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19 results on '"G. Barbarito"'

1. Zoledronic acid boosts γδ T-cell activity in children receiving αβ+ T and CD19+ cell-depleted grafts from an HLA-haplo-identical donor

Author

A. Bertaina, A. Zorzoli, A. Petretto, G. Barbarito, E. Inglese, P. Merli, C. Lavarello, L. P. Brescia, B. De Angelis, G. Tripodi, L. Moretta, F. Locatelli, and I. Airoldi

Subjects
γδ t cells, haematopoietic stem cell transplantation, leukemic patients, proteomic, zoledronic acid, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

We demonstrated that γδ T cells of patients given HLA-haploidentical HSCT after removal of αβ+ T cells and CD19+ B cells are endowed with the capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we tested the hypothesis that infusion of ZOL in patients receiving this type of graft may enhance γδ T-cell cytotoxic activity against leukemia cells. ZOL was infused every 28 d in 43 patients; most were treated at least twice. γδ T cells before and after ZOL treatments were studied in 33 of these 43 patients, till at least 7 mo after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. An induction of Vδ2-cell differentiation, paralleled by increased cytotoxicity of both Vδ1 and Vδ2 cells against primary leukemia blasts was associated with ZOL treatment. Cytotoxic activity was further increased in Vδ2 cells, but not in Vδ1 lymphocytes in those patients given more than one treatment. Proteomic analysis of γδ T cells purified from patients showed upregulation of proteins involved in activation processes and immune response, paralleled by downregulation of proteins involved in proliferation. Moreover, a proteomic signature was identified for each ZOL treatment. Patients given three or more ZOL infusions had a better probability of survival in comparison to those given one or two treatments (86% vs. 54%, respectively, p = 0.008). Our data indicate that ZOL infusion in pediatric recipients of αβ T- and B-cell-depleted HLA-haploidentical HSCT promotes γδ T-cell differentiation and cytotoxicity and may influence the outcome of patients.

Published
2017
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2. Hematopoietic Stem/Progenitor Cells and Engineering: T-ALLO10 INFUSION AFTER AβDEPLETED-HSCT IN CHILDREN AND YOUNG ADULTS WITH HEMATOLOGIC MALIGNANCIES: IMPROVED IMMUNE RECONSTITUTION IN THE ABSENCE OF SEVERE GVHD

Author

A. Bertaina, R. Bacchetta, D.C. Shyr, G. Saini, J. Lee, K. Kristovich, R. Agarwal, O. Klein, K. Melsop, K. Tate, G. Barbarito, L. Oppizzi, P. Chen, A. Cepika, and M. Roncarolo

Subjects
Cancer Research, Transplantation, Oncology, Immunology, Immunology and Allergy, Cell Biology, Genetics (clinical)
Published
2023

4. Intrinsic limits on resolutions in muon- and electron-neutrino charged-current events in the KM3NeT/ORCA detector

Author

Adrian-Martinez, S. Ageron, M. Aiello, S. Albert, A. and Ameli, F. Anassontzis, E. G. Andre, M. Androulakis, G. and Anghinolfi, M. Anton, G. Ardid, M. Avgitas, T. and Barbarino, G. Barbarito, E. Baret, B. Barrios-Marti, J. and Belias, A. Berbee, E. van den Berg, A. Bertin, V. and Beurthey, S. van Beveren, V. Beverini, N. Biagi, S. and Biagioni, A. Billault, M. Bondi, M. Bormuth, R. and Bouhadef, B. Bourlis, G. Bourret, S. Boutonnet, C. and Bouwhuis, M. Bozza, C. Bruijn, R. Brunner, J. Buis, E. and Buompane, R. Busto, J. Cacopardo, G. Caillat, L. and Calamai, M. Calvo, D. Capone, A. Caramete, L. Cecchini, S. Celli, S. Champion, C. Cherubini, S. Chiarella, V. and Chiarelli, L. Chiarusi, T. Circella, M. Classen, L. and Cobas, D. Cocimano, R. Coelho, J. A. B. Coleiro, A. and Colonges, S. Coniglione, R. Cordelli, M. Cosquer, A. and Coyle, P. Creusot, A. Cuttone, G. D'Amato, C. D'Amico, A. D'Onofrio, A. De Bonis, G. De Sio, C. Di Palma, I. and Diaz, A. F. Distefano, C. Donzaud, C. Dornic, D. and Dorosti-Hasankiadeh, Q. Drakopoulou, E. Drouhin, D. and Durocher, M. Eberl, T. Eichie, S. van Eijk, D. El Bojaddaini, I. Elsaesser, D. Enzenhofer, A. Favaro, M. and Fermani, P. Ferrara, G. Frascadore, G. Furini, M. Fusco, L. A. Gal, T. Galata, S. Garufi, F. Gay, P. Gebyehu, M. Giacomini, F. Gialanella, L. Giordano, V. Gizani, N. and Gracia, R. Graf, K. Gregoire, T. Grella, G. Grmek, A. Guerzoni, M. Habel, R. Hallmann, S. van Haren, H. and Harissopulos, S. Heid, T. Heijboer, A. Heine, E. Henry, S. Hernandez-Rey, J. J. Hevinga, M. Hofestaedt, J. and Hugon, C. M. F. Illuminati, G. James, C. W. Jansweijer, P. and Jongen, M. de Jong, M. Kadler, M. Kalekin, O. and Kappes, A. Katz, U. F. Keller, P. Kieft, G. Kiessling, D. Koffeman, E. N. Kooijman, P. Kouchner, A. Kreter, M. and Kulikovskiy, V. Lahmann, R. Lamare, P. Larosa, G. and Leisos, A. Leone, F. Leonora, E. Clark, M. Lindsey and Liolios, A. Llorens Alvarez, C. D. Lo Presti, D. Lohner, H. and Lonardo, A. Lotze, M. Loucatos, S. Maccioni, E. and Mannheim, K. Manzali, M. Margiotta, A. Margotti, A. and Marinelli, A. Maris, O. Markou, C. Martinez-Mora, J. A. and Martini, A. Marzaioli, F. Mele, R. Melis, K. W. Michael, T. Migliozzi, P. Migneco, E. Mijakowski, P. Miraglia, A. and Mollo, C. M. Mongelli, M. Morganti, M. Moussa, A. and Musico, P. Musumeci, M. Navas, S. Nicolau, C. A. Olcina, I. Olivetto, C. Orlando, A. Orzelli, A. Pancaldi, G. and Papaikonomou, A. Papaleo, R. Pavalas, G. E. Peek, H. and Pellegrini, G. Pellegrino, C. Perrina, C. Pfutzner, M. and Piattelli, P. Pikounis, K. Pleinert, M. -O. Poma, G. E. and Popa, V. Pradier, T. Pratolongo, F. Puehlhofer, G. and Pulvirenti, S. Quinn, L. Racca, C. Raffaelli, F. and Randazzo, N. Rauch, T. Real, D. Resvanis, L. Reubelt, J. and Riccobene, G. Rossi, C. Rovelli, A. Saldana, M. and Salvadori, I. Samtleben, D. F. E. Garcia, A. Sanchez Losa, A. Sanchez Sanguineti, M. Santangelo, A. Santonocito, D. and Sapienza, P. Schimmel, F. Schmelling, J. Schnabel, J. and Sciacca, V. Sedita, M. Seitz, T. Sgura, I. Simeone, F. and Sipala, V. Spisso, B. Spurio, M. Stavropoulos, G. and Steijger, J. Stellacci, S. M. Stransky, D. Taiuti, M. and Tayalati, Y. Terrasi, F. Tezier, D. Theraube, S. Timmer, P. Tonnis, C. Trasatti, L. Travaglini, R. Trovato, A. and Tsirigotis, A. Tzamarias, S. Tzamariudaki, E. Vallage, B. Van Elewyck, V. Vermeulen, J. Versari, F. Vicini, P. and Viola, S. Vivolo, D. Volkert, M. Wiggers, L. Wilms, J. de Wolf, E. Zachariadou, K. Zani, S. Zornoza, J. D. and Zuniga, J. KM3NeT Collaboration

Subjects
Physics::Instrumentation and Detectors, Astrophysics::High Energy Astrophysical Phenomena, High Energy Physics::Experiment
Abstract

Studying atmospheric neutrino oscillations in the few-GeV range with a multimegaton detector promises to determine the neutrino mass hierarchy. This is the main science goal pursued by the future KM3NeT/ORCA water Cherenkov detector in the Mediterranean Sea. In this paper, the processes that limit the obtainable resolution in both energy and direction in charged-current neutrino events in the ORCA detector are investigated. These processes include the composition of the hadronic fragmentation products, the subsequent particle propagation and the photon-sampling fraction of the detector. GEANT simulations of neutrino interactions in seawater produced by GENIE are used to study the effects in the 1-20 GeV range. It is found that fluctuations in the hadronic cascade in conjunction with the variation of the inelasticity y are most detrimental to the resolutions. The effect of limited photon sampling in the detector is of significantly less importance. These results will therefore also be applicable to similar detectors/media, such as those in ice.

