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51. Características clínicas y respuesta al tratamiento sistémico de la epiescleritis y escleritis primarias y secundarias, refractarias al tratamiento local

Author

Hernán Valenzuela H, Héctor Gatica R, Patricia Gallardo, Juan Verdaguer D, Juan Verdaguer T, Miguel Cuchacovich T, Guillermo Merino B, and Patricio Pacheco B

Subjects
Vasculitis, medicine.medical_specialty, Systemic disease, Tuberculosis, Cyclophosphamide, business.industry, Scleral diseases, General Medicine, Episcleritis, medicine.disease, Sjögren syndrome, Dermatology, Surgery, Arthritis rheumatoid, Rheumatoid arthritis, medicine, business, Epiescleritis, Uveitis, Scleritis, medicine.drug
Abstract

Background: Scleritis and episcleritis may extend to adjacent ocular tissues with blinding consequences and may be associated with potentially lethal systemic disorders. Aim: To evaluate the ocular complications and systemic disease associations of the different types of scleritis and episcleritis. Patients and methods: Forty six patients with refractory scleritis and episcleritis were studied and treated during the period 1991 to 1998. Results: Necrotizing type was the most common and severe category in the scleritis group of patients. A decrease in vision occurred in 58.3% of patients with scleritis v/s a 23.5% of patients with epiescleritis (p

Published
2000
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53. Kaín letra ngigua

Author

Balderas O., Andrés, Rojas S., Nicodemo, Merino B., Maura, Velásquez M., Sonia, Austin, Jeanne, Kalstrom, Marjorie R., Balderas O., Andrés, Rojas S., Nicodemo, Merino B., Maura, Velásquez M., Sonia, Austin, Jeanne, and Kalstrom, Marjorie R.

Abstract

http://www.sil.org/resources/archives/12712

Published
2005

55. Phase II study to evaluate efficacy and safety of irinotecan, capecitabine, and bevacizumab in patients with metastatic colorectal cancer (mCRC).

Author

Garcia Alfonso, P., primary, Chaves, M., additional, Muñoz Martin, A., additional, Salud Salvia, A., additional, Vilchez, R., additional, Yuste, A., additional, Gravalos Castro, C., additional, Queralt Merino, B., additional, Gonzalez Flores, E., additional, Lopez Ladron, A., additional, Losa, F., additional, Oltra Ferrando, A., additional, Gomez Reina, M. J., additional, Campos, J. M., additional, and Aranda, E., additional

Published
2011
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59. Centros de Salud IHAN (Iniciativa de Humanización de la Atención al Nacimiento y la Lactancia): Una garantía de calidad

Author

Hernández Aguilar, MT., primary, González Lombide, E., additional, Bustinduy Bascarán, A., additional, Arana Cañedo-Argüelles, C., additional, Martínez-Herrera Merino, B., additional, Blanco del Val, A., additional, García Rodríguez, M.I., additional, Aguirre de la Peña, E., additional, and Cárcamo González, G., additional

Published
2009
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65. The impact of year‐round schooling: a review.

Author

Merino, B. J.

Abstract

Year‐round schooling implies that children will be going to school 365 days a year, with only a few holidays off; in reality, year‐round schooling is no one specific plan, but rather the demise of the conventional September to June school calendar. As many as fifty different kinds of year‐round education (YRE) plans have been identified (Univer, 1976), falling for the most part into four broad classifications: extended attendance plans and staggered attendance plans that may be voluntary or mandatory. Extended attendance plans permit children to attend school for longer periods of time than the required state minimum. Staggered attendance plans permit students to be enrolled in school on a staggered basis. The most popular plans in this category are: 45 days in school, 15 on vacation; the Quinmester, five 9‐week terms per year; and Concept 6, six two‐month terms every year. The purpose of this review is to investigate the impact of year‐round schooling on administrative costs, student academic achievement, and attitude among teachers and school staff, as well as the community at large. Special focus is on the impact of year‐round schooling on minority populations.

Published
1983
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67. PERSEO project: Design and methods of the evaluation study,Proyecto PERSEO: Diseño y metodología del estudio de evaluación

Author

Aranceta Bartrina, J., Carmen Pérez-Rodrigo, Campos Amado, J., Calderón Pascual, V., García Cuadra, A., Gavidia Catalán, V., Gil Canalda, I., González Briones, E., Díaz-Ufano, Ma L. L., Merino Merino, B., Monereo Mejías, S., Murillo, J. J., Nieto Poyato, R. M., Pérez Iruela, J., Rodríguez Artalejo, F., Suárez Cortina, L., Varela Moreiras, G., and Veiga Núñez, Ó L.

68. PERSEO project: Design and methods of the evaluation study | Proyecto PERSEO: Diseño y metodología del estudio de evaluación

Author

Javier Aranceta, Pérez Rodrigo, C., Campos Amado, J., Calderón Pascual, V., García Cuadra, A., Gavidia Catalán, V., Gil Canalda, I., González Briones, E., Díaz-Ufano, Ma L. L., Merino Merino, B., Monereo Mejías, S., Murillo, J. J., Nieto Poyato, R. M., Pérez Iruela, J., Rodríguez Artalejo, F., Suárez Cortina, L., Varela Moreiras, G., and Veiga Núñez, Ó L.

70. The EChO science case

Author

Tinetti, Giovanna, Drossart, Pierre, Eccleston, Paul, Hartogh, Paul, Isaak, Kate, Linder, Martin, Lovis, Christophe, Micela, Giusi, Ollivier, Marc, Puig, Ludovic, Ribas, Ignasi, Snellen, Ignas, Swinyard, Bruce, Allard, France, Barstow, Joanna, Cho, James, Coustenis, Athena, Cockell, Charles, Correia, Alexandre, Decin, Leen, de Kok, Remco, Deroo, Pieter, Encrenaz, Therese, Forget, Francois, Glasse, Alistair, Griffith, Caitlin, Guillot, Tristan, Koskinen, Tommi, Lammer, Helmut, Leconte, Jeremy, Maxted, Pierre, Mueller-Wodarg, Ingo, Nelson, Richard, North, Chris, Pallé, Enric, Pagano, Isabella, Piccioni, Guseppe, Pinfield, David, Selsis, Franck, Sozzetti, Alessandro, Stixrude, Lars, Tennyson, Jonathan, Turrini, Diego, Zapatero-Osorio, Mariarosa, Beaulieu, Jean-Philippe, Grodent, Denis, Guedel, Manuel, Luz, David, Nørgaard-Nielsen, Hans Ulrik, Ray, Tom, Rickman, Hans, Selig, Avri, Swain, Mark, Banaszkiewicz, Marek, Barlow, Mike, Bowles, Neil, Branduardi-Raymont, Graziella, du Foresto, Vincent Coudé, Gerard, Jean-Claude, Gizon, Laurent, Hornstrup, Allan, Jarchow, Christopher, Kerschbaum, Franz, Kovacs, Géza, Lagage, Pierre-Olivier, Lim, Tanya, Lopez-Morales, Mercedes, Malaguti, Giuseppe, Pace, Emanuele, Pascale, Enzo, Vandenbussche, Bart, Wright, Gillian, Zapata, Gonzalo Ramos, Adriani, Alberto, Azzollini, Ruymán, Balado, Ana, Bryson, Ian, Burston, Raymond, Colomé, Josep, Crook, Martin, Di Giorgio, Anna, Griffin, Matt, Hoogeveen, Ruud, Ottensamer, Roland, Irshad, Ranah, Middleton, Kevin, Morgante, Gianluca, Pinsard, Frederic, Rataj, Mirek, Reess, Jean-Michel, Savini, Giorgio, Schrader, Jan-Rutger, Stamper, Richard, Winter, Berend, Abe, L., Abreu, M., Achilleos, N., Ade, P., Adybekian, V., Affer, L., Agnor, C., Agundez, M., Alard, C., Alcala, J., Allende Prieto, C., Alonso Floriano, F. J., Altieri, F., Alvarez Iglesias, C. A., Amado, P., Andersen, A., Aylward, A., Baffa, C., Bakos, G., Ballerini, P., Banaszkiewicz, M., Barber, R. J., Barrado, D., Barton, E. J., Batista, V., Bellucci, G., Belmonte Avilés, J. A., Berry, D., Bézard, B., Biondi, D., Błęcka, M., Boisse, I., Bonfond, B., Bordé, P., Börner, P., Bouy, H., Brown, L., Buchhave, L., Budaj, J., Bulgarelli, A., Burleigh, M., Cabral, A., Capria, M. T., Cassan, A., Cavarroc, C., Cecchi-Pestellini, C., Cerulli, R., Chadney, J., Chamberlain, S., Charnoz, S., Christian Jessen, N., Ciaravella, A., Claret, A., Claudi, R., Coates, A., Cole, R., Collura, A., Cordier, D., Covino, E., Danielski, C., Damasso, M., Deeg, H. J., Delgado-Mena, E., Del Vecchio, C., Demangeon, O., De Sio, A., De Wit, J., Dobrijévic, M., Doel, P., Dominic, C., Dorfi, E., Eales, S., Eiroa, C., Espinoza Contreras, M., Esposito, M., Eymet, V., Fabrizio, N., Fernández, M., Femenía Castella, B., Figueira, P., Filacchione, G., Fletcher, L., Focardi, M., Fossey, S., Fouqué, P., Frith, J., Galand, M., Gambicorti, L., Gaulme, P., García López, R. J., Garcia-Piquer, A., Gear, W., Gerard, J.-C., Gesa, L., Giani, E., Gianotti, F., Gillon, M., Giro, E., Giuranna, M., Gomez, H., Gomez-Leal, I., Gonzalez Hernandez, J., González Merino, B., Graczyk, R., Grassi, D., Guardia, J., Guio, P., Gustin, J., Hargrave, P., Haigh, J., Hébrard, E., Heiter, U., Heredero, R. L., Herrero, E., Hersant, F., Heyrovsky, D., Hollis, M., Hubert, B., Hueso, R., Israelian, G., Iro, N., Irwin, P., Jacquemoud, S., Jones, G., Jones, H., Justtanont, K., Kehoe, T., Kerschbaum, F., Kerins, E., Kervella, P., Kipping, D., Koskinen, T., Krupp, N., Lahav, O., Laken, B., Lanza, N., Lellouch, E., Leto, G., Licandro Goldaracena, J., Lithgow-Bertelloni, C., Liu, S. J., Lo Cicero, U., Lodieu, N., Lognonné, P., Lopez-Puertas, M., Lopez-Valverde, M. A., Lundgaard Rasmussen, I., Luntzer, A., Machado, P., MacTavish, C., Maggio, A., Maillard, J.-P., Magnes, W., Maldonado, J., Mall, U., Marquette, J.-B., Mauskopf, P., Massi, F., Maurin, A.-S., Medvedev, A., Michaut, C., Miles-Paez, P., Montalto, M., Montañés Rodríguez, P., Monteiro, M., Montes, D., Morais, H., Morales, J. C., Morales-Calderón, M., Morello, G., Moro Martín, A., Moses, J., Moya Bedon, A., Murgas Alcaino, F., Oliva, E., Orton, G., Palla, F., Pancrazzi, M., Pantin, E., Parmentier, V., Parviainen, H., Peña Ramírez, K. Y., Peralta, J., Perez-Hoyos, S., Petrov, R., Pezzuto, S., Pietrzak, R., Pilat-Lohinger, E., Piskunov, N., Prinja, R., Prisinzano, L., Polichtchouk, I., Poretti, E., Radioti, A., Ramos, A. A., Rank-Lüftinger, T., Read, P., Readorn, K., Rebolo López, R., Rebordão, J., Rengel, M., Rezac, L., Rocchetto, M., Rodler, F., Sánchez Béjar, V. J., Sanchez Lavega, A., Sanromá, E., Santos, N., Sanz Forcada, J., Scandariato, G., Schmider, F.-X., Scholz, A., Scuderi, S., Sethenadh, J., Shore, S., Showman, A., Sicardy, B., Sitek, P., Smith, A., Soret, L., Sousa, S., Stiepen, A., Stolarski, M., Strazzulla, G., Tabernero, H. M., Tanga, P., Tecsa, M., Temple, J., Terenzi, L., Tessenyi, M., Testi, L., Thompson, S., Thrastarson, H., Tingley, B. W., Trifoglio, M., Martín Torres, J., Tozzi, A., Turrini, D., Varley, R., Vakili, F., de Val-Borro, M., Valdivieso, M. L., Venot, O., Villaver, E., Vinatier, S., Viti, S., Waldmann, I., Waltham, D., Ward-Thompson, D., Waters, R., Watkins, C., Watson, D., Wawer, P., Wawrzaszk, A., White, G. J., Widemann, T., Winek, W., Wiśniowski, T., Yelle, R., Yung, Y., Yurchenko, S. N., Tinetti, Giovanna, Drossart, Pierre, Eccleston, Paul, Hartogh, Paul, Isaak, Kate, Linder, Martin, Lovis, Christophe, Micela, Giusi, Ollivier, Marc, Puig, Ludovic, Ribas, Ignasi, Snellen, Ignas, Swinyard, Bruce, Allard, France, Barstow, Joanna, Cho, James, Coustenis, Athena, Cockell, Charles, Correia, Alexandre, Decin, Leen, de Kok, Remco, Deroo, Pieter, Encrenaz, Therese, Forget, Francois, Glasse, Alistair, Griffith, Caitlin, Guillot, Tristan, Koskinen, Tommi, Lammer, Helmut, Leconte, Jeremy, Maxted, Pierre, Mueller-Wodarg, Ingo, Nelson, Richard, North, Chris, Pallé, Enric, Pagano, Isabella, Piccioni, Guseppe, Pinfield, David, Selsis, Franck, Sozzetti, Alessandro, Stixrude, Lars, Tennyson, Jonathan, Turrini, Diego, Zapatero-Osorio, Mariarosa, Beaulieu, Jean-Philippe, Grodent, Denis, Guedel, Manuel, Luz, David, Nørgaard-Nielsen, Hans Ulrik, Ray, Tom, Rickman, Hans, Selig, Avri, Swain, Mark, Banaszkiewicz, Marek, Barlow, Mike, Bowles, Neil, Branduardi-Raymont, Graziella, du Foresto, Vincent Coudé, Gerard, Jean-Claude, Gizon, Laurent, Hornstrup, Allan, Jarchow, Christopher, Kerschbaum, Franz, Kovacs, Géza, Lagage, Pierre-Olivier, Lim, Tanya, Lopez-Morales, Mercedes, Malaguti, Giuseppe, Pace, Emanuele, Pascale, Enzo, Vandenbussche, Bart, Wright, Gillian, Zapata, Gonzalo Ramos, Adriani, Alberto, Azzollini, Ruymán, Balado, Ana, Bryson, Ian, Burston, Raymond, Colomé, Josep, Crook, Martin, Di Giorgio, Anna, Griffin, Matt, Hoogeveen, Ruud, Ottensamer, Roland, Irshad, Ranah, Middleton, Kevin, Morgante, Gianluca, Pinsard, Frederic, Rataj, Mirek, Reess, Jean-Michel, Savini, Giorgio, Schrader, Jan-Rutger, Stamper, Richard, Winter, Berend, Abe, L., Abreu, M., Achilleos, N., Ade, P., Adybekian, V., Affer, L., Agnor, C., Agundez, M., Alard, C., Alcala, J., Allende Prieto, C., Alonso Floriano, F. J., Altieri, F., Alvarez Iglesias, C. A., Amado, P., Andersen, A., Aylward, A., Baffa, C., Bakos, G., Ballerini, P., Banaszkiewicz, M., Barber, R. J., Barrado, D., Barton, E. J., Batista, V., Bellucci, G., Belmonte Avilés, J. A., Berry, D., Bézard, B., Biondi, D., Błęcka, M., Boisse, I., Bonfond, B., Bordé, P., Börner, P., Bouy, H., Brown, L., Buchhave, L., Budaj, J., Bulgarelli, A., Burleigh, M., Cabral, A., Capria, M. T., Cassan, A., Cavarroc, C., Cecchi-Pestellini, C., Cerulli, R., Chadney, J., Chamberlain, S., Charnoz, S., Christian Jessen, N., Ciaravella, A., Claret, A., Claudi, R., Coates, A., Cole, R., Collura, A., Cordier, D., Covino, E., Danielski, C., Damasso, M., Deeg, H. J., Delgado-Mena, E., Del Vecchio, C., Demangeon, O., De Sio, A., De Wit, J., Dobrijévic, M., Doel, P., Dominic, C., Dorfi, E., Eales, S., Eiroa, C., Espinoza Contreras, M., Esposito, M., Eymet, V., Fabrizio, N., Fernández, M., Femenía Castella, B., Figueira, P., Filacchione, G., Fletcher, L., Focardi, M., Fossey, S., Fouqué, P., Frith, J., Galand, M., Gambicorti, L., Gaulme, P., García López, R. J., Garcia-Piquer, A., Gear, W., Gerard, J.-C., Gesa, L., Giani, E., Gianotti, F., Gillon, M., Giro, E., Giuranna, M., Gomez, H., Gomez-Leal, I., Gonzalez Hernandez, J., González Merino, B., Graczyk, R., Grassi, D., Guardia, J., Guio, P., Gustin, J., Hargrave, P., Haigh, J., Hébrard, E., Heiter, U., Heredero, R. L., Herrero, E., Hersant, F., Heyrovsky, D., Hollis, M., Hubert, B., Hueso, R., Israelian, G., Iro, N., Irwin, P., Jacquemoud, S., Jones, G., Jones, H., Justtanont, K., Kehoe, T., Kerschbaum, F., Kerins, E., Kervella, P., Kipping, D., Koskinen, T., Krupp, N., Lahav, O., Laken, B., Lanza, N., Lellouch, E., Leto, G., Licandro Goldaracena, J., Lithgow-Bertelloni, C., Liu, S. J., Lo Cicero, U., Lodieu, N., Lognonné, P., Lopez-Puertas, M., Lopez-Valverde, M. A., Lundgaard Rasmussen, I., Luntzer, A., Machado, P., MacTavish, C., Maggio, A., Maillard, J.-P., Magnes, W., Maldonado, J., Mall, U., Marquette, J.-B., Mauskopf, P., Massi, F., Maurin, A.-S., Medvedev, A., Michaut, C., Miles-Paez, P., Montalto, M., Montañés Rodríguez, P., Monteiro, M., Montes, D., Morais, H., Morales, J. C., Morales-Calderón, M., Morello, G., Moro Martín, A., Moses, J., Moya Bedon, A., Murgas Alcaino, F., Oliva, E., Orton, G., Palla, F., Pancrazzi, M., Pantin, E., Parmentier, V., Parviainen, H., Peña Ramírez, K. Y., Peralta, J., Perez-Hoyos, S., Petrov, R., Pezzuto, S., Pietrzak, R., Pilat-Lohinger, E., Piskunov, N., Prinja, R., Prisinzano, L., Polichtchouk, I., Poretti, E., Radioti, A., Ramos, A. A., Rank-Lüftinger, T., Read, P., Readorn, K., Rebolo López, R., Rebordão, J., Rengel, M., Rezac, L., Rocchetto, M., Rodler, F., Sánchez Béjar, V. J., Sanchez Lavega, A., Sanromá, E., Santos, N., Sanz Forcada, J., Scandariato, G., Schmider, F.-X., Scholz, A., Scuderi, S., Sethenadh, J., Shore, S., Showman, A., Sicardy, B., Sitek, P., Smith, A., Soret, L., Sousa, S., Stiepen, A., Stolarski, M., Strazzulla, G., Tabernero, H. M., Tanga, P., Tecsa, M., Temple, J., Terenzi, L., Tessenyi, M., Testi, L., Thompson, S., Thrastarson, H., Tingley, B. W., Trifoglio, M., Martín Torres, J., Tozzi, A., Turrini, D., Varley, R., Vakili, F., de Val-Borro, M., Valdivieso, M. L., Venot, O., Villaver, E., Vinatier, S., Viti, S., Waldmann, I., Waltham, D., Ward-Thompson, D., Waters, R., Watkins, C., Watson, D., Wawer, P., Wawrzaszk, A., White, G. J., Widemann, T., Winek, W., Wiśniowski, T., Yelle, R., Yung, Y., and Yurchenko, S. N.

