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2. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

Author

Baldassarri, M, Picchiotti, N, Fava, F, Fallerini, C, Benetti, E, Daga, S, Valentino, F, Doddato, G, Furini, S, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Pinto, A, Iuso, N, Gabbi, C, Sciarra, F, Venneri, M, Gori, M, Sanarico, M, Crawley, F, Pagotto, U, Fanelli, F, Mezzullo, M, Dominguez-Garrido, E, Planas-Serra, L, Schluter, A, Colobran, R, Soler-Palacin, P, Lapunzina, P, Tenorio, J, Pujol, A, Castagna, M, Marcelli, M, Isidori, A, Renieri, A, Frullanti, E, Mari, F, Montagnani, F, Di Sarno, L, Tommasi, A, Palmieri, M, Fabbiani, M, Rossetti, B, Zanelli, G, Sestini, F, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Vaghi, M, Monforte, A, Merlini, E, Miraglia, F, Mondelli, M, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Sita, M, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Parisi, S, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mencarelli, M, Lo Rizzo, C, Bargagli, E, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Parati, G, Aguilera-Albesa, S, Albu, S, Casasnovas, C, Velez-Santamaria, V, Horcajada, J, Villar, J, Rodriguez-Palmero, A, Ruiz, M, Seijo, L, Troya, J, Valencia-Ramos, J, Gut, M, Baldassarri M., Picchiotti N., Fava F., Fallerini C., Benetti E., Daga S., Valentino F., Doddato G., Furini S., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Pinto A. M., Iuso N., Gabbi C., Sciarra F., Venneri M. A., Gori M., Sanarico M., Crawley F. P., Pagotto U., Fanelli F., Mezzullo M., Dominguez-Garrido E., Planas-Serra L., Schluter A., Colobran R., Soler-Palacin P., Lapunzina P., Tenorio J., Pujol A., Castagna M. G., Marcelli M., Isidori A. M., Renieri A., Frullanti E., Mari F., Montagnani F., Di Sarno L., Tommasi A., Palmieri M., Fabbiani M., Rossetti B., Zanelli G., Sestini F., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Caldarelli G. P., Spagnesi M., Piacentini P., Bandini M., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Vaghi M., Monforte A. D., Merlini E., Miraglia F. G., Mondelli M. U., Mantovani S., Ludovisi S., Girardis M., Venturelli S., Sita M., Cossarizza A., Antinori A., Vergori A., Emiliozzi A., Rusconi S., Siano M., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Baratti S., Scaggiante R., Gatti F., Parisi S. G., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Monica M. D., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mencarelli M. A., Lo Rizzo C., Bargagli E., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Bosio G., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Parati G., Aguilera-Albesa S., Albu S., Casasnovas C., Velez-Santamaria V., Horcajada J. P., Villar J., Rodriguez-Palmero A., Ruiz M., Seijo L. M., Troya J., Valencia-Ramos J., Gut M., Baldassarri, M, Picchiotti, N, Fava, F, Fallerini, C, Benetti, E, Daga, S, Valentino, F, Doddato, G, Furini, S, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Pinto, A, Iuso, N, Gabbi, C, Sciarra, F, Venneri, M, Gori, M, Sanarico, M, Crawley, F, Pagotto, U, Fanelli, F, Mezzullo, M, Dominguez-Garrido, E, Planas-Serra, L, Schluter, A, Colobran, R, Soler-Palacin, P, Lapunzina, P, Tenorio, J, Pujol, A, Castagna, M, Marcelli, M, Isidori, A, Renieri, A, Frullanti, E, Mari, F, Montagnani, F, Di Sarno, L, Tommasi, A, Palmieri, M, Fabbiani, M, Rossetti, B, Zanelli, G, Sestini, F, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Vaghi, M, Monforte, A, Merlini, E, Miraglia, F, Mondelli, M, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Sita, M, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Parisi, S, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mencarelli, M, Lo Rizzo, C, Bargagli, E, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Parati, G, Aguilera-Albesa, S, Albu, S, Casasnovas, C, Velez-Santamaria, V, Horcajada, J, Villar, J, Rodriguez-Palmero, A, Ruiz, M, Seijo, L, Troya, J, Valencia-Ramos, J, Gut, M, Baldassarri M., Picchiotti N., Fava F., Fallerini C., Benetti E., Daga S., Valentino F., Doddato G., Furini S., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Pinto A. M., Iuso N., Gabbi C., Sciarra F., Venneri M. A., Gori M., Sanarico M., Crawley F. P., Pagotto U., Fanelli F., Mezzullo M., Dominguez-Garrido E., Planas-Serra L., Schluter A., Colobran R., Soler-Palacin P., Lapunzina P., Tenorio J., Pujol A., Castagna M. G., Marcelli M., Isidori A. M., Renieri A., Frullanti E., Mari F., Montagnani F., Di Sarno L., Tommasi A., Palmieri M., Fabbiani M., Rossetti B., Zanelli G., Sestini F., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Caldarelli G. P., Spagnesi M., Piacentini P., Bandini M., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Vaghi M., Monforte A. D., Merlini E., Miraglia F. G., Mondelli M. U., Mantovani S., Ludovisi S., Girardis M., Venturelli S., Sita M., Cossarizza A., Antinori A., Vergori A., Emiliozzi A., Rusconi S., Siano M., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Baratti S., Scaggiante R., Gatti F., Parisi S. G., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Monica M. D., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mencarelli M. A., Lo Rizzo C., Bargagli E., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Bosio G., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Parati G., Aguilera-Albesa S., Albu S., Casasnovas C., Velez-Santamaria V., Horcajada J. P., Villar J., Rodriguez-Palmero A., Ruiz M., Seijo L. M., Troya J., Valencia-Ramos J., and Gut M.

