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3. Clinical factors associated with death in 3044 COVID-19 patients managed in internal medicine wards in Italy: comment

Author

Bandera, A., Nobili, A., Tettamanti, M., Harari, S., Bosari, S., Mannucci, P. M., Scudeller, L., Fusetti, G., Rusconi, L., Dell'Orto, S., Prati, D., Valenti, L., Giovannelli, S., Manunta, M., Lamorte, G., Ferrari, F., Gori, A., Muscatello, A., Mangioni, D., Alagna, L., Bozzi, G., Lombardi, A., Ungaro, R., Ancona, G., Zuglian, G., Bolis, M., Iannotti, N., Ludovisi, S., Comelli, A., Renisi, G., Biscarini, S., Castelli, V., Palomba, E., Fava, M., Fortina, V., Peri, C. A., Saltini, P., Viero, G., Itri, T., Ferroni, V., Pastore, V., Massafra, R., Liparoti, A., Muheberimana, T., Giommi, A., Bianco, R., De Azevedo, R. M., Chitani, G. E., Peyvandi, F., Gualtierotti, R., Ferrari, B., Rossio, R., Boasi, N., Pagliaro, E., Massimo, C., De Caro, M., Montano, N., Vigone, B., Bellocchi, C., Carandina, A., Fiorelli, E., Melli, V., Tobaldini, E., Blasi, F., Aliberti, S., Spotti, M., Terranova, L., Misuraca, S., D'Adda, A., Della Fiore, S., Di Pasquale, M., Contarini, M. M. M., Ori, M., Morlacchi, L., Rossetti, V., Gramegna, A., Pappalettera, M., Cavallini, M., Buscemi, A., Vicenzi, M., Rota, I., Costantino, G., Solbiati, M., Furlan, L., Mancarella, M., Colombo, G., Fanin, A., Passarella, M., Monzani, V., Canetta, C., Rovellini, A., Barbetta, L., Billi, F., Folli, C., Accordino, S., Maira, D., C. M., Hu, Motta, I., Scaramellini, N., Fracanzani, A. L., Lombardi, R., Cespiati, A., Cesari, M., Lucchi, T., Proietti, M., Calcaterra, L., Mandelli, C., Coppola, C., Cerizza, A., Pesenti, A. M., Grasselli, G., Galazzi, A., Monti, I., Galbussera, A. A., Crisafulli, E., Girelli, D., Maroccia, A., Gabbiani, D., Busti, F., Vianello, A., Biondan, M., Sartori, F., Faverio, P., Pesci, A., Zucchetti, S., Bonfanti, P., Rossi, M., Beretta, I., Spolti, A., Elia, D., Cassandro, R., Caminati, A., Cipollone, F., Guagnano, M. T., D'Ardes, D., Rossi, I., Vezzani, F., Spanevello, A., Cherubino, F., Visca, D., Contoli, M., Papi, A., Morandi, L., Battistini, N., Moreo, G. L., Iannuzzi, P., Fumagalli, D., Leone, S., Bandera, A, Nobili, A, Tettamanti, M, Harari, S, Bosari, S, Mannucci, P, Scudeller, L, Fusetti, G, Rusconi, L, Dell'Orto, S, Prati, D, Valenti, L, Giovannelli, S, Manunta, M, Lamorte, G, Ferrari, F, Gori, A, Muscatello, A, Mangioni, D, Alagna, L, Bozzi, G, Lombardi, A, Ungaro, R, Ancona, G, Zuglian, G, Bolis, M, Iannotti, N, Ludovisi, S, Comelli, A, Renisi, G, Biscarini, S, Castelli, V, Palomba, E, Fava, M, Fortina, V, Peri, C, Saltini, P, Viero, G, Itri, T, Ferroni, V, Pastore, V, Massafra, R, Liparoti, A, Muheberimana, T, Giommi, A, Bianco, R, De Azevedo, R, Chitani, G, Peyvandi, F, Gualtierotti, R, Ferrari, B, Rossio, R, Boasi, N, Pagliaro, E, Massimo, C, De Caro, M, Montano, N, Vigone, B, Bellocchi, C, Carandina, A, Fiorelli, E, Melli, V, Tobaldini, E, Blasi, F, Aliberti, S, Spotti, M, Terranova, L, Misuraca, S, D'Adda, A, Della Fiore, S, Di Pasquale, M, Contarini, M, Ori, M, Morlacchi, L, Rossetti, V, Gramegna, A, Pappalettera, M, Cavallini, M, Buscemi, A, Vicenzi, M, Rota, I, Costantino, G, Solbiati, M, Furlan, L, Mancarella, M, Colombo, G, Fanin, A, Passarella, M, Monzani, V, Canetta, C, Rovellini, A, Barbetta, L, Billi, F, Folli, C, Accordino, S, Maira, D, Hu, C, Motta, I, Scaramellini, N, Fracanzani, A, Lombardi, R, Cespiati, A, Cesari, M, Lucchi, T, Proietti, M, Calcaterra, L, Mandelli, C, Coppola, C, Cerizza, A, Pesenti, A, Grasselli, G, Galazzi, A, Monti, I, Galbussera, A, Crisafulli, E, Girelli, D, Maroccia, A, Gabbiani, D, Busti, F, Vianello, A, Biondan, M, Sartori, F, Faverio, P, Pesci, A, Zucchetti, S, Bonfanti, P, Rossi, M, Beretta, I, Spolti, A, Elia, D, Cassandro, R, Caminati, A, Cipollone, F, Guagnano, M, D'Ardes, D, Rossi, I, Vezzani, F, Spanevello, A, Cherubino, F, Visca, D, Contoli, M, Papi, A, Morandi, L, Battistini, N, Moreo, G, Iannuzzi, P, Fumagalli, D, and Leone, S

Subjects
Adult, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Critical Care, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Ce - Letter to the Editor, MEDLINE, Cohort Studies, Hospital, Internal Medicine, Medicine, Humans, Hospital Mortality, Intensive care medicine, Aged, Aged, 80 and over, business.industry, SARS-CoV-2, COVID-19, Middle Aged, Respiration, Artificial, Hospitals, Hospitalization, Survival Rate, Italy, Emergency Medicine, business, Human
Abstract

During the COVID-19 2020 outbreak, a large body of data has been provided on general management and outcomes of hospitalized COVID-19 patients. Yet, relatively little is known on characteristics and outcome of patients managed in Internal Medicine Units (IMU). To address this gap, the Italian Society of Internal Medicine has conducted a nationwide cohort multicentre study on death outcome in adult COVID-19 patients admitted and managed in IMU. This study assessed 3044 COVID-19 patients at 41 referral hospitals across Italy from February 3rd to May 8th 2020. Demographics, comorbidities, organ dysfunction, treatment, and outcomes including death were assessed. During the study period, 697 patients (22.9%) were transferred to intensive care units, and 351 died in IMU (death rate 14.9%). At admission, factors independently associated with in-hospital mortality were age (OR 2.46, p = 0.000), productive cough (OR 2.04, p = 0.000), pre-existing chronic heart failure (OR 1.58, p = 0.017) and chronic obstructive pulmonary disease (OR 1.17, p = 0.048), the number of comorbidities (OR 1.34, p = 0.000) and polypharmacy (OR 1.20, p = 0.000). Of note, up to 40% of elderly patients did not report fever at admission. Decreasing PaO

Published
2022

4. Clinical risk scores for the early prediction of severe outocomes in patients hospitalized for COVID-19: comment

Author

Rossio R., Tettamanti M., Nobili A., Harari S., Mannucci P. M., Bandera A., Peyvandi F., Bosari S., Scudeller L., Fusetti G., Rusconi L., Dell'Orto S., Prati D., Valenti L., Giovannelli S., Manunta M., Lamorte G., Ferrari F., Gori A., Muscatello A., Mangioni D., Alagna L., Bozzi G., Lombardi A., Ungaro R., Ancona G., Zuglian G., Bolis M., Iannotti N., Ludovisi S., Comelli A., Renisi G., Biscarini S., Castelli V., Palomba E., Fava M., Fortina V., Peri C. A., Saltini P., Viero G., Itri T., Ferroni V., Pastore V., Massafra R., Liparoti A., Muheberimana T., Giommi A., Bianco R., De Azevedo R. M., Chitani G. E., Gualtierotti R., Ferrari B., Boasi N., Pagliaro E., Massimo C., De Caro M., Giachi A., Montano N., Vigone B., Bellocchi C., Carandina A., Fiorelli E., Melli V., Tobaldini E., Blasi F., Aliberti S., Spotti M., Terranova L., Misuraca S., D'Adda A., Fiore S. D., Di Pasquale M., Mantero M., Contarini M., Ori M., Morlacchi L., Rossetti V., Gramegna A., Pappalettera M., Cavallini M., Buscemi A., Vicenzi M., Rota I., Costantino G., Solbiati M., Furlan L., Mancarella M., Colombo G., Fanin A., Passarella M., Monzani V., Canetta C., Rovellini A., Barbetta L., Billi F., Folli C., Accordino S., Maira D., Hu C. M., Motta I., Scaramellini N., Fracanzani A. L., Lombardi R., Cespiati A., Cesari M., Lucchi T., Proietti M., Calcaterra L., Mandelli C., Coppola C., Cerizza A., Pesenti A. M., Grasselli G., Galazzi A., Monti I., Galbussera A. A., Crisafulli E., Girelli D., Maroccia A., Gabbiani D., Busti F., Vianello A., Biondan M., Sartori F., Faverio P., Pesci A., Zucchetti S., Bonfanti P., Rossi M., Beretta I., Spolti A., Elia D., Cassandro R., Caminati A., Cipollone F., Guagnano M. T., D'Ardes D., Rossi I., Vezzani F., Spanevello A., Cherubino F., Visca D., Contoli M., Papi A., Morandi L., Battistini N., Moreo G. L., Iannuzzi P., Fumagalli D., Leone S., Rossio, R, Tettamanti, M, Nobili, A, Harari, S, Mannucci, P, Bandera, A, Peyvandi, F, Bosari, S, Scudeller, L, Fusetti, G, Rusconi, L, Dell'Orto, S, Prati, D, Valenti, L, Giovannelli, S, Manunta, M, Lamorte, G, Ferrari, F, Gori, A, Muscatello, A, Mangioni, D, Alagna, L, Bozzi, G, Lombardi, A, Ungaro, R, Ancona, G, Zuglian, G, Bolis, M, Iannotti, N, Ludovisi, S, Comelli, A, Renisi, G, Biscarini, S, Castelli, V, Palomba, E, Fava, M, Fortina, V, Peri, C, Saltini, P, Viero, G, Itri, T, Ferroni, V, Pastore, V, Massafra, R, Liparoti, A, Muheberimana, T, Giommi, A, Bianco, R, De Azevedo, R, Chitani, G, Gualtierotti, R, Ferrari, B, Boasi, N, Pagliaro, E, Massimo, C, De Caro, M, Giachi, A, Montano, N, Vigone, B, Bellocchi, C, Carandina, A, Fiorelli, E, Melli, V, Tobaldini, E, Blasi, F, Aliberti, S, Spotti, M, Terranova, L, Misuraca, S, D'Adda, A, Fiore, S, Di Pasquale, M, Mantero, M, Contarini, M, Ori, M, Morlacchi, L, Rossetti, V, Gramegna, A, Pappalettera, M, Cavallini, M, Buscemi, A, Vicenzi, M, Rota, I, Costantino, G, Solbiati, M, Furlan, L, Mancarella, M, Colombo, G, Fanin, A, Passarella, M, Monzani, V, Canetta, C, Rovellini, A, Barbetta, L, Billi, F, Folli, C, Accordino, S, Maira, D, Hu, C, Motta, I, Scaramellini, N, Fracanzani, A, Lombardi, R, Cespiati, A, Cesari, M, Lucchi, T, Proietti, M, Calcaterra, L, Mandelli, C, Coppola, C, Cerizza, A, Pesenti, A, Grasselli, G, Galazzi, A, Monti, I, Galbussera, A, Crisafulli, E, Girelli, D, Maroccia, A, Gabbiani, D, Busti, F, Vianello, A, Biondan, M, Sartori, F, Faverio, P, Pesci, A, Zucchetti, S, Bonfanti, P, Rossi, M, Beretta, I, Spolti, A, Elia, D, Cassandro, R, Caminati, A, Cipollone, F, Guagnano, M, D'Ardes, D, Rossi, I, Vezzani, F, Spanevello, A, Cherubino, F, Visca, D, Contoli, M, Papi, A, Morandi, L, Battistini, N, Moreo, G, Iannuzzi, P, Fumagalli, D, and Leone, S

Subjects
Male, Outcome Assessment, Disease, 030204 cardiovascular system & hematology, Respiratory failure, 0302 clinical medicine, Risk Factors, Epidemiology, Early prediction, Outcome Assessment, Health Care, 030212 general & internal medicine, Framingham Risk Score, Respiration, Area under the curve, Middle Aged, Hospitalization, Survival Rate, Italy, Artificial, Emergency Medicine, Female, Clinical risk factor, 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Ce - Letter to the Editor, MEDLINE, Risk Assessment, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, Internal Medicine, medicine, Intubation, Intratracheal, Humans, In patient, Derivation, COVID-19, Risk prediction model, SARS-CoV 2, Selection (genetic algorithm), Aged, Retrospective Studies, SARS-CoV-2, business.industry, Retrospective cohort study, Respiration, Artificial, Im - Original, Health Care, Intratracheal, ROC Curve, Intubation, business
Abstract

Coronavirus disease of 2019 (COVID-19) is associated with severe acute respiratory failure. Early identification of high-risk COVID-19 patients is crucial. We aimed to derive and validate a simple score for the prediction of severe outcomes. A retrospective cohort study of patients hospitalized for COVID-19 was carried out by the Italian Society of Internal Medicine. Epidemiological, clinical, laboratory, and treatment variables were collected at hospital admission at five hospitals. Three algorithm selection models were used to construct a predictive risk score: backward Selection, Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest. Severe outcome was defined as the composite of need for non-invasive ventilation, need for orotracheal intubation, or death. A total of 610 patients were included in the analysis, 313 had a severe outcome. The subset for the derivation analysis included 335 patients, the subset for the validation analysis 275 patients. The LASSO selection identified 6 variables (age, history of coronary heart disease, CRP, AST, D-dimer, and neutrophil/lymphocyte ratio) and resulted in the best performing score with an area under the curve of 0.79 in the derivation cohort and 0.80 in the validation cohort. Using a cut-off of 7 out of 13 points, sensitivity was 0.93, specificity 0.34, positive predictive value 0.59, and negative predictive value 0.82. The proposed score can identify patients at low risk for severe outcome who can be safely managed in a low-intensity setting after hospital admission for COVID-19.

Published
2021

5. COVID-19 Network: the response of an Italian Reference Institute to research challenges about a new pandemia

Author

Bosari, S., Scudeller, L., Fusetti, G., Rusconi, L., Dell Orto, S., Prati, D., Valenti, L., Lamorte, G., Manunta, M., Baselli, G., Santoro, L., Gori, A., Bandera, A., Muscatello, A., Mangioni, D., Alagna, L., Bozzi, G., Lombardi, A., Ungaro, R., Itri, T., Ferroni, V., Pastore, V., Massafra, R., Rondolini, I., Peyvandi, F., Gualtierotti, R., Ferrari, B., Rossio, R., Corona, E., Rampi, N., Massimo, C., Montano, N., Vigone, B., Bellocchi, C., Fiorelli, E., Melli, V., Tobaldini, E., Blasi, F., Aliberti, S., Spotti, M., Simonetta, E., Terranova, L., Amati, F., Miele, C., Misuraca, S., D'Adda, A., Della Fiore, S., Di Pasquale, M., Contarini, M.M.M., Ori, M., Morlacchi, L., Rossetti, V., Gramegna, A., Pappalettera, M., Cavallini, M., Vigni, A., Vicenzi, M., Rota, I., Costantino, G., Solbiati, M., Furlan, L., Mancarella, M., Colombo, G., Fanin, A., Monzani, V., Rovellini, A., Barbetta, L., Billi, F., Folli, C., Baldini, M., Motta, I., Scaramellini, N., Fracanzani, A.L., Lombardi, R., Iuculano, F., Cesari, M., Proietti, M., Calcaterra, L., Nobili, A., Tettamanti, M., Monti, I., and Pesenti, A.

