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2. A peptide from the staphylococcal protein Efb binds P-selectin and inhibits the interaction of platelets with leukocytes

Author

Wallis, S, Wolska, N, Englert, H, Posner, M, Upadhyay, A, Renné, T, Eggleston, I, Bagby, S, Pula, G, Wallis, S, Wolska, N, Englert, H, Posner, M, Upadhyay, A, Renné, T, Eggleston, I, Bagby, S, and Pula, G

Abstract

Aims: P-selectin is a key surface adhesion molecule for the interaction of platelets with leukocytes. We have shown previously that the N-terminal domain of Staphylococcus aureus extracellular fibrinogen-binding protein (Efb) binds to P-selectin and interferes with platelet-leukocyte aggregate formation. Here, we aimed to identify the minimal Efb motif required for binding platelets and to characterize its ability to interfering with the formation of platelet-leukocyte aggregates. Methods and Results: Using a library of synthetic peptides, we mapped the platelet-binding site to a continuous 20 amino acid stretch. The peptide Efb68-87 was able to bind to resting and, to a greater extent, thrombin-stimulated platelets in the absence of fibrinogen. Dot blots, pull-down assays and P-selectin glycoprotein ligand-1 (PSGL-1) competitive binding experiments identified P-selectin as the cellular docking site mediating Efb68-87 platelet binding. Accordingly, Efb68-87 did not bind to other blood cells and captured platelets from human whole blood under low shear stress conditions. Efb68-87 did not affect platelet activation as tested by aggregometry, flow cytometry and immunoblotting, but inhibited the formation of platelet-leukocyte aggregates (PLAs). Efb68-87 also interfered with the platelet-dependent stimulation of neutrophil extracellular traps (NETs) formation in vitro. Conclusions: We have identified Efb68-87 as a novel selective platelet-binding peptide. Efb68-87 binds directly to P-selectin and inhibits interactions of platelets with leukocytes that lead to PLA and NET formation. As PLAs and NETs play a key role in thromboinflammation, Efb68-87 is an exciting candidate for the development of novel selective inhibitors of the proinflammatory activity of platelets.

Published
2022

6. Zinc regulates reactive oxygen species generation in platelets

Author

lopes Pires, M. E., Ahmed, N. S., Vara, D., Gibbins, J. M., Pula, G., and Pugh, N.

Subjects
inorganic chemicals, enzymes and coenzymes (carbohydrates), biological sciences, health occupations, bacteria
Abstract

Vascular complications resulting from atherosclerosis development are a major cause of death. Reactive oxygen species (ROS) are produced by platelets during activation, and have been demonstrated to positively regulate platelet activatory responses. Zn2+ is also an important haemostatic cofactor in platelets, acting both as a platelet agonist and secondary messenger. Whilst the effect of Zn2+-dependent signalling mechanisms on ROS production in nucleated cells has been demonstrated, comparable roles in platelets have yet to be investigated. In this study we investigate the relationship between fluctuations in cytosolic Zn2 [Zn2+]i and platelet ROS production. Agonist-evoked ROS production, GSH levels and GPx activity are abrogated in platelets treated with the Zn2+-chelator, TPEN. Conversely, increasing platelet [Zn2+]i using Zn2+ ionophores potentiated ROS generation and decreased GSH levels and GPx activity. Zn2+-dependent ROS production was sensitive to pretreatment with DPI or mitoTEMPO, a NADPH oxidase and mitochondria inhibitors respectively. Increasing [Zn2+]i resulted in increases of Erk1/2 and JNK phosphorylation. Our data are consistent with a functional association between [Zn2+]i and ROS production in platelets that could influence thrombus formation in a clinical context.