Abstract

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. Funding: MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and “Bando Ricerca COVID-19 Toscana” project

Published
2021

3. Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

Author

Baldassarri M., Picchiotti N., Fava F., Fallerini C., Benetti E., Daga S., Valentino F., Doddato G., Furini S., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Pinto A. M., Iuso N., Gabbi C., Sciarra F., Venneri M. A., Gori M., Sanarico M., Crawley F. P., Pagotto U., Fanelli F., Mezzullo M., Dominguez-Garrido E., Planas-Serra L., Schluter A., Colobran R., Soler-Palacin P., Lapunzina P., Tenorio J., Pujol A., Castagna M. G., Marcelli M., Isidori A. M., Renieri A., Frullanti E., Mari F., Montagnani F., Di Sarno L., Tommasi A., Palmieri M., Fabbiani M., Rossetti B., Zanelli G., Sestini F., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Caldarelli G. P., Spagnesi M., Piacentini P., Bandini M., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Vaghi M., Monforte A. D., Merlini E., Miraglia F. G., Mondelli M. U., Mantovani S., Ludovisi S., Girardis M., Venturelli S., Sita M., Cossarizza A., Antinori A., Vergori A., Emiliozzi A., Rusconi S., Siano M., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P. G., Andretta F., Panese S., Baratti S., Scaggiante R., Gatti F., Parisi S. G., Castelli F., Quiros-Roldan E., Antoni M. D., Zanella I., Monica M. D., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mencarelli M. A., Lo Rizzo C., Bargagli E., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Bosio G., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Parati G., Aguilera-Albesa S., Albu S., Casasnovas C., Velez-Santamaria V., Horcajada J. P., Villar J., Rodriguez-Palmero A., Ruiz M., Seijo L. M., Troya J., Valencia-Ramos J., Gut M., Institut Català de la Salut, [Baldassarri M, Fallerini C] Medical Genetics, University of Siena, Italy. Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy. [Picchiotti N] University of Siena, DIISM-SAILAB, Siena, Italy. Department of Mathematics, University of Pavia, Pavia, Italy. [Fava F] Medical Genetics, University of Siena, Italy. Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy. Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Italy. [Benetti E] Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Italy. [Colobran R] Servei d’Immunologia, Àrea de Genètica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Soler-Palacin P] Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Baldassarri M., Picchiotti N., Fava F., Fallerini C., Benetti E., Daga S., Valentino F., Doddato G., Furini S., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Pinto A.M., Iuso N., Gabbi C., Sciarra F., Venneri M.A., Gori M., Sanarico M., Crawley F.P., Pagotto U., Fanelli F., Mezzullo M., Dominguez-Garrido E., Planas-Serra L., Schluter A., Colobran R., Soler-Palacin P., Lapunzina P., Tenorio J., Pujol A., Castagna M.G., Marcelli M., Isidori A.M., Renieri A., Frullanti E., Mari F., Montagnani F., Di Sarno L., Tommasi A., Palmieri M., Fabbiani M., Rossetti B., Zanelli G., Sestini F., Bergantini L., D'Alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M.A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Caldarelli G.P., Spagnesi M., Piacentini P., Bandini M., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., Vaghi M., Monforte A.D., Merlini E., Miraglia F.G., Mondelli M.U., Mantovani S., Ludovisi S., Girardis M., Venturelli S., Sita M., Cossarizza