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1. Clinical identification of malignant pleural effusions

Author

Jia, Jianlong, Marazioti, Antonia, Voulgaridis, Apostolos, Psallidas, Ioannis, Lamort, Anne-Sophie, Iliopoulou, Marianthi, Krontira, Anthi C., Lilis, Ioannis, Asciak, Rachelle, Kanellakis, Nikolaos I., Rahman, Najib M., Karkoulias, Kyriakos, Spiropoulos, Konstantinos, Liu, Ruonan, Kaiser, Jan-Christian, and Stathopoulos, Georgios T.

Published
2024
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2. KRAS signaling in malignant pleural mesothelioma

Author

Marazioti, Antonia, Krontira, Anthi C, Behrend, Sabine J, Giotopoulou, Georgia A, Ntaliarda, Giannoula, Blanquart, Christophe, Bayram, Hasan, Iliopoulou, Marianthi, Vreka, Malamati, Trassl, Lilith, Pepe, Mario A A, Hackl, Caroline M, Klotz, Laura V, Weiss, Stefanie A I, Koch, Ina, Lindner, Michael, Hatz, Rudolph A, Behr, Juergen, Wagner, Darcy E, Papadaki, Helen, Antimisiaris, Sophia G, Jean, Didier, Deshayes, Sophie, Grégoire, Marc, Kayalar, Özgecan, Mortazavi, Deniz, Dilege, Şükrü, Tanju, Serhan, Erus, Suat, Yavuz, Ömer, Bulutay, Pınar, Fırat, Pınar, Psallidas, Ioannis, Spella, Magda, Giopanou, Ioanna, Lilis, Ioannis, Lamort, Anne‐Sophie, and Stathopoulos, Georgios T

Published
2022
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5. KRAS signaling in malignant pleural mesothelioma

Author

Bayram, Hasan (ORCID 0000-0002-5236-766X & YÖK ID 4890); Dilege, Mustafa Şükrü (ORCID 0000-0002-1071-5291 & YÖK ID 122573); Tanju, Serhan (ORCID 0000-0002-2363-233X & YÖK ID 214690); Erus, Suat (ORCID 0000-0002-6162-3266 & YÖK ID 175565); Yavuz, Ömer; Bulutay, Pınar (ORCID 0000-0001-5497-1513 & YÖK ID 133565); Fırat, Pınar Arıkan (ORCID 0000-0001-8340-2678 & YÖK ID 207545), Marazioti, Antonia; Krontira, Anthi C.; Behrend, Sabine J.; Giotopoulou, Georgia A.; Ntaliarda, Giannoula; Blanquart, Christophe; Iliopoulou, Marianthi; Vreka, Malamati; Trassl, Lilith; Pepe, Mario A. A.; Hackl, Caroline M.; Klotz, Laura, V; Weiss, Stefanie A., I; Koch, Ina; Lindner, Michael; Hatz, Rudolph A.; Behr, Juergen; Wagner, Darcy E.; Papadaki, Helen; Antimisiaris, Sophia G.; Jean, Didier; Deshayes, Sophie; Gregoire, Marc; Kayalar, Özgecan; Mortazavi, Deniz; Psallidas, Ioannis; Spella, Magda; Giopanou, Ioanna; Lilis, Ioannis; Lamort, Anne-Sophie; Stathopoulos, Georgios T., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Bayram, Hasan (ORCID 0000-0002-5236-766X & YÖK ID 4890); Dilege, Mustafa Şükrü (ORCID 0000-0002-1071-5291 & YÖK ID 122573); Tanju, Serhan (ORCID 0000-0002-2363-233X & YÖK ID 214690); Erus, Suat (ORCID 0000-0002-6162-3266 & YÖK ID 175565); Yavuz, Ömer; Bulutay, Pınar (ORCID 0000-0001-5497-1513 & YÖK ID 133565); Fırat, Pınar Arıkan (ORCID 0000-0001-8340-2678 & YÖK ID 207545), Marazioti, Antonia; Krontira, Anthi C.; Behrend, Sabine J.; Giotopoulou, Georgia A.; Ntaliarda, Giannoula; Blanquart, Christophe; Iliopoulou, Marianthi; Vreka, Malamati; Trassl, Lilith; Pepe, Mario A. A.; Hackl, Caroline M.; Klotz, Laura, V; Weiss, Stefanie A., I; Koch, Ina; Lindner, Michael; Hatz, Rudolph A.; Behr, Juergen; Wagner, Darcy E.; Papadaki, Helen; Antimisiaris, Sophia G.; Jean, Didier; Deshayes, Sophie; Gregoire, Marc; Kayalar, Özgecan; Mortazavi, Deniz; Psallidas, Ioannis; Spella, Magda; Giopanou, Ioanna; Lilis, Ioannis; Lamort, Anne-Sophie; Stathopoulos, Georgios T., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Abstract

