63 results on '"Stabile, H."'
Search Results
2. Response to comment on multifunctional human CD56lowCD16low NK cells are the prominent subset in bone marrow of both pediatric healthy donors and leukemic patients
- Author
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Stabile, H., Nisti, P., Pagliara, D., Locatelli, Franco, Santoni, A., and Gismondi, A.
- Subjects
Leukemic patients ,Multifunctional human CD56 ,natural killer cells ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Subset ,Bone marrow ,Multifunctional human CD56low CD16low natural killer cells ,Pediatric healthy donors ,Hematology ,low ,CD16 - Published
- 2015
3. Direct evidence of gas-induced laser beam smoothing in the interaction with thin foils
- Author
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Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicola, P, Malka, V, Benocci R., Batani D., Dezulian R., Redaelli R., Lucchini G., Canova F., Stabile H., Faure J., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Koenig M., Tikhonchuk V., Nicola P., Malka V., Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicola, P, Malka, V, Benocci R., Batani D., Dezulian R., Redaelli R., Lucchini G., Canova F., Stabile H., Faure J., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Koenig M., Tikhonchuk V., Nicola P., and Malka V.
- Abstract
The process of laser beam homogenization in a gas medium placed in front of a thin metallic foil has been studied. Experiments were performed using the Prague Asterix Laser System iodine laser [Jungwirth , Phys. Plasmas 8, 2495 (2001)] working at 0.44 mu m wavelength and irradiance of about 10(15) W/cm(2). Homogenization was detected both by directly analyzing the transmitted laser beam and by studying the shock breakout on the foil rear side. Results show that the gas ionization by the laser pulse induces a strong refraction and produces an effective smoothing of large-scale intensity nonuniformities
- Published
- 2009
4. Smoothing of laser energy deposition by gas jets
- Author
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Batani, D, Benocci, R, Dezulian, R, Redaelli, R, Canova, F, Stabile, H, Lucchini, G, Malka, V, Faure, J, Koenig, M, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Limpouch, J, Tikhoncuk, V, Nicolai, P, Batani D., Benocci R., Dezulian R., Redaelli R., Canova F., Stabile H., Lucchini G., Malka V., Faure J., Koenig M., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Limpouch J., Tikhoncuk V., Nicolai P., Batani, D, Benocci, R, Dezulian, R, Redaelli, R, Canova, F, Stabile, H, Lucchini, G, Malka, V, Faure, J, Koenig, M, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Limpouch, J, Tikhoncuk, V, Nicolai, P, Batani D., Benocci R., Dezulian R., Redaelli R., Canova F., Stabile H., Lucchini G., Malka V., Faure J., Koenig M., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Limpouch J., Tikhoncuk V., and Nicolai P.
- Abstract
Smoothing of laser beam non-uniformities using gas jets has been studied. The experiment has been performed with the PALS laser working at 0.44 mu m with an intensity of about 10(15) W/cm(2). The laser beam has been split in two by a prism thus creating an artificial large-scale non-uniformity (approximate to 90 mu m). We recorded time resolved and static images of laser-gas jet interaction with and without an Al target. Multi 1D and 2D simulations show that such interaction acts redistributing the over-intensities over larger surface. This effect has to be attributed to ionization processes with consequent laser beam refraction. Results show that Argon gas jet produces a strong refraction of the laser beam thus strongly reducing the initial two spots separation.
- Published
- 2009
5. Melanoma and immunotherapy bridge 2015 : Naples, Italy. 1-5 December 2015.
- Author
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Nanda, VGY, Peng, W, Hwu, P, Davies, MA, Ciliberto, G, Fattore, L, Malpicci, D, Aurisicchio, L, Ascierto, PA, Croce, CM, Mancini, R, Spranger, S, Gajewski, TF, Wang, Y, Ferrone, S, Vanpouille-Box, C, Wennerberg, E, Pilones, KA, Formenti, SC, Demaria, S, Tang, H, Fu, Y-X, Dummer, R, Puzanov, I, Tarhini, A, Chauvin, J-M, Pagliano, O, Fourcade, J, Sun, Z, Wang, H, Sanders, C, Kirkwood, JM, Chen, T-HT, Maurer, M, Korman, AJ, Zarour, HM, Stroncek, DF, Huber, V, Rivoltini, L, Thurin, M, Rau, T, Lugli, A, Pagès, F, Camarero, J, Sancho, A, Jommi, C, de Coaña, YP, Wolodarski, M, Yoshimoto, Y, Gentilcore, G, Poschke, I, Masucci, GV, Hansson, J, Kiessling, R, Scognamiglio, G, Sabbatino, F, Marino, FZ, Anniciello, AM, Cantile, M, Cerrone, M, Scala, S, D’alterio, C, Ianaro, A, Cirin, G, Liguori, G, Bott, G, Chapman, PB, Robert, C, Larkin, J, Haanen, JB, Ribas, A, Hogg, D, Hamid, O, Testori, A, Lorigan, P, Sosman, JA, Flaherty, KT, Yue, H, Coleman, S, Caro, I, Hauschild, A, McArthur, GA, Sznol, M, Callahan, MK, Kluger, H, Postow, MA, Gordan, R, Segal, NH, Rizvi, NA, Lesokhin, A, Atkins, MB, Burke, MM, Ralabate, A, Rivera, A, Kronenberg, SA, Agunwamba, B, Ruisi, M, Horak, C, Jiang, J, Wolchok, J, Liszkay, G, Maio, M, Mandalà, M, Demidov, L, Stoyakovskiy, D, Thomas, L, de la Cruz-Merino, L, Atkinson, V, Dutriaux, C, Garbe, C, Wongchenko, M, Chang, I, Koralek, DO, Rooney, I, Yan, Y, Dréno, B, Sullivan, R, Patel, M, Hodi, S, Amaria, R, Boasberg, P, Wallin, J, He, X, Cha, E, Richie, N, Ballinger, M, Smith, DC, Bauer, TM, Wasser, JS, Luke, JJ, Balmanoukian, AS, Kaufman, DR, Zhao, Y, Maleski, J, Leopold, L, Gangadhar, TC, Long, GV, Michielin, O, VanderWalde, A, Andtbacka, RHI, Cebon, J, Fernandez, E, Malvehy, J, Olszanski, AJ, Gause, C, Chen, L, Chou, J, Stephen Hodi, F, Brady, B, Mortier, L, Hassel, JC, Rutkowski, P, McNeil, C, Kalinka-Warzocha, E, Lebbé, C, Ny, L, Chacon, M, Queirolo, P, Loquai, C, Cheema, P, Berrocal, A, Eizmendi, KM, Bar-Sela, G, Hardy, H, Weber, JS, Grob, J-J, Marquez-Rodas, I, Schmidt, H, Briscoe, K, Baurain, J-F, Wolchok, JD, Pinto, R, De Summa, S, Garrisi, VM, Strippoli, S, Azzariti, A, Guida, G, Guida, M, Tommasi, S, Jacquelot, N, Enot, D, Flament, C, Pitt, JM, Vimond, N, Blattner, C, Yamazaki, T, Roberti, M-P, Vetizou, M, Daillere, R, Poirier-Colame, V, la Semeraro, M, Caignard, A, Slingluff, CL, Sallusto, F, Rusakiewicz, S, Weide, B, Marabelle, A, Kohrt, H, Dalle, S, Cavalcanti, A, Kroemer, G, Di Giacomo, AM, Wong, P, Yuan, J, Umansky, V, Eggermont, A, Zitvogel, L, Anna, P, Marco, T, Stefania, S, Francesco, M, Mariaelena, C, Gabriele, M, Antonio, AP, Franco, S, Roberti, MP, Enot, DP, Semeraro, M, Jégou, S, Flores, C, Kwon, BS, Anderson, AC, Borg, C, Aubin, F, Ayyoub, M, De Presbiteris, AL, Cordaro, FG, Camerlingo, R, Fratangelo, F, Mozzillo, N, Pirozzi, G, Patriarca, EJ, Caputo, E, Motti, ML, Falcon, R, Miceli, R, Capone, M, Madonna, G, Mallardo, D, Carrier, MV, Panza, E, De Cicco, P, Armogida, C, Ercolano, G, Botti, G, Cirino, G, Sandru, A, Blank, M, Balatoni, T, Olasz, J, Farkas, E, Szollar, A, Savolt, A, Godeny, M, Csuka, O, Horvath, S, Eles, K, Shoenfeld, Y, Kasler, M, Costantini, S, Capone, F, Moradi, F, Berglund, P, Leandersson, K, Linnskog, R, Andersson, T, Prasad, CP, Nigro, CL, Lattanzio, L, Proby, C, Syed, N, Occelli, M, Cauchi, C, Merlano, M, Harwood, C, Thompson, A, Crook, T, Bifulco, K, Ingangi, V, Minopoli, M, Ragone, C, Pessi, A, Mannavola, F, D’Oronzo, S, Felici, C, Tucci, M, Doronzo, A, Silvestris, F, Ferretta, A, Guida, S, Maida, I, Cocco, T, Passarelli, A, Quaresmini, D, Franzese, O, Palermo, B, Di Donna, C, Sperduti, I, Foddai, M, Stabile, H, Gismondi, A, Santoni, A, Nisticò, P, Sponghini, AP, Platini, F, Marra, E, Rondonotti, D, Alabiso, O, Fierro, MT, Savoia, P, Stratica, F, Quaglino, P, Di Monta, G, Corrado, C, Di Marzo, M, Ugo, M, Di Cecilia, ML, Nicola, M, Fusciello, C, Marra, A, Guarrasi, R, Baldi, C, Russo, R, Di Giulio, G, Faiola, V, Zeppa, P, Pepe, S, Gambale, E, Carella, C, Di Paolo, A, De Tursi, M, Marra, L, De Murtas, F, Sorrentino, V, Voinea, S, Panaitescu, E, Bolovan, M, Stanciu, A, Cinca, S, Botti, C, Aquino, G, Anniciello, A, Fortes, C, Mastroeni, S, Caggiati, A, Passarelli, F, Zappalà, A, Capuano, M, Bono, R, Nudo, M, Marino, C, Michelozzi, P, De Biasio, V, Battarra, VC, Formenti, S, Ascierto, ML, McMiller, TL, Berger, AE, Danilova, L, Anders, RA, Netto, GJ, Xu, H, Pritchard, TS, Fan, J, Cheadle, C, Cope, L, Drake, CG, Pardoll, DM, Taube, JM, Topalian, SL, Gnjatic, S, Nataraj, S, Imai, N, Rahman, A, Jungbluth, AA, Pan, L, Venhaus, R, Park, A, Lehmann, FF, Lendvai, N, Cohen, AD, Cho, HJ, Daniel, S, Hirsh, V, Nanda, VGY, Peng, W, Hwu, P, Davies, MA, Ciliberto, G, Fattore, L, Malpicci, D, Aurisicchio, L, Ascierto, PA, Croce, CM, Mancini, R, Spranger, S, Gajewski, TF, Wang, Y, Ferrone, S, Vanpouille-Box, C, Wennerberg, E, Pilones, KA, Formenti, SC, Demaria, S, Tang, H, Fu, Y-X, Dummer, R, Puzanov, I, Tarhini, A, Chauvin, J-M, Pagliano, O, Fourcade, J, Sun, Z, Wang, H, Sanders, C, Kirkwood, JM, Chen, T-HT, Maurer, M, Korman, AJ, Zarour, HM, Stroncek, DF, Huber, V, Rivoltini, L, Thurin, M, Rau, T, Lugli, A, Pagès, F, Camarero, J, Sancho, A, Jommi, C, de Coaña, YP, Wolodarski, M, Yoshimoto, Y, Gentilcore, G, Poschke, I, Masucci, GV, Hansson, J, Kiessling, R, Scognamiglio, G, Sabbatino, F, Marino, FZ, Anniciello, AM, Cantile, M, Cerrone, M, Scala, S, D’alterio, C, Ianaro, A, Cirin, G, Liguori, G, Bott, G, Chapman, PB, Robert, C, Larkin, J, Haanen, JB, Ribas, A, Hogg, D, Hamid, O, Testori, A, Lorigan, P, Sosman, JA, Flaherty, KT, Yue, H, Coleman, S, Caro, I, Hauschild, A, McArthur, GA, Sznol, M, Callahan, MK, Kluger, H, Postow, MA, Gordan, R, Segal, NH, Rizvi, NA, Lesokhin, A, Atkins, MB, Burke, MM, Ralabate, A, Rivera, A, Kronenberg, SA, Agunwamba, B, Ruisi, M, Horak, C, Jiang, J, Wolchok, J, Liszkay, G, Maio, M, Mandalà, M, Demidov, L, Stoyakovskiy, D, Thomas, L, de la Cruz-Merino, L, Atkinson, V, Dutriaux, C, Garbe, C, Wongchenko, M, Chang, I, Koralek, DO, Rooney, I, Yan, Y, Dréno, B, Sullivan, R, Patel, M, Hodi, S, Amaria, R, Boasberg, P, Wallin, J, He, X, Cha, E, Richie, N, Ballinger, M, Smith, DC, Bauer, TM, Wasser, JS, Luke, JJ, Balmanoukian, AS, Kaufman, DR, Zhao, Y, Maleski, J, Leopold, L, Gangadhar, TC, Long, GV, Michielin, O, VanderWalde, A, Andtbacka, RHI, Cebon, J, Fernandez, E, Malvehy, J, Olszanski, AJ, Gause, C, Chen, L, Chou, J, Stephen