33 results on '"Bordini J"'
Search Results
2. P616: THE LOSS OF IΚBΕ INHIBITOR ACCELERATES DISEASE DEVELOPMENT IN CHRONIC LYMPHOCYTIC LEUKEMIA
- Author
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Lenzi, C., primary, Bordini, J., additional, Pseftogkas, A., additional, Morabito, A., additional, Tsiolas, G., additional, Psomopoulos, F. E., additional, Campanella, A., additional, Frenquelli, M., additional, and Ghia, P., additional
- Published
- 2022
- Full Text
- View/download PDF
3. S271: BONE MARROW TFR2 DELETION IMPROVES THE THERAPEUTIC EFFECT OF ACTIVIN LIGAND TRAP RAP-536 IN Β-THALASSEMIC MICE
- Author
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Tanzi, E., primary, Di Modica, S. M, additional, Bordini, J., additional, Olivari, V., additional, Pettinato, M., additional, Pagani, A., additional, Campanella, A., additional, Silvestri, L., additional, and Nai, A., additional
- Published
- 2022
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4. P597: HIGH DOSE IRON IMPAIRS MALIGNANT B-CELL VIABILITY IN CHRONIC LYMPHOCYTIC LEUKEMIA
- Author
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Bordini, J., primary, Lenzi, C., additional, Toscani, L., additional, Ranghetti, P., additional, Perotta, E., additional, Scarfò, L., additional, Ghia, P., additional, and Campanella, A., additional
- Published
- 2022
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5. Acidity and photolability of ruthenium salen nitrosyl and aquo complexes in aqueous solutions
- Author
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Bordini, J., Novaes, D.O., Borissevitch, I.E., Owens, B.T., Ford, P.C., and Tfouni, E.
- Published
- 2008
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6. S1628 TARGETING THE IMMUNOPHILIN FKBP12 BY DRUG REPURPOSING OR RNASE-BASED APPROACHES FOR BMP-SMAD PATHWAY AND HEPCIDIN UPREGULATION IN HEREDITARY HEMOCHROMATOSIS
- Author
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Pettinato, M., primary, Aghajan, M., additional, Dulja, A., additional, Nai, A., additional, Olivari, V., additional, Bordini, J., additional, Campanella, A., additional, Pagani, A., additional, Guo, S., additional, Camaschella, C., additional, and Silvestri, L., additional
- Published
- 2019
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7. PF369 EXPLOITING IRON TOXICITY TO INCREASE VULNERABILITY OF MALIGNANT B CELLS
- Author
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Bordini, J., primary, Brambilla, M., additional, Cerruti, F., additional, Cascio, P., additional, Ranghetti, P., additional, Scarfò, L., additional, Camaschella, C., additional, Ghia, P., additional, and Campanella, A., additional
- Published
- 2019
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8. Iron induces ferroptosis and synergizes with anti-androgen therapy in prostate cancer pre-clinical models
- Author
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Campanella, A., primary, Bordini, J., additional, Morisi, F., additional, Elia, A.R., additional, Cucchiara, V., additional, Bellone, M., additional, Camaschella, C., additional, and Briganti, A., additional
- Published
- 2019
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9. Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice
- Author
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Nai A, Rubio A, Campanella A, Gourbeyre O, Artuso I, Bordini J, Gineste A, Latour C, Besson Fournier C, Lin HY, Coppin H, Roth MP, Silvestri L, Meynard D., CAMASCHELLA , CLARA, Nai, A, Rubio, A, Campanella, A, Gourbeyre, O, Artuso, I, Bordini, J, Gineste, A, Latour, C, Besson Fournier, C, Lin, Hy, Coppin, H, Roth, Mp, Camaschella, Clara, Silvestri, L, and Meynard, D.
- Published
- 2016
10. Induction of iron excess restricts malignant plasma cells expansion and potentiates bortezomib effect in models of multiple myeloma
- Author
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Bordini, J, primary, Galvan, S, additional, Ponzoni, M, additional, Bertilaccio, M T S, additional, Chesi, M, additional, Bergsagel, P L, additional, Camaschella, C, additional, and Campanella, A, additional
- Published
- 2016
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11. 852 - Iron induces ferroptosis and synergizes with anti-androgen therapy in prostate cancer pre-clinical models
- Author
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Campanella, A., Bordini, J., Morisi, F., Elia, A.R., Cucchiara, V., Bellone, M., Camaschella, C., and Briganti, A.
