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1. R&D activities on RF contacts for the ITER ion cyclotron resonance heating launcher

Author

M. Shannon, Stéphane Rasio, B. Beaumont, Marco Pagano, Jean-Marc Delaplanche, K. J. Nicholls, Jean-Michel Bernard, R. Volpe, David Mouyon, D. Thouvenin, A. Argouarch, J. C. Hatchressian, Rob Bamber, Lionel Toulouse, Terence Vigne, Frédéric Durodié, J.M. Verger, J. C. Patterlini, S. Larroque, Philippe Lebourg, P. U. Lamalle, A. Martinez, Karl Vulliez, V. Cantone, Gilles Lombard, Julien Hillairet, Patrick Mollard, B. Soler, Institut de Recherche sur la Fusion par confinement Magnétique (IRFM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), EURATOM/CCFE Fusion Association, Culham Science Centre [Abingdon], ITER organization (ITER), and Ecole Royale Militaire / Koninklijke Militaire School (ERM KMS)

Subjects
Physics - Instrumentation and Detectors, Materials science, Mechanical Engineering, Nuclear engineering, [SPI.PLASMA]Engineering Sciences [physics]/Plasmas, Cyclotron, ICRH, Contact force, law.invention, Stress (mechanics), [SPI.ELEC]Engineering Sciences [physics]/Electromagnetism, Resonator, Nuclear Energy and Engineering, Ion cyclotron resonance heating, RF Contacts, [PHYS.PHYS.PHYS-PLASM-PH]Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph], law, ITER, Test platform, Thermal, Brazing, General Materials Science, Civil and Structural Engineering
Abstract

Embedded RF contacts are integrated within the ITER ICRH launcher to allow assembling, sliding and to lower the thermo-mechanical stress. They have to withstand a peak RF current up to 2.5 kA at 55 MHz in steady-state conditions, in the vacuum environment of themachine.The contacts have to sustain a temperature up to 250{\textdegree}Cduring several days in baking operations and have to be reliable during the whole life of the launcher without degradation. The RF contacts are critical components for the launcher performance and intensive R&D is therefore required, since no RF contactshave so far been qualified at these specifications. In order to test and validate the anticipated RF contacts in operational conditions, CEA has prepared a test platform consisting of a steady-state vacuum pumped RF resonator. In collaboration with ITER Organization and the CYCLE consortium (CYclotronCLuster for Europe), an R&D program has been conducted to develop RF contacts that meet the ITER ICRH launcher specifications. A design proposed by CYCLE consortium, using brazed lamellas supported by a spring to improve thermal exchange efficiency while guaranteeing high contact force, was tested successfully in the T-resonator up to 1.7 kA during 1200 s, but failed for larger current values due to a degradation of the contacts. Details concerning the manufacturing of the brazed contacts on its titanium holder, the RF tests results performed on the resonator and the non-destructive tests analysis of the contacts are given in this paper., Comment: Fusion Engineering and Design, Elsevier, 2015, Available online 21 April 2015

Published
2015

2. Critical heat flux acoustic detection: Methods and application to ITER divertor vertical target monitoring

Author

S. Constans, M. Richou, X. Courtois, Frederic Escourbiac, and V. Cantone

Subjects
Materials science, Critical heat flux, Mechanical Engineering, Divertor, Nuclear engineering, Flow (psychology), Plasma radiation, Plasma, Acoustic wave, Cooling channel, Volumetric flow rate, Nuclear Energy and Engineering, General Materials Science, Civil and Structural Engineering
Abstract

Actively cooled plasma facing components (PFCs) have to exhaust high heat fluxes from plasma radiation and plasma–wall interaction. Critical heat flux (CHF) event may occur in the cooling channel due to unexpected heat loading or operational conditions, and has to be detected as soon as possible. Therefore it is essential to develop means of monitoring based on precursory signals providing an early detection of this destructive phenomenon, in order to be able to stop operation before irremediable damages appear. Capabilities of CHF early detection based on acoustic techniques on PFC mock-ups cooled by pressurised water were already demonstrated. This paper addresses the problem of the detection in case of flow rate reduction and of flow dilution resulting from multiple plasma facing units (PFU) which are hydraulically connected in parallel, which is the case of ITER divertor. An experimental study is launched on a dedicated mock-up submitted to heat loads up to the CHF. It shows that the measurement of the acoustic waves, generated by the cooling phenomena, allows the CHF detection in conditions similar to that of the ITER divertor, with a reasonable number of sensors. The paper describes the mock-ups and the tests sequences, and comments the results.

Published
2013

3. Non-destructive examination of the bonding interface in DEMO divertor fingers

Author

Marc Missirlian, Caroline Hernandez, Nicolas Vignal, V. Cantone, Prachai Norajitra, Marianne Richou, and Luigi Spatafora

Subjects
Fabrication, Materials science, Mechanical Engineering, Nuclear engineering, Divertor, chemistry.chemical_element, Tungsten, Nuclear Energy and Engineering, chemistry, Heat flux, visual_art, Heat transfer, Thermography, Water cooling, visual_art.visual_art_medium, General Materials Science, Tile, Civil and Structural Engineering
Abstract

Plasma facing components (PFCs) with tungsten (W) armor materials for DEMO divertor require a high heat flux removal capability (at least 10 MW/m2 in steady-state conditions). The reference divertor PFC concept is a finger with a tungsten tile as a protection and sacrificial layer brazed to a thimble made of tungsten alloy W – 1% La2O3 (WL10). Defects may be located at the W thimble to W tile interface. As the number of fingers is considerable (>250,000), it is then a major issue to develop a reliable control procedure in order to control with a non-destructive examination the fabrication processes. The feasibility for detecting defect with infrared thermography SATIR test bed is presented. SATIR is based on the heat transient method and is used as an inspection tool in order to assess component heat transfer capability. SATIR tests were performed on fingers integrating or not the complex He cooling system (steel cartridge with jet holes). Millimeter size artificial defects were manufactured and their detectability was evaluated. Results of this study demonstrate that the SATIR method can be considered as a relevant non-destructive technique examination for the defect detection of DEMO divertor fingers.

Published
2013

4. Improvement of non destructive infrared test bed SATIR for examination of actively cooled tungsten armour Plasma Facing Components

Author

Ph. Magaud, X. Courtois, Marc Missirlian, V. Cantone, M. Richou, N. Vignal, and C. Desgranges

Subjects
Thermonuclear fusion, Tokamak, Materials science, Armour, Mechanical Engineering, Divertor, Nuclear engineering, Ultrasonic testing, law.invention, Low emissivity, Nuclear Energy and Engineering, law, Thermography, Emissivity, General Materials Science, Civil and Structural Engineering
Abstract

For steady state (magnetic) thermonuclear fusion devices which need large power exhaust capability and have to withstand heat fluxes in the range 10–20 MW m−2, advanced Plasma Facing Components (PFCs) have been developed. The importance of PFCs for operating tokamaks requests to verify their manufacturing quality before mounting. SATIR is an IR test bed validated and recognized as a reliable and suitable tool to detect cooling defaults on PFCs with CFC armour material. Current tokamak developments implement metallic armour materials for first wall and divertor; their low emissivity causes several difficulties for infrared thermography control. We present SATIR infrared thermography test bed improvements for W monoblocks components without defect and with calibrated defects. These results are compared to ultrasonic inspection. This study demonstrates that SATIR method is fully usable for PFCs with low emissivity armour material.

