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1. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

Author

Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone P.

Published
2020
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3. Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus

Author

Petrillo, Federica, primary, Iervolino, Anna, additional, Angrisano, Tiziana, additional, Jelen, Sabina, additional, Costanzo, Vincenzo, additional, D’Acierno, Mariavittoria, additional, Cheng, Lei, additional, Wu, Qi, additional, Guerriero, Ilaria, additional, Mazzarella, Maria Cristina, additional, De Falco, Alfonso, additional, D’Angelo, Fulvio, additional, Ceccarelli, Michele, additional, Caraglia, Michele, additional, Capasso, Giovambattista, additional, Fenton, Robert A., additional, and Trepiccione, Francesco, additional

Published
2021
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5. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Departmanet of Life Sciences and Medicine [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Neuropathology (Mittelbronn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Interventional Neuroscience (Hertel Group) [research center], n°7.4615.18/Télévie-FNRS [sponsor], n°7.4632.17/Télévie-FNRS [sponsor], 766069/H2020 Marie Skłodowska-Curie Actions [sponsor], Pan-RTK/Fondation Cancer Luxembourg [sponsor], PEARL award - P16/BM/11192868/Fonds National de la Recherche Luxembourg [sponsor], C17/BM/11664971 FNR [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, Niclou, Simone, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Departmanet of Life Sciences and Medicine [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Neuropathology (Mittelbronn Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Interventional Neuroscience (Hertel Group) [research center], n°7.4615.18/Télévie-FNRS [sponsor], n°7.4632.17/Télévie-FNRS [sponsor], 766069/H2020 Marie Skłodowska-Curie Actions [sponsor], Pan-RTK/Fondation Cancer Luxembourg [sponsor], PEARL award - P16/BM/11192868/Fonds National de la Recherche Luxembourg [sponsor], C17/BM/11664971 FNR [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone

Abstract

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology.

Published
2020

6. Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Author

Luxembourg Institute of Health - LIH [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Télévie-FNRS (Grants n°7.4632.17, 4615.18) [sponsor], Fondation Cancer Luxembourg (Pan-RTK Targeting) [sponsor], FNR; CORE Junior C17/BM/11664971/DEMICS [sponsor], GLIOTRAIN ITN funded by the European Union’s Horizon 2020 [sponsor], Marie Skłodowska-Curie grant agreement No 766069 [sponsor], FNR PEARL P16/BM/11192868 grant [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anais, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sebastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, Niclou, Simone, Luxembourg Institute of Health - LIH [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Integrative Cell Signalling (Skupin Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Télévie-FNRS (Grants n°7.4632.17, 4615.18) [sponsor], Fondation Cancer Luxembourg (Pan-RTK Targeting) [sponsor], FNR; CORE Junior C17/BM/11664971/DEMICS [sponsor], GLIOTRAIN ITN funded by the European Union’s Horizon 2020 [sponsor], Marie Skłodowska-Curie grant agreement No 766069 [sponsor], FNR PEARL P16/BM/11192868 grant [sponsor], Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anais, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sebastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone

Abstract

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies.

Published
2020

7. Cystathionine-γ-lyase drives antioxidant defense in cysteine-restricted IDH1-mutant astrocytomas

Author

Cano-Galiano, Andrés, primary, Oudin, Anais, additional, Fack, Fred, additional, Allega, Maria-Francesca, additional, Sumpton, David, additional, Martinez-Garcia, Elena, additional, Dittmar, Gunnar, additional, Hau, Ann-Christin, additional, De Falco, Alfonso, additional, Herold-Mende, Christel, additional, Bjerkvig, Rolf, additional, Meiser, Johannes, additional, Tardito, Saverio, additional, and Niclou, Simone P, additional

Published
2021
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9. Primary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine

Author

Golebiewska, Anna, primary, Hau, Ann-Christin, additional, Oudin, Anaïs, additional, Stieber, Daniel, additional, Yabo, Yahaya A., additional, Baus, Virginie, additional, Barthelemy, Vanessa, additional, Klein, Eliane, additional, Bougnaud, Sébastien, additional, Keunen, Olivier, additional, Wantz, May, additional, Michelucci, Alessandro, additional, Neirinckx, Virginie, additional, Muller, Arnaud, additional, Kaoma, Tony, additional, Nazarov, Petr V., additional, Azuaje, Francisco, additional, De Falco, Alfonso, additional, Flies, Ben, additional, Richart, Lorraine, additional, Poovathingal, Suresh, additional, Arns, Thais, additional, Grzyb, Kamil, additional, Mock, Andreas, additional, Herold-Mende, Christel, additional, Steino, Anne, additional, Brown, Dennis, additional, May, Patrick, additional, Miletic, Hrvoje, additional, Malta, Tathiane M., additional, Noushmehr, Houtan, additional, Kwon, Yong-Jun, additional, Jahn, Winnie, additional, Klink, Barbara, additional, Tanner, Georgette, additional, Stead, Lucy F., additional, Mittelbronn, Michel, additional, Skupin, Alexander, additional, Hertel, Frank, additional, Bjerkvig, Rolf, additional, and Niclou, Simone P., additional

Published
2020
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11. Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus

Author

Michele Caraglia, Francesco Trepiccione, Anna Iervolino, Sabina Jelen, Mariavittoria D'Acierno, Robert A. Fenton, Lei Cheng, Giovambattista Capasso, Qi Wu, Fulvio D'Angelo, Vincenzo Costanzo, Maria Cristina Mazzarella, Alfonso De Falco, Michele Ceccarelli, Federica Petrillo, Ilaria Guerriero, Tiziana Angrisano, Petrillo, Federica, Iervolino, Anna, Angrisano, Tiziana, Jelen, Sabina, Costanzo, Vincenzo, D'Acierno, Mariavittoria, Cheng, Lei, Wu, Qi, Guerriero, Ilaria, Mazzarella, Maria Cristina, De Falco, Alfonso, D'Angelo, Fulvio, Ceccarelli, Michele, Caraglia, Michele, Capasso, Giovambattista, Fenton, Robert A, Trepiccione, Francesco, Petrillo, F., Iervolino, A., Angrisano, T., Jelen, S., Costanzo, V., D'Acierno, M., Cheng, L., Wu, Q., Guerriero, I., Mazzarella, M. C., de Falco, A., D'Angelo, F., Ceccarelli, M., Caraglia, M., Capasso, G., Fenton, R. A., and Trepiccione, F.

Subjects
Male, Ribonuclease III, Epithelial Sodium Channels/metabolism, GATA3 Transcription Factor/genetics, Proteome, MICRORNAS, AQUAPORIN-2, VASOPRESSIN, Diabetes Insipidus, Nephrogenic, urologic and male genital diseases, Epigenesis, Genetic, Mice, Gene expression, Transcriptional regulation, TRANSCRIPTION, RNA Processing, Post-Transcriptional, PHOSPHORYLATION, DNA METHYLATION, GENE-EXPRESSION, Aquaporin 2/genetics, Histone Demethylases, DNA methylation, Ribonuclease III/genetics, Epigenesis, Genetic/genetics, General Medicine, Kidney Tubules, Collecting/physiology, Cell biology, DNA-Binding Proteins, GATA2 Transcription Factor, Nephrology, Aquaporin 2, Female, epigenetic, Polyuria/genetics, ENaC, Transcription Factors/genetics, Down-Regulation, GATA3 Transcription Factor, Biology, Diabetes Insipidus, Nephrogenic/genetics, microRNA, medicine, LITHIUM, Animals, Epigenetics, Kidney Tubules, Collecting, Epithelial Sodium Channels, miRNA, Homeodomain Proteins, urogenital system, Polyuria, Sequence Analysis, RNA, Endoribonuclease Dicer, COLLECTING DUCT, AQP2, GATA2 Transcription Factor/genetics, Nephrogenic diabetes insipidus, medicine.disease, Renal Reabsorption, enzymes and coenzymes (carbohydrates), MicroRNAs/genetics, MicroRNAs, Basic Research, Gene Expression Regulation, biology.protein, Histone Demethylases/genetics, SYSTEMS-LEVEL ANALYSIS, Homeodomain Proteins/genetics, DNA-Binding Proteins/genetics, Dicer, Transcription Factors
Abstract

Water reabsorption along the collecting duct is dependent on the function of aquaporin 2 (AQP2). Currently, information on microRNA (miRNA)-mediated, post-transcriptional regulation of AQP2, which may influence water reabsorption, is limited. In mice, ablation of the Dicer enzyme (crucial for miRNA maturation) in AQP2-expressing cells induces nephrogenic diabetes insipidus (NDI) with dysregulation of the miRNA profile. A major finding is the identification of miRNAs associated with NDI through mediating epigenetic control of AQP2. This study offers novel targets for AQP2 regulation and potential treatment for governing renal water reabsorption.Background MicroRNAs (miRNAs), formed by cleavage of pre-microRNA by the endoribonuclease Dicer, are critical modulators of cell function by post-transcriptionally regulating gene expression.Methods Selective ablation of Dicer in AQP2-expressing cells (DicerAQP2Cre+ mice) was used to investigate the role of miRNAs in the kidney collecting duct of mice.Results The mice had severe polyuria and nephrogenic diabetes insipidus, potentially due to greatly reduced AQP2 and AQP4 levels. Although epithelial sodium channel levels were decreased in cortex and increased in inner medulla, amiloride-sensitive sodium reabsorption was equivalent in DicerAQP2Cre+ mice and controls. Small-RNA sequencing and proteomic analysis revealed 31 and 178 significantly regulated miRNAs and proteins, respectively. Integrated bioinformatic analysis of the miRNAome and proteome suggested alterations in the epigenetic machinery and various transcription factors regulating AQP2 expression in DicerAQP2Cre+ mice. The expression profile and function of three miRNAs (miR-7688-5p, miR-8114, and miR-409-3p) whose predicted targets were involved in epigenetic control (Phf2, Kdm5c, and Kdm4a) or transcriptional regulation (GATA3, GATA2, and ELF3) of AQP2 were validated. Luciferase assays could not demonstrate direct interaction of AQP2 or the three potential transcription factors with miR-7688-5p, miR-8114, and miR-409textendash3p. However, transfection of respective miRNA mimics reduced AQP2 expression. Chromatin immunoprecipitation assays demonstrated decreased Phf2 and significantly increased Kdm5c interactions at the Aqp2 gene promoter in DicerAQP2Cre+ mice, resulting in decreased RNA Pol II association.Conclusions Novel evidence indicates miRNA-mediated epigenetic regulation of AQP2 expression.

Published
2020

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