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRAS(G12D) in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRAS(G12D) lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration., European Union (EU); Horizon 2020; European Research Council 2010 Starting Independent Investigator; ERC Proof of Concept 2015 (ERC-PoC-2015); German Research Society; ALTERNATIVE; German Ministry for Education and Research; German Center for Lung Research Translational Research Grant; Greek State Scholarship Foundation Program; European Union (EU); European Union Social Fund; Greek National Fund; Reinforcement of Postdoctoral Researchers-1 stand 2nd cycles; General Secretariat for Research and Innovation; Hellenic Foundation for Research and Innovation; REPSIRE European Respiratory Society Fellowship; Institut National de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche en Sante Respiratoire des Pays de la Loire; National Research Agency Programme d' Investissements d' Avenir; Pays de la Loire Region Research Program; Ligue Contrele Cancer; Chancellerie des Universites de Paris; Projekt DEAL

Published
2022

6. Lung nodules: A comprehensive review on current approach and management

Author

Loverdos, Konstantinos, Fotiadis, Andreas, Kontogianni, Chrysoula, Iliopoulou, Marianthi, and Gaga, Mina

Subjects
Lung abscess -- Diagnosis -- Care and treatment, Practice guidelines (Medicine) -- Analysis, Radiologists -- Practice, Bronchoscopy, Surgery, Physicians, Lung cancer, Health
Abstract

Byline: Konstantinos. Loverdos, Andreas. Fotiadis, Chrysoula. Kontogianni, Marianthi. Iliopoulou, Mina. Gaga In daily clinical practice, radiologists and pulmonologists are faced with incidental radiographic findings of pulmonary nodules. Deciding how to [...]

Published
2019

8. KRAS signaling in malignant pleural mesothelioma

Author

Marazioti, Antonia, primary, Krontira, Anthi C, additional, Behrend, Sabine J, additional, Giotopoulou, Georgia A, additional, Ntaliarda, Giannoula, additional, Blanquart, Christophe, additional, Bayram, Hasan, additional, Iliopoulou, Marianthi, additional, Vreka, Malamati, additional, Trassl, Lilith, additional, Pepe, Mario A A, additional, Hackl, Caroline M, additional, Klotz, Laura V, additional, Weiss, Stefanie A I, additional, Koch, Ina, additional, Lindner, Michael, additional, Hatz, Rudolph A, additional, Behr, Juergen, additional, Wagner, Darcy E, additional, Papadaki, Helen, additional, Antimisiaris, Sophia G, additional, Jean, Didier, additional, Deshayes, Sophie, additional, Grégoire, Marc, additional, Kayalar, Özgecan, additional, Mortazavi, Deniz, additional, Dilege, Şükrü, additional, Tanju, Serhan, additional, Erus, Suat, additional, Yavuz, Ömer, additional, Bulutay, Pınar, additional, Fırat, Pınar, additional, Psallidas, Ioannis, additional, Spella, Magda, additional, Giopanou, Ioanna, additional, Lilis, Ioannis, additional, Lamort, Anne‐Sophie, additional, and Stathopoulos, Georgios T, additional

