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11. PB1882 DECONSTRUCTING RICHTER SYNDROME TUMOR NICHE: JAGGED-1 LIGAND LEADS THE WAY

Author

Marra, A., primary, Laurenti, M.E., additional, Baldoni, S., additional, Sorcini, D., additional, Pasquino, S., additional, Giansanti, M., additional, Bigerna, B., additional, Rompietti, C., additional, De Falco, F., additional, Del Papa, B., additional, Martino, G., additional, Ascani, S., additional, Mecucci, C., additional, Rosati, E., additional, and Sportoletti, P., additional

Published
2019
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12. Malattie mitocondriali e deficit del complesso III

Author

Conte A, Papa B, FERRAMOSCA, Alessandra, ZARA, Vincenzo, Conte, A, Papa, B, Ferramosca, Alessandra, and Zara, Vincenzo

Abstract

Risulta quanto mai evidente la necessità di ulteriori studi che permettano di rivelare gli aspetti ancora poco chiari dell’assembly del complesso III, nonché evidenziare ulteriori ruoli delle proteine chaperone coinvolte durante il suo processo di biogenesi. La specificità dei tessuti maggiormente colpiti e il sovraccarico di ferro, tipici delle malattie associate a BCS1L, sollevano infatti numerosi interrogativi circa il ruolo di questa proteina, suggerendo possibili funzioni addizionali nei mitocondri, oltre a quella di fattore di assemblaggio del complesso III. Inoltre, nella maggior parte degli individui con carenze del complesso del citocromo bc1 deve essere ancora identificato il difetto molecolare, permettendo di ipotizzare l’esistenza di addizionali fattori di assemblaggio ancora da scoprire3. Allo stato attuale non esistono cure risolutive per il trattamento delle malattie mitocondriali, ma solo terapie che permettono di migliorare i sintomi, in particolare l’intolleranza allo sforzo e l’affaticamento. La loro efficacia varia, comunque, da paziente a paziente e dipende dal deficit enzimatico, nonché dalla gravità dei sintomi. Una comprensione più profonda dei meccanismi molecolari alla base dei disordini mitocondriali potrebbe quindi porre le basi per lo sviluppo di adeguati trattamenti terapeutici.

Published
2015

13. Steatosi epatica ed acidi grassi: ruolo della dieta nel trattamento del fegato grasso

Author

Conte A, Papa B, FERRAMOSCA, Alessandra, ZARA, Vincenzo, Conte, A, Papa, B, Ferramosca, Alessandra, and Zara, Vincenzo

Abstract

La principale caratteristica della patogenesi della NAFLD è l’accumulo di trigliceridi nel fegato, i cui livelli riflettono un equilibrio tra i vari processi metabolici coinvolti nella loro sintesi e smaltimento. In particolare, l’aumento dell’uptake di acidi grassi liberi, in seguito allo stimolo della lipolisi nel tessuto adiposo, e l’induzione della lipogenesi nel fegato contribuiscono primariamente all’insorgenza del fegato steatotico. Recentemente, numerosi studi condotti su modelli animali hanno messo in evidenza il ruolo svolto da alcuni grassi alimentari nella modulazione della lipogenesi epatica, in considerazione dell’importanza che questa via metabolica riveste nella patogenesi della NAFLD. Mentre SFA e MUFA non hanno alcuna significativa influenza sulla via biosintetica degli acidi grassi, l’assunzione di PUFA della serie ω-3 e della serie ω-6, riducendo fortemente l’attività e l’espressione di proteine coinvolte nella lipogenesi, ostacola l’insorgenza della patologia. Pertanto, è possibile modulare il metabolismo lipidico e, in particolare la lipogenesi epatica, intervenendo sull’alimentazione e ricorrendo a particolari combinazioni di acidi grassi. Ciò evidenzia come i grassi alimentari possano essere utilizzati nella prevenzione e nel trattamento di patologie, spesso associate ad abitudini e stili di vita errati, di cui la steatosi epatica ne è un esempio. Alla luce di ciò, i risultati promettenti ottenuti dalla somministrazione di nuovi supplementi dietetici in modelli animali, come l’olio di krill e l’olio di pino coreano, suggeriscono che sarebbe estremamente interessante approfondire gli studi sull’uomo. Ciò potrebbe avere importanti risvolti nella prevenzione e/o nel trattamento della NAFLD, anche in virtù del fatto che, attualmente, non esistono ancora trattamenti farmacologici accertati tramite i quali intervenire su questa patologia.

