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101. Sam68 mediates leptin signaling and action in human granulosa cells: possible role in leptin resistance in PCOS

Author: Antonio Pérez-Pérez, Esther Santamaría-López, Nicolás Prados, Manuel Fernández-Sánchez, Teresa Vilariño-García, Víctor Sánchez-Margalet, Universidad de Sevilla. Departamento de Bioquímica Médica y Biología Molecular e Inmunología, Universidad de Sevilla. Departamento de Cirugía, FEDER Funds, and Instituto de Salud Carlos III (ISCIII)
Subjects: aromatase, Leptin, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 030209 endocrinology & metabolism, lcsh:Diseases of the endocrine glands. Clinical endocrinology, leptin, Signalling pathways, 03 medical and health sciences, Aromatase, 0302 clinical medicine, Endocrinology, Insulin resistance, Downregulation and upregulation, Internal medicine, Internal Medicine, medicine, polycystic ovary syndrome (PCOS), PI3K/AKT/mTOR pathway, lcsh:RC648-665, 030219 obstetrics & reproductive medicine, Leptin receptor, biology, business.industry, Research, Polycystic ovary syndrome (PCOS), digestive, oral, and skin physiology, medicine.disease, Polycystic ovary, Sam68, biology.protein, business, signalling pathways
Abstract: Introduction Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with ovulatory dysfunction, hyperandrogenism, obesity, and insulin resistance, that leads to subfertility. Sam68 is an RNA-binding protein with signaling functions that is ubiquitously expressed, including gonads. Sam68 is recruited to leptin signaling, mediating different leptin actions. Objective We aimed to investigate the role of Sam68 in leptin signaling, mediating the effect on aromatase expression in granulosa cells and the posible implication of Sam68 in the leptin resistance in PCOS. Materials and methods Granulosa cells were from healthy donors (n = 25) and women with PCOS (n = 25), within the age range of 20 to 40 years, from Valencian Infertility Institute (IVI), Seville, Spain. Sam68 expression was inhibited by siRNA method and overexpressed by expression vector. Expression level was analysed by qPCR and immunoblot. Statistical significance was assessed by ANOVA followed by different post-hoc tests. A P value of Results We have found that leptin stimulation increases phosphorylation and expression level of Sam68 and aromatase in granulosa cells from normal donors. Downregulation of Sam68 expression resulted in a lower activation of MAPK and PI3K pathways in response to leptin, whereas overexpression of Sam68 increased leptin stimulation of signaling, enhancing aromatase expression. Granulosa cells from women with PCOS presented lower expression of Sam68 and were resistant to the leptin effect on aromatase expression. Conclusions These results suggest the participation of Sam68 in leptin receptor signaling, mediating the leptin effect on aromatase expression in granulosa cells, and point to a new target in leptin resistance in PCOS.
Published: 2020

102. JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Author: Tamera Barrett, Julie Cavanagh-Kyros, Francisco Javier Cubero, Fátima Sánchez-Cabo, Davide Seruggia, Roger J. Davis, Laura Esteban-Lafuente, Chaobo Chen, Elisa Manieri, Maria J. Monte, María Elena Rodríguez, Guadalupe Sabio, Luis Leiva-Vega, Cintia Folgueira, Manuel Gómez, Alejandro Rosell, Jose J.G. Marin, Alfonso Mora, European Regional Development Fund (ERDF/FEDER), European Commission, European Research Council, Fundación BBVA, Ministerio de Ciencia e Innovación (España), Comunidad de Madrid, Fundación Científica AECC, Instituto de Salud Carlos III - ISCIII, Fundación ProCNIC, National Institutes of Health (United States), Ministerio de Economía y Competitividad (España), La Caixa, Asociación Española Contra el Cáncer, European Cooperation in Science and Technology, AMMF - The Cholangiocarcinoma Charity, Universidad Complutense de Madrid, National Institutes of Health (US), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Fundación Severo Ochoa, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Unión Europea. Comisión Europea, Comunidad de Madrid (España), and National Institutes of Health (Estados Unidos)
Subjects: Male, Medical Sciences, medicine.drug_class, Cholangiocyte proliferation, Peroxisome proliferator-activated receptor, Bile Acids and Salts, Cholangiocarcinoma, 03 medical and health sciences, Mice, 0302 clinical medicine, Cholestasis, medicine, bile acid, Animals, Homeostasis, Humans, Mitogen-Activated Protein Kinase 9, Mitogen-Activated Protein Kinase 8, PPAR alpha, Transcription factor, PPARa, 030304 developmental biology, chemistry.chemical_classification, Mice, Knockout, 0303 health sciences, Multidisciplinary, Bile acid, Chemistry, Kinase, Biological Sciences, medicine.disease, Mice, Inbred C57BL, 030220 oncology & carcinogenesis, Cancer research, PPARa Bile acid, JNK, Steatosis, Signal transduction
Abstract: Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPARα mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome., We are grateful to the CNIC Advanced Imaging and Animal facility for technical support. G.S. (RYC-2009-04972) and F.J.C. (RYC-2014-15242) are investigators of the Ramón y Cajal Program. E.M. was awarded a La Caixa fellowship. C.F. was awarded a Sara Borrell contract (CD19/00078). This work was funded by grants supported in part by funds from the European Regional Development Fund: EU’s Seventh Framework Programme (FP7/2007-2013) ERC 260464, EFSD/Lilly European Diabetes Research Programme Dr. Sabio, 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (Investigadores-BBVA-2017) IN[17]_BBM_BAS_0066, MINECO-FEDER SAF2016-79126-R, and Comunidad de Madrid IMMUNOTHERCAN-CM S2010/BMD-2326 and B2017/BMD-3733 and La Asociación Española contra el Cáncer (to G.S.); EXOHEP-CM S2017/BMD-3727 and the European Cooperation in Science & Technology (COST) Action CA17112 (to F.J.C.); MINECO Retos SAF2016-78711, the AMMF Cholangiocarcinoma Charity 2018/117, NanoLiver-CM Y2018/NMT-4949, UCM-25-2019, ERAB EA/18-14 (to F.J.C.). F.J.C. is a Gilead Liver Research Scholar. Grant DK R01 DK107220 from the NIH (to R.J.D.); and PI16/00598 from Carlos III Institute of Health, Spain (to J.J.G.M.). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades, and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).
Published: 2020

103. Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study

Author: Pietro Ferrari, Fulvio Ricceri, Christina C. Dahm, Kim Overvad, Sabina Sieri, Elisabete Weiderpass, Eleni Peppa, María José Sánchez, Leila Luján Barroso, Marta Solans Margalef, Matthias B. Schulze, Federico Canzian, Giovanna Masala, Florentin Spaeth, Dagfinn Aune, Roel Vermeulen, Tilman Kühn, Delphine Casabonne, Karin Jirstom, Anna Karakatsani, José María Huerta, Yahya Mahamat-Saleh, Paul Brennan, Cecilie Kyrø, Mats Jerkeman, Caroline Besson, Pilar Amiano Exezarreta, Virginia Menéndez, Elio Riboli, Julie A. Schmidt, Rosario Tumino, Sairah L.F. Chen, Marc J. Gunter, Eva Ardanaz, Antonia Trichopoulou, Alexandra Nieters, Marie-Christine Boutron-Ruault, Anne Tjønneland, Fatemeh Saberi Hosnijeh, Sabine Naudin, Salvatore Panico, Centre international de Recherche sur le Cancer (CIRC), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Centre Hospitalier de Versailles André Mignot (CHV), Direction Générale de la Compétitivité, de l’Industrie et des Services, DGCIS Food Standards Agency, FSA Cancer Research UK, CRUK: C864/A14136, C8221/A19170, C570/A16491 RD06/0020 Ministerie van Volksgezondheid, Welzijn en Sport, VWS Université Claude Bernard Lyon 1, UCBL Wellcome Trust, WT Ligue Contre le Cancer 6236 German Cancer Research Center, DKFZ Bundesministerium für Bildung und Forschung, BMBF Department of Health, Australian Government Ministry of Health and Social Solidarity, Greece Kræftens Bekæmpelse, DCS British Heart Foundation, BHF Instituto de Salud Carlos III, ISCIII National Research Council, NRC Mutuelle Générale de l'Education Nationale, MGEN Hellenic Health Foundation, HHF Stroke Association Institut National de la Santé et de la Recherche Médicale, Inserm Fondation Gustave Roussy European Commission, EC Centre International de Recherche sur le Cancer, IARC Deutsche Krebshilfe Cancerfonden World Cancer Research Fund, WCRF Stavros Niarchos Foundation, SNF Ministère des Affaires Sociales et de la Santé: GR‐IARC‐2003‐09‐12‐01 Medical Research Council, MRC: MR/M012190/1, MR/N003284/1, MC‐UU_12015/1, We thank Carine Biessy and Bertrand Hemon for their technical support and contribution to this work. We are also grateful to all the EPIC participants who have been part of the project and to the many other members of the study teams who have enabled this research. This work was supported by the Direction Générale de la Santé (French Ministry of Health, Grant GR‐IARC‐2003‐09‐12‐01), by the European Commission (Directorate General for Health and Consumer Affairs) and the International Agency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark), the Ligue Contre le Cancer, the Institut Gustave Roussy, the Mutuelle Générale de l'Education Nationale and the Institut National de la Santé et de la Recherche Médicale (France), the Deutsche Krebshilfe, the Deutsches Krebsforschungszentrum and the Federal Ministry of Education and Research (Germany), the Hellenic Health Foundation, the Stavros Niarchos Foundation and the Hellenic Ministry of Health and Social Solidarity (Greece), the Italian Association for Research on Cancer and the National Research Council (Italy), the Dutch Ministry of Public Health, Welfare and Sports, the Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, the Dutch Zorg Onderzoek Nederland, the World Cancer Research Fund and Statistics Netherlands (the Netherlands), the Health Research Fund, Regional Governments of Andalucýa, Asturias, Basque Country, Murcia (project 6236) and Navarra, Instituto de Salud Carlos III, Redes de Investigacion Cooperativa (RD06/0020, Spain), the Swedish Cancer Society, the Swedish Scientific Council and the Regional Government of Skåne (Sweden), Cancer Research UK (C864/A14136 to EPIC‐Norfolk, C570/A16491 and C8221/A19170 to EPIC‐Oxford), Medical Research Council (MR/N003284/1 and MC‐UU_12015/1 to EPIC‐Norfolk, MR/M012190/1 to EPIC‐Oxford, and United Kingdom), the Stroke Association, the British Heart Foundation, the Department of Health, the Food Standards Agency and the Wellcome Trust (UK). This work was part of Sabine Naudin's PhD at Claude Bernard Lyon I University (France), funded by Région Auvergne Rhône‐Alpes, ADR 2016 (France).
Subjects: Male, Oncology, Cancer Research, Lymphoma, Body Mass Index, 0302 clinical medicine, Risk Factors, immune system diseases, hemic and lymphatic diseases, Prospective Studies, Prospective cohort study, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Incidence, non-Hodgkin lymphoma, Smoking, Hazard ratio, Middle Aged, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Europe, 030220 oncology & carcinogenesis, Female, EPIC, healthy lifestyle index, Hodgkin lymphoma, prospective study, Life Sciences & Biomedicine, Adult, medicine.medical_specialty, Alcohol Drinking, [SDV.CAN]Life Sciences [q-bio]/Cancer, Diet Surveys, 03 medical and health sciences, Internal medicine, REGRESSION, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Healthy Lifestyle, Exercise, Aged, Science & Technology, business.industry, Proportional hazards model, HODGKINS-LYMPHOMA, Feeding Behavior, medicine.disease, Confidence interval, Etiology, UPDATE, CIGARETTE-SMOKING, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, business, Follow-Up Studies
Abstract: This is the peer reviewed version of the following article: Naudin, S., Margalef, M.S., Hosnijeh, F.S., Nieters, A., Kyrø, C. Tjønneland, A. ... Ferrari, P. (2020) Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study. International Journal of Cancer, 147(6):1649-1656, which has been published in final form at https://doi.org/10.1002/ijc.32977. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non‐Hodgkin lymphoma (NHL) were evaluated in a large‐scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow‐up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1‐standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1‐SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.
Published: 2020

104. Epigenetic regulation of inflammation by microRNAs in post-infectious bronchiolitis obliterans

Author: Duecker, Ruth Pia, de Mir Messa, Inés, Jerkic, Silvija-Pera, Kochems, Annalena, Gottwald, Gabriele, Moreno Galdó, Antonio, Institut Català de la Salut, [Duecker RP, Jerkic SP, Kochems A, Gottwald G] Division for Allergy, Pneumology and Cystic Fibrosis, Department for Children and Adolescence, Goethe University, Frankfurt, Germany. [De Mir Messa I] Unitat de Pneumologia Pediàtrica i Fibrosi Quística, Servei de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Moreno-Galdó A] Unitat de Pneumologia Pediàtrica i Fibrosi Quística, Servei de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. CIBER of Rare Diseases (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: MicroARN, Respiratory Tract Diseases::Bronchial Diseases::Bronchitis::Bronchiolitis::Bronchiolitis Obliterans [DISEASES], Bronquiolitis, enfermedades respiratorias::enfermedades bronquiales::bronquitis::bronquiolitis::bronquiolitis obliterante [ENFERMEDADES], Epigenètica
Abstract: Inflammation; MicroRNA; Post‐infectious bronchiolitis obliterans Inflamación; MicroARN; Bronquiolitis obliterante posinfecciosa Inflamació; MicroARN; Bronquiolitis obliterant postinfecciosa Objectives Post-infectious bronchiolitis obliterans (PiBO) is a rare, chronic disease initiated by severe infection and followed by perpetuating inflammation and obliteration of the small airways. MicroRNAs (miRNAs) have been proposed to play a central role as epigenetic regulators, which control resolution and prevent the uncontrolled progress of inflammation. The aim of this study was to define biomarkers on the level of post-transcriptional gene regulation in order to characterise PiBO. Methods A total of 39 patients with well-defined PiBO and 31 controls from two centres, Barcelona, Spain, and Frankfurt, Germany, were analysed by next-generation sequencing (NGS). The evaluation of the biological targets of the miRNAs was performed by pathway enrichment analysis and protein–protein interaction network analysis respectively. Results Patients with PiBO had significantly lower lung function values and increased airway inflammation in induced sputum as indicated by total cell counts, neutrophils, IL-1β, IL-6, IL-8 and TGF-β compared to controls. Next-generation sequencing analysis revealed a total of 22 dysregulated miRNAs, which passed significance threshold for Padj ≤ 0.001 with 17 being upregulated and 5 being downregulated. Of these dysregulated miRNAs, miR-335-5p, miR-186-5p, miR-30b-5p and miR-30c-5p were further validated using qRT-PCR. Interestingly, these miRNAs are functionally implicated in cytokine–cytokine receptor interaction, TGF-β signalling and FoxO signalling pathway and significantly correlated with lung function values (FEV1). Conclusion Our results demonstrate an aberrant miRNA expression profile in PiBO, which impacts pathways responsible for the regulation of inflammation and fibrosis. The defined miRNAs are useful biomarkers and should be assessed as potential target in the field of miRNA therapeutics. Starke Lunge Foundation. Grant Number: I 1325d 04/11(6)-78
Published: 2022