Published
2021
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9. cAMP response element-binding protein mediates immune-evasion of KRAS-mutant lung adenocarcinoma

Author

Giotopoulou, Georgia A., primary, Ntaliarda, Giannoula, additional, Μarazioti, Antonia, additional, Lilis, Ioannis, additional, Spiropoulou, Nikolitsa, additional, Kalogianni, Foteini, additional, Tourkochristou, Evanthia, additional, Giopanou, Ioanna, additional, Spella, Magda, additional, Iliopoulou, Marianthi, additional, Korfiati, Aigli, additional, Theofilatos, Konstantinos, additional, Mavroudi, Seferina, additional, Mantamadiotis, Theofilos, additional, Goldmann, Torsten, additional, Marwitz, Sebastian, additional, and Stathopoulos, Georgios T., additional

Published
2021
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10. Μελέτη μικροβιολογίας υπεζωκοτικής λοίμωξης στην Ελλάδα

Author

Iliopoulou Marianthi

Subjects
Health Sciences, Επιστήμες Υγείας
Abstract

H γνώση της μικροβιολογίας της υπεζωκοτικής σήψης (επιπλεγμένης παραπνευμονικής και εμπυήματος) είναι απαραίτητη προκειμένου να καθοριστεί η εμπειρική θεραπεία που θα πρέπει να χορηγείται στους ασθενείς. Για την Ελλάδα δεν υπάρχουν στοιχεία σχετικά με την επίπτωσή της στον πληθυσμό ούτε για το μικροβιολογικό προφίλ αυτής. Σκοπός της παρούσας μελέτης είναι να καταγραφούν οι λοιμογόνοι παράγοντες που προκαλούν υπεζωκοτική λοίμωξη στη χώρα, οι ευαισθησίες αυτών στα αντιμικροβιακά φάρμακα, τα κλινικά χαρακτηριστικά των ασθενών που μπορεί να συνδέονται με τα συγκεκριμένα μικρόβια και η έκβαση των ασθενών. Κριτήριο εισαγωγής αποτελεί η θετική καλλιέργεια του υπεζωκοτικού υγρού. Η παρούσα μελέτη έχει δύο σκέλη: το πρώτο αφορά μια αναδρομική περιγραφική μελέτη (Ν=45) και το δεύτερο μια προοπτική μη-παρεμβατική μελέτη (Ν=113). Τα κυριότερα ευρήματα αυτής είναι: Tα πιο κοινά παθογόνα, υπεύθυνα για την υπεζωκοτική λοίμωξη της κοινότητας στην Ελλάδα είναι οι μη πνευμονιοκοκκικοί στρεπτόκοκκοι. Αντιμικροβιακά σχήματα όπως οι αμινοπενικιλλίνες με τον αναστολέα τους μαζί με μια αναπνευστική κινολόνη ή η κεφτριαξόνη μαζί με μία αναπνευστική κινολόνη φαίνεται να είναι πολύ αποτελεσματικά στη θεραπεία της υπεζωκοτικής λοίμωξης της κοινότητας. Τέλος, υπάρχει συσχέτιση ανάμεσα στα κλινικά χαρακτηριστικά των ασθενών κατά την εισαγωγή τους και το υπεύθυνο παθογόνο, στην ύπαρξη αντοχής σε κοινά αντιμικροβιακά σχήματα και στην επιβίωση. Identifying the microbiology of pleural sepsis (complicated parapneumonic pleural effusion and empyema) is necessary to determine the empirical treatment for the patients. There is no data on its impact on the population or its microbiological profile in Greece. The purpose of this study is to identify the infectious agents that cause pleural infection in the country, their susceptibility to antimicrobial drugs, patients’ clinical characteristics that may be associated with these microbes and contribute to patients’ outcome. Inclusion criterion for this study is the positive pleural fluid culture. The present study has two parts: the first concerns a retrospective descriptive study (N = 45) and the second one a prospective non-invasive study (N = 113). The main findings are: The most common pathogens responsible for community-acquired pleural infection (CAPI) in Greece are non-pneumococcal streptococci. Antimicrobial regimens such as aminopenicillins plus their inhibitor along with a respiratory quinolone or ceftriaxone in combination with a respiratory quinolone appear to be very effective in treating CAPI in the current study. Finally, there is a correlation between patients’ clinical characteristics at admission and the pathogen, the existence of resistance to common antimicrobial regimens and survival.

