39 results on '"Ferrarini, M"'
Search Results
2. Functional and phenotypic analysis of T lymphocytes cloned from the skin of patients with systemic sclerosis
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T L Whiteside, V Steen, Ferrarini M, and Thomas A. Medsger
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Adult ,CD4-Positive T-Lymphocytes ,Male ,Systemic disease ,Pathology ,medicine.medical_specialty ,Necrosis ,medicine.medical_treatment ,Immunology ,Biology ,Lymphocyte Activation ,Scleroderma ,Dermis ,medicine ,Humans ,Immunology and Allergy ,Interferon gamma ,Skin ,Lymphokines ,Scleroderma, Systemic ,integumentary system ,T lymphocyte ,Middle Aged ,medicine.disease ,Clone Cells ,medicine.anatomical_structure ,Cytokine ,Concanavalin A ,biology.protein ,Female ,medicine.symptom ,Research Article ,medicine.drug - Abstract
SUMMARY Activated T lymphocytes often accumulate in the‘ower dermis of patients with systemic selerosis (seleroderma) any may play a role in the development of dermal libresis. We propagated and cloned these cells directly from skin biopsies in four of eight cases of early, antreated systemic selerosis with diffuse seleroderma. The cloning frequency estimates were f – 0.20 and f – 0.48 for T cells derived from the skin of two patients versus f - 0.68 and f - 0.96 for autologous blood T lymphocytes, All but one of 24 skin-derived selerederma clones were CD4+. Clonal analyses performed with CD4+ clones from patients and normal controls showed that all but one skin-derived clones synthesized either laterferon-gamma (60%), glycosantinolgycan-stimulatory factor (26%) or both (9%) when induced in vitro by a nitrogen, concanavalin A, but not by antologous dermal fibroblasts. In contrast, blood-derived clones had a different functional phenotype. All skin-derived clones produced tumour accrosis factor-alpha. Our results demonstrate that T lymphecytes obtained from the skin of patients with systemic selerois synthesized cytokoines which could modulale functions of human dermal fibroblasts.
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- 1990
3. miR-29b negatively regulates human osteoclastic cell differentiation and function: Implications for the treatment of multiple myeloma-related bone disease
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Eleonora Iuliano, Pierfrancesco Tassone, Michele Caraglia, Antonio Giordano, Francesco Maria Paolino, Cirino Botta, Manlio Ferrarini, Pierosandro Tagliaferri, Maria Teresa Di Martino, Maria Rita Pitari, Emanuela Leone, Francesco Conforti, Nicola Amodio, Teresa Del Giudice, Marco Rossi, Rossi M., Pitari M.R., Amodio N., Di Martino M.T., Conforti F., Leone E., Botta C., Paolino F.M., Del Giudice T., Iuliano E., Caraglia M., Ferrarini M., Giordano A., Tagliaferri P., Tassone P., Rossi, M, Pitari, Mr, Amodio, N, Di Martino, Mt, Conforti, F, Leone, E, Botta, C, Paolino, Fm, Del Giudice, T, Iuliano, E, Caraglia, Michele, Ferrarini, M, Giordano, A, Tagliaferri, P, and Tassone, P.
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Bone disease ,Physiology ,Cellular differentiation ,Cathepsin K ,Clinical Biochemistry ,Gene Expression ,Osteoclasts ,Osteolysis ,MMP9 ,Cells, Cultured ,Tartrate-resistant acid phosphatase ,Tumor ,Cultured ,Receptor Activator of Nuclear Factor-kappa B ,Genes, fos ,Cell Differentiation ,Osteoblast ,Cell biology ,Isoenzymes ,multiple myeloma ,medicine.anatomical_structure ,Matrix Metalloproteinase 9 ,osteoclast ,Matrix Metalloproteinase 2 ,medicine.medical_specialty ,fos ,Cells ,Acid Phosphatase ,Biology ,Collagen Type I ,Bone resorption ,Cell Line ,Osteoclast ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Bone Resorption ,Osteoblasts ,microRNA ,NFATC Transcription Factors ,Tartrate-Resistant Acid Phosphatase ,miR-29b ,Cell Biology ,medicine.disease ,Actins ,MicroRNAs ,Endocrinology ,Genes ,Multiple Myeloma - Abstract
Skeletal homeostasis relies upon a fine tuning of osteoclast (OCLs)-mediated bone resorption and osteoblast (OBLs)-dependent bone formation. This balance is unsettled by multiple myeloma (MM) cells, which impair OBL function and stimulate OCLs to generate lytic lesions. Emerging experimental evidence is disclosing a key regulatory role of microRNAs (miRNAs) in the regulation of bone homeostasis suggesting the miRNA network as potential novel target for the treatment of MM-related bone disease. Here, we report that miR-29b expression decreases progressively during human OCL differentiation in vitro. We found that lentiviral transduction of miR-29b into OCLs, even in the presence of MM cells, significantly impairs tartrate acid phosphatase (TRAcP) expression, lacunae generation and collagen degradation, which are relevant hallmarks of OCL activity. Accordingly, expression of cathepsin K and metalloproteinase 9 (MMP9) as well as actin ring rearrangement were impaired in the presence of miR-29b. Moreover, we found that canonical targets C-FOS and metalloproteinase 2 are suppressed by constitutive miR-29b expression which also downregulated the master OCL transcription factor, NAFTc-1. Overall, these data indicate that enforced expression of miR-29b impairs OCL differentiation and overcomes OCL activation triggered by MM cells, providing a rationale for miR-29b-based treatment of MM-related bone disease. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc.
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- 2013
4. miR-146a-5p impairs melanoma resistance to kinase inhibitors by targeting COX2 and regulating NFkB-mediated inflammatory mediators
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Elisabetta Ferrero, Marina Ferrarini, Chiara Gargiuli, Viviana Vallacchi, Michele Del Vecchio, Macarena Gomez Lira, Eriomina Shahaj, Mara Cossa, Elena Tamborini, Barbara Vergani, Luca Lalli, Mario Santinami, Barbara Valeri, Monica Rodolfo, Gianfrancesco Gallino, Simona Frigerio, Veronica Huber, Marialuisa Sensi, Licia Rivoltini, Elisabetta Vergani, Lorenza Di Guardo, Matteo Dugo, Ilaria Mattavelli, Biagio Eugenio Leone, Vergani, E, Dugo, M, Cossa, M, Frigerio, S, Di Guardo, L, Gallino, G, Mattavelli, I, Vergani, B, Lalli, L, Tamborini, E, Valeri, B, Gargiuli, C, Shahaj, E, Ferrarini, M, Ferrero, E, Gomez Lira, M, Huber, V, Vecchio, M, Sensi, M, Leone, B, Santinami, M, Rivoltini, L, Rodolfo, M, and Vallacchi, V
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Proto-Oncogene Proteins B-raf ,BRAF/MEK inhibitors ,medicine.medical_treatment ,lcsh:Medicine ,Drug resistance ,Models, Biological ,Biochemistry ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,miR-146a-5p ,Cell Line, Tumor ,microRNA ,medicine ,Humans ,Epigenetics ,BRAF/MEK inhibitor ,lcsh:QH573-671 ,Extracellular Signal-Regulated MAP Kinases ,Melanoma ,Protein Kinase Inhibitors ,Molecular Biology ,030304 developmental biology ,Mitogen-Activated Protein Kinase Kinases ,0303 health sciences ,Kinase ,business.industry ,lcsh:Cytology ,Research ,lcsh:R ,NF-kappa B ,Cell Biology ,medicine.disease ,Gene Expression Regulation, Neoplastic ,Gene expression profiling ,MicroRNAs ,Cyclooxygenase 2 ,Drug Resistance, Neoplasm ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,Inflammation Mediators ,Melanoma resistance ,business ,Proto-Oncogene Proteins c-akt ,COX2 ,Signal Transduction - Abstract
Background Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. Methods The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. Results miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Conclusions Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Graphical Abstract
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- 2020
5. Posterior reversible encephalopathy syndrome and COVID-19: A series of 6 cases from Lombardy, Italy
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Filippo Martinelli Boneschi, Andrea Giorgianni, Sandro Beretta, Federico Carimati, Diego Spagnoli, Maurizio Versino, Stefania Rota, Payam Tabaee Damavandi, Antonio Tetto, Nereo Bresolin, Antonio Colombo, Lorenzo Lorusso, Maria Di Stefano, Paola Melzi, Massimo Ferrarini, Giulia Nastasi, Mattia Pozzato, Paola Banfi, Marco Mauri, Maria Repaci, Margherita Canesi, Gabriele Vinacci, Alessandro Clemenzi, Lucia Princiotta Cariddi, Margherita Marelli, Andrea Salmaggi, Davide Vallauri, Colombo, A, Martinelli Boneschi, F, Beretta, S, Bresolin, N, Versino, M, Lorusso, L, Spagnoli, D, Nastasi, G, Vallauri, D, Rota, S, Repaci, M, Ferrarini, M, Pozzato, M, Princiotta Cariddi, L, Tabaee Damavandi, P, Carimati, F, Banfi, P, Clemenzi, A, Marelli, M, Giorgianni, A, Vinacci, G, Mauri, M, Melzi, P, Di Stefano, M, Tetto, A, Canesi, M, and Salmaggi, A
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Pediatrics ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Encephalopathy ,Assisted ventilation ,lcsh:RC346-429 ,PRES ,03 medical and health sciences ,0302 clinical medicine ,Seizures ,Intensive care ,medicine ,In patient ,030212 general & internal medicine ,COVID-19 ,lcsh:Neurology. Diseases of the nervous system ,Genome search ,business.industry ,Posterior reversible encephalopathy syndrome ,medicine.disease ,Seizure ,Neurology ,Original Article ,business ,030217 neurology & neurosurgery - Abstract
Posterior reversible encephalopathy cases are increasingly being reported in patients affected by COVID-19, but the largest series so far only includes 4 patients. We present a series of 6 patients diagnosed with PRES during COVID-19 hospitalized in 5 Centers in Lombardia, Italy. 5 out of the 6 patients required intensive care assistence and seizures developed at weaning from assisted ventilation. 3 out of 6 patients underwent cerebrospinal fluid analysis which was normal in all cases, with negative PCR for Sars-CoV-2 genome search. PRES occurrence may be less rare than supposed in COVID-19 patients and a high suspicion index is warranted for prompt diagnosis and treatment., Highlights • Posterior reversible encephalopathy syndrome is increasingly being reported in COVID-19 patients. • Weaning from assisted ventilation may be a critical moment in seizure development. • No evidence of viral genome in the cerebrospinal fluid in this cohort
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- 2021
6. Assessment of the 4-factor score: Retrospective analysis of 586 CLL patients receiving ibrutinib. A campus CLL study
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Ilaria Scortechini, Riccardo Moia, Marzia Varettoni, Francesca Romana Mauro, Sara Galimberti, Giovanni Del Poeta, Graziella D'Arrigo, Marta Coscia, Luca Laurenti, Ernesto Vigna, Davide Rossi, Annalisa Biagi, Gianluca Gaidano, Daniele Caracciolo, Riccardo Bomben, Ilaria Angeletti, Gianluigi Reda, Giovanna Cutrona, Daniela Pietrasanta, Gilberto Fronza, Ramona Cassin, Antonino Neri, Aaron Polliack, Annalisa Chiarenza, Yair Herishanu, Fortunato Morabito, Ilaria Del Giudice, Valter Gattei, Francesca Rossi, Roberta Murru, Giovanni Tripepi, Andrea Visentin, Livio Trentin, Antonio Cuneo, Angela Rago, Antonella Zucchetto, Adalgisa Condoluci, Giacomo Loseto, Ugo Consoli, Enrica Antonia Martino, Manlio Ferrarini, Massimo Gentile, Francesco Di Raimondo, Francesco Mendicino, Paolo Sportoletti, Robin Foà, Cirino Botta, Morabito F., Tripepi G., Del Poeta G., Mauro F.R., Reda G., Sportoletti P., Laurenti L., Coscia M., Herishanu Y., Varettoni M., Murru R., Chiarenza A., Visentin A., Condoluci A., Moia R., Pietrasanta D., Loseto G., Consoli U., Scortechini I., Rossi F.M., Zucchetto A., Vigna E., Martino E.A., Mendicino F., Botta C., Caracciolo D., Cassin R., D'Arrigo G., Galimberti S., Rago A., Angeletti I., Biagi A., Del Giudice I., Bomben R., Neri A., Fronza G., Cutrona G., Rossi D., Di Raimondo F., Cuneo A., Gaidano G., Polliack A., Trentin L., Foa R., Ferrarini M., Gattei V., and Gentile M.
