477 results on '"Pozzi A"'
Search Results
2. Lenalidomide plus rituximab for the initial treatment of frail older patients with DLBCL: the FIL_ReRi phase 2 study
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Gini, Guido, Tani, Monica, Tucci, Alessandra, Marcheselli, Luigi, Cesaretti, Marina, Bellei, Monica, Pascarella, Anna, Ballerini, Filippo, Petrini, Mauro, Merli, Francesco, Olivieri, Attilio, Lanza, Francesco, Annibali, Ombretta, Zilioli, Vittorio Ruggero, Liberati, Anna Marina, Tisi, Maria Chiara, Arcari, Annalisa, Marino, Dario, Musuraca, Gerardo, Pavone, Vincenzo, Fabbri, Alberto, Pozzi, Samantha, Mannina, Donato, Plenteda, Caterina, Celli, Melania, and Luminari, Stefano
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- 2023
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3. Prevalence and clinical expression of germ line predisposition to myeloid neoplasms in adults with marrow hypocellularity
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Molteni, Elisabetta, Bono, Elisa, Gallì, Anna, Elena, Chiara, Ferrari, Jacqueline, Fiorelli, Nicolas, Pozzi, Sara, Ferretti, Virginia Valeria, Sarchi, Martina, Rizzo, Ettore, Camilotto, Virginia, Boveri, Emanuela, Cazzola, Mario, and Malcovati, Luca
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- 2023
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4. Cryo-EM structure and functional basis of prothrombin recognition by a type I antiprothrombin antiphospholipid antibody
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Kumar, Suresh, primary, Summers, Brock, additional, Basore, Kathrine, additional, Pengo, Vittorio, additional, Flaumenhaft, Robert, additional, and Pozzi, Nicola, additional
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- 2024
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5. Mutations in atypical hemolytic uremic syndrome provide evidence for the role of calcium in complement factor I
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Java, Anuja, primary, Atkinson, John, additional, Hu, Zheng, additional, and Pozzi, Nicola, additional
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- 2023
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6. Cysteine Sulfenylation of Protein Disulfide Isomerase Links Oxidative Stress to Thrombosis
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Yang, Moua, primary, Flaumenhaft, James, additional, Scartelli, Christina, additional, Patel, Sachin, additional, Carroll, Kate S, additional, Smith, Brian C, additional, Pozzi, Nicola, additional, and Flaumenhaft, Robert, additional
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- 2022
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7. Clinico-Pathological, Cytogenetic and Molecular Similarities and Differences between Primary and Secondary Cutaneous Lymphomas
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Uccella, Silvia, primary, Goteri, Gaia, additional, Maiorana, Antonino, additional, Donati, Valentina, additional, Tibiletti, Maria Grazia, additional, Magnoli, Francesca, additional, Facchi, Sofia, additional, Merchiori, Deborah, additional, Morsia, Erika, additional, Papotti, Robel, additional, Bettelli, Stefania, additional, Forti, Elisa, additional, Galimberti, Sara, additional, Rupoli, Serena, additional, Filosa, Alessandra, additional, Dardanis, Dimitri, additional, Braglia, Luca, additional, Pozzi, Samantha, additional, and Sacchi, Stefano, additional
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- 2022
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8. Serum Level Kinetic of Key Cytokines in Newly Diagnosed Lymphoma Patients during First Line Treatment: Correlation with PET/CT Scan Results and Treatment Outcome
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Cosenza, Maria, primary, Franceschetto, Antonella, additional, Braglia, Luca, additional, Chiavelli, Chiara, additional, Panareo, Stefano, additional, Marcheselli, Luigi, additional, Pozzi, Samantha, additional, and Sacchi, Stefano, additional
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- 2022
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9. Cysteine Sulfenylation of Protein Disulfide Isomerase Links Oxidative Stress to Thrombosis
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Moua Yang, James Flaumenhaft, Christina Scartelli, Sachin Patel, Kate S Carroll, Brian C Smith, Nicola Pozzi, and Robert Flaumenhaft
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
10. Serum Level Kinetic of Key Cytokines in Newly Diagnosed Lymphoma Patients during First Line Treatment: Correlation with PET/CT Scan Results and Treatment Outcome
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Maria Cosenza, Antonella Franceschetto, Luca Braglia, Chiara Chiavelli, Stefano Panareo, Luigi Marcheselli, Samantha Pozzi, and Stefano Sacchi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
11. Clinico-Pathological, Cytogenetic and Molecular Similarities and Differences between Primary and Secondary Cutaneous Lymphomas
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Silvia Uccella, Gaia Goteri, Antonino Maiorana, Valentina Donati, Maria Grazia Tibiletti, Francesca Magnoli, Sofia Facchi, Deborah Merchiori, Erika Morsia, Robel Papotti, Stefania Bettelli, Elisa Forti, Sara Galimberti, Serena Rupoli, Alessandra Filosa, Dimitri Dardanis, Luca Braglia, Samantha Pozzi, and Stefano Sacchi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Exposure of R169 controls protein C activation and autoactivation
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Pozzi, Nicola, Barranco-Medina, Sergio, Chen, Zhiwei, and Di Cera, Enrico
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- 2012
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13. Relationship between clone metrics and clinical outcome in clonal cytopenia
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Chiara Elena, Cinzia Sala, Martina Sarchi, Anna Gallì, Clara Camaschella, Mario Cazzola, Daniela Toniolo, Nicolas Fiorelli, Ettore Rizzo, Emanuela Boveri, Virginia Valeria Ferretti, Paolo Gasparini, Luca Malcovati, Sara Pozzi, Silvia Zibellini, Eulalia Catamo, Elisa Bono, Gabriele Todisco, Jacqueline Ferrari, Elisabetta Molteni, Galli, A., Todisco, G., Catamo, E., Sala, C., Elena, C., Pozzi, S., Bono, E., Ferretti, V. V., Rizzo, E., Molteni, E., Zibellini, S., Sarchi, M., Boveri, E., Ferrari, J., Fiorelli, N., Camaschella, C., Gasparini, P., Toniolo, D., Cazzola, M., and Malcovati, L.
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Adult ,Male ,Myeloid ,Immunology ,Clone (cell biology) ,clonal cytopenia ,Biology ,Biochemistry ,Myeloid Neoplasm ,DNA Methyltransferase 3A ,Cohort Studies ,Young Adult ,Gene Frequency ,medicine ,Humans ,Expressivity (genetics) ,Aged ,Aged, 80 and over ,Cytopenia ,clone metrics ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Phenotype ,medicine.anatomical_structure ,Dysplasia ,Mutation (genetic algorithm) ,Mutation ,clone metric ,Female ,Clonal Hematopoiesis - Abstract
Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.
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- 2021
14. A Personalized Clinical-Decision Tool to Improve the Diagnostic Accuracy of Myelodysplastic Syndromes
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Nathan Radakovich, Manja Meggendorfer, Luca Malcovati, Mikkael A. Sekeres, Jacob Shreve, Cameron Beau Hilton, Yazan Rouphail, Wencke Walter, Stephan Hutter, Sudipto Mukherjee, Cassandra M. Kerr, Babal K. Jha, Anna Gallì, Sarah Pozzi, Aaron T. Gerds, Cassandra M Kerr, Claudia Haferlach, Jaroslaw P. Maciejewski, Torsten Haferlach, and Aziz Nazha
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Cytopenia ,medicine.medical_specialty ,business.industry ,Essential thrombocythemia ,Myelodysplastic syndromes ,Immunology ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,hemic and lymphatic diseases ,Internal medicine ,Cohort ,medicine ,Data monitoring committee ,business ,Myelofibrosis ,Myeloproliferative neoplasm - Abstract
Background While histo- and cytomorphological examinations are central to the diagnosis of myelodysplastic syndromes (MDS), significant inter-observer variability exists. The diagnosis can be challenging in pancytopenic patients (pts) without evidence of dysplasia and is contingent on observer expertise. We developed and externally validated a geno-clinical model that uses mutational data and peripheral blood counts/clinical variables to distinguish MDS from other myeloid malignancies. Methods Clinical and genomic data, including commercially available next-generation sequencing panels, were obtained for patients (pts) treated at the Cleveland Clinic (CC; 652 pts), Munich Leukemia Laboratory (MLL; 1509 pts), and the University of Pavia in Italy (UP, 536 pts). All patients had carried a diagnosis of MDS, chronic myelomonocytic leukemia (CMML), MDS/myeloproliferative neoplasm overlap (MDS/MPN), myeloproliferative neoplasm (MPN; either polycythemia vera, essential thrombocythemia, or myelofibrosis), clonal cytopenia of undetermined significance (CCUS), or idiopathic cytopenia of undetermined significance (ICUS). All diagnoses were established with bone marrow aspiration and according to World Health Organization 2017 criteria. The training cohort included data from CC and UP and randomly divided into learner (80%) and test (20%) cohorts. The final model was independently validated in the MLL cohort. A machine learning algorithm was used to build the model; multiple extraction algorithms were used to extract genomic/clinical variables on both the cohort and individual levels. Performance was evaluated according to the area under the curve of the receiver operating characteristic (ROC-AUC) and accuracy matrices. Results Among the 2697 pts included from all sites, the median age was 70 years [36 - 86]. Median hemoglobin (Hb) was 10.4g/dl [6.9 - 15.7], median platelet count (PLT) was 132 k/dL [14 - 722], median WBC count was 5.3 k/dL [1.4 - 49.9], median ANC was 2.8 k/dL [0.3 - 27.7], median monocyte count was 0.3 k/dL [0 - 9.9], and median lymphocyte count (ALC) was 1.1 k/dL [0.1 - 5.4], and median peripheral blast percentage 0% [0 - 8]. The most commonly mutated genes in all patients were (list top 5 genes) and among pts with MDS were SF3B1 (27%), TET2 (25%), ASXL1 (19%), SRSF2 (16%), and DNMT3A (11%); among patients with MDS-MPN/CMML, the most commonly mutated genes were MDS-MPN/CMML (TET2 46%, ASXL1 34%, SRSF2 29%, RUNX1 13%, CBL 12%) ; among patients with MPNs, the most commonly mutated genes were (JAK2 64%, ASXL1 27%, TET2 14%, DNMT3A 8%, U2AF1 7%); among patients with CCUS the most commonly mutated genes were (TET2 41%, DNMT3A 27%, ASXL1 19%, SRSF2 17%, ZRSR2 10%). The most important features for model predictions (ranked from the most to the least important) included: number of mutations detected/sample, peripheral blast percentage, AMC, JAK2 status, Hb, basophil count, age, eosinophil count, ALC, WBC, EZH2 mutation status, ANC, mutation status of KRAS and SF3B1, platelets, and gender. The final model achieved an average AUROC of 0.95 (95% CI 0.93-0.96) when applied to the test cohort and 0.93 (95% CI 0.91 - 0.94) when it was applied to the MLL cohort. The model also provides individual-level explanations for predictions, providing top differential diagnoses and individual-level explanations of how features influence a putative diagnosis (Figure 1b). Conclusions We developed and externally validated a highly accurate and interpretable model that can distinguish MDS from other myeloid malignancies using clinical and mutational data from a large international cohort. The model can provide personalized interpretations of its outcome and can aid physicians and hematopathologists in recognizing MDS with high accuracy when encountering pts with pancytopenia and with a suspected diagnosis of MDS. Disclosures Sekeres: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; AstraZeneca/MedImmune: Consultancy; Gilead Sciences: Research Funding; Pfizer: Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Nazha:Jazz: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee.
