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15 results on '"Giannetti, K"'

1. Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse

Author

Gambacorta, V, Beretta, S, Ciccimarra, M, Zito, L, Giannetti, K, Andrisani, A, Gnani, D, Zanotti, L, Oliveira, G, Carrabba, M, Cittaro, D, Merelli, I, Ciceri, F, Di Micco, R, Vago, L, Gambacorta V., Beretta S., Ciccimarra M., Zito L., Giannetti K., Andrisani A., Gnani D., Zanotti L., Oliveira G., Carrabba M. G., Cittaro D., Merelli I., Ciceri F., Di Micco R., Vago L., Gambacorta, V, Beretta, S, Ciccimarra, M, Zito, L, Giannetti, K, Andrisani, A, Gnani, D, Zanotti, L, Oliveira, G, Carrabba, M, Cittaro, D, Merelli, I, Ciceri, F, Di Micco, R, Vago, L, Gambacorta V., Beretta S., Ciccimarra M., Zito L., Giannetti K., Andrisani A., Gnani D., Zanotti L., Oliveira G., Carrabba M. G., Cittaro D., Merelli I., Ciceri F., Di Micco R., and Vago L.

Abstract

Immune escape represents a major driver of acute myeloid leukemia (AML) reemergence after allogeneic hematopoietic cell transplantation (allo-HCT), with up to 40% of relapses prompted by nongenomic loss of HLA class II expression in leukemia cells. By integrative analysis of gene expression, DNA methylation, and chromatin accessibility in paired diagnosis/relapse primary samples and in the respective patient-derived xenografts (PDX), we identify the polycomb repressive complex 2 (PRC2) as a key epigenetic driver of this immune escape modality. We report that loss of expression of HLA class II molecules is accompanied by a PRC2-dependent reduction in chromatin accessibility. Pharmacologic inhibition of PRC2 subunits rescues HLA class II expression in AML relapses in vitro and in vivo, with consequent recovery of leukemia recognition by CD4+ T cells. Our results uncover a novel link between epigenetics and leukemia immune escape, which may rapidly translate into innovative strategies to cure or prevent AML posttransplantation relapse.

Published
2022

4. Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis

Author

Daniela Cesana, Anastasia Conti, Eugenio Montini, Stefano Beretta, Riccardo Biavasco, Claudio Doglioni, Serena Scala, Diego Gilioli, Luca Basso-Ricci, Giulio Cavalli, Pierangela Gallina, Maurilio Ponzoni, Raffaella Di Micco, Alessandro Aiuti, Ivan Merelli, Attilio Bondanza, Margherita Norelli, Kety Giannetti, Emanuele Lettera, Lorenzo Dagna, Biavasco, R., Lettera, E., Giannetti, K., Gilioli, D., Beretta, S., Conti, A., Scala, S., Cesana, D., Gallina, P., Norelli, M., Basso-Ricci, L., Bondanza, A., Cavalli, G., Ponzoni, M., Dagna, L., Doglioni, C., Aiuti, A., Merelli, I., Di Micco, R., Montini, E., Biavasco, R, Lettera, E, Giannetti, K, Gilioli, D, Beretta, S, Conti, A, Scala, S, Cesana, D, Gallina, P, Norelli, M, Basso-Ricci, L, Bondanza, A, Cavalli, G, Ponzoni, M, Dagna, L, Doglioni, C, Aiuti, A, Merelli, I, Di Micco, R, and Montini, E

Subjects
0301 basic medicine, Myeloid, General Physics and Astronomy, Systemic inflammation, Mice, Rheumatic diseases, 0302 clinical medicine, Principal Component Analysi, Bone Marrow, Hematopoiesi, Myeloid Cells, Myeloid Cell, Cellular Senescence, Principal Component Analysis, Multidisciplinary, Haematopoietic stem cells, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Histiocytoses, medicine.symptom, Human, Senescence, Proto-Oncogene Proteins B-raf, Science, Green Fluorescent Proteins, Biology, Green Fluorescent Protein, Article, Lentiviru, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cell Cycle Checkpoint, Paracrine Communication, medicine, Animals, Humans, Progenitor cell, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Inflammation, Animal, Tumor Necrosis Factor-alpha, Lentivirus, Hematopoietic Stem Cell, General Chemistry, Cell Cycle Checkpoints, Oncogenes, Histiocytosi, Hematopoietic Stem Cells, digestive system diseases, Hematopoiesis, 030104 developmental biology, Gene Expression Regulation, Humanized mouse, Chronic Disease, Mutation, Cancer research, Bone marrow, Histiocytosis
Abstract

Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (BRAFV600E). All mice transplanted with BRAFV600E-expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. At the basis of this aggressive phenotype, we uncover the engagement of a senescence program, characterized by DNA damage response activation and a senescence-associated secretory phenotype, which affects also non-mutated bystander cells. Mechanistically, we identify TNFα as a key determinant of paracrine senescence and myeloid-restricted hematopoiesis and show that its inhibition dampens inflammation, delays disease onset and rescues hematopoietic defects in bystander cells. Our work establishes that senescence in the human hematopoietic system links oncogene-activation to the systemic inflammation observed in histiocytic neoplasms., BRAF-MAPK activating mutations are reported in histiocytoses—hematological neoplasms with widespread pro-inflammatory myeloid cells. Here, the authors show that an activating mutant BRAF in haematopoietic stem and progenitor cells causes an oncogene-induced senescence response leading to myeloid restricted haematopoiesis, inflammation and histiocytosis.