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- 2019
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12. Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma
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Bordini, J., primary, Bertilaccio, M. T. S., additional, Ponzoni, M., additional, Fermo, I., additional, Chesi, M., additional, Bergsagel, P. L., additional, Camaschella, C., additional, and Campanella, A., additional
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- 2015
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13. Longitudinal analysis of T-cell receptor repertoires reveals shared patterns of antigen-specific response to SARS-CoV-2 infection
- Author
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Gittelman, RM, primary, Lavezzo, E, additional, Snyder, TM, additional, Zahid, HJ, additional, Carty, CL, additional, Elyanow, R, additional, Dalai, S, additional, Kirsch, I, additional, Baldo, L, additional, Manuto, L, additional, Franchin, E, additional, Del Vecchio, C, additional, Pacenti, M, additional, Boldrin, C, additional, Cattai, M, additional, Saluzzo, F, additional, Padoan, A, additional, Plebani, M, additional, Simeoni, F, additional, Bordini, J, additional, Lorè, NI, additional, Lazarevic, D, additional, Cirillo, DM, additional, Ghia, P, additional, Topo, S, additional, Carlson, JM, additional, Robins, HS, additional, Crisanti, A, additional, and Tonon, G, additional
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14. CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism
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Giulia Casorati, Paolo Dellabona, Alessandra Rovida, Matteo Bellone, Jessica Bordini, Matteo Grioni, Arianna Brevi, Maria Teresa Sabrina Bertilaccio, Arianna Calcinotto, Elena Cattaneo, Maurilio Ponzoni, Paolo Ghia, Grioni, M., Brevi, A., Cattaneo, E., Rovida, A., Bordini, J., Bertilaccio, M. T. S., Ponzoni, M., Casorati, G., Dellabona, P., Ghia, P., Bellone, M., and Calcinotto, A.
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,Adoptive cell transfer ,Immunobiology and Immunotherapy ,medicine.drug_class ,Chronic lymphocytic leukemia ,CD40 Ligand ,Mice, Transgenic ,Monoclonal antibody ,Flow cytometry ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Proto-Oncogene Proteins ,hemic and lymphatic diseases ,medicine ,Animals ,CD40 ,Dromaiidae ,biology ,medicine.diagnostic_test ,Chemistry ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Antibody ,CD5 ,CD8 - Abstract
Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5+ B cells in secondary lymphoid organs. In vitro data suggest that CD4+ T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified Eμ-TCL1 mice lacking CD4+ T cells (TCL1+/+AB0), CD40 (TCL1+/+CD40−/−), or CD8+ T cells (TCL1+/+TAP−/−), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4+ T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4+ T cells, thus confirming that CD4+ T cells are essential for CLL development. By contrast, CD8+ T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1+/+TAP−/− mice. Antigen specificity of CD4+ T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L−/− mice, and TCL1+/+CD40−/− mice developed frank CLL. Our data demonstrate that CD8+ T cells restrain CLL progression, whereas CD4+ T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms.
- Published
- 2021
15. Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies
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Paolo Ghia, Federica Morisi, Fulvia Cerruti, Paolo Cascio, Alessandro Campanella, Jessica Bordini, Clara Camaschella, Bordini, J., Morisi, F., Cerruti, F., Cascio, P., Camaschella, C., Ghia, P., and Campanella, A.
- Subjects
0301 basic medicine ,Cancer Research ,Iron ,Pharmacology ,lcsh:RC254-282 ,Article ,Lipid peroxidation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,iron ,Ferroptosis ,Multiple myeloma ,Proteasome ,Lipid oxidation ,medicine ,Chemistry ,Bortezomib ,Cell growth ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ferroptosis ,multiple myeloma ,030104 developmental biology ,proteasome ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Proteasome inhibitor ,Ferric ,medicine.drug - Abstract
Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies.
- Published
- 2020
16. Induction of iron excess restricts malignant plasma cells expansion and potentiates bortezomib effect in models of multiple myeloma
- Author
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P L Bergsagel, S. Galvan, Alessandro Campanella, Maria Teresa Sabrina Bertilaccio, Clara Camaschella, Marta Chesi, Maurilio Ponzoni, Jessica Bordini, Bordini, J., Galvan, S, Ponzoni, Maurilio, Bertilaccio, M. T. S., Chesi, M., Bergsagel, P. L., Camaschella, Clara, and Campanella, A.
