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116 results on '"Borgna, Francesca"'

1. First-in-human administration of terbium-161-labelled somatostatin receptor subtype 2 antagonist ([161Tb]Tb-DOTA-LM3) in a patient with a metastatic neuroendocrine tumour of the ileum

Author

Fricke, Julia, Westerbergh, Frida, McDougall, Lisa, Favaretto, Chiara, Christ, Emanuel, Nicolas, Guillaume P., Geistlich, Susanne, Borgna, Francesca, Fani, Melpomeni, Bernhardt, Peter, van der Meulen, Nicholas P., Müller, Cristina, Schibli, Roger, and Wild, Damian

Published
2024
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6. First-in-human administration of terbium-161-labelled somatostatin receptor subtype 2 antagonist ([161Tb]Tb-DOTA-LM3) in a patient with a metastatic neuroendocrine tumour of the ileum.

Author

Fricke, Julia, Westerbergh, Frida, McDougall, Lisa, Favaretto, Chiara, Christ, Emanuel, Nicolas, Guillaume P., Geistlich, Susanne, Borgna, Francesca, Fani, Melpomeni, Bernhardt, Peter, van der Meulen, Nicholas P., Müller, Cristina, Schibli, Roger, and Wild, Damian

Subjects
SOMATOSTATIN receptors, NEUROENDOCRINE tumors, LINEAR energy transfer, ILEUM, METASTASIS, COMPUTED tomography
Abstract

This article reports on the first-in-human administration of terbium-161-labelled somatostatin receptor subtype 2 antagonist ([161Tb]Tb-DOTA-LM3) in a patient with a metastatic neuroendocrine tumor of the ileum. The patient had previously received long-acting octreotide and underwent a test infusion of [161Tb]Tb-DOTA-LM3. The study found that [161Tb]Tb-DOTA-LM3 showed promising potential as an alternative to the current standard peptide receptor radionuclide therapy for patients with metastatic gastroenteropancreatic neuroendocrine tumors. The research was funded by the Swiss National Science Foundation and supported by other organizations. The study was conducted in accordance with ethical guidelines and the patient provided informed consent. [Extracted from the article]

Published
2024
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7. The development of terbium-155 and terbium-161 towards radiotheragnostic clinical applications

Author

Favaretto, Chiara, primary, Talip, Zeynep, additional, Grundler, Pascal, additional, Geistlich, Susanne, additional, Landolt, Stefan, additional, Schmid, David, additional, Zeevaart, Jan, additional, Köster, Ulli, additional, Zhang, Hui, additional, Borgna, Francesca, additional, Mueller, Cristina, additional, Schibli, Roger, additional, and van der Meulen, Nicholas, additional

Published
2022
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12. Preclinical investigations using [$^{177}$Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer

Author

Tschan, Viviane J, Borgna, Francesca, Busslinger, Sarah D, Stirn, Martina, Rodríguez, Josep M Monné, Bernhardt, Peter, Schibli, Roger; https://orcid.org/0000-0002-1537-3833, Müller, Cristina; https://orcid.org/0000-0001-9357-9688, Tschan, Viviane J, Borgna, Francesca, Busslinger, Sarah D, Stirn, Martina, Rodríguez, Josep M Monné, Bernhardt, Peter, Schibli, Roger; https://orcid.org/0000-0002-1537-3833, and Müller, Cristina; https://orcid.org/0000-0001-9357-9688

Abstract

[$^{177}$Lu]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [$^{177}$Lu]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [$^{177}$Lu]Lu-PSMA-617 and the previously developed [$^{177}$Lu]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands’s therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [$^{177}$Lu]Lu-Ibu-DAB-PSMA (~ 6.6 Gy/MBq) was more effective to inhibit tumor growth than [$^{177}$Lu]Lu-PSMA-617 (~ 4.5 Gy/MBq) and only moderately less potent than [$^{177}$Lu]Lu-PSMA-ALB-56 (~ 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [$^{177}$Lu]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [$^{177}$Lu]Lu-Ibu-DAB-PSMA or [$^{177}$Lu]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [$^{177}$Lu]Lu-Ibu-DAB-PSMA or 30 MBq [$^{177}$Lu]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [$^{177}$Lu]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant

Published
2022

13. The RIB production target for the SPES project

Author

Monetti, Alberto, Andrighetto, Alberto, Petrovich, Carlo, Manzolaro, Mattia, Corradetti, Stefano, Scarpa, Daniele, Rossetto, Francesco, Martinez Dominguez, Fernando, Vasquez, Jesus, Rossignoli, Massimo, Calderolla, Michele, Silingardi, Roberto, Mozzi, Aldo, Borgna, Francesca, Vivian, Gianluca, Boratto, Enrico, Ballan, Michele, Prete, Gianfranco, and Meneghetti, Giovanni

Published
2015
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14. Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms

Author

Borgna, Francesca, primary, Haller, Stephanie, additional, Rodriguez, Josep M. Monné, additional, Ginj, Mihaela, additional, Grundler, Pascal V., additional, Zeevaart, Jan Rijn, additional, Köster, Ulli, additional, Schibli, Roger, additional, van der Meulen, Nicholas P., additional, and Müller, Cristina, additional

Published
2021
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16. Production of Mass-Separated Erbium-169 Towards the First Preclinical in vitro Investigations

Author

Talip, Zeynep, Borgna, Francesca, Müller, Cristina, Schibli, Roger, and van der Meulen, Nicholas P.

Subjects
in vitro studies, electromagnetic isotope separation, lanthanide-separation, activity standardization, laser resonance ionization, Er-169
Abstract

The β−-particle-emitting erbium-169 is a potential radionuclide toward therapy of metastasized cancer diseases. It can be produced in nuclear research reactors, irradiating isotopically-enriched 168Er2O3. This path, however, is not suitable for receptor-targeted radionuclide therapy, where high specific molar activities are required. In this study, an electromagnetic isotope separation technique was applied after neutron irradiation to boost the specific activity by separating 169Er from 168Er targets. The separation efficiency increased up to 0.5% using resonant laser ionization. A subsequent chemical purification process was developed as well as activity standardization of the radionuclidically pure 169Er. The quality of the 169Er product permitted radiolabeling and pre-clinical studies. A preliminary in vitro experiment was accomplished, using a 169Er-PSMA-617, to show the potential of 169Er to reduce tumor cell viability., Frontiers in Medicine, 8, ISSN:2296-858X

Published
2021

17. Preclinical investigations using [177Lu]Lu-Ibu-DAB-PSMA toward its clinical translation for radioligand therapy of prostate cancer.

Author

Tschan, Viviane J., Borgna, Francesca, Busslinger, Sarah D., Stirn, Martina, Rodriguez, Josep M. Monné, Bernhardt, Peter, Schibli, Roger, and Müller, Cristina

Subjects
*PROSTATE cancer, *CANCER treatment, *TUMOR growth, *TREATMENT effectiveness
Abstract