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Oncology ,Male ,chronic B cell leukemia ,chronic lymphocytic leukemia ,ibrutinib ,4-factor score ,prognosis ,Datasets as Topic ,Severity of Illness Index ,chemistry.chemical_compound ,Piperidines ,Retrospective analysis ,Multicenter Studies as Topic ,Chronic ,Leukemia ,Hematology ,Middle Aged ,Prognosis ,Lymphocytic ,Progression-Free Survival ,Ibrutinib ,Female ,medicine.medical_specialty ,real-word study ,Factor score ,Antineoplastic Agents ,Adenine ,Aged ,Follow-Up Studies ,Humans ,Leukemia, Lymphocytic, Chronic, B-Cell ,Proportional Hazards Models ,Protein Kinase Inhibitors ,Reproducibility of Results ,Retrospective Studies ,Risk Assessment ,Survival Analysis ,NO ,Internal medicine ,Severity of illness ,medicine ,Progression-free survival ,Survival analysis ,business.industry ,Proportional hazards model ,B-Cell ,Retrospective cohort study ,Settore MED/15 - MALATTIE DEL SANGUE ,chemistry ,business ,chronic lymphocytic leukaemia - Abstract
Not Available
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- 2021
7. Erdheim-Chester disease: An in vivo human model of Mϕ activation at the crossroad between chronic inflammation and cancer
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Claudio Doglioni, Antonello Villa, Elisabetta Ferrero, Lorenzo Dagna, Riccardo Biavasco, Marina Ferrarini, Giulio Cavalli, Cavalli, G., Dagna, L., Biavasco, R., Villa, A., Doglioni, C., Ferrero, E., and Ferrarini, M.
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0301 basic medicine ,3D culture ,Chemokine ,Erdheim-Chester Disease ,genetic structures ,medicine.medical_treatment ,Immunology ,Inflammation ,Systemic inflammation ,Myeloid Neoplasm ,03 medical and health sciences ,0302 clinical medicine ,cell metabolism ,Neoplasms ,medicine ,cytokine ,Immunology and Allergy ,Animals ,Humans ,biology ,CD68 ,Macrophages ,Histiocytes ,Cell Biology ,Oncogenes ,Macrophage Activation ,medicine.disease ,Cellular Reprogramming ,Histiocytosis ,030104 developmental biology ,Cytokine ,BRAF mutation ,030220 oncology & carcinogenesis ,Erdheim–Chester disease ,Mutation ,biology.protein ,Cancer research ,Disease Susceptibility ,medicine.symptom ,Energy Metabolism ,histiocytosis ,Signal Transduction - Abstract
Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by infiltration of multiple tissues by CD68+ foamy Mϕs (or ‘histiocytes’). Clinical manifestations arise from mass-forming lesions or from tissue and systemic inflammation. ECD histiocytes harbor oncogenic mutations along the MAPK-kinase signaling pathway (BRAFV600E in more than half of the patients), and secrete abundant pro-inflammatory cytokines and chemokines. Based on these features, ECD is considered an inflammatory myeloid neoplasm, and is accordingly managed with targeted kinase inhibitors or immunosuppressive and cytokine-blocking agents. Evidence is emerging that maladaptive metabolic changes, particularly up-regulated glycolysis, represent an additional, mutation-driven feature of ECD histiocytes, which sustains deregulated and protracted pro-inflammatory activation and cytokine production. Besides translational relevance to the management of ECD patients and to the development of new therapeutic approaches, recognition of ECD as a natural human model of chronic, maladaptive Mϕ activation instructs the understanding of Mϕ dysfunction in other chronic inflammatory conditions.
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- 2020
8. A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia
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Annalisa Chiarenza, Valter Gattei, Agostino Steffan, Neil E. Kay, Giovanni D'Arena, Francesca Rossi, Christopher Fegan, Davide Rossi, Fortunato Morabito, Chris Pepper, Jerry Polesel, Massimo Degan, Kari G. Rabe, Riccardo Bomben, Manlio Ferrarini, Enrico Santinelli, Jared A. Cohen, Lodovico Terzi-di-Bergamo, Francesco Di Raimondo, Antonino Neri, Gabriele Pozzato, Luca Laurenti, Antonella Zucchetto, Massimo Gentile, Idanna Innocenti, Giovanna Cutrona, Sameer A. Parikh, Giovanni Del Poeta, Francesco Zaja, Cohen, Ja, Rossi, Fm, Zucchetto, A, Bomben, R, Terzi-di-Bergamo, L, Rabe, Kg, Degan, M, Steffan, A, Polesel, J, Santinelli, E, Innocenti, I, Cutrona, G, D'Arena, G, Pozzato, G, Zaja, F, Chiarenza, A, Rossi, D, Di Raimondo, F, Laurenti, L, Gentile, M, Morabito, F, Neri, A, Ferrarini, M, Fegan, Cd, Pepper, Cj, Del Poeta, G, Parikh, Sa, Kay, Ne, and Gattei, V.
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Oncology ,medicine.medical_specialty ,Prognostic variable ,Chronic lymphocytic leukemia ,Concordance ,Recursive partitioning ,Gene mutation ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Chronic Lymphocytic Leukemia ,Cytogenetics and Molecular Genetics ,business.industry ," ,Hematology ,Articles ,medicine.disease ,Prognosis ,Settore MED/15 ,Leukemia, Lymphocytic, Chronic, B-Cell ,United Kingdom ,Chromosome 17 (human) ,Settore MED/15 - MALATTIE DEL SANGUE ,Italy ,Mutation ,RC0267 ,business ,Trisomy ,Laboratories ,030215 immunology ,Cohort study - Abstract
We present a laboratory-based prognostic calculator (designated CRO score) to risk stratify treatment-free survival in early stage (Rai 0) chronic lymphocytic leukemia developed using a training-validation model in a series of 1,879 cases from Italy, the United Kingdom and the United States. By means of regression analysis, we identified five prognostic variables with weighting as follows: deletion of the short arm of chromosome 17 and unmutated immunoglobulin heavy chain gene status, 2 points; deletion of the long arm of chromosome 11, trisomy of chromosome 12, and white blood cell count>32.0x103/microliter, 1 point. Low, intermediate and high-risk categories were established by recursive partitioning in a training cohort of 478 cases, and then validated in four independent cohorts of 144/395/540/322 cases, as well as in the composite validation cohort. Concordance indices were 0.75 in the training cohort and ranged from 0.63 to 0.74 in the four validation cohorts (0.69 in the composite validation cohort). These findings advocate potential application of our novel prognostic calculator to better stratify early-stage chronic lymphocytic leukemia, and aid case selection in risk-adapted treatment for early disease. Furthermore, they support immunocytogenetic analysis in Rai 0 chronic lymphocytic leukemia being performed at the time of diagnosis to aid prognosis and treatment, particularly in today's chemo-free era.
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- 2019
9. Modeling multiple myeloma-bone marrow interactions and response to drugs in a 3d surrogate microenvironment
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Stefania Girlanda, Marina Ferrarini, Lorenza Pecciarini, Elisabetta Ferrero, Federico Caligaris-Cappio, Magda Marcatti, Giovanni Tonon, Maurilio Ponzoni, Antonello Villa, Silvia Heltai, Barbara Vergani, Fabio Ciceri, Daniela Belloni, Belloni, D, Heltai, S, Ponzoni, M, Villa, A, Vergani, B, Pecciarini, L, Marcatti, M, Girlanda, S, Tonon, G, Ciceri, F, Caligaris-Cappio, F, Ferrarini, M, Ferrero, E, Belloni, Daniela, Heltai, Silvia, Ponzoni, Maurilio, Villa, Antonello, Vergani, Barbara, Pecciarini, Lorenza, Marcatti, Magda, Girlanda, Stefania, Tonon, Giovanni, Ciceri, Fabio, Caligaris-Cappio, Federico, Ferrarini, Marina, and Ferrero, Elisabetta
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0301 basic medicine ,3D model ,medicine.medical_specialty ,Stromal cell ,Cell Survival ,Cell Culture Techniques ,Drug Resistance ,Cell Communication ,Models, Biological ,Article ,Plasma Cell Disorders ,Bortezomib ,03 medical and health sciences ,Bioreactors ,0302 clinical medicine ,Bone Marrow ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Cell Adhesion ,Tumor Microenvironment ,medicine ,Humans ,Multiple myeloma ,Tumor microenvironment ,Hematology ,Chemistry ,Endothelial Cells ,medicine.disease ,Coculture Techniques ,Bone Marrow Microenvironment ,030104 developmental biology ,medicine.anatomical_structure ,Cell culture ,030220 oncology & carcinogenesis ,Cancer research ,Gelatin ,Bone marrow ,Stromal Cells ,Clone (B-cell biology) ,Multiple Myeloma ,medicine.drug - Abstract
Multiple myeloma develops primarily inside the bone marrow microenvironment, that confers pro-survival signals and drug resistance. 3D cultures that reproduce multiple myeloma-bone marrow interactions are needed to fully investigate multiple myeloma pathogenesis and response to drugs. To this purpose, we exploited the 3D Rotary Cell Culture System bioreactor technology for myeloma-bone marrow co-cultures in gelatin scaffolds. The model was validated with myeloma cell lines that, as assessed by histochemical and electron-microscopic analyses, engaged contacts with stromal cells and endothelial cells. Consistently, pro-survival signaling and also cell adhesion-mediated drug resistance were significantly higher in 3D than in 2D parallel co-cultures. The contribution of the VLA-4/VCAM1 pathway to resistance to bortezomib was modeled by the use of VCAM1 transfectants. Soluble factor-mediated drug resistance could be also demonstrated in both 2D and 3D co-cultures. The system was then successfully applied to co-cultures of primary myeloma cells-primary myeloma bone marrow stromal cells from patients and endothelial cells, allowing the development of functional myeloma-stroma interactions and MM cell long-term survival. Significantly, genomic analysis performed in a high-risk myeloma patient demonstrated that culture in bioreactor paralleled the expansion of the clone that ultimately dominated in vivo. Finally, the impact of bortezomib on myeloma cells and on specialized functions of the microenvironment could be evaluated. Our findings indicate that 3D dynamic culture of reconstructed human multiple myeloma microenvironments in bioreactor may represent a useful platform for drug testing and for studying tumor-stroma molecular interactions.
