36 results on '"Granato, Anna Maria"'
Search Results
2. Dendritic cell vaccines as cancer treatment: focus on 13 years of manufacturing and quality control experience in advanced therapy medicinal products
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Granato, Anna Maria, Pancisi, Elena, Piccinini, Claudia, Stefanelli, Monica, Pignatta, Sara, Soldati, Valentina, Carloni, Silvia, Fanini, Francesca, Arienti, Chiara, Bulgarelli, Jenny, Tazzari, Marcella, Scarpi, Emanuela, Passardi, Alessandro, Tauceri, Francesca, La Barba, Giuliano, Maimone, Giuseppe, Baravelli, Stefano, de Rosa, Francesco, Ridolfi, Laura, and Petrini, Massimiliano
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- 2024
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3. Skewing effect of sulprostone on dendritic cell maturation compared with dinoprostone
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Bulgarelli, Jenny, Fiammenghi, Laura, Cassan, Serena, Granato, Anna Maria, Petrini, Massimiliano, Pancisi, Elena, Soldati, Valentina, De Rosa, Francesco, Ridolfi, Laura, Riccobon, Angela, and Guidoboni, Massimo
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- 2018
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4. Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib: Validation study and biological rationale
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Casadei Gardini, Andrea, Faloppi, Luca, De Matteis, Serena, Foschi, Francesco Giuseppe, Silvestris, Nicola, Tovoli, Francesco, Palmieri, Vincenzo, Marisi, Giorgia, Brunetti, Oronzo, Vespasiani-Gentilucci, Umberto, Perrone, Giuseppe, Valgiusti, Martina, Granato, Anna Maria, Ercolani, Giorgio, Negrini, Giulia, Tamburini, Emiliano, Aprile, Giuseppe, Passardi, Alessandro, Santini, Daniele, Cascinu, Stefano, Frassineti, Giovanni Luca, and Scartozzi, Mario
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- 2017
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5. Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma
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De Matteis, Serena, Granato, Anna Maria, Napolitano, Roberta, Molinari, Chiara, Valgiusti, Martina, Santini, Daniele, Foschi, Francesco Giuseppe, Ercolani, Giorgio, Vespasiani Gentilucci, Umberto, Faloppi, Luca, Scartozzi, Mario, Frassineti, Giovanni Luca, and Casadei Gardini, Andrea
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- 2017
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6. Stability Program in Dendritic Cell Vaccines: A "Real-World" Experience in the Immuno-Gene Therapy Factory of Romagna Cancer Center.
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Pancisi, Elena, Granato, Anna Maria, Scarpi, Emanuela, Ridolfi, Laura, Carloni, Silvia, Moretti, Cinzia, Guidoboni, Massimo, De Rosa, Francesco, Pignatta, Sara, Piccinini, Claudia, Soldati, Valentina, Calabrò, Luana, Framarini, Massimo, Stefanelli, Monica, Bulgarelli, Jenny, Tazzari, Marcella, Fanini, Francesca, and Petrini, Massimiliano
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DENDRITIC cells ,CANCER vaccines ,VACCINES ,MEDICAL supplies ,THERAPEUTICS - Abstract
Advanced therapy medical products (ATMPs) are rapidly growing as innovative medicines for the treatment of several diseases. Hence, the role of quality analytical tests to ensure consistent product safety and quality has become highly relevant. Several clinical trials involving dendritic cell (DC)-based vaccines for cancer treatment are ongoing at our institute. The DC-based vaccine is prepared via CD14+ monocyte differentiation. A fresh dose of 10 million DCs is administered to the patient, while the remaining DCs are aliquoted, frozen, and stored in nitrogen vapor for subsequent treatment doses. To evaluate the maintenance of quality parameters and to establish a shelf life of frozen vaccine aliquots, a stability program was developed. Several parameters of the DC final product at 0, 6, 12, 18, and 24 months were evaluated. Our results reveal that after 24 months of storage in nitrogen vapor, the cell viability is in a range between 82% and 99%, the expression of maturation markers remains inside the criteria for batch release, the sterility tests are compliant, and the cell costimulatory capacity unchanged. Thus, the data collected demonstrate that freezing and thawing do not perturb the DC vaccine product maintaining over time its functional and quality characteristics. [ABSTRACT FROM AUTHOR]
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- 2022
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7. Biofunctional characteristics of in situ and invasive breast carcinoma
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Bravaccini, Sara, Granato, Anna Maria, Medri, Laura, Foca, Flavia, Falcini, Fabio, Zoli, Wainer, Ricci, Monica, Lanzanova, Giuseppe, Masalu, Nestory, Serra, Luigi, Buggi, Federico, Folli, Secondo, Silvestrini, Rosella, and Amadori, Dino
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- 2013
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8. Tumor endothelial marker 8 expression levels in dendritic cell-based cancer vaccines are related to clinical outcome
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Venanzi, Franco Maria, Petrini, Massimiliano, Fiammenghi, Laura, Bolli, Elisabetta, Granato, Anna Maria, Ridolfi, Laura, Gabrielli, Federica, Barucca, Alessandra, Concetti, Antonio, Ridolfi, Ruggero, and Riccobon, Angela
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- 2010
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9. Urine Telomerase Activity for the Detection of Bladder Cancer in Females
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Bravaccini, Sara, Sanchini, Maria Aurora, Granato, Anna Maria, Gunelli, Roberta, Nanni, Oriana, Amadori, Dino, Calistri, Daniele, and Silvestrini, Rosella
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- 2007
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10. Biomarker prediction of clinical outcome in operable breast cancer patients treated with tamoxifen
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Scarpi, Emanuela, Paola, Franca De, Sarti, Manuela, Bajorko, Paola, Granato, Anna Maria, Volpi, Annalisa, Nanni, Oriana, Maltoni, Roberta, and Amadori, Dino
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- 2001
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11. Prognostic significance of biologic markers in node-negative breast cancer patients: a prospective study
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Volpi, Annalisa, Paola, Franca De, Nanni, Oriana, Granato, Anna Maria, Bajorko, Paola, Becciolini, Aldo, Scarpi, Emanuela, Riccobon, Angela, Balzi, Manuela, and Amadori, Dino
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- 2000
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12. Radiotherapy and High-Dose Interleukin-2: Clinical and Immunological Results of a Proof of Principle Study in Metastatic Melanoma and Renal Cell Carcinoma.