Published
2015

14. Search for gravitational waves from intermediate mass binary black holes

Author

J. Abadie, 1, Abbott, a. B. P., Abbott, a. R., Abbott, a. T. D., Abernathy, a. M., Accadia, a. T., Acernese, b. F., Adams, b. C., Adhikari, a. R., Affeldt, a. C., Agathos, a. M., Agatsuma, b. K., Ajith, a. P., Allen, a. B., Amador Ceron, a. E., Amariutei, a. D., Anderson, a. S. B., Anderson, a. W. G., Arai, a. K., Arain, a. M. A., Araya, a. M. C., Aston, a. S. M., Astone, a. P., 14a, Atkinson, b. D., Aufmuth, a. P., Aulbert, a. C., Aylott, a. B. E., Babak, a. S., Baker, a. P., Ballardin, a. G., Ballmer, b. S., Barayoga, a. J. C. B., Barker, a. D., Barone, a. F., Barr, b. B., Barsotti, a. L., Barsuglia, a. M., Barton, b. M. A., Bartos, a. I., Bassiri, a. R., Bastarrika, a. M., Basti, a. A., 23a, 23b, Batch, b. J., Bauchrowitz, a. J., Th S. Bauer, a. T.h. S. Bauer, Bebronne, b. M., Beck, b. D., Behnke, a. B., Bejger, a. M., 25c, Beker, b. M. G., Bell, b. A. S., Belletoile, a. A., Belopolski, b. I., Benacquista, a. M., Berliner, a. J. M., Bertolini, a. A., Betzwieser, a. J., Beveridge, a. N., Beyersdorf, a. P. T., Bilenko, a. I. A., Billingsley, a. G., Birch, a. J., Biswas, a. R., Bitossi, a. M., Bizouard, b. M. A., 29a, Black, b. E., Blackburn, a. J. K., Blackburn, a. L., Blair, a. D., Bland, a. B., Blom, a. M., Bock, b. O., Bodiya, a. T. P., Bogan, a. C., Bondarescu, a. R., Bondu, a. F., 33b, Bonelli, b. L., Bonnand, b. R., Bork, b. R., Born, a. M., Boschi, a. V., Bose, b. S., Bosi, a. L., 36a, Bouhou, a. B., Braccini, b. S., Bradaschia, b. C., Brady, b. P. R., Braginsky, a. V. B., Branchesi, a. M., 37a, 37b, Brau, b. J. E., Breyer, a. J., Briant, a. T., Bridges, b. D. O., Brillet, a. A., 33a, Brinkmann, b. M., Brisson, a. V., Britzger, b. M., Brooks, a. A. F., Brown, a. D. A., Bulik, a. T., 25b, Bulten, b. H. J., Buonanno, b. A., Burguet Castell, a. J., Buskulic, a. D., Buy, b. C., Byer, b. R. L., Cadonati, a. L., Cagnoli, a. G., Camp, b. J. B., Campsie, a. P., Cannizzo, a. J., Cannon, a. K., Canuel, a. B., Cao, b. J., Capano, a. C. D., Carbognani, a. F., Carbone, b. L., Caride, a. S., Caudill, a. S., Cavaglia, a. M., Cavalier, a. F., Cavalieri, b. R., Cella, b. G., Cepeda, b. C., Cesarini, a. E., Chaibi, b. O., Chalermsongsak, b. T., Charlton, a. P., Chassande Mottin, a. E., Chelkowski, b. S., Chen, a. W., Chen, a. X., Chen, a. Y., Chincarini, a. A., Chiummo, b. A., Cho, b. H., Chow, a. J., Christensen, a. N., Chua, a. S. S. Y., Chung, a. C. T. Y., Chung, a. S., Ciani, a. G., Clara, a. F., Clark, a. D. E., Clark, a. J., Clayton, a. J. H., Cleva, a. F., Coccia, b. E., 55a, 55b, Cohadon, b. P. F., Colacino, b. C. N., Colas, b. J., Colla, b. A., 14b, Colombini, b. M., Conte, b. A., Conte, b. R., Cook, a. D., Corbitt, a. T. R., Cordier, a. M., Cornish, a. N., Corsi, a. A., Costa, a. C. A., Coughlin, a. M., Coulon, a. J. P., Couvares, b. P., Coward, a. D. M., Cowart, a. M., Coyne, a. D. C., Creighton, a. J. D. E., Creighton, a. T. D., Cruise, a. A. M., Cumming, a. A., Cunningham, a. L., Cuoco, a. E., Cutler, b. R. M., Dahl, a. K., Danilishin, a. S. L., Dannenberg, a. R., D’Antonio, a. S., Danzmann, b. K., Dattilo, a. V., Daudert, b. B., Daveloza, a. H., Davier, a. M., Daw, b. E. J., Day, a. R., Dayanga, b. T., Debra, b. D., Debreczeni, a. G., Del Pozzo, b. W., del Prete, b. M., 59b, Dent, b. T., Dergachev, a. V., Derosa, a. R., Desalvo, a. R., Dhurandhar, a. S., Di Fiore, a. L., Di Lieto, b. A., Di Palma, b. I., Di Paolo Emilio, a. M., 55c, Di Virgilio, b. A., Dı´az, b. M., Dietz, a. A., Donovan, b. F., Dooley, a. K. L., Drago, a. M., 59a, Drever, b. R. W. P., Driggers, a. J. C., Du, a. Z., Dumas, a. J. C., Dwyer, a. S., Eberle, a. T., Edgar, a. M., Edwards, a. M., Effler, a. A., Ehrens, a. P., Endro˝czi, a. G., Engel, b. R., Etzel, a. T., Evans, a. K., Evans, a. M., Evans, a. T., Factourovich, a. M., Fafone, a. V., Fairhurst, b. S., Fan, a. Y., Farr, a. B. F., Fazi, a. D., Fehrmann, a. H., Feldbaum, a. D., Feroz, a. F., Ferrante, a. I., Fidecaro, b. F., Finn, b. L. S., Fiori, a. I., Fisher, b. R. P., Flaminio, a. R., Flanigan, b. M., Foley, a. S., Forsi, a. E., Forte, a. L. A., Fotopoulos, b. N., Fournier, a. J. D., Franc, b. J., Frasca, b. S., Frasconi, b. F., Frede, b. M., Frei, a. M., Frei, a. Z., Freise, a. A., Frey, a. R., Fricke, a. T. T., Friedrich, a. D., Fritschel, a. P., Frolov, a. V. V., Fujimoto, a. M. K., Fulda, a. P. J., Fyffe, a. M., Gair, a. J., Galimberti, a. M., Gammaitoni, b. L., 36b, Garcia, a. J., Ga´spa´r, b. M. E., Gemme, b. G., Geng, b. R., Genin, a. E., Gennai, b. A., Gergely, b. L. A. ´ ., Ghosh, a. S., Giaime, a. J. A., Giampanis, a. S., Giardina, a. K. D., Giazotto, a. A., Gil, b. S., Gill, a. C., Gleason, a. J., Goetz, a. E., Goggin, a. L. M., Gonza´lez, a. G., Gorodetsky, a. M. L., Goßler, a. S., Gouaty, a. R., Graef, b. C., Graff, a. P. B., Granata, a. M., Grant, b. A., Gras, a. S., Gray, a. C., Gray, a. N., Greenhalgh, a. R. J. S., Gretarsson, a. A. M., Greverie, a. C., Grosso, b. R., Grote, a. H., Grunewald, a. S., Guidi, a. G. M., Guido, b. C., Gupta, a. R., Gustafson, a. E. K., Gustafson, a. R., Ha, a. T., Hallam, a. J. M., Hammer, a. D., Hammond, a. G., Hanks, a. J., Hanna, a. C., Hanson, a. J., Harms, a. J., Harry, a. G. M., Harry, a. I. W., Harstad, a. E. D., Hartman, a. M. T., Haughian, a. K., Hayama, a. K., Hayau, a. J. F., Heefner, b. J., Heidmann, a. A., Heintze, b. M. C., Heitmann, a. H., Hello, b. P., Hendry, b. M. A., Heng, a. I. S., Heptonstall, a. A. W., Herrera, a. V., Hewitson, a. M., Hild, a. S., Hoak, a. D., Hodge, a. K. A., Holt, a. K., Holtrop, a. M., Hong, a. T., Hooper, a. S., Hosken, a. D. J., Hough, a. J., Howell, a. E. J., Hughey, a. B., Husa, a. S., Huttner, a. S. H., Huynh Dinh, a. T., Ingram, a. D. R., Inta, a. R., Isogai, a. T., Ivanov, a. A., Izumi, a. K., Jacobson, a. M., James, a. E., Jang, a. Y. J., Jaranowski, a. P., 25d, Jesse, b. E., Johnson, a. W. W., Jones, a. D. I., Jones, a. G., Jones, a. R., Ju, a. L., Kalmus, a. P., Kalogera, a. V., Kandhasamy, a. S., Kang, a. G., Kanner, a. J. B., Kasturi, a. R., Katsavounidis, a. E., Katzman, a. W., Kaufer, A.h., Kawabe, a. K., Kawamura, a. S., Kawazoe, a. F., Kelley, a. D., Kells, a. W., Keppel, a. D. G., Keresztes, a. Z., Khalaidovski, a. A., Khalili, a. F. Y., Khazanov, a. E. A., Kim, a. B., Kim, a. C., Kim, a. H., Kim, a. K., Kim, a. N., Kim, a. Y. M., King, a. P. J., Kinzel, a. D. L., Kissel, a. J. S., Klimenko, a. S., Kokeyama, a. K., Kondrashov, a. V., Koranda, a. S., Korth, a. W. Z., Kowalska, a. I., Kozak, b. D., Kranz, a. O., Kringel, a. V., Krishnamurthy, a. S., Krishnan, a. B., Kro´lak, a. A., 25a, 25e, Kuehn, b. G., Kumar, a. R., Kwee, a. P., Lam, a. P. K., Landry, a. M., Lantz, a. B., Lastzka, a. N., Lawrie, a. C., Lazzarini, a. A., Leaci, a. P., Lee, a. C. H., Lee, a. H. K., Lee, a. H. M., Leong, a. J. R., Leonor, a. I., Leroy, a. N., Letendre, b. N., Li, b. J., Li, a. T. G. F., Liguori, b. N., Lindquist, b. P. E., Liu, a. Y., Liu, a. Z., Lockerbie, a. N. A., Lodhia, a. D., Lorenzini, a. M., Loriette, b. V., 29b, Lormand, b. M., Losurdo, a. G., Lough, b. J., Luan, a. J., Lubinski, a. M., Lu¨ck, a. H., Lundgren, a. A. P., Macdonald, a. E., Machenschalk, a. B., Macinnis, a. M., Macleod, a. D. M., Mageswaran, a. M., Mailand, a. K., Majorana, a. E., Maksimovic, b. I., Man, b. N., Mandel, b. I., Mandic, a. V., Mantovani, a. M., 23c, Marandi, b. A., Marchesoni, a. F., Marion, a. F., Ma´rka, b. S., Ma´rka, a. Z., Markosyan, a. A., Maros, a. E., Marque, a. J., Martelli, b. F., Martin, b. I. W., Martin, a. R. M., Marx, a. J. N., Mason, a. K., Masserot, a. A., Matichard, b. F., Matone, a. L., Matzner, a. R. A., Mavalvala, a. N., Mazzolo, a. G., Mccarthy, a. R., Mcclelland, a. D. E., Mcguire, a. S. C., Mcintyre, a. G., Mciver, a. J., Mckechan, a. D. J. A., Mcwilliams, a. S., Meadors, a. G. D., Mehmet, a. M., Meier, a. T., Melatos, a. A., Melissinos, a. A. C., Mendell, a. G., Mercer, a. R. A., Meshkov, a. S., Messenger, a. C., Meyer, a. M. S., Miao, a. H., Michel, a. C., Miller, b. J., Minenkov, a. Y., Mitrofanov, b. V. P., Mitselmakher, a. G., Mittleman, a. R., Miyakawa, a. O., Moe, a. B., Mohan, a. M., Mohanty, b. S. D., Mohapatra, a. S. R. P., Moraru, a. D., Moreno, a. G., Morgado, a. N., Morgia, b. A., Mori, b. T., Morriss, a. S. R., Mossavi, b. K., Mours, a. B., Mow Lowry, b. C. M., Mueller, a. C. L., Mueller, a. G., Mukherjee, a. S., Mullavey, a. A., Mu¨ ller Ebhardt, a. H., Munch, a. J., Murphy, a. D., Murray, a. P. G., Mytidis, a. A., Nash, a. T., Naticchioni, a. L., Necula, b. V., Nelson, a. J., Newton, a. G., Nguyen, a. T., Nishizawa, a. A., Nitz, a. A., Nocera, a. F., Nolting, b. D., Normandin, a. M. E., Nuttall, a. L., Ochsner, a. E., O’Dell, a. J., Oelker, a. E., Ogin, a. G. H., Oh, a. J. J., Oh, a. S. H., O’Reilly, a. B., O’Shaughnessy, a. R., Osthelder, a. C., Ott, a. C. D., Ottaway, a. D. J., Ottens, a. R. S., Overmier, a. H., Owen, a. B. J., Page, a. A., Pagliaroli, a. G., Palladino, b. L., Palomba, b. C., Pan, b. Y., Pankow, a. C., Paoletti, a. F., Papa, b. M. A., Pasqualetti, b. A., Passaquieti, b. R., Passuello, b. D., Patel, b. P., Pedraza, a. M., Peiris, a. P., Pekowsky, a. L., Penn, a. S., Perreca, a. A., Persichetti, a. G., Phelps, b. M., Pickenpack, a. M., Piergiovanni, a. F., Pietka, b. M., Pinard, b. L., Pinto, b. I. M., Pitkin, a. M., Pletsch, a. H. J., Plissi, a. M. V., Poggiani, a. R., Po¨ld, b. J., Postiglione, a. F., Prato, a. M., Predoi, b. V., Prestegard, a. T., Price, a. L. R., Prijatelj, a. M., Principe, a. M., Privitera, a. S., Prix, a. R., Prodi, a. G. A., Prokhorov, b. L. G., Puncken, a. O., Punturo, a. M., Puppo, a. P., Quetschke, b. V., Quitzow James, a. R., Raab, a. F. J., Rabeling, a. D. S., Ra´cz, b. I., Radkins, b. H., Raffai, a. P., Rakhmanov, a. M., Rankins, a. B., Rapagnani, a. P., Raymond, b. V., Re, a. V., Redwine, b. K., Reed, a. C. M., Reed, a. T., Regimbau, a. T., Reid, b. S., Reitze, a. D. H., Ricci, a. F., Riesen, b. R., Riles, a. K., Robertson, a. N. A., Robinet, a. F., Robinson, b. C., Robinson, a. E. L., Rocchi, a. A., Roddy, b. S., Rodriguez, a. C., Rodruck, a. M., Rolland, a. L., Rollins, b. J. G., Romano, a. J. D., Romano, a. R., Romie, b. J. H., Rosin´ska, a. D., 25f, Ro¨ver, b. C., Rowan, a. S., Ru¨diger, a. A., Ruggi, a. P., Ryan, b. K., Sainathan, a. P., Salemi, a. F., Sammut, a. L., Sandberg, a. V., Sannibale, a. V., Santamarı´a, a. L., Santiago Prieto, a. I., Santostasi, a. G., Sassolas, a. B., Sathyaprakash, b. B. S., Sato, a. S., Saulson, a. P. R., Savage, a. R. L., Schilling, a. R., Schnabel, a. R., Schofield, a. R. M. S., Schreiber, a. E., Schulz, a. B., Schutz, a. B. F., Schwinberg, a. P., Scott, a. J., Scott, a. S. M., Seifert, a. F., Sellers, a. D., Sentenac, a. D., Sergeev, b. A., Shaddock, a. D. A., Shaltev, a. M., Shapiro, a. B., Shawhan, a. P., Shoemaker, a. D. H., Sibley, a. A., Siemens, a. X., Sigg, a. D., Singer, a. A., Singer, a. L., Sintes, a. A. M., Skelton, a. G. R., Slagmolen, a. B. J. J., Slutsky, a. J., Smith, a. J. R., Smith, a. M. R., Smith, a. R. J. E., Smith Lefebvre, a. N. D., Somiya, a. K., Sorazu, a. B., Soto, a. J., Speirits, a. F. C., Sperandio, a. L., Stefszky, b. M., Stein, a. A. J., Stein, a. L. C., Steinert, a. E., Steinlechner, a. J., Steinlechner, a. S., Steplewski, a. S., Stochino, a. A., Stone, a. R., Strain, a. K. A., Strigin, a. S. E., Stroeer, a. A. S., Sturani, a. R., Stuver, b. A. L., Summerscales, a. T. Z., Sung, a. M., Susmithan, a. S., Sutton, a. P. J., Swinkels, a. B., Tacca, b. M., Taffarello, b. L., 59c, Talukder, b. D., Tanner, a. D. B., Tarabrin, a. S. P., Taylor, a. J. R., Taylor, a. R., Thomas, a. P., Thorne, a. K. A., Thorne, a. K. S., Thrane, a. E., Thu¨ring, a. A., Tokmakov, a. K. V., Tomlinson, a. C., Toncelli, a. A., Tonelli, b. M., Torre, b. O., Torres, b. C., Torrie, a. C. I., Tournefier, a. E., Travasso, b. F., Traylor, a. G., Tseng, a. K., Ugolini, a. D., Vahlbruch, a. H., Vajente, a. G., van den Brand, b. J. F. J., Van Den Broeck, b. C., van der Putten, b. S., van Veggel, b. A. A., Vass, a. S., Vasuth, a. M., Vaulin, b. R., Vavoulidis, a. M., Vecchio, b. A., Vedovato, A.g., Veitch, b. J., Veitch, a. P. J., Veltkamp, a. C., Verkindt, a. D., Vetrano, b. F., Vicere, b. A., Villar, b. A. E., Vinet, a. J. Y., Vitale, b. S., Vitale, a. S., Vocca, b. H., Vorvick, a. C., Vyatchanin, a. S. P., Wade, a. A., Wade, a. L., Wade, a. M., Waldman, a. S. J., Wallace, a. L., Wan, a. Y., Wang, a. M., Wang, a. X., Wang, a. Z., Wanner, a. A., Ward, a. R. L., Was, b. M., Weinert, b. M., Weinstein, a. A. J., Weiss, a. R., Wen, a. L., Wessels, a. P., West, a. M., Westphal, a. T., Wette, a. K., Whelan, a. J. T., Whitcomb, a. S. E., White, a. D. J., Whiting, a. B. F., Wilkinson, a. C., Willems, a. P. A., Williams, a. L., Williams, a. R., Willke, a. B., Winkelmann, a. L., Winkler, a. W., Wipf, a. C. C., Wiseman, a. A. G., Wittel, a. H., Woan, a. G., Wooley, a. R., Worden, a. J., Yakushin, a. I., Yamamoto, a. H., Yamamoto, a. K., 59d, A, Yancey, b. C. C., Yang, a. H., Yeaton Massey, a. D., Yoshida, a. S., Yu, a. P., Yvert, a. M., Zadroz´ny, b. A., Zanolin, b. M., Zendri, a. J. P., Zhang, b. F., Zhang, a. L., Zhang, a. W., Zhao, a. C., Zotov, a. N., Zucker, a. M. E., J. Zweizig, a, J. Zweizig, PINTO, INNOCENZO, CALLONI, ENRICO, DE ROSA, ROSARIO, GARUFI, FABIO, MILANO, LEOPOLDO, MOSCA, simona, PARISI, MARIA, Laboratoire d'Annecy de Physique des Particules (LAPP), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS), Unité Scientifique de la Station de Nançay (USN), Observatoire des Sciences de l'Univers en région Centre (OSUC), Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de l'Accélérateur Linéaire (LAL), 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), Institut de Physique de Rennes (IPR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des matériaux avancés (LMA), 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), Astrophysique Relativiste Théories Expériences Métrologie Instrumentation Signaux (ARTEMIS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire des Sciences de l'Univers en région Centre (OSUC), Université Paris sciences et lettres (PSL)-Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Université d'Orléans (UO), 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), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de la Recherche Scientifique (CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), The LIGO Scientific Collaboration, The Virgo Collaboration, Laboratoire d'Annecy de Physique des Particules (LAPP/Laboratoire d'Annecy-le-Vieux de Physique des Particules), APC - Cosmologie, Physique Corpusculaire et Cosmologie - Collège de France (PCC), Collège de France (CdF)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Collège de France (CdF)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-AstroParticule et Cosmologie (APC (UMR_7164)), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7), 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)-Centre National de la Recherche Scientifique (CNRS), AstroParticule et Cosmologie (APC (UMR_7164)), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de la Côte d'Azur, Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), APC - Gravitation (APC-Gravitation), PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Max-Planck-Institut für Gravitationsphysik ( Albert-Einstein-Institut ) (AEI), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Laboratoire d'Annecy de Physique des Particules ( LAPP/Laboratoire d'Annecy-le-Vieux de Physique des Particules ), Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ), Physique Corpusculaire et Cosmologie - Collège de France ( PCC ), Collège de France ( CdF ) -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 ) -Collège de France ( CdF ) -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 ) -AstroParticule et Cosmologie ( APC - UMR 7164 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Observatoire de Paris-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Laboratoire de l'Accélérateur Linéaire ( LAL ), 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 ), Institut de Physique de Rennes ( IPR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire des matériaux avancés ( LMA ), 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 ) -Centre National de la Recherche Scientifique ( CNRS ), AstroParticule et Cosmologie ( APC - UMR 7164 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Astrophysique Relativiste Théories Expériences Métrologie Instrumentation Signaux ( ARTEMIS ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Institut national des sciences de l'Univers ( INSU - CNRS ) -Observatoire de la Côte d'Azur, Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), APC - Gravitation ( APC-Gravitation ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Observatoire de Paris-Université Paris Diderot - Paris 7 ( UPD7 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Max-Planck-Institut für Gravitationsphysik (Albert-Einstein-Institut), Max-Planck-Institut-Max-Planck-Institut, (Astro)-Particles Physics, Mathematical Analysis, J. 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C., Meyer, a. M. S., Miao, a. H., Michel, a. C., Milano, Leopoldo, Miller, b. J., Minenkov, a. Y., Mitrofanov, b. V. P., Mitselmakher, a. G., Mittleman, a. R., Miyakawa, a. O., Moe, a. B., Mohan, a. M., Mohanty, b. S. D., Mohapatra, a. S. R. P., Moraru, a. D., Moreno, a. G., Morgado, a. N., Morgia, b. A., Mori, b. T., Morriss, a. S. R., Mosca, Simona, Mossavi, b. K., Mours, a. B., Mow Lowry, b. C. M., Mueller, a. C. L., Mueller, a. G., Mukherjee, a. S., Mullavey, a. A., Mu¨ ller Ebhardt, a. H., Munch, a. J., Murphy, a. D., Murray, a. P. G., Mytidis, a. A., Nash, a. T., Naticchioni, a. L., Necula, b. V., Nelson, a. J., Newton, a. G., Nguyen, a. T., Nishizawa, a. A., Nitz, a. A., Nocera, a. F., Nolting, b. D., Normandin, a. M. E., Nuttall, a. L., Ochsner, a. E., O’Dell, a. J., Oelker, a. E., Ogin, a. G. H., Oh, a. J. J., Oh, a. S. H., O’Reilly, a. B., O’Shaughnessy, a. R., Osthelder, a. C., Ott, a. C. D., Ottaway, a. D. J., Ottens, a. R. S., Overmier, a. H., Owen, a. B. J., Page, a. 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S., Reitze, a. D. H., Ricci, a. F., Riesen, b. R., Riles, a. K., Robertson, a. N. A., Robinet, a. F., Robinson, b. C., Robinson, a. E. L., Rocchi, a. A., Roddy, b. S., Rodriguez, a. C., Rodruck, a. M., Rolland, a. L., Rollins, b. J. G., Romano, a. J. D., Romano, a. R., Romie, b. J. H., Rosin´ska, a. D., 25f, Ro¨ver, b. C., Rowan, a. S., Ru¨diger, a. A., Ruggi, a. P., Ryan, b. K., Sainathan, a. P., Salemi, a. F., Sammut, a. L., Sandberg, a. V., Sannibale, a. V., Santamarı´a, a. L., Santiago Prieto, a. I., Santostasi, a. G., Sassolas, a. B., Sathyaprakash, b. B. S., Sato, a. S., Saulson, a. P. R., Savage, a. R. L., Schilling, a. R., Schnabel, a. R., Schofield, a. R. M. S., Schreiber, a. E., Schulz, a. B., Schutz, a. B. F., Schwinberg, a. P., Scott, a. J., Scott, a. S. M., Seifert, a. F., Sellers, a. D., Sentenac, a. D., Sergeev, b. A., Shaddock, a. D. A., Shaltev, a. M., Shapiro, a. B., Shawhan, a. P., Shoemaker, a. D. H., Sibley, a. A., Siemens, a. X., Sigg, a. D., Singer, a. A., Singer, a. L., Sintes, a. A. M., Skelton, a. G. R., Slagmolen, a. B. J. J., Slutsky, a. J., Smith, a. J. R., Smith, a. M. R., Smith, a. R. J. E., Smith Lefebvre, a. N. D., Somiya, a. K., Sorazu, a. B., Soto, a. J., Speirits, a. F. C., Sperandio, a. L., Stefszky, b. M., Stein, a. A. J., Stein, a. L. C., Steinert, a. E., Steinlechner, a. J., Steinlechner, a. S., Steplewski, a. S., Stochino, a. A., Stone, a. R., Strain, a. K. A., Strigin, a. S. E., Stroeer, a. A. S., Sturani, a. R., Stuver, b. A. L., Summerscales, a. T. Z., Sung, a. M., Susmithan, a. S., Sutton, a. P. J., Swinkels, a. B., Tacca, b. M., Taffarello, b. L., 59c, Talukder, b. D., Tanner, a. D. B., Tarabrin, a. S. P., Taylor, a. J. R., Taylor, a. R., Thomas, a. P., Thorne, a. K. A., Thorne, a. K. S., Thrane, a. E., Thu¨ring, a. A., Tokmakov, a. K. V., Tomlinson, a. C., Toncelli, a. A., Tonelli, b. M., Torre, b. O., Torres, b. C., Torrie, a. C. I., Tournefier, a. E., Travasso, b. F., Traylor, a. G., Tseng, a. K., Ugolini, a. D., Vahlbruch, a. H., Vajente, a. G., van den Brand, b. J. F. J., Van Den Broeck, b. C., van der Putten, b. S., van Veggel, b. A. A., Vass, a. S., Vasuth, a. M., Vaulin, b. R., Vavoulidis, a. M., Vecchio, b. A., Vedovato, A. g., Veitch, b. J., Veitch, a. P. J., Veltkamp, a. C., Verkindt, a. D., Vetrano, b. F., Vicere, b. A., Villar, b. A. E., Vinet, a. J. Y., Vitale, b. S., Vitale, a. S., Vocca, b. H., Vorvick, a. C., Vyatchanin, a. S. P., Wade, a. A., Wade, a. L., Wade, a. M., Waldman, a. S. J., Wallace, a. L., Wan, a. Y., Wang, a. M., Wang, a. X., Wang, a. Z., Wanner, a. A., Ward, a. R. L., Was, b. M., Weinert, b. M., Weinstein, a. A. J., Weiss, a. R., Wen, a. L., Wessels, a. P., West, a. M., Westphal, a. T., Wette, a. K., Whelan, a. J. T., Whitcomb, a. S. E., White, a. D. J., Whiting, a. B. F., Wilkinson, a. C., Willems, a. P. A., Williams, a. L., Williams, a. R., Willke, a. B., Winkelmann, a. L., Winkler, a. W., Wipf, a. C. C., Wiseman, a. A. G., Wittel, a. H., Woan, a. G., Wooley, a. R., Worden, a. J., Yakushin, a. I., Yamamoto, a. H., Yamamoto, a. K., 59d, A, Yancey, b. C. C., Yang, a. H., Yeaton Massey, a. D., Yoshida, a. S., Yu, a. P., Yvert, a. M., Zadroz´ny, b. A., Zanolin, b. M., Zendri, a. J. P., Zhang, b. F., Zhang, a. L., Zhang, a. W., Zhao, a. C., Zotov, a. N., Zucker, a. M. E., J. Zweizig, A, J., Zweizig, and Pinto, Innocenzo