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- 2018
10. 3D culture of Erdheim-Chester disease tissues unveils histiocyte metabolism as a new therapeutic target
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Antonello Villa, Monica Rodolfo, Elisabetta Ferrero, Lorenzo Dagna, Giulio Cavalli, Marina Ferrarini, Maria Giulia Cangi, Claudio Doglioni, Daniela Belloni, Barbara Vergani, Riccardo Biavasco, Simone Cenci, Villa, Antonello, Belloni, Daniela, Vergani, Barbara, Cenci, Simone, Cavalli, Giulio, Biavasco, Riccardo, Rodolfo, Monica, Cangi, Maria Giulia, Doglioni, Claudio, Dagna, Lorenzo, Ferrero, Elisabetta, Ferrarini, Marina, Villa, A, Belloni, D, Vergani, B, Cenci, S, Cavalli, G, Biavasco, R, Rodolfo, M, Cangi, M, Doglioni, C, Dagna, L, Ferrero, E, and Ferrarini, M
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0301 basic medicine ,Erdheim-Chester Disease ,Letter ,medicine.medical_treatment ,Immunology ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,Bioreactors ,Rheumatology ,medicine ,Humans ,Immunology and Allergy ,Molecular Targeted Therapy ,Vemurafenib ,Protein Kinase Inhibitors ,Histiocyte ,030203 arthritis & rheumatology ,Biochemistry, Genetics and Molecular Biology (all) ,CD68 ,business.industry ,Histiocytes ,medicine.disease ,Infliximab ,Histiocytosis ,030104 developmental biology ,Cytokine ,Erdheim–Chester disease ,Cancer research ,business ,medicine.drug - Abstract
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterised by tissue infiltration by foamy CD68+ CD1a− histiocytes.1 The disease has pleomorphic clinical manifestations, including long bones and extraskeletal involvement, and may be life-threatening, particularly when heart and central nervous system are affected.1 ECD histiocytes secrete proinflammatory cytokines2 and carry activating mutations along the RAS-RAF-MEK-ERK protein kinase signalling pathway, most commonly the BRAFV600E oncogenic mutation.3 4 Accordingly, patients with ECD have been treated with cytokine inhibitors, including infliximab,1 ,5 and, more recently, with the BRAFV600E inhibitor vemurafenib.6 The latter, however, induces sustained but partial clinical responses and recurrences on discontinuation,6 underlining the need for more effective therapeutic strategies. To identify the outcomes downstream constitutive ERK phosphorylation in ECD histiocytes and their response to small molecule-based inhibition, we performed three-dimensional (3D) culture of tissues from three BRAFV600E-mutated ECD patients in the RCCS bioreactor7 (and online supplementary methods) in the presence/absence of vemurafenib or infliximab, used as control.### Supplementary data [annrheumdis-2018-214432supp001.pdf] All patient samples maintained production of prototypical cytokines and chemokines2 in bioreactor, thus validating this technology also for ECD; moreover, infliximab, and, to a lesser degree, vemurafenib, significantly decreased cyto-chemokines …
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- 2018
11. microRNAome Expression in Chronic Lymphocytic Leukemia: Comparison with Normal B-cell Subsets and Correlations with Prognostic and Clinical Parameters
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Serena Matis, Cristian Bassi, Massimo Negrini, Sonia Fabris, Anna Grazia Recchia, Gian Matteo Rigolin, Manuela Ferracin, Monica Colombo, Antonino Neri, Barbara Zagatti, Lucilla D'Abundo, Giandomenico Russo, Fortunato Morabito, George A. Calin, Luca Agnelli, Manlio Ferrarini, Elena Saccenti, Sabrina Bossio, Daniele Reverberi, Marta Lionetti, Massimo Gentile, Pierfrancesco Tassone, Silvia Sabbioni, Giovanna Cutrona, Negrini M, Cutrona G, Bassi C, Fabris S, Zagatti B, Colombo M, Ferracin M, D'Abundo L, Saccenti E, Matis S, Lionetti M, Agnelli L, Gentile M, Recchia AG, Bossio S, Reverberi D, Rigolin G, Calin GA, Sabbioni S, Russo G, Tassone P, Morabito F, Ferrarini M, and Neri A.
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Cancer Research ,tumor suppressor ,Immunoglobulin Heavy Chain ,Chronic lymphocytic leukemia ,B-Lymphocyte Subsets ,Trisomy ,Disease ,Biology ,medicine.disease_cause ,Chromosome Aberration ,survival ,NO ,immune system diseases ,hemic and lymphatic diseases ,microRNA ,CLL patients, profiling reveals, tumor suppressor, down regulation, 17p deletion, mir-34a, cancer, mir29, survival ,medicine ,Chromosomes, Human ,Humans ,cancer ,profiling reveals ,Cells, Cultured ,In Situ Hybridization, Fluorescence ,B cell ,B-Lymphocyte Subset ,Chromosome Aberrations ,mir-34a ,Mutation ,Cancer ,MicroRNA ,mir29 ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,17p deletion ,CLL patients ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,medicine.anatomical_structure ,Oncology ,Immunology ,Disease Progression ,Immunoglobulin Heavy Chains ,IGHV@ ,down regulation ,Human - Abstract
Purpose: Despite its indolent nature, chronic lymphocytic leukemia (CLL) remains an incurable disease. To establish the potential pathogenic role of miRNAs, the identification of deregulated miRNAs in CLL is crucial. Experimental Design: We analyzed the expression of 723 mature miRNAs in 217 early-stage CLL cases and in various different normal B-cell subpopulations from tonsils and peripheral blood. Results: Our analyses indicated that CLL cells exhibited a miRNA expression pattern that was most similar to the subsets of antigen-experienced and marginal zone–like B cells. These normal subpopulations were used as reference to identify differentially expressed miRNAs in comparison with CLL. Differences related to the expression of 25 miRNAs were found to be independent from IGHV mutation status or cytogenetic aberrations. These differences, confirmed in an independent validation set, led to a novel comprehensive description of miRNAs potentially involved in CLL. We also identified miRNAs whose expression was distinctive of cases with mutated versus unmutated IGHV genes or cases with 13q, 11q, and 17p deletions and trisomy 12. Finally, analysis of clinical data in relation to miRNA expression revealed that miR26a, miR532-3p, miR146-5p, and miR29c* were strongly associated with progression-free survival. Conclusion: This study provides novel information on miRNAs expressed by CLL and normal B-cell subtypes, with implication on the cell of origin of CLL. In addition, our findings indicate a number of deregulated miRNAs in CLL, which may play a pathogenic role and promote disease progression. Collectively, this information can be used for developing miRNA-based therapeutic strategies in CLL. Clin Cancer Res; 20(15); 4141–53. ©2014 AACR.
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- 2014
12. Chronic lymphocytic leukemia nurse-like cells express hepatocyte growth factor receptor (c-MET) and indoleamine 2,3-dioxygenase and display features of immunosuppressive type 2 skewed macrophages
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Paolo Giannoni, Giorgia Travaini, Alessandra Pattarozzi, Ivana Pierri, Giovanna Cutrona, Genti Shyti, Laura Ottaggio, Manlio Ferrarini, Marco Calvaruso, Claudio Tripodo, Rodolfo Quarto, Daniela de Totero, Enrico Balleari, Roberto Benelli, Maria Cristina Mingari, Simona Zupo, Gabriella Pietra, Giannoni, P, Pietra, G, Travaini, G, Quarto, R, Shyti, G, Benelli, R, Ottaggio, L, Mingari, MC, Zupo, S, Cutrona, G, Pierri, I, Balleari, E, Pattarozzi, A, Calvaruso, M, Tripodo, C, Ferrarini, M, and de Totero, D.
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STAT3 Transcription Factor ,C-Met ,Stromal cell ,medicine.medical_treatment ,Gene Expression ,Biology ,Monocytes ,chemistry.chemical_compound ,T-Lymphocyte Subsets ,medicine ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Growth factor receptor inhibitor ,Phosphorylation ,Indoleamine 2,3-dioxygenase ,Cells, Cultured ,Follicular dendritic cells ,Macrophages ,Growth factor ,Articles ,Hematology ,Proto-Oncogene Proteins c-met ,Leukemia, Lymphocytic, Chronic, B-Cell ,Coculture Techniques ,Interleukin-10 ,C-MET ,INDOLEAMINE 2,3-DIOXYGENASE ,chronic lymphocytic leukemia, hepatocyte growth factor, c-MET, nurse-like cells ,hepatocyte growth factor ,nurse-like cells ,chemistry ,Hepatocyte Growth Factor Receptor ,Cancer research ,chronic lymphocytic leukemia ,Hepatocyte growth factor ,medicine.drug - Abstract
Hepatocyte growth factor, produced by stromal and follicular dendritic cells, and present at high concentrations in the sera of patients with chronic lymphocytic leukemia, prolongs the survival of leukemic B cells by interacting with their receptor, c-MET. It is, however, unknown whether hepatocyte growth factor influences microenvironmental cells, such as nurse-like cells, which deliver survival signals to the leukemic clone. We evaluated the expression of c-MET on nurse-like cells and monocytes from patients with chronic lymphocytic leukemia and searched for phenotypic/functional features supposed to be influenced by the hepatocyte growth factor/c-MET interaction. c-MET is expressed at high levels on nurse-like cells and at significantly higher levels than normal on monocytes from patients. Moreover, the hepatocyte growth factor/c-MET interaction activates STAT3(TYR705) phosphorylation in nurse-like cells. Indoleamine 2,3-dioxygenase, an enzyme modulating T-cell proliferation and induced on normal monocytes after hepatocyte growth factor treatment, was detected together with interleukin-10 on nurse-like cells, and on freshly-prepared patients' monocytes. Immunohistochemical/immunostaining analyses demonstrated the presence of c-MET(+) and indoleamine 2,3-dioxygenase(+) cells in lymph node biopsies, co-expressed with CD68 and vimentin. Furthermore nurse-like cells and chronic lymphocytic monocytes significantly inhibited T-cell proliferation, prevented by anti-transforming growth factor beta and interleukin-10 antibodies and indoleamine 2,3-dioxygenase inhibitors, and supported CD4(+)CD25(high+)/FOXP3(+) T regulatory cell expansion. We suggest that nurse-like cells display features of immunosuppressive type 2 macrophages: higher hepatocyte growth factor levels, produced by leukemic or other microenvironmental surrounding cells, may cooperate to induce M2 polarization. Hepatocyte growth factor may thus have a dual pathophysiological role: directly through enhancement of survival of the leukemic clone and indirectly by favoring T-cell immunosuppression.
- Published
- 2014
13. Erdheim-Chester disease: report on a case and new insights on its immunopathogenesis
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Lorenzo Dagna, Stefania Girlanda, Marina Ferrarini, Maria Grazia Sabbadini, Nathalie Rizzo, Enrica Bozzolo, Silvia Langheim, Dagna, Lorenzo, Girlanda, S, Langheim, S, Rizzo, N, Bozzolo, Ep, Sabbadini, Mg, and Ferrarini, M.
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medicine.medical_specialty ,Rheumatology ,business.industry ,Erdheim–Chester disease ,medicine ,Pharmacology (medical) ,medicine.disease ,business ,Dermatology - Abstract
In this paper, we describe the release of cyto-chemokines potentially relevant to Erdheim-Chester disease pathogenesis by intra-lesional cells from a patient with skeletal and multiorgan involvements.
