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6. Recommendations for pre-symptomatic genetic testing for hereditary transthyretin amyloidosis in the era of effective therapy: a multicenter Italian consensus

Author

Grandis, M., Obici, L., Luigetti, M., Briani, C., Benedicenti, F., Bisogni, G., Canepa, M., Cappelli, F., Danesino, C., Fabrizi, G. M., Fenu, S., Ferrandes, G., Gemelli, C., Manganelli, F., Mazzeo, A., Melchiorri, L., Perfetto, F., Pradotto, L. G., Rimessi, P., Tini, G., Tozza, S., Trevisan, L., Pareyson, D., and Mandich, P.

Published
2020
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7. Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy

Author

Scala, S, Ferrua, F, Basso-Ricci, L, Dionisio, F, Omrani, M, Quaranta, P, Jofra Hernandez, R, Del Core, L, Benedicenti, F, Monti, I, Giannelli, S, Fraschetta, F, Darin, S, Albertazzi, E, Galimberti, S, Montini, E, Calabria, A, Cicalese, M, Aiuti, A, Scala, Serena, Ferrua, Francesca, Basso-Ricci, Luca, Dionisio, Francesca, Omrani, Maryam, Quaranta, Pamela, Jofra Hernandez, Raisa, Del Core, Luca, Benedicenti, Fabrizio, Monti, Ilaria, Giannelli, Stefania, Fraschetta, Federico, Darin, Silvia, Albertazzi, Elena, Galimberti, Stefania, Montini, Eugenio, Calabria, Andrea, Cicalese, Maria Pia, Aiuti, Alessandro, Scala, S, Ferrua, F, Basso-Ricci, L, Dionisio, F, Omrani, M, Quaranta, P, Jofra Hernandez, R, Del Core, L, Benedicenti, F, Monti, I, Giannelli, S, Fraschetta, F, Darin, S, Albertazzi, E, Galimberti, S, Montini, E, Calabria, A, Cicalese, M, Aiuti, A, Scala, Serena, Ferrua, Francesca, Basso-Ricci, Luca, Dionisio, Francesca, Omrani, Maryam, Quaranta, Pamela, Jofra Hernandez, Raisa, Del Core, Luca, Benedicenti, Fabrizio, Monti, Ilaria, Giannelli, Stefania, Fraschetta, Federico, Darin, Silvia, Albertazzi, Elena, Galimberti, Stefania, Montini, Eugenio, Calabria, Andrea, Cicalese, Maria Pia, and Aiuti, Alessandro

Abstract

Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.

Published
2023

8. Natural history of KBG syndrome in a large European cohort

Author

Loberti, L. (Lorenzo), Bruno, L. P. (Lucia Pia), Granata, S. (Stefania), Doddato, G. (Gabriella), Resciniti, S. (Sara), Fava, F. (Francesca), Carullo, M. (Michele), Rahikkala, E. (Elisa), Jouret, G. (Guillaume), Menke, L. A. (Leonie A.), Lederer, D. (Damien), Vrielynck, P. (Pascal), Ryba, L. (Lukáš), Brunetti-Pierri, N. (Nicola), Lasa-Aranzasti, A. (Amaia), Cueto-González, A. M. (Anna Maria), Trujillano, L. (Laura), Valenzuela, I. (Irene), Tizzano, E. F. (Eduardo F.), Spinelli, A. M. (Alessandro Mauro), Bruno, I. (Irene), Currò, A. (Aurora), Stanzial, F. (Franco), Benedicenti, F. (Francesco), Lopergolo, D. (Diego), Santorelli, F. M. (Filippo Maria), Aristidou, C. (Constantia), Tanteles, G. A. (George A.), Maystadt, I. (Isabelle), Tkemaladze, T. (Tinatin), Reimand, T. (Tiia), Lokke, H. (Helen), Õunap, K. (Katrin), Haanpää, M. K. (Maria K.), Holubová, A. (Andrea), Zoubková, V. (Veronika), Schwarz, M. (Martin), Žordania, R. (Riina), Muru, K. (Kai), Roht, L. (Laura), Tihveräinen, A. (Annika), Teek, R. (Rita), Thomson, U. (Ulvi), Atallah, I. (Isis), Superti-Furga, A. (Andrea), Buoni, S. (Sabrina), Canitano, R. (Roberto), Scandurra, V. (Valeria), Rossetti, A. (Annalisa), Grosso, S. (Salvatore), Battini, R. (Roberta), Baldassarri, M. (Margherita), Mencarelli, M. A. (Maria Antonietta), Lo Rizzo, C. (Caterina), Bruttini, M. (Mirella), Mari, F. (Francesca), Ariani, F. (Francesca), Renieri, A. (Alessandra), Pinto, A. M. (Anna Maria), Loberti, L. (Lorenzo), Bruno, L. P. (Lucia Pia), Granata, S. (Stefania), Doddato, G. (Gabriella), Resciniti, S. (Sara), Fava, F. (Francesca), Carullo, M. (Michele), Rahikkala, E. (Elisa), Jouret, G. (Guillaume), Menke, L. A. (Leonie A.), Lederer, D. (Damien), Vrielynck, P. (Pascal), Ryba, L. (Lukáš), Brunetti-Pierri, N. (Nicola), Lasa-Aranzasti, A. (Amaia), Cueto-González, A. M. (Anna Maria), Trujillano, L. (Laura), Valenzuela, I. (Irene), Tizzano, E. F. (Eduardo F.), Spinelli, A. M. (Alessandro Mauro), Bruno, I. (Irene), Currò, A. (Aurora), Stanzial, F. (Franco), Benedicenti, F. (Francesco), Lopergolo, D. (Diego), Santorelli, F. M. (Filippo Maria), Aristidou, C. (Constantia), Tanteles, G. A. (George A.), Maystadt, I. (Isabelle), Tkemaladze, T. (Tinatin), Reimand, T. (Tiia), Lokke, H. (Helen), Õunap, K. (Katrin), Haanpää, M. K. (Maria K.), Holubová, A. (Andrea), Zoubková, V. (Veronika), Schwarz, M. (Martin), Žordania, R. (Riina), Muru, K. (Kai), Roht, L. (Laura), Tihveräinen, A. (Annika), Teek, R. (Rita), Thomson, U. (Ulvi), Atallah, I. (Isis), Superti-Furga, A. (Andrea), Buoni, S. (Sabrina), Canitano, R. (Roberto), Scandurra, V. (Valeria), Rossetti, A. (Annalisa), Grosso, S. (Salvatore), Battini, R. (Roberta), Baldassarri, M. (Margherita), Mencarelli, M. A. (Maria Antonietta), Lo Rizzo, C. (Caterina), Bruttini, M. (Mirella), Mari, F. (Francesca), Ariani, F. (Francesca), Renieri, A. (Alessandra), and Pinto, A. M. (Anna Maria)

Abstract

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: −0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Published
2022

