Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting

[EN] Latent electrophiles are nowadays very attractive chemical entities for drug discovery, as they are unreactive unless activated upon binding with the specific target. In this work, the utility of 4-trifluoromethyl phenols as precursors of latent electrophiles, quinone methides (QM), for lysine-targeting is demonstrated. These Michael acceptors were photogenerated for specific covalent modification of lysine residues using human serum albumin (HSA) as a model target. The reactive QM-type intermediates I or II, generated upon irradiation of 4-trifluoromethyl-1-naphthol (1)@HSA or 4-(4-trifluorometylphenyl)phenol (2)@HSA complexes, exhibited chemoselective reactivity toward lysine residues leading to amide adducts, which was confirmed by proteomic analysis. For ligand 1, the covalent modification of residues Lys106 and Lys414 (located in subdomains IA and IIIA, respectively) was observed, whereas for ligand 2, the modification of Lys195 (in subdomain IIA) took place. Docking and molecular dynamics simulation studies provided an insight into the molecular basis of the selectivity of 1 and 2 for these HSA subdomains and the covalent modification mechanism. These studies open the opportunity of performing protein silencing by generating reactive ligands under very mild conditions (irradiation) for specific covalent modification of hidden lysine residues.Financial support from the Spanish Ministry of Economy and Competiveness [CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404 (predoctoral fellowship to O.M.-M.)], the Generalitat Valenciana (PROMETEO/2017/075), the Community of Madrid (2016-T1/AMB-1275), the Xunta de Galicia (Centro Singular de Investigacion de Galicia accreditation 2016-2019, ED431G/09 and postdoctoral fellowship to E.L.), and the European Union (European Regional Development Fund, ERDF) is gratefully acknowledged. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+i 2013-2016, funded by ISCIII and FEDER. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae computer.Pérez Ruiz, R.; Molins-Molina, O.; Lence, E.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2018). Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting. The Journal of Organic Chemistry. 83(21):13019-13029. https://doi.org/10.1021/acs.joc.8b01559S1301913029832

Classroom learning and the perception of social responsibility amongst graduate students of management accounting

This study analyzes how learning about social responsibility (SR) can modify the perceptions of university students about the importance of responsible behavior on the part of companies. To this end, a questionnaire was designed and administered to Management Accounting students before (n = 128) and after (n = 71) receiving two training activities on SR. The descriptive results obtained testify to the importance of SR in the views of the sampled students, both before and after receiving the specific learning in SR. In this latter moment, students demonstrated a vision highly committed to the need for SR to be part of the economic agenda. The results also show that there was a significant change in the perception of SR and its implications in terms of benefits and costs before and after receiving the training. All of this suggests that SR training has partially modified students’ perceptions of SR. This paper provides important insights that could be leveraged by university and business school managers for the purpose of designing or modifying curricula related to SR. At the same time, it evaluates the potential of SR learning as a tool for modifying attitudes.Proyecto de Innovación Docente de la Universidad de Jaén “Active learning of Social Responsibility within the Management Accounting subjects”, I2D-UJA 2016–201

The relation between functional performance, falls and previous falls among participants in the Otago programme: a secondary data analysis

Ana Beatriz Bays Moneo pertenece al Otago Project Working GroupFall prevention is a key priority in healthcare policies. Multicomponent exercises reduce the risk of falls. The purpose of this study is to describe the relationship between functional performance and falls after following the Otago multicomponent exercise programme and previous falls. A prospective multi-centre intervention study was performed on 498 patients aged over 65 in primary care, with or without a history of previous falls. Sociodemographic, anthropometric and functionality data were collected. The primary outcome was the occurrence of falls; functional performance was measured using the Tinetti, Short Physical Performance Battery and Timed Up and Go tests. Among the patients, 29.7% referred to previous falls. There was a statistically significant (p < 0.001) increase in falls at 6 months (10.1%) and at 12 months (7.6%) among participants with previous falls in the baseline assessment compared to those without. In addition, the existence of previous falls could be considered a risk factor at 6 and 12 months (OR =2.37, p = 0.002, and OR = 1.76, p = 0.046, respectively). With regard to balance and gait, differences between the groups were observed at 6 months in the Tinetti score (p < 0.001) and in the baseline assessment Timed Up and Go score (p < 0.044). Multicomponent exercises improve the fall rate, balance and gait in older people, although this improvement is less in people with previous falls. Earlier intervention and tailoring of exercises in patients with previous falls could help improve outcomes.The Project coordinated with file codes PI16/01520, PI16/00821, PI16/01316, PI16/01649, PI16/01042, PI16/01159 and PI16/01312 was funded by the Carlos III Health Institute through the Strategic Action in Health 2016 and co-funded by the European Regional Development Fund "A way to make Europe"; PI16CIII/00031 was funded by the Carlos III Health Institute through the 2016 Intramural Strategic Action in Health; 2016111005 was funded by the Government of the Basque Country Department of Health through the 2016 subsidies for research projects; FFIS17/AP/02/was funded by the Autonomous Community of the Region of Murcia through the Region of Murcia Foundation for Health Training and Research