Published
2021

5. Combination of Tevatron searches for the standard model Higgs boson in the W+W- decay mode

Author

Maxim Perfilov, B. Carls, V. Sorin, P. Lukens, Kevin Lannon, P. Verdier, Guenakh Mitselmakher, Guillelmo Gomez-Ceballos, Marcelo Vogel, V. A. Kuzmin, U. K. Yang, Chris Hays, W. T. Fedorko, Y. A. Yatsunenko, M. Mussini, Y. C. Yang, J. Keung, G. C. Blazey, D. Torretta, A. F. Barfuss, L. Bellantoni, Viatcheslav Stolin, Frank Würthwein, M. Shochet, C. Plager, F. Canelli, V. A. Bezzubov, A. Hocker, P. D. Grannis, Jun Guo, Q. Z. Li, Mark Kruse, Alison Lister, J. P. Fernandez, J. P. Negret, J. Nett, Stefano Giagu, Paul Tipton, G. L. Strycker, C. Mesropian, R. Yamada, D. N. Brown, P. Squillacioti, Kazuhiko Hara, J. Osta, Carlos Avila, L. E. Kirsch, Ricardo Eusebi, J. Galyardt, Alexei Safonov, R. Luna-Garcia, Raimund Ströhmer, V. Simak, D. Krop, Sabine Lammers, Jonas Rademacker, D. Amidei, J. M. Heuser, J. Sekaric, Michael A. Strauss, Jean-Francois Grivaz, K. Devaughan, A. T. Goshaw, P. Padley, Michael Hildreth, P. Skubic, A. Semenov, D. Clark, J. Boudreau, Wendy Taylor, M. Pangilinan, Jason Nielsen, G. Introzzi, B. Casal, Mitchell Wayne, N. Miladinovic, Y. Tu, H. Schellman, J. M. Kohli, K. Potamianos, Z. Gunay-Unalan, Darren Price, A. Sanchez-Hernandez, M. Wiok, Sergo Jindariani, Fedor Prokoshin, P. Jonsson, Thomas Hebbeker, Katsufumi Sato, A. J. Slaughter, Stefan Grünendahl, S. Cihangir, V. Zutshi, Yasuyoshi Nagai, Francesco Crescioli, S. Uzunyan, S. W. Lee, P. Ttito-Guzmán, T. Okusawa, B. Gómez, R. Madrak, Chong-Yu Xu, J. Naganoma, B. Tuchming, P. Wagner, V. Bunichev, Shinhong Kim, J. Budagov, Fabrice Couderc, K. Makhoul, Manfred Paulini, B. Tiller, Dmitri Tsybychev, R. L. McCarthy, Thomas LeCompte, Manuela Campanelli, I. Lazzizzera, Eva Halkiadakis, M. Gold, Tetsuo Arisawa, C. Neu, Amnon Harel, W. M. Lee, K. Kondo, Mary Beth Adams, D. Whiteson, I. Shreyber, K. Yamamoto, Malte Renz, Andrew Askew, R. L. Lander, G. De Lorenzo, A. Savoy-Navarro, Allan G Clark, Roger Moore, D. O. Litvintsev, S. Söldner-Rembold, A. Anastassov, G. Giurgiu, L. Sartori, Sooran Kim, O. Poukhov, A. Jonckheere, H. E. Fisk, P. Lebrun, M. N. Mondragon, I. Hall, A. Lobodenko, Wolfgang Wagner, Liang Li, J. C. Yun, J. Lueck, Stephen Wimpenny, S. Carrillo, J. Backusmayes, Martin Grunewald, Nicola D'Ascenzo, J. A. Appel, P. H. Beauchemin, M. Heck, D. Beecher, Peter McIntyre, G. Pauletta, M. Martínez, J. Patrick, E. Strauss, Guennadi Borissov, M. Jones, C. Pagliarone, D. Menezes, Intae Yu, Oliver Stelzer-Chilton, Th Muller, D. W. Jang, R. Van Kooten, B. Y. Han, I. Heredia-De La Cruz, Michael L. Norman, Yongsun Kim, Lev Dudko, Milos Lokajicek, D. Karmanov, M. M. Deninno, Markus Wobisch, R. Magaña-Villalba, S. W. Cho, G. Obrant, B. Whitehouse, S. Y. Jun, Julia Thom, W. C. Fisher, Adrian Buzatu, V. Boisvert, Daria Zieminska, Suneel Dutt, J. E. Kim, Aran Garcia-Bellido, M. D. Corcoran, S. Cabrera, D. E. Pellett, M. Binkley, R. D. Schamberger, M. Corbo, Y. C. Chen, F. Guo, A. J. Martin, C. Vellidis, Darien Wood, Y. Shon, D. K. Cho, T. R. Wyatt, E. Brubaker, Shabnam Jabeen, S. De Cecco, A. Dubey, G. Grenier, Hwi Dong Yoo, Zdenek Hubacek, L. Santi, A. Alton, Meng Wang, Neeti Parashar, L. Pondrom, E. Wicklund, Christoph Paus, C. P. Buszello, S. Hou, A. Das, M. Sosebee, A. Manousakis-Katsikakis, Emily Nurse, M. Merkin, L. Han, Giorgio Chiarelli, A. Rahaman, J. Huston, J. D. Lewis, Yuehong Xie, T. Scanlon, S. Kermiche, W. H. Chung, M. Rominsky, L. Brigliadori, V. M. Abazov, D. Buchholz, I. Ripp-Baudot, R. McNulty, M. Hare, M. Tecchio, A. Gessler, Helio Nogima, I. Razumov, S. Blessing, M. Zielinski, V. Rusu, A. Elagin, Vyacheslav Krutelyov, G. S. Muanza, Jay Dittmann, W. Ashmanskas, D. Hirschbuehl, H. C. Fang, Frederic Deliot, Michele Gallinaro, G. Savage, Peter Wittich, A. Napier, A. Meyer, Scott Snyder, J. Hays, S. Tokar, Suman Bala Beri, C.S. Johnson, G. Sajot, V. Hynek, Robert Hirosky, Alberto Annovi, P. Murat, Y. Hu, D. J. Cox, A. Di Canto, V. Khotilovich, Y. Seiya, O. Atramentov, Elizaveta Shabalina, M. Lancaster, G. Alkhazov, Y. Zheng, Jian Tang, L. Oakes, A. Gresele, Y. N. Kharzheev, A. Varganov, Sudhir Malik, E. G. Zverev, M. Vidal, Ia Iashvili, G. Manca, P. Roy, Raymond Brock, Robin Erbacher, M. Datta, R. Beuselinck, C. Cuenca Almenar, Javier Cuevas, Jean-Arcady Meyer, J. Mülmenstädt, D. V. Bandurin, S. Greder, Y. W. Liu, Iain Alexander Bertram, Virgil E Barnes, M. Padilla, L. Bagby, M. S. Rangel, Jahred Adelman, Jane Nachtman, Graham Wilson, Sergio F Novaes, S. Hossain, B. Jayatilaka, Kyung-Suk Cho, R. E. Hughes, P. Rich, T. Rodriguez, D. Gillberg, H. Wolfe, B. Sanghi, Suyong Choi, J. Parsons, G. Velev, J. M. Hauptman, Cecilia Elena Gerber, V. M. Podstavkov, G. Chlachidze, Michael Rijssenbeek, S. Zelitch, Jeannine Wagner-Kuhr, M. A. Strang, Brajesh C Choudhary, D. Lucchesi, Bernd Stelzer, S. Tkaczyk, F. Vázquez, P. Svoisky, C. Zeitnitz, J. Yamaoka, Arnulf Quadt, Petar Maksimovic, A. Juste, E. De La Cruz-Burelo, A. Attal, E. Pueschel, T. Wright, S. Grinstein, Todd Adams, K. M. Chan, A. S. Ito, A. Melnitchouk, T. Aaltonen, J. Antos, Thorsten Chwalek, Elemer Nagy, C. J. Lin, W. M. Van Leeuwen, M. Fortner, Sarah Catherine Eno, Horst Severini, Tiehui Liu, Rodolfo Carosi, A. Barbaro-Galtieri, R. G. Feild, J. S. Suh, K. Osterberg, D. Mietlicki, S. Richter, Michal Kreps, T. Nunnemann, B. Baldin, Corrinne Mills, G. P. Yeh, C. S. Moon, M. J. Kim, S. J. Park, A. Menzione, M. E. Convery, E. Palencia, J. C. Cully, Aron Soha, M. Cordelli, G. Busetto, Brian L Winer, G. Ginther, G. Bauer, G. Golovanov, M. J. Morello, F. D. Snider, J. Y. Han, N. Giokaris, Junjie Zhu, S. Wolbers, V. V. Tokmenin, L. S. Vertogradov, R. J. Miller, J. Martínez-Ortega, M. Weinberger, Bjoern Penning, G. Facini, M. Kurata, Andrea Castro, G. D. Alexeev, Flera Rizatdinova, M. Milnik, U. Husemann, B. Álvarez González, V. N. Evdokimov, A. Bridgeman, K. Sliwa, S. Klimenko, Evelyn Thomson, C. Deluca, Fabrizio Scuri, D. Wicke, Dennis Stephen Mackin, Andrew Brandt, Kirti Ranjan, Jianming Qian, J. L. Gimmell, V. V. Lipaev, J. Lellouch, H. A. Neal, Ivan-Kresimir Furic, Y. D. Oh, D. Bauer, M. C. Cousinou, V. A. Giakoumopoulou, Carsten Hensel, A. Mukherjee, C. Belanger-Champagne, B. S. Acharya, Nicola Turini, J. Pursley, H. Nilsen, R. G. Wagner, B. Spurlock, G. Piacentino, M. Buehler, A. T. Laasanen, Zeno Dixon Greenwood, Y. Arnoud, Richard B. Lipton, D. W. Gerdes, Pedro G Mercadante, Ph Gris, T. Kuhr, P. Houben, M. H. Kirby, H. Miyake, F. Happacher, Kristian Harder, Dario Bisello, G. Gutierrez, M. D'Errico, Joe Kroll, B. C.K. Casey, X. Wu, T. A. Schwarz, A. Bhatti, P. A. Kasper, Hugh Williams, M. P. Sanders, Ignacio Redondo, Hyun-Chul Kim, Yurii Maravin, Vladimir Gavrilov, A. Aurisano, Teresa Rodrigo, D. Boline, K. Chung, Peter Love, Pushpalatha C Bhat, W. Geng, N. Ranjan, R. Jesik, S. Carron, L. Demortier, S. Dube, S. H. Oh, M. A. Schmidt, Mark Richard James Williams, R. Bernhard, W. E. Cooper, P. N. Dong, D. Khatidze, Giovanni Bellettini, M. Rossi, J. Slaunwhite, D. Cutts, J. T. Linnemann, David T. Johnston, Gordon Watts, Daniela Bortoletto, O. Mundal, K. Yip, P. E. Karchin, P. Haefner, Roman Lysak, M. Iori, C. Bromberg, Duncan Carlsmith, K. A. Johns, Anna Goussiou, Elisabetta Pianori, A. V. Kotwal, Gregorio Bernardi, Andrea Bocci, D. Denisov, X. Zhang, A. Scribano, D. Onoprienko, T. J. Phillips, A. A. Paramanov, K. Ebina, G. Otero y Garzon, M. Trovato, M. Cavalli-Sforza, W. M. Yao, Aaron Dominguez, Jochen Jens Heinrich, W. Geist, Tiefu Zhao, S. Budd, G. A. Thompson, Je Jung, S. W. Youn, P. Polozov, Koji Nakamura, Arnaud Duperrin, S. Neubauer, S. Y. Tsai, Sharon Hagopian, S. Torre, S. Amerio, S. Zucchelli, A. K.A. Maciel, W. Johnson, K. T. Pitts, A. Simonenko, V. Sirotenko, S. Wilbur, J. K. Kraus, J. Weinelt, Greg Landsberg, I. Suslov, K. Herner, N. Khalatyan, S. Yacoob, A. Schmidt, B. Hoeneisen, Lee Sawyer, Maria Agnese Ciocci, A. Mitra, Michael Schmitt, N. Kimura, Hal Evans, Thomas Ferbel, M. Prewitt, Cristina Galea, M. Hartz, T. Wakisaka, Lars Sonnenschein, Zhanqiang Liu, M. Cooke, Tommaso Dorigo, S. Hewamanage, Sinead Farrington, M. P. Schmidt, P. L.M. Podesta-Lerma, D. H. Kim, V. Kaushik, J. F. Bartlett, J. Lys, Stephan Lammel, Lucio Cerrito, R. E. Blair, Jong-Sung Yu, F. Rimondi, Pavol Bartos, N. Ershaidat, E. E. Boos, E. E. Schmidt, Marco Verzocchi, Theodoros Christoudias, S. Lami, Emanuela Barberis, Avraham Yagil, Dean Hidas, Heriberto Castilla-Valdez, J. Morlock, S. Seidel, R. Unalan, L. Stutte, A. Canepa, C. Ferrazza, C. P. Marino, G. Flanagan, A. N. Sisakyan, E. Rogers, P. Totaro, R. Nayyar, Robert Kehoe, Maxwell Chertok, A. Patwa, W. Badgett, J. Clutter, Md. Naimuddin, V. Papadimitriou, M. Kirsch, A.S. Dyshkant, D. Smirnov, George Alverson, K. Tollefson, E. J. Jeon, A. Sukhanov, R. Vilar, N. Krumnack, P. K. Teng, K. S. McFarland, Federico Sforza, Mark Owen, S. Somalwar, Deepak Kar, R. Piegaia, V. V. Glagolev, MarioPaolo Giordani, S. J. De Jong, K. Soustruznik, Ashok Kumar, E. Carrera, I. Bizjak, J. Conway, E. Lee, M. Stanitzki, A. Papaikonomou, M. E. Mattson, M. Arov, Andre Sopczak, G. Hesketh, B. Brau, D. Hedin, Brad Abbott, P. Catastini, T. Tomura, A. Evdokimov, S. Pagan Griso, Robert Snihur, Marcia Begalli, Ulysses Grundler, C. I. Ciobanu, R. L. Wagner, Jiri Kvita, D. Gerbaudo, D. Lam, S. Z. Shalhout, Victoria Jane Martin, R. Martínez-Ballarín, Thomas Peiffer, Alexander Grohsjean, Phillip Gutierrez, Pierre Petroff, A. Golossanov, Shih-Fu Chang, Rainer Wallny, M. Demarteau, Andreas Warburton, Satoru Uozumi, U. Bassler, Andrew Beretvas, R. F. Harr, M. Mathis, Meenakshi Narain, A. Pronko, Arie Bodek, S. Moed, P. J. Van Den Berg, Lev Uvarov, Marc Besancon, D. Benjamin, K. Goulianos, J. Snow, M. Abolins, S. Rolli, Elliott Cheu, T. Schliephake, A. Taffard, Victor Daniel Elvira, Marvin Johnson, K. Peters, Sung Keun Park, Massimo Casarsa, Sergey Burdin, S. Robinson, J. Deng, Gregory R Snow, A. A. Shchukin, P. Movilla Fernandez, M. Shimojima, J. P. Chou, Heimo Saarikko, A. Sedov, M. A. Carrasco-Lizarraga, M. Feindt, M. Eads, Y. Takeuchi, Regina Demina, J. Strologas, C. Calancha, B. Di Ruzza, P. Sinervo, P. Schlabach, S. P. Denisov, V. Parihar, Frank Fiedler, A. L. Lyon, Philip Baringer, F. Garberson, H. W. Kim, N. K. Mondal, Mauro Dell'Orso, Tulika Bose, S. Pashapour, A. Apresyan, E. Kajfasz, Song-Ming Wang, A. V. Kozelov, Samuel Calvet, H. T. Diehl, T. A. Bolton, P. Neustroev, V. Saveliev, F. Azfar, R. Culbertson, C. Haber, O. Norniella, V. V. Shary, A. Boehnlein, M. Lindgren, J. Piper, S. Banerjee, E. Vataga, Dorothee Schaile, Michael Mulhearn, R. St. Denis, J. R. Smith, G. B. Yu, J. Ellison, W. Ketchum, D. Hare, G. Williams, D. Edmunds, Igor Volobouev, Jeroen Hegeman, J. Linacre, T. Moulik, P. de Barbaro, Avto Kharchilava, C. A. Cox, Fumihiko Ukegawa, Sa. Jain, A. Penzo, S. Fuess, K. K. Joo, T. Kurca, Marc Weber, B. Parks, James Russ, Kohei Yorita, T. Hoang, Franco Bedeschi, R. Otec, D. Glenzinski, Alexander Khanov, Jonas Strandberg, P. B. Renton, J. Orduna, S. S. Yu, Tomoko Yoshida, A. B. Wicklund, D. Jamin, Grigory Safronov, S. Chevalier-Théry, J. Thome, S. Chakrabarti, V. Cavaliere, D. Waters, M. Hohlfeld, P. N. Ratoff, D. Toback, Y. Peters, P. Vint, Zhenyu Ye, Maksym Titov, Yuri Gershtein, N. P. Kulkarni, Y. Zeng, P. Rubinov, Daniel Duggan, Ernest Aguilo, Tara Shears, Hua-Lei Yin, A. V. Popov, W. C. Wester, M. Campbell, D. Stentz, A. Loginov, S. Desai, T. Dorland, D. Dagenhart, M. Jaffré, Gustaaf Brooijmans, M. Rescigno, L. S. Ancu, Petr Vokac, Joseph Haley, J. Warchol, P. Lujan, P. Garosi, Christophe Royon, V. Ramakrishnan, Alexander Leflat, J. Asaadi, Y. S. Chung, E. Camacho-Pérez, C. Wolfe, P. Barria, E. James, B. Calpas, L. Lovas, Reinhard Schwienhorst, S. Behari, Luca Scodellaro, H. D. Wahl, Alexander Kupco, F. Badaud, K. L. Byrum, P. Giromini, Andrew White, Gilvan Alves, L. Sexton-Kennedy, R. Forrest, I. Katsanos, Anna Zanetti, G. Compostella, Maxim Goncharov, N. Huske, N. Parua, D. Vilanova, Randy