9. Natural history of KBG syndrome in a large European cohort

Author

Loberti, L, Bruno, L, Granata, S, Doddato, G, Resciniti, S, Fava, F, Carullo, M, Rahikkala, E, Jouret, G, Menke, L, Lederer, D, Vrielynck, P, Ryba, L, Brunetti-Pierri, N, Lasa-Aranzasti, A, Cueto-González, A, Trujillano, L, Valenzuela, I, Tizzano, E, Spinelli, A, Bruno, I, Currò, A, Stanzial, F, Benedicenti, F, Lopergolo, D, Santorelli, F, Aristidou, C, Tanteles, G, Maystadt, I, Tkemaladze, T, Reimand, T, Lokke, H, Õunap, K, Haanpää, M, Holubová, A, Zoubková, V, Schwarz, M, Žordania, R, Muru, K, Roht, L, Tihveräinen, A, Teek, R, Thomson, U, Isis, A, Superti-Furga, A, Buoni, S, Canitano, R, Scandurra, V, Rossetti, A, Grosso, S, Battini, R, Baldassarri, M, Mencarelli, M, Rizzo, C, Bruttini, M, Mari, F, Ariani, F, Renieri, A, Pinto, A, Loberti, Lorenzo, Bruno, Lucia Pia, Granata, Stefania, Doddato, Gabriella, Resciniti, Sara, Fava, Francesca, Carullo, Michele, Rahikkala, Elisa, Jouret, Guillaume, Menke, Leonie A, Lederer, Damien, Vrielynck, Pascal, Ryba, Lukáš, Brunetti-Pierri, Nicola, Lasa-Aranzasti, Amaia, Cueto-González, Anna Maria, Trujillano, Laura, Valenzuela, Irene, Tizzano, Eduardo F, Spinelli, Alessandro Mauro, Bruno, Irene, Currò, Aurora, Stanzial, Franco, Benedicenti, Francesco, Lopergolo, Diego, Santorelli, Filippo Maria, Aristidou, Constantia, Tanteles, George A, Maystadt, Isabelle, Tkemaladze, Tinatin, Reimand, Tiia, Lokke, Helen, Õunap, Katrin, Haanpää, Maria K, Holubová, Andrea, Zoubková, Veronika, Schwarz, Martin, Žordania, Riina, Muru, Kai, Roht, Laura, Tihveräinen, Annika, Teek, Rita, Thomson, Ulvi, Isis, Atallah, Superti-Furga, Andrea, Buoni, Sabrina, Canitano, Roberto, Scandurra, Valeria, Rossetti, Annalisa, Grosso, Salvatore, Battini, Roberta, Baldassarri, Margherita, Mencarelli, Maria Antonietta, Rizzo, Caterina Lo, Bruttini, Mirella, Mari, Francesca, Ariani, Francesca, Renieri, Alessandra, Pinto, Anna Maria, Loberti, L, Bruno, L, Granata, S, Doddato, G, Resciniti, S, Fava, F, Carullo, M, Rahikkala, E, Jouret, G, Menke, L, Lederer, D, Vrielynck, P, Ryba, L, Brunetti-Pierri, N, Lasa-Aranzasti, A, Cueto-González, A, Trujillano, L, Valenzuela, I, Tizzano, E, Spinelli, A, Bruno, I, Currò, A, Stanzial, F, Benedicenti, F, Lopergolo, D, Santorelli, F, Aristidou, C, Tanteles, G, Maystadt, I, Tkemaladze, T, Reimand, T, Lokke, H, Õunap, K, Haanpää, M, Holubová, A, Zoubková, V, Schwarz, M, Žordania, R, Muru, K, Roht, L, Tihveräinen, A, Teek, R, Thomson, U, Isis, A, Superti-Furga, A, Buoni, S, Canitano, R, Scandurra, V, Rossetti, A, Grosso, S, Battini, R, Baldassarri, M, Mencarelli, M, Rizzo, C, Bruttini, M, Mari, F, Ariani, F, Renieri, A, Pinto, A, Loberti, Lorenzo, Bruno, Lucia Pia, Granata, Stefania, Doddato, Gabriella, Resciniti, Sara, Fava, Francesca, Carullo, Michele, Rahikkala, Elisa, Jouret, Guillaume, Menke, Leonie A, Lederer, Damien, Vrielynck, Pascal, Ryba, Lukáš, Brunetti-Pierri, Nicola, Lasa-Aranzasti, Amaia, Cueto-González, Anna Maria, Trujillano, Laura, Valenzuela, Irene, Tizzano, Eduardo F, Spinelli, Alessandro Mauro, Bruno, Irene, Currò, Aurora, Stanzial, Franco, Benedicenti, Francesco, Lopergolo, Diego, Santorelli, Filippo Maria, Aristidou, Constantia, Tanteles, George A, Maystadt, Isabelle, Tkemaladze, Tinatin, Reimand, Tiia, Lokke, Helen, Õunap, Katrin, Haanpää, Maria K, Holubová, Andrea, Zoubková, Veronika, Schwarz, Martin, Žordania, Riina, Muru, Kai, Roht, Laura, Tihveräinen, Annika, Teek, Rita, Thomson, Ulvi, Isis, Atallah, Superti-Furga, Andrea, Buoni, Sabrina, Canitano, Roberto, Scandurra, Valeria, Rossetti, Annalisa, Grosso, Salvatore, Battini, Roberta, Baldassarri, Margherita, Mencarelli, Maria Antonietta, Rizzo, Caterina Lo, Bruttini, Mirella, Mari, Francesca, Ariani, Francesca, Renieri, Alessandra, and Pinto, Anna Maria

Abstract

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: −0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

Published
2022

11. Down Syndrome and Parity

Author

Working Group on Down Syndrome, Clementi, M., Bianca, S., Benedicenti, F., and Tenconi, R.

Published
1999

13. Sleeping Beauty-engineered CAR T cells achieve anti-leukemic activity without severe toxicities

Author

Magnani, C, Gaipa, G, Lussana, F, Belotti, D, Gritti, G, Napolitano, S, Matera, G, Cabiati, B, Buracchi, C, Borleri, G, Fazio, G, Zaninelli, S, Tettamanti, S, Cesana, S, Colombo, V, Quaroni, M, Cazzaniga, G, Rovelli, A, Biagi, E, Galimberti, S, Calabria, A, Benedicenti, F, Montini, E, Ferrari, S, Introna, M, Balduzzi, A, Valsecchi, M, Dastoli, G, Rambaldi, A, Biondi, A, Magnani, Chiara F, Gaipa, Giuseppe, Lussana, Federico, Belotti, Daniela, Gritti, Giuseppe, Napolitano, Sara, Matera, Giada, Cabiati, Benedetta, Buracchi, Chiara, Borleri, Gianmaria, Fazio, Grazia, Zaninelli, Silvia, Tettamanti, Sarah, Cesana, Stefania, Colombo, Valentina, Quaroni, Michele, Cazzaniga, Giovanni, Rovelli, Attilio, Biagi, Ettore, Galimberti, Stefania, Calabria, Andrea, Benedicenti, Fabrizio, Montini, Eugenio, Ferrari, Silvia, Introna, Martino, Balduzzi, Adriana, Valsecchi, Maria Grazia, Dastoli, Giuseppe, Rambaldi, Alessandro, Biondi, Andrea, Magnani, C, Gaipa, G, Lussana, F, Belotti, D, Gritti, G, Napolitano, S, Matera, G, Cabiati, B, Buracchi, C, Borleri, G, Fazio, G, Zaninelli, S, Tettamanti, S, Cesana, S, Colombo, V, Quaroni, M, Cazzaniga, G, Rovelli, A, Biagi, E, Galimberti, S, Calabria, A, Benedicenti, F, Montini, E, Ferrari, S, Introna, M, Balduzzi, A, Valsecchi, M, Dastoli, G, Rambaldi, A, Biondi, A, Magnani, Chiara F, Gaipa, Giuseppe, Lussana, Federico, Belotti, Daniela, Gritti, Giuseppe, Napolitano, Sara, Matera, Giada, Cabiati, Benedetta, Buracchi, Chiara, Borleri, Gianmaria, Fazio, Grazia, Zaninelli, Silvia, Tettamanti, Sarah, Cesana, Stefania, Colombo, Valentina, Quaroni, Michele, Cazzaniga, Giovanni, Rovelli, Attilio, Biagi, Ettore, Galimberti, Stefania, Calabria, Andrea, Benedicenti, Fabrizio, Montini, Eugenio, Ferrari, Silvia, Introna, Martino, Balduzzi, Adriana, Valsecchi, Maria Grazia, Dastoli, Giuseppe, Rambaldi, Alessandro, and Biondi, Andrea