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Bulgarelli, Jenny, Piccinini, Claudia, Petracci, Elisabetta, Pancisi, Elena, Granato, Anna Maria, de Rosa, Francesco, Guidoboni, Massimo, Petrini, Massimiliano, Ancarani, Valentina, Foschi, Giovanni, Romeo, Antonino, Tontini, Luca, De Giorgi, Ugo, Lolli, Cristian, Gentili, Giorgia, Valmorri, Linda, Rossi, Alice, Ferroni, Fabio, Casadei, Carla, and Cortesi, Pietro
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RENAL cell carcinoma ,MELANOMA ,INTERLEUKIN-2 ,PROOF of concept ,RADIOTHERAPY ,T cells ,METASTASIS ,SELF-monitoring (Psychology) ,PSYCHONEUROIMMUNOLOGY - Abstract
High-dose interleukin-2 (HD IL-2) has curative potential in metastatic melanoma (MM) and renal cell carcinoma (RCC). Radiotherapy (RT) kills cancer cells and induces immunomodulatory effects. Prospective trials exploring clinical and immunological properties of combined RT/HD IL-2 are still needed. We designed a phase II, single-arm clinical trial for patients with MM and RCC. The treatment schedule consisted of 3 daily doses of 6-12 Gy of RT to 1-5 non-index metastatic fields, before IL-2 at the first and third treatment cycle. HD IL-2 was administered by continuous infusion for 72 hours and repeated every 3 weeks for up to 4 cycles, thereafter every 4 weeks for a maximum of 2 cycles. The primary endpoint was the immunological efficacy of the combined RT/HD IL-2 treatment (assessed by IFN-γ ELISPOT). Nineteen out of 22 patients were evaluable for immunological and clinical response. Partial response occurred in 3 (15.7%) patients and stable disease was observed in 7 (36.8%). The disease control rate was 52.6% after a median follow up of 39.2 months. According to Common Terminology Criteria for Adverse Events 4.0 (CTCAE 4.0), the majority of toxicities were grade 1-2. Immunological responses were frequent and detected in 16 (84.2%) patients. Increased levels of IL-8 and IL-10 in melanoma, circulating effector memory CD4+ and intratumoral CD8+ T cells in both tumor types were detected after therapy. Overall the treatment was well tolerated and immunologically active. Immunomonitoring and correlative data on tumor and peripheral blood cell subsets suggest that this combination treatment could be a promising strategy for patients progressing after standard treatments. [ABSTRACT FROM AUTHOR]
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- 2021
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13. HER-2 Expression and Cell Proliferation: Prognostic Markers in Patients With Node-Negative Breast Cancer
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Volpi, Annalisa, Nanni, Oriana, De Paola, Franca, Granato, Anna Maria, Mangia, Annita, Monti, Franco, Schittulli, Francesco, De Lena, Mario, Scarpi, Emanuela, Rosetti, Paola, Monti, Manlio, Gianni, Lorenzo, Amadori, Dino, and Paradiso, Angelo
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- 2003
14. Basic fibroblast growth factor and vascular endothelial growth factor serum levels in breast cancer patients and healthy women: useful as diagnostic tools?
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Granato, Anna Maria, Nanni, Oriana, Falcini, Fabio, Folli, Secondo, Mosconi, Gabriella, De Paola, Franca, Medri, Laura, Amadori, Dino, and Volpi, Annalisa
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- 2003
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15. Dendritic Cell Vaccination in Metastatic Melanoma Turns "Non-T Cell Inflamed" Into "T-Cell Inflamed" Tumors.
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Bulgarelli, Jenny, Tazzari, Marcella, Granato, Anna Maria, Ridolfi, Laura, Maiocchi, Serena, de Rosa, Francesco, Petrini, Massimiliano, Pancisi, Elena, Gentili, Giorgia, Vergani, Barbara, Piccinini, Filippo, Carbonaro, Antonella, Leone, Biagio Eugenio, Foschi, Giovanni, Ancarani, Valentina, Framarini, Massimo, and Guidoboni, Massimo
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DENDRITIC cells ,CYTOTOXIC T cells ,SUPPRESSOR cells ,VACCINATION ,T cells - Abstract
Dendritic cell (DC)-based vaccination effectively induces anti-tumor immunity, although in the majority of cases this does not translate into a durable clinical response. However, DC vaccination is characterized by a robust safety profile, making this treatment a potential candidate for effective combination cancer immunotherapy. To explore this possibility, understanding changes occurring in the tumor microenvironment (TME) upon DC vaccination is required. In this line, quantitative and qualitative changes in tumor-infiltrating T lymphocytes (TILs) induced by vaccination with autologous tumor lysate/homogenate loaded DCs were investigated in a series of 16 patients with metastatic melanoma. Immunohistochemistry for CD4, CD8, Foxp3, Granzyme B (GZMB), PDL1, and HLA class I was performed in tumor biopsies collected before and after DC vaccination. The density of each marker was quantified by automated digital pathology analysis on whole slide images. Co-expression of markers defining functional phenotypes, i.e., Foxp3
+ regulatory CD4+ T cells (Treg) and GZMB+ cytotoxic CD8+ T cells, was assessed with sequential immunohistochemistry. A significant increase of CD8+ TILs was found in post-vaccine biopsies of patients who were not previously treated with immune-modulating cytokines or Ipilimumab. Interestingly, along with a maintained tumoral HLA class I expression, after DC vaccination we observed a significant increase of PDL1+ tumor cells, which significantly correlated with intratumoral CD8+ T cell density. This observation might explain the lack of a significant concurrent cytotoxic reactivation of CD8+ T cell, as measured by the numbers of GZMB+ T cells. Altogether these findings indicate that DC vaccination exerts an important role in sustaining or de novo inducing a T cell inflamed TME. However, the strength of the intratumoral T cell activation detected in post-DC therapy lesions is lessened by an occurring phenomenon of adaptive immune resistance, yet the concomitant PDL1 up-regulation. Overall, this study sheds light on DC immunotherapy-induced TME changes, lending the rationale for the design of smarter immune-combination therapies. [ABSTRACT FROM AUTHOR]- Published
- 2019
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16. Complementary vaccination protocol with dendritic cells pulsed with autologous tumour lysate in patients with resected stage III or IV melanoma: protocol for a phase II randomised trial (ACDC Adjuvant Trial).