Hodi, F, Brady, B, Mortier, L, Hassel, JC, Rutkowski, P, McNeil, C, Kalinka-Warzocha, E, Lebbé, C, Ny, L, Chacon, M, Queirolo, P, Loquai, C, Cheema, P, Berrocal, A, Eizmendi, KM, Bar-Sela, G, Hardy, H, Weber, JS, Grob, J-J, Marquez-Rodas, I, Schmidt, H, Briscoe, K, Baurain, J-F, Wolchok, JD, Pinto, R, De Summa, S, Garrisi, VM, Strippoli, S, Azzariti, A, Guida, G, Guida, M, Tommasi, S, Jacquelot, N, Enot, D, Flament, C, Pitt, JM, Vimond, N, Blattner, C, Yamazaki, T, Roberti, M-P, Vetizou, M, Daillere, R, Poirier-Colame, V, la Semeraro, M, Caignard, A, Slingluff, CL, Sallusto, F, Rusakiewicz, S, Weide, B, Marabelle, A, Kohrt, H, Dalle, S, Cavalcanti, A, Kroemer, G, Di Giacomo, AM, Wong, P, Yuan, J, Umansky, V, Eggermont, A, Zitvogel, L, Anna, P, Marco, T, Stefania, S, Francesco, M, Mariaelena, C, Gabriele, M, Antonio, AP, Franco, S, Roberti, MP, Enot, DP, Semeraro, M, Jégou, S, Flores, C, Kwon, BS, Anderson, AC, Borg, C, Aubin, F, Ayyoub, M, De Presbiteris, AL, Cordaro, FG, Camerlingo, R, Fratangelo, F, Mozzillo, N, Pirozzi, G, Patriarca, EJ, Caputo, E, Motti, ML, Falcon, R, Miceli, R, Capone, M, Madonna, G, Mallardo, D, Carrier, MV, Panza, E, De Cicco, P, Armogida, C, Ercolano, G, Botti, G, Cirino, G, Sandru, A, Blank, M, Balatoni, T, Olasz, J, Farkas, E, Szollar, A, Savolt, A, Godeny, M, Csuka, O, Horvath, S, Eles, K, Shoenfeld, Y, Kasler, M, Costantini, S, Capone, F, Moradi, F, Berglund, P, Leandersson, K, Linnskog, R, Andersson, T, Prasad, CP, Nigro, CL, Lattanzio, L, Proby, C, Syed, N, Occelli, M, Cauchi, C, Merlano, M, Harwood, C, Thompson, A, Crook, T, Bifulco, K, Ingangi, V, Minopoli, M, Ragone, C, Pessi, A, Mannavola, F, D’Oronzo, S, Felici, C, Tucci, M, Doronzo, A, Silvestris, F, Ferretta, A, Guida, S, Maida, I, Cocco, T, Passarelli, A, Quaresmini, D, Franzese, O, Palermo, B, Di Donna, C, Sperduti, I, Foddai, M, Stabile, H, Gismondi, A, Santoni, A, Nisticò, P, Sponghini, AP, Platini, F, Marra, E, Rondonotti, D, Alabiso, O, Fierro, MT, Savoia, P, Stratica, F, Quaglino, P, Di Monta, G, Corrado, C, Di Marzo, M, Ugo, M, Di Cecilia, ML, Nicola, M, Fusciello, C, Marra, A, Guarrasi, R, Baldi, C, Russo, R, Di Giulio, G, Faiola, V, Zeppa, P, Pepe, S, Gambale, E, Carella, C, Di Paolo, A, De Tursi, M, Marra, L, De Murtas, F, Sorrentino, V, Voinea, S, Panaitescu, E, Bolovan, M, Stanciu, A, Cinca, S, Botti, C, Aquino, G, Anniciello, A, Fortes, C, Mastroeni, S, Caggiati, A, Passarelli, F, Zappalà, A, Capuano, M, Bono, R, Nudo, M, Marino, C, Michelozzi, P, De Biasio, V, Battarra, VC, Formenti, S, Ascierto, ML, McMiller, TL, Berger, AE, Danilova, L, Anders, RA, Netto, GJ, Xu, H, Pritchard, TS, Fan, J, Cheadle, C, Cope, L, Drake, CG, Pardoll, DM, Taube, JM, Topalian, SL, Gnjatic, S, Nataraj, S, Imai, N, Rahman, A, Jungbluth, AA, Pan, L, Venhaus, R, Park, A, Lehmann, FF, Lendvai, N, Cohen, AD, Cho, HJ, Daniel, S, and Hirsh, V
- Abstract
MELANOMA BRIDGE 2015 KEYNOTE SPEAKER PRESENTATIONS Molecular and immuno-advances K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establishment of drug resistance Gennaro Ciliberto, Luigi Fattore, Debora Malpicci, Luigi Aurisicchio, Paolo Antonio Ascierto, Carlo M. Croce, Rita Mancini K3 Tumor-intrinsic beta-catenin signaling mediates tumor-immune avoidance Stefani Spranger, Thomas F. Gajewski K4 Intracellular tumor antigens as a source of targets of antibody-based immunotherapy of melanoma Yangyang Wang, Soldano Ferrone Combination therapies K5 Harnessing radiotherapy to improve responses to immunotherapy in cancer Claire Vanpouille-Box, Erik Wennerberg, Karsten A. Pilones, Silvia C. Formenti, Sandra Demaria K6 Creating a T cell-inflamed tumor microenvironment overcomes resistance to checkpoint blockade Haidong Tang, Yang Wang, Yang-Xin Fu K7 Biomarkers for treatment decisions? Reinhard Dummer K8 Combining oncolytic therapies in the era of checkpoint inhibitors Igor Puzanov K9 Immune checkpoint blockade for melanoma: should we combine or sequence ipilimumab and PD-1 antibody therapy? Michael A. Postow News in immunotherapy K10 An update on adjuvant and neoadjuvant therapy for melanom Ahmad Tarhini K11 Targeting multiple inhibitory receptors in melanoma Joe-Marc Chauvin, Ornella Pagliano, Julien Fourcade, Zhaojun Sun, Hong Wang, Cindy Sanders, John M. Kirkwood, Tseng-hui Timothy Chen, Mark Maurer, Alan J. Korman, Hassane M. Zarour K12 Improving adoptive immune therapy using genetically engineered T cells David F. Stroncek Tumor microenvironment and biomarkers K13 Myeloid cells and tumor exosomes: a crosstalk for assessing immunosuppression? Veronica Huber, Licia Rivoltini K14 Update on the SITC biomarker taskforce: progress and challenges Magdalena Thurin World-wide immunosc
- Published
- 2016
6. Laser non-uniformity smoothing using gas jets
- Author
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Batani, D, Dezulian, R, Redaelli, R, Benocci, R, Stabile, H, Canova, F, Lucchini, G, Koenig, M, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Desai, T, Tikhonchuk, V, Faure, J, Malka, V, Batani D., Dezulian R., Redaelli R., Benocci R., Stabile H., Canova F., Lucchini G., Koenig M., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Desai T., Tikhonchuk V., Faure J., Malka V., Batani, D, Dezulian, R, Redaelli, R, Benocci, R, Stabile, H, Canova, F, Lucchini, G, Koenig, M, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Desai, T, Tikhonchuk, V, Faure, J, Malka, V, Batani D., Dezulian R., Redaelli R., Benocci R., Stabile H., Canova F., Lucchini G., Koenig M., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Desai T., Tikhonchuk V., Faure J., and Malka V.
- Abstract
An experimental investigation about laser beam homogenization using gas jets is presented in this paper. The results, obtained at PALS iodine laser facility using the 3 omega wavelength and irradiances of about 10(15) W/cm(2), showed that the use of high pressure gas jets (up to 10 bar of Argon) can be effective in reducing strong laser beam non-uniformities artificially introduced by inserting a wedge arrangement on half of the beam.
- Published
- 2008
7. Gas-induced smoothing of laser beams studied by interaction with thin foils
- Author
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Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicolai, P, Malka, V, Benocci R., Batani D., Dezulian R., Redaelli R., Lucchini G., Canova F., Stabile H., Faure J., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Koenig M., Tikhonchuk V., Nicolai Ph., Malka V., Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicolai, P, Malka, V, Benocci R., Batani D., Dezulian R., Redaelli R., Lucchini G., Canova F., Stabile H., Faure J., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Koenig M., Tikhonchuk V., Nicolai Ph., and Malka V.
- Abstract
We studied the process of laser beam homogenization in a gas medium placed in front of a thin metallic foil. Experiments were performed using the Prague PALS iodine laser working at 0.44 mu m wavelength and irradiances of about 10(15) W cm(-2). Homogenization was detected both by directly analysing the transmitted laser beam and by studying the shock breakout on the foil rear side. Results show that the gas ionization by the laser pulse induces a strong refraction and produces an effective smoothing of large-scale intensity non-uniformities.
- Published
- 2008
8. Current advances in smoothing of laser intensity profile
- Author
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Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicolai, P, Malka, V, Benocci R., Batani D., Dezulian R., Redaelli R., Lucchini G., Canova F., Stabile H., Faure J., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Koenig M., Tikhonchuk V., Nicolai Ph., Malka V., Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicolai, P, Malka, V, Benocci R., Batani D., Dezulian R., Redaelli R., Lucchini G., Canova F., Stabile H., Faure J., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Koenig M., Tikhonchuk V., Nicolai Ph., and Malka V.
- Abstract
We present the experimental results, and their analysis, connected to the possibility to control laser inhomogeneities exploiting the non-uniform electron density distribution created by the laser while propagating in a gas jet. The induced self-refraction in the plasma created in the gas medium results in re-distributing local over-intensities over larger surfaces. The experiment at the PALS laser facility has been performed creating a large non-uniformity by a wedge arrangement and recording the static and dynamic images with and without the coupling to an Al target.
- Published
- 2008
9. Recent experiments on the hydrodynamics of laser-produced plasmas conducted at the PALS laboratory
- Author
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Batani, D, Dezulian, R, Redaelli, R, Benocci, R, Stabile, H, Canova, F, Desai, T, Lucchini, G, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Rus, B, Ullschmied, J, Malka, V, Faure, J, Koenig, M, Limpouch, J, Nazarov, W, Pepler, D, Nagai, K, Norimatsu, T, Nishimura, H, Batani D., Dezulian R., Redaelli R., Benocci R., Stabile H., Canova F., Desai T., Lucchini G., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Rus B., Ullschmied J., Malka V., Faure J., Koenig M., Limpouch J., Nazarov W., Pepler D., Nagai K., Norimatsu T., Nishimura H., Batani, D, Dezulian, R, Redaelli, R, Benocci, R, Stabile, H, Canova, F, Desai, T, Lucchini, G, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Rus, B, Ullschmied, J, Malka, V, Faure, J, Koenig, M, Limpouch, J, Nazarov, W, Pepler, D, Nagai, K, Norimatsu, T, Nishimura, H, Batani D., Dezulian R., Redaelli R., Benocci R., Stabile H., Canova F., Desai T., Lucchini G., Krousky E., Masek K., Pfeifer M., Skala J., Dudzak R., Rus B., Ullschmied J., Malka V., Faure J., Koenig M., Limpouch J., Nazarov W., Pepler D., Nagai K., Norimatsu T., and Nishimura H.