Abstract

The discovery of almost two thousand exoplanets has revealed an unexpectedly diverse planet population. We see gas giants in few-day orbits, whole multi-planet systems within the orbit of Mercury, and new populations of planets with masses between that of the Earth and Neptune—all unknown in the Solar System. Observations to date have shown that our Solar System is certainly not representative of the general population of planets in our Milky Way. The key science questions that urgently need addressing are therefore: What are exoplanets made of? Why are planets as they are? How do planetary systems work and what causes the exceptional diversity observed as compared to the Solar System? The EChO (Exoplanet Characterisation Observatory) space mission was conceived to take up the challenge to explain this diversity in terms of formation, evolution, internal structure and planet and atmospheric composition. This requires in-depth spectroscopic knowledge of the atmospheres of a large and well-defined planet sample for which precise physical, chemical and dynamical information can be obtained. In order to fulfil this ambitious scientific program, EChO was designed as a dedicated survey mission for transit and eclipse spectroscopy capable of observing a large, diverse and well-defined planet sample within its 4-year mission lifetime. The transit and eclipse spectroscopy method, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allows us to measure atmospheric signals from the planet at levels of at least 10−4 relative to the star. This can only be achieved in conjunction with a carefully designed stable payload and satellite platform. It is also necessary to provide broad instantaneous wavelength coverage to detect as many molecular species as possible, to probe the thermal structure of the planetary atmospheres and to correct for the contaminating effects of the stellar photosphere. This requires

71. Clinical autonomic nervous system laboratories in Europe. A joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies

Author

Habek, Mario, Leys, Fabian, Krbot Skorić, Magdalena, Reis Carneiro, Diogo, Calandra‐Buonaura, Giovanna, Camaradou, Jennifer, Chiaro, Giacomo, Cortelli, Pietro, Falup‐Pecurariu, Cristian, Granata, Roberta, Guaraldi, Pietro, Helbok, Raimund, Hilz, Max J., Iodice, Valeria, Jordan, Jens, Kaal, Evert C. A., Kamondi, Anita, Pavy Le Traon, Anne, Rocha, Isabel, Sellner, Johann, Senard, Jean Michel, Terkelsen, Astrid, Wenning, Gregor K., Berger, Thomas, Thijs, Roland D., Struhal, Walter, Fanciulli, Alessandra, Adamec, Ivan, Aerts, Arnaud, Canta, Leo L.R., Delamont, Robert Shane, de Lange, Frederik, Del Sorbo, Francesca, Devigili, Grazia, Di Leo, Rita, Dinh, Trang, Fortrat, Jacques‐Olivier, Gierthmühlen, Janne, Hemels, Martin, Köhn, Julia, Krøigård, Thomas, Lipp, Axel, Maier, Andrea, Marinelli, Lucio, Mazzeo, Anna, Milenkovic, Ivan, Motyl, Maciej, Natali Sora, Maria Grazia, Navarro‐Otano, Judith, Nilsen, Kristian Bernhard, Oliveira, Mario, Omland, Petter Moe, Pelliccioni, Giuseppe, Pereon, Yann, Resch, Roland Josef, Rocchi, Camilla, Roche, Frederic, Rutten, Joost, Tijero Merino, Beatriz, Tutaj, Marcin, van der Heijden‐Montfroy, A.M.H.G., van Hoeve, Bas J.A., van Orshoven, Narender, Wang, Ruihao, Z’Graggen, Werner J., Habek M., Leys F., Krbot Skoric M., Reis Carneiro D., Calandra-Buonaura G., Camaradou J., Chiaro G., Cortelli P., Falup-Pecurariu C., Granata R., Guaraldi P., Helbok R., Hilz M.J., Iodice V., Jordan J., Kaal E.C.A., Kamondi A., Pavy Le Traon A., Rocha I., Sellner J., Senard J.M., Terkelsen A., Wenning G.K., Berger T., Thijs R.D., Struhal W., Fanciulli A., Adamec I., Aerts A., Canta L.L.R., Delamont R.S., de Lange F., Del Sorbo F., Devigili G., Di Leo R., Dinh T., Fortrat J.-O., Gierthmuhlen J., Hemels M., Kohn J., Kroigard T., Lipp A., Maier A., Marinelli L., Mazzeo A., Milenkovic I., Motyl M., Natali Sora M.G., Navarro-Otano J., Nilsen K.B., Oliveira M., Omland P.M., Pelliccioni G., Pereon Y., Resch R.J., Rocchi C., Roche F., Rutten J., Tijero Merino B., Tutaj M., van der Heijden-Montfroy A.M.H.G., van Hoeve B.J.A., van Orshoven N., Wang R., Z'Graggen W.J., Cardiology, ACS - Heart failure & arrhythmias, and Repositório da Universidade de Lisboa

Subjects
sweat test, sweat tests, neurological disorders, Autonomic Nervous System, Autonomic Nervous System Disease, (disorders of) autonomic nervous system, cardiovascular autonomic function test, Composite Autonomic Severity Score, orthostatic hypotension, Neurology, syncope, Consciousness, disorders, neurodisparity, Autonomic nervous system, disorders, Surveys and Questionnaire, Neurology (clinical), cardiovascular autonomic function tests, disorders of consciousness (other than epilepsy), neurological disorder, Survey, Laboratorie, Human
Abstract

© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.