Published
2021

11. Immune-evasion of KRAS-mutant lung adenocarcinoma mediated by cAMP response element-binding protein

Author

Giotopoulou, Georgia A., primary, Ntaliarda, Giannoula, additional, Marazioti, Antonia, additional, Lilis, Ioannis, additional, Kalogianni, Foteini, additional, Tourkochristou, Evanthia, additional, Spiropoulou, Nikolitsa, additional, Giopanou, Ioanna, additional, Spella, Magda, additional, Iliopoulou, Marianthi, additional, Korfiati, Aigli, additional, Mantamadiotis, Theofilos, additional, Rosero, Christian, additional, Goldmann, Torsten, additional, Marwitz, Sebastian, additional, and Stathopoulos, Georgios T., additional

Published
2021
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14. Bacteriology, antibiotic resistance and risk stratification of patients with culture-positive, community-acquired pleural infection

Author

Iliopoulou, Marianthi, primary, Skouras, Vasileios, additional, Psaroudaki, Zoe, additional, Makarona, Magda, additional, Vogiatzakis, Evangelos, additional, Tsorlini, Eleni, additional, Katsifa, Eleni, additional, Spyratos, Dionisios, additional, Siopi, Dimitra, additional, Kotsiou, Ourania, additional, Xitsas, Stelios, additional, Martsoukou, Maria, additional, Sigala, Ioanna, additional, and Kalomenidis, Ioannis, additional

Published
2021
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15. KRASsignalling in malignant pleural mesothelioma

Author

Marazioti, Antonia, primary, Blanquart, Christophe, additional, Krontira, Anthi C., additional, Pepe, Mario A. A., additional, Hackl, Caroline M., additional, Iliopoulou, Marianthi, additional, Lamort, Anne-Sophie, additional, Koch, Ina, additional, Lindner, Michael, additional, Hatz, Rudolph A., additional, Wagner, Darcy E., additional, Papadaki, Helen, additional, Antimisiaris, Sophia G., additional, Psallidas, Ioannis, additional, Spella, Magda, additional, Giopanou, Ioanna, additional, Lilis, Ioannis, additional, Grégoire, Marc, additional, and Stathopoulos, Georgios T., additional

Published
2020
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16. Bacteriological and clinical correlates of culture-positive parapneumonic community-acquired pleural infection

Author

Iliopoulou, Marianthi, primary, Skouras, Vasileios, additional, Psaroudaki, Zoe, additional, Makarona, Magda, additional, Vogiatzakis, Evangelos, additional, Tsorlini, Eleni, additional, Katsifa, Eleni, additional, Spyratos, Dionisios, additional, Siopi, Dimitra, additional, Kotsiou, Ourania, additional, Xitsas, Stelios, additional, Petinaki, Efi, additional, Martsoukou, Maria, additional, Tsiafaki, Xanthi, additional, Filaditaki, Vassiliki, additional, Sigala, Ioanna, additional, and Kalomenidis, Ioannis, additional

Published
2020
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17. MTH1 favors mesothelioma progression and mediates paracrine rescue of bystander endothelium from oxidative damage

Author

Magkouta, Sophia F., primary, Pappas, Apostolos G., additional, Vaitsi, Photene C., additional, Agioutantis, Panagiotis C., additional, Pateras, Ioannis S., additional, Moschos, Charalampos A., additional, Iliopoulou, Marianthi P., additional, Kosti, Chrysavgi N., additional, Loutrari, Heleni V., additional, Gorgoulis, Vassilis G., additional, and Kalomenidis, Ioannis T., additional

Published
2020
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18. Clinical identification of malignant pleural effusions

