Amoroso M.R.,University of Naples Federico II |
Matassa D.S.,University of Naples Federico II |
Laudiero G.,University of Naples Federico II |
Egorova A.V.,Telethon Institute of Genetics and Medicine |
And 8 more authors.
Cell Death and Differentiation
Tumor necrosis factor receptor-associated protein-1 (TRAP1) is a mitochondrial (MITO) antiapoptotic heat-shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass-spectrometric analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 colocalize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopic analyses, and interact directly, as confirmed by fluorescence resonance energy transfer analysis. This is the first demonstration of TRAP1's presence in this cellular compartment. TRAP1 silencing by short-hairpin RNAs, in cells exposed to thapsigargin-induced ER stress, correlates with upregulation of BiP/Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, expression of specific MITO proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, as it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of the ER-mitochondria crosstalk. © 2012 Macmillan Publishers Limited All rights reserved. Source
Luminari S.,University of Modena and Reggio Emilia |
Biasoli I.,Federal University of Rio de Janeiro |
Arcaini L.,Fondazione IRCCS Policlinico San Matteo |
Arcaini L.,University of Pavia |
And 16 more authors.
Annals of Oncology
Background: The role of [18F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. Patients and methods: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. Results: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. Conclusions: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source
Rossi E.,University of Padua |
Basso U.,Istituto Oncologico Veneto |
Celadin R.,University of Padua |
Zilio F.,University of Padua |
And 11 more authors.
Clinical Cancer Research
Purpose: This study aimed to detect the M30 neoepitope on circulating tumor cells (CTC) as a tool for quantifying apoptotic CTC throughout disease course and treatment. Experimental Design: An automated sample preparation and analysis platform for computing CTC (CellSearch) was integrated with a monoclonal antibody (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 (CK18) in early apoptosis. The assay was validated using cell lines and blood samples from healthy volunteers and patients with epithelial cancer. Results: M30-positive CTC could be detected in >70% of CTC-positive carcinoma patients, which were free for both chemotherapy and radiologic treatments. The fraction of M30-positive CTC varied from 50% to 80%, depending on the histotype. To investigate the potential application of the M30 CTC assay for the evaluation of response in early phase trials, CTC and M30-positive CTC were enumerated in a small case series of breast cancer patients during treatment. Results indicate that changes in the balance of M30-negative/positive CTC may be used as a dynamic parameter indicating an active disease, as documented by consistent radiologic findings. Conclusions: M30 expression on CTC is detectable by immunofluorescence. The M30-integrated test has potential for monitoring dynamic changes in the quote of apoptotic CTC (in addition to CTC count) to evaluate response in clinical trials of molecularly targeted anticancer therapeutics as well as for translational research, in which there is a pressing need for informative circulating biomarkers. ©2010 AACR. Source
Clemente S.,Johns Hopkins University |
Wu B.,Johns Hopkins University |
Sanguineti G.,Johns Hopkins University |
Fusco V.,IRCCS CROB |
And 3 more authors.
International Journal of Radiation Oncology Biology Physics
Purpose: To investigate the roles of volumetric modulated arc therapy with SmartArc (VMAT-S), intensity-modulated radiation therapy (IMRT), and helical tomotherapy (HT) for oropharyngeal cancer using a simultaneous integrated boost (SIB) approach. Methods and Materials: Eight patients treated with IMRT were selected at random. Plans were computed for both IMRT and VMAT-S (using Pinnacle TPS for an Elekta Infinity linac) along with HT. A three-dose level prescription was used to deliver 70 Gy, 63 Gy, and 58.1 Gy to regions of macroscopic, microscopic high-risk, and microscopic low-risk disease, respectively. All doses were given in 35 fractions. Comparisons were performed on dose-volume histogram data, monitor units per fraction (MU/fx), and delivery time. Results: VMAT-S target coverage was close to that achieved by IMRT, but inferior to HT. The conformity and homogeneity within the PTV were improved for HT over all strategies. Sparing of the organs at risk (OAR) was achieved with all modalities. VMAT-S (along with HT) shortened delivery time (mean, -38%) and reduced MU/fx (mean, -28%) compared with IMRT. Conclusion: VMAT-S represents an attractive solution because of the shorter delivery time and the lower number of MU/fx compared with IMRT. However, in this complex clinical setting, current VMAT-S does not appear to provide any distinct advantage compared with helical tomotherapy. © 2011 Elsevier Inc. Source
Pagano L.,Catholic University |
Valentini C.G.,Catholic University |
Pulsoni A.,University of Rome La Sapienza |
Fisogni S.,University of Brescia |
And 15 more authors.
The objective of this study was to evaluate the clinical features, prognostic factors, and efficacy of treatments in patients with blastic plasmacytoid dendritic cell neoplasm with a leukemic presentation at onset of the disease. In order to do this, a retrospective multicenter study was performed from 2005-2011 in 28 Italian hematology divisions in which 43 cases were collected. Forty-one patients received an induction therapy, consisting of an acute myeloid leukemia-type regimen in 26 patients (60%) and acute lymphoid leukemia/lymphoma-type regimen in 15 patients (35%). Six patients (14%) underwent allogeneic hematopoietic stem cell transplantation. Seventeen patients (41%) achieved a complete remission: seven after acute myeloid leukemia-type treatment and 10 after an acute lymphoid leukemia/lymphoma-type regimen, with a significant advantage for acute lymphoid leukemia/lymphoma-type chemotherapy (P=0.02). Relapse occurred in six of the 17 patients (35%) who achieved complete remission, more frequently after acute lymphoid leukemia/lymphoma-type chemotherapy. The median overall survival was 8.7 months (range, 0.2-32.9). The patients treated with an acute myeloid leukemia-type regimen had an overall survival of 7.1 months (range, 0.2-19.5), whereas that of the patients receiving acute lymphoid leukemia/lymphoma-type chemotherapy was 12.3 months (range, 1-32.9) (P=0.02). The median overall survival of the allogeneic hematopoietic stem cell transplant recipients was 22.7 months (range, 12-32.9), and these patients had a significant survival advantage compared to the non-transplanted patients (median 7.1 months, 0.2-21.3; P=0.03). In conclusion, blastic plasmacytoid dendritic cell neoplasm with bone-marrow involvement is an aggressive subtype of high-risk acute leukemia. The rarity of this disease does not enable prospective clinical trials to identify the better therapeutic strategy, which, at present, is based on clinicians' experience. © 2013 Ferrata Storti Foundation. Source