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1. Biomarker-guided intervention to prevent acute kidney injury after major surgery (BigpAK-2 trial): study protocol for an international, prospective, randomised controlled multicentre trial

Author

Joachim Gerss, Javier Ripollés-Melchor, Emmanuel Futier, Melanie Meersch, Carola Wempe, Detlef Kindgen-Milles, Alexander Zarbock, Markus W Hollmann, Sigismond Lasocki, Thomas Rimmele, Tim Rahmel, Michael Adamzik, Hartmuth Nowak, Ingeborg Welters, Brian Johnston, Ane Abad-motos, Alfredo Abad-gurumeta, Marc Moritz Berger, Davide Ricci, Maurizio Cecconi, Gudrun Kunst, Christian Stoppe, Christian Putensen, Marlies Ostermann, Sascha Ott, Brijesh Patel, Gabriele Baldini, Antoine Lamblin, Karen Williams, Elena Mancini, Christian Arndt, Hinnerk Wulf, Marc Irqsusi, Wim Vandenberghe, John Kellum, Raphael Weiss, Jackie Donovan, Lui G Forni, Giacomo Monti, Céline Monard, Markus A Weigand, Thorsten Brenner, Ulrich Jaschinski, Carlos Lopez, Maxime Leger, Emmanuel Rineau, Philipp Simon, María Gómez-Rojo, Lars Bergmann, Alicia Waite, Savino Spadaro, Alexander Wolf, Andrew Spence, Simon Dubler, Alexander PJ Vlaar, Patrick Schober, Ben C Creagh-Brown, Nandor Marczin, Emilio Maseda, Christian Strauss, Stefano Romagnoli, Christian Nusshag, Ulrich Gobel, Ángel Candela-Toha, Jon Silversides, Nuttha Lumlertgul, Khaschayar Saadat-Gilani, Vincent Legros, Timo Brandenburger, Thomas Dimski, Laura Huthmann, Claude Pelletier, Manon Schleß, Peter Rosenberger, Helene Häberle, Jan Gerrit Haaker, Matthias Gründel, Lucia Cattin, Laura Villarino Villa, Juan Victor Lorente, Christine Martin, Jan Larmann, Wolfgang Bauer, Giovanni Borghi, Benjamin O’Brien, Thilo von Groote, Antoine Guillaume Schneider, Silvia De Rosa, Diego Parise, Alice Bernard, Paula Fernández-Valdes-Bango, Irene Romero Bhathal, A Suarez-de-la-Rica, Gianluca Villa, Raquel García-Álvarez, Antonio Siniscalchi, Richard Ellerkmann, Florian Espeter, Christian Porschen, Mahan Sadjadi, Michael Storck, Tobias Brix, Dana Meschede, Wida Amini, Carina Stenger, Julius Freytag, Jens Brands, Matthias Unterberg, Britta Marko, Fabian Dusse, Wolfgang A Wetsch, Sandra E Stoll, Hendrik Drinhaus, Bernd W Böttiger, Onnen Mörer, Lars-Olav Harnisch, Roswitha Lubjuhn, Daniel Heise, Christian Bode, Andrea Sauer, Konrad Peukert, Lennart Wild, Philippe Kruse, Jan Menzenbach, Valbona Mirakaj, Sabine Hermann, Stefanie Decker, Mona Jung-König, Tobias Hölle, Sarah Dehne, Jörg Reutershan, Thomas Prüfer, Stefan Pielmeier, Indra Wimmelmeier, Michaela Scholz, Andrea Paris, Isabel Christina Gallego Zapata, Holger Pohl, Nirmeen Fayed, Kai Dielmann, Evelyn Martin, Tilo Koch, Alexander Mück, Philipp Deetjen, Ngoc Bich Mehlmann, Peter M Spieth, Andreas Güldner, Axel Rand, Maximillian Ragaller, Martin Mirus, Rebecca Bockholt, Marc Herzog, Maren Kleine-Brüggeney, Ant Isabelle Cristiani, Marion Ohl, Monica Vieira Da Silva, Gilda Filipe de Castro Reblo, Matthias Hilty, Katharina Spanaus, Benedetta Mura, Eleonora Terreni, Francesco Magiotti, Lorenzo Turi, Cristiana Laici, Chiara Capozzi, Andrea Castelli, Massimiliano Greco, Antonio Messina, Gianluca Castellani, Romina Aceto, Vinicio Danzi, Alessandro Rigobello, Massimo De Cal, Monica Zanella, Gaetano Scaramuzzo, Riccardo La Rosa, Paolo Priani, Alberto Volta Carlo, Stefano Turi, Martina Baiardo Redaelli, Marilena Marmiere, Kittisak Weerapolchai, Shelley Lorah, Fabiola D’Amato, Aneta Bociek, Rosario Lim, Benjie Cendreda, Reynaldo Dela Cuesta, Eirini Kosifidou, Zoka Milan, Juliana Fernanda, Emma Clarey, Daveena Meeks, Nicholas J Lees, Marco Scaramuzzi, Orinta Kviatkovske, Adam Glass, Christine Turley, Charlotte Quinn, Syeda Haider, Adam Rossiter, Syed Nasser, Ned Gilbert-Kawai, Tatjana Besse-Hammer, Eric Hoste, Hannah Schaubroeck, Jan De Waele, Jenni Breel, Eline de Klerk, Harm-Jan de Grooth, Lothar Schwarte, Alexander Loer, Alicia Ruiz-Escobar, Diana Fernández-García, Nerea Gómez-Pérez, Pascual Crespo-Aliseda, Cristina Cerro-Zaballos, Cristina Fernández-Martín, Eduardo Martín-Montero, Alejandro Suarez de la Rica, Héctor Berges Gutiérrez, Maria del Pino Heredia Pérez, Maria de los Reyes Bellido Fernández, Liena Izquierdo López, Javier Valiente Lourtau, Ma Angeles Ferre Colomer, Ma Azucena Pajares Moncho, Maria Jesús Montero Hernández, Esther Pérez Sancho, Silvia Polo Matínez, Pedro Rivera Soria, Maider Puyada Jáuregui, Hugo Rivera Ramos, Marta Antelo Adrán, Ramón Adalia Bartolomé, Patricia Galán Menéndez, Laura Llinares Espin, Yuri Santiago Loaiza Aldean, Víctor MoralesAriza, Rosalía Navarro-Perez, Luis Santé-Serna, Pedro de la Calle-Elguezabal, Rubén Sánchez-Martín, Inés De Soto, Pau Vallhonrat Alcántara, Laura Perelló Cerdà, Gal·la Rouras Hurtado, Paula Rodriguez Nieto, John Narros Sicluna, Angel Molero Molinero, Juan Pablo Nocete, Elena Murcia Sánchez, Stanislas Abrard, Marie-Luce Parrouffe, Frank Bidar, Lucie Aupetitgendre, Ugo Schiff, Bertille Paquette, Gaëlle Sellier, Nathalie Borgnetta, Benjamin Brochet, Thierry Floch, Julien Coffinet, and Marion Leclercq-Rouget

Subjects
Medicine
Abstract

Introduction Previous studies demonstrated that the implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guideline-based bundle, consisting of different supportive measures in patients at high risk for acute kidney injury (AKI), might reduce rate and severity of AKI after surgery. However, the effects of the care bundle in broader population of patients undergoing surgery require confirmation.Methods and analysis The BigpAK-2 trial is an international, randomised, controlled, multicentre trial. The trial aims to enrol 1302 patients undergoing major surgery who are subsequently admitted to the intensive care or high dependency unit and are at high-risk for postoperative AKI as identified by urinary biomarkers (tissue inhibitor of metalloproteinases 2*insulin like growth factor binding protein 7 (TIMP-2)*IGFBP7)). Eligible patients will be randomised to receive either standard of care (control) or a KDIGO-based AKI care bundle (intervention). The primary endpoint is the incidence of moderate or severe AKI (stage 2 or 3) within 72 hours after surgery, according to the KDIGO 2012 criteria. Secondary endpoints include adherence to the KDIGO care bundle, occurrence and severity of any stage of AKI, change in biomarker values during 12 hours after initial measurement of (TIMP-2)*(IGFBP7), number of free days of mechanical ventilation and vasopressors, need for renal replacement therapy (RRT), duration of RRT, renal recovery, 30-day and 60-day mortality, intensive care unit length-of-stay and hospital length-of-stay and major adverse kidney events. An add-on study will investigate blood and urine samples from recruited patients for immunological functions and kidney damage.Ethics and dissemination The BigpAK-2 trial was approved by the Ethics Committee of the Medical Faculty of the University of Münster and subsequently by the corresponding Ethics Committee of the participating sites. A study amendment was approved subsequently. In the UK, the trial was adopted as an NIHR portfolio study. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and will guide patient care and further research.Trial registration number NCT04647396.

Published
2023
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2. Prevalence of severe hypercholesterolemia observed in different hospitals in Andalusia and Ceuta

Author

Esther Roldán Fontana, Firma Isabel Rodríguez Sánchez, María Luisa Nieto, Cristina Romero Baldonado, José Vicente García Lario, María Cinta Montilla López, María Herranz, Begoña Gallardo Alguacil, Irene Romero García, Enrique Melguizo Madrid, Manuel Rodríguez Espinosa, Teresa Arrobas Velilla, Elena Bonet Struch, Jacobo Diaz Portillo, Joaquín Bobillo Lobato, Salomé Hijano Villegas, Antonio León Justel, Gema María Varo Sánchez, and Ignacio Vázquez Rico

Subjects
Pediatrics, medicine.medical_specialty, High prevalence, business.industry, Incidence (epidemiology), General Engineering, Early detection, Primary care, Disease, Methods observational, General Earth and Planetary Sciences, Medicine, lipids (amino acids, peptides, and proteins), Risk factor, business, General Environmental Science
Abstract

Severe hypercholesterolaemia is a major cardiovascular risk factor. Early detection and treatment can reduce the incidence of cardiovascular disease. Given the high prevalence of hypercholesterolaemia in Andalusia, the development of a screening strategy for its detection in Primary Care may be an efficient measure. Objective To identify patients in Primary Care with severe hypercholesterolaemia that may increase their cardiovascular risk by reviewing LDL-cholesterol results in computerised laboratory systems. Material and methods Observational, retrospective, multi-centre study in 16 hospitals in Andalusia and Ceuta. Anonymous analytical data were acquired from the different laboratory computer systems for the year 2018, and exclusively from Macarena Hospital for the year 2019. Results From a total of 1,969,035 determinations on ≥18 years old, 2791 patients (0.14%) were detected with LDL-cholesterol >250 mg/dl and from a total of 2.327.211 determinations studied in children under 18 years old, 3804 patients (0.16%) were detected with LDL-cholesterol >135 mg/dl. The highest incidence of possible genetic hypercholesterolaemia in adults corresponded to the province of Seville with 23.6 cases/1000 determinations, while in minors, the highest incidence corresponded to the province of Cadiz with 75 possible cases/1000 determinations. A geographical triangle of greater prevalence is observed between the provinces of Seville, Huelva and Cadiz. Conclusions The development of a screening strategy using a computerised review of LDL-cholesterol in Primary Care detects a large number of subjects with severe hypercholesterolaemia that could benefit from an early intervention.