A., Antinori A., Vergori A., Emiliozzi A., Rusconi S., Siano M., Gabrieli A., Riva A., Francisci D., Schiaroli E., Paciosi F., Scotton P.G., Andretta F., Panese S., Baratti S., Scaggiante R., Gatti F., Parisi S.G., Castelli F., Quiros-Roldan E., Antoni M.D., Zanella I., Monica M.D., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Valente S., Mencarelli M.A., Lo Rizzo C., Bargagli E., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D.A., Mussini C., Bosio G., Martinelli E., Mancarella S., Tavecchia L., Crotti L., Parati G., Aguilera-Albesa S., Albu S., Casasnovas C., Velez-Santamaria V., Horcajada J.P., Villar J., Rodriguez-Palmero A., Ruiz M., Seijo L.M., Troya J., Valencia-Ramos J., Gut M., Baldassarri, M., Picchiotti, N., Fava, F., Fallerini, C., Benetti, E., Daga, S., Valentino, F., Doddato, G., Furini, S., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Pinto, A. M., Iuso, N., Gabbi, C., Sciarra, F., Venneri, M. A., Gori, M., Sanarico, M., Crawley, F. P., Pagotto, U., Fanelli, F., Mezzullo, M., Dominguez-Garrido, E., Planas-Serra, L., Schluter, A., Colobran, R., Soler-Palacin, P., Lapunzina, P., Tenorio, J., Pujol, A., Castagna, M. G., Marcelli, M., Isidori, A. M., Renieri, A., Frullanti, E., Mari, F., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Fabbiani, M., Rossetti, B., Zanelli, G., Sestini, F., Bergantini, L., D'Alessandro, M., Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., Monforte, A. D., Merlini, E., Miraglia, F. G., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Emiliozzi, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Paciosi, F., Scotton, P. G., Andretta, F., Panese, S., Baratti, S., Scaggiante, R., Gatti, F., Parisi, S. G., Castelli, F., Quiros-Roldan, E., Antoni, M. D., Zanella, I., Monica, M. D., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Valente, S., Mencarelli, M. A., Lo Rizzo, C., Bargagli, E., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Crotti, L., Parati, G., Aguilera-Albesa, S., Albu, S., Casasnovas, C., Velez-Santamaria, V., Horcajada, J. P., Villar, J., Rodriguez-Palmero, A., Ruiz, M., Seijo, L. M., Troya, J., Valencia-Ramos, J., Gut, M., Baldassarri, M, Picchiotti, N, Fava, F, Fallerini, C, Benetti, E, Daga, S, Valentino, F, Doddato, G, Furini, S, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Pinto, A, Iuso, N, Gabbi, C, Sciarra, F, Venneri, M, Gori, M, Sanarico, M, Crawley, F, Pagotto, U, Fanelli, F, Mezzullo, M, Dominguez-Garrido, E, Planas-Serra, L, Schluter, A, Colobran, R, Soler-Palacin, P, Lapunzina, P, Tenorio, J, Pujol, A, Castagna, M, Marcelli, M, Isidori, A, Renieri, A, Frullanti, E, Mari, F, Montagnani, F, Di Sarno, L, Tommasi, A, Palmieri, M, Fabbiani, M, Rossetti, B, Zanelli, G, Sestini, F, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, Vaghi, M, Monforte, A, Merlini, E, Miraglia, F, Mondelli, M, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Sita, M, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Paciosi, F, Scotton, P, Andretta, F, Panese, S, Baratti, S, Scaggiante, R, Gatti, F, Parisi, S, Castelli, F, Quiros-Roldan, E, Antoni, M, Zanella, I, Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Di Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mencarelli, M, Lo Rizzo, C, Bargagli, E, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Crotti, L, Parati, G, Aguilera-Albesa, S, Albu, S, Casasnovas, C, Velez-Santamaria, V, Horcajada, J, Villar, J, Rodriguez-Palmero, A, Ruiz, M, Seijo, L, Troya, J, Valencia-Ramos, J, and Gut, M