105. Caracterización molecular y funcional de la neuromelanina y sus análogos en la neurodegeneración

Author: Moreno García, Alexandra, Calero Lara, Miguel, Calero Rueda, Olga, UAM. Departamento de Biología Molecular, and Instituto de Salud Carlos III (ISCIII)
Subjects: Melanina-Síntesis, Biología y Biomedicina / Biología, Enfermedades neurodegenerativas
Abstract: Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de Lectura: 15-07-2022, Historically, neuromelanin (NM) has been considered a waste product of catecholaminergic metabolism. A key feature of NM, as well as all other melanins, is related to their heterocyclic ring-structure with conjugated double bonds that creates a π-bond system across multiple atoms that lowers the energy and stabilizes the molecule. Due to this conformation, melanins have been attributed with many functionalities from which stands out its ability to trap UV–light, free radicals, toxins, and metals. The presence in human brain of NM at localizations related to the main neurodegeneration foci, such as the sustantia nigra (SN) in Parkinson's disease (PD) and the locus coeruleous (LC) in Alzheimer's disease (AD), together with NM ability to absorb free radicals and chelate metals and drugs suggest a physiological role of NM in neurodegeneration. However, despite several reports suggesting the involvement of NM in neurodegenerative disorders, the molecular basis for such observations remains largely unknown. The focus of this doctoral thesis is the molecular and functional characterization of NM and three analogs based on three catecholamines potentially precursors of its synthesis in the brain. The results are divided into chapters composed of several experimental studies, focusing on the characterization at the molecular and functional level of NM and its analogs, while developing new approaches and methodologies for NM analysis. Since NM is a dynamic and complex substance with an undefined composition, as NM proxies, we selected three analogs produced by the oxidation of three catecholamines involved in NM synthesis: pLD, pDA and pNA from L-DOPA, DA or NA, respectively. In this work, by using a repertoire of techniques (thioflavin T aggregation kinetics, transmission electronic microscopy, transgenic C. elegans in vivo model), we demonstrated that NM analogs interact and modulate the aggregation kinetics of amyloid-prone proteins, pointing directly to one of the potential key roles of NM in neurodegeneration. We have also developed monoclonal antibodies against NM as a valuable biochemical tool for in vitro and ex-vivo NM characterization. Although the production of monoclonal antibodies is generally highly standardized for proteins, we were confronted with a polymeric substance with a nature very different from protein antigens that compelled us to develop alternative strategies for immunization by using NM coated to silica beads and an extended immunization protocol. Moreover, through plasma analysis by affinity chromatography and co-immunoprecipitation of NM, we have identified a subset of NM binding proteins and characterized their potential interaction mechanisms. Functional pathways analysis indicated that NM could interfere with inflammation and vascular processes, cytoplasm organization and the respiratory chain. All this events have been linked to AD and PD pathophysiology. Additionally, the use of cell cultures allowed us to study the cytotoxicity and proinflammatory effects triggered by NM. We have found that NM presents a characteristic fluorescence spectrum that can be exploited for the sensitive label-free detection of this substance in brain tissue. However, lipofuscin (LF) aggregates, another aging pigment, also presents an intense fluorescence throughout the brain tissue. By using confocal microscopy with specific settings for the collection of emission spectra in the near infrared region and the use of time-resolved fluorescence, we developed new methodologies to characterize the properties and distribution of NM, distinguishing structures composed of NM, LF or both. The data gathered in this thesis, together with previous findings, provide clues on the role of NM on neurodegenerative processes, changing the NM concept from metabolic “garbage” to an active substance, which is a key actor with a dual role in the physiopathology of neurodegeneration, El trabajo realizado en esta tesis ha sido financiado por Proyecto Mineco “Retos Investigación” miRNA and lipid metabolism markers as potential links between vascular dysfunction and Alzheimer’s pathophysiology. Entidad de realización: CIBER ENFERMEDADES NEURODEGENERATIVAS (CIBERNED). Investigadores: Miguel Medina Padilla (IP); Miguel Calero Lara (Co-IP); Olga Calero Rueda; Luis García Albert; Victoria López Alonso. Convocatoria de Proyectos I+D+i «Retos Investigación». Fecha de inicio-fin: 01/01/2017 - 31/12/2019 y Proyecto Colaborativo Ciberned Neurodegeneración ligada a la neuromelanina en la enfermedad de Parkinson: implicaciones mecanísticas, diagnósticas y terapéuticas. Entidad de realización: CIBER ENFERMEDADES NEURODEGENERATIVAS (CIBERNED) Investigadores principales: Miquel Vila, Ramón Trullás, José Luis Lanciego, José Luis Labandeira, Miguel CalNombre del programa: Proyectos Colaborativos CIBERNED. Fecha de inicio-fin: 01/01/2021 - 31/12/2022
Published: 2022

106. BDNF as a potential mediator between childhood BPA exposure and behavioral function in adolescent boys from the INMA-Granada cohort

Author: Nicolás Olea, Mariana F. Fernández, Fatima Smagulova, Antonio Mundo-López, Alicia Olivas-Martínez, F. Vela-Soria, Vicente Mustieles, Andrea Rodríguez-Carrillo, Shereen Cynthia D'Cruz, Carmen Freire, Arthur David, Iris Reina-Pérez, Juan P. Arrebola, University of Granada [Granada], Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Departamento de Inteligencia Artificial [UPM, Spain] (DIA), Universidad Politécnica de Madrid (UPM), CD17/00212, PT17/0019, Ministerio de Educación, Cultura y Deporte, MECD: FPU 16/03011, FPU 17/01848, RYC-2016-20155, Instituto de Salud Carlos III, ISCIII: CP16/00085, FIS-PI17/01526, Universidad de Granada, UGR, European Regional Development Fund, ERDF: MS16/00085, Ministerio de Economía, Industria y Competitividad, Gobierno de España, MINECO, Universidad de Granada = University of Granada (UGR), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Département des sciences en santé environnementale (DEESSE), and Chard-Hutchinson, Xavier
Subjects: Male, HBM4EU, Environmental Engineering, Adolescent, [SDV]Life Sciences [q-bio], Neurodevelopment, Context (language use), 010501 environmental sciences, 01 natural sciences, Brain-derived neurotrophic factor, Chemical exposure, 03 medical and health sciences, 0302 clinical medicine, Bisphenol A, Phenols, Tandem Mass Spectrometry, Humans, Environmental Chemistry, Prospective Studies, Benzhydryl Compounds, Child, Waste Management and Disposal, 0105 earth and related environmental sciences, Environmental Exposure, University hospital, Pollution, 3. Good health, Adolescence, [SDV] Life Sciences [q-bio], Biomonitoring, Christian ministry, Pediatric unit, Humanities, Clinical evaluation, 030217 neurology & neurosurgery, Chromatography, Liquid
Abstract: This research would not have been achieved without the selfless col-laboration of the INMA-Granada boys and families who took part in the study. Vicente Mustieles, Alicia Olivas-Martinez and Shereen Cynthia D'Cruz were under contract within the HBM4EU project. Additionally, we acknowledge the Biomedical Research Networking Center-CIBER de Epidemiologia y Salud Publica (CIBERESP) , and the Instituto de Salud Carlos III (ISCIII) (FIS-PI16/01820, FIS-PI16/01858, FIS-PI17/01526, and FIS-PI20/01568) . The authors also thank the ISCIII and "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) for the Miguel Servet Type I Program granted to C. Freire (grant no. MS16/00085) , the Sara Borrell postdoctoral research contract granted to F. Vela-Soria (grant no. CD17/00212) , and the Spanish Ministry of Education for the predoctoral fellowships (FPU) granted to A. Rodriguez-Carrillo (FPU 16/03011) and to I. Reina-Perez (FPU 17/01848) . Dr. JP Arrebola is under contract within the Ramon y Cajal Program (RYC-2016-20155, from Ministerio de Economia, Industria y Competitividad, Spain) . The authors also ac-knowledge the contribution of the Pediatric Unit of San Cecilio University Hospital of Granada (recruitment and clinical evaluation) , Marina Molina (field work and biospecimen processing) , Raquel Quesada and Beatriz Suarez (chemical exposure data) and Mario Murcia (data curation) , as well as the Human Genotyping Laboratory at the Spanish National Cancer Research Centre, CeGen-PRB3, which is sup-ported by grant no. PT17/0019, of the PE I + D + i 2013-2016, funded by Instituto de Salud Carlos III (ISCIII) and ERDF. This article will be part of the doctoral thesis developed by Andrea Rodriguez-Carrillo in the context of the "Clinical Medicine and Public Health Program" of the University of Granada (Spain) ., This study was supported in part by the European Union's Horizon 2020 research and innovation program HBM4EU [Grant Agreement No. 733032], Biomedical Research Networking Center-CIBER de Epidemiología y Salud Pública (CIBERESP), and the Instituto de Salud Carlos III (ISCIII) [Grant no. CP16/00085 and FIS-PI17/01526]. The funders had no role in the study design, data collection or analysis, decision to publish, or preparation of the manuscript. Funding for open access charge: Universidad de Granada / CBUA., Background: Bisphenol A (BPA) exposure has been linked to altered behavior in children. Within the European Human Biomonitoring Initiative (HBM4EU), an adverse outcome pathway (AOP) network was constructed supporting the mechanistic link between BPA exposure and brain-derived neurotrophic factor (BDNF). Objective: To test this toxicologically-based hypothesis in the prospective INMA-Granada birth cohort (Spain). Methods: BPA concentrations were quantified by LC-MS/MS in spot urine samples from boys aged 9-11 years, normalized by creatinine and log-2 transformed. At adolescence (15-17 years), blood and urine specimens were collected, and serum and urinary BDNF protein levels were measured using immunoassays. DNA methylation levels at 6 CpGs in Exon IV of the BDNF gene were also assessed in peripheral blood using bisulfite-pyrosequencing. Adolescent's behavior was parent-rated using the Child Behavior Checklist (CBCL/6-18) in 148 boys. Adjusted linear regression and mediation models were fit. Results: Childhood urinary BPA concentrations were longitudinally and positively associated with thought problems (beta = 0.76; 95% CI: 0.02, 1.49) and somatic complaints (beta = 0.80; 95% CI: -0.16, 1.75) at adolescence. BPA concentrations were positively associated with BDNF DNA methylation at CpG6 (beta = 0.21; 95% CI: 0.06, 0.36) and mean CpG methylation (beta = 0.10; 95% CI: 0.01, 0.18), but not with total serum or urinary BDNF protein levels. When independent variables were categorized in tertiles, positive dose-response associations were observed between BPA-thought problems (p-trend = 0.08), BPA-CpG6 (p-trend, Instituto de Salud Carlos III, "Fondo Europeo de Desarrollo Regional" (ISCIII/FEDER) MS16/00085, Sara Borrell postdoctoral research contract grant CD17/00212, Spanish Government FPU 16/03011- FPU 17/01848, Ramon y Cajal Program (Ministerio de Economia, Industria y Competitividad, Spain) RYC-2016-20155, Human Genotyping Laboratory at the Spanish National Cancer Research Centre, CeGen-PRB3 PT17/0019, Instituto de Salud Carlos III European Commission, European Commission
Published: 2022

107. Evaluation of poly (lactic-co-glycolic acid) nanoparticles to improve the therapeutic efficacy of paclitaxel in breast cancer

Author: Laura Cabeza, Mazen M. El-Hammadi, Raul Ortiz, Maria D. Cayero-Otero, Julia Jiménez-López, Gloria Perazzoli, Lucia Martin-Banderas, Jose M. Baeyens, Consolación Melguizo, Jose Prados, Universidad de Sevilla. Departamento de Farmacia y Tecnología Farmacéutica, Universidad de Sevilla, Junta de Andalucía, Instituto de Salud Carlos III, [Cabeza, Laura] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain, [Ortiz, Raul] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain, [Jimenez-Lopez, Julia] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain, [Perazzoli, Gloria] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain, [Melguizo, Consolacion] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain, [Prados, Jose] Univ Granada, Ctr Biomed Res CIBM, Inst Biopathol & Regenerat Med IBIMER, Granada 18100, Spain, [Cabeza, Laura] Univ Granada, Fac Med, Dept Anat & Embryol, Granada 18071, Spain, [Ortiz, Raul] Univ Granada, Fac Med, Dept Anat & Embryol, Granada 18071, Spain, [Melguizo, Consolacion] Univ Granada, Fac Med, Dept Anat & Embryol, Granada 18071, Spain, [Prados, Jose] Univ Granada, Fac Med, Dept Anat & Embryol, Granada 18071, Spain, [Cabeza, Laura] Univ Granada, SAS, Biosanit Inst Granada Ibs GRANADA, Granada 18014, Spain, [Ortiz, Raul] Univ Granada, SAS, Biosanit Inst Granada Ibs GRANADA, Granada 18014, Spain, [Jimenez-Lopez, Julia] Univ Granada, SAS, Biosanit Inst Granada Ibs GRANADA, Granada 18014, Spain, [Perazzoli, Gloria] Univ Granada, SAS, Biosanit Inst Granada Ibs GRANADA, Granada 18014, Spain, [Melguizo, Consolacion] Univ Granada, SAS, Biosanit Inst Granada Ibs GRANADA, Granada 18014, Spain, [Prados, Jose] Univ Granada, SAS, Biosanit Inst Granada Ibs GRANADA, Granada 18014, Spain, [El-Hammadi, Mazen M.] Univ Seville, Fac Pharm, Dept Pharm & Pharmaceut Technol, Seville 41012, Spain, [Cayero-Otero, Maria D.] Univ Seville, Fac Pharm, Dept Pharm & Pharmaceut Technol, Seville 41012, Spain, [Martin-Banderas, Lucia] Univ Seville, Fac Pharm, Dept Pharm & Pharmaceut Technol, Seville 41012, Spain, [Baeyens, Jose M.] Univ Granada, Biomed Res Ctr CIBM, Inst Neurosci, Dept Pharmacol, Granada 18100, Spain, V Plan Propio (University of Seville), Consejeria de Salud de la Junta de Andalucia, and Instituto de Salud Carlos III (ISCIII)
Subjects: Albumin-bound paclitaxel, endocrine system, Paclitaxel, Cancer stem cells, Plga-based nanoparticles, technology, industry, and agriculture, Ovarian-cancer, Pharmaceutical Science, PLGA, General Medicine, Drug-delivery, Intracellular pharmacokinetics, General Biochemistry, Genetics and Molecular Biology, Mice xenografts, In-vitro, Breast cancer, Women, Mice xenografits, Tumor-targeted delivery, Challenges, Blood-pressure
Abstract: Financial support from the V Plan Propio (University of Seville). This work was also supported by Consejeria de Salud de la Junta de Andalucia (PI-0102-2017 and P18-HO-3882) and Instituto de Salud Carlos III (ISCIII) (Project PI19/01478) (FEDER)., Introduction: Paclitaxel (PTX) is a cornerstone in the treatment of breast cancer, the most common type of cancer in women. However, this drug has serious limitations, including lack of tissue-specificity, poor water solubility, and the development of drug resistance. The transport of PTX in a polymeric nanoformulation could overcome these limitations. Methods: In this study, PLGA-PTX nanoparticles (NPs) were assayed in breast cancer cell lines, breast cancer stem cells (CSCs) and multicellular tumor spheroids (MTSs) analyzing cell cycle, cell uptake (Nile Red-NR-) and α-tubulin expression. In addition, PLGA-PTX NPs were tested in vivo using C57BL/6 mice, including a biodistribution assay. Results: PTX-PLGA NPs induced a significant decrease in the PTX IC50 of cancer cell lines (1.31 and 3.03-fold reduction in MDA-MB-231 and E0771 cells, respectively) and CSCs. In addition, MTSs treated with PTX-PLGA exhibited a more disorganized surface and significantly higher cell death rates compared to free PTX (27.9% and 16.3% less in MTSs from MCF-7 and E0771, respectively). PTX-PLGA nanoformulation preserved PTX’s mechanism of action and increased its cell internalization. Interestingly, PTX-PLGA NPs not only reduced the tumor volume of treated mice but also increased the antineoplastic drug accumulation in their lungs, liver, and spleen. In addition, mice treated with PTX-loaded NPs showed blood parameters similar to the control mice, in contrast with free PTX. Conclusion: These results suggest that our PTX-PLGA NPs could be a suitable strategy for breast cancer therapy, improving antitumor drug efficiency and reducing systemic toxicity without altering its mechanism of action., V Plan Propio (University of Seville), Junta de Andalucia PI-0102-2017 P18-HO-3882, Instituto de Salud Carlos III, European Commission PI19/01478
Published: 2022