Published
2021
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3. The Effect of Ethanol Treatment on the Quality of a New Table Grape Cultivar It 681–30 Stored at Low Temperature and after a 7-Day Shelf-Life Period at 20 °C: A Molecular Approach

Author

Irene Romero, M. Teresa Sanchez-Ballesta, M. Isabel Escribano, Carmen Merodio, Maria Vazquez-Hernandez, Manuel Tornel, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), European Commission, and Comisión Interministerial de Ciencia y Tecnología, CICYT (España)

Subjects
0106 biological sciences, Transcription, Genetic, 01 natural sciences, chemistry.chemical_compound, Weight loss, Table grapes, Browning, Low temperature, Vitis, Cultivar, Biology (General), Spectroscopy, Plant Proteins, 0303 health sciences, Chemistry, food and beverages, General Medicine, Computer Science Applications, Cold Temperature, Horticulture, Gases, medicine.symptom, QH301-705.5, Period (gene), low temperature, Aquaporins, Shelf life, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, Food Preservation, Food Quality, medicine, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, 030304 developmental biology, Fruit quality, Ethanol, Organic Chemistry, Table grape, fungi, fruit quality, table grapes, Maillard Reaction, Food Storage, Fruit, Food Preservatives, Postharvest, gene expression, Gene expression, ethanol, Volatilization, Transcription Factors, 010606 plant biology & botany
Abstract

This article belongs to the Special Issue Gene Transcriptional Regulation in Crops during Postharvest., Despite the fact that many studies have examined the effectiveness of different gaseous postharvest treatments applied at low temperature to maintain table grape quality, the use of ethanol vapor has hardly been investigated. Thus, this work has studied the effectiveness of ethanol vapor-generating sachets in the maintenance of It 681–30 table grape quality, a new cultivar, during storage at low temperature and after the shelf-life period at 20 °C. To this end, various quality assessments have been carried out and the effect of the ethanol treatment on the expression of different genes (phenylpropanoids, transcription factors, PRs, and aquaporins) was determined. The results indicated that the application of ethanol vapor reduced the total decay incidence, weight loss, and the rachis browning index in It 681–30 grapes stored at 0 °C and after the shelf-life period at 20 °C, as compared to non-treated samples. Moreover, the modulation of STS7 and the different PR genes analyzed seems to play a part in the molecular mechanisms activated to cope with fungal attacks during the postharvest of It 681–30 grapes, and particularly during the shelf-life period at 20 °C. Furthermore, the expression of aquaporin transcripts was activated in samples showing higher weight loss. Although further work is needed to elucidate the role of ethanol in table grape quality, the results obtained in this work provide new insight into the transcriptional regulation triggered by ethanol treatment., This work was supported by CICYT projects AGL2014-53081-R and AGL2017-85291-R (MINECO/AEI/FEDER, UE).

Published
2021

4. MHC Class I Molecules and Cancer Progression: Lessons Learned from Preclinical Mouse Models

Author

Ignacio Algarra, Irene Romero, and Angel Garcia-Lora

Subjects
biology, Human leukocyte antigen, Major histocompatibility complex, medicine.disease, Primary tumor, Natural killer cell, medicine.anatomical_structure, Antigen, MHC class I, Immunology, Cancer cell, biology.protein, medicine, Cancer research, CD8
Abstract

Major histocompatibility complex (MHC) class I molecules are expressed on the surface of nucleated cells and present peptides derived from endogenous proteins to CD8+ T lymphocytes. In tumor cells, MHC-I molecules may present peptides derived from tumor-associated antigens, which are new proteins expressed or overexpressed in tumor cells. Presentation of these new peptides may allow recognition and destruction of tumor cells by CD8+ T lymphocytes. Loss of MHC-I expression on tumor cells is a widespread and frequent mechanism developed to escape from immunosurveillance. Alteration in MHC-I in both human and murine experimental tumors has been widely reported. This chapter summarizes the role of MHC class I expression on cancer cells in tumor and metastatic progression, as well as its effect on the outcome of immunotherapy in murine experimental tumors. Results were obtained from different tumor clones derived from a fibrosarcoma induced by methylcholanthrene in BALB/c mice, in addition to spontaneous metastases derived from these tumor clones, during more than 30 years of study on murine cancer model GR9. In this tumor model, results show an inverse correlation between MHC-I expression on tumor cells and primary tumor growth, i.e., MHC-I-negative tumors grew more rapidly compared to MHC-I-positive tumors. In contrast, a direct correlation was found between MHC-I expression on primary tumors and spontaneous metastatic capacity. Immunotherapy as an antimetastatic treatment was completely effective against MHC-I highly positive tumors and was partially effective on tumors with intermediate level of MHC-I expression.

Published
2020
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5. Identification of genetic variants associated with Huntington's disease progression

