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3. Valsartan for prevention of recurrent atrial fibrillation

Author

GISSI AF Investigators, Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, Maggioni AP, Lucci D, Di Pasquale G, Tognoni G, Delise P, Bertocchi F, Maiocchi G, Geraci E, Correale E, Lombardi F, Mugelli A, Urso R, Scardi S, Fabbri G, Bartolomei B, Barbato G, Carbonieri E, Ciricugno S, Cosmi F, Pratola C, Rossi MG, Sciarra L, Zeni P, Ceseri M, Atzori A, Bambi F, Baviera M, Bianchini F, Fenicia E, Gianfriddo M, Lonardo G, Luise A, Nota R, Orlando ME, Petrolo R, Pierattini C, Pierota V, Ragno A, Serio C, Tafi A, Tellaroli E, Masson S, Vago T, Gramenzi S, Orso F, Suliman I, Nicolis E, Casola C, Dall'Osso D, Gorini M, Bianchini E, Cabiddu S, Cangioli I, Carnaghi A, Cipressa ML, Cipressa L, Galbiati L, Lorimer A, Priami P, Moccetti T, Vaghi F, Capello AF, Rossetti G, Viada E, Morena L, Delucchi M, Reynaud SG, Allemano P, Massobrio N, Gavazzi A, Taddei F, Mor DA, Bortolini F, Lorini M, Inama G, Durin O, Pirelli S, Spotti A, Procopio R, Cuzzucrea D, Gentile G, Margonato A, Bassanelli G, Tavazzi L, Buzzi MP, Rordorf R, Gualco A, Opasich C, Gronda E, Genovese L, Mattioli R, Donatelli F, Uriarte JA, Rauhe W, Bertagnolli C, Canestrini S, Stefenelli C, Cioffi G, Giovanelli C, Rigatelli G, Boni S, Pasini A, Sitta N, Sacchetta A, Borgese L, Sciascia R, Targa L, Raviele A, Madalosso M, Bertaglia E, Zoppo FC, Capanna M, Fiorencis R, Baracca E, Rossi R, Rossi I, Trappolin R, Morgera T, Barducci E, Baldin MG, Gobbo G, Zardo F, Hrovatin E, Mos L, Vriz O, Sinagra G, Aleksova A, Mazzone C, Fresco C, Rubartelli P, Moroni LA, Camerieri A, Piana M, Mureddu R, Bertoli D, Petacchi R, Pancaldi LG, Gabrieli L, Urbinati S, Pedone C, Di Niro M, Brunelli A, Bosi S, Censi S, Moruzzi P, Pastori P, Modena MG, Malavasi V, Mezzetti M, Melandri F, Zuppiroli A, Fazi A, Testa R, Venturini E, Mazzinghi F, Cosmi D, Santoro GM, Minneci C, Galli M, Paperini L, Bovenzi FM, Cortigiani L, Cocchieri M, Severini D, Arcuri GM, Bagliani G, Bernardinangeli M, Proietti G, Bocconcelli P, Pierantozzi A, Monti F, Giamundo L, Tancredi P, Rossini E, Bianchi C, Bettiol F, Giovannini E, Fera MS, Santini M, Bianconi L, Boccanelli A, Morosetti P, Volpe M, Facciolo C, Vacri A, Romanazzi F, Napoletano C, Piccioni LL, Candelmo F, De Marco G, Arnese MR, Vetrano A, Prinzi D, De Rosa P, Capuano V, Torre S, D'Onofrio A, Ammendola E, Battista R, De Fusco A, Molero U, Iervoglini A, Stefanelli S, Fattore L, Bosco B, Liguori A, Padula G, De Luca I, Sorino M, Colonna P, D'Agostino C, Pierfelice O, Pettinati G, Muscella A, De Lorenzi E, Falco M, Giannattasio C, Baldi N, Clemente MA, D'Alessandro B, Truncellito L, Arabia F, Ciconte VA, Perticone F, Ruberto C, Buffon A, Tomaselli C, De Rosa F, Mazza S, Zampaglione G, Pirozzi AM, Butera A, Levato M, Musacchio D, Polimeni RM, Lacquaniti V, Pulitanò G, Ruggeri A, Provenzano A, Cuccurullo O, Musolino M, Marrari A, Anastasio L, Schiavello M, Comito MG, Gulizia MM, Francese GM, Vasquez L, Coppolino C, Casale A, D'Urso G, Oliva G, Giordano U, Andolina S, Sanfilippo N, Ingrillì F, Accardo S, Grasso S, Buffa L, Serra E., CHIARIELLO, MASSIMO, PERRONE FILARDI, PASQUALE, Delise, P., Bertocchi, F., Maiocchi, G., Geraci, E., Correale, E., Lombardi, F., Mugelli, A., Urso, R., Scardi, S., Fabbri, G., Bartolomei, B., Barbato, G., Carbonieri, E., Ciricugno, S., Cosmi, F., Pratola, C., Rossi, M. G., Sciarra, L., Zeni, P., Ceseri, M., Atzori, A., Bambi, F., Baviera, M., Bianchini, F., Fenicia, E., Gianfriddo, M., Lonardo, G., Luise, A., Nota, R., Orlando, M. E., Petrolo, R., Pierattini, C., Pierota, V., Ragno, A., Serio, C., Tafi, A., Tellaroli, E., Masson, S., Vago, T., Gramenzi, S., Orso, F., Suliman, I., Nicolis, E., Casola, C., Dall'Osso, D., Gorini, M., Bianchini, E., Cabiddu, S., Cangioli, I., Carnaghi, A., Cipressa, M. L., Cipressa, L., Galbiati, L., Lorimer, A., Priami, P., Moccetti, T., Vaghi, F., Capello, A. F., Rossetti, G., Viada, E., Morena, L., Delucchi, M., Reynaud, S. G., Allemano, P., Massobrio, N., Gavazzi, A., Taddei, F., Mor, D. A., Bortolini, F., Lorini, M., Inama, G., Durin, O., Pirelli, S., Spotti, A., Procopio, R., Cuzzucrea, D., Gentile, G., Margonato, A., Bassanelli, G., Tavazzi, L., Buzzi, M. P., Rordorf, R., Gualco, A., Opasich, C., Gronda, E., Genovese, L., Mattioli, R., Donatelli, F., Uriarte, J. A., Rauhe, W., Bertagnolli, C., Canestrini, S., Stefenelli, C., Cioffi, G., Giovanelli, C., Rigatelli, G., Boni, S., Pasini, A., Sitta, N., Sacchetta, A., Borgese, L., Sciascia, R., Targa, L., Raviele, A., Madalosso, M., Bertaglia, E., Zoppo, F. C., Capanna, M., Fiorencis, R., Baracca, E., Rossi, R., Rossi, I., Trappolin, R., Morgera, T., Barducci, E., Baldin, M. G., Gobbo, G., Zardo, F., Hrovatin, E., Mos, L., Vriz, O., Sinagra, G., Aleksova, A., Mazzone, C., Fresco, C., Rubartelli, P., Moroni, L. A., Camerieri, A., Piana, M., Mureddu, R., Bertoli, D., Petacchi, R., Pancaldi, L. G., Gabrieli, L., Urbinati, S., Pedone, C., Di