Published
2020

7. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Author

Halliday, A., Bulbulia, R., Bonati, L. H., Chester, J., Cradduck-Bamford, A., Peto, R., Pan, H., Potter, J., Henning Eckstein, H., Farrell, B., Flather, M., Mansfield, A., Mihaylova, B., Rahimi, K., Simpson, D., Thomas, D., Sandercock, P., Gray, R., Molyneux, A., Shearman, C. P., Rothwell, P., Belli, A., Herrington, W., Judge, P., Leopold, P., Mafham, M., Gough, M., Cao, P., Macdonald, S., Bari, V., Berry, C., Bradshaw, S., Brudlo, W., Clarke, A., Cox, R., Fathers, S., Gaba, K., Gray, M., Hayter, E., Holliday, C., Kurien, R., Lay, M., le Conte, S., Mcmanus, J., Madgwick, Z., Morris, D., Munday, A., Pickworth, S., Ostasz, W., Poorthuis, M., Richards, S., Teixeira, L., Tochlin, S., Tully, L., Wallis, C., Willet, M., Young, A., Casana, R., Malloggi, C., Odero, A., Silani, V., Parati, G., Malchiodi, G., Malferrari, G., Strozzi, F., Tusini, N., Vecchiati, E., Coppi, G., Lauricella, A., Moratto, R., Silingardi, R., Veronesi, J., Zini, A., Ferrero, E., Ferri, M., Gaggiano, A., Labate, C., Nessi, F., Psacharopulo, D., Viazzo, A., Malacrida, G., Mazzaccaro, D., Meola, G., Modafferi, A., Nano, G., Occhiuto, M. T., Righini, P., Stegher, S., Chiarandini, S., Griselli, F., Lepidi, S., Pozzi Mucelli, F., Naccarato, M., D'Oria, M., Ziani, B., Stella, A., Dieng, M., Faggioli, G., Gargiulo, M., Palermo, S., Pini, R., Puddu, G. M., Vacirca, A., Angiletta, D., Desantis, C., Marinazzo, D., Mastrangelo, G., Regina, G., Pulli, R., Bianchi, P., Cireni, L., Coppi, E., Pizzirusso, R., Scalise, F., Sorropago, G., Tolva, V., Caso, V., Cieri, E., Derango, P., Farchioni, L., Isernia, G., Lenti, M., Parlani, G. B., Pupo, G., Pula, G., Simonte, G., Verzini, F., Carimati, F., Delodovici, M. L., Fontana, F., Piffaretti, G., Tozzi, M., Civilini, E., Poletto, G., Reimers, B., Praquin, B., Ronchey, S., Capoccia, L., Mansour, W., Sbarigia, E., Speziale, F., Sirignano, P., Toni, D., Galeotti, R., Gasbarro, V., Mascoli, F., Rocca, T., Tsolaki, E., Bernardini, G., Demarco, E., Giaquinta, A., Patti, F., Veroux, M., Veroux, P., Virgilio, C., Mangialardi, N., Orrico, M., Di Lazzaro, V., Montelione, N., Spinelli, F., Stilo, F., Cernetti, C., Irsara, S., Maccarrone, G., Tonello, D., Visona, A., Zalunardo, B., Chisci, E., Michelagnoli, S., Troisi, N., Masato, M., Dei Negri, M., Pacchioni, A., Sacca, S., Amatucci, G., Cannizzaro, A., Accrocca, F., Ambrogi, C., Barbazza, R., Marcucci, G., Siani, A., Bajardi, G., Savettieri, G., Argentieri, A., Corbetta, R., Quaretti, P., Thyrion, F. Z., Cappelli, A., Benevento, D., De Donato, G., Mele, M. A., Palasciano, G., Pieragalli, D., Rossi, A., Setacci, C., Setacci, F., Palombo, D., Perfumo, M. C., Martelli, E., Paolucci, A., Trimarchi, S., Grassi, V., Grimaldi, L., La Rosa, G., Mirabella, D., Scialabba, M., Sichel, L., D'Angelo, C. L., Fadda, G. F., Kasemi, H., Marino, M., Burzotta, Francesco, Codispoti, F. A., Ferrante, A., Tinelli, Giovanni, Tshomba, Yamume, Vincenzoni, Claudio, Amis, D., Anderson, D., Catterson, M., Clarke, M., Davis, M., Dixit, A., Dyker, A., Ford, G., Jackson, R., Kappadath, S., Lambert, D., Lees, T., Louw, S., Mccaslin, J., Parr, N., Robson, R., Stansby, G., Wales, L., Wealleans, V., Wilson, L., Wyatt, M., Baht, H., Balogun, I., Burger, I., Cosier, T., Cowie, L., Gunathilagan, G., Hargroves, D., Insall, R., Jones, S., Rudenko, H., Schumacher, N., Senaratne, J., Thomas, G., Thomson, A., Webb, T., Brown, E., Esisi, B., Mehrzad, A., Macsweeney, S., Mcconachie, N., Southam, A., Sunman, W., Abdul-Hamiq, A., Bryce, J., Chetter, I., Ettles, D., Lakshminarayan, R., Mitchelson, K., Rhymes, C., Robinson, G., Scott, P., Vickers, A., Ashleigh, R., Butterfield, S., Gamble, E., Ghosh, J., Mccollum, C. N., Welch, M., Welsh, S., Wolowczyk, L., Donnelly, M., D'Souza, S., Egun, A. A., Gregary, B., Joseph, T., Kelly, C., Punekar, S., Rahi, M. A., Raj, S., Seriki, D., Thomson, G., Brown, J., Durairajan, R., Grunwald, I., Guyler, P., Harman, P., Jakeways, M., Khuoge, C., Kundu, A., Loganathan, T., Menon, N., Prabakaran, R. O., Sinha, D., Thompson, V., Tysoe, S., Briley, D., Darby, C., Hands, L., Howard, D., Kuker, W., Schulz, U., Teal, R., Barer, D., Brown, A., Crawford, S., Dunlop, P., Krishnamurthy, R., Majmudar, N., Mitchell, D., Myint, M. P., O'Brien, R., O'Connell, J., Sattar, N., Vetrivel, S., Beard, J., Cleveland, T., Gaines, P., Humphreys, J., Jenkins, A., King, C., Kusuma, D., Lindert, R., Lonsdale, R., Nair, R., Nawaz, S., Okhuoya, F., Turner, D., Venables, G., Dorman, P., Hughes, A., Jones, D., Mendelow, D., Rodgers, H., Raudoniitis, A., Enevoldson, P., Nahser, H., O'Brien, I., Torella, F., Watling, D., White, R., Brown, P., Dutta, D., Emerson, L., Hilltout, P., Kulkarni, S., Morrison, J., Poskitt, K., Slim, F., Smith, S., Tyler, A., Waldron, J., Whyman, M., Bajoriene, M., Baker, L., Colston, A., Eliot-Jones, B., Gramizadeh, G., Lewis-Clarke, C., Mccafferty, L., Oliver, D., Palmer, D., Patil, A., Pegler, S., Ramadurai, G., Roberts, A., Sargent, T., Siddegowda, S., Singh-Ranger, R., Williams, A., Williams, L., Windebank, S., Zuromskis, T., Alwis, L., Angus, J., Asokanathan, A., Fornolles, C., Hardy, D., Hunte, S., Justin, F., Phiri, D., Mitabouana-Kibou, M., Sekaran, L., Sethuraman, S., Tate, M. L., Akyea-Mensah, J., Ball, S., Chrisopoulou, A., Keene, E., Phair, A., Rogers, S., Smyth, J. V., Bicknell, C., Chataway, J., Cheshire, N., Clifton, A., Eley, C., Gibbs, R., Hamady, M., Hazel, B., James, A., Jenkins, M., Khanom, N., Lacey, A., Mireskandari, M., O'Reilly, J., Pereira, A., Sachs, T., Wolfe, J., Davey, P., Rogers, G., Smith, G., Tervit, G., Nichol, I., Parry, A., Young, G., Ashley, S., Barwell, J., Dix, F., Nor, A. M., Parry, C., Birt, A., Davies, P., George, J., Graham, A., Jonker, L., Kelsall, N., Potts, C., Wilson, T., Crinnion, J., Cuenoud, L., Aleksic, N., Babic, S., Ilijevski, N., Radak, Sagic, D., Tanaskovic, S., Colic, M., Cvetic, V., Davidovic, L., Jovanovic, D. R., Koncar, I., Mutavdzic, P., Sladojevic, M., Tomic, I., Debus, E. S., Grzyska, U., Otto, D., Thomalla, G., Barlinn, J., Gerber, J., Haase, K., Hartmann, C., Ludwig, S., Putz, V., Reeps, C., Schmidt, C., Weiss, N., Werth, S., Winzer, S., Gemper, J., Gunther