Author

Davina J Hensman Moss, Antonio F Pardiñas, Douglas Langbehn, Kitty Lo, Blair R Leavitt, Raymund Roos, Alexandra Durr, Simon Mead, Peter Holmans, Lesley Jones, Sarah J Tabrizi, A Coleman, R Dar Santos, J Decolongon, A Sturrock, E Bardinet, C Jauff Ret, D Justo, S Lehericy, C Marelli, K Nigaud, R Valabrègue, SJA van den Bogaard, E M Dumas, J van der Grond, EP t'Hart, C Jurgens, M-N Witjes-Ane, N Arran, J Callaghan, C Stopford, C Frost, R Jones, N Hobbs, N Lahiri, R Ordidge, G Owen, T Pepple, J Read, M Say, E Wild, A Patel, N C Fox, C Gibbard, I Malone, H Crawford, D Whitehead, S Keenan, D M Cash, C Berna, N Bechtel, S Bohlen, A Hoff Man, P Kraus, E Axelson, C Wang, T Acharya, S Lee, W Monaco, C Campbell, S Queller, K Whitlock, M Campbell, E Frajman, C Milchman, A O'Regan, I Labuschagne, J Stout, B Landwehrmeyer, D Craufurd, R Scahill, S Hicks, C Kennard, H Johnson, A Tobin, HD Rosas, R Reilmann, B Borowsky, C Pourchot, S C Andrews, Anne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael Bonelli, Jean-Marc Burgunder, Stephen Dunnett, Joaquim Ferreira, Olivia Handley, Arvid Heiberg, Torsten Illmann, G. Bernhard Landwehrmeyer, Jamie Levey, Maria A. Ramos-Arroyo, Jørgen Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A.C. Roos, A Rojo Sebastián, Sarah Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Monica Bascuñana Garde, Sabrina Betz, Reineke Bos, Jenny Callaghan, Adrien Come, Leonor Correia Guedes, Daniel Ecker, Ana Maria Finisterra, Ruth Fullam, Mette Gilling, Lena Gustafsson, Olivia J Handley, Carina Hvalstedt, Christine Held, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saül Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Michael Orth, Hélène Padieu, Laurent Paterski, Nadia Peppa, Martina Di Renzo, Amandine Rialland, Niini Røren, Pavla Šašinková, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Wildson Vieira da Silva, Marleen R van Walsem, Carina Whalstedt, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Raphael M. Bonelli, Sabine Lilek, Karen Hecht, Brigitte Herranhof, Anna Holl, Hans-Peter Kapfhammer, Michael Koppitz, Markus Magnet, Nicole Müller, Daniela Otti, Annamaria Painold, Karin Reisinger, Monika Scheibl, Helmut Schöggl, Jasmin Ullah, Eva-Maria Braunwarth, Florian Brugger, Lisa Buratti, Eva-Maria Hametner, Caroline Hepperger, Christiane Holas, Anna Hotter, Anna Hussl, Christoph Müller, Werner Poewe, Klaus Seppi, Fabienne Sprenger, Gregor Wenning, Andrea Boogaerts, Godelinde Calmeyn, Isabelle Delvaux, Dirk Liessens, Nele Somers, Michel Dupuit, Cécile Minet, Dominique van Paemel, Pascale Ribaï, Dimphna van Reijen, Jirí Klempír, Veronika Majerová, Jan Roth, Irena Stárková, Lena E. Hjermind, Oda Jacobsen, Jørgen E. Nielsen, Ida Unmack Larsen, Tua Vinther-Jensen, Heli Hiivola, Hannele Hyppönen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau, Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Rekha Barthélémy, Christelle De Bruycker, Maryline Cabaret Anne-Sophie Carette, Eric Decorte Luc Defebvre, Marie Delliaux, Arnaud Delval, Alain Destee, Kathy Dujardin, Marie-Hélène Lemaire, Sylvie Manouvrier, Mireille Peter, Lucie Plomhouse, Bernard Sablonnière, Clémence Simonin, Stéphanie Thibault-Tanchou, Isabelle Vuillaume, Marcellin Bellonet, Hassan Berrissoul, Stéphanie Blin, Françoise Courtin, Cécile Duru, Véronique Fasquel, Olivier Godefroy, Pierre Krystkowiak, Béatrice Mantaux, Martine Roussel, Sandrine Wannepain, Jean-Philippe Azulay, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Laura Mundler, Mathieu Anheim, Celine Julié, Ouhaid Lagha Boukbiza, Nadine Longato, Gabrielle Rudolf, Christine Tranchant, Marie-Agathe Zimmermann, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J. Werner, Harald Gelderblom, Josef Priller, Harald Prüß, Eike Jakob Spruth, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Peter Kotz, Christian Prehn, Carsten Saft, Herwig Lange, Robert Maiwald, Matthias Löhle, Antonia Maass, Simone Schmidt, Cecile Bosredon, Alexander Storch, Annett Wolz, Martin Wolz, Philipp Capetian, Johann Lambeck, Birgit Zucker, Kai Boelmans, Christos Ganos, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Heike Gorzolla, Christoph Schrader, Pawel Tacik, Michael Ribbat, Bernhard Longinus, Katrin Bürk, Jens Carsten Möller, Ida Rissling, Mark Mühlau, Alexander Peinemann, Michael Städtler, Adolf Weindl, Juliane Winkelmann, Cornelia Ziegler, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Eva Hölzner, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Natalia Weber, Matthias Dose, Gabriele Leythäuser, Ralf Marquard, Tina Raab, Alexandra Wiedemann, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Christina Lang, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süßmuth, Sonja Trautmann, Patrick Weydt, Claudia Cormio, Vittorio Sciruicchio, Claudia Serpino, Marina de Tommaso, Sabina Capellari, Pietro Cortelli, Roberto Galassi, Giovanni Rizzo, Roberto Poda, Cesa Scaglione, Elisabetta Bertini, Elena Ghelli, Andrea Ginestroni, Francesca Massaro, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giovanni Abbruzzese, Monica Bandettini di Poggio, Giovanna Ferrandes, Paola Mandich, Roberta Marchese, Alberto Albanese, Daniela Di Bella, Anna Castaldo, Stefano Di Donato, Cinzia Gellera, Silvia Genitrini, Caterina Mariotti, Lorenzo Nanetti, Dominga Paridi, Paola Soliveri, Chiara Tomasello, Giuseppe De Michele, Luigi Di Maio, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Elena Salvatore, Pierpaolo Sorrentino, Enrico Amico, Mariagrazia Favellato, Annamaria Griguoli, Irene Mazzante, Martina Petrollini, Ferdinando Squitieri, Barbara D'Alessio, Chiara Esposito, Rita Bentivoglio, Marina Frontali, Arianna Guidubaldi, Tamara Ialongo, Gioia Jacopini, Carla Piano, Silvia Romano, Francesco Soleti, Maria Spadaro, Monique S.E. van Hout, Marloes E. Verhoeven, Jeroen P.P. van Vugt, A. Marit de Weert, J.J.W. Bolwijn, M. Dekker, B. Kremer, K.L. Leenders, J.C.H. van Oostrom, Simon J.A. van den Bogaard, Eve M. Dumas, Ellen P. 't Hart, Berry Kremer, C.C.P. Verstappen, Olaf Aaserud, Jan Frich C, Ragnhild Wehus, Kathrine Bjørgo, Madeleine Fannemel, Per F. Gørvell, Eirin Lorentzen, Lars Retterstøl, Bodil Stokke, Inga Bjørnevoll, Sigrid Botne Sando, Artur Dziadkiewicz, Malgorzata Nowak, Piotr Robowski, Emilia Sitek, Jaroslaw Slawek, Witold Soltan, Michal Szinwelski, Magdalena Blaszcyk, Magdalena Boczarska-Jedynak, Ewelina Ciach-Wysocka, Agnieszka Gorzkowska, Barbara Jasinska-Myga, Gabriela Klodowska-Duda, Gregorz Opala, Daniel Stompel, Krzysztof Banaszkiewicz, Dorota Bocwinska, Kamila Bojakowska-Jaremek, Malgorzata Dec, Malgorzata Krawczyk, Monika Rudzinska, Elzbieta Szczygiel, Andrzej Szczudlik, Anna Wasielewska, Magdalena Wójcik, Anna Bryl, Anna Ciesielska, Aneta Klimberg, Jerzy Marcinkowski, Husam Samara, Justyna Sempolowicz, Anna Gogol, Piotr Janik, Hubert Kwiecinski, Zygmunt Jamrozik, Jakub Antczak, Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stepniak, Anna Sulek, Elzbieta Zdzienicka, Karolina Zieora-Jakutowicz, Joaquim J Ferreira, Miguel Coelho, Tiago Mendes, Anabela Valadas, Carlos Andrade, Miguel Gago, Carolina Garrett, Maria Rosália Guerra, Carmen Durán Herrera, Patrocinio Moreno Garcia, Miquel Aguilar Barbera, Dolors Badenes Guia, Laura Casas Hernanz, Judit López Catena, Pilar Quiléz Ferrer, Ana Rojo Sebastián, Gemma Tome Carruesco, Jordi Bas, Núria Busquets, Matilde Calopa, Misericordia Floriach Robert, Celia Mareca Viladrich, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Esther Cubo, Cecilia Gil Polo, Natividad Mariscal, Perez Jessica Rivadeneyra, Francisco Barrero, Blas Morales, María Fenollar, Rocío García-Ramos García, Paloma Ortega, Clara Villanueva, Javier Alegre, Mónica Bascuñana, Juan Garcia Caldentey, Marta Fatás Ventura, Guillermo García Ribas, Justo García de Yébenes, José Luis López-Sendón Moreno, Fernando Alonso Frech, Pedro J García Ruíz, Asunción Martínez-Descals, Rosa Guerrero, María José Saiz Artiga, Vicenta Sánchez, María Fuensanta Noguera Perea, Lorenza Fortuna, Salvadora Manzanares, Gema Reinante, María Martirio Antequera Torres, Laura Vivancos Moreau, Sonia González González, Luis Menéndez Guisasola, Carlos Salvador, Esther Suaréz San Martín, Inés Legarda Ramirez, Aranzazú Gorospe, Mónica Rodriguez Lopera, Penelope Navas Arques, María José Torres Rodríguez, Barbara Vives Pastor, Itziar Gaston, Maria Dolores Martinez-Jaurrieta, Jose Manuel Garcia Moreno, Carolina Mendez Lucena, Fatima Damas, Hermoso Eva Pacheco Cortegana, José Chacón Peña, Luis Redondo, Fátima Carrillo, María Teresa Cáceres, Pablo Mir, María José Lama Suarez, Laura Vargas-González, Maria E. Bosca, Francisco Castera Brugada, Juan Andres Burguera, Anabel Campos, Garcia Carmen Peiró Vilaplana, Peter Berglund, Radu Constantinescu, Gunnel Fredlund, Ulrika Høsterey-Ugander, Petra Linnsand, Liselotte Neleborn-Lingefjärd, Magnus Wentzel, Ghada Loutfi, Carina Olofsson, Eva-Lena Stattin, Laila Westman, Birgitta Wikström, Yanik Stebler, Alain Kaelin, Irene Romero, Michael Schüpbach, Sabine Weber Zaugg, Maria Hauer, Roman Gonzenbach, Hans H. Jung, Violeta Mihaylova, Jens Petersen, Roisin Jack, Kirsty Matheson, Zosia Miedzybrodzka, Daniela Rae, Sheila A Simpson, Fiona Summers, Alexandra Ure, Vivien Vaughan, Shahbana Akhtar, Jenny Crooks, Adrienne Curtis, Jenny de Souza, John Piedad, Hugh Rickards, Jan Wright, Elizabeth Coulthard, Louise Gethin, Beverley Hayward, Kasia Sieradzan, Matthew Armstrong, Roger A. 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García, Martínez-Descals, Asunciã³n, Guerrero, Rosa, Artiga, María José Saiz, Sã¡nchez, Vicenta, Perea, María Fuensanta Noguera, Fortuna, Lorenza, Manzanares, Salvadora, Reinante, Gema, Torres, María Martirio Antequera, Moreau, Laura Vivanco, González González, Sonia, Guisasola, Luis Menéndez, Salvador, Carlo, Martã­n, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazãº, Lopera, Mónica Rodriguez, Arques, Penelope Nava, Rodrã­guez, María José Torre, Pastor, Barbara Vive, Gaston, Itziar, Martinez-Jaurrieta, Maria Dolore, Moreno, Jose Manuel Garcia, Lucena, Carolina Mendez, Damas, Fatima, Cortegana, Hermoso Eva Pacheco, Peã±a, José Chacón, Redondo, Lui, Carrillo, Fã¡tima, Teresa Cáceres, Marã­a, Mir, Pablo, Suarez, María José Lama, Vargas-González, Laura, Bosca, Maria E., Brugada, Francisco Castera, Burguera, Juan Andre, Campos, Anabel, Vilaplana, Garcia Carmen Peiró, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Linnsand, Petra, Neleborn-Lingefjärd, Liselotte, Wentzel, Magnu, Loutfi, Ghada, Olofsson, Carina, Stattin, Eva-Lena, Westman, Laila, Wikstrã¶m, Birgitta, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schã¼pbach, Michael, Weber Zaugg, Sabine, Hauer, Maria, Gonzenbach, Roman, Jung, Hans H., Mihaylova, Violeta, Petersen, Jen, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, Simpson, Sheila A, Summers, Fiona, Ure, Alexandra, Vaughan, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Armstrong, Matthew, Barker, Roger A., O'Keefe, Deidre, Di Pietro, Anna, Fisher, Kate, Goodman, Anna, Hill, Susan, Kershaw, Ann, Mason, Sarah, Paterson, Nicole, Raymond, Lucy, Swain, Rachel, Guzman, Natalie Valle, Busse, Monica, Butcher, Cynthia, Clenaghan, Catherine, Hunt, Sarah, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Edwards, Maureen, Carrie, Ho, Hughes, Teresa, Mcgill, Marie, Pearson, Pauline, Porteous, Mary, Smith, Paul, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Burrows, Liz, Chu, Carol, Fletcher, Amy, Gallantrae, Deena, Hamer, Stephanie, Harding, Alison, Klã¶ppel, Stefan, Kraus, Alison, Laver, Fiona, Lewis, Monica, Longthorpe, Mandy, Markova, Ivana, Raman, Ashok, Robertson, Nicola, Silva, Mark, Thomson, Aileen, Wild, Sue, Yardumian, Pam, Evans, Carole, Gallentrae, Deena, Hobson, Emma, Jamieson, Stuart, Musgrave, Hannah, Rowett, Liz, Toscano, Jean, Bourne, Colin, Clapton, Jackie, Clayton, Carole, Dipple, Heather, Freire-Patino, Dawn, Grant, Janet, Gross, Diana, Hallam, Caroline, Middleton, Julia, Murch, Ann, Thompson, Catherine, Alusi, Sundu, Davies, Rhy, Foy, Kevin, Gerrans, Emily, Pate, Louise, Andrews, Thomasin, Dougherty, Andrew, Golding, Charlotte, Kavalier, Fred, Laing, Hana, Lashwood, Alison, Robertson, Dene, Ruddy, Deborah, Santhouse, Alastair, Whaite, Anna, Bruno, Stefania, Doherty, Karen, Haider, Salman, Hensman, Davina, Lahiri, Nayana, Novak, Marianne, Patel, Aakta, Rosser, Elisabeth, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Rogers, Dawn, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Armstrong, Richard, Dixon, Kathryn, Nemeth, Andrea H, Siuda, Gill, Valentine, Ruth, David, Harrison, Hughes, Max, Parkinson, Andrew, Soltysiak, Beverley, Bandmann, Oliver, Bradbury, Alyson, Gill, Paul, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Kazoka, Mbombe, O'Donovan, Kirsty, Taylor, Cat, Tidswell, Katherine, Quarrell, Oliver, Lau, Puay Ngoh, Pica, Emmanul, Tan, Louis, Amsterdam Neuroscience - Neurodegeneration, Neurology, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Moss, Davina J Hensman, Lo, Kitty, Pardiñas, Antonio F, Santos, R Dar, Ret, C Jauff, Valabrègue, R., Witjes-Ane, M. -N., Man, A Hoff, Bachoud-Lévi, Anne-Catherine, Nielsen, Jørgen, Päivärinta, Markku, Sebastián, A Rojo, Wahlström, Jan, Garde, Monica Bascuñana, Laurà, Matilde, Descals, Asunción Martínez, Martinez-Horta, Saül, Mütze, Lisanne, Padieu, Hélène, Røren, Niini, Šašinková, Pavla, Witjes-Ané, Marie-Noelle, Müller, Nicole, Schöggl, Helmut, Müller, Christoph, Minet, Cécile, Ribaï, Pascale, Klempír, Jirí, Majerová, Veronika, Stárková, Irena, Nielsen, Jørgen E., Hyppönen, Hannele, Gohier, Bénédicte, Guérid, Marie-Anne, Duché, Charlotte, Lafoucrière, Danielle, Barthélémy, Rekha, Lemaire, Marie-Hélène, Sablonnière, Bernard, Simonin, Clémence, Thibault-Tanchou, Stéphanie, Blin, Stéphanie, Courtin, Françoise, Duru, Cécile, Fasquel, Véronique, Mantaux, Béatrice, Fluchere, Frédérique, Julié, Celine, Prüß, Harald, Löhle, Matthia, Münchau, Alexander, Bürk, Katrin, Möller, Jens Carsten, Mühlau, Mark, Städtler, Michael, Hölzner, Eva, Leythäuser, Gabriele, Süßmuth, Sigurd, Marchese, Roberta, DI MAIO, Luigi, ’t Hart, Ellen P., Bjørgo, Kathrine, Gørvell, Per F., Retterstøl, Lar, Bjørnevoll, Inga, Wójcik, Magdalena, Guerra, Maria Rosália, Herrera, Carmen Durán, Catena, Judit López, Ferrer, Pilar Quiléz, Sebastián, Ana Rojo, Busquets, Núria, Idiago, Jesús Miguel Ruiz, Fenollar, María, García, Rocío García-Ramo, Bascuñana, Mónica, Ventura, Marta Fatá, Ribas, Guillermo García, de Yébenes, Justo García, Moreno, José Luis López-Sendón, Ruíz, Pedro J García, Martínez-Descals, Asunción, Artiga, María José Saiz, Sánchez, Vicenta, Perea, María Fuensanta Noguera, Torres, María Martirio Antequera, González González, Sonia, Guisasola, Luis Menéndez, Martín, Esther Suaréz San, Ramirez, Inés Legarda, Gorospe, Aranzazú, Lopera, Mónica Rodriguez, Rodríguez, María José Torre, Peña, José Chacón, Carrillo, Fátima, Teresa Cáceres, María, Suarez, María José Lama, Vargas-González, Laura, Vilaplana, Garcia Carmen Peiró, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Wikström, Birgitta, Schüpbach, Michael, Ho, Carrie, Klöppel, Stefan, Harrison, David, Cardiff University, University of Iowa [Iowa City], University of British Columbia (UBC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UCL, Institute of Neurology [London], National Oceanography Centre [Southampton] (NOC), University of Southampton, Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IFR de Neuroimagerie Fonctionnelle (IFR 49), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), CHirurgie, IMagerie et REgénération tissulaire de l’extrémité céphalique - Caractérisation morphologique et fonctionnelle - UR UPJV 7516 (CHIMERE), TRACK-HD investigators, Pardinas, Antonio F, Langbehn, Douglas, Lee, S Hong, TRACK-HD Investigators, and REGISTRY Investigators

Subjects
0301 basic medicine, Oncology, Registrie, Genome-wide association study, Longitudinal Studie, Disease, Bioinformatics, Severity of Illness Index, Principal Component Analysi, Longitudinal Studies, Registries, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Huntington disease, DNA-Binding Proteins, Settore MED/26 - NEUROLOGIA, Adult, Genome-Wide Association Study, Humans, Huntington Disease, MutS Homolog 3 Protein, Principal Component Analysis, Disease Progression, Neurology (clinical), huntingtin gene, age of onest, Huntington’s disease, Human, medicine.medical_specialty, cag repeat, instability, DNA-Binding Protein, Clinical Neurology, Principal component analysis, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, Huntington's disease, Internal medicine, medicine, SNP, genome-wide association study, medicine.disease, R1, meta-analysis, Minor allele frequency, 030104 developmental biology, Age of onset, Trinucleotide repeat expansion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation. Funding The European Commission FP7 NeurOmics project; CHDI Foundation; the Medical Research Council UK; the Brain Research Trust; and the Guarantors of Brain.