Investigation of metabolite-protein interactions by transient absorption spectroscopy and in silico methods

[EN] Transient absorption spectroscopy in combination with in silico methods has been employed to study the interactions between human serum albumin (HSA) and the anti-psychotic agent chlorpromazine (CPZ) as well as its two demethylated metabolites (MCPZ and DCPZ). Thus, solutions containing CPZ, MCPZ or DCPZ and HSA (molar ligand:protein ratios between 1:0 and 1:3) were submitted to laser flash photolysis and the Delta A(max) value at lambda = 470 nm, corresponding to the triplet excited state, was monitored. In all cases, the protein-bound ligand exhibited higher Delta Amax values measured after the laser pulse and were also considerably longer-lived than the non-complexed forms. This is in agreement with an enhanced hydrophilicity of the metabolites, due to the replacement of methyl groups with H that led to a lower extent of protein binding. For the three compounds, laser flash photolysis displacement experiments using warfarin or ibuprofen indicated Sudlow site I as the main binding site. Docking and molecular dynamics simulation studies revealed that the binding mode of the two demethylated ligands with HSA would be remarkable different from CPZ, specially for DCPZ, which appears to come from the different ability of their terminal ammonium groups to stablish hydrogen bonding interactions with the negatively charged residues within the protein pocket (Glu153, Glu292) as well as to allocate the methyl groups in an apolar environment. DCPZ would be rotated 180 degrees in relation to CPZ locating the aromatic ring away from the Sudlow site I of HSA. (C) 2019 Elsevier B.V. All rights reserved.Financial support from Ministerio de Economia, Industria y Competitividad (CTQ2016-78875-P, SAF2016-75638-R, BES-2011-043706), Generalitat Valenciana (Prometeo 2017/075), Xunta de Galicia [Centro Singular de Investigacion de Galicia accreditation 2016-2019 (ED431G/09, ED431B 2018/04) and post-doctoral fellowship to E. L.] and European Union (European Regional Development Fund-ERDF) is gratefully acknowledged. I. A. holds a "Miguel Servet" contract (CP1116/00052) funded by the Carlos III Health Institute. We are grateful to the Centro de Supercomputacion de Galicia (CESGA) for computational facilities.Limones Herrero, D.; Palumbo, F.; Vendrell Criado, V.; Andreu Ros, MI.; Lence, E.; González-Bello, C.; Miranda Alonso, MÁ.... (2020). Investigation of metabolite-protein interactions by transient absorption spectroscopy and in silico methods. Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy. 226:1-8. https://doi.org/10.1016/j.saa.2019.117652S18226Yang, G. X., Li, X., & Snyder, M. (2012). Investigating metabolite–protein interactions: An overview of available techniques. Methods, 57(4), 459-466. doi:10.1016/j.ymeth.2012.06.013S. Hage, D., Anguizola, J., Barnaby, O., Jackson, A., J. Yoo, M., Papastavros, E., … Tong, Z. (2011). Characterization of Drug Interactions with Serum Proteins by Using High-Performance Affinity Chromatography. Current Drug Metabolism, 12(4), 313-328. doi:10.2174/138920011795202938Matsuda, R., Bi, C., Anguizola, J., Sobansky, M., Rodriguez, E., Vargas Badilla, J., … Hage, D. S. (2014). Studies of metabolite–protein interactions: A review. Journal of Chromatography B, 966, 48-58. doi:10.1016/j.jchromb.2013.11.043López-Muñoz, F., Alamo, C., cuenca, E., Shen, W., Clervoy, P., & Rubio, G. (2005). History of the Discovery and Clinical Introduction of Chlorpromazine. Annals of Clinical Psychiatry, 17(3), 