- Abstract
We present a series of experimental results, and their interpretation, connected to various aspects of the hydrodynamics of laser produced plasmas. Experiments were performed using the Prague PALS iodine laser working at 0.44 mu m wavelength and irradiances up to a few 10(14)W/cm(2). By adopting large focal spots and smoothed laser beams, the lateral energy transport and lateral expansion have been avoided. Therefore we could reach a quasi one-dimensional regime for which experimental results can be more easily and property compared to available analytical models.
- Published
- 2007
10. Multifunctional human CD56low CD16low natural killer cells are the prominent subset in bone marrow of both healthy pediatric donors and leukemic patients
- Author
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Stabile, H., primary, Nisti, P., additional, Morrone, S., additional, Pagliara, D., additional, Bertaina, A., additional, Locatelli, F., additional, Santoni, A., additional, and Gismondi, A., additional
- Published
- 2015
- Full Text
- View/download PDF
11. 'Computer-assisted analysis of endothelial cell sprouting: an in vitro assay for the screening of anti-angiogenic compounds'
- Author
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Belleri, M., Stabile, H., Nicoli, S., Ronca, Roberto, and Presta, Marco
- Published
- 2003
12. The bone morphogenic protein antagonist Drm/gremlin is a novel pro- angiogenic factor
- Author
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Stabile, H, Mitola, S, Moroni, E, Belleri, M, Nicoli, S, Coltrini, D, Peri, F, Pessi, A, Orsatti, L, Talamo, F, Castronovo, V, Waltregny, D, Cotelli, F, Ribatti, D, Marco, P, Marco Presta, PERI, FRANCESCO, Stabile, H, Mitola, S, Moroni, E, Belleri, M, Nicoli, S, Coltrini, D, Peri, F, Pessi, A, Orsatti, L, Talamo, F, Castronovo, V, Waltregny, D, Cotelli, F, Ribatti, D, Marco, P, Marco Presta, and PERI, FRANCESCO
- Abstract
Angiogenesis plays a key role in various physiological and pathological conditions, including tumor growth. Drm/gremlin, a member the Dan family of bone morphogenic protein (BMP) antagonists, is commonly thought to affect different processes during growth, differentiation, and development by heterodimerizing various BMPs. Here we identify Drm/gremlin as a novel pro-angiogenic factor expressed by endothelium. Indeed, Drm/gremlin was purified to homogeneity from the conditioned medium of transformed endothelial cells using an endothelial cell sprouting assay to follow protein isolation. Accordingly, recombinant Drm/gremlin stimulates endothelial cell migration and invasion in fibrin and collagen gels, binds with high-affinity to various endothelial cell types, and triggers tyrosine phosphorylation of intracellular signaling proteins. Also, Drm/gremlin induces neovascularization in the chick embryo chorioallantoic membrane. BMP4 does not affect Drm/gremlin interaction with endothelium and both molecules exert a pro-angiogenic activity in vitro and in vivo when administered alone or in combination. Finally, Drm/gremlin is produced by the stroma of human tumor xenografts in nude mice and it is highly expressed in endothelial cells of human lung tumor vasculature when compared to non-neoplastic lung. Our observations point to a novel, previously unrecognized capacity of Drm/gremlin to interact directly with target endothelial cells and to modulate angiogenesis.
- Published
- 2007
13. High Pressure Laser-Generated Shocks and Application to EOS of Carbon
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Batani, D, primary, Dezulian, R, additional, Stabile, H, additional, Tomasini, M, additional, Lucchini, G, additional, Canova, F, additional, Redaelli, R, additional, Koenig, M, additional, Benuzzi, A, additional, Nishimura, H, additional, Ochi, Y, additional, Ullschmied, J, additional, Skala, J, additional, Kralikova, B, additional, Pfeifer, M, additional, Mocek, T, additional, Präg, A, additional, Hall, T, additional, Milani, P, additional, Barborini, E, additional, and Piseri, P, additional
- Published
- 2007
- Full Text
- View/download PDF
14. Synthesis of 99mTc-anti-CD56 Monoclonal Antibody for Molecular Imaging of NK Cells: in Vitro and in Vivo Studies
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Galli, F., Rapisarda, A., Stabile, H., Gaurav Malviya, Bonanno, E., Gismondi, A., Santoni, A., Dierckx, R., and Signore, A.
15. Multicentre harmonisation of a six-colour flow cytometry panel for naïve/memory T cell immunomonitoring
- Author
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Chiara Agrati, Belinda Palermo, Massimo Sanchez, Floriana Iacobone, Mauro Biffoni, Rita Casetti, Giorgio Fedele, Francesca Urbani, Valentina La Sorsa, Pasqualina Leone, Cristina Capuano, Marianna Nuti, Helena Stabile, Iole Macchia, Andrea Rozo Gonzalez, Filippo Belardelli, Carla Buccione, Giovanna Schiavoni, Ilaria Grazia Zizzari, Paola Rizza, Maria Carollo, Cinzia Fionda, Matilde Sinibaldi, Irene Ruspantini, Valentina Tirelli, Concetta Quintarelli, Aurelia Rughetti, Paola Nisticò, Roberta Maggio, Angela Gismondi, Stefania Morrone, Macchia, I., La Sorsa, V., Ruspantini, I., Sanchez, M., Tirelli, V., Carollo, M., Fedele, G., Leone, P., Schiavoni, G., Buccione, C., Rizza, P., Nistico, P., Palermo, B., Morrone, S., Stabile, H., Rughetti, A., Nuti, M., Zizzari, I. G., Fionda, C., Maggio, R., Capuano, C., Quintarelli, C., Sinibaldi, M., Agrati, C., Casetti, R., Rozo Gonzalez, A., Iacobone, F., Gismondi, A., Belardelli, F., Biffoni, M., and Urbani, F.
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Oncology ,Receptors, CCR7 ,medicine.medical_specialty ,CD3 Complex ,Article Subject ,Operating procedures ,Immunology ,T cells ,Color ,CD8-Positive T-Lymphocytes ,flow cytometry ,harmonization ,Immunophenotyping ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,T-Lymphocyte Subsets ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Observer Variation ,medicine.diagnostic_test ,business.industry ,General Medicine ,RC581-607 ,Clinical trial ,030104 developmental biology ,Lazio region ,medicine.anatomical_structure ,Italy ,030220 oncology & carcinogenesis ,Leukocytes, Mononuclear ,Leukocyte Common Antigens ,Immunologic diseases. Allergy ,business ,Observer variation ,Immunologic Memory ,Immunologic memory ,Memory T cell ,Biomarkers ,Research Article - Abstract
Background. Personalised medicine in oncology needs standardised immunological assays. Flow cytometry (FCM) methods represent an essential tool for immunomonitoring, and their harmonisation is crucial to obtain comparable data in multicentre clinical trials. The objective of this study was to design a harmonisation workflow able to address the most effective issues contributing to intra- and interoperator variabilities in a multicentre project. Methods. The Italian National Institute of Health (Istituto Superiore di Sanità, ISS) managed a multiparametric flow cytometric panel harmonisation among thirteen operators belonging to five clinical and research centres of Lazio region (Italy). The panel was based on a backbone mixture of dried antibodies (anti-CD3, anti-CD4, anti-CD8, anti-CD45RA, and anti-CCR7) to detect naïve/memory T cells, recognised as potential prognostic/predictive immunological biomarkers in cancer immunotherapies. The coordinating centre distributed frozen peripheral blood mononuclear cells (PBMCs) and fresh whole blood (WB) samples from healthy donors, reagents, and Standard Operating Procedures (SOPs) to participants who performed experiments by their own equipment, in order to mimic a real-life scenario. Operators returned raw and locally analysed data to ISS for central analysis and statistical elaboration. Results. Harmonised and reproducible results were obtained by sharing experimental set-up and procedures along with centralising data analysis, leading to a reduction of cross-centre variability for naïve/memory subset frequencies particularly in the whole blood setting. Conclusion. Our experimental and analytical working process proved to be suitable for the harmonisation of FCM assays in a multicentre setting, where high-quality data are required to evaluate potential immunological markers, which may contribute to select better therapeutic options.
- Published
- 2020
16. Differential microRNA expression between decidual and peripheral blood natural killer cells in early pregnancy
- Author
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Stefania Morrone, C Carlino, Maria Cristina Albertini, E. Trotta, Maria Rita Rippo, Sabrina Angelini, Carlo Bastianelli, Monsurrò, Antonio Domenico Procopio, Angela Gismondi, Helena Stabile, Angela Santoni, Fabiola Olivieri, Raffaella Lazzarini, Carlino, C., Rippo, M.R., Lazzarini, R., Monsurrò, V., Morrone, S., Angelini, S., Trotta, E., Stabile, H., Bastianelli, C., Albertini, M.C., Olivieri, F., Procopio, A., Santoni, A., and Gismondi, A.
- Subjects
0301 basic medicine ,Peripheral blood natural killer cell ,Decidual natural killer cells ,peripheral blood natural killer cells ,decidua ,pregnancy ,microRNA ,miRNA profiling ,ingenuity pathway analysis ,Cellular differentiation ,Cell ,Biology ,NK placenta miRNA ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Humans ,Regulation of gene expression ,030219 obstetrics & reproductive medicine ,Gene Expression Profiling ,Rehabilitation ,Decidua ,Obstetrics and Gynecology ,Cell sorting ,Cell biology ,Killer Cells, Natural ,Decidual natural killer cell ,Gene expression profiling ,MicroRNAs ,Pregnancy Trimester, First ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Reproductive Medicine ,Ingenuity pathway analysi ,Female - Abstract
Study question Have decidual natural killer (dNK) cells a different microRNA (miRNA or miR) expression pattern compared to NK cells circulating in the peripheral blood (pb) of healthy pregnant women in the first trimester of gestation? Summary answer dNK cells have a unique miRNA profile, showing exclusive expression of a set of miRNAs and significant up- or down-regulation of most of the miRNAs shared with pbNK cells. What is known already dNK cells differ from pbNK cells both phenotypically and functionally, and their origin is still debated. Many studies have indicated that miRNAs regulate several important aspects of NK cell biology, such as development, activation and effector functions. Study design, size, duration Decidua basalis and peripheral blood specimens were collected from women (n = 7) undergoing voluntary termination of gestation in the first trimester of pregnancy. dNK and pbNK cells were then highly purified by cell sorting. Participants/materials, setting, methods miRNAs expression was analysed by quantitative RT-PCR (qRT-PCR)-based arrays using RNA purified from freshly isolated and highly purified pbNK and dNK cells. Results from arrays were validated by qRT-PCR assays. The bioinformatics tool ingenuity pathway analysis (IPA) was applied to determine the cellular network targeted by validated miRNAs and the correlated biological functions. Main results and the role of chance Herein, we identified the most differentially expressed miRNAs in NK cells isolated from peripheral blood and uterine decidua of pregnant women. We found that 36 miRNAs were expressed only in dNK cells and two miRNAs only in pbNK cells. Moreover, 48 miRNAs were commonly expressed by both NK cell preparations although at different levels: 28 were upregulated in dNK cells, while 15 were downregulated compared to pbNK cells. Validation of a selected set (n = 11) of these miRNAs confirmed the differential expression of nine miRNAs: miR-10b and miR-214 expressed only in dNK cells and miR-200a-3p expressed only in pbNK cells; miR-130b-3p, miR-125a-5p, miR-212-3p and miR-454 were upregulated while miR-210-3p and miR-132 were downregulated in dNK cells compared to pbNK cells. IPA network analysis identified a single network connecting all the miRNAs as well as their significant involvement in several classes of functions: 'Organismal injury, Reproductive system disease, Inflammatory disease' and 'Cellular development'. These miRNAs target molecules such as argonaute 2, tumour protein p53, insulin and other genes that belong to the same network and significantly influence cell differentiation and pregnancy. Limitations, reasons for caution In the present study, the cellular network and biological functions modulated by miRNAs differentially expressed in dNK and pbNK cells were identified by IPA considering only molecules and relationships that were with confidence 'experimentally observed' in leucocytes. The decidual and pbNK cells that were analysed here are a heterogeneous population and further study will help to disentangle whether there are differences in miRNA production by the different subsets of NK cells. Wider implications of the findings This is the first study describing a different miRNA expression profile in dNK cells compared to matched pbNK cells during the first trimester of pregnancy. Our findings improved the body of knowledge on dNK cell biology and strongly suggest further investigation into the roles of miRNAs that are differentially expressed in human dNK compared to pbNK cells. Our results suggest that specific miRNAs can modulate dNK cell origin and functions, highlighting a potential role of this miRNA signature in human development and diseases. Study funding/competing interest(s) This work was supported by grants from the Istituto Pasteur, Fondazione Cenci Bolognetti, the European NoE EMBIC within FP6 (Contract number LSHN-CT-2004-512040), Istituto Italiano di Tecnologia, and Ministero dell'Istruzione, dell'Universita e della Ricerca (Ricerche Universitarie), and from Universita Politecnica delle Marche. There are no conflicts of interest to declare.