Published
2017
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6. Restoration of MHC-I on Tumor Cells by Fhit Transfection Promotes Immune Rejection and Acts as an Individualized Immunotherapeutic Vaccine

Author

Alba S-Montalvo, Federico Garrido, Antonia Collado, Angel M. Garcia-Lora, María Pulido, Irene Romero, Virginia Chamorro, Ignacio Algarra, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, [Pulido,M, Chamorro,V, S-Montalvo,A, Garrido,F, Garcia-Lora,AM] Servicio de Análisis Clínicos e Inmunología, UGC Laboratorio Clínico, Hospital Universitario Virgen de las Nieves, Granada, Spain. [Pulido,M, Garcia-Lora,AM] Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain. [Romero,I] UGC Laboratorios, Complejo Hospitalario de Jaén, Jaén, Spain. [Algarra,I] Departamento de Ciencias de la Salud, Universidad de Jaén, Jaén, Spain. [Collado,A] Unidad de Biobanco, Hospital Universitario Virgen de las Nieves, Granada, Spain. [Garrido,F] Departamento de Bioquímica, Biología Molecular e Inmunología III, Universidad de Granada, Granada, Spain., and This work was supported by grants cofinanced by FEDER funds (EU) from the Instituto de Salud Carlos III (PI12/02031, PI14/01978, PI15/00528, PI17/00197, PI19/01179, PT13/0010/0039 and PT17/0015/0041), Worldwide Cancer Research project 15-1166, Junta de Andalucía (Group CTS-143, CTS-3952, CVI-4740 grants). A.M.G.L. was supported by Contract I3-SNS from Junta de Andalucía and ISCIII, I. R. by Rio-Hortega Contract CM12/00033 from ISCIII, and M. P. by ibs.Granada Fellowship 496.

Subjects
Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], 0301 basic medicine, Cancer Research, Ratones, medicine.medical_treatment, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Surface::Histocompatibility Antigens::Histocompatibility Antigens Class I [Medical Subject Headings], 0302 clinical medicine, Cancer immunotherapy, FHIT, vaccine, Organisms::Eukaryota::Animals [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy [Medical Subject Headings], Cytotoxic T cell, Chemicals and Drugs::Complex Mixtures::Biological Products::Vaccines [Medical Subject Headings], Vaccines, biology, Vacuna, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], immune profile, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Tumor antigen, Oncology, 030220 oncology & carcinogenesis, Linfocitos t citotóxicos, immunotherapy, antitumor immunity, Check Tags::Male [Medical Subject Headings], chemical and pharmacologic phenomena, Tumor cells, cytotoxic T lymphocytes, Major histocompatibility complex, lcsh:RC254-282, Article, MHC-I restoration, 03 medical and health sciences, Immune system, MHC class I, medicine, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides [Medical Subject Headings], Diseases::Neoplasms::Neoplasms by Site::Breast Neoplasms [Medical Subject Headings], Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Cytokine-Induced Killer Cells::T-Lymphocytes, Cytotoxic [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Fhit, Immunotherapy, Chemicals and Drugs::Biological Factors::Antigens::Antigens, Neoplasm [Medical Subject Headings], 030104 developmental biology, Cancer research, biology.protein, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Transfer Techniques::Transfection [Medical Subject Headings]
Abstract

The authors thank I. Linares, V. Sanz, A.B. Rodriguez, A.I. Rodriguez and E. Arias for technical advice and R. Davies for editorial assistance., The capacity of cytotoxic-T lymphocytes to recognize and destroy tumor cells depends on the surface expression by tumor cells of MHC class I molecules loaded with tumor antigen peptides. Loss of MHC-I expression is the most frequent mechanism by which tumor cells evade the immune response. The restoration of MHC-I expression in cancer cells is crucial to enhance their immune destruction, especially in response to cancer immunotherapy. Using mouse models, we recovered MHC-I expression in the MHC-I negative tumor cell lines and analyzed their oncological and immunological profile. Fhit gene transfection induces the restoration of MHC-I expression in highly oncogenic MHC-I-negative murine tumor cell lines and genes of the IFN-γ transduction signal pathway are involved. Fhit-transfected tumor cells proved highly immunogenic, being rejected by a T lymphocyte-mediated immune response. Strikingly, this immune rejection was more frequent in females than in males. The immune response generated protected hosts against the tumor growth of non-transfected cells and against other tumor cells in our murine tumor model. Finally, we also observed a direct correlation between FHIT expression and HLA-I surface expression in human breast tumors. Recovery of Fhit expression on MHC class I negative tumor cells may be a useful immunotherapeutic strategy and may even act as an individualized immunotherapeutic vaccine., FEDER funds (EU) from the Instituto de Salud Carlos III PI12/02031 PI14/01978 PI15/00528 PI17/00197 PI19/01179 PT13/0010/0039 PT17/0015/0041, Worldwide Cancer Research 15-1166, Junta de Andalucia CTS-143 CTS-3952 CVI-4740, Instituto de Salud Carlos III, Rio-Hortega Contract from ISCIII CM12/00033, ibs.Granada Fellowship 496

Published
2020
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7. MHC Intratumoral Heterogeneity May Predict Cancer Progression and Response to Immunotherapy

Author

Irene Romero, Cristina Garrido, Ignacio Algarra, Virginia Chamorro, Antonia Collado, Federico Garrido, and Angel M. Garcia-Lora

Subjects
lcsh:Immunologic diseases. Allergy, Male, 0301 basic medicine, Helper T lymphocyte, Fibrosarcoma, medicine.medical_treatment, Immunology, T lymphocytes, Clone (cell biology), chemical and pharmacologic phenomena, Docetaxel, Biology, Oncogenicity, 03 medical and health sciences, 0302 clinical medicine, Immune system, Polysaccharides, Cell Line, Tumor, medicine, Animals, Immunology and Allergy, Cytotoxic T cell, metastases, Original Research, Mice, Inbred BALB C, Histocompatibility Antigens Class I, Cancer, Immunotherapy, medicine.disease, Primary tumor, Disease Models, Animal, 030104 developmental biology, Oligodeoxyribonucleotides, 030220 oncology & carcinogenesis, intratumoral heterogeneity, Cancer research, immunotherapy, MHC, lcsh:RC581-607, Methylcholanthrene
Abstract

An individual tumor can present intratumoral phenotypic heterogeneity, containing tumor cells with different phenotypes that do not present irreversible genetic alterations. We have developed a mouse cancer model, named GR9, derived from a methylcholanthrene-induced fibrosarcoma that was adapted to tissue culture and cloned into different tumor cell lines. The clones showed diverse MHC-I phenotypes, ranging from highly positive to weakly positive MHC-I expression. These MHC-I alterations are due to reversible molecular mechanisms, because surface MHC-I could be recovered by IFN-γ treatment. Cell clones with high MHC-I expression demonstrated low local oncogenicity and high spontaneous metastatic capacity, whereas MHC-I-low clones showed high local oncogenicity and no spontaneous metastatic capacity. Although MHC-I-low clones did not metastasize, they produced MHC-I-positive dormant micrometastases controlled by the host immune system, i.e., in a state of immunodormancy. The metastatic capacity of each clone was directly correlated with the host T-cell subpopulations; thus, a strong decrease in cytotoxic and helper T lymphocytes was observed in mice with numerous metastases derived from MHC-I positive tumor clones but a strong increase was observed in those with dormant micrometastases. Immunotherapy was administered to the hosts after excision of the primary tumor, producing a recovery in their immune status and leading to the complete eradication of overt spontaneous metastases or their decrease. According to these findings, the combination of MHC-I surface expression in primary tumor and metastases with host T-cell subsets may be a decisive indicator of the clinical outcome and response to immunotherapy in metastatic disease, allowing the identification of responders to this approach.

Published
2018
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8. Generation of MHC class I diversity in primary tumors and selection of the malignant phenotype

Author

Federico Garrido, Angel M. Garcia-Lora, Irene Romero, and Natalia Aptsiauri

Subjects
Cancer Research, biology, medicine.medical_treatment, chemical and pharmacologic phenomena, Immunotherapy, Major histocompatibility complex, medicine.disease, Phenotype, Primary tumor, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Oncology, 030220 oncology & carcinogenesis, Immunology, Cancer cell, MHC class I, biology.protein, medicine, 030215 immunology
Abstract

Intratumor heterogeneity among cancer cells is promoted by reversible or irreversible genetic alterations and by different microenvironmental factors. There is considerable experimental evidence of the presence of a variety of malignant cell clones with a wide diversity of major histocompatibility class I (MHC-I) expression during early stages of tumor development. This variety of MHC-I phenotypes may define the evolution of a particular tumor. Loss of MHC-I molecules frequently results in immune escape of MHC-negative or -deficient tumor cells from the host T cell-mediated immune response. We review here the results obtained by our group and other researchers in animal models and humans, showing how MHC-I intratumor heterogeneity may affect local oncogenicity and metastatic progression. In particular, we summarize the data obtained in an experimental mouse cancer model of a methylcholanthrene-induced fibrosarcoma (GR9), in which isolated clones with different MHC-I expression patterns demonstrated distinct local tumor growth rates and metastatic capacities. The observed "explosion of diversity" of MHC-I phenotypes in primary tumor clones and the molecular mechanism ("hard"/irreversible or "soft"/reversible) responsible for a given MHC-I alteration might determine not only the metastatic capacity of the cells but also their response to immunotherapy. We also illustrate the generation of further MHC heterogeneity during metastatic colonization and discuss different strategies to favor tumor rejection by counteracting MHC-I loss. Finally, we highlight the role of MHC-I genes in tumor dormancy and cell cycle control.