Niro, M., Brunelli, A., Bosi, S., Censi, S., Moruzzi, P., Pastori, P., Modena, M. G., Malavasi, V., Mezzetti, M., Melandri, F., Zuppiroli, A., Fazi, A., Testa, R., Venturini, E., Mazzinghi, F., Cosmi, D., Santoro, G. M., Minneci, C., Galli, M., Paperini, L., Bovenzi, F. M., Cortigiani, L., Cocchieri, M., Severini, D., Arcuri, G. M., Bagliani, G., Bernardinangeli, M., Proietti, G., Bocconcelli, P., Pierantozzi, A., Monti, F., Giamundo, L., Tancredi, P., Rossini, E., Bianchi, C., Bettiol, F., Giovannini, E., Fera, M. S., Santini, M., Bianconi, L., Boccanelli, A., Morosetti, P., Volpe, M., Facciolo, C., Vacri, A., Romanazzi, F., Napoletano, C., Piccioni, L. L., Candelmo, F., De Marco, G., Arnese, M. R., Vetrano, A., Prinzi, D., De Rosa, P., Capuano, V., Torre, S., D'Onofrio, A., Ammendola, E., Chiariello, M., Filardi, Pp., Battista, R., De Fusco, A., Molero, U., Iervoglini, A., Stefanelli, S., Fattore, L., Bosco, B., Liguori, A., Padula, G., De Luca, I., Sorino, M., Colonna, P., D'Agostino, C., Pierfelice, O., Pettinati, G., Muscella, A., De Lorenzi, E., Falco, M., Giannattasio, C., Baldi, N., Clemente, M. A., D'Alessandro, B., Truncellito, L., Arabia, F., Ciconte, V. A., Perticone, F., Ruberto, C., Buffon, A., Tomaselli, C., De Rosa, F., Mazza, S., Zampaglione, G., Pirozzi, A. M., Butera, A., Levato, M., Musacchio, D., Polimeni, R. M., Lacquaniti, V., Pulitano, G., Ruggeri, A., Provenzano, A., Cuccurullo, O., Musolino, M., Marrari, A., Anastasio, L., Schiavello, M., Comito, M. G., Gulizia, M. M., Francese, G. M., Vasquez, L., Coppolino, C., Casale, A., D'Urso, G., Oliva, G., Giordano, U., Andolina, S., Sanfilippo, N., Ingrilli, F., Accardo, S., Grasso, S., Buffa, L., Serra, E., Disertori, Marcello, Latini, Roberto, Barlera, Simona, Franzosi, Maria Grazia, Staszewsky, Lidia, Maggioni, Aldo Pietro, Lucci, Donata, Di Pasquale, Giuseppe, Tognoni, Gianni, GISSI AF, Investigator, Disertori, M, Latini, R, Barlera, S, Franzosi, Mg, Staszewsky, L, Maggioni, Ap, Lucci, D, Di Pasquale, G, Tognoni, G, Delise, P, Bertocchi, F, Maiocchi, G, Geraci, E, Correale, E, Lombardi, F, Mugelli, A, Urso, R, Scardi, S, Fabbri, G, Bartolomei, B, Barbato, G, Carbonieri, E, Ciricugno, S, Cosmi, F, Pratola, C, Rossi, Mg, Sciarra, L, Zeni, P, Ceseri, M, Atzori, A, Bambi, F, Baviera, M, Bianchini, F, Fenicia, E, Gianfriddo, M, Lonardo, G, Luise, A, Nota, R, Orlando, Me, Petrolo, R, Pierattini, C, Pierota, V, Ragno, A, Serio, C, Tafi, A, Tellaroli, E, Masson, S, Vago, T, Gramenzi, S, Orso, F, Suliman, I, Nicolis, E, Casola, C, Dall'Osso, D, Gorini, M, Bianchini, E, Cabiddu, S, Cangioli, I, Carnaghi, A, Cipressa, Ml, Cipressa, L, Galbiati, L, Lorimer, A, Priami, P, Moccetti, T, Vaghi, F, Capello, Af, Rossetti, G, Viada, E, Morena, L, Delucchi, M, Reynaud, Sg, Allemano, P, Massobrio, N, Gavazzi, A, Taddei, F, Mor, Da, Bortolini, F, Lorini, M, Inama, G, Durin, O, Pirelli, S, Spotti, A, Procopio, R, Cuzzucrea, D, Gentile, G, Margonato, A, Bassanelli, G, Tavazzi, L, Buzzi, Mp, Rordorf, R, Gualco, A, Opasich, C, Gronda, E, Genovese, L, Mattioli, R, Donatelli, F, Uriarte, Ja, Rauhe, W, Bertagnolli, C, Canestrini, S, Stefenelli, C, Cioffi, G, Giovanelli, C, Rigatelli, G, Boni, S, Pasini, A, Sitta, N, Sacchetta, A, Borgese, L, Sciascia, R, Targa, L, Raviele, A, Madalosso, M, Bertaglia, E, Zoppo, Fc, Capanna, M, Fiorencis, R, Baracca, E, Rossi, R, Rossi, I, Trappolin, R, Morgera, T, Barducci, E, Baldin, Mg, Gobbo, G, Zardo, F, Hrovatin, E, Mos, L, Vriz, O, Sinagra, G, Aleksova, A, Mazzone, C, Fresco, C, Rubartelli, P, Moroni, La, Camerieri, A, Piana, M, Mureddu, R, Bertoli, D, Petacchi, R, Pancaldi, Lg, Gabrieli, L, Urbinati, S, Pedone, C, Di Niro, M, Brunelli, A, Bosi, S, Censi, S, Moruzzi, P, Pastori, P, Modena, Mg, Malavasi, V, Mezzetti, M, Melandri, F, Zuppiroli, A, Fazi, A, Testa, R, Venturini, E, Mazzinghi, F, Cosmi, D, Santoro, Gm, Minneci, C, Galli, M, Paperini, L, Bovenzi, Fm, Cortigiani, L, Cocchieri, M, Severini, D, Arcuri, Gm, Bagliani, G, Bernardinangeli, M, Proietti, G, Bocconcelli, P, Pierantozzi, A, Monti, F, Giamundo, L, Tancredi, P, Rossini, E, Bianchi, C, Bettiol, F, Giovannini, E, Fera, M, Santini, M, Bianconi, L, Boccanelli, A, Morosetti, P, Volpe, M, Facciolo, C, Vacri, A, Romanazzi, F, Napoletano, C, Piccioni, Ll, Candelmo, F, De Marco, G, Arnese, Mr, Vetrano, A, Prinzi, D, De Rosa, P, Capuano, V, Torre, S, D'Onofrio, A, Ammendola, E, Chiariello, Massimo, PERRONE FILARDI, Pasquale, Battista, R, De Fusco, A, Molero, U, Iervoglini, A, Stefanelli, S, Fattore, L, Bosco, B, Liguori, A, Padula, G, De Luca, I, Sorino, M, Colonna, P, D'Agostino, C, Pierfelice, O, Pettinati, G, Muscella, A, De Lorenzi, E, Falco, M, Giannattasio, C, Baldi, N, Clemente, Ma, D'Alessandro, B, Truncellito, L, Arabia, F, Ciconte, Va, Perticone, F, Ruberto, C, Buffon, A, Tomaselli, C, De Rosa, F, Mazza, S, Zampaglione, G, Pirozzi, Am, Butera, A, Levato, M, Musacchio, D, Polimeni, Rm, Lacquaniti, V, Pulitanò, G, Ruggeri, A, Provenzano, A, Cuccurullo, O, Musolino, M, Marrari, A, Anastasio, L, Schiavello, M, Comito, Mg, Gulizia, Mm, Francese, Gm, Vasquez, L, Coppolino, C, Casale, A, D'Urso, G, Oliva, G, Giordano, U, Andolina, S, Sanfilippo, N, Ingrillì, F, Accardo, S, Grasso, S, and Buffa, L