, A., Heiling, B., Jochmann, E., Karvouniari, P., Klingner, C., Mayer, T., Schubert, J., Schulze-Hartung, F., Zanow, J., Bausback, Y., Borger, F., Botsios, S., Branzan, D., Braunlich, S., Holzer, H., Lenzer, J., Piorkowski, C., Richter, N., Schuster, J., Scheinert, D., Schmidt, A., Staab, H., Ulrich, M., Werner, M., Berger, H., Biro, G., Eckstein, H. -H., Kallmayer, M., Kreiser, K., Zimmermann, A., Berekoven, B., Frerker, K., Gordon, V., Torsello, G., Arnold, S., Dienel, C., Storck, M., Biermaier, B., Gissler, H. M., Klotzsch, C., Pfeiffer, T., Schneider, R., Sohl, L., Wennrich, M., Alonso, A., Keese, M., Groden, C., Coster, A., Engelhardt, A., Ratusinski, C. -M., Berg, B., Delle, M., Formgren, J., Gillgren, P., Jarl, L., Kall, T. B., Konrad, P., Nyman, N., Skioldebrand, C., Steuer, J., Takolander, R., Malmstedt, J., Acosta, S., Bjorses, K., Brandt, K., Dias, N., Gottsater, A., Holst, J., Kristmundsson, T., Kuhme, T., Kolbel, T., Lindblad, B., Lindh, M., Malina, M., Ohrlander, T., Resch, T., Ronnle, V., Sonesson, B., Warvsten, M., Zdanowski, Z., Campbell, E., Kjellin, P., Lindgren, H., Nyberg, J., Petersen, B., Plate, G., Parsson, H., Qvarfordt, P., Ignatenko, P., Karpenko, A., Starodubtsev, V., Chernyavsky, M. A., Golovkova, M. S., Komakha, B. B., Zherdev, N. N., Belyasnik, A., Chechulov, P., Kandyba, D., Stepanishchev, I., Csobay-Novak, C., Dosa, E., Entz, L., Nemes, B., Szeberin, Z., Barzo, P., Bodosi, M., Fako, E., Fulop, B., Nemeth, T., Pazdernyik, S., Skoba, K., Voros, E., Chatzinikou, E., Giannoukas, A., Karathanos, C., Koutsias, S., Kouvelos, G., Matsagkas, M., Ralli, S., Rountas, C., Rousas, N., Spanos, K., Brountzos, E., Kakisis, J. D., Lazaris, A., Moulakakis, K. G., Stefanis, L., Tsivgoulis, G., Vasdekis, S., Antonopoulos, C. N., Bellenis, I., Maras, D., Polydorou, A., Polydorou, V., Tavernarakis, A., Ioannou, N., Terzoudi, M., Lazarides, M., Mantatzis, M., Vadikolias, K., Dzieciuchowicz, L., Gabriel, M., Krasinski, Z., Oszkinis, G., Pukacki, F., Slowinski, M., Stanisic, M. -G., Staniszewski, R., Tomczak, J., Zielinski, M., Myrcha, P., Rozanski, D., Drelichowski, S., Iwanowski, W., Koncewicz, K., Bialek, P., Biejat, Z., Czepel, W., Czlonkowska, A., Dowzenko, A., Jedrzejewska, J., Kobayashi, A., Leszczynski, J., Malek, A., Polanski, J., Proczka, R., Skorski, M., Szostek, M., Andziak, P., Dratwicki, M., Gil, R., Nowicki, M., Pniewski, J., Rzezak, J., Seweryniak, P., Dabek, P., Juszynski, M., Madycki, G., Pacewski, B., Raciborski, W., Slowinski, P., Staszkiewicz, W., Bombic, M., Chlouba, V., Fiedler, J., Hes, K., Kostal, P., Sova, J., Kriz, Z., Privara, M., Reif, M., Staffa, R., Vlachovsky, R., Vojtisek, B., Hrbac, T., Kuliha, M., Prochazka, V., Roubec, M., Skoloudik, D., Netuka, D., Steklacova, A., Benes III, V., Buchvald, P., Endrych, L., Sercl, M., Campos, W., Casella, I. B., de Luccia, N., Estenssoro, A. E. V., Presti, C., Puech-Leao, P., Neves, C. R. B., da Silva, E. S., Sitrangulo, C. J., Monteiro, J. A. T., Tinone, G., Bellini Dalio, M., Joviliano, E. E., Pontes Neto, O. M., Serra Ribeiro, M., Cras, P., Hendriks, J. M. H., Hoppenbrouwers, M., Lauwers, P., Loos, C., Yperzeele, L., Geenens, M., Hemelsoet, D., van Herzeele, I., Vermassen, F., Astarci, P., Hammer, F., Lacroix, V., Peeters, A., Verhelst, R., Cirelli, S., Dormal, P., Grimonprez, A., Lambrecht, B., Lerut, P., Thues, E., De Koster, G., Desiron, Q., Maertens de Noordhout, A., Malmendier, D., Massoz, M., Saad, G., Bosiers, M., Callaert, J., Deloose, K., Blanco Canibano, E., Garcia Fresnillo, B., Guerra Requena, M., Morata Barrado, P. C., Muela Mendez, M., Yusta Izquierdo, A., Aparici Robles, F., Blanes Orti, P., Garcia Dominguez, L., Martinez Lopez, R., Miralles Hernandez, M., Tembl Ferrairo, J. I., Chamorro, A., Macho, J., Obach, V., Riambau, V., San Roman, L., Ahlhelm, F. J., Blackham, K., Engelter, S., Eugster, T., Gensicke, H., Gurke, L., Lyrer, P., Mariani, L., Maurer, M., Mujagic, E., Muller, M., Psychogios, M., Stierli, P., Stippich, C., Traenka, C., Wolff, T., Wagner, B., Wiegert, M. M., Clarke, S., Diepers, M., Grochenig, E., Gruber, P., Isaak, A., Kahles, T., Marti, R., Nedeltchev, K., Remonda, L., Tissira, N., Valenca Falcao, M., de Borst, G. J., Lo, R. H., Moll, F. L., Toorop, R., van der Worp, B. H., Vonken, E. J., Kappelle, J. L., Jahrome, O., Vos, F., Schuiling, W., van Overhagen, H., Keunen, R. W. M., Knippenberg, B., Wever, J. J., Lardenoije, J. W., Reijnen, M., Smeets, L., van Sterkenburg, S., Fraedrich, G., Gizewski, E., Gruber, I., Knoflach, M., Kiechl, S., Rantner, B., Abdulamit, T., Bergeron, P., Padovani, R., Trastour, J. -C., Cardon, J. -M., Le Gallou-Wittenberg, A., Allaire, E., Becquemin, J. -P., Cochennec-Paliwoda, F., Desgranges, P., Hosseini, H., Kobeiter, H., Marzelle, J., Almekhlafi, M. A., Bal, S., Barber, P. A., Coutts, S. B., Demchuk, A. M., Eesa, M., Gillies, M., Goyal, M., Hill, M. D., Hudon, M. E., Jambula, A., Kenney, C., Klein, G., Mcclelland, M., Mitha, A., Menon, B. K., Morrish, W. F., Peters, S., Ryckborst, K. J., Samis, G., Save, S., Smith, E. E., Stys, P., Subramaniam, S., Sutherland, G. R., Watson, T., Wong, J. H., Zimmel, L., Flis, V., Matela, J., Miksic, K., Milotic, F., Mrdja, B., Stirn, B., Tetickovic, E., Gasparini, M., Grad, A., Kompara, I., Milosevic, Z., Palmiste, V., Toomsoo, T., Aidashova, B., Kospanov, N., Lyssenko, R., Mussagaliev, D., Beyar, R., Hoffman, A., Karram, T., Kerner, A., Nikolsky, E., Nitecki, S., Andonova, S., Bachvarov, C., Petrov, V., Cvjetko, I., Vidjak, V., Haluzan, D., Petrunic, M., Liu, B., Liu, C. -W., Bartko, D., Beno, P., Rusnak, F., Zelenak, K., Ezura, M., Inoue, T., Kimura, N., Kondo, R., Matsumoto, Y., Shimizu, H., Endo, H., Furui, E., Bakke, S., Krohg-Sorensen, K., Nome, T., Skjelland, M., Tennoe, B., Albuquerque e Castro, J., Alves, G., Bastos Goncalves, F., de Aragao Morais, J., Garcia, A. C., Valentim, H., Vasconcelos, L., Belcastro, F., Cura, F., Zaefferer, P., Abd-Allah, F., Eldessoki, M. H., Heshmat Kassem, H., Soliman Gharieb, H., Colgan, M. P., Haider, S. N., Harbison, J., Madhavan, P., Moore, D., Shanik, G., Kazan, V., Nazzal, M., Ramsey-Williams, V., Burzotta F. (ORCID:0000-0002-6569-9401), Tinelli G. (ORCID:0000-0002-2212-3226), Tshomba