- Published
- 2018
17. Human Papilloma Virus-Dependent HMGA1 Expression Is a Relevant Step in Cervical Carcinogenesis
- Author
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Veronica Veschi, Helena Stabile, Giuseppe Giannini, Alberto Gulino, Isabella Screpanti, Luigi Frati, Massimiliano Mellone, Christian Rinaldi, Isabella Massimi, Marialaura Petroni, Claudio Talora, Silvia Truffa, Mellone M., Rinaldi C., Massimi I., Petroni M., Veschi V., Talora C., Truffa S., Stabile H., Frati L., Screpanti I., Gulino A., and Giannini G.
- Subjects
Uterine Cervical Neoplasm ,Cancer Research ,DNA-Binding Protein ,Biology ,HeLa Cell ,lcsh:RC254-282 ,DNA-binding protein ,RNA interference ,Cell Line, Tumor ,HMGA1a Protein ,RNA, Messenger ,Receptor, Notch1 ,Papillomaviridae ,Papillomavirus Infection ,Psychological repression ,Transcription factor ,Cell Proliferation ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,HMGA ,Oncogene Proteins, Viral ,Cell Transformation, Viral ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,HMGA1 ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,Cancer cell ,Cancer research ,biology.protein ,Female ,Tumor Suppressor Protein p53 ,Human - Abstract
HMGA1 is a member of a small family of architectural transcription factors involved in the coordinate assembly of multiprotein complexes referred to as enhanceosomes. In addition to their role in cell proliferation, differentiation, and development, high-mobility group proteins of the A type (HMGA) family members behave as transforming protoncogenes either in vitro or in animal models. Recent reports indicated that HMGA1 might counteract p53 pathway and provided an interesting hint on the mechanisms determining HMGA's transforming potential. HMGA1 expression is deregulated in a very large array of human tumors, including cervical cancer, but very limited information is available on the molecular mechanisms leading to HMGA1 deregulation in cancer cells. Here, we report that HMGA1 expression is sustained by human papilloma virus (HPV) E6/E7 proteins in cervical cancer, as demonstrated by either E6/E7 overexpression or by repression through RNA interference. Knocking down HMGA1 expression by means of RNA interference, we also showed that it is involved in cell proliferation and contributes to p53 inactivation in this type of neoplasia. Finally, we show that HMGA1 is necessary for the full expression of HPV18 E6 and E7 oncoproteins thus establishing a positive autoregulatory loop between HPV E6/E7 and HMGA1 expression. Copyright © 2008 Neoplasia Press, Inc. All rights reserved.
- Published
- 2008
18. Recent experiments on the hydrodynamics of laser-produced plasmas conducted at the PALS laboratory
- Author
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Keiji Nagai, Wigen Nazarov, F. Canova, E. Krousky, Jérôme Faure, H. Stabile, G. Lucchini, D.A. Pepler, Dimitri Batani, R. Dudzak, Bedrich Rus, Jiri Skala, J. Ullschmied, Takayoshi Norimatsu, Miroslav Pfeifer, Hiroaki Nishimura, Tara Desai, Jiri Limpouch, Roberto Benocci, Victor Malka, R. Dezulian, M. Koenig, K. Masek, R. Redaelli, Dipartimento di Fisica 'Giuseppe Occhialini' = Department of Physics 'Giuseppe Occhialini' [Milano-Bicocca], Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Institute of Physics (PALS), Czech Academy of Sciences [Prague] (CAS), Laboratoire d'optique appliquée (LOA), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Laboratoire pour l'utilisation des lasers intenses (LULI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Doppler Institute/ Department of Mathematics, Czech Technical University in Prague (CTU), University of St Andrews [Scotland], Central Laser Facility, CCLRC Rutherford Appleton Laboratory (RAL), Osaka University [Osaka], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Batani, D, Dezulian, R, Redaelli, R, Benocci, R, Stabile, H, Canova, F, Desai, T, Lucchini, G, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Rus, B, Ullschmied, J, Malka, V, Faure, J, Koenig, M, Limpouch, J, Nazarov, W, Pepler, D, Nagai, K, Norimatsu, T, and Nishimura, H
- Subjects
Plasma Hydrodynamics ,Lateral expansion ,01 natural sciences ,010305 fluids & plasmas ,law.invention ,Optics ,Shock Acceleration ,Laboratory Astrophysics ,law ,0103 physical sciences ,Electrical and Electronic Engineering ,010306 general physics ,Equation of State ,Laser beams ,Physics ,[PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics] ,business.industry ,Plasma ,Condensed Matter Physics ,Laser ,Atomic and Molecular Physics, and Optics ,Wavelength ,Shock Pressure ,Laboratory astrophysic ,business ,Plasma hydrodynamic ,Smoothing ,Energy transport - Abstract
We present a series of experimental results, and their interpretation, connected to various aspects of the hydrodynamics of laser produced plasmas. Experiments were performed using the Prague PALS iodine laser working at 0.44 μm wavelength and irradiances up to a few 1014W/cm2. By adopting large focal spots and smoothed laser beams, the lateral energy transport and lateral expansion have been avoided. Therefore we could reach a quasi one-dimensional regime for which experimental results can be more easily and properly compared to available analytical models.
- Published
- 2007
19. Chemerin Regulates NK Cell Accumulation and Endothelial Cell Morphogenesis in the Decidua during Early Pregnancy
- Author
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Carlino, Claudia, Trotta, Eleonora, Stabile, MARIA HELENA, Morrone, Stefania, Roberta, Bulla, Soriani, Alessandra, Iannitto, MARIA LUISA, Chiara, Agostinis, Carlo, Mocci, Minozzi, Massimo, Aragona, Cesare, Perniola, Giorgia, Francesco, Tedesco, Silvano, Sozzani, Santoni, Angela, Gismondi, Angela, Sozzani, Silvano, Carlino, C., Trotta, E., Stabile, H., Morrone, S., Bulla, Roberta, Soriani, A., Iannitto, M. L., Agostinis, C., Mocci, C., Minozzi, M., Aragona, C., Perniola, G., Tedesco, Francesco, Sozzani, S., Santoni, A., and Gismondi, A.
- Subjects
medicine.medical_specialty ,Chemokine ,Stromal cell ,Endothelium ,NK ,MAP Kinase Signaling System ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Endothelial cell morphogenesis ,Neovascularization, Physiologic ,Biology ,Biochemistry ,Endocrinology ,Cell Movement ,Pregnancy ,Internal medicine ,Decidua ,medicine ,Endocrine Research ,Humans ,Chemerin ,Decidual cells ,RNA, Messenger ,Tube formation ,Biochemistry (medical) ,Endothelial Cells ,Capillaries ,Trophoblasts ,Killer Cells, Natural ,Pregnancy Trimester, First ,medicine.anatomical_structure ,NK, Endothelial Cells, chemerin, Pregnancy ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Female ,Receptors, Chemokine ,Chemokines ,Stromal Cells ,chemerin - Abstract
Context: Although decidual natural killer (NK) cell accumulation and vascular remodeling are critical steps to ensure successful pregnancy, the molecular mechanisms controlling these events are poorly defined. Objective: Herein we analyzed whether chemerin, a recently identified chemoattractant involved in many pathophysiological processes, could be expressed in the uterine compartment and could regulate events relevant for the good outcome of pregnancy. Design: Chemerin expression in human primary culture of stromal (ST) cells, extravillous trophoblast cells, and decidual endothelial cells (DEC) was analyzed by RT-PCR, ELISA, and Western blot. Migration through ST or DEC of peripheral blood and decidual (d) NK cells from pregnant women was performed using a transwell assay. A DEC capillary-like tube formation assay was used to evaluate endothelial morphogenesis. Results: Chemerin is differentially expressed by decidual cells during early pregnancy being present at high levels in ST and extravillous trophoblast cells but not in DEC. Notably, ST cells from pregnant women exhibit and release higher levels of chemerin as compared with ST cells from menopausal or fertile nonpregnant women. Chemerin can support peripheral blood NK cell migration through both DEC and ST cells. Although dNK cells exhibit lower chemerin receptor (CMKLR1) expression than their blood counterpart, CMKLR1 engagement on dNK cells resulted in both ERK activation and migration through decidual ST cells. Interestingly, DEC also express CMKLR1 and undergo ERK activation and capillary-like tube structure formation upon exposure to chemerin. Conclusions: Our data indicate that chemerin is up-regulated during decidualization and might contribute to NK cell accumulation and vascular remodeling during early pregnancy.
- Published
- 2012
20. An alternative role of C1q in cell migration and tissue remodeling: contribution to trophoblast invasion and placental development
- Author
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Helena Stabile, Fleur Bossi, Angela Santoni, Chiara Agostinis, Berhane Ghebrehiwet, Cecilia Garlanda, Paola Spessotto, Angela Gismondi, Guillermina Girardi, Roberta Bulla, Francesco De Seta, Claudio Tripodo, Francesco Tedesco, Carla Guarnotta, Agostinis, C, Bulla, R, Tripodo, C, Gismondi, A, Stabile, H, Bossi, F, Guarnotta, C, Garlanda, C, De Seta, F, Spessotto, P, Santoni, A, Ghebrehiwet, B, Girardi, G, and Tedesco, F
- Subjects
medicine.medical_specialty ,Immunology ,Cell ,Integrin ,Immunoblotting ,chemical and pharmacologic phenomena ,Biology ,Extracellular matrix ,Mice ,Pre-Eclampsia ,immune system diseases ,Pregnancy ,Internal medicine ,medicine ,Cell Adhesion ,Immunology and Allergy ,Animals ,Humans ,Immunoprecipitation ,skin and connective tissue diseases ,Receptor ,Cell adhesion ,reproductive and urinary physiology ,Microscopy, Confocal ,C1q, placental development ,Reverse Transcriptase Polymerase Chain Reaction ,Complement C1q ,Decidua ,Trophoblast ,Placentation ,Immunohistochemistry ,Cell biology ,Trophoblasts ,Mice, Inbred C57BL ,Chemotaxis, Leukocyte ,medicine.anatomical_structure ,Endocrinology ,embryonic structures ,biology.protein ,Female - Abstract
Fetal trophoblast cells invading the decidua in the early phase of pregnancy establish complex interaction with the maternal extracellular matrix. We discovered that C1q was widely distributed in human decidual stroma in the absence of C4 and C3 and was actively synthesized by migrating extravillous trophoblasts. The cells expressed the messages for the three chains of C1q and secreted this complement component that interacted with the proteins of the decidual extracellular matrix. Solid phase-bound C1q promoted trophoblast adhesion and migration, and cell binding to C1q resulted in activation of ERK1/2 MAPKs. Ab inhibition experiments showed that the receptors for the globular head of C1q/p33 and α4β1 integrin were both involved in this process and were colocalized on the cell surface following binding of C1q to trophoblasts. We also found that C1q−/− mice manifested increased frequency of fetal resorption, reduced fetal weight, and smaller litter sizes compared with wild-type mice. C1q deficiency was associated with impaired labyrinth development and decidual vessel remodeling. Collectively, these data suggest that C1q plays an important role in promoting trophoblast invasion of decidua and that defective local production of C1q may be involved in pregnancy disorders, such as pre-eclampsia, characterized by poor trophoblast invasion.