Published
2017

5. Letter of intent for KM3NeT 2.0

Author

Adrian-Martinez, S. Ageron, M. Aharonian, F. Aiello, S. and Albert, A. Ameli, F. Anassontzis, E. Andre, M. and Androulakis, G. Anghinolfi, M. Anton, G. Ardid, M. and Avgitas, T. Barbarino, G. Barbarito, E. Baret, B. and Barrios-Marti, J. Belhorma, B. Belias, A. Berbee, E. van den Berg, A. Bertin, V. Beurthey, S. van Beveren, V. and Beverini, N. Biagi, S. Biagioni, A. Billault, M. Bondi, M. Bormuth, R. Bouhadef, B. Bourlis, G. Bourret, S. and Boutonnet, C. Bouwhuis, M. Bozza, C. Bruijn, R. Brunner, J. Buis, E. Busto, J. Cacopardo, G. Caillat, L. and Calamai, M. Calvo, D. Capone, A. Caramete, L. Cecchini, S. Celli, S. Champion, C. Cherkaoui El Moursli, R. and Cherubini, S. Chiarusi, T. Circella, M. Classen, L. and Cocimano, R. Coelho, J. A. B. Coleiro, A. Colonges, S. and Coniglione, R. Cordelli, M. Cosquer, A. Coyle, P. and Creusot, A. Cuttone, G. D'Amico, A. De Bonis, G. De Rosa, G. De Sio, C. Di Capua, F. Di Palma, I. Diaz Garcia, A. F. Distefano, C. Donzaud, C. Dornic, D. and Dorosti-Hasankiadeh, Q. Drakopoulou, E. Drouhin, D. Drury, L. Durocher, M. Eberl, T. Eichie, S. van Eijk, D. El Bojaddaini, I. El Khayati, N. Elsaesser, D. Enzenhofer, A. and Fassi, F. Favali, P. Fermani, P. Ferrara, G. and Filippidis, C. Frascadore, G. Fusco, L. A. Gal, T. and Galata, S. Garufi, F. Gay, P. Gebyehu, M. Giordano, V. and Gizani, N. Gracia, R. Graf, K. Gregoire, T. Grella, G. Habel, R. Hallmann, S. van Haren, H. Harissopulos, S. and Heid, T. Heijboer, A. Heine, E. Henry, S. and Hernandez-Rey, J. J. Hevinga, M. Hofestaedt, J. Hugon, C. M. F. Illuminati, G. James, C. W. Jansweijer, P. Jongen, M. and de Jong, M. Kadler, M. Kalekin, O. Kappes, A. Katz, U. F. Keller, P. Kieft, G. Kiessling, D. Koffeman, E. N. and Kooijman, P. Kouchner, A. Kulikovskiy, V. Lahmann, R. and Lamare, P. Leisos, A. Leonora, E. Clark, M. Lindsey and Liolios, A. Llorens Alvarez, C. D. Lo Presti, D. Lohner, H. and Lonardo, A. Lotze, M. Loucatos, S. Maccioni, E. and Mannheim, K. Margiotta, A. Marinelli, A. Maris, O. and Markou, C. Martinez-Mora, J. A. Martini, A. Mele, R. and Melis, K. W. Michael, T. Migliozzi, P. Migneco, E. and Mijakowski, P. Miraglia, A. Mollo, C. M. Mongelli, M. and Morganti, M. Moussa, A. Musico, P. Musumeci, M. Navas, S. Nicolau, C. A. Olcina, I. Olivetto, C. Orlando, A. and Papaikonomou, A. Papaleo, R. Pavalas, G. E. Peek, H. and Pellegrino, C. Perrina, C. Pfutzner, M. Piattelli, P. and Pikounis, K. Poma, G. E. Popa, V. Pradier, T. and Pratolongo, F. Puehlhofer, G. Pulvirenti, S. Quinn, L. and Racca, C. Raffaelli, F. Randazzo, N. Rapidis, P. Razis, P. Real, D. Resvanis, L. Reubelt, J. Riccobene, G. and Rossi, C. Rovelli, A. Saldana, M. Salvadori, I. and Samtleben, D. F. E. Garcia, A. Sanchez Losa, A. Sanchez and Sanguineti, M. Santangelo, A. Santonocito, D. Sapienza, P. and Schimmel, F. Schmelling, J. Sciacca, V. Sedita, M. and Seitz, T. Sgura, I. Simeone, F. Siotis, I. Sipala, V. and Spisso, B. Spurio, M. Stavropoulos, G. Steijger, J. and Stellacci, S. M. Stransky, D. Taiuti, M. Tayalati, Y. and Tezier, D. Theraube, S. Thompson, L. Timmer, P. Tonnis, C. Trasatti, L. Trovato, A. Tsirigotis, A. Tzamarias, S. and Tzamariudaki, E. Vallage, B. Van Elewyck, V. Vermeulen, J. Vicini, P. Viola, S. Vivolo, D. Volkert, M. and Voulgaris, G. Wiggers, L. Wilms, J. de Wolf, E. and Zachariadou, K. Zornoza, J. D. Zuniga, J.

Subjects
Astrophysics::High Energy Astrophysical Phenomena, Astrophysics::Instrumentation and Methods for Astrophysics
Abstract

The main objectives of the KM3NeT Collaboration are (i) the discovery and subsequent observation of high-energy neutrino sources in the Universe and (ii) the determination of the mass hierarchy of neutrinos. These objectives are strongly motivated by two recent important discoveries, namely: (1) the high-energy astrophysical neutrino signal reported by IceCube and (2) the sizable contribution of electron neutrinos to the third neutrino mass eigenstate as reported by Daya Bay, Reno and others. To meet these objectives, the KM3NeT Collaboration plans to build a new Research Infrastructure consisting of a network of deep-sea neutrino telescopes in the Mediterranean Sea. A phased and distributed implementation is pursued which maximises the access to regional funds, the availability of human resources and the synergistic opportunities for the Earth and sea sciences community. Three suitable deep-sea sites are selected, namely off-shore Toulon (France), Capo Passero (Sicily, Italy) and Pylos (Peloponnese, Greece). The infrastructure will consist of three so-called building blocks. A building block comprises 115 strings, each string comprises 18 optical modules and each optical module comprises 31 photo-multiplier tubes. Each building block thus constitutes a three-dimensional array of photo sensors that can be used to detect the Cherenkov light produced by relativistic particles emerging from neutrino interactions. Two building blocks will be sparsely configured to fully explore the IceCube signal with similar instrumented volume, different methodology, improved resolution and complementary field of view, including the galactic plane. One building block will be densely configured to precisely measure atmospheric neutrino oscillations.

