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4. Stoma-free Survival After Rectal Cancer Resection With Anastomotic Leakage: Development and Validation of a Prediction Model in a Large International Cohort

Author

Greijdanus, Nynke G., Wienholts, Kiedo, Ubels, Sander, Talboom, Kevin, Hannink, Gerjon, Wolthuis, Albert, de Lacy, Francisco B., Lefevre, Jérémie H., Solomon, Michael, Frasson, Matteo, Rotholtz, Nicolas, Denost, Quentin, Perez, Rodrigo O., Konishi, Tsuyoshi, Panis, Yves, Rutegård, Martin, Hompes, Roel, Rosman, Camiel, van Workum, Frans, Tanis, Pieter J., de Wilt, Johannes H.W., Bremers, Andreas J.A., Ferenschild, Floris T., de Vriendt, Stefanie, D’Hoore, André, Bislenghi, Gabriele, Farguell, Jordi, Lacy, Antonio M., Atienza, Paula González, van Kessel, Charlotte S., Parc, Yann, Voron, Thibault, Collard, Maxime K., Muriel, Jorge Sancho, Cholewa, Hannia, Mattioni, Laura A., Frontali, Alice, Polle, Sebastiaan W., Polat, Fatih, Obihara, Ndidi J., Vailati, Bruna B., Kusters, Miranda, Tuynmann, Jurriaan B., Hazen, Sanne J.A., Grüter, Alexander A.J., Amano, Takahiro, Fujiwara, Hajime, Salomon, Mario, Ruiz, Hernán, Gonzalez, Ricardo, Estefanía, Diego, Avellaneda, Nicolas, Carrie, Augusto, Santillan, Mateo, Pantoja Pachajoa, Diana A., Parodi, Matias, Gielis, Manuel, Binder, Alf-Dorian, Gürtler, Thomas, Riedl, Peter, Badiani, Sarit, Berney, Christophe, Morgan, Matthew, Hollington, Paul, da Silva, Nigel, Nair, Gavin, Ho, Yiu M., Lamparelli, Michael, Kapadia, Raj, Kroon, Hidde M., Dudi-Venkata, Nagendra N., Liu, Jianliang, Sammour, Tarik, Flamey, Nicolas, Pattyn, Paul, Chaoui, Ahmed, Vansteenbrugge, Louis, van den Broek, Nathalie E.J., Vanclooster, Patrick, de Gheldere, Charles, Pletinckx, Pieter, Defoort, Barbara, Dewulf, Maxime, Slavchev, Mihail, Belev, Nikolay, Atanasov, Boyko, Krastev, Panche, Sokolov, Manol, Maslyankov, Svilen, Gribnev, Petar, Pavlov, Vasil, Ivanov, Tsvetomir, Karamanliev, Martin, Filipov, Emil, Tonchev, Pencho, Aigner, Felix, Mitteregger, Martin, Allmer, Caterina, Seitinger, Gerald, Colucci, Nicola, Buchs, Nicolas, Ris, Frédéric, Toso, Christian, Gialamas, Eleftherios, Vuagniaux, Aurélie, Chautems, Roland, Sauvain, Marc-Olivier, Daester, Silvio, von Flüe, Markus, Guenin, Marc-Olivier, Taha-Mehlitz, Stephanie, Hess, Gabriel F., Martínek, Lubomír, Skrovina, Matej, Machackova, Maria, Benčurik, Vladimir, Uluk, Deniz, Pratschke, Johann, Dittrich, Luca S., Guel-Klein, Safak, Perez, Daniel, Grass, Julia-Kristin, Melling, Nathaniel, Mueller, Simone, Iversen, Lene H., Eriksen, Jacob D., Baatrup, Gunnar, Al-Najami, Issam, Bjørsum-Meyer, Thomas, Teras, Jüri, Teras, Roland M., Monib, Fatma A., Abu Elnga Ahmed, Nagm Eldin, Alkady, Eithar, Ali, Ahmed K., Khedr, Gehan Abd Elatti, Abdelaal, Ahmed Samir, Bassyouni Ashoush, Fouad M., Ewedah, Moataz, Elshennawy, Eslam M., Hussein, Mohamed, Fernández-Martínez, Daniel, García-Flórez, Luis J., Fernández-Hevia, María, Suárez-Sánchez, Aida, del Hoyo Aretxabala, Izaskun, Docampo, Iria Losada, Zabala, Jesús Gómez, Tejedor, Patricia, Morales Bernaldo de Quirós, Javier T., Quiroga, Ignacio Bodega, Navarro-Sánchez, Antonio, Darias, Iván Soto, Fernández, Cristina López, de La Cruz Cuadrado, Cristina, Sánchez-Guillén, Luis, López-Rodríguez-Arias, Francisco, Soler-Silva, Álvaro, Arroyo, Antonio, Bernal-Sprekelsen, Juan C., Gómez-Abril, Segundo Á., Gonzálvez, Paula, Torres, María T., Sánchez, Teresa Rubio, Antona, Francisco Blanco, Sánchez Lara, Juan E., Alcázar Montero, José A., Fernández-Martínez, Daniel, García-Flórez, Luis J., Fernández-Hevia, María, Suárez-Sánchez, Aida, Colás-Ruiz, Enrique, Tasende-Presedo, Marta M., Fernández-Hurtado, Ignacio, Cifuentes-Ródenas, José A., Suárez, Marta Castro, Losada, Manuel, Hernández, Miguel, Alonso, Alfredo, Diéguez, Beatriz, Serralta, Daniel, Medina Quintana, Rita E., Gil Lopez, Jose M., Pinto, Francisca Lima, Nieto-Moreno, Elena, Bonito, Alba Correa, Santacruz, Carlos Cerdán, Marcos, Elena Bermejo, Septiem, Javier García, Calero-Lillo, Aránzazu, Alanez-Saavedra, Javier, Muñoz-Collado, Salvador, López-Lara, Manuel, Martínez, María Labalde, Herrero, Eduardo Ferrero, Borda, Francisco Javier García, Villar, Óscar García, Escartín, Jorge, Blas, Juan L., Ferrer, Rocío, Egea, Jorge García, Rodríguez-Infante, Antonio, Mínguez-Ruiz, Germán, Carreño-Villarreal, Guillermo, Pire-Abaitua, Gerardo, Dziakova, Jana, Rodríguez, Carlos Sáez-Cazallas, Pizarro Aranda, María J., Muguerza Huguet, José M., Borda-Arrizabalaga, Nerea, Enriquez-Navascués, José M., Echaniz, Garazi Elorza, Ansorena, Yolanda Saralegui, Estaire-Gómez, Mercedes, Martínez-Pinedo, Carlos, Barbero-Valenzuela, Alejandro, Ruíz-García, Pablo, Kraft, Miquel, Gómez-Jurado, María J., Pellino, Gianluca, Espín-Basany, Eloy, Cotte, Eddy, Panel, Nathalie, Goutard, Claire-Angéline, deÁngelis, Nicola, Lauka, Lelde, Shaikh, Shafaque, Osborne, Laura, Ramsay, George, Nichita, Vladimir-Ion, Bhandari, Santosh, Sarmah, Panchali, Bethune, Rob M., Pringle, Heather C.M., Massey, Lisa, Fowler, George E., Hamid, Hytham K.S., de Simone, Belinda D., Kynaston, James, Bradley, Nicholas, Stienstra, Roxane M., Gurjar, Shashank, Mukherjee, Tanmoy, Chandio, Ashfaq, Ahmed, Safia, Singh, Baljit, Runau, Francois, Chaudhri, Sanjay, Siaw, Oliver, Sarveswaran, Janahan, Miu, Victor, Ashmore, Daniel, Darwich, Haitham, Singh-Ranger, Deepak, Singh, Nirbhaibir, Shaban, Mohamed, Gareb, Fahed, Petropolou, Thalia, Polydorou, Adreas, Dattani, Mit, Afzal, Asma, Bavikatte, Akshay, Sebastian, Boby, Ward, Nicholas, Mishra, Amitabh, Manatakis, Dimitrios, Agalianos, Christos, Tasis, Nikolaos, Antonopoulou, Maria-Ioanna, Karavokyros, Ioannis, Charalabopoulos, Alexandros, Schizas, Dimitrios, Baili, Efstratia, Syllaios, Athanasios, Karydakis, Lysandros, Vailas, Michail, Balalis, Dimitrios, Korkolis, Dimitrios, Plastiras, Aris, Rompou, Aliki, Xenaki, Sofia, Xynos, Evangelos, Chrysos, Emmanuel, Venianaki, Maria, Christodoulidis, Grigorios, Perivoliotis, Konstantinos, Tzovaras, George, Baloyiannis, Ioannis, Ho, Man-Fung, Ng, Simon Siu-man, Mak, Tony Wing-chung, Futaba, Kaori, Šantak, Goran, Šimleša, Damir, osić, Jurica, Zukanović, Goran, Kelly, Michael E., Larkin, John O., McCormick, Paul H., Mehigan, Brian J., Connelly, Tara M., Neary, Peter, Ryan, Jessica, McCullough, Peter, Al-Juaifari, Maytham A., Hammoodi, Hayder, Abbood, Ali Hashim, Calabrò, Marcello, Muratore, Andrea, Terra, Antonio La, Farnesi, Francesca, Feo, Carlo V., Fabbri, Nicolò, Pesce, Antonio, Fazzin, Marta, Roscio, Francesco, Clerici, Federico, Lucchi, Andrea, Vittori, Laura, Agostinelli, Laura, Ripoli, Maria Cristina, Sambucci, Daniele, Porta, Andrea, Sinibaldi, Giovanni, Crescentini, Giacomo, larcinese, Antonella, Picone, Emanuele, Persiani, Roberto, Biondi, Alberto, Pezzuto, Roberto, Lorenzon, Laura, Rizzo, Gianluca, Coco, Claudio, D’Agostino, Luca, Spinelli, Antonino, Sacchi, Matteo M., Carvello, Michele, Foppa, Caterina, Spinelli, Antonino, Sacchi, Matteo M., Carvello, Michele, Foppa, Caterina, Maroli, Annalisa, Palini, Gian M., Garulli, Gianluca, Zanini, Nicola, Delrio, Paolo, Rega, Daniela, Carbone, Fabio, Aversano, Alessia, Pirozzolo, Giovanni, Recordare, Alfonso, DʼAlimonte, Lucrezia, Vignotto, Chiara, Corbellini, Carlo, Sampietro, Gianluca M., Lorusso, Leonardo, Manzo, Carlo A., Ghignone, Federico, Ugolini, Giampaolo, Montroni, Isacco, Pasini, Franceso, Pasini, Francesco, Ballabio, Michele, Bisagni, Pietro, Armao, Francesca T., Longhi, Marco, Ghazouani, Omar, Galleano, Raffaele, Tamini, Nicolò, Oldani, Massimo, Nespoli, Luca, Picciariello, Arcangelo, Altomare, Donato F., Tomasicchio, Giovanni, Lantone, Giuliano, Catena, Fausto, Giuffrida, Mario, Annicchiarico, Alfredo, Perrone, Gennaro, Grossi, Ugo, Santoro, Giulio A., Zanus, Giacomo, Iacomino, Alessandro, Novello, Simone, Passuello, Nicola, Zucchella, Martino, Puca, Lucia, deGiuli, Maurizio, Reddavid, Rossella, Scabini, Stefano, Aprile, Alessandra, Soriero, Domenico, Fioravanti, Emanuela, Rottoli, Matteo, Romano, Angela, Tanzanu, Marta, Belvedere, Angela, Mariani, Nicolò M., Ceretti, Andrea P., Opocher, Enrico, Gallo, Gaetano, Sammarco, Giuseppe, de Paola, Gilda, Pucciarelli, Salvatore, Marchegiani, Francesco, Spolverato, Gaya, Buzzi, Gianluca, Di Saverio, Salomone, Meroni, Paola, Parise, Cristiano, Bottazzoli, Elisa I., Lapolla, Pierfrancesco, Brachini, Gioia, Cirillo, Bruno, Mingoli, Andrea, Sica, Giuseppe, Siragusa, Leandro, Bellato, Vittoria, Cerbo, Daniele, de Pasqual, Carlo A., de Manzoni, Giovanni, di Cosmo, Maria A., Alrayes, Bourhan M.H., Qandeel, Mahmoud W. M., Hani, Mohammad Bani, Rabadi, Alexander, el Muhtaseb, Mohammad S., Abdeen, Basel, Karmi, Fahed, Žilinskas, Justas, Latkauskas, Tadas, Tamelis, Algimantas, Pikūnienė, Ingrida, Šlenfuktas, Vygintas, Poskus, Tomas, Kryzauskas, Marius, Jakubauskas, Matas, Mikalauskas, Saulius, Jakubauskiene, Lina, Hassan, Soha Y., Altrabulsi, Amani, Abdulwahed, Eman, Ghmagh, Reem, Deeknah, Abdulqudus, Alshareea, Entisar, Elhadi, Muhammed, Abujamra, Saleh, Msherghi, Ahmed A., Tababa, Osama W.E., Majbar, Mohammed A., Souadka, Amine, Benkabbou, Amine, Mohsine, Raouf, Echiguer, Sabrillah, Moctezuma-Velázquez, Paulina, Salgado-Nesme, Noel, Vergara-Fernández, Omar, Sainz-Hernández, Juan C., Alvarez-Bautista, Francisco E., Zakaria, Andee D., Zakaria, Zaidi, Wong, Michael P.K., Ismail, Razif, Ibrahim, Aini F., Abdullah, Nik A.N., Julaihi, Rokayah, Bhat, Sameer, OʼGrady, Greg, Bissett, Ian, Lamme, Bas, Musters, Gijsbert D., Dinaux, Anne M., Grotenhuis, Brechtje A., Steller Arend G.J. Aalbers, Ernst J., Leeuwenburgh, Marjolein M., Rutten, Harm J.T., Burger, Jacobus W.A., Bloemen, Johanne G., Ketelaers, Stijn H.J., Waqar, Usama, Chawla, Tabish, Rauf, Hareem, Rani, Pallavi, Talsma, Aaldert K., Scheurink, Lieke, van Praagh, Jasper B., Segelman, Josefin, Nygren, Jonas, Anderin, Kajsa, Tiefenthal, Marit, de Andrés, Beatriz, Beltrán de Heredia, Juan P., Vázquez, Andrea, Gómez, Tania, Golshani, Parisa, Kader, Rawaz, Mohamed, Abudi, Westerterp, Marinke, Marinelli, Andreas, Niemer, Quirine, Doornebosch, Pascal G., Shapiro, Joël, Vermaas, Maarten, de Graaf, Eelco J.R., van Westreenen, Hendrik L., Zwakman, Marije, van Dalsen, Annette D., Vles, Wouter J., Nonner, Joost, Toorenvliet, Boudewijn R., Janssen, Paul T.J., Verdaasdonk, Emiel G.G., Amelung, Femke J., Peeters Renu R. Bahadoer, Koen C.M.J., Holman, Fabian A., Heemskerk, Jeroen, Vosbeek, Noortje, Leijtens, Jeroen W.A., Taverne, Sophie B.M., Heijnen, Bob H.M., El-Massoudi, Youssef, de Groot-van Veen, Irene, Hoff, Christiaan, Jou-Valencia, Daniela, Consten, Esther C.J., Burghgraef, Thijs A., Geitenbeek, Ritch, Hulshof, Lorenzo G.W.L., Slooter, Gerrit D., Reudink, Muriël, Bouvy, Nicole D., Wildeboer, Aurelia C. L., Verstappen, Sonja, Pennings, Alexander J., van den Hengel, Berber, Wijma, Allard G., de Haan, Jael, de Nes, Lindsey C.F., Heesink, Vera, Karsten, Tom, Heidsma, Charlotte M., Koemans, Willem J., Dekker, Jan-Willem T., van der Zijden, Charlène J., Roos, Daphne, Demirkiran, Ahmet, van der Burg, Sjirk, Oosterling, Steven J., Hoogteijling, Tijs J., Wiering, Bastiaan, Smeeing, Diederik P.J., Havenga, Klaas, Lutfi, Hamid, Consten, Esther C.J., Tsimogiannis, Konstantinos, Sköldberg, Filip, Folkesson, Joakim, den Boer, Frank, van Schaik, Ted G., van Gerven, Pieter, Sietses, Colin, Hol, Jeroen C., Boerma, Evert-Jan G., Creemers, Davy M.J., Schultz, Johannes K., Frivold, Tone, Riis, Rolf, Gregussen, Hilde, Busund, Sondre, Sjo, Ole H., Gaard, Maria, Krohn, Nina, Ersryd, Amanda L., Leung, Edmund, Waqar, Usama, Chawla, Tabish, Rauf, Hareem, Rani, Pallavi, Sultan, Hytham, Hajjaj, Baraa Nabil, Alhisi, Ahmed Jehad, Khader, Ahmed A.E., Mendes, Ana Filipa Dias, Semião, Miguel, Faria, Luis Queiroz, Azevedo, Constança, da Costa Devesa, Helena M., Martins, Sónia Fortuna, Rodrigues Jarimba, Aldo M., Ribeiro Marques, Sónia M., Ferreira, Rita Marques, Oliveira, António, Ferreira, Cátia, Pereira, Ricardo, Surlin, Valeriu M., Graure, Giorgiana M., Ramboiu, Stefan Patrascu Sandu D., Negoi, Ionut, Ciubotaru, Cezar, Stoica, Bogdan, Tanase, Ioan, Stoica, Bogdan, Ciubotaru, Cezar, Negoita, Valentina M., Florea, Sabrina, Macau, Florin, Vasile, Mihai, Stefanescu, Victor, Dimofte, Gabriel-Mihail, Luncă, Sorinel, Roată, Cristian-Ene, Mu[Latin Small Letter s with comma below]ină, Ana-Maria, Garmanova, Tatiana, Agapov, Mikhail N., Markaryan, Daniil G., Eduard, Galliamov, Yanishev, Alexey, Abelevich, Alexander, Bazaev, Andrey, Rodimov, Sergey V., Filimonov, Victor B., Melnikov, Andrey A., Suchkov, Igor A., Drozdov, EvgeniyS., Kostromitskiy, Dmitriy N., Sjöström, Olle, Matthiessen, Peter, Baban, Bayar, Gadan, Soran, Jadid, Kaveh Dehlaghi, Staffan, Maria, Park, Jennifer M., Rydbeck, Daniel, Lydrup, Marie-Louise, Buchwald, Pamela, Jutesten, Henrik, Darlin, Lotten, Lindqvist, Ebba, Nilsson, Karl, Larsson, Per-Anders, Jangmalm, Staffan, Košir, Jurij A., Tomažič, Aleš, Grosek, Jan, Božič, Tajda Košir, Zazo, Aya, Zazo, Rama, Fares, Hala, Ayoub, Kusay, Niazi, Ammar, Mansour, Ali, Abbas, Ayman, Tantoura, Mohammad, Hamdan, Alaa, Hassan, Naya, Hasan, Bassam, Saad, Ahmad, Sebai, Amine, Haddad, Anis, Maghrebi, Houcine, Kacem, Montasser, Yalkın, Ömer, Samsa, Mehmet Veysi, Atak, İbrahim, Balci, Bengi, Haberal, Elifcan, Dogan, Lütfi, Gecim, Ibrahim E., Akyol, Cihangir, Koc, Mehmet A., Sivrikoz, Emre, Piyadeoğlu, Deniz, Larkin, John O., avanagh, Dara O., Sökmen, Selman, Bişgin, Tayfun, Günenç, Erşan, Güzel, Melek, Leventoğlu, Sezai, Yüksel, Osman, Kozan, Ramazan, Göbüt, Hüseyin, Cengiz, Fevzi, Erdinc, Kemal, Acar, Nihan Coşgun, Kamer, Erdinc, Özgür, İlker, Aydın, Oguzhan, Keskin, Metin, Bulut, Mehmet Türker, Kulle, Cemil B., Kara, Yasin, Sıbıç, Osman, Özata, İbrahim H., Buğra, Dursun, Balık, Emre, Kulle, Cemil B., Çakır, Murat, Alhardan, Anas, Colak, Elif, CiftciEngin Aybar, Ahmet B., Sari, Ahmet Can, Atici, Semra Demirli, Kaya, Tayfun, Dursun, Ayberk, Calik, Bulent, Özkan, Ömer Faruk, Ülgür, Hanife Şeyda, Düzgün, Özgül, Monson, John, George, Sarah, Woods, Kayla, Al-Eryani, Fatima, Albakry, Rudaina, Coetzee, Emile, Boutall, Adam, Herman, Ayesiga, Warden, Claire, Mugla, Naser, Forgan, Tim, Mia, Imraan, and Lambrechts, Anton