- Published
- 2010
21. Direct evidence of gas-induced laser beam smoothing in the interaction with thin foils
- Author
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R. Redaelli, Jérôme Faure, Miroslav Pfeifer, Vladimir Tikhonchuk, G. Lucchini, R. Dezulian, Roberto Benocci, Victor Malka, E. Krousky, Dimitri Batani, R. Dudzak, Ph. Nicolaï, F. Canova, M. Koenig, Karel Masek, H. Stabile, Jiri Skala, Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicola, P, Malka, V, Dipartimento di Fisica 'Giuseppe Occhialini' = Department of Physics 'Giuseppe Occhialini' [Milano-Bicocca], Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Laboratoire d'optique appliquée (LOA), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), PALS Research Centre, Research Centre, Laboratoire pour l'utilisation des lasers intenses (LULI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes Lasers Intenses et Applications (CELIA), Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), and Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Laser pumping ,01 natural sciences ,ionisation ,010305 fluids & plasmas ,law.invention ,PACS 52.50.Jm ,52.50.Lp ,X-ray laser ,Optics ,law ,Ionization ,plasma heating by laser ,0103 physical sciences ,Ultrafast laser spectroscopy ,010306 general physics ,FOIL method ,Physics ,foils ,[PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics] ,business.industry ,Plasma ,Condensed Matter Physics ,Laser ,foil ,Laser beam quality ,Atomic physics ,business ,plasma shock waves - Abstract
International audience; The process of laser beam homogenization in a gas medium placed in front of a thin metallic foil has been studied. Experiments were performed using the Prague Asterix Laser System iodine laser [ Jungwirth et al., Phys. Plasmas 8, 2495 (2001) ] working at 0.44 μm wavelength and irradiance of about 10^15 W/cm^2. Homogenization was detected both by directly analyzing the transmitted laser beam and by studying the shock breakout on the foil rear side. Results show that the gas ionization by the laser pulse induces a strong refraction and produces an effective smoothing of large-scale intensity nonuniformities.
- Published
- 2009
22. Gas-induced smoothing of laser beams studied by interaction with thin foils
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H. Stabile, R. Redaelli, Jiri Skala, Jérôme Faure, Miroslav Pfeifer, R. Dezulian, Karel Masek, Vladimir Tikhonchuk, M. Koenig, G. Lucchini, Roberto Benocci, Victor Malka, F. Canova, E. Krousky, Dimitri Batani, R. Dudzak, Ph. Nicolaï, Dipartimento di Fisica 'Giuseppe Occhialini' = Department of Physics 'Giuseppe Occhialini' [Milano-Bicocca], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Laboratoire d'optique appliquée (LOA), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), PALS Research Centre, Czech Republic Research center, Laboratoire pour l'utilisation des lasers intenses (LULI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes Lasers Intenses et Applications (CELIA), Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicolai, P, Malka, V, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), and Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)
- Subjects
PACS 52.50.Jm ,52.57.Fg ,52.38.-r ,[PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics] ,Materials science ,business.industry ,Condensed Matter Physics ,Laser ,01 natural sciences ,Beam parameter product ,Homogenization (chemistry) ,010305 fluids & plasmas ,law.invention ,Wavelength ,Optics ,Nuclear Energy and Engineering ,law ,Ionization ,0103 physical sciences ,Laser beam quality ,Smoothing of laser beams, Inertial confinement fusion ,010306 general physics ,business ,Inertial confinement fusion ,FOIL method - Abstract
International audience; We studied the process of laser beam homogenization in a gas medium placed in front of a thin metallic foil. Experiments were performed using the Prague PALS iodine laser working at 0.44 µm wavelength and irradiances of about 10^15 W cm^−2. Homogenization was detected both by directly analysing the transmitted laser beam and by studying the shock breakout on the foil rear side. Results show that the gas ionization by the laser pulse induces a strong refraction and produces an effective smoothing of large-scale intensity non-uniformities.
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- 2008
23. Current advances in smoothing of laser intensity profile
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R. Redaelli, G. Lucchini, Vladimir Tikhonchuk, R. Dezulian, M. Koenig, Jiri Skala, Miroslav Pfeifer, F. Canova, Jérôme Faure, Karel Masek, Roberto Benocci, H. Stabile, Victor Malka, Dimitri Batani, R. Dudzak, Ph. Nicolaï, E. Krousky, Dipartimento di Fisica 'Giuseppe Occhialini' = Department of Physics 'Giuseppe Occhialini' [Milano-Bicocca], Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Laboratoire d'optique appliquée (LOA), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), PALS Research Centre, Czech Republic Research center, Laboratoire pour l'utilisation des lasers intenses (LULI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Centre d'Etudes Lasers Intenses et Applications (CELIA), Université de Bordeaux (UB)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Benocci, R, Batani, D, Dezulian, R, Redaelli, R, Lucchini, G, Canova, F, Stabile, H, Faure, J, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Koenig, M, Tikhonchuk, V, Nicolai, P, Malka, V, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), and Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)
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Nuclear and High Energy Physics ,Electron density ,[PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics] ,Radiation ,Materials science ,business.industry ,laser-generated plasma ,laser smoothing technique ,Laser pumping ,Plasma ,Condensed Matter Physics ,Laser ,01 natural sciences ,Wedge (geometry) ,Electromagnetic radiation ,law.invention ,010309 optics ,Optics ,law ,0103 physical sciences ,General Materials Science ,Laser power scaling ,010306 general physics ,business ,Inertial confinement fusion - Abstract
International audience; We present the experimental results, and their analysis, connected to the possibility to control laser inhomogeneities exploiting the non-uniform electron density distribution created by the laser while propagating in a gas jet. The induced self-refraction in the plasma created in the gas medium results in re-distributing local over-intensities over larger surfaces. The experiment at the PALS laser facility has been performed creating a large non-uniformity by a wedge arrangement and recording the static and dynamic images with and without the coupling to an Al target.
- Published
- 2008
24. Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during early pregnancy
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Helena Stabile, Carlo Mocci, Angela Gismondi, Francesco Tedesco, Angela Santoni, Claudia Carlino, Chiara Agostinis, Fleur Bossi, Roberta Bulla, Filippo Sarazani, Alessandra Soriani, Stefania Morrone, Carlino, C., Stabile, H., Morrone, S., Bulla, Roberta, Soriani, A., Agostinis, Chiara, Bossi, Fleur, Mocci, C., Sarazani, F., Tedesco, Francesco, Santoni, A., and Gismondi, A.
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Male ,medicine.medical_specialty ,Stromal cell ,Time Factors ,NK ,Immunology ,Biology ,Biochemistry ,Interleukin 21 ,pregnancy ,decidua ,Cell Movement ,Pregnancy ,Internal medicine ,medicine ,Decidua ,CXCL10 ,Humans ,Decidual cells ,RNA, Messenger ,CXCL14 ,Cells, Cultured ,Lymphokine-activated killer cell ,Janus kinase 3 ,Gene Expression Profiling ,Cell Biology ,Hematology ,Coculture Techniques ,Cell biology ,Killer Cells, Natural ,Endocrinology ,Interleukin 12 ,Female ,Receptors, Chemokine ,Chemokines ,Stromal Cells - Abstract
During early pregnancy, uterine mucosa decidualization is accompanied by a drastic enrichment of CD56highCD16− natural killer (NK) cells. Decidual NK (dNK) cells differ from peripheral blood NK (pbNK) cells in several ways, but their origin is still unclear. Our results demonstrate that chemokines present in the uterus can support pbNK cell migration through human endothelial and stromal decidual cells. Notably, we observed that pregnant women's pbNK cells are endowed with higher migratory ability compared with nonpregnant women's or male donors' pbNK cells. Moreover, NK cell migration through decidual stromal cells was increased when progesterone-cultured stromal cells were used as substrate, and this correlated with the ability of progesterone to up-regulate stromal cell chemokine expression. Furthermore, we demonstrate that dNK cells migrate through stromal cells using a distinct pattern of chemokines. Finally, we found that pbNK cells acquire a chemokine receptor pattern similar to that of dNK cells when they contact decidual stromal cells. Collectively these results strongly suggest that pbNK cell recruitment to the uterus contributes to the accumulation of NK cells during early pregnancy; that progesterone plays a crucial role in this event; and that pbNK cells undergo reprogramming of their chemokine receptor profile once exposed to uterine microenvironment.
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- 2008
25. Laser non-uniformity smoothing using gas jets
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E. Krousky, R. Dezulian, Miroslav Pfeifer, Dimitri Batani, H. Stabile, R. Dudzak, R. Redaelli, Roberto Benocci, G. Lucchini, Jérôme Faure, Malka, M. Koenig, T. Desai, K. Masek, F. Canova, Jiri Skala, Tikhonchuk, Batani, D, Dezulian, R, Redaelli, R, Benocci, R, Stabile, H, Canova, F, Lucchini, G, Koenig, M, Krousky, E, Masek, K, Pfeifer, M, Skala, J, Dudzak, R, Desai, T, Tikhonchuk, V, Faure, J, and Malka, V
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Laser non-uniformity smoothing, Inertial Confinement Fusion ,History ,Argon ,business.industry ,Chemistry ,chemistry.chemical_element ,Plasma ,Laser ,Beam parameter product ,Computer Science Applications ,Education ,law.invention ,Wavelength ,Optics ,law ,Physics::Accelerator Physics ,Laser beam quality ,business ,Inertial confinement fusion ,Beam (structure) - Abstract
An experimental investigation about laser beam homogenization using gas jets is presented in this paper. The results, obtained at PALS iodine laser facility using the 3 omega wavelength and irradiances of about 10(15) W/cm(2), showed that the use of high pressure gas jets (up to 10 bar of Argon) can be effective in reducing strong laser beam non-uniformities artificially introduced by inserting a wedge arrangement on half of the beam.
- Published
- 2008
26. Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation.
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Scarno G, Mazej J, Laffranchi M, Di Censo C, Mattiola I, Candelotti AM, Pietropaolo G, Stabile H, Fionda C, Peruzzi G, Brooks SR, Tsai WL, Mikami Y, Bernardini G, Gismondi A, Sozzani S, Di Santo JP, Vosshenrich CAJ, Diefenbach A, Gadina M, Santoni A, and Sciumè G
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- Humans, Immunity, Innate, Cell Differentiation, Killer Cells, Natural, Inflammation, STAT4 Transcription Factor genetics, STAT5 Transcription Factor, Antineoplastic Agents
- Abstract
Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require signal transducer and activator of transcription 4 (STAT4) to elicit rapid effector responses and protect against pathogens. By combining genetic and transcriptomic approaches, we uncovered divergent roles for STAT4 in regulating effector differentiation of these functionally related cell types. Stat4 deletion in Ncr1 -expressing cells led to impaired NK cell terminal differentiation as well as to an unexpected increased generation of cytotoxic ILC1 during intestinal inflammation. Mechanistically, Stat4 -deficient ILC1 exhibited upregulation of gene modules regulated by STAT5 in vivo and an aberrant effector differentiation upon in vitro stimulation with IL-2, used as a prototypical STAT5 activator. Moreover, STAT4 expression in NCR
+ innate lymphocytes restrained gut inflammation in the dextran sulfate sodium-induced colitis model limiting pathogenic production of IL-13 from adaptive CD4+ T cells in the large intestine. Collectively, our data shed light on shared and distinctive mechanisms of STAT4-regulated transcriptional control in NK cells and ILC1 required for intestinal inflammatory responses.- Published
- 2023
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27. Nitric Oxide Prevents Glioblastoma Stem Cells' Expansion and Induces Temozolomide Sensitization.