Subjects
Male, medicine.medical_specialty, medicine.medical_treatment, Tetrazoles, Cardiomegaly, Comorbidity, Placebo, Cardioversion, Double-Blind Method, Recurrence, Multicenter trial, Internal medicine, Angiotensin II Type 1 Receptor Blocker, Cardiovascular Disease, Atrial Fibrillation, medicine, Left atrial enlargement, Diabetes Mellitus, Humans, Sinus rhythm, cardiovascular diseases, Prospective Studies, Tetrazole, Proportional Hazards Models, Aged, business.industry, Medicine (all), Hazard ratio, Atrial fibrillation, Diabetes Mellitu, Valine, General Medicine, Middle Aged, medicine.disease, valsartan, atrial fibrillation, Prospective Studie, Valsartan, Cardiovascular Diseases, cardiovascular system, Cardiology, Proportional Hazards Model, Female, business, Angiotensin II Type 1 Receptor Blockers, medicine.drug, Human
Abstract

BACKGROUND: Atrial fibrillation is the most common cardiac arrhythmia, and no current therapy is ideal for control of this condition. Experimental studies suggest that angiotensin II-receptor blockers (ARBs) can influence atrial remodeling, and some clinical studies suggest that they may prevent atrial fibrillation. METHODS: We conducted a large, randomized, prospective, placebo-controlled, multicenter trial to test whether the ARB valsartan could reduce the recurrence of atrial fibrillation. We enrolled patients who were in sinus rhythm but had had either two or more documented episodes of atrial fibrillation in the previous 6 months or successful cardioversion for atrial fibrillation in the previous 2 weeks. To be eligible, patients also had to have underlying cardiovascular disease, diabetes, or left atrial enlargement. Patients were randomly assigned to receive valsartan or placebo. The two primary end points were the time to a first recurrence of atrial fibrillation and the proportion of patients who had more than one recurrence of atrial fibrillation over the course of 1 year. RESULTS: A total of 1442 patients were enrolled in the study. Atrial fibrillation recurred in 371 of the 722 patients (51.4%) in the valsartan group, as compared with 375 of 720 (52.1%) in the placebo group (adjusted hazard ratio, 0.97; 96% confidence interval [CI], 0.83 to 1.14; P = 0.73). More than one episode of atrial fibrillation occurred in 194 of 722 patients (26.9%) in the valsartan group and in 201 of 720 (27.9%) in the placebo group (adjusted odds ratio, 0.89; 99% CI, 0.64 to 1.23; P = 0.34). The results were similar in all predefined subgroups of patients, including those who were not receiving angiotensin-converting-enzyme inhibitors. CONCLUSIONS: Treatment with valsartan was not associated with a reduction in the incidence of recurrent atrial fibrillation. (ClinicalTrials.gov number, NCT00376272.) Copyright © 2009 Massachusetts Medical Society.