Published
2022
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74. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX

Author

Jean-François Emile, Catherine Julié, Karine Le Malicot, Come Lepage, Josep Tabernero, Enrico Mini, Gunnar Folprecht, Jean-Luc Van Laethem, Stéphanie Dimet, Camille Boulagnon-Rombi, Marc-Antoine Allard, Frédérique Penault-Llorca, Jaafar Bennouna, Pierre Laurent-Puig, Julien Taieb, Josef Thaler, Richard Greil, Johannes Gaenzer, Wolfgang Eisterer, Joerg Tschmelitsch, Felix Keil, Hellmut Samonigg, August Zabernigg, Franz Schmid, Günther Steger, Robert Steinacher, Johannes Andel, Björn Jagdt, Alois Lang, Michael Fridrik, Reinhold Függer, Friedrich Hofbauer, Ewald Woell, Dietmar Geissler, Alfred Lenauer, Manfred Prager, Geert D'Haens, Gauthier Demolin, Joseph Kerger, Guido Deboever, Gilbert Ghillebert, Marc Polus, Eric Van Cutsem, Hassan Rezaie Kalantari, Thierry Delaunoit, Jean Charles Goeminne, Marc Peeters, Philippe Vergauwe, Ghislain Houbiers, Yves Humblet, Jos Janssens, Dirk Schrijvers, Erik Vanderstraeten, Jan Vermorken, Daniel Van Daele, Michel Ferrante, Frederic Forget, Alain Hendlisz, Mette Yilmaz, Svend Erik Nielsen, Lene Vestermark, Jim Larsen, Mohamed-Ayman Zawadi, Olivier Bouche, Laurent Mineur, Jaafar Bennouna-Louridi, Louis Marie Dourthe, Marc Ychou, Eveline Boucher, Denis Pezet, Francoise Desseigne, Michel Ducreux, Patrick Texereau, Laurent Miglianico, Philippe Rougier, Serge Fratte, Charles-Briac Levache, Yacine Merrouche, Stephen Ellis, Christophe Locher, Jean-Francois Ramee, Claire Garnier, Frederic Viret, Bruno Chauffert, Isabelle Cojean-Zelek, Pierre Michel, Cedric Lecaille, Christian Borel, Jean-Francois Seitz, Denis Smith, Catherine Lombard-Bohas, Thierry Andre, Jean-Marc Gornet, Francine Fein, Marie-Aude Coulon-Sfairi, Marie-Christine Kaminsky, Jean-Paul Lagasse, Dominique Luet, Pierre-Luc Etienne, Mohamed Gasmi, Andre Vanoli, Suzanne Nguyen, Thomas Aparicio, Hervé Perrier, Noel Stremsdoerfer, Philippe Laplaige, Dominique Arsene, Dominique Auby, Laurent Bedenne, Romain Coriat, Bernard Denis, Patrick Geoffroy, Gilles Piot, Yves Becouarn, Gilbert Bordes, Gael Deplanque, Olivier Dupuis, Frederic Fruge, Rosine Guimbaud, Thierry Lecomte, Gérard Lledo, Iradej Sobhani, Amani Asnacios, Ahmed Azzedine, Christophe Desauw, Marie-Pierre Galais, Dany Gargot, You-Heng Lam, Abakar Abakar-Mahamat, Jean-Francois Berdah, Sylviane Catteau, Marie-Christine Clavero-Fabri, Jean-Francois Codoul, Jean-Louis Legoux, Denis Goldfain, Pierre Guichard, Denis Pere Verge, Jocelyne Provencal, Bruno Vedrenne, Catherine Brezault-Bonnet, Denis Cleau, Jean-Paul Desir, David Fallik, Bruno Garcia, Marie-Hélène Gaspard, Dominique Genet, Johannes Hartwig, Yves Krummel, Tamara Matysiak Budnik, Vanessa Palascak-Juif, Harizo Randrianarivelo, Yves Rinaldi, Albert Aleba, Ariane Darut-Jouve, Aimery de Gramont, Herve Hamon, Frederic Wendehenne, Axel Matzdorff, Michael Konrad Stahl, Wolfgang Schepp, Martin Burk, Lothar Mueller, Michael Geissler, Luisa Mantovani-Loeffler, Thomas Hoehler, Walter Asperger, Hendrik Kroening, Ludwig Fischer von Weikersthal, Stefan Fuxius, Matthias Groschek, Johannes Meiler, Tanja Trarbach, Jacqueline Rauh, Nicolas Ziegenhagen, Albrecht Kretzschmar, Ullrich Graeven, Arnd Nusch, Goetz von Wichert, Ralf-Dieter Hofheinz, Gerhard Kleber, Karl-Heinz Schmidt, Ursula Vehling-Kaiser, Claudia Baum, Jochen Schuette, Georg Martin Haag, Wilhelm Holtkamp, Jochen Potenberg, Tobias Reiber, Georg Schliesser, Hans-Joachim Schmoll, Wolfgang Schneider-Kappus, Wolfgang Abenhardt, Claudio Denzlinger, Jan Henning, Bartscht Marxsen, Hans Guenter Derigs, Helmut Lambertz, Ingulf Becker-Boost, Karel Caca, Christian Constantin, Thomas Decker, Henning Eschenburg, Sigrun Gabius, Holger Hebart, Albrecht Hoffmeister, Heinz-August Horst, Stephan Kremers, Malte Leithaeuser, Sebastian Mueller, Siegfried Wagner, Severin Daum, Frank Schlegel, Martina Stauch, Volker Heinemann, Evaristo Maiello, Luciano Latini, Alberto Zaniboni, Dino Amadori, Giuseppe Aprile, Sandro Barni, Rodolfo Mattioli, Andrea Martoni, Rodolfo Passalacqua, Mario Nicolini, Enzo Pasquini, Carla Rabbi, Enrico Aitini, Alberto Ravaioli, Carlo Barone, Guido Biasco, Stefano Tamberi, Angelo Gambi, Claudio Verusio, Marina Marzola, Giorgio Lelli, Corrado Boni, Stefano Cascinu, Paolo Bidoli, Massimo Vaghi, Giorgio Cruciani, Francesco Di Costanzo, Alberto Sobrero, Roberto Petrioli, Massimo Aglietta, Oscar Alabiso, Federico Capuzzo, Alfredo Falcone, Domenico Cristi Corsi, Roberto Labianca, Stefania Salvagni, Silvana Chiara, Libero Ciuffreda, Francesco Ferraù, Francesco Giuliani, Sara Lonardi, Nicola Gebbia, Giovanni Mantovani, Evaristo Sanches, Juan Carlos Mellidez, Pedro Santos, Joao Freire, Cristina Sarmento, Luis Costa, Antonio Moreira Pinto, Sergio Barroso, Jorge Espirito Santo, Fátima Guedes, Amélia Monteiro, Anabela Sa, Irene Furtado, Ramon Salazar, Enrique Aranda Aguilar, Fernando Rivera Herrero, Javier Sastre Valera, Manuel Valladares Ayerbes, Jaime Feliu Batlle, Silvia Gil, Albert Abad Esteve, Carlos Garcia-Giron, Guillermo Lopez Vivanco, Antonia Salud Salvia, Vicente Alonso Orduña, Ruth Vera Garcia, Javier Gallego, Bartomeu Massuti Sureda, Jordi Remon, Maria Jose Safont Aguilera, Luis Cirera Nogueras, Bernado Queralt Merino, Cristina Gravalos Castro, Purificacion Martinez de Prado, Carlos Pijaume Pericay, Manuel Constenla Figueiras, Inmaculada Guasch Jordan, Maria Jose Gome Reina, Amelia Lopez-Ladron Garcia, Antonio Arrivi Garcia-Ramos, Andres Cervantes, Carlos Fernandez Martos, Eugenio Marcuello Gaspar, Ines Cabezas Montero, Pilar Escudero Emperador, Ana Leon Carbonero, Manuel Gallen Castillo, Teresa Garcia Garcia, Jose Garcia Lopez, Encarnacion Gonzalez Flores, Monica Guillot Morales, Marta Llanos Muñoz, Ana López Martín, Joan Maurel, Juan Carlos Camara, Rosario Dueñas Garcia, Mercedes Salgado, Isabel Hernandez Busquier, Teresa Checa Ruiz, Adelaida Lacasta Muñoa, Miquel Nogue Aliguer, Amalia Velasco Ortiz de Taranco, Miguel Mendez Ureña, Ferran Losa Gaspa, Jose Juan Ponce, Carlos Bosch Roig, Pedro Valero Jimenez, Antonio Galan Brotons, Santiago Albiol Rodriguez, Jose Ales Martinez, Liliana Canosa Ruiz, Margarita Centelles Ruiz, John Bridgewater, Rob Glynne-Jones, Saad Tahir, Tamas Hickish, Jim Cassidy, Leslie Samuel, UE 1373 Fourrages Environnement Ruminants Lusignan, Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Environnement et Agronomie ( E.A. ) -Biologie et Amélioration des Plantes ( BAP ) -Fourrages Environnement Ruminants Lusignan ( FERLUS ), Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Service de Biostatistique, Fédération Francophone de la Cancérologie Digestive, FFCD, Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hépato-gastroentérologie et cancérologie digestive (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Vall d'Hebron University Hospital [Barcelona], Dpt of Internal Medicine, Section of Immunoallergology and Respiratory [Florence] Diseases, University of Florence, Carl Gustav Carus University Hospital, Erasme Hospital, Brussels, Centre Hepato-Biliaire, AP-HP Hôpital Paul Brousse, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Institut de cancérologie de l'Ouest - Nantes ( ICO Nantes ), CRLCC Paul Papin-CRLCC René Gauducheau, Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université de Nantes ( UN ), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique ( MEPPOT - U1147 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Klinikum Wels Grieskirchen, Oncology department [Salzburg], Salzburger Landesklinikum - Uniklinikum Salzburg ( SALK ), Institute of Chemical Reaction Engineering, Hamburg University of Technology, Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung ( AWI ), Department of Medical Oncology, Medical University Vienna, Department of Internal Medicine, Hospital of Steyr, Department Internal Medicine 3, Centre for Hematology and Medical Oncology, General Hospital Linz, Department Medicine LKH, Institut für Festköperfirschung, Institut des Sciences Moléculaires de Marseille ( ISM2 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Centrale de Marseille ( ECM ) -Aix Marseille Université ( AMU ), University Hospitals Leuven [Leuven], Katholieke Universiteit Leuven ( KU Leuven ), Pharmacology and Toxicology, Ahvaz Jundishapur University of Medical Sciences, Institut de Biologie Computationnelle ( IBC ), Centre de Coopération Internationale en Recherche Agronomique pour le Développement ( CIRAD ) -Institut National de la Recherche Agronomique ( INRA ) -Institut National de Recherche en Informatique et en Automatique ( Inria ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Sciences Moléculaires ( ISM ), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique ( CNRS ), Faculty of Veterinary Medicine, Ghent University [Belgium] ( UGENT ), Medical Oncology, Antwerp University Hospital [Edegem], Recombinaison et Expression Génétique, Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier de L'Ardenne (Libramont), Department of Cardiology [Sivas, Turkey], Cumhuriyet University [Sivas, Turkey], Department of Earth Sciences, Durham University, Department of Oncology, Rigshospitalet [Copenhagen], Odense Hospital, CP Kelco ApS, Centre Hospitalier Universitaire de Reims ( CHU Reims ), Institut de Recherche en Cancérologie de Montpellier ( IRCM - U1194 Inserm - UM ), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Université du Québec à Montréal ( UQAM ), Université Panthéon-Sorbonne ( UP1 ), École nationale supérieure d'architecture de Nantes ( ENSA Nantes ), Department of Hepatogastroenterology and Oncology, Hopital Ambroise Pare, 9, Avenue Charles de Gaulle, 92104, Boulogne Cedex, France., Hôpital Ambroise Paré, CH Belfort-Montbéliard, Polyclinique Francheville, Institut de Cancérologie de la Loire Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne ( CHU de Saint-Etienne ), Centre Hospitalier de Meaux, Service d'hématologie, Clinique Catherine de Sienne, Unité de recherche sur les Biopolymères, Interactions Assemblages ( BIA ), Institut National de la Recherche Agronomique ( INRA ), Université de la Méditerranée - Aix-Marseille 2, Centre hospitalier universitaire d'Amiens ( CHU Amiens-Picardie ), CHU Amiens-Picardie, Pôle oncologie médicale, Hôpital des Diaconesses, Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bretagne Occidentale - École de sages-femmes ( UBO UFR MSS ESF ), Université de Brest ( UBO ) -Centre Hospitalier Régional Universitaire de Brest ( CHRU Brest ), Service d'oncologie digestive et hépato-gastro-entérologie [Hôpital de la Timone - APHM], Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Service d'Oncologie Médicale [CHU Saint -Antoine], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Service Gastro-Entérologie, CHU Besançon, Université de Franche-Comté ( UFC ) -Université de Franche-Comté ( UFC ), Centre Alexis Vautrin ( CAV ), Ecophysiologie Végétale, Agronomie et Nutritions ( EVA ), Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Recherche Agronomique ( INRA ), Image et ville ( IV ), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Département informatique ( INFO ), Université européenne de Bretagne ( UEB ) -Télécom Bretagne-Institut Mines-Télécom [Paris], Service de Gastro-entérologie [Avicenne], Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Agence de l'Environnement et de la Maîtrise de l'Energie - ADEME, Service d'hépato-gastroentérologie, CHU Caen-Hôpital côte de nacre, Département de Médecine, Centre hospitalier de Libourne, Service d'Hépato-Gastro-Entérologie (CHU de Dijon), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Fondation FondaMental, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor, Variabilité de réponse aux psychotropes ( VariaPsy - U1144 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Diderot - Paris 7 ( UPD7 ), Département d'oncologie digestive, Institut Bergonié - CRLCC Bordeaux, Hôpital St Joseph, Service de Gynécologie et d'Obstétrique ( CHU Lyon ), Hospices Civils de Lyon ( HCL ), Gastro - Entérologie et Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Génétique, Immunothérapie, Chimie et Cancer ( GICC ), Université de Tours-Centre National de la Recherche Scientifique ( CNRS ), Université Montpellier 1 ( UM1 ), Service de gastro-entérologie - Hôpital Henri Mondor, Laboratoire Matière et Systèmes Complexes ( Laboratoire MSC ), Université Paris Diderot - Paris 7 ( UPD7 ) -UFR de Physique, France, Amériques, Espagne – Sociétés, pouvoirs, acteurs ( FRAMESPA ), Université Toulouse - Jean Jaurès ( UT2J ) -Centre National de la Recherche Scientifique ( CNRS ), Regional Hospital of Orleans, Histoire, Archéologie et littératures des Mondes chrétiens et musulmans médiévaux ( CIHAM ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -École des hautes études en sciences sociales ( EHESS ) -Université Jean Moulin - Lyon III ( UJML ) -Université d'Avignon et des Pays de Vaucluse ( UAPV ) -Centre National de la Recherche Scientifique ( CNRS ), Neurobiologie des signaux intercellulaires ( NSI ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Dept Med Genet, Hôpital Erasme (Bruxelles), Polyclinique de Limoges - site François Chénieux [Limoges], Clinique Médicale B, CHU Strasbourg, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Hôpital Européen [Fondation Ambroise Paré - Marseille], Asklepios Klinikum Uckermark GmbH, DESY, Notkestr 85, D-22607 Hamburg, Germany, NASA Ames Research Center ( ARC ), Department of Chemistry, Center for Structural Biology, Vanderbilt University [Nashville], Biostatistique et Processus Spatiaux ( BIOSP ), Institute of Ecology [Jena], Friedrich-Schiller-Universität Jena, University of Rostock [Germany], Universität Stuttgart [Stuttgart], Oneonta, Zentrum für Innere Medizin, Klinikum Schwäbisch Gmünd/Stauferklinik, Physiopathologie du stress pancréatique, Institut Armand Frappier ( INRS-IAF ), Institut National de la Recherche Scientifique [Québec] ( INRS ) -Réseau International des Instituts Pasteur ( RIIP ) -Institut Armand Frappier, Institut de Mathématiques de Marseille ( I2M ), Aix Marseille Université ( AMU ) -Ecole Centrale de Marseille ( ECM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Department of Computer Science [Freiburg], University of Freiburg [Freiburg], Institut für Mathematik [Berlin], Technische Universität Berlin ( TUB ), Department of Information Engineering, Computer Science and Mathematics, Università degli Studi dell'Aquila [L'Aquila] ( UNIVAQ.IT ), Department of Animal Sciences, North Carolina Agricultural and Technical State University, FEEM, Romagna Cancer Registry, IRST, Luigi Pierantoni Hospital, Observatoire sociologique du changement ( OSC ), Sciences Po-Centre National de la Recherche Scientifique ( CNRS ), Dipartimento di Chimica, Fisica e Ambiente, Università degli Studi di Udine - University of Udine [Italie], Department of Nuclear Medicine, PET/CT Centre, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Clinica di Oncologia Medica, AO Ospedali Riuniti, Università Politecnica delle Marche [Ancona] ( UNIVPM ), Universidade Nova de Lisboa ( UNINOVA ), Ottawa Hospital Research Institute [Ottawa] ( OHRI ), Oncologia Medica, Ospedali Riuniti, Ospedale 'San Vincenzo', NIPE, CIPES, European Synchrotron Radiation Facility ( ESRF ), Departamento de Engenharia Informática, Faculdade de Engenharia [Porto] ( FEUP ), Universidade do Porto [Porto]-Universidade do Porto [Porto], 3Decide, Unité de recherche Amélioration, Génétique et Physiologie Forestières ( UAGPF ), Universidade Federal de Campina Grande [Campina Grande] ( UFCG ), Instituto de Engenharia de Sistemas e Computadores ( INESC ), Departamento de Ciências Biológicas, Universidade Regional do Cariri ( URCA Brasil ), Department of Biochemistry and Molecular Biology [Barcelona, Spain], Universitat de Barcelona ( UB ), Associated Unit to Consejo Superior de Investigaciones Científicas - CSIC [Barcelona, Spain], University of Barcelona-Institute of Biomedicine - IBUB [Barcelona, Spain], IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau ( CARE ), Institut de recherches sur la catalyse et l'environnement de Lyon ( IRCELYON ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'analyse