113-135. doi:10.1080/10401230591002002Beckett, A. H., Beaven, M. A., & Robinson, A. E. (1963). Metabolism of chlorpromazine in humans. Biochemical Pharmacology, 12(8), 779-794. doi:10.1016/0006-2952(63)90108-4Chetty, M., Moodley, S. V., & Miller, R. (1994). Important Metabolites to Measure in Pharmacodynamic Studies of Chlorpromazine. Therapeutic Drug Monitoring, 16(1), 30-36. doi:10.1097/00007691-199402000-00004Hubbard, J. W., Midha, K. K., Hawes, E. M., McKAY, G., Marder, S. R., Aravagiri, M., & Korchinski, E. D. (1993). Metabolism of Phenothiazine and Butyrophenone Antipsychotic Drugs. British Journal of Psychiatry, 163(S22), 19-24. doi:10.1192/s0007125000292556García, C., Oyola, R., Piñero, L. E., Arce, R., Silva, J., & Sánchez, V. (2005). Substitution and Solvent Effects on the Photophysical Properties of Several Series of 10-Alkylated Phenothiazine Derivatives. The Journal of Physical Chemistry A, 109(15), 3360-3371. doi:10.1021/jp044530jNavaratnam, S., Parsons, B. J., Phillips, G. O., & Davies, A. K. (1978). Laser flash photolysis study of the photoionisation of chlorpromazine and promazine in solution. Journal of the Chemical Society, Faraday Transactions 1: Physical Chemistry in Condensed Phases, 74(0), 1811. doi:10.1039/f19787401811Palumbo, F., Garcia-Lainez, G., Limones-Herrero, D., Coloma, M. D., Escobar, J., Jiménez, M. C., … Andreu, I. (2016). Enhanced photo(geno)toxicity of demethylated chlorpromazine metabolites. Toxicology and Applied Pharmacology, 313, 131-137. doi:10.1016/j.taap.2016.10.024Garcia, C., Smith, G. A., McGimpsey, W. G., Kochevar, I. E., & Redmond, R. W. (1995). Mechanism and Solvent Dependence for Photoionization of Promazine and Chlorpromazine. Journal of the American Chemical Society, 117(44), 10871-10878. doi:10.1021/ja00149a010Nath, S., & Sapre, A. V. (2001). Photoinduced electron transfer from chloropromazine and promethazine to chloroalkanes accompanied by cleavage of C–Cl bond. Chemical Physics Letters, 344(1-2), 138-146. doi:10.1016/s0009-2614(01)00685-6Joshi, R., Ghanty, T. K., & Mukherjee, T. (2008). Reactions and structural investigation of chlorpromazine radical cation. Journal of Molecular Structure, 888(1-3), 401-408. doi:10.1016/j.molstruc.2008.01.025He, X. M., & Carter, D. C. (1992). Atomic structure and chemistry of human serum albumin. Nature, 358(6383), 209-215. doi:10.1038/358209a0Sharples, D. (1974). The binding of chlorpromazine to human serum albumin. Journal of Pharmacy and Pharmacology, 26(8), 640-641. doi:10.1111/j.2042-7158.1974.tb10679.xVerbeeck, R. K., Cardinal, J.-A., Hill, A. G., & Midha, K. K. (1983). Binding of phenothiazine neuroleptics to plasma proteins. Biochemical Pharmacology, 32(17), 2565-2570. doi:10.1016/0006-2952(83)90019-9Silva, D., Cortez, C. M., & Louro, S. R. W. (2004). Quenching of the intrinsic fluorescence of bovine serum albumin by chlorpromazine and hemin. Brazilian Journal of Medical and Biological Research, 37(7), 963-968. doi:10.1590/s0100-879x2004000700004Lázaro, E., Lowe, P. J., Briand, X., & Faller, B. (2008). New Approach To Measure Protein Binding Based on a Parallel Artificial Membrane Assay and Human Serum Albumin. Journal of Medicinal Chemistry, 51(7), 2009-2017. doi:10.1021/jm7012826Kaddurah-Daouk, R., Kristal, B. S., & Weinshilboum, R. M. (2008). Metabolomics: A Global Biochemical Approach to Drug Response and Disease. Annual Review of Pharmacology and Toxicology, 48(1), 653-683. doi:10.1146/annurev.pharmtox.48.113006.094715Korkuć, P., & Walther, D. (2015). Physicochemical characteristics of structurally determined metabolite-protein and