Subjects
Nuclear and High Energy Physics, Physics and Astronomy (miscellaneous), Stellar mass, Astrophysics::High Energy Astrophysical Phenomena, FOS: Physical sciences, General Relativity and Quantum Cosmology (gr-qc), Astrophysics, Astrophysics::Cosmology and Extragalactic Astrophysics, FORMS, 01 natural sciences, General Relativity and Quantum Cosmology, Gravitational waves, [ PHYS.GRQC ] Physics [physics]/General Relativity and Quantum Cosmology [gr-qc], Settore FIS/05 - Astronomia e Astrofisica, interferometers, Binary black hole, 0103 physical sciences, Astronomy, Astrophysics and Cosmology, 010303 astronomy & astrophysics, Astrophysics::Galaxy Astrophysics, QC, LIGO Scientific Collaboration, QB, Physics, [PHYS]Physics [physics], Solar mass, 010308 nuclear & particles physics, Gravitational wave, 5TH, Settore FIS/01 - Fisica Sperimentale, Astronomy, Mass ratio, LIGO, 3. Good health, [PHYS.GRQC]Physics [physics]/General Relativity and Quantum Cosmology [gr-qc], GROWTH, Stellar black hole, [PHYS.ASTR]Physics [physics]/Astrophysics [astro-ph], CLUSTERS, INSPIRALLING COMPACT BINARIES
Abstract