Published
2014
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9. Experiencia en el manejo de inmunosupresores con los fármacos inhibidores de proteasa frente al virus de la hepatitis C

Author

Jesús Ruiz Ramos, María José Fernández Megía, Patricia Marrero Álvarez, María Remedios Marqués Miñana, José Luis Poveda Andrés, and Irene Romero Hernández

Subjects
Gynecology, medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, medicine, business
Abstract

Resumen Introduccion Los farmacos antivirales frente al virus de la hepatitis C (VHC) presentan un numero importante de interacciones. El objetivo de este estudio es describir la interaccion de telaprevir, boceprevir y sofosbuvir con los farmacos inmunosupresores en pacientes trasplantados. Metodos Estudio observacional retrospectivo de pacientes trasplantados hepaticos con infeccion por VHC que iniciaron tratamiento con telaprevir, boceprevir o sofosbuvir. Se recogieron las dosis, pautas posologicas y niveles plasmaticos de tacrolimus, ciclosporina y sirolimus previas y posteriores al inicio del tratamiento antiviral. Se calculo la variacion media de dosis e intervalo de dosificacion, asi como la modificacion de los niveles de inmunosupresor tras iniciar el tratamiento. Resultados Se incluyeron 35 pacientes. En pacientes tratados con telaprevir (n = 18), la dosis de ciclosporina se redujo una media de 59,1% (SD = 14,6%), obteniendose una reduccion media de 14,6% (18,8%) en los niveles plasmaticos. En cuanto a tacrolimus, la dosis se redujo en un 34,3% (31,7%) aumentando el intervalo de dosificacion una media de 73,4 (38,2) horas. Con ello, los niveles se incrementaron un 59,7% (89,6%). En los pacientes tratados con boceprevir (n = 4), tacrolimus se inicio con una reduccion del 18,1% (9,8%) de la dosis inicial y un aumento medio en el intervalo de dosificacion de 12,0 (16,9) horas, observandose una reduccion media del 37,7% (21,8%) en los niveles plasmaticos. El tratamiento con sofosbuvir (n = 13) no mostro variaciones importantes en los niveles de inmunosupresores. Conclusiones La interaccion de telaprevir y boceprevir con los farmacos inmunosupresores requiere un ajuste de la dosis previa de los mismos al inicio del tratamiento, asi como una monitorizacion rigurosa de sus niveles plasmaticos.

Published
2014
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10. Metastases in Immune-Mediated Dormancy: A New Opportunity for Targeting Cancer

Author

Angel M. Garcia-Lora, Irene Romero, and Federico Garrido

Subjects
Cancer Research, chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Biology, Metastasis, Drug Delivery Systems, Immune system, Neoplasms, MHC class I, medicine, Animals, Humans, Cytotoxic T cell, Neoplasm Metastasis, Clinical Trials as Topic, medicine.disease, Killer Cells, Natural, CTL, Oncology, Immunology, Cancer cell, biology.protein, Dormancy, Immunotherapy, T-Lymphocytes, Cytotoxic, Cancer dormancy
Abstract

The aim of any anticancer treatment is to avoid, control, or eliminate disseminated tumor cells. Clinical and experimental evidence has revealed that metastases can remain in a latency state, that is, metastasis dormancy. Three mechanisms are thought to be involved in cancer dormancy: cellular dormancy, angiogenic dormancy, and immune-mediated dormancy. Here, we review the mechanisms and cells involved in immune-mediated cancer dormancy and discuss current and future immunotherapeutic strategies. Recent results indicate that the immune system can restrain disseminated cancer cells, promoting their permanent dormancy. CD8+ T lymphocytes play a relevant role in maintaining immune equilibrium with metastatic dormant cells, and MHC class I surface expression on tumor cells may also be involved. Natural killer (NK) cells have an activator function that triggers a cytotoxic T lymphocyte (CTL) response. Furthermore, immune dormancy promotes cancer cell growth arrest and angiogenic control. Immunotherapeutic interventions in metastatic dormancy may help to control or eradicate cancer disease. Treatments that activate or increase the CTL immune response or reverse cancer cell–induced CTL immunosuppression might be useful to restrain or destroy metastatic cells. These objectives may be achieved by recovering or increasing MHC class I surface expression on cancer cells or even by activating NK cells. Immune-mediated metastasis dormancy provides an opportunity for targeting cancer in novel immune treatments. Cancer Res; 74(23); 6750–7. ©2014 AACR.

Published
2014
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11. An O-methyltransferase modifies accumulation of methylated anthocyanins in seedlings of tomato

Author

Asaph Aharoni, Nikolay S. Outchkourov, Jules Beekwilder, Michiel Lammers, Robert Hall, Noa Ziklo, Adèle van Houwelingen, Irene Romero de la Fuente, Maria Victoria Gomez Roldan, Bio-Interactions and Plant Health, Plant Research International, Droevendaalsesteeg, Wageningen, The Netherlands, and Institute of Plant Sciences Paris-Saclay

Subjects
0106 biological sciences, [SDV]Life Sciences [q-bio], Plant Science, medicine.disease_cause, 01 natural sciences, Substrate Specificity, Anthocyanins, Solanum lycopersicum, Gene Expression Regulation, Plant, Gene expression, Laboratorium voor Plantenfysiologie, plant transformation, ComputingMilieux_MISCELLANEOUS, Phylogeny, transcription factor, Plant Proteins, 2. Zero hunger, 0303 health sciences, biology, food and beverages, Methylation, Plants, Genetically Modified, O-methyltransferase, Hypocotyl, PRI Bioscience, Biochemistry, Multigene Family, BIOS Applied Metabolic Systems, metabolome, Laboratory of Plant Physiology, Molecular Sequence Data, Context (language use), system, 03 medical and health sciences, expression, Genetics, medicine, Gene silencing, Genetically modified tomato, Gene Silencing, BIOS Plant Development Systems, Escherichia coli, Gene, 030304 developmental biology, Flavonoids, fungi, Cell Biology, Methyltransferases, fruit, infection, carbohydrates (lipids), Seedlings, biology.protein, biosynthesis, protein, petunia-hybrida, 010606 plant biology & botany
Abstract

Anthocyanins contribute to the appearance of fruit by conferring to them a red, blue or purple colour. In a food context, they have also been suggested to promote consumer health. In purple tomato tissues, such as hypocotyls, stems and purple fruits, various anthocyanins accumulate. These molecules have characteristic patterns of modification, including hydroxylations, methylations, glycosylations and acylations. The genetic basis for many of these modifications has not been fully elucidated, and nor has their role in the functioning of anthocyanins. In this paper, AnthOMT, an O-methyltransferase (OMT) mediating the methylation of anthocyanins, has been identified and functionally characterized using a combined metabolomics and transcriptomics approach. Gene candidates were selected from the draft tomato genome, and their expression was subsequently monitored in a tomato seedling system comprising three tissues and involving several time points. In addition, we also followed gene expression in wild-type red and purple transgenic tomato fruits expressing Rosea1 and Delila transcription factors. Of the 57 candidates identified, only a single OMT gene showed patterns strongly correlating with both accumulation of anthocyanins and expression of anthocyanin biosynthesis genes. This candidate (AnthOMT) was compared to a closely related caffeoyl CoA OMT by recombinant expression in Escherichia coli, and then tested for substrate specificity. AnthOMT showed a strong affinity for glycosylated anthocyanins, while other flavonoid glycosides and aglycones were much less preferred. Gene silencing experiments with AnthOMT resulted in reduced levels of the predominant methylated anthocyanins. This confirms the role of this enzyme in the diversification of tomato anthocyanins.

Published
2014
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12. Clinical manifestations of intermediate allele carriers in Huntington disease