- Published
- 2010
14. Redox homeostasis modulates the sensitivity of myeloma cells to bortezomib
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Marina Ferrarini, Silvia Nerini-Molteni, Federico Caligaris-Cappio, Roberto Sitia, Sara Cozza, NERINI MOLTENI, S, Ferrarini, M, Cozza, S, CALIGARIS CAPPIO, F, and Sitia, Roberto
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Antineoplastic Agents ,Biology ,Antioxidants ,Bortezomib ,chemistry.chemical_compound ,Tumor Cells, Cultured ,medicine ,Homeostasis ,Humans ,Protease Inhibitors ,Buthionine sulfoximine ,Multiple myeloma ,Cell Death ,Dose-Response Relationship, Drug ,GCLM ,ATF4 ,Hematology ,Glutathione ,medicine.disease ,Activating Transcription Factor 4 ,Boronic Acids ,Acetylcysteine ,Neoplasm Proteins ,chemistry ,Proteasome ,Pyrazines ,Cancer research ,Proteasome inhibitor ,Drug Screening Assays, Antitumor ,Multiple Myeloma ,Oxidation-Reduction ,Transcription Factor CHOP ,medicine.drug - Abstract
The use of proteasome inhibitors have been a major advance in the treatment of multiple myeloma (MM), but their mechanisms of action remain largely unclear. A better understanding of the cellular events downstream of proteasome inhibition is essential to improve the response and identify new combination therapies for MM and other malignancies. This study analysed the relationships between redox homeostasis and bortezomib treatment in MM cells. Our data showed that decreasing intracellular glutathione through buthionine sulfoximine treatment strongly enhances bortezomib toxicity, whilst antioxidants protect MM cells from bortezomib-mediated cell death. Bortezomib treatment decreases intracellular glutathione both in MM cell lines and in malignant plasma cells obtained from MM patients. Glutamate-cysteine ligase (GCLM) and haem-oxygenase-1 (HMOX1), two genes involved in the Nrf-2-mediated antioxidant response, as well as two eIF2alpha-downstream transcription factors, activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP), are upregulated, indicating that redox-related adaptive responses are initiated in bortezomib-treated MM cells. These findings demonstrate tight links between sensitivity to proteasome inhibition and redox homeostasis in MM cells and have potential implications for treatment.
- Published
- 2008
15. B cell chronic lymphocytic leukaemia/small lymphocytic lymphoma: role of ZAP70 determination on bone marrow biopsy specimens
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Cristina Campidelli, Rocio Orduz, Simona Zupo, Giovanna Cutrona, Vincenzo Callea, Pier Luigi Zinzani, Manlio Ferrarini, Elena Sabattini, Stefano Pileri, Fortunato Morabito, Sabattini E, Orduz R, Campidelli C, Zinzani PL, Callea V, Zupo S, Cutrona G, Morabito F, Ferrarini M, and Pileri S.
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Male ,Pathology ,medicine.medical_specialty ,Biopsy ,Chronic lymphocytic leukemia ,Blotting, Western ,Immunoglobulin Variable Region ,Pathology and Forensic Medicine ,Immunoenzyme Techniques ,Bone Marrow ,Biomarkers, Tumor ,medicine ,Humans ,Aged ,Aged, 80 and over ,ZAP-70 Protein-Tyrosine Kinase ,biology ,medicine.diagnostic_test ,ZAP70 ,General Medicine ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Leukemia ,medicine.anatomical_structure ,Mutation ,biology.protein ,Immunohistochemistry ,Immunoglobulin heavy chain ,Original Article ,Female ,Bone marrow ,Antibody ,Immunoglobulin Heavy Chains - Abstract
Background: The course of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) partly depends on the mutational status of the variable region of immunoglobulin heavy chain genes (IgV H ), which defines two subgroups of tumours: mutated and unmutated. The expression of zeta-associated protein 70 (ZAP70) is significantly associated with the more aggressive unmutated forms. Aims: To assess the feasibility of the ZAP70 immunohistochemical test on bone-marrow biopsy (BMB) specimens and to compare the results with those of western blotting (WB) and IgV H mutational status assessed on neoplastic cells from peripheral blood. Methods: 26 patients with CLL/SLL detected on BMB and with known IgV H mutational status were selected. ZAP70 was determined by immunohistochemistry (IHC) comparing three antibodies from different sources (Upstate, Cell Signaling, Santa Cruz, California, USA) and two different methods (APAAP and EnVision + ). In 23 cases, ZAP70 WB results were also available. Results: ZAP70 determination on BMB specimens turned out to be easily feasible with routine procedures with reagents from Upstate and Cell Signaling. The results were concordant with those obtained with WB and mutational status analysis in >80% of the cases with both reagents. Three of four discordant cases were mutated/ZAP70 positive, with two staining weakly for ZAP70 on both WB and IHC. Conclusions: The study confirms the role of ZAP70 as a possible surrogate of mutational status and emphasises its application in routine diagnostics; it discloses a small subset of discordant cases (mutated/ZAP70 weakly positive) that clinically cluster with the more favourable forms.
- Published
- 2007
16. BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim-Chester disease
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Marina Ferrarini, Riccardo Biavasco, Lorenzo Dagna, Andreas von Deimling, Maria Giulia Cangi, Claudio Doglioni, Alvise Berti, B. Guglielmi, Maria Grazia Sabbadini, Corrado Campochiaro, Vito Lampasona, Greta Grassini, Giulio Cavalli, Elena DalCin, Cangi, Mg, Biavasco, R, Cavalli, G, Grassini, G, Dal Cin, E, Campochiaro, C, Guglielmi, B, Berti, A, Lampasona, V, von Deimling, A, Sabbadini, Mg, Ferrarini, M, Doglioni, Claudio, and Dagna, Lorenzo
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Adult ,Male ,Proto-Oncogene Proteins B-raf ,Senescence ,Erdheim-Chester Disease ,Pathology ,medicine.medical_specialty ,genetic structures ,Immunology ,Polymerase Chain Reaction ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Rheumatology ,Biopsy ,medicine ,Humans ,Immunology and Allergy ,Cellular Senescence ,Histiocyte ,Aged ,Inflammation ,medicine.diagnostic_test ,business.industry ,Histiocytes ,Oncogenes ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Histiocytosis ,Mutation ,Erdheim–Chester disease ,Leukocytes, Mononuclear ,Female ,Gene polymorphism ,business ,Sequence Analysis - Abstract
Objectives Erdheim-Chester disease (ECD) is a rare form of histiocytosis characterised by uncontrolled chronic inflammation. The oncogenic BRAF V600E mutation has been reported in biopsies in 19 out of 37 patients with ECD from the largest published cohort, but never found in the patients’ peripheral blood. Also, the role of the mutation in the pathogenesis of the disease has not been elucidated yet. BRAF V600E has been associated with oncogene-induced senescence (OIS), a protective mechanism against oncogenic events, characterised by the induction of proinflammatory pathways. Methods We verified the BRAF status in biopsies and peripheral blood from 18 patients with ECD from our cohort and matched controls by means of immunohistochemistry and of an ultrasensitive assay, based on the combination of a locked nucleic acid PCR and pyrosequencing. Droplet digital PCR was used to confirm the findings. We also evaluated the presence of senescence markers in ECD histiocytes. Results BRAF V600E mutation was present in all the biopsy and peripheral blood samples from patients with ECD and in none of the controls. ECD histiocytes and a fraction of circulating monocytes from patients with ECD showed signs of a constitutive activation of the MAPK pathway. Moreover, BRAF-mutated histiocytes expressed markers of OIS. Conclusions The oncogenic BRAF V600E mutation is present in biopsies and in the peripheral blood from all patients with ECD who were evaluated and is associated with OIS. These findings have significant implications for the pathogenesis, diagnosis and treatment of ECD.
- Published
- 2015
17. Angiopoietin-2 in Bone Marrow milieu promotes Multiple Myeloma-associated angiogenesis
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Magda Marcatti, Fabio Ciceri, Lorenzo Veschini, Federico Caligaris Cappio, Daniela Belloni, Maurilio Ponzoni, Marina Ferrarini, Elisabetta Ferrero, Angelo Corti, Belloni, D, Marcatti, M, Ponzoni, Maurilio, Ciceri, Fabio, Veschini, L, Corti, Angelo, Caligaris Cappio, F, Ferrarini, M, and Ferrero, E.
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Adult ,Male ,Vascular Endothelial Growth Factor A ,Angiogenesis ,MAP Kinase Signaling System ,Biology ,Angiopoietin-2 ,Bone Marrow ,medicine ,Angiopoietin-1 ,Human Umbilical Vein Endothelial Cells ,Humans ,Protein kinase B ,Multiple myeloma ,Aged ,Aged, 80 and over ,Neovascularization, Pathologic ,Cell Biology ,Middle Aged ,medicine.disease ,Receptor, TIE-2 ,Endothelial stem cell ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Case-Control Studies ,Immunology ,cardiovascular system ,Cancer research ,Female ,Bone marrow ,Multiple Myeloma ,hormones, hormone substitutes, and hormone antagonists ,Monoclonal gammopathy of undetermined significance - Abstract
Angiopoietin-2 (Ang-2) is involved in angiogenesis in both solid and hematological malignancies. In Multiple Myeloma (MM), serum Ang-2 correlates with disease progression and response to therapy. To address the patho-physiologic role of Ang-2 in MM associated angiogenesis, we used sera from patients with active MM, which contained significantly higher levels of the molecule, compared to those from patients with smoldering MM and Monoclonal Gammopathy of Undetermined Significance. MM Bone Marrow (BM) sera with high Ang-2 concentration specifically contributed to endothelial cell (EC) activation, while Ang-1 containing sera maintained EC stabilization. The functional dichotomy of Ang-1 and Ang-2 was confirmed by the triggering of distinctive signaling pathways down-stream the common Tie-2 receptor, i.e., the Akt or the ERK- phosphorylation pathway. Notably, Ang-2 but not VEGF serum levels correlated with BM micro-vessel density, further underscoring the key role of Ang-2 in angiogenesis. Western Blot, RT-PCR and immunocytochemistry identified MMEC as the major source of Ang-2, at variance with MM cells and CD14(+) BM monocytes. These data suggest that Ang-2 produced in the BM milieu may contribute to MM angiogenesis and suggest that the molecule can be further exploited both as angiogenesis biomarker and as a potential therapeutic target. (C) 2014 Elsevier Inc. All rights reserved.
- Published
- 2015
18. Adeno-Associated Virus-Mediated Transduction of VEGF165 Improves Cardiac Tissue Viability and Functional Recovery After Permanent Coronary Occlusion in Conscious Dogs
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Fabio A. Recchia, Xiaobin Xu, Axel Linke, Thomas H. Hintze, Nikola Arsic, Lorena Zentilin, Matteo Ferrarini, Mauro Giacca, Serena Zacchigna, Ferrarini, M, Arsic, N, RECCHIA F., A, Zentilin, L, Zacchigna, S, Xu, X, Linke, A, Giacca, Mauro, and Hintze, T. H.