Abstract

BACKGROUND. Chimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability. METHODS. We report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells. RESULTS. The cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD–). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion. CONCLUSION. SB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.

Published
2020

16. Characteristics of a nationwide cohort of patients presenting with isolated hypogonadotropic hypogonadism (IHH)

Author

Bonomi, Marco, primary, Vezzoli, Valeria, additional, Krausz, Csilla, additional, Guizzardi, Fabiana, additional, Vezzani, Silvia, additional, Simoni, Manuela, additional, Bassi, Ivan, additional, Duminuco, Paolo, additional, Di Iorgi, Natascia, additional, Giavoli, Claudia, additional, Pizzocaro, Alessandro, additional, Russo, Gianni, additional, Moro, Mirella, additional, Fatti, Letizia, additional, Ferlin, Alberto, additional, Mazzanti, Laura, additional, Zatelli, Maria Chiara, additional, Cannavò, Salvo, additional, Isidori, Andrea M, additional, Pincelli, Angela Ida, additional, Prodam, Flavia, additional, Mancini, Antonio, additional, Limone, Paolo, additional, Tanda, Maria Laura, additional, Gaudino, Rossella, additional, Salerno, Mariacarolina, additional, Francesca, Pregnolato, additional, Maghnie, Mohamad, additional, Maggi, Mario, additional, Persani, Luca, additional, _, _, additional, Aimaretti, G, additional, Altobelli, M, additional, Ambrosio, M R, additional, Andrioli, M, additional, Angeletti, G, additional, Arecco, F, additional, Arnaldi, G, additional, Arosio, M, additional, Balsamo, A, additional, Baldassarri, M, additional, Bartalena, L, additional, Bazzoni, N, additional, Beccaria, L, additional, Beck-Peccoz, P, additional, Bellastella, G, additional, Bellizzi, M, additional, Benedicenti, F, additional, Bernasconi, S, additional, Bizzarri, C, additional, Bona, G, additional, Bonadonna, S, additional, Borretta, G, additional, Boschetti, M, additional, Brunani, A, additional, Brunelli, V, additional, Buzi, F, additional, Cacciatore, C, additional, Cangiano, B, additional, Cappa, M, additional, Casalone, R, additional, Cassio, A, additional, Cavarzere, P, additional, Cherubini, V, additional, Ciampani, T, additional, Cicognani, D, additional, Cignarelli, A, additional, Cisternino, M, additional, Colombo, P, additional, Corbetta, S, additional, Corciulo, N, additional, Corona, G, additional, Cozzi, R, additional, Crivellaro, C, additional, Dalle Mule, I, additional, Danesi, L, additional, D’Elia, A V, additional, degli Uberti, E, additional, De Leo, S, additional, Della Valle, E, additional, De Marchi, M, additional, Di Iorgi, N, additional, Di Mambro, A, additional, Fabbri, A, additional, Foresta, C, additional, Forti, G, additional, Franceschi, A R, additional, Garolla, A, additional, Ghezzi, M, additional, Giacomozzi, C, additional, Giusti, M, additional, Grosso, E, additional, Guabello, G, additional, Guarneri, M P, additional, Grugni, G, additional, Isidori, A M, additional, Lanfranco, F, additional, Lania, A, additional, Lanzi, R, additional, Larizza, L, additional, Lenzi, A, additional, Loche, S, additional, Loli, P, additional, Lombardi, V, additional, Maggio, M C, additional, Mandrile, G, additional, Manieri, C, additional, Mantovani, G, additional, Marelli, S, additional, Marzullo, M, additional, Mencarelli, M A, additional, Migone, N, additional, Motta, G, additional, Neri, G, additional, Padova, G, additional, Parenti, G, additional, Pasquino, B, additional, Pia, A, additional, Piantanida, E, additional, Pignatti, E, additional, Pilotta, A, additional, Pivetta, B, additional, Pollazzon, M, additional, Pontecorvi, A, additional, Porcelli, P, additional, Pozzan, G B, additional, Pozzobon, G, additional, Radetti, G, additional, Razzore, P, additional, Rocchetti, L, additional, Roncoroni, R, additional, Rossi, G, additional, Sala, E, additional, Salvatoni, A, additional, Salvini, F, additional, Secco, A, additional, Segni, M, additional, Selice, R, additional, Sgaramella, P, additional, Sileo, F, additional, Sinisi, A A, additional, Sirchia, F, additional, Spada, A, additional, Tresoldi, A, additional, Vigneri, R, additional, Weber, G, additional, and Zucchini, S, additional

Published
2018
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18. Preclinical evaluation of donor-derived sleeping beauty modified CD19CAR+ lymphocytes for the treatment of acute lymphoblastic leukemia

Author

Magnani, C., primary, Mezzanotte, C., additional, Cappuzzello, C., additional, Benedicenti, F., additional, Belotti, D., additional, Cabiati, B., additional, Bardini, M., additional, Fazio, G., additional, Cazzaniga, G., additional, Cooper, L., additional, Montini, E., additional, Gaipa, G., additional, Biondi, A., additional, and Biagi, E., additional

Published
2017
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19. The genotoxic potential of lentiviral vector integration is modulated by the interplay between vector design and mouse genotype

Author

Cesana D., Ranzani M., Volpin M., Bartholomae C., Merella S., Benedicenti F., Sergi L. Sergi, SanVito F., Brombin C, Nonis A., Di Serio C., Doglioni C., VonKalle C., Schmidt M., Naldini L., Montini E., Cesana, D., Ranzani, M., Volpin, M., Bartholomae, C., Merella, S., Benedicenti, F., Sergi, Sergi L., Sanvito, F., Brombin, C, Nonis, A., Di Serio, C., Doglioni, C., Vonkalle, C., Schmidt, M., Naldini, L., and Montini, E.

