@article {1625, title = {Anti-leukemic activity of dasatinib in both p53(wild-type) and p53(mutated) B malignant cells.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Feb}, pages = {417-22}, abstract = {

The multi-kinase inhibitor dasatinib induced a variable but significant decrease of viability in both p53(wild-type) (EHEB, JVM-2, JVM-3) and p53(mutated) (MEC-1, MEC-2, BJAB) prolymphocytic B leukemic cells, due to a combination of cell cycle block in G1 and apoptosis. Antibody phospho-kinase array analysis revealed that dasatinib inhibited the phosphorylation of various kinases, including ERK1/2 and p38/MAPK as well as of STAT3 transcription factors, in both p53(wild-type) and p53(mutated) cells. Therefore, dasatinib might offer a novel therapeutic strategy not only for p53(wild-type), but also for p53(mutated) B malignancies that have the worst prognosis and urgently need innovative therapeutic approaches.

}, keywords = {Antineoplastic Agents, Apoptosis, B-Lymphocytes, Cell Line, Tumor, Cell Survival, G1 Phase Cell Cycle Checkpoints, Granulocyte Precursor Cells, Humans, Leukemia, Prolymphocytic, B-Cell, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mutation, p38 Mitogen-Activated Protein Kinases, Phosphorylation, Protein Kinase Inhibitors, Pyrimidines, STAT3 Transcription Factor, Thiazoles, Time Factors, Tumor Suppressor Protein p53}, issn = {1573-0646}, doi = {10.1007/s10637-010-9564-6}, author = {Bosco, Raffaella and Rabusin, Marco and Voltan, Rebecca and Celeghini, Claudio and Corallini, Federica and Capitani, Silvano and Secchiero, Paola} } @article {1717, title = {In vivo anti-lymphoma activity of an agonistic human recombinant anti-TRAIL-R2 minibody.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Feb}, pages = {405-7}, abstract = {

A new single-chain fragment variable (scFv) to TRAIL-R2 receptor produced as minibody (MB2.23) was characterized for anti-lymphoma activity in vivo. For this purpose, a disseminated lymphoma model was generated by intraperitoneal inoculation of BJAB cells in severe combined immunodeficiency mice. Two weekly injections with MB2.23 (10~mg/kg) were able to significantly increase the median survival time of lymphoma-bearing animals with respect to the vehicle-treated control mice, providing a rationale for further investigating the use of MB2.23 in anticancer therapy.

}, keywords = {Animals, Humans, Immunotherapy, Injections, Intraperitoneal, Lymphoma, B-Cell, Mice, Mice, SCID, Receptors, TNF-Related Apoptosis-Inducing Ligand, Single-Chain Antibodies, Time Factors, Xenograft Model Antitumor Assays}, issn = {1573-0646}, doi = {10.1007/s10637-010-9519-y}, author = {Zauli, Giorgio and Corallini, Federica and Zorzet, Sonia and Grill, Vittorio and Marzari, Roberto and Secchiero, Paola} } @article {1699, title = {Mesenchymal stem cells display hepato-protective activity in lymphoma bearing xenografts.}, journal = {Invest New Drugs}, volume = {30}, year = {2012}, month = {2012 Apr}, pages = {803-7}, abstract = {

A disseminated model of non-Hodgkin{\textquoteright}s lymphoma with prevalent liver metastasis was generated by intraperitoneal (i.p.) injection of EBV(+) B lymphoblastoid SKW6.4 in nude-SCID mice. The survival of SKW6.4 xenografts (median survival = 27 days) was significantly improved when hyaluronan scaffolds embedded with mesenchimal stem cells (MSC) were implanted in the abdominal area 4 days after SKW6.4 injection (median survival = 39.5 days). Mice implanted with MSC showed a significant improvement of hepatic functionality in lymphoma xenografts, as demonstrated by measurement of serum ALT/AST levels. Co-culture of MSC with lymphoma cells enhanced the release of hepatocyte growth factor (HGF) by MSC. These data suggest that hyaluronan-embedded MSC exert anti-lymphoma activity by ameliorating hepatic functionality.