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Ridolfi, Laura, de Rosa, Francesco, Fiammenghi, Laura, Petrini, Massimiliano, Granato, Anna Maria, Ancarani, Valentina, Pancisi, Elena, Soldati, Valentina, Cassan, Serena, Bulgarelli, Jenny, Riccobon, Angela, Gentili, Giorgia, Nanni, Oriana, Framarini, Massimo, Tauceri, Francesca, and Guidoboni, Massimo
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Introduction Surgery is one of the treatments of choice for patients with a single metastasis from melanoma but is rarely curative. Such patients could potentially benefit from consolidation immunotherapy. Vaccination with dendritic cells (DCs) loaded with tumour antigens elicits a tumourspecific immune response. In our experience, patients who developed delayed type hypersensitivity (DTH) after DC vaccination showed a median overall survival (OS) of 22.9 monthsvs4.8 months for DTH-negative cases. A phase II randomised trial showed an advantage OS of a DC vaccine over a tumour cell-based vaccine (2-year OS 72% vs31%, respectively). Given that there is no standard therapy after surgical resection of single metastases, we planned a study to compare vaccination with DCs pulsed with autologous tumour lysate versus follow-up. Methods and analysis This is a randomised phase II trial in patients with resected stage III/IV melanoma. Assuming a median relapse-free survival (RFS) of 7.0 months for the standard group and 11.7 months for the experimental arm (HR 0.60), with a two-sided tailed alpha of 0.10, 60 patients per arm must be recruited. An interim futility analysis will be performed at 18 months. The DC vaccine, produced in accordance with Good Manufacturing Practice guidelines, consists of autologous DCs loaded with autologous tumour lysate and injected intradermally near lymph nodes. Vaccine doses will be administered every 4 weeks for six vaccinations and will be followed by 3 million unit/day of interleukin-2 for 5 days. Tumour restaging, blood sampling for immunological biomarkers and DTH testing will be performed every 12 weeks. Ethics and dissemination The protocol, informed consent and accompanying material given to patients were submitted by the investigator to the Ethics Committee for review. The local Ethics Committee and the Italian Medicines Agency approved the protocol (EudraCT code no.2014-005123-27). Results will be published in a peerreviewed international scientific journal. [ABSTRACT FROM AUTHOR]
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- 2018
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17. Results from the first step of a phase II study of vaccination with autologous dendritic cells loaded with autologous tumour homogenate in glioblastoma.
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Ridolfi, Laura, Gurrieri, Lorena, Riva, Nada, Bulgarelli, Jenny, De Rosa, Francesco, Guidoboni, Massimo, Fausti, Valentina, Ranallo, Nicoletta, Tazzari, Marcella, Petrini, Massimiliano, Granato, Anna Maria, Pancisi, Elena, Foca, Flavia, Dall'Agata, Monia, Amadori, Elena, Cortesi, Pietro, Gamboni, Alessandro, Pasini, Giuseppe, Ibrahim, Toni, and Tosatto, Luigino
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- 2023
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18. Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients.
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Ridolfi, Laura, Petrini, Massimiliano, Granato, Anna Maria, Gentilcore, Giusy, Simeone, Ester, Ascierto, Paolo Antonio, Pancisi, Elena, Ancarani, Valentina, Fiammenghi, Laura, Guidoboni, Massimo, Rosa, Francesco de, Valmorri, Linda, Scarpi, Emanuela, Luisa Nicoletti, Stefania Vittoria, Baravelli, Stefano, Riccobon, Angela, and Ridolfi, Ruggero
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DENDRITIC cells ,VACCINATION ,T cells ,MELANOMA ,FISSURELLIDAE ,INTERLEUKIN-2 ,LYMPHOCYTES ,IMMUNOTHERAPY ,PATIENTS - Abstract
Background: In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4
+ CD25++ Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion. Methods: Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2. Results: Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells. Conclusions: Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growthstimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome. [ABSTRACT FROM AUTHOR]- Published
- 2013
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19. FRET microscopy autologous tumor lysate processing in mature dendritic cell vaccine therapy.
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Fiammenghi, Laura, Ancarani, Valentina, Rosales, Tilman, Knutson, Jay R., Petrini, Massimiliano, Granato, Anna Maria, Pancisi, Elena, Ridolfi, Laura, Ridolfi, Ruggero, Riccobon, Angela, and Neyroz, Paolo
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DENDRITIC cells ,PEPTIDES ,MAJOR histocompatibility complex ,IMMUNOGENETICS ,MELANOMA ,NEUROENDOCRINE tumors - Abstract
Background: Antigen processing by dendritic cells (DC) exposed to specific stimuli has been well characterized in biological studies. Nonetheless, the question of whether autologous whole tumor lysates (as used in clinical trials) are similarly processed by these cells has not yet been resolved. Methods: In this study, we examined the transfer of peptides from whole tumor lysates to major histocompatibility complex class II molecules (MHC II) in mature dendritic cells (mDC) from a patient with advanced melanoma. Tumor antigenic peptides-MHC II proximity was revealed by Förster Resonance Energy Transfer (FRET) measurements, which effectively extends the application of fluorescence microscopy to the molecular level (<100?). Tumor lysates were labelled with Alexa-488, as the donor, and mDC MHC II HLA-DR molecules were labelled with Alexa-546-conjugated IgG, as the acceptor. Results: We detected significant energy transfer between donor and acceptor-labelled antibodies against HLA-DR at the membrane surface of mDC. FRET data indicated that fluorescent peptide-loaded MHC II molecules start to accumulate on mDC membranes at 16 hr from the maturation stimulus, steeply increasing at 22 hr with sustained higher FRET detected up to 46 hr. Conclusions: The results obtained imply that the patient mDC correctly processed the tumor specific antigens and their display on the mDC surface may be effective for several days. These observations support the rationale for immunogenic efficacy of autologous tumor lysates. [ABSTRACT FROM AUTHOR]
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- 2010
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20. Iressa strengthens the cytotoxic effect of docetaxel in NSCLC models that harbor specific molecular characteristics.
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Rosetti, Marco, Zoli, Wainer, Tesei, Anna, Ulivi, Paola, Fabbri, Francesco, Vannini, Ivan, Brigliadori, Giovanni, Granato, Anna Maria, Amadori, Dino, and Silvestrini, Rosella
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CYTOLOGICAL research ,SMALL cell lung cancer ,LUNG cancer ,DOCETAXEL ,PROTEIN-tyrosine kinases - Abstract
Non-small cell lung cancer (NSCLC) is the most lethal malignant tumor and is also considered one of the most chemoresistant cancers. Despite the benefits obtained from platinum-based therapy, the majority of patients treated will progress and die. In the continuing quest for personalized therapy based on the biomolecular characteristics of each single patient, clinical practice now seems to be oriented towards combining conventional drugs with molecular-targeted agents. In the present study, we evaluated the antitumor activity of docetaxel, one of the most widely used drugs for second-line treatment, and Iressa, an EGFR-targeting tyrosine kinase inhibitor, administered singly or in sequence. The study was performed on three human NSCLC cell lines (ChaGo-K1, CAEP and RAL) that exhibit different expression of proliferation and apoptosis-related markers, and do not harbor EGFR mutations. The efficacy of docetaxel and Iressa differed in the three cell lines and an important synergistic interaction was observed with the sequence 1-h docetaxel → 72-h Iressa during which Iressa doubled the fraction of docetaxel-induced apoptotic cells, amplifying a caspase-dependent apoptosis and inhibiting docetaxel-induced p21 hyperexpression. Moreover, the important role of MAPK-dependent modulation of this molecular marker was shown using a specific inhibitor. The results from the present preclinical study demonstrate the cytotoxic activity of Iressa and its ability to increase taxane activity in a model that does not harbor EGFR-specific mutations, thus highlighting the importance of focusing on alternative molecular targets of Iressa activity. J. Cell. Physiol. 212:710–716, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
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- 2007
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21. Do Serum Angiogenic Growth Factors Provide Additional Information to That of Conventional Markers in Monitoring the Course of Metastatic Breast Cancer?