Published
2013

20. New liver cancer genes identified by lentiviral vector-based insertional mutagenesis in mice are associated to differential survival in hepatocellular carcinoma patients

Author

Ranzani M, Cesana D, Bartholomae CC, Sanvito F, Pala M, Benedicenti F, Gallina P, Sergi LS, Merella S, Bulfone A, Doglioni C, von Kalle C, Kim YJ, Schmidt M, Tonon G, Naldini L, Montini E, Ranzani, M, Cesana, D, Bartholomae, Cc, Sanvito, F, Pala, M, Benedicenti, F, Gallina, P, Sergi, L, Merella, S, Bulfone, A, Doglioni, C, von Kalle, C, Kim, Yj, Schmidt, M, Tonon, G, Naldini, L, and Montini, E

Published
2012

21. New Graph-Based Algorithm for Comprehensive Identification and Tracking Retroviral Integration Sites

Author

Calabria, A, Beretta, S, Merelli, I, Spinozzi, G, Brasca, S, Benedicenti, F, Tenderini, E, Biffi, A, Montini, E, CALABRIA, ANDREA, BERETTA, STEFANO, MERELLI, IVAN, SPINOZZI, GIULIO, Montini, E., Calabria, A, Beretta, S, Merelli, I, Spinozzi, G, Brasca, S, Benedicenti, F, Tenderini, E, Biffi, A, Montini, E, CALABRIA, ANDREA, BERETTA, STEFANO, MERELLI, IVAN, SPINOZZI, GIULIO, and Montini, E.

Published
2016

22. Immunotherapy of acute leukemia by chimeric antigen receptormodified lymphocytes using an improved Sleeping Beauty transposon platform

Author

Magnani, C, Turazzi, N, Benedicenti, F, Calabria, A, Tenderini, E, Tettamanti, S, Giordano Attianese, G, Cooper, L, Aiuti, A, Montini, E, Biondi, A, Biagi, E, Magnani, C, Turazzi, N, Benedicenti, F, Calabria, A, Tenderini, E, Tettamanti, S, Giordano Attianese, G, Cooper, L, Aiuti, A, Montini, E, Biondi, A, and Biagi, E

Abstract

Chimeric antigen receptor (CAR)-modified T-cell adoptive immunotherapy is a remarkable therapeutic option proven effective in the treatment of hematological malignancies. In order to optimize cell manufacturing, we sought to develop a novel clinical-grade protocol to obtain CAR-modified cytokine-induced killer cells (CIKs) using the Sleeping Beauty (SB) transposon system. Administration of irradiated PBMCs overcame cell death of stimulating cells induced by non-viral transfection, enabling robust gene transfer together with efficient T-cell expansion. Upon single stimulation, we reached an average of 60% expression of CD123- and CD19- specific 3rd generation CARs (CD28/OX40/TCRzeta). Furthermore, modified cells displayed persistence of cell subsets with memory phenotype, specific and effective lytic activity against leukemic cell lines and primary blasts, cytokine secretion, and proliferation. Adoptive transfer of CD123.CAR or CD19.CAR lymphocytes led to a significant anti-tumor response against acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) disseminated diseases in NSG mice. Notably, we found no evidence of integration enrichment near cancer genes and transposase expression at the end of the differentiation. Taken all together, our findings describe a novel donor-derived non-viral CAR approach that may widen the repertoire of available methods for T cell-based immunotherapy.

Published
2016

23. Identification of new human liver cancer genes by a novel lentiviral vector-based insertional mutagenesis approach in three mouse models of hepatocarcinogenesis

Author

Ranzani M, Cesana D, Bartholomae C, Sanvito F, Pala M, Benedicenti F, Sergi LS, Bulfone A, Doglioni C, von Kalle C, Schmidt M, Tonon G, Naldini L, Montini E, Ranzani, M, Cesana, D, Bartholomae, C, Sanvito, F, Pala, M, Benedicenti, F, Sergi, L, Bulfone, A, Doglioni, C, von Kalle, C, Schmidt, M, Tonon, G, Naldini, L, and Montini, E

Published
2011

24. Lentiviral vector-based insertional mutagenesis identifies new clinically relevant cancer genes involved in the pathogenesis of hepatocellular carcinoma

Author

Ranzani M, Cesana D, Bartholomae C, Sanvito F, Pala M, Benedicenti F, Gallina P, Sergi L, Merella S, Bulfone A, Doglioni C, von Kalle C, Kim YJ, Schmidt M, Tonon G, Naldini L, Montini E, Ranzani, M, Cesana, D, Bartholomae, C, Sanvito, F, Pala, M, Benedicenti, F, Gallina, P, Sergi, L, Merella, S, Bulfone, A, Doglioni, C, von Kalle, C, Kim, Yj, Schmidt, M, Tonon, G, Naldini, L, and Montini, E

Published
2011

27. The Italian National Rare Diseases Registry

Author

Taruscio, D, Kodra, Y, Ferrari, G, Vittozzi, L, Annicchiarico, G, Attolini, E, Antonelli, A, Barone, R, Bembi, B, Deroma, L, Bianchi, F, Berni, C, Borsellino, L, Scondotto, S, Benedicenti, F, Zuech, P, Casucci, P, Patisso, Mc, Di Lallo, D, Di Nunzio ML, Di Palma, A., Volta, M, Vizioli, M, Facchin, P, Mazzucato, M, Gabrielli, O, Della Casa, R, Scala, I, Baraldo, G, Daina, E, Palka, G, Roccatello, Dario, Modena, V, Rossi, M, Tripaldi, D, and Angione, A.

Subjects
Male, Italy, National Health Programs, Regional, National and European actions in the field of Rare Diseases, Epidemiological Monitoring, Humans, rare diseases, Female, Registries, Community Networks
Abstract

Rare disease registries are a priority at European level and specific actions are being implemented by the European Commission to support their development.In Italy, a National Registry of rare diseases has been established in 2001 as a network of regional registries. The latter have gradually been established and the full coverage of the Italian territory was attained during 2011.Here we describe the basic features of the National Registry of rare diseases; the activities carried out to promote consistent operations in the regional registries; and the overall quality and composition of the records collected.After a validation process, including removal of duplicate records, 110,841 records of patients with rare diseases, single and with group denominations, are stored in the National Registry of rare diseases. They correspond to the overall diagnoses communicated to national registry by regional registries up to 30 June 2012.The quality of the data collected by the the National Registry of rare diseases has been assessed with respect to completeness and consistency of procedures. Variables characterising case and diagnosis showed a very limited number of missing values. Records reported at least one case of 485 rare conditions.To date, the National Registry of rare diseases is a surveillance system with the main objective of producing epidemiologic evidence on rare diseases in Italy, and of supporting policy making and health services planning.Data quality still represents a limitation for any sound epidemiological estimate of rare diseases in Italy. However, improvements of the quality of collected data and the completeness of case notifications should be strengthened.