Published
2013

5. Recent development toward the use of infrared thermography as a non destructive technique for defect detection in tungsten plasma facing components

Author

Marianne Richou, Frederic Escourbiac, Marc Missirlian, V. Cantone, N. Vignal, and B. Riccardi

Subjects
Nuclear and High Energy Physics, Materials science, business.industry, Infrared, Divertor, chemistry.chemical_element, Plasma, Tungsten, Heat sink, Optics, Nuclear Energy and Engineering, chemistry, Nondestructive testing, visual_art, Thermography, visual_art.visual_art_medium, General Materials Science, Tile, business
Abstract

For ITER divertor Plasma Facing Components (PFCs), tens of thousands of armor/heat sink interfaces will be produced by the industry. Statistically, there is a probability that interfaces with defects be delivered. The defect detection with Non Destructive Techniques (NDT) is then a major challenge. NDT should provide a detectability threshold below the critical defect size. For a defect located all along the axial length of a component, the critical defect size at interface is about 50° for W monoblock (resp. 6 mm for W flat tile). It is defined with thermo-mechanical fatigue behaviour under 10 MW m−2 for W monoblock (resp. 5 MW m−2 for W flat tile). The purpose of this paper is to study the armor/heat sink defect detection of tungsten components (flat tile and monoblock geometries) with SATIR test bed (Infrared thermography NDT). We demonstrate that SATIR is a relevant NDT to detect defect of W components.

Published
2011

6. Fatigue lifetime of repaired high heat flux components for ITER divertor

Author

S. Constans, B. Riccardi, N. Vignal, C. Desgranges, M. Richou, V. Cantone, P. Gavila, and Marc Missirlian

Subjects
Thermal fatigue, Materials science, Flux (metallurgy), Nuclear Energy and Engineering, Mechanical Engineering, Nuclear engineering, Divertor, General Materials Science, High heat, Civil and Structural Engineering
Abstract

Thermal fatigue behaviour of repaired monoblocks was assessed from High Heat Flux (HHF) tests up to 20 MW m−2 on 11 components. Among these components, 8 monoblocks were repaired (2 CFC and 6 tungsten). These components were manufactured by two EU industries: ANSALDO Ricerche and PLANSEE. Non destructive examination was performed on SATIR thermography test bed before and after HHF tests. SATIR results show that repaired monoblocks have a good thermal exhaust capability before HHF tests. For all monoblocks, no degradation of thermal properties was noticed during cycles at 10 MW m−2. After hundreds of cycles at 20 MW m−2, two W repaired monoblock melted. Post-HHF SATIR examination revealed a degradation of thermal properties which is systematic for W melted monoblocks and non-systematic for W repaired ones. For CFC repaired monoblocks, no damage was observed up to 20 MW m−2. For the first ITER divertor set, specifications for the pre-qualification are that CFC (Resp. W) components have to sustain in steady state 1000 cycles at 10 MW m−2 (Resp. 3 MW m−2) followed by 1000 cycles at 20 MW m−2 (Resp. 5 MW m−2). For the first ITER divertor set, the repair process is validated for CFC and W monoblocks.

Published
2011

7. Infrared thermography inspection of the ITER vertical target qualification prototypes manufactured by European industry using SATIR

Author

V. Cantone, Marianne Richou, Mario Merola, Frederic Escourbiac, N. Vignal, S. Constans, A. Durocher, and B. Riccardi

Subjects
Engineering, Tokamak, business.industry, Mechanical Engineering, Nuclear engineering, Divertor, Context (language use), Fusion power, law.invention, Nuclear Energy and Engineering, Heat flux, law, Thermography, General Materials Science, business, High heat, Heat flow, Civil and Structural Engineering
Abstract

High heat flux loaded components which will be installed in the ITER Divertor require a heat flux removal capability in the range 5–10 MW/m2 at steady-state and up to 20 MW/m2 in transients. Within the ITER plasma facing components procurement context, each party should demonstrate its technical capability to carry out the manufacturing with the required quality. This is achieved through the successful manufacturing and testing of medium-size qualification prototypes. Each Qualification Prototype consists of three high heat flux units mounted onto an actively cooled supporting structure. Currently, the SATIR method has been identified by the ITER Organization as the basic test to decide upon the final acceptance of the ITER Divertor components. SATIR testing was performed on each CFC part of European HHF units prior to the insertion of the twisted tape and prior to assembling the units onto the steel support structure. The paper deals with SATIR results of all qualification prototypes manufactured by European industry.

Published
2009

8. Experimental activity on the definition of acceptance criteria for the ITER divertor plasma facing components

Author

B. Riccardi, Marianne Richou, N. Vignal, S. Constans, V. Cantone, Mario Merola, I. Bobin, J.L. Jouvelot, Frederic Escourbiac, and A. Durocher

Subjects
Tokamak, Materials science, Armour, Mechanical Engineering, Divertor, Nuclear engineering, Fusion power, Heat sink, law.invention, Nuclear Energy and Engineering, Heat flux, law, Acceptance testing, visual_art, visual_art.visual_art_medium, General Materials Science, Tile, Civil and Structural Engineering
Abstract

Tens of thousands of armor/heat sink joints will be produced by the industry during the manufacturing of ITER divertor PFC, statistically, there is a probability that joints with defects be delivered. The purpose of this paper is to study the detection and evolution during operation of calibrated defects artificially implemented on samples, as an experimental basis for the definition of acceptance criteria for the bond armor/heat sink in the frame of industrial manufacturing conditions.It was found that current CFC monoblock design option was compatible with the heat loads specified at the lower part of the vertical target (up to 20 MW/m2), including the presence of armor/heat sink defects (up to 50° extension for a location at 0° or 45°) detectable with NDE techniques developed in Europe (US, SATIR). The current W monoblock design appeared suitable for the upper part of the vertical target with defects extension up to 50°, but is not adapted for heat flux of 20 MW/m2. The studied W flat tile design proved to be compatible with fluxes of 5 MW/m2 but unable to sustain cycling fluxes of 10 MW/m2.