et d'architecture des systèmes [Toulouse] ( LAAS ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Institut National Polytechnique [Toulouse] ( INP ), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier ( ICGM ICMMM ), Université Montpellier 1 ( UM1 ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de Ciencia de Materiales de Madrid [Madrid] ( ICMM ), Interactions, Corpus, Apprentissages, Représentations ( ICAR ), École normale supérieure - Lyon ( ENS Lyon ) -Université Lumière - Lyon 2 ( UL2 ) -INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique ( CNRS ), Institut d'Investigacions Biomèdiques August Pi i Sunyer ( IDIBAPS ), North Region Cancer Registry of Portugal, UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux ( EPOC ), Observatoire aquitain des sciences de l'univers ( OASU ), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Department of Paediatrics and Intensive Care, Hospital Universitari Sant Joan de Deu, Laboratoire de Psychologie Sociale ( LPS ), Aix Marseille Université ( AMU ), Universitat de València ( UV ), Instituto de Cienca de Materiales de Madrid [Madrid] ( ICMM ), Biology, New Mexico State University, New Mexico State University, Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ), Centre de recherche sur les Ions, les MAtériaux et la Photonique ( CIMAP - UMR 6252 ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Supérieure d'Ingénieurs de Caen ( ENSICAEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université de Caen Normandie ( UNICAEN ), Normandie Université ( NU ), Institut d'Electronique et de Télécommunications de Rennes ( IETR ), Université de Nantes ( UN ) -Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National des Sciences Appliquées - Rennes ( INSA Rennes ) -CentraleSupélec-Centre National de la Recherche Scientifique ( CNRS ), Computer Science Department - Carnegie Mellon University, University of Pittsburgh, Laboratoire de Sciences Actuarielle et Financière ( SAF ), Université de Lyon-Université de Lyon, Instituto de Oncologia Corachan ( IDOC ), Laboratoire d'informatique de l'école normale supérieure ( LIENS ), École normale supérieure - Paris ( ENS Paris ) -Centre National de la Recherche Scientifique ( CNRS ), Experimental Quantum Optics and Photonics Group, University of Strathclyde, Institut de recherches Asiatiques ( IrAsia ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Européen de Réalité Virtuelle ( CERV ), École Nationale d'Ingénieurs de Brest ( ENIB ), Sol Agro et hydrosystème Spatialisation ( SAS ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Grenoble Institut des Neurosciences ( GIN ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Grenoble-Université Joseph Fourier - Grenoble 1 ( UJF ), Centre de recherche cerveau et cognition ( CERCO ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire Géomatériaux et Environnement ( LGE ), Université Paris-Est Marne-la-Vallée ( UPEM ), Hôpital Ambroise Paré [AP-HP], Université Paris-Saclay, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Centre hépato-biliaire (CHB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Université de Nantes (UN), Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Salzburger Landesklinikum - Uniklinikum Salzburg (SALK), Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung (AWI), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut de Biologie Computationnelle (IBC), Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), Antwerp University Hospital [Edegem] (UZA), Hillerød Hospital, Copenhagen University Hospital-Copenhagen University Hospital, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université du Québec à Montréal = University of Québec in Montréal (UQAM), Université Paris 1 Panthéon-Sorbonne (UP1), École nationale supérieure d'architecture de Nantes (ENSA Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bretagne Occidentale - École de sages-femmes (UBO UFR MSS ESF), Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Alexis Vautrin (CAV), Ecophysiologie Végétale, Agronomie et Nutritions (EVA), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Recherche Agronomique (INRA), Image et ville (IV), Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Département informatique (INFO), Université européenne de Bretagne - European University of Brittany (UEB)-Télécom Bretagne-Institut Mines-Télécom [Paris] (IMT), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agence de l'Environnement et de la Maîtrise de l'Energie (ADEME), Service d'Hépato-Gastro-Enterologie et Nutrition [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Libourne, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation FondaMental [Créteil], Variabilité de réponse aux Psychotropes (VariaPsy - U1144), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Service de Gynécologie et d'Obstétrique (CHU Lyon), Hospices Civils de Lyon (HCL), Génétique, immunothérapie, chimie et cancer (GICC), UMR 7292 CNRS [2012-2017] (GICC UMR 7292 CNRS), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1), Service de gastro-entérologie [Henri Mondor AP-HP, Créteil], Hôpital Henri Mondor-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Hôpital privé Toulon Hyères : Sainte Marguerite, Clinique des Quatre Pavillons, Lormont, France, Neurobiologie des signaux intercellulaires (NSI), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), NASA Ames Research Center (ARC), Biostatistique et Processus Spatiaux (BioSP), Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], University of Rostock, State University of New York at Oneonta (SUNY Oneonta), State University of New York (SUNY), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS), Institut de Mathématiques de Marseille (I2M), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Centre National de la Recherche Scientifique (CNRS), Klinikum Deggendorf, Technische Universität Berlin (TU), Università degli Studi dell'Aquila (UNIVAQ), North Carolina A&T State University, University of North Carolina System (UNC)-University of North Carolina System (UNC), Observatoire sociologique du changement (OSC), Sciences Po (Sciences Po)-Centre National de la Recherche Scientifique (CNRS), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Università Politecnica delle Marche [Ancona] (UNIVPM), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ottawa Hospital Research Institute [Ottawa] (OHRI), European Synchrotron Radiation Facility (ESRF), Departamento de Engenharia Informática [Porto], Faculdade de Engenharia da Universidade do Porto (FEUP), Universidade do Porto-Universidade do Porto, Universidade Federal de Campina Grande [Campina Grande] (UFCG), Instituto de Engenharia de Sistemas e Computadores (INESC), Universidade Regional do Cariri (URCA Brasil), Universitat de Barcelona (UB), IRCELYON-Catalytic and Atmospheric Reactivity for the Environment (CARE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM ICMMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut de Chimie du CNRS (INC), Instituto de Ciencia de Materiales de Madrid (ICMM), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Interactions, Corpus, Apprentissages, Représentations (ICAR), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines (ENS LSH)-Centre National de la Recherche Scientifique (CNRS), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), UMR 5805 Environnements et Paléoenvironnements Océaniques et Continentaux (EPOC), Observatoire aquitain des sciences de l'univers (OASU), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Hospital Universitario de Valme, Anenida de Bellavista s/n, Sevilla 41014, Spain, Hospital Son Llatzer, Universitat de València (UV), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hospital Universitari Son Espases, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Instituto de Oncologia Corachan (IDOC), Laboratoire d'informatique de l'école normale supérieure (LIENS), École normale supérieure - Paris (ENS Paris), Institut de recherches Asiatiques (IrAsia), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre Européen de Réalité Virtuelle (CERV), École Nationale d'Ingénieurs de Brest (ENIB), Sol Agro et hydrosystème Spatialisation (SAS), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche cerveau et cognition (CERCO), Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Géomatériaux et Environnement (LGE), Université Paris-Est Marne-la-Vallée (UPEM), Fédération Francophone de Cancérologie Digestive (FFCD), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service d'Oncologie Médicale [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Institut National de la Recherche Agronomique (INRA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Department of Information Engineering, Computer Science and Mathematics = Dipartimento di Ingegneria e Scienze dell'Informazione e Matematica [L'Aquila] (DISIM), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier (ICGM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Département d'informatique - ENS Paris (DI-ENS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Aix Marseille Université (AMU), Institute of Biomedicine - IBUB [Barcelona, Spain]-University of Barcelona, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche en Informatique et en Automatique (Inria)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Université Sciences et Technologies - Bordeaux 1-Université Montesquieu - Bordeaux 4-Institut de Chimie du CNRS (INC), AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Environnement et Agronomie (E.A.)-Biologie et Amélioration des Plantes (BAP)-Fourrages Environnement Ruminants Lusignan (FERLUS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, University of Florence (UNIFI), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut de cancérologie de l'Ouest - Nantes (ICO Nantes), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Ghent University [Belgium] (UGENT), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université du Québec à Montréal (UQAM), Université Panthéon-Sorbonne (UP1), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université de Franche-Comté (UFC)-Université de Franche-Comté (UFC), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Optimisation Thérapeutique en Neuropsychopharmacologie (VariaPsy - U1144), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Hôpital Jean Minjoz, Biostatistique et Processus Spatiaux (BIOSP), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Technische Universität Berlin (TUB), Università degli Studi dell'Aquila [L'Aquila] (UNIVAQ.IT), Universidade Nova de Lisboa (NOVA), Faculdade de Engenharia [Porto] (FEUP), Unité de recherche Amélioration, Génétique et Physiologie Forestières (UAGPF), IRCELYON-Caractérisation et remédiation des polluants dans l'air et l'eau (CARE), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-INRP-Ecole Normale Supérieure Lettres et Sciences Humaines-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Sciences et Technologies - Bordeaux 1-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS Paris)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut des sciences du cerveau de Toulouse. (ISCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Emile, J, Julie, C, Le Malicot, K, Lepage, C, Tabernero, J, Mini, E, Folprecht, G, Van Laethem, J, Dimet, S, Boulagnon-Rombi, C, Allard, M, Penault-Llorca, F, Bennouna, J, Laurent-Puig, P, Taieb, J, Bidoli, P, Emile, J. -F., Julie, C., Le Malicot, K., Lepage, C., Tabernero, J., Mini, E., Folprecht, G., Van Laethem, J. -L., Dimet, S., Boulagnon-Rombi, C., Allard, M. -A., Penault-Llorca, F., Bennouna, J., Laurent-Puig, P., Taieb, J., Thaler, J., Greil, R., Gaenzer, J., Eisterer, W., Tschmelitsch, J., Keil, F., Samonigg, H., Zabernigg, A., Schmid, F., Steger, G., Steinacher, R., Andel, J., Jagdt, B., Lang, A., Fridrik, M., Fugger, R., Hofbauer, F., Woell, E., Geissler, D., Lenauer, A., Prager, M., D'Haens, G., Demolin, G., Kerger, J., Deboever, G., Ghillebert, G., Polus, M., Van Cutsem, E., Kalantari, H. R., Delaunoit, T., Goeminne, J. C., Peeters, M., Vergauwe, P., Houbiers, G., Humblet, Y., Janssens, J., Schrijvers, D., Vanderstraeten, E., Vermorken, J., Van Daele, D., Ferrante, M., Forget, F., Hendlisz, A., Yilmaz, M., Nielsen, S. E., Vestermark, L., Larsen, J., Zawadi, M. -A., Bouche, O., Mineur, L., Bennouna-Louridi, J., Dourthe, L. M., Ychou, M., Boucher, E., Pezet, D., Desseigne, F., Ducreux, M., Texereau, P., Miglianico, L., Rougier, P., Fratte, S., Levache, C. -B., Merrouche, Y., Ellis, S., Locher, C., Ramee, J. -F., Garnier, C., Viret, F., Chauffert, B., Cojean-Zelek, I., Michel, P., Lecaille, C., Borel, C., Seitz, J. -F., Smith, D., Lombard-Bohas, C., Andre, T., Gornet, J. -M., Fein, F., Coulon-Sfairi, M. -A., Kaminsky, M. -C., Lagasse, J. -P., Luet, D., Etienne, P. -L., Gasmi, M., Vanoli, A., Nguyen, S., Aparicio, T., Perrier, H., Stremsdoerfer, N., Laplaige, P., Arsene, D., Auby, D., Bedenne, L., Coriat, R., Denis, B., Geoffroy, P., Piot, G., Becouarn, Y., Bordes, G., Deplanque, G., Dupuis, O., Fruge, F., Guimbaud, R., Lecomte, T., Lledo, G., Sobhani, I., Asnacios, A., Azzedine, A., Desauw, C., Galais, M. -P., Gargot, D., Lam, Y. -H., Abakar-Mahamat, A., Berdah, J. -F., Catteau, S., Clavero-Fabri, M. -C., Codoul, J. -F., Legoux, J. -L., Goldfain, D., Guichard, P., Verge, D. P., Provencal, J., Vedrenne, B., Brezault-Bonnet, C., Cleau, D., Desir, J. -P., Fallik, D., Garcia, B., Gaspard, M. -H., Genet, D., Hartwig, J., Krummel, Y., Budnik, T. M., Palascak-Juif, V., Randrianarivelo, H., Rinaldi, Y., Aleba, A., Darut-Jouve, A., de Gramont, A., Hamon, H., Wendehenne, F., Matzdorff, A., Stahl, M. K., Schepp, W., Burk, M., Mueller, L., Geissler, M., Mantovani-Loeffler, L., Hoehler, T., Asperger, W., Kroening, H., von Weikersthal, L. F., Fuxius, S., Groschek, M., Meiler, J., Trarbach, T., Rauh, J., Ziegenhagen, N., Kretzschmar, A., Graeven, U., Nusch, A., von Wichert, G., Hofheinz, R. -D., Kleber, G., Schmidt, K. -H., Vehling-Kaiser, U., Baum, C., Schuette, J., Haag, G. M., Holtkamp, W., Potenberg, J., Reiber, T., Schliesser, G., Schmoll, H. -J., Schneider-Kappus, W., Abenhardt, W., Denzlinger, C., Henning, J., Marxsen, B., Derigs, H. G., Lambertz, H., Becker-Boost, I., Caca, K., Constantin, C., Decker, T., Eschenburg, H., Gabius, S., Hebart, H., Hoffmeister, A., Horst, H. -A., Kremers, S., Leithaeuser, M., Mueller, S., Wagner, S., Daum, S., Schlegel, F., Stauch, M., Heinemann, V., Maiello, E., Latini, L., Zaniboni, A., Amadori, D., Aprile, G., Barni, S., Mattioli, R., Martoni, A., Passalacqua, R., Nicolini, M., Pasquini, E., Rabbi, C., Aitini, E., Ravaioli, A., Barone, C., Biasco, G., Tamberi, S., Gambi, A., Verusio, C., Marzola, M., Lelli, G., Boni, C., Cascinu, S., Bidoli, P., Vaghi, M., Cruciani, G., Di Costanzo, F., Sobrero, A., Petrioli, R., Aglietta, M., Alabiso, O., Capuzzo, F., Falcone, A., Corsi, D. C., Labianca, R., Salvagni, S., Chiara, S., Ciuffreda, L., Ferrau, F., Giuliani, F., Lonardi, S., Gebbia, N., Mantovani, G., Sanches, E., Mellidez, J. C., Santos, P., Freire, J., Sarmento, C., Costa, L., Pinto, A. M., Barroso, S., Santo, J. E., Guedes, F., Monteiro, A., Sa, A., Furtado, I., Salazar, R., Aguilar, E. A., Herrero, F. R., Valera, J. S., Ayerbes, M. V., Batlle, J. F., Gil, S., Esteve, A. A., Garcia-Giron, C., Vivanco, G. L., Salvia, A. S., Orduna, V. A., Garcia, R. V., Gallego, J., Sureda, B. M., Remon, J., Safont Aguilera, M. J., Nogueras, L. C., Merino, B. Q., Castro, C. G., de Prado, P. M., Pericay, C. P., Figueiras, M. C., Jordan, I. G., Gome Reina, M. J., Garcia, A. L. -L., Garcia-Ramos, A. A., Cervantes, A., Martos, C. F., Gaspar, E. M., Montero, I. C., Emperador, P. E., Carbonero, A. L., Castillo, M. G., Garcia, T. G., Lopez, J. G., Flores, E. G., Morales, M. G., Munoz, M. L., Martin, A. L., Maurel, J., Camara, J. C., Garcia, R. D., Salgado, M., Busquier, I. H., Ruiz, T. C., Munoa, A. L., Aliguer, M. N., de Taranco, A. V. O., Urena, M. M., Gaspa, F. L., Ponce, J. J., Roig, C. B., Jimenez, P. V., Brotons, A. G., Rodriguez, S. A., Martinez, J. A., Ruiz, L. C., Ruiz, M. C., Bridgewater, J., Glynne-Jones, R., Tahir, S., Hickish, T., Cassidy, J., and Samuel, L.