Published
2014

29. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection

Author

Montini, E., Cesana, D., Schmidt, M., Sanvito, F., Bartholomae, C., Ranzani, M., Benedicenti, F., Sergi, Ls, Alessandro Ambrosi, Ponzoni, M., Doglioni, C., Di Serio, C., Kalle, C., Naldini, L., Montini, E, Cesana, D, Schmidt, M, Sanvito, F, Bartholomae, C, Ranzani, M, Benedicenti, F, Sergi, L, Ambrosi, A, Ponzoni, M, Doglioni, C, Di Serio, C, von Kalle, C, and Naldini, L

Published
2008

31. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia

Author

Kohl, S., Zobor, D., Chiang, W.C., Weisschuh, N., Staller, J., Menendez, I.G., Chang, S., Beck, S.C., Garrido, M. Garcia, Sothilingam, V., Seeliger, M.W., Stanzial, F., Benedicenti, F., Inzana, F., Heon, E, Vincent, A., Beis, J., Strom, T.M., Rudolph, G., Roosing, S., Hollander, A.I. den, Cremers, F.P.M., Lopez, I., Ren, H., Moore, A.T., Webster, A.R., Michaelides, M., Koenekoop, R.K., Zrenner, E., Kaufman, R.J., Tsang, S.H., Wissinger, B., Lin, J.H., Kohl, S., Zobor, D., Chiang, W.C., Weisschuh, N., Staller, J., Menendez, I.G., Chang, S., Beck, S.C., Garrido, M. Garcia, Sothilingam, V., Seeliger, M.W., Stanzial, F., Benedicenti, F., Inzana, F., Heon, E, Vincent, A., Beis, J., Strom, T.M., Rudolph, G., Roosing, S., Hollander, A.I. den, Cremers, F.P.M., Lopez, I., Ren, H., Moore, A.T., Webster, A.R., Michaelides, M., Koenekoop, R.K., Zrenner, E., Kaufman, R.J., Tsang, S.H., Wissinger, B., and Lin, J.H.

Abstract

Item does not contain fulltext, Achromatopsia (ACHM) is an autosomal recessive disorder characterized by color blindness, photophobia, nystagmus and severely reduced visual acuity. Using homozygosity mapping and whole-exome and candidate gene sequencing, we identified ten families carrying six homozygous and two compound-heterozygous mutations in the ATF6 gene (encoding activating transcription factor 6A), a key regulator of the unfolded protein response (UPR) and cellular endoplasmic reticulum (ER) homeostasis. Patients had evidence of foveal hypoplasia and disruption of the cone photoreceptor layer. The ACHM-associated ATF6 mutations attenuate ATF6 transcriptional activity in response to ER stress. Atf6(-/-) mice have normal retinal morphology and function at a young age but develop rod and cone dysfunction with increasing age. This new ACHM-related gene suggests a crucial and unexpected role for ATF6A in human foveal development and cone function and adds to the list of genes that, despite ubiquitous expression, when mutated can result in an isolated retinal photoreceptor phenotype.

Published
2015

32. adLIMS: A customized open source software that allows bridging clinical and basic molecular research studies

Author

Calabria, A, Spinozzi, G, Benedicenti, F, Tenderini, E, Montini, E, CALABRIA, ANDREA, SPINOZZI, GIULIO, Montini, E., Calabria, A, Spinozzi, G, Benedicenti, F, Tenderini, E, Montini, E, CALABRIA, ANDREA, SPINOZZI, GIULIO, and Montini, E.

Abstract

Background: Many biological laboratories that deal with genomic samples are facing the problem of sample tracking, both for pure laboratory management and for efficiency. Our laboratory exploits PCR techniques and Next Generation Sequencing (NGS) methods to perform high-throughput integration site monitoring in different clinical trials and scientific projects. Because of the huge amount of samples that we process every year, which result in hundreds of millions of sequencing reads, we need to standardize data management and tracking systems, building up a scalable and flexible structure with web-based interfaces, which are usually called Laboratory Information Management System (LIMS). Methods: We started collecting end-users' requirements, composed of desired functionalities of the system and Graphical User Interfaces (GUI), and then we evaluated available tools that could address our requirements, spanning from pure LIMS to Content Management Systems (CMS) up to enterprise information systems. Our analysis identified ADempiere ERP, an open source Enterprise Resource Planning written in Java J2EE, as the best software that also natively implements some highly desirable technological advances, such as the high usability and modularity that grants high use-case flexibility and software scalability for custom solutions. Results: We extended and customized ADempiere ERP to fulfil LIMS requirements and we developed adLIMS. It has been validated by our end-users verifying functionalities and GUIs through test cases for PCRs samples and pre-sequencing data and it is currently in use in our laboratories. adLIMS implements authorization and authentication policies, allowing multiple users management and roles definition that enables specific permissions, operations and data views to each user. For example, adLIMS allows creating sample sheets from stored data using available exporting operations. This simplicity and process standardization may avoid manual errors and infor

Published
2015

33. Lentiviral Hematopoietic Stem Cell Gene Therapy Benefits Metachromatic Leukodystrophy

Author

Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale Sabrina, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo W.B, Nalini A. L. Mehta N.A.L, Cicalese M.P, Casiraghi M, Boelens J.B, Del Carro U, Dow D.J, Schmidt M, Assanelli, A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo M.G, Aiuti A, Sessa M, and Naldini L.

