management of CN0 Low‐grade Mucoepidermoid Carcinomas of Salivary Glands: Prospective Multicentre Study of 152 Cases of the French Network of Rare Head and Neck Tumors (REFCOR).” Clinical Otolaryngology, July 14, 2020, coa.13600. https://doi.org/10.1111/coa.13600.
Balança, Camille-Charlotte, Clara-Maria Scarlata, Marie Michelas, Christel Devaud, Victor Sarradin, Camille Franchet, Carlos Martinez Gomez, et al. “Dual Relief of T-Lymphocyte Proliferation and Effector Function Underlies Response to PD-1 Blockade in Epithelial Malignancies.” Cancer Immunology Research 8, no. 7 (July 2020): 869–82. https://doi.org/10.1158/2326-6066.CIR-19-0855.
Lemaire, Emilien, Philippe Schultz, Sébastien Vergez, Christian Debry, Jérome Sarini, Benjamin Vairel, Guillaume de Bonnecaze, Catherine Takeda-Raguin, Bastien Cabarrou, and Agnès Dupret-Bories. “Risk Factors for Pharyngocutaneous Fistula After Total Pharyngolaryngectomy.” Ear, Nose, & Throat Journal, February 25, 2020, 145561319901035. https://doi.org/10.1177/0145561319901035.
Sueur, Gabrielle, Alison Boutet, Mathilde Gotanègre, Véronique Mansat-De Mas, Arnaud Besson, Stéphane Manenti, and Sarah Bertoli. “STAT5-Dependent Regulation of CDC25A by MiR-16 Controls Proliferation and Differentiation in FLT3-ITD Acute Myeloid Leukemia.” Scientific Reports 10, no. 1 (February 5, 2020): 1906. https://doi.org/10.1038/s41598-020-58651-x.
Atallah, Sarah, Antoine Moya-Plana, Olivier Malard, Gilles Poissonnet, Nicolas Fakhry, Jérémie Bettoni, Patrice Gallet, et al. “Should a Neck Dissection Be Performed on Patients with CN0 Adenoid Cystic Carcinoma? A REFCOR Propensity Score Matching Study.” European Journal of Cancer (Oxford, England: 1990), January 30, 2020. https://doi.org/10.1016/j.ejca.2019.12.026.
Mazerolle, Paul, Philippe Gorphe, Benjamin Vairel, Agnès Dupret-Bories, Stéphane Temam, Léonor Chaltiel, and Sébastien Vergez. “Management of the Irradiated N0-Neck during Salvage Pharyngo-Laryngeal Surgery.” European Journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology, January 9, 2020. https://doi.org/10.1016/j.ejso.2020.01.011.
Lièvre, Astrid, Anthony Turpin, Isabelle Ray-Coquard, Karine Le Malicot, Juliette Thariat, Guido Ahle, Cindy Neuzillet, et al. “Risk Factors for Coronavirus Disease 2019 (COVID-19) Severity and Mortality among Solid Cancer Patients and Impact of the Disease on Anticancer Treatment: A French Nationwide Cohort Study (GCO-002 CACOVID-19).” European Journal of Cancer 141 (2020): 62–81. https://doi.org/10.1016/j.ejca.2020.09.035.
Bozec, Alexandre, Claire Majoufre, Marie De Boutray, Jocelyn Gal, Emmanuel Chamorey, Lise-Marie Roussel, Pierre Philouze, et al. “Oral and Oropharyngeal Cancer Surgery with Free-Flap Reconstruction in the Elderly: Factors Associated with Long-Term Quality of Life, Patient Needs and Concerns. A GETTEC Cross-Sectional Study.” Surgical Oncology 35 (2020): 81–88. https://doi.org/10.1016/j.suronc.2020.08.014.
Bosc, Claudie, Nicolas Broin, Marjorie Fanjul, Estelle Saland, Thomas Farge, Charly Courdy, Aurélie Batut, et al. “Autophagy Regulates Fatty Acid Availability for Oxidative Phosphorylation through Mitochondria-Endoplasmic Reticulum Contact Sites.” Nature Communications 11, no. 1 (2020): 4056. https://doi.org/10.1038/s41467-020-17882-2.