Published
2016

6. A method to stabilise the performance of negatively fed KM3NeT photomultipliers

Author

Adrián-Martínez, S. Ageron, M. Aiello, S. Albert, A. Ameli, F. Anassontzis, E.G. Andre, M. Androulakis, G. Anghinolfi, M. Anton, G. Ardid, M. Avgitas, T. Barbarino, G. Barbarito, E. Baret, B. Barrios-Martí, J. Belias, A. Berbee, E. Van Den Berg, A. Bertin, V. Beurthey, S. Van Beveren, V. Beverini, N. Biagi, S. Biagioni, A. Billault, M. Bondì, M. Bormuth, R. Bouhadef, B. Bourlis, G. Bourret, S. Boutonnet, C. Bouwhuis, M. Bozza, C. Bruijn, R. Brunner, J. Buis, E. Buompane, R. Busto, J. Cacopardo, G. Caillat, L. Calamai, M. Calvo, D. Capone, A. Caramete, L. Cecchini, S. Celli, S. Champion, C. Cherubini, S. Chiarella, V. Chiarelli, L. Chiarusi, T. Circella, M. Classen, L. Cobas, D. Cocimano, R. Coelho, J.A.B. Coleiro, A. Colonges, S. Coniglione, R. Cordelli, M. Cosquer, A. Coyle, P. Creusot, A. Cuttone, G. D'Amato, C. D'Amico, A. D'Onofrio, A. De Bonis, G. De Sio, C. Di Capua, F. Di Palma, I. Distefano, C. Donzaud, C. Dornic, D. Dorosti-Hasankiadeh, Q. Drakopoulou, E. Drouhin, D. Durocher, M. Eberl, T. Eichie, S. Van Eijk, D. El Bojaddaini, I. Elsaesser, D. Enzenhöfer, A. Favaro, M. Fermani, P. Ferrara, G. Frascadore, G. Furini, M. Fusco, L.A. Gal, T. Galatà, S. Garufi, F. Gay, P. Gebyehu, M. Giacomini, F. Gialanella, L. Giordano, V. Gizani, N. Gracia, R. Graf, K. Grégoire, T. Grella, G. Grmek, A. Guerzoni, M. Habel, R. Hallmann, S. Van Haren, H. Harissopulos, S. Heid, T. Heijboer, A. Heine, E. Henry, S. Hernández-Rey, J.J. Hevinga, M. Hofestädt, J. Hugon, C.M.F. Illuminati, G. James, C.W. Jansweijer, P. Jongen, M. De Jong, M. Kadler, M. Kalekin, O. Kappes, A. Katz, U.F. Keller, P. Kieft, G. Kießling, D. Koffeman, E.N. Kooijman, P. Kouchner, A. Kreter, M. Kulikovskiy, V. Lahmann, R. Lamare, P. Leisos, A. Leonora, E. Clark, M.L. Liolios, A. Alvarez, C.D.L. Lo Presti, D. Löhner, H. Lonardo, A. Lotze, M. Loucatos, S. Maccioni, E. Mannheim, K. Manzali, M. Margiotta, A. Margotti, A. Marinelli, A. Mariš, O. Markou, C. Martínez-Mora, J.A. Martini, A. Marzaioli, F. Mele, R. Melis, K.W. Michael, T. Migliozzi, P. Migneco, E. Mijakowski, P. Miraglia, A. Mollo, C.M. Mongelli, M. Morganti, M. Moussa, A. Musico, P. Musumeci, M. Nicolau, C.A. Olcina, I. Olivetto, C. Orlando, A. Orzelli, A. Pancaldi, G. Paolucci, A. Papaikonomou, A. Papaleo, R. Pǎvǎlaš, G.E. Peek, H. Pellegrini, G. Pellegrino, C. Perrina, C. Pfutzner, M. Piattelli, P. Pikounis, K. Poma, G.E. Popa, V. Pradier, T. Pratolongo, F. Pühlhofer, G. Pulvirenti, S. Quinn, L. Racca, C. Raffaelli, F. Randazzo, N. Real, D. Resvanis, L. Reubelt, J. Riccobene, G. Rossi, C. Rovelli, A. Saldaña, M. Salvadori, I. Samtleben, D.F.E. Sánchez García, A. Sánchez Losa, A. Sanguineti, M. Santangelo, A. Santonocito, D. Sapienza, P. Schimmel, F. Schmelling, J. Schnabel, J. Sciacca, V. Sedita, M. Seitz, T. Sgura, I. Simeone, F. Sipala, V. Spisso, B. Spurio, M. Stavropoulos, G. Steijger, J. Stellacci, S.M. Stransky, D. Taiuti, M. Tayalati, Y. Terrasi, F. Tézier, D. Theraube, S. Timmer, P. Tönnis, C. Trasatti, L. Travaglini, R. Trovato, A. Tsirigotis, A. Tzamarias, S. Tzamariudaki, E. Vallage, B. Van Elewyck, V. Vermeulen, J. Versari, F. Vicini, P. Viola, S. Vivolo, D. Volkert, M. Wiggers, L. Wilms, J. De Wolf, E. Zachariadou, K. Zani, S. Zornoza, J.D. Zúñiga, J.

Abstract

The KM3NeT research infrastructure, currently under construction in the Mediterranean Sea, will host neutrino telescopes for the identification of neutrino sources in the Universe and for studies of the neutrino mass hierarchy. These telescopes will house hundreds of thousands of photomultiplier tubes that will have to be operated in a stable and reliable fashion. In this context, the stability of the dark counts has been investigated for photomultiplier tubes with negative high voltage on the photocathode and held in insulating support structures made of 3D printed nylon material. Small gaps between the rigid support structure and the photomultiplier tubes in the presence of electric fields can lead to discharges that produce dark count rates that are highly variable. A solution was found by applying the same insulating varnish as used for the high voltage bases directly to the outside of the photomultiplier tubes. This transparent conformal coating provides a convenient and inexpensive method of insulation. © 2016 IOP Publishing Ltd and Sissa Medialab srl.

Published
2016

7. The prototype detection unit of the KM3NeT detector: KM3NeT Collaboration

Author

Adrián-Martínez, S. Ageron, M. Aharonian, F. Aiello, S. Albert, A. Ameli, F. Anassontzis, E.G. Androulakis, G.C. Anghinolfi, M. Anton, G. Anvar, S. Ardid, M. Avgitas, T. Balasi, K. Band, H. Barbarino, G. Barbarito, E. Barbato, F. Baret, B. Baron, S. Barrios, J. Belias, A. Berbee, E. van den Berg, A.M. Berkien, A. Bertin, V. Beurthey, S. van Beveren, V. Beverini, N. Biagi, S. Biagioni, A. Bianucci, S. Billault, M. Birbas, A. Boer Rookhuizen, H. Bormuth, R. Bouché, V. Bouhadef, B. Bourlis, G. Boutonnet, C. Bouwhuis, M. Bozza, C. Bruijn, R. Brunner, J. Cacopardo, G. Caillat, L. Calamai, M. Calvo, D. Capone, A. Caramete, L. Caruso, F. Cecchini, S. Ceres, A. Cereseto, R. Champion, C. Château, F. Chiarusi, T. Christopoulou, B. Circella, M. Classen, L. Cocimano, R. Coleiro, A. Colonges, S. Coniglione, R. Cosquer, A. Costa, M. Coyle, P. Creusot, A. Cuttone, G. D’Amato, C. D’Amico, A. De Bonis, G. De Rosa, G. Deniskina, N. Destelle, J.-J. Distefano, C. Di Capua, F. Donzaud, C. Dornic, D. Dorosti-Hasankiadeh, Q. Drakopoulou, E. Drouhin, D. Drury, L. Durand, D. Eberl, T. Elsaesser, D. Enzenhöfer, A. Fermani, P. Fusco, L.A. Gajanana, D. Gal, T. Galatà, S. Garufi, F. Gebyehu, M. Giordano, V. Gizani, N. Gracia Ruiz, R. Graf, K. Grasso, R. Grella, G. Grmek, A. Habel, R. van Haren, H. Heid, T. Heijboer, A. Heine, E. Henry, S. Hernández-Rey, J.J. Herold, B. Hevinga, M.A. van der Hoek, M. Hofestädt, J. Hogenbirk, J. Hugon, C. Hößl, J. Imbesi, M. James, C.W. Jansweijer, P. Jochum, J. de Jong, M. Jongen, M. Kadler, M. Kalekin, O. Kappes, A. Kappos, E. Katz, U. Kavatsyuk, O. Keller, P. Kieft, G. Koffeman, E. Kok, H. Kooijman, P. Koopstra, J. Korporaal, A. Kouchner, A. Kreykenbohm, I. Kulikovskiy, V. Lahmann, R. Lamare, P. Larosa, G. Lattuada, D. Le Provost, H. Leismüller, K.P. Leisos, A. Lenis, D. Leonora, E. Lindsey Clark, M. Llorens Alvarez, C.D. Löhner, H. Lonardo, A. Loucatos, S. Louis, F. Maccioni, E. Mannheim, K. Manolopoulos, K. Margiotta, A. Mariş, O. Markou, C. Martínez-Mora, J.A. Martini, A. Masullo, R. Melis, K.W. Michael, T. Migliozzi, P. Migneco, E. Miraglia, A. Mollo, C.M. Mongelli, M. Morganti, M. Mos, S. Moudden, Y. Musico, P. Musumeci, M. Nicolaou, C. Nicolau, C.A. Orlando, A. Orzelli, A. Papaikonomou, A. Papaleo, R. Păvălaş, G.E. Peek, H. Pellegrino, C. Pellegriti, M.G. Perrina, C. Piattelli, P. Pikounis, K. Popa, V. Pradier, T. Priede, M. Pühlhofer, G. Pulvirenti, S. Racca, C. Raffaelli, F. Randazzo, N. Rapidis, P.A. Razis, P. Real, D. Resvanis, L. Reubelt, J. Riccobene, G. Rovelli, A. Saldaña, M. Samtleben, D.F.E. Sanguineti, M. Santangelo, A. Sapienza, P. Schmelling, J. Schnabel, J. Sciacca, V. Sedita, M. Seitz, T. Sgura, I. Simeone, F. Sipala, V. Spitaleri, A. Spurio, M. Stavropoulos, G. Steijger, J. Stolarczyk, T. Stransky, D. Taiuti, M. Terreni, G. Tézier, D. Théraube, S. Thompson, L.F. Timmer, P. Trasatti, L. Trovato, A. Tselengidou, M. Tsirigotis, A. Tzamarias, S. Tzamariudaki, E. Vallage, B. Van Elewyck, V. Vermeulen, J. Vernin, P. Vicini, P. Viola, S. Vivolo, D. Werneke, P. Wiggers, L. Wilms, J. de Wolf, E. van Wooning, R.H.L. Zonca, E. Zornoza, J.D. Zúñiga, J. Zwart, A.