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Organoplatinum Compounds, Colorectal cancer, medicine.medical_treatment, Medizin, Leucovorin, Prospective cohort study, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, FOLFOX, Organoplatinum Compounds/therapeutic use, Antineoplastic Combined Chemotherapy Protocols, tudy, Lymphocytes, Prospective Studies, Leucovorin/therapeutic use, Middle Aged, Prognosis, 3. Good health, Colorectal carcinoma, Fluorouracil, 030220 oncology & carcinogenesis, Predictive value of tests, Colonic Neoplasms, Biomarker (medicine), Lymphocytes/pathology, Female, Adjuvant, medicine.drug, Adult, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, Fluorouracil/therapeutic use, Biomarkers, Tumor/analysis, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Predictive Value of Tests, Biomarker, Immune response, Internal medicine, medicine, Biomarkers, Tumor, Humans, Survival analysis, Aged, business.industry, medicine.disease, Survival Analysis, Surgery, 030104 developmental biology, Prospective cohort&nbsp, Multivariate Analysis, Colonic Neoplasms/diagnosis, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, business
Abstract

IF 6.029; International audience; BackgroundThe prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.Patients and methodsAccording to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.ResultsAmong the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.ConclusionAlthough this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Published
2017
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75. Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner.

Author

Sanz-Martos AB, Roca M, Plaza A, Merino B, Ruiz-Gayo M, and Olmo ND

Subjects
Animals, Male, Female, Mice, Mice, Inbred C57BL, Neuronal Plasticity drug effects, Neuronal Plasticity physiology, Spatial Learning drug effects, Spatial Learning physiology, Receptors, AMPA metabolism, Spatial Memory drug effects, Spatial Memory physiology, Memory drug effects, Memory physiology, Long-Term Potentiation drug effects, Long-Term Potentiation physiology, Receptors, N-Methyl-D-Aspartate metabolism, Synaptic Transmission drug effects, Synaptic Transmission physiology, Dietary Fats pharmacology, Hippocampus drug effects, Hippocampus metabolism, Diet, High-Fat adverse effects, Sex Characteristics
Abstract

Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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76. Novel Applications in Controlled Drug Delivery Systems by Integrating Osmotic Pumps and Magnetic Nanoparticles.

Author

Navarro-Tumar D, García-Merino B, González-Fernández C, Ortiz I, San-Román MF, and Bringas E

Subjects
Humans, Osmotic Pressure, Osmolar Concentration, Magnetite Nanoparticles chemistry, Drug Delivery Systems methods, Osmosis
Abstract

The alarming rise in chronic diseases worldwide highlights the urgent need to overcome the limitations of conventional drug delivery systems. In this context, osmotic pumps are able to release drugs by differential osmotic pressure, achieving a controlled rate independent of physiological factors and reducing the dosing frequency. As osmotic pumps are based on the phenomenon of osmosis, the choice of high osmolality draw solutions (DSs) is a critical factor in the successful delivery of the target drug. Therefore, one alternative that has received particular attention is the formulation of DSs with magnetic nanoparticles (MNPs) due to their easy recovery, negligible reverse solute flux (RSF), and their possible tailor-made functionalization to generate high osmotic gradients. In this work, the possible integration of DSs formulated with MNPs in controlled drug delivery systems is discussed for the first time. In particular, the main potential advantages that these novel medical devices could offer, including improved scalability, regeneration, reliability, and enhanced drug delivery performance, are provided and discussed. Thus, the results of this review may demonstrate the potential of MNPs as osmotic agents, which could be useful for advancing the design of osmotic pump-based drug delivery systems.

Published
2024
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77. Environmental fluoxetine promotes skin cell proliferation and wound healing.