Published
2023
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5. The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate

Author

Bobardt, Michael, Kuo, Joseph, Chatterji, Udayan, Chanda, Sumit, Little, Susan J, Wiedemann, Norbert, Vuagniaux, Gregoire, and Gallay, Philippe A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, HIV/AIDS, Infectious Diseases, 5.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Animals, Anti-HIV Agents, Azocines, Benzhydryl Compounds, CD4-Positive T-Lymphocytes, Female, HIV-1, Humans, Inhibitor of Apoptosis Proteins, Mice, NF-kappa B p52 Subunit, Signal Transduction, Transcription Factor RelB, Ubiquitin-Protein Ligases, Virus Latency, General Science & Technology
Abstract

Antiretroviral therapy (ART) suppresses HIV replication, but does not cure the infection because replication-competent virus persists within latently infected CD4+ T cells throughout years of therapy. These reservoirs contain integrated HIV-1 genomes and can resupply active virus. Thus, the development of strategies to eliminate the reservoir of latently infected cells is a research priority of global significance. In this study, we tested efficacy of a new inhibitor of apoptosis protein antagonist (IAPa) called Debio 1143 at reversing HIV latency and investigated its mechanisms of action. Debio 1143 activates HIV transcription via NF-kB signaling by degrading the ubiquitin ligase baculoviral IAP repeat-containing 2 (BIRC2), a repressor of the non-canonical NF-kB pathway. Debio 1143-induced BIRC2 degradation results in the accumulation of NF-κB-inducing kinase (NIK) and proteolytic cleavage of p100 into p52, leading to nuclear translocation of p52 and RELB. Debio 1143 greatly enhances the binding of RELB to the HIV-1 LTR. These data indicate that Debio 1143 activates the non-canonical NF-kB signaling pathway by promoting the binding of RELB:p52 complexes to the HIV-1 LTR, resulting in the activation of the LTR-dependent HIV-1 transcription. Importantly, Debio 1143 reverses viral latency in HIV-1 latent T cell lines. Using knockdown (siRNA BIRC2), knockout (CRIPSR NIK) and proteasome machinery neutralization (MG132) approaches, we found that Debio 1143-mediated HIV latency reversal is BIRC2 degradation- and NIK stabilization-dependent. Debio 1143 also reverses HIV-1 latency in resting CD4+ T cells derived from ART-treated patients or HIV-1-infected humanized mice under ART. Interestingly, daily oral administration of Debio 1143 in cancer patients at well-tolerated doses elicited BIRC2 target engagement in PBMCs and induced a moderate increase in cytokines and chemokines mechanistically related to NF-kB signaling. In conclusion, we provide strong evidences that the IAPa Debio 1143, by initially activating the non-canonical NF-kB signaling and subsequently reactivating HIV-1 transcription, represents a new attractive viral latency reversal agent (LRA).

Published
2019

6. Exploratory window‐of‐opportunity trial to investigate the tumor pharmacokinetics/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer

Author

Carlos Gomez‐Roca, Caroline Even, Christophe Le Tourneau, Neus Basté, Jean‐Pierre Delord, Jerome Sarini, Sebastien Vergez, Stephane Temam, Caroline Hoffmann, Philippe Rochaix, Edith Borcoman, Bruno Gavillet, Elisabeth Rouits, Annick Ménétrey, Franck Brichory, Daniela Purcea, Gregoire Vuagniaux, and Claudio Zanna

Subjects
Therapeutics. Pharmacology, RM1-950, Public aspects of medicine, RA1-1270
Abstract

Abstract Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF‐κB signaling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre‐operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day [D]1–15 +/‐ 2); Debio 1143 (200 mg/day D1–15 +/‐ 2) plus cisplatin (40 mg/m2 D 1 and 8); cisplatin alone (40 mg/m2 D 1 and 8; EudraCT: 2014‐004655‐31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary end point; effect of Debio 1143 on cellular IAP‐1 (cIAP‐1). Levels of cIAP‐1/‐2, X‐linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs), including CD8+ T cells, programmed cell death protein 1 (PD‐1), PD‐ligand 1 (PD‐L1), and gene expression were also analyzed. Twenty‐three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n = 13), mean tumor concentrations of Debio 1143 were 18‐fold (maximum 55.2‐fold) greater than in plasma, exceeding the half‐maximal inhibitory concentration for cIAPs and XIAP by 100 to 1000‐fold, with significant engagement/degradation of cIAP‐1 (p

Published
2022
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7. Treatment of acute appendicitis in France by type of hospital: Patient profiles are different but practices and results are the same, a prospective cohort study of 1241 patients

Author

Barbois, Sandrine, Gaget, Olivier, Quesada, Jean-louis, Foote, Alison, Laverriere, Marie-Hélène, Abba, Julio, Charrière, Bérénice, Nzamushe, Jean-Robert, Pautrat, Karine, Tan, Virianne, Regimbeau, Jean-Marc, Abet, Emeric, Dubois, Joelle, Lermite, Emilie, Passot, Guillaume, Mauvais, François, Varatharajah, Sharmini, Bensignor, Thierry, Pirlet, Isabelle, Herrero, Astrid, Riboud, Romain, Blanc, Benjamin, Monneuse, Olivier, Merdrignac, Aude, Mechaoui, Hamida, Briennon, Xavier, Massalou, Damien, Dubuisson, Vincent, Moreno-Lopez, Nathan, Schwarz, Lilian, Atger, Jérôme, Vuagniaux, Aurélie, Pichot-Delahaye, Virginie, Rasata, Lala Julien, Mustafa, Samer Al, Villar, Frédéric, Allaoua, Smail, Putinier, Jean-Baptiste, Lakkis, Zaher, Bouteloup, Pierre-Yves, Malgoire, Jean-Yves, Mathonnet, Muriel, Varlet, François, Scalabre, Aurélien, Mutter, Didier, Frandon, Julien, Tidadini, Fatah, and Arvieux, Catherine

Published
2021
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8. Case Law - A Family Foundation Taxed Twice On The Same Event?

Author

Vuagniaux, Pierre-Yves

Subjects
Foundations (Endowments) -- Laws, regulations and rules -- Taxation, Tax law -- Interpretation and construction -- Cases, Inheritance tax -- Laws, regulations and rules, Income tax -- Laws, regulations and rules, Company legal issue, Government regulation, Tax law, Business, international
Abstract

Judgment summary - Administrative Chamber of the Geneva Court of Justice, judgment of 6 February 2024 (ATA/183/2024) The assets of a family foundation are subject to inheritance tax, by class [...]

