Instituto Superiore Sanita

Rome, Italy

Instituto Superiore Sanita

Rome, Italy
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The Ministry of Health of the Italian government requires for Italian Comprehensive Cancer Centers, called Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), to be certified according to international models. In this perspective, considering of particular interest the recent model for accreditation of cancer centers developed by the Organisation of European Cancer Institutes (OECI), the network of Italian IRCCS participating in Alleanza Contro il Cancro activated a project, supported in 2010 by the Ministry of Health, with the primary objective to verify the applicability of the OECI model to the Italian network of IRCCS. All 11 cancer IRCCS took part in the project. We describe in detail the activities performed, the results reached, and the impact of the initiative on the National Health Service. The initiative was concluded in November 2015 with the certification of all the Italian cancer IRCCS. Italy is the only European country that has applied the modern and tailored accreditation model of OECI to all their cancer centers. © 2015 INTM.

Garofalo C.,Rizzoli Orthopaedic Institute | Mancarella C.,Rizzoli Orthopaedic Institute | Grilli A.,Rizzoli Orthopaedic Institute | Manara M.C.,Rizzoli Orthopaedic Institute | And 8 more authors.
Molecular Endocrinology | Year: 2012

IGF system contributes significantly to many human malignancies. Targeting IGF-I receptor (IGF-IR) has been reported to be active against several tumors, but particular efficacy was observed only against a minority of Ewing's sarcoma patients. Identification of mechanisms of acquired resistance to anti- IGF-IR agents is mandatory to individualize their use in clinics and optimize cure costs. In this study, we compared gene expression profiles of cells made resistant with three different anti-IGF-IR drugs (human antibodies AVE1642, Figitumumab, or tyrosine kinase inhibitor NVP-AEW541) to highlight common and distinctive mechanisms of resistance. Among common mechanisms, we identified two molecular signatures that distinguish sensitive from resistant cells. Annotation analysis indicated some common altered pathways, such as insulin signaling, MAPK pathway, endocytosis, and modulation of some members of the interferon-induced transmembrane protein family. Among distinctive pathways/ processes, resistance to human antibodies involves mainly genes regulating neural differentiation and angiogenesis, whereas resistance to NVP-AEW541 is mainly associated with alterations in genes concerning inflammation and antigen presentation. Evaluation of the common altered pathways indicated that resistant cells seem to maintain intact the IGF-IR internalization/degradation route of sensitive cells but constantly down-regulated its expression. In resistant cells, the loss of proliferative stimulus, normally sustained by IGF-I/IGF-IR autocrine loop in Ewing's sarcoma cells, is compensated by transcriptional up-regulation of IGF-II and insulin receptor-A; this signaling seems to favor the MAPK pathway over the v-akt murine thymoma viral oncogene homolog 1 pathway. Overall, complexity of IGF system requires analytical evaluation of its components to select those patients that may really benefit from this targeted therapy and support the idea of cotargeting IGF-IR and insulin receptor-A to increase the efficacy. © 2012 by The Endocrine Society.

Nakatani F.,Rizzoli Orthopaedic Institute | Ferracin M.,University of Ferrara | Manara M.C.,Rizzoli Orthopaedic Institute | Ventura S.,Rizzoli Orthopaedic Institute | And 11 more authors.
Journal of Pathology | Year: 2012

Identification of factors to detect chemotherapy-resistant tumours at diagnosis is a first priority for risk-adapted therapy in the oncology of children and young adults, where more individualized, effective, and less toxic treatments are highly desirable. In this study, we analysed the miRNAs discriminating Ewing's sarcoma (EWS) patients with different clinical outcomes in order to identify new indicators of prognosis. miRNA expression was investigated in 49 primary EWSs by using the Agilent human miRNA microarray v.2 and/or qRT-PCR. Statistical power of the samples studied for miRNA expression was verified, indicating adequate sample size. Microarray analysis defined a signature of five miRNAs (miR-34a, miR-23a, miR-92a, miR-490-3p, and miR-130b) as an independent predictor of risk for disease progression and survival. Validation analysis in the extended sample set indicated that both miR-34a and miR-490-3p achieved sufficient statistical power to predict prognosis. Results were particularly robust for miR-34a, which appeared associated with either event-free or overall survival and emerged as a significant predictor also after multivariate analysis. Patients with the highest expression of miR-34a did not experience adverse events in 5 years; in contrast, patients with the lowest expression recurred within 2 years. High expression of miR34a can be detected also in paraffin-embedded tissues by in situ hybridization, thus contributing to an easy routine evaluation of this miRNA. Functional analysis of miR-34a in EWS cell lines indicated that when miR-34a expression was enforced, cells were less proliferative, less malignant, and sensitized to doxorubicin and vincristine. Expression of miR-34a could be increased in p53wt cells by treatment with nutlin-3a. Accordingly, nutlin-3a synergizes with doxorubicin. Overall, our data indicate that miR-34a expression is a strong predictor of outcome in EWS. Restoration of miR-34a activity may be useful to decrease malignancy and increase tumour sensitivity to current drugs, so sparing excessive long-term toxicity to EWS patients. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Varricchio L.,Mount Sinai School of Medicine | Masselli E.,Mount Sinai School of Medicine | Alfani E.,Instituto Superiore Sanita | Battistini A.,Instituto Superiore Sanita | And 10 more authors.
Blood | Year: 2011

