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102 results on '"Grazia, Giulia"'

101. Vers un exprit neuveau?

Author

P. Galante, P. Galante, R. Capozzi, A. Picone, F. Visconti, R. Pavia, Aglieri Rinella Tiziano, Alison Aurosa, Antoniciello Manuela, Autilio Vera, Balzano Daniele, Beigli Fereshteh, Berkmen Hulya, Bianchi Roberto, Bologna Roberto, Boni Federica, Bozkurt Esma, Calabrò Marco, Calcagno Gisella, Cengiz Huseyin, Cestarello Vanna, Ciotoli Pina, Cocina Grazia Giulia, Collotti Francesco, Coskun Hulya, Daidone Isabella, Del Monaco Anna Irene, Diker Nazire, Donelli Andrea, Elif Kırpık, Eryazicioglu Erdem, Faiferri Massimo, Franchino Rossella, Frettoloso Caterina, Gallucci Pierpaolo, Girginkaya Akdag Suzan, Giunta Santo,Gregory Paola, Gritti Andrea,Gulmez Kemal,Güney Efsun Ekenyazici, Hodebert Laurent, Hosseini Seyed Jamalaldin, Insetti Maria Italia, Koseoglu Emine, Macaione Ina, Marras Cristina, Marzot Nicola, Menegatti Francesco, Montella Ilaria, Morea Claudia, Occhiuto Rita, Pagano Lilia, Parrivecchio Laura, Pavia Rosario, Pavia Rosario, Pusceddu Fabrizio, Resta Giuseppe, Sansò Claudia, Sarro Adriana, Sbacchi, P. Galante, and Galante, P.

Subjects
Architettura, Fondazioni, Archetipi
Abstract

Il contributo presenta la raccolta degli atti del convegno. Il fenomeno delle migrazioni è proposto come un 'rappel à l'ordre' per gli architetti costretti a rifondare le ragioni di un mestiere e reinverare il ruolo civile della disciplina.

Published
2016

102. Primary cross-resistance to BRAFV600E-, MEK1/2- and PI3K/mTOR-specific inhibitors in BRAF-mutant melanoma cells counteracted by dual pathway blockade.

Author

Penna I, Molla A, Grazia G, Cleris L, Nicolini G, Perrone F, Picciani B, Del Vecchio M, de Braud F, Mortarini R, and Anichini A

Subjects
Animals, Apoptosis drug effects, Blotting, Western, Cell Proliferation drug effects, Female, Humans, MAP Kinase Kinase 1 genetics, MAP Kinase Kinase 1 metabolism, MAP Kinase Kinase 2 genetics, MAP Kinase Kinase 2 metabolism, Melanoma metabolism, Melanoma pathology, Mice, Mice, SCID, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction drug effects, TOR Serine-Threonine Kinases genetics, TOR Serine-Threonine Kinases metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm drug effects, MAP Kinase Kinase 1 antagonists & inhibitors, MAP Kinase Kinase 2 antagonists & inhibitors, Melanoma drug therapy, Mutation genetics, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins B-raf antagonists & inhibitors, TOR Serine-Threonine Kinases antagonists & inhibitors
Abstract

Intrinsic cross-resistance to inhibition of different signaling pathways may hamper development of combinatorial treatments in melanoma, but the relative frequency of this phenotype and the strategies to overcome this hurdle remain poorly understood. Among 49 BRAF-mutant melanoma cell lines from patients not previously treated with target therapy, 21 (42.9%) showed strong primary resistance (IC50 > 1 μM) to a BRAFV600E inhibitor. Most of the BRAF-inhibitor-resistant cell lines showed also strong or intermediate cross-resistance to MEK1/2- and to PI3K/mTOR-specific inhibitors. Primary cross-resistance was confirmed in an independent set of 23 BRAF-mutant short-term melanoma cell cultures. MEK1/2 and PI3K/mTOR co-targeting was the most effective approach, compared to BRAF and PI3K/mTOR dual blockade, to counteract primary resistance to BRAF inhibition and the cross-resistant phenotype. This was shown by extensive drug interaction analysis, tumor growth inhibition assays in-vivo, p-ERK and p-AKT inhibition, promotion of melanoma apoptosis, apoptosis-related protein modulation, activation of effector caspases and selective modulation of genes involved in melanoma drug resistance and belonging to the ERK/MAPK and PI3K/AKT canonical pathways. Compared to co-targeting of mutant BRAF and PI3K/mTOR, the association of a MEK1/2 and a PI3K/mTOR inhibitor was more effective in the activation of Bax and of caspase-3 and in the induction of caspase-dependent melanoma apoptosis. Furthermore Bax silencing reduced the latter effects. These results suggest that intrinsic resistance to BRAF inhibition is frequently associated with primary cross-resistance to MEK and PI3K/mTOR blockade in BRAF-mutant melanoma and provide pre-clinical evidence for a combinatorial approach to counteract this phenotype.

Published
2016
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