Published
2024

10. Stoma-free survival after anastomotic leak following rectal cancer resection: worldwide cohort of 2470 patients

Author

Greijdanus, N, Wienholts, K, Ubels, S, Talboom, K, Hannink, G, Wolthuis, A, de Lacy, F, Lefevre, J, Solomon, M, Frasson, M, Rotholtz, N, Denost, Q, Perez, R, Konishi, T, Panis, Y, Rutegard, M, Hompes, R, Rosman, C, van Workum, F, Tanis, P, de Wilt, J, Bremers, A, Ferenschild, F, de Vriendt, S, D'Hoore, A, Bislenghi, G, Farguell, J, Lacy, A, Atienza, P, van Kessel, C, Parc, Y, Voron, T, Collard, M, Muriel, J, Cholewa, H, Mattioni, L, Frontali, A, Polle, S, Polat, F, Obihara, N, Vailati, B, Kusters, M, Tuynmann, J, Hazen, S, Gruter, A, Amano, T, Fujiwara, H, Salomon, M, Ruiz, H, Gonzalez, R, Estefania, D, Avellaneda, N, Carrie, A, Santillan, M, Pachajoa, D, Parodi, M, Gielis, M, Binder, A, Gurtler, T, Riedl, P, Badiani, S, Berney, C, Morgan, M, Hollington, P, da Silva, N, Nair, G, Ho, Y, Lamparelli, M, Kapadia, R, Kroon, H, Dudi-Venkata, N, Liu, J, Sammour, T, Flamey, N, Pattyn, P, Chaoui, A, Vansteenbrugge, L, van den Broek, N, Vanclooster, P, de Gheldere, C, Pletinckx, P, Defoort, B, Dewulf, M, Slavchev, M, Belev, N, Atanasov, B, Krastev, P, Sokolov, M, Maslyankov, S, Gribnev, P, Pavlov, V, Ivanov, T, Karamanliev, M, Filipov, E, Tonchev, P, Aigner, F, Mitteregger, M, Allmer, C, Seitinger, G, Colucci, N, Buchs, N, Ris, F, Toso, C, Gialamas, E, Vuagniaux, A, Chautems, R, Sauvain, M, Daester, S, von Flue, M, Guenin, M, Taha-Mehlitz, S, Hess, G, Martinek, L, Skrovina, M, Machackova, M, Bencurik, V, Uluk, D, Pratschke, J, Dittrich, L, Guel-Klein, S, Perez, D, Grass, J, Melling, N, Mueller, S, Iversen, L, Eriksen, J, Baatrup, G, Al-Najami, I, Bjorsum-Meyer, T, Teras, J, Teras, R, Monib, F, Ahmed, N, Alkady, E, Ali, A, Khedr, G, Abdelaal, A, Ashoush, F, Ewedah, M, Elshennawy, E, Hussein, M, Fernandez-Martinez, D, Garcia-Florez, L, Fernandez-Hevia, M, Suarez-Sanchez, A, Aretxabala, I, Docampo, I, Zabala, J, Tejedor, P, Morales Bernaldo de Quiros, J, Quiroga, I, Navarro-Sanchez, A, Darias, I, Fernandez, C, de La Cruz Cuadrado, C, Sanchez-Guillen, L, Lopez-Rodriguez-Arias, F, Soler-Silva, A, Arroyo, A, Bernal-Sprekelsen, J, Gomez-Abril, S, Gonzalvez, P, Torres, M, Sanchez, T, Antona, F, Lara, J, Montero, J, Mendoza-Moreno, F, Diez-Alonso, M, Matias-Garcia, B, Quiroga-Valcarcel, A, Colas-Ruiz, E, Tasende-Presedo, M, Fernandez-Hurtado, I, Cifuentes-Rodenas, J, Suarez, M, Losada, M, Hernandez, M, Alonso, A, Dieguez, B, Serralta, D, Quintana, R, Lopez, J, Pinto, F, Nieto-Moreno, E, Bonito, A, Santacruz, C, Marcos, E, Septiem, J, Calero-Lillo, A, Alanez-Saavedra, J, Munoz-Collado, S, Lopez-Lara, M, Martinez, M, Herrero, E, Borda, F, Villar, O, Escartin, J, Blas, J, Ferrer, R, Egea, J, Rodriguez-Infante, A, Minguez-Ruiz, G, Carreno-Villarreal, G, Pire-Abaitua, G, Dziakova, J, Rodriguez, C, Aranda, M, Huguet, J, Borda-Arrizabalaga, N, Enriquez-Navascues, J, Echaniz, G, Ansorena, Y, Estaire-Gomez, M, Martinez-Pinedo, C, Barbero-Valenzuela, A, Ruiz-Garcia, P, Kraft, M, Gomez-Jurado, M, Pellino, G, Espin-Basany, E, Cotte, E, Panel, N, Goutard, C, de Angelis, N, Lauka, L, Shaikh, S, Osborne, L, Ramsay, G, Nichita, V, Bhandari, S, Sarmah, P, Bethune, R, Pringle, H, Massey, L, Fowler, G, Hamid, H, de Simone, B, Kynaston, J, Bradley, N, Stienstra, R, Gurjar, S, Mukherjee, T, Chandio, A, Ahmed, S, Singh, B, Runau, F, Chaudhri, S, Siaw, O, Sarveswaran, J, Miu, V, Ashmore, D, Darwich, H, Singh-Ranger, D, Singh, N, Shaban, M, Gareb, F, Petropolou, T, Polydorou, A, Dattani, M, Afzal, A, Bavikatte, A, Sebastian, B, Ward, N, Mishra, A, Manatakis, D, Agalianos, C, Tasis, N, Antonopoulou, M, Karavokyros, I, Charalabopoulos, A, Schizas, D, Baili, E, Syllaios, A, Karydakis, L, Vailas, M, Balalis, D, Korkolis, D, Plastiras, A, Rompou, A, Xenaki, S, Xynos, E, Chrysos, E, Venianaki, M, Christodoulidis, G, Perivoliotis, K, Tzovaras, G, Baloyiannis, I, Ho, M, Ng, S, Mak, T, Futaba, K, Santak, G, Simlesa, D, Cosic, J, Zukanovic, G, Kelly, M, Larkin, J, Mccormick, P, Mehigan, B, Connelly, T, Neary, P, Ryan, J, Mccullough, P, Al-Juaifari, M, Hammoodi, H, Abbood, A, Calabro, M, Muratore, A, La Terra, A, Farnesi, F, Feo, C, Fabbri, N, Pesce, A, Fazzin, M, Roscio, F, Clerici, F, Lucchi, A, Vittori, L, Agostinelli, L, Ripoli, M, Sambucci, D, Porta, A, Sinibaldi, G, Crescentini, G, Larcinese, A, Picone, E, Persiani, R, Biondi, A, Pezzuto, R, Lorenzon, L, Rizzo, G, Coco, C, D'Agostino, L, Spinelli, A, Sacchi, M, Carvello, M, Foppa, C, Maroli, A, Palini, G, Garulli, G, Zanini, N, Delrio, P, Rega, D, Carbone, F, Aversano, A, Pirozzolo, G, Recordare, A, D'Alimonte, L, Vignotto, C, Corbellini, C, Sampietro, G, Lorusso, L, Manzo, C, Ghignone, F, Ugolini, G, Montroni, I, Pasini, F, Ballabio, M, Bisagni, P, Armao, F, Longhi, M, Ghazouani, O, Galleano, R, Tamini, N, Oldani, M, Nespoli, L, Picciariello, A, Altomare, D, Tomasicchio, G, Lantone, G, Catena, F, Giuffrida, M, Annicchiarico, A, Perrone, G, Grossi, U, Santoro, G, Zanus, G, Iacomino, A, Novello, S, Passuello, N, Zucchella, M, Puca, L, Degiuli, M, Reddavid, R, Scabini, S, Aprile, A, Soriero, D, Fioravanti, E, Rottoli, M, Romano, A, Tanzanu, M, Belvedere, A, Mariani, N, Ceretti, A, Opocher, E, Gallo, G, Sammarco, G, de Paola, G, Pucciarelli, S, Marchegiani, F, Spolverato, G, Buzzi, G, Di Saverio, S, Meroni, P, Parise, C, Bottazzoli, E, Lapolla, P, Brachini, G, Cirillo, B, Mingoli, A, Sica, G, Siragusa, L, Bellato, V, Cerbo, D, de Pasqual, C, de Manzoni, G, di Cosmo, M, Alrayes, B, Qandeel, M, Hani, M, Rabadi, A, el Muhtaseb, M, Abdeen, B, Karmi, F, Zilinskas, J, Latkauskas, T, Tamelis, A, Pikuniene, I, Slenfuktas, V, Poskus, T, Kryzauskas, M, Jakubauskas, M, Mikalauskas, S, Jakubauskiene, L, Hassan, S, Altrabulsi, A, Abdulwahed, E, Ghmagh, R, Deeknah, A, Alshareea, E, Elhadi, M, Abujamra, S, Msherghi, A, Tababa, O, Majbar, M, Souadka, A, Benkabbou, A, Mohsine, R, Echiguer, S, Moctezuma-Velazquez, P, Salgado-Nesme, N, Vergara-Fernandez, O, Sainz-Hernandez, J, Alvarez-Bautista, F, Zakaria, A, Zakaria, Z, Wong, M, Ismail, R, Ibrahim, A, Abdullah, N, Julaihi, R, Bhat, S, O'Grady, G, Bissett, I, Lamme, B, Musters, G, Dinaux, A, Grotenhuis, B, Steller, E, Aalbers, A, Leeuwenburgh, M, Rutten, H, Burger, J, Bloemen, J, Ketelaers, S, Waqar, U, Chawla, T, Rauf, H, Rani, P, Talsma, A, Scheurink, L, van Praagh, J, Segelman, J, Nygren, J, Anderin, K, Tiefenthal, M, de Andres, B, Beltran de Heredia, J, Vazquez, A, Gomez, T, Golshani, P, Kader, R, Mohamed, A, Westerterp, M, Marinelli, A, Niemer, Q, Doornebosch, P, Shapiro, J, Vermaas, M, de Graaf, E, van Westreenen, H, Zwakman, M, van Dalsen, A, Vles, W, Nonner, J, Toorenvliet, B, Janssen, P, Verdaasdonk, E, Amelung, F, Peeters, K, Bahadoer, R, Holman, F, Heemskerk, J, Vosbeek, N, Leijtens, J, Taverne, S, Heijnen, B, El-Massoudi, Y, de Groot-Van Veen, I, Hoff, C, Jou-Valencia, D, Consten, E, Burghgraef, T, Geitenbeek, R, Hulshof, L, Slooter, G, Reudink, M, Bouvy, N, Wildeboer, A, Verstappen, S, Pennings, A, van den Hengel, B, Wijma, A, de Haan, J, de Nes, L, Heesink, V, Karsten, T, Heidsma, C, Koemans, W, Dekker, J, van der Zijden, C, Roos, D, Demirkiran, A, van der Burg, S, Oosterling, S, Hoogteijling, T, Wiering, B, Smeeing, D, Havenga, K, Lutfi, H, Tsimogiannis, K, Skoldberg, F, Folkesson, J, den Boer, F, van Schaik, T, van Gerven, P, Sietses, C, Hol, J, Boerma, E, Creemers, D, Schultz, J, Frivold, T, Riis, R, Gregussen, H, Busund, S, Sjo, O, Gaard, M, Krohn, N, Ersryd, A, Leung, E, Sultan, H, Hajjaj, B, Alhisi, A, Khader, A, Mendes, A, Semiao, M, Faria, L, Azevedo, C, da Costa Devesa, H, Martins, S, Jarimba, A, Marques, S, Ferreira, R, Oliveira, A, Ferreira, C, Pereira, R, Surlin, V, Graure, G, Ramboiu, S, Negoi, I, Ciubotaru, C, Stoica, B, Tanase, I, Negoita, V, Florea, S, Macau, F, Vasile, M, Stefanescu, V, Dimofte, G, Lunca, S, Roata, C, Musina, A, Garmanova, T, Agapov, M, Markaryan, D, Eduard, G, Yanishev, A, Abelevich, A, Bazaev, A, Rodimov, S, Filimonov, V, Melnikov, A, Suchkov, I, Drozdov, E, Kostromitskiy, D, Sjostrom, O, Matthiessen, P, Baban, B, Gadan, S, Jadid, K, Staffan, M, Park, J, Rydbeck, D, Lydrup, M, Buchwald, P, Jutesten, H, Darlin, L, Lindqvist, E, Nilsson, K, Larsson, P, Jangmalm, S, Kosir, J, Tomazic, A, Grosek, J, Bozic, T, Zazo, A, Zazo, R, Fares, H, Ayoub, K, Niazi, A, Mansour, A, Abbas, A, Tantoura, M, Hamdan, A, Hassan, N, Hasan, B, Saad, A, Sebai, A, Haddad, A, Maghrebi, H, Kacem, M, Yalkin, O, Samsa, M, Atak, I, Balci, B, Haberal, E, Dogan, L, Gecim, I, Akyol, C, Koc, M, Sivrikoz, E, Piyadeoglu, D, Avanagh, D, Sokmen, S, Bisgin, T, Gunenc, E, Guzel, M, Leventoglu, S, Yuksel, O, Kozan, R, Gobut, H, Cengiz, F, Erdinc, K, Acar, N, Kamer, E, Ozgur, I, Aydin, O, Keskin, M, Bulut, M, Kulle, C, Kara, Y, Sibic, O, Ozata, I, Bugra, D, Balik, E, Cakir, M, Alhardan, A, Colak, E, Aybar, A, Sari, A, Atici, S, Kaya, T, Dursun, A, Calik, B, Ozkan, O, Ulgur, H, Duzgun, O, Monson, J, George, S, Woods, K, Al-Eryani, F, Albakry, R, Coetzee, E, Boutall, A, Herman, A, Warden, C, Mugla, N, Forgan, T, Mia, I, Lambrechts, A, Greijdanus N. G., Wienholts K., Ubels S., Talboom K., Hannink G., Wolthuis A., de Lacy F. B., Lefevre J. H., Solomon M., Frasson M., Rotholtz N., Denost Q., Perez R. O., Konishi T., Panis Y., Rutegard M., Hompes R., Rosman C., van Workum F., Tanis P. J., de Wilt J. H. W., Bremers A. J. A., Ferenschild F. T., de Vriendt S., D'Hoore A., Bislenghi G., Farguell J., Lacy A. M., Atienza P. G., van Kessel C. S., Parc Y., Voron T., Collard M. K., Muriel J. S., Cholewa H., Mattioni L. A., Frontali A., Polle S. W., Polat F., Obihara N. J., Vailati B. B., Kusters M., Tuynmann J. B., Hazen S. J. A., Gruter A. A. J., Amano T., Fujiwara H., Salomon M., Ruiz H., Gonzalez R., Estefania D., Avellaneda N., Carrie A., Santillan M., Pachajoa D. A. P., Parodi M., Gielis M., Binder A. -D., Gurtler T., Riedl P., Badiani S., Berney C., Morgan M., Hollington P., da Silva N., Nair G., Ho Y. M., Lamparelli M., Kapadia R., Kroon H. M., Dudi-Venkata N. N., Liu J., Sammour T., Flamey N., Pattyn P., Chaoui A., Vansteenbrugge L., van den Broek N. E. J., Vanclooster P., de Gheldere C., Pletinckx P., Defoort B., Dewulf M., Slavchev M., Belev N., Atanasov B., Krastev P., Sokolov M., Maslyankov S., Gribnev P., Pavlov V., Ivanov T., Karamanliev M., Filipov E., Tonchev P., Aigner F., Mitteregger M., Allmer C., Seitinger G., Colucci N., Buchs N., Ris F., Toso C., Gialamas E., Vuagniaux A., Chautems R., Sauvain M. -O., Daester S., von Flue M., Guenin M. -O., Taha-Mehlitz S., Hess G. F., Martinek L., Skrovina M., Machackova M., Bencurik V., Uluk D., Pratschke J., Dittrich L. S., Guel-Klein S., Perez D., Grass J. -K., Melling N., Mueller S., Iversen L. H., Eriksen J. D., Baatrup G., Al-Najami I., Bjorsum-Meyer T., Teras J., Teras R. M., Monib F. A., Ahmed N. E. A. E., Alkady E., Ali A. K., Khedr G. A. E., Abdelaal A. S., Ashoush F. M. B., Ewedah M., Elshennawy E. M., Hussein M., Fernandez-Martinez D., Garcia-Florez L. J., Fernandez-Hevia M., Suarez-Sanchez A., Aretxabala I. D. H., Docampo I. L., Zabala J. G., Tejedor P., Morales Bernaldo de Quiros J. T., Quiroga I. B., Navarro-Sanchez A., Darias I. S., Fernandez C. L., de La Cruz Cuadrado C., Sanchez-Guillen L., Lopez-Rodriguez-Arias F., Soler-Silva A., Arroyo A., Bernal-Sprekelsen J. C., Gomez-Abril S. A., Gonzalvez P., Torres M. T., Sanchez T. R., Antona F. B., Lara J. E. S., Montero J. A. A., Mendoza-Moreno F., Diez-Alonso M., Matias-Garcia B., Quiroga-Valcarcel A., Colas-Ruiz E., Tasende-Presedo M. M., Fernandez-Hurtado I., Cifuentes-Rodenas J. A., Suarez M. C., Losada M., Hernandez M., Alonso A., Dieguez B., Serralta D., Quintana R. E. M., Lopez J. M. G., Pinto F. L., Nieto-Moreno E., Bonito A. C., Santacruz C. C., Marcos E. B., Septiem J. G., Calero-Lillo A., Alanez-Saavedra J., Munoz-Collado S., Lopez-Lara M., Martinez M. L., Herrero E. F., Borda F. J. G., Villar O. G., Escartin J., Blas J. L., Ferrer R., Egea J. G., Rodriguez-Infante A., Minguez-Ruiz G., Carreno-Villarreal G., Pire-Abaitua G., Dziakova J., Rodriguez C. S. -C., Aranda M. J. P., Huguet J. M. M., Borda-Arrizabalaga N., Enriquez-Navascues J. M., Echaniz G. E., Ansorena Y. S., Estaire-Gomez M., Martinez-Pinedo C., Barbero-Valenzuela A., Ruiz-Garcia P., Kraft M., Gomez-Jurado M. J., Pellino G., Espin-Basany E., Cotte E., Panel N., Goutard C. -A., de Angelis N., Lauka L., Shaikh S., Osborne L., Ramsay G., Nichita V. -I., Bhandari S., Sarmah P., Bethune R. M., Pringle H. C. M., Massey L., Fowler G. E., Hamid