Relationship between the risk of falling and prescribed medication in community-dwelling elderly subjects.

Abstract Introduction: The risk of falling increases with age. A third of the population over 65 has one or more falls per year. Objetive: to know the relationship between drug prescription and falls in the elderly. Materials and Methods: a study was carried out through a community intervention in individuals ≥ 70 years of age. Results: The sample was composed of 249 participants, 160 women (64%), with a mean age of 74.47 years (SD 5.33). During the 12 months prior to the study, the mean of falls per person was 0.5 (SD 0.94), the mean of the risk factors was 2.73 (SD 1.4) and the mean of the medication prescribed was 4.2 (SD 3.0). The percentage of the reduction of falls after the study was 12%. The amount of medication prescribed correlated with the incidence of falls before and after the study, r=0.193, p=0.002 y r2=0.170, p=0.009, respectively. Prior to the study, the individuals who were prescribed beta-blockers and antidepressants, had a fall incidence of 0.74 (SD 1.14) and 1.22 (SD 1.09), respectively, however after the intervention there was no relationship between drug prescription and falls. Conclusions: the fall prevention community program was effective since it prevented the negative effects of medication on falls. An interdisciplinary community intervention reduces the global incidence of falls and the incidence of falls related to some specific medication

Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS

[EN] The human genome is constantly attacked by endogenous and exogenous agents (ultraviolet light, xenobiotics, reactive oxygen species), which can induce chemical transformations leading to DNA lesions. To combat DNA damage, cells have developed several repair mechanisms; however, if the repair is defective, DNA lesions lead to permanent mutations. Single-cell gel electrophoresis (COMET assay) is a sensitive and well-established technique for quantifying DNA damage in individual cells. Nevertheless, this tool lacks relationship with mutagenesis. Therefore, to identify errors that give rise to mutations it would be convenient to test an alternative known procedure, such as next generation sequencing (NGS). Thus, the present work aims to evaluate the photomutagenicity of neuroleptic drug chlorpromazine (CPZ), and its N-demethylated metabolites using COMET assay and to test NGS as an alternative method to assess photomutagenesis. In this context, upon exposure to UVA radiation, COMET assay reveals CPZ-photosensitized DNA damage partially repaired by cells. Conversely with this result, metabolites demethylchlorpromazine (DMCPZ) and didemethylchlorpromazine (DDMCPZ) promote extensive DNA-photodamage, hardly repaired under the same conditions. Parallel assessment of mutagenesis by NGS is consistent with these results with minor discrepancies for DDMCPZ. To our knowledge, this is the first example demonstrating the utility of NGS for evaluating drug-induced photomutagenicity.This study was funded by the Carlos III Institute (ISCIII) of Health (Grants: PI15/00303, PI18/00540, PI16/01877, CPII16/00052, the Thematic Networks and Co-operative Research Centres: ARADyAL RD16/0006/0004 and RD16/0006/0030), IB16170, GR18145 from Junta de Extremadura, Spain, co-funded by European Regional Development Fund and Generalitat Valenciana Prometeo/2017/075. We would also like to thank M. Dolores Coloma for technical assistance in the preliminary experiments.Agúndez, JA.; García-Martín, E.; Garcia-Lainez, G.; Miranda Alonso, MÁ.; Andreu Ros, MI. (2020). Photomutagenicity of chlorpromazine and its N-demethylated metabolites assessed by NGS. Scientific Reports. 10(1):1-6. https://doi.org/10.1038/s41598-020-63651-yS16101Bjelland, S. & Seeberg, E. Mutagenicity, toxicity and repair of DNA base damage induced by oxidation. Mutat. Res. 531, 37–80 (2003).Friedberg, E. C. A brief history of the DNA repair field. Cell Res. 18, 3–7 (2008).Cadet, J. & Wagner, J. R. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb. Perspect. Biol. 5, (2013).Bauer, N. C., Corbett, A. H. & Doetsch, P. W. The current state of eukaryotic DNA base damage and repair. Nucleic Acids Res. 43, 10083–10101 (2015).Cadet, J. & Davies, K. J. A. Oxidative DNA damage & repair: An introduction. Free Radic. Biol. Med. 107, 2–12 (2017).Sancar, A., Lindsey-Boltz, L. A., Unsal-Kaçmaz, K. & Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 73, 39–85 (2004).Roos, W. P., Thomas, A. D. & Kaina, B. DNA damage and the balance between survival and death in cancer biology. Nat. Rev. Cancer 16, 20–33 (2016).Møller, P. Assessment of reference values for DNA damage detected by the comet assay in human blood cell DNA. Mutat. Res. 612, 84–104 (2006).Azqueta, A. & Collins, A. R. The essential comet assay: a comprehensive guide to measuring DNA damage and repair. Arch. Toxicol. 87, 949–968 (2013).Collins, A. R. et al. Controlling variation in the comet assay. Front. Genet. 5, 359 (2014).Møller, P. The comet assay: ready for 30 more years. Mutagenesis 33, 1–7 (2018).Shendure, J. & Ji, H. Next-generation DNA sequencing. Nat. Biotechnol. 26, 1135–1145 (2008).Metzker, M. L. Sequencing technologies—the next generation. Nat. Rev. Genet. 11, 31 (2010).Gawad, C., Koh, W. & Quake, S. R. Single-cell genome sequencing: current state of the science. Nat. Rev. Genet. 17, 175–188 (2016).Schwarz, U. I., Gulilat, M. & Kim, R. B. The Role of Next-Generation Sequencing in Pharmacogenetics and Pharmacogenomics. Cold Spring Harb. Perspect. Med. 9, (2019).Epstein, J. H., Brunsting, L. A., Petersen, M. C. & Schwarz, B. E. A study of photosensitivity occurring with chlorpromazine therapy. J. Invest. Dermatol. 28, 329–338 (1957).Kochevar, I. E., Chung, F. L. & Jeffrey, A. M. Photoaddition of chlorpromazine to DNA. Chem. Biol. Interact. 51, 273–284 (1984).Palumbo, F. et al. Enhanced photo(geno)toxicity of demethylated chlorpromazine metabolites. Toxicol. Appl. Pharmacol. 313, 131–137 (2016).Miki, Y. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266, 66–71 (1994).Wooster, R. et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378, 789–792 (1995)