drug-protein binding events with respect to binding specificity. Frontiers in Molecular Biosciences, 2. doi:10.3389/fmolb.2015.00051Ohnmacht, C. M., Chen, S., Tong, Z., & Hage, D. S. (2006). Studies by biointeraction chromatography of binding by phenytoin metabolites to human serum albumin. Journal of Chromatography B, 836(1-2), 83-91. doi:10.1016/j.jchromb.2006.03.043Roelofs, K. G., Wang, J., Sintim, H. O., & Lee, V. T. (2011). Differential radial capillary action of ligand assay for high-throughput detection of protein-metabolite interactions. Proceedings of the National Academy of Sciences, 108(37), 15528-15533. doi:10.1073/pnas.1018949108Jimenez, M., & Miranda, M. (2015). Triplet Excited States as a Source of Relevant (Bio)Chemical Information. Current Topics in Medicinal Chemistry, 14(23), 2734-2742. doi:10.2174/1568026614666141216100907Jiménez, M. C., Miranda, M. A., & Vayá, I. (2005). Triplet Excited States as Chiral Reporters for the Binding of Drugs to Transport Proteins. Journal of the American Chemical Society, 127(29), 10134-10135. doi:10.1021/ja0514489Vayá, I., Bueno, C. J., Jiménez, M. C., & Miranda, M. A. (2006). Use of Triplet Excited States for the Study of Drug Binding to Human and Bovine Serum Albumins. ChemMedChem, 1(9), 1015-1020. doi:10.1002/cmdc.200600061Vayá, I., Jiménez, M. C., & Miranda, M. A. (2008). Transient Absorption Spectroscopy for Determining Multiple Site Occupancy in Drug−Protein Conjugates. A Comparison between Human and Bovine Serum Albumins Using Flurbiprofen Methyl Ester as a Probe. The Journal of Physical Chemistry B, 112(9), 2694-2699. doi:10.1021/jp076960qPérez-Ruiz, R., Bueno, C. J., Jiménez, M. C., & Miranda, M. A. (2010). In situ Transient Absorption Spectroscopy to Assess Competition between Serum Albumin and Alpha-1-Acid Glycoprotein for Drug Transport. The Journal of Physical Chemistry Letters, 1(5), 829-833. doi:10.1021/jz1000227Nuin, E., Jiménez, M. C., Sastre, G., Andreu, I., & Miranda, M. A. (2013). Drug–Drug Interactions within Protein Cavities Probed by Triplet–Triplet Energy Transfer. The Journal of Physical Chemistry Letters, 4(10), 1603-1607. doi:10.1021/jz400640sAlonso, R., Yamaji, M., Jiménez, M. C., & Miranda, M. A. (2010). Enhanced Photostability of the Anthracene Chromophore in Aqueous Medium upon Protein Encapsulation. The Journal of Physical Chemistry B, 114(34), 11363-11369. doi:10.1021/jp104900rAlonso, R., Jiménez, M. C., & Miranda, M. A. (2011). Stereodifferentiation in the Compartmentalized Photooxidation of a Protein-Bound Anthracene. Organic Letters, 13(15), 3860-3863. doi:10.1021/ol201209hKitamura, K., Fujitani, K., Takahashi, K., Tanaka, Y., Hirako, S., Kotani, C., … Takegami, S. (2000). Synthesis of [N-13CH3] drugs (chlorpromazine, triflupromazine and promazine). Journal of Labelled Compounds and Radiopharmaceuticals, 43(9), 865-872. doi:10.1002/1099-1344(200008)43:93.0.co;2-eGhuman, J., Zunszain, P. A., Petitpas, I., Bhattacharya, A. A., Otagiri, M., & Curry, S. (2005). Structural Basis of the Drug-binding Specificity of Human Serum Albumin. Journal of Molecular Biology, 353(1), 38-52. doi:10.1016/j.jmb.2005.07.075Pérez-Ruiz, R., Molins-Molina, O., Lence, E., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2018). Photogeneration of Quinone Methides as Latent Electrophiles for Lysine Targeting. The Journal of Organic Chemistry, 83(21), 13019-13029. doi:10.1021/acs.joc.8b01559Roe, D. R., & Cheatham, T. E. (2013). PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. Journal of Chemical Theory and Computation, 9(7), 3084-3095. doi:10.1021/ct400341