108. DNA methylation changes associated with prenatal mercury exposure

Author: Lozano, Manuel, Yousefi, Paul, Broberg, Karin, Soler-Blasco, Raquel, Miyashita, Chihiro, Pesce, Giancarlo, Kim, Woo Jin, Rahman, Mohammad, Bakulski, Kelly, Haug, Line, Ikeda-Araki, Atsuko, Huel, Guy, Park, Jaehyun, Relton, Caroline, Vrijheid, Martine, Rifas-Shiman, Sheryl, Oken, Emily, Dou, John, Kishi, Reiko, Gutzkow, Kristine, Annesi-Maesano, Isabella, Won, Sungho, Hivert, Marie-France, Fallin, M. Daniele, Vafeiadi, Marina, Ballester, Ferran, Bustamante, Mariona, Llop, Sabrina, Universitat de València (UV), University of Bristol [Bristol], Karolinska Institutet [Stockholm], Lund University [Lund], Hokkaido Information University, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Kangwon National University, Harvard Medical School [Boston] (HMS), University of Michigan [Dearborn], University of Michigan System, Norwegian Institute of Public Health [Oslo] (NIPH), Seoul National University [Seoul] (SNU), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Spanish Consortium for Research on Epidemiology and Public Health, CIBER de Epidemiología y Salud Pública (CIBERESP), Universitat Pompeu Fabra [Barcelona] (UPF), Institut Desbrest de santé publique (IDESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Johns Hopkins University (JHU), University of Crete [Heraklion] (UOC), 1999SGR 00241, 15/0025, 17/00260, 20/0006, FIS-FEDER PI16/1288, FIS-FEDER PI19/1338, FIS-FEDER-PI03–1615, FIS-FEDER-PI06/0867, FIS-PI04/1436, FIS-PI08/1151, FIS-PI11/00610, MC_UU_00011/5, National Institutes of Health, NIH: R37 HD034568, National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK: R01 DK10324, National Institute of Neurological Disorders and Stroke, NINDS: 06A1, 1 UO1 NS 047537–01, National Institute of Environmental Health Sciences, NIEHS: N01-ES-75558, Z01-ES-49019, Centre International de Recherche sur le Cancer, CIRC, Japan Agency for Medical Research and Development, AMED: JPMH18950314, JPMH19188595, Wellcome Trust, WT: 102215/2/13/2, Horizon 2020 Framework Programme, H2020: 874583, Medical Research Council, MRC: MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5, MC_UU_12013_8, WT088806, Biotechnology and Biological Sciences Research Council, BBSRC: BB/I025263/1, BB/I025751/1, European Commission, EC: 261357, European Research Council, ERC: 268479, University of Bristol, Japan Society for the Promotion of Science, KAKEN, Ministry of Education, Culture, Sports, Science and Technology, Monbusho: JP15H04780, JP16H02645, JP18H03035, JP18K10022, JP18K10042, JP19H01071, JP19K10576, JP19K10636, JP19K20457, JP19K22730, JPMEERF20145054, JPMEERF20175053, JPMEERF20205002, Bundesministerium für Bildung und Forschung, BMBF, Generalitat Valenciana, GVA: 090,430, BEST/2020/059, Ministry of Health, Labour and Welfare, MHLW: JPMH14427175, JPMH17932352, JPMH19189425, Helse- og Omsorgsdepartementet, Ministry of Environment, MOE: 2017001360005, Korea Environmental Industry and Technology Institute, KEITI, Instituto de Salud Carlos III, ISCIII: CB06/02/0041, INMA G03/176, Ministerio de Ciencia e Innovación, MICINN: MTM2015-68140-R, Seventh Framework Programme, FP7: R01HL111108, R01NR013945, Norges Forskningsråd: 221097, Institut National Du Cancer, INCa, Horizon 2020: 733206, Ministry of Internal Affairs and Communications, MIC: JPMI10001, Consejería de Educación e Investigación, The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research , NIH/NIEHS (contract no N01-ES-75558 ), NIH/NINDS (grant no. 1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537–06A1 ). MoBa1 and MoBa 2 are supported by the Intramural Research Program of the NIH , National Institute of Environmental Health Sciences ( Z01-ES-49019 ) and Norwegian Research Council /BIOBANK (grant no 221097 ). The work in MoBa3 was supported in part by a Postdoctoral Fellowship grant from the Ulleval Hospitals Research Council (now under Oslo University Hospital) and travel grants from the Unger-Vetlesens foundation and the Norwegian American Womens Club , all to M.C.M.K. MoBa3 epigenomics data analyses were funded by INCA/Plan Cancer-EVA-INSERM, France, and the International Childhood Cancer Cohort Consortium (I4C), and performed by the Epigenetics Group at the International Agency for Research on Cancer (IARC, Lyon, France), A.G. was supported by the grant from INCA /Plan Cancer-EVA-INSERM (France, 2015) to Z.H. and also by the IARC Postdoctoral Fellowship, partially supported by the EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND)., ALSPAC study was funded by the UK Medical Research Council and the Wellcome Trust (grant ref: 102215/2/13/2 ) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, PY and CR, who will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). The Accessible Resource for Integrated Epigenomics Studies (ARIES), was funded by the UK Biotechnology and Biological Sciences Research Council ( BB/I025751/1 and BB/I025263/1 ). Additional epigenetic profiling of ALSPAC was supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit and the University of Bristol ( MC_UU_12013_1 , MC_UU_12013_2 , MC_UU_12013_5 and MC_UU_12013_8 ), the Wellcome Trust ( WT088806 ) and the United States National Institute of Diabetes and Digestive and Kidney Diseases ( R01 DK10324 ). PY and CR are supported by the UK MRC Integrative Epidemiology Unit ( MC_UU_00011/5 )., The Project Viva cohort is funded by NIH grants R01HL111108 , R01NR013945 , and R37 HD034568 ., The Hokkaido-Sapporo Study is supported by Grant-in-Aid for Scientific Research from the Japanese Ministry of Health , Labour and Welfare ( JPMH14427175 , JPMH19189425 , JPMH17932352 ), the Japan Society for the Promotion of Science, the Ministry of Education, Culture, Sports, Science and Technology ( JP16H02645 , JP19H01071 , JP18H03035 , JP15H04780 , JP19K10576 , JP19K10636 , JP18K10042 , JP18K10022 , JP19K22730 , JP19K20457 ), and an Environment Research and Technology Development fund ( JPMEERF20145054 , JPMEERF20175053 , JPMEERF20205002 ), AMED ( JPMH19188595 , JPMH18950314 ), and Ministry of Internal Affairs and Communications ( JPMI10001 )., Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III ( Red INMA G03/176 , CB06/02/0041 ), Spanish Ministry of Health ( FIS-PI04/1436 , FIS-PI08/1151 including FEDER funds, FIS-PI11/00610 , FIS-FEDER-PI06/0867 , FIS-FEDER-PI03–1615 , FIS-FEDER PI16/1288 , FIS-FEDER PI19/1338, Miguel Servet FEDER 15/0025 and 20/0006, FIS-FSE : 17/00260 ), Generalitat de Catalunya-CIRIT 1999SGR 00241 , Generalitat Valenciana BEST/2020/059 , Fundacio ́ La Marato ́ de TV3 ( 090,430 ), EU Commission ( 261357 -MeDALL: Mechanisms of the Development of ALLergy), and European Research Council ( 268479 -BREATHE: Brain dEvelopment and Air polluTion ultrafine particles in school childrEn)., The authors would also like to thank Ingvild Essen for thorough field work, Heidi Marie Nordheim for biological sample management and the MoBa administrative unit (MoBa). The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research . We are grateful to all the participating families in Norway who take part in this on-going cohort study., The Rhea project was financially supported by European projects , and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011–2014, ‘Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–2015). The work was also supported by MICINN ( MTM2015-68140-R ), Centro Nacional de Genotipado - CEGEN-PRB2-ISCIII, the H2020 -EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583 ) (ATHLETE project), and from the European Union's Horizon 2020 research and innovation programme (grant Agreement number: 733206 ) (Early Life stressors and Lifecycle Health (LIFECYCLE))., This study was supported by the Korean Environment Industry & Technology Institute ( KEITI ) through 'the Environmental Health Action Program', funded by Korea Ministry of Environment ( 2017001360005 )., ALSPAC. ALSPAC study is extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. We would like to acknowledge Oliver Lyttleton, Hashem Shihab, Nabila Kazmi and Geoff Woodward for their earlier contribution to the generation of ARIES data (ALSPAC methylation data). INMA, The authors would like to thank all the participants for their generous collaboration. full roster of the INMA project investigators can be found at http://www.proyectoinma.org/presentacion-inma/listado-investigadores/en_listado-investigadores.html. MoBa, The authors would also like to thank Ingvild Essen for thorough field work, Heidi Marie Nordheim for biological sample management and the MoBa administrative unit (MoBa). The MoBa Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. We are grateful to all the participating families in Norway who take part in this on-going cohort study. Project Viva, Project Viva researchers would like to thank all mothers, children and families for their ongoing participation. RHEA, The authors would like to thank Georgia Chalkiadaki and Danai Feida for biological sample management, to Eirini Michalaki, Mariza Kampouri, Anny Kyriklaki and Minas Iakovidis for field study performance and to Maria Fasoulaki for administrative assistance. SAPPORO-HOKKAIDO, We would like to express our appreciation to all of the study participants of the Hokkaido Study on Environment and Children? Health. We also express our profound gratitude to all personnel in the hospitals and clinics that collaborated with the study, including Sapporo Toho Hospital, Keiai Hospital, Endo Kikyo Maternity Clinic, Shiroishi Hospital, Memuro Municipal Hospital, Aoba Ladies Clinic, Obihiro-Kyokai Hospital, Akiyama Memorial Hospital, Sapporo Medical University Hospital, Hokkaido University Hospital, Kitami Red Cross Hospital, Hoyukai Sapporo Hospital, Gorinbashi Hospital, Hashimoto Clinic, Asahikawa Medical College Hospital, Hakodate Central General Hospital, Ohji General Hospital, Nakashibetsu Municipal Hospital, Sapporo Tokushukai Hospital, Asahikawa Red Cross Hospital, Wakkanai City Hospital, Kushiro Rosai Hospital, Sapporo-Kosei General Hospital, Shibetsu City General Hospital, Nikko Memorial Hospital, Sapporo City General Hospital, Kohnan Hospital, Hakodate City Hospital, Hokkaido Monbetsu Hospital, Tenshi Hospital, Hakodate Goryoukaku Hospital, Nakamura Hospital, Kin-ikyo Sapporo Hospital, Kitami Lady's Clinic, Engaru-Kosei General Hospital, Kushiro Red Cross Hospital, Nayoro City General Hospital, and Obihiro-Kosei General Hospital. We also deeply express our gratitude to the staff of The Hokkaido Study on Environment and Children's Health for their considerable efforts to support our study, including N. Goto, O. Hayashi, T. Hikichi, N. Kanda, K. Kunita, K. Miura, Y. Shibasaki, K. Sugawara, K. Tanaka, E. Toyama, and T. Yoshikawa. Special thanks to Ms. Mimi Takahashi on her effort to support writing this manuscript.ALSPAC study was funded by the UK Medical Research Council and the Wellcome Trust (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, PY and CR, who will serve as guarantors for the contents of this paper. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Accessible Resource for Integrated Epigenomics Studies (ARIES), was funded by the UK Biotechnology and Biological Sciences Research Council (BB/I025751/1 and BB/I025263/1). Additional epigenetic profiling of ALSPAC was supported by the UK Medical Research Council (MRC) Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2, MC_UU_12013_5 and MC_UU_12013_8), the Wellcome Trust (WT088806) and the United States National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK10324). PY and CR are supported by the UK MRC Integrative Epidemiology Unit (MC_UU_00011/5).Main funding of the epigenetic studies in INMA were grants from Instituto de Salud Carlos III (Red INMA G03/176, CB06/02/0041), Spanish Ministry of Health (FIS-PI04/1436, FIS-PI08/1151 including FEDER funds, FIS-PI11/00610, FIS-FEDER-PI06/0867, FIS-FEDER-PI03?1615, FIS-FEDER PI16/1288, FIS-FEDER PI19/1338, FIS-FSE: 17/00260), Generalitat de Catalunya-CIRIT 1999SGR 00241, Generalitat Valenciana BEST/2020/059, Fundacio ? La Marato ? de TV3 (090,430), EU Commission (261357-MeDALL: Mechanisms of the Development of ALLergy), and European Research Council (268479-BREATHE: Brain dEvelopment and Air polluTion ultrafine particles in school childrEn).This study was supported by the Korean Environment Industry & Technology Institute (KEITI) through ?the Environmental Health Action Program?, funded by Korea Ministry of Environment (2017001360005).The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant no.1 UO1 NS 047537?01 and grant no.2 UO1 NS 047537?06A1). MoBa1 and MoBa 2 are supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES-49019) and Norwegian Research Council/BIOBANK (grant no 221097). The work in MoBa3 was supported in part by a Postdoctoral Fellowship grant from the Ulleval Hospitals Research Council (now under Oslo University Hospital) and travel grants from the Unger-Vetlesens foundation and the Norwegian American Womens Club, all to M.C.M.K. MoBa3 epigenomics data analyses were funded by INCA/Plan Cancer-EVA-INSERM, France, and the International Childhood Cancer Cohort Consortium (I4C), and performed by the Epigenetics Group at the International Agency for Research on Cancer (IARC, Lyon, France), A.G. was supported by the grant from INCA/Plan Cancer-EVA-INSERM (France, 2015) to Z.H. and also by the IARC Postdoctoral Fellowship, partially supported by the EC FP7 Marie Curie Actions-People-Co-funding of regional, national and international programmes (COFUND).The Project Viva cohort is funded by NIH grants R01HL111108, R01NR013945, and R37 HD034568.The Rhea project was financially supported by European projects, and the Greek Ministry of Health (Program of Prevention of Obesity and Neurodevelopmental Disorders in Preschool Children, in Heraklion district, Crete, Greece: 2011?2014, Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012?2015). The work was also supported by MICINN (MTM2015-68140-R), Centro Nacional de Genotipado-CEGEN-PRB2-ISCIII, the H2020-EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583) (ATHLETE project), and from the European Union's Horizon 2020 research and innovation programme (grant Agreement number: 733206) (Early Life stressors and Lifecycle Health (LIFECYCLE)).The Hokkaido-Sapporo Study is supported by Grant-in-Aid for Scientific Research from the Japanese Ministry of Health, Labour and Welfare (JPMH14427175, JPMH19189425, JPMH17932352), the Ministry of Education, Culture, Sports, Science and Technology (JP16H02645, JP19H01071, JP18H03035, JP15H04780, JP19K10576, JP19K10636, JP18K10042, JP18K10022, JP19K22730, JP19K20457), and an Environment Research and Technology Development fund (JPMEERF20145054, JPMEERF20175053, JPMEERF20205002), AMED (JPMH19188595, JPMH18950314), and Ministry of Internal Affairs and Communications (JPMI10001)., European Project: 261357,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MEDALL(2010), HAL UVSQ, Équipe, and Mechanisms of the Development of ALLergy - MEDALL - - EC:FP7:HEALTH2010-12-01 - 2015-05-31 - 261357 - VALID
Subjects: [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, [SDV.TOX] Life Sciences [q-bio]/Toxicology, DNA methylation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Prenatal exposure, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.EE.SANT] Life Sciences [q-bio]/Ecology, environment/Health, Methylmercury, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Mercury, ALSPAC, HELIX study, PACE
Abstract: International audience; Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (β = 2.28 × 10−4, p-value = 5.87 × 10−5) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (β = 0.004, p-value = 4.97 × 10−5), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (β = 0.002, p-value = 4.81 × 10−7) in GRK1 and cg02212000 (β = −0.001, p-value = 8.13 × 10−7) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.
Published: 2022

109. Estudio para evaluar la eficacia clínica de plasma convaleciente frente a tratamiento estándar en pacientes hospitalizados por COVID 19