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- 2020
15. Prevalence, Domain Specificity, and Residue Specificity of IgG, IgM, and IgA Anti-β2GPI Antibodies in Tetra-Positive Antiphospholipid Syndrome Patients: Identification of Two Non-Overlapping Epitopes in Domain I of β2GPI
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Kumar, Suresh, Pengo, Vittorio, and Pozzi, Nicola
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- 2023
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16. Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity
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Nyström, Alexander, Shaik, Zabeena P., Gullberg, Donald, Krieg, Thomas, Eckes, Beate, Zent, Roy, Pozzi, Ambra, and Iozzo, Renato V.
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- 2009
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17. Relationship between clone metrics and clinical outcome in clonal cytopenia
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Gallì, Anna, primary, Todisco, Gabriele, additional, Catamo, Eulalia, additional, Sala, Cinzia, additional, Elena, Chiara, additional, Pozzi, Sara, additional, Bono, Elisa, additional, Ferretti, Virginia Valeria, additional, Rizzo, Ettore, additional, Molteni, Elisabetta, additional, Zibellini, Silvia, additional, Sarchi, Martina, additional, Boveri, Emanuela, additional, Ferrari, Jacqueline, additional, Fiorelli, Nicolas, additional, Camaschella, Clara, additional, Gasparini, Paolo, additional, Toniolo, Daniela, additional, Cazzola, Mario, additional, and Malcovati, Luca, additional
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- 2021
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18. A Personalized Clinical-Decision Tool to Improve the Diagnostic Accuracy of Myelodysplastic Syndromes
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Radakovich, Nathan, Meggendorfer, Manja, Malcovati, Luca, Sekeres, Mikkael A., Shreve, Jacob, Hilton, Cameron Beau, Rouphail, Yazan, Walter, Wencke, Hutter, Stephan, Mukherjee, Sudipto, Kerr, Cassandra M., Jha, Babal K., Gallì, Anna, Pozzi, Sarah, Gerds, Aaron T., Haferlach, Claudia, Maciejewski, Jaroslaw P., Haferlach, Torsten, and Nazha, Aziz
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- 2020
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19. Functional analysis of the cytoplasmic domain of the integrin α1 subunit in endothelial cells
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Abair, Tristin D., Bulus, Nada, Borza, Corina, Sundaramoorthy, Munirathinam, Zent, Roy, and Pozzi, Ambra
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- 2008
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20. α2β1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell–specific manner
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Zhang, Zhonghua, Ramirez, Norma E., Yankeelov, Thomas E., Li, Zhengzhi, Ford, Laura E., Qi, Ying, Pozzi, Ambra, and Zutter, Mary M.
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- 2008
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21. Preclinical Efficacy and Biological Effects of Venetoclax and Ixazomib in Combination in Lymphoma Cells
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Cosenza, Maria, primary, Sacchi, Stefano, additional, and Pozzi, Samantha, additional
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- 2020
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22. Genotype-Phenotype Correlations in Patients with Myeloid Malignancies Using Explainable Artificial Intelligence
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Radakovich, Nathan, primary, Malcovati, Luca, additional, Meggendorfer, Manja, additional, Sekeres, Mikkael A., additional, Shreve, Jacob, additional, Hilton, Cameron Beau, additional, Rouphail, Yazan, additional, Walter, Wencke, additional, Hutter, Stephan, additional, Gallì, Anna, additional, Pozzi, Sarah, additional, Gerds, Aaron T., additional, Mukherjee, Sudipto, additional, Kerr, Cassandra M, additional, Jha, Babal K., additional, Haferlach, Claudia, additional, Maciejewski, Jaroslaw P., additional, Haferlach, Torsten, additional, and Nazha, Aziz, additional
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- 2020
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23. Genotype-Phenotype Correlations in Patients with Myeloid Malignancies Using Explainable Artificial Intelligence
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Stephan Hutter, Manja Meggendorfer, Aziz Nazha, Luca Malcovati, Torsten Haferlach, Babal K. Jha, Mikkael A. Sekeres, Jacob Shreve, Yazan Rouphail, Sarah Pozzi, Claudia Haferlach, Cassandra M Kerr, Nathan Radakovich, Anna Gallì, Jaroslaw P. Maciejewski, Sudipto Mukherjee, Wencke Walter, Aaron T. Gerds, and Cameron Beau Hilton
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Chromosome 7 (human) ,Oncology ,medicine.medical_specialty ,Cytopenia ,Myeloid ,Essential thrombocythemia ,business.industry ,Myelodysplastic syndromes ,Immunology ,Chronic myelomonocytic leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chromosome 17 (human) ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Internal medicine ,medicine ,business ,Myelofibrosis - Abstract
Background: Myelodysplastic syndromes (MDS) and related myeloid malignancies are highly variable in both their clinical manifestations and underlying genetic abnormalities. While few mutations in myeloid malignancies are considered disease-defining, significant and complex associations between these genes exist and can influence the clinical characteristics and disease phenotype. Here, we took advantage of a large, international cohort of patients with myeloid malignancies to define genotype-phenotype relationships using state of the art machine learning models. Methods Data were collected for patients (pts) from the Cleveland Clinic (CC; 652 pts), Munich Leukemia Laboratory (MLL; 1509 pts), and the University of Pavia in Italy (UP; 536 patients). Clinical data including CBC at time of diagnosis and a genomic panel of 20 commonly mutated genes in myeloid malignancies were analyzed. Gene-gene correlations within disease subtypes, individual genes' co-occurrence or exclusivity within disease subtypes, and the co-occurrence or exclusivity of individual genes with clinically meaningful features including karyotypic abnormalities and severe cytopenias (defined as hemoglobin < 8 g/dL, platelets < 50k/dL, and ANC < 1k/dL) were evaluated using multiple machine learning/correlation/feature extraction algorithms. Results 2697 pts were included, 1630 (60%) with MDS, 399 (15%) with chronic myelomonocytic leukemia (CMML), 142 (5%) with idiopathic cytopenia of undetermined significance (ICUS), 129 (5%) with MDS-MPN overlap syndromes (MDS-MPN), 95 (4%) with primary myelofibrosis (PMF), 93 (3%) with clonal cytopenia of undetermined significance (CCUS), 52 (2%) with essential thrombocythemia (ET), 41 (2%) with polycythemia vera (PV), and 26 (1%) with other myeloproliferative neoplasms (MPNs). The median age at diagnosis for the entire cohort was 70 years [36 - 86]. Of patients with karyotype data available, 1091 pts (50%) had a normal karyotype, 17 (1%) had chromosome 17 abnormalities, 96 (4%) had chromosome 7 abnormalities, 145 (7%) had chromosome 5 abnormalities, and 123 (6%) had a complex karyotype. The most commonly mutated genes were: TET2 (28%), ASXL1 (22%), SF3B1 (22%), SRSF2 (19), JAK2 (11%), DNMT3A (9%), RUNX1 (9%), and U2AF1 (6%) SF3B1 mutations were associated with normal karyotype (NK), age 1 k/dL, platelets (plts) >50 k/dL, marrow blasts (MB) Clinical characteristics were also associated with specific genomic alterations (Figure 1). For example, NK correlated with the presence of SF3B1, ZRSR2, DNMT3A, a higher number of mutations, and absence of TP53, ASXL1, or KRAS; chromosome 5, 7, and 17 abnormalities were associated with a lower mutation number and the presence of TP53 mutations; complex karyotype correlated with the absence of TET2 and SF3B1 and the presence of TP53; age < 65 was associated with the presence of NRAS and JAK2 mutations and the absence of TET2, SF3B1, and SRSF2 mutations; hemoglobin < 8 g/dL positively correlated with mutation number and SF3B1 mutations and negatively correlated with TET2 mutations; ANC < 1 negatively correlated with JAK2, SF3B1, and DNMT3A mutations; platelets < 50k/dL negatively correlated with SF3B1 and JAK2 mutations, and positively correlated with the number of mutations; and MB Conclusions We applied machine learning techniques to reveal the complex relationships between mutational data and the clinical characteristics of several myeloid malignancies using a large, international patient cohort. In addition to correctly identifying previously described genotype-phenotype relationships, we identified several other intriguing relationships such as the relationship of particular mutations to the development of different cytopenias, demonstrating the potential utility for machine learning approaches in interrogating genomic data. Disclosures Sekeres: BMS: Consultancy; Pfizer: Consultancy; Takeda/Millenium: Consultancy. Gerds:Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Research Funding; Sierra Oncology: Research Funding; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Apexx Oncology: Consultancy; Celgene: Consultancy, Research Funding; Roche/Genentech: Research Funding. Mukherjee:Aplastic Anemia and MDS International Foundation: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Nazha:Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Jazz: Research Funding; Incyte: Speakers Bureau.