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Cubo E., Ramos-Arroyo M. A., Martinez-Horta S., Martinez-Descalls A., Calvo S., Gil-Polo CAnne-Catherine Bachoud-Lévi, Anna Rita Bentivoglio, Ida Biunno, Raphael M Bonelli, Jean-Marc Burgunder, Stephen B Dunnett, Joaquim J Ferreira, Olivia J Handley, Arvid Heiberg, Torsten Illmann, G Bernhard Landwehrmeyer, Jamie Levey, Maria Ramos-Arroyo, Jørgen E Nielsen, Susana Pro Koivisto, Markku Päivärinta, Raymund A C Roos, Ana Rojo Sebastián, Sarah J Tabrizi, Wim Vandenberghe, Christine Verellen-Dumoulin, Tereza Uhrova, Jan Wahlström, Jacek Zaremba, Verena Baake, Katrin Barth, Adrien Come, Leonor Correia Guedes, Ana Maria Finisterra, Monica Bascuñana Garde, Reineke Bos, Sabrina Betz, Jenny Callaghan, Selene Capodarca, Sébastien Charpentier, Wildson Vieira da Silva, Martina Di Renzo, Daniel Ecker, Ruth Fullam, Camille Genoves, Mette Gilling, Carina Hvalstedt, Christine Held, Andrea Horta-Barba, Kerstin Koppers, Claudia Lamanna, Matilde Laurà, Asunción Martínez Descals, Saul Martinez-Horta, Tiago Mestre, Sara Minster, Daniela Monza, Lisanne Mütze, Martin Oehmen, Helene Padieu, Laurent Paterski, Nadia Peppa, Beate Rindal, Dawn Rogers, Niini Røren, Pavla Šašinková, Yuri Seliverstov, Catherine Taylor, Erika Timewell, Jenny Townhill, Patricia Trigo Cubillo, Marleen R van Walsem, Marie-Noelle Witjes-Ané, Grzegorz Witkowski, Abigail Wright, Elizaveta Yudina, Daniel Zielonka, Eugeniusz Zielonka, Paola Zinzi, Cécile Minet, Pascale Ribaï, Dominique Van Paemel, Lena Hjermind, Oda Jacobsen, Suzanne Lindquist, Jørgen Nielsen, Lisbeth Regeur, Jette Stockholm, Ida Unmack Larsen, Christina Vangsted-Hansen, Tua Vinther-Jensen, Pia Eklund, Heli Hiivola, Hannele Hypponen, Kirsti Martikainen, Katri Tuuha, Philippe Allain, Dominique Bonneau Marie Bost, Bénédicte Gohier, Marie-Anne Guérid, Audrey Olivier, Julie Prouzet, Adriana Prundean, Clarisse Scherer-Gagou, Christophe Verny, Blandine Babiloni, Sabrina Debruxelles, Charlotte Duché, Cyril Goizet, Laetitia Jameau, Danielle Lafoucrière, Umberto Spampinato, Anne-Catherine Bachoud-Lévi, Farideh Badei, Lotfi Boudali, Catherine Bourdet, Laurent Cléret, Maryline Couette, Cécile Focseneanu, Laurie Lemoine, Graça Morgado, Mehdi Sebaiti, Claire Thiriez, Laetitia Vervoitte, Katia Youssov, Jean-Philippe Azulay, Christelle Chabot, Marie Delfini, Alexandre Eusebio, Frédérique Fluchere, Christine Garreau, Aicha Ghenam, Hélène Grosjean, Laura Mundler, Marielle Nowak, Roland Raseta, Maïté Bertrand, Fabienne Calvas, Samia Cheriet, Laurent Marquine, Michèle Pierre, Jérémie Pariente, Sandrine Rolland, Alice Seris, Valérie Vaquie, Christoph Michael Kosinski, Eva Milkereit, Daniela Probst, Kathrin Reetz, Christian Sass, Johannes Schiefer, Christiane Schlangen, Cornelius J Werner, Gisa Ellrichmann, Lennard Herrmann, Rainer Hoffmann, Barbara Kaminski, Carsten Saft, Kai Boelmans, Christos Ganos, Ines Goerendt, Walburgis Heinicke, Ute Hidding, Jan Lewerenz, Alexander Münchau, Michael Orth, Jenny Schmalfeld, Lars Stubbe, Simone Zittel, Gabriele Diercks, Dirk Dressler, Flverly Francis, Sabine Gayde-Stephan, Heike Gorzolla, Bianca Kramer, Rebecca Minschke, Christoph Schrader, Pawel Tacik, Natalie Bechtel, Heike Beckmann, Stefan Bohlen, Nicole Göpfert, Eva Hölzner, Herwig Lange, Ralf Reilmann, Stefanie Rohm, Silke Rumpf, Sigrun Schepers, Nathalia Weber, Michael Bachmeier, Matthias Dose, Nina Hofstetter, Ralf Marquard, Alzbeta Mühlbäck, Andrea Buck, Julia Connemann, Carolin Geitner, Andrea Kesse, Bernhard Landwehrmeyer, Franziska Lezius, Solveig Nepper, Anke Niess, Ariane Schneider, Daniela Schwenk, Sigurd Süssmuth, Sonja Trautmann, Patrick Weydt, Stephan Klebe, Thomas Musacchio, Christine Leypold, Kerstin Nöth, Claudia Cormio, Marina de Tommaso, Anna Rita Dellomonaco, Olimpia Difruscolo, Giovanni Franco, Vittorio Sciruicchio, Claudia Serpino, Michela Figorilli, Francesco Marrosu, Antonella Muroni, Valeria Piras, Melisa Vacca, Caterina Bartoli, Elisabetta Bertini, Fernanda Fortunato, Elena Ghelli, Andrea Ginestroni, Claudia Mechi, Marco Paganini, Silvia Piacentini, Silvia Pradella, Anna Maria Romoli, Sandro Sorbi, Giuseppe De Michele, Luigi Di Maio, Carlo Rinaldi, Marco Massarelli, Silvio Peluso, Alessandro Roca, Cinzia Valeria Russo, Pierpaolo Sorrentino, Elena Salvatore, Tecla Tucci, Milena Cannella, Valentina Codella, Francesca De Gregorio, Annunziata De Nicola, Francesca Elifani, Tiziana Martino, Francesca Lovo, Irene Mazzante, Martina Petrollini, Maria Simonelli, Ferdinando Squitieri, Maurizio Vezza, Barbara D'Alessio, Chiara Esposito, Giulia Coarelli, Michela Ferraldeschi, Marina Frontali, Gioia Jacopini, Giovanni Ristori, Silvia Romano, Monique S E van Hout, Jeroen P P van Vugt, A Marit de Weert, Marloes Verhoeven, Simon J A van den Bogaard, Eve M Dumas, Ellen P 't Hart, Milou Jacobs, Anne Kampstra, Anne Schoonderbeek, Nils Olav Aanonsen, Olaf Aaserud, Liv Barnett, Kathrine Bjørgo, Nancy Borgerød, Elisabeth Dramstad, Madeleine Fannemel, Jan Frich, Helen Gundersen, Per Gørvell, Kathrine Haggag, Cecilie Haggag 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Katarzyna Jachinska, Wioletta Krysa, Maryla Rakowicz, Przemyslaw Richter, Rafal Rola, Danuta Ryglewicz, Halina Sienkiewicz-Jarosz, Iwona Stępniak, Anna Sułek, Elzbieta Zdzienicka, Karolina Ziora-Jakutowicz, Cristina Januário, Filipa Júlio, Ana Salgueiro, Miguel Coelho, Tiago Mendes, Mário Miguel Rosa, Anabela Valadas, Cristina Semedo, Ana Calado, Joana Morgado, Margarida Dias, Manuel Almeida, Carmen Durán Herrera, Patrocinio Garcia Moreno, Jordi Bas, Núria Busquets, Matilde Calopa, Serge Jaumà Classen, Nadia Rodríguez Dedichá, Miquel Aguilar Barbera, Sonia Arribas Pardo, Dolors Badenes Guia, Noemi Calzado, Laura Casas Hernanz, Juan Pablo Tartari Díaz-Zorita, Judit López Catena, Pilar Quiléz Ferrer, Gemma Tome Carruesco, Misericordia Floriach Robert, Cèlia Mareca Viladrich, Elvira Roca, Jesús Miguel Ruiz Idiago, Antonio Villa Riballo, Antonia Campolongo, Ramon Fernandez de Bobadilla, Jaime Kulisevsky Bojarsky, Javier Pagonabarraga, Jesus Perez Perez, Carolina Villa, Maria Angeles Acera 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Laura, Pablo Tartari Díaz-Zorita, Juan, López Catena, Judit, Quiléz Ferrer, Pilar, Tome Carruesco, Gemma, Floriach Robert, Misericordia, Mareca Viladrich, Cèlia, Roca, Elvira, Miguel Ruiz Idiago, Jesú, Villa Riballo, Antonio, Campolongo, Antonia, Fernandez de Bobadilla, Ramon, Kulisevsky Bojarsky, Jaime, Pagonabarraga, Javier, Perez Perez, Jesu, Villa, Carolina, Angeles Acera Gil, Maria, Berganzo Corrales, Koldo, Carlos Gomez Esteban, Juan, González, Amaia, Tijero Merino, Beatriz, Cubo, Esther, Mariscal, Natividad, Gutierrez Romero, Sandra, Matías Arbelo, José, Malo de Molina, Rocío, Martín, Idaira, Manuel Periañez, Juan, Udaeta, Beatriz, Alonso-Frech, Fernando, Frades, Belén, Ávila Villanueva, Marina, Ascension Zea Sevilla, Maria, Alonso Frech, Fernando, Del Mar Fenollar, María, García-Ramos García, Rocío, Villanueva, Clara, Bascuñana, Mónica, Fatás Ventura, Marta, García Caldentey, Juan, García Ribas, Guillermo, García de Yébenes, Justo, Luis López-Sendón Moreno, José, Mañanes Barral, Verónica, Feliz Feliz, Cici, José García Ruíz, Pedro, García, Ana, Guerrero López, Rosa, Herranz Bárcenas, Antonio, Martínez-Descals, Asunción, Martínez Pueyo, Angel, Puertas Martin, Veronica, Rodríguez Martínez, Noelia, José Sainz Artiga, María, Sánchez, Vicenta, Del Val Fernandez, Javier, Antúnez Almagro, Carmen, Manzanares, Salvadora, Marín Muñoz, Juan, Martirio Antequera Torres, María, Noguera Perea, Fuensanta, Vivancos Moreau, Laura, González, Sonia, Menéndez Guisasola, Lui, Salvador, Carlo, Ribacoba, René, Sánchez Lozano, Pablo, Para Prieto, Marta, Gorospe, Aránzazu, Legarda Ramirez, Iné, Navas Arques, Penelope, Rodriguez Lopera, Monica, Vives Pastor, Barbara, Gaston, Itziar, Antonia Ramos-Arroyo, Maria, Dolores Martinez-Jaurrieta, Maria, Manuel García Moreno, José, Mendez Lucena, Carolina, Chacón Peña, José, Damas Hermoso, Fátima, Pacheco Cortegana, Eva, Redondo, Lui, Melgar Fernandez, Cristina, Paredes Mata, Maite, Dolores Romero Lemos, Maria, Bosca, Maria, Andres Burguera, Juan, Castera Brugada Carmen Peiró Vilaplana, Francisco, Bellosta Diago, Elena, López Del Val, Javier, Martinez Martinez, Laura, López, Elena, Berglund, Peter, Constantinescu, Radu, Fredlund, Gunnel, Høsterey-Ugander, Ulrika, Neleborn-Lingefjärd, Liselotte, Stebler, Yanik, Kaelin, Alain, Romero, Irene, Schüpbach, Michael, Weber Zaugg, Sabine, Downie, Lorna, Jack, Roisin, Matheson, Kirsty, Miedzybrodzka, Zosia, Rae, Daniela, A Simpson, Sheila, Summers, Fiona, Ure, Alexandra, Vaughn, Vivien, Akhtar, Shahbana, Crooks, Jenny, Curtis, Adrienne, de Souza, Jenny, Piedad, John, Rickards, Hugh, Wright, Jan, Coulthard, Elizabeth, Gethin, Louise, Hayward, Beverley, Sieradzan, Kasia, Busse, Monica, Butcher, Cynthia, Dunnett, Stephen, Clenaghan, Catherine, Hunt, Sarah, Jones, Lesley, Jones, Una, Khalil, Hanan, Owen, Michael, Price, Kathleen, Rosser, Anne, Brockie, Peter, Foster, Jillian, Johns, Nicola, Mckenzie, Sue, Rothery, Jean, Thomas, Gareth, Yates, Shona, Andrew, Alyson, Frost, Julie, Noad, Rupert, Cosgrove, Jeremy, Gallantree, Deena, Hamer, Stephanie, Hobson, Emma, Jamieson, Stuart, Kraus, Alison, Longthorpe, Mandy, Markova, Ivana, Musgrave, Hannah, Peacy, Caroline, Raman, Ashok, Rowett, Liz, Toscano, Jean, Wild, Sue, Clayton, Carole, Yardumian, Pam, Dipple, Heather, Freire- Patino, Dawn, Hallam, Caroline, Middleton, Julia, Anjum, Uruj, Coebergh, Jan, Eddy, Charlotte, Lahiri, Nayana, Mcentagart, Meriel, Patton, Michael, Peterson, Maria, Rose, Sarah, Andrews, Thomasin, Brown, Stefanie, Bruno, Stefania, Chu, Elvina, Doherty, Karen, Golding, Charlotte, Haider, Salman, Hensman, Davina, Lewis, Monica, Novak, Marianne, Patel, Aakta, Read, Joy, Robertson, Nicola, Rosser, Elisabeth, Tabrizi, Sarah, Taylor, Rachel, Warner, Thoma, Wild, Edward, Arran, Natalie, Bek, Judith, Craufurd, David, Hare, Marianne, Howard, Liz, Huson, Susan, Johnson, Liz, Jones, Mary, Krishnamoorthy, Ashok, Murphy, Helen, Oughton, Emma, Partington-Jones, Lucy, Sollom, Andrea, Snowden, Julie, Stopford, Cheryl, Thompson, Jennifer, Trender-Gerhard, Iri, Verstraelen, Nichola, Westmoreland, Leann, Cass, Ginette, Davidson, Lynn, Davison, Jill, Fullerton, Neil, Holmes, Katrina, Komati, Suresh, Mcdonnell, Sharon, Mohammed, Zeid, Morgan, Karen, Savage, Loi, Singh, Baldev, Wood, Josh, H Nemeth, Andrea, Siuda, Gill, Valentine, Ruth, Dixon, Kathryn, Armstrong, Richard, Harrison, David, Hughes, Max, Large, Sandra, O Donovan, John, Palmer, Amy, Parkinson, Andrew, Soltysiak, Beverley, Timings, Leanne, Williams, Josh, Bandmann, Oliver, Bradbury, Alyson, Fairtlough, Helen, Fillingham, Kay, Foustanos, Isabella, Gill, Paul, Kazoka, Mbombe, O'Donovan, Kirsty, Nevitt, Louise, Quarrell, Oliver, Taylor, Cat, Tidswell, Katherine, Gowers, Lesley, Powell, Kingsley, Bethwaite, Pamela, Edwards, Rachel, Fuller, Kathleen, Phillips, Michelle, Cubo, E., Ramos-Arroyo, M. A., Martinez-Horta, S., Martinez-Descalls, A., Russo, C. V., Calvo, S., Gil-Polo, C., Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Ramos-Arroyo, María A., Martínez-Descalls, Asunción, Calvo, Sara, and Gil-Polo, Cecilia

Subjects
0301 basic medicine, Registrie, Adult, Male, medicine.medical_specialty, Aging, Heterozygote, Genetic counseling, Motor Disorders, Disease, Severity of Illness Index, 03 medical and health sciences, Cognition Disorder, 0302 clinical medicine, Trinucleotide Repeats, Internal medicine, medicine, Humans, Registries, Allele, Motor Disorder, Alleles, Huntingtin Protein, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Medicine (all), Trinucleotide Repeat, Cognition, Genetic Status, Middle Aged, Phenotype, Europe, Settore MED/26 - NEUROLOGIA, 030104 developmental biology, Huntington Disease, Case-Control Studies, Cohort, medicine (all), neurology (clinical), controlled clinical trial (topic), Quality of Life, Female, Neurology (clinical), business, Case-Control Studie, Cognition Disorders, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Human
Abstract

International audience; OBJECTIVE: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry.METHODS: We assessed a cohort of participants at risk with RESULTS: Of 12,190 participants, 657 (5.38%) with CONCLUSIONS: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling.CLINICALTRIALSGOV IDENTIFIER: NCT01590589.