Author: Diago Sempere, Elena Isabel, Avendaño Solá, Cristina, UAM. Departamento de Medicina, and Instituto de Salud Carlos III (ISCIII)
Subjects: Medicina
Abstract: Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de Lectura: 10-06-2022, La inmunoterapia pasiva con plasma convaleciente (PC) es un tratamiento potencial para COVID-19, para el cual la evidencia de ensayos clínicos controlados no es concluyente. Objetivo: Determinar si la terapia con PC agregada al estándar de tratamiento es clínicamente superior al estándar de tratamiento solo. Diseño: Ensayo clínico multicéntrico, aleatorizado, abierto, realizado en 27 hospitales de España. Los pacientes hospitalizados por neumonía COVID-19 dentro de los 7 días desde el inicio de los síntomas y sin ventilación mecánica o dispositivos de alto flujo de oxígeno fueron asignados al azar para recibir PC como terapia adicional al tratamiento estándar utilizando un sistema de asignación oculto. El estado clínico del paciente se evaluó con una escala COVID-19 ordinal de siete categorías diariamente hasta el alta y los días 15, 29 y 60. La variable principal de eficacia se estableció como el porcentaje de pacientes en categorías 5 (hospitalizados, con ventilación no invasiva o dispositivos de oxígeno de alto flujo), 6 (hospitalizado, con ventilación mecánica invasiva o ECMO) o 7 (muerte) a los 14 días. Resultados: 350 pacientes fueron aleatorizados entre abril de 2020 y febrero de 2021, 179 asignados a PC y 171 a grupo control. La proporción de pacientes que en el día 15 habían empeorado a categorías 5, 6 o 7 fue del 11,7% en el grupo PC frente al 16,4% en el grupo control el día 15 (p = 0,20) y del 8,4% frente al 16,4%, respectivamente, el día 29 (p = 0,02). La diferencia en la supervivencia global no alcanzó significación estadística (HR 0,46, IC 0,19-1,14, rango logarítmico p=0,09). No hubo diferencias significativas en otras variables secundarios. Los análisis de subgrupos planificados previamente no confirman la hipótesis de un mayor beneficio del PC en los pacientes hospitalizados y tratados a los pocos días de los síntomas, pero sugieren beneficio del PC en pacientes mayores de 75 años y en aquellos sin anticuerpos anti-SARS-CoV-2 en el momento de la inclusión. Conclusiones y relevancia: El PC añadido al estándar de tratamiento no mostró un beneficio estadísticamente significativo en la variable principal predefinida. El beneficio estadísticamente significativo a día 29 y los resultados del análisis de subgrupos planificado previamente sugieren que se debe completar su evaluación para aclarar cuál puede ser el momento oportuno para su administración, las poblaciones concretas en las que puede existir beneficio y la dosis que se debería administrar, con un umbral mínimo de anticuerpos con la afinidad adecuada
Published: 2022

110. Novel genes and sex differences in COVID-19 severity

Author: Cruz, Raquel, Diz-de Almeida, Silvia, López de Heredia, Miguel, Quintela, Inés, Ceballos, Francisco C., Pita, Guillermo, Lorenzo-Salazar, José M, González-Montelongo, Rafaela, Gago-Domínguez, Manuela, Sevilla Porras, Marta, Tenorio Castaño, Jair Antonio, Nevado, Julian, Aguado, Jose María, Aguilar, Carlos, Aguilera-Albesa, Sergio, Almadana, Virginia, Almoguera, Berta, Alvarez, Nuria, Andreu-Bernabeu, Álvaro, Arana-Arri, Eunate, Arango, Celso, Arranz, María J, Artiga, Maria-Jesus, Baptista-Rosas, Raúl C, Barreda-Sánchez, María, Belhassen-Garcia, Moncef, Bezerra, Joao F., Bezerra, Marcos A C, Boix-Palop, Lucía, Brion, María, Brugada, Ramón, Bustos, Matilde, Calderón, Enrique J., Carbonell, Cristina, Castano, Luis, Castelao, Jose E., Conde-Vicente, Rosa, Cordero-Lorenzana, M Lourdes, Cortes-Sanchez, Jose L., Corton, Marta, Darnaude, M Teresa, De Martino-Rodríguez, Alba, Del Campo-Pérez, Victor, Diaz de Bustamante, Aranzazu, Domínguez-Garrido, Elena, Luchessi, Andre D., Eiros, Rocío, Estigarribia Sanabria, Gladys Mercedes, Carmen Fariñas, María, Fernández-Robelo, Uxía, Fernández-Rodríguez, Amanda, Fernández-Villa, Tania, Gil-Fournier, Belén, Gómez-Arrue, Javier, González Álvarez, Beatriz, Gonzalez Bernaldo de Quirós, Fernan, González-Peñas, Javier, Gutiérrez-Bautista, Juan F., Herrero, María José, Herrero-Gonzalez, Antonio, Jimenez-Sousa, María A, Lattig, María Claudia, Liger Borja, Anabel, Lopez-Rodriguez, Rosario, Mancebo, Esther, Martín-López, Caridad, Martín, Vicente, Martinez-Nieto, Oscar, Martinez-Lopez, Iciar, Martinez-Resendez, Michel F., Martinez-Perez, Angel, Mazzeu, Juliana F., Merayo Macías, Eleuterio, Minguez, Pablo, Moreno Cuerda, Victor, Silbiger, Vivian N., Oliveira, Silviene F., Ortega-Paino, Eva, Parellada, Mara, Paz-Artal, Estela, Santos, Ney P C, Pérez-Matute, Patricia, Perez, Patricia, Pérez-Tomás, M Elena, Perucho, Teresa, Pinsach-Abuin, Mel Lina, Pompa-Mera, Ericka N., Porras-Hurtado, Gloria L., Pujol, Aurora, Ramiro León, Soraya, Resino, Salvador, Fernandes, Marianne R., Rodríguez-Ruiz, Emilio, Rodriguez-Artalejo, Fernando, Rodriguez-Garcia, José A, Ruiz Cabello, Francisco, Ruiz-Hornillos, Javier, Ryan, Pablo, Soria, José Manuel, Souto, Juan Carlos, Tamayo, Eduardo, Tamayo-Velasco, Alvaro, Taracido-Fernandez, Juan Carlos, Teper, Alejandro, Torres-Tobar, Lilian, Urioste, Miguel, Valencia-Ramos, Juan, Yáñez, Zuleima, Zarate, Ruth, Nakanishi, Tomoko, Pigazzini, Sara, Degenhardt, Frauke, Butler-Laporte, Guillaume, Maya-Miles, Douglas, Bujanda, Luis, Bouysran, Youssef, Palom, Adriana, Ellinghaus, David, Martínez-Bueno, Manuel, Rolker, Selina, Amitrano, Sara, Roade, Luisa, Fava, Francesca, Spinner, Christoph D., Prati, Daniele, Bernardo, David, Garcia, Federico, Darcis, Gilles, Fernández-Cadenas, Israel, Holter, Jan Cato, Banales, Jesus M., Frithiof, Robert, Duga, Stefano, Asselta, Rosanna, Pereira, Alexandre C., Romero-Gómez, Manuel, Nafría-Jiménez, Beatriz, Hov, Johannes R., Migeotte, Isabelle, Renieri, Alessandra, Planas, Anna M., Ludwig, Kerstin U., Buti, Maria, Rahmouni, Souad, Alarcón-Riquelme, Marta E., Schulte, Eva C., Franke, Andre, Karlsen, Tom H., Valenti, Luca, Zeberg, Hugo, Richards, Brent, Ganna, Andrea, Boada, Mercè, de Rojas, Itziar, Ruiz, Agustín, Sánchez-Juan, Pascual, Real, Luis Miguel, Guillen-Navarro, Encarna, Ayuso, Carmen, González-Neira, Anna, Riancho, José A, Rojas-Martinez, Augusto, Flores, Carlos, Lapunzina, Pablo, Carracedo, Angel, 0000-0002-6964-8898, 0000-0001-7463-2148, 0000-0002-3166-5086, 0000-0003-1374-0756, 0000-0001-9510-5646, 0000-0001-7516-3179, 0000-0001-5388-0396, 0000-0002-3875-5367, 0000-0003-3818-0871, 0000-0002-8541-2519, 0000-0003-3765-6778, Institut Català de la Salut, [Cruz R] Centro Nacional de Genotipado (CEGEN), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain. Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. [Diz-de Almeida S] Centro Singular de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. [López de Heredia M] Centre for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. [Quintela I] Centro Nacional de Genotipado (CEGEN), Universidade de Santiago de Compostela, Santiago de Compostela, Spain. [Ceballos FC] Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología (CNM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Pita G] Spanish National Cancer Research Centre, Human Genotyping-CEGEN Unit, Madrid, Spain. [Palom A] Unitat Hepàtica, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Grup de Recerca de les Malalties Hepàtiques, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Buti M] Centre for Biomedical Network Research on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain. Unitat Hepàtica, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Universidad de Cantabria, SCOURGE Cohort Group, HOSTAGE Cohort Group, GRA@CE Cohort Group, Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación Amancio Ortega, Banco Santander, Estrella de Levante, Fundación La Caixa, Agencia Estatal de Investigación (España), Cabildo Insular de Tenerife (España), Fundación Canaria de Investigación Sanitaria, Institute for Molecular Medicine Finland, University of Helsinki, Data Science Genetic Epidemiology Lab, European Commission, Colabora Mujer, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, and Gobierno de Canarias (España)
Subjects: INTERFERON, EXPRESSION, Male, Settore MED/09 - Medicina Interna, COVID-19 (Malaltia) - Aspectes genètics, GENETICS, Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Diàtesi, AUTOZYGOSITY, Polymorphism, Single Nucleotide, fenómenos fisiológicos reproductivos y urinarios::fenómenos fisiológicos de la reproducción::características sexuales [FENÓMENOS Y PROCESOS], Genetics, virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Humans, Genetic Predisposition to Disease, HOMOZYGOSITY, Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Sex Characteristics [PHENOMENA AND PROCESSES], Molecular Biology, Genetics (clinical), Malalties - Factors sexuals, fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Sex Characteristics, RANGE, ANDROGEN RECEPTOR, COVID-19, RUNS, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], ASSOCIATION, General Medicine, Middle Aged, Genetic Loci, 1182 Biochemistry, cell and molecular biology, Female, LUNG, Genome-Wide Association Study
Abstract: Here, we describe the results of a genome-wide study conducted in 11939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P= 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided., Instituto de Salud Carlos III European Commission COV20_00622 COV20/00792 COV20_00181 COV20_1144 PI20/00876, European Union (ERDF) 'A way of making Europe', Fundacion Amancio Ortega, Banco de Santander, Estrella de Levante S.A., Colabora Mujer Association, La Caixa Foundation, Agencia Estatal de Investigacion RTC-2017-6471-1, Cabildo Insular de Tenerife (Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19) CGIEU0000219140, Fundacion Canaria Instituto de Investigacion Sanitaria de Canarias PIFIISC20/57
Published: 2022

111. Impact of COVID-19 Lockdown in Eating Disorders: A Multicentre Collaborative International Study

Author: Isabel Baenas, Mikel Etxandi, Lucero Munguía, Roser Granero, Gemma Mestre-Bach, Isabel Sánchez, Emilio Ortega, Alba Andreu, Violeta L. Moize, Jose-Manuel Fernández-Real, Francisco J. Tinahones, Carlos Diéguez, Gema Frühbeck, Daniel Le Grange, Kate Tchanturia, Andreas Karwautz, Michael Zeiler, Hartmut Imgart, Annika Zanko, Angela Favaro, Laurence Claes, Ia Shekriladze, Eduardo Serrano-Troncoso, Raquel Cecilia-Costa, Teresa Rangil, Maria Eulalia Loran-Meler, José Soriano-Pacheco, Mar Carceller-Sindreu, Rosa Navarrete, Meritxell Lozano, Raquel Linares, Carlota Gudiol, Jordi Carratala, Maria T. Plana, Montserrat Graell, David González-Parra, José A. Gómez-del Barrio, Ana R. Sepúlveda, Jéssica Sánchez-González, Paulo P. P. Machado, Anders Håkansson, Ferenc Túry, Bea Pászthy, Daniel Stein, Hana Papezová, Jana Gricova, Brigita Bax, Mikhail F. Borisenkov, Sergey V. Popov, Denis G. Gubin, Ivan M. Petrov, Dilara Isakova, Svetlana V. Mustafina, Youl-Ri Kim, Michiko Nakazato, Nathalie Godart, Robert van Voren, Tetiana Ilnytska, Jue Chen, Katie Rowlands, Ulrich Voderholzer, Alessio M. Monteleone, Janet Treasure, Susana Jiménez-Murcia, Fernando Fernández-Aranda, Universidade do Minho, Institut Català de la Salut, [Baenas I, Munguía L, Sánchez I] Department of Psychiatry, Bellvitge University Hospital-IDIBELL, 08907 Barcelona, Spain. CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, 28029 Barcelona, Spain. Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Programme, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain. [Etxandi M] Department of Psychiatry, Bellvitge University Hospital-IDIBELL, 08907 Barcelona, Spain. [Granero R] CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, 28029 Barcelona, Spain. Psychoneurobiology of Eating and Addictive Behaviors Group, Neurosciences Programme, Bellvitge Biomedical Research Institute (IDIBELL), 08908 Barcelona, Spain. Department of Psychobiology and Methodology, School of Psychology, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain. [Mestre-Bach G] Facultad de Ciencias de la Salud, Universidad Internacional de La Rioja, 26006 La Rioja, Spain. [Fernández-Real JM] CIBER Fisiopatología Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, 28029 Barcelona, Spain. Departament de Diabetis, Endocrinologia i Nutrició, Hospital Universitari de Girona Dr. Josep Trueta, Institut Català de la Salut (ICS), Girona, Spain. Institut d'Investigació Biomèdica de Girona (IDIBGi), Salt, Spain. Departament de Ciències Mèdiques, Universitat de Girona, Girona, Spain, Hospital Universitari de Girona Dr Josep Trueta, Baenas, I., Etxandi, M., Munguia, L., Granero, R., Mestre-Bac, G., Sanchez, I., Ortega, E., Andreu, A., Moize, V. L., Fernandez-Real, J. -M., Tinahones, F. J., Dieguez, C., Fruhbeck, G., Grange, D. L., Tchanturia, K., Karwautz, A., Zeiler, M., Imgart, H., Zanko, A., Favaro, A., Claes, L., Shekriladze, I., Serrano-Troncoso, E., Cecilia-Costa, R., Rangil, T., Loran-Meler, M. E., Soriano-Pacheco, J., Carceller-Sindreu, M., Navarrete, R., Lozano, M., Linares, R., Gudiol, C., Carratala, J., Plana, M. T., Graell, M., Gonzalez-Parra, D., Gomez-Del Barrio, J. A., Sepulveda, A. R., Sanchez-Gonzalez, J., Machado, P. P. P., Hakansson, A., Tury, F., Paszthy, B., Stein, D., Papezova, H., Gricova, J., Bax, B., Borisenkov, M. F., Popov, S. V., Gubin, D. G., Petrov, I. M., Isakova, D., Mustafina, S. V., Kim, Y. -R., Nakazato, M., Godart, N., Van Voren, R., Ilnytska, T., Chen, J., Rowlands, K., Voderholzer, U., Monteleone, A. M., Treasure, J., Jimenez-Murcia, S., Fernandez-Aranda, F., Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Fundação para a Ciência e a Tecnologia (Portugal), European Commission, Generalitat de Catalunya, Fundación Ciudadanía y Valores, Hospital Universitario de Bellvitge, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, CB21/13/00009, INT19/00046, PI17/01167, PI20/132, Fundação para a Ciência e a Tecnologia, FCT: POCI-01-0145-FEDER-028145, Consejo Nacional de Ciencia y Tecnología, CONACYT, Ministerio de Economía y Competitividad, MINECO: PSI2015-68701-R, European Regional Development Fund, ERDF: 728018, Eat2beNICE/ H2020-SFS-2016-2, Departament de Salut, Generalitat de Catalunya: SLT006/17/00077, Acknowledgments: We thank CERCA Programme/Generalitat de Catalunya for institutional support. This manuscript and research was supported by grants from the Department of Health of the Generalitat de Catalunya by the call Pla estratègic de recerca i innovació en salut (PERIS, SLT006/17/00077), the Ministerio de Economía y Competitividad (PSI201568701R), Fondo de Inves-tigación Sanitario (FIS) (INT19/00046, PI17/01167, PI20/132), CIBERINFEC (CB21/13/00009) and co-funded by FEDER funds /European Regional Development Fund (ERDF), a way to build Europe (Eat2beNICE/ H2020-SFS-2016-2, Ref 728018, and PRIME/ H2020-SC1-BHC-2018-2020, Ref: 847879). CIBEROBN, CIBERSAM, CIBERINFEC and CIBERDEM are all initiatives of Instituto de Salud Carlos III (ISCIII). GMB is supported by a postdoctoral grant from FUNCIVA. PPM was supported, in part, by a Portuguese Foundation for Science and Technology grant (POCI-01-0145-FEDER-028145). IB was partially supported by a Post-Residency Grant from the Research Committee of the University Hospital of Bellvitge (HUB, Barcelona, Spain) 2020–2021. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript., Funding: Fondo Investigación Sanitario-FIS, Grant/Award Numbers: FIS, INT19/00046, PI17/01167, Ministerio de Economía y Competitividad, Grant/Award Number: PSI2015-68701-R, Portuguese Foundation for Science and Technology grant, Grant/Award Number: POCI-01-0145-FEDER-028145, Consejo Nacional de Ciencia y Tecnología, and European Regional Development Fund.
Subjects: Male, Internationality, Mental Disorders::Feeding and Eating Disorders [PSYCHIATRY AND PSYCHOLOGY], Longitudinal Studie, COVID-19 (Malaltia), trastornos mentales::trastornos alimentarios y de la ingestión de alimentos [PSIQUIATRÍA Y PSICOLOGÍA], virosis::infecciones por virus ARN::infecciones por Nidovirales::infecciones por Coronaviridae::infecciones por Coronavirus [ENFERMEDADES], Pandèmia de COVID-19, 2020, TX341-641, Longitudinal Studies, Child, COVID-19 Isolation Eating Scale (CIES), COVID-19 lockdown, eating disorders, eating symptoms, psychological impact, Adolescent, Adult, Asia, COVID-19, Europe, Feeding and Eating Disorders, Female, Humans, Quarantine, SARS-CoV-2, Social Isolation, Young Adult, Nutrition and Dietetics, Eating disorder, Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [DISEASES], Environment and Public Health::Public Health::Public Health Practice::Communicable Disease Control::Infection Control::Quarantine [HEALTH CARE], OBESITY, Ciências Sociais::Psicologia, Confinament, características del estudio::estudio multicéntrico [CARACTERÍSTICAS DE PUBLICACIONES], Life Sciences & Biomedicine, MENTAL-HEALTH, Human, COVID-19 isolation eating scale (CIES), COVID-19 Pandemic, 2020, Article, Feeding and Eating Disorder, Trastorns de la conducta alimentària, Eating symptom, Science & Technology, Nutrition & Dietetics, Nutrition. Foods and food supply, ambiente y salud pública::salud pública::práctica de la salud pública::control de enfermedades transmisibles::control de infecciones::cuarentena [ATENCIÓN DE SALUD], Study Characteristics::Multicenter Study [PUBLICATION CHARACTERISTICS], Human medicine, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Food Science
Abstract: Data Availability Statement: Individuals may inquire with Fernández-Aranda regarding availability of the data as there is ongoing studies using the data. To avoid overlapping research efforts, Fernández-Aranda will consider a request on a case-by-case basis., Background. The COVID-19 lockdown has had a significant impact on mental health. Patients with eating disorders (ED) have been particularly vulnerable. Aims. (1) To explore changes in eating-related symptoms and general psychopathology during lockdown in patients with an ED from various European and Asian countries; and (2) to assess differences related to diagnostic ED subtypes, age, and geography. Methods. The sample comprised 829 participants, diagnosed with an ED according to DSM-5 criteria from specialized ED units in Europe and Asia. Participants were assessed using the COVID-19 Isolation Scale (CIES). Results. Patients with binge eating disorder (BED) experienced the highest impact on weight and ED symptoms in comparison with other ED subtypes during lockdown, whereas individuals with other specified feeding and eating disorders (OFSED) had greater deterioration in general psychological functioning than subjects with other ED subtypes. Finally, Asian and younger individuals appeared to be more resilient. Conclusions. The psychopathological changes in ED patients during the COVID-19 lockdown varied by cultural context and individual variation in age and ED diagnosis. Clinical services may need to target preventive measures and adapt therapeutic approaches for the most vulnerable patients., Fondo Investigacion Sanitario-FIS, Grant/Award Numbers: FIS, INT19/00046, PI17/01167; Ministerio de Economia y Competitividad, Grant/Award Number: PSI2015-68701-R; Portuguese Foundation for Science and Technology grant, Grant/Award Number: POCI-01-0145-FEDER-028145; Consejo Nacional de Ciencia y Tecnologia; Generalitat de Catalunya; European Regional Development Fund., We thank CERCA Programme/Generalitat de Catalunya for institutional support. This manuscript and research was supported by grants from the Department of Health of the Generalitat de Catalunya by the call Pla estratègic de recerca i innovació en salut (PERIS, SLT006/17/00077), the Ministerio de Economía y Competitividad (PSI201568701R), Fondo de Investigación Sanitario (FIS) (INT19/00046, PI17/01167, PI20/132), CIBERINFEC (CB21/13/00009) and co-funded by FEDER funds /European Regional Development Fund (ERDF), a way to build Europe (Eat2beNICE/ H2020-SFS-2016-2; Ref 728018; and PRIME/ H2020-SC1-BHC-2018-2020; Ref: 847879). CIBEROBN, CIBERSAM, CIBERINFEC and CIBERDEM are all initiatives of Instituto de Salud Carlos III (ISCIII). GMB is supported by a postdoctoral grant from FUNCIVA. PPM was supported, in part, by a Portuguese Foundation for Science and Technology grant (POCI-01-0145-FEDER-028145). IB was partially supported by a Post-Residency Grant from the Research Committee of the University Hospital of Bellvitge (HUB; Barcelona, Spain) 2020–2021. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2021
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112. New Therapeutic Approaches for Allergy: A Review of Cell Therapy and Bio- or Nano-Material-Based Strategies