H. K. S., de Simone B. D., Kynaston J., Bradley N., Stienstra R. M., Gurjar S., Mukherjee T., Chandio A., Ahmed S., Singh B., Runau F., Chaudhri S., Siaw O., Sarveswaran J., Miu V., Ashmore D., Darwich H., Singh-Ranger D., Singh N., Shaban M., Gareb F., Petropolou T., Polydorou A., Dattani M., Afzal A., Bavikatte A., Sebastian B., Ward N., Mishra A., Manatakis D., Agalianos C., Tasis N., Antonopoulou M. -I., Karavokyros I., Charalabopoulos A., Schizas D., Baili E., Syllaios A., Karydakis L., Vailas M., Balalis D., Korkolis D., Plastiras A., Rompou A., Xenaki S., Xynos E., Chrysos E., Venianaki M., Christodoulidis G., Perivoliotis K., Tzovaras G., Baloyiannis I., Ho M. -F., Ng S. S., Mak T. W. -C., Futaba K., Santak G., Simlesa D., Cosic J., Zukanovic G., Kelly M. E., Larkin J. O., McCormick P. H., Mehigan B. J., Connelly T. M., Neary P., Ryan J., McCullough P., Al-Juaifari M. A., Hammoodi H., Abbood A. H., Calabro M., Muratore A., La Terra A., Farnesi F., Feo C. V., Fabbri N., Pesce A., Fazzin M., Roscio F., Clerici F., Lucchi A., Vittori L., Agostinelli L., Ripoli M. C., Sambucci D., Porta A., Sinibaldi G., Crescentini G., Larcinese A., Picone E., Persiani R., Biondi A., Pezzuto R., Lorenzon L., Rizzo G., Coco C., D'Agostino L., Spinelli A., Sacchi M. M., Carvello M., Foppa C., Maroli A., Palini G. M., Garulli G., Zanini N., Delrio P., Rega D., Carbone F., Aversano A., Pirozzolo G., Recordare A., D'Alimonte L., Vignotto C., Corbellini C., Sampietro G. M., Lorusso L., Manzo C. A., Ghignone F., Ugolini G., Montroni I., Pasini F., Ballabio M., Bisagni P., Armao F. T., Longhi M., Ghazouani O., Galleano R., Tamini N., Oldani M., Nespoli L., Picciariello A., Altomare D. F., Tomasicchio G., Lantone G., Catena F., Giuffrida M., Annicchiarico A., Perrone G., Grossi U., Santoro G. A., Zanus G., Iacomino A., Novello S., Passuello N., Zucchella M., Puca L., deGiuli M., Reddavid R., Scabini S., Aprile A., Soriero D., Fioravanti E., Rottoli M., Romano A., Tanzanu M., Belvedere A., Mariani N. M., Ceretti A. P., Opocher E., Gallo G., Sammarco G., de Paola G., Pucciarelli S., Marchegiani F., Spolverato G., Buzzi G., Di Saverio S., Meroni P., Parise C., Bottazzoli E. I., Lapolla P., Brachini G., Cirillo B., Mingoli A., Sica G., Siragusa L., Bellato V., Cerbo D., de Pasqual C. A., de Manzoni G., di Cosmo M. A., Alrayes B. M. H., Qandeel M. W. M., Hani M. B., Rabadi A., el Muhtaseb M. S., Abdeen B., Karmi F., Zilinskas J., Latkauskas T., Tamelis A., Pikuniene I., Slenfuktas V., Poskus T., Kryzauskas M., Jakubauskas M., Mikalauskas S., Jakubauskiene L., Hassan S. Y., Altrabulsi A., Abdulwahed E., Ghmagh R., Deeknah A., Alshareea E., Elhadi M., Abujamra S., Msherghi A. A., Tababa O. W. E., Majbar M. A., Souadka A., Benkabbou A., Mohsine R., Echiguer S., Moctezuma-Velazquez P., Salgado-Nesme N., Vergara-Fernandez O., Sainz-Hernandez J. C., Alvarez-Bautista F. E., Zakaria A. D., Zakaria Z., Wong M. P. K., Ismail R., Ibrahim A. F., Abdullah N. A. N., Julaihi R., Bhat S., O'Grady G., Bissett I., Lamme B., Musters G. D., Dinaux A. M., Grotenhuis B. A., Steller E. J., Aalbers A. G. J., Leeuwenburgh M. M., Rutten H. J. T., Burger J. W. A., Bloemen J. G., Ketelaers S. H. J., Waqar U., Chawla T., Rauf H., Rani P., Talsma A. K., Scheurink L., van Praagh J. B., Segelman J., Nygren J., Anderin K., Tiefenthal M., de Andres B., Beltran de Heredia J. P., Vazquez A., Gomez T., Golshani P., Kader R., Mohamed A., Westerterp M., Marinelli A., Niemer Q., Doornebosch P. G., Shapiro J., Vermaas M., de Graaf E. J. R., van Westreenen H. L., Zwakman M., van Dalsen A. D., Vles W. J., Nonner J., Toorenvliet B. R., Janssen P. T. J., Verdaasdonk E. G. G., Amelung F. J., Peeters K. C. M. J., Bahadoer R. R., Holman F. A., Heemskerk J., Vosbeek N., Leijtens J. W. A., Taverne S. B. M., Heijnen B. H. M., El-Massoudi Y., de Groot-Van Veen I., Hoff C., Jou-Valencia D., Consten E. C. J., Burghgraef T. A., Geitenbeek R., Hulshof L. G. W. L., Slooter G. D., Reudink M., Bouvy N. D., Wildeboer A. C. L., Verstappen S., Pennings A. J., van den Hengel B., Wijma A. G., de Haan J., de Nes L. C. F., Heesink V., Karsten T., Heidsma C. M., Koemans W. J., Dekker J. -W. T., van der Zijden C. J., Roos D., Demirkiran A., van der Burg S., Oosterling S. J., Hoogteijling T. J., Wiering B., Smeeing D. P. J., Havenga K., Lutfi H., Tsimogiannis K., Skoldberg F., Folkesson J., den Boer F., van Schaik T. G., van Gerven P., Sietses C., Hol J. C., Boerma E. -J. G., Creemers D. M. J., Schultz J. K., Frivold T., Riis R., Gregussen H., Busund S., Sjo O. H., Gaard M., Krohn N., Ersryd A. L., Leung E., Sultan H., Hajjaj B. N., Alhisi A. J., Khader A. A. E., Mendes A. F. D., Semiao M., Faria L. Q., Azevedo C., da Costa Devesa H. M., Martins S. F., Jarimba A. M. R., Marques S. M. R., Ferreira R. M., Oliveira A., Ferreira C., Pereira R., Surlin V. M., Graure G. M., Ramboiu S. P. S. D., Negoi I., Ciubotaru C., Stoica B., Tanase I., Negoita V. M., Florea S., Macau F., Vasile M., Stefanescu V., Dimofte G. -M., Lunca S., Roata C. -E., Musina A. -M., Garmanova T., Agapov M. N., Markaryan D. G., Eduard G., Yanishev A., Abelevich A., Bazaev A., Rodimov S. V., Filimonov V. B., Melnikov A. A., Suchkov I. A., Drozdov E. S., Kostromitskiy D. N., Sjostrom O., Matthiessen P., Baban B., Gadan S., Jadid K. D., Staffan M., Park J. M., Rydbeck D., Lydrup M. -L., Buchwald P., Jutesten H., Darlin L., Lindqvist E., Nilsson K., Larsson P. -A., Jangmalm S., Kosir J. A., Tomazic A., Grosek J., Bozic T. K., Zazo A., Zazo R., Fares H., Ayoub K., Niazi A., Mansour A., Abbas A., Tantoura M., Hamdan A., Hassan N., Hasan B., Saad A., Sebai A., Haddad A., Maghrebi H., Kacem M., Yalkin O., Samsa M. V., Atak I., Balci B., Haberal E., Dogan L., Gecim I. E., Akyol C., Koc M. A., Sivrikoz E., Piyadeoglu D., Avanagh D. O., Sokmen S., Bisgin T., Gunenc E., Guzel M., Leventoglu S., Yuksel O., Kozan R., Gobut H., Cengiz F., Erdinc K., Acar N. C., Kamer E., Ozgur I., Aydin O., Keskin M., Bulut M. T., Kulle C. B., Kara Y., Sibic O., Ozata I. H., Bugra D., Balik E., Cakir M., Alhardan A., Colak E., Aybar A. B. C., Sari A. C., Atici S. D., Kaya T., Dursun A., Calik B., Ozkan O. F., Ulgur H. S., Duzgun O., Monson J., George S., Woods K., Al-Eryani F., Albakry R., Coetzee E., Boutall A., Herman A., Warden C., Mugla N., Forgan T., Mia I., Lambrechts A., Greijdanus, N, Wienholts, K, Ubels, S, Talboom, K, Hannink, G, Wolthuis, A, de Lacy, F, Lefevre, J, Solomon, M, Frasson, M, Rotholtz, N, Denost, Q, Perez, R, Konishi, T, Panis, Y, Rutegard, M, Hompes, R, Rosman, C, van Workum, F, Tanis, P, de Wilt, J, Bremers, A, Ferenschild, F, de Vriendt, S, D'Hoore, A, Bislenghi, G, Farguell, J, Lacy, A, Atienza, P, van Kessel, C, Parc, Y, Voron, T, Collard, M, Muriel, J, Cholewa, H, Mattioni, L, Frontali, A, Polle, S, Polat, F, Obihara, N, Vailati, B, Kusters, M, Tuynmann, J, Hazen, S, Gruter, A, Amano, T, Fujiwara, H, Salomon, M, Ruiz, H, Gonzalez, R, Estefania, D, Avellaneda, N, Carrie, A, Santillan, M, Pachajoa, D, Parodi, M, Gielis, M, Binder, A, Gurtler, T, Riedl, P, Badiani, S, Berney, C, Morgan, M, Hollington, P, da Silva, N, Nair, G, Ho, Y, Lamparelli, M, Kapadia, R, Kroon, H, Dudi-Venkata, N, Liu, J, Sammour, T, Flamey, N, Pattyn, P, Chaoui, A, Vansteenbrugge, L, van den Broek, N, Vanclooster, P, de Gheldere, C, Pletinckx, P, Defoort, B, Dewulf, M, Slavchev, M, Belev, N, Atanasov, B, Krastev, P, Sokolov, M, Maslyankov, S, Gribnev, P, Pavlov, V, Ivanov, T, Karamanliev, M, Filipov, E, Tonchev, P, Aigner, F, Mitteregger, M, Allmer, C, Seitinger, G, Colucci, N, Buchs, N, Ris, F, Toso, C, Gialamas, E, Vuagniaux, A, Chautems, R, Sauvain, M, Daester, S, von Flue, M, Guenin, M, Taha-Mehlitz, S, Hess, G, Martinek, L, Skrovina, M, Machackova, M, Bencurik, V, Uluk, D, Pratschke, J, Dittrich, L, Guel-Klein, S, Perez, D, Grass, J, Melling, N, Mueller, S, Iversen, L, Eriksen, J, Baatrup, G, Al-Najami, I, Bjorsum-Meyer, T, Teras, J, Teras, R, Monib, F, Ahmed, N, Alkady, E, Ali, A, Khedr, G, Abdelaal, A, Ashoush, F, Ewedah, M, Elshennawy, E, Hussein, M, Fernandez-Martinez, D, Garcia-Florez, L, Fernandez-Hevia, M, Suarez-Sanchez, A, Aretxabala, I, Docampo, I, Zabala, J, Tejedor, P, Morales Bernaldo de Quiros, J, Quiroga, I, Navarro-Sanchez, A, Darias, I, Fernandez, C, de La Cruz Cuadrado, C, Sanchez-Guillen, L, Lopez-Rodriguez-Arias, F, Soler-Silva, A, Arroyo, A, Bernal-Sprekelsen, J, Gomez-Abril, S, Gonzalvez, P, Torres, M, Sanchez, T, Antona, F, Lara, J, Montero, J, Mendoza-Moreno, F, Diez-Alonso, M, Matias-Garcia, B, Quiroga-Valcarcel, A, Colas-Ruiz, E, Tasende-Presedo, M, Fernandez-Hurtado, I, Cifuentes-Rodenas, J, Suarez, M, Losada, M, Hernandez, M, Alonso, A, Dieguez, B, Serralta, D, Quintana, R, Lopez, J, Pinto, F, Nieto-Moreno, E, Bonito, A, Santacruz, C, Marcos, E, Septiem, J, Calero-Lillo, A, Alanez-Saavedra, J, Munoz-Collado, S, Lopez-Lara, M, Martinez, M, Herrero, E, Borda, F, Villar, O, Escartin, J, Blas, J, Ferrer, R, Egea, J, Rodriguez-Infante, A, Minguez-Ruiz, G, Carreno-Villarreal, G, Pire-Abaitua, G, Dziakova, J, Rodriguez, C, Aranda, M, Huguet, J, Borda-Arrizabalaga, N, Enriquez-Navascues, J, Echaniz, G, Ansorena, Y, Estaire-Gomez, M, Martinez-Pinedo, C, Barbero-Valenzuela, A, Ruiz-Garcia, P, Kraft, M, Gomez-Jurado, M, Pellino, G, Espin-Basany, E, Cotte, E, Panel, N, Goutard, C, de Angelis, N, Lauka, L, Shaikh, S, Osborne, L, Ramsay, G, Nichita, V, Bhandari, S, Sarmah, P, Bethune, R, Pringle, H, Massey, L, Fowler, G, Hamid, H, de Simone, B, Kynaston, J, Bradley, N, Stienstra, R, Gurjar, S, Mukherjee, T, Chandio, A, Ahmed, S, Singh, B, Runau, F, Chaudhri, S, Siaw, O, Sarveswaran, J, Miu, V, Ashmore, D, Darwich, H, Singh-Ranger, D, Singh, N, Shaban, M, Gareb, F, Petropolou, T, Polydorou, A, Dattani, M, Afzal, A, Bavikatte, A, Sebastian, B, Ward, N, Mishra, A, Manatakis, D, Agalianos, C, Tasis, N, Antonopoulou, M, Karavokyros, I, Charalabopoulos, A, Schizas, D, Baili, E, Syllaios, A, Karydakis, L, Vailas, M, Balalis, D, Korkolis, D, Plastiras, A, Rompou, A, Xenaki, S, Xynos, E, Chrysos, E, Venianaki, M, Christodoulidis, G, Perivoliotis, K, Tzovaras, G, Baloyiannis, I, Ho, M, Ng, S, Mak, T, Futaba, K, Santak, G, Simlesa, D, Cosic, J, Zukanovic, G, Kelly, M, Larkin, J, Mccormick, P, Mehigan, B, Connelly, T, Neary, P, Ryan, J, Mccullough, P, Al-Juaifari, M, Hammoodi, H, Abbood, A, Calabro, M, Muratore, A, La Terra, A, Farnesi, F, Feo, C, Fabbri, N, Pesce, A, Fazzin, M, Roscio, F, Clerici, F, Lucchi, A, Vittori, L, Agostinelli, L, Ripoli, M, Sambucci, D, Porta, A, Sinibaldi, G, Crescentini, G, Larcinese, A, Picone, E, Persiani, R, Biondi, A, Pezzuto, R, Lorenzon, L, Rizzo, G, Coco, C, D'Agostino, L, Spinelli, A, Sacchi, M, Carvello, M, Foppa, C, Maroli, A, Palini, G, Garulli, G, Zanini, N, Delrio, P, Rega, D, Carbone, F, Aversano, A, Pirozzolo, G, Recordare, A, D'Alimonte, L, Vignotto, C, Corbellini, C, Sampietro, G, Lorusso, L, Manzo, C, Ghignone, F, Ugolini, G, Montroni, I, Pasini, F, Ballabio, M, Bisagni, P, Armao, F, Longhi, M, Ghazouani, O, Galleano, R, Tamini, N, Oldani, M, Nespoli, L, Picciariello, A, Altomare, D, Tomasicchio, G, Lantone, G, Catena, F, Giuffrida, M, Annicchiarico, A, Perrone, G, Grossi, U, Santoro, G, Zanus, G, Iacomino, A, Novello, S, Passuello, N, Zucchella, M, Puca, L, Degiuli, M, Reddavid, R, Scabini, S, Aprile, A, Soriero, D, Fioravanti, E, Rottoli, M, Romano, A, Tanzanu, M, Belvedere, A, Mariani, N, Ceretti, A, Opocher, E, Gallo, G, Sammarco, G, de Paola, G, Pucciarelli, S, Marchegiani, F, Spolverato, G, Buzzi, G, Di Saverio, S, Meroni, P, Parise, C, Bottazzoli, E, Lapolla, P, Brachini, G, Cirillo, B, Mingoli, A, Sica, G, Siragusa, L, Bellato, V, Cerbo, D, de Pasqual, C, de Manzoni, G, di Cosmo, M, Alrayes, B, Qandeel, M, Hani, M, Rabadi, A, el Muhtaseb, M, Abdeen, B, Karmi, F, Zilinskas, J, Latkauskas, T, Tamelis, A, Pikuniene, I, Slenfuktas, V, Poskus, T, Kryzauskas, M, Jakubauskas, M, Mikalauskas, S, Jakubauskiene, L, Hassan, S, Altrabulsi, A, Abdulwahed, E, Ghmagh, R, Deeknah, A, Alshareea, E, Elhadi, M, Abujamra, S, Msherghi, A, Tababa, O, Majbar, M, Souadka, A, Benkabbou, A, Mohsine, R, Echiguer, S, Moctezuma-Velazquez, P, Salgado-Nesme, N, Vergara-Fernandez, O, Sainz-Hernandez, J, Alvarez-Bautista, F, Zakaria, A, Zakaria, Z, Wong, M, Ismail, R, Ibrahim, A, Abdullah, N, Julaihi, R, Bhat, S, O'Grady, G, Bissett, I, Lamme, B, Musters, G, Dinaux, A, Grotenhuis, B, Steller, E, Aalbers, A, Leeuwenburgh, M, Rutten, H, Burger, J, Bloemen, J, Ketelaers, S, Waqar, U, Chawla, T, Rauf, H, Rani, P, Talsma, A, Scheurink, L, van