Ruchti, Joe Incandela, L. Nodulman, J. N. Bellinger, M. D'onofrio, T. Miao, P. Mättig, X. B. Bu, D. Chokheli, R. Kephart, K. Gibson, M. M. Meijer, L. Ristori, N. S. Lockyer, Roberto Rossin, A. Boveia, Aidan Robson, Kevin Burkett, T. Yasuda, R. Illingworth, N. Moggi, D. Errede, S. Beale, Chuan-Ming Liu, G. Punzi, John Hobbs, Yuji Enari, Y. Kato, L. Zivkovic, J. Guimaraes Da Costa, J. Barreto, D. Tonelli, Alexey Ferapontov, M. Wetstein, I. V. Gorelov, H. S. Budd, M. A. Houlden, Andrew Mehta, Jacobo Konigsberg, L. Duflot, J. K. Lim, Stefano Camarda, Frank Chlebana, F. Ptohos, B. Åsman, L. Pinera, A. P. Heinson, S. Malde, M. A. Pleier, P. Renkel, P. Mehtala, M. Giunta, A. Artikov, S. Schlobohm, H. Greenlee, D. M. Strom, Matthew Herndon, E. Lipeles, M. K. Jha, A. Bross, Christopher George Tully, M. Hussein, Benjamin Kilminster, Serban Protopopescu, Barry Blumenfeld, M. Aoki, Andy Haas, G. Weber, D. Chakraborty, J. S. Lee, Don Lincoln, Erich Varnes, S. Shiraishi, S. Kwang, M. Hurwitz, S. R. Hahn, M. Vesterinen, N. Osman, A. Deisher, T. R. Junk, Patrick Slattery, A. Chandra, J. Yoh, D. A. Stoyanova, C. L. McGivern, Gervasio Gomez, Michael Begel, Andrey Korytov, Eduardo De Moraes Gregores, Luiz Mundim, R. Takashima, T. H. Burnett, Amitabh Lath, Anna Sfyrla, Paola Giannetti, B. A. Barnett, Giorgio Apollinari, J. A. Benitez, Teruki Kamon, P. Mazzanti, Craig Blocker, Ulrich Heintz, D. Cauz, Kaori Maeshima, P. K. Mal, H. S. Lee, Frank Filthaut, Paolo Mastrandrea, M. Diesburg, P. Wilson, J. E. Garcia, A. Tanasijczuk, T. Davies, C. S. Hill, Sandra Leone, S. Uvarov, B. Quinn, W. K. Sakumoto, C. Schwanenberger, Alice Bean, C. Grosso-Pilcher, I. Oksuzian, N. Goldschmidt, Volker Buescher, Peter Bussey, T. Gadfort, Maria Elena Pol, Kai Yi, C. M. Ginsburg, R. Roser, Ivan Vila, P. F. Shepard, B. Rutherford, Alexander Ivanov, N. Van Remortel, S. C. Hsu, Reisaburo Tanaka, Guido Volpi, Nikos Varelas, O. González, Bing Zhou, Luis Mendoza, R. K. Shivpuri, S. Donati, Kenichi Hatakeyama, M. Franklin, D. R. Claes, Gavin Davies, Philippe Calfayan, Itsuo Nakano, Harald Fox, S. M. Lietti, Y. Scheglov, J. C. Freeman, Kaushik De, A. Ruiz, Giuseppe Latino, Alan Garfinkel, Jan Stark, Fabrizio Margaroli, S. Errede, Maiko Takahashi, Henry Lubatti, J. Cammin, I. A. Vasilyev, Vipin Bhatnagar, A. Cerri, R. Partridge, Markus Frank, P. M. Tuts, D. MacQueen, H. Gerberich, Kenneth Bloom, V. L. Malyshev, Mark Neubauer, R. Orava, G. Lungu, R. D. Field, D. J. Kong, W. C. Yang, Department of Physics, Helsinki Institute of Physics, CDF Collaboration, D0 Collaboration, Laboratoire de Physique Subatomique et de Cosmologie (LPSC), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique Corpusculaire - Clermont-Ferrand (LPC), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Physique Nucléaire et de Hautes Énergies (LPNHE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de l'Accélérateur Linéaire (LAL), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris-Sud - Paris 11 (UP11), Institut de Physique Nucléaire de Lyon (IPNL), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3), CDF, D0, Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Universidad de Cantabria, T. 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PHILLIPS, G. PIACENTINO, E. PIANORI, R. PIEGAIA, L. PINERA, J. PIPER, K. PITTS, C. PLAGER, M.-A. PLEIER, P. L. M. PODESTA-LERMA, V. M. PODSTAVKOV, M.-E. POL, P. POLOZOV, L. PONDROM, A. V. POPOV, K. POTAMIANOS, O. POUKHOV, M. PREWITT, D. PRICE, F. PROKOSHIN,U, A. PRONKO, S. PROTOPOPESCU, F. PTOHOS, E. PUESCHEL, G. PUNZI, J. PURSLEY, J. QIAN, A. QUADT, B. QUINN, J. RADEMACKER,§, A. RAHAMAN, V. RAMAKRISHNAN, M. S. RANGEL, K. RANJAN, N. RANJAN, P. N. RATOFF, I. RAZUMOV, I. REDONDO, P. RENKEL, P. RENTON, M. RENZ, M. RESCIGNO, P. RICH, S. RICHTER, M. RIJSSENBEEK, F. RIMONDI, I. RIPP-BAUDOT, L. RISTORIA, F. RIZATDINOVA, S. ROBINSON, A. ROBSON, T. RODRIGO, T. RODRIGUEZ, E. ROGERS, S. ROLLI, M. ROMINSKY, R. ROSER, M. ROSSIA, R. ROSSIN, P. ROY, C. ROYON, P. RUBINOV, R. RUCHTI, A. RUIZ, J. RUSS, V. RUSU, B. RUTHERFORD, H. SAARIKKO, A. SAFONOV, G. SAFRONOV, G. SAJOT, W. K. SAKUMOTO, A. SÁNCHEZ-HERNÁNDEZ, M. P. SANDERS, B. SANGHI, L. SANTI, L. SARTORIA, K. SATO, G. SAVAGE, V. SAVELIEV, A. SAVOY-NAVARRO, L. SAWYER, T. SCANLON, D. SCHAILE, R. D. SCHAMBERGER, Y. SCHEGLOV, H. SCHELLMAN, P. SCHLABACH, T. SCHLIEPHAKE, S. SCHLOBOHM, A. SCHMIDT, E. E. SCHMIDT, M. A. SCHMIDT, M. P. SCHMIDT, M. SCHMITT, C. SCHWANENBERGER, T. SCHWARZ, R. SCHWIENHORST, L. SCODELLARO, A. SCRIBANO, F. SCURIA, A. SEDOV, S. SEIDEL, Y. SEIYA, J. SEKARIC, A. SEMENOV, H. SEVERINI, L. SEXTON-KENNEDY, F. SFORZA, A. SFYRLA, E. SHABALINA, S. Z. SHALHOUT, V. SHARY, A. A. SHCHUKIN, T. SHEARS, P. F. SHEPARD, M. SHIMOJIMA,O, S. SHIRAISHI, R. K. SHIVPURI, M. SHOCHET, Y. SHON, I. SHREYBER, V. SIMAK, A. SIMONENKO, P. SINERVO, V. SIROTENKO, A. SISAKYAN, P. SKUBIC, P. SLATTERY, A. J. SLAUGHTER, J. SLAUNWHITE, K. SLIWA, D. SMIRNOV, J. R. SMITH, F. D. SNIDER, R. SNIHUR, G. R. SNOW, J. SNOW, S. SNYDER, A. SOHA, S. SÖLDNER-REMBOLD, S. SOMALWAR, L. SONNENSCHEIN, A. SOPCZAK, V. SORIN, M. SOSEBEE, K. SOUSTRUZNIK, B. SPURLOCK, P. SQUILLACIOTIC,A, M. STANITZKI, J. STARK, R. ST. DENIS, B. STELZER, O. STELZER-CHILTON, D. STENTZ, V. STOLIN, D. A. STOYANOVA, J. STRANDBERG, M. A. STRANG, E. STRAUSS, M. STRAUSS, R. STRÖHMER, J. STROLOGAS, D. STROM, G. L. STRYCKER, L. STUTTE, J. S. SUH, A. SUKHANOV, I. SUSLOV, P. SVOISKY, A. TAFFARD, M. TAKAHASHI, R. TAKASHIMA, Y. TAKEUCHI, R. TANAKA, A. TANASIJCZUK, J. TANG, W. TAYLOR, M. TECCHIO, P. K. TENG, J. THOM, J. THOME, G. A. THOMPSON, E. THOMSON, B. TILLER, P. TIPTON, M. TITOV, S. TKACZYK, D. TOBACK, S. TOKAR, V. V. TOKMENIN, K. TOLLEFSON, T. TOMURA, D. TONELLI, S. TORRE, D. TORRETTA, P. TOTARO, M. TROVATO, S.-Y. TSAI, D. TSYBYCHEV, P. TTITO-GUZMÁN, B. TUCHMING, Y. TU, C. TULLY, N. TURINI, P. M. TUTS, F. UKEGAWA, R. UNALAN, S. UOZUMI, L. UVAROV, S. UVAROV, S. UZUNYAN, P. J. VAN DEN BERG, R. VAN KOOTEN, W. M. VAN LEEUWEN, N. VAN REMORTEL, N. VARELAS, A. VARGANOV, E. W. VARNES, I. A. VASILYEV, E. VATAGAD,A, F. VÁZQUEZ,H, G. VELEV, C. VELLIDIS, P. VERDIER, L. S. VERTOGRADOV, M. VERZOCCHI, M. VESTERINEN, M. VIDAL, I. VILA, D. VILANOVA, R. VILAR, P. VINT, M. VOGEL, P. VOKAC, I. VOLOBOUEV,S, G. VOLPI, P. WAGNER, R. G. WAGNER, R. L. WAGNER, W. WAGNER,W, J. WAGNER-KUHR, H. D. WAHL, T. WAKISAKA, R. WALLNY, M. H. L. S. WANG, S. M. WANG, A. WARBURTON, J. WARCHOL, D. WATERS, G. WATTS, M. WAYNE, G. WEBER, M. WEBER, M. WEINBERGER, J. WEINELT, W. C. WESTER, III, M. WETSTEIN, A. WHITE, B. WHITEHOUSE, D. WHITESON, D. WICKE, A. B. WICKLUND, E. WICKLUND, S. WILBUR, G. WILLIAMS, H. H. WILLIAMS, M. R. J. WILLIAMS, G. W. WILSON, P. WILSON, S. J. WIMPENNY, B. L. WINER, P. WITTICH, M. WOBISCH, S. WOLBERS, C. WOLFE, H. WOLFE, D. R. WOOD, T. WRIGHT, X. WU, F. WÜRTHWEIN, T. R. WYATT, Y. XIE, C. XU, S. YACOOB, A. YAGIL, R. YAMADA, K. YAMAMOTO, J. YAMAOKA, U. K. YANG,M, W.-C. YANG, Y. C. YANG, W. M. YAO, T. YASUDA, Y. A. YATSUNENKO, Z. YE, G. P. YEH, K. YI,I, H. YIN, K. YIP, J. YOH, H. D. YOO, K. YORITA, T. YOSHIDA,F, S. W. YOUN, G. B. YU, I. YU, J. YU, S. S. YU, J. C. YUN, A. ZANETTIA, C. ZEITNITZ, S. ZELITCH, Y. ZENG, X. ZHANG, T. ZHAO, Y. ZHENG, B. ZHOU, J. ZHU, M. ZIELINSKI, D. ZIEMINSKA, L. ZIVKOVIC, S. ZUCCHELLI, V. ZUTSHI, E. G. ZVEREV, D0 (Tevatron, IHEF, IOP, FNWI), Universidad de Buenos Aires, Centro Brasileiro de Pesquisas Físicas, Universidade do Estado do Rio de Janeiro (UERJ), Universidade Federal do ABC (UFABC), Universidade Estadual Paulista (UNESP), McGill University, Simon Fraser University, University of Science and Technology of China, Academia Sinica, Universidad de los Andes, Faculty of Mathematics and Physics, Czech Technical University in Prague, Academy of Sciences, Universidad San Francisco de Quito, University of Helsinki, CNRS/IN2P3, Institut National Polytechnique de Grenoble, Irfu/SPP, RWTH Aachen University, Universität Bonn, Universität Freiburg, Georg-August-Universität Göttingen, Karlsruhe Institute of Technology, Universität Mainz, Ludwig-Maximilians-Universität München, University of Wuppertal, University of Athens, Panjab University, Delhi University, Tata Institute of Fundamental Research, University College Dublin, Istituto Nazionale di Fisica Nucleare Bologna, University of Bologna, Istituto Nazionale di Fisica Nucleare, Sezione di Padova-Trento, University of Padova, Istituto Nazionale di Fisica Nucleare Pisa, University of Pisa, University of Siena, Scuola Normale Superiore, Sezione di Roma 1, Sapienza Università di Roma, Istituto Nazionale di Fisica Nucleare Trieste/Udine, University of Trieste, Okayama University, Osaka City University, University of Tsukuba, Waseda University, Kyungpook National University, Korea University, SungKyunKwan University, CINVESTAV, NIKHEF, Radboud University Nijmegen/NIKHEF, Joint Institute for Nuclear Research, Institution for Theoretical and Experimental Physics, Moscow State University, Institute for High Energy Physics, Petersburg Nuclear Physics Institute, Comenius University, Universitat Autonoma de Barcelona, Medioambientales y Tecnologicas, University of Cantabria, Stockholm University, University of Geneva, Glasgow University, Lancaster University, University of Liverpool, Imperial College London, University College London, The University of Manchester, University of Oxford, University of Arizona, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Yale University, University of Florida, Florida State University, Argonne National Laboratory, Fermi National Accelerator Laboratory, University of Chicago, University of Illinois at Chicago, Northern Illinois University, Northwestern University, University of Illinois, Indiana University, Purdue University Calumet, University of Notre Dame, Purdue University, Iowa State University, University of Kansas, Kansas State University, Louisiana Tech University, The Johns Hopkins University, University of Maryland, Boston University, Northeastern University, Harvard University, Massachusetts Institute of Technology, Tufts University, Brandeis University, University of Michigan, Wayne State University, Michigan State University, University of Mississippi, University of Nebraska, Rutgers University, Princeton University, University of New Mexico, State University of New York, Columbia University, The Rockefeller University, University of Rochester, Brookhaven National Laboratory, Duke University, The Ohio State University, Langston University, University of Oklahoma, Oklahoma State University, University of Pennsylvania, Carnegie Mellon University, University of Pittsburgh, Brown University, University of Texas, Texas A and M University, Southern Methodist University, Rice University, Baylor University, University of Virginia, University of Washington, University of Wisconsin, Sezione di Cagliari, University of Toronto, TRIUMF, York University, Seoul National University, Sungkyunkwan University, Institute of Science and Technology Information, Chonnam National University, Chonbuk National University, Institute of Experimental Physics, University of Cyprus, University of Edinburgh, Fukui Prefecture, Kinki University, Universidad Iberoamericana, University of Iowa, University of California Irvine, Cornell University, University of London, University of Manchester, Inc., Nagasaki Institute of Applied Science, Obninsk State University, University de Oviedo, Texas Tech University, CSIC-Universitat de Valencia, Universidad Tecnica Federico Santa Maria, Bergische Universität Wuppertal, Yarmouk University, J. Stefan Institute, Augustana College, SLAC, ICREA/IFAE, Centro de Investigacion en Computacion-IPN, Universidad Autonoma de Sinaloa, Universiẗt Bern, University of Massachusetts Amherst, Universiteit Antwerpen, University of Bristol, University of California Santa Cruz, Chinese Academy of Sciences, Clark, Allan Geoffrey, Garcia Navarro, Jose Enrique, Lister, Alison, and Wu, Xin