Published
2009

9. Investigation on Thermal Strain in Full Size ITER Conductors

Author

Denis Bessette, H. Cloez, P. Decool, and V. Cantone

Subjects
Materials science, Capacitive sensing, Nuclear engineering, Superconducting magnet, Fusion power, Condensed Matter Physics, Electronic, Optical and Magnetic Materials, Conductor, Thermal conductivity, Nuclear magnetic resonance, Operating temperature, Electromagnetic coil, Electrical and Electronic Engineering, Electrical conductor
Abstract

The TF magnetic system of the international thermonuclear experimental reactor (ITER) will be composed of 18 superconducting coils assembled in a torus. The design of these large coils relies on the use of a circular cable-in-conduit conductor (CICC) composed of a cable of about one thousand twisted Nb3Sn and copper strands embedded in a thin steel jacket. The different thermal contractions of the materials composing this conductor during the cool down from the Nb3Sn heat treatment reaction temperature (about 920 K) to the operating temperature (about 5 K) result in a compressive strain on the superconducting Nb3Sn filaments which leads to a degradation of the conductor critical current. The qualification of the ITER conductor prototypes will be performed by testing short straight full size samples in the unique European test facility SULTAN at PSI (Switzerland). A comparison of the performance of the toroidal field model coil (TFMC) conductor in a short straight sample and in the coil has shown indications that the sample performance is better, apparently because the thermal strain in Nb3Sn is lower. It looks possible that this could have been caused by a slippage between the cable and the jacket in the joints at the sample ends during the heat treatment. In this case, these kind of short straight samples could not be relevant for conductor qualification. An investigation on the thermal strain by destructive examination of different TFMC conductor samples, including one leg of the TFMC short sample tested in 1999 in the SULTAN facility, was performed at CEA Cadarache. The paper reports on the different strain measurements, proposes an analytical approach of the results in order to conclude on the relevance of straight samples.

Published
2008

10. Single daily dose of cefodizime in patients with community-acquired pneumonia: an open-label, controlled, randomized study. The Italian Multicentre Community-Acquired Pneumonia Group

Author

M, De Palma, D, Rocchi, G, Canepa, A, Peri, and V, Cantone

Subjects
Adult, Male, Adolescent, Ceftriaxone, Cefotaxime, Middle Aged, Injections, Intramuscular, Cephalosporins, Community-Acquired Infections, Double-Blind Method, Italy, Pneumonia, Bacterial, Humans, Female, Aged, Half-Life
Abstract

The objective of this study was to compare the clinical and bacteriologic efficacy and safety of cefodizime 1 g intramuscularly (IM) once daily (group A) versus cefodizime 1 g IM twice daily (group B) and versus ceftriaxone 1 g IM once daily (group C) in patients with community-acquired pneumonia. A total of 298 patients, affected by bronchopneumonia or pneumonia with known or suspected bacterial cause, new focal signs on examination of chest, and radiographic evidence of a recent infiltrate, were randomized in three comparable groups. The infection was rated as mild, moderate, or severe. A total of 283 patients were assessable for efficacy: 95 in group A, 94 in group B, and 94 in group C. Mean (+/- SD) duration of treatment was 5.96 +/- 1.39 days in group A, 6.24 +/- 1.57 days in group B, and 6.66 +/- 1.95 days in group C. Symptoms such as purulent sputum, cough, and dyspnea improved significantly after treatment in all groups; temperature normalized by about day 3. Clinical efficacy was rated good in 94.74% of patients in group A, in 92.55% in group B, and in 87.23% in group C. Positive bacteriologic cultures were obtained before treatment from 144 patients: bacteriologic responses were rated good in 98.11%, 98.08%, and 92.80% in groups A, B, and C, respectively. No significant differences were found between the three treatment groups for any measures of clinical efficacy. No serious adverse event occurred in any of the groups. We conclude that cefodizime 1 g IM once daily is an effective dosing regimen in the treatment of patients with community-acquired pneumonia.

Published
1995

11. Assessment of CFC grades under thermal fatigue for the ITER inner vertical target

Author

S. Constans, C. Desgranges, M. Richou, B. Riccardi, V. Cantone, P. Gavila, Marc Missirlian, and N. Vignal

Subjects
Thermal fatigue, Materials science, Heat flux, Armour, Acceptance testing, Nuclear engineering, Composite number, Thermal, Erosion, Temperature cycling, Condensed Matter Physics, Mathematical Physics, Atomic and Molecular Physics, and Optics
Abstract

For plasma-facing components (PFCs), carbon-fiber composite (CFC) armor material should have specific technical requirements. CFCs must have good mechanical and thermal properties suitable for the PFC manufacturing process, in-service needs and inspection requirements. Inspection after manufacturing and thermal behaviour under thermal fatigue loads of PFCs made of different CFC grades (N31, NB31, N11, NB41, DMS814, DMS780, Dunlop 3D and SGL Sigrabond) were studied. After manufacturing, all the components satisfied the acceptance criteria, and components manufactured with CFCs with the same fibers in the x- and y-directions have a better heat removal capability than components manufactured with CFCs with fibers different in the x- and y-directions. High heat flux-tested components endured correctly the thermal cycling (up to 1000 cycles at 20 MW m−2) without water leakage, but for a few monoblock tiles, depending on the CFC grade, erosion was observed.

Published
2011

12. Hematoporphyrin derivative photoradiation therapy in murine solid tumors

Author

Angelo Nicolin, L. Ricci, Ornella Marelli, P. Franco, Rinaldo Cubeddu, V. Cantone, A. Andreoni, and Gianfranco Canti

Subjects
Cancer Research, Pathology, medicine.medical_specialty, Lung Neoplasms, Fibrosarcoma, Mice, Inbred Strains, Metastatic tumor, chemistry.chemical_compound, Mice, medicine, Animals, Fiber Optic Technology, Red light, Melanoma, Optical Fibers, Laser light, Hematoporphyrin, business.industry, medicine.disease, Hematoporphyrins, Oncology, chemistry, Photochemotherapy, Photoradiation Therapy, Laser Therapy, business, Median survival, Neoplasm Transplantation
Abstract

The cytocidal activity of light-activated hematoporphyrin derivative (Hpd) in experimental and human tumors is under investigation in many laboratories. This activity is based upon preferential incorporation of Hpd in malignant tissues and its photosensibilization by red light. Treatment of mice bearing MS-2 fibrosarcoma and B 16 melanoma, a metastatic tumor, with Hpd and laser light, externally or delivered through a quartz fiber optic imbedded directly into the tumor, significantly prolonged the median survival time. This therapy was compared with surgical excision of primary tumors, and preliminary results on metastatic neoplasm suggest that the photoradiation therapy is more effective than surgery.