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Iron ,Plasma Cells ,Bortezomib ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Internal medicine ,Animals ,Humans ,Medicine ,Multiple myeloma ,Cell Proliferation ,Hematology ,Cell Death ,business.industry ,medicine.disease ,Lymphoma ,Haematopoiesis ,Leukemia ,Anesthesiology and Pain Medicine ,030104 developmental biology ,Oncology ,Apoptosis ,030220 oncology & carcinogenesis ,Immunology ,Disease Progression ,Cancer research ,Stem cell ,Multiple Myeloma ,business ,medicine.drug - Abstract
Induction of iron excess restricts malignant plasma cells expansion and potentiates bortezomib effect in models of multiple myeloma
- Published
- 2016
17. Bone marrow Tfr2 deletion improves the therapeutic efficacy of the activin-receptor ligand trap RAP-536 in β-thalassemic mice.
- Author
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Tanzi E, Di Modica SM, Bordini J, Olivari V, Pagani A, Furiosi V, Silvestri L, Campanella A, and Nai A
- Subjects
- Animals, Mice, Erythropoiesis drug effects, Immunoglobulin Fc Fragments pharmacology, Immunoglobulin Fc Fragments therapeutic use, Mice, Knockout, Bone Marrow drug effects, Bone Marrow metabolism, Erythropoietin therapeutic use, Erythropoietin pharmacology, Gene Deletion, Activin Receptors, Type II, beta-Thalassemia drug therapy, beta-Thalassemia genetics, Receptors, Transferrin genetics, Recombinant Fusion Proteins therapeutic use, Recombinant Fusion Proteins pharmacology
- Abstract
β-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for β-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor β pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbb
th3/+ thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbbth3/+ mice with or without hematopoietic Tfr2 (Tfr2BMKO /Hbbth3/+ ) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbbth3/+ and Tfr2BMKO /Hbbth3/+ animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)- Published
- 2024
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18. IκBε deficiency accelerates disease development in chronic lymphocytic leukemia.
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Bordini J, Lenzi C, Frenquelli M, Morabito A, Pseftogas A, Belloni D, Mansouri L, Tsiolas G, Perotta E, Ranghetti P, Gandini F, Genova F, Hägerstrand D, Gavriilidis G, Keisaris S, Pechlivanis N, Davi F, Kay NE, Langerak AW, Pospisilova S, Scarfò L, Makris A, Psomopoulos FE, Stamatopoulos K, Rosenquist R, Campanella A, and Ghia P
- Subjects
- Animals, Humans, Mice, Adenine analogs & derivatives, Adenine pharmacology, Cell Movement, Cell Proliferation, Piperidines pharmacology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, NF-kappa B metabolism, I-kappa B Proteins genetics, I-kappa B Proteins metabolism
- Abstract
The NFKBIE gene, which encodes the NF-κB inhibitor IκBε, is mutated in 3-7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-κB activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIE gene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIE expression and investigated its role in controlling NF-κB activity and disease expansion. We found that IκBε loss leads to NF-κB pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIE inactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. IκBε deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-κB pathway in CLL and paves the way to translate these findings into novel therapeutic options., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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19. TENT5C/FAM46C modulation in vivo reveals a trade-off between antibody secretion and tumor growth in multiple myeloma.
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Resnati M, Pennacchio S, Viviani L, Perini T, Materozzi M, Orfanelli U, Bordini J, Molteni R, Nuvolone M, Da Vià M, Lazzaroni F, Bolli N, Cenci S, and Milan E
- Subjects
- Humans, Animals, Mice, Multiple Myeloma pathology, Multiple Myeloma immunology, Multiple Myeloma metabolism
- Published
- 2024
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20. Disrupting pro-survival and inflammatory pathways with dimethyl fumarate sensitizes chronic lymphocytic leukemia to cell death.