Subjects
Particle physics, Astrophysics::High Energy Astrophysical Phenomena, Tevatron, FOS: Physical sciences, General Physics and Astronomy, Elementary particle, ddc:500.2, PARTON DISTRIBUTIONS, HADRON COLLIDERS, QCD, NNLO, 7. Clean energy, 01 natural sciences, 114 Physical sciences, High Energy Physics - Experiment, Standard Model, Nuclear physics, High Energy Physics - Experiment (hep-ex), Particle decay, 0103 physical sciences, [PHYS.HEXP]Physics [physics]/High Energy Physics - Experiment [hep-ex], Grand Unified Theory, Fermilab, TEVATRON, Nuclear Experiment, 010306 general physics, Boson, Physics, HIGGS BOSON, 010308 nuclear & particles physics, High Energy Physics::Phenomenology, 3. Good health, Higgs boson, CDF, Physics::Accelerator Physics, High Energy Physics::Experiment, +W%2B+W-+|+W%3A+pair+production+|+W%3A+leptonic+decay+|+dilepton%3A+final+state+|+jet%3A+multiplicity+|+cross+section%3A+upper+limit+|+mass+dependence+|+Higgs+particle%3A+mass+|+background+|+DZERO+|+CDF+|+Batavia+TEVATRON+Coll+|+anti-p+p+-->+Higgs+particle+anything+|+anti-p+p+-->+Higgs+particle+anything+intermediate+boson+anything+|+anti-p+p+-->+Higgs+particle+anything+quark+antiquark+anything+|+1960+GeV-cms%22">Anti-p p: interaction | Higgs particle: search for | gluon gluon: fusion | intermediate boson: fusion | quark antiquark: annihilation | Higgs particle: decay | Higgs particle --> W+ W- | W: pair production | W: leptonic decay | dilepton: final state | jet: multiplicity | cross section: upper limit | mass dependence | Higgs particle: mass | background | DZERO | CDF | Batavia TEVATRON Coll | anti-p p --> Higgs particle anything | anti-p p --> Higgs particle anything intermediate boson anything | anti-p p --> Higgs particle anything quark antiquark anything | 1960 GeV-cms
Abstract