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- 2020
24. Preclinical Efficacy and Biological Effects of Venetoclax and Ixazomib in Combination in Lymphoma Cells
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Samantha Pozzi, Stefano Sacchi, and Maria Cosenza
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Programmed cell death ,Chemistry ,Cell growth ,Venetoclax ,Bortezomib ,Immunology ,Cell Biology ,Hematology ,Cell cycle ,Biochemistry ,Ixazomib ,chemistry.chemical_compound ,Apoptosis ,Cancer research ,medicine ,G1 phase ,medicine.drug - Abstract
Introduction. Bcl-2 family proteins comprise anti-apoptotic and pro-apoptotic proteins. Interaction between these proteins, as well as severe regulation of their expression, mediates cell survival and can quickly induce cell death. Venetoclax is Bcl-2-targeting that has shown preclinical and clinical activity in hematologic malignancies. Due to the development of resistance and the loss of dependence on the target protein, the monotherapy may be insufficient for maximal effectiveness. To circumvent the resistance mechanisms, many preclinical studies have shown that combination of venetoclax with other agents may represent a more effective therapeutic strategy. Ubiquitin-proteasome signaling pathway is a potential target that plays an important role in the proteolysis of key regulatory proteins. Proteasome inhibitors include ixazomib that inhibits cell growth and induces apoptosis in hematological malignancies cells resistant to conventional therapies and bortezomib. Objective: To analyze the preclinical efficacy and associated biological effects of venetoclax combined with ixazomib in a panel of lymphoma cell lines with diverse expression levels of Bcl-2 and other Bcl-2 family proteins. Methods: 12 lymphoma cell lines including FL (RL, WSU-NHL, Karpas422), MCL (Jeko1, Granta519), DLBCL (OCI-LY3, OCI-LY18), CTCL (Hut-78), ALCL (Karpas299), HL (L1236, L540), CLL (Mec1) and two MCL primary patient samples were exposed to venetoclax (0.01 - 8 µM) and ixazomib (10 - 2000 nM) alone for 24 - 72 hours to calculate IC50. Subsequently, lymphoma cells were exposed to venetoclax (0.015 - 25 nM) in combination with ixazomib (0.015 - 0.5 nM) for 24 hours. Cell viability was determined by MTT. Coefficient of synergy (combination index - CI) was calculated using CalcuSyn. Cell cycle and induction of apoptosis were evaluated by flow cytometry and changes in Bcl-2 family members, caspase activation and AKT phosphorylation were determined by western blotting. Results. In vitro, venetoclax and ixazomib alone induced cell death in a dose- and time-dependent manner against lymphoma cell lines. The IC50 is between 0.5 and 8 µM for venetoclax and between 12 and 1250 nM for ixazomib. The combination of venetoclax (0.03, 0.06, 12.5, 25 nM) with ixazomib (0.03, 0.06, 0.25, 0.5 nM) produced a synergistic effect (CI < 1) after 24 h of treatment in the most lymphoma cells lines leading to inhibition of cell growth and induction of apoptosis between 26 % and 59 % accompanied by increased with cleavage of caspases-3, -9 and PARP. We observed an additive effect (CI = 1) in Jeko1 (MCL) and MEC1 cells (CLL) and antagonist effect (CI > 1) Hut-78 cells (CTCL). Synergistic effect has been seen in two MCL primary patient samples (CI = 0.5 - 0.7). In sensitive lymphoma cells, the combination abrogated colony formation in the methylcellulose medium. When lymphoma cell lines were co-cultured with mesenchymal stromal cells with both drugs we observed a decrease of cell viability and a fraction of apoptotic cells indicating that drug combination may overcome the tumor promoting effects of stromal cells. The apoptosis induced in FL and Granta519 cells (MCL) by drug combination was accompanied by partial downregulation of Bcl-2 and strong upregulation of Bax, Bad, Bim and Noxa proteins. Jeko-1 cells were less sensitive to venetoclax-ixazomib combination-induced apoptosis. Western blot analysis showed a differential expression of Bcl-2, Mcl-1 and Bcl-XL proteins in FL, MCL and HL cell lines. Jeko-1 cells showed a normal expression of Bcl-2 and Mcl-1 proteins and high Bcl-xL protein level. Co-expression of related anti-apoptotic Bcl-2 family proteins could limit activity of treatment. Combined treatment induced G0/G1 cell cycle arrest and increased the sub-G1 population that was linked by the upregulation of p27 and p21. In addition, in RL, WSU-NHL and Granta519, enhanced cell death is associated with AKT inactivation and with a reduction of p-4EBP1, leading to decreased levels of c-MYC. Conclusion. Venetoclax exhibits strong synergistic activity with ixazomib in lymphoma cells. Studies are still ongoing and signaling pathways that promote the combination of venetoclax with ixazomib are to be analyzed. These data offer a rationale to continue exploring venetoclax-ixazomib combination and suggest that suppression of Bcl-2 family protein driven survival signaling may be one important mechanism for combination synergy. Disclosures No relevant conflicts of interest to declare.