Published
2020
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7. Regular Wine Consumption in Chronic Heart Failure: Impact on Outcomes, Quality of Life, and Circulating Biomarkers

Author

Cosmi, Franco, Di Giulio, Paola, Masson, Serge, Finzi, Andrea, Marfisi, Rosa Maria, Cosmi, Deborah, Scarano, Marco, Tognoni, Gianni, Maggioni, Aldo P., Porcu, Maurizio, Boni, Silvana, Cutrupi, Giovanni, Tavazzi, Luigi, Latini, Roberto Tavazzi, L, Tognoni, G, Barlera, S, Franzosi, Mg, Latini, R, Lucci, D, Maggioni, Ap, Marchioli, R, Nicolosi, Gl, Porcu, M, Yusuf, S, Camerini, F, Cohn, Jn, Decarli, A, Pitt, B, Sleight, P, Poole-Wilson, Pa, Geraci, E, Scherillo, M, Fabbri, G, Bartolomei, B, Bertoli, D, Cobelli, F, Fresco, C, Ledda, A, Levantesi, G, Opasich, C, Rusconi, F, Sinagra, G, Turazza, F, Volpi, A, Ceseri, M, Alongi, G, Atzori, A, Bambi, F, Bastarolo, D, Bianchini, F, Cangioli, I, Canu, V, Caporusso, C, Cenni, G, Cintelli, L, Cocchio, M, Confente, A, Fenicia, E, Friso, G, Gianfriddo, M, Grilli, G, Lazzaro, B, Lonardo, G, Luise, A, Nota, R, Orlando, M, Petrolo, R, Pierattini, C, Pierota, V, Provenzani, A, Quartuccio, V, Ragno, A, Serio, C, Spolaor, A, Tafi, A, Tellaroli, E, Ghio, S, Ghizzardi, E, Masson, S, Crociati, L, Rovere, Mt, Corra, U, Di Giulio, P, Finzi, A, Gorini, M, Gonzini, L, Milani, V, Orsini, G, Bianchini, E, Cabiddu, S, Cipressa, L, Cipressa, Ml, Di Bitetto, G, Ferri, B, Galbiati, L, Lorimer, A, Pera, C, Priami, P, Rossi, Mg, Pasotti, E, Vaghi, F, Roncarolo, P, Zunino, Mt, Matta, F, Actis, E, Gaita, F, Azzaro, G, Zanetta, M, Paino, Am, Parravicini, U, Vegis, D, Conte, R, Ferraro, P, De Bernardi, A, Morelloni, S, Fagnani, M, Lucchina, Pg, Montagna, L, Bellone, E, Sappe, D, Ferraro, F, Delucchi, M, Reynaud, Sg, Dore, M, La, A, Massobrio, N, Bo, L, Trinchero, R, Imazio, M, Brocchi, G, Nejrotti, A, Rissone, L, Gabasio, S, Zocchi, C, Randazzo, S, Crenna, A, Giannuzzi, P, Bonanomi, E, Mezzani, A, De Marchi, M, Begliuomini, G, Gianonatti, Ca, Gavazzi, A, Grosu, A, Cas, Ld, Nodari, S, Garyfallidis, P, Bertoletti, A, Bonifazi, C, Arisi, S, Mascaro, F, Fraccarollo, M, Dell, S, Sfolcini, M, Bortolini, F, Raccagni, D, Turelli, A, Santarone, M, Miglierina, E, Sormani, L, Jemoli, R, Tettamanti, F, Pirelli, S, Bianchi, C, Verde, S, Mariani, M, Ziacchi, V, Ferrazza, A, Russo, A, Bortolotti, M, Pasini, Gf, Jones, Kn, Cuzzucrea, D, Gullace, G, Carbone, C, Granata, A, De, S, Del Rosso, G, Inserra, C, Renaldini, E, Zappa, C, Moretti, M, Zanini, R, Ferrari, M, Cei, A, Lissi, C, Dovico, E, Fiorentini, C, Palermo, P, Brusoni, B, Negrini, M, Heyman, J, Danzi, Gb, Frigerio, M, Beretta, L, Sachero, A, Casazza, F, Squadroni, L, Lombardi, F, Marano, L, Margonato, A, Fragasso, G, Febo, Oc, Aiolfi, E, Olmetti, F, Grieco, A, Antonazzo, V, Specchia, G, Mortara, A, Robustelli, F, Songini, Mg, Schweiger, C, Frisinghelli, A, Palvarini, M, Campana, C, Scelsi, L, Marsan, Na, Gualco, A, De Feo, S, Iannone, Ma, Diaco, T, Zaniboni, D, Milanesi, G, Nassiacos, D, Meloni, S, Giani, P, Nicoli, T, Malinverni, C, Gusmini, A, Pozzoni, L, Bisiani, G, Margaroli, P, Schizzarotto, A, Daverio, A, Morelli, E, Occhi, G, Partesana, N, Bandini, P, Rosella, Mg, Giustiniani, S, Cucchi, G, Pedretti, R, Raimondo, R, Vaninetti, R, Fedele, A, Ghezzi, I, Rezzonico, E, Salerno, Ja, Morandi, F, Salvucci, F, Valenti, C, Graziano, G, Romano, M, Cimminiello, C, Mangone, I, Lombardo, M, Quorso, P, Marinoni, G, Breghi, M, Erckert, M, Dienstl, A, Mirante, G, Stefenelli, C, Cioffi, G, Buczkowska, E, Bonanome, A, Bazzanini, F, Parissenti, L, Serafini, C, Catania, G, Tarantini, L, Rigatelli, G, Boni, S, Pasini, A, Masini, E, Zampiero, Aa, Zanchetta, M, Franceschetto, L, Delise, P, Marcon, C, Sacchetta, A, Borgese, L, Artusi, L, Casolino, P, Corbara, F, Banzato, A, Barbiero, M, Aldegheri, Mp, Bazzucco, R, Crivellenti, G, Raviele, A, Zanella, C, Pascotto, P, Sarto, P, Milan, S, Barbieri, E, Girardi, P, Dalla, W, Mule, Jd, Di Sipio ML, Cazzin, R, Milan, D, Zonzin, P, Carraro, M, Rossi, R, Carbonieri, E, Rossi, I, Stritoni, P, Meneghetti, P, Risica, G, Tenderini, Pl, Vassanelli, C, Zanolla, L, Perini, G, Brighetti, G, Chiozza, R, Giuliano, G, Baldin, Mg, Gortan, R, Cesanelli, R, Piazza, R, Mos, L, Vriz, O, Pavan, D, Pascottini, G, Alberti, E, Werren, M, Solinas, L, Longaro, F, Fioretti, P, Albanese, Mc, Miani, D, Gianrossi, R, Pende, A, Rubartelli, P, Magaia, O, Caruso, D, Faraguti, As, Magliani, L, Miccoli, F, Guglielmino, G, Cantarelli, A, Orlandi, S, Vallebona, A, Pozzati, A, Brega, G, Pancaldi, Lg, Vandelli, R, Urbinati, S, Poci, Mg, Zoli, M, Costa, Gm, Guiducci, U, Zobbi, G, Tartagni, F, Tisselli, A, Gentili, A, Pieri, P, Cagnetta, E, Bendinelli, S, Barbieri, A, Conti, R, Ferrari, R, Merlini, F, Fucili, A, Moruzzi, P, Buia, E, Galvani, M, Ferrini, D, Baggioni, G, Yiannacopulu, P, Canè, G, Bonfiglioli, A, Zandomeneghi, R, Brugioni, L, Giannini, A, Di, R, Giuliani, M, Rusconi, L, Del Corso, P, Piovaccari, G, Bologna, F, Venturi, P, Melandri, F, Bagni, E, Bolognese, L, Perticucci, R, Zuppiroli, A, Nannini, M, Consoli, N, Petrone, P, Pipitò, C, Colombi, L, Bernardi, D, Mariani, Pr, Testa, R, Mazzinghi, F, Cosmi, F, Cosmi, D, Zipoli, A, Cecchi, A, Castelli, G, Ciaccheri, M, Mori, F, Pieri, F, Valoti, P, Chiarantini, D, Santoro, Gm, Minneci, C, Marchi, F, Milli, M, Zambaldi, G, Geri, Aa, Cipriani, M, Alessandri, M, Severi, S, Stefanelli, S, Comella, A, Poddighe, R, Digiorgio, A, Carluccio, M, Berti, S, Rizza, A, Bonatti, V, Molendi, V, Brancato, A, D'Aprile, N, Giappichini, G, Del Vecchio, S, Mantini, G, De Tommasi, F, Meucci, G, Cordoni, M, Bechi, S, Barsotti, L, Baldini, P, Romei, M, Scopelliti, G, Lauri, G, Pestelli, F, Furiozzi, F, Cocchieri, M, Severini, D, Patriarchi, F, Chiocchi, P, Buccolieri, M, Martinelli, S, Wee, A, Angelici, F, Bernardinangeli, M, Proietti, G, Biscottini, B, Panciarola, R, Marinacci, L, Perna, Gp, Gabrielli, D, Moraca, A, Moretti, L, Partemi, L, Gregori, G, Amici, R, Patteri, G, Capone, P, Savini, E, Morgagni, Gl, Paccaloni, L, Pezzuoli, F, Carincola, S, Papi, S, De Crescentini, S, Gerardi, P, Midi, P, Gallenzi, E, Pajes, G, Mancone, C, Di, V, Di Gennaro, M, Calcagno, S, Toscano, S, Antonicoli, S, Carta, F, Giorgi, G, Comito, F, Daniele, E, Goretti, Sm, Ciarla, O, Gelfo, Pg, Acquaviva, A, Testa, D, Testa, G, Pagliaro, Fa, Russo, F, Vetta, F, Marchese, I, Di, G, D'Ambrosio, A, Leggio, F, Del Sindaco, D, Lacchè, A, Avallone, A, Risa, Mp, Azzolini, P, Baldo, E, Giovannini, E, Pulignano, G, Tondo, C, Picchio, E, Biffani, E, Tanzi, P, Pozzar, F, Farnetti, F, Azzarito, M, Santini, M, Varveri, A, Ferraiuolo, G, Valtorta, C, Gaspardone, A, Barbato, G, Ceci, V, Aspromonte, N, Bellocci, F, Colizzi, C, Fedele, F, Perez, Fi, Galati, A, Rossetti, A, Mainella, A, Ciuffetta, D, Matteucci, C, Busi, G, De, A, Farina, G, Granatelli, A, Leone, F, Frasca, F, Castellani, G, Massaro, G, Mastrogiuseppe, G, Vacri, A, De Sanctis, F, Cioli, M, Di Luzio, S, Napoletano, C, Piccioni, Ll, De Simone, G, Ottaviano, A, Mazza, V, Spedaliere, C, Staniscia, Td, Calgione, E, De Marco, G, Chiacchio, T, Di, T, Romanzi, S, Salvatore, G, Golino, P, Palermo, A, Mascia, F, Vetrano, A, Vinciguerra, A, Caliendo, L, Longobardi, R, De Caro, G, Di Nola, R, Piemonte, F, Prinzi, D, De Rosa, P, De, V, Riello, F, Capuano, V, Vecchio, G, Landi, M, Amato, S, Garofalo, M, D'Avino, M, Sensale, P, Maiolica, O, Santoro, R, Caso, P, Miceli, D, Maurea, N, Bianchi, U, Crispo, C, Chiariello, M, Filardi, Pp, Russo, L, Capuano, N, Ungaro, G, Vergara, G, Scafuro, F, D'Angelo, G, Campaniello, C, Bottiglieri, P, Volpe, A, Battista, R, De Risi, L, Cardillo, G, Sibilio, G, Marino, Ap, Silvestri, F, Predotti, P, Iervoglini, A, De Matteis, C, Sarnicola, P, Matarazzo, Mm, Baldi, S, Iuliano, V, Astarita, C, Cuccaro, P, Liguori, A, Liguori, G, Gregorio, G, Petraglia, L, Antonelli, G, Amodio, G, De Luca, I, Franchini, G, Lenti, Ml, Cavallari, D, D'Agostino, C, Scalera, G, Altamura, Cm, Russo, M, Mascolo, Ar, Pettinati, G, Ciricugno, Sa, Scrutinio, D, Passantino, A, Mastrangelo, D, Di Masi, A, De, R, Cannone, M, Dibiase, F, Pensato, M, Loliva, F, Trapani, F, Panettieri, I, Leone, L, Di, M, Carrone, M, Gallone, V, Cocco, F, Costantini, M, Tritto, C, Cavalieri, F, Stella, L, Magliari, F, Callerame, M, De Giorgi, A, Pellegrino, L, Correra, M, Portulano, V, Nisi, Gl, Grassi, G, Cristallo, E, De Laura, D, Salerno, C, Fanelli, R, Villella, M, Pede, S, Renna, A, De Lorenzi, E, Urso, L, Lenti, V, Peluso, A, Baldi, N, Polimeni, G, Palma, P, Lauletta, R, Tagliamonte, E, Cirillo, T, Centonze, G, D'Alessandro, B, Truncellito, L, Mecca, D, Petruzzi, Ma, Coviello, Ro, Lopizzo, A, Chiaffitelli, M, Barbuzzi, S, Gubelli, S, Germinario, G, Cosentino, N, Mingrone, A, Vico, R, Borrello, G, Mazza, Ml, Cimino, R, Galasso, D, Cassadonte, F, Talarico, U, Perticone, F, Cassano, S, Catapano, F, Calemme, S, Feraco, E, Cloro, C, Misuraca, G, Caporale, R, Vigna, L, Spagnuolo, V, De Rosa, F, Spadafora, G, Zampaglione, G, Russo, R, Schipani, Fa, Ferragina, Af, Stranieri, D, Musca, G, Carpino, C, Bencardino, P, Raimondo, F, Musacchio, D, Pulitano, G, Ruggeri, A, Provenzano, A, Salituri, S, Musolino, M, Calandruccio, S, Marrari, A, Tripodi, E, Scali, R, Anastasio, L, Arone, A, Aragona, P, Donnangelo, L, Comito, Mg, Bilotta, F, Vaccaro, I, Rametta, R, Ventura, V, Bonvegna, A, Alì, A, Cinnirella, C, Raineri, M, Pompeo, F, Ingurgio, Nc, Carini, V, Coco, R, Giunta, G, Leonardi, G, Randazzo, V, Di Blasi, V, Tamburino, C, Russo, G, Mangiameli, S, Cardillo, R, Castelli, D, Inserra, V, Arena, A, Gulizia, Mm, Raciti, S, Rapisarda, G, Romano, R, Prestifilippo, P, Braschi, Gb, Ledda, G, Terrazzino, R, De Caro, M, Scilabra, G, Graffagnino, B, Grassi, R, Scimone, Gf, Vasquez, L, Coppolino, C, Casale, A, Castelli, M, D'Urso, G, D'Antonio, E, Presti, Ll, Badalamenti, E, Conti, P, Sanfilippo, N, Cirrincione, V, Cinà, Mt, Cusimano, G, Taormina, A, Giuliano, P, Bajardi, A, Mandala, V, Canonico, A, Geraci, G, Sabella, Fp, Enia, F, Floresta, Am, Cascio, Il, Gumina, D, Cavallaro, A, Piccione, G, Ferrante, R, Blandino, M, Iudicello, Ms, Mossuti, E, Romano, G, Lombardo, L, Monastra, P, Di Vincenzo, D, Orru, P, Muscas, F, Giardina, G, Corda, M, Locci, G, Podda, A, Ledda, M, Siddi, P, Lai, C, Pili, G, Mercuro, G, Mureddu, G, Ganau, A, Meloni, G, Poddighe, G, Sanna, G., Cosmi, Franco, Di Giulio, Paola, Masson, Serge, Finzi, Andrea, Marfisi, Rosa Maria, Cosmi, Deborah, Scarano, Marco, Tognoni, Gianni, Maggioni, Aldo P, Porcu, Maurizio, Boni, Silvana, Cutrupi, Giovanni, Tavazzi, Luigi, Latini, Roberto, on behalf of the GISSI-HF, Investigator, Margonato, Alberto, DI GIULIO, Paola, Maggioni, Aldo P., GISSI HF, Investigator, and Sinagra, Gianfranco