Author: Paris, Juan L., de la Torre, Paz, Flores, Ana I., [Paris,JL] Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain. [Paris,JL] Andalusian Centre for Nanomedicine and Biotechnology-BIONAND, Málaga, Spain. [de la Torre,P, Flores,AI] Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., This work was funded by Instituto de Salud Carlos III (ISCIII), Ministry of Economy, Industry, and Competitiveness, co-funded by the European Regional Development Fund, grants number PI18/01278, and and PI 20/012 by Fundacion Francisco Soria Melguizo. J.L.P holds a 'Sara Borrell' fellowship (CD19/00250) from ISCIII, co-funded by the European Social Fund ('El FSE invierte en futuro').
Subjects: Allergy, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Neurotransmitter Agents::Histamine Agents::Histamine Antagonists [Medical Subject Headings], Nanoestructuras, Alergia e inmunología, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Adrenal Cortex Hormones [Medical Subject Headings], Cell therapy, Biomaterials, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunosuppression::Desensitization, Immunologic [Medical Subject Headings], Tratamiento basado en trasplante de células y tejidos, Materiales biocompatibles, Nano-materials, Immunotherapy, Inmunoterapia, Chemicals and Drugs::Biological Factors::Antigens::Allergens [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Cell- and Tissue-Based Therapy [Medical Subject Headings], Diseases::Immune System Diseases::Hypersensitivity::Hypersensitivity, Immediate::Food Hypersensitivity [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Prevalence [Medical Subject Headings]
Abstract: Allergy constitutes a major health issue due to its large prevalence. The established therapeutic approaches (allergen avoidance, antihistamines, and corticosteroids) do not address the underlying causes of the pathology, highlighting the need for other long-term treatment options. Antigen-specific immunotherapy enables the long-term control of allergic diseases by promoting immunological tolerance to the allergen. However, efficacious immunotherapies are not available for all possible allergens, and the risk of undesired reactions during therapy remains a concern, especially in patients with severe allergic reactions. In this context, two types of therapeutic strategies appear especially promising for the future in the context of allergy: cell therapy and bio- or nano-material-based therapy. In this review, the main strategies developed this far in these two types of strategies are discussed, with several examples illustrating the different approaches. Yes
Published: 2021

113. Circulating Tumor Cells in Hepatocellular Carcinoma: A Comprehensive Review and Critical Appraisal

Author: Espejo-Cruz, María Lola, González-Rubio, Sandra, Zamora-Olaya, Javier, Amado-Torres, Víctor, Alejandre, Rafael, Sánchez-Frías, Marina, Ciria, Rubén, De la Mata, Manuel, Rodríguez-Perálvarez, Manuel, Ferrín, Gustavo, [Espejo-Cruz,ML, González-Rubio,S, Zamora-Olaya,J, Amado-Torres,V, Alejandre,R, Ciria,R, De la Mata,M, Rodríguez-Perálvarez,M, Ferrín,G] Maimónides Institute of Biomedical Research (IMIBIC), University of Córdoba, Córdoba, Spain. [Zamora-Olaya,J, Rodríguez-Perálvarez,M] Department of Hepatology and Liver Transplantation, Reina Sofía University Hospital, Avda. Córdoba, Spain. [Sánchez-Frías,M] Department of Pathology, Reina Sofía University Hospital, Córdoba, Spain. [Ciria,R] Department of Hepatobiliary Surgery and Liver Transplantation, Reina Sofía University Hospital, Córdoba, Spain. [De la Mata,M, Ferrín,G] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., and This work was supported by the 'Plan Nacional de I+D+I Proyectos de Investigación en Salud of Instituto de Salud Carlos III (ISCIII), Subdirección General de Evaluación and Fondo Europeo de Desarrollo Regional (FEDER)' (grant number PI18/01736). G.F. was supported by the CIBERehd. S.G.-R. is supported by the 'Consejería de Salud y Familias de la Junta de Andalucía and Fondo Social Europeo' (grant number RH-0075-2020). M.L.E.-C. was supported by the ISCIII (grant number FI19/00357).
Subjects: Liquid biopsy, Hepatocellular carcinoma, Therapeutic target, Terapéutica, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics [Medical Subject Headings], Circulating tumor cells, Dynamic changes, Neoplasias hepáticas, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Diseases::Digestive System Diseases::Liver Diseases::Liver Neoplasms::Carcinoma, Hepatocellular [Medical Subject Headings], Diseases::Digestive System Diseases::Liver Diseases [Medical Subject Headings], Biopsia líquida, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Early Diagnosis [Medical Subject Headings], Liver cancer, Carcinoma hepatocelular, Células neoplásicas circulantes, Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological [Medical Subject Headings], Diseases::Neoplasms::Neoplastic Processes::Neoplasm Metastasis::Neoplastic Cells, Circulating [Medical Subject Headings]
Abstract: Hepatocellular carcinoma (HCC) is the fifth most common neoplasm and a major cause of cancer-related death worldwide. There is no ideal biomarker allowing early diagnosis of HCC and tumor surveillance in patients receiving therapy. Liquid biopsy, and particularly circulating tumor cells (CTCs), have emerged as a useful tool for diagnosis and monitoring therapeutic responses in different tumors. In the present manuscript, we evaluate the current evidence supporting the quantitative and qualitative assessment of CTCs as potential biomarkers of HCC, as well as technical aspects related to isolation, identification, and classification of CTCs. Although the dynamic assessment of CTCs in patients with HCC may aid the decision-making process, there are still many uncertainties and technical caveats to be solved before this methodology has a true impact on clinical practice guidelines. More studies are needed to identify the optimal combination of surface markers, to increase the efficiency of ex-vivo expansion of CTCs, or even to target CTCs as a potential therapeutic strategy to prevent HCC recurrence after surgery or to hamper tumor progression and extrahepatic spreading. Yes
Published: 2021

114. Effect on an Oral Nutritional Supplement with β-Hydroxy-β-methylbutyrate and Vitamin D on Morphofunctional Aspects, Body Composition, and Phase Angle in Malnourished Patients

Author: Isabel Cornejo-Pareja, Maria Ramirez, Maria Camprubi-Robles, Ricardo Rueda, Isabel Maria Vegas-Aguilar, Jose Manuel Garcia-Almeida, [Cornejo-Pareja,I, Vegas-Aguilar,IM, Garcia-Almeidam,JM] Department of Endocrinology and Nutrition, Virgen de la Victoria Hospital (IBIMA), Malaga University, Malaga, Spain. [Cornejo-Pareja,I, Garcia-Almeidam,JM] Centro de Investigacion Biomedica en Red de la Fisiopatología de la Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Malaga, Spain. [Ramirez,M, Camprubi-Robles,M, Rueda,R] Abbott Nutrition, Research and Development, Granada, Spain., and I.C.-P. was the recipient of a postdoctoral grant (Río Hortega CM 17/00169) and is now the recipient of a postdoctoral grant (Juan Rodes JR 19/00054) from the Instituto de Salud Carlos III and cofounded by Fondo Europeo de Desarrollo Regional-FEDER. This study was a collaboration between the Institution and Abbott Laboratories. The company covered the publication cost.
Subjects: Male, Desnutrición, Time Factors, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies::Retrospective Studies [Medical Subject Headings], Phenomena and Processes::Physical Phenomena::Time::Time Factors [Medical Subject Headings], Administration, Oral, Body composition, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Dietary Proteins [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Eating, Nutritional status, Neoplasms, Estado nutricional, Phenomena and Processes::Digestive System and Oral Physiological Phenomena::Digestive System Physiological Phenomena::Digestive System Processes::Eating [Medical Subject Headings], TX341-641, Nutritional Physiological Phenomena, body cell mass, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Nutritional Status [Medical Subject Headings], Vitamin D, Health Care::Health Services Administration::Quality of Health Care::Quality Indicators, Health Care::Standard of Care [Medical Subject Headings], Phenomena and Processes::Metabolic Phenomena::Body Composition [Medical Subject Headings], Cancer, Nutrition and Dietetics, Hand Strength, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Administration Routes::Administration, Oral [Medical Subject Headings], Anatomy::Musculoskeletal System::Muscles [Medical Subject Headings], Middle Aged, Diseases::Neoplasms [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet::Energy Intake [Medical Subject Headings], Neoplasias, phase angle, Health Care::Health Services Administration::Organization and Administration::Records as Topic::Diet Records [Medical Subject Headings], Suplementos dietéticos, Oral nutritional supplements, Technology and Food and Beverages::Food and Beverages::Food::Dietary Supplements [Medical Subject Headings], Body Composition, oral nutritional supplements, Female, Dietary Proteins, Muscle loss, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Malnutrition [Medical Subject Headings], Vitamina D, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size::Body Weight [Medical Subject Headings], Nutritional Status, Check Tags::Male [Medical Subject Headings], Chemicals and Drugs::Polycyclic Compounds::Steroids::Secosteroids::Vitamin D [Medical Subject Headings], Músculos, malnutrition, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet [Medical Subject Headings], muscle loss, cancer, β-hydroxy-β-methylbutyrate, Article, Valerates, Humans, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Composición corporal, Retrospective Studies, β-hydroxy-β-methylbuty rate, Nutrition. Foods and food supply, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Muscle Strength::Hand Strength [Medical Subject Headings], Body Weight, Malnutrition, Peso corporal, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Body weight, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena [Medical Subject Headings], Phase angle, Check Tags::Female [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Carboxylic Acids::Acids, Acyclic::Valerates [Medical Subject Headings], Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Movement::Motor Activity::Exercise [Medical Subject Headings], Dietary Supplements, Body cell mass, Energy Intake, Food Science
Abstract: This is a retrospective study of data from clinical practice to observe the effect of a high-calorie, high-protein oral nutritional supplement (ONS) with β-hydroxy-β-methylbutyrate (HMB) on nutritional status, body weight, and muscle-related parameters in 283 adult patients with or at risk of malnutrition under standard of care, 63% being cancer patients. They were recommended to increase physical activity and energy and protein intake from regular diet plus two servings per day of a specialized ONS enriched with HMB or standard ONS for up to 6 months. Dietary records, adherence and tolerance to ONS, nutritional status, body composition, handgrip strength, and blood analysis at the beginning and the end of the intervention were recorded. This program improved nutritional status from 100% malnourished or at risk of malnutrition at baseline to 80% well-nourished at final visit. It also increased body weight by 3.6–3.8 kg, fat-free mass by 0.9 to 1.3 kg, and handgrip strength by 4.7 to 6.2 kg. In a subgroup of patients (n = 43), phase angle (PhA), and body cell mass (BCM) increased only in the patients receiving the ONS enriched with HMB (0.95 (0.13) vs. −0.36 (0.4), and 2.98 (0.5) vs. −0.6 (1.5) kg, mean difference (SE) from baseline for PhA and BCM, respectively), suggesting the potential efficacy of this supplement on muscle health.
Published: 2021

115. Multiepitope Dendrimeric Antigen-Silica Particle Composites as Nano-Based Platforms for Specific Recognition of IgEs