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- 2020
25. Safety Profile for Lenalidomide-Based and Non-Lenalidomide-Based First-Line Therapy for Multiple Myeloma in Transplant Ineligible Patients: Real-World Evidence from a European Post-Authorization Safety Study
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Cavo, Michele, primary, De Stefano, Valerio, additional, Ramirez Payer, Angel, additional, Wiesholzer, Martin, additional, Tromp, Yvonne, additional, Vanstraelen, Gaëtan, additional, Schaedlich, Baerbel, additional, Valentine, Richez, additional, Dhanasiri, Sujith, additional, Kueenburg, Elisabeth, additional, Rosettani, Barbara, additional, Martin, Claire, additional, Pozzi, Stefano, additional, Bacon, Pamela, additional, and Gamberi, Barbara, additional
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- 2019
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26. COO, MYC / BCL2 Status and R-IPI Define a Group of Poor Prognosis DLBCL Patients in a Real-World Clinical Setting
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Bettelli, Stefania, primary, Marcheselli, Raffaella, additional, Pozzi, Samantha, additional, Marcheselli, Luigi, additional, Papotti, Robel, additional, Forti, Elisa, additional, Cox, M. Christina Christina, additional, Di Napoli, Arianna, additional, Tadmor, Tamar, additional, Maiorana, Antonino, additional, Donati, Valentina, additional, Galimberti, Sara, additional, and Sacchi, Stefano, additional
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- 2019
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27. X-Ray Crystallographic and Single-Molecule Fluorescence Studies of Beta-2 Glycoprotein I Reveal an Alternative Mechanism of Autoantibody Recognition
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Planer, William, primary, Chen, Zhiwei, primary, Chinnaraj, Mathivanan, primary, Zuo, Xiaobing, primary, Pengo, Vittorio, primary, Macor, Paolo, primary, Tedesco, Francesco, primary, and Pozzi, Nicola, primary
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- 2019
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28. Homozygosity for -2518 G Allele Variant of MCP-1 Predisposes to Adverse Presentation and Outcome in Primary Myelofibrosis
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Masselli, Elena, primary, Carubbi, Cecilia, additional, Pozzi, Giulia, additional, Percesepe, Antonio, additional, Campanelli, Rita, additional, Villani, Laura, additional, Gobbi, Giuliana, additional, Rosti, Vittorio, additional, Massa, Margherita, additional, Barosi, Giovanni, additional, and Vitale, Marco, additional
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- 2019
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29. Safety Profile for Lenalidomide-Based and Non-Lenalidomide-Based First-Line Therapy for Multiple Myeloma in Transplant Ineligible Patients: Real-World Evidence from a European Post-Authorization Safety Study
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Gaëtan Vanstraelen, Elisabeth Kueenburg, Barbara Rosettani, Michele Cavo, Pamela Bacon, Stefano Pozzi, Richez Valentine, Martin Wiesholzer, Barbara Gamberi, Valerio De Stefano, Claire Martin, Angel Ramirez Payer, Yvonne Tromp, Baerbel Schaedlich, and Sujith Dhanasiri
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Melphalan ,Oncology ,medicine.medical_specialty ,Surrogate endpoint ,business.industry ,Bortezomib ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Prednisone ,Internal medicine ,medicine ,business ,Multiple myeloma ,Febrile neutropenia ,Lenalidomide ,medicine.drug - Abstract
BACKGROUND: Real-world data can provide important information on the safety profile for recommended treatment options, but these data are collected infrequently. The ongoing post-authorization safety study (PASS) MM-034 (NCT03106324) is a prospective non-interventional study in patients (pts) with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible. This study allows for the collection of robust safety data for currently recommended regimens for the management of these pts. Global guidelines recommend lenalidomide (LEN) regimens, such as LEN plus dexamethasone (DEX; Rd) and LEN plus bortezomib (BORT) plus DEX (Vd), and BORT regimens, including BORT plus melphalan plus prednisone (VMP). METHODS: Transplant-ineligible adult pts with NDMM initiating therapy in centers throughout Europe are being enrolled in the ongoing MM-034 trial. Pts receiving any first-line regimen are eligible, but the decision for which treatment regimen will be used must be made prior to study inclusion. The primary endpoint is the incidence of cardiovascular events. Secondary endpoints include the incidence of renal impairment, infections, and second primary malignancies. In this analysis, the safety profiles of Rd, Vd, and VMP were compared. RESULTS: As of April 12, 2019, 145 Rd, 53 Vd, and 83 VMP pts were enrolled in the study (evaluable cohort). At the time of data cutoff, treatment was ongoing in 64.8% of Rd pts, 41.5% of Vd pts, and 61.4% of VMP pts. Median age was 79 years in Rd pts and 75 years in both Vd and VMP pts. The proportion of pts with ISS stage III disease was higher in the Vd group (24.8% Rd vs 32.1% Vd vs 24.1% VMP), and more pts in the VMP group were male (49.7% Rd vs 58.5% Vd vs 65.1% VMP). Adverse events (AEs) of all grades confirmed the expected side effects. Any-grade neutropenia occurred in 7.6%, 11.3%, and 13.3% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia occurred in 6.2%, 5.7%, and 12.0%, respectively. However, any-grade febrile neutropenia was seen only in the VMP group, at 2.4%, but not in the other 2 groups. Any-grade polyneuropathy was reported in 1.4% of Rd pts, but in 18.9% of Vd pts and 19.3% of VMP pts. Any-grade infections of all kinds occurred in 28.3% of Rd pts, 41.5% of Vd pts, and 20.5% of VMP pts, with pneumonia in 3.4%, 11.3%, and 2.4% of Rd, Vd, and VMP pts, respectively. Any-grade thrombosis was reported in 4.8% of Rd pts and 3.8% of Vd pts and in no VMP pts. Grade 3/4 AEs occurred in 42.8% of Rd pts, 52.8% of Vd pts, and 43.4% of VMP pts. Grade 3/4 neutropenia was reported in 4.8%, 9.4%, and 8.4% of Rd, Vd, and VMP pts, respectively, and thrombocytopenia in 2.8%, 0%, and 8.4%, respectively. Grade 3/4 infections were lower in Rd pts (6.9% vs 24.5% Vd and 12.0% VMP); pneumonia, the most important of these, was reported in 0.7%, 5.7%, and 2.4% of Rd, Vd, and VMP pts, respectively. Grade 3/4 peripheral neuropathy was not seen in the Rd group; however, it was reported in 3.8% of Vd pts and 2.4% of VMP pts. Grade 3/4 venous thrombosis was reported in only 0.7% of Rd pts, with no events reported in the Vd and VMP groups. CONCLUSIONS: The results from this analysis, along with those from a previous analysis of cardiovascular events in the LEN-treated and non-LEN treated cohorts of pts from the European PASS MM-034 study (De Stefano, EHA 2019), provide real-world evidence for the safety profile of Rd as first-line therapy and support the role of Rd in the treatment of pts with NDMM who are transplant ineligible. Disclosures Cavo: celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tromp:Janssen: Other: Grant. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Kueenburg:Celgene: Consultancy. Rosettani:Celgene International: Employment. Martin:Celgene: Employment. Pozzi:Celgene: Consultancy. Bacon:Celgene: Employment, Equity Ownership. Gamberi:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Front-line treatment (of any type) was at the discretion of the investigator.
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- 2019
30. Homozygosity for -2518 G Allele Variant of MCP-1 Predisposes to Adverse Presentation and Outcome in Primary Myelofibrosis
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Giovanni Barosi, Elena Masselli, Marco Vitale, Antonio Percesepe, Rita Campanelli, Giuliana Gobbi, Vittorio Rosti, Laura Villani, Giulia Pozzi, Margherita Massa, and Cecilia Carubbi
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biology ,business.industry ,Anemia ,Immunology ,C-reactive protein ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Leukemia ,Severity of illness ,biology.protein ,Medicine ,Leukocytosis ,medicine.symptom ,Allele ,Presentation (obstetrics) ,business ,Myelofibrosis - Abstract
Primary myelofibrosis (PMF) is the most aggressive Philadelphia-negative myeloproliferative neoplasm. Heterogeneity in disease phenotype and outcome led to investigate the influence of germline host genetic variations on disease onset and evolution. We recently found that patients with secondary myelofibrosis are enriched in the polymorphic allele variant of the -2518 A/G SNP of the Monocyte Chemoattractant Protein-1 (MCP-1), and that this SNP correlates with disease severity (Masselli E. et al, Leukemia 2018). Here, we examined the interactive effects of MCP-1 allele variants with the baseline phenotype in PMF, and how these variants impact the disease progression. MCP-1 -2518 SNP genotyping was performed by TaqMan Predesigned SNP Genotyping Assays on DNA extracted from peripheral blood granulocytes of 201 PMF patients and 249 matched local control subjects (CTRL). One-hundred and nineteen out of 201 PMF were males (59.2%). Median age was 52y (18-80y). N.103 patients (51.2%) were pre-fibrotic PMF. Driver mutations occurred as follows: 123 (61.2%) harbored a JAK2V617F mutation, 47 (23.4%) had CALR mutations, 20 (9.9%) were triple negative and n.8 (4%) had MPL mutations. Three patients had both JAK2V617F and CALR mutation. After a median follow-up of 84.7 months, 37 patients (18.4%) died, 38 (18%) experienced blast transformation (BT) and 23 patients (11.4%) received allogeneic hematopoietic stem cell transplantation (ASCT). Median age of CTRL was 64y (28-85y), and 132/249 (53%) were males. Consistently with our previous report, PMF displayed similar genotypic and allelic frequencies of the local control population (O.R., 1.04). The G allele distribution was also similar in JAK2V617Fpos vs. JAK2V617Fneg PMF and did not correlate with the allele burden (O.R., 1.29 and 1.51, respectively). After verifying that PMF with only 1 copy of the risk allele (A/G), had a similar risk of the reference group with 0 copies (A/A), we used a recessive genetic model to compare PMF with 2 copies of the risk variant (G/G, hereby referred as the MCP-1 high-risk group) vs. A/A+A/G PMF (the MCP-1 low-risk group). Genotype-phenotype correlations with disease parameters at the time of diagnosis were performed by χ2/Fisher exact test. We found that the MCP-1 high risk group displayed a significantly higher frequency, at the time of diagnosis, of severe anemia, massive splenomegaly, elevated LDH and higher levels of hs-CRP (high-sensitivity C-reactive protein) (see Table). These results indicate that MCP-1 high-risk variant has a role in determining the disease phenotype and the pro-inflammatory microenvironment of PMF. Additionally, we assessed whether the MCP-1 high-risk variant could predispose the acquisition of risk factors in PMF. On the basis of the recessive genetic model, we found that the MCP-1 high-risk group was about four times as likely to progress to leukocytosis as was the reference group (HR, 4.16; 95% CI; 1.37 to 12.5; P=0.011). To weight the clinical relevance of our findings, we tested whether the MCP-1 high-risk variant might affect the disease progression. ASCT occurrence resulted significantly higher in the high-risk group as compared to the low-risk (HR = 3.22; 95% CI, 1.06 to 10; P=0.038). In the composite endpoint model that considered death for any cause, BT or ASCT, PMF carrying the high-risk genotype presented a shorter time to event as compared to the low-risk group (HR, 2.56; 95% CI, 1.19 to 5.55; P=0.016). In conclusion, the MCP-1 SNP appears to identify PMF patients at higher chance to present with adverse hematological features and more likely to progress rapidly to either death, BT or ASCT. Table. Disclosures No relevant conflicts of interest to declare.