Y. (ORCID:0000-0001-7304-7553), Vincenzoni C., Halliday, A., Bulbulia, R., Bonati, L. H., Chester, J., Cradduck-Bamford, A., Peto, R., Pan, H., Potter, J., Henning Eckstein, H., Farrell, B., Flather, M., Mansfield, A., Mihaylova, B., Rahimi, K., Simpson, D., Thomas, D., Sandercock, P., Gray, R., Molyneux, A., Shearman, C. P., Rothwell, P., Belli, A., Herrington, W., Judge, P., Leopold, P., Mafham, M., Gough, M., Cao, P., Macdonald, S., Bari, V., Berry, C., Bradshaw, S., Brudlo, W., Clarke, A., Cox, R., Fathers, S., Gaba, K., Gray, M., Hayter, E., Holliday, C., Kurien, R., Lay, M., le Conte, S., Mcmanus, J., Madgwick, Z., Morris, D., Munday, A., Pickworth, S., Ostasz, W., Poorthuis, M., Richards, S., Teixeira, L., Tochlin, S., Tully, L., Wallis, C., Willet, M., Young, A., Casana, R., Malloggi, C., Odero, A., Silani, V., Parati, G., Malchiodi, G., Malferrari, G., Strozzi, F., Tusini, N., Vecchiati, E., Coppi, G., Lauricella, A., Moratto, R., Silingardi, R., Veronesi, J., Zini, A., Ferrero, E., Ferri, M., Gaggiano, A., Labate, C., Nessi, F., Psacharopulo, D., Viazzo, A., Malacrida, G., Mazzaccaro, D., Meola, G., Modafferi, A., Nano, G., Occhiuto, M. T., Righini, P., Stegher, S., Chiarandini, S., Griselli, F., Lepidi, S., Pozzi Mucelli, F., Naccarato, M., D'Oria, M., Ziani, B., Stella, A., Dieng, M., Faggioli, G., Gargiulo, M., Palermo, S., Pini, R., Puddu, G. M., Vacirca, A., Angiletta, D., Desantis, C., Marinazzo, D., Mastrangelo, G., Regina, G., Pulli, R., Bianchi, P., Cireni, L., Coppi, E., Pizzirusso, R., Scalise, F., Sorropago, G., Tolva, V., Caso, V., Cieri, E., Derango, P., Farchioni, L., Isernia, G., Lenti, M., Parlani, G. B., Pupo, G., Pula, G., Simonte, G., Verzini, F., Carimati, F., Delodovici, M. L., Fontana, F., Piffaretti, G., Tozzi, M., Civilini, E., Poletto, G., Reimers, B., Praquin, B., Ronchey, S., Capoccia, L., Mansour, W., Sbarigia, E., Speziale, F., Sirignano, P., Toni, D., Galeotti, R., Gasbarro, V., Mascoli, F., Rocca, T., Tsolaki, E., Bernardini, G., Demarco, E., Giaquinta, A., Patti, F., Veroux, M., Veroux, P., Virgilio, C., Mangialardi, N., Orrico, M., Di Lazzaro, V., Montelione, N., Spinelli, F., Stilo, F., Cernetti, C., Irsara, S., Maccarrone, G., Tonello, D., Visona, A., Zalunardo, B., Chisci, E., Michelagnoli, S., Troisi, N., Masato, M., Dei Negri, M., Pacchioni, A., Sacca, S., Amatucci, G., Cannizzaro, A., Accrocca, F., Ambrogi, C., Barbazza, R., Marcucci, G., Siani, A., Bajardi, G., Savettieri, G., Argentieri, A., Corbetta, R., Quaretti, P., Thyrion, F. Z., Cappelli, A., Benevento, D., De Donato, G., Mele, M. A., Palasciano, G., Pieragalli, D., Rossi, A., Setacci, C., Setacci, F., Palombo, D., Perfumo, M. C., Martelli, E., Paolucci, A., Trimarchi, S., Grassi, V., Grimaldi, L., La Rosa, G., Mirabella, D., Scialabba, M., Sichel, L., D'Angelo, C. L., Fadda, G. F., Kasemi, H., Marino, M., Burzotta, Francesco, Codispoti, F. A., Ferrante, A., Tinelli, Giovanni, Tshomba, Yamume, Vincenzoni, Claudio, Amis, D., Anderson, D., Catterson, M., Clarke, M., Davis, M., Dixit, A., Dyker, A., Ford, G., Jackson, R., Kappadath, S., Lambert, D., Lees, T., Louw, S., Mccaslin, J., Parr, N., Robson, R., Stansby, G., Wales, L., Wealleans, V., Wilson, L., Wyatt, M., Baht, H., Balogun, I., Burger, I., Cosier, T., Cowie, L., Gunathilagan, G., Hargroves, D., Insall, R., Jones, S., Rudenko, H., Schumacher, N., Senaratne, J., Thomas, G., Thomson, A., Webb, T., Brown, E., Esisi, B., Mehrzad, A., Macsweeney, S., Mcconachie, N., Southam, A., Sunman, W., Abdul-Hamiq, A., Bryce, J., Chetter, I., Ettles, D., Lakshminarayan, R., Mitchelson, K., Rhymes, C., Robinson, G., Scott, P., Vickers, A., Ashleigh, R., Butterfield, S., Gamble, E., Ghosh, J., Mccollum, C. N., Welch, M., Welsh, S., Wolowczyk, L., Donnelly, M., D'Souza, S., Egun, A. A., Gregary, B., Joseph, T., Kelly, C., Punekar, S., Rahi, M. A., Raj, S., Seriki, D., Thomson, G., Brown, J., Durairajan, R., Grunwald, I., Guyler, P., Harman, P., Jakeways, M., Khuoge, C., Kundu, A., Loganathan, T., Menon, N., Prabakaran, R. O., Sinha, D., Thompson, V., Tysoe, S., Briley, D., Darby, C., Hands, L., Howard, D., Kuker, W., Schulz, U., Teal, R., Barer, D., Brown, A., Crawford, S., Dunlop, P., Krishnamurthy, R., Majmudar, N., Mitchell, D., Myint, M. P., O'Brien, R., O'Connell, J., Sattar, N., Vetrivel, S., Beard, J., Cleveland, T., Gaines, P., Humphreys, J., Jenkins, A., King, C., Kusuma, D., Lindert, R., Lonsdale, R., Nair, R., Nawaz, S., Okhuoya, F., Turner, D., Venables, G., Dorman, P., Hughes, A., Jones, D., Mendelow, D., Rodgers, H., Raudoniitis, A., Enevoldson, P., Nahser, H., O'Brien, I., Torella, F., Watling, D., White, R., Brown, P., Dutta, D., Emerson, L., Hilltout, P., Kulkarni, S., Morrison, J., Poskitt, K., Slim, F., Smith, S., Tyler, A., Waldron, J., Whyman, M., Bajoriene, M., Baker, L., Colston, A., Eliot-Jones, B., Gramizadeh, G., Lewis-Clarke, C., Mccafferty, L., Oliver, D., Palmer, D., Patil, A., Pegler, S., Ramadurai, G., Roberts, A., Sargent, T., Siddegowda, S., Singh-Ranger, R., Williams, A., Williams, L., Windebank, S., Zuromskis, T., Alwis, L., Angus, J., Asokanathan, A., Fornolles, C., Hardy, D., Hunte, S., Justin, F., Phiri, D., Mitabouana-Kibou, M., Sekaran, L., Sethuraman, S., Tate, M. L., Akyea-Mensah, J., Ball, S., Chrisopoulou, A., Keene, E., Phair, A., Rogers, S., Smyth, J. V., Bicknell, C., Chataway, J., Cheshire, N., Clifton, A., Eley, C., Gibbs, R., Hamady, M., Hazel, B., James, A., Jenkins, M., Khanom, N., Lacey, A., Mireskandari, M., O'Reilly, J., Pereira, A., Sachs, T., Wolfe, J., Davey, P., Rogers, G., Smith, G., Tervit, G., Nichol, I., Parry, A., Young, G., Ashley, S., Barwell, J., Dix, F., Nor, A. M., Parry, C., Birt, A., Davies, P., George, J., Graham, A., Jonker, L., Kelsall, N., Potts, C., Wilson, T., Crinnion, J., Cuenoud, L., Aleksic, N., Babic, S., Ilijevski, N., Radak, Sagic, D., Tanaskovic, S., Colic, M., Cvetic, V., Davidovic, L., Jovanovic, D. R., Koncar, I., Mutavdzic, P., Sladojevic, M., Tomic, I., Debus, E. S., Grzyska, U., Otto, D., Thomalla, G., Barlinn, J., Gerber, J., Haase, K., Hartmann, C., Ludwig, S., Putz, V., Reeps, C., Schmidt, C., Weiss, N., Werth, S., Winzer, S., Gemper, J., Gunther, A., Heiling, B., Jochmann, E., Karvouniari, P., Klingner, C., Mayer, T., Schubert, J., Schulze-Hartung, F., Zanow, J., Bausback, Y., Borger, F., Botsios, S., Branzan, D., Braunlich, S., Holzer, H., Lenzer, J., Piorkowski, C., Richter, N., Schuster, J., Scheinert, D., Schmidt, A., Staab, H., Ulrich, M., Werner, M., Berger, H., Biro, G., Eckstein, H. -H., Kallmayer, M., Kreiser, K., Zimmermann, A., Berekoven, B., Frerker, K., Gordon, V., Torsello, G., Arnold, S., Dienel, C., Storck, M., Biermaier, B., Gissler, H. M., Klotzsch, C., Pfeiffer, T., Schneider, R., Sohl, L., Wennrich, M., Alonso, A., Keese, M., Groden, C., Coster, A., Engelhardt, A., Ratusinski, C. -M., Berg, B., Delle, M., Formgren, J., Gillgren, P., Jarl, L., Kall, T. B., Konrad, P., Nyman, N., Skioldebrand, C., Steuer, J., Takolander, R., Malmstedt, J., Acosta, S., Bjorses, K., Brandt, K., Dias, N., Gottsater, A., Holst, J., Kristmundsson, T., Kuhme, T., Kolbel, T., Lindblad, B., Lindh, M., Malina, M., Ohrlander, T., Resch, T., Ronnle, V., Sonesson, B., Warvsten, M., Zdanowski, Z., Campbell, E., Kjellin, P., Lindgren, H., Nyberg, J., Petersen, B., Plate, G., Parsson, H., Qvarfordt, P., Ignatenko, P., Karpenko, A., Starodubtsev, V., Chernyavsky, M. A., Golovkova, M. S., Komakha, B. B., Zherdev, N. N., Belyasnik, A., Chechulov, P., Kandyba, D., Stepanishchev, I., Csobay-Novak, C., Dosa, E., Entz, L., Nemes, B., Szeberin, Z., Barzo, P., Bodosi, M., Fako, E., Fulop, B., Nemeth, T., Pazdernyik, S., Skoba, K., Voros, E., Chatzinikou, E., Giannoukas, A., Karathanos, C., Koutsias, S., Kouvelos, G., Matsagkas, M., Ralli, S., Rountas, C., Rousas, N., Spanos, K., Brountzos, E., Kakisis, J. D., Lazaris, A., Moulakakis, K. G., Stefanis, L., Tsivgoulis, G., Vasdekis, S., Antonopoulos, C. N., Bellenis, I., Maras, D., Polydorou, A., Polydorou, V., Tavernarakis, A., Ioannou, N., Terzoudi, M., Lazarides, M., Mantatzis, M., Vadikolias, K., Dzieciuchowicz, L., Gabriel, M., Krasinski, Z., Oszkinis, G., Pukacki, F., Slowinski, M., Stanisic, M. -G., Staniszewski, R., Tomczak, J., Zielinski, M., Myrcha, P., Rozanski, D., Drelichowski, S., Iwanowski, W., Koncewicz, K., Bialek, P., Biejat, Z., Czepel, W., Czlonkowska, A., Dowzenko, A., Jedrzejewska, J., Kobayashi, A., Leszczynski, J., Malek, A., Polanski, J., Proczka, R., Skorski, M., Szostek, M., Andziak, P., Dratwicki, M., Gil, R., Nowicki, M., Pniewski, J., Rzezak, J., Seweryniak, P., Dabek, P., Juszynski, M., Madycki, G., Pacewski, B., Raciborski, W., Slowinski, P., Staszkiewicz, W., Bombic, M., Chlouba, V., Fiedler, J., Hes, K., Kostal, P., Sova, J., Kriz, Z., Privara, M., Reif, M., Staffa, R., Vlachovsky, R., Vojtisek, B., Hrbac, T., Kuliha, M., Prochazka, V., Roubec, M., Skoloudik, D., Netuka, D., Steklacova, A., Benes III, V., Buchvald, P., Endrych, L., Sercl, M., Campos, W., Casella, I. B., de Luccia, N., Estenssoro, A. E. V., Presti, C., Puech-Leao, P., Neves, C. R. B., da Silva, E. S., Sitrangulo, C. J., Monteiro, J. A. T., Tinone, G., Bellini Dalio, M., Joviliano, E. E., Pontes Neto, O. M., Serra Ribeiro, M., Cras, P., Hendriks, J. M. H., Hoppenbrouwers, M., Lauwers, P., Loos, C., Yperzeele, L., Geenens, M., Hemelsoet, D., van Herzeele, I., Vermassen, F., Astarci, P., Hammer, F., Lacroix, V., Peeters, A., Verhelst, R., Cirelli, S., Dormal, P., Grimonprez, A., Lambrecht, B., Lerut, P., Thues, E., De Koster, G., Desiron, Q., Maertens de Noordhout, A., Malmendier, D., Massoz, M., Saad, G., Bosiers, M., Callaert, J., Deloose, K., Blanco Canibano, E., Garcia Fresnillo, B., Guerra Requena, M., Morata Barrado, P. C., Muela Mendez, M., Yusta Izquierdo, A., Aparici Robles, F., Blanes Orti, P., Garcia Dominguez, L., Martinez Lopez, R., Miralles Hernandez, M., Tembl Ferrairo, J. I., Chamorro, A., Macho, J., Obach, V., Riambau, V., San Roman, L., Ahlhelm, F. J., Blackham, K., Engelter, S., Eugster, T., Gensicke, H., Gurke, L., Lyrer, P., Mariani, L., Maurer, M., Mujagic, E., Muller, M., Psychogios, M., Stierli, P., Stippich, C., Traenka, C., Wolff, T., Wagner, B., Wiegert, M. M., Clarke, S., Diepers, M., Grochenig, E., Gruber, P., Isaak, A., Kahles, T., Marti, R., Nedeltchev, K., Remonda, L., Tissira, N., Valenca Falcao, M., de Borst, G. J., Lo, R. H., Moll, F. L., Toorop, R., van der Worp, B. H., Vonken, E. J., Kappelle, J. L., Jahrome, O., Vos, F., Schuiling, W., van Overhagen, H., Keunen, R. W. M., Knippenberg, B., Wever, J. J., Lardenoije, J. W., Reijnen, M., Smeets, L., van Sterkenburg, S., Fraedrich, G., Gizewski, E., Gruber, I., Knoflach, M., Kiechl, S., Rantner, B., Abdulamit, T., Bergeron, P., Padovani, R., Trastour, J. -C., Cardon, J. -M., Le Gallou-Wittenberg, A., Allaire, E., Becquemin, J. -P., Cochennec-Paliwoda, F., Desgranges, P., Hosseini, H., Kobeiter, H., Marzelle, J., Almekhlafi, M. A., Bal, S., Barber, P. A., Coutts, S. B., Demchuk, A. M., Eesa, M., Gillies, M., Goyal, M., Hill, M. D., Hudon, M. E., Jambula, A., Kenney, C., Klein, G., Mcclelland, M., Mitha, A., Menon, B. K., Morrish, W. F., Peters, S., Ryckborst, K. J., Samis, G., Save, S., Smith, E. E., Stys, P., Subramaniam, S., Sutherland, G. R., Watson, T., Wong, J. H., Zimmel, L., Flis, V., Matela, J., Miksic, K., Milotic, F., Mrdja, B., Stirn, B., Tetickovic, E., Gasparini, M., Grad, A., Kompara, I., Milosevic, Z., Palmiste, V., Toomsoo, T., Aidashova, B., Kospanov, N., Lyssenko, R., Mussagaliev, D., Beyar, R., Hoffman, A., Karram, T., Kerner, A., Nikolsky, E., Nitecki, S., Andonova, S., Bachvarov, C., Petrov, V., Cvjetko, I., Vidjak, V., Haluzan, D., Petrunic, M., Liu, B., Liu, C. -W., Bartko, D., Beno, P., Rusnak, F., Zelenak, K., Ezura, M., Inoue, T., Kimura, N., Kondo, R., Matsumoto, Y., Shimizu, H., Endo, H., Furui, E., Bakke, S., Krohg-Sorensen, K., Nome, T., Skjelland, M., Tennoe, B., Albuquerque e Castro, J., Alves, G., Bastos Goncalves, F., de Aragao Morais, J., Garcia, A. C., Valentim, H., Vasconcelos, L., Belcastro, F., Cura, F., Zaefferer, P., Abd-Allah, F., Eldessoki, M. H., Heshmat Kassem, H., Soliman Gharieb, H., Colgan, M. P., Haider, S. N., Harbison, J., Madhavan, P., Moore, D., Shanik, G., Kazan, V., Nazzal, M., Ramsey-Williams, V., Burzotta F. (ORCID:0000-0002-6569-9401), Tinelli G. (ORCID:0000-0002-2212-3226), Tshomba Y. (ORCID:0000-0001-7304-7553), and Vincenzoni C.