We present the results of a weakly modeled burst search for gravitational waves from mergers of non-spinning intermediate mass black holes (IMBH) in the total mass range 100--450 solar masses and with the component mass ratios between 1:1 and 4:1. The search was conducted on data collected by the LIGO and Virgo detectors between November of 2005 and October of 2007. No plausible signals were observed by the search which constrains the astrophysical rates of the IMBH mergers as a function of the component masses. In the most efficiently detected bin centered on 88+88 solar masses, for non-spinning sources, the rate density upper limit is 0.13 per Mpc^3 per Myr at the 90% confidence level., Comment: 13 pages, 4 figures: data for plots and archived public version at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=62326, see also the public announcement at http://www.ligo.org/science/Publication-S5IMBH/

Published
2012

15. Effects of Eradication Therapy Success on Symptoms of Duodenal Ulcer Disease with or without Reflux Oesophagitis

Author

Filipec-Kanizaj, T., Katicic, M., Papa, B., Prskalo, M., Ticak, M., ColicCvrlje, V, Mihalic, S. Naumovski, Skurla, B., and Sabaric, B.

Subjects
Gastrointestinal diseases -- Research, Health, Research
Abstract

[11/02] [*] Effects of Eradication Therapy Success on Symptoms of Duodenal Ulcer Disease with or without Reflux Oesophagitis Aim: role of eradication therapy (ET) on symptoms occurrence in duodenal ulcers [...]

Published
2001

16. Relation of H. pylori Infection and associated Gastritis Phenotypes to Proximal and Distal Gastric Carcinoma Types

Author

Prskalo, M., Katicic, M., Filipec, T., Papa, B., Sabaric, B., Ticak, M., Colic, V. Cvrlje, Mihalic, S. Naumovski, Skurla, B., Presecki, V., and Dzebro, S.

Subjects
Gastrointestinal diseases -- Research, Health, Research
Abstract

M. Prskalo [1] M. Katicic [1] T. Filipec [1] B. Papa [1] B. Sabaric [1] M. Ticak [1] V. Cvrlje Colic [1] S. Naumovski Mihalic [1] B. Skurla [1] V. [...]

Published
2001

17. Does Helicobacter pylori Infection Differ in Prevalence between the Haematologic Patients and Healthy Population?

Author

Ticak, M., Katicic, M., Prskalo, M., Sabaric, B., Skurla, B., Papa, B., Cvrlje, V. Colic, Mihalic, S. Naumovski, and Filipec, T.

Subjects
Helicobacter infections -- Research, Helicobacter pylori -- Research, Gastrointestinal diseases -- Research, Health, Research
Abstract

[6/33] Does Helicobacter pylori Infection Differ in Prevalence between the Haematologic Patients and Healthy Population? Aim: To establish whether H. pylori infection prevalence differs between the haematologic patients and healthy [...]

Published
2001

19. West Africa's Efforts to Build Regional Security: An Analysis of Past ECOWAS Interventions to Determine what is Needed to Increase its Peacekeeping Capabilities

Author

ARMY COMMAND AND GENERAL STAFF COLL FORT LEAVENWORTH KS, Dieye, Papa B., ARMY COMMAND AND GENERAL STAFF COLL FORT LEAVENWORTH KS, and Dieye, Papa B.

Abstract

The rise in the number of intra-state conflicts, following the end of the Cold War, and the reluctance of traditional extra regional actors to intervene, have thrust upon the region the onus of resolving its own conflicts. This determination to assume the security responsibility as a prerequisite for sustainable development resulted in a series of interventions by a regional force under the Economic Community of West African States (ECOWAS) umbrella. As a result, ECOWAS is the most experienced organization in Africa, and even beyond, in terms of conflict management. This experience has resulted in the realization that the region needs to increase the current ECOWAS PKO capabilities to make the ECOWAS Standby Force (ESF) a more effective security force. This new mechanism structure under the construct of one of Africa's Regional Economic Communities (REC) is generating hope in terms of local capabilities able to sustain a peace management model designed by Africans themselves. Political will, as well as full dedication by ECOWAS member states, remain minimum requirements to ensure that a greater PKO capability is realized., The original document contains color images.

Published
2010

20. A revised NOTCH1 mutation frequency still impacts survival while the allele burden predicts early progression in chronic lymphocytic leukemia

Author

Sportoletti, P, primary, Baldoni, S, additional, Del Papa, B, additional, Aureli, P, additional, Dorillo, E, additional, Ruggeri, L, additional, Plebani, S, additional, Amico, V, additional, Di Tommaso, A, additional, Rosati, E, additional, Marconi, P, additional, Di Ianni, M, additional, and Falzetti, F, additional

Published
2013
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25. Mesenchymal stem cells ( MSCs) from scleroderma patients ( SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells ( Tregs) with a functional phenotype: implications for cellular-based therapy

Author

Cipriani, P., Di Benedetto, P., Liakouli, V., Del Papa, B., Di Padova, M., Di Ianni, M., Marrelli, A., Alesse, E., and Giacomelli, R.

Subjects
SCLERODERMA (Disease) treatment, MESENCHYMAL stem cells, IMMUNOREGULATION, T cells, PHENOTYPES, LYMPHOCYTES, INTERLEUKIN-6, CELL proliferation
Abstract

Systemic sclerosis ( SSc) is a chronic disease, with early activation of the immune system. The aim of our work was to address how SSc-mesenchymal stem cells ( MSCs), although senescent, might preserve specific immunomodulatory abilities during SSc. MSCs were obtained from 10 SSc patients and 10 healthy controls ( HC). Senescence was evaluated by assessing cell cycle, β-galactosidase (β- Gal) activity, p21 and p53 expression; doxorubicin was used as acute senescence stimulus to evaluate their ability to react in stressed conditions. Immunomodulatory abilities were studied co-culturing MSCs with peripheral blood mononuclear cells ( PBMCs) and CD4+ cells, in order to establish both their ability to block proliferation in mixed lymphocyte reaction and in regulatory T cells ( Tregs) induction. SSc- MSC showed an increase of senescence biomarkers. Eighty per cent of MSCs were in G0- G1 phase, without significant differences between SSc and HC. SSc- MSCs showed an increased positive β- Gal staining and higher p21 transcript level compared to HC cells. After doxorubicin, β- Gal staining increased significantly in SSc- MSCs. On the contrary, doxorubicin abolished p21 activation and elicited p53 induction both in SSc- and HC- MSCs. Interleukin ( IL)-6 and transforming growth factor ( TGF)-β-related transcripts and their protein levels were significantly higher in SSc- MSCs. The latter maintained their immunosuppressive effect on lymphocyte proliferation and induced a functionally regulatory phenotype on T cells, increasing surface expression of CD69 and restoring the regulatory function which is impaired in SSc. Increased activation of the IL-6 pathway observed in our cells might represent an adaptive mechanism to senescence, but preserving some specific cellular functions, including immunosuppression. [ABSTRACT FROM AUTHOR]

Published
2013
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26. Immunomagnetic isolation of CD4+CD25+FoxP3+ natural T regulatory lymphocytes for clinical applications.

Author

Di Ianni, M., Del Papa, B., Cecchini, D., Bonifacio, E., Moretti, L., Zei, T., Iacucci Ostini, R., Falzetti, F., Fontana, L., Tagliapietra, G., Maldini, C., Martelli, M. F., and Tabilio, A.

Subjects
*T cells, *IMMUNOSUPPRESSION, *IMMUNOREGULATION, *GRAFT versus host disease, *CELL transplantation, *THERAPEUTICS
Abstract

Although CD4+/CD25+ T regulatory cells (Tregs) are a potentially powerful tool in bone marrow transplantation, a prerequisite for clinical use is a cell-separation strategy complying with good manufacturing practice guidelines. We isolated Tregs from standard leukapheresis products using double-negative selection (anti-CD8 and anti-CD19 monoclonal antibodies) followed by positive selection (anti-CD25 monoclonal antibody). The final cell fraction (CD4+/CD25+) showed a mean purity of 93·6% ± 1·1. Recovery efficiency was 81·52% ± 7·4. The CD4+/CD25+bright cells were 28·4% ± 6·8. The CD4+/CD25+ fraction contained a mean of 51·9% ± 15·1 FoxP3 cells and a mean of 18·9% ± 11·5 CD127 cells. Increased FoxP3 and depleted CD127 mRNAs in CD4+CD25+FoxP3+ cells were in line with flow cytometric results. In Vβ spectratyping the complexity scores of CD4+/CD25+ cells and CD4+/CD25- cells were not significantly different, indicating that Tregs had a broad T cell receptor repertoire. The inhibition assay showed that CD4+/CD25+ cells inhibited CD4+/CD25- cells in a dose-dependent manner (mean inhibition percentages: 72·4 ± 8·9 [ratio of T responder (Tresp) to Tregs, 1:2]; 60·8% ± 20·5 (ratio of Tresp to Tregs, 1:1); 25·6 ± 19·6 (ratio of Tresp to Tregs, 1:0·1)). Our study shows that negative/positive Treg selection, performed using the CliniMACS device and reagents, enriches significantly CD4+CD25+FoxP3+ cells endowed with immunosuppressive capacities. The CD4+CD25+FoxP3+ population is a source of natural Treg cells that are depleted of CD8+ and CD4+/CD25- reacting clones which are potentially responsible for triggering graft- versus-host disease (GvHD). Cells isolated by means of this approach might be used in allogeneic haematopoietic cell transplantation to facilitate engraftment and reduce the incidence and severity of GvHD without abrogating the potential graft- versus-tumour effect. [ABSTRACT FROM AUTHOR]

Published
2009
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27. Helicobacter pylori infection in patients with liver cirrhosis.

Author

Naumovski-Mihalic, S., Katicic, M., Colic-Cvrlje, V., Scrbec, B., Papa, B., and Sabaric, B.