Author

Rodriguez-Barucg Q, Garcia AA, Garcia-Merino B, Akinmola T, Okotie-Eboh T, Francis T, Bringas E, Ortiz I, Wade MA, Dowle A, Joyce DA, Hardman MJ, Wilkinson HN, and Beltran-Alvarez P

Subjects
Humans, Water Pollutants, Chemical toxicity, Cell Line, Selective Serotonin Reuptake Inhibitors pharmacology, Serotonin metabolism, Fluoxetine pharmacology, Wound Healing drug effects, Cell Proliferation drug effects, Keratinocytes drug effects, Skin drug effects
Abstract

This study investigates the effects of environmentally-relevant concentrations of fluoxetine (FLX, commercial name: Prozac) on wound healing. Pollution of water systems with pharmaceutical and personal care products, including antidepressants such as FLX and other selective serotonin reuptake inhibitors, is a growing environmental concern. Environmentally-relevant FLX concentrations are known to impact physiological functions and behaviour of aquatic animals, however, the effects of exposure on humans are currently unknown. Using a combination of human skin biopsies and a human keratinocyte cell line, we show that exposure to environmental FLX promotes wound closure. We show dose-dependent increases in wound closure with FLX concentrations from 125 ng/l. Using several -omics and pharmaceutical approaches, we demonstrate that the mechanisms underlying enhanced wound closure are increased cell proliferation and serotonin signalling. Transcriptomic analysis revealed 350 differentially expressed genes after exposure. Downregulated genes were enriched in pathways related to mitochondrial function and metabolism, while upregulated genes were associated with cell proliferation and tissue morphogenesis. Kinase profiling showed altered phosphorylation of kinases linked to the MAPK pathway. Consistent with this, phosphoproteomic analyses identified 235 differentially phosphorylated proteins after exposure, with enriched GO terms related to cell cycle, division, and protein biosynthesis. Treatment of skin biopsies and keratinocytes with ketanserin, a serotonin receptor antagonist, reversed the increase in wound closure observed upon exposure. These findings collectively show that exposure to environmental FLX promotes wound healing through modulating serotonin signalling, gene expression and protein phosphorylation, leading to enhanced cell proliferation. Our results justify a transition from the study of behavioural effects of environmental FLX in aquatic animals to the investigation of effects of exposure on wound healing in aquatic and terrestrial animals, including direct impacts on human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2024
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78. Plasma Neurofilament Light Chain: A Potential Biomarker for Neurological Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Author

Azcue N, Tijero-Merino B, Acera M, Pérez-Garay R, Fernández-Valle T, Ayo-Mentxakatorre N, Ruiz-López M, Lafuente JV, Gómez Esteban JC, and Del Pino R

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder characterized by heterogeneous symptoms, which lack specific biomarkers for its diagnosis. This study aimed to investigate plasma neurofilament light chain (NfL) levels as a potential biomarker for ME/CFS and explore associations with cognitive, autonomic, and neuropathic symptoms. Here, 67 ME/CFS patients and 43 healthy controls (HCs) underwent comprehensive assessments, including neuropsychological evaluation, autonomic nervous system (ANS) testing, and plasma NfL level analysis. ME/CFS patients exhibited significantly higher plasma NfL levels compared to HC (F = 4.30, p < 0.05). Correlations were observed between NfL levels and cognitive impairment, particularly in visuospatial perception (r = -0.42; p ≤ 0.001), verbal memory (r = -0.35, p ≤ 0.005), and visual memory (r = -0.26; p < 0.05) in ME/CFS. Additionally, higher NfL levels were associated with worsened autonomic dysfunction in these patients, specifically in parasympathetic function (F = 9.48, p ≤ 0.003). In ME/CFS patients, NfL levels explained up to 17.2% of the results in cognitive tests. Unlike ME/CFS, in HC, NfL levels did not predict cognitive performance. Elevated plasma NfL levels in ME/CFS patients reflect neuroaxonal damage, contributing to cognitive dysfunction and autonomic impairment. These findings support the potential role of NfL as a biomarker for neurological dysfunction in ME/CFS. Further research is warranted to elucidate underlying mechanisms and clinical implications.

Published
2024
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79. Roadmap towards safe and sustainable advanced and innovative materials. (Outlook for 2024-2030).

Author

Cassee FR, Bleeker EAJ, Durand C, Exner T, Falk A, Friedrichs S, Heunisch E, Himly M, Hofer S, Hofstätter N, Hristozov D, Nymark P, Pohl A, Soeteman-Hernández LG, Suarez-Merino B, Valsami-Jones E, and Groenewold M

Abstract

The adoption of innovative advanced materials holds vast potential, contingent upon addressing safety and sustainability concerns. The European Commission advocates the integration of Safe and Sustainable by Design (SSbD) principles early in the innovation process to streamline market introduction and mitigate costs. Within this framework, encompassing ecological, social, and economic factors is paramount. The NanoSafety Cluster (NSC) delineates key safety and sustainability areas, pinpointing unresolved issues and research gaps to steer the development of safe(r) materials. Leveraging FAIR data management and integration, alongside the alignment of regulatory aspects, fosters informed decision-making and innovation. Integrating circularity and sustainability mandates clear guidance, ensuring responsible innovation at every stage. Collaboration among stakeholders, anticipation of regulatory demands, and a commitment to sustainability are pivotal for translating SSbD into tangible advancements. Harmonizing standards and test guidelines, along with regulatory preparedness through an exchange platform, is imperative for governance and market readiness. By adhering to these principles, the effective and sustainable deployment of innovative materials can be realized, propelling positive transformation and societal acceptance., Competing Interests: All authors declare that they have no interests to declare.•Flemming R. Cassee, National Institute of Public Health and the Environment (RIVM), the Netherlands & Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands•Eric A.J. Bleeker, National Institute of Public Health and the Environment (RIVM), the Netherlands•Cyrille Durand, TEMAS Solutions GmbH, Hausen, Switzerland•Thomas Exner, Seven Past Nine, Cerknica, Slovenia•Andreas Falk, BioNanoNet Forschungsgesellschaft mbH (BNN), Austria•Steffi Friedrichs, AcumenIST SRL, Brussels, Belgium•Elisabeth Heunisch, Federal Institute for Occupational Safety and Health (BAuA), Germany•Martin Himly, Paris Lodron University of Salzburg, Austria•Sabine Hofer, Paris Lodron University of Salzburg, Austria•Norbert Hofstätter, Paris Lodron University of Salzburg, Austria•Danail Hristozov, East European Research and Innovation Enterprise Ltd, Bulgaria•Penny Nymark, Institute of Environmental Medicine, Karolinska Institute, Solna, Sweden•Anna Pohl, Federal Institute for Occupational Safety and Health (BAuA), Germany•Lya G. Soeteman-Hernández, National Institute of Public Health and the Environment (RIVM), the Netherlands•Blanca Suarez-Merino, TEMAS Solutions GmbH, Hausen, Switzerland•Eugenia Valsami-Jones, School of Geography, Earth and Environmental Sciences, University of Birmingham, Birmingham, United Kingdom•Monique Groenewold,National Institute of Public Health and the Environment (RIVM), the Netherlands, (© 2024 The Authors.)

Published
2024
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80. Environmental and Health Impacts of Graphene and Other Two-Dimensional Materials: A Graphene Flagship Perspective.

Author

Lin H, Buerki-Thurnherr T, Kaur J, Wick P, Pelin M, Tubaro A, Carniel FC, Tretiach M, Flahaut E, Iglesias D, Vázquez E, Cellot G, Ballerini L, Castagnola V, Benfenati F, Armirotti A, Sallustrau A, Taran F, Keck M, Bussy C, Vranic S, Kostarelos K, Connolly M, Navas JM, Mouchet F, Gauthier L, Baker J, Suarez-Merino B, Kanerva T, Prato M, Fadeel B, and Bianco A

Abstract

Two-dimensional (2D) materials have attracted tremendous interest ever since the isolation of atomically thin sheets of graphene in 2004 due to the specific and versatile properties of these materials. However, the increasing production and use of 2D materials necessitate a thorough evaluation of the potential impact on human health and the environment. Furthermore, harmonized test protocols are needed with which to assess the safety of 2D materials. The Graphene Flagship project (2013-2023), funded by the European Commission, addressed the identification of the possible hazard of graphene-based materials as well as emerging 2D materials including transition metal dichalcogenides, hexagonal boron nitride, and others. Additionally, so-called green chemistry approaches were explored to achieve the goal of a safe and sustainable production and use of this fascinating family of nanomaterials. The present review provides a compact survey of the findings and the lessons learned in the Graphene Flagship.

Published
2024
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81. An unusual manifestation of Langerhans cell histiocytosis in the gastrointestinal tract.

Author

Rayón Moreno L, Pérez Garvin A, Bernardo B, and Merino B

Abstract

Langerhans cell histiocytosis (LCH) is a monoclonal proliferative disease that can affect multiple organs. It is a rare disorder, and children are the most commonly affected. Its classification depends on whether the disease is localized (usually bone or skin) or systemic. We present the case of a 49-year-old woman with a previous diagnosis of LCH in 2018 with only cutaneous involvement, managed with topical corticosteroids. After developing hypertransaminasemia, a PET-CT scan was performed, showing dissemination of the disease with bone, hepatosplenic and gynecological involvement. In addition, hypermetabolic lesions were described in the cecum with ileocecal adenopathies. A colonoscopy was performed showing in the cecum and ascending colon multiple sessile polyps of 5-10mm with central fibrin-coated erosions, from which biopsies were obtained. Histology revealed typical features of LCH with positive staining for CD1A, S100 and Langerin.

Published
2024
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83. Pharmacological activation of insulin-degrading enzyme improves insulin secretion and glucose tolerance in diet-induced obese mice.

Author

Sanz-González A, Cózar-Castellano I, Broca C, Sabatier J, Acosta GA, Royo M, Hernándo-Muñoz C, Torroba T, Perdomo G, and Merino B

Subjects
Mice, Humans, Animals, Insulin Secretion, Mice, Obese, Glucose metabolism, Insulin metabolism, Diet, High-Fat adverse effects, Insulysin metabolism, Insulysin pharmacology, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 metabolism, Insulin-Secreting Cells metabolism, Islets of Langerhans metabolism
Abstract

Aim: To investigate the use of synthetic preimplantation factor (sPIF) as a potential therapeutic tool for improving glucose-stimulated insulin secretion (GSIS), glucose tolerance and insulin sensitivity in the setting of diabetes., Materials and Methods: We used a preclinical murine model of type 2 diabetes (T2D) induced by high-fat diet (HFD) feeding for 12 weeks. Saline or sPIF (1 mg/kg/day) was administered to mice by subcutaneously implanted osmotic mini-pumps for 25 days. Glucose tolerance, circulating insulin and C-peptide levels, and GSIS were assessed. In addition, β-cells (Min-6) were used to test the effects of sPIF on GSIS and insulin-degrading enzyme (IDE) activity in vitro. The effect of sPIF on GSIS was also tested in human islets., Results: GSIS was enhanced 2-fold by sPIF in human islets ex vivo. Furthermore, continuous administration of sPIF to HFD mice increased circulating levels of insulin and improved glucose tolerance, independently of hepatic insulin clearance. Of note, islets isolated from mice treated with sPIF exhibited restored β-cell function. Finally, genetic (shRNA-IDE) or pharmacological (6bK) inactivation of IDE in Min-6 abolished sPIF-mediated effects on GSIS, showing that both the protein and its protease activity are required for its action., Conclusions: We conclude that sPIF is a promising secretagogue for the treatment of T2D., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Published
2023
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84. A roadmap to strengthen standardisation efforts in risk governance of nanotechnology.

Author

Rasmussen K, Bleeker EAJ, Baker J, Bouillard J, Fransman W, Kuhlbusch TAJ, Resch S, Sergent JA, Soeteman-Hernandez LG, Suarez-Merino B, and Porcari A

Subjects
Economic Factors, Educational Status, Reference Standards, Nanotechnology, Nanostructures
Abstract

A roadmap was developed to strengthen standardisation activities for risk governance of nanotechnology. Its baseline is the available standardised and harmonised methods for nanotechnology developed by the International Organization for Standardization (ISO), the European Committee for Standardization (CEN), and the Organisation for Economic Co-operation and Development (OECD). In order to identify improvements and needs for new themes in standardisation work, an analysis of the state-of-the-art concepts and interpretations of risk governance of nanotechnology was performed. Eleven overall areas of action were identified, each including a subset of specific topics. Themes addressed include physical chemical characterisation, assessment of hazard, exposure, risk and socio-economic factors, as well as education & training and social dialogue. This has been visualised in a standardisation roadmap spanning a timeframe of ten years and including key outcomes and highlights of the analysis. Furthermore, the roadmap indicates potential areas of action for harmonisation and standardisation (H&S) for nanomaterials and nanotechnology. It also includes an evaluation of the current level (limited, moderate, intense) of ongoing H&S activities and indicates the time horizon for the different areas of action. As the identified areas differ in their state of development, the number and type of actions varied widely amongst the different actions towards achieving standardisation. Thus, priority areas were also identified. The overall objective of these actions is to strengthen risk governance towards a safe use of nanomaterials and nano-related products. Though not explicitly addressed, risk-based legislation and policies are supported via the proposed H&S actions., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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85. Perception of facial expressions involves emotion specific somatosensory cortex activations which are shaped by alexithymia.