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Mantione ME, Meloni M, Sana I, Bordini J, Del Nero M, Riba M, Ranghetti P, Perotta E, Ghia P, Scarfò L, and Muzio M
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- Mice, Animals, Humans, Dimethyl Fumarate pharmacology, Dimethyl Fumarate therapeutic use, NF-kappa B metabolism, Leukocytes, Mononuclear metabolism, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Apoptosis, Mice, Transgenic, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Microenvironmental signals strongly influence chronic lymphocytic leukemia (CLL) cells through the activation of distinct membrane receptors, such as B-cell receptors, and inflammatory receptors, such as Toll-like receptors (TLRs). Inflammatory pathways downstream of these receptors lead to NF-κB activation, thus protecting leukemic cells from apoptosis. Dimethyl fumarate (DMF) is an anti-inflammatory and immunoregulatory drug used to treat patients with multiple sclerosis and psoriasis in which it blocks aberrant NF-κB pathways and impacts the NRF2 antioxidant circuit. Our in vitro analysis demonstrated that increasing concentrations of DMF reduce ATP levels and lead to the apoptosis of CLL cells, including cell lines, splenocytes from Eµ-TCL1-transgenic mice, and primary leukemic cells isolated from the peripheral blood of patients. DMF showed a synergistic effect in association with BTK inhibitors in CLL cells. DMF reduced glutathione levels and activated the NRF2 pathway; gene expression analysis suggested that DMF downregulated pathways related to NFKB and inflammation. In primary leukemic cells, DMF disrupted the TLR signaling pathways induced by CpG by reducing the mRNA expression of NFKBIZ, IL6, IL10 and TNFα. Our data suggest that DMF targets a vulnerability of CLL cells linked to their inflammatory pathways, without impacting healthy donor peripheral blood mononuclear cells., (© 2024. The Author(s).)
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- 2024
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21. PYK2 is overexpressed in chronic lymphocytic leukaemia: A potential new therapeutic target.
- Author
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Sbrana FV, Fiordi B, Bordini J, Belloni D, Barbaglio F, Russo L, Scarfò L, Ghia P, and Scielzo C
- Subjects
- Animals, Mice, Focal Adhesion Kinase 2 genetics, Focal Adhesion Kinase 2 metabolism, B-Lymphocytes metabolism, Tumor Microenvironment, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Chronic Lymphocytic Leukaemia (CLL) is the most common adult B-cell leukaemia and despite improvement in patients' outcome, following the use of targeted therapies, it remains incurable. CLL supportive microenvironment plays a key role in both CLL progression and drug resistance through signals that can be sensed by the main components of the focal adhesion complex, such as FAK and PYK2 kinases. Dysregulations of both kinases have been observed in several metastatic cancers, but their role in haematological malignancies is still poorly defined. We characterized FAK and PYK2 expression and observed that PYK2 expression is higher in leukaemic B cells and its overexpression significantly correlates with their malignant transformation. When targeting both FAK and PYK2 with the specific inhibitor defactinib, we observed a dose-response effect on CLL cells viability and survival. In vivo treatment of a CLL mouse model showed a decrease of the leukaemic clone in all the lymphoid organs along with a significant reduction of macrophages and of the spleen weight and size. Our results first define a possible prognostic value for PYK2 in CLL, and show that both FAK and PYK2 might become putative targets for both CLL and its microenvironment (e.g. macrophages), thus paving the way to an innovative therapeutic strategy., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Published
- 2023
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22. Subcapsular Sinus Macrophages Promote Melanoma Metastasis to the Sentinel Lymph Nodes via an IL1α-STAT3 Axis.
- Author
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Virgilio T, Bordini J, Cascione L, Sartori G, Latino I, Molina Romero D, Leoni C, Akhmedov M, Rinaldi A, Arribas AJ, Morone D, Seyed Jafari SM, Bersudsky M, Ottolenghi A, Kwee I, Chiaravalli AM, Sessa F, Hunger RE, Bruno A, Mortara L, Voronov E, Monticelli S, Apte RN, Bertoni F, and Gonzalez SF
- Subjects
- Animals, Mice, Sentinel Lymph Node Biopsy, Lymphatic Metastasis pathology, Macrophages metabolism, Lymph Nodes pathology, Tumor Microenvironment, Sentinel Lymph Node pathology, Melanoma pathology, Lymphatic Vessels metabolism, Lymphatic Vessels pathology, Skin Neoplasms pathology
- Abstract
During melanoma metastasis, tumor cells originating in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN). This process facilitates tumor cell spread across the body. Here, we characterized the innate inflammatory response to melanoma in the metastatic microenvironment of the sLN. We found that macrophages located in the subcapsular sinus (SS) produced protumoral IL1α after recognition of tumoral antigens. Moreover, we confirmed that the elimination of LN macrophages or the administration of an IL1α-specific blocking antibody reduced metastatic spread. To understand the mechanism of action of IL1α in the context of the sLN microenvironment, we applied single-cell RNA sequencing to microdissected metastases obtained from animals treated with the IL1α-specific blocking antibody. Among the different pathways affected, we identified STAT3 as one of the main targets of IL1α signaling in metastatic tumor cells. Moreover, we found that the antitumoral effect of the anti-IL1α was not mediated by lymphocytes because Il1r1 knockout mice did not show significant differences in metastasis growth. Finally, we found a synergistic antimetastatic effect of the combination of IL1α blockade and STAT3 inhibition with stattic, highlighting a new immunotherapy approach to preventing melanoma metastasis., (©2022 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2022
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23. Longitudinal analysis of T cell receptor repertoires reveals shared patterns of antigen-specific response to SARS-CoV-2 infection.