Praagh, J, Segelman, J, Nygren, J, Anderin, K, Tiefenthal, M, de Andres, B, Beltran de Heredia, J, Vazquez, A, Gomez, T, Golshani, P, Kader, R, Mohamed, A, Westerterp, M, Marinelli, A, Niemer, Q, Doornebosch, P, Shapiro, J, Vermaas, M, de Graaf, E, van Westreenen, H, Zwakman, M, van Dalsen, A, Vles, W, Nonner, J, Toorenvliet, B, Janssen, P, Verdaasdonk, E, Amelung, F, Peeters, K, Bahadoer, R, Holman, F, Heemskerk, J, Vosbeek, N, Leijtens, J, Taverne, S, Heijnen, B, El-Massoudi, Y, de Groot-Van Veen, I, Hoff, C, Jou-Valencia, D, Consten, E, Burghgraef, T, Geitenbeek, R, Hulshof, L, Slooter, G, Reudink, M, Bouvy, N, Wildeboer, A, Verstappen, S, Pennings, A, van den Hengel, B, Wijma, A, de Haan, J, de Nes, L, Heesink, V, Karsten, T, Heidsma, C, Koemans, W, Dekker, J, van der Zijden, C, Roos, D, Demirkiran, A, van der Burg, S, Oosterling, S, Hoogteijling, T, Wiering, B, Smeeing, D, Havenga, K, Lutfi, H, Tsimogiannis, K, Skoldberg, F, Folkesson, J, den Boer, F, van Schaik, T, van Gerven, P, Sietses, C, Hol, J, Boerma, E, Creemers, D, Schultz, J, Frivold, T, Riis, R, Gregussen, H, Busund, S, Sjo, O, Gaard, M, Krohn, N, Ersryd, A, Leung, E, Sultan, H, Hajjaj, B, Alhisi, A, Khader, A, Mendes, A, Semiao, M, Faria, L, Azevedo, C, da Costa Devesa, H, Martins, S, Jarimba, A, Marques, S, Ferreira, R, Oliveira, A, Ferreira, C, Pereira, R, Surlin, V, Graure, G, Ramboiu, S, Negoi, I, Ciubotaru, C, Stoica, B, Tanase, I, Negoita, V, Florea, S, Macau, F, Vasile, M, Stefanescu, V, Dimofte, G, Lunca, S, Roata, C, Musina, A, Garmanova, T, Agapov, M, Markaryan, D, Eduard, G, Yanishev, A, Abelevich, A, Bazaev, A, Rodimov, S, Filimonov, V, Melnikov, A, Suchkov, I, Drozdov, E, Kostromitskiy, D, Sjostrom, O, Matthiessen, P, Baban, B, Gadan, S, Jadid, K, Staffan, M, Park, J, Rydbeck, D, Lydrup, M, Buchwald, P, Jutesten, H, Darlin, L, Lindqvist, E, Nilsson, K, Larsson, P, Jangmalm, S, Kosir, J, Tomazic, A, Grosek, J, Bozic, T, Zazo, A, Zazo, R, Fares, H, Ayoub, K, Niazi, A, Mansour, A, Abbas, A, Tantoura, M, Hamdan, A, Hassan, N, Hasan, B, Saad, A, Sebai, A, Haddad, A, Maghrebi, H, Kacem, M, Yalkin, O, Samsa, M, Atak, I, Balci, B, Haberal, E, Dogan, L, Gecim, I, Akyol, C, Koc, M, Sivrikoz, E, Piyadeoglu, D, Avanagh, D, Sokmen, S, Bisgin, T, Gunenc, E, Guzel, M, Leventoglu, S, Yuksel, O, Kozan, R, Gobut, H, Cengiz, F, Erdinc, K, Acar, N, Kamer, E, Ozgur, I, Aydin, O, Keskin, M, Bulut, M, Kulle, C, Kara, Y, Sibic, O, Ozata, I, Bugra, D, Balik, E, Cakir, M, Alhardan, A, Colak, E, Aybar, A, Sari, A, Atici, S, Kaya, T, Dursun, A, Calik, B, Ozkan, O, Ulgur, H, Duzgun, O, Monson, J, George, S, Woods, K, Al-Eryani, F, Albakry, R, Coetzee, E, Boutall, A, Herman, A, Warden, C, Mugla, N, Forgan, T, Mia, I, Lambrechts, A, Greijdanus N. G., Wienholts K., Ubels S., Talboom K., Hannink G., Wolthuis A., de Lacy F. B., Lefevre J. H., Solomon M., Frasson M., Rotholtz N., Denost Q., Perez R. O., Konishi T., Panis Y., Rutegard M., Hompes R., Rosman C., van Workum F., Tanis P. J., de Wilt J. H. W., Bremers A. J. A., Ferenschild F. T., de Vriendt S., D'Hoore A., Bislenghi G., Farguell J., Lacy A. M., Atienza P. G., van Kessel C. S., Parc Y., Voron T., Collard M. K., Muriel J. S., Cholewa H., Mattioni L. A., Frontali A., Polle S. W., Polat F., Obihara N. J., Vailati B. B., Kusters M., Tuynmann J. B., Hazen S. J. A., Gruter A. A. J., Amano T., Fujiwara H., Salomon M., Ruiz H., Gonzalez R., Estefania D., Avellaneda N., Carrie A., Santillan M., Pachajoa D. A. P., Parodi M., Gielis M., Binder A. -D., Gurtler T., Riedl P., Badiani S., Berney C., Morgan M., Hollington P., da Silva N., Nair G., Ho Y. M., Lamparelli M., Kapadia R., Kroon H. M., Dudi-Venkata N. N., Liu J., Sammour T., Flamey N., Pattyn P., Chaoui A., Vansteenbrugge L., van den Broek N. E. J., Vanclooster P., de Gheldere C., Pletinckx P., Defoort B., Dewulf M., Slavchev M., Belev N., Atanasov B., Krastev P., Sokolov M., Maslyankov S., Gribnev P., Pavlov V., Ivanov T., Karamanliev M., Filipov E., Tonchev P., Aigner F., Mitteregger M., Allmer C., Seitinger G., Colucci N., Buchs N., Ris F., Toso C., Gialamas E., Vuagniaux A., Chautems R., Sauvain M. -O., Daester S., von Flue M., Guenin M. -O., Taha-Mehlitz S., Hess G. F., Martinek L., Skrovina M., Machackova M., Bencurik V., Uluk D., Pratschke J., Dittrich L. S., Guel-Klein S., Perez D., Grass J. -K., Melling N., Mueller S., Iversen L. H., Eriksen J. D., Baatrup G., Al-Najami I., Bjorsum-Meyer T., Teras J., Teras R. M., Monib F. A., Ahmed N. E. A. E., Alkady E., Ali A. K., Khedr G. A. E., Abdelaal A. S., Ashoush F. M. B., Ewedah M., Elshennawy E. M., Hussein M., Fernandez-Martinez D., Garcia-Florez L. J., Fernandez-Hevia M., Suarez-Sanchez A., Aretxabala I. D. H., Docampo I. L., Zabala J. G., Tejedor P., Morales Bernaldo de Quiros J. T., Quiroga I. B., Navarro-Sanchez A., Darias I. S., Fernandez C. L., de La Cruz Cuadrado C., Sanchez-Guillen L., Lopez-Rodriguez-Arias F., Soler-Silva A., Arroyo A., Bernal-Sprekelsen J. C., Gomez-Abril S. A., Gonzalvez P., Torres M. T., Sanchez T. R., Antona F. B., Lara J. E. S., Montero J. A. A., Mendoza-Moreno F., Diez-Alonso M., Matias-Garcia B., Quiroga-Valcarcel A., Colas-Ruiz E., Tasende-Presedo M. M., Fernandez-Hurtado I., Cifuentes-Rodenas J. A., Suarez M. C., Losada M., Hernandez M., Alonso A., Dieguez B., Serralta D., Quintana R. E. M., Lopez J. M. G., Pinto F. L., Nieto-Moreno E., Bonito A. C., Santacruz C. C., Marcos E. B., Septiem J. G., Calero-Lillo A., Alanez-Saavedra J., Munoz-Collado S., Lopez-Lara M., Martinez M. L., Herrero E. F., Borda F. J. G., Villar O. G., Escartin J., Blas J. L., Ferrer R., Egea J. G., Rodriguez-Infante A., Minguez-Ruiz G., Carreno-Villarreal G., Pire-Abaitua G., Dziakova J., Rodriguez C. S. -C., Aranda M. J. P., Huguet J. M. M., Borda-Arrizabalaga N., Enriquez-Navascues J. M., Echaniz G. E., Ansorena Y. S., Estaire-Gomez M., Martinez-Pinedo C., Barbero-Valenzuela A., Ruiz-Garcia P., Kraft M., Gomez-Jurado M. J., Pellino G., Espin-Basany E., Cotte E., Panel N., Goutard C. -A., de Angelis N., Lauka L., Shaikh S., Osborne L., Ramsay G., Nichita V. -I., Bhandari S., Sarmah P., Bethune R. M., Pringle H. C. M., Massey L., Fowler G. E., Hamid H. K. S., de Simone B. D., Kynaston J., Bradley N., Stienstra R. M., Gurjar S., Mukherjee T., Chandio A., Ahmed S., Singh B., Runau F., Chaudhri S., Siaw O., Sarveswaran J., Miu V., Ashmore D., Darwich H., Singh-Ranger D., Singh N., Shaban M., Gareb F., Petropolou T., Polydorou A., Dattani M., Afzal A., Bavikatte A., Sebastian B., Ward N., Mishra A., Manatakis D., Agalianos C., Tasis N., Antonopoulou M. -I., Karavokyros I., Charalabopoulos A., Schizas D., Baili E., Syllaios A., Karydakis L., Vailas M., Balalis D., Korkolis D., Plastiras A., Rompou A., Xenaki S., Xynos E., Chrysos E., Venianaki M., Christodoulidis G., Perivoliotis K., Tzovaras G., Baloyiannis I., Ho M. -F., Ng S. S., Mak T. W. -C., Futaba K., Santak G., Simlesa D., Cosic J., Zukanovic G., Kelly M. E., Larkin J. O., McCormick P. H., Mehigan B. J., Connelly T. M., Neary P., Ryan J., McCullough P., Al-Juaifari M. A., Hammoodi H., Abbood A. H., Calabro M., Muratore A., La Terra A., Farnesi F., Feo C. V., Fabbri N., Pesce A., Fazzin M., Roscio F., Clerici F., Lucchi A., Vittori L., Agostinelli L., Ripoli M. C., Sambucci D., Porta A., Sinibaldi G., Crescentini G., Larcinese A., Picone E., Persiani R., Biondi A., Pezzuto R., Lorenzon L., Rizzo G., Coco C., D'Agostino L., Spinelli A., Sacchi M. M., Carvello M., Foppa C., Maroli A., Palini G. M., Garulli G., Zanini N., Delrio P., Rega D., Carbone F., Aversano A., Pirozzolo G., Recordare A., D'Alimonte L., Vignotto C., Corbellini C., Sampietro G. M., Lorusso L., Manzo C. A., Ghignone F., Ugolini G., Montroni I., Pasini F., Ballabio M., Bisagni P., Armao F. T., Longhi M., Ghazouani O., Galleano R., Tamini N., Oldani M., Nespoli L., Picciariello A., Altomare D. F., Tomasicchio G., Lantone G., Catena F., Giuffrida M., Annicchiarico A., Perrone G., Grossi U., Santoro G. A., Zanus G., Iacomino A., Novello S., Passuello N., Zucchella M., Puca L., deGiuli M., Reddavid R., Scabini S., Aprile A., Soriero D., Fioravanti E., Rottoli M., Romano A., Tanzanu M., Belvedere A., Mariani N. M., Ceretti A. P., Opocher E., Gallo G., Sammarco G., de Paola G., Pucciarelli S., Marchegiani F., Spolverato G., Buzzi G., Di Saverio S., Meroni P., Parise C., Bottazzoli E. I., Lapolla P., Brachini G., Cirillo B., Mingoli A., Sica G., Siragusa L., Bellato V., Cerbo D., de Pasqual C. A., de Manzoni G., di Cosmo M. A., Alrayes B. M. H., Qandeel M. W. M., Hani M. B., Rabadi A., el Muhtaseb M. S., Abdeen B., Karmi F., Zilinskas J., Latkauskas T., Tamelis A., Pikuniene I., Slenfuktas V., Poskus T., Kryzauskas M., Jakubauskas M., Mikalauskas S., Jakubauskiene L., Hassan S. Y., Altrabulsi A., Abdulwahed E., Ghmagh R., Deeknah A., Alshareea E., Elhadi M., Abujamra S., Msherghi A. A., Tababa O. W. E., Majbar M. A., Souadka A., Benkabbou A., Mohsine R., Echiguer S., Moctezuma-Velazquez P., Salgado-Nesme N., Vergara-Fernandez O., Sainz-Hernandez J. C., Alvarez-Bautista F. E., Zakaria A. D., Zakaria Z., Wong M. P. K., Ismail R., Ibrahim A. F., Abdullah N. A. N., Julaihi R., Bhat S., O'Grady G., Bissett I., Lamme B., Musters G. D., Dinaux A. M., Grotenhuis B. A., Steller E. J., Aalbers A. G. J., Leeuwenburgh M. M., Rutten H. J. T., Burger J. W. A., Bloemen J. G., Ketelaers S. H. J., Waqar U., Chawla T., Rauf H., Rani P., Talsma A. K., Scheurink L., van Praagh J. B., Segelman J., Nygren J., Anderin K., Tiefenthal M., de Andres B., Beltran de Heredia J. P., Vazquez A., Gomez T., Golshani P., Kader R., Mohamed A., Westerterp M., Marinelli A., Niemer Q., Doornebosch P. G., Shapiro J., Vermaas M., de Graaf E. J. R., van Westreenen H. L., Zwakman M., van Dalsen A. D., Vles W. J., Nonner J., Toorenvliet B. R., Janssen P. T. J., Verdaasdonk E. G. G., Amelung F. J., Peeters K. C. M. J., Bahadoer R. R., Holman F. A., Heemskerk J., Vosbeek N., Leijtens J. W. A., Taverne S. B. M., Heijnen B. H. M., El-Massoudi Y., de Groot-Van Veen I., Hoff C., Jou-Valencia D., Consten E. C. J., Burghgraef T. A., Geitenbeek R., Hulshof L. G. W. L., Slooter G. D., Reudink M., Bouvy N. D., Wildeboer A. C. L., Verstappen S., Pennings A. J., van den Hengel B., Wijma A. G., de Haan J., de Nes L. C. F., Heesink V., Karsten T., Heidsma C. M., Koemans W. J., Dekker J. -W. T., van der Zijden C. J., Roos D., Demirkiran A., van der Burg S., Oosterling S. J., Hoogteijling T. J., Wiering B., Smeeing D. P. J., Havenga K., Lutfi H., Tsimogiannis K., Skoldberg F., Folkesson J., den Boer F., van Schaik T. G., van Gerven P., Sietses C., Hol J. C., Boerma E. -J. G., Creemers D. M. J., Schultz J. K., Frivold T., Riis R., Gregussen H., Busund S., Sjo O. H., Gaard M., Krohn N., Ersryd A. L., Leung E., Sultan H., Hajjaj B. N., Alhisi A. J., Khader A. A. E., Mendes A. F. D., Semiao M., Faria L. Q., Azevedo C., da Costa Devesa H. M., Martins S. F., Jarimba A. M. R., Marques S. M. R., Ferreira R. M., Oliveira A., Ferreira C., Pereira R., Surlin V. M., Graure G. M., Ramboiu S. P. S. D., Negoi I., Ciubotaru C., Stoica B., Tanase I., Negoita V. M., Florea S., Macau F., Vasile M., Stefanescu V., Dimofte G. -M., Lunca S., Roata C. -E., Musina A. -M., Garmanova T., Agapov M. N., Markaryan D. G., Eduard G., Yanishev A., Abelevich A., Bazaev A., Rodimov S. V., Filimonov V. B., Melnikov A. A., Suchkov I. A., Drozdov E. S., Kostromitskiy D. N., Sjostrom O., Matthiessen P., Baban B., Gadan S., Jadid K. D., Staffan M., Park J. M., Rydbeck D., Lydrup M. -L., Buchwald P., Jutesten H., Darlin L., Lindqvist E., Nilsson K., Larsson P. -A., Jangmalm S., Kosir J. A., Tomazic A., Grosek J., Bozic T. K., Zazo A., Zazo R., Fares H., Ayoub K., Niazi A., Mansour A., Abbas A., Tantoura M., Hamdan A., Hassan N., Hasan B., Saad A., Sebai A., Haddad A., Maghrebi H., Kacem M., Yalkin O., Samsa M. V., Atak I., Balci B., Haberal E., Dogan L., Gecim I. E., Akyol C., Koc M. A., Sivrikoz E., Piyadeoglu D., Avanagh D. O., Sokmen S., Bisgin T., Gunenc E., Guzel M., Leventoglu S., Yuksel O., Kozan R., Gobut H., Cengiz F., Erdinc K., Acar N. C., Kamer E., Ozgur I., Aydin O., Keskin M., Bulut M. T., Kulle C. B., Kara Y., Sibic O., Ozata I. H., Bugra D., Balik E., Cakir M., Alhardan A., Colak E., Aybar A. B. C., Sari A. C., Atici S. D., Kaya T., Dursun A., Calik B., Ozkan O. F., Ulgur H. S., Duzgun O., Monson J., George S., Woods K., Al-Eryani F., Albakry R., Coetzee E., Boutall A., Herman A., Warden C., Mugla N., Forgan T., Mia I., and Lambrechts A.

Abstract

Background: The optimal treatment of anastomotic leak after rectal cancer resection is unclear. This worldwide cohort study aimed to provide an overview of four treatment strategies applied. Methods: Patients from 216 centres and 45 countries with anastomotic leak after rectal cancer resection between 2014 and 2018 were included. Treatment was categorized as salvage surgery, faecal diversion with passive or active (vacuum) drainage, and no primary/secondary faecal diversion. The primary outcome was 1-year stoma-free survival. In addition, passive and active drainage were compared using propensity score matching (2: 1). Results: Of 2470 evaluable patients, 388 (16.0 per cent) underwent salvage surgery, 1524 (62.0 per cent) passive drainage, 278 (11.0 per cent) active drainage, and 280 (11.0 per cent) had no faecal diversion. One-year stoma-free survival rates were 13.7, 48.3, 48.2, and 65.4 per cent respectively. Propensity score matching resulted in 556 patients with passive and 278 with active drainage. There was no statistically significant difference between these groups in 1-year stoma-free survival (OR 0.95, 95 per cent c.i. 0.66 to 1.33), with a risk difference of -1.1 (95 per cent c.i. -9.0 to 7.0) per cent. After active drainage, more patients required secondary salvage surgery (OR 2.32, 1.49 to 3.59), prolonged hospital admission (an additional 6 (95 per cent c.i. 2 to 10) days), and ICU admission (OR 1.41, 1.02 to 1.94). Mean duration of leak healing did not differ significantly (an additional 12 (-28 to 52) days). Conclusion: Primary salvage surgery or omission of faecal diversion likely correspond to the most severe and least severe leaks respectively. In patients with diverted leaks, stoma-free survival did not differ statistically between passive and active drainage, although the increased risk of secondary salvage surgery and ICU admission suggests residual confounding.

Published
2023

12. The inhibitor of apoptosis proteins antagonist Debio 1143 promotes the PD-1 blockade-mediated HIV load reduction in blood and tissues of humanized mice.

Author

Michael Bobardt, Joseph Kuo, Udayan Chatterji, Norbert Wiedemann, Gregoire Vuagniaux, and Philippe Gallay

Subjects
Medicine, Science
Abstract

The immune checkpoint programmed cell death protein 1 (PD-1) plays a major role in T cell exhaustion in cancer and chronic HIV infection. The inhibitor of apoptosis protein antagonist Debio 1143 (D1143) enhances tumor cell death and synergizes with anti-PD-1 agents to promote tumor immunity and displayed HIV latency reversal activity in vitro. We asked in this study whether D1143 would stimulate the potency of an anti-human PD-1 monoclonal antibody (mAb) to reduce HIV loads in humanized mice. Anti-PD-1 mAb treatment decreased PD-1+ CD8+ cell population by 32.3% after interruption of four weeks treatment, and D1143 co-treatment further reduced it from 32.3 to 73%. Anti-PD-1 mAb administration reduced HIV load in blood by 94%, and addition of D1143 further enhanced this reduction from 94 to 97%. D1143 also more profoundly promoted with the anti-PD-1-mediated reduction of HIV loads in all tissues analyzed including spleen (71 to 96.4%), lymph nodes (64.3 to 80%), liver (64.2 to 94.4), lung (64.3 to 80.1%) and thymic organoid (78.2 to 98.2%), achieving a >5 log reduction of HIV loads in CD4+ cells isolated from tissues 2 weeks after drug treatment interruption. Ex vivo anti-CD3/CD28 stimulation increased the ability to activate exhausted CD8+ T cells in infected mice having received in vivo anti-PD-1 treatment by 7.9-fold (5 to 39.6%), and an additional increase by 1.7-fold upon D1143 co-treatment (39.6 to 67.3%). These findings demonstrate for the first time that an inhibitor of apoptosis protein antagonist enhances in a statistically manner the effects of an immune check point inhibitor on antiviral immunity and on HIV load reduction in tissues of humanized mice, suggesting that the combination of two distinct classes of immunomodulatory agents constitutes a promising anti-HIV immunotherapeutic approach.

Published
2020
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19. Supplementary Data from Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Author

Le Tourneau, Christophe, primary, Tao, Yungan, primary, Gomez-Roca, Carlos, primary, Cristina, Valerie, primary, Borcoman, Edith, primary, Deutsch, Eric, primary, Bahleda, Rastislav, primary, Calugaru, Valentin, primary, Modesto, Anouchka, primary, Rouits, Elisabeth, primary, Gollmer, Kathrin, primary, Vuagniaux, Gregoire, primary, Crompton, Philippa, primary, Zanna, Claudio, primary, Szyldergemajn, Sergio, primary, Delord, Jean-Pierre, primary, and Bourhis, Jean, primary

Published
2023
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21. Data from Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Author

Jean Bourhis, Jean-Pierre Delord, Sergio Szyldergemajn, Claudio Zanna, Philippa Crompton, Gregoire Vuagniaux, Kathrin Gollmer, Elisabeth Rouits, Anouchka Modesto, Valentin Calugaru, Rastislav Bahleda, Eric Deutsch, Edith Borcoman, Valerie Cristina, Carlos Gomez-Roca, Yungan Tao, and Christophe Le Tourneau

Abstract

Purpose:Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.Patients and Methods:Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.Results:Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3–4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.Conclusions:The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.