Published
2009

4. Valsartan for prevention of recurrent atrial fibrillation (New England Journal of Medicine (2009) 360, (1606-1617))

Author

Delise, P., Bertocchi, F., Maiocchi, G., Geraci, E., Correale, E., Lombardi, F., Mugelli, A., Urso, R., Scardi, S., Fabbri, G., Bartolomei, B., Barbato, G., Carbonieri, E., Ciricugno, S., Cosmi, F., Pratola, C., Rossi, M. G., Sciarra, L., Zeni, P., Ceseri, M., Atzori, A., Bambi, F., Baviera, M., Bianchini, F., Fenicia, E., Gianfriddo, M., Lonardo, G., Luise, A., Nota, R., Orlando, M. E., Petrolo, R., Pierattini, C., Pierota, V., Ragno, A., Serio, C., Tafi, A., Tellaroli, E., Masson, S., Vago, T., Gramenzi, S., Orso, F., Suliman, I., Nicolis, E., Casola, C., Dall Osso, D., Gorini, M., Bianchini, E., Cabiddu, S., Cangioli, I., Carnaghi, A., Cipressa, M. L., Cipressa, L., Galbiati, L., Lorimer, A., Priami, P., Moccetti, T., Vaghi, F., Capello, A. F., Rossetti, G., Viada, E., Morena, L., Delucchi, M., Reynaud, S. G., Allemano, P., Massobrio, N., Gavazzi, A., Taddei, F., Mor, D. A., Bortolini, F., Lorini, M., Inama, G., Durin, O., Pirelli, S., Spotti, A., Procopio, R., Cuzzucrea, D., Gentile, G., Margonato, A., Bassanelli, G., Tavazzi, L., Buzzi, M. P., Rordorf, R., Gualco, A., Opasich, C., Gronda, E., Genovese, L., Mattioli, R., Donatelli, F., Uriarte, J. A., Rauhe, W., Bertagnolli, C., Canestrini, S., Stefenelli, C., Cioffi, G., Giovanelli, C., Rigatelli, G., Boni, S., Pasini, A., Sitta, N., Sacchetta, A., Borgese, L., Sciascia, R., Targa, L., Raviele, A., Madalosso, M., Bertaglia, E., Franco Zoppo, Capanna, M., Fiorencis, R., Baracca, E., Rossi, R., Rossi, I., Trappolin, R., Morgera, T., Barducci, E., Baldin, M. G., Gobbo, G., Zardo, F., Hrovatin, E., Mos, L., Vriz, O., Sinagra, G., Aleksova, A., Mazzone, C., Fresco, C., Rubartelli, P., Moroni, L. A., Camerieri, A., Piana, M., Mureddu, R., Bertoli, D., Petacchi, R., Pancaldi, L. G., Gabrieli, L., Urbinati, S., Pedone, C., Di Niro, M., Brunelli, A., Bosi, S., Censi, S., Moruzzi, P., Pastori, P., Modena, M. G., Malavasi, V., Mezzetti, M., Melandri, F., Zuppiroli, A., Fazi, A., Testa, R., Venturini, E., Mazzinghi, F., Cosmi, D., Santoro, G. M., Minneci, C., Galli, M., Paperini, L., Bovenzi, F. M., Cortigiani, L., Cocchieri, M., Severini, D., Arcuri, G. M., Bagliani, G., Bernardinangeli, M., Proietti, G., Bocconcelli, P., Pierantozzi, A., Monti, F., Giamundo, L., Tancredi, P., Rossini, E., Bianchi, C., Bettiol, F., Giovannini, E., Fera, M. S., Santini, M., Bianconi, L., Boccanelli, A., Morosetti, P., Volpe, M., Facciolo, C., Vacri, A., Romanazzi, F., Napoletano, C., Piccioni, L. L., Candelmo, F., Marco, G., Arnese, M. R., Vetrano, A., Prinzi, D., Rosa, P., Capuano, V., Torre, S., D Onofrio, A., Ammendola, E., Chiariello, M., Filardi, Pp, Battista, R., Fusco, A., Molero, U., Iervoglini, A., Stefanelli, S., Fattore, L., Bosco, B., Liguori, A., Padula, G., Luca, I., Sorino, M., Colonna, P., D Agostino, C., Pierfelice, O., Pettinati, G., Muscella, A., Lorenzi, E., Falco, M., Giannattasio, C., Baldi, N., Clemente, M. A., D Alessandro, B., Truncellito, L., Arabia, F., Ciconte, V. A., Perticone, F., Ruberto, C., Buffon, A., Tomaselli, C., Rosa, F., Mazza, S., Zampaglione, G., Pirozzi, A. M., Butera, A., Levato, M., Musacchio, D., Polimeni, R. M., Lacquaniti, V., Pulitano, G., Ruggeri, A., Provenzano, A., Cuccurullo, O., Musolino, M., Marrari, A., Anastasio, L., Schiavello, M., Comito, M. G., Gulizia, M. M., Francese, G. M., Vasquez, L., Coppolino, C., Casale, A., D Urso, G., Oliva, G., Giordano, U., Andolina, S., Sanfilippo, N., Ingrilli, F., Accardo, S., Grasso, S., Buffa, L., Serra, E., Disertori, M., Latini, R., Barlera, S., Franzosi, M. G., Staszewsky, L., Maggioni, A. P., Lucci, D., Di