8 results on '"Follenzi, Antonia"'
Search Results
2. Hemostasis and endothelial functionality: the double face of coagulation factors
- Author
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Olgasi, Cristina, primary, Assanelli, Simone, additional, Cucci, Alessia, additional, and Follenzi, Antonia, additional
- Published
- 2024
- Full Text
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3. Therapeutic potential of fetal liver cells transplantation in hemophilia A mice
- Author
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Merlin, Simone, primary, Akula, Saicharan, additional, Cottonaro, Alessia, additional, Garcia-Leal, Tamara, additional, Serrano, Luis Javier, additional, Borroni, Ester, additional, Kalandadze, Vakhtang, additional, Galiano, Rocio, additional, Borsotti, Chiara, additional, Liras, Antonio, additional, Sanchez, María José, additional, and Follenzi, Antonia, additional
- Published
- 2023
- Full Text
- View/download PDF
4. Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia
- Author
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Diop, Fary, primary, Moia, Riccardo, additional, Favini, Chiara, additional, Spaccarotella, Elisa, additional, De Paoli, Lorenzo, additional, Bruscaggin, Alessio, additional, Spina, Valeria, additional, Terzi-di-Bergamo, Lodovico, additional, Arruga, Francesca, additional, Tarantelli, Chiara, additional, Deambrogi, Clara, additional, Rasi, Silvia, additional, Adhinaveni, Ramesh, additional, Patriarca, Andrea, additional, Favini, Simone, additional, Sagiraju, Sruthi, additional, Jabangwe, Clive, additional, Kodipad, Ahad A., additional, Peroni, Denise, additional, Mauro, Francesca R., additional, Giudice, Ilaria Del, additional, Forconi, Francesco, additional, Cortelezzi, Agostino, additional, Zaja, Francesco, additional, Bomben, Riccardo, additional, Rossi, Francesca Maria, additional, Visco, Carlo, additional, Chiarenza, Annalisa, additional, Rigolin, Gian Matteo, additional, Marasca, Roberto, additional, Coscia, Marta, additional, Perbellini, Omar, additional, Tedeschi, Alessandra, additional, Laurenti, Luca, additional, Motta, Marina, additional, Donaldson, David, additional, Weir, Phil, additional, Mills, Ken, additional, Thornton, Patrick, additional, Lawless, Sarah, additional, Bertoni, Francesco, additional, Poeta, Giovanni Del, additional, Cuneo, Antonio, additional, Follenzi, Antonia, additional, Gattei, Valter, additional, Boldorini, Renzo Luciano, additional, Catherwood, Mark, additional, Deaglio, Silvia, additional, Foà, Robin, additional, Gaidano°, Gianluca, additional, and Rossi°, Davide, additional
- Published
- 2019
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5. Deciphering the Ets-1/2-mediated transcriptional regulation of F8 gene identifies a minimal F8 promoter for hemophilia A gene therapy.
- Author
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Famà R, Borroni E, Merlin S, Airoldi C, Pignani S, Cucci A, Corà D, Bruscaggin V, Scardellato S, Faletti S, Pelicci G, Pinotti M, Walker GE, and Follenzi A
- Subjects
- Animals, Endothelial Cells, Genetic Therapy, Lentivirus genetics, Mice, Factor VIII genetics, Hemophilia A genetics, Hemophilia A therapy
- Abstract
A major challenge in the development of a gene therapy for hemophilia A (HA) is the selection of cell type- or tissue-specific promoters to ensure factor VIII (FVIII) expression without eliciting an immune response. As liver sinusoidal endothelial cells (LSECs) are the major FVIII source, understanding the transcriptional F8 regulation in these cells would help optimize the minimal F8 promoter (pF8) to efficiently drive FVIII expression. In silico analyses predicted several binding sites (BS) for the E26 transformation-specific (Ets) transcription factors Ets-1 and Ets-2 in the pF8. Reporter assays demonstrated a significant up-regulation of pF8 activity by Ets-1 or Ets-1/Est-2 combination, while Ets2 alone was ineffective. Moreover, Ets-1/Ets-2-DNA binding domain mutants (DBD) abolished promoter activation only when the Ets-1 DBD was removed, suggesting that pF8 up-regulation may occur through Ets-1/Ets-2 interaction with Ets-1 bound to DNA. pF8 carrying Ets-BS deletions unveiled two Ets-BS essential for pF8 activity and response to Ets overexpression. Lentivirus-mediated delivery of GFP or FVIII cassettes driven by the shortened promoters led to GFP expression mainly in endothelial cells in the liver and to long-term FVIII activity without inhibitor formation in HA mice. These data strongly support the potential application of these promoters in HA gene therapy.