Abstract

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA

Published
2021

14. Zinc regulates reactive oxygen species generation in platelets.

Author

Lopes-Pires, M.E., Ahmed, N. S., Vara, D., Gibbins, J. M., Pula, G., and Pugh, N.

Subjects
REACTIVE oxygen species, BLOOD platelets, ZINC supplements, NADPH oxidase, ZINC, BLOOD platelet activation
Abstract

Vascular complications resulting from atherosclerosis development are a major cause of death. Reactive oxygen species (ROS) are produced by platelets during activation, and have been demonstrated to positively regulate platelet activatory responses. Zn2+ is also an important hemostatic cofactor in platelets, acting both as a platelet agonist and second messenger. Whilst the effect of Zn2+-dependent signaling mechanisms on ROS production in nucleated cells has been demonstrated, comparable roles in platelets have yet to be investigated. In this study we investigated the relationship between fluctuations in cytosolic Zn2 [Zn2+]i and platelet ROS production. Agonist-evoked ROS production, GSH levels and GPx activity are abrogated in platelets treated with the Zn2+-chelator, TPEN. Conversely, increasing platelet [Zn2+]i using Zn2+ ionophores potentiated ROS generation and decreased GSH levels and GPx activity. Zn2+-dependent ROS production was sensitive to pretreatment with DPI or mitoTEMPO, NADPH oxidase and mitochondria inhibitors respectively. Increasing [Zn2+]i resulted in increases of Erk1/2 and JNK phosphorylation. Our data are consistent with a functional association between [Zn2+]i and ROS production in platelets that could influence thrombus formation in a clinical context. [ABSTRACT FROM AUTHOR]

Published
2021
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15. Direct Activation of NADPH Oxidase 2 by 2-Deoxyribose-1-Phosphate Triggers Nuclear Factor Kappa B-Dependent Angiogenesis

Author

Vara, D, Watt, J, Fortunato, T, Mellor, H, Burgess, M, Wicks, K, Mace, K, Reeksting, S, Lubben, A, Wheeler-Jones, C, Pula, G, and Soft Tissue Biomech. & Tissue Eng.

Subjects
Vascular Endothelial Growth Factor A, Lydia Becker Institute, Neovascularization, Physiologic, NF-κB, Cell Line, angiogenesis, SDG 3 - Good Health and Well-being, Reactive Oxygen Species/metabolism, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, endothelial, NADPH, Humans, Endothelial Cells/drug effects, Vascular Endothelial Growth Factor A/metabolism, NF-kappa B, Endothelial Cells, Neovascularization, Physiologic/drug effects, ROS, NOX, NADPH Oxidase 2/metabolism, Oxidative Stress, Original Research Communications, NF-kappa B/metabolism, NADPH Oxidase 2, cardiovascular system, Ribosemonophosphates/pharmacology, Ribosemonophosphates, Reactive Oxygen Species, circulatory and respiratory physiology
Abstract

Aims: Deoxyribose-1-phosphate (dRP) is a proangiogenic paracrine stimulus released by cancer cells, platelets, and macrophages and acting on endothelial cells. The objective of this study was to clarify how dRP stimulates angiogenic responses in human endothelial cells. Results: Live cell imaging, electron paramagnetic resonance, pull-down of dRP-interacting proteins, followed by immunoblotting, gene silencing of different NADPH oxidases (NOXs), and their regulatory cosubunits by small interfering RNA (siRNA) transfection, and experiments with inhibitors of the sugar transporter glucose transporter 1 (GLUT1) were utilized to demonstrate that dRP acts intracellularly by directly activating the endothelial NOX2 complex, but not NOX4. Increased reactive oxygen species generation in response to NOX2 activity leads to redox-dependent activation of the transcription factor nuclear factor kappa B (NF-κB), which, in turn, induces vascular endothelial growth factor receptor 2 (VEGFR2) upregulation. Using endothelial tube formation assays, gene silencing by siRNA, and antibody-based receptor inhibition, we demonstrate that the activation of NF-κB and VEGFR2 is necessary for the angiogenic responses elicited by dRP. The upregulation of VEGFR2 and NOX2-dependent stimulation of angiogenesis by dRP were confirmed in excisional wound and Matrigel plug vascularization assays in vivo using NOX2−/− mice. Innovation: For the first time, we demonstrate that dRP acts intracellularly and stimulates superoxide anion generation by direct binding and activation of the NOX2 enzymatic complex. Conclusions: This study describes a novel molecular mechanism underlying the proangiogenic activity of dRP, which involves the sequential activation of NOX2 and NF-κB and upregulation of VEGFR2. Antioxid. Redox Signal. 28, 110–130.

Published
2018
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19. Direct activation of NADPH oxidase 2 by 2-deoxyribose-1-phosphate triggers nuclear factor kappa B-dependent angiogenesis

Author

Vara, D., Watt, J.M., Fortunato, T.M., Mellor, H., Burgess, M., Wicks, K., Mace, K., Reeksting, S., Lubben, A., Wheeler-Jones, C.P.D., Pula, G., Vara, D., Watt, J.M., Fortunato, T.M., Mellor, H., Burgess, M., Wicks, K., Mace, K., Reeksting, S., Lubben, A., Wheeler-Jones, C.P.D., and Pula, G.

Abstract

Aims: Deoxyribose-1-phosphate (dRP) is a proangiogenic paracrine stimulus released by cancer cells, platelets, and macrophages and acting on endothelial cells. The objective of this study was to clarify how dRP stimulates angiogenic responses in human endothelial cells. Results: Live cell imaging, electron paramagnetic resonance, pull-down of dRP-interacting proteins, followed by immunoblotting, gene silencing of different NADPH oxidases (NOXs), and their regulatory cosubunits by small interfering RNA (siRNA) transfection, and experiments with inhibitors of the sugar transporter glucose transporter 1 (GLUT1) were utilized to demonstrate that dRP acts intracellularly by directly activating the endothelial NOX2 complex, but not NOX4. Increased reactive oxygen species generation in response to NOX2 activity leads to redox-dependent activation of the transcription factor nuclear factor kappa B (NF-κB), which, in turn, induces vascular endothelial growth factor receptor 2 (VEGFR2) upregulation. Using endothelial tube formation assays, gene silencing by siRNA, and antibody-based receptor inhibition, we demonstrate that the activation of NF-κB and VEGFR2 is necessary for the angiogenic responses elicited by dRP. The upregulation of VEGFR2 and NOX2-dependent stimulation of angiogenesis by dRP were confirmed in excisional wound and Matrigel plug vascularization assays in vivo using NOX2-/- mice. Innovation: For the first time, we demonstrate that dRP acts intracellularly and stimulates superoxide anion generation by direct binding and activation of the NOX2 enzymatic complex. Conclusions: This study describes a novel molecular mechanism underlying the proangiogenic activity of dRP, which involves the sequential activation of NOX2 and NF-κB and upregulation of VEGFR2.