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Male ,Vascular Endothelial Growth Factor A ,Coronary Stenosi ,Physiology ,Myocardial Infarction ,Infarction ,Transduction, Genetic ,Dog ,Medicine ,Myocardial infarction ,Ejection fraction ,biology ,VEGF receptor ,Cardiac muscle ,Heart ,AAV vector ,Angiogenesi ,medicine.anatomical_structure ,Cardiology ,Genetic Vector ,Cardiac regeneration ,Cardiology and Cardiovascular Medicine ,Human ,Artery ,medicine.medical_specialty ,Genetic Vectors ,Neovascularization, Physiologic ,AAV vectors ,Angiogenesis ,Gene therapy ,VEGF receptors ,Adenoviridae ,Animals ,Coronary Stenosis ,Dogs ,Genetic Therapy ,Humans ,Transduction ,Genetic ,Internal medicine ,Physiologic ,Neovascularization ,Animal ,business.industry ,Skeletal muscle ,medicine.disease ,Troponin ,Surgery ,Coronary occlusion ,biology.protein ,business - Abstract
We have previously shown that VEGF165 gene delivery into ischemic skeletal muscle exerts not only proangiogenic, but also remarkable antiapoptotic and proregenerative activity. The aim of this study was to determine whether recombinant adeno-associated virus (rAAV)-mediated gene delivery of VEGF165 into cardiac muscle, during acute myocardial infarction, exerts a protective effect to promote long-term functional recovery. Acute infarction of the anterior LV wall was induced in 12 chronically instrumented dogs by permanent occlusion of the LAD coronary artery. Four hours after occlusion, rAAV-VEGF165 or rAAV-LacZ (n=6 each; 5×10 12 viral particles per animal) was directly injected with an echo-guided needle into the dysfunctional cardiac wall. LV and arterial pressure, dP/dt max , and ejection fraction were not significantly different between the two groups over time. In contrast, in the infarcted region, at four weeks after infarction, fractional shortening was 75±18% and −3±15% of baseline and length-pressure area was 54±15% and 0.8±15% of baseline in VEGF165 versus LacZ, respectively ( P P
- Published
- 2006
19. A Relapsing Inflammatory Syndrome and Active Human Herpesvirus 8 Infection
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Francesco Broccolo, Lorenzo Dagna, Paolo Lusso, Mauro S. Malnati, Maria Grazia Sabbadini, Luisa Praderio, Marina Ferrarini, Carlo Terenzio Paties, Loredana Sarmati, Dagna, Lorenzo, Broccolo, F, Paties, Ct, Ferrarini, M, Sarmati, L, Praderio, L, Sabbadini, Mg, Lusso, P, Malnati, Ms, Dagna, L, Paties, C, Sabbadini, M, and Malnati, M
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Pathology ,peripheral blood mononuclear cell ,recurrent disease ,correlation analysis ,viruses ,rash ,lymphatic system disease ,medicine.disease_cause ,Recurrence ,middle aged ,Edema ,Gammaherpesvirinae ,Viral ,Human herpesvirus 8 ,fever ,serodiagnosis ,Herpesviridae Infection ,immunocompetence ,Synovitis ,biology ,Human immunodeficiency virus ,adult ,article ,hyperplasia ,virus diseases ,Sarcoma ,Herpesviridae Infections ,General Medicine ,lymph node ,Viral Load ,Hyperplasia ,Rash ,virology ,Lymphatic disease ,female ,arthritis ,priority journal ,Synoviti ,Herpesvirus 8, Human ,Immunocompetence ,medicine.symptom ,Arthriti ,Human ,virus DNA ,medicine.medical_specialty ,Settore MED/17 - Malattie Infettive ,Kaposi ,Virus ,Herpesviridae ,histology ,blood ,lymphadenopathy ,HIV Seronegativity ,medicine ,case report ,cell proliferation ,clinical feature ,edema ,Herpes virus infection ,human ,Kaposi sarcoma ,splenomegaly ,virus load ,isolation and purification ,pathology ,synovitis ,Arthritis ,DNA, Viral ,Exanthema ,Female ,Humans ,Lymph Nodes ,Lymphatic Diseases ,Middle Aged ,Sarcoma, Kaposi ,Splenomegaly ,Herpesvirus 8 ,business.industry ,DNA ,medicine.disease ,biology.organism_classification ,Immunology ,Lymphatic Disease ,business - Abstract
We describe an immunocompetent 61-year-old woman who was negative for human immunodeficiency virus and who had recurrent human herpesvirus 8 (HHV-8) infection associated with a relapsing systemic inflammatory syndrome characterized by fever, lymphadenopathy, splenomegaly, edema, arthrosynovitis, and rash. Kaposi's sarcoma developed 10 months after the initial clinical presentation. A correlation was documented between the recurrent clinical manifestations and the HHV-8 load in plasma and peripheral-blood mononuclear cells. Histologic examination of an enlarged lymph node heavily infected with HHV-8 revealed an atypical lymphoproliferative disorder characterized by paracortical hyperplasia and collapsed primary and secondary follicles.
- Published
- 2005
20. An unusual transthyretin gene missense mutation (TTR Phe33Val) linked to familial amyloidotic polyneuropathy
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Elio Agostoni, Roberta Frigerio, Nicolo' Rizzuto, Gian Maria Fabrizi, Carlo Ferrarese, Laura Brighina, Guido Cavaletti, Patrizia Santoro, Moreno Ferrarini, Tiziana Cavallaro, Frigerio, R, Fabrizi, G, Ferrarini, M, Cavallaro, T, Brighina, L, Santoro, P, Agostoni, E, Cavaletti, G, Rizzuto, N, and Ferrarese, C
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Adult ,medicine.medical_specialty ,phenylalanine ,Genetic Linkage ,hereditary amyloidosis ,familial amyloidotic polyneuropathy ,transthyretin ,mutation ,valine ,Mutation, Missense ,medicine.disease_cause ,Exon ,Sural Nerve ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Prealbumin ,Missense mutation ,Transversion ,Amyloid Neuropathies, Familial ,Mutation ,biology ,business.industry ,Restrictive cardiomyopathy ,nutritional and metabolic diseases ,Autosomal dominant trait ,hereditary amyloidosi ,medicine.disease ,Pedigree ,Transthyretin ,Endocrinology ,biology.protein ,Female ,business ,Polyneuropathy - Abstract
Familial amyloidotic polyneuropathy is a rare autosomal dominant disease, with clinical symptoms beginning in most kindreds within the third to seventh decades of life. The primary defect results from one of a number of mutations in the transthyretin (TTR) gene. Over 80 mutations in the TTR gene have been described. Most mutations give rise to adult onset progressive peripheral and autonomic neuropathy, due to amyloid deposition within the nerves, and often subclinical cardiac amyloid and vitreous deposits. We report here the clinical and molecular characterization of a rare TTR missense mutation discovered in a young woman from Macedonia, showing severe axonal sensory-motor polyneuropathy, restrictive cardiomyopathy and bilateral vitreous deposits. The transthyretin gene, analyzed by direct nucleotide sequencing, demonstrated a T to G transversion at nucleotide 183 in the exon 2 which is predicted to cause a heterozygous valine for phenylalanine substitution at codon 33 (TTR Phe33Val). This mutation has been previously reported only twice, without complete clinical descriptions.
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- 2004
21. Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease
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Nancy Feeley, Juvianee Estrada-Veras, Filip Janku, Giulio Cavalli, Augusto Vaglio, Julien Haroche, Kenneth L. McClain, Lorenzo Dagna, Mark L. Heaney, Laurent Arnaud, Thomas V. Colby, David M. Hyman, Eli L. Diamond, Marina Ferrarini, Elisabetta Ferrero, Paul J. Scheel, Omar Abdel-Wahab, Diamond, El, Dagna, Lorenzo, Hyman, Dm, Cavalli, G, Janku, F, Estrada Veras, J, Ferrarini, M, Abdel Wahab, O, Heaney, Ml, Scheel, Pj, Feeley, Nk, Ferrero, E, Mcclain, Kl, Vaglio, A, Colby, T, Arnaud, L, and Haroche, J.
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medicine.medical_specialty ,Pathology ,genetic structures ,business.industry ,Immunology ,MEDLINE ,Cell Biology ,Hematology ,Disease ,medicine.disease ,Biochemistry ,Non-Langerhans cell histiocytosis ,Histiocytosis ,Critical appraisal ,Histiocytoses ,Erdheim–Chester disease ,medicine ,Medical diagnosis ,Intensive care medicine ,business - Abstract
Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.
- Published
- 2014
22. TNF-alpha in Erdheim-Chester disease pericardial effusion promotes endothelial leakage in vitro and is neutralized by infliximab
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Lorenzo Dagna, Elisabetta Ferrero, Claudio Doglioni, Marina Ferrarini, Daniela Belloni, Angelo Corti, Ferrero, E, Belloni, D, Corti, A, Doglioni, Claudio, Dagna, Lorenzo, and Ferrarini, M.
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Pathology ,medicine.medical_specialty ,biology ,business.industry ,medicine.disease ,Pericardial effusion ,Infliximab ,In vitro ,Rheumatology ,Erdheim–Chester disease ,medicine ,biology.protein ,Pharmacology (medical) ,Antibody ,business ,medicine.drug - Published
- 2014
23. Blockade of the Fas-triggered intracellular signaling pathway in human melanomas is circumvented by cytotoxic lymphocytes
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Maria Pia Protti, Clara Sciorati, Claudio Rugarli, Marina Ferrarini, Maria Adele Imro, Silvia Heltai, Carlo Pellicciari, Patrizia Rovere, Angelo A. Manfredi, Ferrarini, M, Imro, Ma, Sciorati, C, Heltai, S, Protti, Mp, Pellicciari, C, ROVERE QUERINI, Patrizia, Manfredi, ANGELO ANDREA M. A., and Rugarli, C.
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Cytotoxicity, Immunologic ,Cancer Research ,Ceramide ,Fas Ligand Protein ,Skin Neoplasms ,Apoptosis ,Biology ,Lymphocyte Activation ,Fas ligand ,Jurkat Cells ,chemistry.chemical_compound ,Immune system ,Antigens, CD ,Tumor Cells, Cultured ,medicine ,Humans ,Cytotoxic T cell ,fas Receptor ,Melanoma ,Cells, Cultured ,Membrane Glycoproteins ,Receptors, Antigen, T-Cell, gamma-delta ,Flow Cytometry ,Fas receptor ,medicine.disease ,Coculture Techniques ,Clone Cells ,Oncology ,chemistry ,Immunology ,Cancer research ,Interleukin-2 ,Intracellular ,Signal Transduction ,T-Lymphocytes, Cytotoxic - Abstract
Fas and Fas ligand (FasL) have been found both in lymphoid and in non-lymphoid malignancies, and are thought to play a role in the interplay between tumors and the immune system. Here we investigated Fas/FasL expression, function and intracellular signalling pathways in human melanomas. Of 5 melanoma cell lines, 3 expressed Fas at their surface, and all of them expressed FasL. FasL was functional, since it triggered Fas-induced apoptosis of human T lymphocytes clones. Conversely, cross-linking of Fas molecule with a specific monoclonal antibody failed to induce apoptosis in any of the melanomas tested, or ceramide intracellular accumulation or caspase-3 activation, pointing to an early alteration in the Fas-triggered signaling cascade. All melanomas retained the ability to undergo apoptosis induced by cytotoxic lymphocytes, which was mediated by the granule exocytosis mechanism. This suggests that melanoma cells evade immune-mediated Fas-triggered apoptosis via a selective blockade of the Fas apoptotic pathway. Cytotoxic lymphocytes, however, may circumvent tumor resistance to Fas-induced death via granzyme-mediated apoptosis, further supporting the development of immunotherapeutic strategies in the treatment of cancer.
- Published
- 1999
24. Phenotypic and Functional Characterization of Human Tonsillar Subepithelial (SE) B Cells
- Author
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Manlio Ferrarini, Anna Favre, Mariella Dono, Carlo Tacchetti, Nicholas Chiorazzi, Carlo E. Grossi, Simona Zupo, Adriano Augliera, Vito L. Burgio, Dono, M., Zupo, S., Burgio, V. L., Augliera, A., Tacchetti, Carlo, Favre, A., Grossi, C. E., Chiorazzi, N., and Ferrarini, M.
- Subjects
B-Lymphocytes ,General Neuroscience ,Palatine Tonsil ,Apoptosis ,Immunoglobulin D ,Biology ,Antigens, T-Independent ,Molecular biology ,Phenotype ,General Biochemistry, Genetics and Molecular Biology ,Palatine tonsil ,Immunophenotyping ,medicine.anatomical_structure ,History and Philosophy of Science ,medicine ,biology.protein ,Animals ,Humans ,Lymphocyte Culture Test, Mixed ,Cells, Cultured - Published
- 1997
25. Ex-vivo dynamic 3-D culture of human tissues in the RCCS™ bioreactor allows the study of Multiple Myeloma biology and response to therapy
- Author
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Nathalie Steimberg, Elisabetta Ferrero, Maurilio Ponzoni, Angiola Berenzi, Daniela Belloni, Marina Ferrarini, Stefania Girlanda, Federico Caligaris-Cappio, Giovanna Mazzoleni, Ferrarini, M, Steimberg, N, Ponzoni, Maurilio, Belloni, D, Berenzi, A, Girlanda, S, Caligaris Cappio, F, Mazzoleni, G, and Ferrero, E.