Subjects
Male, Health Status, Left, Wine, Comorbidity, Ventricular Function, Left, Health Statu, Quality of life, Risk Factors, Surveys and Questionnaires, Prevalence, Ventricular Function, Surveys and Questionnaire, Depression (differential diagnoses), Depression, Medicine (all), Middle Aged, Prognosis, biological marker, Italy, Female, Risk assessment, Cardiology and Cardiovascular Medicine, biological markers, Human, Cardiac function curve, Vasculitis, medicine.medical_specialty, Vasculiti, Alcohol Drinking, Prognosi, Lower risk, Risk Assessment, Internal medicine, medicine, Humans, Protective Factor, Aged, Heart Failure, business.industry, Risk Factor, Stroke Volume, Biomarker, quality of life, wine, aged, alcohol drinking, biomarkers, chronic disease, comorbidity, depression, female, heart failure, humans, italy, male, middle aged, prevalence, prognosis, protective factors, risk assessment, risk factors, stroke volume, surveys and questionnaires, vasculitis, ventricular function, left, health status, cardiology and cardiovascular medicine, Biomarkers, Chronic Disease, Protective Factors, Quality of Life, medicine.disease, Clinical trial, Heart failure, Physical therapy, business
Abstract

Background— Moderate, regular alcohol consumption is generally associated with a lower risk of cardiovascular events but data in patients with chronic heart failure are scarce. We evaluated the relations between wine consumption, health status, circulating biomarkers, and clinical outcomes in a large Italian population of patients with chronic heart failure enrolled in a multicenter clinical trial. Methods and Results— A brief questionnaire on dietary habits was administered at baseline to 6973 patients enrolled in the Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca-Heart Failure (GISSI-HF) trial. The relations between wine consumption, fatal and nonfatal clinical end points, quality of life, symptoms of depression, and circulating biomarkers of cardiac function and inflammation (in subsets of patients) were evaluated with simple and multivariable-adjusted statistical models. Almost 56% of the patients reported drinking at least 1 glass of wine per day. After adjustment, clinical outcomes were not significantly different in the predefined 4 groups of wine consumption. However, patients with more frequent wine consumption had a significantly better perception of health status (Kansas City Cardiomyopathy Questionnaire score, adjusted P P =0.01), and lower plasma levels of biomarkers of vascular inflammation (osteoprotegerin and C-terminal proendothelin-1, adjusted P P =0.01) after adjusting for possible confounders. Conclusions— We show for the first time in a large cohort of patients with chronic heart failure that moderate wine consumption is associated with a better perceived and objective health status, lower prevalence of depression, and less vascular inflammation, but does not translate into more favorable clinical 4-year outcomes. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT0033633.

Published
2015

10. Ultraviolet and visual variability of Theta CrB during a normal B-phase following a shell phase (1980-1985)

Author

Doazan, V, Marlborough, J. M, Morossi, C, Peters, G. J, and Rusconi, L

Subjects
Astrophysics
Abstract

Based on far-UV and visual observations made between 1980 and 1985, the phenomena characterizing the end of a shell phase of Theta-CrB, and the normal B-phase following it, are described as part of a long-term study of Be stars. The strength, shape, and velocity of the C IV, Si IV, and Al III resonance lines, and the Fe III lines of low excitation, show associated variability patterns over the whole range of ionization observable in the IUE and visual spectra. The observed variability pattern consists of a one-year narrow-line stage where the lines show narrow absorption cores close to rest wavelength, a two-year series of abrupt changes between a weak and a strong line, and a damping out of these variations leaving the observed spectrum in a lower ionization state. The existence of a phase-lag between similar phenomena occurring in the superionized and subionized/normally ionized regions, is noted.

Published
1986

11. The 'spem' (studio policentrico elettrocateteri membrane): a multicenter study on membrane leads.

Author

Rusconi L, Sigliano R, and Mininno A

Abstract

SPEM is a multicenter randomized double-blind study performed to test the acute and chronic electrophysiological behavior of three different ventricular leads: (1) an ion exchange membrane with 30-[mu]g dexamethasone elution in a contoured activated carbon tip lead (Membrane 1400T, 30 patients); (2) the same lead design without steroid (Membrane 1401T, 24 patients); and (3) the same lead design without steroid or membrane (control group, 27 patients). Twenty-three of the 81 patients were women; the mean age for all patients was 74 ± 10 years. Parameters are calculated both in uni- and bipolar configuration at implant and at follow-up after 1, 5, 15, 30, 90, 180, and 360 days. Implant threshold (chronaxie = 0.413 ± 0.280 ms, rheobase = 0.264 ± 0.099 V), signal amplitude (13.45 ± 5.87 mV), and slew rate (2.05 ± 1.38 V/s) reveal no significant differences. Pacing impedance values both at implant (unipolar 571 ± 165 ; bipolar 505 ± 123 ) and at follow-ups (unipolar 480 ± 72 ; bipolar 518 ± 75 ) are slightly lower in the unipolar configuration. At 15 and 30-day follow-ups, control group and nonsteroid leads show a higher threshold value growth fin unipolar from 0.16 ± 0.11 to 1.19 ± 0.85 [mu]J; in bipolar from 0.18 ± 0.13 to 1.24 ± 0.08 [mu]J) than the membrane steriod leads (in unipolar from 0.13 ± 0.11 to 0.70 ± 0.39 [mu]J; in bipolar from 0.23 ± 0.32 to 0.76 ± 0.36 [mu]J); the threshold of nonsteroid leads decreases after 1-3 months and it settles at the same threshold level of the leads with membrane and steroid (in unipolar 0.60 ± 0.33 [mu]J; in bipolar 0.55 ± 0.26 [mu]J), which has been stable since the first month. The ion exchange membrane is effective in reducing the chronic pacing threshold like acute steroid elution at low doses, but membrane alone does not prevent an acute pacing threshold increase through the first month postimplant. [ABSTRACT FROM AUTHOR]

Published
1998
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13. A low pulse pressure is an independent predictor of mortality in heart failure: Data from a large nationwide cardiology database (IN-CHF registry)

Author

Schillaci, Giuseppe, Di Luzio, Silvia, Coluccini, Mario, Gonzini, Lucio, Porcu, Maurizio, Pozzar, Francesco, Maggioni, Aldo P, Investigators, Mezzani, A, Bielli, M, Milanese, U, Ugliengo, G, Pozzi, R, Rabajoli, F, Bosimini, E, Begliuomini, G, Ferrari, A, Barzizza, F, Valsecchi, Mg, Dadda, F, Faggiano, P, Castiglioni, G, Gibelli, G, Turelli, Al, Belluschi, R, Bianchi, C, Emanuelli, C, Gramenzi, S, Foti, G, Agnelli, D, Mascioli, G, Cazzani, E, Zanelli, E, Domenighini, D, Castelli, C, Moroni, E, Gara, S, Guzzetti, S, Muzzupappa, S, Turiel, M, Cappiello, E, Sandrone, G, Recalcati, F, Valenti, D, Achilli, F, Vincenzi, A, Rusconi, F, Palvarini, M, Ghio, S, Fontana, A, Giusti, A, Scelsi, L, Sebastiani, R, Ceresa, M, Nassiacos, D, Meloni, S, Nicoli, T, Bandini, P, Pedretti, R, Paolucci, M, Amati, L, Ravetta, M, Morandi, F, Provasoli, S, Bertolini, A, Imperiale, D, Agen, W, Planca, E, Quorso, P, Ferro, A, Pedrolli, C, Russo, P, Tarantini, L, Candelpergher, G, Cannarozzo, Pp, De Cian, F, Agnoli, A, Stefanini, Mg, Cacciavillani, L, Boffa, Gm, Mario, L, Renosto, G, Stritoni, P, Varotto, L, Penzo, M, Perini, G, Giuliano, G, Barducci, E, Piazza, R, Albanese, Mc, Fresco, C, Picco, F, Venturini, P, Camerini, A, Griffo, R, Derchi, G, Delfino, L, Pizzorno, L, Mazzantini, S, Torre, F, Orlandi, S, Bertoli, D, Gentile, A, Naccarella, F, Gatti, M, Coluccini, M, Morgagni, G, Alfano, G, Reggianini, L, Sansoni, S, Serra, W, Passerini, F, Del Corso, P, Rusconi, L, Marzaloni, M, Mezzetti, M, Gambarati, Gp, Mariani, Pr, Volterrani, C, Venturi, F, Zambaldi, G, Casolo, G, Moschi, G, Geri Brandinelli, G, Miracapillo, G, Boni, A, Italiani, G, Vergoni, W, Paci, Ap, Lattanzi, F, Reisenhofer, B, Severini, D, Taddei, T, Dalle Luche, A, Comella, A, Gasperini, U, Cocchieri, M, Alunni, G, Bosi, E, Panciarola, R, Maragoni, G, Bardelli, G, Testarmata, P, Pasetti, L, Budini, A, Gabrielli, D, Coderoni, B, Midi, P, Romaniello, C, Del Sindaco, D, Leggio, F, Terranova, A, Pulignano, G, Pozzar, P, Ansalone, G, Magris, B, Giannantoni, P, Cacciatore, G, Bottero, G, Scaffidi, G, Valtorta, C, Salustri, A, Amaddeo, F, Barbato, G, Aspromonte, N, Baldo, V, Baldo, E, Frattaroli, C, Mariani, A, Di Marco, G, Levantesi, G, Potena, Ap, Colonna, N, Montano, A, Sensale, P, Maiolica, O, Somelli, A, Napolitano, F, Provvisiero, P, Bottiglieri, P, Ciriello, N, Angelini, E, Andriulo, C, De Santis, F, Cocco, F, Pennetta, A, Mariello, F, Magliari, F, De Giorgi, A, Callerame, M, Santoro, V, Pede, S, Renna, A, De Donno, O, De Lorenzi, E, Polimeni, V, Russo, Va, Mangia, R, Truncellito, L, Cariello, Fp, Affinita, M, Perticone, F, Cloro, C, Borelli, D, Matta, M, Lopresti, D, Misuraca, A, Caporale, R, Chiappetta, P, Tripodi, E, Tassone, F, Salituri, S, Errigo, C, Meringolo, G, Donnangelo, L, Canonico, G, Coco, R, Franco, M, Coglitore, A, Donato, A, Di Tano, G, Cento, D, DE GREGORIO, Cesare, Mongiovì, M, Schillaci, Am, Mirto, U, Clemenza, F, Ingrillì, F, Cavallaro, A, Aloisi, B, Ledda, G, Rizzo, C, Porcu, M, Salis, S, Pistis, L, Pili, G, Piras, S, Maoddi, I, and Uras, F.

Subjects
Adult, Male, medicine.medical_specialty, Blood Pressure, Independent predictor, Low pulse pressure, Predictive Value of Tests, Internal medicine, Humans, Medicine, Aged, Female, Follow-Up Studies, Heart Failure, Italy, Middle Aged, Pulse, Registries, Stroke Volume, business.industry, medicine.disease, Heart failure, Cardiology, Cardiology and Cardiovascular Medicine, business
Abstract

A high pulse pressure (PP) predicts cardiovascular mortality in hypertension and in the elderly. We analyzed the data from the Italian Network of Congestive Heart Failure Registry to test the prognostic role of PP in patients with heart failure.A total of 8660 patients with heart failure (mean age 64 +/- 12 years, 73% male) were divided into four groups according to their PP (40, 40-49, 50-59, andor = 60 mmHg), and followed prospectively.After 1 year, 995 patients (11.5%) died. Both the mean arterial pressure and systolic blood pressure were found to be inversely associated with mortality at univariate and multivariate analyses. An inverse univariate relation was observed between PP and all-cause mortality. An excess mortality risk in the lowest PP group (odds ratio 1.40, 95% confidence interval 1.09-1.79 vs the highest PP group) was confirmed in a multivariate analysis which took into account the effect of several other variables, including mean arterial pressure. Similar findings were obtained for cardiovascular mortality. When we replaced systolic blood pressure with mean arterial pressure in the model, PP did not retain its independent prognostic role, possibly because of the high co-linearity between these two variables (r = 0.87).For any given level of mean arterial pressure, a low PP is an independent predictor of all-cause and cardiovascular death in patients with heart failure. The association may be partly related to the strong influence of low systolic blood pressure on mortality. Different pathophysiological mechanisms may underlie the opposite prognostic significance of PP in hypertension and heart failure.

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23. Prognostic Impact of Diabetes and Prediabetes on Survival Outcomes in Patients With Chronic Heart Failure: A Post-Hoc Analysis of the GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca-Heart Failure) Trial