Published
1983

13. Science and technology research and development in support to ITER and the Broader Approach at CEA

Author

A. Bécoulet, G.T. Hoang, J. Abiteboul, J. Achard, T. Alarcon, J. Alba-Duran, L. Allegretti, S. Allfrey, S. Amiel, J.M. Ané, T. Aniel, G. Antar, A. Argouarch, A. Armitano, J. Arnaud, D. Arranger, J.F. Artaud, D. Audisio, M. Aumeunier, E. Autissier, L. Azcona, A. Back, A. Bahat, X. Bai, B. Baiocchi, D. Balaguer, S. Balme, C. Balorin, O. Barana, D. Barbier, A. Barbuti, V. Basiuk, O. Baulaigue, P. Bayetti, C. Baylard, S. Beaufils, A. Beaute, M. Bécoulet, Z. Bej, S. Benkadda, F. Benoit, G. Berger-By, J.M. Bernard, A. Berne, B. Bertrand, E. Bertrand, P. Beyer, A. Bigand, G. Bonhomme, G. Borel, A. Boron, C. Bottereau, H. Bottollier-Curtet, C. Bouchand, F. Bouquey, C. Bourdelle, J. Bourg, S. Bourmaud, S. Brémond, F. Bribiesca Argomedo, M. Brieu, C. Brun, V. Bruno, J. Bucalossi, H. Bufferand, Y. Buravand, L. Cai, V. Cantone, B. Cantone, E. Caprin, T. Cartier-Michaud, A. Castagliolo, J. Belo, V. Catherine-Dumont, G. Caulier, J. Chaix, M. Chantant, M. Chatelier, D. Chauvin, J. Chenevois, B. Chouli, L. Christin, D. Ciazynski, G. Ciraolo, F. Clairet, R. Clapier, H. Cloez, M. Coatanea-Gouachet, L. Colas, G. Colledani, L. Commin, P. Coquillat, E. Corbel, Y. Corre, J. Cottet, P. Cottier, X. Courtois, I. Crest, R. Dachicourt, M. Dapena Febrer, C. Daumas, H.P.L. de Esch, B. De Gentile, C. Dechelle, J. Decker, P. Decool, V. Deghaye, J. Delaplanche, E. Delchambre-Demoncheaux, L. Delpech, C. Desgranges, P. Devynck, J. Dias Pereira Bernardo, G. Dif-Pradalier, L. Doceul, Y. Dong, D. Douai, H. Dougnac, N. Dubuit, J.-L. Duchateau, L. Ducobu, B. Dugue, N. Dumas, R. Dumont, A. Durocher, F. Duthoit, A. Ekedahl, D. Elbeze, A. Escarguel, J. Escop, F. Faïsse, G. Falchetto, J. Farjon, M. Faury, N. Fedorzack, P. Féjoz, C. Fenzi, F. Ferlay, P. Fiet, M. Firdaouss, M. Francisquez, B. Franel, J. Frauche, Y. Frauel, R. Futtersack, X. Garbet, J. Garcia, J. Gardarein, L. Gargiulo, P. Garibaldi, P. Garin, D. Garnier, E. Gauthier, O. Gaye, A. Geraud, M. Gerome, V. Gervaise, M. Geynet, P. Ghendrih, I. Giacalone, S. Gibert, C. Gil, S. Ginoux, L. Giovannangelo, S. Girard, G. Giruzzi, C. Goletto, R. Goncalves, R. Gonde, M. Goniche, R. Goswami, C. Grand, V. Grandgirard, B. Gravil, C. Grisolia, G. Gros, A. Grosman, J. Guigue, D. Guilhem, C. Guillemaut, B. Guillerminet, Z. Guimaraes Filho, R. Guirlet, J. P. Gunn, O. Gurcan, F. Guzman, S. Hacquin, F. Hariri, F. Hasenbeck, J.C. Hatchressian, P. Hennequin, C. Hernandez, P. Hertout, S. Heuraux, J. Hillairet, C. Honore, G. Hornung, M. Houry, I. Hunstad, T. Hutter, P. Huynh, V. Icard, F. Imbeaux, M. Irishkin, L. Isoardi, J. Jacquinot, J. Jacquot, G. Jiolat, M. Joanny, E. Joffrin, J. Johner, P. Joubert, L. Jourd'Heuil, M. Jouve, C. Junique, D. Keller, C. Klepper, D. Kogut, M. Kubič, F. Labassé, B. Lacroix, Y. Lallier, V. Lamaison, R. Lambert, S. Larroque, G. Latu, Y. Lausenaz, C. Laviron, R. Le, A. Le Luyer, C. Le Niliot, Y. Le Tonqueze, P. Lebourg, T. Lefevre, F. Leroux, L. Letellier, Y. Li, M. Lipa, J. Lister, X. Litaudon, F. Liu, T. Loarer, G. Lombard, P. Lotte, M. Lozano, J. Lucas, H. Lütjens, P. Magaud, P. Maget, R. Magne, J.-F. Mahieu, P. Maini, P. Malard, L. Manenc, Y. Marandet, G. Marbach, J.-L. Marechal, L. Marfisi, M. Marle, C. Martin, V. Martin, G. Martin, A. Martinez, P. Martino, R. Masset, D. Mazon, N. Mellet, L. Mercadier, A. Merle, D. Meshcheriakov, P. Messina, O. Meyer, L. Millon, M. Missirlian, J. Moerel, D. Molina, P. Mollard, V. Moncada, P. Monier-Garbet, D. Moreau, M. Moreau, P. Moreau, P. Morel, T. Moriyama, Y. Motassim, G. Mougeolle, D. Moulton, G. Moureau, D. Mouyon, M. Naim Habib, E. Nardon, V. Négrier, J. Nemeth, C. Nguyen, M. Nguyen, L. Nicolas, T. Nicolas, S. Nicollet, E. Nilsson, B. N'Konga, F. Noel, A. Nooman, C. Norscini, R. Nouailletas, P. Oddon, T. Ohsako, F. Orain, M. Ottaviani, M. Pagano, F. Palermo, S. Panayotis, H. Parrat, J.-Y. Pascal, C. Passeron, P. Pastor, J. Patterlini, K. Pavy, A.-L. Pecquet, B. Pégourié, C. Peinturier, T. Pelletier, B. Peluso, V. Petrzilka, Y. Peysson, E. Pignoly, R. Pirola, C. Pocheau, E. Poitevin, V. Poli, S. Poli, F. Pompon, I. Porchy, C. Portafaix, M. Preynas, P. Prochet, M. Prou, A. Ratnani, D. Raulin, N. Ravenel, S. Renard, B. Ricaud, M. Richou, G. Ritz, H. Roche, P. Roubin, C. Roux, K. Ruiz, F. Sabathier, R. Sabot, A. Saille, F. Saint-Laurent, R. Sakamoto, S. Salasca, T. Salmon, F. Samaille, S. Sanchez, A. Santagiustina, B. Saoutic, Y. Sarazin, P. Sardain, J. Schlosser, M. Schneider, J. Schwob, J. Segui, N. Seguin, G. Selig, D. Serret, J. Signoret, A. Simonin, M. Soldaini, B. Soler, C. Soltane, S. Song, F. Sourbier, J. Sparagna, P. Spitz, P. Spuig, A. Storelli, A. Strugarek, P. Tamain, M. Tena, J. Theis, O. Thomine, D. Thouvenin, A. Torre, L. Toulouse, J. Travère, E. Tsitrone, B. Turck, J. Urban, J.-C. Vallet, J. Vallory, A. Valognes, J. Van Helvoirt, S. Vartanian, J.-M. Verger, L. Vermare, C. Vermare, D. Vezinet, K. Vicente, J. Vidal, N. Vignal, T. Vigne, F. Villecroze, E. Villedieu, B. Vincent, B. Volpe, D. Volpe, R. Volpe, J. Wagrez, H. Wang, T. Wauters, O. Wintersdorff, E. Wittebol, B. Zago, L. Zani, D. Zarzoso, Y. Zhang, W. Zhong, X.L. Zou, Institut de Recherche sur la Fusion par confinement Magnétique (IRFM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Physique des interactions ioniques et moléculaires (PIIM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Jean Lamour (IJL), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Physique des Plasmas (LPP), Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École polytechnique (X)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de Physique Théorique [Palaiseau] (CPHT), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), and Université de Lorraine (UL)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Nuclear and High Energy Physics, Engineering, Tokamak, business.industry, Superconducting magnet, Tore Supra, Condensed Matter Physics, 7. Clean energy, 01 natural sciences, Phase (combat), 010305 fluids & plasmas, law.invention, Procurement, Runaway electrons, law, [PHYS.PHYS.PHYS-PLASM-PH]Physics [physics]/Physics [physics]/Plasma Physics [physics.plasm-ph], 0103 physical sciences, Systems engineering, 010306 general physics, business, ComputingMilieux_MISCELLANEOUS
Abstract