In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor

[EN] The epidermal growth factor receptors EGFR and HER2 are the main targets for tyrosine kinase inhibitors (TKIs). The quinazoline derivative lapatinib (LAP) is used since 2007 as dual TKI in the treatment of metastatic breast cancer and currently, it is used as an oral anticancer drug for the treatment of solid tumors such as breast and lung cancer. Although hepatotoxicity is its main side effect, it makes sense to investigate the ability of LAP to induce photosensitivity reactions bearing in mind that BRAF (serine/threonine-protein kinase B-Raf) inhibitors display a considerable phototoxic potential and that afloqualone, a quinazoline-marketed drug, causes photodermatosis. Metabolic bioactivation of LAP by CYP3A4 and CYP3A5 leads to chemically reactiveN-dealkylated (N-LAP) andO-dealkylated (O-LAP) derivatives. In this context, the aim of the present work is to explore whether LAP and itsN- andO-dealkylated metabolites can induce photosensitivity disorders by evaluating their photo(geno)toxicity through in vitro studies, including cell viability as well as photosensitized protein and DNA damage. As a matter of fact, our work has demonstrated that not only LAP, but also its metaboliteN-LAP have a clear photosensitizing potential. They are both phototoxic and photogenotoxic to cells, as revealed by the 3T3 NRU assay and the comet assay, respectively. By contrast, theO-LAP does not display relevant photobiological properties. Remarkably, the parent drug LAP shows the highest activity in membrane phototoxicity and protein oxidation, whereasN-LAP is associated with the highest photogenotoxicity, through oxidation of purine bases, as revealed by detection of 8-Oxo-dG.This study was funded by the Carlos III Institute (ISCIII) of Health (Grants: PI16/01877, CPII16/00052, ARADyAL RD16/0006/0030) co-funded by European Regional Development Fund, the Spanish Government (RYC-2015-17737, CTQ2017-89416-R,) and Generalitat Valenciana (Prometeo/2017/075). We would also like to thank IIS La Fe Microscopy Unit for technical assistance.García-Laínez, G.; Vayá Pérez, I.; Marín, MP.; Miranda Alonso, MÁ.; Andreu Ros, MI. (2021). In vitro assessment of the photo(geno)toxicity associated with Lapatinib, a Tyrosine Kinase inhibitor. Archives of Toxicology. 95(1):169-178. https://doi.org/10.1007/s00204-020-02880-6S16917895