[177Lu]Lu-Ibu-DAB-PSMA was previously characterized with moderate albumin-binding properties enabling high tumor accumulation but reasonably low retention in the blood. The aim of this study was to investigate [177Lu]Lu-Ibu-DAB-PSMA in preclinical in vivo experiments and compare its therapeutic efficacy and potential undesired side effects with those of [177Lu]Lu-PSMA-617 and the previously developed [177Lu]Lu-PSMA-ALB-56. BALB/c nude mice without tumors were investigated on Day 10 and 28 after injection of 10 MBq radioligand. It was revealed that most plasma parameters were in the same range for all groups of mice and histopathological examinations of healthy tissue did not show any alternations in treated mice as compared to untreated controls. Based on these results, a therapy study over twelve weeks was conducted with PC-3 PIP tumor-bearing mice for comparison of the radioligands's therapeutic efficacy up to an activity of 10 MBq (1 nmol) per mouse. In agreement with the increased mean absorbed tumor dose, [177Lu]Lu-Ibu-DAB-PSMA (~ 6.6 Gy/MBq) was more effective to inhibit tumor growth than [177Lu]Lu-PSMA-617 (~ 4.5 Gy/MBq) and only moderately less potent than [177Lu]Lu-PSMA-ALB-56 (~ 8.1 Gy/MBq). As a result, the survival of mice treated with 2 MBq of an albumin-binding radioligand was significantly increased (p < 0.05) compared to that of mice injected with [177Lu]Lu-PSMA-617 or untreated controls. The majority of mice treated with 5 MBq or 10 MBq [177Lu]Lu-Ibu-DAB-PSMA or [177Lu]Lu-PSMA-ALB-56 were still alive at study end. Hemograms of immunocompetent mice injected with 30 MBq [177Lu]Lu-Ibu-DAB-PSMA or 30 MBq [177Lu]Lu-PSMA-617 showed values in the same range as untreated controls. This was, however, not the case for mice treated with [177Lu]Lu-PSMA-ALB-56 which revealed a drop in lymphocytes and hemoglobin at Day 10 and Day 28 after injection. The data of this study demonstrated a significant therapeutic advantage of [177Lu]Lu-Ibu-DAB-PSMA over [177Lu]Lu-PSMA-617 and a more favorable safety profile as compared to that of [177Lu]Lu-PSMA-ALB-56. Based on these results, [177Lu]Lu-Ibu-DAB-PSMA may has the potential for a clinical translation. [ABSTRACT FROM AUTHOR]

Published
2022
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18. Terbium-149 for targeted alpha therapy

Author

Borgna, Francesca, Favaretto, Chiara, Grundler, Pascal, Johnston, Karl, Köster, Ulli, Müller, Cristina, Talip, Zeynep, and van der Meulen, Nick

Subjects
Detectors and Experimental Techniques
Published
2021

22. Preliminary evaluation of the production of non-carrier added 111Ag as core of a therapeutic radiopharmaceutical in the framework of ISOLPHARM_Ag experiment

Author

Ballan, Michele, primary, Tosato, Marianna, additional, Verona, Marco, additional, Caeran, Michele, additional, Borgna, Francesca, additional, Vettorato, Elisa, additional, Corradetti, Stefano, additional, Zangrando, Lisa, additional, Sgaravatto, Massimo, additional, Verlato, Marco, additional, Asti, Mattia, additional, Marzaro, Giovanni, additional, Mastrotto, Francesca, additional, Di Marco, Valerio, additional, Maniglio, Devid, additional, Bisio, Alessandra, additional, Motta, Antonella, additional, Quaranta, Alberto, additional, Zenoni, Aldo, additional, Pastore, Paolo, additional, Realdon, Nicola, additional, and Andrighetto, Alberto, additional

Published
2020
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23. Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Potential Theranostic Applications

Author

Nizou, Gwladys, primary, Favaretto, Chiara, additional, Borgna, Francesca, additional, Grundler, Pascal V., additional, Saffon-Merceron, Nathalie, additional, Platas-Iglesias, Carlos, additional, Fougère, Olivier, additional, Rousseaux, Olivier, additional, van der Meulen, Nicholas P., additional, Müller, Cristina, additional, Beyler, Maryline, additional, and Tripier, Raphaël, additional

Published
2020
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24. Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Po-Tential Theranostic Applications

Author

Nizou, Gwladys, primary, Favaretto, Chiara, primary, Borgna, Francesca, primary, Grundler, Pascal V., primary, Saffon-Merceron, Nathalie, primary, Platas-Iglesias, Carlos, primary, Fougère, Olivier, primary, Rousseaux, Olivier, primary, van der Meulen, Nicholas, primary, Müller, Cristina, primary, Beyler, Maryline, primary, and Tripier, Raphael, primary

Published
2020
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31. Novel Methods for the Production of Radionuclides of Medical Interest With Accelerators