Glucocorticoid receptor (GR) agonists increase erythropoiesis in vivo and in vitro. To clarify the effect of the dominant negative GRβ isoform (unable to bind STAT-5) on erythropoiesis, erythroblast (EB) expansion cultures of mononuclear cells from 18 healthy (nondiseased) donors (NDs) and 16 patients with polycythemia vera (PV) were studied. GRβ was expressed in all PV EBs but only in EBs from 1 ND. The A3669G polymorphism, which stabilizes GRβ mRNA, had greater frequency in PV (55%; n = 22; P = .0028) and myelofibrosis (35%; n = 20) patients than in NDs (9%; n = 22) or patients with essential thrombocythemia (6%; n = 15). Dexamethasone stimulation of ND cultures increased the number of immature EBs characterized by low GATA1 and β-globin expression, but PV cultures generated great numbers of immature EBs with low levels of GATA1 and β-globin irrespective of dexamethasone stimulation. In ND EBs, STAT-5 was not phosphorylated after dexamethasone and erythropoietin treatment and did not form transcriptionally active complexes with GRα, whereas in PV EBs, STAT-5 was constitutively phosphorylated, but the formation of GR/STAT-5 complexes was prevented by expression of GRβ. These data indicate that GRβ expression and the presence of A3669G likely contribute to development of erythrocytosis in PV and provide a potential target for identification of novel therapeutic agents. © 2011 by The American Society of Hematology.

Migliaccio A.R.,Mount Sinai School of Medicine | Migliaccio A.R.,Instituto Superiore Sanita | Whitsett C.,Kings County Hospital Center | Papayannopoulou T.,University of Washington | Sadelain M.,Sloan Kettering Cancer Center
Cell Stem Cell | Year: 2012

Recent advances have increased excitement about the potential for therapeutic production of red blood cells (RBCs) in vitro. However, generation of RBCs in the large numbers required for transfusion remains a significant challenge. In this article, we summarize recent progress in producing RBCs from various cell sources, and discuss the hurdles that remain for translation into the clinical arena. © 2012 Elsevier Inc.

Bonci D.,Instituto Superiore Sanita
Recent Patents on Cardiovascular Drug Discovery | Year: 2010

MicroRNAs (miRNAs) are a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of miRNAs has been described in various disease states including cancer and cardiac disease. A particular miRNA that was consistently reported to be upregulated in both cancer and various forms of cardiovascular diseases is miR-21. MiR-21 exerts oncogenic activity and therefore is considered as an oncomir. In the cardiovascular system miR-21 is enriched in fibroblasts and contributes to the development of fibrosis and heart failure. MiR-21 therefore emerges as an interesting candidate for the development of therapeutic strategies against many forms of cancer as well as heart diseases. Indeed, treatment with anti-miR-21 oligonucleotides reduced breast cancer growth. Inhibition of miR-21 by synthetic miRNA antagonists (antagomirs) improved heart function in a cardiac disease model. The same beneficial effects were observed in miR-21 knockout mice subjected to pressure-overload of the left ventricle underlining the key role of miR-21 as a therapeutic target. We here overview the current patent situation about the therapeutic use of miR-21 modulation in cancer and cardiovascular disease. © 2010 Bentham Science Publishers Ltd.