Author

Marco Dauriz, Giovanni Targher, Pier Luigi Temporelli, Donata Lucci, Lucio Gonzini, Gian Luigi Nicolosi, Roberto Marchioli, Gianni Tognoni, Roberto Latini, Franco Cosmi, Luigi Tavazzi, Aldo Pietro Maggioni, Simona Barlera, Maria Grazia Franzosi, Aldo P. Maggioni, Maurizio Porcu, Salim Yusuf, Fulvio Camerini, Jay N. Cohn, Adriano Decarli, Bertram Pitt, Peter Sleight, Philip A. Poole‐Wilson, Enrico Geraci, Marino Scherillo, Gianna Fabbri, Barbara Bartolomei, Daniele Bertoli, Franco Cobelli, Claudio Fresco, Antonietta Ledda, Giacomo Levantesi, Cristina Opasich, Franco Rusconi, Gianfranco Sinagra, Fabio Turazza, Alberto Volpi, Martina Ceseri, Gianluca Alongi, Antonio Atzori, Filippo Bambi, Desiree Bastarolo, Francesca Bianchini, Iacopo Cangioli, Vittoriana Canu, Concetta Caporusso, Gabriele Cenni, Laura Cintelli, Michele Cocchio, Alessia Confente, Eva Fenicia, Giorgio Friso, Marco Gianfriddo, Gianluca Grilli, Beatrice Lazzaro, Giuseppe Lonardo, Alessia Luise, Rachele Nota, Mariaelena Orlando, Rosaria Petrolo, Chiara Pierattini, Valeria Pierota, Alessandro Provenzani, Velia Quartuccio, Anna Ragno, Chiara Serio, Alvise Spolaor, Arianna Tafi, Elisa Tellaroli, Stefano Ghio, Elisa Ghizzardi, Serge Masson, Lella Crociati, Maria Teresa La Rovere, Ugo Corrà, Andrea Finzi, Marco Gorini, Valentina Milani, Giampietro Orsini, Elisa Bianchini, Silvia Cabiddu, Ilaria Cangioli, Laura Cipressa, Maria Lucia Cipressa, Giuseppina Di Bitetto, Barbara Ferri, Luisa Galbiati, Andrea Lorimer, Carla Pera, Paola Priami, Antonella Vasamì, T. Moccetti, M.G. Rossi, E. Pasotti, F. Vaghi, P. Roncarolo, M.T. Zunino, F. Matta, E. Actis Perinetto, F. Gaita, G. Azzaro, M. Zanetta, A.M. Paino, U. Parravicini, D. Vegis, R. Conte, P. Ferraro, A. De Bernardi, S. Morelloni, M. Fagnani, P. Greco Lucchina, L. Montagna, E. Bellone, D. Sappè, F. Ferraro, M. Delucchi, S.G. Reynaud, M. Dore, A. La Brocca, N. Massobrio, L. Bo, R. Trinchero, M. Imazio, G. Brocchi, A. Nejrotti, L. Rissone, S. Gabasio, C. Zocchi, S. Randazzo, A. Crenna, P. Giannuzzi, E. Bonanomi, A. Mezzani, M. De Marchi, G. Begliuomini, C.A. Gianonatti, A. Gavazzi, A. Grosu, L. Dei Cas, S. Nodari, P. Garyfallidis, A. Bertoletti, C. Bonifazi, S. Arisi, F. Mascaro, M. Fraccarollo, S. Dell'Orto, M. Sfolcini, F. Bortolini, D. Raccagni, A. Turelli, M. Santarone, E. Miglierina, L. Sormani, R. Jemoli, F. Tettamanti, S. Pirelli, C. Bianchi, S. Verde, M. Mariani, V. Ziacchi, A. Ferrazza, A. Russo, M. Bortolotti, G.F. Pasini, A. Volpi, K.N. Jones, D. Cuzzucrea, G. Gullace, C. Carbone, A. Granata, S. De Servi, G. Del Rosso, C. Inserra, E. Renaldini, C. Zappa, M. Moretti, R. Zanini, M. Ferrari, E. Moroni, A. Cei, C. Lissi, E. Dovico, C. Fiorentini, P. Palermo, B. Brusoni, M. Negrini, J. Heyman, G.B. Danzi, A. Finzi, M. Frigerio, F. Turazza, L. Beretta, A. Sachero, F. Casazza, L. Squadroni, F. Lombardi, L. Marano, A. Margonato, G. Fragasso, O.C. Febo, E. Aiolfi, F. Olmetti, A. Grieco, V. Antonazzo, G. Specchia, A. Mortara, F. Robustelli, M.G. Songini, C. Schweiger, A. Frisinghelli, M. Palvarini, C. Campana, L. Scelsi, N. Ajmone Marsan, F. Cobelli, A. Gualco, C. Opasich, S. De Feo, R. Mazzucco, M.A. Iannone, T. Diaco, D. Zaniboni, G. Milanesi, D. Nassiacos, S. Meloni, P. Giani, T. Nicoli, C. Malinverni, A. Gusmini, L. Pozzoni, G. Bisiani, P. Margaroli, A. Schizzarotto, A. Daverio, G. Occhi, N. Partesana, P. Bandini, M.G. Rosella, S. Giustiniani, G. Cucchi, R. Pedretti, R. Raimondo, R. Vaninetti, A. Fedele, I. Ghezzi, E. Rezzonico, J.A. Salerno Uriarte, F. Morandi, F. Salvucci, C. Valenti, G. Graziano, M. Romanò, C. Cimminiello, I. Mangone, M. Lombardo, P. Quorso, G. Marinoni, M. Breghi, M. Erckert, A. Dienstl, G. Mirante Marini, C. Stefenelli, G. Cioffi, E. Buczkowska, A. Bonanome, F. Bazzanini, L. Parissenti, C. Serafini, G. Catania, L. Tarantini, G. Rigatelli, S. Boni, A. Pasini, E. Masini, A.A. Zampiero, M. Zanchetta, L. Franceschetto, P. Delise, C. Marcon, A. Sacchetta, L. Borgese, L. Artusi, P. Casolino, F. Corbara, A. Banzato, M. Barbiero, M.P. Aldegheri, R. Bazzucco, G. Crivellenti, A. Raviele, C. Zanella, P. Pascotto, P. Sarto, S. Milan, E. Barbieri, P. Girardi, W. Dalla Villa, J. Dalle Mule, M.L. Di Sipio, R. Cazzin, D. Milan, P. Zonzin, M. Carraro, R. Rossi, E. Carbonieri, I. Rossi, P. Stritoni, P. Meneghetti, G. Risica, P.L. Tenderini, C. Vassanelli, L. Zanolla, G. Perini, G. Brighetti, R. Chiozza, G. Giuliano, R. Gortan, R. Cesanelli, G.L. Nicolosi, R. Piazza, L. Mos, O. Vriz, D. Pavan, G. Pascottini, E. Alberti, M. Werren, L. Solinas, G. Sinagra, F. Longaro, P. Fioretti, M.C. Albanese, D. Miani, R. Gianrossi, A. Pende, P. Rubartelli, O. Magaia, S. Domenicucci, D. Caruso, A.S. Faraguti, L. Magliani, F. Miccoli, G. Guglielmino, D. Bertoli, A. Cantarelli, S. Orlandi, A. Vallebona, A. Pozzati, G. Brega, L.G. Pancaldi, R. Vandelli, S. Urbinati, M.G. Poci, M. Zoli, G.M. Costa, U. Guiducci, G. Zobbi, F. Tartagni, A. Tisselli, A. Gentili, P. Pieri, E. Cagnetta, S. Bendinelli, A. Barbieri, R. Conti, R. Ferrari, F. Merlini, A. Fucili, P. Moruzzi, E. Buia, M. Galvani, D. Ferrini, G. Baggioni, P. Yiannacopulu, G. Canè, A. Bonfiglioli, R. Zandomeneghi, L. Brugioni, A. Giannini, R. Di Ruvo, M. Giuliani, L. Rusconi, P. Del Corso, G. Piovaccari, F. Bologna, P. Venturi, F. Melandri, E. Bagni, L. Bolognese, R. Perticucci, A. Zuppiroli, M. Nannini, N. Consoli, P. Petrone, C. Pipitò, L. Colombi, D. Bernardi, P.R. Mariani, R. Testa, F. Mazzinghi, F. Cosmi, D. Cosmi, A. Zipoli, A. Cecchi, G. Castelli, M. Ciaccheri, F. Mori, F. Pieri, P. Valoti, D. Chiarantini, G.M. Santoro, C. Minneci, F. Marchi, M. Milli, G. Zambaldi, A.A. Brandinelli Geri, M. Cipriani, M. Alessandri, S. Severi, S. Stefanelli, A. Comella, R. Poddighe, A. Digiorgio, M. Carluccio, S. Berti, A. Rizza, V. Bonatti, V. Molendi, A. Brancato, N. D'Aprile, G. Giappichini, S. Del Vecchio, G. Mantini, F. De Tommasi, G. Meucci, M. Cordoni, S. Bechi, L. Barsotti, P. Baldini, M. Romei, G. Scopelliti, G. Lauri, F. Pestelli, F. Furiozzi, M. Cocchieri, D. Severini, F. Patriarchi, P. Chiocchi, M. Buccolieri, S. Martinelli, A. Wee, F. Angelici, M. Bernardinangeli, G. Proietti, B. Biscottini, R. Panciarola, L. Marinacci, G.P. Perna, D. Gabrielli, A. Moraca, L. Moretti, L. Partemi, G. Gregori, R. Amici, G. Patteri, P. Capone, E. Savini, G.L. Morgagni, L. Paccaloni, F. Pezzuoli, S. Carincola, S. Papi, S. De Crescentini, P. Gerardi, P. Midi, E. Gallenzi, G. Pajes, C. Mancone, V. Di Spirito, M. Di Gennaro, S. Calcagno, S. Toscano, S. Antonicoli, F. Carta, G. Giorgi, F. Comito, E. Daniele, O. Ciarla, P.G. Gelfo, A. Acquaviva, D. Testa, G. Testa, F.A. Pagliaro, F. Russo, F. Vetta, I. Marchese, G. Di Sciascio, A. D'Ambrosio, F. Leggio, D. Del Sindaco, A. Lacchè, A. Avallone, M.P. Risa, P. Azzolini, E. Baldo, E. Giovannini, G. Pulignano, C. Tondo, E. Picchio, E. ani, P. Tanzi, F. Pozzar, F. Farnetti, M. Azzarito, M. Santini, A. Varveri, G. Ferraiuolo, C. Valtorta, A. Gaspardone, G. Barbato, V. Ceci, N. Aspromonte, F. Bellocci, C. Colizzi, F. Fedele, F.I. Perez, A. Galati, A. Rossetti, A. Mainella, D. etta, C. Matteucci, G. Busi, A. De Angelis, G. Farina, A. Granatelli, F. Leone, F. Frasca, R. Di Giovambattista, G. Castellani, G. Massaro, G. Mastrogiuseppe, A. Vacri, F. De Sanctis, M. Cioli, S. Di Luzio, C. Napoletano, L.L. Piccioni, G. De Simone, A. Ottaviano, V. Mazza, C. Spedaliere, D. Staniscia, E. Calgione, G. De Marco, T. Chiacchio, T. Di Napoli, S. Romanzi, G. Salvatore, P. Golino, A. Palermo, F. Mascia, A. Vetrano, A. Vinciguerra, L. Caliendo, R. Longobardi, G. De Caro, R. Di Nola, F. Piemonte, D. Prinzi, P. De Rosa, V. De Rosa, F. Riello, V. Capuano, G. Vecchio, M. Landi, S. Amato, M. Garofalo, M. D'Avino, P. Sensale, O. Maiolica, R. Santoro, P. Caso, D. Miceli, N. Maurea, U. Bianchi, C. Crispo, M. Chiariello, P. Perrone Filardi, L. Russo, N. Capuano, G. Ungaro, G. Vergara, F. Scafuro, G. D'Angelo, C. Campaniello, P. Bottiglieri, A. Volpe, R. Battista, L. De Risi, G. Cardillo, G. Sibilio, A.P. Marino, F. Silvestri, P. Predotti, A. Iervoglini, C. De Matteis, P. Sarnicola, M.M. Matarazzo, S. Baldi, V. Iuliano, C. Astarita, P. Cuccaro, A. Liguori, G. Liguori, G. Gregorio, L. Petraglia, G. Antonelli, G. Amodio, I. De Luca, D. Traversa, G. Franchini, M.L. Lenti, D. Cavallari, C. D'Agostino, G. Scalera, C.M. Altamura, M. Russo, A.R. Mascolo, G. Pettinati, S.A. Ciricugno, D. Scrutinio, A. Passantino, D. Mastrangelo, A. Di Masi, R. De Carne, M. Cannone, F. Dibiase, M. Pensato, F. Loliva, F. Trapani, I. Panettieri, L. Leone, M. Di Biase, M. Carrone, V. Gallone, F. Cocco, M. Costantini, C. Tritto, F. Cavalieri, L. Stella, F. Magliari, M. Callerame, A. De Giorgi, L. Pellegrino, M. Correra, V. Portulano, G.L. Nisi, G. Grassi, E. Cristallo, D. De Laura, C. Salerno, R. Fanelli, M. Villella, S. Pede, A. Renna, E. De Lorenzi, L. Urso, V. Lenti, A. Peluso, N. Baldi, G. Polimeni, P. Palma, R. Lauletta, E. Tagliamonte, T. Cirillo, B. Silvestri, G. Centonze, B. D'Alessandro, L. Truncellito, D. Mecca, M.A. Petruzzi, R.O.M. Coviello, A. Lopizzo, M. telli, S. Barbuzzi, S. Gubelli, G. Germinario, N. Cosentino, A. Mingrone, R. Vico, G. Borrello, M.L. Mazza, R. Cimino, D. Galasso, F. Cassadonte, U. Talarico, F. Perticone, S. Cassano, F. Catapano, S. Calemme, E. Feraco, C. Cloro, G. Misuraca, R. Caporale, L. Vigna, V. Spagnuolo, F. De Rosa, G. Spadafora, G. Zampaglione, R. Russo, F.A. Schipani, A.F. Ferragina, D. Stranieri, G. Musca, C. Carpino, P. Bencardino, F. Raimondo, D. Musacchio, G. Pulitanò, A. Ruggeri, A. Provenzano, S. Salituri, M. Musolino, S. Calandruccio, A. Marrari, E. Tripodi, R. Scali, L. Anastasio, A. Arone, P. Aragona, L. Donnangelo, M.G.A. Comito, F. Bilotta, I. Vaccaro, R. Rametta, V. Ventura, A. Bonvegna, A. Alì, C. Cinnirella, M. Raineri, F. Pompeo, N. Cascio Ingurgio, V. Carini, R. Coco, G. Giunta, G. Leonardi, V. Randazzo, V. Di Blasi, C. Tamburino, G. Russo, S. Mangiameli, R. Cardillo, D. Castelli, V. Inserra, A. Arena, M.M. Gulizia, S. Raciti, G. Rapisarda, R. Romano, P. Prestifilippo, G.B. Braschi, G. Ledda, R. Terrazzino, M. De Caro, G. Scilabra, B. agnino, R. Grassi, G. Di Tano, G.F. Scimone, L. Vasquez, C. Coppolino, A. Casale, M. Castelli, G. D'Urso, E. D'Antonio, L. Lo Presti, E. Badalamenti, P. Conti, N. Sanfilippo, V. Cirrincione, M.T. Cinà, G. Cusimano, A. Taormina, P. Giuliano, A. Bajardi, V. Mandalà, A. Canonico, G. Geraci, F.P. Sabella, F. Enia, A.M. Floresta, I. Lo Cascio, D. Gumina, A. Cavallaro, G. Piccione, R. Ferrante, M. Blandino, M.S. Iudicello, E. Mossuti, G. Romano, L. Lombardo, P. Monastra, D. Di Vincenzo, M. Porcu, P. Orrù, F. Muscas, G. Giardina, M. Corda, G. Locci, A. Podda, M. Ledda, P. Siddi, C. Lai, G. Pili, G. Mercuro, G. Mureddu, A. Ganau, G. Meloni, G. Poddighe, G. Sanna, Dauriz, Marco, Targher, Giovanni, Temporelli, Pier Luigi, Lucci, Donata, Gonzini, Lucio, Nicolosi, Gian Luigi, Marchioli, Roberto, Tognoni, Gianni, Latini, Roberto, Cosmi, Franco, Tavazzi, Luigi, Maggioni, Aldo Pietro, on behalf of the GISSI-HF, Investigator, Margonato, Alberto, Moccetti, T., Rossi, M. G., Pasotti, E., Vaghi, F., Roncarolo, P., Zunino, M. T., Matta, F., Actis Perinetto, E., Gaita, F., Azzaro, G., Zanetta, M., Paino, A. M., Parravicini, U., Vegis, D., Conte, R., Ferraro, P., De Bernardi, A., Morelloni, S., Fagnani, M., Greco Lucchina, P., Montagna, L., Bellone, E., Sappè, D., Ferraro, F., Delucchi, M., Reynaud, S. G., Dore, M., La Brocca, A., Massobrio, N., Bo, L., Trinchero, R., Imazio, M., Brocchi, G., Nejrotti, A., Rissone, L., Gabasio, S., Zocchi, C., Randazzo, S., Crenna, A., Giannuzzi, P., Bonanomi, E., Mezzani, A., De Marchi, M., Begliuomini, G., Gianonatti, C. A., Gavazzi, A., Grosu, A., Dei Cas, L., Nodari, S., Garyfallidis, P., Bertoletti, A., Bonifazi, C., Arisi, S., Mascaro, F., Fraccarollo, M., Dell'Orto, S., Sfolcini, M., Bortolini, F., Raccagni, D., Turelli, A., Santarone, M., Miglierina, E., Sormani, L., Jemoli, R., Tettamanti, F., Pirelli, S., Bianchi, C., Verde, S., Mariani, M., Ziacchi, V., Ferrazza, A., Russo, A., Bortolotti, M., Pasini, G. F., Volpi, A., Jones, K. N., Cuzzucrea, D., Gullace, G., Carbone, C., Granata, A., De Servi, S., Del Rosso, G., Inserra, C., Renaldini, E., Zappa, C., Moretti, M., Zanini, R., Ferrari, M., Moroni, E., Cei, A., Lissi, C., Dovico, E., Fiorentini, C., Palermo, P., Brusoni, B., Negrini, M., Heyman, J., Danzi, G. B., Finzi, A., Frigerio, M., Turazza, F., Beretta, L., Sachero, A., Casazza, F., Squadroni, L., Lombardi, F., Marano, L., Margonato, A., Fragasso, G., Febo, O. C., Aiolfi, E., Olmetti, F., Grieco, A., Antonazzo, V., Specchia, G., Mortara, A., Robustelli, F., Songini, M. G., Schweiger, C., Frisinghelli, A., Palvarini, M., Campana, C., Scelsi, L., Ajmone Marsan, N., Cobelli, F., Gualco, A., Opasich, C., De Feo, S., Mazzucco, R., Iannone, M. A., Diaco, T., Zaniboni, D., Milanesi, G., Nassiacos, D., Meloni, S., Giani, P., Nicoli, T., Malinverni, C., Gusmini, A., Pozzoni, L., Bisiani, G., Margaroli, P., Schizzarotto, A., Daverio, A., Occhi, G., Partesana, N., Bandini, P., Rosella, M. G., Giustiniani, S., Cucchi, G., Pedretti, R., Raimondo, R., Vaninetti, R., Fedele, A., Ghezzi, I., Rezzonico, E., Salerno Uriarte, J. A., Morandi, F., Salvucci, F., Valenti, C., Graziano, G., Romanò, M., Cimminiello, C., Mangone, I., Lombardo, M., Quorso, P., Marinoni, G., Breghi, M., Erckert, M., Dienstl, A., Mirante Marini, G., Stefenelli, C., Cioffi, G., Buczkowska, E., Bonanome, A., Bazzanini, F., Parissenti, L., Serafini, C., Catania, G., Tarantini, L., Rigatelli, G., Boni, S., Pasini, A., Masini, E., Zampiero, A. A., Zanchetta, M., Franceschetto, L., Delise, P., Marcon, C., Sacchetta, A., Borgese, L., Artusi, L., Casolino, P., Corbara, F., Banzato, A., Barbiero, M., Aldegheri, M. P., Bazzucco, R., Crivellenti, G., Raviele, A., Zanella, C., Pascotto, P., Sarto, P., Milan, S., Barbieri, E., Girardi, P., Dalla Villa, W., Dalle Mule, J., Di Sipio, M. L., Cazzin, R., Milan, D., Zonzin, P., Carraro, M., Rossi, R., Carbonieri, E., Rossi, I., Stritoni, P., Meneghetti, P., Risica, G., Tenderini, P. L., Vassanelli, C., Zanolla, L., Perini, G., Brighetti, G., Chiozza, R., Giuliano, G., Baldin, M. G., Gortan, R., Cesanelli, R., Nicolosi, G. L., Piazza, R., Mos, L., Vriz, O., Pavan, D., Pascottini, G., Alberti, E., Werren, M., Solinas, L., Sinagra, G., Longaro, F., Fioretti, P., Albanese, M. C., Miani, D., Gianrossi, R., Pende, A., Rubartelli, P., Magaia, O., Domenicucci, S., Caruso, D., Faraguti, A. S., Magliani, L., Miccoli, F., Guglielmino, G., Bertoli, D., Cantarelli, A., Orlandi, S., Vallebona, A., Pozzati, A., Brega, G., Pancaldi, L. G., Vandelli, R., Urbinati, S., Poci, M. G., Zoli, M., Costa, G. M., Guiducci, U., Zobbi, G., Tartagni, F., Tisselli, A., Gentili, A., Pieri, P., Cagnetta, E., Bendinelli, S., Barbieri, A., Conti, R., Ferrari, R., Merlini, F., Fucili, A., Moruzzi, P., Buia, E., Galvani, M., Ferrini, D., Baggioni, G., Yiannacopulu, P., Canè, G., Bonfiglioli, A., Zandomeneghi, R., Brugioni, L., Giannini, A., Di Ruvo, R., Giuliani, M., Rusconi, L., Del Corso, P., Piovaccari, G., Bologna, F., Venturi, P., Melandri, F., Bagni, E., Bolognese, L., Perticucci, R., Zuppiroli, A., Nannini, M., Consoli, N., Petrone, P., Pipitò, C., Colombi, L., Bernardi, D., Mariani, P. R., Testa, R., Mazzinghi, F., Cosmi, F., Cosmi, D., Zipoli, A., Cecchi, A., Castelli, G., Ciaccheri, M., Mori, F., Pieri, F., Valoti, P., Chiarantini, D., Santoro, G. M., Minneci, C., Marchi, F., Milli, M., Zambaldi, G., Brandinelli Geri, A. A., Cipriani, M., Alessandri, M., Severi, S., Stefanelli, S., Comella, A., Poddighe, R., Digiorgio, A., Carluccio, M., Berti, S., Rizza, A., Bonatti, V., Molendi, V., Brancato, A., D'Aprile, N., Giappichini, G., Del Vecchio, S., Mantini, G., De Tommasi, F., Meucci, G., Cordoni, M., Bechi, S., Barsotti, L., Baldini, P., Romei, M., Scopelliti, G., Lauri, G., Pestelli, F., Furiozzi, F., Cocchieri, M., Severini, D., Patriarchi, F., Chiocchi, P., Buccolieri, M., Martinelli, S., Wee, A., Angelici, F., Bernardinangeli, M., Proietti, G., Biscottini, B., Panciarola, R., Marinacci, L., Perna, G. P., Gabrielli, D., Moraca, A., Moretti, L., Partemi, L., Gregori, G., Amici, R., Patteri, G., Capone, P., Savini, E., Morgagni, G. L., Paccaloni, L., Pezzuoli, F., Carincola, S., Papi, S., De Crescentini, S., Gerardi, P., Midi, P., Gallenzi, E., Pajes, G., Mancone, C., Di Spirito, V., Di Gennaro, M., Calcagno, S., Toscano, S., Antonicoli, S., Carta, F., Giorgi, G., Comito, F., Daniele, E., Ciarla, O., Gelfo, P. G., Acquaviva, A., Testa, D., Testa, G., Pagliaro, F. A., Russo, F., Vetta, F., Marchese, I., Di Sciascio, G., D'Ambrosio, A., Leggio, F., Del Sindaco, D., Lacchè, A., Avallone, A., Risa, M. P., Azzolini, P., Baldo, E., Giovannini, E., Pulignano, G., Tondo, C., Picchio, E., Biffani, E., Tanzi, P., Pozzar, F., Farnetti, F., Azzarito, M., Santini, M., Varveri, A., Ferraiuolo, G., Valtorta, C., Gaspardone, A., Barbato, G., Ceci, V., Aspromonte, N., Bellocci, F., Colizzi, C., Fedele, F., Perez, F. I., Galati, A., Rossetti, A., Mainella, A., Ciuffetta, D., Matteucci, C., Busi, G., De Angelis, A., Farina, G., Granatelli, A., Leone, F., Frasca, F., Di Giovambattista, R., Castellani, G., Massaro, G., Mastrogiuseppe, G., Vacri, A., De Sanctis, F., Cioli, M., Di Luzio, S., Napoletano, C., Piccioni, L. L., De Simone, G., Ottaviano, A., Mazza, V., Spedaliere, C., Staniscia, D., Calgione, E., De Marco, G., Chiacchio, T., Di Napoli, T., Romanzi, S., Salvatore, G., Golino, P., Palermo, A., Mascia, F., Vetrano, A., Vinciguerra, A., Caliendo, L., Longobardi, R., De Caro, G., Di Nola, R., Piemonte, F., Prinzi, D., De Rosa, P., De Rosa, V., Riello, F., Capuano, V., Vecchio, G., Landi, M., Amato, S., Garofalo, M., D'Avino, M., Sensale, P., Maiolica, O., Santoro, R., Caso, P., Miceli, D., Maurea, N., Bianchi, U., Crispo, C., Chiariello, M., Perrone Filardi, P., Russo, L., Capuano, N., Ungaro, G., Vergara, G., Scafuro, F., D'Angelo, G., Campaniello, C., Bottiglieri, P., Volpe, A., Battista, R., De Risi, L., Cardillo, G., Sibilio, G., Marino, A. P., Silvestri, F., Predotti, P., Iervoglini, A., De Matteis, C., Sarnicola, P., Matarazzo, M. M., Baldi, S., Iuliano, V., Astarita, C., Cuccaro, P., Liguori, A., Liguori, G., Gregorio, G., Petraglia, L., Antonelli, G., Amodio, G., De Luca, I., Traversa, D., Franchini, G., Lenti, M. L., Cavallari, D., D'Agostino, C., Scalera, G., Altamura, C. M., Russo, M., Mascolo, A. R., Pettinati, G., Ciricugno, S. A., Scrutinio, D., Passantino, A., Mastrangelo, D., Di Masi, A., De Carne, R., Cannone, M., Dibiase, F., Pensato, M., Loliva, F., Trapani, F., Panettieri, I., Leone, L., Di Biase, M., Carrone, M., Gallone, V., Cocco, F., Costantini, M., Tritto, C., Cavalieri, F., Stella, L., Magliari, F., Callerame, M., De Giorgi, A., Pellegrino, L., Correra, M., Portulano, V., Nisi, G. L., Grassi, G., Cristallo, E., De Laura, D., Salerno, C., Fanelli, R., Villella, M., Pede, S., Renna, A., De Lorenzi, E., Urso, L., Lenti, V., Peluso, A., Baldi, N., Polimeni, G., Palma, P., Lauletta, R., Tagliamonte, E., Cirillo, T., Silvestri, B., Centonze, G., D'Alessandro, B., Truncellito, L., Mecca, D., Petruzzi, M. A., Coviello, R. O. M., Lopizzo, A., Chiaffitelli, M., Barbuzzi, S., Gubelli, S., Germinario, G., Cosentino, N., Mingrone, A., Vico, R., Borrello, G., Mazza, M. L., Cimino, R., Galasso, D., Cassadonte, F., Talarico, U., Perticone, F., Cassano, S., Catapano, F., Calemme, S., Feraco, E., Cloro, C., Misuraca, G., Caporale, R., Vigna, L., Spagnuolo, V., De Rosa, F., Spadafora, G., Zampaglione, G., Russo, R., Schipani, F. A., Ferragina, A. F., Stranieri, D., Musca, G., Carpino, C., Bencardino, P., Raimondo, F., Musacchio, D., Pulitanò, G., Ruggeri, A., Provenzano, A., Salituri, S., Musolino, M., Calandruccio, S., Marrari, A., Tripodi, E., Scali, R., Anastasio, L., Arone, A., Aragona, P., Donnangelo, L., Comito, M. G. A., Bilotta, F., Vaccaro, I., Rametta, R., Ventura, V., Bonvegna, A., Alì, A., Cinnirella, C., Raineri, M., Pompeo, F., Cascio Ingurgio, N., Carini, V., Coco, R., Giunta, G., Leonardi, G., Randazzo, V., Di Blasi, V., Tamburino, C., Russo, G., Mangiameli, S., Cardillo, R., Castelli, D., Inserra, V., Arena, A., Gulizia, M. M., Raciti, S., Rapisarda, G., Romano, R., Prestifilippo, P., Braschi, G. B., Ledda, G., Terrazzino, R., De Caro, M., Scilabra, G., Graffagnino, B., Grassi, R., Di Tano, G., Scimone, G. F., Vasquez, L., Coppolino, C., Casale, A., Castelli, M., D'Urso, G., D'Antonio, E., Lo Presti, L., Badalamenti, E., Conti, P., Sanfilippo, N., Cirrincione, V., Cinà, M. T., Cusimano, G., Taormina, A., Giuliano, P., Bajardi, A., Mandalà, V., Canonico, A., Geraci, G., Sabella, F. P., Enia, F., Floresta, A. M., Lo Cascio, I., Gumina, D., Cavallaro, A., Piccione, G., Ferrante, R., Blandino, M., Iudicello, M. S., Mossuti, E., Romano, G., Lombardo, L., Monastra, P., Di Vincenzo, D., Porcu, M., Orrù, P., Muscas, F., Giardina, G., Corda, M., Locci, G., Podda, A., Ledda, M., Siddi, P., Lai, C., Pili, G., Mercuro, G., Mureddu, G., Ganau, A., Meloni, G., Poddighe, G., Sanna, G., Barlera, Simona, Franzosi, Maria Grazia, Porcu, Maurizio, Yusuf, Salim, Camerini, Fulvio, Cohn, Jay N., Decarli, Adriano, Pitt, Bertram, Sleight, Peter, Poole-Wilson, Philip A., Geraci, Enrico, Scherillo, Marino, Fabbri, Gianna, Bartolomei, Barbara, Bertoli, Daniele, Cobelli, Franco, Fresco, Claudio, Ledda, Antonietta, Levantesi, Giacomo, Opasich, Cristina, Rusconi, Franco, Sinagra, Gianfranco, Turazza, Fabio, Volpi, Alberto, Ceseri, Martina, Alongi, Gianluca, Atzori, Antonio, Bambi, Filippo, Bastarolo, Desiree, Bianchini, Francesca, Cangioli, Iacopo, Canu, Vittoriana, Caporusso, Concetta, Cenni, Gabriele, Cintelli, Laura, Cocchio, Michele, Confente, Alessia, Fenicia, Eva, Friso, Giorgio, Gianfriddo, Marco, Grilli, Gianluca, Lazzaro, Beatrice, Lonardo, Giuseppe, Luise, Alessia, Nota, Rachele, Orlando, Mariaelena, Petrolo, Rosaria, Pierattini, Chiara, Pierota, Valeria, Provenzani, Alessandro, Quartuccio, Velia, Ragno, Anna, Serio, Chiara, Spolaor, Alvise, Tafi, Arianna, Tellaroli, Elisa, Ghio, Stefano, Ghizzardi, Elisa, Masson, Serge, Crociati, Lella, La Rovere, Maria Teresa, Corrà, Ugo, Di Giulio, Paola, Finzi, Andrea, Gorini, Marco, Milani, Valentina, Orsini, Giampietro, Bianchini, Elisa, Cabiddu, Silvia, Cangioli, Ilaria, Cipressa, Laura, Cipressa, Maria Lucia, Di Bitetto, Giuseppina, Ferri, Barbara, Galbiati, Luisa, Lorimer, Andrea, Pera, Carla, Priami, Paola, and Vasamì, Antonella