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Granato, Anna Maria, Frassineti, Giovanni Luca, Giovannini, Noemi, Ballardini, Michela, Nanni, Oriana, Maltoni, Roberta, Amadori, Dino, and Volpi, Annalisa
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FIBROBLAST growth factors ,VASCULAR endothelial growth factors ,BREAST cancer treatment ,CANCER chemotherapy ,TUMOR markers ,ANTINEOPLASTIC agents ,DRUG monitoring ,ENZYME-linked immunosorbent assay - Abstract
Objective:Our work evaluated the potential role of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) serum levels with respect to that of conventional serum tumour markers, CEA and CA 15-3, in monitoring the course of metastatic breast cancer in 56 female patients treated with cytotoxic chemotherapy. Methods: VEGF and bFGF concentrations were determined using a quantitative sandwich enzyme immunoassay technique. The positive predictive value (PPV) of each marker and of marker combinations for different types of clinical response was calculated. Results: The highest PPV for overall disease control was shown by bFGF (70%), which also showed the highest PPV for both partial response (36.4%) and stable disease (63.2%). CEA showed the highest predictive value for progression (69.2%). A combined increase in CEA and bFGF or VEGF was associated with disease progression in all patients. Conclusions:Information provided by angiogenic factor levels seems to be independent of and is possibly complementary to that provided by conventional serum markers. bFGF showed the maximum predictive value for disease control and provided additional information to that obtained from CEA or CA 15-3 evaluation. It could therefore be a promising candidate for monitoring response to chemotherapy in advanced breast cancer. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2006
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22. Immunosuppression in renal cancer: differential expression of signal transduction molecules in tumor-infiltrating, near-tumor tissue, and peripheral blood lymphocytes.
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Riccobon, Angela, Gunelli, Roberta, Ridolfi, Ruggero, De Paola, Franca, Flamini, Emanuela, Fiori, Massimo, Saltutti, Carlo, Petrini, Massimiliano, Fiammenghi, Laura, Stefanelli, Monica, Granato, Anna Maria, Ettore Cuzzocrea, Diego, Amadori, Dino, and Cuzzocrea, Diego Ettore
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T cell receptors ,T cells ,CELLULAR signal transduction ,PROTEIN kinases ,CANCER ,IMMUNOLOGICAL tolerance - Abstract
Alterations in the expression of signal activation molecules, such as the T-cell receptor (TCR) zeta and epsilon chains and p56lck tyrosine kinase, are described in tumor-infiltrating lymphocytes (TIL). The aim of this study was to ascertain if such molecules were present in near-tumor-tissue lymphocytes (NTTL) and peripheral blood lymphocytes (PBL), as well as TIL, of renal cell carcinoma patients, to verify whether this tumor induces immunosuppression only locally or affects distant lymphocytes as well. Tissue from the tumor and from healthy nearby sites, as well as blood samples, were obtained from 27 consecutive patients who had undergone radical nephrectomy for renal cell carcinoma. Phenotype analysis and immunohistochemical staining of the TCR zeta and epsilon chains and p56lck were performed with standard techniques on TIL, NTTL, and PBL, and values were compared for each patient. Low expression of the TCR zeta chain and an almost complete absence of TCR epsilon chain and p56lck expression was observed in TIL (median values: 10% for zeta chain and 0% for epsilon and p56lck). In NTTL, these signal transduction molecules were expressed by a higher percentage of cells (60%, 50%, and 60%, respectively; p=0.000 vs. TIL), whereas PBL showed an almost normal expression of zeta and epsilon chains (80% and 90%, respectively; p=0.000 vs. TIL). Conversely, p56lck was detected in a greater proportion of NTTL than PBL (50% vs. 10%; p=0.001). The absence or the very low expression of signaling activation molecules in TIL compared with NTTL and PBL in renal cancer patients suggest that tumor-induced immunosuppression generally occurs or starts locally. [ABSTRACT FROM AUTHOR]
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- 2004
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23. Vascular endothelial growth factor and prognosis in patients with node-negative breast cancer.
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De Paola, Franca, Granato, Anna Maria, Scarpi, Emanuela, Monti, Franco, Medri, Laura, Bianchi, Simonetta, Amadori, Dino, and Volpi, Annalisa
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- 2002
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24. Potency Assessment of Dendritic Cell Anticancer Vaccine: Validation of the Co-Flow DC Assay.
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Carloni, Silvia, Piccinini, Claudia, Pancisi, Elena, Soldati, Valentina, Stefanelli, Monica, Granato, Anna Maria, Ibrahim, Toni, and Petrini, Massimiliano
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DENDRITIC cells ,T cells ,QUALITY control ,CELL proliferation ,CELLULAR therapy ,FLUORESCENT dyes - Abstract
For many years, oncological clinical trials have taken advantage of dendritic cells (DC) for the design of DC-based cellular therapies. This has required the design of suitable quality control assays to evaluate the potency of these products. The purpose of our work was to develop and validate a novel bioassay that uses flow cytometry as a read-out measurement. In this method, CD3+ cells are labeled with a fluorescent dye and the DC costimulatory activity is measured by the degree of T cell proliferation caused by the DC–T cell interaction. The validation of the method was achieved by the evaluation of essential analytical parameters defined by international guidelines. Our results demonstrated that the method could be considered specific, selective, and robust. The comparison between measured values and estimated true values confirmed a high level of accuracy and a lack of systematic error. Repeated experiments have shown the reproducibility of the assay and the proportionality between the potency and the DC amount has proven its linearity. Our results suggest that the method is compliant with the guidelines and could be adopted as a quality control assay or batch-release testing within GMP facilities. [ABSTRACT FROM AUTHOR]
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- 2021
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25. Role of SIRT-3, p-mTOR and HIF-1α in Hepatocellular Carcinoma Patients Affected by Metabolic Dysfunctions and in Chronic Treatment with Metformin.
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De Matteis, Serena, Bandini, Erika, Ghetti, Martina, Marisi, Giorgia, Santini, Daniele, Faloppi, Luca, Scartozzi, Mario, Cascinu, Stefano, Casadei-Gardini, Andrea, Scarpi, Emanuela, Granato, Anna Maria, Vespasiani-Gentilucci, Umberto, La Barba, Giuliano, Foschi, Francesco Giuseppe, Cravero, Paola, Frassineti, Giovanni Luca, Gramantieri, Laura, Cucchetti, Alessandro, and Ercolani, Giorgio
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LIVER cancer ,METABOLIC disorders ,SIRTUINS ,RAPAMYCIN ,HYPOXIA-inducible factors - Abstract
The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1α) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1α expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1α as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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26. Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised "proof-of-principle" phase II study.