Subjects
Physics::Instrumentation and Detectors
Abstract

A prototype detection unit of the KM3NeT deep-sea neutrino telescope has been installed at 3500m depth 80 km offshore the Italian coast. KM3NeT in its final configuration will contain several hundreds of detection units. Each detection unit is a mechanical structure anchored to the sea floor, held vertical by a submerged buoy and supporting optical modules for the detection of Cherenkov light emitted by charged secondary particles emerging from neutrino interactions. This prototype string implements three optical modules with 31 photomultiplier tubes each. These optical modules were developed by the KM3NeT Collaboration to enhance the detection capability of neutrino interactions. The prototype detection unit was operated since its deployment in May 2014 until its decommissioning in July 2015. Reconstruction of the particle trajectories from the data requires a nanosecond accuracy in the time calibration. A procedure for relative time calibration of the photomultiplier tubes contained in each optical module is described. This procedure is based on the measured coincidences produced in the sea by the $$^{40}$$40K background light and can easily be expanded to a detector with several thousands of optical modules. The time offsets between the different optical modules are obtained using LED nanobeacons mounted inside them. A set of data corresponding to 600 h of livetime was analysed. The results show good agreement with Monte Carlo simulations of the expected optical background and the signal from atmospheric muons. An almost background-free sample of muons was selected by filtering the time correlated signals on all the three optical modules. The zenith angle of the selected muons was reconstructed with a precision of about 3$$^\circ $$∘. © 2016, The Author(s).

Published
2016

8. Deep sea tests of a prototype of the KM3NeT digital optical module: KM3NeT Collaboration

Author

Adrián-Martínez, S. Ageron, M. Aharonian, F. Aiello, S. Albert, A. Ameli, F. Anassontzis, E.G. Anghinolfi, M. Anton, G. Anvar, S. Ardid, M. de Asmundis, R. Balasi, K. Band, H. Barbarino, G. Barbarito, E. Barbato, F. Baret, B. Baron, S. Belias, A. Berbee, E. van den Berg, A.M. Berkien, A. Bertin, V. Beurthey, S. van Beveren, V. Beverini, N. Biagi, S. Bianucci, S. Billault, M. Birbas, A. Boer Rookhuizen, H. Bormuth, R. Bouché, V. Bouhadef, B. Bourlis, G. Bouwhuis, M. Bozza, C. Bruijn, R. Brunner, J. Cacopardo, G. Caillat, L. Calamai, M. Calvo, D. Capone, A. Caramete, L. Caruso, F. Cecchini, S. Ceres, A. Cereseto, R. Champion, C. Château, F. Chiarusi, T. Christopoulou, B. Circella, M. Classen, L. Cocimano, R. Colonges, S. Coniglione, R. Cosquer, A. Costa, M. Coyle, P. Creusot, A. Curtil, C. Cuttone, G. D’Amato, C. D’Amico, A. De Bonis, G. De Rosa, G. Deniskina, N. Destelle, J.-J. Distefano, C. Donzaud, C. Dornic, D. Dorosti-Hasankiadeh, Q. Drakopoulou, E. Drouhin, D. Drury, L. Durand, D. Eberl, T. Eleftheriadis, C. Elsaesser, D. Enzenhöfer, A. Fermani, P. Fusco, L.A. Gajana, D. Gal, T. Galatà, S. Gallo, F. Garufi, F. Gebyehu, M. Giordano, V. Gizani, N. Gracia Ruiz, R. Graf, K. Grasso, R. Grella, G. Grmek, A. Habel, R. van Haren, H. Heid, T. Heijboer, A. Heine, E. Henry, S. Hernández-Rey, J.J. Herold, B. Hevinga, M.A. van der Hoek, M. Hofestädt, J. Hogenbirk, J. Hugon, C. Hößl, J. Imbesi, M. James, C. Jansweijer, P. Jochum, J. de Jong, M. Kadler, M. Kalekin, O. Kappes, A. Kappos, E. Katz, U. Kavatsyuk, O. Keller, P. Kieft, G. Koffeman, E. Kok, H. Kooijman, P. Koopstra, J. Korporaal, A. Kouchner, A. Koutsoukos, S. Kreykenbohm, I. Kulikovskiy, V. Lahmann, R. Lamare, P. Larosa, G. Lattuada, D. Le Provost, H. Leisos, A. Lenis, D. Leonora, E. Lindsey Clark, M. Liolios, A. Llorens Alvarez, C.D. Löhner, H. Lo Presti, D. Louis, F. Maccioni, E. Mannheim, K. Manolopoulos, K. Margiotta, A. Mariş, O. Markou, C. Martínez-Mora, J.A. Martini, A. Masullo, R. Michael, T. Migliozzi, P. Migneco, E. Miraglia, A. Mollo, C. Mongelli, M. Morganti, M. Mos, S. Moudden, Y. Musico, P. Musumeci, M. Nicolaou, C. Nicolau, C.A. Orlando, A. Orzelli, A. Papageorgiou, K. Papaikonomou, A. Papaleo, R. Păvălaş, G.E. Peek, H. Pellegrino, C. Pellegriti, M.G. Perrina, C. Petridou, C. Piattelli, P. Pikounis, K. Popa, V. Pradier, T. Priede, M. Pühlhofer, G. Pulvirenti, S. Racca, C. Raffaelli, F. Randazzo, N. Rapidis, P.A. Razis, P. Real, D. Resvanis, L. Reubelt, J. Riccobene, G. Rovelli, A. Royon, J. Saldaña, M. Samtleben, D.F.E. Sanguineti, M. Santangelo, A. Sapienza, P. Savvidis, I. Schmelling, J. Schnabel, J. Sedita, M. Seitz, T. Sgura, I. Simeone, F. Siotis, I. Sipala, V. Solazzo, M. Spitaleri, A. Spurio, M. Stavropoulos, G. Steijger, J. Stolarczyk, T. Stransky, D. Taiuti, M. Terreni, G. Tézier, D. Théraube, S. Thompson, L.F. Timmer, P. Trapierakis, H.I. Trasatti, L. Trovato, A. Tselengidou, M. Tsirigotis, A. Tzamarias, S. Tzamariudaki, E. Vallage, B. Van Elewyck, V. Vermeulen, J. Vernin, P. Viola, S. Vivolo, D. Werneke, P. Wiggers, L. Wilms, J. de Wolf, E. van Wooning, R.H.L. Yatkin, K. Zachariadou, K. Zonca, E. Zornoza, J.D. Zúñiga, J. Zwart, A.

