@article {3541, title = {Modulation of circulating cytokine-chemokine profile in patients affected by chronic venous insufficiency undergoing surgical hemodynamic correction.}, journal = {J Immunol Res}, volume = {2014}, year = {2014}, month = {2014}, pages = {473765}, abstract = {

The expression of proinflammatory cytokines/chemokines has been reported in in vitro/ex vivo settings of chronic venous insufficiency (CVI), but the identification of circulating mediators that might be associated with altered hemodynamic forces or might represent innovative biomarkers is still missing. In this study, the circulating levels of 31 cytokines/chemokines involved in inflammatory/angiogenic processes were analysed in (i) CVI patients at baseline before surgical hemody namic correction, (ii) healthy subjects, and (iii) CVI patients after surgery. In a subgroup of CVI patients, in whom the baseline levels of cytokines/chemokines were analyzed in paired blood samples obtained from varicose vein and forearm vein, EGF, PDGF, and RANTES were increased at the varicose vein site as compared to the general circulation. Moreover, while at baseline, CVI patients showed increased levels of 14 cytokines/chemokines as compared to healthy subjects, 6 months after surgery, 11 cytokines/chemokines levels were significantly reduced in the treated CVI patients as compared to the CVI patients before surgery. Of note, a patient who exhibited recurrence of the disease 6 months after surgery, showed higher levels of EGF, PDGF, and RANTES compared to nonrecurrent patients, highlighting the potential role of the EGF/PDGF/RANTES triad as sensitive biomarkers in the context of CVI.

}, keywords = {Adult, Aged, Chemokines, Chronic Disease, Cytokines, Female, Hemodynamics, Humans, Male, Middle Aged, Saphenous Vein, Varicose Veins, Venous Insufficiency}, issn = {2314-7156}, doi = {10.1155/2014/473765}, author = {Tisato, Veronica and Zauli, Giorgio and Gianesini, Sergio and Menegatti, Erica and Brunelli, Laura and Manfredini, Roberto and Zamboni, Paolo and Secchiero, Paola} } @article {1892, title = {MCL1 down-regulation plays a critical role in mediating the higher anti-leukaemic activity of the multi-kinase inhibitor Sorafenib with respect to Dasatinib.}, journal = {Br J Haematol}, volume = {157}, year = {2012}, month = {2012 May}, pages = {510-4}, keywords = {Antineoplastic Agents, Benzenesulfonates, Cell Line, Tumor, Down-Regulation, Humans, Leukemia, Myeloid, Acute, Myeloid Cell Leukemia Sequence 1 Protein, Niacinamide, Phenylurea Compounds, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-bcl-2, Pyridines, Pyrimidines, Thiazoles}, issn = {1365-2141}, doi = {10.1111/j.1365-2141.2012.09042.x}, author = {Secchiero, Paola and Melloni, Elisabetta and Voltan, Rebecca and Norcio, Alessia and Celeghini, Claudio and Zauli, Giorgio} } @article {1866, title = {The MDM2 inhibitor Nutlin-3 modulates dendritic cell-induced T cell proliferation.}, journal = {Hum Immunol}, volume = {73}, year = {2012}, month = {2012 Apr}, pages = {342-5}, abstract = {

Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, has been recently taken into consideration as a promising therapeutic tool for tumor treatment based on its ability to stabilize and activate the p53 transcription factor pathway. Since Nutlin-3 displays non cell-autonomous tumor-suppressor activities, we wanted to investigate its effect on dendritic cell functions, given the central role of these cells in the modulation of the immune response. We found that Nutlin-3 alone slightly affected the levels of major histocompatibility complex and costimulatory molecules and significantly promoted the ability of dendritic cells to stimulate T cells in the mixed lymphocyte reaction. Taken together, our findings suggest that the ability of Nutlin-3 to modulate dendritic cell functions and therefore lymphocyte proliferation might represent an additional important mechanism by which Nutlin-3 exerts its non cell-autonomous tumor-suppression function.

}, keywords = {Dendritic Cells, Humans, Imidazoles, Immunologic Factors, Immunophenotyping, Lymphocyte Activation, Piperazines, Proto-Oncogene Proteins c-mdm2, T-Lymphocytes}, issn = {1879-1166}, doi = {10.1016/j.humimm.2012.01.018}, author = {Gasparini, Chiara and Tommasini, Alberto and Zauli, Giorgio} } @article {1975, title = {Merkel-cell polyomavirus (MCPyV) is rarely associated to B-chronic lymphocytic leukemia (1 out of 50) samples and occurs late in the natural history of the disease.}, journal = {J Clin Virol}, volume = {55}, year = {2012}, month = {2012 Dec}, pages = {367-9}, abstract = {

BACKGROUND: Previous studies have reported conflicting results on the frequency and potential pathogenetic role of Merkel-cell polyomavirus (MCPyV) in B-chronic lymphocytic leukemia (B-CLL).

OBJECTIVES: To evaluate the association of MCPyV to B-CLL and to investigate the occurrence of MCPyV infection in relationship to the natural history of B-CLL.

STUDY DESIGN: Samples of primary B-CLL peripheral blood mononuclear cells were obtained from two distinct University Hospitals of Italy from January 2010. For one B-CLL patient, it was possible to retrospectively examine the blood sample at diagnosis of B-CLL (March 2004) and several pathological tissues of cutaneous tumors occurring during the course of the disease.