}, keywords = {Alanine Transaminase, Animals, Aspartate Aminotransferases, Biological Markers, Cell Communication, Cell Line, Tumor, Cell Survival, Coculture Techniques, Hepatocyte Growth Factor, Humans, Hyaluronic Acid, Liver, Liver Neoplasms, Lymphoma, Non-Hodgkin, Mesenchymal Stem Cell Transplantation, Mesenchymal Stromal Cells, Mice, Mice, Nude, Mice, SCID, Time Factors, Tissue Scaffolds, Xenograft Model Antitumor Assays}, issn = {1573-0646}, doi = {10.1007/s10637-010-9534-z}, author = {Secchiero, Paola and Corallini, Federica and Zavan, Barbara and Tripodo, Claudio and Vindigni, Vincenzo and Zauli, Giorgio} } @article {1612, title = {Association of tumor necrosis factor-related apoptosis-inducing ligand with total and cardiovascular mortality in older adults.}, journal = {Atherosclerosis}, volume = {215}, year = {2011}, month = {2011 Apr}, pages = {452-8}, abstract = {

OBJECTIVE: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) exhibits biological activity on vascular cells in vitro. Rapid variation of circulating TRAIL levels occurs during acute coronary ischemia, suggesting that biological pathways involving TRAIL may be activated during ischemic heart disease. However, whether differential levels of soluble TRAIL in normal individuals are associated with adverse health outcomes has not been investigated. We tested the hypothesis that TRAIL levels predict mortality in a population based sample of community dwelling men and women.

METHODS: Plasma TRAIL level was measured by ELISA at baseline in 1282 adults (mean age 68 years) enrolled in the InCHIANTI study. Vital status was ascertained over the six-year follow-up.

RESULTS: In multivariable Cox regression analysis adjusted for potential confounders including prevalent cardiovascular diseases (CVD), ankle-brachial index, electrocardiogram abnormalities, and inflammatory markers, baseline TRAIL levels were inversely related to all-cause mortality (p=0.008). In stratified analyses, the prognostic effect of TRAIL level was strong and highly significant in participants with prevalent CVD (N=321), (lowest versus highest quartile: HR 3.1; 95\% CI 1.5-6.5) while it was negligible in those free of CVD (p value for the interaction term between CVD status and TRAIL levels=0.038). Similar findings were obtained when CVD mortality was considered as the outcome of interest.

CONCLUSIONS: In older patients with CVD, low levels of TRAIL were associated with increased risk of death over a period of 6 years. Lower concentration of circulating TRAIL may be related to the clinical evolution of older adults with CVD.

}, keywords = {Adult, Aged, Ankle Brachial Index, Cardiovascular Diseases, Female, Follow-Up Studies, Humans, Italy, Male, Middle Aged, TNF-Related Apoptosis-Inducing Ligand}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2010.11.004}, author = {Volpato, Stefano and Ferrucci, Luigi and Secchiero, Paola and Corallini, Federica and Zuliani, Giovanni and Fellin, Renato and Guralnik, Jack M and Bandinelli, Stefania and Zauli, Giorgio} } @article {1710, title = {Osteoprotegerin induces morphological and functional alterations in mouse pancreatic islets.}, journal = {Mol Cell Endocrinol}, volume = {331}, year = {2011}, month = {2011 Jan 1}, pages = {136-42}, abstract = {

Although serum osteoprotegerin (OPG) is significantly increased in diabetic subjects, its potential role in beta cell dysfunction has not been investigated. This study aimed to assess the effect of full-length OPG administered in vivo in mice on pancreatic islet structure and function and its interaction with the renin-angiotensin system (RAS). OPG-treated mice showed increased islet monocyte/macrophage infiltration, fibrosis and apoptosis with reduction of islet function. The remodeling of islet architecture was associated with increased pancreatic expression of components of the RAS, growth factor genes (transforming growth factor β and connective tissue growth factor) and inflammatory molecules (monocyte chemotactic protein-1 and vascular adhesion molecule type 1). Prevention of these changes with improvement of insulin secretion was observed in ramipril treated animals. Our data suggest that OPG might play an important role in promoting beta cell dysfunction and that the upregulation of the local RAS represents one possible mechanism responsible for the OPG-induced beta cell dysfunction.