Author: Violeta Gil-Ocaña, Isabel M. Jimenez, Cristobalina Mayorga, Inmaculada Doña, Jose Antonio Céspedes, Maria I. Montañez, Yolanda Vida, Maria J. Torres, Ezequiel Perez-Inestrosa, [Gil-Ocaña,V, Vida,Y, Perez-Inestrosa,E] Universidad de Málaga-Instituto de Investigación Biomédica de Málaga (IBIMA), Dpto. Química Orgánica, Málaga, Spain. [Gil-Ocaña,V, Mayorga,C, Montañez,MI, Torres,MJ, Perez-Inestrosa,E] Centro Andaluz de Nanomedicina y Biotecnología-BIONAND, Parque Tecnológico de Andalucía, Málaga, Spain. [Jimenez,IM, Doña,I, Céspedes,JA., Torres,MJ] Allergy Research Group, Instituto de Investigación Biomédica de Málaga-Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain. [Jimenez,IM, Torres,MJ] Allergy Unit, Hospital Regional Universitario de Málaga, Málaga, Spain. [Torres,MJ] Universidad de Málaga-Instituto de Investigación Biomédica de Málaga (IBIMA), Dpto. Medicina, Málaga, Spain., and This work was supported by the Spanish Ministerio de Ciencia e Innovación (Proyectos de I+D+I «Programación Conjunta Internacional», EuroNanoMed 2019 (PCI2019-111825-2), Ministerio de Ciencia y Educación (PID2019-104293GB-I00), Instituto de Salud Carlos III (ISCIII) of MINECO (grants cofunded by ERDF: ‘‘Una manera de hacer Europa’’ (Euronanomed Program AC19/00082, PI20/01734, PI18/00095, RETIC ARADYAL, RD16/0006/0001 and RD16/0006/0012, and Miguel Servet II program (CPII20/00028)), Junta de Andalucía and Universidad de Málaga (UMA18-FEDERJA-007), Andalusian Regional Ministry of Health (PE-0172-2018) and Nicolas Monardes Program (RC-0004-2021).
Subjects: Male, Chemicals and Drugs::Biological Factors:: [Medical Subject Headings], silica nanoparticles, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Reproductive Control Agents::Fertility Agents::Fertility Agents, Female [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Persons::Persons::Men::Nurses, Male [Medical Subject Headings], Immunology and Allergy, Biepitope nanocomposites, Aprobación de pruebas de diagnóstico, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin E [Medical Subject Headings], Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Original Research, Penicilinas, Diagnostic test, Middle Aged, Silicon Dioxide, Silica nanoparticles, Specific IgE, diagnostic test, penicillins, Female, Hipersensibilidad a las drogas, Persons::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Adult, Dendrimers, Adolescent, Dendrimeric antigen, Immunology, specific IgE, Chemicals and Drugs::Inorganic Chemicals::Silicon Compounds::Silicon Dioxide [Medical Subject Headings], Penicillins, Chemicals and Drugs::Inorganic Chemicals::Minerals::Silicon Dioxide [Medical Subject Headings], Persons::Persons::Age Groups::Adolescent [Medical Subject Headings], Young Adult, Humans, Antigens, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Chemicals and Drugs::Biological Factors::Antigens [Medical Subject Headings], Technology and Food and Beverages::Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles [Medical Subject Headings], Aged, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Drug allergy, Immunoglobulin E, RC581-607, dendrimeric antigen, biepitope nanocomposites, Nanoparticles, Immunologic diseases. Allergy, Chemicals and Drugs::Macromolecular Substances::Polymers::Dendrimers [Medical Subject Headings], drug allergy
Abstract: β-lactam antibiotics (BLs) are the drugs most frequently involved in drug hypersensitivity reactions. However, current in vitro diagnostic tests have limited sensitivity, partly due to a poor understanding of in vivo drug–protein conjugates that both induce the reactions and are immunologically recognized. Dendrimeric Antigen-Silica particle composites (DeAn@SiO2), consisting on nanoparticles decorated with BL-DeAns are promising candidates for improving the in vitro clinical diagnostic practice. In this nano-inspired system biology, the synthetic dendrimer plays the role of the natural carrier protein, emulating its haptenation by drugs and amplifying the multivalence. Herein, we present the design and synthesis of new multivalent mono- and bi-epitope DeAn@SiO2, using amoxicillin and/or benzylpenicillin allergenic determinants as ligands. The homogeneous composition of nanoparticles provides high reproducibility and quality, which is critical for in vitro applications. The suitable functionalization of nanoparticles allows the anchoring of DeAn, minimizing the nonspecific interactions and facilitating the effective exposure to specific IgE; while the larger interaction area increments the likelihood of capturing specific IgE. This achievement is particularly important for improving sensitivity of current immunoassays since IgE levels in BL allergic patients are very low. Our data suggest that these new nano-based platforms provide a suitable tool for testing IgE recognition to more than one BL simultaneously. Immunochemical studies evidence that mono and bi-epitope DeAn@SiO2 composites could potentially allow the diagnosis of patients allergic to any of these drugs with a single test. These organic–inorganic hybrid materials represent the basis for the development of a single screening for BL-allergies.
Published: 2021

116. Dietary fatty acids, macronutrient substitutions, food sources and incidence of coronary heart disease: Findings from the EPIC-CVD case-cohort study across nine european countries

Author: Matthias B. Schulze, Vittorio Krogh, Rosario Tumino, Nita G. Forouhi, Christina C. Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Angela M. Wood, Yvonne T. van der Schouw, Guri Skeie, Laura Johnson, Fumiaki Imamura, Ivonne Sluijs, José R Quirós, Elisabete Weiderpass, Nicholas J. Wareham, Timothy J. Key, Adam S. Butterworth, Giovanna Masala, Alicia K Heath, Albert Koulman, Conchi Moreno-Iribas, Inge Huybrechts, John Danesh, Stephen J. Sharp, Salvatore Panico, Carlotta Sacerdote, Aurora Perez-Cornago, Olle Melander, Rudolf Kaaks, Elio Riboli, Tammy Y.N. Tong, María José Sánchez, Rajiv Chowdhury, Ju-Sheng Zheng, Miguel Rodríguez-Barranco, W M Monique Verschuren, Marinka Steur, Ingegerd Johansson, Heiner Boeing, Anne Tjønneland, Carmen Santiuste, Antonia Trichopoulou, Maria Wennberg, Jolanda M. A. Boer, Marcela Guevara, Cecilie Kyrø, Raul Zamora-Ros, Liher Imaz, Tilman Kühn, Marianne Uhre Jakobsen, Ulrika Ericson, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, G0800270, MR/L003120/1, Pfizer, AstraZeneca, Kræftens Bekæmpelse, DCS, Deutsches Krebsforschungszentrum, DKFZ, Centre International de Recherche sur le Cancer, CIRC, Merck Sharp and Dohme, MSD, Seventh Framework Programme, FP7: HEALTH-F2-2012-279233, National Research Council, NRC, University of Maryland School of Public Health, SPH, Medical Research Council, MRC: MC_UU_00006/1, National Institute for Health Research, NIHR, British Heart Foundation, BHF: RG/18/13/33946, RG13/13/30194, SP/09/002, Cancer Research UK, CRUK: C8221/A29017, MR/M012190/1, World Cancer Research Fund, WCRF, Imperial College London, European Research Council, ERC: 268834, Institut National de la Santé et de la Recherche Médicale, Inserm, Bundesministerium für Bildung und Forschung, BMBF, Cancerfonden, Ministerie van Volksgezondheid, Welzijn en Sport, VWS, Ligue Contre le Cancer, Vetenskapsrådet, VR, Instituto de Salud Carlos III, ISCIII, European Social Fund, ESF, Sixth Framework Programme, FP6: LSHM_CT_2006_037197, Associazione Italiana per la Ricerca sul Cancro, AIRC, Deutsche Krebshilfe, Akademi Sains Malaysia, ASM: MR/P013880/1, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, MGEN, UCLH Biomedical Research Centre, NIHR BRC: BRC-1215-20014, NIHR Imperial Biomedical Research Centre, BRC, Hellenic Health Foundation, HHF: CP15/00100, IS-BRC-1215-20014, MC_UU_00006/3, Dr Danesh reports grants, personal fees and non-financial support from Merck Sharp & Dohme, grants, personal fees, and nonfinancial support from Novartis, grants from Pfizer, and grants from AstraZeneca outside the submitted work. He is member of the International Cardiovascular and Metabolic Advisory Board for Novartis (since 2010), the Steering Committee of UK Biobank (since 2011), the MRC International Advisory Group (ING) member, London (since 2013), the MRC High Throughput Science ‘Omics Panel Member, London (since 2013), the Scientific Advisory Committee for Sanofi (since 2013), the International Cardiovascular and Metabolism Research and Development Portfolio Committee for Novartis, and the Astra Zeneca Genomics Advisory Board (2018). Dr Butterworth reports grants outside of this work from AstraZeneca, Biogen, BioMarin, Bioverativ, Merck, Novartis, Pfizer, and Sanofi and personal fees from Novartis. The remaining authors have no disclosures to report., EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270, MR/L003120/1), British Heart Foundation (BHF) (SP/09/002, RG13/13/30194, RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark), Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany), Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy), Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands), Health Research Fund– Instituto de Salud Carlos III, Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain), Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden), Cancer Research UK (14136 to EPIC-Norfolk, C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R.Z.-R. thanks the 'Miguel Servet' program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund–European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart). R.C. was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award., Steur, Marinka [0000-0002-9028-0290], Imamura, Fumiaki [0000-0002-6841-8396], Key, Timothy J [0000-0003-2294-307X], Chowdhury, Rajiv [0000-0003-4881-5690], Guevara, Marcela [0000-0001-9242-6364], Jakobsen, Marianne U [0000-0001-6518-4136], Johansson, Ingegerd [0000-0002-9227-8434], Weiderpass, Elisabete [0000-0003-2237-0128], Boer, Jolanda MA [0000-0002-9714-4304], Boutron-Ruault, Marie-Christine [0000-0002-5956-5693], Heath, Alicia K [0000-0001-6517-1300], Huybrechts, Inge [0000-0003-3838-855X], Imaz, Liher [0000-0002-3777-4953], Masala, Giovanna [0000-0002-5758-9069], Zamora-Ros, Raul [0000-0002-6236-6804], Perez-Cornago, Aurora [0000-0002-5652-356X], Tong, Tammy YN [0000-0002-0284-8959], Wareham, Nicholas J [0000-0003-1422-2993], Forouhi, Nita G [0000-0002-5041-248X], and Apollo - University of Cambridge Repository
Subjects: Saturated fat, Physiology, Coronary Disease, 030204 cardiovascular system & hematology, EPIC, Cohort Studies, 0302 clinical medicine, Medicine, Cardiac and Cardiovascular Systems, 030212 general & internal medicine, 1102 Cardiorespiratory Medicine and Haematology, 2. Zero hunger, chemistry.chemical_classification, Nutrition and Dietetics, Kardiologi, Primary prevention, Incidence, Incidence (epidemiology), Fatty Acids, Fatty acids in human nutrition, 3. Good health, Europe, Näringslära, Coronary heart disease, Dietary guidelines, Cardiology and Cardiovascular Medicine, Polyunsaturated fatty acid, Cohort study, Malalties coronàries, 03 medical and health sciences, SDG 3 - Good Health and Well-being, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Àcids grassos en la nutrició, Diseases of the circulatory (Cardiovascular) system, Humans, Nutritional epidemiology, business.industry, Nutrients, Dietary Fats, chemistry, Food, RC666-701, SPS Exercise, Nutrition and Health Sciences, business
Abstract: EPIC-CVD was supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), and the European Research Council (268834). The coordinating center was supported by core funding from the: United Kingdom MRC (G0800270; MR/L003120/1), British Heart Foundation (BHF) (SP/09/002; RG13/13/30194; RG/18/13/33946), and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC) (BRC-1215-20014).* The establishment of the study subcohort was supported by the European Union Sixth Framework Programme (grant LSHM_CT_ 2006_037197 to the InterAct project) and the MRC Epidemiology Unit (grant MC_UU_00006/1). The coordination of EPIC is financially supported by International Agency for Research on Cancer and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by NIHR Imperial BRC. The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France); German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam-Rehbruecke, Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro--AIRC--Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands (the Netherlands); Health Research Fund-Instituto de Salud Carlos III, Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), MRC (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). EPIC-Greece was supported by the Hellenic Health Foundation (Greece). M.S., N.J.W., N.G.F., and F.I. acknowledge support from MRC Epidemiology Unit (MC_UU_ 00006/1 and MC_UU_00006/3). N.J.W. and N.G.F. acknowledge support from NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215--20014) and NGF is a NIHR Senior Investigator Award holder. M.S. was also supported by BHF for part of this work while working in the BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. R. Z.-R. thanks the "Miguel Servet" program (CP15/00100) from the Institute of Health Carlos III (co-funded by the European Social Fund--European Social Fund Investing in Your Future). A.W. was supported by a BHF-Turing Cardiovascular Data Science Award and by the European Commission-Innovative Medicines Initiative (BigData@Heart).R.C.was funded by a MRC-Newton project grant to study genetic risk factors of cardiovascular disease among Southeast Asian people and the Academy of Sciences Malaysia (grant no. MR/P013880/1) and a United Kingdom Research and Innovation-Global Challenges Research Fund Project Grant to study risk factors of noncommunicable diseases in Bangladesh. J.D. holds a BHF Professorship and a NIHR Senior Investigator Award. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organization. The funders of the study had no role in study design, data collection, analysis, data interpretation, or writing of the article, or in the decision to submit for publication. M.S. had full access to all the data in the study, and M.S. and N.G.F. had final responsibility for the decision to submit for publication., BACKGROUND: There is controversy about associations between total dietary fatty acids, their classes (saturated fatty acids [SFAs], monounsaturated fatty acids, and polyunsaturated fatty acids), and risk of coronary heart disease (CHD). Specifically, the relevance of food sources of SFAs to CHD associations is uncertain. METHODS AND RESULTS: We conducted a case-cohort study involving 10 529 incident CHD cases and a random subcohort of 16 730 adults selected from a cohort of 385 747 participants in 9 countries of the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We estimated multivariable adjusted country-specific hazard ratios (HRs) and 95% CIs per 5% of energy intake from dietary fatty acids, with and without isocaloric macronutrient substitutions, using Prentice-weighted Cox regression models and pooled results using random-effects meta-analysis. We found no evidence for associations of the consumption of total or fatty acid classes with CHD, regardless of macronutrient substitutions. In analyses considering food sources, CHD incidence was lower per 1% higher energy intake of SFAs from yogurt (HR, 0.93 [95% CI, 0.88–0.99]), cheese (HR, 0.98 [95% CI, 0.96–1.00]), and fish (HR, 0.87 [95% CI, 0.75–1.00]), but higher for SFAs from red meat (HR, 1.07 [95% CI, 1.02–1.12]) and butter (HR, 1.02 [95% CI, 1.00–1.04]). CONCLUSIONS: This observational study found no strong associations of total fatty acids, SFAs, monounsaturated fatty acids, and polyunsaturated fatty acids, with incident CHD. By contrast, we found associations of SFAs with CHD in opposite directions dependent on the food source. These findings should be further confirmed, but support public health recommendations to consider food sources alongside the macronutrients they contain, and suggest the importance of the overall food matrix., European Commission Framework Programme 7 HEALTH-F2-2012-279233, European Research Council (ERC), European Commission 268834, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) G0800270 MR/L003120/1, British Heart Foundation SP/09/002 RG13/13/30194 RG/18/13/33946, National Institute for Health Research (NIHR) BRC-1215-20014, European Commission LSHM_CT_ 2006_037197, Medical Research Council UK (MRC) MC_UU_ 00006/1 MC_UU_00006/3, International Agency for Research on Cancer, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de l'Education Nationale, Institut National de la Sante et de la Recherche Medicale (France), German Cancer Aid, German Cancer Research Center, German Institute of Human Nutrition Potsdam, Rehbruecke, Federal Ministry of Education and Research (Germany), Fondazione AIRC per la ricerca sul cancro, Compagnia di San Paolo, Dutch Ministry of Public Health, Welfare and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Zorg Onderzoek Nederland, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III, Junta de Andalucia, Regional Government of Asturias, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Catalan Institute of Oncology (Spain), Swedish Cancer Society, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, Medical Research Council UK (MRC) 1000143 MR/M012190/1, Hellenic Health Foundation (Greece), NIHR* Cambridge BRC: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, British Heart Foundation, Institute of Health Carlos III (European Social Fund-European Social Fund Investing in Your Future) CP15/00100, BHF-Turing Cardiovascular Data Science Award, European Commission-Innovative Medicines Initiative (BigData@Heart), MRC-Newton project grant MR/P013880/1, United Kingdom Research and Innovation-Global Challenges Research Fund, NIHR Senior Investigator Award
Published: 2021