- Author
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Gittelman RM, Lavezzo E, Snyder TM, Zahid HJ, Carty CL, Elyanow R, Dalai S, Kirsch I, Baldo L, Manuto L, Franchin E, Del Vecchio C, Pacenti M, Boldrin C, Cattai M, Saluzzo F, Padoan A, Plebani M, Simeoni F, Bordini J, Lorè NI, Lazarević D, Cirillo DM, Ghia P, Toppo S, Carlson JM, Robins HS, Crisanti A, and Tonon G
- Subjects
- CD4-Positive T-Lymphocytes, Humans, Receptors, Antigen, T-Cell metabolism, SARS-CoV-2, Spike Glycoprotein, Coronavirus, COVID-19
- Abstract
T cells play a prominent role in orchestrating the immune response to viral diseases, but their role in the clinical presentation and subsequent immunity to SARS-CoV-2 infection remains poorly understood. As part of a population-based survey of the municipality of Vo', Italy, conducted after the initial SARS-CoV-2 outbreak, we sampled the T cell receptor (TCR) repertoires of the population 2 months after the initial PCR survey and followed up positive cases 9 and 15 months later. At 2 months, we found that 97.0% (98 of 101) of cases had elevated levels of TCRs associated with SARS-CoV-2. T cell frequency (depth) was increased in individuals with more severe disease. Both depth and diversity (breadth) of the TCR repertoire were positively associated with neutralizing antibody titers, driven mostly by CD4+ T cells directed against spike protein. At the later time points, detection of these TCRs remained high, with 90.7% (78 of 96) and 86.2% (25 of 29) of individuals having detectable signal at 9 and 15 months, respectively. Forty-three individuals were vaccinated by month 15 and showed a significant increase in TCRs directed against spike protein. Taken together, these results demonstrate the central role of T cells in mounting an immune defense against SARS-CoV-2 that persists out to 15 months.
- Published
- 2022
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24. CANCOL, a Computer-Assisted Annotation Tool to Facilitate Colocalization and Tracking of Immune Cells in Intravital Microscopy.
- Author
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Pizzagalli DU, Bordini J, Morone D, Pulfer A, Carrillo-Barberà P, Thelen B, Ceni K, Thelen M, Krause R, and Gonzalez SF
- Subjects
- Animals, Artifacts, Cell Tracking, Computers, Mice, Cell Communication, Intravital Microscopy methods
- Abstract
Two-photon intravital microscopy (2P-IVM) has become a widely used technique to study cell-to-cell interactions in living organisms. Four-dimensional imaging data obtained via 2P-IVM are classically analyzed by performing automated cell tracking, a procedure that computes the trajectories followed by each cell. However, technical artifacts, such as brightness shifts, the presence of autofluorescent objects, and channel crosstalking, affect the specificity of imaging channels for the cells of interest, thus hampering cell detection. Recently, machine learning has been applied to overcome a variety of obstacles in biomedical imaging. However, existing methods are not tailored for the specific problems of intravital imaging of immune cells. Moreover, results are highly dependent on the quality of the annotations provided by the user. In this study, we developed CANCOL, a tool that facilitates the application of machine learning for automated tracking of immune cells in 2P-IVM. CANCOL guides the user during the annotation of specific objects that are problematic for cell tracking when not properly annotated. Then, it computes a virtual colocalization channel that is specific for the cells of interest. We validated the use of CANCOL on challenging 2P-IVM videos from murine organs, obtaining a significant improvement in the accuracy of automated tracking while reducing the time required for manual track curation., (Copyright © 2022 by The American Association of Immunologists, Inc.)
- Published
- 2022
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25. CD4+ T cells sustain aggressive chronic lymphocytic leukemia in Eμ-TCL1 mice through a CD40L-independent mechanism.