Subjects
Blood Glucose, Male, Glycated Hemoglobin A, heart failure, Kaplan-Meier Estimate, prediabetes, 030204 cardiovascular system & hematology, time factors, Settore MED/11, cause of death, 0302 clinical medicine, Glycemic control, prediabetic state, Cause of Death, italy, middle aged, Prevalence, 80 and over, double-blind method, blood glucose, risk factors, 030212 general & internal medicine, Prediabetes, Rosuvastatin Calcium, humans, rosuvastatin calcium, Cause of death, Original Research, Metabolic Syndrome, Aged, 80 and over, adult, Chronic heart failure, Diabetes mellitus, Heart failure, Mortality, Cardiology and Cardiovascular Medicine, Hazard ratio, chronic heart failure, diabetes mellitus, glycemic control, mortality, Treatment Outcome, Adolescent, Biomarkers, Chronic Disease, Diabetes Mellitus, Fatty Acids, Omega-3, Double-Blind Method, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hospitalization, Heart Failure, Italy, Prediabetic State, Risk Assessment, Proportional Hazards Models, Risk Factors, Time Factors, risk assessment, Middle Aged, kaplan-meier estimate, aged, female, Prediabete, young adult, Female, omega-3, Human, hospitalization, Adult, medicine.medical_specialty, Diabetes mellitu, proportional hazards models, Time Factor, hydroxymethylglutaryl-coa reductase inhibitors, prevalence, fatty acids, 03 medical and health sciences, Young Adult, male, Internal medicine, Post-hoc analysis, glycated hemoglobin a, medicine, Intensive care medicine, Aged, Glycated Hemoglobin, Proportional hazards model, business.industry, Risk Factor, biomarkers, Biomarker, medicine.disease, Clinical trial, adolescent, Proportional Hazards Model, treatment outcome, aged, 80 and over, chronic disease, fatty acids, omega-3, cardiology and cardiovascular medicine, Hydroxymethylglutaryl-CoA Reductase Inhibitor, business
Abstract

Background The independent prognostic impact of diabetes mellitus ( DM ) and prediabetes mellitus (pre‐ DM ) on survival outcomes in patients with chronic heart failure has been investigated in observational registries and randomized, clinical trials, but the results have been often inconclusive or conflicting. We examined the independent prognostic impact of DM and pre‐ DM on survival outcomes in the GISSI ‐HF (Gruppo Italiano per lo Studio della Sopravvivenza nella Insufficienza Cardiaca‐Heart Failure) trial. Methods and Results We assessed the risk of all‐cause death and the composite of all‐cause death or cardiovascular hospitalization over a median follow‐up period of 3.9 years among the 6935 chronic heart failure participants of the GISSI ‐ HF trial, who were stratified by presence of DM (n=2852), pre‐ DM (n=2013), and non‐ DM (n=2070) at baseline. Compared with non‐ DM patients, those with DM had remarkably higher incidence rates of all‐cause death (34.5% versus 24.6%) and the composite end point (63.6% versus 54.7%). Conversely, both event rates were similar between non‐ DM patients and those with pre‐ DM . Cox regression analysis showed that DM , but not pre‐ DM , was associated with an increased risk of all‐cause death (adjusted hazard ratio, 1.43; 95% CI , 1.28–1.60) and of the composite end point (adjusted hazard ratio, 1.23; 95% CI , 1.13–1.32), independently of established risk factors. In the DM subgroup, higher hemoglobin A1c was also independently associated with increased risk of both study outcomes (all‐cause death: adjusted hazard ratio, 1.21; 95% CI , 1.02–1.43; and composite end point: adjusted hazard ratio, 1.14; 95% CI , 1.01–1.29, respectively). Conclusions Presence of DM was independently associated with poor long‐term survival outcomes in patients with chronic heart failure. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00336336.