Oxidatively Generated Lesions as Internal Photosensitizers for Pyrimidine Dimerization in DNA

[EN] In this work, the attention is focused on UVA-photosensitized reactions triggered by a DNA chromophore-containing lesion, namely 5-formyluracil. This is a major oxidatively generated lesion that exhibits an enhanced light absorption in the UVB-UVA region. The mechanistic study combining photochemical and photobiological techniques shows that irradiation of S-formyluracil leads to a triplet excited state capable of sensitizing formation of cyclobutane pyrimidine dimers in DNA via a triplet-triplet energy transfer. This demonstrates for the first time that oxidatively generated DNA damage can behave as an intrinsic sensitizer and result in an important extension of the active fraction of the solar spectrum with photocarcinogenic potential. Overall, this raises the question of an aggravated photomutagenicity of the 5-formyluracil lesion.The present work was supported by Spanish Government (CTQ2015-70164-P, Severo Ochoa program/SEV-2012-0267, BES-2013-066566, CSIC 2016801007), Instituto de Salud Carlos III (RD16/0006/0030, FIS PI16/01877), Generalitat Valenciana (Prometeo/2017/075).Aparici-Espert, MI.; García-Laínez, G.; Andreu Ros, MI.; Miranda Alonso, MÁ.; Lhiaubet, VL. (2018). Oxidatively Generated Lesions as Internal Photosensitizers for Pyrimidine Dimerization in DNA. ACS Chemical Biology. 13(3):542-547. https://doi.org/10.1021/acschembio.7b01097S54254713