SOCS3 deregulation contributes to aberrant activation of the JAK/STAT pathway in precursor T-cell neoplasms

Despite the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway being frequently altered in T-ALL/LBL, no specific therapy has been approved for T-ALL/LBL patients with constitutive signalling by JAK/STAT, so there is an urgent need to identify pathway members that may be potential therapeutic targets. In the present study, we searched for JAK/STAT pathway members potentially modulated through aberrant methylation and identified SOCS3 hypermethylation as a recurrent event in T-ALL/LBL. Additionally, we explored the implications of SOCS3 deregulation in T-ALL/LBL and demonstrated that SOCS3 counteracts the constitutive activation of the JAK/STAT pathway through different molecular mechanisms. Therefore, SOCS3 emerges as a potential therapeutic target in T-ALL/LBLComunidad de Madrid, Grant/Award Number: B2017/BMD-3778; LINFOMAS-CM; Fundación Científica Asociación Española Contra el Cáncer, Grant/Award Number: PROYE18054PIRI; Fundación Ramón Areces, Grant/Award Number: CIVP19S7917; Instituto de Investigación Sanitaria Fundación Jiménez Díaz; Ministerio de Ciencia, Innovación y Universidades, Grant/ Award Number: RTI2018- 093330-B-I00 and MCIU/FEDER; Ministerio de Economía y Competitividad, Grant/Award Number: SAF2015-70561-R and MINECO/FEDE