Subjects
Physics::Instrumentation and Detectors, Astrophysics::Instrumentation and Methods for Astrophysics
Abstract

The first prototype of a photo-detection unit of the future KM3NeT neutrino telescope has been deployed in the deep waters of the Mediterranean Sea. This digital optical module has a novel design with a very large photocathode area segmented by the use of 31 three inch photomultiplier tubes. It has been integrated in the ANTARES detector for in-situ testing and validation. This paper reports on the first months of data taking and rate measurements. The analysis results highlight the capabilities of the new module design in terms of background suppression and signal recognition. The directionality of the optical module enables the recognition of multiple Cherenkov photons from the same40 K decay and the localisation of bioluminescent activity in the neighbourhood. The single unit can cleanly identify atmospheric muons and provide sensitivity to the muon arrival directions. © 2014, The Author(s).

Published
2014

9. Expansion cone for the 3-inch PMTs of the KM3NeT optical modules

Author

Adrian-Martinez, S. Ageron, M. Aguilar, J.A. Aharonian, F. Aiello, S. Albert, A. Alexandri, M. Ameli, M. Anassontzis, E.G. Anghinolfi, M. Anton, G. Anvar, S. Ardid, M. Assis Jesus, A. Aubert, J.-J. Bakker, R. Ball, A.E. Barbarino, G. Barbarito, E. Barbato, F. Baret, B. De Bel, M. Belias, A. Bellou, N. Berbee, E. Berkien, A. Bersani, A. Bertin, V. Beurthey, S. Biagi, S. Bigongiari, C. Bigourdan, B. Billault, M. De Boer, R. Boer Rookhuizen, H. Bonori, M. Borghini, M. Bou-Cabo, M. Bouhadef, B. Bourlis, G. Bouwhuis, M. Bradbury, S. Brown, A. Bruni, F. Brunner, J. Brunoldi, M. Busto, J. Cacopardo, G. Caillat, L. Calvo Díaz-Aldagalán, D. Calzas, A. Canals, M. Capone, A. Carr, J. Castorina, E. Cecchini, S. Ceres, A. Cereseto, R. Chaleil, Th. Chateau, F. Chiarusi, T. Choqueuse, D. Christopoulou, P.E. Chronis, G. Ciaffoni, O. Circella, M. Cocimano, R. Cohen, F. Colijn, F. Coniglione, R. Cordelli, M. Cosquer, A. Costa, M. Coyle, P. Craig, J. Creusot, A. Curtil, C. D'Amico, A. Damy, G. De Asmundis, R. De Bonis, G. Decock, G. Decowski, P. Delagnes, E. De Rosa, G. Distefano, C. Donzaud, C. Dornic, D. Dorosti-Hasankiadeh, Q. Drogou, J. Drouhin, D. Druillole, F. Drury, L. Durand, D. Durand, G.A. Eberl, T. Emanuele, U. Enzenhöfer, A. Ernenwein, J.-P. Escoffier, S. Espinosa, V. Etiope, G. Favali, P. Felea, D. Ferri, M. Ferry, S. Flaminio, V. Folger, F. Fotiou, A. Fritsch, U. Gajanana, D. Garaguso, R. Gasparini, G.P. Gasparoni, F. Gautard, V. Gensolen, F. Geyer, K. Giacomelli, G. Gialas, I. Giordano, V. Giraud, J. Gizani, N. Gleixner, A. Gojak, C. Gómez-González, J.P. Graf, K. Grasso, D. Grimaldi, A. Groenewegen, R. Guédé, Z. Guillard, G. Guilloux, F. Habel, R. Hallewell, G. Van Haren, H. Van Heerwaarden, J. Heijboer, A. Heine, E. Hernández-Rey, J.J. Herold, B. Van De Hoek, M. Hogenbirk, J. Hößl, J. Hsu, C.C. Imbesi, M. Jamieson, A. Jansweijer, P. De Jong, M. Jouvenot, F. Kadler, M. Kalantar-Nayestanaki, N. Kalekin, O. Kappes, A. Karolak, M. Katz, U.F. Kavatsyuk, O. Keller, P. Kiskiras, Y. Klein, R. Kok, H. Kontoyiannis, H. Kooijman, P. Koopstra, J. Kopper, C. Korporaal, A. Koske, P. Kouchner, A. Koutsoukos, S. Kreykenbohm, I. Kulikovskiy, V. Laan, M. La Fratta, C. Lagier, P. Lahmann, R. Lamare, P. Larosa, G. Lattuada, D. Leisos, A. Lenis, D. Leonora, E. Le Provost, H. Lim, G. Llorens, C.D. Lloret, J. Löhner, H. Lo Presti, D. Lotrus, P. Louis, F. Lucarelli, F. Lykousis, V. Malyshev, D. Mangano, S. Marcoulaki, E.C. Margiotta, A. Marinaro, G. Marinelli, A. Maris, O. Markopoulos, E. Markou, C. Martínez-Mora, J.A. Martini, A. Marvaldi, J. Masullo, R. Maurin, G. Migliozzi, P. Migneco, E. Minutoli, S. Miraglia, A. Mollo, C.M. Mongelli, M. Monmarthe, E. Morganti, M. Mos, S. Motz, H. Moudden, Y. Mul, G. Musico, P. Musumeci, M. Naumann, Ch. Neff, M. Nicolaou, C. Orlando, A. Palioselitis, D. Papageorgiou, K. Papaikonomou, A. Papaleo, R. Papazoglou, I.A. Pǎvǎlas, G.E. Peek, H.Z. Perkin, J. Piattelli, P. Popa, V. Pradier, T. Presani, E. Priede, I.G. Psallidas, A. Rabouille, C. Racca, C. Radu, A. Randazzo, N. Rapidis P.a. Razis, P. Real, D. Reed, C. Reito, S. Resvanis, L.K. Riccobene, G. Richter, R. Roensch, K. Rolin, J. Rose, J. Roux, J. Rovelli, A. Russo, A. Russo, G.V. Salesa, F. Samtleben, D. Sapienza, P. Schmelling, J.-W. Schmid, J. Schnabel, J. Schroeder, K. Schuller, J.-P. Schussler, F. Sciliberto, D. Sedita, M. Seitz, T. Shanidze, R. Simeone, F. Siotis, I. Sipala, V. Sollima, C. Sparnocchia, S. Spies, A. Spurio, M. Staller, T. Stavrakakis, S. Stavropoulos, G. Steijger, J. Stolarczyk, Th. Stransky, D. Taiuti, M. Taylor, A. Thompson, L. Timmer, P. Tonoiu, D. Toscano, S. Touramanis, C. Trasatti, L. Traverso, P. Trovato, A. Tsirigotis, A. Tzamarias, S. Tzamariudaki, E. Urbano, F. Vallage, B. Van Elewyck, V. Vannoni, G. Vecchi, M. Vernin, P. Viola, S. Vivolo, D. Wagner, S. Werneke, P. White, R.J. Wijnker, G. Wilms, J. De Wolf, E. Yepes, H. Zhukov, V. Zonca, E. Zornoza, J.D. Zúñiga, J.

Subjects
Physics::Instrumentation and Detectors, Astrophysics::Instrumentation and Methods for Astrophysics
Abstract

Detection of high-energy neutrinos from distant astrophysical sources will open a new window on the Universe. The detection principle exploits the measurement of Cherenkov light emitted by charged particles resulting from neutrino interactions in the matter containing the telescope. A novel multi-PMT digital optical module (DOM) was developed to contain 31 3-inch photomultiplier tubes (PMTs). In order to maximize the detector sensitivity, each PMT will be surrounded by an expansion cone which collects photons that would otherwise miss the photocathode. Results for various angles of incidence with respect to the PMT surface indicate an increase in collection efficiency by 30% on average for angles up to 45° with respect to the perpendicular. Ray-tracing calculations could reproduce the measurements, allowing to estimate an increase in the overall photocathode sensitivity, integrated over all angles of incidence, by 27% (for a single PMT). Prototype DOMs, being built by the KM3NeT consortium, will be equipped with these expansion cones.© 2013 IOP Publishing Ltd and Sissa Medialab srl.