Hydrogen Abstraction from the C15 Position of the Cholesterol Skeleton

[EN] Cholesterol (Ch) is an integral part of cell membrane, where it is prone to oxidation. In humans, oxidation of Ch is commonly linked to various pathologies like Alzheimer's disease, atherosclerosis, and even cancer, which proceed via mechanisms involving enzymatic and free radical pathways. The latter begin with hydrogen abstraction (HA) from Ch by a reactive free radical. It has been established that the most efficient HA from Ch occurs at C7, although HA from C4 by peroxyl radicals has recently been observed. Conversely, HA from Ch positions other than the thermodynamically preferred C7 or C4 has never been reported. We have designed a Ch derivative where a benzophenone moiety is linked to C7 by a covalent bond. This mirrors a specific orientation of Ch within a confined environment. Product analysis and time-resolved spectroscopic studies reveal an unprecedented HA from C15, which is a thermodynamically unfavorable position. This indicates that a specific topology of reactants is crucial for the reactivity of Ch. The relative orientation of the reactants can also be relevant in biological membranes, where Ch, polyunsaturated fatty acids, and numerous oxidizing species are confined in highly restricted and anisotropic environments.This work was supported by the Carlos III Institute of Health (Grants No. PII6/01877, "Miguel Servet fellowship" CPII16/00052 to I.A.), and by the Generalitat Valenciana (Prometeo 2017/075). We would like to thank Dr Fedora Grande for sending an exchange student (M.B.). D.N. and G.G. thank NAWI Graz for support.Palumbo, F.; Andreu Ros, MI.; Brunetti, M.; Schmallegger, M.; Gescheidt, G.; Neshchadin, D.; Miranda Alonso, MÁ. (2019). Hydrogen Abstraction from the C15 Position of the Cholesterol Skeleton. The Journal of Organic Chemistry. 84(23):15184-15191. https://doi.org/10.1021/acs.joc.9b02181S15184151918423Zerbinati, C., & Iuliano, L. (2017). Cholesterol and related sterols autoxidation. Free Radical Biology and Medicine, 111, 151-155. doi:10.1016/j.freeradbiomed.2017.04.013Schroepfer, G. J. (2000). Oxysterols: Modulators of Cholesterol Metabolism and Other Processes. Physiological Reviews, 80(1), 361-554. doi:10.1152/physrev.2000.80.1.361Girotti, A. W., & Korytowski, W. (2017). Cholesterol Hydroperoxide Generation, Translocation, and Reductive Turnover in Biological Systems. Cell Biochemistry and Biophysics, 75(3-4), 413-419. doi:10.1007/s12013-017-0799-0Poli, G., Biasi, F., & Leonarduzzi, G. (2013). Oxysterols in the pathogenesis of major chronic diseases. Redox Biology, 1(1), 125-130. doi:10.1016/j.redox.2012.12.001Buttari, B., Segoni, L., Profumo, E., D’Arcangelo, D., Rossi, S., Facchiano, F., … Riganò, R. (2013). 7-Oxo-cholesterol potentiates pro-inflammatory signaling in human M1 and M2 macrophages. Biochemical Pharmacology, 86(1), 130-137. doi:10.1016/j.bcp.2013.04.008Scheinost, J., Wang, H., Boldt, G., Offer, J., & Wentworth, P. (2008). Cholesterolseco-Sterol-Induced Aggregation of Methylated Amyloid-β Peptidesâ Insights into Aldehyde-Initiated Fibrillization of Amyloid-β. Angewandte Chemie International Edition, 47(21), 3919-3922. doi:10.1002/anie.200705922Shahidi, F., & Zhong, Y. (2010). Lipid oxidation and improving the oxidative stability. Chemical Society Reviews, 39(11), 4067. doi:10.1039/b922183mZielinski, Z. A. M., & Pratt, D. A. (2017). Lipid Peroxidation: Kinetics, Mechanisms, and Products. The Journal of Organic Chemistry, 82(6), 2817-2825. doi:10.1021/acs.joc.7b00152Bignon, E., Marazzi, M., Besancenot, V., Gattuso, H., Drouot, G., Morell, C., … Monari, A. (2017). Ibuprofen and ketoprofen potentiate UVA-induced cell death by a photosensitization process. Scientific Reports, 7(1). doi:10.1038/s41598-017-09406-8Bagheri, H., Lhiaubet, V., Montastruc, J. L., & Chouini-Lalanne, N. (2000). Photosensitivity to Ketoprofen. Drug Safety, 22(5), 