Pasquale, G., Tognoni, G., Delise, P., Bertocchi, F., Maiocchi, G., Geraci, E., Correale, E., Lombardi, F., Mugelli, A., Urso, R., Scardi, S., Fabbri, G., Bartolomei, B., Barbato, G., Carbonieri, E., Ciricugno, S., Cosmi, F., Pratola, C., Rossi, M. G., Sciarra, L., Zeni, P., Ceseri, M., Atzori, A., Bambi, F., Baviera, M., Bianchini, F., Fenicia, E., Gianfriddo, M., Lonardo, G., Luise, A., Nota, R., Orlando, M. E., Petrolo, R., Pierattini, C., Pierota, V., Ragno, A., Serio, C., Tafi, A., Tellaroli, E., Masson, S., Vago, T., Gramenzi, S., Orso, F., Suliman, I., Nicolis, E., Casola, C., Dall'Osso, D., Gorini, M., Bianchini, E., Cabiddu, S., Cangioli, I., Carnaghi, A., Cipressa, M. L., Cipressa, L., Galbiati, L., Lorimer, A., Priami, P., Moccetti, T., Vaghi, F., Capello, A. F., Rossetti, G., Viada, E., Morena, L., Delucchi, M., Reynaud, S. G., Allemano, P., Massobrio, N., Gavazzi, A., Taddei, F., Mor, D. A., Bortolini, F., Lorini, M., Inama, G., Durin, O., Pirelli, S., Spotti, A., Procopio, R., Cuzzucrea, D., Gentile, G., Margonato, A., Bassanelli, G., Tavazzi, L., Buzzi, M. P., Rordorf, R., Gualco, A., Opasich, C., Gronda, E., Genovese, L., Mattioli, R., Donatelli, F., Uriarte, J. A., Rauhe, W., Bertagnolli, C., Canestrini, S., Stefenelli, C., Cioffi, G., Giovanelli, C., Rigatelli, G., Boni, S., Pasini, A., Sitta, N., Sacchetta, A., Borgese, L., Sciascia, R., Targa, L., Raviele, A., Madalosso, M., Bertaglia, E., Zoppo, F. C., Capanna, M., Fiorencis, R., Baracca, E., Rossi, R., Rossi, I., Trappolin, R., Morgera, T., Barducci, E., Baldin, M. G., Gobbo, G., Zardo, F., Hrovatin, E., Mos, L., Vriz, O., Sinagra, G., Aleksova, A., Mazzone, C., Fresco, C., Rubartelli, P., Moroni, L. A., Camerieri, A., Piana, M., Mureddu, R., Bertoli, D., Petacchi, R., Pancaldi, L. G., Gabrieli, L., Urbinati, S., Pedone, C., Di Niro, M., Brunelli, A., Bosi, S., Censi, S., Moruzzi, P., Pastori, P., Modena, M. G., Malavasi, V., Mezzetti, M., Melandri, F., Zuppiroli, A., Fazi, A., Testa, R., Venturini, E., Mazzinghi, F., Cosmi, D., Santoro, G. M., Minneci, C., Galli, M., Paperini, L., Bovenzi, F. M., Cortigiani, L., Cocchieri, M., Severini, D., Arcuri, G. M., Bagliani, G., Bernardinangeli, M., Proietti, G., Bocconcelli, P., Pierantozzi, A., Monti, F., Giamundo, L., Tancredi, P., Rossini, E., Bianchi, C., Bettiol, F., Giovannini, E., Fera, M. S., Santini, M., Bianconi, L., Boccanelli, A., Morosetti, P., Volpe, M., Facciolo, C., Vacri, A., Romanazzi, F., Napoletano, C., Piccioni, L. L., Candelmo, F., De Marco, G., Arnese, M. R., Vetrano, A., Prinzi, D., De Rosa, P., Capuano, V., Torre, S., D'Onofrio, A., Ammendola, E., Chiariello, M., Filardi, Pp., Battista, R., De Fusco, A., Molero, U., Iervoglini, A., Stefanelli, S., Fattore, L., Bosco, B., Liguori, A., Padula, G., De Luca, I., Sorino, M., Colonna, P., D'Agostino, C., Pierfelice, O., Pettinati, G., Muscella, A., De Lorenzi, E., Falco, M., Giannattasio, C., Baldi, N., Clemente, M. A., D'Alessandro, B., Truncellito, L., Arabia, F., Ciconte, V. A., Perticone, F., Ruberto, C., Buffon, A., Tomaselli, C., De Rosa, F., Mazza, S., Zampaglione, G., Pirozzi, A. M., Butera, A., Levato, M., Musacchio, D., Polimeni, R. M., Lacquaniti, V., Pulitano, G., Ruggeri, A., Provenzano, A., Cuccurullo, O., Musolino, M., Marrari, A., Anastasio, L., Schiavello, M., Comito, M. G., Gulizia, M. M., Francese, G. M., Vasquez, L., Coppolino, C., Casale, A., D'Urso, G., Oliva, G., Giordano, U., Andolina, S., Sanfilippo, N., Ingrilli, F., Accardo, S., Grasso, S., Buffa, L., Serra, E., Disertori, Marcello, Latini, Roberto, Barlera, Simona, Franzosi, Maria Grazia, Staszewsky, Lidia, Maggioni, Aldo Pietro, Lucci, Donata, Di Pasquale, Giuseppe, and Tognoni, Gianni

Subjects
Medicine (all)
Published
2009

11. Discovery and optimization of 4-pyrazolyl-2-aminopyrimidine derivatives as potent spleen tyrosine kinase (SYK) inhibitors.