117. Evolution of Metabolic Phenotypes of Obesity in Coronary Patients after 5 Years of Dietary Intervention: From the CORDIOPREV Study

Author: Juan Luis Romero-Cabrera, Javier Delgado-Lista, Laura Martin-Piedra, Pablo Perez-Martinez, Raúl M. Luque, Jose Lopez-Miranda, Antonio P. Arenas de Larriva, Javier Caballero-Villarraso, Juan F. Alcala-Diaz, Jose D Torres-Peña, Francisco M. Gutierrez-Mariscal, [Martin-Piedra,L, Alcala-Diaz,JF, Gutierrez-Mariscal,FM, Arenas de Larriva,AP, Romero-Cabrera,JL, Torres-Peña,JD, Perez-Martinez,P, Lopez-Miranda,J, Delgado-Lista,J] Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba, Spain. [Martin-Piedra,L, Delgado-Lista,J] Maimonides Institute for Biomedical Research in Cordoba (IMIBIC), Córdoba, Spain. [Martin-Piedra,L, Delgado-Lista,J] Department of Medical and Surgical Sciences, Univerisity of Cordoba, Córdoba, Spain. Martin-Piedra,L, Luqye,RM, Delgado-Lista,J] CIBER in Physiopathology of Obesity and Nutrition, Instituto de Salud Carlos III, Madrid, Spain. [Caballero-Villarraso,J] Biochemical Laboratory, Maimonides Institute for Biomedical Research in Cordoba, Reina Sofia University Hospital, University of Cordoba, Córdoba, Spain. [Luque,RM] Maimonides Institute of Biomedical Research of Córdoba, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain., and The CORDIOPREV study was supported by the Fundación Patrimonio Comunal Olivarero (CORDIOPREV-CEAS, 1/2016 to Jose Lopez-Miranda). This study also received research grants from the Ministerio de Ciencia e Innovación (AGL2012-39615, AGL2015-67896-P and PID2019-104362RB-I00 to Jose Lopez-Miranda), integrated into the framework of the National Plan for Scientific Research, Technological Development and Innovation 2013–2016, co-financed by the Instituto de Salud Carlos III (ISCIII) of Spain and also by the Directorate General for Assessment and Promotion of Research and the EU’s European Regional Development Fund (FEDER). This work has been supported in part by the Spanish Government of Investigation, Development and Innovation (SAF2017-84135-R), including FEDER co-funding.
Subjects: Male, Health Care::Health Care Facilities, Manpower, and Services::Health Services::Preventive Health Services::Secondary Prevention [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Mediterranean diet, Health Status, fatty liver index, Obesidad, Physiology, Metabolically healthy obese, Diet, Mediterranean, Body Mass Index, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Weight loss, metabolically healthy obese, Medicine, TX341-641, Diet, Fat-Restricted, Metabolic Syndrome, Secondary prevention, diet intervention, Low-fat diet, coronary patients, Nutrition and Dietetics, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Diet, Mediterranean [Medical Subject Headings], metabolically unhealthy obese, Fatty liver, Middle Aged, Phenotype, Female, Dieta, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Demography::Health Status [Medical Subject Headings], medicine.symptom, Persons::Persons::Age Groups::Adult::Young Adult [Medical Subject Headings], Fenotipo, Adult, Diet intervention, Coronary patients, Diseases::Digestive System Diseases::Liver Diseases::Fatty Liver [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Mass Index [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet [Medical Subject Headings], low-fat diet, Article, Young Adult, Liver fat, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Follow-Up Studies [Medical Subject Headings], Humans, Obesity, Metabolically unhealthy obese, Obesidad metabólica benigna, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Diet, Fat-Restricted [Medical Subject Headings], Aged, Dieta con restricción de grasas, Enfermedad coronaria, Fatty liver index, Nutrition. Foods and food supply, business.industry, Hígado graso, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], medicine.disease, Dieta mediterránea, obesity metabolic phenotypes, Diet, Obesity metabolic phenotypes, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Fatty Liver, Check Tags::Female [Medical Subject Headings], business, Body mass index, Food Science
Abstract: Background: Obesity phenotypes with different metabolic status have been described previously. We analyzed metabolic phenotypes in obese coronary patients during a 5-year follow-up, and examined the factors influencing this evolution. Methods: The CORDIOPREV study is a randomized, long-term secondary prevention study with two healthy diets: Mediterranean and low-fat. All obese patients were classified as either metabolically healthy obese (MHO) or metabolically unhealthy obese (MUO). We evaluated the changes in the metabolic phenotypes and related variables after 5 years of dietary intervention. Results: Initially, 562 out of the 1002 CORDIOPREV patients were obese. After 5 years, 476 obese patients maintained their clinical and dietary visits, 71.8% of MHO patients changed to unhealthy phenotypes (MHO-Progressors), whereas the MHO patients who maintained healthy phenotypes (MHO-Non-Progressors) lost more in terms of their body mass index (BMI) and had a lower fatty liver index (FLI-score) (p &lt, 0.05). Most of the MUO (92%) patients maintained unhealthy phenotypes (MUO-Non-Responders), but 8% became metabolically healthy (MUO-Responders) after a significant decrease in their BMI and FLI-score, with improvement in all metabolic criteria. No differences were found among dietary groups. Conclusions: A greater loss of weight and liver fat is associated with a lower progression of the MHO phenotype to unhealthy phenotypes. Likewise, a marked improvement in these parameters is associated with regression from MUO to healthy phenotypes.
Published: 2021

118. Gut Microbiota Metabolism of Bile Acids Could Contribute to the Bariatric Surgery Improvements in Extreme Obesity

Author: Patricia Ruiz-Limón, Juan Alcaide, Gracia María Martín-Núñez, Eduardo Garcia-Fuentes, Luis Ocaña-Wilhelmi, Isabel Moreno-Indias, Carolina Gutiérrez-Repiso, Francisco J. Tinahones, [Ocaña-Wilhelmi,L] Departamento de Especialidades Quirúrgicas, Bioquímica e Inmunología, Universidad de Málaga, Málaga, Spain. [Ocaña-Wilhelmi,L] Unidad de Gestión Clínica de Cirugía General y del Aparato Digestivo, Hospital Universitario Virgen de la Victoria, Málaga, Spain. [Martín-Núñez,GM, Ruiz-Limón,P, Alcaide,J, Gutiérrez-Repisom,C, Tinahones,FJ, Moreno-Indias,I] Department of Endocrinology and Nutrition, Virgen de la Victoria Hospital, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga University, Málaga, Spain. [Martín-Núñez,GM, Moreno-Indias,I] Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [García-Fuentes,E] Department of Gastroenterology, Virgen de la Victoria University Hospital, Institute of Biomedical Research in Málaga (IBIMA), Málaga University, Málaga, Spain. [García-Fuentes,E] CIBER Enfermedades Hepáticas y Digestivas-CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain., GMN is supported by a grant from Ministerio de Economía, Industria y Competitivi dad ('Juan de la Cierva-Formación' contract (FJCI-2017-34349). PRL was supported by a 'Sara Borrell' postdoctoral contract (CD19/00216) from the ISCIII-Madrid (Spain), co-financed by the Fondo Europeo de Desarrollo Regional-FEDER. J.A. was supported by a 'PFIS' predoctoral contract (FI19/00177). CGR and IMI are supported by Miguel Servet program from Instituto de Salud Carlos III cofounded by Fondo Europeo de Desarrollo Regional—FEDER (CP20/00066 and CP16/00163, respectively). E.G.F. is supported by 'Nicolás Monardes' program from the Consejería de Salud de la Junta de Andalucía (C-0031-2016). This work was supported in part by grants from ISCIII cofounded by Fondo Europeo de Desarrollo Regional—FEDER, PI18/01160, CP16/00163, and as well as UMA18-FEDERJA-116 founded by Junta de Andalucía (Fondo Europeo de Desarrollo Regional-FEDER).
Subjects: Sleeve gastrectomy, medicine.medical_specialty, Microbioma gastrointestinal, medicine.drug_class, Technology and Food and Beverages::Food and Beverages::Food::Dietary Supplements::Probiotics [Medical Subject Headings], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, bariatric surgery, Veillonella, Obesidad, Chemicals and Drugs::Polycyclic Compounds::Steroids::Bile Acids and Salts [Medical Subject Headings], Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose [Medical Subject Headings], Gut microbiota, Gut flora, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Bariatrics::Bariatric Surgery [Medical Subject Headings], Biochemistry, Microbiology, digestive system, Article, Ácidos y sales biliares, Enterobacteriaceae, Weight loss, medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Digestive System Surgical Procedures::Gastrectomy [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight::Body Weight Changes::Weight Loss [Medical Subject Headings], Molecular Biology, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae [Medical Subject Headings], Cirugía bariátrica, bile acids, Bariatric surgery, biology, Bile acid, gut microbiota, business.industry, Probióticos, Metabolism, biology.organism_classification, QR1-502, Bile acids, Surgery, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Anaerobic Bacteria::Gram-Negative Anaerobic Straight, Curved, and Helical Rods::Veillonellaceae::Veillonella [Medical Subject Headings], Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity::Obesity, Morbid [Medical Subject Headings], medicine.symptom, business, Phenomena and Processes::Physiological Phenomena::Physiological Processes::Homeostasis [Medical Subject Headings], Homeostasis
Abstract: Bariatric surgery is the only procedure to obtain and maintain weight loss in the long term, although the mechanisms driving these benefits are not completely understood. In the last years, gut microbiota has emerged as one of the drivers through its metabolites, especially secondary bile acids. In the current study, we have compared the gut microbiota and the bile acid pool, as well as anthropometric and biochemical parameters, of patient with morbid obesity who underwent bariatric surgery by two different techniques, namely Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Gut microbiota populations differed after the respective procedures, particularly with respect to the Enterobacteriaceae family. Both techniques resulted in changes in the bile acids pool, but RYGB was the procedure which suffered the greatest changes, with a reduction in most of their levels. Blautia and Veillonella were the two genera that more relationships showed with secondary bile acids, indicating a possible role in their formation and inhibition, respectively. Correlations with the anthropometric and biochemical variables showed that secondary bile acids could have a role in the amelioration of the glucose and HDL-cholesterol levels. Thus, we have observed a possible relationship between the interaction of the bile acids pool metabolized by the gut microbiota in the metabolic improvements obtained by bariatric surgery in the frame of morbid obesity, deserving further investigation in greater cohorts to decipher the role of each bile acid in the homeostasis of the host for their possible use in the development of microbiota-based therapeutics, such as new drugs, postbiotics or probiotics.
Published: 2021

119. Passage Number-Induced Replicative Senescence Modulates the Endothelial Cell Response to Protein-Bound Uremic Toxins

Author: Pedro Aljama, Fatima Guerrero, Sagrario Soriano, Victoria Pulido, Juan Antonio Moreno, María José Velasco Jiménez, Teresa Obrero, Andrés Carmona, Alejandro Martin-Malo, [Guerrero,F, Carmona,A, Jimenez,MJ, Obrero,T, Pulido,V, Moreno,JA, Soriano,S, Martín-Malo,A, Aljama,P] Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Córdoba, Spain. [Guerrero,F, Aljama,P] Department of Medicine, University of Cordoba, Córdoba, Spain. [Moreno,JA] Department of Cell Biology, Physiology and Immunology, University of Cordoba, Córdoba, Spain. [Soriano,S, Martín-Malo,A] Nephrology Unit, Reina Sofia University Hospital, Córdoba, Spain. [Soriano,S, Martín-Malo,A] Spanish Renal Research Network, Institute of Health Carlos III, Madrid, Spain., and This work was supported by the Plan Nacional de I+D+ I Proyectos de Investigación en Salud of Instituto de Salud Carlos III (ISCIII), Subdirección General de Evaluación, Fondos de Desarrollo Regional (FEDER) (PI15/01785, PI17/01785, PI17/00130 and PI20/00375), Spanish Society of Nephrology (Premio Baxter 2018) and Junta de Andalucía Grants (PI-0268-2018 and PIGE-0052-2020). J.A.M. is a senior researcher supported by the Spanish Ministry of Science and Innovation (RYC-2017-22369). A.C. is supported by Consejería de Transformación Económica, Industria, Conocimiento y Universidades de la Junta de Andalucía, cofinanciado por la Unión Europea a través del Fondo Social Europeo 'FSE invierte en tu futuro' (DOC_01428). The APC was funded by Junta de Andalucía Grants (PI-0268-2018).
Subjects: Aging, senescence, Senescencia, Health, Toxicology and Mutagenesis, Endothelial cells, Cell, Envejecimiento, Toxicology, P-cresol, Umbilical vein, endothelial dysfunction, Anatomy::Cardiovascular System::Blood Vessels::Endothelium, Vascular [Medical Subject Headings], Diseases::Female Urogenital Diseases and Pregnancy Complications::Female Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Renal Insufficiency, Chronic [Medical Subject Headings], Indoxyl sulfate, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Movement [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Cresols, Cell Movement, Hidroxitolueno butilado, Endothelial dysfunction, Cellular Senescence, Anatomy::Cells::Epithelial Cells::Endothelial Cells::Human Umbilical Vein Endothelial Cells [Medical Subject Headings], Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Renal Insufficiency, Chronic [Medical Subject Headings], Chemistry, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Indoles::Indican [Medical Subject Headings], Cell migration, endothelial cells, Cell biology, Endothelial stem cell, medicine.anatomical_structure, Medicine, Senescence, Premature aging, Tóxinas urémicas, Article, p-cresol, Chemicals and Drugs::Inorganic Chemicals::Oxygen Compounds::Reactive Oxygen Species [Medical Subject Headings], Human Umbilical Vein Endothelial Cells, medicine, Humans, Renal Insufficiency, Chronic, indoxyl sulfate, aging, Células endoteliales, Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Phenols::Cresols [Medical Subject Headings], medicine.disease, Apoptosis, Endothelium, Vascular, Indican, Indicán
Abstract: Endothelial aging may be induced early in pathological situations. The uremic toxins indoxyl sulfate (IS) and p-cresol (PC) accumulate in the plasma of chronic kidney disease (CKD) patients, causing accelerated endothelial aging, increased cardiovascular events and mortality. However, the mechanisms by which uremic toxins exert their deleterious effects on endothelial aging are not yet fully known. Thus, the aim of the present study is to determine the effects of IS and PC on endothelial damage and early senescence in cultured human umbilical vein endothelial cells (HUVECs). Hence, we establish an in vitro model of endothelial damage mediated by different passages of HUVECs and stimulated with different concentrations of IS and PC to evaluate functional effects on the vascular endothelium. We observe that cell passage-induced senescence is associated with apoptosis, ROS production and decreased endothelial proliferative capacity. Similarly, we observe that IS and PC cause premature aging in a dose-dependent manner, altering HUVECs’ regenerative capacity, and decreasing their cell migration and potential to form vascular structures in vitro. In conclusion, IS and PC cause accelerated aging in HUVECs, thus contributing to endothelial dysfunction associated with CKD progression.
Published: 2021

120. Trends in gender of authors of original research in oncology among major medical journals: a retrospective bibliometric study