Chabrillac, Emilien, Benoît Chaput, and Sébastien Vergez. “Circumferential Pharyngectomy in Laryngectomised Patient and Pharyngeal Reconstruction by Tubed Free Flap.” European Archives of Oto-Rhino-Laryngology 277, no. 9 (2020): 2641–45. https://doi.org/10.1007/s00405-020-06056-x.
Lechien, Jerome R., Carlos M. Chiesa‐Estomba, Sammy Place, Yves Van Laethem, Pierre Cabaraux, Quentin Mat, Kathy Huet, et al. “Clinical and Epidemiological Characteristics of 1420 European Patients with Mild‐to‐moderate Coronavirus Disease 2019.” Journal of Internal Medicine 288, no. 3 (2020): 335–44. https://doi.org/10.1111/joim.13089.
Carsuzaa, Florent, Philippe Gorphe, Sébastien Vergez, Olivier Malard, Nicolas Fakhry, Christian Righini, Pierre Philouze, et al. “Consensus on Resectability in N3 Head and Neck Squamous Cell Carcinomas: GETTEC Recommendations.” Oral Oncology 106 (2020): 104733. https://doi.org/10.1016/j.oraloncology.2020.104733.
McGrath, Brendan A, Michael J Brenner, Stephen J Warrillow, Vinciya Pandian, Asit Arora, Tanis S Cameron, José Manuel Añon, et al. “Tracheostomy in the COVID-19 Era: Global and Multidisciplinary Guidance.” The Lancet Respiratory Medicine 8, no. 7 (2020): 717–25. https://doi.org/10.1016/S2213-2600(20)30230-7.
Lechien, Jerome R., Carlos M. Chiesa-Estomba, Pierre Cabaraux, Quentin Mat, Kathy Huet, Bernard Harmegnies, Mihaela Horoi, et al. “Features of Mild-to-Moderate COVID-19 Patients With Dysphonia.” Journal of Voice, 2020, S0892199720301831. https://doi.org/10.1016/j.jvoice.2020.05.012.
Thariat, Juliette, Antoine Moya Plana, Benjamin Vérillaud, Sébastien Vergez, François Régis-Ferrand, Laurence Digue, Caroline Even, et al. “Diagnostic, pronostic et traitement des carcinomes nasosinusiens (hors mélanomes, sarcomes et lymphomes).” Bulletin du Cancer 107, no. 5 (2020): 601–11. https://doi.org/10.1016/j.bulcan.2020.02.013.
Herviou, Pauline, Morgane Le Bras, Leïla Dumas, Corinne Hieblot, Julia Gilhodes, Gianluca Cioci, Jean-Philippe Hugnot, et al. “HnRNP H/F Drive RNA G-Quadruplex-Mediated Translation Linked to Genomic Instability and Therapy Resistance in Glioblastoma.” Nature Communications 11, no. 1 (27 2020): 2661. https://doi.org/10.1038/s41467-020-16168-x.
PUBLICATIONS 2019
Potet, Pauline, Guillaune De Bonnecaze, Emilien Chabrillac, Agnès Dupret-Bories, Sébastien Vergez, and Benoit Chaput. “Closure of Radial Forearm Free Flap Donor Site: A Comparative Study between Keystone Flap and Skin Graft.” Head & Neck, October 17, 2019. https://doi.org/10.1002/hed.25977.
Dupret-Bories, Agnès, Mathieu Roumiguie, Guillaume De Bonnecaze, Jérome Sarini, Benjamin Vairel, Sébastien Vergez, and Bastien Benbassat. “The Super Thin External Pudendal Artery (STEPA) Free Flap for Oropharyngeal Reconstruction - A Case Report.” Microsurgery, September 11, 2019. https://doi.org/10.1002/micr.30512.
Chabrillac, Emilien, Amélie Lusque, Zoé Cavallier, Raphaël Lopez, Thomas Filleron, Jérôme Sarini, Nicolas Meyer, and Sébastien Vergez. “Cutaneous Squamous Cell Carcinoma Tumour Size Is Associated with Sentinel Lymph Node Metastasis in a Cohort of 69 Patients.” Acta Dermato-Venereologica, August 13, 2019. https://doi.org/10.2340/00015555-3293.