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- 2019
31. X-Ray Crystallographic and Single-Molecule Fluorescence Studies of Beta-2 Glycoprotein I Reveal an Alternative Mechanism of Autoantibody Recognition
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Xiaobing Zuo, Zhiwei Chen, Nicola Pozzi, Mathivanan Chinnaraj, Vittorio Pengo, Paolo Macor, Francesco Tedesco, and William Planer
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chemistry.chemical_classification ,Chemistry ,Immunology ,Autoantibody ,Cell Biology ,Hematology ,Crystal structure ,Single-molecule experiment ,Biochemistry ,Fluorescence ,Amino acid ,Crystallography ,Beta 2-Glycoprotein I ,Molecule ,Surface plasmon resonance - Abstract
Background. Antiphospholipid antibodies (aPL) recognizing an epitope comprising residues R39-R43 in the N-terminal domain, Domain I (DI), of beta-2 glycoprotein I (b2GPI) are considered among the most pathogenic in patients with Antiphospholipid Syndrome (APS). How such autoantibodies engage b2GPI at the molecular level remains incompletely understood. Aim. To better understand how pathogenic anti-DI antibodies engage b2GPI at the molecular level. Results. Under physiological conditions, b2GPI is believed to adopt a closed conformation featuring an intramolecular interaction between DI and DV with amino acids R39 and R43 in DI being masked by DV. This conformation is therefore predicted to be immunologically inert, incapable of reacting against pathogenic anti-DI antibodies. Once bound to the membranes, however, b2GPI is believed to undergo a dramatic conformational change which liberates DI to the solvent. To get a better grasp of the molecular flexibility of b2GPI under conditions relevant to physiology, we expressed and purified fully-glycosylated human recombinant b2GPI (hr-b2GPI) from HEK293 cells at high yield and purity suitable for structural biology and biophysical studies. After native purification, we found that the recombinant protein bound to heparin and negatively charged phospholipids with affinities comparable to those obtained for b2GPI that was purified from plasma using the perchloric acid method (p-b2GPI); hr-b2GPI also displayed similar reactivity against anti-b2GPI immunoglobulin G antibodies that were isolated from 5 APS patients. Surprisingly, hr-b2GPI and p-b2GPI were structurally similar, too. The X-ray crystal structures of hr-b2GPI and p-b2GPI solved at 2.6 and 2.4 Å resolution were superimposable documenting a J-shaped elongated conformation of the molecule in which DI was located > 90 Å away from the C-terminal DV. Both structures were characterized by 22 oxidized cysteine residues forming 11 disulfide bonds, 4 N-glycosylations, and an intact yet flexible phospholipid-binding loop in DV. Since crystallization occurred at high salt concentrations, validation of the crystal structure of hr-b2GPI in solution was obtained by single-molecule Förster Resonance Energy Transfer (smFRET) and small-angle X-ray scattering (SAXS), while surface plasmon resonance (SPR) was used to probe the binding of a recently developed monoclonal anti-DI antibody, i.e., MBBS, to hr-b2GPI and p-b2GPI in solution. In keeping with the X-ray structural data, donor and acceptor fluorophores incorporated at positions 13/312 in DI and DV and 112/312 in DII and DV reported no measurable energy transfer whereas probes located at positions 13/112 in DI and DII displayed very high energy transfer. Likewise, the scattering profiles of the recombinant and plasma purified proteins returned similar hydrodynamic radii characteristic of elongated, flexible protein structures, and not circular. Notably, both hr-b2GPI and p-b2GPI in the elongated conformation were capable of interacting with MBBS without the need of phospholipids, even though addition of negatively charged phospholipids decreased the apparent dissociation affinity constant due to a reduction of the dissociation rate constant and a remarkable time-dependent accumulation of b2GPI onto the lipid surface, suggestive of a phospholipid-induced oligomerization mechanism. Conclusions. This study demonstrates that human b2GPI can adopt an elongated conformation in solution that is primed for phospholipid, heparin, and autoantibodies binding with DI constitutively exposed to the solvent. The fact that phospholipid-bound b2GPI is a better antigen for anti-DI autoantibody under physiological conditions as compared to the elongated form in solution can be explained by the relatively low affinity and bivalency of such autoantibodies that likely recognize a peptide motif pattern rather than a specific sequence of residues. Whether other context-dependent conformational changes occur after binding of the protein to the lipid surface, thus facilitating aPL binding, remain to be established. Since our studies failed to detect the closed form of b2GPI previously documented by electron and atomic force microscopy studies, it is possible that this conformation may arise from chemical and/or posttranslational modifications that occur in vivo while the protein circulates in the plasma. Disclosures No relevant conflicts of interest to declare.
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- 2019
32. Ofatumumab Is Active and Safe in Patients with Relapsed/Refractory Splenic Marginal Zone Lymphoma (SMZL): Results from the Interim Analysis of an Italian Multicenter Phase 2 Study (MORE trial)
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Scarfo, Lydia, primary, Ferrari, Silvia, additional, Frustaci, Annamaria Maria, additional, Tani, Monica, additional, Pozzi, Samantha, additional, Scarano, Eloise, additional, Colia, Maria, additional, Ranghetti, Pamela, additional, Ponzoni, Maurilio, additional, Ronchi, Paola, additional, Ferreri, Andres JM, additional, and Ghia, Paolo, additional
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- 2018
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33. Combination of Momelotinib and Citarinostat Show Strong Synergistic Effect in Lymphoid Cell Lines Co-Targeting JAK2/STAT3 and HDAC6
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Cosenza, Maria, primary, Civallero, Monica, additional, Sacchi, Stefano, additional, and Pozzi, Samantha, additional
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- 2018
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34. Prognostication of Diffuse Large B-Cell Lymphoma By Lympho2Cx Assay and BCL2 and MYC Expression: Application in a Real Life Context of 154 Patients
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Bettelli, Stefania, primary, Marcheselli, Raffaella, additional, Manfredini, Samantha, additional, Bari, Alessia, additional, Pozzi, Samantha, additional, Cox, M. Christina Christina, additional, Marcheselli, Luigi, additional, Di Napoli, Arianna, additional, Levy, Ilana, additional, Forti, Elisa, additional, Tadmor, Tamar, additional, Maiorana, Antonino, additional, and Sacchi, Stefano, additional
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- 2018
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35. Higher Monocyte Chemoattractant Protein-1 Levels in Myelofibrosis Are Sustained By the rs1024611 Single Nucleotide Polymorphism and Correlate with Disease Subtype and Severity
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Masselli, Elena, primary, Pozzi, Giulia, additional, Carubbi, Cecilia, additional, Pagliaro, Luca, additional, Follini, Elena, additional, Cambò, Benedetta, additional, Crugnola, Monica, additional, Gobbi, Giuliana, additional, Mirandola, Prisco, additional, Aversa, Franco, additional, and Vitale, Marco, additional
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- 2018
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36. Bone marrow transplantation from unrelated donors: the impact of mismatches with substitutions at position 116 of the human leukocyte antigen class I heavy chain
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Ferrara, Giovanni B., Bacigalupo, Andrea, Lamparelli, Teresa, Lanino, Edoardo, Delfino, Laura, Morabito, Anna, Parodi, Anna M., Pera, Cinzia, Pozzi, Sarah, Sormani, Maria P., Bruzzi, Paolo, Bordo, Domenico, Bolognesi, Martino, Bandini, Giuseppe, Bontadini, Andrea, Barbanti, Mario, and Frumento, Guido
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- 2001
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37. Combination of Momelotinib and Citarinostat Show Strong Synergistic Effect in Lymphoid Cell Lines Co-Targeting JAK2/STAT3 and HDAC6
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Samantha Pozzi, Stefano Sacchi, Monica Civallero, and Maria Cosenza
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Stromal cell ,medicine.diagnostic_test ,biology ,Chemistry ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,HDAC6 ,medicine.disease ,Caspase 8 ,Biochemistry ,Flow cytometry ,Cell biology ,Cell culture ,medicine ,biology.protein ,Cytotoxicity ,Caspase - Abstract
Introduction. Janus kinases (JAKs) are well described signaling kinases comprising four family members JAK1, JAK2, JAK3 and TYK2 that are essential in hematological malignancy, as JAK mutations have been shown to contribute to the pathogenesis of myeloproliferative disorders. Momelotinib is a potent inhibitor of JAK1/JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. HDAC6 has been reported to be overexpressed in lymphoid cells and its inhibition has demonstrated activity in preclinical and clinical study of lymphoproliferative disease. Citarinostat, a second generation HDAC6 selective inhibitor, is a well-tolerated compound compared with nonselective HDAC inhibitors, with reduced potency against Class I HDACs while retaining anticancer effectiveness. Both drugs are currently under investigation in clinical trials, they show a good toxicity profile and are both orally available. Methods. Momelotinib and citarinostat alone and in combination were tested in 12 lymphoid cell lines: WSU-NHL, RL, Karpas422 (follicular lymphoma), Granta519, Jeko1 (mantle cell lymphoma), Hut78 (cutaneous T cell lymphoma), Karpas299 (anaplastic large cell lymphoma), L540, L1236 (Hodgkin's lymphoma), U266, RPMI8266 (multiple myeloma) and MEC1 (chronic lymphocytic leukemia). Synergistic interaction was evaluated using the Chou-Talalay method. Annexin V staining, ROS generation, cell cycle and migration assay were determined by flow cytometry. ATP levels and Mitochondrial Membrane Potential (ΔΨm) were evaluated by fluorometric assay. Lactate levels and Cyt-C were evaluated by colorimetric assay. Activity of caspases-8,-9 and 3 was measured using colorimetric assay. ER stress and apoptosis-related proteins and JAK2/STAT3 were detected by western blotting. Clonogenic survival was studied with the methylcellulose clonogenic assay. Co-cultures with bone marrow stromal cells were also performed. Results. The combination of momelotinib (1 μM) and citarinostat (4 μM) at 24 h showed a synergistic effect in WSU-NHL, RL, Karpas422, Jeko1, Hut78, Karpas299, L540, RPMI8226 and U266 cells with CI values < 1 and antagonist effect in L1236, Granta519 and Mec1 cells with CI > 1. We studied seven lymphoid cell lines (WSU-NHL, RL, Karpas422, Jeko1, L-540) which were particularly sensitive to the drug combination and two cell lines (L-1236, Granta-519) that showed an IC > 1. Drug combination exhibited a strong cytotoxicity, evidenced by reduction of mitochondrial depolarization, depletion of ATP and lactate levels and Cyt-C release from the mitochondria but also by increase in cellular apoptotic index and reactive oxygen species levels, leading to arrest in the sub-G0/G1 phase of the cell cycle. Apoptosis induced by the drug combination was exerted via the mitochondrial apoptotic pathway as demonstrated by upregulation of caspase-9 that was especially evident in WSU-NHL and Karpas422 with a fold increase of 3.2 and 3.8. The extrinsic apoptotic pathway was active in Karpas422 and Jeko1 cells as evaluated by upregulation of caspase-8 but not in WSU-NHL, RL and L540. The apoptosis was associated with activation of caspase-3, PARP and with increased hallmarks of ER stress and was mediated by the increased expression of the pro-apoptotic proteins Bad, Bax and Bim and downregulation of Bcl2, Bcl-xL and Mcl-1. Drug combination inhibited the migration induced by CXCL12 (chemoattractant known as stromal-cell derived factor-1, SDF-1α), reduced clonogenic survival and suppressed cell viability of lymphoid cells when co-cultured with bone marrow mesenchymal stromal cells targeting JAK2/STAT3 pathway and confirming acetylation of acetyl-α tubulin. Conclusion. Due to the good toxicity profile and the oral administration, combined therapy with momelotinib and citarinostat may represent a promising novel therapeutic modality for hematological malignancies. The study is ongoing and further investigation is required. Disclosures No relevant conflicts of interest to declare.