339-349. doi:10.2165/00002018-200022050-00002Breslow, R. (1980). Biomimetic control of chemical selectivity. Accounts of Chemical Research, 13(6), 170-177. doi:10.1021/ar50150a002Breslow, R., Baldwin, S., Flechtner, T., Kalicky, P., Liu, S., & Washburn, W. (1973). Remote oxidation of steroids by photolysis of attached benzophenone groups. Journal of the American Chemical Society, 95(10), 3251-3262. doi:10.1021/ja00791a031Zielinski, Z. A. M., & Pratt, D. A. (2016). Cholesterol Autoxidation Revisited: Debunking the Dogma Associated with the Most Vilified of Lipids. Journal of the American Chemical Society, 138(22), 6932-6935. doi:10.1021/jacs.6b03344Garrec, J., Monari, A., Assfeld, X., Mir, L. M., & Tarek, M. (2014). Lipid Peroxidation in Membranes: The Peroxyl Radical Does Not «Float». The Journal of Physical Chemistry Letters, 5(10), 1653-1658. doi:10.1021/jz500502qFarez, M. F., Quintana, F. J., Gandhi, R., Izquierdo, G., Lucas, M., & Weiner, H. L. (2009). Toll-like receptor 2 and poly(ADP-ribose) polymerase 1 promote central nervous system neuroinflammation in progressive EAE. Nature Immunology, 10(9), 958-964. doi:10.1038/ni.1775Björkhem, I., Lövgren-Sandblom, A., Piehl, F., Khademi, M., Pettersson, H., Leoni, V., … Diczfalusy, U. (2011). High levels of 15-oxygenated steroids in circulation of patients with multiple sclerosis: fact or fiction? Journal of Lipid Research, 52(1), 170-174. doi:10.1194/jlr.d011072Davies, H. M. L., & Morton, D. (2017). Collective Approach to Advancing C–H Functionalization. ACS Central Science, 3(9), 936-943. doi:10.1021/acscentsci.7b00329Gutekunst, W. R., & Baran, P. S. (2014). Applications of C–H Functionalization Logic to Cyclobutane Synthesis. The Journal of Organic Chemistry, 79(6), 2430-2452. doi:10.1021/jo4027148Neshchadin, D., Palumbo, F., Sinicropi, M. S., Andreu, I., Gescheidt, G., & Miranda, M. A. (2013). Topological control in radical reactions of cholesterol in model dyads. Chemical Science, 4(4), 1608. doi:10.1039/c3sc22109aAndreu, I., Morera, I. M., Boscá, F., Sanchez, L., Camps, P., & Miranda, M. A. (2008). Cholesterol–diaryl ketone stereoisomeric dyads as models for «clean» type I and type II photooxygenation mechanisms. Organic & Biomolecular Chemistry, 6(5), 860. doi:10.1039/b718068cAndreu, I., Palumbo, F., Tilocca, F., Morera, I. M., Boscá, F., & Miranda, M. A. (2011). Solvent Effects in Hydrogen Abstraction from Cholesterol by Benzophenone Triplet Excited State. Organic Letters, 13(15), 4096-4099. doi:10.1021/ol2016059Boscá, F., Andreu, I., Morera, I. M., Samadi, A., & Miranda, M. A. (2003). Chiral discrimination in the intramolecular abstraction of allylic hydrogens by benzophenone triplets. Chem. Commun., (13), 1592-1593. doi:10.1039/b303263aKaptein, R., & Oosterhoff, L. J. (1969). Chemically induced dynamic nuclear polarization III (anomalous multiplets of radical coupling and disproportionation products). Chemical Physics Letters, 4(4), 214-216. doi:10.1016/0009-2614(69)80105-3Closs, G. L. (1969). Mechanism explaining nuclear spin polarizations in radical combination reactions. Journal of the American Chemical Society, 91(16), 4552-4554. doi:10.1021/ja01044a043Vollenweider, J.-K., Fischer, H., Hennig, J., & Leuschner, R. (1985). Time-resolved CIDNP in laser flash photolysis of aliphatic ketones. A quantitative analysis. Chemical Physics, 97(2-3), 217-234. doi:10.1016/0301-0104(85)87033-6Neshchadin, D., Levinn, R., Gescheidt, G., & Batchelor, S. N. (2010). Probing the Antioxidant Activity of Polyphenols by CIDNP: From Model Compounds to Green Tea and Red Wine. Chemistry - A European Journal, 16(23), 7008-7016. doi:10.1002/chem.200903238Kier, L. B. (1981). Quantitation of Solvent Polarity Based on Molecular Structure. 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Restos de macromamíferos en la terraza t12 del Guadalquivir en la Rinconada (Sevilla): presencia de Hippopotamus amphibius Linneo, 1758.