Published
2013

10. Detection potential of the KM3NeT detector for high-energy neutrinos from the Fermi bubbles

Author

Adrián-Martínez, S. Ageron, M. Aguilar, J.A. Aharonian, F. Aiello, S. Albert, A. Alexandri, M. Ameli, F. Anassontzis, E.G. Anghinolfi, M. Anton, G. Anvar, S. Ardid, M. Assis Jesus, A. Aubert, J.-J. Bakker, R. Ball, A.E. Barbarino, G. Barbarito, E. Barbato, F. Baret, B. De Bel, M. Belias, A. Bellou, N. Berbee, E. Berkien, A. Bersani, A. Bertin, V. Beurthey, S. Biagi, S. Bigongiari, C. Bigourdan, B. Billault, M. De Boer, R. Boer Rookhuizen, H. Bonori, M. Borghini, M. Bou-Cabo, M. Bouhadef, B. Bourlis, G. Bouwhuis, M. Bradbury, S. Brown, A. Bruni, F. Brunner, J. Brunoldi, M. Busto, J. Cacopardo, G. Caillat, L. Calvo Díaz-Aldagalán, D. Calzas, A. Canals, M. Capone, A. Carr, J. Castorina, E. Cecchini, S. Ceres, A. Cereseto, R. Chaleil, T. Chateau, F. Chiarusi, T. Choqueuse, D. Christopoulou, P.E. Chronis, G. Ciaffoni, O. Circella, M. Cocimano, R. Cohen, F. Colijn, F. Coniglione, R. Cordelli, M. Cosquer, A. Costa, M. Coyle, P. Craig, J. Creusot, A. Curtil, C. D'Amico, A. Damy, G. De Asmundis, R. De Bonis, G. Decock, G. Decowski, P. Delagnes, E. De Rosa, G. Distefano, C. Donzaud, C. Dornic, D. Dorosti-Hasankiadeh, Q. Drogou, J. Drouhin, D. Druillole, F. Drury, L. Durand, D. Durand, G.A. Eberl, T. Emanuele, U. Enzenhöfer, A. Ernenwein, J.-P. Escoffier, S. Espinosa, V. Etiope, G. Favali, P. Felea, D. Ferri, M. Ferry, S. Flaminio, V. Folger, F. Fotiou, A. Fritsch, U. Gajanana, D. Garaguso, R. Gasparini, G.P. Gasparoni, F. Gautard, V. Gensolen, F. Geyer, K. Giacomelli, G. Gialas, I. Giordano, V. Giraud, J. Gizani, N. Gleixner, A. Gojak, C. Gómez-González, J.P. Graf, K. Grasso, D. Grimaldi, A. Groenewegen, R. Guédé, Z. Guillard, G. Guilloux, F. Habel, R. Hallewell, G. Van Haren, H. Van Heerwaarden, J. Heijboer, A. Heine, E. Hernández-Rey, J.J. Herold, B. Hillebrand, T. Van De Hoek, M. Hogenbirk, J. Hößl, J. Hsu, C.C. Imbesi, M. Jamieson, A. Jansweijer, P. De Jong, M. Jouvenot, F. Kadler, M. Kalantar-Nayestanaki, N. Kalekin, O. Kappes, A. Karolak, M. Katz, U.F. Kavatsyuk, O. Keller, P. Kiskiras, Y. Klein, R. Kok, H. Kontoyiannis, H. Kooijman, P. Koopstra, J. Kopper, C. Korporaal, A. Koske, P. Kouchner, A. Koutsoukos, S. Kreykenbohm, I. Kulikovskiy, V. Laan, M. La Fratta, C. Lagier, P. Lahmann, R. Lamare, P. Larosa, G. Lattuada, D. Leisos, A. Lenis, D. Leonora, E. Le Provost, H. Lim, G. Llorens, C.D. Lloret, J. Löhner, H. Lo Presti, D. Lotrus, P. Louis, F. Lucarelli, F. Lykousis, V. Malyshev, D. Mangano, S. Marcoulaki, E.C. Margiotta, A. Marinaro, G. Marinelli, A. Mariş, O. Markopoulos, E. Markou, C. Martínez-Mora, J.A. Martini, A. Marvaldi, J. Masullo, R. Maurin, G. Migliozzi, P. Migneco, E. Minutoli, S. Miraglia, A. Mollo, C.M. Mongelli, M. Monmarthe, E. Morganti, M. Mos, S. Motz, H. Moudden, Y. Mul, G. Musico, P. Musumeci, M. Naumann, C. Neff, M. Nicolaou, C. Orlando, A. Palioselitis, D. Papageorgiou, K. Papaikonomou, A. Papaleo, R. Papazoglou, I.A. Pǎvǎlaş, G.E. Peek, H.Z. Perkin, J. Piattelli, P. Popa, V. Pradier, T. Presani, E. Priede, I.G. Psallidas, A. Rabouille, C. Racca, C. Radu, A. Randazzo, N. Rapidis, P.A. Razis, P. Real, D. Reed, C. Reito, S. Resvanis, L.K. Riccobene, G. Richter, R. Roensch, K. Rolin, J. Rose, J. Roux, J. Rovelli, A. Russo, A. Russo, G.V. Salesa, F. Samtleben, D. Sapienza, P. Schmelling, J.-W. Schmid, J. Schnabel, J. Schroeder, K. Schuller, J.-P. Schussler, F. Sciliberto, D. Sedita, M. Seitz, T. Shanidze, R. Simeone, F. Siotis, I. Sipala, V. Sollima, C. Sparnocchia, S. Spies, A. Spurio, M. Staller, T. Stavrakakis, S. Stavropoulos, G. Steijger, J. Stolarczyk, T. Stransky, D. Taiuti, M. Taylor, A. Thompson, L. Timmer, P. Tonoiu, D. Toscano, S. Touramanis, C. Trasatti, L. Traverso, P. Trovato, A. Tsirigotis, A. Tzamarias, S. Tzamariudaki, E. Urbano, F. Vallage, B. Van Elewyck, V. Vannoni, G. Vecchi, M. Vernin, P. Viola, S. Vivolo, D. Wagner, S. Werneke, P. White, R.J. Wijnker, G. Wilms, J. De Wolf, E. Yepes, H. Zhukov, V. Zonca, E. Zornoza, J.D. Zúñiga, J.

Subjects
Astrophysics::High Energy Astrophysical Phenomena, High Energy Physics::Experiment
Abstract

A recent analysis of the Fermi Large Area Telescope data provided evidence for a high-intensity emission of high-energy gamma rays with a E-2 spectrum from two large areas, spanning 50° above and below the Galactic centre (the "Fermi bubbles"). A hadronic mechanism was proposed for this gamma-ray emission making the Fermi bubbles promising source candidates of high-energy neutrino emission. In this work Monte Carlo simulations regarding the detectability of high-energy neutrinos from the Fermi bubbles with the future multi-km3 neutrino telescope KM3NeT in the Mediterranean Sea are presented. Under the hypothesis that the gamma-ray emission is completely due to hadronic processes, the results indicate that neutrinos from the bubbles could be discovered in about one year of operation, for a neutrino spectrum with a cutoff at 100 TeV and a detector with about 6 km3 of instrumented volume. The effect of a possible lower cutoff is also considered. © 2012 Elsevier B.V. All rights reserved.

Published
2013

11. Model-Based Antithymocyte Globulin in αβhaplo-Hematopoietic Stem Cell Transplantation Facilitates Engraftment, Expedites T Cell Recovery, and Mitigates the Risk of Acute Graft-versus-Host Disease.