Author

Arslanova I, Meletaki V, Calvo-Merino B, and Forster B

Subjects
Humans, Somatosensory Cortex, Emotions physiology, Anger, Perception, Affective Symptoms, Facial Expression
Abstract

Somatosensory cortex (SCx) has been shown to crucially contribute to early perceptual processes when judging other's emotional facial expressions. Here, we investigated the specificity of SCx activity to angry, happy, sad and neutral emotions and the role of personality factors. We assessed participants' alexithymia (TAS-20) and depression (BDI) levels, their cardioceptive abilities and recorded changes in neural activity in a facial emotion judgment task. During the task, we presented tactile probes to reveal neural activity in SCx which was then isolated from visual carry-over responses. We further obtain SCx emotion effects by subtracting SCx activity elicited by neutral emotion expressions from angry, happy, and sad expressions. We find preliminary evidence for distinct modulations of SCx activity to angry and happy expressions. Moreover, the SCx anger response was predicted by individual differences in trait alexithymia. Thus, emotion expressions of others may be distinctly presented in the observer's neural body representation and may be shaped by their personality trait., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Published
2023
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86. Fast and reliable analysis of pH-responsive nanocarriers for drug delivery using microfluidic tools.

Author

García-Merino B, Bringas E, and Ortiz I

Subjects
Humans, Microfluidics, Drug Delivery Systems, Silicon Dioxide, Hydrogen-Ion Concentration, Drug Liberation, Drug Carriers, Nanoparticles
Abstract

During the last decades, there has been growing interest in the application of functionalized mesoporous nanomaterials as stimuli-responsive carriers for drug delivery. However, at present there is not a standardized methodology to evaluate their performance. The limitations of the different techniques reported in literature give rise to the necessity for new, simple, and cost-effective alternatives. This work constitutes a step forward in the development of advanced in vitro procedures for testing the behavior of nanocarriers, proposing a novel microfluidic platform. To test the capacity of the reported tool, the performance of amino-functionalized MCM-41 nanoparticles has been assessed. These materials show a pH-responsive mechanism, which prevents the drug release at acidic conditions, maximizing its distribution at neutral pH, thus, the selected release medium mimicked gastrointestinal conditions. As a first approximation, the delivery of Ru(bipy) 3 2+ was evaluated, proving the advantages of the proposed microfluidic system: i) continuous flow of particles and media, ii) rigorous control of the residence time, temperature and pH, iii) enhanced mixing, iv) possibility to simulate different human body conditions and, v) possible integration with the continuous synthesis of nanocarriers. Finally, the microfluidic tool was used to analyze the delivery of the anti-inflammatory drug ibuprofen., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Published
2023
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87. Schedule-induced alcohol intake during adolescence sex dependently impairs hippocampal synaptic plasticity and spatial memory.

Author

Sanz-Martos AB, Fuentes-Verdugo E, Merino B, Morales L, Pérez V, Capellán R, Pellón R, Miguéns M, and Del Olmo N

Subjects
Rats, Female, Male, Animals, Rats, Wistar, Long-Term Potentiation physiology, Hippocampus metabolism, Ethanol metabolism, Alcohol Drinking, Receptors, N-Methyl-D-Aspartate metabolism, Spatial Memory, Neuronal Plasticity physiology
Abstract

In a previous study, we demonstrated that intermittent ethanol administration in male adolescent animals impaired hippocampus-dependent spatial memory, particularly under conditions of excessive ethanol administration. In this current study, we subjected adolescent male and female Wistar rats an alcohol schedule-induced drinking (SID) procedure to obtain an elevated rate of alcohol self-administration and assessed their hippocampus-dependent spatial memory. We also studied hippocampal synaptic transmission and plasticity, as well as the expression levels of several genes involved in these mechanisms. Both male and female rats exhibited similar drinking patterns throughout the sessions of the SID protocol reaching similar blood alcohol levels in all the groups. However, only male rats that consumed alcohol showed spatial memory deficits which correlated with inhibition of hippocampal synaptic plasticity as long-term potentiation. In contrast, alcohol did not modify hippocampal gene expression of AMPA and NMDA glutamate receptor subunits, although there are differences in the expression levels of several genes relevant to synaptic plasticity mechanisms underlying learning and memory processes, related to alcohol consumption as Ephb2, sex differences as Pi3k or the interaction of both factors such as Pten. In conclusion, elevated alcohol intake during adolescence seems to have a negative impact on spatial memory and hippocampal synaptic plasticity in a sex dependent manner, even both sexes exhibit similar blood alcohol concentrations and drinking patterns., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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88. Predictors of long-term neutralizing antibody titers following COVID-19 vaccination by three vaccine types: the BOOST study.

Author

Prather AA, Dutcher EG, Robinson J, Lin J, Blackburn E, Hecht FM, Mason AE, Fromer E, Merino B, Frazier R, O'Bryan J, Drury S, and Epel ES

Subjects
Male, Female, Humans, BNT162 Vaccine, COVID-19 Vaccines, 2019-nCoV Vaccine mRNA-1273, Ad26COVS1, Pandemics, Vaccination, Antibodies, Neutralizing, COVID-19 prevention & control, Vaccines
Abstract

As concerns related to the COVID-19 pandemic continue, it is critical to understand the impact of vaccination type on neutralizing antibody response durability as well as to identify individual difference factors related to decline in neutralization. This was a head-to-head comparison study following 498 healthy, community volunteers who received the BNT162b2 (n = 287), mRNA-1273 (n = 149), and Ad26.COV2.S (n = 62). Participants completed questionnaires and underwent blood draws prior to vaccination, 1 month, and 6 months after the vaccination series, and neutralizing antibody (nAB) titers at 1- and 6-months post vaccination were quantified using a high-throughput pseudovirus assay. Over 6 months of follow-up, nABs declined in recipients of BNT162b2 and mRNA-1273, while nABs in recipients of Ad26.COV2.S showed a significant increase. At the 6-month time point, nABs to Ad26.COV2.S were significantly higher than nABs to BNT162b2 and equivalent to mRNA-1273. Irrespective of follow-up timing, being older was associated with lower nAB for participants who received BNT162b2 and Ad26.COV2.S but not for those who received mRNA-1273. A higher baseline BMI was associated with a lower nAB for Ad26.COV2.S recipients but not for recipients of other vaccines. Women and non-smokers showed higher nAB compared to men and current smokers, respectively. The durability of neutralizing antibody responses differed by vaccine type and several sociodemographic factors that predicted response. These findings may inform booster recommendations in the future., (© 2023. The Author(s).)

Published
2023
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89. TRAAC framework to improve regulatory acceptance and wider usability of tools and methods for safe innovation and sustainability of manufactured nanomaterials.

Author

Shandilya N, Barreau MS, Suarez-Merino B, Porcari A, Pimponi D, Jensen KA, Fransman W, and Franken R

Subjects
Humans, Reproducibility of Results, Risk Management, Risk Assessment methods, Europe, Nanostructures
Abstract

There has been an increasing use of advanced materials, particularly manufactured nanomaterials, in industrial applications and consumer products in the last two decades. It has instigated concerns about the sustainability, in particular, risks and uncertainties regarding the interactions of the manufactured nanomaterials with humans and the environment. Consequently, significant resources in Europe and beyond have been invested into the development of tools and methods to support risk mitigation and risk management, and thus facilitate the research and innovation process of manufactured nanomaterials. The level of risk analysis is increasing, including assessment of socio-economic impacts, and sustainability aspects, moving from a conventional risk-based approach to a wider safety-and-sustainability-by-design perspective. Despite these efforts on tools and methods development, the level of awareness and use of most of such tools and methods by stakeholders is still limited. Issues of regulatory compliance and acceptance, reliability and trust, user-friendliness and compatibility with the users' needs are some of the factors which have been traditionally known to hinder their widespread use. Therefore, a framework is presented to quantify the readiness of different tools and methods towards their wider regulatory acceptance and downstream use by different stakeholders. The framework diagnoses barriers which hinder regulatory acceptance and wider usability of a tool/method based on their Transparency, Reliability, Accessibility, Applicability and Completeness (TRAAC framework). Each TRAAC pillar consists of criteria which help in evaluating the overall quality of the tools and methods for their (i) compatibility with regulatory frameworks and (ii) usefulness and usability for end-users, through a calculated TRAAC score based on the assessment. Fourteen tools and methods were assessed using the TRAAC framework as proof-of-concept and for user variability testing. The results provide insights into any gaps, opportunities, and challenges in the context of each of the 5 pillars of the TRAAC framework. The framework could be, in principle, adapted and extended to the evaluation of other type of tools & methods, even beyond the case of nanomaterials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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90. Effects of saturated versus unsaturated fatty acids on metabolism, gliosis, and hypothalamic leptin sensitivity in male mice.

Author

Fernández-Felipe J, Valencia-Avezuela M, Merino B, Somoza B, Cano V, Sanz-Martos AB, Frago LM, Fernández-Alfonso MS, Ruiz-Gayo M, and Chowen JA

Subjects
Mice, Male, Animals, Dietary Fats, Fatty Acids, Unsaturated pharmacology, Obesity metabolism, Hypothalamus metabolism, Fatty Acids metabolism, RNA, Messenger metabolism, Leptin, Gliosis metabolism
Abstract

Background: Development of obesity and its comorbidities is not only the result of excess energy intake, but also of dietary composition. Understanding how hypothalamic metabolic circuits interpret nutritional signals is fundamental to advance towards effective dietary interventions., Objective: We aimed to determine the metabolic response to diets enriched in specific fatty acids., Methods: Male mice received a diet enriched in unsaturated fatty acids (UOLF) or saturated fatty acids (SOLF) for 8 weeks., Results: UOLF and SOLF mice gained more weight and adiposity, but with no difference between these two groups. Circulating leptin levels increased on both fatty acid-enriched diet, but were higher in UOLF mice, as were leptin mRNA levels in visceral adipose tissue. In contrast, serum non-esterified fatty acid levels only rose in SOLF mice. Hypothalamic mRNA levels of NPY decreased and of POMC increased in both UOLF and SOLF mice, but only SOLF mice showed signs of hypothalamic astrogliosis and affectation of central fatty acid metabolism. Exogenous leptin activated STAT3 in the hypothalamus of all groups, but the activation of AKT and mTOR and the decrease in AMPK activation in observed in controls and UOLF mice was not found in SOLF mice., Conclusions: Diets rich in fatty acids increase body weight and adiposity even if energy intake is not increased, while increased intake of saturated and unsaturated fatty acids differentially modify metabolic parameters that could underlie more long-term comorbidities. Thus, more understanding of how specific nutrients affect metabolism, weight gain, and obesity associated complications is necessary.

Published
2023
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91. Effect of a high-fat diet and leptin on STAT3 phosphorylation in hippocampal astrocytes.

Author

Naranjo V, Merino B, Del Olmo N, Frago LM, Chowen JA, Ruiz-Gayo M, and Cano González V

Subjects
Male, Animals, Mice, Phosphorylation, Hippocampus, Brain, Diet, High-Fat adverse effects, Astrocytes
Abstract

Objective: The aim of the current study was to evaluate the influence of HFD on the functionality of LepR by quantifying phosphorylated levels of 705Tyr-STAT3 in hippocampus astrocytes from mice that consumed an HFD either during the juvenile or the adult period., Methods: Five- and eight-week-old male mice, fed during 8 weeks with either control chow or HFD, received a single dose of leptin and their brains were prepared for immunofluorescence to identify double-positive GFAP/p705Tyr-STAT3 cells., Results: HFD intake led to increased pSTAT3 immunoreactivity in GFAP+ cells in the CA1/CA3 hippocampus areas. The effect was observed both in adolescent and adult mice. Leptin increased pSTAT3 immunoreactivity in control animals but was devoid of effect in HFD mice. HFD itself has no effect on the number of GFAP+ cells., Conclusions: Our data show that regular intake of HFD enhances STAT3 signaling in CA1/CA3 astrocytes, an effect that could be linked to the increase of leptin triggered by HFD. The increase of pSTAT3 might be integral to homeostatic mechanisms aimed at maintaining hippocampus function., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Published
2023
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92. Saturated and unsaturated triglyceride-enriched diets modify amino acid content in the mice hippocampus.