The T12 terrace of the Guadalquivir River has been found to be the point of reference in the paleontological macrommal fauna of the second half of the Middle Pleistocene together with the associated acheulean industry. The presence of a hippopotamus of great dimensions found in the base of the terrace opens a new interpretation of the chronology and the climatic environment at the beginning of the formation of the terrace during the MIS 12

Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques

[EN] Triflusal is a platelet aggregation inhibitor chemically related to acetylsalicylic acid, which is used for the prevention and/or treatment of vascular thromboembolisms, which acts as a prodrug. Actually, after oral administration it is absorbed primarily in the small intestine, binds to plasma proteins (99%) and is rapidly biotransformed in the liver into its deacetylated active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). In healthy humans, the half-life of triflusal is ca. 0.5 h, whereas for HTB it is ca. 35 h. From a pharmacological point of view, it is interesting to note that HTB is itself highly active as a platelet anti-aggregant agent. Indeed, studies on the clinical profile of both drug and metabolite have shown no significant differences between them. It has been evidenced that HTB displays ability to induce photoallergy in humans. This phenomenon involves a cell-mediated immune response, which is initiated by covalent binding of a light-activated photosensitizer (or a species derived therefrom) to a protein. In this context, small proteins like ubiquitin could be appropriate models for investigating covalent binding by means of MS/MS and peptide fingerprint analysis. In previous work, it was shown that HTB forms covalent photoadducts with isolated lysine. Interestingly, ubiquitin contains seven lysine residues that could be modified by a similar reaction. With this background, the aim of the present work is to explore adduct formation between the triflusal metabolite and ubiquitin as model protein upon sunlight irradiation, combining proteomic and photophysical (fluorescence and laser flash photolysis) techniques. Photophysical and proteomic analysis demonstrates monoadduct formation as the major outcome of the reaction. Interestingly, addition can take place at any of the E-amino groups of the lysine residues of the protein and involves replacement of the trifluoromethyl moiety with a new amide function. This process can in principle occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects.Financial support from the Generalitat Valenciana (Prometeo Program), the Spanish Government (MINECO CTQ2015-70164-P to VL-V and SAF2012-36519 to DP-S) and the Carlos III Institute of Health (Grant RIRAAF, RETICS program, RD12/0013/0009 to MM and RD12/0013/0008 to DP-S, and Miguel Servet Contract CP11/00154 for IA) is gratefully acknowledged.Nuin Pla, NE.; Pérez-Sala, D.; Lhiaubet-Vallet, VL.; Andreu Ros, MI.; Miranda Alonso, MÁ. (2016). Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques. Frontiers in Pharmacology. 7(277). https://doi.org/10.3389/fphar.2016.00277S727

Liquid crystalline and nonlinear optical properties of bent-shaped compounds derived from 3,49-biphenylene.

9 pages, 6 figures, 3 tables.The synthesis of different bent-core molecules derived from 3,49-biphenylene bearing azo, azoxy, imine or ester linkages in their lateral structures is reported. Structure–activity relationships for their liquid crystalline behaviour are discussed. SmCP, USmCP and Colob mesophases are found depending on the type and number of these connecting units. The sequence ester#azoxy . imine . azo can be proposed for the mesophase range, with significant differences observed in terms of mesopahase stabilization. SHG studies on these compounds give nonlinear coefficients in the range of 1–8 pm V21. The molecular origin for these values is analyzed semi- uantitatively. It was concluded that the SHG performance of bent-core mesogens in general can still be increased substantially. An approach to improve the properties of these materials is briefly outlined.This work was supported by projects MAT2003-07806-C02 and MAT2006-13571-C02 (CICYT-FEDER) from Spain-EU and by the DGA (Spain) and University of the Basque Country (Project. Nu 9/UPV 00060.310-13562/2001). I. P. and I. A. also thank DGA and the Ministry of Education of Spain, respectively, for grants.Peer reviewe

Eficacia de la tomografía computarizada en la determinación de la resecabilidad del carcinoma de páncreas: correlación con los hallazgos histopatológicos, evaluación de factores que influyen en su valoración