11 páginas, 4 figuras, 1 tabla.-- CDF Collaboration: et al., We combine searches by the CDF and D0 Collaborations for a Higgs boson decaying to W+W-. The data correspond to an integrated total luminosity of 4.8 (CDF) and 5.4 (D0) fb(-1) of p (p) over bar collisions at root s = 1.96 TeV at the Fermilab Tevatron collider. No excess is observed above background expectation, and resulting limits on Higgs boson production exclude a standard model Higgs boson in the mass range 162-166 GeV at the 95% C.L., We thank the Fermilab staff and the technical staffs of the participating institutions for their vital contributions. This work was supported by DOE and NSF (USA), CONICET and UBACyT (Argentina), CNPq, FAPERJ, FAPESP and FUNDUNESP (Brazil), CRC Program, CFI, NSERC and WestGrid Project (Canada), CAS and CNSF (China), Colciencias (Colombia), MSMT and GACR (Czech Republic), Academy of Finland (Finland), CEA and CNRS/IN2P3 (France), BMBF and DFG (Germany), Ministry of Education, Culture, Sports, Science and Technology (Japan), World Class University Program, National Research Foundation (Korea), KRF and KOSEF (Korea), DAE and DST (India), SFI (Ireland),INFN (Italy), CONACyT (Mexico), NSC(Republic of China), FASI, Rosatom and RFBR (Russia), Slovak R&D Agency (Slovakia), Ministerio de Ciencia e Innovación, and Programa Consolider-Ingenio 2010 (Spain), The Swedish Research Council (Sweden), Swiss National Science Foundation (Switzerland), FOM (The Netherlands), STFC and the Royal Society (UK), and the A.P. Sloan Foundation (USA).