Author

Barbarito G, Hiroshima L, Oppizzi L, Saini G, Kristovich K, Klein O, Hosszu K, Boehlke K, Gupta A, Mcavoy D, Shyr D, Boelens JJ, and Bertaina A

Subjects
Humans, Child, Male, Female, Adolescent, Child, Preschool, Acute Disease, Infant, Receptors, Antigen, T-Cell, alpha-beta metabolism, Graft vs Host Disease prevention & control, Antilymphocyte Serum therapeutic use, Antilymphocyte Serum administration & dosage, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation methods, T-Lymphocytes immunology, T-Lymphocytes drug effects
Abstract

In αβ T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αβhaplo-HSCT) recipients, antithymocyte globulin (ATG; Thymoglobulin) is used for preventing graft rejection and graft-versus-host disease (GVHD). The optimal dosing remains to be established, however. Here we present the first comparative analysis of 3 different ATG dosing strategies and their impact on immune reconstitution and GVHD. Our study aimed to evaluate the effects of 3 distinct dosing strategies of ATG on engraftment success, αβ + and γδ + T cell immune reconstitution, and the incidence and severity of acute GVHD in recipients of αβhaplo-HSCT. This comparative analysis included 3 cohorts of pediatric patients with malignant (n = 36) or nonmalignant (n = 8) disease. Cohorts 1 and 2 were given fixed ATG doses, whereas cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW). Cohort 3 showed a 0% incidence of day 100 grade II-IV acute GVHD, compared to 48% in cohort 1 and 27% in cohort 2. Furthermore, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4 + and CD8 + naïve T cells by day 90 (P = .04 and .03, respectively). Additionally, we found that the reconstitution and maturation of γδ + T cells post-HSCT was not impacted across all 3 cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T cell-replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (P = .007). Conversely, a post-HSCT ATG exposure of 10 to 15 AU*day/mL was optimal for improving day 100 CD4 + (P = .058) and CD8 + (P = .03) immune reconstitution without increasing the risk of relapse or nonrelapse mortality. This study represents the first comparative analysis of ATG exposure in αβhaplo-HSCT recipients. Our findings indicate that (1) a 1- to 2-fold ATG to ATLG bioequivalence is more effective than previously established standards, and (2) ATG exposure post-HSCT does not adversely affect γδ + T cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and day 100 acute GVHD while also promoting early CD4 + /CD8 + immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Published
2024
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12. Extracellular release of damaged mitochondria induced by prehematopoietic stem cell transplant conditioning exacerbates GVHD.

Author

Vijayan V, Yan H, Lohmeyer JK, Prentiss KA, Patil RV, Barbarito G, Lopez I, Elezaby A, Peterson K, Baker J, Ostberg NP, Bertaina A, Negrin RS, Mochly-Rosen D, Weinberg K, and Haileselassie B

Subjects
Animals, Mice, Humans, Disease Models, Animal, Antigen-Presenting Cells metabolism, Antigen-Presenting Cells immunology, Graft vs Host Disease etiology, Graft vs Host Disease metabolism, Hematopoietic Stem Cell Transplantation adverse effects, Mitochondria metabolism, Transplantation Conditioning methods
Abstract

Abstract: Despite therapeutic advancements, graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT). In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing pathogen-associated molecular patterns, result in activation of host antigen-presenting cells (APCs) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APCs. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of major histocompatibility complex II (MHC-II), costimulatory CD86, and proinflammatory cytokines, resulting in increased donor T-cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC-mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggest that pre-HSCT conditioning results in extracellular release of damaged mitochondria, which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria after conditioning could serve as a novel strategy for GVHD prevention., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Published
2024
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13. Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia.

Author

Bertaina A, Grimm PC, Weinberg K, Parkman R, Kristovich KM, Barbarito G, Lippner E, Dhamdhere G, Ramachandran V, Spatz JM, Fathallah-Shaykh S, Atkinson TP, Al-Uzri A, Aubert G, van der Elst K, Green SG, Agarwal R, Slepicka PF, Shah AJ, Roncarolo MG, Gallo A, Concepcion W, and Lewis DB

Subjects
Arteriosclerosis genetics, Arteriosclerosis therapy, Graft Rejection prevention & control, Humans, Kidney physiology, Pulmonary Embolism genetics, Pulmonary Embolism therapy, Transplantation Conditioning methods, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes therapy, Kidney Transplantation adverse effects, Nephrotic Syndrome genetics, Nephrotic Syndrome therapy, Osteochondrodysplasias genetics, Osteochondrodysplasias therapy, Primary Immunodeficiency Diseases genetics, Primary Immunodeficiency Diseases therapy
Abstract

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αβ T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.)., (Copyright © 2022 Massachusetts Medical Society.)

Published
2022
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14. γδ T Cells: The Ideal Tool for Cancer Immunotherapy.

Author

Yazdanifar M, Barbarito G, Bertaina A, and Airoldi I

Subjects
Animals, Cell Proliferation, Clinical Trials as Topic, Humans, Lymphocyte Activation immunology, T-Lymphocytes cytology, Immunotherapy, Neoplasms immunology, Neoplasms therapy, T-Lymphocytes immunology
Abstract

γδ T cells have recently gained considerable attention as an attractive tool for cancer adoptive immunotherapy due to their potent anti-tumor activity and unique role in immunosurveillance. The remarkable success of engineered T cells for the treatment of hematological malignancies has revolutionized the field of adoptive cell immunotherapy. Accordingly, major efforts are underway to translate this exciting technology to the treatment of solid tumors and the development of allogeneic therapies. The unique features of γδ T cells, including their major histocompatibility complex (MHC)-independent anti-cancer activity, tissue tropism, and multivalent response against a broad spectrum of the tumors, render them ideal for designing universal 'third-party' cell products, with the potential to overcome the challenges of allogeneic cell therapy. In this review, we describe the crucial role of γδ T cells in anti-tumor immunosurveillance and we summarize the different approaches used for the ex vivo and in vivo expansion of γδ T cells suitable for the development of novel strategies for cancer therapy. We further discuss the different transduction strategies aiming at redirecting or improving the function of γδ T cells, as well as, the considerations for the clinical applications.

Published
2020
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15. Zoledronic acid boosts γδ T-cell activity in children receiving αβ + T and CD19 + cell-depleted grafts from an HLA-haplo-identical donor.

Author

Bertaina A, Zorzoli A, Petretto A, Barbarito G, Inglese E, Merli P, Lavarello C, Brescia LP, De Angelis B, Tripodi G, Moretta L, Locatelli F, and Airoldi I

Abstract

We demonstrated that γδ T cells of patients given HLA-haploidentical HSCT after removal of αβ + T cells and CD19 + B cells are endowed with the capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we tested the hypothesis that infusion of ZOL in patients receiving this type of graft may enhance γδ T-cell cytotoxic activity against leukemia cells. ZOL was infused every 28 d in 43 patients; most were treated at least twice. γδ T cells before and after ZOL treatments were studied in 33 of these 43 patients, till at least 7 mo after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. An induction of Vδ2-cell differentiation, paralleled by increased cytotoxicity of both Vδ1 and Vδ2 cells against primary leukemia blasts was associated with ZOL treatment. Cytotoxic activity was further increased in Vδ2 cells, but not in Vδ1 lymphocytes in those patients given more than one treatment. Proteomic analysis of γδ T cells purified from patients showed upregulation of proteins involved in activation processes and immune response, paralleled by downregulation of proteins involved in proliferation. Moreover, a proteomic signature was identified for each ZOL treatment. Patients given three or more ZOL infusions had a better probability of survival in comparison to those given one or two treatments (86% vs. 54%, respectively, p = 0.008). Our data indicate that ZOL infusion in pediatric recipients of αβ T- and B-cell-depleted HLA-haploidentical HSCT promotes γδ T-cell differentiation and cytotoxicity and may influence the outcome of patients.

Published
2016
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16. SNAI2/Slug gene is silenced in prostate cancer and regulates neuroendocrine differentiation, metastasis-suppressor and pluripotency gene expression.