Équipe 107 : Physique des plasmas chauds; International audience; In parallel to the direct contribution to the procurement phase of ITER and Broader Approach, CEA has initiated research & development programmes, accompanied by experiments together with a significant modelling effort, aimed at ensuring robust operation, plasma performance, as well as mitigating the risks of the procurement phase. This overview reports the latest progress in both fusion science and technology including many areas, namely the mitigation of superconducting magnet quenches, disruption-generated runaway electrons, edge-localized modes (ELMs), the development of imaging surveillance, and heating and current drive systems for steady-state operation. The WEST (W Environment for Steady-state Tokamaks) project, turning Tore Supra into an actively cooled W-divertor platform open to the ITER partners and industries, is presented.

14. Identification of 2,4-Dinitro-Biphenyl-Based Compounds as MAPEG Inhibitors.

Author

Di Micco S, Terracciano S, Pierri M, Cantone V, Liening S, König S, Garscha U, Hofstetter RK, Koeberle A, Werz O, Bruno I, and Bifulco G

Subjects
Molecular Docking Simulation, 5-Lipoxygenase-Activating Proteins, Prostaglandin-E Synthases metabolism, Glutathione Transferase, Biphenyl Compounds pharmacology
Abstract

We identified 2,4-dinitro-biphenyl-based compounds as new inhibitors of leukotriene C 4 synthase (LTC 4 S) and 5-lipoxygenase-activating protein (FLAP), both members of the "Membrane Associated Proteins in Eicosanoid and Glutathione metabolism" (MAPEG) family involved in the biosynthesis of pro-inflammatory eicosanoids. By molecular docking we evaluated the putative binding against the targets of interest, and by applying cell-free and cell-based assays we assessed the inhibition of LTC 4 S and FLAP by the small molecules at low micromolar concentrations. The present results integrate the previously observed inhibitory profile of the tested compounds against another MAPEG member, i. e., microsomal prostaglandin E 2 synthase (mPGES)-1, suggesting that the 2,4-dinitro-biphenyl scaffold is a suitable molecular platform for a multitargeting approach to modulate pro-inflammatory mediators in inflammation and cancer treatment., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Published
2022
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15. A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4-Thiazolidinedione-Based Molecules as New Dual mPGES-1/5-LO Inhibitors.

Author

Lauro G, Terracciano S, Cantone V, Ruggiero D, Fischer K, Pace S, Werz O, Bruno I, and Bifulco G

Subjects
A549 Cells, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents chemistry, Drug Evaluation, Preclinical, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Models, Molecular, Molecular Structure, Prostaglandin-E Synthases metabolism, Thiazolidinediones chemical synthesis, Thiazolidinediones chemistry, Anti-Inflammatory Agents pharmacology, Arachidonate 5-Lipoxygenase metabolism, Enzyme Inhibitors pharmacology, Prostaglandin-E Synthases antagonists & inhibitors, Thiazolidinediones pharmacology
Abstract

Dual inhibition of microsomal prostaglandin E 2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO), two key enzymes involved in pro-inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4-thiazolidinedione-based mPGES-1/5-LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent-based chemical route for the decoration of the 2,4-thiazolidinedione core, a large library of virtual compounds was built (∼2.0×10 4 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid- and low- micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4-thiazolidinedione central core, facilitating the identification of novel anti-inflammatory agents endowed with a promising and safer pharmacological profile., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2020
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16. Novel benzoxanthene lignans that favorably modulate lipid mediator biosynthesis: A promising pharmacological strategy for anti-inflammatory therapy.

Author

Gerstmeier J, Kretzer C, Di Micco S, Miek L, Butschek H, Cantone V, Bilancia R, Rizza R, Troisi F, Cardullo N, Tringali C, Ialenti A, Rossi A, Bifulco G, Werz O, and Pace S

Subjects
Adult, Animals, Arachidonate 5-Lipoxygenase physiology, Arthritis, Rheumatoid drug therapy, HEK293 Cells, Humans, Leukocytes metabolism, Macrophages metabolism, Mice, Prostaglandin-E Synthases antagonists & inhibitors, Anti-Inflammatory Agents pharmacology, Leukotrienes biosynthesis, Lignans pharmacology
Abstract

Lipid mediators (LM) encompass pro-inflammatory prostaglandins (PG) and leukotrienes (LT) but also specialized pro-resolving mediators (SPM) which display pivotal bioactivities in health and disease. Pharmacological intervention with inflammatory disorders such as osteoarthritis and rheumatoid arthritis commonly employs anti-inflammatory drugs that can suppress PG and LT formation, which however, possess limited effectiveness and side effects. Here, we report on the discovery and characterization of the two novel benzoxanthene lignans 1 and 2 that modulate select LM biosynthetic enzymes enabling the switch from pro-inflammatory LT to SPM biosynthesis as potential pharmacological strategy to intervene with inflammation. In cell-free assays, compound 1 and 2 inhibit microsomal prostaglandin E 2 synthase-1 and leukotriene C 4 synthase (IC 50  ∼ 0.6-3.4 µM) and potently interfere with 5-lipoxygenase (5-LOX), the key enzyme in LT biosynthesis (IC 50  = 0.04 and 0.09 µM). In human neutrophils, monocytes and M1 and M2 macrophages, compound 1 and 2 efficiently suppress LT biosynthesis (IC 50  < 1 µM), accompanied by elevation of 15-LOX-derived LM including SPM. In zymosan-induced murine peritonitis, compound 1 and 2 ameliorated self-limited inflammation along with suppression of early LT formation and elevation of subsequent SPM biosynthesis in vivo. Together, these novel benzoxanthene lignans promote the LM class switch from pro-inflammatory towards pro-resolving LM to terminate inflammation, suggesting their suitability as novel leads for pharmacotherapy of arthritis and related inflammatory disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
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17. Discovery of 3-hydroxy-3-pyrrolin-2-one-based mPGES-1 inhibitors using a multi-step virtual screening protocol.

Author

Lauro G, Cantone V, Potenza M, Fischer K, Koeberle A, Werz O, Riccio R, and Bifulco G

Abstract

Targeting microsomal prostaglandin E 2 synthase-1 (mPGES-1) represents an efficient strategy for the development of novel drugs against inflammation and cancer with potentially reduced side effects. With this aim, a virtual screening was performed on a large library of commercially available molecules using the X-ray structure of mPGES-1 co-complexed with a potent inhibitor. Combining fast ligand-based shape alignment, molecular docking experiments, and qualitative analysis of the binding poses, a small set of molecules was selected for the subsequent steps of validation of the biological activity. Compounds 2 and 3 , bearing the 3-hydroxy-3-pyrrolin-2-one nucleus, showed mPGES-1-inhibitory activity in the low micromolar range. These data highlighted the applicability of the reported virtual screening protocol for the selection of new mPGES-1 inhibitors as promising anti-inflammatory/anti-cancer drugs.