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- 2018
38. Prognostication of Diffuse Large B-Cell Lymphoma By Lympho2Cx Assay and BCL2 and MYC Expression: Application in a Real Life Context of 154 Patients
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Antonino Maiorana, Luigi Marcheselli, Ilana Levy, Elisa Forti, Samantha Pozzi, Samantha Manfredini, Stefania Bettelli, Stefano Sacchi, Arianna Di Napoli, Alessia Bari, Tamar Tadmor, Raffaella Marcheselli, and M. Christina Cox
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Univariate analysis ,biology ,business.industry ,Immunology ,Complete remission ,RNA ,Context (language use) ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,biology.protein ,Cancer research ,Medicine ,Immunohistochemistry ,Antibody ,business ,Diffuse large B-cell lymphoma ,Neprilysin - Abstract
BACKGROUND: About one third of patients with diffuse large B-cell lymphoma (DLBCL) eventually die from their disease. Thus, it is extremely important to identify powerful and reliable predictive and prognostic markers. In real life patient management, the clinical relevance of the assessment of the Cell of Origin (COO), of MYC and BCL2 protein overexpression, is still not fully clarified. The aim of the study is to evaluate the predictive and prognostic value of COO with Lympho2Cx assay by Nanostring technology and BCL2 and MYC overexpression by immunohistochemistry (IHC), in a real-life context. METHODS: This is a retrospective multicenter study which recruited 154 DLBCL patients treated with R-containing regimen between June 2010 and December 2016 in Modena, Rome (Italy) and Haifa (Israel). All clinical data were recorded at diagnosis and during follow up, including response assessment and survival outcome. COO was determined on formalin-fixed paraffin-embedded diagnostic specimens either by IHC using a panel of antibodies which included CD10, BCL6, MUM1 (i.e. Hans algorithm), or at RNA level with Lymph2Cx assay by Nanostring technology. Expression of MYC and BCL2 was evaluated by IHC. Event free survival (EFS) is defined as the time from diagnosis to the time of last follow-up, or to one of the following events: any response other than complete remission (CR) at the end of therapy or death from any cause. It is assessed by Kaplan-Meier estimates and groups of risk are compared using the log rank test. RESULT: We have currently evaluated the data of 60% (95 out of the 154) of the patients enrolled in the study (Tab 1). After a median follow up of 49 months, EFS is 63% (95CI 51-72%). In univariate analysis, the variables with the greatest impact on the response and on EFS are absolute granulocyte count and BCL2 expression (MYC ongoing). Patients with low IPI showed better survival in comparison with patients with high IPI, but the difference is not statistically significant. By IHC non-GCB subtype was more common than GCB (56% vs. 44%); by Nanostring ABC, GCB and unclassified subtypes were 33%, 50% and 17%, respectively, and K statistics was 0,647, showing a substantial agreement between the results obtained by IHC and by Lympho2Cx assay. No statistically significant differences were observed in EFS among ABC, GCB and unclassified subtypes. However, BCL2 protein overexpression in ABC subtype is associated with shorter EFS. CONCLUSION: Early retrospective studies showed a survival advantage for GCB-type disease. Clinical trial data evaluating the impact of COO determined by GEP on prognosis have shown inconsistent results with 2 studies observing inferior survival of ABC subtype and 2 German studies showing no significant differences in PFS or OS among COO subtypes. Determination of COO by Lympho2Cx is attractive as it is relatively easy and rapid to perform and potentially applicable to clinical practice. However, these preliminary results do not support, at this point, its use as prognostic factor in clinical practice. The analysis of the remaining 59 patients will help to clarify the role Lympho2Cx assay in the context of real life. Table 1. Patients baseline characteristics. Disclosures Tadmor: ABBVIE: Consultancy; ROCHE: Research Funding; JNJ: Consultancy; NOVARTIS: Consultancy; PFIEZER: Consultancy.
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- 2018
39. Higher Monocyte Chemoattractant Protein-1 Levels in Myelofibrosis Are Sustained By the rs1024611 Single Nucleotide Polymorphism and Correlate with Disease Subtype and Severity
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Giulia Pozzi, Marco Vitale, Benedetta Cambò, Franco Aversa, Prisco Mirandola, Elena Masselli, Luca Pagliaro, Cecilia Carubbi, Giuliana Gobbi, Elena Follini, and Monica Crugnola
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business.industry ,Immunology ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Molecular biology ,Peripheral blood mononuclear cell ,Leukemia ,Genotype ,medicine ,SNP ,Allele ,Myelofibrosis ,business ,Myeloproliferative neoplasm - Abstract
Introduction: Host genetic variations have an essential role in the mutational landscape of Philadelphia-negative myeloproliferative neoplasm (MPNs), with JAK2 46/1 and TERT rs2736100 polymorphisms predisposing to disease onset (Tapper W et al, Nat Commun. 2015). However, the contribution of inherited factors in disease phenotype and evolution is poorly characterized. We recently demonstrated that the -2518 A/G SNP of the Monocyte Chemoattractant Protein-1 (MCP-1, rs1024611) is an inherited host genetic factor associated with secondary myelofibrosis (sMF) and a biomarker of disease severity in MF, correlating with adverse hematologic characteristics at the time of diagnosis, such as higher IPSS risk category (Masselli E et al, Leukemia 2018). Here we aimed to: i) provide a correlation between MF patients' genetic readout, chemokine expression/production and hematopoietic progenitor differentiation, ii) correlate MCP-1 levels with disease subtype and severity. Methods: 16 MF patients were genotyped for MCP-1 SNP by TaqMan Predesigned SNP Genotyping Assays and added to our previously reported dataset (Masselli E et al, Leukemia 2018), reaching 81 MF (20 prePMF, 36 overtPMF and 25 sMF). Samples from 15 therapy-naïve MF were dedicated to in vitro-experiments. Eleven healthy subjects and 4 apheresis bags were utilized as controls (CTRL). MF were stratified according to their rs1024611 genotype in A/A (wild types), A/G and G/G (polymorphics). Peripheral blood mononuclear cells (MNCs) were isolated by Ficoll-Hypaque gradient, in part pelleted (resting, T0) and in part seeded in RPMI-1640 medium and activated with 1.1 ng/ml of IL-1β for 20h (T1). CD34+-cells were purified from MF peripheral blood and from apheresis by immunomagnetic selection and differentiated toward the MK lineage as described in Masselli E et al, Leukemia 2015, up to 14 days. MK differentiation was assessed by CD41-flow cytometric expression. MCP-1 levels were evaluated by real-time PCR and western blot. Results: We confirmed, in a cohort of 81 MF patients, that polymorphic subjects were significantly more frequent in sMF vs. PMF (17/25, 68% vs. 21/56, 37.5%, respectively, P=.011, Fig.1A). Of note, sMF was significantly more frequent in A/G and G/G individuals than either prePMF (6/20, 30%, P=.011) or overtPMF (15/36, 41.7%, P=.034, Fig.1B). In overall MF patients, a higher frequency of allele-G carriers was also confirmed in IPSS int-2/high vs. low/int-1 risk group (17/25, 68% vs. 19/51, 37.3%, respectively, P=.011, Fig.1C - all comparisons made by Χ2 test). We proved that MF MNCs significantly over-expressed MCP-1 mRNA and protein as compared to CTRL MNCs at basal state (P=.04 and P=.006 by t-test, respectively, Fig.1D-E), consistently with reports from Tefferi et al. on serum ELISA (Tefferi A et al, JCO 2011). Of note, basal MCP-1 mRNA levels in MF correlated with genotypes, with polymorphic patients displaying significantly higher transcript levels vs. wild types (~20-times higher 2-ΔΔCT, P=.018 by t-test). When MF MNCs were stimulated ex-vivo with IL-1β, a dose-dependent effect of the SNP on MCP-1 expression was observed, with A/G patients displaying >20-times higher and G/G patients showing >60-times-higher fold-increase in MCP-1 expression as compared to wild types (P Conclusions: Our data proved a dose-dependent effect of the rs1024611 SNP on MCP-1 production in MF and establish a correlation between patients' genetic readout and chemokine levels. These results suggest that MF patients harboring the G allele - and thus producing more MCP-1 - are genetically prone to a higher inflammatory burden, to display a more severe disease and abnormal MK differentiation. Disclosures Aversa: Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Astellas: Honoraria; Basilea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.