Author

Cervi G, D'Alessio R, Bindi S, Buffa L, Burocchi A, Canevari G, Modugno M, Motto I, Saturno G, and Orsini P

Subjects
Humans, Syk Kinase metabolism, Intracellular Signaling Peptides and Proteins metabolism, Signal Transduction, Phosphorylation, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases, Hematologic Neoplasms drug therapy, Pyrimidines
Abstract

Spleen tyrosine kinase (Syk) is a key signal transduction mediator of the B cell receptor (BCR) signaling pathway. Abnormal BCR signaling plays a key role in initiation and development of B-cell-derived hematological malignancies, therefore, Syk represents a potential target for inhibiting the BCR signaling resulting in a therapeutic effect in these cancers. Herein, we describe a novel series of SYK inhibitors with 4-(3'-pyrazolyl)-2-amino-pyrimidine scaffold. Extensive study of structure-activity relationships led to the identification of 1 (NMS-0963), a highly potent Syk inhibitor (IC 50  = 3 nM) endowed with high selectivity within a panel of tested kinases and high antiproliferative activity in SYK-dependent BaF3-TEL/SYK cells and in other BCR-dependent hematological tumor cell lines. Additionally, 1 effectively inhibited Syk phosphorylation and downstream signaling mediators of the BCR in treated cells. In in vivo pharmacokinetics studies, 1, displayed good pharmacokinetics properties, with linear exposure with dose and excellent oral bioavailability. These findings suggest that 1 is a promising new Syk inhibitor for treating BCR-dependent hematological cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Published
2024
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12. Correction to Discovery of Entrectinib: A New 3-Aminoindazole as a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

Author

Menichincheri M, Ardini E, Magnaghi P, Avanzi N, Banfi P, Bossi R, Buffa L, Canevari G, Ceriani L, Colombo M, Corti L, Donati D, Fasolini M, Felder E, Fiorelli C, Fiorentini F, Galvani A, Isacchi A, Borgia AL, Marchionni C, Nesi M, Orrenius C, Panzeri A, Pesenti E, Rusconi L, Saccardo MB, Vanotti E, Perrone E, and Orsini P

Published
2019
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13. Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

Author

Menichincheri M, Ardini E, Magnaghi P, Avanzi N, Banfi P, Bossi R, Buffa L, Canevari G, Ceriani L, Colombo M, Corti L, Donati D, Fasolini M, Felder E, Fiorelli C, Fiorentini F, Galvani A, Isacchi A, Borgia AL, Marchionni C, Nesi M, Orrenius C, Panzeri A, Pesenti E, Rusconi L, Saccardo MB, Vanotti E, Perrone E, and Orsini P

Subjects
Administration, Oral, Anaplastic Lymphoma Kinase, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Benzamides administration & dosage, Benzamides chemistry, Blood-Brain Barrier drug effects, Blotting, Western, Cell Membrane Permeability drug effects, Cell Proliferation drug effects, Crystallization, Crystallography, X-Ray, Dogs, Humans, Indazoles administration & dosage, Indazoles chemistry, Lung Neoplasms metabolism, Lung Neoplasms pathology, Mice, Mice, Nude, Mice, SCID, Microsomes, Liver drug effects, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins antagonists & inhibitors, Rats, Rats, Wistar, Receptor, trkA antagonists & inhibitors, Receptor, trkB antagonists & inhibitors, Receptor, trkC antagonists & inhibitors, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Benzamides pharmacology, Drug Discovery, Indazoles pharmacology, Lung Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Receptor Protein-Tyrosine Kinases antagonists & inhibitors
Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.

Published
2016
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14. Molecular mechanism of WW-domain binding protein-2 coactivation function in estrogen receptor signaling.

Author

Buffa L, Saeed AM, and Nawaz Z

Subjects
Adaptor Proteins, Signal Transducing genetics, Base Sequence, Blotting, Western, Chromatin Assembly and Disassembly, Chromatin Immunoprecipitation, DNA Primers, Humans, MCF-7 Cells, Promoter Regions, Genetic, RNA, Small Interfering, Receptors, Estrogen genetics, Trans-Activators, Adaptor Proteins, Signal Transducing metabolism, Receptors, Estrogen metabolism, Signal Transduction
Abstract

The link between breast cancer and estrogen receptor (ER) is well established. The ER is a hormone-inducible transcription factor that, upon binding to its ligand, regulates the expression of a variety of genes mainly involved in cell proliferation and differentiation. Coactivators are proteins recruited by the hormone-activated receptor, which allow or enhance the ER transactivation functions by acting as chromatin remodeling enzymes or adaptors between ER and the transcriptional machinery. Our laboratory has previously identified the WW-domain binding protein-2 (WBP-2) as a bona fide coactivator of ER. However, the molecular mechanism underlying WBP-2 coactivation function was not clear yet. In this study, we explore and identify the mechanism by which WBP-2 acts as coactivator of ER. Our data show that WBP-2 is involved in the regulation of ER target genes, and its expression is required for the proper expression of some ER target genes. To clarify the molecular mechanism by which WBP-2 regulates ER function, we performed chromatin immunoprecipitation assays. We demonstrate here that WBP-2 binds to the ER target gene promoter pS2 promoter and is required for the binding of the phosphorylated form of RNA polymerase II (associated with active transcription/elongation) to the same promoter. Furthermore, we also show that WBP-2 is essential for the recruitment of the histone acetyl transferase p300, an important chromatin modifier enzyme and for histone acetylation at the same target region. Collectively, our data indicate that WBP-2 enhances ER transactivation function at certain genes by facilitating the recruitment and/or the stabilization of a histone modifier enzyme that favors a relaxed chromatin structure, permissive of transcription., (Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.)

Published
2013
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15. Biophysical basis of the binding of WWOX tumor suppressor to WBP1 and WBP2 adaptors.