Published
2018
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18. Discovery of a benzenesulfonamide-based dual inhibitor of microsomal prostaglandin E 2 synthase-1 and 5-lipoxygenase that favorably modulates lipid mediator biosynthesis in inflammation.

Author

Cheung SY, Werner M, Esposito L, Troisi F, Cantone V, Liening S, König S, Gerstmeier J, Koeberle A, Bilancia R, Rizza R, Rossi A, Roviezzo F, Temml V, Schuster D, Stuppner H, Schubert-Zsilavecz M, Werz O, Hanke T, and Pace S

Subjects
Animals, Anti-Inflammatory Agents chemistry, Cells, Cultured, HEK293 Cells, Humans, Inflammation drug therapy, Inflammation enzymology, Inflammation metabolism, Lipoxygenase Inhibitors chemistry, Macrophages drug effects, Macrophages enzymology, Macrophages metabolism, Male, Mice, Molecular Docking Simulation, Prostaglandin-E Synthases metabolism, Sulfonamides chemistry, Benzenesulfonamides, Anti-Inflammatory Agents pharmacology, Arachidonate 5-Lipoxygenase metabolism, Lipoxygenase Inhibitors pharmacology, Prostaglandin-E Synthases antagonists & inhibitors, Sulfonamides pharmacology
Abstract

Leukotrienes (LTs) and prostaglandin (PG)E 2 , produced by 5-lipoxygenase (5-LO) and microsomal prostaglandin E 2 synthase-1 (mPGES-1), respectively, are key players in inflammation, and pharmacological suppression of these lipid mediators (LM) represents a strategy to intervene with inflammatory disorders. Previous studies revealed that the benzenesulfonamide scaffold displays efficient 5-LO-inhibitory properties. Here, we structurally optimized benzenesulfonamides which led to an N-phenylbenzenesulfonamide derivative (compound 47) with potent inhibitory activities (IC 50  = 2.3 and 0.4 μM for isolated 5-LO and 5-LO in intact cells, respectively). Compound 47 prevented the interaction of 5-LO with its activating protein (FLAP) at the nuclear envelope in transfected HEK293 cells as shown by in situ proximity ligation assay. Comprehensive assessment of the LM profile produced by human macrophages revealed the ability of 47 to selectively down-regulate pro-inflammatory LMs (i.e. LTs and PGE 2 ) in M1 but to enhance the formation of pro-resolving LMs (i.e. resolvins and maresins) in M2 macrophages. Moreover, 47 strongly inhibited LT formation and cell infiltration in two in vivo models of acute inflammation (i.e., peritonitis and air pouch sterile inflammation in mice). Together, 47 represents a novel LT biosynthesis inhibitor with an attractive pharmacological profile as anti-inflammatory drug that also promotes the biosynthesis of pro-resolving LM., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Published
2018
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19. Discovery of new potent molecular entities able to inhibit mPGES-1.

Author

Di Micco S, Terracciano S, Cantone V, Fischer K, Koeberle A, Foglia A, Riccio R, Werz O, Bruno I, and Bifulco G

Subjects
Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Humans, Molecular Docking Simulation, Prostaglandin-E Synthases chemistry, Prostaglandin-E Synthases metabolism, Protein Conformation, Drug Discovery, Enzyme Inhibitors pharmacology, Prostaglandin-E Synthases antagonists & inhibitors
Abstract

mPGES-1, a glutathione-dependent membrane protein is involved in the last step of PGE 2 production and has been well recognized as a strategic target for the development of anti-inflammatory and anti-cancer agents. It has been proven to selectively control the PGE 2 levels induced by inflammatory stimuli, with neither affecting PGE 2 constitutively produced, nor homeostatic prostanoids, so that its modulation can represent a better strategy to control PGE 2 related disorders, compared to the use of the classical anti-inflammatory drugs, endowed with severe side effects. Despite the intensive research on the identification of potent mPGES-1 inhibitors as attractive candidates for drug development, none of the disclosed molecules, except for LY3023705, which recently entered clinical trials, are available for clinical use, therefore the discovery of new effective mPGES-1 inhibitors with increased drug-like properties are urgently needed. Continuing our work aimed at identifying new chemical platforms able to interact with this enzyme, here we describe the discovery of potent mPGES-1 modulators, featuring a 1-fluoro-2,4-dinitro-biphenyl-based scaffold, by processing and docking a small collection of synthetically accessible molecules, built around two main fragments, disclosed in our in silico screening. The top scoring hits obtained have been synthesized and tested, and five of the predicted compounds showed to potently inhibit mPGES-1 enzyme, without affecting COX enzymes activities., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Published
2018
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20. Cyclic Diarylheptanoids from Corylus avellana Green Leafy Covers: Determination of Their Absolute Configurations and Evaluation of Their Antioxidant and Antimicrobial Activities.

Author

Cerulli A, Lauro G, Masullo M, Cantone V, Olas B, Kontek B, Nazzaro F, Bifulco G, and Piacente S

Subjects
Algorithms, Anti-Infective Agents chemistry, Antioxidants chemistry, Bacillus cereus drug effects, Diarylheptanoids chemistry, Escherichia coli drug effects, Flavonoids analysis, Hydrogen Peroxide pharmacology, Italy, Lipid Peroxidation, Microbial Sensitivity Tests, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Extracts chemistry, Plant Leaves chemistry, Pseudomonas aeruginosa drug effects, Staphylococcus aureus drug effects, Stereoisomerism, Anti-Infective Agents isolation & purification, Anti-Infective Agents pharmacology, Antioxidants isolation & purification, Antioxidants pharmacology, Corylus chemistry, Diarylheptanoids isolation & purification, Diarylheptanoids pharmacology
Abstract

The methanol extract of the leafy covers of Corylus avellana, source of the Italian PGI (protected geographical indication) product "Nocciola di Giffoni", afforded two new cyclic diarylheptanoids, giffonins T and U (2 and 3), along with two known cyclic diarylheptanoids, a quinic acid, flavonoid-, and citric acid derivatives. The structures of giffonins T and U were determined as highly hydroxylated cyclic diarylheptanoids by 1D and 2D NMR experiments. Their relative configurations were assigned by a combined quantum mechanical/NMR approach, comparing the experimental 13 C/ 1 H NMR chemical shift data and the related predicted values. The absolute configurations of carpinontriol B (1) and giffonins T and U (2 and 3) were assigned by comparison of their experimental electronic circular dichroism curves with the TDDFT-predicted curves. The ability of the compounds to inhibit the lipid peroxidation induced by H 2 O 2 and H 2 O 2 /Fe 2+ was determined by measuring the concentration of thiobarbituric acid reactive substances. Furthermore, the antimicrobial activity of the methanol extract of leafy covers of C. avellana and of the isolated compounds against the Gram-positive strains Bacillus cereus and Staphylococcus aureus and the Gram-negative strains Escherichia coli and Pseudomonas aeruginosa was evaluated. Carpinontriol B (1) and giffonin U (3) at 40 μg/disk caused the formation of zones of inhibition.