INTRODUCCIÓN/JUSTIFICACIÓN DEL ESTUDIO El carcinoma pancreático constituye un problema de salud creciente a nivel mundial, siendo considerado en la actualidad el segundo tumor digestivo más frecuente, por detrás del carcinoma colorrectal. El adenocarcinoma ductal pancreático (ACDP), procedente del páncreas exocrino, es la estirpe más frecuente del carcinoma pancreático, suponiendo el 95% de estas neoplasias. A pesar de los múltiples avances diagnósticos y terapéuticos, el ACDP continúa presentando una alta tasa de mortalidad, siendo considerado la cuarta causa de muerte oncológica en los países desarrollados, con una tasa de mortalidad similar a la de incidencia. Esto se debe a que la enfermedad suele ser silente al inicio, por lo que, en el momento del diagnóstico, aproximadamente el 40-50% de los casos presentan metástasis y alrededor del 40% de los pacientes padecen una enfermedad localmente avanzada, en los que la cirugía no está indicada dada la alta morbimortalidad de estas intervenciones, sin que exista un aumento en la supervivencia al practicarlas. Actualmente, la resección quirúrgica completa es el único tratamiento potencialmente curativo de estos tumores. La optimización del acto quirúrgico y la posibilidad de realizar resecciones vasculares han supuesto un importante aumento de la probabilidad de resección completa. Sin embargo, sólo los estadíos iniciales (I-II) se benefician de la cirugía, lo que supone únicamente un 10-15% de los pacientes. Por otro lado, los tumores con criterios borderline de resecabilidad, pueden ser candidatos a una terapia neoadyuvante que posibilite la intervención quirúrgica posterior. La tomografía multidetector (TCMD) supone hoy en día la técnica de imagen más utilizada en el diagnóstico y estadificación inicial del ACDP. Sin embargo, esta técnica no está exenta de falsos positivos y negativos que dan lugar a discrepancias radiopatológicas, y que es preciso conocer con el fin de intentar mejorar el manejo diagnóstico de estos tumores. La realización de una correcta estadificación inicial, lo más precisa posible, es crucial para la selección de una adecuada selección de la actitud terapéutica en cada caso. DESARROLLO DEL ESTUDIO Se revisó la base de datos del Subcomité de Tumores Hepato-Biliares de un Hospital Terciario, de la cual se obtuvieron, una vez aplicados los criterios de inclusión y exclusión, un total de 75 pacientes con diagnóstico de ACDP, intervenidos en dicho Hospital en el período comprendido entre el 1 de enero de 2010 y el 30 de junio de 2015. Un radiólogo con experiencia en Radiología Digestiva valoró cada uno de los 75 estudios diagnósticos de TCMD, registrando múltiples variables relacionadas principalmente con la extensión local tumoral, así como signos de mal pronóstico asociados a estos tumores. Por otro lado, un equipo de anatomopatólogos revisó las 75 piezas quirúrgicas, estudiando múltiples variables histopatológicas, que posteriormente se correlacionaron con las citadas variables radiológicas. Además de la correlación radio-patológica, se realizó una correlación radio-quirúrgica en relación con la afectación vascular detectada en la TCMD y en el acto quirúrgico. Finalmente, se llevó a cabo un estudio de correlación interobservador de la valoración de la resecabilidad tumoral realizada por dos profesionales con experiencia similar en radiología digestiva. CONCLUSIONES 1. La TCMD es una técnica útil en la determinación de ausencia de infiltración tumoral del tejido graso retroperitoneal en el ACDP. Sin embargo, no es una técnica fiable para asegurar la existencia de dicha infiltración, por presentar una alta tasa de falsos positivos. 2. La afectación del tejido graso retroperitoneal peripancreático, así como del tejido graso circundante a la AMS, VMS y Tr.C, representan patrones radiológicos de alta probabilidad de invasión perineural en el estudio de TC. Sin embargo, en ausencia de estos patrones, la TC no puede descartar dicha invasión. 3. La TCMD permite descartar la infiltración vascular en el ACDP en ausencia de contacto tumor-vaso. Sin embargo, la identificación de dicho contacto no es un patrón radiológico específico de infiltración tumoral. Por ello, en los casos de sospecha de infiltración vascular mediante TC, consideramos de utilidad la inclusión de la USE para confirmar o descartar dicha infiltración. 4. El contacto tumor-vaso inferior al 50% de la circunferencia vascular presenta un porcentaje elevado de infiltración tumoral, por lo que no puede considerarse un signo de baja probabilidad de infiltración vascular. 5. Los criterios utilizados en la valoración de la resecabilidad del ACDP mediante TC están sujetos a una amplia subjetividad, que se reflejó en la moderada correlación interobservador existente en nuestro estudio. Estas discrepancias entre observadores deben ser consideradas en las decisiones terapéuticas posteriores, principalmente en la valoración de los casos con criterios de resecabilidad borderline. 6. La presencia de factores inflamatorios pancreáticos y peripancreáticos justifica en la mayoría de los casos la elevada tasa de falsos positivos de la TC en la identificación de extensión extraglandular tumoral, infiltración de la grasa retroperitoneal, afectación vascular y en la sobreestimación del tamaño tumoral. 7. Dado el importante porcentaje de tumores borderline y la correlación hallada entre este tipo de tumores y la existencia de patrones histopatológicos de mal pronóstico, debería considerarse en nuestro centro la administración de terapia neoadyuvante en estos casos, en el intento de reducir la tasa de recidiva. 8. El estudio mediante TCMD de los ACDP considerados resecables o con criterios borderline de resecabilidad no permite descartar de manera fiable los signos considerados de mal pronóstico en el estudio histopatológico, como son, la extensión extraglandular, la infiltración de la grasa retroperitoneal, la invasión perineural o la infiltración de los extremos quirúrgicos de resección