Author

McDonald CB, Buffa L, Bar-Mag T, Salah Z, Bhat V, Mikles DC, Deegan BJ, Seldeen KL, Malhotra A, Sudol M, Aqeilan RI, Nawaz Z, and Farooq A

Subjects
Adaptor Proteins, Signal Transducing metabolism, Amino Acid Motifs, Amino Acid Sequence, Binding Sites, Biophysics, Humans, Ligands, Molecular Sequence Data, Protein Folding, Protein Structure, Tertiary, Transfection, WW Domain-Containing Oxidoreductase, Adaptor Proteins, Signal Transducing chemistry, Oxidoreductases chemistry, Oxidoreductases metabolism, Tumor Suppressor Proteins chemistry, Tumor Suppressor Proteins metabolism
Abstract

The WW-containing oxidoreductase (WWOX) tumor suppressor participates in a diverse array of cellular activities by virtue of its ability to recognize WW-binding protein 1 (WBP1) and WW-binding protein 2 (WBP2) signaling adaptors among a wide variety of other ligands. Herein, using a multitude of biophysical techniques, we provide evidence that while the WW1 domain of WWOX binds to PPXY motifs within WBP1 and WBP2 in a physiologically relevant manner, the WW2 domain exhibits no affinity toward any of these PPXY motifs. Importantly, our data suggest that while R25/W44 residues located within the binding pocket of a triple-stranded β-fold of WW1 domain are critical for the recognition of PPXY ligands, they are replaced by the chemically distinct E66/Y85 duo at structurally equivalent positions within the WW2 domain, thereby accounting for its failure to bind PPXY ligands. Predictably, not only does the introduction of E66R/Y85W double substitution within the WW2 domain result in gain of function but the resulting engineered domain, hereinafter referred to as WW2_RW, also appears to be a much stronger binding partner of WBP1 and WBP2 than the wild-type WW1 domain. We also show that while the WW1 domain is structurally disordered and folds upon ligand binding, the WW2 domain not only adopts a fully structured conformation but also aids stabilization and ligand binding to WW1 domain. This salient observation implies that the WW2 domain likely serves as a chaperone to augment the physiological function of WW1 domain within WWOX. Collectively, our study lays the groundwork for understanding the molecular basis of a key protein-protein interaction pertinent to human health and disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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16. Biophysical analysis of binding of WW domains of the YAP2 transcriptional regulator to PPXY motifs within WBP1 and WBP2 adaptors.

Author

McDonald CB, McIntosh SK, Mikles DC, Bhat V, Deegan BJ, Seldeen KL, Saeed AM, Buffa L, Sudol M, Nawaz Z, and Farooq A

Subjects
Adaptor Proteins, Signal Transducing metabolism, Amino Acid Motifs, Calorimetry, Crystallography, X-Ray, Humans, Intracellular Signaling Peptides and Proteins metabolism, Phosphoproteins metabolism, Protein Binding, Protein Structure, Tertiary, Thermodynamics, Trans-Activators, Transcription Factors, YAP-Signaling Proteins, Adaptor Proteins, Signal Transducing chemistry, Intracellular Signaling Peptides and Proteins chemistry, Phosphoproteins chemistry
Abstract

The YAP2 transcriptional regulator mediates a plethora of cellular functions, including the newly discovered Hippo tumor suppressor pathway, by virtue of its ability to recognize WBP1 and WBP2 signaling adaptors among a wide variety of other ligands. Herein, using isothermal titration calorimery and circular dichroism in combination with molecular modeling and molecular dynamics, we provide evidence that the WW1 and WW2 domains of YAP2 recognize various PPXY motifs within WBP1 and WBP2 in a highly promiscuous and subtle manner. Thus, although both WW domains strictly require the integrity of the consensus PPXY sequence, nonconsensus residues within and flanking this motif are not critical for high-affinity binding, implying that they most likely play a role in stabilizing the polyproline type II helical conformation of the PPXY ligands. Of particular interest is the observation that both WW domains bind to a PPXYXG motif with highest affinity, implicating a preference for a nonbulky and flexible glycine one residue to the C-terminal side of the consensus tyrosine. Importantly, a large set of residues within both WW domains and the PPXY motifs appear to undergo rapid fluctuations on a nanosecond time scale, suggesting that WW-ligand interactions are highly dynamic and that such conformational entropy may be an integral part of the reversible and temporal nature of cellular signaling cascades. Collectively, our study sheds light on the molecular determinants of a key WW-ligand interaction pertinent to cellular functions in health and disease.

Published
2011
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17. 3,4,5-Trisubstituted-1,2,4-4H-triazoles as WT and Y188L mutant HIV-1 non-nucleoside reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses.

Author

Cichero E, Buffa L, and Fossa P

Subjects
Ligands, Quantitative Structure-Activity Relationship, HIV Reverse Transcriptase antagonists & inhibitors, Models, Molecular, Mutant Proteins antagonists & inhibitors, Reverse Transcriptase Inhibitors chemistry, Triazoles chemistry
Abstract

3,4,5-Trisubstituted-1,2,4-4H-triazoles (TTs) have recently been identified as a new class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. Two series of triazoles have been studied, one of which was also screened against the Y188L mutant. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) has been used to elucidate the atomic details of the RT/TT interactions and to identify the most important features impacting the TT antiretroviral activity. Two 3D-QSAR CoMFA and CoMSIA models were derived, using the TT pEC₅₀ values measured against wild-type (WT) HIV-1 (model A) and the Y188L mutant form (model B), respectively, as the dependent variable. The final model A CoMSIA (r(ncv)²  = 0.97, r(cv)²  = 0.89, SEE = 0.314, and r(pred)²  = 0.82) and model B CoMSIA (r(ncv)²  = 0.91, r(cv)²  = 0.61, SEE = 0.236, and r(pred)²  = 0.73) analyses were more predictive. The results allowed us to obtain useful information for the design of new compounds with improved potency towards WT HIV-1 or that are potentially active against the Y188L mutant.

Published
2011
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18. ICA69 is a novel Rab2 effector regulating ER-Golgi trafficking in insulinoma cells.