Published
2017
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21. Anti-inflammatory and analgesic activity of carnosol and carnosic acid in vivo and in vitro and in silico analysis of their target interactions.

Author

Maione F, Cantone V, Pace S, Chini MG, Bisio A, Romussi G, Pieretti S, Werz O, Koeberle A, Mascolo N, and Bifulco G

Subjects
Abietanes administration & dosage, Abietanes isolation & purification, Analgesics administration & dosage, Analgesics isolation & purification, Animals, Anti-Inflammatory Agents administration & dosage, Anti-Inflammatory Agents isolation & purification, Computer Simulation, Disease Models, Animal, Dose-Response Relationship, Drug, Humans, Inflammation drug therapy, Inflammation pathology, Lipoxygenase Inhibitors administration & dosage, Lipoxygenase Inhibitors isolation & purification, Lipoxygenase Inhibitors pharmacology, Male, Mice, Molecular Docking Simulation, Monocytes drug effects, Monocytes metabolism, Neutrophils drug effects, Neutrophils metabolism, Pain drug therapy, Pain pathology, Prostaglandin-E Synthases antagonists & inhibitors, Salvia chemistry, Abietanes pharmacology, Analgesics pharmacology, Anti-Inflammatory Agents pharmacology
Abstract

Background and Purpose: The diterpenoids carnosol (CS) and carnosic acid (CA) from Salvia spp. exert prominent anti-inflammatory activities but their molecular mechanisms remained unclear. Here we investigated the effectiveness of CS and CA in inflammatory pain and the cellular interference with their putative molecular targets., Experimental Approach: The effects of CS and CA in different models of inflammatory pain were investigated. The inhibition of key enzymes in eicosanoid biosynthesis, namely microsomal prostaglandin E 2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) was confirmed by CS and CA, and we determined the consequence on the eicosanoid network in activated human primary monocytes and neutrophils. Molecular interactions and binding modes of CS and CA to target enzymes were analyzed by docking studies., Key Results: CS and CA displayed significant and dose-dependent anti-inflammatory and anti-nociceptive effects in carrageenan-induced mouse hyperalgesia 4 h post injection of the stimuli, and also inhibited the analgesic response in the late phase of the formalin test. Moreover, both compounds potently inhibited cell-free mPGES-1 and 5-LO activity and preferentially suppressed the formation of mPGES-1 and 5-LO-derived products in cellular studies. Our in silico analysis for mPGES-1 and 5-LO supports that CS and CA are dual 5-LO/mPGES-1 inhibitors., Conclusion and Implications: In summary, we propose that the combined inhibition of mPGES-1 and 5-LO by CS and CA essentially contributes to the bioactivity of these diterpenoids. Our findings pave the way for a rational use of Salvia spp., traditionally used as anti-inflammatory remedy, in the continuous expanding context of nutraceuticals., Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc., (© 2016 The British Pharmacological Society.)

Published
2017
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22. Identification of novel microsomal prostaglandin E 2 synthase-1 (mPGES-1) lead inhibitors from Fragment Virtual Screening.

Author

Lauro G, Manfra M, Pedatella S, Fischer K, Cantone V, Terracciano S, Bertamino A, Ostacolo C, Gomez-Monterrey I, De Nisco M, Riccio R, Novellino E, Werz O, Campiglia P, and Bifulco G

Subjects
Anti-Inflammatory Agents pharmacology, Antineoplastic Agents pharmacology, Crystallography, X-Ray, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Molecular Structure, User-Computer Interface, Anti-Inflammatory Agents chemistry, Antineoplastic Agents chemistry, Drug Evaluation, Preclinical methods, Prostaglandin-E Synthases antagonists & inhibitors
Abstract

Identification of new microsomal prostaglandin E 2 synthase-1 (mPGES-1) inhibitors is currently sought for the treatment of cancer and inflammation. Here we show the results of a Fragment Virtual Screening campaign using the X-ray crystal structure of human mPGES-1 (PDB code: 4AL0). Among the fragments selected and biologically tested, 6 (9H-indeno [1,2-b] [1,2,5]oxadiazolo [3,4-e]pyrazin-9-one) showed the most promising mPGES-1 inhibitory activity (∼30% inhibition at 10 μM). A minimal structure-based optimization of 6 led to compounds 15, 20 and 21, with a promising enhancement of the inhibitory activity (IC 50  = 4.6 ± 0.2 μM for 15; IC 50  = 2.4 ± 1.0 μM for 20; IC 50  = 2.4 ± 0.8 μM for 21). The unprecedented chemical core and the possibility of synthesizing novel derivatives reveal a new and attractive field of action for the development of mPGES-1 inhibitors with potential anti-inflammatory and anticancer properties., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Published
2017
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23. Giffonins J-P, Highly Hydroxylated Cyclized Diarylheptanoids from the Leaves of Corylus avellana Cultivar "Tonda di Giffoni".

Author

Masullo M, Cantone V, Cerulli A, Lauro G, Messano F, Russo GL, Pizza C, Bifulco G, and Piacente S

Subjects
Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic pharmacology, Diarylheptanoids chemistry, Diarylheptanoids pharmacology, Drug Screening Assays, Antitumor, Humans, Italy, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Leaves chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Corylus chemistry, Diarylheptanoids isolation & purification
Abstract

Two new diaryl ether heptanoids, giffonins J and K (1 and 2), along with five new diarylheptanoids, giffonins L-P (3-7), were isolated from a methanol extract of the leaves of Corylus avellana cultivar "Tonda di Giffoni". These compounds were identified as highly hydroxylated cyclized diarylheptanoids by 1D- and 2D-NMR experiments. The relative configurations of giffonins J-P (1-7) were established by a combined QM (quantum mechanical)/NMR approach, comparing the experimental (13)C/(1)H NMR chemical shift data and the related predicted values. The cytotoxic activities of giffonins J-P (1-7) were evaluated against the human osteosarcoma U2Os and SAOs cell lines.

Published
2015
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24. Molecular mechanism of tanshinone IIA and cryptotanshinone in platelet anti-aggregating effects: an integrated study of pharmacology and computational analysis.

Author

Maione F, Cantone V, Chini MG, De Feo V, Mascolo N, and Bifulco G

Subjects
Animals, Drugs, Chinese Herbal pharmacology, Male, Molecular Docking Simulation, Molecular Structure, Purinergic P2Y Receptor Antagonists pharmacology, Rats, Wistar, Abietanes pharmacology, Blood Platelets drug effects, Phenanthrenes pharmacology, Platelet Aggregation drug effects
Abstract

Tanshinone IIA and cryptotanshinone are two pharmacologically active diterpenoids extracted from the roots of Salvia milthiorriza Bunge, a plant used in Chinese traditional medicine for the treatment of some cardiovascular and cerebrovascular disease. Until now, the molecular mechanisms of action of these two diterpenoids on platelets are partially known. To clarify this aspect, here we utilized an integrated study of pharmacology and computational analysis. Our results demonstrate that cryptotanshinone is able to inhibit in a concentration dependent manner the rat platelet aggregation and also is endowed of Gi-coupled P2Y12 receptor antagonist as demonstrated by docking studies. This computational method was also performed for tanshinone IIA demonstrating even for this diterpenoid an interaction with the same receptor. The findings from our study enable a better understanding of tanshinone IIA and cryptotanshinone biological properties, which could ultimately lead to the development of novel pharmaceutical strategies for the treatment and/or prevention of some cardiovascular disease., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Published
2015
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25. Long-term death and recurrence in patients with acute venous thromboembolism: the MASTER registry.