Subjects
0301 basic medicine, Oncology, Male, lcsh:Medicine, Disease, COVID-19 (Malaltia), Severity of Illness Index, Androgen, Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gonadal Hormones::Gonadal Steroid Hormones::Testosterone Congeners::Testosterone [CHEMICALS AND DRUGS], 0302 clinical medicine, Risk Factors, Receptors, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Testosterone, Other subheadings::/therapeutic use [Other subheadings], Amino Acids, Peptides, and Proteins::Proteins::Receptors, Cytoplasmic and Nuclear::Receptors, Steroid::Receptors, Androgen [CHEMICALS AND DRUGS], Testosterona, Androgen receptor gene, COVID-19, LASSO logistic regression, Viral infection and host genome, WES, Aged, Case-Control Studies, Critical Care, Female, Genome, Human, Humans, Middle Aged, Peptides, Polymorphism, Single Nucleotide, Receptors, Androgen, SARS-CoV-2, Spain, lcsh:R5-920, Genome, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], General Medicine, Single Nucleotide, Testosterona - Ús terapèutic, Homes -- Malalties, androgen receptor gene, testosterone, viral infection and host genome, 030220 oncology & carcinogenesis, Cohort, Peptide, aminoácidos, péptidos y proteínas::proteínas::receptores citoplásmicos y nucleares::receptores de esteroides::receptores de andrógenos [COMPUESTOS QUÍMICOS Y DROGAS], Androgens, lcsh:Medicine (General), Case-Control Studie, Research Paper, hormonas, sustitutos de hormonas y antagonistas de hormonas::hormonas::hormonas gonadales::hormonas esteroides gonadales::congéneres de la testosterona::testosterona [COMPUESTOS QUÍMICOS Y DROGAS], Human, medicine.medical_specialty, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Andrògens - Receptors, Internal medicine, Severity of illness, medicine, Adjuvant therapy, Allele, Polymorphism, business.industry, Otros calificadores::/uso terapéutico [Otros calificadores], Public health, Risk Factor, lcsh:R, Case-control study, Androgen receptor, 030104 developmental biology, business, Andrògens
Abstract

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Gen receptor d'andrògens; Infecció vírica i genoma de l’hoste Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Gen receptor de andrógenos; Infección viral y genoma del huésped Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Androgen receptor gene; Viral infection and host genome Background While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men

Published
2021

7. Near optimal load-adaptive distributed Dynamic Channel Allocation strategies in cellular mobile networks

Author

Baiocchi, Andrea and Sestini, F.

Subjects
Radio interference, Telecommunication traffic, Mathematical models, Dynamic channel allocation (DCA), Signal to noise ratio, Cellular radio systems, Frequency allocation, Channel capacity, Computer simulation, Adaptive control systems, Algorithms, Adaptive control systems,Algorithms,Channel capacity,Computer simulation,Frequency allocation,Mathematical models,Probability,Radio interference,Signal to noise ratio,Telecommunication traffic,Dynamic channel allocation (DCA),Cellular radio systems, Probability
Published
1996

10. Chemical Notes

Author

Sestini, F. and Vorak, V. D.

Published
1880

34. La biblioteca Cardelli a Roma nel XVIII secolo. Notizie a partire da una memoria inedita della contessa marchigiana Giustina Pianetti Cardelli

Author

Fiammetta Sabba, A. Petrucciani, V. Sestini, F. Valacchi, and Fiammetta Sabba

Subjects
Inventari, Memorie di viaggio, Archivio di Stato di Roma, Roma XVIII secolo, Cataloghi, Biblioteca Cardelli, Archivio Storico Capitolino
Abstract

A Roma negli ultimi decenni del Settecento gli eruditi e gli aristocratici sceglievano tra i salotti più ambiti quello della contessa marchigiana Giustina Pianetti, vedova Cardelli, erede di una ricchissima biblioteca formata dal marito Francesco Maria. Attraverso una inedita memoria della contessa, conservata nel diario di viaggio del bibliotecario Angelo Maria Bandini, e cataloghi scoperti nell'Archivio di Stato di Roma e nell'Archivio Capitolino, se ne rintraccia la storia legata alla biblioteca di Gregorio Alessandro Capponi, e il contenuto ricchissimo di stampati e manoscritti, alcuni dei quali con questa ricerca sono stati rintracciati.