Author

Buffa L, Fuchs E, Pietropaolo M, Barr F, and Solimena M

Subjects
Binding Sites, Cell Line, Tumor, Chromogranin A metabolism, Coatomer Protein metabolism, Endoplasmic Reticulum metabolism, Golgi Apparatus metabolism, Humans, Insulin Secretion, Insulinoma pathology, Pancreatic Neoplasms pathology, Protein Binding, Protein Transport, Receptor-Like Protein Tyrosine Phosphatases, Class 8 metabolism, Secretory Vesicles metabolism, Autoantigens metabolism, Insulin metabolism, Insulinoma metabolism, Pancreatic Neoplasms metabolism, rab2 GTP-Binding Protein metabolism
Abstract

Islet cell autoantigen of 69kDa (ICA69) is a small GTPase-binding protein of unknown function. ICA69 is enriched in the Golgi complex and its N-terminal half contains a BAR domain, a module that can bind/bend membranes and interacts with phospholipids. Here we show that in insulinoma INS-1 cells ICA69 binds to the small GTPase Rab2, which regulates the transport of COPI vesicles between the endoplasmic reticulum and the Golgi complex. Rab2 binds to ICA69 in a GTP-dependent fashion and recruits it to membranes. Over-expression of either Rab2 or ICA69 in INS-1 cells results in a phenotype characterized by: (i) impaired anterograde transport of the secretory granule protein precursors pro-ICA512 and chromogranin A; (ii) reduction of stimulated insulin secretion. Taken together, these data identify ICA69 as a novel Rab2 effector and point to its role in regulating the early transport of insulin secretory granule proteins.

Published
2008
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19. Ca2+/phospholipid-binding and syntaxin-binding of native synaptotagmin I.

Author

Popoli M, Venegoni A, Buffa L, and Racagni G

Subjects
Animals, Barium metabolism, Biosensing Techniques, Cattle, Chromatography, Affinity, Exocytosis, Kinetics, Membrane Glycoproteins isolation & purification, Nerve Tissue Proteins isolation & purification, Protein Binding, Qa-SNARE Proteins, Recombinant Proteins metabolism, Strontium metabolism, Synaptotagmin I, Synaptotagmins, Calcium metabolism, Calcium-Binding Proteins, Membrane Glycoproteins metabolism, Membrane Proteins metabolism, Nerve Tissue Proteins metabolism, Phosphatidylserines metabolism
Abstract

Synaptotagmin, a synaptic vesicle protein endowed with multiple properties, is the putative calcium sensor in neuroexocytosis. Ca2+/phospholipid binding and syntaxin binding activity of synaptotagmin were previously investigated using recombinant fusion proteins. In phospholipid binding the EC50 for calcium obtained was different when fusion proteins containing one (C2A) or both (C2A+C2B) binding domains were used. It was alternatively proposed that one or both synaptotagmin binding domains are important for calcium-sensing and triggering of transmitter release. In this study the binding activity of native full-length synaptotagmin, immobilized on beads, was investigated. We found the kinetic parameters of Ca2+/phospholipid binding to be compatible with the role of calcium sensor for synaptotagmin (EC50 for calcium = 72 +/- 7 microM), with the two C2 domains supporting separate and complementary calcium sensing properties. The binding of native syntaxin to synaptotagmin was measurable in the absence of calcium, but was markedly stimulated (2.2-fold) in the presence of mM calcium. It may be speculated that the two domains have a synergistic action in fast synchronous transmitter release, whereas C2B domain alone may support slow asynchronous release, working as a high affinity calcium sensor.

Published
1997
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20. Long-term blockade of serotonin reuptake affects synaptotagmin phosphorylation in the hippocampus.

Author

Popoli M, Venegoni A, Vocaturo C, Buffa L, Perez J, Smeraldi E, and Racagni G

Subjects
Animals, Calcium-Calmodulin-Dependent Protein Kinases metabolism, Cerebral Cortex metabolism, Fluvoxamine pharmacology, Male, Membrane Glycoproteins analysis, Nerve Tissue Proteins analysis, Phosphorylation, Rats, Rats, Sprague-Dawley, Synaptotagmins, Calcium-Binding Proteins, Hippocampus metabolism, Membrane Glycoproteins metabolism, Nerve Tissue Proteins metabolism, Selective Serotonin Reuptake Inhibitors pharmacology
Abstract

Synaptic vesicle trafficking and transmitter release from presynaptic terminals are precisely regulated by a complex array of protein/protein interactions. Several of these proteins are substrates of endogenous protein kinases present in presynaptic terminals. The activity of Ca2+/calmodulin-dependent protein kinase II(CaMKII), one of the kinases involved in the modulation of transmitter release, was previously shown to increase in the hippocampus after long-term blockade of 5-hydroxytryptamine (5-HT) reuptake (a treatment known to elicit an increase in 5-HT release in this area). To investigate the changes induced in presynaptic protein phosphorylation by 5-HT reuptake blockade and concomitant CaMKII up-regulation, we analyzed two major CaMKII presynaptic substrates (synapsin I and synaptotagmin). All 5-HT reuptake blockers that we used, which induce an increase in CaMKII activity and autophosphorylation, also caused a large (2-3-fold) increase in the Ca2+/calmodulin-dependent post hoc phosphorylation of synaptotagmin. Conversely, the phosphorylation of synapsin I is much less affected. The change in synaptotagmin phosphorylation, as determined through immunoprecipitation and quantitative immunoblot analysis after fluvoxamine treatment, is due exclusively to increased phosphate incorporation (presumably caused by the increased kinase activity) and not to a change in the level of substrate protein after the treatment. Thus, drugs known to induce an increase in 5-HT release simultaneously induce an increase in the activity of presynaptic CaMKII and in the phosphate incorporation (post hoc) by a major CaMKII substrate in synaptic vesicles (synaptotagmin). This finding establishes a link between the facilitation of transmitter release induced by antidepressant drugs and the phosphorylation of synaptotagmin by CaMKII.

Published
1997
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