Published
2013

34. Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

Author

Lorena, Travaglini, Francesco, Brancati, Jennifer, Silhavy, Miriam, Iannicelli, Elizabeth, Nickerson, Nadia, Elkhartoufi, Eric, Scott, Emily, Spencer, Stacey, Gabriel, Sophie, Thomas, Bruria, Ben Zeev, Enrico, Bertini, Eugen, Boltshauser, Malika, Chaouch, Maria, Roberta Cilio, Mirjam, M. de Jong, Hulya, Kayserili, Gonul, Ogur, Andrea, Poretti, Sabrina, Signorini, Graziella, Uziel, Maha, S. Zaki, Ali Pacha, L, Zankl, A, Leventer, R, Grattan Smith, P, Janecke, A, Koch, J, Freilinger, M, D'Hooghe, M, Sznajer, Y, Vilain, C, Van Coster, R, Demerleir, L, Dias, K, Moco, C, Moreira, A, Ae Kim, C, Maegawa, G, Dakovic, I, Loncarevic, D, Mejaski Bosnjak, V, Petkovic, D, Abdel Salam GM, Abdel Aleem, A, Marti, I, Pinard, Jm, Quijano Roy, S, Sigaudy, S, de Lonlay, P, Romano, S, Verloes, A, Touraine, R, Koenig, M, Dollfus, H, Flori, E, Fradin, M, Lagier Tourenne, C, Messer, J, Collignon, P, Penzien, Jm, Bussmann, C, Merkenschlager, A, Philippi, H, Kurlemann, G, Grundmann, K, Dacou Voutetakis, C, Kitsiou Tzeli, S, Pons, R, Jerney, J, Halldorsson, S, Johannsdottir, J, Ludvigsson, P, Phadke, Sr, Girisha, Km, Doshi, H, Udani, V, Kaul, M, Stuart, B, Magee, A, Spiegel, R, Shalev, S, Mandel, H, Lev, D, Michelson, M, Idit, M, Ben Zeev, B, Gershoni Baruch, R, Ficcadenti, A, Fischetto, R, Gentile, M, Della Monica, M, Pezzani, M, Graziano, C, Seri, M, Benedicenti, F, Stanzial, F, Borgatti, R, Romaniello, R, Accorsi, P, Battaglia, S, Fazzi, E, Giordano, L, Pinelli, L, Boccone, L, Barone, R, Sorge, G, Briatore, E, Bigoni, S, Ferlini, A, Donati, Ma, Biancheri, R, Caridi, G, Divizia, Mt, Faravelli, F, Ghiggeri, G, Mirabelli, M, Pessagno, A, Rossi, A, Uliana, V, Amorini, M, Briguglio, M, Briuglia, S, Salpietro, Cd, Tortorella, G, Adami, A, Bonati, Mt, Castorina, P, D'Arrigo, S, Lalatta, F, Marra, G, Moroni, I, Pantaleoni, C, Riva, D, Scelsa, B, Spaccini, L, Del Giudice, E, Ludwig, K, Permunian, A, Suppiej, A, Macaluso, C, Pichiecchio, A, Battini, R, Di Giacomo, M, Priolo, M, Timpani, P, Pagani, G, Di Sabato ML, Emma, F, Leuzzi, V, Mancini, F, Majore, S, Micalizzi, A, Parisi, P, Romani, M, Stringini, G, Zanni, G, Ulgheri, L, Pollazzon, M, Renieri, Alessandra, Belligni, E, Grosso, E, Pieri, I, Silengo, M, Devescovi, R, Greco, D, Romano, C, Cazzagon, M, Simonati, A, Al Tawari AA, Bastaki, L, Mégarbané, A, Sabolic Avramovska, V, Said, E, Stromme, P, Koul, R, Rajab, A, Azam, M, Barbot, C, Salih, Ma, Tabarki, B, Jocic Jakubi, B, Martorell Sampol, L, Rodriguez, B, Pascual Castroviejo, I, Gener, B, Puschmann, A, Starck, L, Capone, A, Lemke, J, Fluss, J, Niedrist, D, Hennekam, Rc, Wolf, N, Gouider Khouja, N, Kraoua, I, Ceylaner, S, Teber, S, Akgul, M, Anlar, B, Comu, S, Kayserili, H, Yüksel, A, Akcakus, M, Caglayan, Ao, Aldemir, O, Al Gazali, L, Sztriha, L, Nicholl, D, Woods, Cg, Bennett, C, Hurst, J, Sheridan, E, Barnicoat, A, Hemingway, C, Lees, M, Wakeling, E, Blair, E, Bernes, S, Sanchez, H, Clark, Ae, Demarco, E, Donahue, C, Sherr, E, Hahn, J, Sanger, Td, Gallager, Te, Daugherty, C, Krishnamoorthy, Ks, Sarco, D, Walsh, Ca, Mckanna, T, Milisa, J, Chung, Wk, De Vivo DC, Raynes, H, Schubert, R, Seward, A, Brooks, Dg, Goldstein, A, Caldwell, J, Finsecke, E, Maria, Bl, Holden, K, Cruse, Rp, Karaca, E, Swoboda, Kj, Viskochil, D, Dobyns, Wb, Colin, Johnson, Tania, Attié Bitach, Joseph, G. Gleeson, Enza, Maria Valente, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Human Genetics, Paediatrics, OMÜ, University of Zurich, Valente, Enza Maria, Fluss, Joel Victor, Travaglini, L, Brancati, F, Silhavy, J, Iannicelli, M, Nickerson, E, Elkhartoufi, N, Scott, E, Spencer, E, Gabriel, S, Thomas, S, Ben Zeev, B, Bertini, E, Boltshauser, E, Chaouch, M, Cilio, Mr, de Jong, Mm, Kayserili, H, Ogur, G, Poretti, A, Signorini, S, Uziel, G, Zaki, M, Johnson, C, Atti? Bitach, T, Gleeson, Jg, Valente, Em, International JSRD Study, Group, and DEL GIUDICE, Ennio

Subjects
Male, Ciliata -- Anatomy, Proband, 10039 Institute of Medical Genetics, Meckel syndrome, RPGRIP1L, Syndromes, INPP5E, MODIFIER, Phosphoric Monoester Hydrolases/genetics, Ciliopathies, Polycystic Kidney Diseases/diagnosis/genetics, CILIUM, 0302 clinical medicine, Gene Frequency, Cerebellum, Prenatal Diagnosis, RETINAL DEGENERATION, Prevalence, MECKEL, ciliopathies, Joubert syndrome and related disorders, Eye Abnormalities, Child, Genetics (clinical), Encephalocele, Joubert syndrome, Genetics, Polycystic Kidney Diseases, 0303 health sciences, ddc:618, Cerebellar Diseases/diagnosis/genetics, Kidney Diseases, Cystic, Pedigree, 3. Good health, Phenotype, Child, Preschool, Medical genetics, Female, Retinitis Pigmentosa, FORM, Ciliary Motility Disorders, Heterozygote, medicine.medical_specialty, 2716 Genetics (clinical), Adolescent, Molecular Sequence Data, Encephalocele/diagnosis/genetics, AHI1, 610 Medicine & health, Biology, Retina, Article, Ciliopathies, INPP5E, Joubert syndrome and related disorders, Meckel syndrome, NO, Ciliary Motility Disorders/diagnosis/genetics, 03 medical and health sciences, 1311 Genetics, Cerebellar Diseases, REVEALS, medicine, Humans, Abnormalities, Multiple, Amino Acid Sequence, Kidney Diseases, Cystic/diagnosis/genetics, abnormalities, multiple, adolescent, amino acid sequence, cerebellar diseases, cerebellum, child, preschool, ciliary motility disorders, encephalocele, eye abnormalities, female, heterozygote, humans, infant, kidney diseases, cystic, male, molecular sequence data, pedigree, phosphoric monoester hydrolases, polycystic kidney diseases, prenatal diagnosis, prevalence, retina, gene frequency, mutation, phenotype, 030304 developmental biology, Eye Abnormalities/diagnosis/genetics, COACH SYNDROME, Retina/abnormalities, Genetic heterogeneity, Respiration disorders -- Therapy, Infant, medicine.disease, Phosphoric Monoester Hydrolases, INPP5E mutation, 10036 Medical Clinic, Mutation, 030217 neurology & neurosurgery
Abstract

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain–hindbrain malformation known as the ‘molar tooth sign’. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS foetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus., peer-reviewed

Published
2013

35. VISPA: a computational pipeline for the identification and analysis of genomic vector integration sites

Author

Calabria, A, Leo, S, Benedicenti, F, Cesana, D, Spinozzi, G, Orsini, M, Merella, S, Stupka, E, Zanetti, G, Montini, E, CALABRIA, ANDREA, SPINOZZI, GIULIO, Montini, E., Calabria, A, Leo, S, Benedicenti, F, Cesana, D, Spinozzi, G, Orsini, M, Merella, S, Stupka, E, Zanetti, G, Montini, E, CALABRIA, ANDREA, SPINOZZI, GIULIO, and Montini, E.

