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Zannoni G.F.,Catholic University of the Sacred Heart | Improta G.,Laboratory of Clinical Research and Advanced Diagnostics | Chiarello G.,Catholic University of the Sacred Heart | Pettinato A.,Ospedale Cannizzaro | And 4 more authors.
Virchows Archiv | Year: 2014

Ovarian clear cell carcinoma (OCCC) is a subtype of epithelial ovarian cancer with characteristic biological features and aggressive clinical behavior. OCCCs show a pattern of gene mutations different from other type I ovarian malignancies, notably a higher frequency of PIK3CA mutations. In low grade serous ovarian cancer, KRAS and BRAF mutations are frequent, but little data are available on the mutational status of these genes in OCCCs. To clarify this issue, we designed a clinicopathological study with the aim to establish the incidence of KRAS, NRAS, and BRAF hot spot mutations in OCCC. Between December 2006 and June 2012, 22 patients with a proven diagnosis of OCCC were admitted to our Institutions. In all cases, final diagnosis was established according to FIGO and WHO criteria. All women received complete surgical staging. The PyroMark Q24 system (Qiagen GmbH, Hilden, Germany) was used for pyrosequencing analysis of KRAS, NRAS, and BRAF hot spot regions on 2.5-μm sections of formalin-fixed paraffin-embedded tissue from primary OCCC. Pyrosequencing analysis of KRAS, NRAS, and BRAF hot spot regions revealed the presence of mutations only at codon 12 in exon 2 of KRAS in 3 of 22 (14 %) cases. We found no mutations in the hot spot regions of NRAF (exons 2, 3, 4) or BRAF (exon 15). The median age of women with a KRAS mutated OCCC was 74 years. These OCCC were unilateral FIGO stage IA lesions in two cases associated with foci of endometriosis. We conclude that in 14 % of OCCCs, a KRAS mutation occurs in codon 2 exon 2. NRAS and BRAF mutations were not found. © 2014 Springer-Verlag.


Tataranni T.,Laboratory of Pre Clinical and Translational Research | Agriesti F.,Laboratory of Pre Clinical and Translational Research | Mazzoccoli C.,Laboratory of Pre Clinical and Translational Research | Ruggieri V.,Laboratory of Pre Clinical and Translational Research | And 8 more authors.
British Journal of Haematology | Year: 2015

The iron chelator deferasirox (DFX) prevents complications related to transfusional iron overload in several haematological disorders characterized by marrow failure. It is also able to induce haematological responses in a percentage of treated patients, particularly in those affected by myelodysplastic syndromes. The underlying mechanisms responsible for this feature, however, are still poorly understood. In this study, we investigated the effect of DFX-treatment in human haematopoietic/progenitor stem cells, focussing on its impact on the redox balance, which proved to control the interplay between stemness maintenance, self-renewal and differentiation priming. Here we show, for the first time, that DFX treatment induces a significant diphenyleneiodonium-sensitive reactive oxygen species (ROS) production that leads to the activation of POU5F1 (OCT4), SOX2 and SOX17 gene expression, relevant in reprogramming processes, and the reduction of the haematopoietic regulatory proteins CTNNB1 (β-Catenin) and BMI1. These DFX-mediated events were accompanied by decreased CD34 expression, increased mitochondrial mass and up-regulation of the erythropoietic marker CD71 (TFRC) and were compound-specific, dissimilar to deferoxamine. Our findings would suggest a novel mechanism by which DFX, probably independently on its iron-chelating property but through ROS signalling activation, may influence key factors involved in self-renewal/differentiation of haematopoietic stem cells. © 2015 John Wiley & Sons Ltd.