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Salvatori L, Malatesta S, Illi B, Somma MP, Fionda C, Stabile H, Fontanella RA, and Gaetano C
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- Humans, Temozolomide therapeutic use, Nitric Oxide metabolism, Dacarbazine therapeutic use, Cell Line, Tumor, Cell Proliferation, Cell Cycle, Stem Cells metabolism, Drug Resistance, Neoplasm, Neoplastic Stem Cells metabolism, Antineoplastic Agents, Alkylating pharmacology, Antineoplastic Agents, Alkylating therapeutic use, Glioblastoma metabolism, Brain Neoplasms metabolism
- Abstract
Glioblastoma multiforme (GBM) has high mortality and recurrence rates. Malignancy resilience is ascribed to Glioblastoma Stem Cells (GSCs), which are resistant to Temozolomide (TMZ), the gold standard for GBM post-surgical treatment. However, Nitric Oxide (NO) has demonstrated anti-cancer efficacy in GBM cells, but its potential impact on GSCs remains unexplored. Accordingly, we investigated the effects of NO, both alone and in combination with TMZ, on patient-derived GSCs. Experimentally selected concentrations of diethylenetriamine/NO adduct and TMZ were used through a time course up to 21 days of treatment, to evaluate GSC proliferation and death, functional recovery, and apoptosis. Immunofluorescence and Western blot analyses revealed treatment-induced effects in cell cycle and DNA damage occurrence and repair. Our results showed that NO impairs self-renewal, disrupts cell-cycle progression, and expands the quiescent cells' population. Consistently, NO triggered a significant but tolerated level of DNA damage, but not apoptosis. Interestingly, NO/TMZ cotreatment further inhibited cell cycle progression, augmented G0 cells, induced cell death, but also enhanced DNA damage repair activity. These findings suggest that, although NO administration does not eliminate GSCs, it stunts their proliferation, and makes cells susceptible to TMZ. The resulting cytostatic effect may potentially allow long-term control over the GSCs' subpopulation.
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- 2023
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28. Role of NF-κB Signaling in the Interplay between Multiple Myeloma and Mesenchymal Stromal Cells.
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Cippitelli M, Stabile H, Kosta A, Petillo S, Lucantonio L, Gismondi A, Santoni A, and Fionda C
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- Humans, NF-kappa B metabolism, Signal Transduction, Transcription Factors metabolism, Stromal Cells metabolism, Tumor Microenvironment, Multiple Myeloma pathology, Mesenchymal Stem Cells metabolism
- Abstract
Nuclear factor-κB (NF-κB) transcription factors play a key role in the pathogenesis of multiple myeloma (MM). The survival, proliferation and chemoresistance of malignant plasma cells largely rely on the activation of canonical and noncanonical NF-κB pathways. They are triggered by cancer-associated mutations or by the autocrine and paracrine production of cytokines and growth factors as well as direct interaction with cellular and noncellular components of bone marrow microenvironment (BM). In this context, NF-κB also significantly affects the activity of noncancerous cells, including mesenchymal stromal cells (MSCs), which have a critical role in disease progression. Indeed, NF-κB transcription factors are involved in inflammatory signaling that alters the functional properties of these cells to support cancer evolution. Moreover, they act as regulators and/or effectors of pathways involved in the interplay between MSCs and MM cells. The aim of this review is to analyze the role of NF-κB in this hematologic cancer, focusing on NF-κB-dependent mechanisms in tumor cells, MSCs and myeloma-mesenchymal stromal cell crosstalk.
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- 2023
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29. Age-dependent NK cell dysfunctions in severe COVID-19 patients.
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Fionda C, Ruggeri S, Sciumè G, Laffranchi M, Quinti I, Milito C, Palange P, Menichini I, Sozzani S, Frati L, Gismondi A, Santoni A, and Stabile H
- Subjects
- Humans, SARS-CoV-2, Killer Cells, Natural, Transforming Growth Factor beta, COVID-19, Skin Diseases
- Abstract
Natural Killer (NK) cells are key innate effectors of antiviral immune response, and their activity changes in ageing and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated the age-related changes of NK cell phenotype and function during SARS-CoV-2 infection, by comparing adult and elderly patients both requiring mechanical ventilation. Adult patients had a reduced number of total NK cells, while elderly showed a peculiar skewing of NK cell subsets towards the CD56
low CD16high and CD56neg phenotypes, expressing activation markers and check-point inhibitory receptors. Although NK cell degranulation ability is significantly compromised in both cohorts, IFN-γ production is impaired only in adult patients in a TGF-β-dependent manner. This inhibitory effect was associated with a shorter hospitalization time of adult patients suggesting a role for TGF-β in preventing an excessive NK cell activation and systemic inflammation. Our data highlight an age-dependent role of NK cells in shaping SARS-CoV-2 infection toward a pathophysiological evolution., 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 © 2022 Fionda, Ruggeri, Sciumè, Laffranchi, Quinti, Milito, Palange, Menichini, Sozzani, Frati, Gismondi, Santoni and Stabile.)- Published
- 2022
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30. GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells.
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Kosta A, Mekhloufi A, Lucantonio L, Zingoni A, Soriani A, Cippitelli M, Gismondi A, Fazio F, Petrucci MT, Santoni A, Stabile H, and Fionda C
- Subjects
- Humans, Ligands, NF-kappa B genetics, NF-kappa B metabolism, Signal Transduction, Histocompatibility Antigens Class I genetics, Histocompatibility Antigens Class I metabolism, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Multiple Myeloma genetics, Multiple Myeloma metabolism, NK Cell Lectin-Like Receptor Subfamily K genetics, NK Cell Lectin-Like Receptor Subfamily K metabolism
- Abstract
NKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transcription and translation, but the molecular mechanisms sustaining their basal expression in MM cells remain poorly understood. Here, we evaluated the role of the growth arrest specific 6 (GAS6)/TAM signaling pathway in the regulation of NKG2D ligand expression and MM recognition by NK cells. Our data showed that GAS6 as well as MERTK and AXL depletion in MM cells results in MICA downregulation and inhibition of NKG2D-mediated NK cell degranulation. Noteworthy, GAS6 derived from bone marrow stromal cells (BMSCs) also increases MICA expression at both protein and mRNA level in human MM cell lines and in primary malignant plasma cells. NF-kB activation is required for these regulatory mechanisms since deletion of a site responsive for this transcription factor compromises the induction of mica promoter by BMSCs. Accordingly, knockdown of GAS6 reduces the capability of BMSCs to activate NF-kB pathway as well as to enhance MICA expression in MM cells. Taken together, these results shed light on molecular mechanism underlying NKG2D ligand regulation and identify GAS6 protein as a novel autocrine and paracrine regulator of basal expression of MICA in human MM cells., 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 © 2022 Kosta, Mekhloufi, Lucantonio, Zingoni, Soriani, Cippitelli, Gismondi, Fazio, Petrucci, Santoni, Stabile and Fionda.)
- Published
- 2022
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31. NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis.
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Fionda C, Scarno G, Stabile H, Molfetta R, Di Censo C, Gismondi A, Paolini R, Sozzani S, Santoni A, and Sciumè G
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Immunity, Innate, Killer Cells, Natural, Mice, Colorectal Neoplasms, Lymphocytes
- Abstract
Colorectal cancer (CRC) is one of the most common malignancies and leading causes of cancer-related deaths worldwide. Despite its complex pathogenesis and progression, CRC represents a well-fitting example of how the immune contexture can dictate the disease outcome. The presence of cytotoxic lymphocytes, both CD8
+ T cells and natural killer (NK) cells, represents a relevant prognostic factor in CRC and is associated with a better overall survival. Together with NK cells, other innate lymphocytes, namely, innate lymphoid cells (ILCs), have been found both in biopsies of CRC patients and in murine models of intestinal cancer, playing both pro- and anti-tumor activities. In particular, several type 1 innate lymphoid cells (ILC1) with cytotoxic functions have been recently described, and evidence in mice shows a role for both NK cells and ILC1 in controlling CRC metastasis. In this review, we provide an overview of the features of NK cells and the expanding spectrum of innate lymphocytes with cytotoxic functions. We also comment on both the described and the potential roles these innate lymphocytes can play during the progression of intestinal cancer leading to metastasis. Finally, we discuss recent advances in the molecular mechanisms underlying the functional regulation of cytotoxic innate lymphocytes in CRC.- Published
- 2022
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32. The Regulatory Activity of Noncoding RNAs in ILCs.
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Grimaldi A, Pietropaolo G, Stabile H, Kosta A, Capuano C, Gismondi A, Santoni A, Sciumè G, and Fionda C
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- Animals, Humans, MicroRNAs genetics, MicroRNAs metabolism, RNA, Circular genetics, RNA, Circular metabolism, RNA, Untranslated metabolism, Gene Expression Regulation, Immunity, Innate genetics, Lymphocytes metabolism, RNA, Untranslated genetics
- Abstract
Innate lymphoid cells (ILCs) are innate lymphocytes playing essential functions in protection against microbial infections and participate in both homeostatic and pathological contexts, including tissue remodeling, cancer, and inflammatory disorders. A number of lineage-defining transcription factors concurs to establish transcriptional networks which determine the identity and the activity of the distinct ILC subsets. However, the contribution of other regulatory molecules in controlling ILC development and function is also recently emerging. In this regard, noncoding RNAs (ncRNAs) represent key elements of the complex regulatory network of ILC biology and host protection. ncRNAs mostly lack protein-coding potential, but they are endowed with a relevant regulatory activity in immune and nonimmune cells because of their ability to control chromatin structure, RNA stability, and/or protein synthesis. Herein, we summarize recent studies describing how distinct types of ncRNAs, mainly microRNAs, long ncRNAs, and circular RNAs, act in the context of ILC biology. In particular, we comment on how ncRNAs can exert key effects in ILCs by controlling gene expression in a cell- or state-specific manner and how this tunes distinct functional outputs in ILCs.
- Published
- 2021
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33. Role of Aiolos and Ikaros in the Antitumor and Immunomodulatory Activity of IMiDs in Multiple Myeloma: Better to Lose Than to Find Them.
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Cippitelli M, Stabile H, Kosta A, Petillo S, Gismondi A, Santoni A, and Fionda C
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Differentiation drug effects, Cell Line, Tumor, Cell Proliferation, Cell Survival, Humans, Ikaros Transcription Factor genetics, Immunity drug effects, Immunomodulation drug effects, Lenalidomide pharmacology, Lymphocytes cytology, Mice, Multiple Myeloma immunology, Thalidomide pharmacology, Ikaros Transcription Factor physiology, Multiple Myeloma drug therapy
- Abstract
The Ikaros zing-finger family transcription factors (IKZF TFs) are important regulators of lymphocyte development and differentiation and are also highly expressed in B cell malignancies, including Multiple Myeloma (MM), where they are required for cancer cell growth and survival. Moreover, IKZF TFs negatively control the functional properties of many immune cells. Thus, the targeting of these proteins has relevant therapeutic implications in cancer. Indeed, accumulating evidence demonstrated that downregulation of Ikaros and Aiolos, two members of the IKZF family, in malignant plasma cells as well as in adaptative and innate lymphocytes, is key for the anti-myeloma activity of Immunomodulatory drugs (IMiDs). This review is focused on IKZF TF-related pathways in MM. In particular, we will address how the depletion of IKZF TFs exerts cytotoxic effects on MM cells, by reducing their survival and proliferation, and concomitantly potentiates the antitumor immune response, thus contributing to therapeutic efficacy of IMiDs, a cornerstone in the treatment of this neoplasia.
- Published
- 2021
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34. Corrigendum to "Multicentre Harmonisation of a Six-Colour Flow Cytometry Panel for Naïve/Memory T Cell Immunomonitoring".
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Macchia I, La Sorsa V, Ruspantini I, Sanchez M, Tirelli V, Carollo M, Fedele G, Leone P, Schiavoni G, Buccione C, Rizza P, Nisticò P, Palermo B, Morrone S, Stabile H, Rughetti A, Nuti M, Zizzari IG, Fionda C, Maggio R, Capuano C, Quintarelli C, Sinibaldi M, Agrati C, Casetti R, Rozo Gonzalez A, Iacobone F, Gismondi A, Belardelli F, Biffoni M, and Urbani F
- Abstract
[This corrects the article DOI: 10.1155/2020/1938704.]., (Copyright © 2020 Iole Macchia et al.)
- Published
- 2020
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35. Multicentre Harmonisation of a Six-Colour Flow Cytometry Panel for Naïve/Memory T Cell Immunomonitoring.