Author

Corradetti, Stefano, Andrighetto, Alberto, Ballan, Michele, Borgna, Francesca, Di Marco, Valerio, Marzaro, Giovanni, and Realdon, Nicola

Subjects
Applications, Accelerator Physics
Abstract

Radionuclides for radiopharmaceuticals preparation are currently produced in cyclotrons, generators or nuclear reactors. However, none of these modes is free from serious issues, like: high costs of targets, production of undesired radionuclide contaminants, long and expensive separation methods and formation of long-lived radioactive wastes. For this purpose, novel methods are being developed for the production of highly pure radionuclides. The ISOL (Isotope Separation On-Line) method can be applied to produce high purity radionuclides of medium and heavy masses. ISOL is nowadays established as a major method for the production of high intensity and high quality radioactive ion beams for nuclear physics studies. The SPES-ISOLPHARM project at INFN-LNL (Istituto Nazionale di Fisica Nucleare ’ Laboratori Nazionali di Legnaro) aims to provide a feasibility study for an innovative technology for the production of high specific activity radionuclides based on the ISOL method. The ongoing experimental activities on primary and secondary (ion collectors) targets production, construction and testing of the selection and transport apparatus will be presented., Proceedings of the 14th Int. Conf. on Heavy Ion Accelerator Technology, HIAT2018, Lanzhou, China

Published
2019
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32. In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs

Author

Schniering, Janine, Borgna, Francesca, Siwowska, Klaudia, Benešová, Martina, Cohrs, Susan, Hasler, Roger, van der Meulen, Nicholas P, Maurer, Britta, Schibli, Roger, Müller, Cristina, University of Zurich, and Müller, Cristina

Subjects
1313 Molecular Medicine, 3002 Drug Discovery, 10051 Rheumatology Clinic and Institute of Physical Medicine, 3003 Pharmaceutical Science, 610 Medicine & health
Published
2018

34. THE SPES FACILITY AS AN INTENSE NEUTRON SOURCE: RADIATION RESISTANCE OF POLYMERIC MATERIALS AND RESIDUAL ACTIVATION CALCULATIONS

Author

Borgna Francesca, Aldo Zenoni, Corradetti Stefano, Giorgio Donzella, Antonietta Donzella, Monetti Alberto, Ballan Michele, Andrea Avanzini, M. Ferrari, Davide Battini, Rossignoli Massimo, Lisa Centofante, Stefano Pandini, D'Agostini Fabio, Andrighetto Alberto, Fabio Bignotti, Scarpa Daniele, Turcato Davide, and Manzolaro Mattia

Subjects
radiation resistance, Materials science, neutron damage, Monte Carlo calculations, polymeric materials, neutron activation, O-ring prediction map, Component failure, ISOL facility, Monte Carlo calculations, neutron activation, neutron damage, O-ring prediction map, radiation resistance, polymeric materials, SPES, SPES, Residual, Neutron damage, Nuclear physics, ISOL facility, Component failure, Media Technology, Neutron source, Radiation resistance, Neutron activation
Published
2018

36. Therapeutic Potential of 47Sc in Comparison to 177Lu and 90Y: Preclinical Investigations

Author

Siwowska, Klaudia, primary, Guzik, Patrycja, additional, Domnanich, Katharina A., additional, Monné Rodríguez, Josep M., additional, Bernhardt, Peter, additional, Ponsard, Bernard, additional, Hasler, Roger, additional, Borgna, Francesca, additional, Schibli, Roger, additional, Köster, Ulli, additional, van der Meulen, Nicholas P., additional, and Müller, Cristina, additional

Published
2019
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41. The ISOLPHARM Project for the Production of High Specific Activity Radionuclides for Medical Applications

Author

Ballan, Michele, Andrighetto, Alberto, Borgna, Francesca, Corradetti, Stefano, Duatti, Adriano, and Realdon, Nicola