- Subjects
Male ,Vascular Endothelial Growth Factor A ,Pathology ,Cell Culture Techniques ,Cancer Treatment ,Cell Communication ,Plasma Cell Disorders ,Bortezomib ,Rats, Sprague-Dawley ,Hematologic Cancers and Related Disorders ,Tissue culture ,Bioreactors ,Engineering ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Multiple myeloma ,Multidisciplinary ,Neovascularization, Pathologic ,Hematology ,Middle Aged ,Boronic Acids ,Immunohistochemistry ,Oncology ,Pyrazines ,Medicine ,Female ,Antiangiogenesis Therapy ,Multiple Myeloma ,Proteasome Inhibitors ,Research Article ,Biotechnology ,medicine.drug ,Adult ,Genetic Markers ,medicine.medical_specialty ,Histology ,Science ,Bone Marrow Cells ,Bioengineering ,Biology ,Bone and Bones ,Angiopoietin-2 ,In vivo ,medicine ,Animals ,Humans ,Aged ,Tibia ,Beta-2 microglobulin ,Chemotherapy and Drug Treatment ,medicine.disease ,Rats ,Cell culture ,Proteasome inhibitor ,Cancer research ,beta 2-Microglobulin ,Ex vivo - Abstract
Three-dimensional (3-D) culture models are emerging as invaluable tools in tumor biology, since they reproduce tissue-specific structural features and cell-cell interactions more accurately than conventional 2-D cultures. Multiple Myeloma, which depends on myeloma cell-Bone Marrow microenvironment interactions for development and response to drugs, may particularly benefit from such an approach. An innovative 3-D dynamic culture model based on the use of the RCCS™ Bioreactor was developed to allow long-term culture of myeloma tissue explants. This model was first validated with normal and pathological explants, then applied to tissues from myeloma patients. In all cases, histological examination demonstrated maintenance of viable myeloma cells inside their native microenvironment, with an overall well preserved histo-architecture including bone lamellae and vessels. This system was then successfully applied to evaluate the cytotoxic effects exerted by the proteasome inhibitor Bortezomib not only on myeloma cells but also on angiogenic vessels. Moreover, as surrogate markers of specialized functions expressed by myeloma cells and microenvironment, β2 microglobulin, VEGF and Angiopoietin-2 levels, as well as Matrix Metalloproteases activity, were evaluated in supernatants from 3D cultures and their levels reflected the effects of Bortezomib treatment. Notably, determination of β2 microglobulin levels in supernatants from Bortezomib-treated samples and in patients'sera following Bortezomib-based therapies disclosed an overall concordance in the response to the drug ex vivo and in vivo. Our findings indicate, as a proof of principle, that 3-D, RCCS™ bioreactor-based culture of tissue explants can be exploited for studying myeloma biology and for a pre-clinical approach to patient-targeted therapy.
- Published
- 2013
26. Tumor necrosis factor α as a master regulator of inflammation in Erdheim-Chester disease: rationale for the treatment of patients with infliximab
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Maria Grazia Sabbadini, Marina Ferrarini, Claudio Doglioni, Angelo Corti, B. Guglielmi, Lorenzo Dagna, Gabriele Fragasso, Silvia Langheim, Francesco De Cobelli, Dagna, Lorenzo, Corti, Angelo, Langheim, S, Guglielmi, B, DE COBELLI, Francesco, Doglioni, C, Fragasso, G, Sabbadini, MARIA GRAZIA, and Ferrarini, M.
- Subjects
Chemokine CCL11 ,Male ,Cancer Research ,medicine.medical_specialty ,Erdheim-Chester Disease ,Inflammation ,Cytokines metabolism ,Medicine ,Humans ,Tumor necrosis factor α ,biology ,business.industry ,Tumor Necrosis Factor-alpha ,Master regulator ,Antibodies, Monoclonal ,Middle Aged ,medicine.disease ,Infliximab ,Oncology ,Erdheim–Chester disease ,Cancer research ,Physical therapy ,biology.protein ,Cytokines ,medicine.symptom ,Antibody ,business ,medicine.drug - Published
- 2012
27. Synthetic miR-34a mimics as a novel therapeutic agent for Multiple Myeloma: in vitro and in vivo evidence
- Author
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Kenneth C. Anderson, Umberto Foresta, Vera Tomaino, Marco Rossi, Francesco Conforti, Manlio Ferrarini, Masood A. Shammas, Marta Lionetti, Massimo Negrini, Eugenio Morelli, Michele Caraglia, Annamaria Gulla, Pierfrancesco Tassone, Nicola Amodio, Pierosandro Tagliaferri, Nikhil C. Munshi, Maria Eugenia Gallo Cantafio, Antonino Neri, Maria Teresa Di Martino, Maria Rita Pitari, Emanuela Leone, Di Martino, Mt, Leone, E, Amodio, N, Foresta, U, Lionetti, M, Pitari, Mr, Gallo Cantafio, Me, Gullà, A, Conforti, F, Morelli, E, Tomaino, V, Rossi, M, Negrini, M, Ferrarini, M, Caraglia, Michele, Shammas, Ma, Munshi, Nc, Anderson, Kc, Neri, A, Tagliaferri, P, and Tassone, P.
- Subjects
Male ,Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,Apoptosis ,Mice, SCID ,Biology ,Transfection ,Article ,Cell Line ,Mice ,chemistry.chemical_compound ,Transduction, Genetic ,In vivo ,plasma cell leukemia ,microRNA ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Genes, Tumor Suppressor ,Cell Proliferation ,Tumor microenvironment ,Cell growth ,Lentivirus ,Genetic Therapy ,In vitro ,Tumor Burden ,multiple myeloma ,MicroRNAs ,SCID-synth-hu model ,Oncology ,chemistry ,Cell culture ,miRNAs ,Cancer research ,RNA Interference ,miR-34a ,Growth inhibition ,Neoplasm Transplantation - Abstract
Purpose: Deregulated expression of miRNAs has been shown in multiple myeloma (MM). A promising strategy to achieve a therapeutic effect by targeting the miRNA regulatory network is to enforce the expression of miRNAs that act as tumor suppressor genes, such as miR-34a. Experimental Design: Here, we investigated the therapeutic potential of synthetic miR-34a against human MM cells in vitro and in vivo. Results: Either transient expression of miR-34a synthetic mimics or lentivirus-based miR-34a-stable enforced expression triggered growth inhibition and apoptosis in MM cells in vitro. Synthetic miR-34a downregulated canonic targets BCL2, CDK6, and NOTCH1 at both the mRNA and protein level. Lentiviral vector-transduced MM xenografts with constitutive miR-34a expression showed high growth inhibition in severe combined immunodeficient (SCID) mice. The anti-MM activity of lipidic-formulated miR-34a was further shown in vivo in two different experimental settings: (i) SCID mice bearing nontransduced MM xenografts; and (ii) SCID-synth-hu mice implanted with synthetic 3-dimensional scaffolds reconstituted with human bone marrow stromal cells and then engrafted with human MM cells. Relevant tumor growth inhibition and survival improvement were observed in mice bearing TP53-mutated MM xenografts treated with miR-34a mimics in the absence of systemic toxicity. Conclusions: Our findings provide a proof-of-principle that formulated synthetic miR-34a has therapeutic activity in preclinical models and support a framework for development of miR-34a–based treatment strategies in MM patients. Clin Cancer Res; 18(22); 6260–70. ©2012 AACR.
- Published
- 2012
28. miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1
- Author
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Antonino Neri, Marzia Leotta, Fortunato Morabito, Kenneth C. Anderson, Valter Agosti, Pierosandro Tagliaferri, Gabriella Misso, Anna Maria Gullà, Nikhil C. Munshi, Michele Caraglia, M T Di Martino, Marco Rossi, Maria Rita Pitari, Emanuela Leone, Francesco Conforti, Marta Lionetti, Nicola Amodio, Umberto Foresta, Manlio Ferrarini, Mariateresa Fulciniti, Pierfrancesco Tassone, Amodio, N, Di Martino, Mt, Foresta, U, Leone, E, Lionetti, M, Leotta, M, Gullà, Am, Pitari, Mr, Conforti, F, Rossi, M, Agosti, V, Fulciniti, M, Misso, Gabriella, Morabito, F, Ferrarini, M, Neri, A, Caraglia, Michele, Munshi, Nc, Anderson, Kc, Tagliaferri, P, and Tassone, P.
- Subjects
Male ,Cancer Research ,Sp1 Transcription Factor ,Immunology ,Down-Regulation ,Apoptosis ,Mice, SCID ,Biology ,Sp1 ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,plasma cell leukemia ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Transcription factor ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Feedback, Physiological ,Plasma cell leukemia ,Regulation of gene expression ,0303 health sciences ,Sp1 transcription factor ,microRNA ,Bortezomib ,miR-29b ,bortezomib ,Cell Biology ,medicine.disease ,Boronic Acids ,Molecular biology ,Gene Expression Regulation, Neoplastic ,multiple myeloma ,MicroRNAs ,Proteasome ,Pyrazines ,030220 oncology & carcinogenesis ,miRNAs ,Proteasome inhibitor ,Cancer research ,Original Article ,medicine.drug - Abstract
MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells.
- Published
- 2012
29. The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia
- Author
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Fortunato Morabito, Anna Grazia Recchia, Antonio Pinto, Rosaria De Filippi, Katja Zirlik, Claudio Tripodo, Manlio Ferrarini, Giovanni Del Poeta, Barbara Amoroso, Vincenzo Gigliotti, Emanuela Morelli, Massimo Gentile, Ernesto Vigna, Luca Laurenti, Rosa Calemma, Stefano Molica, Giovanna Cutrona, Antonino Neri, Morabito, F, DE FILIPPI, Rosaria, Laurenti, L, Zirlik, K, Recchia, Ag, Gentile, M, Morelli, E, Vigna, E, Gigliotti, V, Calemma, R, Amoroso, B, Neri, A, Cutrona, G, Ferrarini, M, Molica, S, Del Poeta, G, Tripodo, C, Pinto, A., De Filippi, R, Recchia, AG, and Cutrona
- Subjects
Male ,Chronic lymphocytic leukemia ,MICROENVIRONMENT ,PROGRESSION ,CD38 ,GUIDELINES ,Biochemistry ,Cohort Studies ,Bone Marrow ,LYMPHOMA ,Medicine ,Aged, 80 and over ,Hematology ,Middle Aged ,Prognosis ,Leukemia ,B-CELLS ,Monoclonal ,Disease Progression ,Biological Markers ,Female ,IGHV@ ,Algorithms ,Adult ,medicine.medical_specialty ,DISORDERS ,CLINICAL-SIGNIFICANCE ,CD38 EXPRESSION ,CLL ,DIAGNOSIS ,Immunology ,Immunoglobulin light chain ,Immunoglobulin kappa-Chains ,Immunoglobulin lambda-Chains ,Humans ,Survival analysis ,Aged ,business.industry ,Cytogenetics ,Cell Biology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Analysis ,Cancer research ,Immunoglobulin Light Chains ,Lymph Nodes ,business ,Settore MED/15 - Malattie del Sangue ,Biomarkers ,Follow-Up Studies - Abstract
Identification of patients at risk of early disease progression is the mainstay of tailored management in chronic lymphocytic leukemia (CLL). Although application of established biomarkers is limited by intrinsic detection/readout complexities, abnormality of κ and λ serum-free light chain ratio [sFLC (κ/λ)] was proposed as a straightforward prognosticator in CLL. By analyzing 449 therapy-naive patients, we show that an abnormal sFLC(κ/λ), along with CD38, ZAP-70, IGHV mutations, cytogenetics and stage, independently predicts treatment-free survival (TFS) but becomes prognostically irrelevant if the cumulative amount of clonal and nonclonal FLCs [sFLC(κ + λ)], a variable associated with cytogenetic risk, exceeds the threshold of 60.6 mg/mL. Patients with sFLC(κ + λ) above cut-off displayed a poorer TFS outcome, irrespective of sFLC(κ/λ). Only ZAP-70, cytogenetics, stage, and TFS remained associated with sFLC(κ + λ) in a multivariate model. By assigning 1 point each for these variables, the 3-year probability of TFS was 94.8%, 84.5%, 61.6%, and 21.1% for patients scoring 0, 1, 2, and 3 + 4, respectively (P < .0001). These data, and the demonstration that monoclonal and polyclonal B cells concur to FLC synthesis in tumor tissues, suggest that sFLC(κ/λ) and sFLC(κ + λ) mirror distinct biologic processes in CLL. sFLC(κ + λ) assessment represents a sensitive and cost-effective tool for identifying CLL patients requiring early treatment.