Subjects
HELICOBACTER pylori infections, GASTRITIS, PEPTIC ulcer
Abstract

Background: HP infection currently is the most important etiologic agent in the development of chronic active gastritis, gastric and duodenal ulcers,carcinoma and Malt-lymphoma of the stomach. Moreover HP infection has also been associated with various extradigestive diseases. Aim: The aim of our study was to investigate the possible pathogenetic role of Helicobacter pylori (HP) infection in patients with cirrhosis of the liver. Patients and Methods: 235 patients (M/F 155/80, aged 24-86 yo) suffered from liver cirrhosis, were hospitalised during five years in ICU, University Hospital Merkur Zagreb, and were included in the study. They were divided into three groups according to the Child's classification for cirrhotic severity (A — good, B — fair and C poor). In adition,the patients were divided according to the presence or absence of each of the following:ascites, splenomegaly, oesophageal varices, bilirubin level and known risk factor for hepatic encephalopathy (gastrointestinal bleeding, azothemia, hepatorenal syndrome, infection and severity of disease). All patients had upper gastro-intestinal endoscopy and the gastroduodenal pathology was identified. Helicobacter pylori (HP) infection was confirmed by gastric histology. Results: 143 (60,85%) patients were HP positive. 79 (33,61%) patients were admitted because of upper GI bleeding. In this group, 61 (77,21%) were HP positive (χ² test 13.38, p = 0.003, CI = 0.32-0.42). The highest rates of HP infection were found among patients in Child's class C. We found significant difference in HP positive rate between the patients with and without oesophageal varices too. 113 (69,36%) patients had encephalopathy, and 88 (77,87%) of those were infected with HP, compared with only 48,3% patients without encephalopathy (χ² test 17.58, p = 0.002 CI = 0.54-0.62). Conclusion: According to our results we found that HP infection was higher among patients with cirrhosis and acute Gl bleeding, as... [ABSTRACT FROM AUTHOR]

Published
2002

28. Mesenchymal stem cells (MSCs) from scleroderma patients (SSc) preserve their immunomodulatory properties although senescent and normally induce T regulatory cells (Tregs) with a functional phenotype: implications for cellular-based therapy

Author

V. Liakouli, Edoardo Alesse, Alessandra Marrelli, Roberto Giacomelli, M. Di Padova, Paola Cipriani, P. Di Benedetto, M Di Ianni, B. Del Papa, Cipriani, Paola, Di Benedetto, P, Liakouli, V, Del Papa, B, DI PADOVA, Monica, Di Ianni, M, Marrelli, A, Alesse, Edoardo, and Giacomelli, Roberto

Subjects
Antigens, Differentiation, T-Lymphocyte, Cyclin-Dependent Kinase Inhibitor p21, Senescence, senescence, Immunology, Cell- and Tissue-Based Therapy, Lymphocyte proliferation, Biology, T-Lymphocytes, Regulatory, Peripheral blood mononuclear cell, Immunomodulation, Immune system, Antigens, CD, Transforming Growth Factor beta, Humans, Immunology and Allergy, Lectins, C-Type, immunomodulatory abilities, skin and connective tissue diseases, mesenchymal stem cell, Cells, Cultured, Cellular Senescence, mesenchymal stem cells, Cell Proliferation, Scleroderma, Systemic, integumentary system, Interleukin-6, Mesenchymal stem cell, Interleukin, Mesenchymal Stem Cells, Original Articles, beta-Galactosidase, Mixed lymphocyte reaction, Coculture Techniques, Doxorubicin, Cancer research, immunomodulatory abilitie, Tumor Suppressor Protein p53, Stem cell
Abstract

Summary Systemic sclerosis (SSc) is a chronic disease, with early activation of the immune system. The aim of our work was to address how SSc–mesenchymal stem cells (MSCs), although senescent, might preserve specific immunomodulatory abilities during SSc. MSCs were obtained from 10 SSc patients and 10 healthy controls (HC). Senescence was evaluated by assessing cell cycle, β-galactosidase (β-Gal) activity, p21 and p53 expression; doxorubicin was used as acute senescence stimulus to evaluate their ability to react in stressed conditions. Immunomodulatory abilities were studied co-culturing MSCs with peripheral blood mononuclear cells (PBMCs) and CD4+ cells, in order to establish both their ability to block proliferation in mixed lymphocyte reaction and in regulatory T cells (Tregs) induction. SSc–MSC showed an increase of senescence biomarkers. Eighty per cent of MSCs were in G0–G1 phase, without significant differences between SSc and HC. SSc–MSCs showed an increased positive β-Gal staining and higher p21 transcript level compared to HC cells. After doxorubicin, β-Gal staining increased significantly in SSc–MSCs. On the contrary, doxorubicin abolished p21 activation and elicited p53 induction both in SSc– and HC–MSCs. Interleukin (IL)-6 and transforming growth factor (TGF)-β-related transcripts and their protein levels were significantly higher in SSc–MSCs. The latter maintained their immunosuppressive effect on lymphocyte proliferation and induced a functionally regulatory phenotype on T cells, increasing surface expression of CD69 and restoring the regulatory function which is impaired in SSc. Increased activation of the IL-6 pathway observed in our cells might represent an adaptive mechanism to senescence, but preserving some specific cellular functions, including immunosuppression.

Published
2013

29. The dimerization of the yeast cytochrome bc1 complex is an early event and is independent of Rip1

Author

Benedetta Papa, Vincenzo Zara, Annalea Conte, Alessandra Ferramosca, Conte, A, Papa, B, Ferramosca, Alessandra, and Zara, Vincenzo

Subjects
Yeast mitochondria, Saccharomyces cerevisiae Proteins, Cytochrome, Saccharomyces cerevisiae, Biology, Models, Biological, Electron Transport Complex IV, Electron Transport Complex III, Cytochrome C1, Cytochrome c oxidase, Rip1, Cytochrome bc1 biogenesis, Molecular Biology, Cytochrome bc1 complex, Cytochrome b, yeast mitochondria, Cytochrome c, Cell Biology, Mitochondria, Nuclear Pore Complex Proteins, Transmembrane domain, Biochemistry, cytochrome bc1 biogenesi, Multiprotein Complexes, cytochrome bc1 complex, Coenzyme Q – cytochrome c reductase, biology.protein, Biophysics, Protein Multimerization, Gene Deletion, Biogenesis
Abstract

In Saccharomyces cerevisiae the mature cytochrome bc1 complex exists as an obligate homo-dimer in which each monomer consists of ten distinct protein subunits inserted into or bound to the inner mitochondrial membrane. Among them, the Rieske iron–sulfur protein (Rip1), besides its catalytic role in electron transfer, may be implicated in the bc1 complex dimerization. Indeed, Rip1 has the globular domain containing the catalytic center in one monomer while the transmembrane helix interacts with the adjacent monomer. In addition, the lack of Rip1 leads to the accumulation of an immature bc1 intermediate, only loosely associated with cytochrome c oxidase.In this study we have investigated the biogenesis of the yeast cytochrome bc1 complex using epitope tagged proteins to purify native assembly intermediates. We showed that the dimerization process is an early event during bc1 complex biogenesis and that the presence of Rip1, differently from previous proposals, is not essential for this process. We also investigated the multi-step model of bc1 assembly thereby lending further support to the existence of bona fide subcomplexes during bc1 maturation in the inner mitochondrial membrane. Finally, a new model of cytochrome bc1 complex assembly, in which distinct intermediates sequentially interact during bc1 maturation, has been proposed.

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31. Pulsed, Resting and Peroxy Forms of Cytochrome Oxidase

Author

F. Malatesta, Giovanni Antonini, Paolo Sarti, Maurizio Brunori, M. T. Wilson, S. PAPA, B. CHANCE AND L. ERNSTER EDS, Antonini, Giovanni, Francesco, Malatesta, Paolo, Sarti, MICHAEL T., Wilson, and Maurizio, Brunori

Subjects
chemistry.chemical_classification, chemistry.chemical_compound, Electron transfer, Enzyme, Cytochrome, biology, chemistry, biology.protein, Cytochrome c oxidase, Molecular oxygen, Photochemistry, Catalysis, Carbon monoxide
Abstract

Two functionally distinct states of cytochrome oxidase were initially demonstrated by kinetic experiments and the difference in the catalytic activity between these two states was attributed to a faster internal electron transfer observed in the so-called “pulsed” enzyme, which is obtained by exposing the reduced enzyme to molecular oxygen (1). This result was supported by the finding that the rate of reduction of cytochrome a is the same in the two functional states of the enzyme (2).

Published
1987

32. Electron exchange between cytochromes a

Author

PAOLO SARTI, FRANCESCO MALATESTA, MICHAEL T. WILSON AND MAURIZIO BRUNORI, ANTONINI, GIOVANNI, S. PAPA, B. CHANCE AND L. ERNSTER EDS., Paolo, Sarti, Francesco, Malatesta, Antonini, Giovanni, and MICHAEL T., WILSON AND MAURIZIO BRUNORI

Published
1988

33. NOTCH1 -mutated chronic lymphocytic leukemia displays high endoplasmic reticulum stress response with druggable potential.

Author

Silva Barcelos EC, Rompietti C, Adamo FM, Dorillo E, De Falco F, Del Papa B, Baldoni S, Nogarotto M, Esposito A, Capoccia S, Geraci C, Sorcini D, Stella A, Arcaleni R, Tini V, Imbroisi Valle Errera F, Rosati E, and Sportoletti P

Abstract

Introduction: Constitutive activation of NOTCH1 -wild-type (NT1-WT) signaling is associated with poor outcomes in chronic lymphocytic leukemia (CLL), and NOTCH1 mutation (c.7541_7542delCT), which potentiates NOTCH1 signaling, worsens the prognosis. However, the specific mechanisms of NOTCH1 deregulation are still poorly understood. Accumulative evidence mentioned endoplasmic reticulum (ER) stress/unfolded protein response (UPR) as a key targetable pathway in CLL. In this study, we investigated the impact of NOTCH1 deregulation on CLL cell response to ER stress induction, with the aim of identifying new therapeutic opportunities for CLL., Methods: We performed a bioinformatics analysis of NOTCH1 -mutated (NT1-M) and NT1-WT CLL to identify differentially expressed genes (DEGs) using the rank product test. Quantitative real-time polymerase chain reaction (qPCR), Western blotting, cytosolic Ca 2+ , and annexin V/propidium iodide (PI) assay were used to detect curcumin ER stress induction effects. A median-effect equation was used for drug combination tests. The experimental mouse model Eμ-TCL1 was used to evaluate the impact of ER stress exacerbation by curcumin treatment on the progression of leukemic cells and NOTCH1 signaling., Results and Discussion: Bioinformatics analysis revealed gene enrichment of the components of the ER stress/UPR pathway in NT1-M compared to those in NT1-WT CLL. Ectopic expression of NOTCH1 mutation upregulated the levels of ER stress response markers in the PGA1 CLL cell line. Primary NT1-M CLL was more sensitive to curcumin as documented by a significant perturbation in Ca 2+ homeostasis and higher expression of ER stress/UPR markers compared to NT1-WT cells. It was also accompanied by a significantly higher apoptotic response mediated by C/EBP homologous protein (CHOP) expression, caspase 4 cleavage, and downregulation of NOTCH1 signaling in NT1-M CLL cells. Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells. In Eμ-TCL1 leukemic mice, the administration of curcumin activated ER stress in splenic B cells ex vivo and significantly reduced the percentage of CD19 + /CD5 + cells infiltrating the spleen, liver, and bone marrow (BM). These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Silva Barcelos, Rompietti, Adamo, Dorillo, De Falco, Del Papa, Baldoni, Nogarotto, Esposito, Capoccia, Geraci, Sorcini, Stella, Arcaleni, Tini, Imbroisi Valle Errera, Rosati and Sportoletti.)