Published
2017
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24. Synaptophysin I selectively specifies the exocytic pathway of Synaptobrevin2/VAMP2

Author

Chiara Agnese Colombo, Fabio Benfenati, Flavia Valtorta, Dario Bonanomi, Laura Rusconi, Bonanomi, D, Rusconi, L, Colombo, C, Benfenati, F, and Valtorta, F

Subjects
Dynamins, Vesicle fusion, Vesicle-Associated Membrane Protein 2, Recombinant Fusion Proteins, Synaptophysin, Biochemistry, Synaptic vesicle, Exocytosis, Animals, Humans, Molecular Biology, Dynamin, Neurons, VAMP2, biology, Cell Membrane, SNAP25, Cell Biology, Cell biology, Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins, Protein Transport, Membrane protein, nervous system, biology.protein, sense organs, Research Article, HeLa Cells, Subcellular Fractions
Abstract

Biogenesis and recycling of synaptic vesicles are accompanied by sorting processes that preserve the molecular composition of the compartments involved. In the present study, we have addressed the targeting of synaptobrevin 2/VAMP2 (vesicle-associated membrane protein 2), a critical component of the synaptic vesicle­-fusion machinery, in a heterotypic context where its sorting is not confounded by the presence of other neuron-specific molecules. Ectopically expressed synaptophysin I interacts with VAMP2 and alters its default surface targeting to a prominent vesicular distribution, with no effect on the targeting of other membrane proteins. Protein–protein interaction is not sufficient for the control of VAMP2 sorting, which is mediated by the C-terminal domain of synaptophysin I. Synaptophysin I directs the sorting of VAMP2 to vesicles before surface delivery, without influencing VAMP2 endocytosis. Consistent with this, dynamin and α-SNAP (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein) mutants which block trafficking at the plasma membrane do not abrogate the effect of synaptophysin I on VAMP2 sorting. These results indicate that the sorting determinants of synaptic vesicle proteins can operate independently of a neuronal context and implicate the association of VAMP2 with synaptophysin I in the specification of the pathway of synaptic vesicle biogenesis.

Published
2007

25. 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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26. Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder.

Author

Vigli D, Rusconi L, Valenti D, La Montanara P, Cosentino L, Lacivita E, Leopoldo M, Amendola E, Gross C, Landsberger N, Laviola G, Kilstrup-Nielsen C, Vacca RA, and De Filippis B

Subjects
Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Brain metabolism, Disease Models, Animal, Disease Progression, Epileptic Syndromes metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Mitochondria metabolism, Phosphorylation drug effects, Prepulse Inhibition physiology, Protein Serine-Threonine Kinases deficiency, Protein Serine-Threonine Kinases genetics, Random Allocation, Receptors, Serotonin metabolism, Spasms, Infantile metabolism, Brain drug effects, Epileptic Syndromes drug therapy, Mitochondria drug effects, Piperazines pharmacology, Prepulse Inhibition drug effects, Serotonin Receptor Agonists pharmacology, Spasms, Infantile drug therapy
Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioural and physiological symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a critical role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 year old Cdkl5-null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HT 7 R) with the agonist molecule LP-211 (0.25 mg/kg once/day for 7 days) partially rescues the abnormal phenotype and brain molecular alterations in Cdkl5-null male mice. In particular, LP-211 treatment completely normalizes the prepulse inhibition defects observed in Cdkl5-null mice and, at a molecular level, restores the abnormal cortical phosphorylation of rpS6, a downstream target of mTOR and S6 kinase, which plays a direct role in regulating protein synthesis. Moreover, we demonstrate for the first time that mitochondria show prominent functional abnormalities in Cdkl5-null mouse brains that can be restored by pharmacological stimulation of brain 5-HT 7 R., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2019
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27. The antidepressant tianeptine reverts synaptic AMPA receptor defects caused by deficiency of CDKL5.

Author

Tramarin M, Rusconi L, Pizzamiglio L, Barbiero I, Peroni D, Scaramuzza L, Guilliams T, Cavalla D, Antonucci F, and Kilstrup-Nielsen C

Subjects
Animals, Antidepressive Agents administration & dosage, Disks Large Homolog 4 Protein genetics, Epileptic Syndromes genetics, Epileptic Syndromes pathology, Gene Expression Regulation drug effects, Hippocampus drug effects, Hippocampus physiopathology, Humans, Mice, Mutation, Neurogenesis drug effects, Neurons drug effects, Neurons pathology, Phosphorylation, Primary Cell Culture, Protein Serine-Threonine Kinases deficiency, Spasms, Infantile genetics, Spasms, Infantile pathology, Synapses drug effects, Synapses genetics, Epileptic Syndromes drug therapy, Protein Serine-Threonine Kinases genetics, Receptors, AMPA genetics, Spasms, Infantile drug therapy, Thiazepines administration & dosage
Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a complex neurological disorder, characterized by infantile seizures, impairment of cognitive and motor skills and autistic features. Loss of Cdkl5 in mice affects dendritic spine maturation and dynamics but the underlying molecular mechanisms are still far from fully understood. Here we show that Cdkl5 deficiency in primary hippocampal neurons leads to deranged expression of the alpha-amino-3-hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPA-R). In particular, a dramatic reduction of expression of the GluA2 subunit occurs concomitantly with its hyper-phosphorylation on Serine 880 and increased ubiquitination. Consequently, Cdkl5 silencing skews the composition of membrane-inserted AMPA-Rs towards the GluA2-lacking calcium-permeable form. Such derangement is likely to contribute, at least in part, to the altered synaptic functions and cognitive impairment linked to loss of Cdkl5. Importantly, we find that tianeptine, a cognitive enhancer and antidepressant drug, known to recruit and stabilise AMPA-Rs at the synaptic sites, can normalise the expression of membrane inserted AMPA-Rs as well as the number of PSD-95 clusters, suggesting its therapeutic potential for patients with mutations in CDKL5.

Published
2018
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28. The neurosteroid pregnenolone reverts microtubule derangement induced by the loss of a functional CDKL5-IQGAP1 complex.

Author

Barbiero I, Peroni D, Tramarin M, Chandola C, Rusconi L, Landsberger N, and Kilstrup-Nielsen C

Subjects
Actins metabolism, Animals, COS Cells, Cell Movement physiology, Chlorocebus aethiops, HeLa Cells, Humans, Mice, Microtubule-Associated Proteins metabolism, Microtubules metabolism, Microtubules pathology, Neoplasm Proteins metabolism, Neurons metabolism, Neurotransmitter Agents metabolism, Protein Binding, ras GTPase-Activating Proteins genetics, ras GTPase-Activating Proteins metabolism, Pregnenolone metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism
Abstract

CDKL5 is a protein kinase that plays a key role for neuronal functions as testified by the onset of complex neuronal dysfunctions in patients with genetic lesions in CDKL5. Here we identify a novel interactor of CDKL5, IQGAP1, a fundamental regulator of cell migration and polarity. In accordance with a functional role of this interaction, depletion of CDKL5 impairs cell migration and impedes the localization of IQGAP1 at the leading edge. Moreover, we demonstrate that CDKL5 is required for IQGAP1 to form a functional complex with its effectors, Rac1 and the microtubule plus end tracking protein CLIP170. These defects eventually impact on the microtubule association of CLIP170, thus deranging their dynamics. CLIP170 is a cellular target of the neurosteroid pregnenolone; by blocking CLIP170 in its active conformation, pregnenolone is capable of restoring the microtubule association of CLIP170 in CDKL5 deficient cells and rescuing morphological defects in neurons devoid of CDKL5. These findings provide novel insights into CDKL5 functions and pave the way for target-specific therapeutic strategies for individuals affected with CDKL5-disorder., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2017
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29. 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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30. CDKL5 and Shootin1 Interact and Concur in Regulating Neuronal Polarization.

Author

Nawaz MS, Giarda E, Bedogni F, La Montanara P, Ricciardi S, Ciceri D, Alberio T, Landsberger N, Rusconi L, and Kilstrup-Nielsen C

Subjects
Animals, Hippocampus cytology, Mice, Nerve Tissue Proteins genetics, Protein Serine-Threonine Kinases genetics, Axons metabolism, Cell Polarity physiology, Hippocampus metabolism, Nerve Tissue Proteins metabolism, Protein Serine-Threonine Kinases metabolism
Abstract

In the last years, the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene has been associated with epileptic encephalopathies characterized by the early onset of intractable epilepsy, severe developmental delay, autistic features, and often the development of Rett syndrome-like features. Still, the role of CDKL5 in neuronal functions is not fully understood. By way of a yeast two hybrid screening we identified the interaction of CDKL5 with shootin1, a brain specific protein acting as a determinant of axon formation during neuronal polarization. We found evidence that CDKL5 is involved, at least in part, in regulating neuronal polarization through its interaction with shootin1. Indeed, the two proteins interact in vivo and both are localized in the distal tip of outgrowing axons. By using primary hippocampal neurons as model system we find that adequate CDKL5 levels are required for axon specification. In fact, a significant number of neurons overexpressing CDKL5 is characterized by supernumerary axons, while the silencing of CDKL5 disrupts neuronal polarization. Interestingly, shootin1 phosphorylation is reduced in neurons silenced for CDKL5 suggesting that the kinase affects, directly or indirectly, the post-translational modification of shootin1. Finally, we find that the capacity of CDKL5 to generate surplus axons is attenuated in neurons with reduced shootin1 levels, in agreement with the notion that two proteins act in a common pathway. Altogether, these results point to a role of CDKL5 in the early steps of neuronal differentiation that can be explained, at least in part, by its association with shootin1.

Published
2016
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31. Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5.

Author

La Montanara P, Rusconi L, Locarno A, Forti L, Barbiero I, Tramarin M, Chandola C, Kilstrup-Nielsen C, and Landsberger N

Subjects
Animals, Apoptosis, Blotting, Western, Cells, Cultured, Cerebral Cortex cytology, Cerebral Cortex metabolism, Electrophysiology, Fluorescent Antibody Technique, Hippocampus cytology, Hippocampus metabolism, Mice, Neurons cytology, Phosphorylation, Protein Biosynthesis, Protein Phosphatase 1 genetics, Protein Serine-Threonine Kinases genetics, Proteolysis, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Receptors, N-Methyl-D-Aspartate genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Neurons metabolism, Proteasome Endopeptidase Complex metabolism, Protein Phosphatase 1 metabolism, Protein Serine-Threonine Kinases metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Synapses physiology
Abstract

Mutations in the X-linked CDKL5 (cyclin-dependent kinase-like 5) gene have been associated with several forms of neurodevelopmental disorders, including atypical Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy. Accordingly, loss of CDKL5 in mice results in autistic-like features and impaired neuronal communication. Although the biological functions of CDKL5 remain largely unknown, recent pieces of evidence suggest that CDKL5 is involved in neuronal plasticity. Herein, we show that, at all stages of development, neuronal depolarization induces a rapid increase in CDKL5 levels, mostly mediated by extrasomatic synthesis. In young neurons, this induction is prolonged, whereas in more mature neurons, NMDA receptor stimulation induces a protein phosphatase 1-dependent dephosphorylation of CDKL5 that is mandatory for its proteasome-dependent degradation. As a corollary, neuronal activity leads to a prolonged induction of CDKL5 levels in immature neurons but to a short lasting increase of the kinase in mature neurons. Recent results demonstrate that many genes associated with autism spectrum disorders are crucial components of the activity-dependent signaling networks regulating the composition, shape, and strength of the synapse. Thus, we speculate that CDKL5 deficiency disrupts activity-dependent signaling and the consequent synapse development, maturation, and refinement., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Published
2015
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32. MeCP2 post-translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis?

Author

Bellini E, Pavesi G, Barbiero I, Bergo A, Chandola C, Nawaz MS, Rusconi L, Stefanelli G, Strollo M, Valente MM, Kilstrup-Nielsen C, and Landsberger N

Abstract

Although Rett syndrome (RTT) represents one of the most frequent forms of severe intellectual disability in females worldwide, we still have an inadequate knowledge of the many roles played by MeCP2 (whose mutations are responsible for most cases of RTT) and their relevance for RTT pathobiology. Several studies support a role of MeCP2 in the regulation of synaptic plasticity and homeostasis. At the molecular level, MeCP2 is described as a repressor capable of inhibiting gene transcription through chromatin compaction. Indeed, it interacts with several chromatin remodeling factors, such as HDAC-containing complexes and ATRX. Other studies have inferred that MeCP2 functions also as an activator; a role in regulating mRNA splicing and in modulating protein synthesis has also been proposed. Further, MeCP2 avidly binds both 5-methyl- and 5-hydroxymethyl-cytosine. Recent evidence suggests that it is the highly disorganized structure of MeCP2, together with its post-translational modifications (PTMs) that generate and regulate this functional versatility. Indeed, several reports have demonstrated that differential phosphorylation of MeCP2 is a key mechanism by which the methyl binding protein modulates its affinity for its partners, gene expression and cellular adaptations to stimuli and neuronal plasticity. As logic consequence, generation of phospho-defective Mecp2 knock-in mice has permitted associating alterations in neuronal morphology, circuit formation, and mouse behavioral phenotypes with specific phosphorylation events. MeCP2 undergoes various other PTMs, including acetylation, ubiquitination and sumoylation, whose functional roles remain largely unexplored. These results, together with the genome-wide distribution of MeCP2 and its capability to substitute histone H1, recall the complex regulation of histones and suggest the relevance of quickly gaining a deeper comprehension of MeCP2 PTMs, the respective writers and readers and the consequent functional outcomes.

Published
2014
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33. What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy.

Author

Kilstrup-Nielsen C, Rusconi L, La Montanara P, Ciceri D, Bergo A, Bedogni F, and Landsberger N

Subjects
Animals, Epilepsy diagnosis, Epilepsy metabolism, Humans, Intellectual Disability diagnosis, Intellectual Disability genetics, Intellectual Disability metabolism, Lennox Gastaut Syndrome, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Rett Syndrome diagnosis, Rett Syndrome genetics, Rett Syndrome metabolism, Signal Transduction genetics, Spasms, Infantile diagnosis, Spasms, Infantile genetics, Spasms, Infantile metabolism, Epilepsy genetics, Mutation genetics, Protein Serine-Threonine Kinases physiology
Abstract

In the last few years, the X-linked serine/threonine kinase cyclin-dependent kinase-like 5 (CDKL5) has been associated with early-onset epileptic encephalopathies characterized by the manifestation of intractable epilepsy within the first weeks of life, severe developmental delay, profound hypotonia, and often the presence of some Rett-syndrome-like features. The association of CDKL5 with neurodevelopmental disorders and its high expression levels in the maturing brain underscore the importance of this kinase for proper brain development. However, our present knowledge of CDKL5 functions is still rather limited. The picture that emerges from the molecular and cellular studies suggests that CDKL5 functions are important for regulating both neuronal morphology through cytoplasmic signaling pathways and activity-dependent gene expression in the nuclear compartment. This paper surveys the current state of CDKL5 research with emphasis on the clinical symptoms associated with mutations in CDKL5, the different mechanisms regulating its functions, and the connected molecular pathways. Finally, based on the available data we speculate that CDKL5 might play a role in neuronal plasticity and we adduce and discuss some possible arguments supporting this hypothesis.

Published
2012
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34. Extrasynaptic N-methyl-D-aspartate (NMDA) receptor stimulation induces cytoplasmic translocation of the CDKL5 kinase and its proteasomal degradation.