}, keywords = {Animals, Apoptosis, Blood Glucose, Blood Pressure, Body Weight, Cell Lineage, Cell Movement, Chemokine CCL2, Connective Tissue Growth Factor, Fibrosis, Gene Expression Regulation, Humans, Insulin, Islets of Langerhans, Macrophages, Mice, Monocytes, Organ Size, Osteoprotegerin, Peptidyl-Dipeptidase A, Receptor, Angiotensin, Type 1, Systole, Transforming Growth Factor beta, Vascular Cell Adhesion Molecule-1}, issn = {1872-8057}, doi = {10.1016/j.mce.2010.08.019}, author = {Toffoli, Barbara and Bernardi, Stella and Candido, Riccardo and Sabato, Nicoletta and Carretta, Renzo and Corallini, Federica and Secchiero, Paola and Zauli, Giorgio and Fabris, Bruno} } @article {1817, title = {Trail down-regulates the release of osteoprotegerin (OPG) by primary stromal cells.}, journal = {J Cell Physiol}, volume = {226}, year = {2011}, month = {2011 Sep}, pages = {2279-86}, abstract = {

The soluble member of the TNF-R superfamily osteoprotegerin (OPG) is abundantly released under basal conditions by both mesenchymal stem cells (MSC) and fibroblasts and by endothelial cells upon stimulation with inflammatory cytokines. Since MSC, fibroblasts and endothelial cells represent key elements of the normal and tumor microenvironment and express detectable levels of surface TRAIL receptors, we investigated the effect of TRAIL on OPG release. Unexpectedly, recombinant TRAIL decreased the spontaneous OPG release in all cell types examined. Moreover, TRAIL decreased OPG release also in stromal cells co-cultured with lymphoma cells and counteracted the OPG induction by TN-alpha in HUVEC and MSC. Such down-regulation was not due to a masking effect in the ELISA quantification of the OPG released in the culture supernatants due to binding of OPG to its ligands (TRAIL and RANKL), as demonstrated by competition experiments with recombinant TRAIL and by the lack of RANKL release/induction. In addition, OPG down-regulation was not due to induction of cytotoxic effects by TRAIL, since the degree of apoptosis in response to TRAIL was negligible in all primary cell types. With regards to the possible molecular mechanism accounting for the down-regulation of OPG release by TRAIL, we found that treatment of MSC with TRAIL significantly decreased the phosphorylation levels of p38/MAPK. There is a suggestion that this pathway is involved in the stabilization of OPG mRNA. In this respect, the ability of TRAIL to decrease the release of OPG, in the absence of cell cytotoxicity, was mimicked by the p38/MAPK inhibitor SB203580.

}, keywords = {Bone Marrow Cells, Cell Death, Cells, Cultured, Coculture Techniques, Down-Regulation, Endothelial Cells, Enzyme Activation, Enzyme-Linked Immunosorbent Assay, Fibroblasts, Humans, MAP Kinase Signaling System, Mesenchymal Stromal Cells, Osteoprotegerin, p38 Mitogen-Activated Protein Kinases, Protein Binding, Recombinant Proteins, Stromal Cells, TNF-Related Apoptosis-Inducing Ligand, Tumor Necrosis Factor-alpha}, issn = {1097-4652}, doi = {10.1002/jcp.22564}, author = {Corallini, Federica and Celeghini, Claudio and Rimondi, Erika and di Iasio, Maria Grazia and Gonelli, Arianna and Secchiero, Paola and Zauli, Giorgio} } @article {1642, title = {Circulating levels of frizzled-related protein (FRZB) are increased in patients with early rheumatoid arthritis and decrease in response to disease-modifying antirheumatic drugs.}, journal = {Ann Rheum Dis}, volume = {69}, year = {2010}, month = {2010 Sep}, pages = {1733-4}, keywords = {Antirheumatic Agents, Arthritis, Rheumatoid, Biological Markers, Glycoproteins, Humans}, issn = {1468-2060}, doi = {10.1136/ard.2009.125732}, author = {Corallini, Federica and Secchiero, Paola and Castellino, Gabriella and Montecucco, Maurizio and Trotta, Francesco and Zauli, Giorgio} }