Author

Marazioti, Antonia, primary, Voulgaridis, Apostolos, additional, Psallidas, Ioannis, additional, Lamort, Anne-Sophie, additional, Iliopoulou, Marianthi, additional, Krontira, Anthi C., additional, Lilis, Ioannis, additional, Asciak, Rachelle, additional, Kanellakis, Nikolaos I., additional, Rahman, Najib M., additional, Karkoulias, Kyriakos, additional, Spiropoulos, Konstantinos, additional, Kaiser, Jan-Christian, additional, and Stathopoulos, Georgios T., additional

Published
2020
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23. Invasive Mechanical Ventilation: When and to whom? Indications and complications of Invasive Mechanical Ventilation.

Author

Theodoulou, Danai, Alevrakis, Emmanouil, Iliopoulou, Marianthi, Karampitsakos, Theodoros, Katsaras, Matthaios, Tsipilis, Stamatios, Tzimopoulos, Konstantinos, Koutsoukou, Antonia, and Rovina, Nikoletta

Subjects
INTENSIVE care units, TRACHEA intubation, CHRONICALLY ill, RESPIRATORY insufficiency, ENDOTRACHEAL suctioning
Abstract

Although emergency endotracheal intubation and mechanical ventilation (MV) are undoubtedly a life-saving intervention, deciding when and whom to support remains challenging. Common indications include respiratory failure, shock, coma and operative procedures that require analgesia and sedation. Endotracheal intubation is well known for its potential difficulty and mechanical ventilation is associated with complications that may aggravate the critically ill patient. Although MV is used in intensive care units in order to maintain adequate gas exchange and decrease the work of breathing, these goals may be difficult to achieve if there is no proper interaction between patient and ventilator (patient-ventilator asynchrony). Therefore, it is important that clinicians suspect, recognize and resolve appropriately any adverse consequence associated with this intervention. Finally, with the widespread use of mechanical ventilation, ethical challenges arise; patients with terminal illnesses can be kept alive, with little to no prospect of having their underlying condition cured or improved. Of paramount importance is for chronically ill patients to partake in the decision to institute or withhold MV after being appropriately informed for its indications and limitations. [ABSTRACT FROM AUTHOR]

Published
2020

27. Myeloid-derived interleukin-1β drives oncogenic KRAS-NF-κΒ addiction in malignant pleural effusion

Author

Marazioti, Antonia, primary, Lilis, Ioannis, additional, Vreka, Malamati, additional, Apostolopoulou, Hara, additional, Kalogeropoulou, Argyro, additional, Giopanou, Ioanna, additional, Giotopoulou, Georgia A., additional, Krontira, Anthi C., additional, Iliopoulou, Marianthi, additional, Kanellakis, Nikolaos I., additional, Agalioti, Theodora, additional, Giannou, Anastasios D., additional, Jones-Paris, Celestial, additional, Iwakura, Yoichiro, additional, Kardamakis, Dimitrios, additional, Blackwell, Timothy S., additional, Taraviras, Stavros, additional, Spella, Magda, additional, and Stathopoulos, Georgios T., additional

Published
2018
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32. A conditional mouse model of malignant pleural mesothelioma

Author

Krontira, Anthi, primary, Vreka, Malamati, additional, Iliopoulou, Marianthi, additional, Lilis, Ioannis, additional, Agalioti, Theodora, additional, Spiropoulou, Nicoleta, additional, Giotopoulou, Georgia, additional, Rinkevich, Yuval, additional, Spella, Magda, additional, Stathopoulos, Georgios, additional, and Marazioti, Antonia, additional

Published
2016
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33. A role for cAMP-responsive element binding protein in lung adenocarcinoma

Author

Marazioti, Antonia, primary, Spiropoulou, Nikolitsa, additional, Lilis, Ioannis, additional, Giannou, Anastasios, additional, Vreka, Malamati, additional, Kanellakis, Nikolaos, additional, Iliopoulou, Marianthi, additional, Agalioti, Theodora, additional, Spella, Magda, additional, and Stathopoulos, Georgios, additional

Published
2015
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34. Mouse models of malignant pleural effusion.