Published
2023
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34. Equine synovial sepsis laboratory submissions yield a low rate of positive bacterial culture and a high prevalence of antimicrobial resistance.

Author

Pearson GB, Papa B, Mosaddegh A, Cooper H, Aprea M, Pigott J, Altier C, Cazer CL, and Reesink HL

Subjects
Animals, Horses, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial, Prevalence, Synovial Fluid, Microbial Sensitivity Tests veterinary, Sepsis epidemiology, Sepsis veterinary, Sepsis drug therapy, Horse Diseases diagnosis, Horse Diseases epidemiology, Horse Diseases drug therapy
Abstract

Objective: To investigate (1) variables associated with the likelihood of obtaining a positive culture, (2) commonly isolated microorganisms, and (3) antimicrobial resistance patterns of isolates from horses with presumptive synovial sepsis., Samples: Synovial fluid, synovium, and bone samples from equine cases with presumptive synovial sepsis submitted to the Cornell University Animal Health Diagnostic Center from 2000 to 2020 for microbial culture and antimicrobial sensitivity testing., Procedures: Univariable and multivariable analyses were performed to determine the effect of variables on the likelihood of positive culture. Frequency distributions for isolated organisms and antimicrobial resistance were generated. Multidrug resistance patterns and associations were assessed with association rule mining., Results: The positive culture rate for all samples was 37.4%, while the positive culture rate among samples confirmed to be septic by a combination of clinical pathological variables and case details was 43%. Blood culture vial submissions were 1.7 times more likely to yield a positive culture compared to samples submitted in a serum tube. Structure sampled, tissue submitted, and horse age were associated with a positive culture. Staphylococcus spp (23.7%), Streptococcus spp (22.4%), and Enterococcus spp (9.67%) were commonly isolated. Multidrug resistance prevalence decreased from 92% (2000 to 2009) to 76% (2010 to 2020) of gram-negative isolates and 60% (2000 to 2009) to 52% (2010 to 2020) of gram-positive isolates., Clinical Relevance: The positive culture rate from synovial fluid submissions with traditional sampling and culture methods remains low and may be optimized by submitting samples in blood culture vials. Overall, antimicrobial resistance was frequently observed but did not increase from the first to second decade for most genera.

Published
2023
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35. Therapeutic Targeting Potential of Novel Silver Nanoparticles Coated with Anti-CD20 Antibody against Chronic Lymphocytic Leukemia.

Author

Adamo FM, Silva Barcelos EC, De Falco F, Dorillo E, Rompietti C, Sorcini D, Stella A, Del Papa B, Baldoni S, Esposito A, Geraci C, Arcaleni R, Pennetta C, Ragonese F, Moretti L, Mameli M, Di Ianni M, Rosati E, Fioretti B, and Sportoletti P

Abstract

Background: Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances made in CLL therapy with the new target agents, in some cases, relapses and resistance could occur, making the discovery of new alternatives to manage CLL refractoriness necessary. To provide new therapeutic strategies for CLL, we investigated the anti-leukemic activity of silver nanoparticles (AgNPs), whose impact on CLL cells has been poorly explored., Methods: We studied the action mechanisms of AgNPs in vitro through flow cytometry and molecular analyses. To improve the bioavailability of AgNPs, we generated AgNPs coated with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) and carried out imaging-based approaches and in vivo experiments to evaluate specificity, drug uptake, and efficacy., Results: AgNPs reduced the viability of primary CLL cells and the HG-3 cell line by inducing an intrinsic apoptotic pathway characterized by Bax/Bcl-2 imbalance, caspase activation, and PARP degradation. Early apoptotic events triggered by AgNPs included enhanced Ca 2+ influx and ROS overproduction. AgNPs synergistically potentiated the cytotoxicity of Venetoclax, Ibrutinib, and Bepridil. In vitro, the AgNPs@Rituximab conjugates were rapidly internalized within CLL cells and strongly prolonged the survival of CLL xenograft models compared to each unconjugated single agent., Conclusions: AgNPs showed strong anti-leukemic activity in CLL, with the potential for clinical translation in combination with agents used in CLL. The increased specificity of AgNPs@Rituximab toward CLL cells could be relevant for overcoming in vivo AgNPs' non-specific distribution and increasing their efficacy.

Published
2023
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36. Synovial sepsis diagnostics and antimicrobial resistance: a one-health perspective.

Author

Pearson GB, Ysebaert MP, Papa B, and Reesink HL

Subjects
Humans, Animals, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Drug Resistance, Bacterial, One Health, Sepsis diagnosis, Sepsis drug therapy, Sepsis veterinary, Anti-Infective Agents
Abstract

This article, as part of the Currents in One Health series, reviews the current state of diagnostics for synovial sepsis. Synovial sepsis is a condition that affects veterinary and human medicine and requires coordinated efforts from both parties, as well as environmental considerations to accurately diagnose and preserve effective treatments. The article discusses best practices to identify the causative agent in septic synovitis, trends in bacterial identification and antimicrobial resistance patterns across common bacterial species, and a one-health perspective to optimize diagnostics across species. Antimicrobial resistance is a challenge facing both human and veterinary medicine and requires mindful and attentive prescribing to reduce the development of antimicrobial resistance and preserve antimicrobials for future application. The current standard of care for bacterial identification in veterinary practice is culture and antimicrobial susceptibility; however, positive culture rates from synovial sepsis cases often remain < 50%. Recent developments in advanced bacterial identification present opportunities for improved bacterial identification in synovial sepsis. Increased bacterial isolation will also help guide empirical antimicrobial therapy. Utilizing information and recommendations from both the human and veterinary literature will improve timely and accurate bacterial identification and therefore rapid and effective treatment of synovial sepsis across species and limit the development of antimicrobial resistance.

Published
2023
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37. Metacarpophalangeal Joint Pathology and Bone Mineral Density Increase with Exercise but Not with Incidence of Proximal Sesamoid Bone Fracture in Thoroughbred Racehorses.

Author

Noordwijk KJ, Chen L, Ruspi BD, Schurer S, Papa B, Fasanello DC, McDonough SP, Palmer SE, Porter IR, Basran PS, Donnelly E, and Reesink HL

Abstract

Proximal sesamoid bone (PSB) fracture is the leading cause of fatal musculoskeletal injury in Thoroughbred racehorses in Hong Kong and the US. Efforts are underway to investigate diagnostic modalities that could help identify racehorses at increased risk of fracture; however, features associated with PSB fracture risk are still poorly understood. The objectives of this study were to (1) investigate third metacarpal (MC3) and PSB density and mineral content using dual-energy X-ray absorptiometry (DXA), computed tomography (CT), Raman spectroscopy, and ash fraction measurements, and (2) investigate PSB quality and metacarpophalangeal joint (MCPJ) pathology using Raman spectroscopy and CT. Forelimbs were collected from 29 Thoroughbred racehorse cadavers ( n = 14 PSB fracture, n = 15 control) for DXA and CT imaging, and PSBs were sectioned for Raman spectroscopy and ash fraction measurements. Bone mineral density (BMD) was greater in MC3 condyles and PSBs of horses with more high-speed furlongs. MCPJ pathology, including palmar osteochondral disease (POD), MC3 condylar sclerosis, and MC3 subchondral lysis were greater in horses with more high-speed furlongs. There were no differences in BMD or Raman parameters between fracture and control groups; however, Raman spectroscopy and ash fraction measurements revealed regional differences in PSB BMD and tissue composition. Many parameters, including MC3 and PSB bone mineral density, were strongly correlated with total high-speed furlongs.

Published
2023
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38. GSK3β is a critical, druggable component of the network regulating the active NOTCH1 protein and cell viability in CLL.

Author

De Falco F, Rompietti C, Sorcini D, Esposito A, Scialdone A, Baldoni S, Del Papa B, Adamo FM, Silva Barcelos EC, Dorillo E, Stella A, Di Ianni M, Screpanti I, Sportoletti P, and Rosati E

Subjects
Cell Survival genetics, Humans, Protein Phosphatase 2 genetics, Proto-Oncogene Proteins c-akt metabolism, Glycogen Synthase Kinase 3 beta genetics, Glycogen Synthase Kinase 3 beta metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Receptor, Notch1 genetics, Receptor, Notch1 metabolism
Abstract

NOTCH1 alterations have been associated with chronic lymphocytic leukemia (CLL), but the molecular mechanisms underlying NOTCH1 activation in CLL cells are not completely understood. Here, we show that GSK3β downregulates the constitutive levels of the active NOTCH1 intracellular domain (N1-ICD) in CLL cells. Indeed, GSK3β silencing by small interfering RNA increases N1-ICD levels, whereas expression of an active GSK3β mutant reduces them. Additionally, the GSK3β inhibitor SB216763 enhances N1-ICD stability at a concentration at which it also increases CLL cell viability. We also show that N1-ICD is physically associated with GSK3β in CLL cells. SB216763 reduces GSK3β/N1-ICD interactions and the levels of ubiquitinated N1-ICD, indicating a reduction in N1-ICD proteasomal degradation when GSK3β is less active. We then modulated the activity of two upstream regulators of GSK3β and examined the impact on N1-ICD levels and CLL cell viability. Specifically, we inhibited AKT that is a negative regulator of GSK3β and is constitutively active in CLL cells. Furthermore, we activated the protein phosphatase 2 A (PP2A) that is a positive regulator of GSK3β, and has an impaired activity in CLL. Results show that either AKT inhibition or PP2A activation reduce N1-ICD expression and CLL cell viability in vitro, through mechanisms mediated by GSK3β activity. Notably, for PP2A activation, we used the highly specific activator DT-061, that also reduces leukemic burden in peripheral blood, spleen and bone marrow in the Eµ-TCL1 adoptive transfer model of CLL, with a concomitant decrease in N1-ICD expression. Overall, we identify in GSK3β a key component of the network regulating N1-ICD stability in CLL, and in AKT and PP2A new druggable targets for disrupting NOTCH1 signaling with therapeutic potential., (© 2022. The Author(s).)

Published
2022
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39. Quantification of the Immune Content in Neuroblastoma: Deep Learning and Topological Data Analysis in Digital Pathology.