Abstract

The analysis of the genomic distribution of viral vector genomic integration sites is a key step in hematopoietic stem cell-based gene therapy applications, allowing to assess both the safety and the efficacy of the treatment and to study the basic aspects of hematopoiesis and stem cell biology. Identifying vector integration sites requires ad-hoc bioinformatics tools with stringent requirements in terms of computational efficiency, flexibility, and usability. We developed VISPA (Vector Integration Site Parallel Analysis), a pipeline for automated integration site identification and annotation based on a distributed environment with a simple Galaxy web interface. VISPA was successfully used for the bioinformatics analysis of the follow-up of two lentiviral vector-based hematopoietic stem-cell gene therapy clinical trials. Our pipeline provides a reliable and efficient tool to assess the safety and efficacy of integrating vectors in clinical settings

Published
2014

36. MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert Syndrome related disorder with liver involvement

Author

Brancati, F., Iannicelli, M., Travaglini, L., Mazzotta, A., Bertini, E., Boltshauser, E., D?arrigo, S., Emma, F., Fazzi, E., Gallizzi, R., Gentile, M., Loncarevic, D., Mejaski-Bosnjak, V., Pantaleoni, C., Rigoli, L., Salpietro, C. D., Signorini, S., Stringini, G. R., Verloes, A., Zabloka, D., Dallapiccola, B., Gleeson, J. G., Valente, E. M., Zankl, A., Leventer, R., Smith, P. G., Janecke, A., D?hooghe, M., Sznajer, Y., Van Coster, R., Demerleir, L., Dias, K., Moco, C., Moreira, A., Ae Kim, C., Maegawa, G., Petkovic, D., Abdel-Salam, G. M. H., Abdel-Aleem, A., Zaki, M. S., Marti, I., Quijano-Roy, S., Sigaudy, S., De Lonlay, P., Romano, S., Touraine, R., Koenig, M., Lagier-Tourenne, C., Messer, J., Collignon, P., Wolf, N., Philippi, H., Tzeli, S. K., Halldorsson, S., Johannsdottir, J., Ludvigsson, P., Phadke, S. R., Udani, V., Stuart, B., Magee, A., Lev, D., Michelson, M., Ben-Zeev, B., Fischetto, R., Benedicenti, F., Stanzial, F., Borgatti, R., Accorsi, P., Battaglia, S., Giordano, L., Pinelli, L., Boccone, L., Bigoni, S., Ferlini, A., Donati, M. A., Caridi, G., Divizia, M. T., Faravelli, F., Ghiggeri, G., Pessagno, A., Briuglia, S., Tortorella, G., Adami, A., Castorina, P., Lalatta, F., Marra, G., Riva, D., Scelsa, B., Spaccini, L., Uziel, G., Giudice, E. D., Laverda, A. M., Ludwig, K., Permunian, A., Suppiej, A., Uggetti, C., Battini, R., Giacomo, M. D., Cilio, M. R., Di Sabato, M. L., Leuzzi, V., Parisi, P., Pollazzon, M., Silengo, M., De Vescovi, R., Greco, D., Romano, C., Cazzagon, M., Simonati, A., Al-Tawari, A. A., Bastaki, L., M('e)garban('e), A., Sabolic Avramovska, V., De Jong, M. M., Stromme, P., Koul, R., Rajab, A., Azam, M., Barbot, C., Martorell Sampol, L., Rodriguez, B., Pascual-Castroviejo, I., Teber, S., Anlar, B., Comu, S., Karaca, E., Kayserili, H., Y, Brancati, F, Iannicelli, M, Travaglini, L, Mazzotta, A, Bertini, E, Boltshauser, E, D'Arrigo, S, Emma, F, Fazzi, E, Gallizzi, R, Gentile, M, Loncarevic, D, Mejaski Bosnjak, V, Pantaleoni, C, Rigoli, L, Salpietro, Cd, Signorini, S, Stringini, Gr, Verloes, A, Zabloka, D, Dallapiccola, B, Gleeson, Jg, Valente, Em, International, JSRD Study Group, DEL GIUDICE, Ennio, and Pediatric surgery

Subjects
Pathology, medicine.medical_specialty, TMEM67, DNA Mutational Analysis, Molecular Sequence Data, education, Biology, Article, Joubert syndrome, NO, MKS3, COACH, Multiple Abnormalities, Nephronophthisis, Amino Acid Sequence, Base Sequence, Humans, Liver, Magnetic Resonance Imaging, Membrane Proteins, Mutation, Phenotype, RNA Splice Sites, Syndrome, Genetics, medicine, congenital hepatic fibrosis, Abnormalities, Multiple, Meckel syndrome, COACH syndrome, Joubert syndrome and related disorders, Genetics (clinical), Aplasia, medicine.disease, MKS3/TMEM67 mutation, COACH Syndrome, Ciliopathy, RPGRIP1L, Congenital hepatic fibrosis, human activities
Abstract

MKS3/TMEM67 mutations are a major cause of COACH Syndrome, a Joubert syndrome related disorder with liver involvement. The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the molar tooth sign, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs.

Published
2009

38. Down syndrome and parity

Author

Clementi, Maurizio, Bianca, S, Benedicenti, F, Tenconi, R, and Working Group on Down Syndrome

Subjects
Gynecology, medicine.medical_specialty, Down syndrome, Obstetrics, business.industry, Public Health, Environmental and Occupational Health, medicine, Prenatal diagnosis, medicine.disease, business, Parity (mathematics), Genetics (clinical)
Abstract

Objective: To investigate the effect of parity on Down syndrome (DS). Methods: The study was conducted on data from Northeast Italy (NEI) (1981–1996) and Sicily (ISMAC) (1991–1996) Congenital Malformation Registries. In these areas, all DS births are recorded and confirmed by chromosomal analysis; the NEI Registry also registers pregnancy terminations (TOPs) after prenatal diagnosis of DS. In order to estimate the effect of parity independently of the mother’s age and to reduce the truncation effect, different age classes and three classes of parity (1, 2–4, >4) were defined. Results: The study sample consisted of 1,088 consecutive newborns and 169 consecutive fetuses affected by DS. In both NEI and ISMAC samples, we found a significantly increased risk of having a DS child for multiparas ≥35 years of age. In the NEI sample, the inclusion of TOP data did not seem to modify this finding. In the ISMAC sample, a significantly reduced risk for primiparas was found at all ages. Conclusions: Our data confirm a higher risk of having a DS child in women with parity >4. As this effect is evident only in women ≥35 years age, its practical impact is null because these women are usually offered prenatal diagnosis in any case. However, the mechanisms involved, if this association is true, are very intriguing and the observation should stimulate scientific studies allowing a better knowledge of the nondisjunction mechanism.

Published
2004

41. Stable Expression Of Chimeric Antigen Receptors (CARs) By Sleeping Beauty-Mediated Gene Transfer and Efficient Expansion Of Leukemia-Specific Cytokine-Induced Killer (CIK) Cells

Author

Magnani, C, Turazzi, N, Benedicenti, F, Attianese, G, Tettamanti, S, Montini, E, Cooper, L, Aiuti, A, Biondi, A, Biagi, E, MAGNANI, CHIARA FRANCESCA, TURAZZI, NICE, BIONDI, ANDREA, BIAGI, ETTORE, Magnani, C, Turazzi, N, Benedicenti, F, Attianese, G, Tettamanti, S, Montini, E, Cooper, L, Aiuti, A, Biondi, A, Biagi, E, MAGNANI, CHIARA FRANCESCA, TURAZZI, NICE, BIONDI, ANDREA, and BIAGI, ETTORE

Published
2013

42. Detection of congenital anomalies by fetal ultrasonographic examination across Europe

Author

Stoll, C, Tenconi, R, Clementi, M, Haeusler, M, Barišić, I, Matejić, R, Garne, E, De Vignan, C, Vodovar, V, Alembik, Y, Dott, B, Froster, UG, Queisser-Luft, A, Wiesel, A, Benedicenti, F, Bianca, S, Ettore, G, Carit, E, Bianchi, F, Kucinskas, V, Utkus, A, De Walle, HEK, Zandwijken, GRJ, Garcia Minaur, S, Aranguren, G, Salvador, J, Baena, N, Addor, MC, Pescia, G, Oshovska, T, Gordienko, I, Boyd, PA, and Wellesley, DG