Author

Iliopoulou, Marianthi, Marazioti, Antonia, and Stathopoulos, Georgios T.

Subjects
*PLEURAL effusions, *ANIMAL models in research, *CANCER, *NEOVASCULARIZATION, *ANIMAL models of inflammation
Abstract

Malignant pleural effusion (MPE) is a common complication of advanced malignancies, particularly lung and breast cancer. The survival time of patients with MPE is often short, with poor quality of life. The pleural space normally contains a thin film of fluid that is regulated by the balance between production from systemic blood vessel filtration and lymphatic absorption. Tumourinduced disturbances of the pleural fluid production and clearance processes result in the development of MPE. Until recently the specific mechanisms underlying pleural fluid accumulation were poorly defined because studies of MPE pathogenesis were limited by a lack of animal models that could reproduce the pathobiology of human MPE. During the past decade, various research groups have established experimental models that mimic human pleural malignancies, including mice models that require either immunocompromised or immunocompetent mice for propagation of human or murine cancer induced-MPE, respectively. The experimental modelling of MPE has provided new insight into the biological behaviour of tumour cells and tumour-host interactions in the pleural cavity, paving the way for improved management of this end-stage condition. [ABSTRACT FROM AUTHOR]

Published
2013

35. Pleural Mesothelioma in a young male patient.

Author

Voulgaridis, Apostolos, Apollonatou, Vasiliki, Lykouras, Dimosthenis, Giannopoulos, Achilleas, Iliopoulou, Marianthi, Kraniotis, Pantelis, Karkoulias, Kiriakos, and Spiropoulos, Konstantinos

Subjects
LUNG cancer, MESOTHELIOMA
Abstract

The article presents a case study of a 33-year-old male smoker with prolonged fever and unilateral pleural effusion whose video-assisted thoracoscopy revealed malignant tumors with characteristics of epithelioid mesothelioma.

Published
2014

36. KRAS signaling in malignant pleural mesothelioma

Author

Antonia Marazioti, Anthi C Krontira, Sabine J Behrend, Georgia A Giotopoulou, Giannoula Ntaliarda, Christophe Blanquart, Hasan Bayram, Marianthi Iliopoulou, Malamati Vreka, Lilith Trassl, Mario A A Pepe, Caroline M Hackl, Laura V Klotz, Stefanie A I Weiss, Ina Koch, Michael Lindner, Rudolph A Hatz, Juergen Behr, Darcy E Wagner, Helen Papadaki, Sophia G Antimisiaris, Didier Jean, Sophie Deshayes, Marc Grégoire, Özgecan Kayalar, Deniz Mortazavi, Şükrü Dilege, Serhan Tanju, Suat Erus, Ömer Yavuz, Pınar Bulutay, Pınar Fırat, Ioannis Psallidas, Magda Spella, Ioanna Giopanou, Ioannis Lilis, Anne‐Sophie Lamort, Georgios T Stathopoulos, Ludwig Maximilian University [Munich] (LMU), University of Patras [Patras], German Center for Lung Research, Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Koç University, Asklepios Klinikum Uckermark GmbH, Lund University [Lund], Institute of Chemical Engineering and High Temperature Chemical Processes, (FORTH/ICE-HT), Foundation for Research and Technology - Hellas (FORTH), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), 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)-Sorbonne Université (SU)-Université de Paris (UP), University of Patras, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Bernardo, Elizabeth, Bayram, Hasan (ORCID 0000-0002-5236-766X & YÖK ID 4890), Dilege, Mustafa Şükrü (ORCID 0000-0002-1071-5291 & YÖK ID 122573), Tanju, Serhan (ORCID 0000-0002-2363-233X & YÖK ID 214690), Erus, Suat (ORCID 0000-0002-6162-3266 & YÖK ID 175565), Yavuz, Ömer, Bulutay, Pınar (ORCID 0000-0001-5497-1513 & YÖK ID 133565), Fırat, Pınar Arıkan (ORCID 0000-0001-8340-2678 & YÖK ID 207545), Marazioti, Antonia, Krontira, Anthi C., Behrend, Sabine J., Giotopoulou, Georgia A., Ntaliarda, Giannoula, Blanquart, Christophe, Iliopoulou, Marianthi, Vreka, Malamati, Trassl, Lilith, Pepe, Mario A. A., Hackl, Caroline M., Klotz, Laura, V, Weiss, Stefanie A., I, Koch, Ina, Lindner, Michael, Hatz, Rudolph A., Behr, Juergen, Wagner, Darcy E., Papadaki, Helen, Antimisiaris, Sophia G., Jean, Didier, Deshayes, Sophie, Gregoire, Marc, Kayalar, Özgecan, Mortazavi, Deniz, Psallidas, Ioannis, Spella, Magda, Giopanou, Ioanna, Lilis, Ioannis, Lamort, Anne-Sophie, Stathopoulos, Georgios T., Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine

Subjects
Mesothelioma, Medicine (General), Lung Neoplasms, endocrine system diseases, Pleural Neoplasms, Respiratory System, [SDV.CAN]Life Sciences [q-bio]/Cancer, QH426-470, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, Mice, 0302 clinical medicine, R5-920, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, KRAS, Animals, Humans, BAP1, TP53, neoplasms, 030304 developmental biology, 0303 health sciences, Tumor Suppressor Proteins, Mesothelioma, Malignant, Bap1, Kras, Nf2, Tp53, Asbestos, asbestos, Research and experimental medicine, TP53 Subject Categories Cancer, respiratory tract diseases, NF2, 030220 oncology & carcinogenesis, Molecular Medicine, Ubiquitin Thiolesterase, Signal Transduction
Abstract

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRAS(G12D) in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRAS(G12D) lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration., European Union (EU); Horizon 2020; European Research Council 2010 Starting Independent Investigator; ERC Proof of Concept 2015 (ERC-PoC-2015); German Research Society; ALTERNATIVE; German Ministry for Education and Research; German Center for Lung Research Translational Research Grant; Greek State Scholarship Foundation Program; European Union (EU); European Union Social Fund; Greek National Fund; Reinforcement of Postdoctoral Researchers-1 stand 2nd cycles; General Secretariat for Research and Innovation; Hellenic Foundation for Research and Innovation; REPSIRE European Respiratory Society Fellowship; Institut National de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS); Institut de Recherche en Sante Respiratoire des Pays de la Loire; National Research Agency Programme d' Investissements d' Avenir; Pays de la Loire Region Research Program; Ligue Contrele Cancer; Chancellerie des Universites de Paris; Projekt DEAL

Published
2021
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37. Λειτουργική μελέτη της διαγονιδιακής μεταφοράς στην υπεζωκοτική κοιλότητα

Author

Σταθόπουλος, Γεώργιος, Iliopoulou, Marianthi, Βουκελάτου, Γεωργία, and Καρδαμάκης, Δημήτριος

Subjects
Malignant pleural effusion, Διαγονιδιακή μεταφορά, 616.25, Pleura, Κακοήθης υπεζωκοτική συλλογή (ΚΥΣ), Υπεζωκότας, Gene transfer
Abstract