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de Rosa, Francesco, Ridolfi, Laura, Ridolfi, Ruggero, Gentili, Giorgia, Valmorri, Linda, Nanni, Oriana, Petrini, Massimiliano, Fiammenghi, Laura, Granato, Anna Maria, Ancarani, Valentina, Pancisi, Elena, Soldati, Valentina, Cassan, Serena, Riccobon, Angela, Parisi, Elisabetta, Romeo, Antonino, Turci, Livia, and Guidoboni, Massimo
- Abstract
Background: Vaccination with dendritic cells (DC) loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side-effects. Patients with advanced melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed.Methods/design: This is a phase II, "proof-of-principle", randomized, open-label trial of vaccination with autologous DC loaded with tumor lysate or homogenate in metastatic melanoma patients combined with immunomodulating RT and/or preleukapheresis IFN-α. All patients will receive four bi-weekly doses of the vaccine during the induction phase and monthly doses thereafter for up to a maximum of 14 vaccinations or until confirmed progression. Patients will be randomized to receive:(1.) three daily doses of 8 Gy up to 12 Gy radiotherapy delivered to one non-index metastatic field between vaccine doses 1 and 2 and, optionally, between doses 7 and 8, using IMRT-IMAT techniques;(2.) daily 3 MU subcutaneous IFN-α for 7 days before leukapheresis;(3.) both 1 and 2;(4.) neither 1 nor 2.At least six patients eligible for treatment will be enrolled per arm. Daily 3 MU IL-2 will be administered subcutaneously for 5 days starting from the second day after each vaccine dose. Serial DTH testing and blood sampling to evaluate treatment-induced immune response will be performed. Objective response will be evaluated according to immune-related response criteria (irRC).Discussion: Based upon the emerging role of radiotherapy as an immunologic modifier, we designed a randomized phase II trial adding radiotherapy and/or preleukapheresis IFN-α to our DC vaccine in metastatic melanoma patients. Our aim was to find the best combination of complementary interventions to enhance anti-tumor response induced by DC vaccination, which could ultimately lead to better survival and milder toxicity. [ABSTRACT FROM AUTHOR]- Published
- 2014
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27. Role of SIRT-3, p-mTOR and HIF-1α in Hepatocellular Carcinoma Patients Affected by Metabolic Dysfunctions and in Chronic Treatment with Metformin
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Francesco Giuseppe Foschi, Andrea Casadei-Gardini, Alessandro Cucchetti, Giorgia Marisi, Paola Cravero, Laura Gramantieri, Emanuela Scarpi, Giovanni Luca Frassineti, Anna Maria Granato, Erika Bandini, Giorgio Ercolani, Daniele Santini, Umberto Vespasiani-Gentilucci, Stefano Cascinu, Luca Faloppi, Giuliano La Barba, Serena De Matteis, Mario Scartozzi, Martina Ghetti, De Matteis, Serena, Scarpi, Emanuela, Granato, Anna, Vespasiani-Gentilucci, Umberto, La Barba, Giuliano, Foschi, Francesco, Bandini, Erika, Ghetti, Martina, Marisi, Giorgia, Cravero, Paola, Gramantieri, Laura, Cucchetti, Alessandro, Ercolani, Giorgio, Santini, Daniele, Frassineti, Giovanni, Faloppi, Luca, Scartozzi, Mario, Cascinu, Stefano, Casadei-Gardini, Andrea, Granato, Anna Maria, Foschi, Francesco Giuseppe, and Frassineti, Giovanni Luca
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0301 basic medicine ,Oncology ,Male ,Drug resistance ,lcsh:Chemistry ,0302 clinical medicine ,Sirtuin 3 ,lcsh:QH301-705.5 ,Spectroscopy ,Aged, 80 and over ,biology ,diabetes ,TOR Serine-Threonine Kinases ,Liver Neoplasms ,General Medicine ,Middle Aged ,Computer Science Applications ,Metformin ,metformin ,non-alcoholic steatohepatitis ,Liver ,Liver Neoplasm ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Sirtuin ,Female ,medicine.drug ,Human ,Adult ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Article ,Catalysis ,metabolic syndrome ,Inorganic Chemistry ,03 medical and health sciences ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,Hypoglycemic Agents ,Physical and Theoretical Chemistry ,Molecular Biology ,Aged ,Hypoglycemic Agent ,business.industry ,Diabetes ,Metabolic syndrome ,Non-alcoholic steatohepatitis ,Organic Chemistry ,Cancer ,medicine.disease ,Hypoxia-Inducible Factor 1, alpha Subunit ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Diabetes Mellitus, Type 2 ,diabete ,Etiology ,biology.protein ,business ,non-alcoholic steatohepatiti - Abstract
The incidence of hepatocellular carcinoma deriving from metabolic dysfunctions has increased in the last years. Sirtuin- (SIRT-3), phospho-mammalian target of rapamycin (p-mTOR) and hypoxia-inducible factor- (HIF-1&alpha, ) are involved in metabolism and cancer. However, their role in hepatocellular carcinoma (HCC) metabolism, drug resistance and progression remains unclear. This study aimed to better clarify the biological and clinical function of these markers in HCC patients, in relation to the presence of metabolic alterations, metformin therapy and clinical outcome. A total of 70 HCC patients were enrolled: 48 and 22 of whom were in early stage and advanced stage, respectively. The expression levels of the three markers were assessed by immunohistochemistry and summarized using descriptive statistics. SIRT-3 expression was higher in diabetic than non-diabetic patients, and in metformin-treated than insulin-treated patients. Interestingly, p-mTOR was higher in patients with metabolic syndrome than those with different etiology, and, similar to SIRT-3, in metformin-treated than insulin-treated patients. Moreover, our results describe a slight, albeit not significant, benefit of high SIRT-3 and a significant benefit of high nuclear HIF-1&alpha, expression in early-stage patients, whereas high levels of p-mTOR correlated with worse prognosis in advanced-stage patients. Our study highlighted the involvement of SIRT-3 and p-mTOR in metabolic dysfunctions that occur in HCC patients, and suggested SIRT-3 and HIF-1&alpha, as predictors of prognosis in early-stage HCC patients, and p-mTOR as target for the treatment of advanced-stage HCC.