- Author
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Grioni M, Brevi A, Cattaneo E, Rovida A, Bordini J, Bertilaccio MTS, Ponzoni M, Casorati G, Dellabona P, Ghia P, Bellone M, and Calcinotto A
- Subjects
- Animals, CD4-Positive T-Lymphocytes, CD40 Ligand genetics, Mice, Mice, Transgenic, Proto-Oncogene Proteins, Dromaiidae, Leukemia, Lymphocytic, Chronic, B-Cell genetics
- Abstract
Chronic lymphocytic leukemia (CLL) is caused by the progressive accumulation of mature CD5+ B cells in secondary lymphoid organs. In vitro data suggest that CD4+ T lymphocytes also sustain survival and proliferation of CLL clones through CD40L/CD40 interactions. In vivo data in animal models are conflicting. To clarify this clinically relevant biological issue, we generated genetically modified Eμ-TCL1 mice lacking CD4+ T cells (TCL1+/+AB0), CD40 (TCL1+/+CD40-/-), or CD8+ T cells (TCL1+/+TAP-/-), and we monitored the appearance and progression of a disease that mimics aggressive human CLL by flow cytometry and immunohistochemical analyses. Findings were confirmed by adoptive transfer of leukemic cells into mice lacking CD4+ T cells or CD40L or mice treated with antibodies depleting CD4 T cells or blocking CD40L/CD40 interactions. CLL clones did not proliferate in mice lacking or depleted of CD4+ T cells, thus confirming that CD4+ T cells are essential for CLL development. By contrast, CD8+ T cells exerted an antitumor activity, as indicated by the accelerated disease progression in TCL1+/+TAP-/- mice. Antigen specificity of CD4+ T cells was marginal for CLL development, because CLL clones efficiently proliferated in transgenic mice whose CD4 T cells had a T-cell receptor with CLL-unrelated specificities. Leukemic clones also proliferated when transferred into wild-type mice treated with monoclonal antibodies blocking CD40 or into CD40L-/- mice, and TCL1+/+CD40-/- mice developed frank CLL. Our data demonstrate that CD8+ T cells restrain CLL progression, whereas CD4+ T cells support the growth of leukemic clones in TCL1 mice through CD40-independent and apparently noncognate mechanisms., (© 2021 by The American Society of Hematology.)
- Published
- 2021
- Full Text
- View/download PDF
26. Iron Induces Cell Death and Strengthens the Efficacy of Antiandrogen Therapy in Prostate Cancer Models.
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Bordini J, Morisi F, Elia AR, Santambrogio P, Pagani A, Cucchiara V, Ghia P, Bellone M, Briganti A, Camaschella C, and Campanella A
- Subjects
- Animals, Cell Proliferation, Humans, Male, Mice, Prostatic Neoplasms pathology, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Androgen Antagonists pharmacology, Anilides pharmacology, Apoptosis, Drug Synergism, Iron pharmacology, Nitriles pharmacology, Prostatic Neoplasms drug therapy, Tosyl Compounds pharmacology
- Abstract
Purpose: In search of novel strategies to improve the outcome of advanced prostate cancer, we considered that prostate cancer cells rearrange iron homeostasis, favoring iron uptake and proliferation. We exploited this adaptation by exposing prostate cancer preclinical models to high-dose iron to induce toxicity and disrupt adaptation to androgen starvation., Experimental Design: We analyzed markers of cell viability and mechanisms underlying iron toxicity in androgen receptor-positive VCaP and LNCaP, castration-resistant DU-145 and PC-3, and murine TRAMP-C2 cells treated with iron and/or the antiandrogen bicalutamide. We validated the results in vivo in VCaP and PC-3 xenografts and in TRAMP-C2 injected mice treated with iron and/or bicalutamide., Results: Iron was toxic for all prostate cancer cells. In particular, VCaP, LNCaP, and TRAMP-C2 were highly iron sensitive. Toxicity was mediated by oxidative stress, which primarily affected lipids, promoting ferroptosis. In highly sensitive cells, iron additionally caused protein damage. High-basal iron content and oxidative status defined high iron sensitivity. Bicalutamide-iron combination exacerbated oxidative damage and cell death, triggering protein oxidation also in poorly iron-sensitive DU-145 and PC-3 cells. In vivo , iron reduced tumor growth in TRAMP-C2 and VCaP mice. In PC-3 xenografts, bicalutamide-iron combination caused protein oxidation and successfully impaired tumor expansion while single compounds were ineffective. Macrophages influenced body iron distribution but did not limit the iron effect on tumor expansion., Conclusions: Our models allow us to dissect the direct iron effect on cancer cells. We demonstrate the proof of principle that iron toxicity inhibits prostate cancer cell proliferation, proposing a novel tool to strengthen antiandrogen treatment efficacy., (©2020 American Association for Cancer Research.)