Coppola V.,Instituto Superiore Sanita | De Maria R.,Instituto Superiore Sanita | De Maria R.,Mediterranean Institute of Oncology | Bonci D.,Instituto Superiore Sanita
Endocrine-Related Cancer | Year: 2010

Despite much progress in prostate cancer management, new diagnostic, prognostic and therapeutic tools are needed to predict disease severity, choose among the available treatments and establish more effective therapies for advanced prostate cancer. In the last few years, compelling evidence has documented the role of microRNAs as new broad-spectrum oncogenes or tumour suppressor genes, thus their use as diagnostic, prognostic and therapeutic biomolecules is envisaged. This review extensively and critically summarizes the current knowledge about microRNAderegulation in prostate cancer disease, underlining present limits and future perspectives. © 2010 Society for Endocrinology.

Migliaccio A.R.,Mount Sinai School of Medicine | Migliaccio A.R.,Instituto Superiore Sanita | Masselli E.,Mount Sinai School of Medicine | Varricchio L.,Mount Sinai School of Medicine | Whitsett C.,Mount Sinai School of Medicine
Blood Reviews | Year: 2012

Blood transfusion is indispensable for modern medicine. In developed countries, the blood supply is adequate and safe but blood for alloimmunized patients is often unavailable. Concerns are increasing that donations may become inadequate in the future as the population ages prompting a search for alternative transfusion products. Improvements in culture conditions and proof-of-principle studies in animal models have suggested that ex-vivo expanded red cells may represent such a product. Compared to other cell therapies transfusion poses the unique challenge of requiring great cell doses (2.5×10 12 cells vs 10 7 cells). Although production of such cell numbers is theoretically possible, current technologies generate red cells in numbers sufficient only for safety studies. It is conceived that by the time these studies will be completed, technical barriers to mass cell production will have been eliminated making transfusion with ex-vivo generated red cells a reality. © 2011 Elsevier Ltd.

Genco A.,University of Rome La Sapienza | Dellepiane D.,Ceva Hospital | Baglio G.,Instituto Superiore Sanita | Cappelletti F.,Ceva Hospital | And 6 more authors.
Obesity Surgery | Year: 2013

Background: The objective of this study is the comparison of a new intragastric balloon recently introduced, the Adjustable Balloon System (ABS), with the BioEnterics intragastric balloon (BIB) in terms of tolerance, safety, and weight loss parameters. Methods: A case-control study was done: 40 patients were matched with 80 controls. To achieve the same duration therapy (12 months), a single ABS positioning was compared with a BIB followed by another BIB (6 + 6 months). Length of procedure, hospital stay, complications, and weight loss parameters after 6 months (time of first BIB removal) and after 12 months from baseline (time of Spatz and second BIB removal) were considered. Statistical analysis was done by means of Student's t test, χ2 test, or Fisher's test. P < 0.05 was considered significant. Results: Mortality, positioning, and extraction complications were absent. Both the devices were well tolerated with slight duration of post placement symptoms. During this study, the Spatz balloon was adjusted with inflation of 200 cm3 of saline (total, 800 cm 3) in 9/40 (22.5 %) patients, for poor weight loss after first 6-months treatment. In the Spatz group, there occurred 7/40 complications linked to the device and in 6/7 patients the balloon was removed. At the end of the study, the weight loss parameters were similar between groups: BMI 31.0 ± 11.8 (Spatz group) vs 31.3 ± 12.3 (BIB group) (p = Ns). Conclusions: The idea of dynamic balloon therapy needs to be confirmed with wider series. The rate of complication reported is very high, and several studies regarding safety and efficacy are needed. © 2013 Springer Science+Business Media New York.

Coppola V.,Instituto Superiore Sanita
Methods in molecular biology (Clifton, N.J.) | Year: 2010

The manipulation of cell differentiation is important to create new sources for the treatment of degenerative diseases or solve cell depletion after aggressive therapy against cancer. In this chapter, the use of a tissue-specific promoter lentiviral vector to obtain a myocardial pure lineage from murine embryonic stem cells (mES) is described in detail. Since the cardiac isoform of troponin I gene product is not expressed in skeletal or other muscle types, short mouse cardiac troponin proximal promoter is used to drive reporter genes. Cells are infected simultaneously with two lentiviral vectors, the first expressing EGFP to monitor the transduction efficiency, and the other expressing a puromycin resistance gene to select the specific cells of interest. This technical approach describes a method to obtain a pure cardiomyocyte population and can be applied to other lineages of interest.

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