Published
2023
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22. Supplementary Data - Figure 1 from SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Author

Bo Lu, Zhiyong Yuan, Grégoire Vuagniaux, Norbert Wiedemann, Neal S. McCall, and Zhen Tao

Abstract

Dendritic cell infiltration is increased by combination therapy with ART and Debio 1143. Tumors harvested 12 days after ART were analyzed for CD45+CD11b+Cd11c+CD86+ dendritic cells by flow cytometry. Statistical differences were assessed using the unpaired student t-test. P-values are indicated as follows: *p

Published
2023
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23. Supplementary Data from Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Author

Jean Bourhis, Jean-Pierre Delord, Sergio Szyldergemajn, Claudio Zanna, Philippa Crompton, Gregoire Vuagniaux, Kathrin Gollmer, Elisabeth Rouits, Anouchka Modesto, Valentin Calugaru, Rastislav Bahleda, Eric Deutsch, Edith Borcoman, Valerie Cristina, Carlos Gomez-Roca, Yungan Tao, and Christophe Le Tourneau

Abstract

Supplementary Methods (DLT & efficay) and Tables S1 (Grade 3-4 AEs in {greater than or equal to}2 patients), S2 (late onset toxicity), S3 (PK parameters)

Published
2023
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24. Supplementary Data - Figure 4 from SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Author

Bo Lu, Zhiyong Yuan, Grégoire Vuagniaux, Norbert Wiedemann, Neal S. McCall, and Zhen Tao

Abstract

CD8+ T cells are required for the efficacy of Debio 1143/ART combination therapy in an LLC mouse model without OVA expression. The CD8 depletion experiment (Figure 4A) was repeated using LLC cells, rather than LLC-OVA cells (n=12 mice per group). LLC tumors were again allowed to grow in mice. On Day 9, mice were treated with anti-CD8 antibody, IgG (vehicle control), ART (30Gy), Debio 1143, or a combination of the three as shown (n=12 per group). Statistical differences were assessed using the unpaired student t-test. P-values are indicated as follows: *p

Published
2023
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25. Data from SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Author

Bo Lu, Zhiyong Yuan, Grégoire Vuagniaux, Norbert Wiedemann, Neal S. McCall, and Zhen Tao

Abstract

Purpose:Adaptive antitumor immunity following ablative radiotherapy (ART) is attenuated by host myeloid-derived suppressor cell (MDSC), tumor-associated macrophage (TAM), and regulatory T-cell (Treg) infiltrates. We hypothesized treatment with ART and a secondary mitochondrial-derived activators of caspase (SMAC) mimetic could reverse the immunosuppressive lung cancer microenvironment to favor adaptive immunity.Experimental Design:To evaluate for synergy between ART and the SMAC mimetic Debio 1143 and the dependence upon CD8+ T cells and TNFα, we used LLC-OVA syngeneic mouse model of lung cancer and treated them with Debio 1143 and/or ART (30 Gy) with or without anti-CD8, anti-TNFα, or anti-IFNγ antibodies. Tumor-infiltrating OVA-specific CD8+ T cells, Tc1 effector cells, MDSCs, TAMs, and Tregs, were quantified by flow cytometry. Tc1-promoting cytokines TNFα, IFNγ, and IL1β and the immunosuppressive IL10 and Arg-1 within LLC-OVA tumor tissue or mouse serum were measured by RT-PCR and ELISA.Results:ART delayed tumor growth, and the addition of Debio 1143 greatly enhanced its efficacy, which included several complete responses. These complete responders rejected an LLC-OVA tumor rechallenge. ART and Debio 1143 synergistically induced a tumor-specific, Tc1 cellular and cytokine response while eliminating immunosuppressive cells and cytokines from the tumor microenvironment. Depletion of CD8+ cells, TNFα, and IFNγ with blocking antibody abrogated synergy between ART and Debio 1143 and partially restored tumor-infiltrating MDSCs.Conclusions:Debio 1143 augments the tumor-specific adaptive immunity induced by ART, while reversing host immunosuppressive cell infiltrates in the tumor microenvironment in a TNFα, IFNγ, and CD8+ T-cell–dependent manner. This provides a novel strategy to enhance the immunogenicity of ART.

Published
2023
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26. Supplementary Data - Figure 2 from SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Author

Bo Lu, Zhiyong Yuan, Grégoire Vuagniaux, Norbert Wiedemann, Neal S. McCall, and Zhen Tao

Abstract

Analysis of tumor tissues demonstrates effective CD8 depletion. Tumors harvested from mice treated with anti-CD8 antibody (right) in Figure 4 were analyzed for CD8 by flow cytometry with tumors treated with ART alone (left) shown for reference. Tumors were harvested at the same time point as other flow cytometry experiments, day 12 after ART.

Published
2023
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27. Supplementary Data - Figure 3 from SMAC Mimetic Debio 1143 and Ablative Radiation Therapy Synergize to Enhance Antitumor Immunity against Lung Cancer

Author

Bo Lu, Zhiyong Yuan, Grégoire Vuagniaux, Norbert Wiedemann, Neal S. McCall, and Zhen Tao

Abstract

Intrinsic Sensitivity to Debio 1143, ionizing radiation, and their combination. Cell viability was measured using the CellTiter 96® Aqueous Non-Radioactive Cell Proliferation Assay kit (Promega, Madison, WI, USA) in the presence of varying concentrations of Debio 1143. Cell lines were cultured in DMEM (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum (Invitrogen) and 1% penicillin/streptomycin (Invitrogen). 3000 cells/well were seeded into 96-well plates in triplicate. MTT assay was performed at 72 hours after treatment. At 37 {degree sign}C in humidified 5% CO2 plates were read at the absorbance of 490-nm on a microplate reader (SpectraMax M5, Phoenix, AZ). Relative cell viability of an individual sample was calculated by normalizing their absorbance to that of the corresponding control. (B) For the clonogenic assays, LLC-OVA cells were seeded into 35-mm dishes and then treated with or without Debio 1143 (10 µmol/L) and/or radiation (B) or ART (C), as indicated, in complete media for 10 days. Cell clusters containing at least 50 cells were regarded as one colony. The remaining cells were fixed with methanol (1%) and formaldehyde (1%), stained with 0.5% crystal violet, and photographed using a digital scanner. (B) At lower doses of radiation, the linear quadratic model was used to estimate survival fraction. (C) For the clonogenic assay of ablative radiation, relative colony percent formation was calculated in comparison to the plating efficiency of the 0Gy group. Statistical differences were assessed using the unpaired student t-test. P-values are indicated as follows: *p

Published
2023
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28. The inhibitor apoptosis protein antagonist Debio 1143 Is an attractive HIV-1 latency reversal candidate.

Author

Michael Bobardt, Joseph Kuo, Udayan Chatterji, Sumit Chanda, Susan J Little, Norbert Wiedemann, Gregoire Vuagniaux, and Philippe A Gallay

Subjects
Medicine, Science
Abstract

Antiretroviral therapy (ART) suppresses HIV replication, but does not cure the infection because replication-competent virus persists within latently infected CD4+ T cells throughout years of therapy. These reservoirs contain integrated HIV-1 genomes and can resupply active virus. Thus, the development of strategies to eliminate the reservoir of latently infected cells is a research priority of global significance. In this study, we tested efficacy of a new inhibitor of apoptosis protein antagonist (IAPa) called Debio 1143 at reversing HIV latency and investigated its mechanisms of action. Debio 1143 activates HIV transcription via NF-kB signaling by degrading the ubiquitin ligase baculoviral IAP repeat-containing 2 (BIRC2), a repressor of the non-canonical NF-kB pathway. Debio 1143-induced BIRC2 degradation results in the accumulation of NF-κB-inducing kinase (NIK) and proteolytic cleavage of p100 into p52, leading to nuclear translocation of p52 and RELB. Debio 1143 greatly enhances the binding of RELB to the HIV-1 LTR. These data indicate that Debio 1143 activates the non-canonical NF-kB signaling pathway by promoting the binding of RELB:p52 complexes to the HIV-1 LTR, resulting in the activation of the LTR-dependent HIV-1 transcription. Importantly, Debio 1143 reverses viral latency in HIV-1 latent T cell lines. Using knockdown (siRNA BIRC2), knockout (CRIPSR NIK) and proteasome machinery neutralization (MG132) approaches, we found that Debio 1143-mediated HIV latency reversal is BIRC2 degradation- and NIK stabilization-dependent. Debio 1143 also reverses HIV-1 latency in resting CD4+ T cells derived from ART-treated patients or HIV-1-infected humanized mice under ART. Interestingly, daily oral administration of Debio 1143 in cancer patients at well-tolerated doses elicited BIRC2 target engagement in PBMCs and induced a moderate increase in cytokines and chemokines mechanistically related to NF-kB signaling. In conclusion, we provide strong evidences that the IAPa Debio 1143, by initially activating the non-canonical NF-kB signaling and subsequently reactivating HIV-1 transcription, represents a new attractive viral latency reversal agent (LRA).

Published
2019
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29. Exploratory window‐of‐opportunity trial to investigate the tumor pharmacokinetics/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer

Author

Edith Borcoman, Christophe Le Tourneau, Grégoire Vuagniaux, Sébastien Vergez, Jérôme Sarini, Neus Baste, Philippe Rochaix, Franck Brichory, Annick Menetrey, Stéphane Temam, Claudio Zanna, Elisabeth Rouits, Carlos Gomez-Roca, Jean-Pierre Delord, Daniela Purcea, Caroline Hoffmann, Caroline Even, and Bruno Gavillet

Subjects
030213 general clinical medicine, medicine.medical_treatment, RM1-950, Inhibitor of apoptosis, 030226 pharmacology & pharmacy, General Biochemistry, Genetics and Molecular Biology, Inhibitor of Apoptosis Proteins, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Tumor Microenvironment, Humans, General Pharmacology, Toxicology and Pharmaceutics, Cisplatin, Tumor microenvironment, Clinical Trials as Topic, Tumor-infiltrating lymphocytes, business.industry, Squamous Cell Carcinoma of Head and Neck, General Neuroscience, Brief Report, Research, General Medicine, Immunotherapy, XIAP, Apoptosis, Pharmacogenetics, Cancer research, Brief Reports, Therapeutics. Pharmacology, Public aspects of medicine, RA1-1270, business, medicine.drug
Abstract

Inhibitor of apoptosis proteins (IAPs) regulate apoptosis and modulate NF‐κB signaling thereby driving expression of genes involved in immune/inflammatory responses. The orally available IAP antagonist Debio 1143 has potential to enhance tumor response to chemoradiotherapy and/or immunotherapy. Patients with pre‐operative squamous cell carcinomas of the head and neck (SCCHN) received: Debio 1143 monotherapy (200 mg/day [D]1–15 +/‐ 2); Debio 1143 (200 mg/day D1–15 +/‐ 2) plus cisplatin (40 mg/m2 D 1 and 8); cisplatin alone (40 mg/m2 D 1 and 8; EudraCT: 2014‐004655‐31). Pharmacokinetic/pharmacodynamic effects were assessed in plasma and resected tumors. Primary end point; effect of Debio 1143 on cellular IAP‐1 (cIAP‐1). Levels of cIAP‐1/‐2, X‐linked inhibitor of apoptosis protein (XIAP), tumor infiltrating lymphocytes (TILs), including CD8+ T cells, programmed cell death protein 1 (PD‐1), PD‐ligand 1 (PD‐L1), and gene expression were also analyzed. Twenty‐three of 26 patients completed treatment. In the Debio 1143 monotherapy cohort (n = 13), mean tumor concentrations of Debio 1143 were 18‐fold (maximum 55.2‐fold) greater than in plasma, exceeding the half‐maximal inhibitory concentration for cIAPs and XIAP by 100 to 1000‐fold, with significant engagement/degradation of cIAP‐1 (p

Published
2022

34. Correlation of Naturally Occurring HIV-1 Resistance to DEB025 with Capsid Amino Acid Polymorphisms

Author

Brigitte Rosenwirth, Jean-Maurice Dumont, Grégoire Vuagniaux, Michael D. Bobardt, Philippe A. Gallay, and Roger G. Ptak

Subjects
DEB025, alisporivir, cyclophilin inhibitors, cyclosporines, HIV/retroviruses, HIV capsid, natural resistance, Microbiology, QR1-502
Abstract

DEB025 (alisporivir) is a synthetic cyclosporine with inhibitory activity against human immunodeficiency virus type-1 (HIV-1) and hepatitis C virus (HCV). It binds to cyclophilin A (CypA) and blocks essential functions of CypA in the viral replication cycles of both viruses. DEB025 inhibits clinical HIV-1 isolates in vitro and decreases HIV-1 virus load in the majority of patients. HIV-1 isolates being naturally resistant to DEB025 have been detected in vitro and in nonresponder patients. By sequence analysis of their capsid protein (CA) region, two amino acid polymorphisms that correlated with DEB025 resistance were identified: H87Q and I91N, both located in the CypA-binding loop of the CA protein of HIV-1. The H87Q change was by far more abundant than I91N. Additional polymorphisms in the CypA-binding loop (positions 86, 91 and 96), as well as in the N-terminal loop of CA were detected in resistant isolates and are assumed to contribute to the degree of resistance. These amino acid changes may modulate the conformation of the CypA-binding loop of CA in such a way that binding and/or isomerase function of CypA are no longer necessary for virus replication. The resistant HIV-1 isolates thus are CypA-independent.

Published
2013
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35. Evaluation of the microbiota-sparing properties of the anti-staphylococcal antibiotic afabicin.