- Published
- 2020
- Full Text
- View/download PDF
27. Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies.
- Author
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Bordini J, Morisi F, Cerruti F, Cascio P, Camaschella C, Ghia P, and Campanella A
- Abstract
Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies.
- Published
- 2020
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28. Kinetico-mechanistic studies on methemoglobin generation by biologically active thiosemicarbazone iron(III) complexes.
- Author
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Basha MT, Bordini J, Richardson DR, Martinez M, and Bernhardt PV
- Subjects
- Humans, Iron chemistry, Kinetics, Models, Molecular, Oxidation-Reduction, Protein Structure, Secondary, Solutions, Structure-Activity Relationship, Antineoplastic Agents chemistry, Coordination Complexes chemistry, Iron Chelating Agents chemistry, Methemoglobin chemistry, Oxyhemoglobins chemistry, Pyridines chemistry, Thiosemicarbazones chemistry
- Abstract
The oxidation of human oxyhemoglobin (HbO
2 ) to methemoglobin (metHb) is an undesirable side effect identified in some promising thiosemicarbazone anti-cancer drugs. This is attributable to oxidation reactions driven by FeIII complexes of these drugs formed in vivo. In this work the FeIII complexes of selected 2-benzoylpyridine thiosemicarbazones (HBpT), 2-acetylpyridine thiosemicarbazones (HApT), and the clinically trialled thiosemicarbazone, Triapine® (3-amino-2-pyridinecarboxaldehyde thiosemicarbazone, H3-AP), have been studied. This was achieved by time-resolved UV-Visible absorption spectroscopy and the sequential oxidation of the α- and β-chains of HbO2 at distinctly different rates has been identified. A key structural element, namely a terminal -NH2 group on the thiosemicarbazone moiety, was found to be an important common feature of the most active HbO2 oxidising complexes that were investigated. Therefore, these studies indicate that an unsubstituted -NH2 moiety at the terminus of the thiosemicarbazone group should be avoided in the design of future compounds from this class., (Copyright © 2015 Elsevier Inc. All rights reserved.)- Published
- 2016
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29. Fresh-frozen bone allografts in maxillary ridge augmentation: histologic analysis.
- Author
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Contar CM, Sarot JR, da Costa MB, Bordini J, de Lima AA, Alanis LR, Trevilatto PC, and Machado MÂ
- Subjects
- Adult, Bone Density, Bone Regeneration, Collagen chemistry, Female, Freezing, Humans, Male, Middle Aged, Transplantation, Heterologous, Alveolar Ridge Augmentation methods, Bone Transplantation methods, Maxilla surgery
- Abstract
Bone allograft has become an alternative to autogenous bone due to its decreased operative trauma and the almost unlimited supply of reconstructive material. The aim of the present study was to histologically evaluate the suitability of fresh-frozen bone graft (test group) used in maxillary ridge augmentation, comparing it to autogenous bone (native maxilla: control group). During the re-entry procedures, 9 months after the fresh-frozen allogeneic bone blocks were placed in the atrophic maxillary ridges, bone cores were removed with a trephine bur from test and control treatments in the same patient. Routine histologic processing using hematoxylin and eosin and Picrosirius staining was performed. Mature and immature collagen area and density analysis were carried out for both groups under polarization. The results of Student's t test for paired samples (P > .05) showed no statistically significant difference in mature and immature collagen area or density percentage between test and control groups. Histologically similar bone formation patterns were observed in both groups. We concluded that fresh-frozen bone allograft is a biologically acceptable alternative for augmentation of the deficient alveolar ridge, showing a similar collagen pattern to that of autogenous bone.
- Published
- 2011
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30. Maxillary ridge augmentation with fresh-frozen bone allografts.