Published
2016

13. Discrepancies requiring clarification in cancer patients: a risk predictive model

Author

María Victoria Manzano Martín, Jose Manuel Baena Cañada, María José Martínez-Bautista, Jesús Francisco Sierra-Sánchez, Triana González-Carrascosa Vega, and Irene Romero-Hernández

Subjects
medicine.medical_specialty, Multivariate analysis, Receiver operating characteristic, business.industry, Colorectal cancer, Incidence (epidemiology), Cancer, Retrospective cohort study, medicine.disease, Logistic regression, Surgery, Internal medicine, medicine, Cytostatic drugs, General Pharmacology, Toxicology and Pharmaceutics, business
Abstract

Purpose Medication reconciliation has been proved to be a safe and effective strategy for preventing medication errors. However, the use of this strategy and the need for its implementation in cancer patients has not been adequately studied. This study was performed to develop a predictive model of the risk of discrepancies that need clarification (DNCs) in cancer patients. Material and methods A retrospective observational study was designed in order to develop a predictive model of the risk of DNCs in cancer patients. Patients diagnosed with breast or colon cancer during 2010 who received chemotherapy and were treated with any chronic medication were included. As endpoints, the incidence of DNCs, drugs involved and risk factors for DNCs were measured. After detecting DNCs, a statistical analysis was performed using ­multivariate logistic regression with dependent variable discrepancies. The predictive model building was performed using the Hosmer–Lemeshow test. Results A total of 168 patients were included, 83% of whom were taking home medication. At least one DNC was detected in 50.7% of patients, with a total of 131 DNCs. Multivariate analysis identified two independent variables as predictors of the occurrence of DNCs: the number of cytostatic agents (OR 1.24, 95% 1.03 to 1.49, p=0.026) and the number of target drugs (OR 1.77, 95% CI 1.37 to 2.29, p

Published
2012
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14. MHC class I molecules act as tumor suppressor genes regulating the cell cycle gene expression, invasion and intrinsic tumorigenicity of melanoma cells

Author

Angel M. Garcia-Lora, Laura Paco, Irene Romero, Julia Stefansky, Enrique Berruguilla, Ignacio Algarra, Federico Garrido, Cristina Garrido, and Antonia Collado

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Cancer Research, Cell, Genes, MHC Class I, Mice, Nude, Fatty Acid-Binding Proteins, Major histocompatibility complex, Mice, Cell Movement, Cell Line, Tumor, MHC class I, medicine, Animals, Humans, Genes, Tumor Suppressor, Neoplasm Invasiveness, Melanoma, Cell Proliferation, biology, Cell Cycle, Histocompatibility Antigens Class I, General Medicine, Transfection, Cell cycle, medicine.disease, Cell Cycle Gene, Cell biology, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, biology.protein, Cyclin A1
Abstract

The alteration of MHC class I (MHC-I) expression is a frequent event during cancer progression, allowing tumor cells to evade the immune system. We report that the loss of one major histocompatibility complex haplotype in human melanoma cells not only allowed them to evade immunosurveillance but also increased their intrinsic oncogenic potential. A second successive defect in MHC-I expression, MHC-I total downregulation, gave rise to melanoma cells that were more oncogenic per se in vivo and showed a higher proliferation rate and greater migratory and invasive potential in vitro. All these processes were reversed by restoring MHC-I expression via human leukocite antigen-A2 gene transfection. MHC-I cell surface expression was inversely correlated with intrinsic oncogenic potential. Modifications in the expression of various cell cycle genes were correlated with changes in MHC-I expression; the most important differences among the melanoma cell lines were in the transcriptional level of AP2-alpha, cyclin A1 and p21WAF1/CIP1. According to these results, altered MHC-I expression in malignant cells can directly increase their intrinsic oncogenic and invasive potential and modulate the expression of cell cycle genes. These findings suggest that human leukocite antigen class I molecules may act directly as tumor suppressor genes in melanoma.

Published
2012
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15. Immunotherapy eradicates metastases with reversible defects in MHC class I expression

Author

Federico Garrido, Angel M. Garcia-Lora, Antonia Collado, Bárbara Cancela, Irene Romero, Enrique Berruguilla, Ignacio Algarra, and Cristina Garrido

Subjects
Male, Cancer Research, Lung Neoplasms, Fibrosarcoma, medicine.medical_treatment, Lymphocyte, Immunology, Clone (cell biology), Docetaxel, Immunotherapy, Adoptive, Mice, Chemoimmunotherapy, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, MHC class I, medicine, Animals, Humans, Immunology and Allergy, Lymph node, Mice, Inbred BALB C, biology, Histocompatibility Antigens Class I, Immunotherapy, medicine.disease, Combined Modality Therapy, Primary tumor, medicine.anatomical_structure, Oncology, Lymphatic Metastasis, biology.protein, Proteoglycans, Taxoids, medicine.drug
Abstract

Tumor or metastatic cells lose MHC class I (MHC-I) expression during cancer progression as an escape mechanism from immune surveillance. These defects in MHC-I may be reversible by cytokines or different agents (soft lesions) or irreversible due to structural defects (hard lesions). The nature of these MHC-I alterations might determine the success or failure of immunotherapy treatments. In this study, we have used an MHC-I-positive murine fibrosarcoma tumor clone, GR9-A7, which generates multiple lung and lymph node metastases with reversible MHC-I alterations after treatment with IFN-γ. Four different antitumor treatments were carried out after primary tumor excision to determine their capacity to inhibit spontaneous metastatic colonization of the GR9-A7 tumor clone. We found that 2 different immunotherapy protocols (CpG plus autologous irradiated-GR9-A7 cells and protein-bound polysaccharide K (PSK) and 1 chemoimmunotherapy (docetaxel plus PSK) induced eradication of metastases. In contrast, chemotherapy with docetaxel alone produced only partial reduction in the number of metastases. Flow cytometric analysis of lymphocyte populations showed an immunosuppression in GR9-A7 tumor-bearing host, which could be reverted by immunotherapy treatments. Our results suggest that irreversible or reversible MHC-I alterations in tumor target cells may determine its progression or regression independently of the type of immunotherapy used.

Published
2011
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16. Prehabilitation in the elderly: Is it possible?

Author

Irene Romero, Gloria Nohales, Jordi Vallés, Marc Sadurni, Lluís Cecchini, and Marta Corcoy

Subjects
medicine.medical_specialty, Nutrition and Dietetics, business.industry, Endocrinology, Diabetes and Metabolism, Prehabilitation, Physical therapy, Medicine, business
Published
2018
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17. The crucial role of ¿- and K-segments in the in vitro functionality of Vitis vinifera dehydrin DHN1a

Author

Mª Isabel Escribano, Raquel Rosales, Mª Teresa Sanchez-Ballesta, Carmen Merodio, and Irene Romero

Subjects
Electrophoresis, Antifungal Agents, Protein–DNA interaction, Dehydrin, Microbial Sensitivity Tests, Plant Science, In Vitro Techniques, Horticulture, Biology, medicine.disease_cause, Biochemistry, Malate dehydrogenase, law.invention, Gene Expression Regulation, Plant, Stress, Physiological, law, Freezing, Escherichia coli, medicine, Vitis, Antifungal activity, Molecular Biology, Gene, Plant Proteins, Botrytis cinerea, Regulation of gene expression, Base Sequence, Dehydration, Abiotic stress, fungi, Temperature, food and beverages, DNA, General Medicine, biology.organism_classification, Cryoprotection, Recombinant Proteins, Droughts, Vitis vinifera, Recombinant DNA, Botrytis, Dehydration protection, Alternative splicing
Abstract

Dehydrins (DHNs), group II LEA (Late Embryogenesis Abundant) proteins, are among the most commonly observed proteins which accumulate in plants in response to cold and any other environmental factors, causing the dehydration of cells. In previous studies, we isolated a YSK2-type VvcDHN1a gene from table grapes (Vitis vinifera cv. Cardinal) which presented two spliced variants (the spliced, DHN1a_s and the unspliced, DHN1a_u). Their expression was induced by low temperature storage and CO2, although with different accumulation patterns. DHN1a_u codifies for a truncated YS protein lacking ¿- and K-segments, which might affect its functionality. In this work, we expressed both DHN1a_s and DHN1a_u recombinant proteins in Escherichia coli. We carried out a number of in vitro assays to analyze the implications that ¿- and K-segments have in the protective role of VvcDHN1 against different abiotic stresses and their antifungal activity against the fungal pathogen Botrytis cinerea. Our results showed that unlike DHN1a_u, DHN1a_s has a potent cryoprotective effect on lactate dehydrogenase activity, protects malate dehydrogenase against dehydration and partially inhibits B. cinerea growth. Moreover, the DHN1a promoter presented cis-regulatory elements related to cold and drought, as well as biotic stress-related elements. We also observed that both spliced variants interact weakly with DNA, suggesting that K-segments are not involved in DNA binding. Overall, this work highlights the crucial role of ¿- and K-segments in DHNs function in plant response to abiotic stress showing for the first time, the potential role of the V. vinifera DHN1a_s in the protection against freezing and dehydration as well as inhibiting B. cinerea growth., This work was supported by CICYT project AGL2011-26742 and by the European Union under the 7th Framework Programme FP7-PEOPLE-2012-CIG No. 321694. R.R. and I.R. were supported by a postdoctoral JAE contract from the CSIC and a postdoctoral Juan de la Cierva contract from the MICINN, respectively. The work benefited from the networking activities within the European COST Action FA1106-QualityFruit.

Published
2014

18. Influence of the stage of ripeness on phenolic metabolism and antioxidant activity in table grapes exposed to different CO2 treatments

Author

Carlos Fernandez Caballero, Carmen Merodio, Irene Romero, María T. Sanchez-Ballesta, and María I. Escribano

Subjects
chemistry.chemical_classification, Antioxidant, Phenylpropanoid, Chemistry, medicine.medical_treatment, Flavonoid, fungi, food and beverages, Horticulture, Ripeness, chemistry.chemical_compound, Pigment, Polyphenol, visual_art, Anthocyanin, Botany, visual_art.visual_art_medium, medicine, Food science, Phenols, Agronomy and Crop Science, Food Science
Abstract

We have analyzed the influence of the stage of ripeness on L-phenylalanine ammonia-lyase (PAL) gene expression, accumulation of anthocyanins and total phenolics, and on antioxidant activity in the skin of table grapes treated with 20% CO2 + 20% O2 + 60 % N2 for 3 or 6 d at low temperature (0 °C). The residual effect of high CO2 treatment after transfer to air was also studied. In early harvested grapes, neither the anthocyanin content nor the accumulation of VcPAL mRNA was affected by any of the CO2 treatments applied. However, in late harvested grapes, the duration of high CO2 treatment determined its effect and a 6 d treatment with CO2 sustained higher levels of total phenolics and anthocyanin accumulation, and VcPAL expression than observed in untreated late harvested grapes. The increased antioxidant capacity was correlated with the total amount of phenolics and anthocyanins. Conversely, in grapes treated for 3 d with CO2 the phenylpropanoid pathway did not appear to be induced and a relationship between antioxidant activity and anthocyanins was not observed. Thus, further studies are needed to identify the most important antioxidants in these treated fruit. © 2009 Elsevier B.V. All rights reserved., This work was supported by research grants AGL2008-02949 from CICYT (Spain

Published
2009

19. Characterization of an antifungal and cryoprotective class i chitinase from table grape berries (Vitis vinifera Cv. Cardinal)

Author

M. Isabel Escribano, Oscar Goñi, Irene Romero, Carmen Merodio, Carlos Fernandez-Caballero, and M. Teresa Sanchez-Ballesta

Subjects
Antifungal, medicine.drug_class, Molecular Sequence Data, Class I chitinase, Gene Expression, Berry, Biology, Cryoprotective Agents, Freezing, Gene expression, Botany, Escherichia coli, medicine, Vitis, Amino Acid Sequence, Vitis vinifera, Plant Proteins, L-Lactate Dehydrogenase, Chitinases, Table grape, General Chemistry, Recombinant Proteins, Fungicides, Industrial, Fruit, Chitinase, biology.protein, sense organs, General Agricultural and Biological Sciences, Sequence Alignment
Abstract

Gene expression of a class I chitinase (Vcchit1b) in the skin of table grapes was analyzed as a molecular marker for changes induced at low temperature and also to study the effect of high CO2 levels modulating transcript levels at 0 °C. An active recombinant VcCHIT1b was overexpressed in Escherichia coli, and as the protein was produced as insoluble inclusion bodies, it was solubilized and refolded. The purified recombinant chitinase showed an optimum pH of 6.0 and a temperature of 50 °C, retaining activity at 0 and -10 °C. Purified chitinase exerted in vitro antifungal activity against Botrytis cinerea. Furthermore, recombinant chitinase was able to cryoprotect lactate dehydrogenase against freeze/thaw inactivation. However, the recombinant VcCHIT1b did not show any antifreeze activity when the thermal hysteresis activity was measured using differential scanning calorimetry. © 2009 American Chemical Society.