Author

Nowakowska, J, Cameron, D R, Martino, A De, Kühn, J, Fresne-Languille, S Le, Leuillet, S, Amouzou, Y, Wittke, F, Carton, T, Vacon, F Le, Chaves, R L, Nicolas-Metral, V, and Vuagniaux, G

Subjects
GUT microbiome, HUMAN microbiota, ORAL drug administration, LINEZOLID, ANTIBIOTICS, MOXIFLOXACIN
Abstract

Background Antibiotic use is associated with collateral damage to the healthy microbiota. Afabicin is a first-in-class prodrug inhibitor of the FabI enzyme that, when converted to the pharmacologically active agent afabicin desphosphono, demonstrates a staphylococcal-specific spectrum of activity. An expected benefit of highly targeted antibiotics such as afabicin is microbiome preservation. Objectives To compare the effects of oral treatment with afabicin and standard-of-care antibiotics upon the murine gut microbiota, and to assess the effects of oral afabicin treatment on the human gut microbiota. Methods Gut microbiota effects of a 10 day oral course of afabicin treatment were monitored in mice and compared with clindamycin, linezolid and moxifloxacin at human-equivalent dose levels using 16S rDNA sequencing. Further, the gut microbiota of healthy volunteers was longitudinally assessed across 20 days of oral treatment with afabicin 240 mg twice daily. Results Afabicin treatment did not significantly alter gut microbiota diversity (Shannon H index) or richness (rarefied Chao1) in mice. Only limited changes to taxonomic abundances were observed in afabicin-treated animals. In contrast, clindamycin, linezolid and moxifloxacin each caused extensive dysbiosis in the murine model. In humans, afabicin treatment was not associated with alterations in Shannon H or rarefied Chao1 indices, nor relative taxonomic abundances, supporting the findings from the animal model. Conclusions Oral treatment with afabicin is associated with preservation of the gut microbiota in mice and healthy subjects. [ABSTRACT FROM AUTHOR]

Published
2023
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43. Exploratory window‐of‐opportunity trial to investigate the tumor pharmacokinetics/pharmacodynamics of the IAP antagonist Debio 1143 in patients with head and neck cancer

Author

Gomez‐Roca, Carlos, primary, Even, Caroline, additional, Le Tourneau, Christophe, additional, Basté, Neus, additional, Delord, Jean‐Pierre, additional, Sarini, Jerome, additional, Vergez, Sebastien, additional, Temam, Stephane, additional, Hoffmann, Caroline, additional, Rochaix, Philippe, additional, Borcoman, Edith, additional, Gavillet, Bruno, additional, Rouits, Elisabeth, additional, Ménétrey, Annick, additional, Brichory, Franck, additional, Purcea, Daniela, additional, Vuagniaux, Gregoire, additional, and Zanna, Claudio, additional

Published
2021
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44. Abstract 3443: The IAP antagonist xevinapant, in combination with high-dose cisplatin chemoradiotherapy, induces NF-kB and apoptotic pathway biomarkers in patients with high-risk locally advanced squamous cell carcinoma of the head and neck

Author

Luke Piggott, Bruno Gavillet, Franck Brichory, Kathrin Gollmer, Florilene Bouisset, and Gregoire Vuagniaux

Subjects
Cancer Research, Oncology
Abstract

Introduction: Inhibitor of Apoptosis Proteins (IAPs) regulate apoptosis and modulate NF-kB signaling, which in turn drives the expression of genes involved in immune and inflammatory responses. Xevinapant (XVT) (a.k.a Debio 1143) is an orally available IAP antagonist shown to enhance tumor response to radiation through the proapoptotic cytokine TNFα and caspase activation. Results from a double-blind, multicenter, randomized, phase II trial in patients with high-risk locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) revealed significant improvement in overall survival (OS), progression free survival (PFS) and duration of response with XVT in combination with high-dose cisplatin chemoradiotherapy (CRT) vs CRT alone (NCT02022098). We analyzed XVT pharmacodynamic (PD) biomarker time-concentration profiles and explored the association of PD changes over time with clinical efficacy and safety parameters. Methods: Three serum PD biomarkers were measured during cycle 1: caspase-cleaved cytokeratin 18 fragment (CKM30), a biomarker of epithelial apoptosis, MCP1 and TNFα, both NF-kB target genes. Time course changes in PD biomarker exposure, measured by their Area Under the Curve (AUC), were tested for association with clinical efficacy and safety endpoints, by linear, logistic, and Cox Proportional Hazard models. Clinical response parameters included locoregional control (LRC) at 18 months from end of treatment (EOT), PFS, duration of LRC, time to distant relapse (TTDR), OS and complete response (CR) 6 months after EOT. Results: The biomarker analysis set was composed of all patients with baseline PD assessments and at least one post-baseline measurement and included 35 and 40 patients in the XVT and placebo (PBO) arms, respectively. All three serum PD biomarkers increased upon administration of CRT + XVT during cycle 1. The increase in CKM30 and MCP1 levels was significantly higher in the CRT + XVT arm vs the CRT + PBO arm, as tested by linear mixed effect models (CKM30: p = 0.0167; MCP1: p = 0.0135). Interestingly, CKM30 AUC appeared to be correlated with response in CRT + XVT but not CRT + PBO (based on LRC at month 18 or CR at month 6). No associations between any of the three biomarkers were observed with the safety endpoints explored. Conclusions: Xevinapant has demonstrated promising activity in combination with CRT in LA-SCCHN. The outcome of the exploratory PD analyses indicates that XVT modulates NF-kB signaling, leading to serum increases in MCP1 and TNFα while further augmenting CRT-induced apoptotic marker CKM30. Our findings further characterize the mechanism of action of XVT and how it may ultimately result in enhanced clinical responses to CRT. Citation Format: Luke Piggott, Bruno Gavillet, Franck Brichory, Kathrin Gollmer, Florilene Bouisset, Gregoire Vuagniaux. The IAP antagonist xevinapant, in combination with high-dose cisplatin chemoradiotherapy, induces NF-kB and apoptotic pathway biomarkers in patients with high-risk locally advanced squamous cell carcinoma of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3443.

Published
2022
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45. Abstract 2303: The WEE1 inhibitor Debio 0123 enhances the efficacy of standard of care DNA damaging agents in lung cancer models

Author

Luke Piggott, Anne Vaslin-Chessex, Noemie Luong, Benjamin Tschumi, and Gregoire Vuagniaux

Subjects
Cancer Research, Oncology
Abstract

Introduction: The WEE1 tyrosine kinase is activated upon DNA damage and regulates the G2-M and S phase cell cycle checkpoints. Inhibition of WEE1, in conjunction with genetic alterations and/or addition of a DNA damaging agent, results in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treating cancer. Debio 0123 is a WEE1 specific inhibitor previously shown to sensitize cancer cells to DNA damaging agents which is currently being assessed in combination with carboplatin in patients with advanced solid malignancies. Small cell lung cancer (SCLC) is an aggressive disease with poor clinical outcomes that carries a high mutational burden and genomic instability. Here we investigated the ability of Debio 0123 to enhance SCLC response to standard of care (SOC) DNA damaging agents carboplatin and etoposide in vitro and in vivo. Methods: SCLC cell lines were treated with Debio 0123 alone or in combination with etoposide or carboplatin in vitro and apoptosis assessed by flow cytometry. In vivo SCLC patient derived- or cell line derived-xenograft (PDX or CDX, respectively) models were treated with Debio 0123 orally in combination with either carboplatin or etoposide alone or as a triple combination. Tumor growth inhibition was assessed over 3 cycles of treatment and tolerability of the combinations evaluated by monitoring body weight changes. Results: Debio 0123 synergized with carboplatin and etoposide in vitro leading to a significant increase in the induction of apoptosis. Additionally, Debio 0123 significantly improved the tumor growth inhibitory effect of etoposide and carboplatin in both PDX and CDX models of SCLC in vivo. Triple combination of carboplatin, etoposide and Debio 0123 was well tolerated at therapeutically relevant dosing and resulted in significantly improved tumor response when compared to carboplatin and etoposide treatments alone or to the double combination. Conclusions: Taken together these results highlight that inhibiting WEE1 with Debio 0123 significantly improves tumor response to SOC DNA damaging agents in models of SCLC, providing the foundation for future clinical exploration of Debio 0123 in SCLC. Citation Format: Luke Piggott, Anne Vaslin-Chessex, Noemie Luong, Benjamin Tschumi, Gregoire Vuagniaux. The WEE1 inhibitor Debio 0123 enhances the efficacy of standard of care DNA damaging agents in lung cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2303.

Published
2022
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47. Facteurs cliniques préopératoires associés à l’appendicectomie laparoscopique ambulatoire

Author

VUAGNIAUX, Aurélie

Abstract

L’appendicectomie laparoscopique pour appendicite aigüe selon un mode ambulatoire est décrite dans la littérature et réalisable comme le suggèrent certaines études1-3. Toutefois, s’agissant d’une chirurgie d’urgence et en l’absence de critères précis pour l’éligibilité des patients, l’appendicectomie ambulatoire est encore peu répandue. Le but de cette étude a été d’évaluer les facteurs cliniques préopératoires associé au succès de l’appendicectomie ambulatoire. Le deuxième but a été de créer sur la base de ces facteurs, un score prédictif afin de sélectionner les patients pour une appendicectomie ambulatoire. Il s’agit d’une analyse rétrospective. L’appendicectomie ambulatoire a été définie comme une hospitalisation de moins de 24heures (avec/sans nuit). Nous avons inclus tous les patients ayant bénéficiés d’une appendicectomie laparoscopique en urgence dans le service de Chirurgie Viscérale du CHUV entre Janvier 2013 et Juin 2015. Plusieurs variables préopératoires, cliniques et biologiques, ont été comparées entre le groupe « appendicectomie ambulatoire » et « appendicectomie avec hospitalisation ». Une analyse logistique de régression a été utilisée pour identifier les variables associées à l’appendicectomie ambulatoire. Ces variables ont été utilisées ensuite pour créer un score prédictif de l’appendicectomie ambulatoire. Au total, 578 patients ont été inclus dans l’étude, 303 (53%) dans le groupe « ambulatoire » et 275 (48%) dans le groupe « hospitalisation ». Après analyse multivariée, cinq facteurs sont indépendamment associés à une appendicectomie ambulatoire : les hommes (p=0.010), un score ASA I-II (p=0.037), l’absence de défense généralisée (p=0.019), une CRP

Published
2021

48. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy

Author

Millay, Douglas P., Sargent, Michelle A., Osinska, Hanna, Baines, Christopher P., Barton, Elisabeth R., Vuagniaux, Gregoire, Sweeney, H. Lee, Robbins, Jeffrey, and Molkentin, Jeffery D.

Abstract

Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death (1). Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D (Ppif) rendered mitochondria largely insensitive to the calcium overload-induced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking [delta]-sarcoglycan ([Scgd.sup.-/-] mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2, encoding the [alpha]-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in [Scgd.sup.-/-] mice. Thus, mitochondria'-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases., The muscular dystrophies are inherited disorders that mostly affect striated muscle tissue, resulting in progressive muscle weakness, wasting and, in many instances, premature death (1). Many characterized mutations in humans [...]

Published
2008

49. Recovery to Usual Activity After Outpatient Anorectal Surgery

Author

Reza Djafarrian, Dieter Hahnloser, Aurélie Vuagniaux, Céline Duvoisin, Nicolas Demartines, Martin Hübner, and David C. Martin

Subjects
Adult, Male, medicine.medical_specialty, Time Factors, Visual analogue scale, Anal Canal, 030230 surgery, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Return to Work, Quality of life, Interquartile range, Internal medicine, Surveys and Questionnaires, medicine, Humans, Postoperative Period, Prospective Studies, Exercise, Aged, business.industry, Vascular surgery, Middle Aged, Cardiac surgery, Rectal Diseases, Cardiothoracic surgery, 030220 oncology & carcinogenesis, Preoperative Period, Quality of Life, Surgery, Female, business, Abdominal surgery, Cohort study
Abstract

Most elective anorectal procedures are performed in an outpatient setting, and the supposed recovery time is short. The aim of the present study was to assess return to usual physical activity (UPA), return to work and quality of life (QOL). This prospective single-center cohort study included consecutive patients undergoing outpatient anorectal procedures. Physical and work activities were assessed using the validated International Physical Activity Questionnaire 7 days before surgery and 7, 14 and 30 days thereafter. In addition, patients were inquired daily on their postoperative QOL until postoperative day (POD)10 on a visual analogue scale (0–10). Patients were stratified by their preoperative physical activity score (POPAS; low, moderate and high). Out of 379 patients, 100 (63 men) were included with a median age of 40 years [interquartile range (IQR) 27]. General QOL was rated at a median of 8/10 (IQR 3.5) at POD10. On POD30, only 69% and 71% of patients had returned to UPA and work, respectively. Patients who returned to UPA at POD30 had a better median QOL at POD10 than those who did not (9 vs. 7/10, p = 0.015). Patients with low POPAS and moderate POPAS returned to UPA earlier than patients with high POPAS (83%, 86% and 44% on POD30, respectively, p = 0.005). Return to UPA and work after outpatient anorectal surgery took longer than expected despite a good QOL 10 days after surgery. High physical activity was associated with longer recovery time. These elements should be emphasized during preoperative counseling.

Published
2020

50. Inhibition of mitochondrial permeability transition improves functional recovery and reduces mortality following acute myocardial infarction in mice

Author

Gomez, Ludovic, Thibault, Helene, Gharib, Adbdallah, Dumont, Jean-Maurice, Vuagniaux, Gregoire, Scalfaro, Pietro, Derumeaux, Genevieve, and Ovize, Michel

Subjects
Heart cells -- Research, Cellular control mechanisms -- Research, Heart attack -- Research, Myocardial ischemia -- Research, Cardiovascular research, Biological sciences
Abstract

Inhihition of mitochondrial permeability transition pore (mPTP) opening by cyclosporin A or ischemic postconditioning attenuates lethal reperfusion injury. Its impact on major post-myocardial infarction events, including worsening of left ventricular (LV) function and death, remains unknown. We sought to determine whether pharmacological or postconditioning-induced inhibition of mPTP opening might improve functional recovery and survival following myocardial infarction in mice. Anesthetized mice underwent 25 min of ischemia and 24 h (protocol 1) or 30 days (protocol 2) of reperfusion. At reperfusion, they received no intervention (control), postconditioning (3 cycles of 1 min ischemia-1 min reperfusion), or intravenous injection of the mPTP inhibitor Debio-025 (10 mg/kg). At 24 h of reperfusion, mitochondria were isolated from the region at risk for assessment of the [Ca.sup.2+] retention capacity (CRC). Infarct size was measured by triphenyltetrazolium chloride staining. At 30 days of reperfusion, mortality and LV contractile function (echocardiography) were evaluated. Postconditioning and Debio-025 significantly improved [Ca.sup.2+] retention capacity (132 [+ or -] 13 and 153 [+ or -] 31 vs. 53 [+ or -] 16 nmol [Ca.sup.2+]/mg protein in control) and reduced infarct size to 35 [+ or -] 4 and 32 [+ or -] 7% of area at risk vs. 61 [+ or -] 6% in control (P < 0.05). At 30 days, ejection fraction averaged 74 [+ or -] 6 and 77 [+ or -] 6% in postconditioned and Debio-025 groups, respectively, vs. 62 [+ or -] 12% in the control group (P < 0.05). At 30 days, survival was improved from 58% in the control group to 92 and 89% in postconditioned and Debio-025 groups, respectively. Inhibition of mitochondrial permeability transition at reperfusion improves functional recovery and mortality in mice. ischemic postconditioning; left ventricular contractile function; mitochondrial permeability transition pore

Published
2007

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