Vertidos tóxicos al río Guadiamar: propuestas técnicas para su corrección

Inmediatamente de producirse el vertido tóxico al río Guadiamar, el Grupo T.A.R. se lanzó sin pensarlo dos veces a la búsqueda de soluciones técnicas a un panorama desolador y de efectos desconocidos, todos ellos amenazantes. El ácido “se comía el suelo inundado” por la riada, el agua retenida en Entremuros a pH 3, y con un enorme contenido de metales pesados, ocupaba una extensión de kilómetros. Nos hundimos en el agua hasta el cuello, y cuando nos cubría cogimos la barca, metimos el río a pedazos en nuestro laboratorio, para trabajar todas las hipótesis, ensayar todas las posibilidades. Peleando con la realidad le sacamos datos al Guadiamar, diseñamos actuaciones, poniéndole ingeniería a cuantas hipótesis nos planteaba la situación. En primera fila observamos las mejores actuaciones que nadie diseñó. El propio río, activando sus defensas naturales, mejoró la calidad del agua retenida en el dique de Entremuros subiendo el pH y precipitando los metales pesados. Los mecanismos de entrada de los metales pesados en la cadena trófica parecían ser lentos, dando tiempo a que la retirada de los lodos tóxicos llevada a cabo por la Administración fuera eficaz y diera tiempo a realizar tanto esfuerzo. Aunque el Guadiamar ha trabajado muy duro en su propia recuperación, con su ayuda hemos elaborado una gran cantidad de propuestas técnicas; unas para actuaciones de emergencia, otras a corto, medio y largo plazo. También hemos dado forma a un Plan frente a las previsibles avenidas de este primer otoño después del vertido. Nuestro objetivo ha sido poner a disposición soluciones preparadas para todo tipo de problemas, en primera o en segunda instancia. Prevenir no solo una o dos contingencias, se ha tratado de estar preparado para la mayor cantidad de eventualidades posibles. Por ello algunas serán utilizables, otras estarán en reserva, y muchas irían al cajón de los papeles. Pero ahí están por si acaso. Este libro recoge los trabajos de campo, los ensayos de laboratorio y la ingeniería desarrollada en los primeros cuatro meses. Durante el siguiente preparamos la edición del mismo, mientras, en paralelo, continuábamos en el trabajo experimental y el diseño. Cuando se cumpla el quinto mes, el 25 de Septiembre de 1998, lo presentaremos, ciento cincuenta días después... Con la financiación de la Diputación de Sevilla hemos preparado la primera edición en formato CD Rom e Internet, con muy poco coste para acceder a su contenido. En poco tiempo saldrá la edición en papel, con la misma financiación que la primera. Nos gustaría que este documento fuera entendido como lo que es, en nuestra opinión, una llamada urgente al debate de las ideas. Tratamos de ofrecer la información necesaria y el foro donde recoger las propuestas que seguramente muchos pueden aportar sin saber como transmitir sus experiencias. El Grupo de Tratamiento de Aguas Residuales (T.A.R.) abre con este libro la MESA DE DISCUSIÓN, para buscar un poco de luz, avanzar en las soluciones técnicas a la inmensa tarea de recuperar el río Guadiamar. El libro presenta lagunas, unas por la enorme prisa, otra por falta de datos, muchas por nuestra escasez de conocimientos. Dicen en España que “lo mejor es enemigo de lo bueno”...,y nos gustaría recoger ideas hoy mejor que mañana, que podría ser tarde. Nos comprometemos a seguir trabajando en soluciones técnicas, innovaciones tecnológicas e investigación aplicada a la recuperación del Guadiamar, a conocer lo ocurrido y su remedio. Nos comprometemos a publicar de la misma forma los resultados obtenidos, de manera que la discusión y el debate sigan siempre abiertos. El grupo T.A.R. podría ser un punto de intercambio de conocimientos universal, abierto, respetuoso y tolerante, universitario en definitiva, y por tanto útil en el cumplimiento de sus obligaciones. La primera necesidad de responder urgentemente, está dando paso a unas actuaciones programadas, a medida de los efectos de las correcciones introducidas. Deben instaurarse políticas de prevención y nuevas actuaciones para recuperar el Guadiamar, mejorar urgentemente las condiciones del entorno. Aprender de las soluciones adoptadas y generar mejores prácticas, puede ser una buena conclusión del trabajo realizado por tanta gente. Lo que empezó siendo una carrera de velocidad se nos convierte en un maratón, ya no hay que correr explosivamente, hay que mantener un ritmo en la carrera; hay que persistir en el esfuerzo todos los días durante mucho tiempo. Este nuevo desafío sigue siendo duro y difícil. Podéis contar con el Grupo T.A.R. para recorrer el duro camino de la Recuperación