Author

Verso M, Agnelli G, Ageno W, Imberti D, Moia M, Palareti G, Pistelli R, and Cantone V

Subjects
Age Distribution, Cohort Studies, Comorbidity, Female, Humans, Incidence, Italy epidemiology, Longitudinal Studies, Male, Middle Aged, Recurrence, Risk Assessment, Sex Distribution, Survival Analysis, Survival Rate, Anticoagulants therapeutic use, Registries, Venous Thrombosis mortality, Venous Thrombosis therapy
Abstract

Background: The long-term clinical outcome of VTE has been essentially assessed in cohorts of selected patients. The aim of this multicenter registry was to prospectively assess the long-term clinical outcome in a cohort of unselected patients with objectively confirmed acute VTE., Materials and Methods: Death and VTE recurrence at 24 months were the main study outcomes. Univariate and multivariate survival analyses were performed according to the Kaplan-Meyer and Cox proportional hazard model, respectively., Results: 2119 patients with acute VTE were included in the registry: 1541 (72.7%) with deep vein thrombosis, 206 (9.7%) with pulmonary embolism and 372 (17.6%) with both. Information about death was available in 2021 patients (95.4%) and about recurrence in 1988 patients (93.8%). 167 patients (4.55% patient-year) died during follow-up. After adjusting for age, cancer (Hazard ratio [HR]: 7.2; 95%CI 4.8-10.8), long-term heparin treatment (HR: 2.5; 95%CI 1.8-3.5), in-hospital management of VTE (HR: 2.0; 95%CI 1.3-3.0), and ileo-caval thrombosis (HR: 1.7; 95%CI 1.2-2.4) were found to be independent predictors of death. 124 (3.63% patient-year) patients had a VTE recurrence during follow-up. In-hospital management of VTE (HR: 1.8; 95%CI 1.2-2.9), male gender (HR: 1.7; 95%CI 1.2-2.4) were independent risk factors for recurrent VTE. Cancer (HR: 1.6; 95%CI 1.0-2.8) showed a trend for increased risk of VTE recurrence (p=0.056). The reported rate of major bleeding was 2.5%., Conclusions: In a large cohort of unselected VTE patients, cancer, ileo-caval thrombosis, long-term heparin treatment and in-hospital management were associated with increased mortality during long-term follow-up. In-hospital management, male gender were associated with an increased risk of VTE recurrence., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Published
2012
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26. Single daily dose of cefodizime in patients with community-acquired pneumonia: an open-label, controlled, randomized study. The Italian Multicentre Community-Acquired Pneumonia Group.

Author

De Palma M, Rocchi D, Canepa G, Peri A, and Cantone V

Subjects
Adolescent, Adult, Aged, Cefotaxime administration & dosage, Cefotaxime adverse effects, Cefotaxime therapeutic use, Ceftriaxone administration & dosage, Ceftriaxone therapeutic use, Cephalosporins administration & dosage, Cephalosporins adverse effects, Community-Acquired Infections drug therapy, Community-Acquired Infections microbiology, Double-Blind Method, Female, Half-Life, Humans, Injections, Intramuscular, Italy, Male, Middle Aged, Pneumonia, Bacterial microbiology, Cefotaxime analogs & derivatives, Cephalosporins therapeutic use, Pneumonia, Bacterial drug therapy
Abstract

The objective of this study was to compare the clinical and bacteriologic efficacy and safety of cefodizime 1 g intramuscularly (IM) once daily (group A) versus cefodizime 1 g IM twice daily (group B) and versus ceftriaxone 1 g IM once daily (group C) in patients with community-acquired pneumonia. A total of 298 patients, affected by bronchopneumonia or pneumonia with known or suspected bacterial cause, new focal signs on examination of chest, and radiographic evidence of a recent infiltrate, were randomized in three comparable groups. The infection was rated as mild, moderate, or severe. A total of 283 patients were assessable for efficacy: 95 in group A, 94 in group B, and 94 in group C. Mean (+/- SD) duration of treatment was 5.96 +/- 1.39 days in group A, 6.24 +/- 1.57 days in group B, and 6.66 +/- 1.95 days in group C. Symptoms such as purulent sputum, cough, and dyspnea improved significantly after treatment in all groups; temperature normalized by about day 3. Clinical efficacy was rated good in 94.74% of patients in group A, in 92.55% in group B, and in 87.23% in group C. Positive bacteriologic cultures were obtained before treatment from 144 patients: bacteriologic responses were rated good in 98.11%, 98.08%, and 92.80% in groups A, B, and C, respectively. No significant differences were found between the three treatment groups for any measures of clinical efficacy. No serious adverse event occurred in any of the groups. We conclude that cefodizime 1 g IM once daily is an effective dosing regimen in the treatment of patients with community-acquired pneumonia.

Published
1995
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27. Influenza vaccination with adjuvant RU41740 in the elderly.

Author

Profeta ML, Guidi G, Meroni PL, Palmieri R, Palladino G, Cantone V, and Zanussi C

Subjects
Adjuvants, Immunologic immunology, Aged, Antibodies, Viral analysis, Glycoproteins immunology, Humans, Influenza A virus immunology, Influenza B virus immunology, Adjuvants, Immunologic administration & dosage, Bacterial Proteins, Glycoproteins administration & dosage, Influenza Vaccines immunology, Influenza, Human prevention & control, Vaccination
Published
1987
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28. Hematoporphyrin derivative photoradiation therapy in murine solid tumors.

Author

Canti G, Ricci L, Cantone V, Franco P, Marelli O, Andreoni A, Cubeddu R, and Nicolin A

Subjects
Animals, Fiber Optic Technology, Fibrosarcoma surgery, Laser Therapy, Lung Neoplasms prevention & control, Lung Neoplasms secondary, Melanoma surgery, Mice, Mice, Inbred Strains, Neoplasm Transplantation, Optical Fibers, Fibrosarcoma drug therapy, Hematoporphyrins therapeutic use, Melanoma drug therapy, Photochemotherapy methods
Abstract

The cytocidal activity of light-activated hematoporphyrin derivative (Hpd) in experimental and human tumors is under investigation in many laboratories. This activity is based upon preferential incorporation of Hpd in malignant tissues and its photosensibilization by red light. Treatment of mice bearing MS-2 fibrosarcoma and B16 melanoma, a metastastic tumor, with Hpd and laser light, externally or delivered through a quartz fiber optic imbedded directly into the tumor, significantly prolonged the median survival time. This therapy was compared with surgical excision of primary tumors, and preliminary results on metastatic neoplasm suggest that the photoradiation therapy is more effective than surgery.

Published
1983
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