Author

Rusconi L, Kilstrup-Nielsen C, and Landsberger N

Subjects
Active Transport, Cell Nucleus drug effects, Active Transport, Cell Nucleus physiology, Animals, Cell Nucleus genetics, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Enzymologic physiology, Glutamic Acid pharmacology, Hippocampus cytology, Humans, Mice, Neurons cytology, Proteasome Endopeptidase Complex genetics, Protein Serine-Threonine Kinases genetics, Receptors, N-Methyl-D-Aspartate genetics, Cell Nucleus metabolism, Hippocampus metabolism, Neurons metabolism, Proteasome Endopeptidase Complex metabolism, Protein Serine-Threonine Kinases metabolism, Receptors, N-Methyl-D-Aspartate metabolism
Abstract

Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been found in patients with epileptic encephalopathy characterized by early onset intractable epilepsy, including infantile spasms and other types of seizures, severe developmental delay, and often the development of Rett syndrome-like features. Despite its clear involvement in proper brain development, CDKL5 functions are still far from being understood. In this study, we analyzed the subcellular localization of the endogenous kinase in primary murine hippocampal neurons. CDKL5 was localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments. Nevertheless, glutamate stimulation was able to induce the exit of the kinase from the nucleus and its subsequent accumulation in the perinuclear cytoplasm. Moreover, we found that sustained glutamate stimulation promoted CDKL5 proteasomal degradation. Both events were mediated by the specific activation of extrasynaptic pool of N-methyl-d-aspartate receptors. Proteasomal degradation was also induced by withdrawal of neurotrophic factors and hydrogen peroxide treatment, two different paradigms of cell death. Altogether, our results indicate that both subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-D-aspartate receptors and suggest regulation of CDKL5 by cell death pathways.

Published
2011
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35. Identification of candidate substrates for poly(ADP-ribose) polymerase-2 (PARP2) in the absence of DNA damage using high-density protein microarrays.

Author

Troiani S, Lupi R, Perego R, Depaolini SR, Thieffine S, Bosotti R, and Rusconi L

Subjects
Adenosine Diphosphate metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Humans, Minichromosome Maintenance Complex Component 2, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Nuclear Proteins genetics, Nuclear Proteins metabolism, Poly(ADP-ribose) Polymerases genetics, Tacrolimus Binding Proteins genetics, Tacrolimus Binding Proteins metabolism, DNA Damage, Poly(ADP-ribose) Polymerases metabolism, Protein Array Analysis methods
Abstract

Poly(ADP-ribose) polymerase-2 (PARP2) belongs to the ADP-ribosyltransferase family of enzymes that catalyze the addition of ADP-ribose units to acceptor proteins, thus affecting many diverse cellular processes. In particular, PARP2 shares with PARP1 and, as recently highlighted, PARP3 the sole property of being catalytically activated by DNA-strand breaks, implying key downstream functions in the cellular response to DNA damage for both enzymes. However, evidence from several studies suggests unique functions for PARP2 in additional processes, possibly mediated through its basal, DNA-damage unstimulated ADP-ribosylating activity. Here, we describe the development and application of a protein microarray-based approach tailored to identify proteins that are ADP-ribosylated by PARP2 in the absence of DNA damage mimetics and might thus represent useful entry points to the exploration of novel PARP2 functions. Several candidate substrates for PARP2 were identified and global hit enrichment analysis showed a clear enrichment in translation initiation and RNA helicase molecular functions. In addition, the top scoring candidates FK506-binding protein 3 and SH3 and cysteine-rich domain-containing protein 1 were selected and confirmed in a complementary assay format as substrates for unstimulated PARP2., (© 2011 The Authors Journal compilation © 2011 FEBS.)

Published
2011
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36. Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase.

Author

Colombo R, Caldarelli M, Mennecozzi M, Giorgini ML, Sola F, Cappella P, Perrera C, Depaolini SR, Rusconi L, Cucchi U, Avanzi N, Bertrand JA, Bossi RT, Pesenti E, Galvani A, Isacchi A, Colotta F, Donati D, and Moll J

Subjects
Aneuploidy, Animals, Antineoplastic Agents chemistry, Cell Cycle Proteins chemistry, Cell Growth Processes drug effects, HCT116 Cells, HeLa Cells, Humans, Mice, Mice, Nude, Models, Molecular, Molecular Targeted Therapy methods, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases chemistry, Protein-Tyrosine Kinases, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Cell Cycle Proteins antagonists & inhibitors, Mitosis drug effects, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrazoles pharmacology, Quinazolines pharmacology, Spindle Apparatus drug effects
Abstract

MPS1 kinase is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. It has been found aberrantly overexpressed in a wide range of human tumors and is necessary for tumoral cell proliferation. Here we report the identification and characterization of NMS-P715, a selective and orally bioavailable MPS1 small-molecule inhibitor, which selectively reduces cancer cell proliferation, leaving normal cells almost unaffected. NMS-P715 accelerates mitosis and affects kinetochore components localization causing massive aneuploidy and cell death in a variety of tumoral cell lines and inhibits tumor growth in preclinical cancer models. Inhibiting the SAC could represent a promising new approach to selectively target cancer cells., (©2010 AACR.)

Published
2010
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37. Crystal structures of anaplastic lymphoma kinase in complex with ATP competitive inhibitors.

Author

Bossi RT, Saccardo MB, Ardini E, Menichincheri M, Rusconi L, Magnaghi P, Orsini P, Avanzi N, Borgia AL, Nesi M, Bandiera T, Fogliatto G, and Bertrand JA

Subjects
Anaplastic Lymphoma Kinase, Animals, Cell Line, Enzyme Inhibitors chemistry, Humans, Protein Structure, Tertiary, Protein-Tyrosine Kinases genetics, Protein-Tyrosine Kinases metabolism, Receptor Protein-Tyrosine Kinases, Spodoptera, Models, Molecular, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases chemistry, Pyrimidines chemistry
Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the development of several human cancers and, as a result, is a recognized target for the development of small-molecule inhibitors for the treatment of ALK-positive malignancies. Here, we present the crystal structures of the unphosphorylated human ALK kinase domain in complex with the ATP competitive ligands PHA-E429 and NVP-TAE684. Analysis of these structures provides valuable information concerning the specific characteristics of the ALK active site as well as giving indications about how to obtain selective ALK inhibitors. In addition, the ALK-KD-PHA-E429 structure led to the identification of a potential regulatory mechanism involving a link made between a short helical segment immediately following the DFG motif and an N-terminal two-stranded beta-sheet. Finally, mapping of the activating mutations associated with neuroblastoma onto our structures may explain the roles these residues have in the activation process.

Published
2010
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38. Identification of Myb-binding protein 1A (MYBBP1A) as a novel substrate for aurora B kinase.

Author

Perrera C, Colombo R, Valsasina B, Carpinelli P, Troiani S, Modugno M, Gianellini L, Cappella P, Isacchi A, Moll J, and Rusconi L

Subjects
Amino Acid Sequence, Aurora Kinase B, Aurora Kinases, Binding Sites, Cell Line, DNA-Binding Proteins, HeLa Cells, Humans, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins chemistry, Nuclear Proteins genetics, Nucleocytoplasmic Transport Proteins antagonists & inhibitors, Nucleocytoplasmic Transport Proteins chemistry, Nucleocytoplasmic Transport Proteins genetics, Phosphorylation, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, RNA Interference, RNA-Binding Proteins, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Serine chemistry, Substrate Specificity, Transcription Factors, Nuclear Proteins metabolism, Nucleocytoplasmic Transport Proteins metabolism, Protein Serine-Threonine Kinases metabolism
Abstract

Aurora kinases are mitotic enzymes involved in centrosome maturation and separation, spindle assembly and stability, and chromosome condensation, segregation, and cytokinesis and represent well known targets for cancer therapy because their deregulation has been linked to tumorigenesis. The availability of suitable markers is of crucial importance to investigate the functions of Auroras and monitor kinase inhibition in in vivo models and in clinical trials. Extending the knowledge on Aurora substrates could help to better understand their biology and could be a source for clinical biomarkers. Using biochemical, mass spectrometric, and cellular approaches, we identified MYBBP1A as a novel Aurora B substrate and serine 1303 as the major phosphorylation site. MYBBP1A is phosphorylated in nocodazole-arrested cells and is dephosphorylated upon Aurora B silencing or by treatment with Danusertib, a small molecule inhibitor of Aurora kinases. Furthermore, we show that MYBBP1A depletion by RNA interference causes mitotic progression delay and spindle assembly defects. MYBBP1A has until now been described as a nucleolar protein, mainly involved in transcriptional regulation. The results presented herein show MYBBP1A as a novel Aurora B kinase substrate and reveal a not yet recognized link of this nucleolar protein to mitosis.

Published
2010
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39. Methyl-CpG-binding protein 2 is phosphorylated by homeodomain-interacting protein kinase 2 and contributes to apoptosis.

Author

Bracaglia G, Conca B, Bergo A, Rusconi L, Zhou Z, Greenberg ME, Landsberger N, Soddu S, and Kilstrup-Nielsen C

Subjects
Amino Acid Substitution physiology, Animals, Apoptosis drug effects, Carrier Proteins antagonists & inhibitors, Cells, Cultured, DNA metabolism, Embryo, Mammalian, HeLa Cells, Humans, Methyl-CpG-Binding Protein 2 genetics, Mice, Mutant Proteins genetics, Mutant Proteins metabolism, NIH 3T3 Cells, Phosphorylation drug effects, Phosphorylation genetics, Protein Binding drug effects, Protein Binding genetics, Protein Serine-Threonine Kinases antagonists & inhibitors, RNA, Small Interfering pharmacology, Serine genetics, Serine metabolism, Apoptosis genetics, Carrier Proteins metabolism, Methyl-CpG-Binding Protein 2 metabolism, Methyl-CpG-Binding Protein 2 physiology, Protein Serine-Threonine Kinases metabolism
Abstract

Mutations in the methyl-CpG-binding protein 2 (MeCP2) are associated with Rett syndrome and other neurological disorders. MeCP2 represses transcription mainly by recruiting various co-repressor complexes. Recently, MeCP2 phosphorylation at Ser 80, Ser 229 and Ser 421 was shown to occur in the brain and modulate MeCP2 silencing activities. However, the kinases directly responsible for this are largely unknown. Here, we identify the homeodomain-interacting protein kinase 2 (HIPK2) as a kinase that binds MeCP2 and phosphorylates it at Ser 80 in vitro and in vivo. HIPK2 modulates cell proliferation and apoptosis, and the neurological defects of Hipk2-null mice indicate its role in proper brain functions. We show that MeCP2 cooperates with HIPK2 in induction of apoptosis and that Ser 80 phosphorylation is required together with the DNA binding of MeCP2. These data are, to our knowledge, the first that describe a kinase associating with MeCP2, causing its specific phosphorylation in vivo and, furthermore, they reinforce the role of MeCP2 in regulating cell growth.

Published
2009
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40. A Perl procedure for protein identification by Peptide Mass Fingerprinting.

Author

Tiengo A, Barbarini N, Troiani S, Rusconi L, and Magni P

Subjects
Algorithms, Databases, Protein, Peptide Library, Proteins classification, Proteomics methods, Computational Biology methods, Peptide Mapping methods, Proteins chemistry, Software
Abstract

Background: One of the topics of major interest in proteomics is protein identification. Protein identification can be achieved by analyzing the mass spectrum of a protein sample through different approaches. One of them, called Peptide Mass Fingerprinting (PMF), combines mass spectrometry (MS) data with searching strategies in a suitable database of known protein to provide a list of candidate proteins ranked by a score. To this aim, several algorithms and software tools have been proposed. However, the scoring methods and mainly the statistical evaluation of the results can be significantly improved., Results: In this work, a Perl procedure for protein identification by PMF, called MsPI (Mass spectrometry Protein Identification), is presented. The implemented scoring methods were derived from the literature. MsPI implements a strategy to remove the contaminant masses present in the acquired spectra. Moreover, MsPI includes a statistical method to assign to each candidate protein, in addition to the scoring value, a p-value. Results obtained by MsPI on a dataset of 10 protein samples were compared with those achieved using two other software tools, i.e. Piums and Mascot. Piums implements one of the scoring methods available in MsPI, while Mascot is one of the most frequently used software tools in the protein identification field. MsPI scripts are available for downloading on the web site http://aimed11.unipv.it/MsPI., Conclusion: The performances of MsPI seem to be better than those of Piums and Mascot. In fact, on the considered dataset, MsPI includes in its candidate proteins list, the "true" proteins nine times over ten, whereas Piums includes in its list the "true" proteins only four time over ten. Even if Mascot also correctly includes in the candidates list the "true" proteins nine times over ten, it provides longer candidate lists, therefore increasing the number of false positives when the molecular weight of the proteins in the sample is approximatively known (e.g. by the 1-D/2-D electrophoresis gel). Moreover, being MsPI a Perl tool, it can be easily extended and customized by the final users.

Published
2009
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41. CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail.

Author

Rusconi L, Salvatoni L, Giudici L, Bertani I, Kilstrup-Nielsen C, Broccoli V, and Landsberger N

Subjects
Adult, Animals, Brain metabolism, Cell Nucleus metabolism, Female, HeLa Cells, Humans, Mice, Mice, Inbred C57BL, Middle Aged, Protein Structure, Tertiary, Subcellular Fractions metabolism, Gene Expression Regulation, Gene Expression Regulation, Developmental, Neurons metabolism, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases physiology
Abstract

Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome (RTT), West syndrome, and X-linked infantile spasms, sharing the common feature of mental retardation and early seizures. CDKL5 is a rather uncharacterized kinase, but its involvement in RTT seems to be explained by the fact that it works upstream of MeCP2, the main cause of Rett syndrome. To understand the role of this kinase for nervous system functions and to address if molecular mechanisms are involved in regulating its distribution and activity, we studied the ontogeny of CDKL5 expression in developing mouse brains by immunostaining and Western blotting. The expression profile of CDKL5 was compared with that of MeCP2. The two proteins share a general expression profile in the adult mouse brain, but CDKL5 levels appear to be highly modulated at the regional level. Its expression is strongly induced in early postnatal stages, and in the adult brain CDKL5 is present in mature neurons, but not in astroglia. Interestingly, the presence of CDKL5 in the cell nucleus varies at the regional level of the adult brain and is developmentally regulated. CDKL5 shuttles between the cytoplasm and the nucleus and the C-terminal tail is involved in localizing the protein to the cytoplasm in a mechanism depending on active nuclear export. Accordingly, Rett derivatives containing disease-causing truncations of the C terminus are constitutively nuclear, suggesting that they might act as gain of function mutations in this cellular compartment.

Published
2008
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42. The structure of P-TEFb (CDK9/cyclin T1), its complex with flavopiridol and regulation by phosphorylation.

Author

Baumli S, Lolli G, Lowe ED, Troiani S, Rusconi L, Bullock AN, Debreczeni JE, Knapp S, and Johnson LN

Subjects
Amino Acid Sequence, Animals, Binding Sites, Cyclin T, Cyclins chemistry, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Sequence Alignment, Cyclin-Dependent Kinase 9 chemistry, Cyclin-Dependent Kinase 9 metabolism, Cyclins metabolism, Flavonoids metabolism, Piperidines metabolism
Abstract

The positive transcription elongation factor b (P-TEFb) (CDK9/cyclin T (CycT)) promotes mRNA transcriptional elongation through phosphorylation of elongation repressors and RNA polymerase II. To understand the regulation of a transcriptional CDK by its cognate cyclin, we have determined the structures of the CDK9/CycT1 and free cyclin T2. There are distinct differences between CDK9/CycT1 and the cell cycle CDK CDK2/CycA manifested by a relative rotation of 26 degrees of CycT1 with respect to the CDK, showing for the first time plasticity in CDK cyclin interactions. The CDK9/CycT1 interface is relatively sparse but retains some core CDK-cyclin interactions. The CycT1 C-terminal helix shows flexibility that may be important for the interaction of this region with HIV TAT and HEXIM. Flavopiridol, an anticancer drug in phase II clinical trials, binds to the ATP site of CDK9 inducing unanticipated structural changes that bury the inhibitor. CDK9 activity and recognition of regulatory proteins are governed by autophosphorylation. We show that CDK9/CycT1 autophosphorylates on Thr186 in the activation segment and three C-terminal phosphorylation sites. Autophosphorylation on all sites occurs in cis.