Published
2020

35. Analytical performance of free testosterone calculated by direct immunoluminometric method compared with the Vermeulen equation: results from a clinical series.

Author

Dalmiglio C, Bombardieri A, Mattii E, Sestini F, Fioravanti C, Castagna MG, Fiorini M, Dotta F, and Cantara S

Subjects
Humans, Female, Male, Middle Aged, Adult, Sensitivity and Specificity, Aged, Luminescent Measurements methods, Luminescent Measurements standards, Reproducibility of Results, Young Adult, Testosterone blood
Abstract

Introduction: Testosterone (T) is a hormone that is crucial for primary and secondary sexual development in both males and females. Free testosterone (FT) represents the biologically active form of T, and its measurement is of great importance in clinical practice. While application of either equilibrium dialysis or ultrafiltration is considered to be the gold standard for FT assessment, these methods are expensive and not widely accessible. As an alternative, the Vermeulen formula is a commonly utilized calculated method., Methods: This clinical study, including 190 consecutive patients, was carried out to compare FT levels obtained through direct immunoluminometric assay and the Vermeulen formula. The comparison was performed using Passing-Bablok and Deming regression as well as the Bland-Altman plot. Sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were assessed., Results: The calculated method employing the Vermeulen formula was considered the gold standard. Passing-Bablok regression indicated a good agreement between the two methods, with slopes close to 1 for the whole series. Although the Bland-Altman plot demonstrated overall agreement, a potential proportional bias was observed in females. Deming regression confirmed excellent agreement and reliable estimates. Sensitivity and specificity analysis revealed that the direct method had a sensitivity of 75.0% and a specificity of 93.4% in all patients. However, sensitivity improved to 81.0% in males and dropped to 18.2% in females likely due to the low number of true positive cases., Conclusion: The direct method exhibited comparable performance to the calculated method, but caution should be exercised when interpreting results, particularly in females. Further studies are necessary to validate its sensitivity and specificity in larger series., (© 2024. The Author(s), under exclusive licence to Hellenic Endocrine Society.)

Published
2024
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36. Transient Hypogonadism Is Associated With Heart Rate-Corrected QT Prolongation and Torsades de Pointes Risk During Active Systemic Inflammation in Men.

Author

Lazzerini PE, Cantara S, Bertolozzi I, Accioli R, Salvini V, Cartocci A, D'Errico A, Sestini F, Bisogno S, Cevenini G, Capecchi M, Laghi-Pasini F, Castagna MG, Acampa M, Boutjdir M, and Capecchi PL

Subjects
C-Reactive Protein, DNA-Binding Proteins, Electrocardiography, Estradiol, Gonadal Steroid Hormones, Heart Rate, Humans, Inflammation complications, Interleukin-6, Male, Risk Factors, Testosterone, Hypogonadism complications, Hypogonadism diagnosis, Long QT Syndrome chemically induced, Torsades de Pointes chemically induced, Torsades de Pointes diagnosis
Abstract

Background Systemic inflammation and male hypogonadism are 2 increasingly recognized "nonconventional" risk factors for long-QT syndrome and torsades de pointes (TdP). Specifically, inflammatory cytokines prolong, while testosterone shortens the heart rate-corrected QT interval (QTc) via direct electrophysiological effects on cardiomyocytes. Moreover, several studies demonstrated important interplays between inflammation and reduced gonad function in men. We hypothesized that, during inflammatory activation in men, testosterone levels decrease and that this enhances TdP risk by contributing to the overall prolonging effect of inflammation on QTc. Methods and Results We investigated (1) the levels of sex hormones and their relationship with inflammatory markers and QTc in male patients with different types of inflammatory diseases, during active phase and recovery; and (2) the association between inflammatory markers and sex hormones in a cohort of male patients who developed extreme QTc prolongation and TdP, consecutively collected over 10 years. In men with active inflammatory diseases, testosterone levels were significantly reduced, but promptly normalized in association with the decrease in C-reactive protein and interleukin-6 levels. Reduction of testosterone levels, which also inversely correlated with 17-β estradiol over time, significantly contributed to inflammation-induced QTc prolongation. In men with TdP, both active systemic inflammation and hypogonadism were frequently present, with significant correlations between C-reactive protein, testosterone, and 17-β estradiol levels; in these patients, increased C-reactive protein and reduced testosterone were associated with a worse short-term outcome of the arrhythmia. Conclusions During systemic inflammatory activation, interleukin-6 elevation is associated with reduced testosterone levels in males, possibly deriving from an enhanced androgen-to-estrogen conversion. While transient, inflammatory hypotestosteronemia is significantly associated with an increased long-QT syndrome/TdP risk in men.