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Macchia I, La Sorsa V, Ruspantini I, Sanchez M, Tirelli V, Carollo M, Fedele G, Leone P, Schiavoni G, Buccione C, Rizza P, Nisticò P, Palermo B, Morrone S, Stabile H, Rughetti A, Nuti M, Zizzari IG, Fionda C, Maggio R, Capuano C, Quintarelli C, Sinibaldi M, Agrati C, Casetti R, Rozo Gonzalez A, Iacobone F, Gismondi A, Belardelli F, Biffoni M, and Urbani F
- Subjects
- Biomarkers blood, CD3 Complex blood, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Color standards, Flow Cytometry methods, Humans, Immunologic Memory, Italy, Leukocyte Common Antigens blood, Leukocytes, Mononuclear immunology, Observer Variation, Receptors, CCR7 blood, T-Lymphocyte Subsets immunology, Flow Cytometry standards, Immunophenotyping standards, T-Lymphocyte Subsets classification
- Abstract
Background: Personalised medicine in oncology needs standardised immunological assays. Flow cytometry (FCM) methods represent an essential tool for immunomonitoring, and their harmonisation is crucial to obtain comparable data in multicentre clinical trials. The objective of this study was to design a harmonisation workflow able to address the most effective issues contributing to intra- and interoperator variabilities in a multicentre project., Methods: The Italian National Institute of Health (Istituto Superiore di Sanità, ISS) managed a multiparametric flow cytometric panel harmonisation among thirteen operators belonging to five clinical and research centres of Lazio region (Italy). The panel was based on a backbone mixture of dried antibodies (anti-CD3, anti-CD4, anti-CD8, anti-CD45RA, and anti-CCR7) to detect naïve/memory T cells, recognised as potential prognostic/predictive immunological biomarkers in cancer immunotherapies. The coordinating centre distributed frozen peripheral blood mononuclear cells (PBMCs) and fresh whole blood (WB) samples from healthy donors, reagents, and Standard Operating Procedures (SOPs) to participants who performed experiments by their own equipment, in order to mimic a real-life scenario. Operators returned raw and locally analysed data to ISS for central analysis and statistical elaboration., Results: Harmonised and reproducible results were obtained by sharing experimental set-up and procedures along with centralising data analysis, leading to a reduction of cross-centre variability for naïve/memory subset frequencies particularly in the whole blood setting., Conclusion: Our experimental and analytical working process proved to be suitable for the harmonisation of FCM assays in a multicentre setting, where high-quality data are required to evaluate potential immunological markers, which may contribute to select better therapeutic options., Competing Interests: Each contributing author declares to have no competing interests., (Copyright © 2020 Iole Macchia et al.)
- Published
- 2020
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36. Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor.
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Mekhloufi A, Kosta A, Stabile H, Molfetta R, Zingoni A, Soriani A, Cippitelli M, Paolini R, Gismondi A, Ricciardi MR, Petrucci MT, Masuelli L, Caracciolo G, Palchetti S, Santoni A, and Fionda C
- Abstract
Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays a prominent role in NK cell anti-MM response engaging the ligands poliovirus receptor (PVR) and nectin-2 on malignant PCs. Here, we analysed the role of MM patient-derived BMSCs in the regulation of PVR expression. We found that BMSCs enhance PVR surface expression on MM cells and promote their NK cell-mediated recognition. PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBα blocked PVR upregulation. IL-8 plays a prominent role in these mechanisms since blockade of CXCR1/2 receptors as well as depletion of the cytokine via RNA interference prevents the enhancement of PVR expression by BMSC-derived conditioned medium. Interestingly, IL-8 is associated with stromal microvesicles which are also required for PVR upregulation via CXCR1/CXCR2 signaling activation. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of PVR expression in cancer cells.
- Published
- 2020
- Full Text
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37. CD155: A Multi-Functional Molecule in Tumor Progression.
- Author
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Molfetta R, Zitti B, Lecce M, Milito ND, Stabile H, Fionda C, Cippitelli M, Gismondi A, Santoni A, and Paolini R
- Subjects
- Disease Progression, Humans, Neoplasms metabolism, Immunologic Surveillance immunology, Neoplasms immunology, Neoplasms pathology, Receptors, Virus metabolism
- Abstract
CD155 is an adhesion molecule belonging to the Nectin/Nectin-like family often overexpressed on tumor cells and involved in many different processes such as cell adhesion, migration and proliferation. In contrast to these pro-tumorigenic functions, CD155 is also a ligand for the activating receptor DNAM-1 expressed on cytotoxic lymphocytes including Natural Killer (NK) cells and involved in anti-tumor immune response. However, during tumor progression inhibitory receptors for CD155 are up-regulated on the surface of effector cells, contributing to an impairment of their cytotoxic capacity. In this review we will focus on the roles of CD155 as a ligand for the activating receptor DNAM-1 regulating immune surveillance against cancer and as pro-oncogenic molecule favoring tumor proliferation, invasion and immune evasion. A deeper understanding of the multiple roles played by CD155 in cancer development contributes to improving anti-tumor strategies aimed to potentiate immune response against cancer., Competing Interests: The authors declare no conflict of interest.
- Published
- 2020
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38. Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer.
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Fionda C, Stabile H, Cerboni C, Soriani A, Gismondi A, Cippitelli M, and Santoni A
- Abstract
Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic., Competing Interests: The authors declare no conflict of interest.
- Published
- 2020
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39. NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells.
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Stabile H, Nisti P, Fionda C, Pagliara D, Gaspari S, Locatelli F, Santoni A, and Gismondi A
- Abstract
T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56
low CD16low NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given α/βT-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56low CD16low NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-γ Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56low CD16low NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56low CD16low NK cells in the T-cell-depleted haplo-HSC transplanted patients.- Published
- 2019
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40. The POU-Domain Transcription Factor Oct-6/POU3F1 as a Regulator of Cellular Response to Genotoxic Stress.
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Fionda C, Di Bona D, Kosta A, Stabile H, Santoni A, and Cippitelli M
- Abstract
DNA damage and the generation of reactive oxygen species (ROS) are key mechanisms of apoptotic cell death by commonly used genotoxic drugs. However, the complex cellular response to these pharmacologic agents remains yet to be fully characterized. Several studies have described the role of transcription factor octamer-1 (Oct-1)/Pit-1, Oct-1/2, and Unc-86 shared domain class 2 homeobox 1 (POU2F1) in the regulation of the genes important for cellular response to genotoxic stress. Evaluating the possible involvement of other POU family transcription factors in these pathways, we revealed the inducible expression of Oct-6/POU3F1, a regulator of neural morphogenesis and epidermal differentiation, in cancer cells by genotoxic drugs. The induction of Oct-6 occurs at the transcriptional level via reactive oxygen species (ROS) and ataxia telangiectasia mutated- and Rad3-related (ATR)-dependent mechanisms, but in a p53 independent manner. Moreover, we provide evidence that Oct-6 may play a role in the regulation of cellular response to DNA damaging agents. Indeed, by using the shRNA approach, we demonstrate that in doxorubicin-treated H460 non-small-cell lung carcinoma (NSCLC) cells, Oct-6 depletion leads to a reduced G2-cell cycle arrest and senescence, but also to increased levels of intracellular ROS and DNA damage. In addition, we could identify p21 and catalase as Oct-6 target genes possibly mediating these effects. These results demonstrate that Oct-6 is expressed in cancer cells after genotoxic stress, and suggests its possible role in the control of ROS, DNA damage response (DDR), and senescence., 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.
- Published
- 2019
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41. Key Role of the CD56 low CD16 low Natural Killer Cell Subset in the Recognition and Killing of Multiple Myeloma Cells.
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Vulpis E, Stabile H, Soriani A, Fionda C, Petrucci MT, Mariggio' E, Ricciardi MR, Cippitelli M, Gismondi A, Santoni A, and Zingoni A
- Abstract
Natural Killer (NK) cells play a pivotal role in the immunosurveillance of Multiple Myeloma (MM), but it is still undefined whether the NK cell functional properties underlying their protective activity against MM are confined to distinct NK cell populations. Interestingly, herein we report that the CD56
low CD16low NK cell subset displayed higher cytolytic activity compared to the other NK cell subsets (i.e., CD56high CD16+/- , CD56low CD16high ) against MM cells and its activity was impaired in MM patients. Decreased DNAM-1 expression levels were observed on the CD56low CD16low NK cells during MM progression. Evaluating NK cell subset frequency after autologous hematopoietic stem cell transplantation, we found that CD56low CD16low NK cells recovered earlier after transplantation. Overall, our data denote a key role of CD56low CD16low subpopulation in the killing of MM cells and suggest that the reconstitution of CD56low CD16low subpopulation after HSCT could be a useful approach of adoptive immunotherapy in the treatment of relapsed/refractory MM patients.- Published
- 2018
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42. Innate immune activating ligand SUMOylation affects tumor cell recognition by NK cells.
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Zitti B, Molfetta R, Fionda C, Quatrini L, Stabile H, Lecce M, de Turris V, Ricciardi MR, Petrucci MT, Cippitelli M, Gismondi A, Santoni A, and Paolini R
- Subjects
- Biomarkers, Cell Line, Tumor, Cell Membrane metabolism, Cytotoxicity, Immunologic, Gene Expression, Humans, Intracellular Space, Multiple Myeloma immunology, Multiple Myeloma metabolism, Nectins genetics, Nectins metabolism, Protein Transport, Receptors, Virus genetics, Receptors, Virus metabolism, Signal Transduction, Sumoylation, Antigens, Differentiation, T-Lymphocyte metabolism, Immunity, Innate, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Neoplasms immunology, Neoplasms metabolism
- Abstract
Natural Killer cells are innate lymphocytes involved in tumor immunosurveillance. They express activating receptors able to recognize self-molecules poorly expressed on healthy cells but up-regulated upon stress conditions, including transformation. Regulation of ligand expression in tumor cells mainly relays on transcriptional mechanisms, while the involvement of ubiquitin or ubiquitin-like modifiers remains largely unexplored. Here, we focused on the SUMO pathway and demonstrated that the ligand of DNAM1 activating receptor, PVR, undergoes SUMOylation in multiple myeloma. Concurrently, we found that PVR is preferentially located in intracellular compartments in human multiple myeloma cell lines and malignant plasma cells and that inhibition of the SUMO pathway promotes its translocation to the cell surface, increasing tumor cell susceptibility to NK cell-mediated cytolysis. Our findings provide the first evidence of an innate immune activating ligand regulated by SUMOylation, and confer to this modification a novel role in impairing recognition and killing of tumor cells.
- Published
- 2017
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43. Reconstitution of multifunctional CD56 low CD16 low natural killer cell subset in children with acute leukemia given α/β T cell-depleted HLA-haploidentical haematopoietic stem cell transplantation.
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Stabile H, Nisti P, Peruzzi G, Fionda C, Pagliara D, Brescia PL, Merli P, Locatelli F, Santoni A, and Gismondi A
- Abstract
We recently described the CD56
low CD16low subset of Natural Killer (NK) cells that both mediate cytotoxic activity and produce IFNγ, being more abundant in bone marrow (BM) than in peripheral blood (PB) of pediatric normal subjects. Given the multifunctional properties of this subset, we examined its development and functional recovery in a cohort of children undergoing α/β T-cell depleted HLA-haploidentical haematopoietic stem cell transplantation (HSCT). The results obtained indicate that CD56low CD16low NK cells are present in both PB and BM already at one month post-HSCT, with an increased frequency in BM of graft recipients as compared with normal subjects. During the first 6 months after HSCT, no difference in CD56low CD16low NK cells distribution between PB and BM was observed. In comparison to normal subjects, CD56low CD16low NK cells from transplanted patients show lower expression levels of CD25 and CD127 and higher levels of CD122, and accordingly, produce higher amounts of IFNγ after stimulation with IL-12 plus IL-15. The recovery of NK-cell cytotoxicity after HSCT was strictly restricted to CD56low CD16low NK cells, and their ability to degranulate against K562 target cells or autologous leukemic blasts was completely restored only one year after HSCT. Based on the phenotypic and functional ability of reconstituted CD56low CD16low NK cells, we suggest that they play an important role in host defense against leukemia relapse and infections after HSCT, and represent an ideal candidate for approaches of adoptive immunotherapy.- Published
- 2017
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44. Role of Distinct Natural Killer Cell Subsets in Anticancer Response.