- Published
- 2019
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28. Metformin and insulin impact on clinical outcome in patients with advanced hepatocellular carcinoma receiving sorafenib. Validation study and biological rationale
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Oronzo Brunetti, Serena De Matteis, Andrea Casadei Gardini, Giorgio Ercolani, Emiliano Tamburini, Daniele Santini, Mario Scartozzi, Giuseppe Perrone, Giovanni Luca Frassineti, Nicola Silvestris, Francesco Tovoli, Umberto Vespasiani-Gentilucci, Luca Faloppi, Giuseppe Aprile, Martina Valgiusti, Giulia Negrini, Stefano Cascinu, Alessandro Passardi, Giorgia Marisi, Francesco Giuseppe Foschi, Anna Maria Granato, Vincenzo Palmieri, Casadei Gardini, Andrea, Faloppi, Luca, De Matteis, Serena, Foschi, Francesco Giuseppe, Silvestris, Nicola, Tovoli, Francesco, Palmieri, Vincenzo, Marisi, Giorgia, Brunetti, Oronzo, Vespasiani-Gentilucci, Umberto, Perrone, Giuseppe, Valgiusti, Martina, Granato, Anna Maria, Ercolani, Giorgio, Negrini, Giulia, Tamburini, Emiliano, Aprile, Giuseppe, Passardi, Alessandro, Santini, Daniele, Cascinu, Stefano, Frassineti, Giovanni Luca, and Scartozzi, Mario
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,Time Factors ,Type II diabetes mellitus ,Databases, Factual ,Hepatocellular carcinoma ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Antineoplastic Agent ,0302 clinical medicine ,Retrospective Studie ,Sirtuin 3 ,Insulin ,Drug Interactions ,Aged, 80 and over ,Clinical pathology ,SIRT-3 ,Liver Neoplasms ,NASH ,hepatocellular carcinoma ,Sorafenib ,Middle Aged ,Immunohistochemistry ,Metformin ,Treatment Outcome ,Drug Interaction ,Italy ,Liver Neoplasm ,030220 oncology & carcinogenesis ,Female ,Liver cancer ,medicine.drug ,Human ,Phenylurea Compound ,Adult ,Niacinamide ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Time Factor ,Type II diabetes mellitu ,Protein Kinase Inhibitor ,Antineoplastic Agents ,Disease-Free Survival ,03 medical and health sciences ,Internal medicine ,NAFLD ,medicine ,Humans ,Hypoglycemic Agents ,In patient ,neoplasms ,Protein Kinase Inhibitors ,Aged ,Retrospective Studies ,Hypoglycemic Agent ,business.industry ,Phenylurea Compounds ,sorafenib ,metformin ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Diabetes Mellitus, Type 2 ,Drug Resistance, Neoplasm ,business - Abstract
Purpose In 2015, we published a study on a small series of patients with hepatocellular carcinoma (HCC) treated chronically with metformin for type II diabetes mellitus (DM2) who showed a poorer response to sorafenib. The aim of the present study was to validate the prognostic significance of metformin in HCC patients treated with sorafenib, providing a biological rationale for the mechanism of resistance to sorafenib in patients on chronic metformin therapy, and to clarify the role of sirtuin-3 (SIRT-3), a protein involved in metabolic diseases and acknowledged as a tumour suppressor in HCC, in this resistance. Patients and methods We analysed 279 patients consecutively treated with sorafenib for the clinical analysis. Of the 86 (30%) patients with DM2, 52 (19%) were on chronic treatment with metformin and 34 (12%) with insulin. We included 43 patients with HCC for the biological study: 19 (44.1%) were diabetic and 14 (73.7%) of these received metformin for DM2. SIRT-3 expression was investigated by immunohistochemistry (IHC) in formalin-fixed and paraffin-embedded (FFPE) samples. Results In HCC patients undergoing chronic treatment with metformin, the use of sorafenib was associated with poor progression-free survival (PFS) and overall survival (OS) (1.9 and 6.6 months, respectively) compared to 3.7 months and 10.8 months, respectively, for patients without DM2 and 8.4 months and 16.6 months, respectively, for patients on insulin (P
- Published
- 2017
29. Interplay Between SIRT-3, Metabolism and Its Tumor Suppressor Role in Hepatocellular Carcinoma
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Luca Faloppi, Martina Valgiusti, Giovanni Luca Frassineti, Mario Scartozzi, Roberta Napolitano, Francesco Giuseppe Foschi, Umberto Vespasiani Gentilucci, Giorgio Ercolani, Daniele Santini, Serena De Matteis, Andrea Casadei Gardini, Anna Maria Granato, Chiara Molinari, De Matteis, S, Granato, Am, Napolitano, R, Molinari, C, Valgiusti, M, Santini, D, Foschi, Fg, Ercolani, G, Vespasiani Gentilucci, U, Faloppi, L, Scartozzi, M, Frassineti, Gl, Casadei Gardini, A4., De Matteis, Serena, Granato, Anna Maria, Napolitano, Roberta, Molinari, Chiara, Valgiusti, Martina, Santini, Daniele, Foschi, Francesco Giuseppe, Ercolani, Giorgio, Vespasiani Gentilucci, Umberto, Faloppi, Luca, Scartozzi, Mario, Frassineti, Giovanni Luca, and Casadei Gardini, Andrea
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,tumor suppressor ,Hepatocellular carcinoma ,Physiology ,Nicotinamide adenine dinucleotide ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,Metabolic Diseases ,law ,Metabolism ,SIRT-3 ,Tumor suppressor ,Gastroenterology ,Neoplasms ,Sirtuin 3 ,Internal medicine ,hepatocellular carcinoma ,medicine ,Humans ,Chronic stress ,biology ,Tumor Suppressor Proteins ,Liver Neoplasms ,Neurodegeneration ,Cancer ,medicine.disease ,030104 developmental biology ,Histone ,Endocrinology ,chemistry ,biology.protein ,Cancer research ,Suppressor ,NAD+ kinase - Abstract
Sirtuins (SIRT), first described as nicotinamide adenine dinucleotide (NAD + )-dependent type III histone deacetylases, are produced by cells to support in the defense against chronic stress conditions such as metabolic syndromes, neurodegeneration, and cancer. SIRT-3 is one of the most studied members of the mitochondrial sirtuins family. In particular, its involvement in metabolic diseases and its dual role in cancer have been described. In the present review, based on the evidence of SIRT-3 involvement in metabolic dysfunctions, we aimed to provide an insight into the multifaceted role of SIRT-3 in many solid and hematological tumors with a particular focus on hepatocellular carcinoma (HCC). SIRT-3 regulatory effect and involvement in metabolism dysfunctions may have strong implications in HCC development and treatment. Research literature widely reports the relationship between metabolic disorders and HCC development. This evidence suggests a putative bridge role of SIRT-3 between metabolic diseases and HCC. However, further studies are necessary to demonstrate such interconnection.