- Published
- 2021
- Full Text
- View/download PDF
6. Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia.
- Author
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Diop F, Moia R, Favini C, Spaccarotella E, De Paoli L, Bruscaggin A, Spina V, Terzi-di-Bergamo L, Arruga F, Tarantelli C, Deambrogi C, Rasi S, Adhinaveni R, Patriarca A, Favini S, Sagiraju S, Jabangwe C, Kodipad AA, Peroni D, Mauro FR, Giudice ID, Forconi F, Cortelezzi A, Zaja F, Bomben R, Rossi FM, Visco C, Chiarenza A, Rigolin GM, Marasca R, Coscia M, Perbellini O, Tedeschi A, Laurenti L, Motta M, Donaldson D, Weir P, Mills K, Thornton P, Lawless S, Bertoni F, Poeta GD, Cuneo A, Follenzi A, Gattei V, Boldorini RL, Catherwood M, Deaglio S, Foà R, Gaidano G, and Rossi D
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Baculoviral IAP Repeat-Containing 3 Protein, Cyclophosphamide therapeutic use, Humans, Mutation, Prognosis, Retrospective Studies, Rituximab therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3 -mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3 -mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P <0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P <0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P =0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
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7. Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation.
- Author
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Chen H, Choesang T, Li H, Sun S, Pham P, Bao W, Feola M, Westerman M, Li G, Follenzi A, Blanc L, Rivella S, Fleming RE, and Ginzburg YZ
- Subjects
- Animals, Antibodies, Neutralizing pharmacology, Bone Morphogenetic Protein 2 agonists, Bone Morphogenetic Protein 2 antagonists & inhibitors, Bone Morphogenetic Protein 2 metabolism, Bone Morphogenetic Protein 6 genetics, Bone Morphogenetic Protein 6 metabolism, Butadienes pharmacology, Cytokines genetics, Cytokines metabolism, Disease Models, Animal, Gene Expression Regulation, Hepatocytes drug effects, Hepatocytes metabolism, Hepcidins agonists, Hepcidins antagonists & inhibitors, Hepcidins metabolism, Humans, Liver drug effects, Liver metabolism, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinase 1 antagonists & inhibitors, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 antagonists & inhibitors, Mitogen-Activated Protein Kinase 3 metabolism, Muscle Proteins genetics, Muscle Proteins metabolism, Nitriles pharmacology, Phosphorylation drug effects, RNA, Messenger antagonists & inhibitors, RNA, Messenger genetics, RNA, Messenger metabolism, Signal Transduction, Smad Proteins genetics, Smad Proteins metabolism, beta-Thalassemia metabolism, beta-Thalassemia pathology, Apoproteins pharmacology, Bone Morphogenetic Protein 2 genetics, Hepcidins genetics, Mitogen-Activated Protein Kinase 1 genetics, Mitogen-Activated Protein Kinase 3 genetics, Transferrin pharmacology, beta-Thalassemia genetics
- Abstract
Iron overload results in significant morbidity and mortality in β-thalassemic patients. Insufficient hepcidin is implicated in parenchymal iron overload in β-thalassemia and approaches to increase hepcidin have therapeutic potential. We have previously shown that exogenous apo-transferrin markedly ameliorates ineffective erythropoiesis and increases hepcidin expression in Hbb(th1/th1) (thalassemic) mice. We utilize in vivo and in vitro systems to investigate effects of exogenous apo-transferrin on Smad and ERK1/2 signaling, pathways that participate in hepcidin regulation. Our results demonstrate that apo-transferrin increases hepcidin expression in vivo despite decreased circulating and parenchymal iron concentrations and unchanged liver Bmp6 mRNA expression in thalassemic mice. Hepatocytes from apo-transferrin-treated mice demonstrate decreased ERK1/2 pathway and increased serum BMP2 concentration and hepatocyte BMP2 expression. Furthermore, hepatocyte ERK1/2 phosphorylation is enhanced by neutralizing anti-BMP2/4 antibodies and suppressed in vitro in a dose-dependent manner by BMP2, resulting in converse effects on hepcidin expression, and hepatocytes treated with MEK/ERK1/2 inhibitor U0126 in combination with BMP2 exhibit an additive increase in hepcidin expression. Lastly, bone marrow erythroferrone expression is normalized in apo-transferrin treated thalassemic mice but increased in apo-transferrin injected wild-type mice. These findings suggest that increased hepcidin expression after exogenous apo-transferrin is in part independent of erythroferrone and support a model in which apo-transferrin treatment in thalassemic mice increases BMP2 expression in the liver and other organs, decreases hepatocellular ERK1/2 activation, and increases nuclear Smad to increase hepcidin expression in hepatocytes., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