- Published
- 2011
30. Two novel Italian CADASIL families from Central Italy with mutation CGC-TGC at codon 1006 in the exon 19 Notch3 gene
- Author
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F Selvaggio, Gabriella Cacchiò, Michele Ragno, Luigi Trojano, Federica Taioli, Moreno Ferrarini, Maria Scarcella, Gian Maria Fabrizi, G Sirocchi, Ragno, M, Fabrizi, Gm, Cacchio, G, Scarcella, M, Sirocchi, G, Selvaggio, F, Taioli, F, Ferrarini, M, and Trojano, Luigi
- Subjects
Male ,Pediatrics ,medicine.medical_specialty ,Neurology ,DNA Mutational Analysis ,CADASIL ,Dermatology ,Neuropsychological Tests ,Arginine ,Asymptomatic ,Vascular dementia ,Leukoencephalopathy ,Neuropsychology ,medicine ,Genetics ,Humans ,Cysteine ,Cognitive impairment ,Psychiatry ,Pathological ,Receptor, Notch3 ,Aged ,Family Health ,Receptors, Notch ,business.industry ,General Medicine ,Exons ,Middle Aged ,medicine.disease ,Psychiatry and Mental health ,Migraine ,Italy ,Mutation ,Female ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Here we describe clinical, neuropsychological and neuroradiological findings in 6 subjects belonging to two unrelated Italian cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) kindreds from the same geographic area who shared a common Arg1006Cys mutation. Subjects from Family A were virtually asymptomatic, and yet showed MRI pathological findings and a cluster of sub-clinical neuropsychological defects mainly centred on the visuospatial domain; patients from Family B had presented several clinically relevant episodes and showed a general cognitive impairment compatible with the clinical picture of vascular dementia. The present clinical observations are consistent with the hypothesis of a geographical clustering for CADASIL, and highlight that sub-clinical cognitive impairment may help to identify this syndrome in families presenting with only migraine.
- Published
- 2006
31. Double-edged effect of Vgamma9/Vdelta2 T lymphocytes on viral expression in an in vitro model of HIV-1/mycobacteria co-infection
- Author
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Marina Ferrarini, Adriano Lazzarin, Priscilla Biswas, Barbara Mantelli, Claudio Fortis, Angelo A. Manfredi, Guido Poli, Biswas, P, Ferrarini, M, Mantelli, B, Fortis, C, Poli, Guido, Lazzarin, A, and Manfredi, ANGELO ANDREA M. A.
- Subjects
Gene Expression Regulation, Viral ,medicine.medical_treatment ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,Apoptosis ,HIV Infections ,Virus Replication ,Models, Biological ,Cell Line ,Mycobacterium tuberculosis ,Interferon-gamma ,Hemiterpenes ,Organophosphorus Compounds ,medicine ,Immunology and Allergy ,Potency ,Humans ,fas Receptor ,Mycobacterium Infections ,biology ,Tumor Necrosis Factor-alpha ,Intracellular parasite ,U937 Cells ,biology.organism_classification ,Flow Cytometry ,Virology ,Cytokine ,Viral replication ,Cell culture ,HIV-1 ,Cell activation ,Cell Division - Abstract
A reciprocal influence exists between mycobacteria and HIV: HIV-infected individuals are more susceptible to mycobacterial infections and, on the other hand, mycobacterial infection results inacceleration of HIV disease progression. Vgamma9/Vdelta2 T lymphocytes are known to participate in the defense against intracellular pathogens, including Mycobacterium tuberculosis. Indeed, they kill mycobacteria-infected macrophages and, upon recognition of mycobacterial Ag, release TNF-alpha and IFN-gamma, which are also up-regulators of HIV expression. To assess whether mycobacteria-activated gamma delta T lymphocytes contribute to the enhancement of HIV replication, we established an in vitro model mimicking HIV and mycobacteria co-infection with the latently HIV-infected promonocytic U1 cell line and Vgamma9/Vdelta2 peripheral lymphocytes stimulated with mycobacterial Ag. gamma delta T cell activation determined two distinct, but connected effects, namely U1cell death and HIV expression. Both effects were mainly mediated by release of TNF-alpha and IFN-gamma from activated gamma delta lymphocytes, although Fas-FasL interaction also contributed to U1 apoptosis. The final outcome on U1 survival, and thus, on HIV expression, highly depended on mycobacterial Ag concentration coupled to the differential secretory potency of gamma delta cells. In particular, the induction of viral expression prevailed at low Ag concentration and with lower cytokine production by mycobacteria-activated gamma delta cells. Notably, during the course of HIV infection, Vgamma9/Vdelta2 lymphocytes are reported to be functionally impaired and may thus indirectly influence the progression of HIV disease. In addition, a predominant inhibition of viral replication was encountered when mycobacteria-activated gamma delta T cells were co-cultured with primary HIV-infected macrophages. Thus, we suggest that specific recognition of mycobacterial Ag by gamma delta T lymphocytes in co-infected individuals may modulate viral replication through the complex array of soluble factors released.
- Published
- 2003
32. CD30 ligation differentially affects CXCR4-dependent HIV-1 replication and soluble CD30 secretion in non-Hodgkin cell lines and in gamma delta T lymphocytes
- Author
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Priscilla Biswas, Barbara Mantelli, Adriano Lazzarin, Marina Ferrarini, Fanny Delfanti, Guido Poli, Biswas, P, Mantelli, B, Delfanti, F, Ferrarini, M, Poli, Guido, and Lazzarin, A.
- Subjects
Receptors, CXCR4 ,CD30 ,T-Lymphocytes ,CD3 ,Immunology ,Human immunodeficiency virus (HIV) ,Ki-1 Antigen ,Biology ,medicine.disease_cause ,CXCR4 ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Immunology and Allergy ,Secretion ,integumentary system ,Lymphoma, Non-Hodgkin ,NF-kappa B ,Receptors, Antigen, T-Cell, gamma-delta ,Up-Regulation ,Cell biology ,Viral replication ,Cell culture ,HIV-1 ,Cancer research ,biology.protein ,Ligation - Abstract
We studied whether signaling through CD30, a member of the TNF receptor family, affected acute infection with HIV-1, encompassing its entire replicative cycle. Several non-Hodgkin cell lines, targets of CXCR4-dependent (X4) HIV-1 infection, were positive for CD30 expression. CD30 ligation induced up-regulation of viral replication only in certain CD30(+) cell lines. Enhancement of X4 virus replication by CD30 engagement inversely correlated with both CD30 surface density and constitutive NF-kappaB activation. Conversely, expression of CD30, but not of other members of the TNF receptor family, was proportional to constitutive NF-kappaB binding. Concomitantly, secretion of soluble (s) CD30 increased in all cell lines by CD30 ligation. sCD30 release was enhanced by engagement of CD30 alone and, to a greater extent, by co-engagement of CD3 also in primary gammadelta T lymphocytes, along with complementary modulations of their surface CD30 expression. sCD30-containing supernatant specifically inhibited HIV-1 expression induced by CD30 engagement in chronically infected ACH-2 T cells; thus sCD30 may act as a negative feed-back molecule. In conclusion, we have delineated novel features of CD30 biology and underline the peculiar link of CD30 expression to constitutive NF-kappaB activation which is pivotal to both HIV replication and cell survival.
- Published
- 2003
33. Fas, apoptosis and the cell cycle
- Author
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Patrizia Rovere, Silvia Heltai, Marina Ferrarini, Angelo A. Manfredi, Manfredi, ANGELO ANDREA M. A., ROVERE QUERINI, Patrizia, Heltai, S, and Ferrarini, M.
- Subjects
Fas Ligand Protein ,Membrane Glycoproteins ,business.industry ,Cell Cycle ,Immunology ,Apoptosis ,Cell cycle ,Fas ligand ,Tumor Cells, Cultured ,Cancer research ,Humans ,Medicine ,fas Receptor ,business - Published
- 1996
34. Constitutive expression of the heat shock protein 72 kDa in human melanoma cells
- Author
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Marina Ferrarini, Silvia Heltai, Matteo Bellone, Maria Pia Protti, Claudio Rugarli, Angelo A. Manfredi, Protti, Mp, Heltai, S, Bellone, M, Ferrarini, M, Manfredi, ANGELO ANDREA M. A., and Rugarli, C.
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Cytoplasm ,Biology ,In Vitro Techniques ,Flow cytometry ,Heat shock protein ,Gene expression ,medicine ,Humans ,Neoplastic transformation ,HSP70 Heat-Shock Proteins ,HSP90 Heat-Shock Proteins ,Neoplasm Metastasis ,Melanoma ,Cells, Cultured ,medicine.diagnostic_test ,medicine.disease ,Flow Cytometry ,In vitro ,Oncology ,Cancer research ,biology.protein ,Tumor necrosis factor alpha ,Antibody - Abstract
Heat shock proteins (hsp) are a family of proteins characteristically produced under stress conditions in normal cells. Overexpression of hsp 70 kDa protects tumoral cells from tumor necrosis factor cytotoxicity and is related to drug resistance. In this study we investigated whether hsp are abnormally expressed in melanoma cells in vivo. Antibodies directed against hsp 72 and hsp 90 were used to identify hsp on non-stressed neoplastic cells derived from surgical specimens of two primary and four metastatic melanomas. Hsp 72 and hsp 90 were always present at high level in the cytoplasm of melanoma cells. It is possible that the activation of hsp genes during neoplastic transformation confers a selective advantage to tumoral cells in vivo, allowing them to escape the immunological surveillance.
- Published
- 1994
35. SENSITIVITIES AND PREDICTIVE VALUES OF PARACLINICAL TESTS FOR DIAGNOSING MULTIPLE-SCLEROSIS
- Author
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Francesco Riti, Ludovico D'Incerti, Vittorio Martinelli, M. Ferrarini, Vittorio Cosi, A. Citterio, Giuliano Avanzini, Graziella Filippini, Roberto Bergamaschi, F. Zappoli, Maurizio Sberna, Nadia Colombo, G. Comi, Giuseppe Scotti, Adriana Campi, L. Bevilacqua, Massimo Filippi, Mario Savoiardo, Filippini, G, Comi, Giancarlo, Cosi, V, Bevilacqua, L, Ferrarini, M, Martinelli, V, Bergamaschi, R, Filippi, Massimo, Citterio, A, Dincerti, L, Campi, A, Sberna, M, Riti, F, Avanzini, G, Colombo, N, Zappoli, F, Scotti, G, and Savoiardo, M.