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Stabile H, Fionda C, Gismondi A, and Santoni A
- Abstract
Natural killer (NK) cells, the prototypic member of innate lymphoid cells, are important effectors of anticancer immune response. These cells can survey and control tumor initiation due to their capability to recognize and kill malignant cells and to regulate the adaptive immune response via cytokines and chemokines release. However, several studies have shown that tumor-infiltrating NK cells associated with advanced disease can have profound functional defects and display protumor activity. This evidence indicates that NK cell behavior undergoes crucial alterations during cancer progression. Moreover, a further level of complexity is due to the extensive heterogeneity and plasticity of these lymphocytes, implying that different NK cell subsets, endowed with specific phenotypic and functional features, may be involved and play distinct roles in the tumor context. Accordingly, many studies reported the enrichment of selective NK cell subsets within tumor tissue, whereas the underlying mechanisms are not fully elucidated. A malignant microenvironment can significantly impact NK cell activity, by recruiting specific subpopulations and/or influencing their developmental programming or the acquisition of a mature phenotype; in particular, neoplastic, stroma and immune cells, or tumor-derived factors take part in these processes. In this review, we will summarize and discuss the recently acquired knowledge on the possible contribution of distinct NK cell subsets in the control and/or progression of solid and hematological malignancies. Moreover, we will address emerging evidence regarding the role of different components of tumor microenvironment on shaping NK cell response.
- Published
- 2017
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45. Polyfunctional Melan-A-specific tumor-reactive CD8(+) T cells elicited by dacarbazine treatment before peptide-vaccination depends on AKT activation sustained by ICOS.
- Author
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Franzese O, Palermo B, Di Donna C, Sperduti I, Ferraresi V, Stabile H, Gismondi A, Santoni A, and Nisticò P
- Abstract
The identification of activation pathways linked to antitumor T-cell polyfunctionality in long surviving patients is of great relevance in the new era of immunotherapy. We have recently reported that dacarbazine (DTIC) injected one day before peptide-vaccination plus IFN-α improves the antitumor lytic activity and enlarges the repertoire of Melan-A-specific T-cell clones, as compared with vaccination alone, impacting the overall survival of melanoma patients. To identify the mechanisms responsible for this improvement of the immune response, we have analyzed the endogenous and treatment-induced antigen (Ag)-specific response in a panel of Melan-A-specific CD8(+) T-cell clones in terms of differentiation phenotype, inhibitory receptor profile, polyfunctionality and AKT activation. Here, we show that Melan-A-specific CD8(+) T cells isolated from patients treated with chemoimmunotherapy possess a late differentiated phenotype as defined by the absence of CD28 and CD27 co-stimulatory molecules and high levels of LAG-3, TIM-3 and PD-1 inhibitory receptors. Nevertheless, they show higher proliferative potential and an improved antitumor polyfunctional effector profile in terms of co-production of TNF-α, IFNγ and Granzyme-B (GrB) compared with cells derived from patients treated with vaccination alone. Polyfunctionality is dependent on an active AKT signaling related to the engagement of the co-stimulatory molecule ICOS. We suggest that this phenotypic and functional signature is dictated by a fine-tuned balance between TCR triggering, AKT activation, co-stimulatory and inhibitory signals induced by chemoimmunotherapy and may be associated with antitumor T cells able to protect patients from tumor recurrence.
- Published
- 2016
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46. Effector Functions of Natural Killer Cell Subsets in the Control of Hematological Malignancies.
- Author
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Gismondi A, Stabile H, Nisti P, and Santoni A
- Abstract
Treatment of hematological malignant disorders has been improved over the last years, but high relapse rate mainly attributable to the presence of minimal residual disease still persists. Therefore, it is of great interest to explore novel therapeutic strategies to obtain long-term remission. Immune effector cells, and especially natural killer (NK) cells, play a crucial role in the control of hematological malignancies. In this regard, the efficiency of allogeneic stem cell transplantation clearly depends on the immune-mediated graft versus leukemia effect without the risk of inducing graft versus host disease. Alloreactive donor NK cells generated following hematopoietic stem cell transplantation ameliorate the outcome of leukemia patients; in addition, in vivo transfer of in vitro expanded NK cells represents a crucial tool for leukemia treatment. To improve NK cell effector functions against resistant leukemia cells, novel immunotherapeutic strategies are oriented to the identification, isolation, expansion, and administration of particular NK cell subsets endowed with multifunctional anti-tumor potential and tropism toward tumor sites. Moreover, the relationship between the emergence and persistence of distinct NK cell subsets during post-graft reconstitution and the maintenance of a remission state is still rather unclear.
- Published
- 2015
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47. In Vivo Imaging of Natural Killer Cell Trafficking in Tumors.
- Author
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Galli F, Rapisarda AS, Stabile H, Malviya G, Manni I, Bonanno E, Piaggio G, Gismondi A, Santoni A, and Signore A
- Subjects
- Animals, Antibodies, Monoclonal, CD56 Antigen, Cell Line, Tumor, Humans, Mice, Mice, Nude, Mice, SCID, Neoplasm Transplantation, Radionuclide Imaging, Tissue Distribution, Killer Cells, Natural diagnostic imaging, Neoplasms diagnostic imaging, Neoplasms immunology, Radiopharmaceuticals pharmacokinetics, Technetium pharmacokinetics
- Abstract
Unlabelled: Natural killer cells (NKs) are important effectors of the innate immune system, with marked antitumor activity. Imaging NK trafficking in vivo may be relevant to following up the efficacy of new therapeutic approaches aiming at increasing tumor-infiltrating NKs (TINKs). The specific aims of present study were to efficiently target NKs using a 99mTc-anti-CD56 and to image human NK trafficking in SCID mice bearing human cancer., Methods: The anti-CD56 monoclonal antibody (mAb) was radiolabeled with 99mTc, and in vitro quality controls were performed to test labeling efficiency, stability, and binding affinity to CD56. In vivo biodistribution was determined by injecting 5.5 MBq (104 ng) of radiolabeled antibody in the tail vein of SCID mice, which were then sacrificed at 1, 3, 6, and 24 h after injection. Targeting experiments were performed on 2 groups of SCID mice inoculated subcutaneously with increasing numbers of human NKs in the right thigh (from 2.5×10(6) to 40×10(6)) and human granulocytes (CD56-) or anaplastic thyroid cancer (ARO) cells in the contralateral thigh as control. TINK trafficking imaging was achieved by injecting 5.5 MBq of 99mTc-anti-CD56 mAb in SCID mice bearing ARO tumor xenografts in the right thigh, 24 h after being reconstituted with 10(5), 10(6), or 10(7) human NKs., Results: Anti-CD56 mAb was radiolabeled, achieving a radiochemical purity of more than 97% and a specific activity of 3,700 MBq/mg and retaining biochemical integrity and binding activity. In vivo studies revealed physiologic uptake in the liver and kidneys. Targeting experiments confirmed the specificity of labeled antibody to CD56+ cells. Human NK cells injected in CD1 nude mice accumulated in the ARO tumors within 24 h and were imaged as early as 3 h after intravenous administration of (99m)Tc-anti-CD56., Conclusion: 99mTc-anti-CD56 is a promising tool for in vivo imaging of TINK cell trafficking., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)
- Published
- 2015
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48. Response to comment on Multifunctional human CD56low CD16low NK cells are the prominent subset in bone marrow of both pediatric healthy donors and leukemic patients.
- Author
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Stabile H, Nisti P, Pagliara D, Locatelli F, Santoni A, and Gismondi A
- Subjects
- Humans, Bone Marrow Cells metabolism, CD56 Antigen metabolism, Immunophenotyping, Killer Cells, Natural metabolism, Leukemia metabolism, Lymphocyte Subsets metabolism, Receptors, IgG metabolism
- Published
- 2015
- Full Text
- View/download PDF
49. Multifunctional human CD56 low CD16 low natural killer cells are the prominent subset in bone marrow of both healthy pediatric donors and leukemic patients.
- Author
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Stabile H, Nisti P, Morrone S, Pagliara D, Bertaina A, Locatelli F, Santoni A, and Gismondi A
- Subjects
- Adult, Age Factors, Bone Marrow Cells immunology, Case-Control Studies, Cell Degranulation immunology, Chemokines metabolism, Child, Child, Preschool, Cytotoxicity, Immunologic, Humans, Interferons biosynthesis, Killer Cells, Natural immunology, Leukemia immunology, Leukocytes, Mononuclear metabolism, Lymphocyte Count, Lymphocyte Subsets immunology, Phenotype, Platelet Glycoprotein GPIb-IX Complex metabolism, Bone Marrow Cells metabolism, CD56 Antigen metabolism, Immunophenotyping, Killer Cells, Natural metabolism, Leukemia metabolism, Lymphocyte Subsets metabolism, Receptors, IgG metabolism
- Abstract
We phenotypically and functionally characterized a distinct CD56(low) natural killer cell subset based on CD16 expression levels in bone marrow and peripheral blood of healthy children and pediatric patients with acute lymphoblastic leukemia. Our findings demonstrate for the first time that CD56(low)CD16(low) natural killer cells are more abundant in bone marrow than in peripheral blood and that their frequency is further increased in children with acute lymphoblastic leukemia. Bone marrow and peripheral blood CD56(low)CD16(low) natural killer cells compared with CD56(low)CD16(high) natural killer cells express lower levels of killer inhibitory receptors, higher levels of CD27, CD127, CD122, CD25, but undetectable levels of CD57, suggesting that they have a higher proliferative and differentiation potential. Moreover, CD56(low)CD16(low) natural killer cells display higher levels of CXCR4 and undetectable levels of CX3CR1 and can be consistently and rapidly mobilized in peripheral blood in response to CXCR4 antagonist. Unlike CD56(low)CD16(high), both bone marrow and peripheral blood CD56(low)CD16(low) natural killer cells release IFNγ following cytokine stimulation, and represent the major cytotoxic natural killer cell population against K562 or acute lymphoblastic leukemia target cells. All these data suggest that CD56(low)CD16(low) natural killer cells are multifunctional cells, and that the presence of hematologic malignancies affects their frequency and functional ability at both tumor site and in the periphery., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
- Full Text
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50. Chemerin regulates NK cell accumulation and endothelial cell morphogenesis in the decidua during early pregnancy.
- Author
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Carlino C, Trotta E, Stabile H, Morrone S, Bulla R, Soriani A, Iannitto ML, Agostinis C, Mocci C, Minozzi M, Aragona C, Perniola G, Tedesco F, Sozzani S, Santoni A, and Gismondi A
- Subjects
- Capillaries metabolism, Cell Movement immunology, Chemokines genetics, Decidua blood supply, Decidua physiology, Endothelial Cells physiology, Female, Humans, Intercellular Signaling Peptides and Proteins, Neovascularization, Physiologic physiology, Pregnancy, RNA, Messenger metabolism, Receptors, Chemokine genetics, Receptors, Chemokine metabolism, Stromal Cells cytology, Stromal Cells physiology, Trophoblasts cytology, Trophoblasts physiology, Chemokines metabolism, Decidua cytology, Endothelial Cells cytology, Killer Cells, Natural cytology, MAP Kinase Signaling System physiology, Pregnancy Trimester, First physiology
- Abstract
Context: Although decidual natural killer (NK) cell accumulation and vascular remodeling are critical steps to ensure successful pregnancy, the molecular mechanisms controlling these events are poorly defined., Objective: Herein we analyzed whether chemerin, a recently identified chemoattractant involved in many pathophysiological processes, could be expressed in the uterine compartment and could regulate events relevant for the good outcome of pregnancy., Design: Chemerin expression in human primary culture of stromal (ST) cells, extravillous trophoblast cells, and decidual endothelial cells (DEC) was analyzed by RT-PCR, ELISA, and Western blot. Migration through ST or DEC of peripheral blood and decidual (d) NK cells from pregnant women was performed using a transwell assay. A DEC capillary-like tube formation assay was used to evaluate endothelial morphogenesis., Results: Chemerin is differentially expressed by decidual cells during early pregnancy being present at high levels in ST and extravillous trophoblast cells but not in DEC. Notably, ST cells from pregnant women exhibit and release higher levels of chemerin as compared with ST cells from menopausal or fertile nonpregnant women. Chemerin can support peripheral blood NK cell migration through both DEC and ST cells. Although dNK cells exhibit lower chemerin receptor (CMKLR1) expression than their blood counterpart, CMKLR1 engagement on dNK cells resulted in both ERK activation and migration through decidual ST cells. Interestingly, DEC also express CMKLR1 and undergo ERK activation and capillary-like tube structure formation upon exposure to chemerin., Conclusions: Our data indicate that chemerin is up-regulated during decidualization and might contribute to NK cell accumulation and vascular remodeling during early pregnancy.
- Published
- 2012
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