Published
2022
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37. Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab.

Author

Brilli L, Danielli R, Ciuoli C, Calabrò L, Di Giacomo AM, Cerase A, Paffetti P, Sestini F, Porcelli B, Maio M, and Pacini F

Subjects
Adrenocorticotropic Hormone blood, Age of Onset, Aged, Antineoplastic Agents therapeutic use, Cohort Studies, Female, Follow-Up Studies, Humans, Hypophysitis diagnostic imaging, Ipilimumab therapeutic use, Magnetic Resonance Imaging, Male, Melanoma drug therapy, Middle Aged, Pituitary Function Tests, Prevalence, Prostatic Neoplasms drug therapy, Thyrotropin blood, Antineoplastic Agents adverse effects, Hypophysitis chemically induced, Hypophysitis epidemiology, Ipilimumab adverse effects, Melanoma complications, Prostatic Neoplasms complications
Abstract

Objective: Ipilimumab is a human monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4, that has been shown to significantly improve survival in patients with metastatic melanoma. Blocking cytotoxic T-lymphocyte antigen-4 elicits T cell activation, proliferation and anti-tumor response, but can also trigger immune-related adverse events. Among immune-related endocrinopathies, hypophysitis represents the most frequent, with an incidence up to 17% in patients treated with ipilimumab., Design and Methods: We report nine cases of ipilimumab-induced hypophysitis in a cohort of 273 patients treated with ipilimumab between 2006 and 2015, as part of clinical trials or after its marketing. Thyroid function tests were scheduled at screening and during follow up (every 21 days) in all patients. Cortisol, adrenocorticotropic hormone, follicle-stimulating hormone, luteinizing hormone, and estradiol (for females) or testosterone (for males), prolactin, growth hormone, insulin-like growth factor 1 were measured only in case of clinical suspicion., Results: The incidence of hypophysitis was 3.3%. The most frequent pituitary failure was adrenocorticotropic hormone and thyroid stimulating hormone secretion with a complete recovery of thyroid stimulating hormone, but not of adrenocorticotropic hormone during follow up. All patients had negative pituitary antibodies. The main symptoms at diagnosis were fatigue and headache., Conclusion: Clinicians should be aware about the risk of hypophysitis during treatment with immune check-point inhibitors and the necessity of investigating pituitary function during therapy. Pituitary magnetic resonance imaging does not seem pivotal for a definite diagnosis if not performed at the onset of disease.

Published
2017
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38. IFNγ-Inducible Chemokines Decrease upon Selenomethionine Supplementation in Women with Euthyroid Autoimmune Thyroiditis: Comparison between Two Doses of Selenomethionine (80 or 160 μg) versus Placebo.

Author

Pilli T, Cantara S, Schomburg L, Cenci V, Cardinale S, Heid EC, Kühn EC, Cevenini G, Sestini F, Fioravanti C, D'Hauw G, and Pacini F

Abstract

Background: Several studies have suggested that selenium may influence the natural history of autoimmune thyroiditis (AIT). Recently, IFNγ-inducible chemokines (CXCL-9, -10 and -11) were shown to be elevated in AIT patients., Objective: This prospective, randomized, controlled study was conducted to evaluate the effect of two doses of selenomethionine (Semet; 80 or 160 µg/day) versus placebo in euthyroid women with AIT, in terms of reduction of anti-thyroid antibodies, CXCL-9, -10 and -11 and improvement of thyroid echogenicity, over 12 months., Patients and Methods: Sixty patients, aged 21-65 years, were equally randomized into 3 groups: placebo, 80 µg/day of Semet (80-Semet) or 160 µg/day of Semet (160-Semet)., Results: Anti-thyroperoxidase antibody (TPOAb) levels remained unaffected by Semet supplementation; anti-thyroglobulin antibody levels showed a significant reduction in the 160-Semet and the placebo group at 12 months. No significant change in thyroid echogenicity, thyroid volume and quality of life was observed within and between the groups. Subclinical hypothyroidism was diagnosed in 2 patients of the placebo group versus 1 patient in each Semet group. Serum CXCL-9 and -10 were significantly reduced in both Semet groups at 6 and 12 months, while they remained unchanged or increased in the placebo group. CXCL-11, TNFα and IFNγ showed a transient decrease at 6 months in both Semet groups but returned nearly to the basal levels at 12 months., Conclusions: Semet supplementation had no positive effect on thyroid echogenicity or TPOAb in our patients. However, we observed a Semet-dependent downregulation of the IFNγ-inducible chemokines, especially CXCL-9 and -10, which may serve as helpful biomarkers in future selenium supplementation trials.