- Published
- 2017
30. First step results from a phase II study of a dendritic cell vaccine in glioblastoma patients (CombiG-vax).
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Ridolfi L, Gurrieri L, Riva N, Bulgarelli J, De Rosa F, Guidoboni M, Fausti V, Ranallo N, Calpona S, Tazzari M, Petrini M, Granato AM, Pancisi E, Foca F, D'Allagata M, Bondi I, Amadori E, Cortesi P, Zani C, Ancarani V, Gamboni A, Polselli A, Pasini G, Bartolini D, Maimone G, Arpa D, and Tosatto L
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- Humans, Middle Aged, Female, Male, Adult, Aged, Temozolomide therapeutic use, Temozolomide administration & dosage, Progression-Free Survival, Glioblastoma therapy, Glioblastoma immunology, Glioblastoma mortality, Cancer Vaccines immunology, Cancer Vaccines therapeutic use, Cancer Vaccines administration & dosage, Cancer Vaccines adverse effects, Dendritic Cells immunology, Dendritic Cells transplantation, Brain Neoplasms therapy, Brain Neoplasms immunology, Brain Neoplasms mortality
- Abstract
Background: Glioblastoma (GBM) is a poor prognosis grade 4 glioma. After surgical resection, the standard therapy consists of concurrent radiotherapy (RT) and temozolomide (TMZ) followed by TMZ alone. Our previous data on melanoma patients showed that Dendritic Cell vaccination (DCvax) could increase the amount of intratumoral-activated cytotoxic T lymphocytes., Methods: This is a single-arm, monocentric, phase II trial in two steps according to Simon's design. The trial aims to evaluate progression-free survival (PFS) at three months and the safety of a DCvax integrated with standard therapy in resected GBM patients. DCvax administration begins after completion of RT-CTwith weekly administrations for 4 weeks, then is alternated monthly with TMZ cycles. The primary endpoints are PFS at three months and safety. One of the secondary objectives is to evaluate the immune response both in vitro and in vivo (DTH skin test)., Results: By December 2022, the first pre-planned step of the study was concluded with the enrollment, treatment and follow up of 9 evaluable patients. Two patients had progressed within three months after leukapheresis, but none had experienced DCvax-related G3-4 toxicities Five patients experienced a positive DTH test towards KLH and one of these also towards autologous tumor homogenate. The median PFS from leukapheresis was 11.3 months and 12.2 months from surgery., Conclusions: This combination therapy is well-tolerated, and the two endpoints required for the first step have been achieved. Therefore, the study will proceed to enroll the remaining 19 patients. (Eudract number: 2020-003755-15 https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-003755-15/IT)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ridolfi, Gurrieri, Riva, Bulgarelli, De Rosa, Guidoboni, Fausti, Ranallo, Calpona, Tazzari, Petrini, Granato, Pancisi, Foca, D'Allagata, Bondi, Amadori, Cortesi, Zani, Ancarani, Gamboni, Polselli, Pasini, Bartolini, Maimone, Arpa and Tosatto.)
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- 2024
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31. Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients.
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Ridolfi L, Petrini M, Granato AM, Gentilcore G, Simeone E, Ascierto PA, Pancisi E, Ancarani V, Fiammenghi L, Guidoboni M, de Rosa F, Valmorri L, Scarpi E, Nicoletti SV, Baravelli S, Riccobon A, and Ridolfi R
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- Adult, Aged, CTLA-4 Antigen metabolism, Dacarbazine therapeutic use, Female, Forkhead Transcription Factors metabolism, Hemocyanins, Humans, Interleukin-2 metabolism, Interleukin-2 Receptor alpha Subunit metabolism, Male, Melanoma immunology, Middle Aged, Temozolomide, Treatment Outcome, Cancer Vaccines therapeutic use, Dacarbazine analogs & derivatives, Dendritic Cells cytology, Melanoma therapy, T-Lymphocytes, Regulatory cytology
- Abstract
Background: In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion., Methods: Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2., Results: Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells., Conclusions: Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome.
- Published
- 2013
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32. Dendritic cell-based vaccine in advanced melanoma: update of clinical outcome.
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Ridolfi L, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E, Brolli C, Selva M, Scarpi E, Valmorri L, Nicoletti SV, Guidoboni M, Riccobon A, and Ridolfi R
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- Adult, Aged, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Disease Progression, Female, Follow-Up Studies, Humans, Male, Melanoma diagnosis, Melanoma mortality, Melanoma pathology, Middle Aged, Neoplasm Staging, Prognosis, Retrospective Studies, Skin Neoplasms diagnosis, Skin Neoplasms mortality, Skin Neoplasms pathology, Survival Analysis, Treatment Outcome, Cancer Vaccines therapeutic use, Dendritic Cells immunology, Immunotherapy, Adoptive methods, Melanoma therapy, Skin Neoplasms therapy
- Abstract
Dendritic cells (DCs) are unique specialized antigen-presenting cells capable of priming naive T cells and inducing antigen-specific cytotoxic T lymphocytes. This study presents an update of clinical results from a DC-based phase I-II clinical vaccine trial in stage IV melanoma. From 2003 to 2010, 27 patients with metastatic melanoma were treated with mature DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin and with subcutaneous low-dose interleukin-2. Delayed-type hypersensitivity (DTH) tests for in-vivo immunomonitoring were performed at baseline and every four vaccinations thereafter. Two complete, two mixed and six partial responses, and five stable diseases were observed (overall response, 37.0%; clinical benefit, 55.5%). All 15 responders showed DTH positivity. A median overall survival of 22.9 months [95% confidence interval (CI): 13.4-61.3] for DTH-positive patients (19) and 4.8 months (95% CI: 3.9-11.9) for DTH-negative patients (8; log rank=7.26; P=0.007) was observed. The overall median overall survival was 16 months (95% CI: 9-33). Our results would seem to highlight a relationship between positive-DTH test and an improved survival.
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- 2011
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33. Unexpected high response rate to traditional therapy after dendritic cell-based vaccine in advanced melanoma: update of clinical outcome and subgroup analysis.
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Ridolfi L, Petrini M, Fiammenghi L, Granato AM, Ancarani V, Pancisi E, Scarpi E, Guidoboni M, Migliori G, Sanna S, Tauceri F, Verdecchia GM, Riccobon A, Valmorri L, and Ridolfi R
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- Adult, Aged, Cancer Vaccines administration & dosage, Cancer Vaccines adverse effects, Combined Modality Therapy, Female, Hemocyanins therapeutic use, Humans, Hypersensitivity, Delayed etiology, Hypersensitivity, Delayed immunology, Interleukin-2 therapeutic use, Male, Melanoma immunology, Melanoma mortality, Melanoma secondary, Middle Aged, Survival Rate, Treatment Outcome, Vaccination, Cancer Vaccines therapeutic use, Dendritic Cells immunology, Drug Therapy statistics & numerical data, Melanoma therapy, Radiotherapy statistics & numerical data
- Abstract
We reviewed the clinical results of a dendritic cell-based phase II clinical vaccine trial in stage IV melanoma and analyzed a patient subgroup treated with standard therapies after stopping vaccination. From 2003 to 2009, 24 metastatic melanoma patients were treated with mature dendritic cells pulsed with autologous tumor lysate and keyhole limpet hemocyanin and low-dose interleukin-2. Overall response (OR) to vaccination was 37.5% with a clinical benefit of 54.1%. All 14 responders showed delayed type hypersensitivity positivity. Median overall survival (OS) was 15 months (95% CI, 8-33). Eleven patients underwent other treatments (3 surgery, 2 biotherapy, 2 radiotherapy, 2 chemotherapy, and 4 biochemotherapy) after stopping vaccination. Of these, 2 patients had a complete response and 5 a partial response, with an OR of 63.6%. Median OS was 34 months (range 16-61). Our results suggest that therapeutic DC vaccination could favor clinical response in patients after more than one line of therapy.