Author

Bussola N, Papa B, Melaiu O, Castellano A, Fruci D, and Jurman G

Subjects
Cloud Computing, Deep Learning, Female, Humans, Lymphocytes metabolism, Male, Neural Networks, Computer, Neuroblastoma diagnostic imaging, Image Interpretation, Computer-Assisted methods, Neuroblastoma immunology
Abstract

We introduce here a novel machine learning (ML) framework to address the issue of the quantitative assessment of the immune content in neuroblastoma (NB) specimens. First, the EUNet, a U-Net with an EfficientNet encoder, is trained to detect lymphocytes on tissue digital slides stained with the CD3 T-cell marker. The training set consists of 3782 images extracted from an original collection of 54 whole slide images (WSIs), manually annotated for a total of 73,751 lymphocytes. Resampling strategies, data augmentation, and transfer learning approaches are adopted to warrant reproducibility and to reduce the risk of overfitting and selection bias. Topological data analysis (TDA) is then used to define activation maps from different layers of the neural network at different stages of the training process, described by persistence diagrams (PD) and Betti curves. TDA is further integrated with the uniform manifold approximation and projection (UMAP) dimensionality reduction and the hierarchical density-based spatial clustering of applications with noise (HDBSCAN) algorithm for clustering, by the deep features, the relevant subgroups and structures, across different levels of the neural network. Finally, the recent TwoNN approach is leveraged to study the variation of the intrinsic dimensionality of the U-Net model. As the main task, the proposed pipeline is employed to evaluate the density of lymphocytes over the whole tissue area of the WSIs. The model achieves good results with mean absolute error 3.1 on test set, showing significant agreement between densities estimated by our EUNet model and by trained pathologists, thus indicating the potentialities of a promising new strategy in the quantification of the immune content in NB specimens. Moreover, the UMAP algorithm unveiled interesting patterns compatible with pathological characteristics, also highlighting novel insights into the dynamics of the intrinsic dataset dimensionality at different stages of the training process. All the experiments were run on the Microsoft Azure cloud platform.

Published
2021
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40. NK Cells in Chronic Lymphocytic Leukemia and Their Therapeutic Implications.

Author

Sportoletti P, De Falco F, Del Papa B, Baldoni S, Guarente V, Marra A, Dorillo E, Rompietti C, Adamo FM, Ruggeri L, Di Ianni M, and Rosati E

Subjects
Biomarkers, Cell Communication, Disease Management, Humans, Immune System immunology, Immune System metabolism, Immunotherapy adverse effects, Immunotherapy methods, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Ligands, Protein Binding, Receptors, Natural Killer Cell genetics, Receptors, Natural Killer Cell metabolism, Treatment Outcome, Tumor Escape genetics, Tumor Escape immunology, Disease Susceptibility, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Leukemia, Lymphocytic, Chronic, B-Cell etiology, Leukemia, Lymphocytic, Chronic, B-Cell metabolism
Abstract

Key features of chronic lymphocytic leukemia (CLL) are defects in the immune system and the ability of leukemic cells to evade immune defenses and induce immunosuppression, resulting in increased susceptibility to infections and disease progression. Several immune effectors are impaired in CLL, including T and natural killer (NK) cells. The role of T cells in defense against CLL and in CLL progression and immunotherapy has been extensively studied. Less is known about the role of NK cells in this leukemia, and data on NK cell alterations in CLL are contrasting. Besides studies showing that NK cells have intrinsic defects in CLL, there is a large body of evidence indicating that NK cell dysfunctions in CLL mainly depend on the escape mechanisms employed by leukemic cells. In keeping, it has been shown that NK cell functions, including antibody-dependent cellular cytotoxicity (ADCC), can be retained and/or restored after adequate stimulation. Therefore, due to their preserved ADCC function and the reversibility of CLL-related dysfunctions, NK cells are an attractive source for novel immunotherapeutic strategies in this disease, including chimeric antigen receptor (CAR) therapy. Recently, satisfying clinical responses have been obtained in CLL patients using cord blood-derived CAR-NK cells, opening new possibilities for further exploring NK cells in the immunotherapy of CLL. However, notwithstanding the promising results of this clinical trial, more evidence is needed to fully understand whether and in which CLL cases NK cell-based immunotherapy may represent a valid, alternative/additional therapeutic option for this leukemia. In this review, we provide an overview of the current knowledge about phenotypic and functional alterations of NK cells in CLL and the mechanisms by which CLL cells circumvent NK cell-mediated immunosurveillance. Additionally, we discuss the potential relevance of using NK cells in CLL immunotherapy.

Published
2021
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41. NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status.

Author

Baldoni S, Del Papa B, De Falco F, Dorillo E, Sorrentino C, Rompietti C, Adamo FM, Nogarotto M, Cecchini D, Mondani E, Silva Barcelos EC, Moretti L, Mameli MG, Fabi B, Sorcini D, Stella A, Giancola R, Guardalupi F, Ulbar F, Plebani S, Guarente V, Rosati E, Di Nicola M, Marchioni M, Di Ianni M, and Sportoletti P

Abstract

NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of NOTCH1 mutations on clinical course of CLL has been widely studied, the prognostic role of NOTCH1 activation in CLL remains to be defined. Here, we analyzed the activation of NOTCH1/NOTCH2 (ICN1/ICN2) and the expression of JAGGED1 (JAG1) in 163 CLL patients and evaluated their impact on TTFT (Time To First Treatment) and OS (Overall Survival). NOTCH1 activation (ICN1+) was found in 120/163 (73.6%) patients. Among them, 63 (52.5%) were NOTCH1 mutated (ICN1+/mutated) and 57 (47.5%) were NOTCH1 wild type (ICN1+/WT). ICN1+ patients had a significant reduction of TTFT compared to ICN1-negative (ICN1-). In the absence of NOTCH1 mutations, we found that the ICN1+/WT group had a significantly reduced TTFT compared to ICN1- patients. The analysis of IGHV mutational status showed that the distribution of the mutated/unmutated IGHV pattern was similar in ICN1+/WT and ICN1- patients. Additionally, TTFT was significantly reduced in ICN1+/ICN2+ and ICN1+/JAG1+ patients compared to ICN1-/ICN2- and ICN1-/JAG1- groups. Our data revealed for the first time that NOTCH1 activation is a negative prognosticator in CLL and is not correlated to NOTCH1 and IGHV mutational status. Activation of NOTCH2 and JAGGED1 expression might also influence clinical outcomes in this group, indicating the need for further dedicated studies. The evaluation of different NOTCH network components might represent a new approach to refine CLL risk stratification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Baldoni, Del Papa, De Falco, Dorillo, Sorrentino, Rompietti, Adamo, Nogarotto, Cecchini, Mondani, Silva Barcelos, Moretti, Mameli, Fabi, Sorcini, Stella, Giancola, Guardalupi, Ulbar, Plebani, Guarente, Rosati, Di Nicola, Marchioni, Di Ianni and Sportoletti.)

Published
2021
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42. Clinical-Grade Expanded Regulatory T Cells Are Enriched with Highly Suppressive Cells Producing IL-10, Granzyme B, and IL-35.

Author

Ulbar F, Villanova I, Giancola R, Baldoni S, Guardalupi F, Fabi B, Olioso P, Capone A, Sola R, Ciardelli S, Del Papa B, Brattelli A, Ricciardi I, Taricani S, Sabbatinelli G, Iuliani O, Passeri C, Sportoletti P, Santarone S, Pierini A, Calabrese G, Falzetti F, Bonfini T, Accorsi P, Ruggeri L, Martelli MF, Velardi A, and Di Ianni M

Subjects
Animals, Forkhead Transcription Factors, Granzymes, Interleukin-10, Mice, Graft vs Host Disease prevention & control, T-Lymphocytes, Regulatory
Abstract

In the setting of T cell-depleted, full-haplotype mismatched transplantation, adoptive immunotherapy with regulatory T cells (Tregs) and conventional T cells (Tcons) can prevent graft-versus-host disease (GVHD) and improve post-transplantation immunologic reconstitution and is associated with a powerful graft-versus-leukemia effect. To improve the purity and the quantity of the infused Tregs, good manufacturing practices (GMP)-compatible expansion protocols are needed. Here we expanded Tregs using an automated, clinical-grade protocol. Cells were extensively characterized in vitro, and their efficiency was tested in vivo in a mouse model. Tregs were selected by CliniMacs (CD4 + CD25 + , 94.5 ± 6.3%; FoxP3 + , 63.7 ± 11.5%; CD127 + , 20 ± 3%; suppressive activity, 60 ± 7%), and an aliquot of 100 × 10 6 was expanded for 14 days using the CliniMACS Prodigy System, obtaining 684 ± 279 × 10 6 cells (CD4 + CD25 + , 99.6 ± 0.2%; FoxP3 + , 82 ± 8%; CD127 + , 1.1 ± 0.8%; suppressive activity, 75 ± 12%). CD39 and CTLA4 expression levels increased from 22.4 ± 12% to 58.1 ± 13.3% (P < .05) and from 20.4 ± 6.7% to 85.4 ± 9.8% (P < .01), respectively. TIM3 levels increased from .4 ± .05% to 29 ± 16% (P < .05). Memory Tregs were the prevalent population, whereas naive Tregs almost disappeared at the end of the culture. mRNA analysis displayed significant increases in CD39, IL-10, granzyme B, and IL-35 levels at the end of culture period (P < .05). Conversely, IFNγ expression decreased significantly by day +14. Expanded Tregs were sorted according to TIM3, CD39, and CD62L expression levels (purity >95%). When sorted populations were analyzed, TIM3 + cells showed significant increases in IL-10 and granzyme B (P < .01) .When expanded Tregs were infused in an NSG murine model, mice that received Tcons only died of GVHD, whereas mice that received both Tcons and Tregs survived without GVHD. GMP grade expanded cells that display phenotypic and functional Treg characteristics can be obtained using a fully automated system. Treg suppression is mediated by multiple overlapping mechanisms (eg, CTLA-4, CD39, IL-10, IL-35, TGF-β, granzyme B). TIM3 + cells emerge as a potentially highly suppressive population. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Published
2020
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43. Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia.

Author

Del Papa B, Baldoni S, Dorillo E, De Falco F, Rompietti C, Cecchini D, Cantelmi MG, Sorcini D, Nogarotto M, Adamo FM, Mezzasoma F, Silva Barcelos EC, Albi E, Iacucci Ostini R, Di Tommaso A, Marra A, Montanaro G, Martelli MP, Falzetti F, Di Ianni M, Rosati E, and Sportoletti P

Subjects
Adenine analogs & derivatives, Humans, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Piperidines, Protein Kinase Inhibitors pharmacology, Receptor, Notch1 genetics, Receptors, Antigen, B-Cell genetics, Signal Transduction, Treatment Outcome, Tumor Cells, Cultured, Apoptosis, Biomarkers, Tumor metabolism, Drug Resistance, Neoplasm, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Pyrazoles pharmacology, Pyrimidines pharmacology, Receptor, Notch1 metabolism, Receptors, Antigen, B-Cell metabolism
Abstract

Purpose: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), has improved the outcomes of chronic lymphocytic leukemia (CLL), but primary resistance or relapse are issues of increasing significance. While the predominant mechanism of action of BTKi is the B-cell receptor (BCR) blockade, many off-target effects are unknown. We investigated potential interactions between BCR pathway and NOTCH1 activity in ibrutinib-treated CLL to identify new mechanisms of therapy resistance and markers to monitor disease response., Experimental Design: NOTCH activations was evaluated either in vitro and ex vivo in CLL samples after ibrutinib treatment by Western blotting. Confocal proximity ligation assay (PLA) experiments and analyses of down-targets of NOTCH1 by qRT-PCR were used to investigate the cross-talk between BTK and NOTCH1., Results: In vitro ibrutinib treatment of CLL significantly reduced activated NOTCH1/2 and induced dephosphorylation of eIF4E, a NOTCH target in CLL. BCR stimulation increased the expression of activated NOTCH1 that accumulated in the nucleus leading to HES1, DTX1, and c-MYC transcription. Results of in situ PLA experiments revealed the presence of NOTCH1-ICD/BTK complexes, whose number was reduced after ibrutinib treatment. In ibrutinib-treated CLL patients, leukemic cells showed NOTCH1 activity downregulation that deepened over time. The NOTCH1 signaling was restored at relapse and remained activated in ibrutinib-resistant CLL cells., Conclusions: We demonstrated a strong clinical activity of ibrutinib in a real-life context. The ibrutinib clinical efficacy was associated with NOTCH1 activity downregulation that deepened over time. Our data point to NOTCH1 as a new molecular partner in BCR signaling with potential to further improve CLL-targeted treatments., (©2019 American Association for Cancer Research.)