Subjects
Cyclotron Applications, Accelerator Physics
Abstract

ISOLPHARM is a branch of the INFN-LNL SPES project*, aimed at the production of radioisotopes for medical applications according to the ISOL technique. Such an innovative method will allow to obtain radiopharmaceuticals with very high specific activity. In this context a primary proton beam, extracted from a cyclotron will directly impinge a target, where the produced isotopes are extracted and accelerated, and finally, after mass separation, only the desired nuclei are deposed on a secondary target. This work is focused in the design and study of the aforementioned production targets for a selected set of isotopes, in particular for 64Cu, 89Sr, 90Y, 125I and 131I. 64Cu will be produced impinging Ni targets, otherwise the SPES UCx target is planned to be used. Different target configurations are being studied by means of the Monte Carlo based code FLUKA for the isotope production calculation and the Finite Element Method based software ANSYS ® for the temperature level evaluation. An appropriate secondary target substrate for implanting the produced isotopes is under study alongside with a system for its dissolution and repartition into radiopharmaceutical doses., Proceedings of the 21st Int. Conf. on Cyclotrons and their Applications, Cyclotrons2016, Zurich, Switzerland

Published
2017
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43. Early Evaluation of Copper Radioisotope Production at ISOLPHARM

Author

Borgna, Francesca, primary, Ballan, Michele, additional, Favaretto, Chiara, additional, Verona, Marco, additional, Tosato, Marianna, additional, Caeran, Michele, additional, Corradetti, Stefano, additional, Andrighetto, Alberto, additional, Di Marco, Valerio, additional, Marzaro, Giovanni, additional, and Realdon, Nicola, additional

Published
2018
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44. UCx target preparations and characterizations

Author

Andrighetto, Alberto, primary, Corradetti, Stefano, additional, Manzolaro, Mattia, additional, Scarpa, Daniele, additional, Monetti, Alberto, additional, Rossignoli, Massimo, additional, Borgna, Francesca, additional, Ballan, Michele, additional, Agostini, Mattia, additional, D’Agostini, Fabio, additional, Ferrari, Matteo, additional, and Zenoni, Aldo, additional

Published
2018
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45. Pharmaceutical development of the ISOL technique for the production of radionuclides and their applications in targeted radionuclide therapy

Author

Borgna, Francesca and Borgna, Francesca

Abstract

Radiopharmaceuticals are the fundamental tool for nuclear medicine procedures, enabling imaging and therapy of cancer after administration of a radioligand. Imaging or therapy are performed with radionuclides that are bound to a ligand, which selectively accumulates into cancer tissues. The discovery of new radionuclides on one side and the optimization of ligands on the other are fundamental parts of the research in the radiopharmaceutical field. In the first part of this thesis work we aimed at the development of a new technique for the production of pure radionuclides. The study was born from the collaboration between the Department of Pharmaceutical and Pharmacological Sciences (DSF) of the University of Padua (UniPD) and the Legnaro National Laboratories (LNL) of the National Institute for Nuclear Physics (INFN), where the Selective Production of Exotic Species (SPES) project is under development. This project aims at the production of Radioactive Ion Beams (RIBs) by means of the Isotope Separation On-Line technique (ISOL), which can be exploited for radionuclides production. Thanks to mass separation, a feature of the ISOL technique, radionuclides can be produced at high purity because isotopic contaminants can be cleared away easily. Suitable secondary targets (chapter 2) were developed to allow ion beams collection, depending on the accelerated ions. To verify the suitability of the method for radionuclides production, tests with accelerated stable ion beams were carried out and are described in chapter 3. The SPES test bench was used for the elements ionization and acceleration. The beams were collected on the produced secondary targets and quantified. The tests were carried out for yttrium, iodine and copper, elements interesting for the production of 90Y, 125/127/131I and 64/67Cu. The ISOL method guarantees the purification of the radionuclides from the isotopic contaminants, but isobaric and pseudo-isobaric contaminants can be present in the beam and thu

Published
2017

46. The SPES Target and Ion Source unit

Author

Manzolaro, Mattia, Monetti, Alberto, Andrighetto, Alberto, Corradetti, Stefano, Borgna, Francesca, Realdon, Nicola, Scarpa, D., Lollo, M., Pasquato, F., Rossignoli, Massimo, Silingardi, R., Mozzi, A., Boratto, E., Ballan, M., Vivian, Gianluca, Sattin, N., Martin, L., Conventi, D., Prete, G., Biasetto, Lisa, Oboe, Roberto, Nicolosi, Piergiorgio, Meneghetti, Giovanni, Colombo, Paolo, Tomaselli, A., Guerzoni, M., Michinelli, R., Margotti, A., Cristofolini, I., Mariotti, E., Ferrari, M., and Zenoni, A.