Published
2010
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6. A p38 MAPK-ROS axis fuels proliferation stress and DNA damage during CRISPR-Cas9 gene editing in hematopoietic stem and progenitor cells.

Author

Della Volpe L, Midena F, Vacca R, Tavella T, Alessandrini L, Farina G, Brandas C, Lo Furno E, Giannetti K, Carsana E, Naldini MM, Barcella M, Ferrari S, Beretta S, Santoro A, Porcellini S, Varesi A, Gilioli D, Conti A, Merelli I, Gentner B, Villa A, Naldini L, and Di Micco R

Subjects
Animals, Mice, Humans, Mice, Inbred C57BL, Cell Differentiation genetics, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Hematopoietic Stem Cells metabolism, CRISPR-Cas Systems genetics, p38 Mitogen-Activated Protein Kinases metabolism, p38 Mitogen-Activated Protein Kinases genetics, Gene Editing methods, DNA Damage genetics, Cell Proliferation genetics, Reactive Oxygen Species metabolism
Abstract

Ex vivo activation is a prerequisite to reaching adequate levels of gene editing by homology-directed repair (HDR) for hematopoietic stem and progenitor cell (HSPC)-based clinical applications. Here, we show that shortening culture time mitigates the p53-mediated DNA damage response to CRISPR-Cas9-induced DNA double-strand breaks, enhancing the reconstitution capacity of edited HSPCs. However, this results in lower HDR efficiency, rendering ex vivo culture necessary yet detrimental. Mechanistically, ex vivo activation triggers a multi-step process initiated by p38 mitogen-activated protein kinase (MAPK) phosphorylation, which generates mitogenic reactive oxygen species (ROS), promoting fast cell-cycle progression and subsequent proliferation-induced DNA damage. Thus, p38 inhibition before gene editing delays G1/S transition and expands transcriptionally defined HSCs, ultimately endowing edited cells with superior multi-lineage differentiation, persistence throughout serial transplantation, enhanced polyclonal repertoire, and better-preserved genome integrity. Our data identify proliferative stress as a driver of HSPC dysfunction with fundamental implications for designing more effective and safer gene correction strategies for clinical applications., Competing Interests: Declaration of interests R.D.M., L.d.V., F.M., A.C., L.N., and S.F. are inventors of patents on applications of gene editing in HSPCs owned and managed by the San Raffaele Scientific Institute and the Telethon Foundation. L.N. is a founder and quota holder of GeneSpire., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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7. One-step rapid tracking and isolation of senescent cells in cellular systems, tissues, or animal models via GLF16.