- Full Text
- View/download PDF
8. Extrahepatic sources of factor VIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of mice with hemophilia A.
- Author
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Zanolini D, Merlin S, Feola M, Ranaldo G, Amoruso A, Gaidano G, Zaffaroni M, Ferrero A, Brunelleschi S, Valente G, Gupta S, Prat M, and Follenzi A
- Subjects
- Animals, Blood Coagulation genetics, Disease Models, Animal, Endothelial Cells pathology, Factor VIII genetics, Factor VIII metabolism, Fetal Blood cytology, Fetal Blood metabolism, Gene Expression Regulation, Graft Survival, Hemophilia A blood, Hemophilia A genetics, Hemophilia A pathology, Hemorrhage blood, Hemorrhage genetics, Hepatocytes metabolism, Hepatocytes pathology, Humans, Kupffer Cells pathology, Liver metabolism, Liver pathology, Megakaryocytes metabolism, Megakaryocytes pathology, Mice, Mice, Inbred NOD, Mice, SCID, Monocytes metabolism, Monocytes pathology, Phenotype, Transplantation, Heterologous, Cord Blood Stem Cell Transplantation, Endothelial Cells metabolism, Factor VIII biosynthesis, Hemophilia A therapy, Hemorrhage prevention & control, Kupffer Cells metabolism
- Abstract
A large fraction of factor VIII in blood originates from liver sinusoidal endothelial cells although extrahepatic sources also contribute to plasma factor VIII levels. Identification of cell-types other than endothelial cells with the capacity to synthesize and release factor VIII will be helpful for therapeutic approaches in hemophilia A. Recent cell therapy and bone marrow transplantation studies indicated that Küpffer cells, monocytes and mesenchymal stromal cells could synthesize factor VIII in sufficient amount to ameliorate the bleeding phenotype in hemophilic mice. To further establish the role of blood cells in expressing factor VIII, we studied various types of mouse and human hematopoietic cells. We identified factor VIII in cells isolated from peripheral and cord blood, as well as bone marrow. Co-staining for cell type-specific markers verified that factor VIII was expressed in monocytes, macrophages and megakaryocytes. We additionally verified that factor VIII was expressed in liver sinusoidal endothelial cells and endothelial cells elsewhere, e.g., in the spleen, lungs and kidneys. Factor VIII was well expressed in sinusoidal endothelial cells and Küpffer cells isolated from human liver, whereas by comparison isolated human hepatocytes expressed factor VIII at very low levels. After transplantation of CD34(+) human cord blood cells into NOD/SCIDγNull-hemophilia A mice, fluorescence activated cell sorting of peripheral blood showed >40% donor cells engrafted in the majority of mice. In these animals, plasma factor VIII activity 12 weeks after cell transplantation was up to 5% and nine of 12 mice survived after a tail clip-assay. In conclusion, hematopoietic cells, in addition to endothelial cells, express and secrete factor VIII: this information should offer further opportunities for understanding mechanisms of factor VIII synthesis and replenishment., (Copyright© Ferrata Storti Foundation.)
- Published
- 2015
- Full Text
- View/download PDF
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