Author

Esposito S, Russo MV, Airoldi I, Tupone MG, Sorrentino C, Barbarito G, Di Meo S, and Di Carlo E

Subjects
Adenocarcinoma secondary, Aged, Blotting, Western, Cell Line, Tumor, DNA Methylation genetics, Down-Regulation, Gene Silencing, Humans, Immunohistochemistry, Laser Capture Microdissection, Male, Middle Aged, Neoplasm Metastasis, Prostatic Neoplasms pathology, Real-Time Polymerase Chain Reaction, Snail Family Transcription Factors, Adenocarcinoma pathology, Cell Differentiation genetics, Gene Expression Regulation, Neoplastic genetics, Prostatic Neoplasms genetics, Transcription Factors genetics
Abstract

Prostate Cancer (PCa)-related deaths are mostly due to metastasization of poorly differentiated adenocarcinomas often endowed with neuroendocrine differentiation (NED) areas.The SNAI2/Slug gene is a major regulator of cell migration and tumor metastasization. We here assessed its biological significance in NED, and metastatic potential of PCa.SNAI2 expression was down-regulated in most PCa epithelia, in association with gene promoter methylation, except for cell clusters forming: a. the expansion/invasion front of high-grade PCa, b. NED areas, or c. lymph node metastasis.Knockdown of SNAI2 in PC3 cells down-regulated the expression of neural-tissue-associated adhesion molecules, Neural-Cadherin, Neural-Cadherin-2, Neuronal-Cell-Adhesion-Molecule, and of the NED marker Neuron-Specific Enolase, whereas it abolished Chromogranin-A expression. The metastasis-suppressor genes, Nm23-H1 and KISS1, were up-regulated, while the pluripotency genes SOX2, NOTCH1, CD44v6, WWTR1/TAZ and YAP1 were dramatically down-regulated. Over-expression of SNAI2 in DU145 cells substantiated its ability to regulate metastasis-suppressor, NED and pluripotency genes. In PCa and lymph node metastasis, expression of SOX2 and NOTCH1 was highly related to that of SNAI2.In conclusion, I. SNAI2 silencing in PCa may turn-off the expression of NED markers and pluripotency genes, while turning-on that of specific metastasis-suppressors, II. SNAI2 expression in selected PCa cells, by regulating their self-renewal, NED and metastatic potential, endows them with highly malignant properties. SNAI2 may thus constitute a key target for modern approaches to PCa progression.

Published
2015
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17. γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes.

Author

Airoldi I, Bertaina A, Prigione I, Zorzoli A, Pagliara D, Cocco C, Meazza R, Loiacono F, Lucarelli B, Bernardo ME, Barbarito G, Pende D, Moretta A, Pistoia V, Moretta L, and Locatelli F

Subjects
Adolescent, Cell Degranulation, Cells, Cultured, Child, Child, Preschool, Female, Humans, Infant, Male, T-Lymphocytes cytology, Antigens, CD19 analysis, B-Lymphocytes cytology, Hematopoietic Stem Cell Transplantation methods, Leukemia therapy, Receptors, Antigen, T-Cell, alpha-beta analysis, Receptors, Antigen, T-Cell, gamma-delta analysis, T-Lymphocytes transplantation
Abstract

We prospectively assessed functional and phenotypic characteristics of γδ T lymphocytes up to 7 months after HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) depleted of αβ(+) T cells and CD19(+) B cells in 27 children with either malignant or nonmalignant disorders. We demonstrate that (1) γδ T cells are the predominant T-cell population in patients during the first weeks after transplantation, being mainly, albeit not only, derived from cells infused with the graft and expanding in vivo; (2) central-memory cells predominated very early posttransplantation for both Vδ1 and Vδ2 subsets; (3) Vδ1 cells are specifically expanded in patients experiencing cytomegalovirus reactivation and are more cytotoxic compared with those of children who did not experience reactivation; (4) these subsets display a cytotoxic phenotype and degranulate when challenged with primary acute myeloid and lymphoid leukemia blasts; and (5) Vδ2 cells are expanded in vitro after exposure to zoledronic acid (ZOL) and efficiently lyse primary lymphoid and myeloid blasts. This is the first detailed characterization of γδ T cells emerging in peripheral blood of children after CD19(+) B-cell and αβ(+) T-cell-depleted haplo-HSCT. Our results can be instrumental to the development of clinical trials using ZOL for improving γδ T-cell killing capacity against leukemia cells. This trial was registered at www.clinicaltrials.gov as #NCT01810120., (© 2015 by The American Society of Hematology.)

Published
2015
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18. Interleukin-27 re-educates intratumoral myeloid cells and down-regulates stemness genes in non-small cell lung cancer.

Author

Airoldi I, Tupone MG, Esposito S, Russo MV, Barbarito G, Cipollone G, and Di Carlo E

Subjects
Aged, Animals, Carcinoma, Non-Small-Cell Lung genetics, Cell Proliferation drug effects, Down-Regulation drug effects, Female, Humans, Immunotherapy methods, Kruppel-Like Factor 4, Lung Neoplasms genetics, Male, Mice, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Middle Aged, Myeloid Cells pathology, Neoplastic Stem Cells pathology, Recombinant Proteins pharmacology, Xenograft Model Antitumor Assays, Carcinoma, Non-Small-Cell Lung drug therapy, Cytokines metabolism, Interleukin-27 pharmacology, Lung Neoplasms drug therapy, Myeloid Cells drug effects, Neoplastic Stem Cells drug effects
Abstract

Current therapies for Non-Small Cell Lung Cancer (NSCLC) still fail to significantly increase its survival rate. Here we asked whether Interleukin(IL)-27, which has revealed powerful antitumor activity and is toxicity-free in humans, is a promising therapeutic choice for NSCLC patients. IL-27's effects were tested on Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) cell lines and xenograft models. IL-27Receptor(R) expression was assessed in lung tissues from 78 NSCLC patients. In vitro, IL-27 was ineffective on cancer cell proliferation or apoptosis, but fostered CXCL3/GROγ/MIP2β expression. In vitro and in vivo, IL-27 down-regulated stemness-related genes, namely SONIC HEDGEHOG in AC cells, and OCT4A, SOX2, NOTCH1, KLF4 along with Nestin, SNAI1/SNAIL, SNAI2/SLUG and ZEB1, in SCC cells. In vivo, IL-27 hampered both AC and SCC tumor growth in association with a prominent granulocyte- and macrophage-driven colliquative necrosis, CXCL3 production, and a reduced pluripotency- and EMT-related gene expression. Myeloablation of tumor-bearing hosts mostly abolished IL-27's antitumor effects. In clinical samples, IL-27R expression was found in AC, SCC, pre-cancerous lesions and tumor infiltrating myeloid cells, and correlated with advanced stages of disease. Our data suggest that even immunocompromised or advancer NSCLC patients may benefit from IL-27's antitumor properties based on its ability to drive myeloid cells towards antitumor activities, and down-regulate stemness- and EMT-related genes in cancer cells.

Published
2015
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19. Electrophoretic separation of purified myelin: a method to improve the protein pattern resolving.

Author

Ravera S, Bartolucci M, Barbarito G, Calzia D, and Panfoli I

Subjects
Animals, Blotting, Western, Cattle, Cholic Acids chemistry, Detergents chemistry, Dithiothreitol chemistry, Glucosides chemistry, Protein Denaturation, Reducing Agents chemistry, Urea chemistry, Electrophoresis, Polyacrylamide Gel methods, Myelin Proteins isolation & purification, Myelin Sheath chemistry
Abstract

Myelin sheath is a lipid-rich membrane, consisting of 70% lipid and 30% proteins, that is involved in physiological and pathological processes. For this reason its protein composition has been often investigated, principally by two-dimensional electrophoresis; however, the consistent lipid content makes it difficult to obtain good proteins separation. To improve the resolution of myelin proteins in a denaturing monodimensional gel electrophoresis, we examined several mixtures for the denaturation of the sample, utilizing different detergents and reducing agents. The definition of the protein pattern was analyzed by both "Blue Silver" Coomassie staining and Western Blot analysis against myelin basic protein, one of the most represented myelin proteins. The best resolution is observed when the sample was incubated with a mixture containing 1.25% dithiothreitol, 4 M urea, and 1% dodecyl maltoside or 1 % 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate, prior to addition of denaturing agents. In conclusion, this work describes a novel method to improve the separation of myelin proteins in a monodimensional gel electrophoresis. It may be also useful for investigating other lipid-rich samples.

Published
2013
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