Author

Magkouta S, Veroutis D, Pousias A, Papaspyropoulos A, Giannetti K, Pippa N, Lougiakis N, Kambas K, Lagopati N, Polyzou A, Georgiou M, Chountoulesi M, Pispas S, Foutadakis S, Kyrodimos E, Pouli N, Marakos P, Kotsinas A, Verginis P, Valakos D, Vatsellas G, Petty R, Thanos D, Demaria M, Evangelou K, Di Micco R, and Gorgoulis VG

Subjects
Animals, Cell Separation, Flow Cytometry, Models, Animal, Fluorescent Dyes, Cellular Senescence
Abstract

Identification and isolation of senescent cells is challenging, rendering their detailed analysis an unmet need. We describe a precise one-step protocol to fluorescently label senescent cells, for flow cytometry and fluorescence microscopy, implementing a fluorophore-conjugated Sudan Black-B analog, GLF16. Also, a micelle-based approach allows identification of senescent cells in vivo and in vitro, enabling live-cell sorting for downstream analyses and live in vivo tracking. Our protocols are applicable to cellular systems, tissues, or animal models where senescence is present. For complete details on the use and execution of this protocol, please refer to Magkouta et al. 1 ., Competing Interests: Declaration of interests Pending patents: (1) Greek Patent Application 20230100019 and (2) University of Dundee 20230100019, regarding SBB analogs hydrophilic compounds on chemical synthesis, method(s), and application(s) use., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2024
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8. The transcription factor HIF2α partakes in the differentiation block of acute myeloid leukemia.

Author

Magliulo D, Simoni M, Caserta C, Fracassi C, Belluschi S, Giannetti K, Pini R, Zapparoli E, Beretta S, Uggè M, Draghi E, Rossari F, Coltella N, Tresoldi C, Morelli MJ, Di Micco R, Gentner B, Vago L, and Bernardi R

Subjects
Humans, Transcription Factors metabolism, Tretinoin pharmacology, Tretinoin metabolism, Tretinoin therapeutic use, Gene Expression Regulation, Cell Differentiation, Leukemia, Myeloid, Acute drug therapy, Leukemia, Promyelocytic, Acute drug therapy
Abstract

One of the defining features of acute myeloid leukemia (AML) is an arrest of myeloid differentiation whose molecular determinants are still poorly defined. Pharmacological removal of the differentiation block contributes to the cure of acute promyelocytic leukemia (APL) in the absence of cytotoxic chemotherapy, but this approach has not yet been translated to non-APL AMLs. Here, by investigating the function of hypoxia-inducible transcription factors HIF1α and HIF2α, we found that both genes exert oncogenic functions in AML and that HIF2α is a novel regulator of the AML differentiation block. Mechanistically, we found that HIF2α promotes the expression of transcriptional repressors that have been implicated in suppressing AML myeloid differentiation programs. Importantly, we positioned HIF2α under direct transcriptional control by the prodifferentiation agent all-trans retinoic acid (ATRA) and demonstrated that HIF2α blockade cooperates with ATRA to trigger AML cell differentiation. In conclusion, we propose that HIF2α inhibition may open new therapeutic avenues for AML treatment by licensing blasts maturation and leukemia debulking., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

Published
2023
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9. Lifespan and telomere length variation across populations of wild-derived African killifish.

Author

Reichard M, Giannetti K, Ferreira T, Maouche A, Vrtílek M, Polačik M, Blažek R, and Ferreira MG

Subjects
Animals, Female, Male, Longevity genetics, Telomere Shortening genetics, Telomere genetics, Fundulidae genetics, Cyprinodontiformes genetics
Abstract

Telomeres and telomerase prevent the continuous erosion of chromosome-ends caused by lifelong cell division. Shortened telomeres are associated with age-related pathologies. While short telomere length is positively correlated with increased lethality at the individual level, in comparisons across species short telomeres are associated with long (and not short) lifespans. Here, we tested this contradiction between individual and evolutionary patterns in telomere length using African annual killifish. We analysed lifespan and telomere length in a set of captive strains derived from well-defined wild populations of Nothobranchius furzeri and its sister species, N. kadleci, from sites along a strong gradient of aridity which ultimately determines maximum natural lifespan. Overall, males were shorter-lived than females, and also had shorter telomeres. Male lifespan (measured in controlled laboratory conditions) was positively associated with the amount of annual rainfall in the site of strain origin. However, fish from wetter climates had shorter telomeres. In addition, individual fish which grew largest over the juvenile period possessed shorter telomeres at the onset of adulthood. This demonstrates that individual condition and environmentally-driven selection indeed modulate the relationship between telomere length and lifespan in opposite directions, validating the existence of inverse trends within a single taxon. Intraindividual heterogeneity of telomere length (capable to detect very short telomeres) was not associated with mean telomere length, suggesting that the shortest telomeres are controlled by regulatory pathways other than those that determine mean telomere length. The substantial variation in telomere length between strains from different environments identifies killifish as a powerful system in understanding the adaptive value of telomere length., (© 2021 John Wiley & Sons Ltd.)

Published
2022
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10. Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse.

Author

Gambacorta V, Beretta S, Ciccimarra M, Zito L, Giannetti K, Andrisani A, Gnani D, Zanotti L, Oliveira G, Carrabba MG, Cittaro D, Merelli I, Ciceri F, Di Micco R, and Vago L

Subjects
Chromatin genetics, Chromatin immunology, Epigenesis, Genetic, Hematopoietic Stem Cell Transplantation, Histocompatibility Antigens Class II biosynthesis, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II immunology, Humans, Recurrence, Tumor Escape genetics, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute therapy, Polycomb Repressive Complex 2 genetics, Polycomb Repressive Complex 2 immunology
Abstract

Immune escape represents a major driver of acute myeloid leukemia (AML) reemergence after allogeneic hematopoietic cell transplantation (allo-HCT), with up to 40% of relapses prompted by nongenomic loss of HLA class II expression in leukemia cells. By integrative analysis of gene expression, DNA methylation, and chromatin accessibility in paired diagnosis/relapse primary samples and in the respective patient-derived xenografts (PDX), we identify the polycomb repressive complex 2 (PRC2) as a key epigenetic driver of this immune escape modality. We report that loss of expression of HLA class II molecules is accompanied by a PRC2-dependent reduction in chromatin accessibility. Pharmacologic inhibition of PRC2 subunits rescues HLA class II expression in AML relapses in vitro and in vivo, with consequent recovery of leukemia recognition by CD4+ T cells. Our results uncover a novel link between epigenetics and leukemia immune escape, which may rapidly translate into innovative strategies to cure or prevent AML posttransplantation relapse., Significance: Loss of HLA class II expression represents a frequent mechanism of leukemia posttransplantation relapse. Here we identify PRC2 as the main epigenetic driver of this immune escape modality and show that its chemical inhibition can reinstate a proficient graft-versus-leukemia effect, providing an innovative rationale for personalized epigenetic immunotherapies. See related commentary by Köhler and Zeiser, p. 1410. This article is highlighted in the In This Issue feature, p. 1397., (©2022 The Authors; Published by the American Association for Cancer Research.)