Caivano A.,Laboratory of Preclinical and Translational Research | Laurenzana I.,Laboratory of Preclinical and Translational Research | De Luca L.,Laboratory of Preclinical and Translational Research | La Rocca F.,Laboratory of Preclinical and Translational Research | And 12 more authors.
Tumor Biology | Year: 2015

Many cell types release extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, which play a role in physiology and diseases. Presence and phenotype of circulating EVs in hematological malignancies (HMs) remain largely unexplored. The aim of this study was to characterize EVs in peripheral blood of HM patients compared to healthy subjects (controls). We isolated serum EVs from patients with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), Waldenstrom’s macroglobulinemia (WM), Hodgkin’s lymphoma (HL), multiple myeloma (MM), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS), and controls. EVs were isolated from serum of peripheral blood by ultracentrifuge steps and analyzed by flow cytometry to define count, size, and immunophenotype. MV levels were significantly elevated in WM, HL, MM, AML, and some MPNs and, though at a lesser degree, in CLL and NHL as compared to healthy controls. HL, MM, and MPNs generated a population of MVs characterized by lower size (below 0.3 μm) when compared to controls. MVs from patients specifically expressed tumor-related antigens, such as CD19 in B cell neoplasms, CD38 in MM, CD13 in myeloid tumors, and CD30 in HL. Both total and antigen-specific count of MVs significantly correlated with different HM clinical features such as Rai stage in CLL, International Prognostic Scoring System in WM, International Staging System in MM, and clinical stage in HL. MVs may represent a novel biomarker in HMs. © 2015, International Society of Oncology and BioMarkers (ISOBM).


Condelli V.,Laboratory of Pre Clinical and Translational Research | Lettini G.,Laboratory of Pre Clinical and Translational Research | Patitucci G.,Pathology Unit | D'auria F.,Laboratory of Clinical Research and Advanced Diagnostics | And 3 more authors.
Biopreservation and Biobanking | Year: 2014

Biobanks of fresh, unfixed human normal and malignant tissues represent a valuable source for gene expression analysis in translational cancer research and molecular pathology. However, the success of molecular and cellular analysis in both clinical and translational research is strongly dependent on the collection, handling, storage, and quality control of fresh human tissue samples. The aim of this study was to evaluate an innovative vacuum-based refrigerated system, as a logistically feasible technology to increase the collection of tissue specimens, preserving the integrity of cellular and molecular components. We tested randomly-selected tissues stored under vacuum at 4 C by using endpoints important for research and diagnosis, including tissue morphology, epitope stability, and RNA integrity. Gene expression was evaluated by qualitative and quantitative RT analysis of selected housekeeping and tissue-specific genes. Tissue morphology and overall protein stability were generally well preserved, being compromised only in gallbladder tissue. By contrast, phosphoprotein and RNA analysis demonstrated a time-dependent degree of degradation, with progressive loss of stability from 24 to 72 hours. However, this reduction in RNA quality did not represent a limitation for successful expression analysis of selected genes. Indeed, a comparative qualitative and quantitative RT-PCR analysis showed that RNA extracted from tissues stored under vacuum is suitable for gene expression profiling, but requires highly sensitive technologies, such as quantitative RT-PCR. These data suggest that the refrigerated vacuum-based system represents a suitable and feasible technology for routine transport of fresh specimens from surgery to biobanks, thus increasing the opportunity to collect biospecimens. © Mary Ann Liebert, Inc.


Soma P.F.,Healthcare Burns Unit | Pettinato A.,Pathology Unit | Agnone A.M.,Dental Institute | Donia C.,Unit of Plastic Surgery | And 2 more authors.
Oncology Letters | Year: 2014

Primary oral malignant melanoma is a rare condition, accounting for 1.3-1.4% of all melanomas, usually presenting with an aggressive clinical behavior. The present study reports the clinicopathological findings of two cases of oral malignant melanoma and discusses the epidemiology, diagnosis and current therapeutic approaches for this uncommon condition. In the first case the patient presented with a pigmented lesion located on the lower mucosal lip. The patient showed no nodal metastases and therefore, underwent a wedge resection. After seven months, the patient presented with neck lymph nodes and multiple visceral metastases. Molecular analysis of BRAF, using a pyrosequencing approach, revealed the presence of BRAF V600E mutation. The patient developed multiple visceral metastases, but refused treatment and was lost to follow-up. In the second case, no BRAF V600E mutation was found, but the patient exhibited a pigmented patch in the lower gingival mucosa, which was excised by surgical treatment. The patient was followed up by an oncologist, but did not undergo an additional therapy and is currently alive with no evidence of visceral metastases at one year following the diagnosis.

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