RESULTS: Only one out of 50 B-CLL blood samples examined was positive for MCPyV DNA. Retrospective analysis revealed that MCPyV DNA was absent in peripheral blood sample at diagnosis, becoming present only in advanced disease stages also in tonsil tissue as well as in a biopsy of differentiated squamous cell carcinoma.

CONCLUSIONS: The association with MCPyV seems to represent a rare and late event during the natural history of B-CLL.

}, keywords = {Aged, Aged, 80 and over, Blood, Female, Humans, Italy, Leukemia, Lymphocytic, Chronic, B-Cell, Male, Merkel cell polyomavirus, Middle Aged, Palatine Tonsil, Polyomavirus Infections, Prevalence, Skin, Tumor Virus Infections}, issn = {1873-5967}, doi = {10.1016/j.jcv.2012.08.011}, author = {Comar, Manola and Cuneo, Antonio and Maestri, Iva and Melloni, Elisabetta and Pozzato, Gabriele and Soffritti, Olga and Secchiero, Paola and Zauli, Giorgio} } @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 {1729, title = {miR-34a induces the downregulation of both E2F1 and B-Myb oncogenes in leukemic cells.}, journal = {Clin Cancer Res}, volume = {17}, year = {2011}, month = {2011 May 1}, pages = {2712-24}, abstract = {

PURPOSE: To elucidate new molecular mechanisms able to downregulate the mRNA levels of key oncogenes, such as B-Myb and E2F1, in a therapeutic perspective.

EXPERIMENTAL DESIGN: B-Myb and E2F1 mRNA levels were evaluated in primary B chronic lymphocytic leukemia (B-CLL, n = 10) and acute myeloid leukemia (AML, n = 5) patient cells, in a variety of p53(wild-type) and p53(mutated/deleted) leukemic cell lines, as well as in primary endothelial cells and fibroblasts. Knockdown experiments with siRNA for p53 and E2F1 and overexpression experiments with miR34a were conducted to elucidate the role of these pathways in promoting B-Myb downregulation.

RESULTS: In vitro exposure to Nutlin-3, a nongenotoxic activator of p53, variably downregulated the expression of B-Myb in primary leukemic cells and in p53(wild-type) myeloid (OCI, MOLM) and lymphoblastoid (SKW6.4, EHEB) but not in p53(mutated) (NB4, BJAB, MAVER) or p53(deleted) (HL-60) leukemic cell lines. The transcriptional repression of B-Myb was also observed in primary normal endothelial cells and fibroblasts. B-Myb downregulation played a critical role in the cell-cycle block in G(1) phase induced by Nutlin-3, as shown by transfection experiments with specific siRNA. Moreover, we have provided experimental evidence suggesting that miR-34a is a central mediator in the repression of B-Myb both directly and through E2F1.

CONCLUSIONS: Owing to the role of B-Myb and E2F1 transcription factors in controlling cell-cycle progression of leukemic cells, the downregulation of these oncogenes by miR-34a suggests the usefulness of therapeutic approaches aimed to modulate the levels of miR-34a.

}, keywords = {Base Sequence, Cell Cycle Proteins, Cell Line, Tumor, Cells, Cultured, Down-Regulation, E2F1 Transcription Factor, Gene Expression Regulation, Leukemic, HCT116 Cells, HL-60 Cells, Humans, Imidazoles, Leukemia, MicroRNAs, Models, Biological, Oncogenes, Piperazines, Sequence Homology, Nucleic Acid, Trans-Activators, Transfection}, issn = {1078-0432}, doi = {10.1158/1078-0432.CCR-10-3244}, author = {Zauli, Giorgio and Voltan, Rebecca and di Iasio, Maria Grazia and Bosco, Raffaella and Melloni, Elisabetta and Sana, Maria Elena and Secchiero, Paola} } @article {1758, title = {Molecular targets for selective killing of TRAIL-resistant leukemic cells.}, journal = {Expert Opin Ther Targets}, volume = {15}, year = {2011}, month = {2011 Aug}, pages = {931-42}, abstract = {

INTRODUCTION: TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family of cytokines, and shows promising therapeutic activity against solid tumors and lymphomas, in a variety of Phase I and II clinical trials. In contrast, primary leukemias have shown poor susceptibility to TRAIL-mediated cytotoxicity, suggesting the need for sensitizing TRAIL-resistant leukemic cells, by combining soluble recombinant TRAIL either with chemotherapeutic drugs, or with targeted small molecules.

AREAS COVERED: This review discusses potential therapeutic applications of combinations able to restore the sensitivity of leukemic cells to either recombinant TRAIL or anti-TRAIL-receptor agonistic antibodies for the treatment of hematological malignancies.

EXPERT OPINION: Up-to-date knowledge of the most innovative anti-leukemic therapies including functional screening of specific-sensitizers, enhancing TRAIL-mediated cytotoxicity. Strategies aimed to enhance TRAIL-mediated apoptosis, include the combination of novel sensitizers, functionally identified from libraries of pharmaceutically active, synthetic or naturally derived compounds. Other approaches aim to employ the administration of stem cells engineered to express TRAIL, in the leukemic stem cell niche, and promise to be a successful treatment with reduced specific toxicity.

}, keywords = {Humans, Leukemia, TNF-Related Apoptosis-Inducing Ligand}, issn = {1744-7631}, doi = {10.1517/14728222.2011.580278}, author = {Zauli, Giorgio and Bosco, Raffaella and Secchiero, Paola} }