Published
2015
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39. Reference range of serum calcitonin in pediatric population.

Author

Castagna MG, Fugazzola L, Maino F, Covelli D, Memmo S, Sestini F, Fioravanti C, Ferraris Fusarini C, Scapellato C, Macchini F, Cevenini G, and Pacini F

Subjects
Adolescent, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Reference Values, Calcitonin blood
Abstract

Background: Children belonging to the multiple endocrine neoplasia type 2 (MEN 2) pedigree and carrying germline RET mutations are candidates for prophylactic thyroidectomy, the timing of which is based on the mutation-associated risk and the calcitonin (CT) levels., Design: The aim of this study was to establish the reference range for serum CT in a pediatric population. The study included 2740 subjects (1339 females and 1401 males) ranging in age from 1 day to 16 years and undergoing blood testing for any medical condition not affecting serum CT., Results: Overall, serum CT was undetectable in 61.5% of the samples and detectable in 38.5%. Detectable samples were more frequent in the first 2 years of life. Thereafter, undetectable samples became more frequent, particularly in females. Mean serum CT concentrations were higher in the first year of life (9.81 ± 8.8 pg/mL; range, 2.0-48.9 pg/mL) and the second year of life (4.56 ± 2.64 pg/mL; range, 2.0-14.7 pg/mL). A significant decrease of serum CT levels was observed thereafter (P < .001), and starting from the third year of life serum CT levels were similar to those found in adults. No gender difference was found in any age group. Based on these results, age-specific CT reference ranges are needed in the pediatric population, and especially in the first 2 years of life., Conclusions: This is the first study defining the reference range for serum CT in the pediatric population and large enough to be statistically meaningful. Our proposal may facilitate the process of decision making when dealing with gene carriers of MEN 2.

Published
2015
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40. Glucagon and insulin cord blood levels in very preterm, late preterm and full-term infants.

Author

Bagnoli F, Vodo F, Vodo S, Conte ML, Tomasini B, Vodo Z, Pasqui L, and Sestini F

Subjects
Apgar Score, Cesarean Section, Female, Humans, Infant, Newborn, Insulin Resistance, Male, Fetal Blood chemistry, Glucagon blood, Infant, Extremely Premature blood, Infant, Premature blood, Insulin blood
Abstract

Background: The cause of hyperglycemia, a frequent disorder of glucose homeostasis in very preterm infants, is still unknown., Objectives: Determine the glucagon and insulin plasma levels at birth in healthy, appropriate for gestational age (AGA) infants born by elective cesarean section (ECS), at different gestational age., Methods: Glucagon, insulin and the homeostasis model of assessment-insulin resistance (HOMA-IR) index were measured in cord blood in 52 AGA infants divided into three groups: ≤30 weeks, very preterm (VP, n=16); 35-37 weeks, late preterm (LP, n=18); ≥38 weeks, full term (FT, n=18)., Results: In all enrolled infants, Apgar score at 5 min after birth was 7 to 9. In VP infants, glucagon levels were higher than those in LP (533±116 vs. 211±28 pg/mL) (p<0.001) and FT infants (533±116 vs. 226±20 pg/mL) (p<0.001). Insulin levels were higher in VP than in LP (8.61±2.48 vs. 3.98±0.94 mU/L) (p<0.001) and FT infants (8.61±2.48 vs. 4.56±1.2 mU/L) (p<0.001). HOMA-IR index was higher in VP than in LP and FT infants (30.6±10.2 vs. 11.9±3.04 and 13.5±1.6, respectively) (p<0.001)., Conclusion: We concluded that very low gestational age is associated with high glucagon plasma levels and insulin-resistance, which could explain hyperglycemia in the very preterm infants.