Published
2022
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12. Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation and histiocytosis.

Author

Biavasco R, Lettera E, Giannetti K, Gilioli D, Beretta S, Conti A, Scala S, Cesana D, Gallina P, Norelli M, Basso-Ricci L, Bondanza A, Cavalli G, Ponzoni M, Dagna L, Doglioni C, Aiuti A, Merelli I, Di Micco R, and Montini E

Subjects
Animals, Bone Marrow pathology, Cell Cycle Checkpoints genetics, Chronic Disease, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Gene Expression Regulation, Green Fluorescent Proteins metabolism, Histiocytosis complications, Humans, Inflammation complications, Lentivirus genetics, Mice, Mutation genetics, Paracrine Communication, Principal Component Analysis, Proto-Oncogene Proteins B-raf genetics, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Necrosis Factor-alpha metabolism, Cellular Senescence genetics, Hematopoiesis genetics, Hematopoietic Stem Cells metabolism, Histiocytosis pathology, Inflammation pathology, Myeloid Cells pathology, Oncogenes
Abstract

Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (BRAF V600E ). All mice transplanted with BRAF V600E -expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. At the basis of this aggressive phenotype, we uncover the engagement of a senescence program, characterized by DNA damage response activation and a senescence-associated secretory phenotype, which affects also non-mutated bystander cells. Mechanistically, we identify TNFα as a key determinant of paracrine senescence and myeloid-restricted hematopoiesis and show that its inhibition dampens inflammation, delays disease onset and rescues hematopoietic defects in bystander cells. Our work establishes that senescence in the human hematopoietic system links oncogene-activation to the systemic inflammation observed in histiocytic neoplasms., (© 2021. The Author(s).)

Published
2021
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13. Telomere shortening produces an inflammatory environment that increases tumor incidence in zebrafish.

Author

Lex K, Maia Gil M, Lopes-Bastos B, Figueira M, Marzullo M, Giannetti K, Carvalho T, and Ferreira MG

Subjects
Animals, Disease Models, Animal, Humans, Melanoma genetics, Melanoma immunology, Telomerase genetics, Telomerase metabolism, Telomere genetics, Telomere Shortening, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha immunology, Zebrafish genetics, Zebrafish immunology, Zebrafish Proteins genetics, Zebrafish Proteins metabolism, Melanoma metabolism, Telomere metabolism, Zebrafish metabolism
Abstract

Cancer incidence increases exponentially with age when human telomeres are shorter. Similarly, telomerase reverse transcriptase ( tert ) mutant zebrafish have premature short telomeres and anticipate cancer incidence to younger ages. However, because short telomeres constitute a road block to cell proliferation, telomere shortening is currently viewed as a tumor suppressor mechanism and should protect from cancer. This conundrum is not fully understood. In our current study, we report that telomere shortening promotes cancer in a noncell autonomous manner. Using zebrafish chimeras, we show increased incidence of invasive melanoma when wild-type (WT) tumors are generated in tert mutant zebrafish. Tissues adjacent to melanoma lesions (skin) and distant organs (intestine) in tert mutants exhibited higher levels of senescence and inflammation. In addition, we transferred second generation (G2) tert blastula cells into WT to produce embryo chimeras. Cells with very short telomeres induced increased tumor necrosis factor1-α (TNF1-α) expression and senescence in larval tissues in a noncell autonomous manner, creating an inflammatory environment. Considering that inflammation is protumorigenic, we transplanted melanoma-derived cells into G2 tert zebrafish embryos and observed that tissue environment with short telomeres leads to increased tumor development. To test if inflammation was necessary for this effect, we treated melanoma transplants with nonsteroid anti-inflammatory drugs and show that higher melanoma dissemination can be averted. Thus, apart from the cell autonomous role of short telomeres in contributing to genome instability, we propose that telomere shortening with age causes systemic chronic inflammation leading to increased tumor incidence., Competing Interests: The authors declare no competing interest.

Published
2020
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14. PDGF-B: The missing piece in the mosaic of PDGF family role in craniofacial development.

Author

Corsinovi D, Giannetti K, Cericola A, Naef V, and Ori M

Subjects
Animals, Cadherins metabolism, Cell Adhesion, Cell Movement, Embryo, Nonmammalian, Facial Bones embryology, Mice, Neural Crest cytology, Signal Transduction, Skull embryology, Xenopus laevis embryology, Xenopus laevis growth & development, Facial Bones growth & development, Proto-Oncogene Proteins c-sis physiology, Skull growth & development
Abstract

Background: The platelet-derived growth factor (PDGF) family consists of four ligands (PDGF-A, PDGF-B, PDGF-C, PDGF-D) and two tyrosine kinase receptors (PDGFR-α and PDGFR-β). In vertebrates, PDGF signaling influences cell proliferation, migration, and matrix deposition, and its up-regulation is implicated in cancer progression. Despite this evidence, the role of each family member during embryogenesis is still incomplete and partially controversial. In particular, study of the role of pdgf signaling during craniofacial development has been focused on pdgf-a, while the role of pdgf-b is almost unknown due to the lethal phenotypes of pdgf-b-null mice., Results: By using a pdgf-b splice-blocking morpholino approach, we highlighted impairment of neural crest cell (NCC) migration in Xenopus laevis morphants, leading to alteration of NCC derivatives formation, such as cranial nerves and cartilages. We also uncovered a possible link between pdgf-b and the expression of cadherin superfamily members cdh6 and cdh11, which mediate cell-cell adhesion promoting NCC migration., Conclusions: Our results suggested that pdgf-b signaling is involved in cranial NCC migration and it is required for proper formation of craniofacial NCC derivatives. Taken together, these data unveiled a new role for pdgf-b during vertebrate development, contributing to complete the picture of pdgf signaling role in craniofacial development., (© 2019 Wiley Periodicals, Inc.)

Published
2019
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15. Platelet derived growth factor B gene expression in the Xenopus laevis developing central nervous system.

Author

Giannetti K, Corsinovi D, Rossino C, Appolloni I, Malatesta P, and Ori M

Subjects
Animals, Carcinogenesis genetics, Central Nervous System embryology, Proto-Oncogene Proteins c-sis metabolism, Signal Transduction genetics, Xenopus laevis, Central Nervous System metabolism, Gene Expression Regulation, Developmental, Proto-Oncogene Proteins c-sis genetics
Abstract

Platelet-derived growth factor B (PDGF-B) belongs to the mitogen and growth factor family and like the other members it has many roles in cell differentiation, proliferation and migration during development, adult life and in pathological conditions. Among them it has been observed that aberrant PDGF signalling is frequently linked to glioma development and progression, and Pdgf-b over-expression in mouse neural progenitors leads to the formation of gliomas. Despite this evidence, the mechanisms underlying PDGF-B driven tumorigenesis and its role during brain development are not fully understood. In order to contribute to clarifying possible new roles of pdgf-b signalling, we present here the embryonic gene expression pattern of pdgf-b, so far unknown in early vertebrate development. By using Xenopus laevis as a model system we performed qRT-PCR and whole mount in situ hybridization. Pdgf-b mRNA is expressed in discrete regions of the developing central nervous system, in the cranial nerve placodes and in the notochord. We also compared the gene expression of pdgf-b with that of its receptor pdgfr-α suggesting so far unsuspected roles for this signalling pathway during the development of specific embryonic structures.

Published
2016
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