Published
2019
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44. GATA1 epigenetic deregulation contributes to the development of AML with NPM1 and FLT3-ITD cooperating mutations.

Author

Sportoletti P, Celani L, Varasano E, Rossi R, Sorcini D, Rompietti C, Strozzini F, Del Papa B, Guarente V, Spinozzi G, Cecchini D, Bereshchenko O, Haferlach T, Martelli MP, Falzetti F, and Falini B

Subjects
Animals, Female, GATA1 Transcription Factor physiology, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myeloid, Acute etiology, Leukemia, Myeloid, Acute genetics, Mice, Mice, Knockout, Nucleophosmin, Prognosis, Tandem Repeat Sequences, fms-Like Tyrosine Kinase 3 physiology, Biomarkers, Tumor genetics, Epigenesis, Genetic, GATA1 Transcription Factor genetics, Leukemia, Myeloid, Acute pathology, Mutation, Nuclear Proteins genetics, fms-Like Tyrosine Kinase 3 genetics
Published
2019
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45. IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation.

Author

De Falco F, Del Papa B, Baldoni S, Sabatini R, Falzetti F, Di Ianni M, Martelli MP, Mezzasoma F, Pelullo M, Marconi P, Sportoletti P, Screpanti I, and Rosati E

Subjects
Apoptosis genetics, Cell Line, Tumor, Cell Survival genetics, Female, Gene Expression Regulation, Leukemic genetics, Humans, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Protein Kinase C-delta genetics, RNA, Small Interfering genetics, Receptor, Notch1 genetics, Receptor, Notch2 genetics, Signal Transduction, Interleukin-4 genetics, Jagged-1 Protein genetics, Leukemia, Lymphocytic, Chronic, B-Cell genetics
Abstract

As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. In other cell types, it has been shown that after Notch engagement, Jagged1 not only activates Notch in signal-receiving cell, but also undergoes proteolytic activation in signal-sending cell, triggering a signaling with biological effects. We investigated whether Jagged1 expressed in CLL cells undergoes proteolytic processing and/or is able to induce Notch activation through autocrine/paracrine loops, focusing on the effect that CLL prosurvival factor IL-4 could exert on the Notch-Jagged1 system in these cells. We found that Jagged1 was constitutively processed in CLL cells and generated an intracellular fragment that translocated into the nucleus, and an extracellular fragment released into the culture supernatant. IL-4 enhanced expression of Jagged1 and its intracellular fragments, as well as Notch1/2 activation. The IL-4-induced increase in Notch1/2 activation was independent of the concomitant upregulated Jagged1 levels. Indeed, blocking Notch-Jagged1 interactions among CLL cells with Jagged1 neutralizing antibodies did not affect the expression of the Notch target Hes1. Notably, anti-Jagged1 antibodies partially prevented the IL-4-induced increase in Jagged1 processing and cell viability, suggesting that Jagged1 processing is one of the events contributing to IL-4-induced CLL cell survival. Consistent with this, Jagged1 silencing by small interfering RNA partially counteracted the capacity of IL-4 to promote CLL cell survival. Investigating the pathways whereby IL-4 promoted Notch1/2 activation in CLL cells independent of Jagged1, we found that PI3Kδ/AKT and PKCδ were involved in upregulating Notch1 and Notch2 proteins, respectively. Overall, this study provides new insights into the Notch-ligand system in CLL cells and suggests that targeting this system may be exploited as a novel/additional therapy approach for CLL.

Published
2018
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46. NOTCH and Graft-Versus-Host Disease.

Author

Di Ianni M, Del Papa B, Baldoni S, Di Tommaso A, Fabi B, Rosati E, Natale A, Santarone S, Olioso P, Papalinetti G, Giancola R, Accorsi P, Di Bartolomeo P, Sportoletti P, and Falzetti F

Subjects
Animals, Cell Differentiation, HLA Antigens immunology, Humans, Receptors, Notch genetics, Signal Transduction, Transplantation, Homologous, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation, Receptors, Notch metabolism, T-Lymphocytes immunology
Abstract

In allogeneic hematopoietic stem cell transplantation, which is the major curative therapy for hematological malignancies, T cells play a key role in the development of graft-versus-host disease (GvHD). NOTCH pathway is a conserved signal transduction system that regulates T cell development and differentiation. The present review analyses the role of the NOTCH signaling as a new regulator of acute GvHD. NOTCH signaling could also represent a new therapeutic target for GvHD.

Published
2018
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47. NOTCH1 Aberrations in Chronic Lymphocytic Leukemia.

Author

Rosati E, Baldoni S, De Falco F, Del Papa B, Dorillo E, Rompietti C, Albi E, Falzetti F, Di Ianni M, and Sportoletti P

Abstract

Chronic lymphocytic leukemia (CLL) is an incurable B-cell neoplasm characterized by highly variable clinical outcomes. In recent years, genomic and molecular studies revealed a remarkable heterogeneity in CLL, which mirrored the clinical diversity of this disease. These studies profoundly enhanced our understanding of leukemia cell biology and led to the identification of new biomarkers with potential prognostic and therapeutic significance. Accumulating evidence indicates a key role of deregulated NOTCH1 signaling and NOTCH1 mutations in CLL. This review highlights recent discoveries that improve our understanding of the pathophysiological NOTCH1 signaling in CLL and the clinical impact of NOTCH1 mutations in retrospective and prospective trials. In addition, we discuss the rationale for a therapeutic strategy aiming at inhibiting NOTCH1 signaling in CLL, along with an overview on the currently available NOTCH1-directed approaches.

Published
2018
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48. NOTCH1 Is Aberrantly Activated in Chronic Lymphocytic Leukemia Hematopoietic Stem Cells.

Author

Di Ianni M, Baldoni S, Del Papa B, Aureli P, Dorillo E, De Falco F, Albi E, Varasano E, Di Tommaso A, Giancola R, Accorsi P, Rotta G, Rompietti C, Silva Barcelos EC, Campese AF, Di Bartolomeo P, Screpanti I, Rosati E, Falzetti F, and Sportoletti P

Abstract

To investigate chronic lymphocytic leukemia (CLL)-initiating cells, we assessed NOTCH1 mutation/expression in hematopoietic stem cells (HSCs). In NOTCH1- mutated CLL, we detected subclonal mutations in 57% CD34+/CD38- HSCs. NOTCH1 mutation was present in 66% CD34+/CD38+ progenitor cells displaying an increased mutational burden compared to HSCs. Flow cytometric analysis revealed significantly higher NOTCH1 activation in CD34+/CD38- and CD34+/CD38+ cells from CLL patients, regardless NOTCH1 mutation compared to healthy donors. Activated NOTCH1 resulted in overexpression of the NOTCH1 target c-MYC. We conclude that activated NOTCH1 is an early event in CLL that may contribute to aberrant HSCs in this disease.

Published
2018
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49. Clinical-Grade-Expanded Regulatory T Cells Prevent Graft-versus-Host Disease While Allowing a Powerful T Cell-Dependent Graft-versus-Leukemia Effect in Murine Models.

Author

Del Papa B, Ruggeri L, Urbani E, Baldoni S, Cecchini D, Zei T, Iacucci Ostini R, Crescenzi B, Carotti A, Pierini A, Sportoletti P, Di Bartolomeo P, Falzetti F, Mecucci C, Velardi A, Martelli MF, and Di Ianni M

Subjects
Animals, Disease Models, Animal, Graft vs Leukemia Effect, Mice, Mice, Inbred NOD, Mice, SCID, Graft vs Host Disease prevention & control, T-Lymphocytes, Regulatory metabolism, Transplantation, Haploidentical methods
Abstract

We developed a good manufacturing practices-compatible expansion protocol to improve number and purity of regulatory T cells (Tregs) available for clinical trials. Six clinical-grade separation procedures were performed, followed by expansion with high-dose interleukin (IL)-2, anti-CD3/anti-CD28 TCR stimulation, and rapamycin for 19 days achieving a median of 8.5-fold (range, 6.25 to 13.7) expansion. FOXP3 expression was stably maintained over the culture period, while the percentage of CD127 was significantly reduced. The in vitro suppression assay showed a strong Mixed Lymphocytes Reaction inhibition. In vitro amplification did not induce any karyotypic modification. To evaluate the graft-versus-host disease (GVHD)/graft-versus-leukemia (GVL) bifunctional axis, expanded Tregs and conventional T cells (Tcons) were tested in NOD/SCID/IL2Rgnull mice injected with primary acute myeloid leukemia (AML) cells, AML cell line, acute lymphoid leukemia Philadelphia cell line, or Burkitt-like lymphoma cell line. All mice that received leukemia cells together with expanded Tregs and Tcons were rescued from leukemia and survived without GVHD, showing that Treg expansion procedure did not compromise GVHD control and the strong Tcon-mediated GVL activity. This report might represent the basis for treating high-risk leukemia and/or relapsed/refractory leukemia patients with high-dose Treg/Tcons., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Published
2017
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50. Criticality meets learning: Criticality signatures in a self-organizing recurrent neural network.

Author

Del Papa B, Priesemann V, and Triesch J

Subjects
Learning, Neural Networks, Computer
Abstract

Many experiments have suggested that the brain operates close to a critical state, based on signatures of criticality such as power-law distributed neuronal avalanches. In neural network models, criticality is a dynamical state that maximizes information processing capacities, e.g. sensitivity to input, dynamical range and storage capacity, which makes it a favorable candidate state for brain function. Although models that self-organize towards a critical state have been proposed, the relation between criticality signatures and learning is still unclear. Here, we investigate signatures of criticality in a self-organizing recurrent neural network (SORN). Investigating criticality in the SORN is of particular interest because it has not been developed to show criticality. Instead, the SORN has been shown to exhibit spatio-temporal pattern learning through a combination of neural plasticity mechanisms and it reproduces a number of biological findings on neural variability and the statistics and fluctuations of synaptic efficacies. We show that, after a transient, the SORN spontaneously self-organizes into a dynamical state that shows criticality signatures comparable to those found in experiments. The plasticity mechanisms are necessary to attain that dynamical state, but not to maintain it. Furthermore, onset of external input transiently changes the slope of the avalanche distributions - matching recent experimental findings. Interestingly, the membrane noise level necessary for the occurrence of the criticality signatures reduces the model's performance in simple learning tasks. Overall, our work shows that the biologically inspired plasticity and homeostasis mechanisms responsible for the SORN's spatio-temporal learning abilities can give rise to criticality signatures in its activity when driven by random input, but these break down under the structured input of short repeating sequences.

Published
2017
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