Published
2014
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41. Prevalence of parietal cell antibodies in a large cohort of patients with autoimmune thyroiditis.

Author

Checchi S, Montanaro A, Ciuoli C, Brusco L, Pasqui L, Fioravanti C, Sestini F, and Pacini F

Subjects
Adolescent, Adult, Age Distribution, Aged, Aged, 80 and over, Antibodies, Autoimmune Diseases immunology, Child, Female, Humans, Male, Middle Aged, Steroid 21-Hydroxylase immunology, Thyroiditis, Autoimmune epidemiology, Autoantibodies blood, Parietal Cells, Gastric immunology, Thyroiditis, Autoimmune immunology
Abstract

Background: Autoimmune thyroiditis (AIT) may be associated with other organ-specific autoimmune disorders, including autoimmune gastritis, but the prevalence of this association is not entirely quantified. The aim of this study was to investigate the prevalence of parietal cell antibodies (PCA) in a large cohort of consecutive patients with AIT., Methods: We retrospectively studied 2016 consecutive women and 258 men with AIT seen at our referral center in the period from 2004 to 2008. All patients were screened for the presence of PCA in the serum., Results: The prevalence of serum PCA in female patients was 29.7% and progressively increased from 13% in the first-second decade of life to peak at 42% in the ninth decade. During follow up, 21.1% of the PCA-positive patients converted to PCA-negative status. Mean (±standard deviation) basal PCA levels in this group were significantly lower (32 ± 28 U/mL) compared with those remaining PCA positive (129 ± 200 U/mL). A similar prevalence (29.8%) with a similar age-dependency was found in male patients., Conclusions: In conclusion, our study demonstrates a high, age-dependent prevalence of PCA in an unselected large population of patients with AIT.

Published
2010
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42. Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies.

Author

Checchi S, Montanaro A, Pasqui L, Ciuoli C, Cevenini G, Sestini F, Fioravanti C, and Pacini F

Subjects
Adult, Aged, Aged, 80 and over, Biomarkers, Biopsy, Female, Gastric Mucosa pathology, Gastrins blood, Gastritis, Atrophic pathology, Gastroscopy, Humans, Male, Middle Aged, Pepsinogen A blood, Predictive Value of Tests, ROC Curve, Thyroid Function Tests, Autoantibodies analysis, Gastritis, Atrophic blood, Ghrelin blood, Parietal Cells, Gastric immunology
Abstract

Aim: Autoimmune gastritis is frequently associated with autoimmune thyroiditis and other organ-specific autoimmune diseases, and may lead to atrophic body gastritis (ABG). We studied the diagnostic use of the measurement of serum ghrelin compared with other markers of gastric damage in predicting the presence of ABG in patients with autoimmune gastritis., Methods: We studied 233 patients with autoimmune gastritis and 211 control subjects. All patients and control subjects were screened for circulating parietal cell antibodies (PCAs) and were tested for serum ghrelin, gastrin, pepsinogen I and II, and anti-Helicobacter pylori antibody levels. A total of 52 patients and 28 control subjects underwent a gastric endoscopy., Results: In PCA/positive patients, mean (+/-sd) serum ghrelin levels were significantly lower (238 +/- 107 pmol/liter), and mean (+/-sd) serum gastrin levels were significantly higher (81.2 +/- 128.3 ng/ml), with respect to PCA/negative patients (282 +/- 104 pmol/liter and 20.7 +/- 13.3 ng/ml, respectively; P < 0.0001). Serum ghrelin and gastrin levels were inversely correlated (P = 0.004). A total of 40 patients had ABG documented by the gastric biopsy (90% in PCA/positive patients and 10% in PCA/negative patients). The receiver operating characteristic curve analysis revealed that a cutoff value for serum ghrelin of 188 pmol/liter was associated with the highest sensitivity and specificity (97.3 and 100%, respectively) in detecting gastric atrophy and was superior to gastrin (P = 0.012), PCA (P = 0.002), and the pepsinogen I/II ratio (P = 0.016) measurements., Conclusions: Our study demonstrates that ghrelin secretion is negatively affected by autoimmune gastritis, and its serum level represents the most sensitive and specific noninvasive marker for selecting patients at high risk for ABG.

Published
2007
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