Published
2008
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43. PHA-739358, a potent inhibitor of Aurora kinases with a selective target inhibition profile relevant to cancer.

Author

Carpinelli P, Ceruti R, Giorgini ML, Cappella P, Gianellini L, Croci V, Degrassi A, Texido G, Rocchetti M, Vianello P, Rusconi L, Storici P, Zugnoni P, Arrigoni C, Soncini C, Alli C, Patton V, Marsiglio A, Ballinari D, Pesenti E, Fancelli D, and Moll J

Subjects
Animals, Aurora Kinase B, Aurora Kinases, Benzamides pharmacokinetics, Benzamides therapeutic use, Cell Line, Tumor, Cell Proliferation drug effects, Female, Humans, Immunohistochemistry, Male, Mice, Mice, Nude, Neoplasms enzymology, Phosphorylation, Pyrazoles pharmacokinetics, Pyrazoles therapeutic use, Rats, Rats, Sprague-Dawley, Benzamides pharmacology, Neoplasms drug therapy, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrazoles pharmacology
Abstract

PHA-739358 is a small-molecule 3-aminopyrazole derivative with strong activity against Aurora kinases and cross-reactivities with some receptor tyrosine kinases relevant for cancer. PHA-739358 inhibits all Aurora kinase family members and shows a dominant Aurora B kinase inhibition-related cellular phenotype and mechanism of action in cells in vitro and in vivo. p53 status-dependent endoreduplication is observed upon treatment of cells with PHA-739358, and phosphorylation of histone H3 in Ser(10) is inhibited. The compound has significant antitumor activity in different xenografts and spontaneous and transgenic animal tumor models and shows a favorable pharmacokinetic and safety profile. In vivo target modulation is observed as assessed by the inhibition of the phosphorylation of histone H3, which has been validated preclinically as a candidate biomarker for the clinical phase. Pharmacokinetics/pharmacodynamics modeling was used to define drug potency and to support the prediction of active clinical doses and schedules. We conclude that PHA-739358, which is currently tested in clinical trials, has great therapeutic potential in anticancer therapy in a wide range of cancers.

Published
2007
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44. Crystal structure of the T315I Abl mutant in complex with the aurora kinases inhibitor PHA-739358.

Author

Modugno M, Casale E, Soncini C, Rosettani P, Colombo R, Lupi R, Rusconi L, Fancelli D, Carpinelli P, Cameron AD, Isacchi A, and Moll J

Subjects
Aurora Kinases, Crystallography, X-Ray, Drug Resistance, Neoplasm genetics, Humans, Imatinib Mesylate, Models, Molecular, Mutant Proteins chemistry, Mutant Proteins metabolism, Piperazines pharmacology, Protein Binding, Proto-Oncogene Proteins c-abl metabolism, Pyrimidines pharmacology, Benzamides chemistry, Benzamides metabolism, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins c-abl chemistry, Proto-Oncogene Proteins c-abl genetics, Pyrazoles chemistry, Pyrazoles metabolism
Abstract

Mutations in the kinase domain of Bcr-Abl are the most common cause of resistance to therapy with imatinib in patients with chronic myelogenous leukemia (CML). Second-generation Bcr-Abl inhibitors are able to overcome most imatinib-resistant mutants, with the exception of the frequent T315I substitution, which is emerging as a major cause of resistance to these drugs in CML patients. Structural studies could be used to support the drug design process for the development of inhibitors able to target the T315I substitution, but until now no crystal structure of the T315I Abl mutant has been solved. We show here the first crystal structure of the kinase domain of Abl T315I in complex with PHA-739358, an Aurora kinase inhibitor currently in clinical development for solid and hematologic malignancies. This compound inhibits in vitro the kinase activity of wild-type Abl and of several mutants, including T315I. The cocrystal structure of T315I Abl kinase domain provides the structural basis for this activity: the inhibitor associates with an active conformation of the kinase domain in the ATP-binding pocket and lacks the steric hindrance imposed by the substitution of threonine by isoleucine.

Published
2007
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45. Synaptophysin I selectively specifies the exocytic pathway of synaptobrevin 2/VAMP2.

Author

Bonanomi D, Rusconi L, Colombo CA, Benfenati F, and Valtorta F

Subjects
Animals, Cell Membrane metabolism, Dynamins metabolism, HeLa Cells, Humans, Neurons cytology, Neurons metabolism, Protein Transport, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins metabolism, Subcellular Fractions metabolism, Synaptophysin genetics, Vesicle-Associated Membrane Protein 2 genetics, Exocytosis physiology, Synaptophysin metabolism, Vesicle-Associated Membrane Protein 2 metabolism
Abstract

Biogenesis and recycling of synaptic vesicles are accompanied by sorting processes that preserve the molecular composition of the compartments involved. In the present study, we have addressed the targeting of synaptobrevin 2/VAMP2 (vesicle-associated membrane protein 2), a critical component of the synaptic vesicle--fusion machinery, in a heterotypic context where its sorting is not confounded by the presence of other neuron-specific molecules. Ectopically expressed synaptophysin I interacts with VAMP2 and alters its default surface targeting to a prominent vesicular distribution, with no effect on the targeting of other membrane proteins. Protein-protein interaction is not sufficient for the control of VAMP2 sorting, which is mediated by the C-terminal domain of synaptophysin I. Synaptophysin I directs the sorting of VAMP2 to vesicles before surface delivery, without influencing VAMP2 endocytosis. Consistent with this, dynamin and alpha-SNAP (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein) mutants which block trafficking at the plasma membrane do not abrogate the effect of synaptophysin I on VAMP2 sorting. These results indicate that the sorting determinants of synaptic vesicle proteins can operate independently of a neuronal context and implicate the association of VAMP2 with synaptophysin I in the specification of the pathway of synaptic vesicle biogenesis.

Published
2007
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46. Structures of the human eIF4E homologous protein, h4EHP, in its m7GTP-bound and unliganded forms.

Author

Rosettani P, Knapp S, Vismara MG, Rusconi L, and Cameron AD

Subjects
Amino Acid Sequence, Binding Sites, Calorimetry, Conserved Sequence, Crystallography, X-Ray, Eukaryotic Initiation Factor-4E genetics, Eukaryotic Initiation Factor-4E metabolism, Evolution, Molecular, Guanosine Triphosphate metabolism, Humans, Molecular Sequence Data, Mutation, Peptides chemistry, Protein Binding, RNA Cap-Binding Proteins genetics, RNA Cap-Binding Proteins metabolism, RNA Caps chemistry, Eukaryotic Initiation Factor-4E chemistry, Guanosine Triphosphate chemistry, Models, Molecular, RNA Cap-Binding Proteins chemistry
Abstract

All eukaryotic cellular mRNAs contain a 5' m(7)GpppN cap. In addition to conferring stability to the mRNA, the cap is required for pre-mRNA splicing, nuclear export and translation by providing an anchor point for protein binding. In translation, the interaction between the cap and the eukaryotic initiation factor 4E (eIF4E) is important in the recruitment of the mRNAs to the ribosome. Human 4EHP (h4EHP) is a homologue of eIF4E. Like eIF4E it is able to bind the cap but it appears to play a different cellular role, possibly being involved in the fine-tuning of protein expression levels. Here we use X-ray crystallography and isothermal titration calorimetry (ITC) to investigate further the binding of cap analogues and peptides to h4EHP. m(7)GTP binds to 4EHP 200-fold more weakly than it does to eIF4E with the guanine base sandwiched by a tyrosine and a tryptophan instead of two tryptophan residues as seen in eIF4E. The tyrosine resides on a loop that is longer in h4EHP than in eIF4E. The consequent conformational difference between the proteins allows the tyrosine to mimic the six-membered ring of the tryptophan in eIF4E and adopt an orientation that is similar to that seen for equivalent residues in other non-homologous cap-binding proteins. In the absence of ligand the binding site is incompletely formed with one of the aromatic residues being disordered and the side-chain of the other adopting a novel conformation. A peptide derived from the eIF4E inhibitory protein, 4E-BP1 binds h4EHP 100-fold less strongly than eIF4E but in a similar manner. Overall the data, combined with sequence analyses of 4EHP from evolutionary diverse species, strongly support the hypothesis that 4EHP plays a physiological role utilizing both cap-binding and protein-binding functions but which is distinct from eIF4E.

Published
2007
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47. Functional consequences of mutations in CDKL5, an X-linked gene involved in infantile spasms and mental retardation.

Author

Bertani I, Rusconi L, Bolognese F, Forlani G, Conca B, De Monte L, Badaracco G, Landsberger N, and Kilstrup-Nielsen C

Subjects
Animals, Brain metabolism, Cell Nucleus metabolism, Humans, Infant, Newborn, Methyl-CpG-Binding Protein 2 chemistry, Mice, NIH 3T3 Cells, Protein Structure, Tertiary, Chromosomes, Human, X, Intellectual Disability genetics, Mutation, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases physiology, Spasms, Infantile genetics
Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions.

Published
2006
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48. PHA-680632, a novel Aurora kinase inhibitor with potent antitumoral activity.

Author

Soncini C, Carpinelli P, Gianellini L, Fancelli D, Vianello P, Rusconi L, Storici P, Zugnoni P, Pesenti E, Croci V, Ceruti R, Giorgini ML, Cappella P, Ballinari D, Sola F, Varasi M, Bravo R, and Moll J

Subjects
Animals, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Aurora Kinase B, Aurora Kinases, Biomarkers, Tumor antagonists & inhibitors, Biomarkers, Tumor metabolism, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemistry, Enzyme Inhibitors therapeutic use, HL-60 Cells, HeLa Cells, Humans, Inhibitory Concentration 50, Mice, Mice, Transgenic, Molecular Structure, Phenotype, Phosphorylation drug effects, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Pyrazoles therapeutic use, Pyrroles therapeutic use, Recombinant Proteins antagonists & inhibitors, Recombinant Proteins genetics, Recombinant Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction methods, Antineoplastic Agents pharmacology, Enzyme Inhibitors pharmacology, Mammary Neoplasms, Experimental drug therapy, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrazoles pharmacology, Pyrroles pharmacology
Abstract

Purpose: Aurora kinases play critical roles during mitosis in chromosome segregation and cell division. The aim of this study was to determine the preclinical profile of a novel, highly selective Aurora kinase inhibitor, PHA-680632, as a candidate for anticancer therapy., Experimental Design: The activity of PHA-680632 was assayed in a biochemical ATP competitive kinase assay. A wide panel of cell lines was evaluated for antiproliferative activity. Cell cycle analysis. Immunohistochemistry, Western blotting, and Array Scan were used to follow mechanism of action and biomarker modulation. Specific knockdown of the targets by small interfering RNA was followed to validate the observed phenotypes. Efficacy was determined in different xenograft models and in a transgenic animal model of breast cancer., Results: PHA-680632 is active on a wide range of cancer cell lines and shows significant tumor growth inhibition in different animal tumor models at well-tolerated doses. The mechanism of action of PHA-680632 is in agreement with inhibition of Aurora kinases. Histone H3 phosphorylation in Ser10 is mediated by Aurora B kinase, and our kinetic studies on its inhibition by PHA-680632 in vitro and in vivo show that phosphorylation of histone H3 is a good biomarker to follow activity of PHA-680632., Conclusions: PHA-680632 is the first representative of a new class of Aurora inhibitors with a high potential for further development as an anticancer therapeutic. On treatment, different cell lines respond differentially, suggesting the absence of critical cell cycle checkpoints that could be the basis for a favorable therapeutic window.

Published
2006
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49. Role of ventricular Autocapture function in increasing longevity of DDDR pacemakers: a prospective study.

Author

Boriani G, Rusconi L, Biffi M, Pavia L, Sassara M, Malfitano D, Bongiorni MG, Padeletti L, Filice I, Sanfelici D, Maffei P, Vicentini A, and Branzi A

Subjects
Adult, Aged, Aged, 80 and over, Cross-Over Studies, Equipment Failure, Female, Heart Block physiopathology, Heart Block therapy, Humans, Male, Middle Aged, Prospective Studies, Cardiac Pacing, Artificial, Electric Power Supplies, Pacemaker, Artificial, Ventricular Function
Abstract

Aims: Autocapture is an algorithm for automatic adaptation of ventricular output to capture threshold. The aim of this prospective study was to estimate the effects of ventricular Autocapture algorithm on DDD-DDDR pacemaker longevity., Methods and Results: Eighty-three patients implanted with a DDD-DDDR pacemaker (Affinity or Entity; St Jude Medical, USA) were enrolled and the Autocapture function was activated pre-discharge. Ventricular pulse duration was randomly programmed at 0.3 or 0.4 ms, with a cross-over at 8-12 weeks and again at 13-14 months. Diagnostic data were retrieved from device memory and by calculating battery current drain from long-term threshold recordings; device longevity was estimated at the following settings: Autocapture with a pulse duration of 0.3 and 0.4 ms, respectively, standard output (3.5 V, 0.4 ms) and conventional low output programming (2.5 V, 0.4 ms). According to a series of assumptions, Autocapture was associated with a 55-60% increase in estimated device longevity compared with standard output programming and a 6-7% increase in longevity compared with low output programming. No significant differences were found between Autocapture programmed with a pulse duration of 0.3 or 0.4 ms. In projections to a 10-year follow-up, use of the Autocapture function resulted in a 42% reduction in pacing-related estimated costs compared with standard output programming at 3.5 V, 0.4 ms., Conclusion: Pacing with constant adaptation of ventricular output in dual-chamber devices has the potential to increase generator longevity and to reduce sizeably pacing-related costs compared with standard programming.

Published
2006
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50. Regulation of the wild-type and Y1235D mutant Met kinase activation.

Author

Cristiani C, Rusconi L, Perego R, Schiering N, Kalisz HM, Knapp S, and Isacchi A

Subjects
Animals, Aspartic Acid genetics, Base Sequence, Binding Sites, Carbazoles antagonists & inhibitors, Enzyme Inhibitors pharmacology, Gene Silencing, Humans, Indole Alkaloids, Kinetics, Neoplasm Metastasis genetics, Neoplasm Metastasis pathology, Phenotype, Phosphorylation, Phosphotyrosine chemistry, Phosphotyrosine metabolism, Protein Conformation, Proto-Oncogene Proteins c-met chemistry, Proto-Oncogene Proteins c-met genetics, Receptor Protein-Tyrosine Kinases chemistry, Receptor Protein-Tyrosine Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Transduction, Genetic, Tumor Cells, Cultured, Tyrosine genetics, Mutation, Proto-Oncogene Proteins c-met metabolism
Abstract

Met receptor tyrosine kinase plays a crucial role in the regulation of a large number of cellular processes and, when deregulated by overexpression or mutations, leads to tumor growth and invasion. The Y1235D mutation identified in metastases was shown to induce constitutive activation and a motile-invasive phenotype on transduced carcinoma cells. Wild-type Met activation requires phosphorylation of both Y1234 and Y1235 in the activation loop. We mapped the major phosphorylation sites in the kinase domain of a recombinant Met protein and identified the known residues Y1234 and Y1235 as well as a new phosphorylation site at Y1194 in the hinge region. Combining activating and silencing mutations at these sites, we characterized in depth the mechanism of activation of wild-type and mutant Met proteins. We found that the phosphotyrosine mimetic mutation Y1235D is sufficient to confer constitutive kinase activity, which is not influenced by phosphorylation at Y1234. However, the specific activity of this mutant was lower than that observed for fully activated wild-type Met and induced less phosphorylation of Y1349 in the signaling site, indicating that this mutation cannot entirely compensate for a phosphorylated tyrosine at this position. The Y1194F silencing mutation yielded an enzyme that could be activated to a similar extent as the wild type but with significantly slower activation kinetics, underlying the importance of this residue, which is conserved among different tyrosine kinase receptors. Finally, we observed different interactions of wild-type and mutant Met with the inhibitor K252a that may have therapeutic implications for the selective inhibition of this kinase.

Published
2005
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