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- 2018
40. Co-Targeting Jak Signaling Pathway and Histone Deacetylases Produces Synergistic Activity in Haematologic Malignancies Cell Lines
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Civallero, Monica, primary, Cosenza, Maria, additional, Pozzi, Samantha, additional, and Sacchi, Stefano, additional
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- 2016
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41. Ricolinostat (ACY-1215), a Selective HDAC6 Inhibitor, Alone and in Combination with Bendamustine Is Effective in Preclinical Studies in Lymphoma Cell Lines
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Cosenza, Maria, primary, Civallero, Monica, additional, Quayle, Steven N, additional, Sacchi, Stefano, additional, and Pozzi, Samantha, additional
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- 2016
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42. The Absolute Monocyte Count at Diagnosis Could Improve the Prognostic Role of the End of Treatment 18-FDG-PET in Diffuse Large B Cell Lymphoma (DLBCL) Patients
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Marcheselli, Raffaella, primary, Franceschetto, Antonella, additional, Marcheselli, Luigi, additional, Bari, Alessia, additional, Pozzi, Samantha, additional, Barbolini, Monica, additional, Rossetti, Virginia, additional, D'Apollo, Rosaria, additional, Prandini, Napoleone, additional, and Sacchi, Stefano, additional
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- 2016
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43. Pomaba Novel Monoclonal Type-I Antiphospholipid Antibody, Reduces Thrombin Generation By Selectively Binding to the Open Form of Prothrombin
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Kumar, Suresh, Merrill-Skoloff, Glenn, Pengo, Vittorio, Flaumenhaft, Robert, and Pozzi, Nicola
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Background.Anti-prothrombin (anti-PT) antibodies are a type of antiphospholipid antibodies frequently found in antiphospholipid syndrome (APS) patients. Previously, we identified two types of anti-PT antibodies, one binding to epitopes in kringle-1 that are hidden in the closed form but available in the open form (Type-I), and another one in which the epitopes are located in fragment-1 but accessible in both forms (Type-II). Our understanding of their functional characteristics remains limited. Goal.To identify Type-I monoclonal antibodies for mechanistic studies. Methods.Type-I anti-prothrombin antibodies were generated by immunizing mice with fragment-1 and producing monoclonal antibodies using hybridoma technology. Binding mechanisms and epitope recognition for one representative Type-I antibody, POmAb, were elucidated using surface plasmon resonance (SPR), single-molecule FRET (smFRET), and cryo-electron microscopy (cryo-EM). Functional evaluations were performed in human plasma and with purified components. In vivohemostatic activity was assessed in a laser injury model of the cremasteric arteriole followed by intravital microscopy. Results.Type-I antibodies recognizing kringle-1 were obtained from immunization experiments. One of them, POmAb (Prothrombin Open monoclonal Antibody), was selected for in-depth mechanistic and structural studies. SPR studies showed that POmAb binds to the open form of prothrombin with low nanomolar affinity, and binding was impaired by the mutations S91A and Y93A in kringle-1. smFRET provided evidence of conformational selection, where POmAb preferentially selects the open conformation of prothrombin, thereby shifting the equilibrium towards the open form. Cryo-EM studies of the POmAb-prothrombin complex revealed an extended binding interface in kringle-1 which overlaps with the region occupied by the serine protease domain in the closed form, explaining why POmAb binds to the open form. In human plasma, POmAb prolonged the activated partial thromboplastin time and Russel's viper venom time, though the effect was modest. Further investigations using purified proteins and antibody fragments confirmed that POmAb reduces thrombin generation, although it does not completely abolish it, as the inhibition of thrombin generation occurs through a non-competitive mechanism with prothrombinase. In vivostudies corroborated in vitrofindings, further proving reduced fibrin accumulation at the site of injury. Conclusions.We discovered POmAb, a Type-I antiphospholipid antibody. We demonstrated that it selectively binds to the open form of prothrombin, resulting in reduced thrombin generation. POmAb represents a novel tool for studying the role of Type-I antibodies in APS and advances the provocative new idea of conformational trapping of prothrombin as a novel class of anticoagulants.
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- 2023
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44. Mitotic Dysregulation Sensitizes Malignant Stem Cells to CHK1 Inhibition in SF3B1-Mutant Myeloid Neoplasms
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Sarchi, Martina, Clough, Courtnee A., Crosse, Edie I., Kim, Jason, Baquero Galvis, Laura D., Gallì, Anna, Creamer, J. Philip, Stewart, Sintra, Pozzi, Sara, Molteni, Elisabetta, Elena, Chiara, Bradley, Robert K., Malcovati, Luca, and Doulatov, Sergei
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Myelodysplastic syndromes (MDS) arise from the acquisition of driver mutations in hematopoietic stem cells (HSCs). Splicing factor SF3B1 mutations are recurrent initiating lesions, found in up to 30% of patients with MDS. SF3B1mutations are associated with aberrant splicing marked by recognition of alternative 3' splice sites (a3'ss). However, the causal role of mis-spliced genes in disease pathogenesis remains largely unexplored. Although SF3B1mutations and downstream mis-spliced genes provide attractive therapeutic targets, targeted therapies remain unavailable.
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- 2023
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45. Co-Targeting Jak Signaling Pathway and Histone Deacetylases Produces Synergistic Activity in Haematologic Malignancies Cell Lines
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Samantha Pozzi, Monica Civallero, Maria Cosenza, and Stefano Sacchi
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Ruxolitinib ,Cell cycle checkpoint ,Chemistry ,Immunology ,Cutaneous T-cell lymphoma ,Cell Biology ,Hematology ,Cell cycle ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Apoptosis ,medicine ,Cancer research ,Mantle cell lymphoma ,Vorinostat ,B cell ,medicine.drug - Abstract
Background and Objectives. Jak pathway is abnormally activated in multiple hematologic malignancies. Ruxolitinib, a JAK1/2 inhibitor, is currently prescribed in the clinical practice for the treatment of myelofibrosis; it is orally available and has a very manageable toxicity profile. Aberrant expression and activity of HDACs are also implicated in several types of tumors and HDAC inhibitors are under investigation in vitro and in clinical trials for the treatment of cancer. Vorinostat is a pan HDAC inhibitor with recognized efficacy in hematological disease, and ongoing studies are evaluating the best combination. Based on these considerations we screened a series of hematologic malignancies cell lines, in order to explore whether low doses of Ruxolitinib and Vorinostat might identify a new possible drug combination, with low toxicity profile. Methods. We tested Ruxolitinib and Vorinostat alone and in combination in 12 cell lines: Hodgkin Lymphoma (L1236, L540), B cell lymphomas (RPMI, WSU-NHL, Karpas422, RL) mantle cell lymphoma (Granta519, Jeko1), multiple myeloma (U266, RPMI8266), chronic limphocytic leukemia (MEK1), anaplastic lymphoma (Karpas299) and cutaneous T cell lymphoma (HUT78). The synergism was assessed by Chou-Talalay method. Effect of the treatment on cell cycle, apoptosis, caspase activation and ROS generation was evaluated by flow cytometry. Jak expression, apoptosis-regulating proteins and the phosphorylation status of protein kinases were studied by western blot analysis. Co-coltures with bone marrow stromal cells were also performed. Results. At 24h of treatment with ruxolitinib all the cell lines tested showed an homogeneous pattern of response, with IC50 around 20 nM; at 48h IC50 ranged from 0.1 to 2nM, with 4 cell lines more sensitive to the treatment (WSU-NHL, Karpas422, RL, HUT78) compared with the rest. The treatment with vorinostat induced an homogeneous response, both at 24h (IC50=40 uM) and 48h (IC50=5-10 uM). The combination treatment with a ratio R:V=0.1 nM:1 uM and 0.5nM:5uM showed a various range of results: a clear synergistic interaction of Ruxolitinib and Vorinostat was observed at 24h using low concentrations of two compounds in L1236, RL, RPMI, MEK1 and Karpas 299. There was no synergistic effects in mantle cell lymphoma cell lines, and a minor synergism in Karpas 422, a cell line that is known for carrying both t:(14;18) and t:(4;11) chromosomal translocation. The effect of the combination was additive on the remaining cell lines. The results were similar at 48 hours of treatment. The combination induced a marked increase in G2-M arrest and enhanced cell apoptosis in all cell lines. Accordingly the expression of apoptosis-regulating proteins, in particular BIM and Bad (SET-2), were up-regulated with down-regulation of Bcl-2 and Mcl-1 (HEL). Particularly evident was the effect of the combination on autophagy with decreased expression of p62 and a dramatic reactive oxygen species (ROS) accumulation in the cell lines in which the combination of the two drugs resulted highly synergistic. In addition, cell lines more sensitive to the combination of the two drugs showed a greater effect of the treatment on phosphorylation status of Jak, STAT3, STAT5, Akt and mTOR proteins. By co-culturing cells lines and primary BMSCs, we observed that Ruxolitinib and Vorinostat alone did not exert their anti-tumour activity in some cell lines. Conclusions. This study showed that the combination of Ruxolitinib and Vorinostat provokes significant changes in cell viability, apoptosis, cell cycle arrest, autophagy and ROS generation in several cell lines of hematologic malignancies alone and co-cultured. Because the bone microenvironment plays such an important role in the resistance to conventional therapies, the ability of Ruxolitinib combined with Vorinostat to overcome these factors is encouraging. Collectively, these findings create a compelling rationale to determine the in vivo activity of Ruxolitinib/Vorinostat combination. Disclosures No relevant conflicts of interest to declare.