Author

Fernández-Felipe J, Sanz-Martos AB, Marcos A, Lorenzo MP, Cano V, Merino B, Ambrosio E, Del Olmo N, and Ruiz-Gayo M

Subjects
Male, Mice, Animals, Triglycerides, Diet, Hippocampus, Serine, Palmitic Acid, Amino Acids, Fatty Acids
Abstract

Elevated intake of fat modulates l-glutamate (l-Glu) turnover within the hippocampus (HIP). Our aim has been to investigate the effect of saturated vs unsaturated fat on the content of l-Glu and other amino acids involved in synaptic transmission within the HIP. The study was carried out in male mice fed (2 h or 8 weeks) with standard chow or with diets enriched either with saturated (SOLF) or unsaturated triglycerides (UOLF). An in vitro assay was performed in HIP slices incubated with palmitic (PA), oleic (OA), or lauric acid (LA). Amino acids were quantified by capillary electrophoresis. While both diets increased the amount of l-Glu and l-aspartate and decreased l-glutamine levels, only UOLF affected d-serine and taurine levels. γ-Aminobutyric acid was specifically decreased by SOLF. In vitro assays revealed that PA and OA modified l-Glu, glycine, l-serine and d-serine concentration. Our results suggest that fatty acids contained in SOLF and UOLF have an impact on HIP amino acid turnover that may account, at least partially, for the functional changes evoked by these diets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Published
2023
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93. Regional specific effect of saturated vs unsaturated fat on leptin receptor signalling in mice brain areas regulating feeding.

Author

Fernández-Felipe J, López LL, Cano V, Sánchez-Hita E, Belén Sanz A, Chowen JA, Del Olmo N, Ruiz-Gayo M, and Merino B

Subjects
Animals, Male, Mice, AMP-Activated Protein Kinases, Fats, Unsaturated administration & dosage, Hypothalamus metabolism, Leptin metabolism, Proto-Oncogene Proteins c-akt, Suppressor of Cytokine Signaling Proteins metabolism, Brain metabolism, Receptors, Leptin metabolism
Abstract

Leptin receptors (LepR) are expressed in brain areas controlling food intake homeostasis, such as the hypothalamus, the hippocampus and the prefrontal cortex. In a previous study we reported that long-term intake of saturated and monounsaturated fat alters hypothalamic LepR signalling. The current study aims at investigating the effect of foods high in either saturated (SOLF) or monounsaturated fat (UOLF) on LepR functionality in the hippocampus and the prefrontal cortex. Male mice were placed on SOLF/UOLF (eight weeks), then treated with recombinant murine leptin (1 mg/kg). After 60 min, brain regions were dissected and processed for western blot of phosphorylated STAT3 (pSTAT3), Akt (pAkt) and AMPK (pAMPK). Levels of SOCS3 were also quantified. SOLF itself increased basal levels of pSTAT3, while UOLF impaired leptin-induced phosphorylation of both Akt and AMPK. SOCS3 levels were specifically increased by UOLF within the prefrontal cortex. Our results show that SOLF and UOLF differently affect LepR signalling within the hippocampus and the prefrontal cortex, which points to the complex effect of saturated and unsaturated fat on brain function, particularly in areas regulating food intake., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Published
2023
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95. A systematic quality evaluation and review of nanomaterial genotoxicity studies: a regulatory perspective.

Author

Siivola KM, Burgum MJ, Suárez-Merino B, Clift MJD, Doak SH, and Catalán J

Subjects
DNA Damage, Databases, Factual, Reproducibility of Results, Metal Nanoparticles, Nanostructures chemistry, Nanostructures toxicity
Abstract

The number of publications in the field of nanogenotoxicology and the amount of genotoxicity data on nanomaterials (NMs) in several databases generated by European Union (EU) funded projects have increased during the last decade. In parallel, large research efforts have contributed to both our understanding of key physico-chemical (PC) parameters regarding NM characterization as well as the limitations of toxicological assays originally designed for soluble chemicals. Hence, it is becoming increasingly clear that not all of these data are reliable or relevant from the regulatory perspective. The aim of this systematic review is to investigate the extent of studies on genotoxicity of NMs that can be considered reliable and relevant by current standards and bring focus to what is needed for a study to be useful from the regulatory point of view. Due to the vast number of studies available, we chose to limit our search to two large groups, which have raised substantial interest in recent years: nanofibers (including nanotubes) and metal-containing nanoparticles. Focusing on peer-reviewed publications, we evaluated the completeness of PC characterization of the tested NMs, documentation of the model system, study design, and results according to the quality assessment approach developed in the EU FP-7 GUIDEnano project. Further, building on recently published recommendations for best practices in nanogenotoxicology research, we created a set of criteria that address assay-specific reliability and relevance for risk assessment purposes. Articles were then reviewed, the qualifying publications discussed, and the most common shortcomings in NM genotoxicity studies highlighted. Moreover, several EU projects under the FP7 and H2020 framework set the aim to collectively feed the information they produced into the eNanoMapper database. As a result, and over the years, the eNanoMapper database has been extended with data of various quality depending on the existing knowledge at the time of entry. These activities are highly relevant since negative results are often not published. Here, we have reviewed the NanoInformaTIX instance under the eNanoMapper database, which hosts data from nine EU initiatives. We evaluated the data quality and the feasibility of use of the data from a regulatory perspective for each experimental entry., (© 2022. The Author(s).)

Published
2022
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96. Effect of Lauric vs. Oleic Acid-Enriched Diets on Leptin Autoparacrine Signalling in Male Mice.

Author

Fernández-Felipe J, Plaza A, Domínguez G, Pérez-Castells J, Cano V, Cioni F, Del Olmo N, Ruiz-Gayo M, and Merino B

Abstract

High-fat diets enriched with lauric acid (SOLF) do not enhance leptin production despite expanding white adipose tissue (WAT). Our study aimed at identifying the influence of SOLF vs. oleic acid-enriched diets (UOLF) on the autoparacrine effect of leptin and was carried out on eight-week-old mice consuming control chow, UOLF or SOLF. Phosphorylation of kinases integral to leptin receptor (LepR) signalling pathways (705Tyr-STAT3, 473Ser-Akt, 172Thr-AMPK), adipocyte-size distribution, fatty acid content, and gene expression were analyzed in WAT. SOLF enhanced basal levels of phosphorylated proteins but reduced the ability of leptin to enhance kinase phosphorylation. In contrast, UOLF failed to increase basal levels of phosphorylated proteins and did not modify the effect of leptin. Both SOLF and UOLF similarly affected adipocyte-size distribution, and the expression of genes related with adipogenesis and inflammation. WAT composition was different between groups, with SOLF samples mostly containing palmitic, myristic and lauric acids (>48% w/w) and UOLF WAT containing more than 80% (w/w) of oleic acid. In conclusion, SOLF appears to be more detrimental than UOLF to the autoparacrine leptin actions, which may have an impact on WAT inflammation. The effect of SOLF and UOLF on WAT composition may affect WAT biophysical properties, which are able to condition LepR signaling., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this reported research.

Published
2022
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97. Insulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulation.

Author

Merino B, Casanueva-Álvarez E, Quesada I, González-Casimiro CM, Fernández-Díaz CM, Postigo-Casado T, Leissring MA, Kaestner KH, Perdomo G, and Cózar-Castellano I

Subjects
Animals, Cell Proliferation genetics, Glucagon metabolism, Hyperplasia genetics, Hyperplasia metabolism, Insulin metabolism, Mice, alpha-Synuclein metabolism, Diabetes Mellitus, Type 2 metabolism, Glucagon-Secreting Cells metabolism, Insulin-Secreting Cells metabolism, Insulysin genetics, Insulysin metabolism
Abstract

Aims/hypothesis: Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon-secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo., Methods: We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining., Results: Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia., Conclusions/interpretation: We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabetes., (© 2022. The Author(s).)

Published
2022
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98. Cholecystokinin promotes functional expression of the aquaglycerol channel aquaporin 7 in adipocytes.

Author

Plaza A, Merino B, and Ruiz-Gayo M

Subjects
Animals, Glycerol metabolism, Lipolysis, Rats, Receptor, Insulin metabolism, Sincalide metabolism, Adipocytes metabolism, Aquaporins genetics, Aquaporins metabolism, Cholecystokinin metabolism, Insulins metabolism
Abstract

Background and Purpose: Cholecystokinin (CCK) promotes triglyceride storage and adiponectin production in white adipose tissue (WAT), suggesting that CCK modulates WAT homeostasis. Our goal was to investigate the role of CCK in regulating the expression and function of the aquaglycerol channel aquaporin 7 (AQP7), a protein that is pivotal for maintaining adipocyte homeostasis and preserving insulin responsiveness., Experimental Approach: The effect of the bioactive fragment of CCK, CCK-8, in regulating adipose AQP7 expression and glycerol efflux was assessed in rats as well as in preadipocytes. Moreover, the involvement of insulin receptors in the effects of CCK-8 was characterized in preadipocytes lacking insulin receptors., Key Results: CCK-8 induced AQP7 gene expression in rat WAT, concomitantly increasing plasma glycerol concentration. In isolated preadipocytes, CCK-8 also enhanced both AQP7 expression and glycerol leakage. The effects of CCK-8 were independent of the lipolysis rate, as CCK-8 failed to promote fatty acid release by adipocytes. In addition, CCK-8 did not enhance hormone sensitive lipase phosphorylation, which is the rate-limiting step of lipolysis. Moreover, the effects of CCK-8 were dependent on the activation of protein kinase B and PPARγ. Silencing insulin receptor expression inhibited CCK-8-induced Aqp7 expression in preadipocytes. Furthermore, insulin enhanced the effect of CCK-8., Conclusions and Implications: CCK regulates AQP7 expression and function, and this effect is dependent on insulin. Accordingly, CCK receptor agonists could be suitable for preserving and improving insulin responsiveness in WAT., (© 2022 The British Pharmacological Society.)

Published
2022
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99. Primary Cilia in Pancreatic β- and α-Cells: Time to Revisit the Role of Insulin-Degrading Enzyme.

Author

Pablos M, Casanueva-Álvarez E, González-Casimiro CM, Merino B, Perdomo G, and Cózar-Castellano I

Subjects
Cilia, Pancreatic Hormones, Signal Transduction physiology, Glucagon-Secreting Cells, Insulysin
Abstract

The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed in primary cilium. Rare genetic disorders that affect cilia integrity and function, such as Bardet-Biedl syndrome and Alström syndrome, have awoken interest in studying the biology of cilium. In this review, we discuss recent evidence suggesting emerging roles of primary cilium and cilia-mediated signaling pathways in the regulation of pancreatic β- and α-cell functions, and its implications in regulating glucose homeostasis., 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., (Copyright © 2022 Pablos, Casanueva-Álvarez, González-Casimiro, Merino, Perdomo and Cózar-Castellano.)

Published
2022
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100. Butyric Acid Precursor Tributyrin Modulates Hippocampal Synaptic Plasticity and Prevents Spatial Memory Deficits: Role of PPARγ and AMPK.

Author

Belén Sanz-Martos A, Fernández-Felipe J, Merino B, Cano V, Ruiz-Gayo M, and Del Olmo N

Subjects
AMP-Activated Protein Kinases metabolism, AMP-Activated Protein Kinases pharmacology, Animals, Butyric Acid metabolism, Butyric Acid pharmacology, Hippocampus, Long-Term Potentiation physiology, Male, Memory Disorders metabolism, Mice, Mice, Inbred C57BL, N-Methylaspartate metabolism, Neuronal Plasticity, Receptors, N-Methyl-D-Aspartate metabolism, Scopolamine Derivatives metabolism, Scopolamine Derivatives pharmacology, Triglycerides, PPAR gamma metabolism, PPAR gamma pharmacology, Spatial Memory physiology
Abstract

Background: Short chain fatty acids (SCFA), such as butyric acid (BA), derived from the intestinal fermentation of dietary fiber and contained in dairy products, are gaining interest in relation to their possible beneficial effects on neuropsychological disorders., Methods: C57BL/6J male mice were used to investigate the effect of tributyrin (TB), a prodrug of BA, on hippocampus (HIP)-dependent spatial memory, HIP synaptic transmission and plasticity mechanisms, and the expression of genes and proteins relevant to HIP glutamatergic transmission., Results: Ex vivo studies, carried out in HIP slices, revealed that TB can transform early-LTP into late-LTP (l-LTP) and to rescue LTP-inhibition induced by scopolamine. The facilitation of l-LTP induced by TB was blocked both by GW9662 (a PPARγ antagonist) and C-Compound (an AMPK inhibitor), suggesting the involvement of both PPARγ and AMPK on TB effects. Moreover, 48-hour intake of a diet containing 1% TB prevented, in adolescent but not in adult mice, scopolamine-induced impairment of HIP-dependent spatial memory. In the adolescent HIP, TB upregulated gene expression levels of Pparg, leptin, and adiponectin receptors, and that of the glutamate receptor subunits AMPA-2, NMDA-1, NMDA-2A, and NMDA-2B., Conclusions: Our study shows that TB has a positive influence on LTP and HIP-dependent spatial memory, which suggests that BA may have beneficial effects on memory., (© The Author(s) 2022. Published by Oxford University Press on behalf of CINP.)

Published
2022
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