El juego musical como recurso de calidad de la enseñanza

Memoria ID-0208. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2014-2015

Guía de práctica clínica SENPE/SEGHNP/SEFH sobre nutrición parenteral pediátrica

Introduction: Parenteral nutrition (PN) in childhood is a treatment whose characteristics are highly variable depending on the age and pathology of the patient. Material and methods: The Standardization and Protocols Group of the Spanish Society for Parenteral and Enteral Nutrition (SENPE) is an interdisciplinary group formed by members of the SENPE, the Spanish Society of Gastroenterology, Hepatology and Pediatric Nutrition (SEGHNP) and the Spanish Society of Hospital Pharmacy (SEFH) that intends to update this issue. For this, a detailed review of the literature has been carried out, looking for the evidences that allow us to elaborate a Clinical Practice Guide following the criteria of the Oxford Center for Evidence-Based Medicine. Results: This manuscript summarizes the recommendations regarding indications, access routes, requirements, modifications in special situations, components of the mixtures, prescription and standardization, preparation, administration, monitoring, complications and home NP. The complete document is published as a monographic number. Conclusions: This guide is intended to support the prescription of pediatric PN. It provides the basis for rational decisions in the context of the existing evidence. No guidelines can take into account all of the often compelling individual clinical circumstances.Introducción: la nutrición parenteral (NP) en la infancia es un tratamiento cuyas características son muy variables en función de la edad y la patología que presente el paciente. Material y métodos: el grupo de Estandarización y Protocolos de la Sociedad Española de Nutrición Parenteral y Enteral (SENPE) es un grupo interdisciplinar formado por miembros de la SENPE, Sociedad Española de Gastroenterología, Hepatología y Nutrición Pediátrica (SEGHNP) y Sociedad Española de Farmacia Hospitalaria (SEFH) que pretende poner al día este tema. Para ello, se ha realizado una revisión pormenorizada de la literatura buscando las evidencias que nos permiten elaborar una Guía de Práctica Clínica siguiendo los criterios del Oxford Centre for Evidence-Based Medicine. Resultados: este manuscrito expone de forma resumida las recomendaciones en cuanto a indicaciones, vías de acceso, requerimientos, modificaciones en situaciones especiales, componentes de las mezclas, prescripción y estandarización, preparación, administración, monitorización, complicaciones y NP domiciliaria. El documento completo se publica como número monográfico. Conclusiones: esta guía pretende servir de apoyo para la prescripción de la NP pediátrica. Constituye la base para tomar decisiones en el contexto de la evidencia existente. Ninguna guía puede tener en cuenta todas las circunstancias clínicas individuale

Photoactive assemblies of organic compounds and biomolecules: drug-protein supramolecular systems

[EN] The properties of singlet and triplet excited states are strongly medium-dependent. Hence, these species constitute valuable tools as reporters to probe compartmentalised microenvironments, including drug@protein supramolecular systems. In the present review, the attention is focused on the photophysical properties of the probe drugs (rather than those of the protein chromophores) using transport proteins (serum albumins and 1-acid glycoproteins) as hosts. Specifically, fluorescence measurements allow investigating the structural and dynamic properties of biomolecules or their complexes. Thus, the emission quantum yields and the decay kinetics of the drug singlet excited states provide key information to determine important parameters such as the stoichiometry of the complex, the binding constant, the relative degrees of occupancy of the different compartments, etc. Application of the FRET concept allows determining donor-acceptor interchromophoric distances. In addition, anisotropy measurements can be related to the orientation of the drug within the binding sites, where the degrees of freedom for conformational relaxation are restricted. Transient absorption spectroscopy is also a potentially powerful tool to investigate the binding of drugs to proteins, where formation of encapsulated triplet excited states is favoured over other possible processes leading to ionic species (i. e. radical ions), and their photophysical properties are markedly sensitive to the microenvironment experienced within the protein binding sites. Even under aerobic conditions, the triplet lifetimes of protein-complexed drugs are remarkably long, which provides a broad dynamic range for identification of distinct triplet populations or for chiral discrimination. Specific applications of the laser flash photolysis technique include the determination of drug distribution among the bulk solution and the protein binding sites, competition of two types of proteins to bind a 3 drug, occurrence of drug-drug interactions within protein binding sites, enzymatic-like activity of the protein or determination of enantiomeric compositions. The use of proteins as supramolecular hosts modifies the photoreactivity of encapsulated substrates by providing protection against oxygen or other external reagents, by imposing conformational restrictions in the binding pockets, or by influencing the stereochemical outcome. In this review, a selected group of examples is presented including decarboxylation, dehalogenation, nucleophilic addition, dimerisation, oxidation, Norrish type II reaction, photo-Fries rearrangement and 6 electrocyclisationFinancial support from the Spanish Government (CTQ2010-14882, JCI-2011-09926, RyC-2007-00476), from the EU (PCIG12-GA-2012-334257), from the Universitat Politènica de València (SP20120757) and from the Consellería de Educació, Cultura i Esport (PROMETEOII/2013/005, GV/2013/051) is gratefully acknowledged.Vayá Pérez, I.; Lhiaubet-Vallet, VL.; Jiménez Molero, MC.; Miranda Alonso, MÁ. (2014). Photoactive assemblies of organic compounds and biomolecules: drug-protein supramolecular systems. Chemical Society Reviews. 43:4102-4122. https://doi.org/10.1039/C3CS60413FS410241224

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1