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- 2016
46. The Absolute Monocyte Count at Diagnosis Could Improve the Prognostic Role of the End of Treatment 18-FDG-PET in Diffuse Large B Cell Lymphoma (DLBCL) Patients
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Samantha Pozzi, Rosaria D'Apollo, Virginia Rossetti, Luigi Marcheselli, Alessia Bari, Napoleone Prandini, Antonella Franceschetto, Monica Barbolini, Stefano Sacchi, and Raffaella Marcheselli
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Oncology ,Fluorodeoxyglucose ,medicine.medical_specialty ,Framingham Risk Score ,business.industry ,Immunology ,Combination chemotherapy ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Surgery ,B symptoms ,Median follow-up ,Internal medicine ,medicine ,Progression-free survival ,medicine.symptom ,business ,Diffuse large B-cell lymphoma ,Progressive disease ,medicine.drug - Abstract
Background Despite the majority of DLBCL patients achieve long-term disease-free survival with standard chemo-immunotherapy, almost 30% of patients relapse or have refractory disease (1).Thus, there is an unmet need to identify patients with resistant disease as early as possible with the aim to change or intensify the treatment. The Revised International Prognostic Score (R-IPI) is considered a reliable tool for predicting outcome of DLBCL patients, but it is not able to predict the early outcome in individual patients. The importance of positron emission tomography (PET) to detect treatment failure in Hodgkin lymphoma patients has been highly recognized and International guidelines recently suggested that PET-computed tomography (PET-CT) can be used to determine the response assessment by Deauville criteria in fluorodeoxyglucose (FDG)-avid lymphomas (2). In a large series of patients, we recently showed that absolute monocyte count (AMC) has prognostic value in patients with DLBCL (3). Here, we analyze the role of PET at the end of treatment compared with the value of AMC at diagnosis, showing a close correlation between the two of them, and if the data will be confirmed, the combination of AMC at diagnosis to the final PET (F-PET) response might allow more accurate identification of patients outcome. Patients and Method At Modena Cancer Center approximately 200 patients affected by DLBCL have been treated between 2007 and 1014. So far we collected and analyzed the data of the first 32 patients treated between 2012 and 2014, and further analysis will be extended to the quinquennial 2007-2012. Data are comprehensive of clinical characteristics, blood differential, response to the therapy, survival outcome and PET scan. Patients were treated with rituximab and combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like. The response was evaluated based on 2007 Cheson criteria. The PET results were revised using Deauville criteria, and F-PET with score >3 was considered positive. AMC at diagnosis > 630/mmc were considered predictive of poor prognosis. Pearson correlation coefficient was computed to evaluate the correlation by AMC in continuous form with Deauville score. Progression free survival (PFS) was assessed by Kaplan-Meier estimates and compared by risk groups using the log-rank (LR) test and permutated LR (10000 Monte Carlo Simulation). Results Here we report the earliest results of an ongoing study, based on the analysis of the first 32 patients. The median age was 60 years (range 25-83), 44% were males, 69% had stage III-IV, and 22% had B symptoms. After chemo-immuno therapy 75% of patients obtained a complete response, 13% partial response and 13% had progressive disease. The 22 patients with F-PET negative showed a median AMC of 630/mmc, while the 9 patients with F-PET positive had a median AMC of 670/mm3, p=0.019. The median follow up was 29 months (range:10-50), and at 2 years the PFS for all patients was 78% (95%CI: 60-89%). The PFS at 2 years based on the F-PET was 86% (95%CI: 63-95%) for PET negative, and 56% (95%CI: 20-80%) for PET positive (Fig1). The LR test between the curves and permutated LR was statistically significant (p=0.029 and p=0.020). The PFS at 2 years by AMC 630/mmc at diagnosis was 84% (95%CI: 63-94%), and 57% (95%CI: 17-84%),respectively (Fig1). The LR test between the curves and permutated LR was marginally statistically significant (p=0.079 and p=0.050) . The Pearson correlation showed a good positive linear correlation of AMC with Deauville score (R=0.8). Conclusion . Although retrospective and with a limited number of patients enrolled so far, our study shows that both F-PET evaluated with Deauville criteria and AMC at the diagnosis are strong prognostic factors, able to discriminate patients with different PFS. We hypothesize that the similar trend of the two curves is the expression of two aspects of the disease, with positive PET reflecting the persistence of the lymphoma, and the elevated AMC in the peripheral blood a biomarker of the tumor microenvironment/cytokines. Based on this hypothesis and on the strong prognostic value of both parameters, we will try to compute a risk score, after the analysis of the entire cohort. References:Morton LM et al. 2006; 107:265.Tadmor T, et al. Haematologica. 2014; 99:125.Meignan M, et al. Leuk Lymphoma. 2012; 53, 1876. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2016
47. The Impact of Driver Mutations of JAK2, Calr, or MPL in Patients with Myelofibrosis Undergoing Hemopoietic Stem Cell Transplantation
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Bacigalupo, Andrea, primary, Pozzi, Sarah, additional, van Lint, Maria Teresa, additional, Bregante, Stefania, additional, Barosi, Gianni, additional, Pietra, Daniela, additional, Rumi, Elisa, additional, Milanesi, Chiara, additional, and Cazzola, Mario, additional
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- 2015
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48. Calcium-Carbonate Nanocapsules Improve the Efficacy of BEZ235 in Lymphoma a Cell Line: A Promising New Technology of Drug Delivery
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Civallero, Monica, primary, Vergaro, Viviana, additional, Citti, Cinzia, additional, Cosenza, Maria, additional, Cannazza, Giuseppe, additional, Parenti, Carlo, additional, Bari, Alessia, additional, Ciccarella, Giuseppe, additional, Sacchi, Stefano, additional, and Pozzi, Samantha, additional
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- 2015
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49. Neutrophil to Lymphocyte Ratio at Diagnosis Is an Independent Prognostic Factor in Diffuse Large B-Cell Lymphoma: Results of a Large Multicenter Study Involving 931 Patients
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Marcheselli, Luigi, primary, Bari, Alessia, additional, Marcheselli, Raffaella, additional, Tadmor, Tamar, additional, Pozzi, Samantha, additional, Cox, Maria Christina, additional, Baldini, Luca, additional, Ferrari, Angela, additional, Ferri, Paola, additional, Federico, Massimo, additional, Polliack, Aaron, additional, and Sacchi, Stefano, additional
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- 2015
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50. Allogeneic STEM CELL Transplants for Patients with Myelofibrosis: Changes in the Transplant Platform and Improved the Outcome
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Bregante, Stefania, primary, Dominietto, Alida, additional, Ghiso, Anna, additional, Raiola, Anna Maria, additional, Gualandi, Francesca, additional, Varaldo, Riccardo, additional, Di Grazia, Carmen, additional, Lamparelli, Teresa, additional, Luchetti, Silvia, additional, Geroldi, Simona, additional, Casarino, Lucia, additional, Pozzi, Sarah, additional, Tedone, Elisabetta, additional, van Lint, Maria Teresa, additional, Galaverna, Federica, additional, Barosi, Gianni, additional, and Bacigalupo, Andrea, additional
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- 2015
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