Published
2018

20. Respiratory Function in CAPD

Author

DiPaolo, N., Pula, G., Buoncristiani, U., Giomarelli, P. P., DeMia, M., Biagioli, B., Zei, E., Manescalchi, F., Rossi, P., Maher, John F., editor, and Winchester, James F., editor

Published
1986
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24. Vascular regenerative surgery : promised land for tissue engineers?

Author

Fortunato, T.M., De Bank, P.A., Pula, G., Fortunato, T.M., De Bank, P.A., and Pula, G.

Abstract

Cardiovascular cell therapy is a promising new eld for the development of treatments for cardiovascular diseases, which remain a major cause of mortality around the world. In this review, we highlight the options currently available for the development of speci c cell therapy approaches applied to regeneration of cardiac and vascular tissues. Different cell types have attracted a lot of attention and extensive investigations for the treatment of vascular diseases, including embryonic stem cells, mesenchymal stem cells, induced pluripotent stem cells, and endothelial progenitors. The combination of human cells and increasingly safe and physiologically compliant biomaterials is currently offering an unprecedented opportunity to develop effective cell therapy for either major blood vessels or the microvasculature. Ef cacy and safety of cell therapy are the challenges for the new generation of regenerative medicine scientists determined to develop new remedies for car- diovascular diseases. Here we present the state of the art in this biomedical eld and the options in terms of cell types and biomaterials currently available for cardiovascular cell therapy.

Published
2017

25. Prospective evaluation of ultrasound and biochemical-based multivariable models for the prediction of late pre-eclampsia

Author

FARINA, ANTONIO, RAPACCHIA, GIUSEPPINA, FRENI STERRANTINO, ANNA, Pula G, MORANO, DANILA, RIZZO, NICOLA, Farina A, Rapacchia G, Freni Sterrantino A, Pula G, Morano D, and Rizzo N.

Subjects
Adult, PAPP-A, Pregnancy Trimester, Third, Screening for pre-eclampsia, Logistic regression analysis, Prospective risk estimation, Pregnancy Trimester, First, Logistic Models, Pre-Eclampsia, Predictive Value of Tests, Pregnancy, Doppler, Humans, Pregnancy-Associated Plasma Protein-A, Chorionic Gonadotropin, beta Subunit, Human, Female, Prospective Studies, Biomarkers, Ultrasonography
Abstract

Objective: Prospective assignment at 11+0 to 13+6weeks of risk for late pre-eclampsia (PE) using eight logistic regression-based statistical models. Methods: Five hundred and fifty-four pregnancies. Uterine artery pulsatility index, parity, body mass index, mean arterial pressure, pregnancy-associated plasma protein-A, free β-human chorionic gonadotrophin and maternal age, were combined to obtain 'a posteriori risk of PE'. Results: We observed 39 cases (7%) of late PE. There were 12 cases of severe PE and 27 of mild PE. According to the models used, the estimated detection rate ranged from 38.5% to 84.6% with a false-positive rate of 10%. The median risk ratio (estimated median risk of PE in affected pregnancies divided by estimated risk of PE in unaffected pregnancies) ranged between 1.66 and 7.61. The most reproducible biochemical-based model was a mixed model encompassing maternal history and pregnancy-associated plasma protein-A. Conclusion: Some of the multivariable models drawn from the literature accurately predicted the late PE occurrence. The failure of some models may be because of the population in question not bearing several of the risk factors used to generate the models proposed. An effective combined screening at first trimester for late PE seems possible. © 2011 John Wiley & Sons, Ltd.

Published
2011

26. Extracellular fibrinogen-binding protein (Efb) from staphylococcus aureus inhibits the formation of platelet-leukocyte complexes

Author

Posner, MG, Upadhyay, A, Abubaker, AA, Fortunato, TM, Vara, D, Canobbio, I, Bagby, S, Pula, G, Posner, MG, Upadhyay, A, Abubaker, AA, Fortunato, TM, Vara, D, Canobbio, I, Bagby, S, and Pula, G

Abstract

© 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Extracellular fibrinogen-binding protein (Efb) from Staphylococcus aureus inhibits platelet activation, although its mechanism of action has not been established. In this study, we discovered that the N-terminal region of Efb (Efb-N) promotes platelet binding of fibrinogen and that Efb-N binding to platelets proceeds via two independent mechanisms: fibrinogen-mediated and fibrinogen-independent. By proteomic analysis of Efb-interacting proteins within platelets and confirmation by pulldown assays followed by immunoblotting, we identified P-selectin and multimerin-1 as novel Efb interaction partners. The interaction of both P-selectin and multimerin-1 with Efb is independent of fibrinogen.Wefocused on Efb interaction with P-selectin. Excess of P-selectin extracellular domain significantly impaired Efb binding by activated platelets, suggesting that P-selectin is the main receptor for Efb on the surface of activated platelets. Efb-N interaction with P-selectin inhibited P-selectin binding to its physiological ligand, P-selectin glycoprotein ligand-1 (PSGL-1), both in cell lysates and in cell-free assays. Because of the importance of P-selectin-PSGL-1 binding in the interaction between platelets and leukocytes, we tested human whole blood and found that Efb abolishes the formation of platelet- monocyte and platelet-granulocyte complexes. In summary, we present evidence that in addition to its documented antithrombotic activity, Efb can play an immunoregulatory role via inhibition of P-selectin-PSGL-1-dependent formation of platelet- leukocyte complexes.

Published
2016

27. The novel NOX inhibitor 2-acetylphenothiazine impairs collagen-dependent thrombus formation in a GPVI-dependent manner

Author

Vara, D, Campanella, M, and Pula, G

Subjects
Membrane Glycoproteins, Platelet Aggregation, NADPH Oxidases, Thrombosis, Platelet Glycoprotein GPIIb-IIIa Complex, Platelet Membrane Glycoproteins, In Vitro Techniques, Platelet Activation, Research Papers, Platelet Adhesiveness, Fibrinolytic Agents, Phenothiazines, NADPH Oxidase 2, NADPH Oxidase 1, Humans, Collagen, Signal Transduction
Abstract

NADPH oxidases (NOXs) contribute to platelet activation by a largely unknown mechanism. Here, we studied the effect of the novel NOX inhibitor 2-acetylphenothiazine (2-APT) on human platelet functional responses and intracellular signaling pathways.The generation of superoxide ions was assessed by single cell imaging on adhering platelets using dihydroethidium (DHE), while other reactive oxygen species (ROS) were detected with 5-(and-6)-carboxy-2',7'-dichlorodihydrofluorescein diacetate (CM-H(2)-DCFDA). Whole blood thrombus formation, washed platelet aggregation, integrin αIIbβ3 inside-out signalling, Syk phosphorylation and PKC activation were analysed to understand the functional consequences of NOX inhibition by 2-APT in platelets.Superoxide ion generation stimulated by platelet adhesion on collagen and fibrinogen was significantly inhibited by 2-APT in concentration-dependent manner (IC(50) = 306 nM and 227 nM, respectively), whereas cumulative ROS accumulation was not affected by this pharmacological agent. 2-APT also abolished collagen-dependent whole blood thrombus formation and washed platelet aggregation in response to collagen but not thrombin. The activation of integrin αIIbβ3 and PKC in response to the GPVI-specific agonist collagen-related peptide (CRP) was significantly reduced, whereas the same responses to thrombin were not significantly affected by 2-APT. Finally, Syk activation in response to collagen but not thrombin was inhibited by 2-APT.Taken together, our results suggest that 2-APT attenuates GPVI-specific signalling and is a novel inhibitor of collagen-induced platelet responses. Therefore, NOXs could represent a novel target for the discovery of anti-thrombotic drugs.