"Snorkelling" vs. "diving" in mixed micelles probed by means of a molecular bathymeter

[EN] A photoactive bathymeter based on a carboxylic acid moiety covalently linked to a signalling methoxynaphthalene (MNP) fluorophore has been designed to prove the concept of "snorkelling" vs. "diving" in mixed micelles (MM). The carboxylic acid "floats" on the MM surface, while the MNP unit sinks deep in MM. The rate constants of MNP fluorescence quenching by iodide, which remains basically in water, consistently decrease with increasing spacer length, revealing different regions. This is associated with the distance MNP should "dive" in MM to achieve protection from aqueous reactants. Unequivocal proof of the exergonic photoinduced electron transfer was obtained from the UV-visible spectral signature of I-3(-) upon steady-state photolysis. The applicability of the bathymeter was examined upon testing a family of MNP derivatives. The obtained results were validated by comparison with different lipophilicity tests: (i) a modified version of the K-ow partition coefficient and (ii) the retention factor on thin layer chromatography. This concept could potentially be extended to test drugs or pharmacophores exhibiting any photoactive moiety.Financial support from the Spanish Government (SEV-2016-0683), Red RETICS de Investigacion de Reacciones Adversas a Alergenos y Farmacos (RIRAAF), Instituto de Salud Carlos III (RD012/0013, RD16/0006/0030, FIS PI16/01877), VLC-Campus and the Generalitat Valenciana (Prometeo Program) is gratefully acknowledged.Rodríguez Muñiz, GM.; Gomez Mendoza, M.; Nuin Pla, NE.; Andreu Ros, MI.; Marín García, ML.; Miranda Alonso, MÁ. (2017). "Snorkelling" vs. "diving" in mixed micelles probed by means of a molecular bathymeter. Organic & Biomolecular Chemistry. 15(48):10281-10288. https://doi.org/10.1039/c7ob02595eS10281102881548Porter, C. J. H., Trevaskis, N. L., & Charman, W. N. (2007). 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