Le Guevelou, Jennifer, Sabrina Lebars, Emmanuel Kammerer, Ludovic de Gabory, Sebastien Vergez, François Janot, Bertrand Baujat, et al. “Head and Neck Cancer during Pregnancy.” Head & Neck, July 22, 2019. https://doi.org/10.1002/hed.25877.
Carsuzaa, Florent, Juliette Thariat, Philippe Gorphe, Christian Righini, Alain Cosmidis, Sébastien Thureau, Maximilien Roge, et al. “Surgery or Radiotherapy of the Primary Tumor in T1-2 Head and Neck Squamous Cell Carcinoma with Resectable N3 Nodes: A Multicenter GETTEC Study.” Annals of Surgical Oncology, July 1, 2019. https://doi.org/10.1245/s10434-019-07589-0.
Modesto, Anouchka, Thibaut Galissier, Amélie Lusque, Jean-Pierre Delord, Emmanuelle Uro-Coste, Jérôme Sarini, Frédéric Mouchet, et al. “Definitive Radiochemotherapy or Initial Surgery for Oropharyngeal Cancer : To What Extent Can P16 Expression Be Used in the Decision Process?” Strahlentherapie Und Onkologie: Organ Der Deutschen Rontgengesellschaft ... [et Al], March 15, 2019. https://doi.org/10.1007/s00066-019-01451-8.
Torossian, Avedis, Nicolas Broin, Julie Frentzel, Camille Daugrois, Sarah Gandarillas, Talal Al Saati, Laurence Lamant, Pierre Brousset, Sylvie Giuriato, and Estelle Espinos. “Blockade of Crizotinib-Induced BCL2 Elevation in ALK-Positive Anaplastic Large Cell Lymphoma Triggers Autophagy Associated with Cell Death.” Haematologica, January 24, 2019. https://doi.org/10.3324/haematol.2017.181966.
Franchini, Don-Marc, Olivia Lanvin, Marie Tosolini, Emilie Patras de Campaigno, Anne Cammas, Sarah Péricart, Clara-Maria Scarlata, et al. “Microtubule-Driven Stress Granule Dynamics Regulate Inhibitory Immune Checkpoint Expression in T Cells.” Cell Reports 26, no. 1 (January 2, 2019): 94-107.e7. https://doi.org/10.1016/j.celrep.2018.12.014.
Calvayrac, Olivier, Ada Nowosad, Stéphanie Cabantous, Lin-Po Lin, Sarah Figarol, Pauline Jeannot, Murielle P. Serres, et al. “Cytoplasmic P27Kip1 Promotes Tumorigenesis via Suppression of RhoB Activity.” The Journal of Pathology 247, no. 1 (January 2019): 60–71. https://doi.org/10.1002/path.5167.

TEAM MEMBERS

Béatriz Hernandez-Suarez
Etudiant ou stagiaire / PhD student or Trainee
Estelle Espinos
Enseignant-chercheur / Teacher-researcher
Catherine Zanibellato
Ingénieur ou technicien / Engineer or Technician
Stefania Millevoi
Chercheur / Researcher
Pauline Herviou
Etudiant ou stagiaire / PhD student or Trainee
Anne Cammas
Chercheur / Researcher
Alice Desprairies
Etudiant ou stagiaire / PhD student or Trainee
Axel Arthur
Etudiant ou stagiaire / PhD student or Trainee
Stéphane Manenti
Chercheur / Researcher
Leïla Dumas
Etudiant ou stagiaire / PhD student or Trainee
Sébastien Bourdon
Etudiant ou stagiaire / PhD student or Trainee

 PARTNERSHIPS & FUNDING

Centre de Recherches en Cancérologie de Toulouse

Centre de Recherches en Cancérologie de Toulouse (Oncopole)

Toulouse – FR

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05 82 74 15 75

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