Published
2012

42. Neoral versus sandimmun: clinical impact and modification of immunosuppressive therapy in cardiac transplantation

Author

Maccherini, M, primary, Bernazzali, S, additional, Diciolla, F, additional, Giunti, G, additional, Bizzarri, F, additional, Lisi, G.F, additional, Davoli, G, additional, Biagioli, B, additional, Giomarelli, P.P, additional, Simeone, F, additional, Caciorgna, M, additional, Marchetti, L, additional, Pula, G, additional, Sani, G, additional, and Toscano, M, additional

Published
1998
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43. Vaginal delivery rate in post-term pregnancies with one versus more than one dinoprostone gel administrations: an observational study.

Author

FARINA, A., BERNABINI, D., RAPACCHIA, G., ZANELLO, M., CURTI, A., DE MUSSO, F., PULA, G., PEDRAZZI, A., and RIZZO, N.

Subjects
DELIVERY (Obstetrics), DINOPROSTONE, PREGNANCY, OBSTETRICS, CHILDBIRTH
Abstract

The article presents a study on the probability of a successful vaginal delivery in post-term low-risk women by using predictors based on the number of dinoprostone gel applications. Topics discussed include the difference in vaginal delivery rates for women who had one gel administration and those who received either two or three gel administrations and the lower rate of vaginal delivery among women who require more than one gel administration.

Published
2013

44. Sonographic evaluation of the lower uterine segment thickness in women with a single previous Cesarean section.

Author

SANLORENZO, O., FARINA, A., PULA, G., ZANELLO, M., PEDRAZZI, A., MARTINA, T., GABRIELLI, S., SIMONAZZI, G., and RIZZO, N.

Subjects
TRANSVAGINAL ultrasonography, CESAREAN section, PREGNANCY, VAGINAL birth after cesarean, DELIVERY (Obstetrics)
Abstract

The article discusses a study which evaluated the lower uterine segment (LUS) thickness through transvaginal sonography in pregnancies with a single previous Cesarean section. Topics discussed include the correlation of obtained LUS measurements with intraoperative observations and a predictive cut-off value to select the best candidates for a vaginal birth after Cesarean delivery (VBAC). It was concluded that a thickness less than 1.8 millimeters can be considered a valid cut-off value.

Published
2013

45. Novel isoforms of CaBP 3337 (Annexin V) from mammalian brain: structural and phosphorylation differences that suggest distinct biological roles

Author

Learmonth, M.P., primary, Howell, S.A., additional, Harris, A.C.M., additional, Amess, B., additional, Patel, Y., additional, Giambanco, I., additional, Bianchi, R., additional, Pula, G., additional, Ceccarelli, P., additional, Donato, R., additional, Green, B.N., additional, and Aitken, A., additional

Published
1992
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47. Agonist-induced internalization of metabotropic glutamate receptor 1A: structural determinants for protein kinase C- and G protein-coupled receptor kinase-mediated internalization.

Author

Mundell, S.J., Pula, G., Carswell, K., Roberts, P.J., and Kelly, E.

Subjects
*G proteins, *RADIOLIGAND assay, *NEUROTRANSMITTERS
Abstract

To investigate the role of the intracellular C-terminal tail of the rat metabotropic glutamate receptor 1a (mGlu1a) in receptor regulation, we constructed three C-terminal tail deletion mutants (Arg847stop, DM-I; Arg868stop, DM-II; Val893stop, DM-III). Quantification of glutamate-induced internalization provided by ELISA indicated that DM-III, like the wild-type mGlu1a, underwent rapid internalization whilst internalization of DM-I and DM-II was impaired. The selective inhibitor of protein kinase C (PKC), GF109203X, which significantly reduced glutamate-induced mGlu1a internalization, had no effect on the internalization of DM-I, DM-II, or DM-III. In addition activation by carbachol of endogenously expressed (M)1 (muscarinic acetylcholine receptors, which induces PKC- and Ca[SUP2+]-calmodulin-dependent protein kinase II-dependent internalization of mGlu1a, produced negligible internalization of the deletion mutants. Co-expression of a dominant negative mutant form of G protein-coupled receptor kinase 2 (DNM-GRK2; Lys220Arg) significantly attenuated glutamate-induced internalization of mGlu1a and DM-III, whilst internalization of DM-I and DM-II was not significantly affected. The glutamate- induced internalization of mGlu1a and DM-III, but not of DM-I or DM-II, was inhibited by expression of DNM-arrestin [arrestin-2(319-418)]. In addition glutamate-induced rapid translocation of arrestin-2-Green Fluorescent Protein (arr-2-GFP) from cytosol to membrane was only observed in cells expressing mGlu1a or DM-III. Functionally, in cells expressing mGlu1a, glutamate-stimulated inositol phosphate accumulation was increased in the presence of PKC inhibition, but so too was that in cells expressing DM-II and DM-III. Together these results indicate that different PKC mechanisms regulate the desensitization and internalization of mGlu1a. Furthermore, PKC regulation of mGlu1a internalization requires the distal C terminus of the receptor (Ser894-Leu1199), whilst in contrast... [ABSTRACT FROM AUTHOR]

Published
2003
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48. Agonist-induced internalization of the metabotropic glutamate receptor 1a is arrestin- and dynamin-dependent.

Author

Mundell, S.J., Matharu, A-L., Pula, G., Roberts, P.J., and Kelly, E.

Subjects
GLUTAMIC acid, HEMAGGLUTININ, PHYSIOLOGY
Abstract

At present, little is known regarding the mechanism of metabotropic glutamate receptor (mGluR) trafficking. To facilitate this characterization we inserted a haemagglutinin (HA) epitope tag in the extracellular N-terminal domain of the rat mGluR1a. In human embryonic kidney cells (HEK293), transiently transfected with HA-mGluR1a, the epitope-tagged receptor was primarily localized to the cell surface prior to agonist stimulation. Following stimulation with glutamate (10 µm; 30 min) the HA-mGluR1a underwent internalization to endosomes. Further quantification of receptor internalization was provided by ELISA experiments which showed rapid agonist-induced internalization of the HA-mGluR1a. To determine whether agonist-induced mGluR1a internalization is an arrestin- and dynamin-dependent process, cells were cotransfected with HA-mGluR1a and either of these dynamin-K44A or arrestin-2 (319–418). Expression of either dominant negative mutant constructs with receptor strongly inhibited glutamate-induced (10 µm; 30 min) HA-mGluR1a internalization. In addition, wild-type arrestin-2-green fluorescent protein (arrestin-2-GFP) or arrestin-3-GFP underwent agonist-induced translocation from cytosol to membrane in HEK293 cells coexpressing HA-mGluR1a. Taken together our observations demonstrate that agonist-induced internalization of mGluR1a is an arrestin- and dynamin-dependent process. [ABSTRACT FROM AUTHOR]

Published
2001
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