- Author
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Contar CM, Sarot JR, Bordini J Jr, Galvão GH, Nicolau GV, and Machado MA
- Subjects
- Adult, Atrophy, Bone Regeneration physiology, Bone Resorption surgery, Bone Screws, Bone Transplantation methods, Dental Implants, Female, Follow-Up Studies, Humans, Male, Maxillary Diseases surgery, Middle Aged, Osseointegration physiology, Plastic Surgery Procedures methods, Surgical Flaps, Transplantation, Homologous, Alveolar Ridge Augmentation methods, Bone Transplantation pathology, Cryopreservation methods, Maxilla surgery
- Abstract
Purpose: The present investigation clinically and histologically evaluated the use of fresh-frozen bone in the reconstruction of maxillary alveolar ridges to confirm the effective bone fill and support for the placement of dental implants., Patients and Methods: Fifteen patients who had atrophic maxillary ridge necessitating bone block grafts prior to implant placement were submitted to maxillary reconstructions performed with human block grafts of tibia fresh-frozen chips. Nine months later the re-entry procedures were carried out and at this time a bone core was removed from the grafts for histological analysis., Results: Thirty-four blocks were placed, and the number of blocks each patient received ranged from 1 to 4. During the re-entry procedures, all of the grafts were found to be firm in consistency, well-incorporated, and vascularized. A total of 51 implants were placed over the grafts with a minimum of 40-Newton torque in all cases. None of the implants were lost. The follow-up period ranged from 24 to 35 months. The histological analysis revealed a living bone that showed features characteristic of mature and compact osseous tissue surrounded by marrow spaces., Conclusion: Bone allografts can be successful as graft material for the treatment of maxillary ridge defects. If adequate surgical techniques are adopted, this type of bone graft can be safely used in regions of implant placement as a suitable alternative to autogenous grafts.
- Published
- 2009
- Full Text
- View/download PDF
31. Multiple compound odontomas in the jaw: case report and analysis of the literature.
- Author
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Bordini J Jr, Contar CM, Sarot JR, Fernandes A, and Machado MA
- Subjects
- Adolescent, Humans, Jaw Neoplasms surgery, Male, Maxillary Sinus Neoplasms surgery, Neoplasms, Multiple Primary surgery, Odontoma surgery, Jaw Neoplasms pathology, Maxillary Sinus Neoplasms pathology, Neoplasms, Multiple Primary pathology, Odontoma pathology
- Published
- 2008
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32. Photochemical release of nitric oxide from a regenerable, sol-gel encapsulated Ru-salen-nitrosyl complex.
- Author
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Bordini J, Ford PC, and Tfouni E
- Subjects
- Light, Molecular Structure, Organometallic Compounds radiation effects, Phase Transition, Photochemistry, Spectroscopy, Fourier Transform Infrared, Nitric Oxide chemistry, Organometallic Compounds chemistry, Silicon Dioxide chemistry
- Abstract
Light activation leads to release of NO from a silicate sol-gel material SG-RuNO prepared from the ruthenium complex, [Ru(salen)(OH2)(NO)]+ (salen = N,N'-bis-(salicylidene)ethyl-enediaminato); after photochemical NO photolabilization, SG-RuNO can be regenerated from the spent material via the subsequent reaction with aqueous nitrite.
- Published
- 2005
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33. Nitric oxide photorelease from ruthenium salen complexes in aqueous and organic solutions.
- Author
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Bordini J, Hughes DL, Da Motta Neto JD, and da Cunha CJ
- Subjects
- Crystallography, X-Ray, Electrochemistry, Electron Spin Resonance Spectroscopy, Kinetics, Models, Molecular, Photochemistry, Quantum Theory, Solutions, Spectrophotometry, Infrared, Spectrophotometry, Ultraviolet, Spectroscopy, Fourier Transform Infrared, Ethylenediamines chemistry, Nitric Oxide chemistry, Ruthenium Compounds chemistry
- Abstract
The complexes [Ru(salen)(NO)Cl] and [Ru(salen)(NO)(H(2)O)](+) were shown to release the nitrosyl ligand as nitric oxide upon exposure to visible light in organic and aqueous solutions respectively, by means of UV-visible, EPR, and FTIR spectroscopies. The former was prepared by a new synthetic route and had its structure determined by single-crystal X-ray diffraction. A crystal of the dichloromethane solvate is orthorhombic, space group Fdd2 (No. 43) and formula C(16)H(14)ClN(3)O(3)Ru.CH(2)Cl(2), with Z = 16 and cell parameters a = 25.489(4), b = 33.435(4), and c = 9.3716(9) A. The electronic absorption spectra of the complexes were calculated using the INDO/S method. The water-soluble complex is a potential drug for antitumoral phototreatment.
- Published
- 2002
- Full Text
- View/download PDF
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