Subjects
Congenital anomalies, Ultrasonographic examination
Abstract

Objectives: Birth defects are a major health burden. Primary prevention is at present emerging, i.e. folate supplementation. When it is not possible, as is still the case for most birth defects, research is needed to determine how an optimal provision of prenatal diagnosis and use of services can be achieved. Ultrasound scans in the midtrimester of pregnancy are now a routine part of antenatal care in most European countries. The objective of this study was to evaluate the prenatal diagnosis of congenital anomalies by fetal ultrasonographic examination across Europe. Methods: Data from 20 registries of congenital malformations in 12 European countries were included. The prenatal ultrasound screening programs in the countries ranged from no routine screening to 3 fetal scans offered, including 2 for biometric purposes and 1 for search of congenital anomalies, the anomaly scan. Results: There were 8, 126 cases with congenital anomalies with an overall prenatal detection rate of 44.3%. Termination of pregnancy was performed in 1, 657 cases (21.8%). There was significant variation in the prenatal detection rate between regions with the lowest detection rate in registries of countries without routine fetal screening (Denmark and The Netherlands) and the highest detection rate in registries of countries with at least 1 anomaly scan (France, Germany, Italy, Spain, UK). However, there were large variations among the registries with a high detection rate. There were significant differences in the prenatal detection rate and proportion of induced abortions between isolated anomalies and associated anomalies (chromosomal aberrations, recognized syndromes, and multiple without chromosomal aberrations or recognized syndromes). Conclusions: Prenatal detection rate of congenital anomalies by fetal scan varies significantly between registries of European countries even with the same screening policy. Prenatal detection of congenital anomalies is significantly higher when associated malformations are present. The rate of induced abortions varies between registries of countries even with the same detection rate of congenital anomalies. The variation described may be due to cultural and policy differences.

Published
2001

45. HSC gene therapy trial for Metachromatic Leukodystrophy: first report on gene marking efficiency

Author

Biffi, A., maria sessa, Plati, T., Lorioli, L., Montini, E., Benedicenti, F., Salomoni, M., Vallanti, G., Radrizzani, M., Fumagalli, F., Casiraghi, M., Kabbara, N., Ciceri, F., Aiuti, A., Rovelli, A., Roncarolo, M. G., Naldini, L., Biffi, A, Sessa, M, Plati, T, Lorioli, L, Montini, E, Benedicenti, F, Salomoni, M, Vallanti, G, Radrizzani, M, Fumagalli, F, Casiraghi, M, Kabbara, N, Ciceri, Fabio, Aiuti, A, Rovelli, A, Roncarolo, Mg, and Naldini, L.

46. The genetic landscape of Joubert syndrome in Italy

Author

Serpieri, V., Nuovo, S., Micalizzi, A., D Abrusco, F., Accorsi, P., roberta battini, Benedicenti, F., Bertini, E., Bigoni, S., Bonati, M., Borgatti, R., Briguglio, M., Casella, A., Ciccone, R., D Arrigo, S., Dotti, M., Emma, F., Fazzi, E., Ginevrino, M., Giordano, L., Moroni, I., Romani, M., Romaniello, R., Signorini, S., Stanzial, F., Vanacore, N., Zanni, G., and Valente, E.

47. Prenatal ultrasound diagnosis of congenital diaphragmatic hernia - Associated malformations, chromosomal abnormalities and pregnancy outcome

Author

Barišić, I., Garne, E., Clementi, M., Häusler, M., Gjergja, R., Stoll, C., Žužek, A., Vondraček, N., Mozetič, Z. M., Vigan, C., Vodovar, V., Alembik, Y., Dott, B., Froster, U. G., Queisser-Luft, A., Wiesel, A., Tenconi, R., Benedicenti, F., Bianca, S., Ettore, G., Cariati, E., Bianchi, F., Lithuania Kucinskas, V., Utkus, A., Walle, H. E. K., Zandwijken, G. R. J., Salvador, J., Garcia-Minaur, S., Aranguren, G., Neus Baena, Addor, M. -C, Pescia, G., Oshovska, T., Gordienko, I., Boyd, P. A., and Wellesley, D. G.

50. Hematopoietic reconstitution dynamics of mobilized- and bone marrow-derived human hematopoietic stem cells after gene therapy

Author

Serena Scala, Francesca Ferrua, Luca Basso-Ricci, Francesca Dionisio, Maryam Omrani, Pamela Quaranta, Raisa Jofra Hernandez, Luca Del Core, Fabrizio Benedicenti, Ilaria Monti, Stefania Giannelli, Federico Fraschetta, Silvia Darin, Elena Albertazzi, Stefania Galimberti, Eugenio Montini, Andrea Calabria, Maria Pia Cicalese, Alessandro Aiuti, Scala, S, Ferrua, F, Basso-Ricci, L, Dionisio, F, Omrani, M, Quaranta, P, Jofra Hernandez, R, Del Core, L, Benedicenti, F, Monti, I, Giannelli, S, Fraschetta, F, Darin, S, Albertazzi, E, Galimberti, S, Montini, E, Calabria, A, Cicalese, M, and Aiuti, A

Subjects
Multidisciplinary, General Physics and Astronomy, General Chemistry, gene therapy, General Biochemistry, Genetics and Molecular Biology
Abstract

Mobilized peripheral blood is increasingly used instead of bone marrow as a source of autologous hematopoietic stem/progenitor cells for ex vivo gene therapy. Here, we present an unplanned exploratory analysis evaluating the hematopoietic reconstitution kinetics, engraftment and clonality in 13 pediatric Wiskott-Aldrich syndrome patients treated with autologous lentiviral-vector transduced hematopoietic stem/progenitor cells derived from mobilized peripheral blood (n = 7), bone marrow (n = 5) or the combination of the two sources (n = 1). 8 out of 13 gene therapy patients were enrolled in an open-label, non-randomized, phase 1/2 clinical study (NCT01515462) and the remaining 5 patients were treated under expanded access programs. Although mobilized peripheral blood- and bone marrow- hematopoietic stem/progenitor cells display similar capability of being gene-corrected, maintaining the engineered grafts up to 3 years after gene therapy, mobilized peripheral blood-gene therapy group shows faster neutrophil and platelet recovery, higher number of engrafted clones and increased gene correction in the myeloid lineage which correlate with higher amount of primitive and myeloid progenitors contained in hematopoietic stem/progenitor cells derived from mobilized peripheral blood. In vitro differentiation and transplantation studies in mice confirm that primitive hematopoietic stem/progenitor cells from both sources have comparable engraftment and multilineage differentiation potential. Altogether, our analyses reveal that the differential behavior after gene therapy of hematopoietic stem/progenitor cells derived from either bone marrow or mobilized peripheral blood is mainly due to the distinct cell composition rather than functional differences of the infused cell products, providing new frames of references for clinical interpretation of hematopoietic stem/progenitor cell transplantation outcome.

Published
2023

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