Η κακοήθης υπεζωκοτική συλλογή (ΚΥΣ), προκαλούμενη από μεταστατικά αδενοκαρκινώματα είτε από πρωτοπαθή μεσοθηλιώματα, αποτελεί μείζον κλινικό πρόβλημα καθώς σηματοδοτεί συστηματική νεοπλασματική διασπορά και χαμηλό προσδόκιμο επιβίωσης. Η τρέχουσα αντιμετώπισή της είναι μη αιτιολογική και συχνά αναποτελεσματική. Ενώ τα νεοπλάσματα που προκαλούν ΚΥΣ φέρουν καλά χαρακτηρισμένες μεταλλάξεις και ο υπεζωκότας θεωρείται προνομιακή ανατομική θέση γονιδιακής θεραπείας, οι μέχρι τώρα μελέτες της αποτελεσματικότητας της υπεζωκοτικής διαγονιδιακής μεταφοράς υπήρξαν αποσπασματικές. ΣΚΟΠΟΣ: Σκοπός της παρούσας μελέτης είναι ο χαρακτηρισμός της έκτασης, της αποτελεσματικότητας και της λειτουργικότητας της διαγονιδιακής μεταφοράς τόσο στο φυσιολογικό υπεζωκοτικό μεσοθήλιο, όσο και και στον πάσχοντα υπεζωκότα με πρωτοπαθείς ή μεταστατικούς όγκους. ΥΛΙΚΑ ΚΑΙ ΜΕΘΟΔΟΙ: Υγιείς ποντικοί φυσικού τύπου C57BL/6 και διαγονιδιακοί ποντικοί-ιχνηλάτες mT.mG έλαβαν ενδοϋπεζωκοτικές εγχύσεις 5 x 108 μολυσματικών μονάδων αδενοϊών τύπου 5 (Ad) που κωδικοποιούν τα γονίδια της λουσιφεράσης (Luc), της πράσινης φθορίζουσας πρωτεΐνης (GFP) και της Cre ρεκομπινάσης. Η αποτελεσματικότητα της διαγονιδιακής μεταφοράς μελετήθηκε με απεικόνιση βιοφωταύγειας/βιοφθορισμού, καθώς και με φθορίζουσα μικροσκοπία. Τα πειράματα επαναλήφθηκαν σε ποντικούς με ΚΥΣ, οι οποίες προκλήθηκαν μέσω υπεζωκοτικής έγχυσης 150.000 κυττάρων συγγενικού μεσοθηλιώματος υπεζωκότα (ΑΕ17) και αδενοκαρκινώματος πνεύμονα (LLC). Προκειμένου να μελετηθεί αν οι αδενοϊοί σε ποιο βαθμό μπορούν να διαμολύνουν κύτταρα in vitro , ανθρώπινες και ποντικίσιες κυτταρικές σειρές , φυσιολογικές και καρκινικές , διαμολύνθηκαν με 10ng/μl Ad-luc και Ad-GFP. AΠΟΤΕΛΕΣΜΑΤΑ: Η θωρακική φωτεινή εκπομπή ποντικών C57BL/6 κορυφώθηκε την πρώτη και υποχώρησε τη δεύτερη εβδομάδα μετά ενδοϋπεζωκοτική έγχυση Ad-Luc . Δύο εβδομάδες μετά από ενδοϋπεζωκοτική χορήγηση Ad-Cre σε ποντικούς mT.mG παρατηρήθηκε διάχυτη εξάλειψη του ερυθρού και εμφάνιση πράσινου φθορίζοντος σήματος σε όλες τις υπεζωκοτικές επιφάνειες, το οποίο εντοπιζόταν κατ’ αποκλειστικότητα στο μεσοθήλιο. Δύο εβδομάδες μετά από έγχυση Ad-Cre σε ποντικούς mT.mG που είχαν αναπτύξει όγκους παρατηρήθηκε πράσινος φθορισμός μαζί με τον κόκκκινο μέσα στους όγκους. Στατιστικώς σημαντική διαμόλυνση παρατηρήθηκε in vitro στα κύτταρα φυσιολογικού μεσοθηλίου, μεσοθηλιώματος ανθρώπου και ποντικού , αδενοκαρκινώματος πνεύμονα και παγκρέατος ποντικού. ΣΥΜΠΕΡΑΣΜΑΤΑ: Η ενδοϋπεζωκοτική έγχυση ανασυνδυασμένων αδενοιών αποτελεί αποτελεσματική μέθοδο διαγονιδιακής μεταφοράς στο φυσιολογικό και παθολογικό υπεζωκοτικό μεσοθήλιο. Ο βαθμός της διαγονιδιακής μεταφοράς επιβεβαιώνεται με τη διαμόλυνση φυσιολογικών και καρκινικών κυτταρικών σειρών in vitro.

Published
2013

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