Published
2016

47. Design and Testing of the SPES Target – Ion Source Temperature Monitoring System

Author

M. Ballan1, 2, Andrighetto, A., Manzolaro, M., Corradetti, S., Borgna, Francesca, Monetti, Alberto, Scarpa, D., Lollo, M., Rossignoli, Massimo, Silingardi, R., Mozzi, A., Boratto, E., Vivian, G., Sattin, N., Martin, L., Conventi, D., Pasquato, F., Prete, G., Biasetto, Lisa, Oboe, Roberto, Nicolosi, Piergiorgio, Meneghetti, Giovanni, Colombo, Paolo, Realdon, Nicola, Tomaselli, A., Guerzoni, M., Michinelli, R., Margotti, A., Cristofolini, I., Mariotti, E., Ferrari, M., and Zenoni, A.

Published
2016

48. The SPES RIB Production Complex

Author

Andrighetto, Alberto, Ballan, Michele, Bisoffi, Giovanni, Boratto, Enrico, Borgna, Francesca, Corradetti, Stefano, Ferrari, Marco, Guerzoni, Marco, Manzolaro, Mattia, Margotti, Anselmo, Meneghetti, Giovanni, Monetti, Alberto, Mozzi, Aldo, Oboe, Roberto, Prete, Gianfranco, Rossignoli, Massimo, Scarpa, Daniele, Silingardi, Roberto, Vivian, Gianluca, and Zenoni, Aldo

Subjects
Radioactive Ion Beam Facilities, Accelerator Physics
Abstract

The SPES project at Laboratori di Legnaro of INFN (Italy) is concentrating on the production of neutron-rich radioactive nuclei by the Uranium fission at a rate of 10¹³ fission/s. The emphasis to neutron-rich isotopes is justified by the fact that this vast territory has been little explored in the last years. The Radioactive Ion Beam (RIB) will be produced by ISOL technique using the 40 MeV proton-induced fission on a Direct Target of UCx. The most critical element of the SPES project is the Multi-Foil Direct Target. Up to day the proposed target represents an innovation in term of capability to sustain the primary beam power of about 8kW. The reaction products are extracted from the target by thermal process, ionized and injected into the re-accelerator stage. During the talk will be presented the recent developments on the fabrication, characterization, and on-line testing of carbide targets. In addition, developments related to the ion-source activities using the surface, plasma and laser ion sources technique it will be reported. Finally, will be shown the experimental test results on target remote handling., Proceedings of the 13th Heavy Ion Accelerator Technology Conference, HIAT2015, Yokohama, Japan

Published
2016
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50. Time dependent thermal study for the SPES Target – Ion Source system

Author

Ballan, M., Manzolaro, Mattia, Andrighetto, Alberto, Scarpa, D., Lollo, M., Rossignoli, Massimo, Silingardi, R., Corradetti, Stefano, Borgna, Francesca, Vasquez, J., Monetti, Alberto, Calderolla, M., Mozzi, A., Boratto, E., Conventi, D., Visentin, E., Prete, G., Biasetto, Lisa, Oboe, Roberto, Bertocco, Matteo, Nicolosi, Piergiorgio, Meneghetti, Giovanni, Colombo, Paolo, Tomaselli, ANGELO RODOLFO, Guerzoni, M., Michinelli, R., Margotti, A., Cristofolini, I., Mariotti, E., and Zenoni, A.

Published
2015

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