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- 2010
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34. Do serum angiogenic growth factors provide additional information to that of conventional markers in monitoring the course of metastatic breast cancer?
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Granato AM, Frassineti GL, Giovannini N, Ballardini M, Nanni O, Maltoni R, Amadori D, and Volpi A
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- Adult, Aged, Female, Humans, Middle Aged, Neoplasm Metastasis, Postmenopause, Premenopause, Reproducibility of Results, Angiogenic Proteins blood, Biomarkers, Tumor blood, Breast Neoplasms blood, Breast Neoplasms pathology, Fibroblast Growth Factor 2 blood, Vascular Endothelial Growth Factor A blood
- Abstract
Objective: Our work evaluated the potential role of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) serum levels with respect to that of conventional serum tumour markers, CEA and CA 15-3, in monitoring the course of metastatic breast cancer in 56 female patients treated with cytotoxic chemotherapy., Methods: VEGF and bFGF concentrations were determined using a quantitative sandwich enzyme immunoassay technique. The positive predictive value (PPV) of each marker and of marker combinations for different types of clinical response was calculated., Results: The highest PPV for overall disease control was shown by bFGF (70%), which also showed the highest PPV for both partial response (36.4%) and stable disease (63.2%). CEA showed the highest predictive value for progression (69.2%). A combined increase in CEA and bFGF or VEGF was associated with disease progression in all patients., Conclusions: Information provided by angiogenic factor levels seems to be independent of and is possibly complementary to that provided by conventional serum markers. bFGF showed the maximum predictive value for disease control and provided additional information to that obtained from CEA or CA 15-3 evaluation. It could therefore be a promising candidate for monitoring response to chemotherapy in advanced breast cancer., (Copyright (c) 2006 S. Karger AG, Basel.)
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- 2006
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35. Basic fibroblast growth factor and vascular endothelial growth factor serum levels in breast cancer patients and healthy women: useful as diagnostic tools?
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Granato AM, Nanni O, Falcini F, Folli S, Mosconi G, De Paola F, Medri L, Amadori D, and Volpi A
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- Aged, Aged, 80 and over, Biomarkers, Tumor biosynthesis, Breast Neoplasms blood, Breast Neoplasms metabolism, Case-Control Studies, Female, Fibroblast Growth Factor 2 biosynthesis, Humans, Immunoenzyme Techniques methods, Immunohistochemistry, Middle Aged, Sensitivity and Specificity, Vascular Endothelial Growth Factor A biosynthesis, Biomarkers, Tumor blood, Breast Neoplasms diagnosis, Fibroblast Growth Factor 2 blood, Vascular Endothelial Growth Factor A blood
- Abstract
Introduction: The aim of the present study was to analyze the relationship between the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in breast cancer cells and the corresponding serum levels in individual patients. The study also evaluated the potential of serum levels of the two growth factors as diagnostic markers in a case-control study., Methods: VEGF expression and bFGF expression were determined in 62 and 63 tumor samples, respectively. Serum VEGF and bFGF levels were determined in 54 and 65 healthy women and in 69 and 73 breast cancer patients, respectively, using a quantitative sandwich enzyme immunoassay technique., Results: A direct correlation was observed between VEGF expression and bFGF expression in individual tumors (P = 0.001) and between serum levels (P = 0.038) in individual patients, but not between tumor cell expression and the corresponding serum level for either growth factor. Median values of serum levels in healthy women and breast cancer patients were not different for VEGF (P = 0.055), but were significantly different for bFGF (P < 0.001). The receiver operating characteristic curve identified a serum bFGF concentration of 1.0 pg/ml, with 84.9% sensitivity and 63.1% specificity, as the best cut-off value to discriminate between healthy women and breast cancer patients. An age-based subgroup analysis showed that serum values of patients older than 70 years of age mainly contributed to the high accuracy., Conclusions: Our data repropose bFGF as a noninvasive diagnostic tool for breast cancer.
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- 2004
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36. p27/kip1 expression in normal epithelium, benign and neoplastic breast lesions.
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De Paola F, Vecci AM, Granato AM, Liverani M, Monti F, Innoceta AM, Gianni L, Saragoni L, Ricci M, Falcini F, Amadori D, and Volpi A
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- Breast Neoplasms pathology, Carcinoma in Situ metabolism, Carcinoma in Situ pathology, Cyclin-Dependent Kinase Inhibitor p27, Cyclin-Dependent Kinases antagonists & inhibitors, Disease Progression, Epithelial Cells metabolism, Fibroadenoma metabolism, Fibroadenoma pathology, Immunoenzyme Techniques, Neoplasm Invasiveness, Precancerous Conditions metabolism, Tumor Cells, Cultured, Breast metabolism, Breast Neoplasms metabolism, Cell Cycle Proteins metabolism, Enzyme Inhibitors metabolism, Tumor Suppressor Proteins metabolism
- Abstract
The development of cancer in the breast and in other sites is a complex process requiring a number of different genetic and epigenetic alterations. The accumulation of the genetic changes is thought to underlie the progression from precancerous lesions to carcinomas. The expression of p27/kip1 protein, a cyclin-dependent kinase inhibitor, was investigated by immunohistochemistry in normal epithelial specimens, benign alterations, and malignant lesions of the breast. The number of p27/kip1-positive cells ranged from none to more than 98% in the overall series. Wide ranges of p27/kip1-positive cells were consistently observed within each histological category, but the median value progressively decreased in typical hyperplasia and fibroadenoma, with an even more marked reduction in malignant lesions, compared with normal epithelium. Moreover, the percentage of cells expressing p27/kip1 in tumours was about three times lower in invasive than in in situ lesions and was inversely related to tumour size, but not to lymph node involvement. In conclusion, the degree to which p27 expression is altered in typical hyperplastic lesions and fibroadenomas indicates that the deregulation of p27 may occur very early on during breast cell transformation, but the usefulness of its determination to categorize subgroups of lesions at different risk of evolution remains somewhat doubtful., (Copyright 2001 John Wiley & Sons, Ltd.)
- Published
- 2002
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