Published
2009

20. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis

Author

Federico Garrido, Irene Romero, Enrique Berruguilla, Ignacio Algarra, Angel M. Garcia-Lora, Eva Jiménez-Medina, Antonia Collado, [Jiménez-Medina,E, Berruguilla,E, Romero,I, Garrido,F, Garcia-Lora,A] Servicio de Análisis Clínicos e Inmunologia, Hospital Universitario Virgen de las Nieves, Universidad de Granada, Granada, Spain. [Algarra, I] Departamento de Ciencias de la Salud, Universidad Jaén, Jaén, Spain. [Collado, A] Unidad de Investigación, Hospital Universitario Virgen de las Nieves, Granada, Spain., and AGL was supported by FIS Postdoctoral Research Contract CP03/00111. Studies were partially supported by a grant from Kureha Chemical Industry (Japan).

Subjects
Proteínas Fúngicas, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Cancer Research, Ratones, Melanoma, Experimental, Apoptosis, Pharmacology, Hongos, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Jurkat Cells, Mice, Polisacáridos, Ensayos de Selección de Medicamentos Antitumorales, Melanoma Experimental, Medicine, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::Jurkat Cells [Medical Subject Headings], Lymphocytes, Células HeLa, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle [Medical Subject Headings], Melanoma, Fungal proteins, Fungal protein, Ciclo Celular, Cell Cycle, Linfocitos, Biological activity, Células Jurkat, Cell cycle, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Chemicals and Drugs::Carbohydrates::Polysaccharides [Medical Subject Headings], Humanos, Chemicals and Drugs::Carbohydrates::Polysaccharides::Proteoglycans [Medical Subject Headings], medicine.anatomical_structure, Oncology, Drug screening assays, Immunologic factors, Proteoglycans, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal::Disease Models, Animal::Neoplasms, Experimental::Melanoma, Experimental [Medical Subject Headings], Research Article, Línea Celular, Proteoglicanos, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Drug Screening Assays, Antitumor [Medical Subject Headings], lcsh:RC254-282, Natural killer cell, Fungal Proteins, In vivo, Polysaccharides, Cell Line, Tumor, Genetics, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes [Medical Subject Headings], Animals, Humans, Immunologic Factors, HeLa cells, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Growth Processes::Cell Proliferation [Medical Subject Headings], Cell Proliferation, Factores Inmunológicos, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Fungal Proteins [Medical Subject Headings], business.industry, Cell growth, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Immunologic Factors [Medical Subject Headings], Fungi, Proliferación de la Célula, In vitro, Organisms::Eukaryota::Fungi [Medical Subject Headings], Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis [Medical Subject Headings], Jurkat cells, Animales, Drug Screening Assays, Antitumor, business, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor::HeLa Cells [Medical Subject Headings], HeLa Cells
Abstract

Background Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated., Methods The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells., Results PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation., Conclusion These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells., AGL was supported by FIS Postdoctoral Research Contract CP03/00111. Studies were partially supported by a grant from Kureha Chemical Industry (Japan).

Published
2008

21. Functionality of a class I beta-1,3-glucanase from skin of table grapes berries

Author

Oscar Goñi, Irene Romero, M. Isabel Escribano, M. Teresa Sanchez-Ballesta, Carmen Merodio, and Carlos Fernandez-Caballero

Subjects
chemistry.chemical_classification, Table grape, Plant Science, General Medicine, Biology, Glucanase, medicine.disease_cause, law.invention, chemistry.chemical_compound, Enzyme, chemistry, Biochemistry, law, Lactate dehydrogenase, Gene expression, Genetics, medicine, Recombinant DNA, Heterologous expression, Agronomy and Crop Science, Escherichia coli
Abstract

We have analyzed gene expression of a class I β-1,3-glucanase (Vcgns1), in the skin of red table grapes (Vitis vinifera cv. Cardinal) as a marker for changes in response to low temperature, and also to assess how high CO2 levels (20% CO2 plus 20% O2) modulated its transcript accumulation at 0 °C. To elucidate the possible physiological role of class I β-1,3-glucanase in table grapes as a cryoprotectant, and/or an antifreeze, we also report on recombinant expression of Vcgns1. The results indicate that storage at 0 °C for 3 days increased Vcgns1 mRNA levels and β-1,3-glucanase activity in the skin of non-treated grapes. However, the accumulation of the transcripts, and the level of glucanase activity, were lower in the skin of grapes after 3 days of CO2 treatment, as well as when treated fruit were transferred to air. By using heterologous expression of the Vcgns1 cDNA in Escherichia coli, we showed that it encoded a protein with glucanase activity with an optimum pH and temperature of 6 and 45 °C, respectively, and a high stability at 0 °C. Furthermore, the purified VcGNS1 exhibited in vitro cryoprotective activity for the freeze labile l-lactate dehydrogenase (LDH) enzyme. In contrast, when the thermal hysteresis activity (THA) of the recombinant VcGNS1 was measured, using differential scanning calorimetry (DSC), the results indicated that it did not show antifreeze activity. The high stability of the recombinant protein at 0 °C, and its cryoprotective activity shown in this work suggest that VcGNS1 may participate in the response of table grape to combat low temperature conditions. © 2008 Elsevier Ireland Ltd. All rights reserved., This work was supported by grants from the Spanish Ministry of Education and Science (AGL2005-04502/ALI) and Comunidad Autonoma de Madrid (200670M050).

Published
2008

22. Involvement of the phenylpropanoid pathway in the response of table grapes to low temperature and high CO2 levels

Author

J. B. Jiménez, Mª Teresa Sanchez-Ballesta, Carmen Merodio, Ángel González-Ureña, Mª Isabel Escribano, J.M. Orea, and Irene Romero

Subjects
Chalcone synthase, chemistry.chemical_classification, Antioxidant, biology, Phenylpropanoid, Chemistry, medicine.medical_treatment, Table grape, fungi, food and beverages, Phenylalanine, Horticulture, Resveratrol, chemistry.chemical_compound, Enzyme, Biochemistry, Anthocyanin, biology.protein, medicine, Food science, Agronomy and Crop Science, Food Science
Abstract

We have analyzed the responses induced by low temperature storage (0 °C) in red table grape (Vitis vinifera L. cv. Cardinal) and also the effect of a 3 day treatment of high CO2 levels (20% CO2 plus 20% O2). At the transcriptional level we studied the key phenylpropanoid enzymes l-phenylalanine ammonia-lyase (PAL), chalcone synthase (CHS) and stilbene synthase (STS), together with the final products of some of these enzymes, such as trans-resveratrol and total anthocyanin, and their involvement in antioxidant activity. The results, using previously isolated partial cDNAs, indicated that storage at 0 °C for 3 days increased VcPAL, VcSTS and VcCHS mRNA levels in the skin of non-treated grapes, decreasing slightly thereafter. In contrast, the accumulation of these transcripts was lower in the skin of grapes after 3 days of CO2 treatment, and was undetectable when treated fruit were transferred to air. Low temperature modulated total anthocyanin levels and antioxidant capacity in non-treated grapes, and reduced the trans-resveratrol content in both treated and non-treated grapes, although the decrease was higher in CO2-treated grapes. The overall results indicated that CO2-treated grapes could be less sensitive to temperature shifts during the first stages of storage at 0 °C, reducing the expression levels of phenylpropanoid genes and the accumulation of total anthocyanins and antioxidant activity. © 2007 Elsevier B.V. All rights reserved., This work was supported by research grants (AGL2005-04502/ALI and AGL2002-02308) from the CICYT (Spain) and CTQ2004-3468 from the MEC of Spain

Published
2007

23. A novel preclinical murine model of immune-mediated metastatic dormancy

Author

Angel M. Garcia-Lora, Irene Romero, and Federico Garrido

Subjects
dormancy, business.industry, animal model, Immunology, Disease progression, T lymphocytes, immunosurveillance, Disease, Bioinformatics, Immunosurveillance, Immune system, Oncology, Murine model, MHC class I, Cancer research, Immunology and Allergy, Medicine, Dormancy, metastases, business, Author's View, Cancer dormancy, Immune mechanisms
Abstract

The mechanisms underlying cancer dormancy are poorly understood. We have developed a preclinical murine model in which immunosurveillance restrains spontaneous metastases in permanent dormancy. The model faithfully recapitulates human metastatic dormancy and may be useful to decipher the immune mechanisms constraining disease progression, thereby facilitating the development of novel immunotherapeutic approaches to control metastatic disease.

Published
2014
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24. Prevalence of school detention and associated sociocultural factors.

Author

Gabriela Amaya López, Claudia Irene Romero Oronoz, and María Catalina Pírez García

Subjects
Palabras claves: Dificultad de aprendizaje, retraso escolar, niños Keywords: learning disability, school delay, children, Medicine, Medicine (General), R5-920
Abstract

El término dificultad de aprendizaje alude a factores intrínsecos y extrínsecos del individuo, que pueden intervenir negativamente en el aprendizaje escolar. El análisis de las causas de fracaso escolar desde la perspectiva de salud puede contribuir a optimizar el desarrollo de políticas educativas. Se realizó un estudio descriptivo transversal de niños de 8 a 14 años, asistidos en la Policlínica Municipal de La Paloma (Montevideo, Uruguay), entre julio del 2012 y marzo del 2013. Se definió retraso escolar como la repetición de un año escolar y fracaso a la repetición de 2 o más años. Ingresaron 120 niños.La media de edad fue 9,8 años. La prevalencia de retraso escolar fue de 40%, y de fracaso escolar 21,6%. Se detectaron como posibles factores asociados al retraso/fracaso escolar la no concurrencia a educación inicial y el antecedente de hermanos repetidores.

Published
2014

25. Prevalencia de retraso escolar y factores socioculturales asociados.

Author

Gabriela Amaya López, Claudia Irene Romero Oronoz, and María Catalina Pírez García

Subjects
Palabras claves, Dificultad de aprendizaje, retraso escolar, niños Keywords, learning disability, school delay, Medicine, Medicine (General), R5-920
Abstract

El término dificultad de aprendizaje alude a factores intrínsecos y extrínsecos del individuo, que pueden intervenir negativamente en el aprendizaje escolar. El análisis de las causas de fracaso escolar desde la perspectiva de salud puede contribuir a optimizar el desarrollo de políticas educativas. Se realizó un estudio descriptivo transversal de niños de 8 a 14 años, asistidos en la Policlínica Municipal de La Paloma (Montevideo, Uruguay), entre julio del 2012 y marzo del 2013. Se definió retraso escolar como la repetición de un año escolar y fracaso a la repetición de 2 o más años. Ingresaron 120 niños.La media de edad fue 9,8 años. La prevalencia de retraso escolar fue de 40%, y de fracaso escolar 21,6%. Se detectaron como posibles factores asociados al retraso/fracaso escolar la no concurrencia a educación inicial y el antecedente de hermanos repetidores.

Published
2014

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