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Multiple Sclerosis ,Optic Neuritis ,Neurology ,Adolescent ,Sensitivity and Specificity ,Asymptomatic ,Antibodies ,White matter ,Central nervous system disease ,Predictive Value of Tests ,medicine ,Humans ,Prospective Studies ,Evoked potential ,Neuroradiology ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Brain ,Cerebrospinal Fluid Proteins ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,medicine.anatomical_structure ,Evoked Potentials, Visual ,Female ,Neurology (clinical) ,Radiology ,medicine.symptom ,business - Abstract
The sensitivities and predictive values of visual, somatosensory, and brain auditory evoked potentials (EPs), cerebrospinal fluid oligoclonal banding (CSF-OB) and magnetic resonance imaging (MRI) were evaluated for the early diagnosis of clinically definite multiple sclerosis (CDMS). Paraclinical evidence of asymptomatic lesions allows a diagnosis of CDMS. Eighty-two patients in whom MS was suspected but diagnosis of CDMS was not possible entered the study prospectively. Paraclinical examinations were performed at entry. Patients were examined and underwent EPs every 6 months, and MRI yearly. After a mean follow-up of 2.9 years, 28 patients (34%) had developed CDMS (McDonald-Halliday criteria). The initial MRI was strongly suggestive of MS in 19 of these (68%), while 27 (96%) had at least one MS-like abnormality in the initial MRI. CSF-OB and EPs had lower sensitivities. CDMS developed during follow-up in 19 of the 36 patients (53%) who had an initial MRI strongly suggestive of MS but in only 1 of the 25 who had normal MRI when first studied. These results support previous conclusions that MRI is the most sensitive test for detecting white matter asymptomatic lesions, and the most predictive for the diagnosis of CDMS.
- Published
- 1994
36. Presence of T-cell subset abnormalities in newly diagnosed cases of multiple sclerosis and relationship with short-term clinical activity
- Author
-
A. Dufour, Vittorio Martinelli, Graziella Filippini, Marica Eoli, L. Bevilacqua, Clara Milanese, G. Comi, L. LaMantia, S. Heltaj, Vittorio Cosi, Andrea Salmaggi, M. Ferrarini, Eoli, M, Ferrarini, M, Dufour, A, Heltaj, S, Bevilacqua, L, Comi, Giancarlo, Cosi, V, Filippini, G, Martinelli, V, Milanese, C, LA MANTIA, L, and Salmaggi, A.
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,Neurology ,Multiple Sclerosis ,Adolescent ,Pathogenesis ,Cerebrospinal fluid ,Antigens, CD ,Recurrence ,T-Lymphocyte Subsets ,medicine ,Humans ,Neuroradiology ,medicine.diagnostic_test ,business.industry ,Multiple sclerosis ,Magnetic resonance imaging ,Middle Aged ,medicine.disease ,Peripheral blood lymphocyte ,Neurology (clinical) ,business ,CD8 ,Follow-Up Studies - Abstract
Abnormalities of T-cell subsets in patients with multiple sclerosis are well known; in order to assess whether immunological abnormalities are relevant in the pathogenesis of the disease after its clinical onset, peripheral blood lymphocyte subsets (CD3+, CD4+, CD4(+)-CD45RA+, CD4+CD45RA-, CD8+, CD8+CD57+, CD57+, CD25+) were analysed serially in 25 patients at the first clinical episode suggestive of inflammatory demyelinating disease and in an equal number of age- and sex-matched controls. During the follow-up period (12-18 months, mean 14) 6 of 25 patients presented new relapses: in this subgroup of patients, significant changes in CD4+ ratio (% CD4+CD45RA-/%CD4+CD45RA+) were detected in comparison both with healthy controls and with clinically stable patients. Patients clinically stable at follow-up did not display immunological abnormalities, regardless of the presence or absence of cerebrospinal fluid and/or magnetic resonance imaging alterations consistent with multiple sclerosis. These findings suggest a possible prognostic role of early T-cell subset imbalance in multiple sclerosis.
- Published
- 1993
37. Differentiation in the I.29 B cell lymphoma: precommitment to IgA or IgE switch in individual IgM+ clones
- Author
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Daniela Vismara, Roberto Biassoni, Cristina M. Alberini, Roberto Sitia, Sandro Deambrosis, FERRARINI M., PERNIS B., Sitia, Roberto, Alberini, C., Biassoni, R., Deambrosis, A., and Vismara, D.
- Subjects
biology ,Alternative splicing ,Immunoglobulin light chain ,Immunoglobulin D ,Molecular biology ,Isotype ,medicine.anatomical_structure ,Immunoglobulin class switching ,Immunology ,biology.protein ,medicine ,Antibody ,Gene ,B cell - Abstract
Blymphocytes undergo during their development several sequential rearrangements at the immunoglobulin (Ig) loci (1). The first event is a D-JH recombination that usually takes place at both the heavy chain (IgH) loci, and is then followed by rearrangement of one of the numerous VHgenes to the DJHcomplex (2). When a functional VDJ rearrangement has taken place, synthesis of μ Polypeptide ensues and rearragments of the light chain loci begin. A K-λ hyerarchy has been demonstrated in both human and mouse B cells (3,4). A successful heavy chain gene recombination stops any further rearrangement at the IgH locus (5,6), and possibly stimulates IgL recombination. Similarly the creation of a productive light chain gene blocks further recombinations at the IgL loci (5). Subsequently IgM molecules are synthetized and expressed on the cell surface by lymphocytes (7). The latter may coexpress IgD through alternative splicing of the VDJ - Cμ -C δ transcription unit (8). IgM+ B cell may undergo a second recombinatorial event at the IgH locus, termed isotype switching. This event generally implies the deletion of Cμ, Cδ and all the CHgenes which are located 5′ to the one CH gene that will be expressed (9,10). Although the sequences mediating switch recombination have been isolated and determined (9–11), rather little is known about the mechanisms regulating isotype switching. The question of how an IgM+B lymphocyte decides which CH gene to recombine is still open. It is well known that certain antigens or routes of immunization result in vivo in the predominance of a given isotype (12). On the other hand several in vitro experiments have shown that more than one isotype can be produced by the progeny of a single B cell (13–15). Isotype switching is not the only differentiative option of an IgM+ B cell. The latter may infact respond to antigen or mitogen by differentiating into IgM secreting plasmacells (7). It is generally accepted that plasmacell may undergo a very limited number of divisions.
- Published
- 1986
38. Expression of a receptor for sheep erythrocytes by B lymphocytes from a chronic lymphocytic leukemia patient
- Author
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Roberto Sitia, Leprini A, Riccardo Ghio, Antonio Zicca, Luca Sciariada, Manlio Ferrarini, Sitia, Roberto, Sciariada, L., Zicca, A., Leprini, A., Ghio, R., and Ferrarini, M.
- Subjects
Pathology ,medicine.medical_specialty ,Erythrocytes ,Rosette Formation ,medicine.drug_class ,Lymphocyte ,Proteolysis ,Chronic lymphocytic leukemia ,Immunology ,Receptors, Antigen, B-Cell ,Receptors, Fc ,Biology ,Monoclonal antibody ,Lymphocyte Activation ,Pathology and Forensic Medicine ,medicine ,Immunology and Allergy ,Humans ,Receptor ,Aged ,B-Lymphocytes ,medicine.diagnostic_test ,Red Cell ,Receptors, IgG ,Antibodies, Monoclonal ,medicine.disease ,Molecular biology ,Leukemia, Lymphoid ,medicine.anatomical_structure ,Immunoglobulin G ,biology.protein ,Female ,Antibody ,Clone (B-cell biology) - Abstract
A patient with a B-cell chronic lymphocytic leukemia, whose lymphocytes also formed rosettes with sheep red cells, is described. The B-cell nature of the malignant lymphocytes was determined by surface marker analysis, and cytochemical and ultrastructural studies. The lymphocyte membrane immunoglobulin (IgG1K) did not have anti-sheep red cell activity and was not responsible for the binding of sheep erythrocytes to the leukemic cells as shown by (i) the failure to inhibit rosette formation with anti-immunoglobulin reagents and (ii) the different sensitivity to proteolysis of the membrane immunoglobulin and the sheep erythrocyte receptor. The malignant lymphocytes expressed a receptor for sheep erythrocytes similar to that of normal T cells since they stained with monoclonal antibodies directed against the sheep red cell receptors. Furthermore these antibodies blocked rosette formation. Endogenous labeling experiments demonstrated that the patient's cells produced IgG both of the membrane and of the secretory type. The latter molecular form was also actively secreted. Ultrastructural studies demonstrated that the malignant clone comprised cells at different maturational stages and with different secretory properties. These findings were confirmed by the analysis of intracytoplasmic acid hydrolases, which are normally expressed at late maturational stages. These data are consistent with the hypothesis that a process of maturation was occurring within the malignant clone.
- Published
- 1983
39. Lymphocyte membrane immunoglobulins: similarities between human IgD and mouse IgD-like molecules
- Author
-
Roberto Sitia, Giorgio Corte, A. Bargellesi, Manlio Ferrarini, Sitia, Roberto, Corte, G., Ferrarini, M, and Bargellesi, A.
- Subjects
Lymphocyte ,Immunology ,Molecular Conformation ,Fluorescent Antibody Technique ,Receptors, Antigen, B-Cell ,Spleen ,Pronase ,Immunofluorescence ,Immunoglobulin D ,Iodine Radioisotopes ,Mice ,medicine ,Animals ,Humans ,Immunology and Allergy ,Lymphocytes ,Gel electrophoresis ,Mice, Inbred BALB C ,biology ,medicine.diagnostic_test ,Molecular biology ,Molecular Weight ,medicine.anatomical_structure ,Biochemistry ,biology.protein ,Electrophoresis, Polyacrylamide Gel ,Bone marrow ,Antibody - Abstract
131I-labeled IgD-like molecules extracted from the membrane of mouse spleen, and lymph node cells and their constitutive chains have been characterized by sodium dodecyl sulfate polyacrylamide slab gel electrophoresis (SDS-PAGE) followed by radioautography. Unreduced mouse IgD-like molecules concentrated in two definite bands (IgD1 and IgD2). IgD, migrated slightly ahead of 131I-labeled mouse membrane IgM and displayed a mobility very similar to that of 131I-labeled IgD extracted from the membrane of human tonsil cells. IgD2 migrated faster than both IgD1 and human membrane IgD (mIgD), but slower than 14C-labeled mouse IgG2 b used as marker. The different mobility of IgD1 and IgD2 was due to difference in size of their respective H-chains (δ1 and δ2), as shown by SDS-PAGE analysis of the two molecules after reduction. Mol.wt. determination of IgD1, IgD2 and of the corresponding constitutive chains are consistent with an H2L2 structure. IgD1 and IgD2 were partially replaced following prolonged dialysis by molecules with a SDS-PAGE mobility consistent with an HL structure, IgD3. In contrast to that found for spleen and lymph node, IgD1 only was detected on the surface of bone marrow cells. Immunofluorescence experiments have shown that while the majority of mouse lymph node or spleen cells bear IgM and IgD, IgM was found to be the predominant Ig class on the surface of bone marrow cells, although a certain number of IgD-IgM and a few IgD-positive cells were found. Experiments where mouse lymphocytes have been treated with pronase have indicated that, in analogy with mlgD of primates, mouse IgD-like molecules are very labile and can be removed from the cell surface by very mild proteolytic treatment.
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