Author: Daniel Sánchez, Shing Fung Lee, Chi Leung Chiang, Irene Oi Ling Wong, Bizu Gelaye, Miguel Angel Luque Fernandez, Denise Shuk Ting Cheung, María José Sánchez, [Lee,SF, Chiang,CL] Department of Clinical Oncology, University of Hong Kong, Hong Kong. [Lee,SF, Chiang,CL] Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong. [Redondo Sánchez,D, Sánchez,MJ, Luque Fernandez,MA] Department of Non-Communicable Disease and Cancer Epidemiology, Instituto de Investigacion Biosanitaria de Granada (ibs.GRANADA), University of Granada, Granada, Spain. [Redondo Sánchez,D, Luque Fernandez,MA] Andalusian School of Public Health, Granada, Spain. [Redondo Sánchez,D, Luque Fernandez,MA] Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. [Sánchez,MJ] Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain. [Gelaye,B, Luque Fernandez,MA] Department of Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA. [Gelaye,B] Psychiatry, Harvard Medical School, Boston, Massachusetts, USA. [Wong,IOL] School of Public Health, University of Hong Kong, Hong Kong. [Cheung,DST] School of Nursing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong. [Luque Fernandez,MA] Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK., and MALF was supported by the Spanish National Health Institute Carlos III (Instituto de Salud Carlos III - ISCIII), Miguel Servet-I Investigator Grant/Award Number CP17/ 00206-EU-FEDER.
Subjects: Male, Health Care::Environment and Public Health::Public Health::Epidemiologic Factors::Reproductive History::Parity [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies::Retrospective Studies [Medical Subject Headings], Epidemiology, statistics & research methods, Medical Oncology, Disciplines and Occupations::Health Occupations::Medicine::Internal Medicine::Medical Oncology [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Paridad, Medicine, Oncólogos, Oncologists, General Medicine, Oncología médica, Parity, Oncology, Information Science::Information Science::Communications Media::Publications::Bibliography as Topic::Bibliometrics [Medical Subject Headings], epidemiology, Female, Periodicals as Topic, medicine.medical_specialty, Estudios de género, Check Tags::Male [Medical Subject Headings], Original research, Bibliometric, Information Science::Information Science::Communications Media::Publications::Serial Publications::Periodicals as Topic [Medical Subject Headings], Information Science::Information Science::Communication::Language::Language Arts::Writing::Authorship [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Incidence [Medical Subject Headings], Bibliometría, Humans, Statistics & research methods, Retrospective Studies, National health, business.industry, Gender, Authorship, Adult oncology, Check Tags::Female [Medical Subject Headings], Bibliometrics, Family medicine, adult oncology, Autoria, Information Science::Information Science::Information Storage and Retrieval::Databases as Topic::Databases, Bibliographic::PubMed [Medical Subject Headings], business, Disciplines and Occupations::Natural Science Disciplines::Science::Research::Biomedical Research::Outcome Assessment (Health Care) [Medical Subject Headings]
Abstract: MALF was supported by the Spanish National Health Institute Carlos III (Instituto de Salud Carlos III -ISCIII), Miguel Servet--I Investigator Grant/Award Number CP17/00206--EU--FEDER., Objective We evaluated the temporal trend in gender ratios of first and last authors in the field of oncological research published in major general medical and oncology journals and examined the gender pattern in coauthorship. Design We conducted a retrospective study in PubMed using the R package RISmed. We retrieved original research articles published in four general medical journals and six oncology specialty journals. These journals were selected based on their impact factors and popularity among oncologists. We identified the names of first and last authors from 1 January 2002 to 31 December 2019. The gender of the authors was identified and validated using the Gender API database (https:// gender-api. com/). Primary and secondary outcome measures The percentages of first and last authors by gender and the gender ratios (male to female) and temporal trends in gender ratios of first and last authors were determined. Results We identified 34 624 research articles, in which 32 452 had the gender of both first and last authors identified. Among these 11 650 (33.6%) had women as the first author and 7908 (22.8%) as the last author, respectively. The proportion of female first and last authors increased from 26.6% and 16.2% in 2002, to 32.9% and 27.5% in 2019, respectively. However, the gender ratio (male to female) of first and last authors decreased by 1.5% and 2.6% per year, respectively, which were statistically significant (first author: incidence rate ratio (IRR) 0.98, 95% CI 0.97 to 1.00; last author: IRR 0.97, 95% CI 0.96 to 0.99). Male first and last authorship was the most common combination. Male–female and female– female pairs increased by 2.0% and 5.0%, respectively (IRR 1.02, 95% CI 1.01 to 1.03 and IRR 1.05, 95% CI 1.04 to 1.06, respectively). Conclusions The continued under-representation of women means that more efforts to address parity for advancement of women in academic oncology are needed., Spanish National Health Institute Carlos III (Instituto de Salud Carlos III -ISCIII) CP17/00206--EU--FEDER
Published: 2021

121. Real-Life Impact of Glucocorticoid Treatment in COVID-19 Mortality: A Multicenter Retrospective Study

Author: Muñoz-Gómez, Ana, Fernández-Cruz, Ana, Lavilla-Olleros, Cristina, Giner-Galvañ, Vicente, Ausín-García, Cristina, Wikman, Philip, Bendala-Estrada, Alejandro D., Vargas, Juan A., Rubio-Rivas, Manuel, Laureiro, Jaime, Fernández-Bermúdez, Daniel, Buonaiuto, Verónica A., Larriva, Antonio P. Arenas de, Pascual-Pérez, María de los Reyes, Alcalá-Pedrajas, José N., Ruiz, Ane Labirua-Iturburu, Hernández-Milián, Almudena, Mazo, Marta Gómez del, Antequera, Beatriz, Mella-Pérez, Carmen, Navas-Alcántara, María de la Sierra, Soto-Delgado, Juan F., Gámez-Mancera, Rosa M., Sardiña-González, Cristina, Meijide-Míguez, Héctor, Ramos-Rincón, José M., Gómez-Huelgas, Ricardo, Network, on behalf of the SEMI-COVID-19 Network on behalf of the SEMI-COVID-19, [Muñoz-Gómez,A] Internal Medicine Department, Hospital de Parla, Madrid, Spain. [Fernández-Cruz,A] Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro—Segovia de Arana, Madrid, Spain. [Lavilla-Olleros,C, Ausín-García,C, Bendala-Estrada,AD] Internal Medicine Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain. [Giner-Galvañ,V, Wikman,P] Internal Medicine Department, Hospital Clínico Universitario de Sant Joan d’Alacant, Fundación para el Fomento de la Investigación Sanitaria y Biomédica en la Comunidad Valenciana (FISABIO), Alicante, Spain. [Vargas,JA] Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Instituto de Investigación Sanitaria Puerta de Hierro—Segovia de Arana, Madrid, Spain. [Rubio-Rivas,M] Department of Internal Medicine, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain. [Laureiro,J] Doce de Octubre University Hospital, Madrid, Spain. [Fernández-Bermúdez,D] Internal Medicine Department, Costa del Sol Hospital, Marbella, Spain. [Buonaiuto,VA, and Gómez-Huelgas R] Internal Medicine Department, Regional University Hospital of Málaga, Biomedical Research Institute of Málaga (IBIMA), University of Málaga (UMA), Málaga, Spain. [Arenas de Larriva,AP] Lipids and Atherosclerosis Unit, Department of Internal Medicine, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Reina Sofia University Hospital, University of Córdoba, Córdoba, Spain. [Arenas de Larriva,AP] CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Pascual-Pérez,MLR] Internal Medicine Department, University General Hospital of Elda, Alicante, Spain. [Alcalá-Pedrajas,JN] Internal Medicine Department, Pozoblanco Regional Hospital, Córdoba, Spain. [Labirua-Iturburu Ruiz,A] Santa Marina Hospital, Bilbao, Spain. [Hernández-Milián,A] Internal Medicine Department, Son Llàtzer University Hospital, Palma de Mallorca, Spain. [Gómez Del Mazo,M] Internal Medicine Department, San Pedro Hospital, Logroño, Spain. [Antequera,B] Internal Medicine Department, Sagunto Hospital, Valencia, Spain. [Mella-Pérez,C] Universitary Hospital Complex of Ferrol, A Coruña, Spain. [Navas-Alcántara,MS] Internal Medicine Department, Infanta Margarita Hospital, Cabra, Córdoba, Spain. [Soto-Delgado,JF] Internal Medicine Department, University Hospital of Salamanca, Salamanca, Spain. [Gámez-Mancera,RM] Internal Medicine Department, University Hospital Virgen del Rocío, Sevilla, Spain. [Sardiña-González,C] Internal Medicine Department, Monforte de Lemos Public Hospital, Lugo, Spain. [Meijide-Míguez,H] Internal Medicine Department, Quironsalud Hospital, A Coruña, Spain. [Ramos-Rincón,JM] Department of Clinical Medicine, Miguel Hernandez University of Elche, Alicante, Spain.
Subjects: medicine.medical_specialty, ARDS, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies::Retrospective Studies [Medical Subject Headings], medicine.medical_treatment, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Confidence Intervals [Medical Subject Headings], Article, Steroid, corticosteroids, Estudios retrospectivos, Diseases::Respiratory Tract Diseases::Respiration Disorders::Respiratory Insufficiency [Medical Subject Headings], Internal medicine, medicine, Mortalitat, Mortality, Glucocorticoides, Corticoesteroides, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospitals [Medical Subject Headings], Chemicals and Drugs::Polycyclic Compounds::Steroids [Medical Subject Headings], business.industry, SARS-CoV-2, COVID-19, Retrospective cohort study, General Medicine, medicine.disease, mortality, Diseases::Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [Medical Subject Headings], Confidence interval, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Propensity Score [Medical Subject Headings], Cortisone, body regions, Pneumonia, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Adrenal Cortex Hormones::Glucocorticoids [Medical Subject Headings], Respiratory failure, Cortisona, Mortalidad, Propensity score matching, Diseases::Respiratory Tract Diseases::Respiration Disorders::Respiratory Distress Syndrome, Adult [Medical Subject Headings], Medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Mortality::Hospital Mortality [Medical Subject Headings], business, Glucocorticoid, medicine.drug
Abstract: We aimed to determine the impact of steroid use in COVID-19 in-hospital mortality, in a retrospective cohort study of the SEMICOVID19 database of admitted patients with SARS-CoV-2 laboratory-confirmed pneumonia from 131 Spanish hospitals. Patients treated with corticosteroids were compared to patients not treated with corticosteroids, and adjusted using a propensity-score for steroid treatment. From March–July 2020, 5.262 (35.26%) were treated with corticosteroids and 9.659 (64.73%) were not. In-hospital mortality overall was 20.50%, it was higher in patients treated with corticosteroids than in controls (28.5% versus 16.2%, OR 2.068 [95% confidence interval, 1.908 to 2.242], p = 0.0001), however, when adjusting by occurrence of ARDS, mortality was significantly lower in the steroid group (43.4% versus 57.6%, OR 0.564 [95% confidence interval, 0.503 to 0.633], p = 0.0001). Moreover, the greater the respiratory failure, the greater the impact on mortality of the steroid treatment. When adjusting these results including the propensity score as a covariate, in-hospital mortality remained significantly lower in the steroid group (OR 0.774 [0.660 to 0.907], p = 0.002). Steroid treatment reduced mortality by 24% relative to no steroid treatment (RRR 0.24). These results support the use of glucocorticoids in COVID-19 in this subgroup of patients.
Published: 2021
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122. Elevated Anti-SARS-CoV-2 Antibodies and IL-6, IL-8, MIP-1β, Early Predictors of Severe COVID-19

Author: Vasso Skouridou, Ana Serna-Gallego, Manuel Crespo, Ezequiel Ruiz-Mateos, Alexandre Pérez, Alicia Gutierrez-Valencia, Esperanza Muñoz-Muela, Ciara K. O'Sullivan, Maria Trujillo-Rodriguez, María M Bobillo, Cristina Martínez, Jorge Julio Cabrera-Alvar, Lucia Patiño, Irene Vieitez, Eva Poveda, Mariluz Botero-Gallego, Helena Codina, [Codina,H, Patiño,L, Bobillo,MM, Pérez,A, Poveda,E] Group of Virology and Pathogenesis, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVigo, Vigo, Spain. [Vieitez,I] Rare Diseases & Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-Uvigo, Vigo, Spain. [Gutierrez-Valencia,A, Serna-Gallego,A, Trujillo-Rodríguez,M, Muñoz-Muela,E, Ruiz-Mateos,E] Clinic Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, IBiS, Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain. [Skouridou,V, Botero-Gallego,M, O’Sullivan,CK] INTERFIBIO Consolidated Research Group, Departament d’ Enginyeria Quimica, Universitat Rovira i Virgili, Tarragona, Spain. [Martínez,C] Methodology and Statistics Unit, Galicia Sur Health Research Institute (IIS Galicia Sur)-Complexo Hospitalario Universitario de Vigo, SERGAS-UVigo, Vigo, Spain. [Pérez,A, Crespo,M] Infectious Diseases Unit, Department of Internal Medicine, Complexo Hospitalario Universitario de Vigo, IIS Galicia Sur, SERGAS-UVigo, Vigo, Spain. [Cabrera-Alvar,JJ] Microbiology Service, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-Uvigo, Vigo, Spain. [O'Sullivan,CK] Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain., This work was supported by the Plan Estatal de I+D+I 2013-2016 and 2017–2020 and cofinanced by the Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación y Fomento de la investigación del Fondo Europeo de Desarrollo Regional (FEDER), Fondo COVID19 of Instituto de Salud Carlos III (COV20/00698), RETICS, Red de Investigación en SIDA [RD16/0025/0026], and Fundación Biomédica Galicia Sur. E.R-M. was supported by the Spanish Research Council (CSIC) and by the research grant CV20-85418 from the Consejería de Transformación Económica, Industria, Conocimiento y Universidades (Junta de Andalucía). A.P. was supported by the Instituto de Salud Carlos III, Subprograma Rio Hortega (CM20/00243). A.G.-V. was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund ('A way to achieve Europe'), Subprograma Miguel Servet (CP19/00159). E.M.M. was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund ('A way to achieve Europe'), Subprogram PFIS (FI19/00304). C.K. was supported by Fondo COVID19 of Instituto de Salud Carlos III (COV20/00823)., Instituto de Salud Carlos III, European Commission, Fundación Biomédica Galicia Sur, Consejo Superior de Investigaciones Científicas (España), Junta de Andalucía, Vieitez, Irene [0000-0001-9241-0207], Poveda, Eva [0000-0003-4835-9875], Vieitez, Irene, Poveda, Eva, Red Española de Investigación en SIDA, Martínez, Cristina, Trujillo-Rodríguez, María, Muñoz-Muela, Esperanza, Pérez-González, Alexandre, Cabrera-Alvar, Jorge Julio, Martínez, Cristina [0000-0002-9073-3464], Trujillo-Rodríguez, María [0000-0002-4716-4294], Muñoz-Muela, Esperanza [0000-0002-5432-986X], Pérez-González, Alexandre [0000-0003-4836-6768], and Cabrera-Alvar, Jorge Julio [0000-0002-0397-0868]
Subjects: Phenomena and Processes::Physical Phenomena::Mechanical Phenomena::Kinetics [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interleukins::Interleukin-6 [Medical Subject Headings], severe COVID-19, Disease, Gastroenterology, law.invention, Persistence (computer science), Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], law, Diagnosis, Viral load, Biology (General), Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interleukins::Interleukin-8 [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin M [Medical Subject Headings], biology, Diagnóstico, Anti-SARS-CoV-2 antibodies, Citocinas, Intensive care unit, viral load, Cytokines, Antibody, anti-SARS-CoV-2 antibodies, Microbiology (medical), medicine.medical_specialty, Anticuerpos, QH301-705.5, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interleukins::Interleukin-1 [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Microbiology, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospital Units::Intensive Care Units [Medical Subject Headings], Article, Proinflammatory cytokine, Immune system, Virology, Internal medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Follow-Up Studies [Medical Subject Headings], medicine, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Viral [Medical Subject Headings], Interleukin 8, Interleukin 6, Beta (finance), Severe COVID-19, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin A [Medical Subject Headings], business.industry, SARS-CoV-2, COVID-19, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Diseases::Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [Medical Subject Headings], cytokines, Carga viral, Check Tags::Female [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Microbiological Techniques::Viral Load [Medical Subject Headings], biology.protein, RNA, business, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Blood Proteins::Immunoproteins::Immunoglobulins::Antibodies::Immunoglobulin Isotypes::Immunoglobulin G [Medical Subject Headings]
Abstract: Viral and host immune kinetics during acute COVID-19 and after remission of acute symptoms need better characterization. SARS-CoV-2 RNA, anti-SARS-CoV-2 IgA, IgM, and IgG antibodies, and proinflammatory cytokines were measured in sequential samples from hospitalized COVID-19 patients during acute infection and six months following diagnosis. Twenty four laboratory confirmed COVID-19 patients with mild/moderate and severe COVID-19 were included. Most were males (83%) with a median age of 61 years. Twenty one percent were admitted to the intensive care unit (ICU) and eight of them (33.3%) met the criteria for severe COVID-19 disease. A delay in SARS-CoV-2 levels’ decline during the first six days of follow up, and viral load persistence until month 3 were related to severe COVID-19, but not viral load levels at the diagnosis. Higher levels of anti-SARS-CoV-2 IgA, IgM, IgG and the cytokines IL-6, IL-8 and MIP-1β at the diagnosis time were related to the severe COVID-19 outcome. Higher levels of MIP-1β, IL-1β, MIP-1α and IFN-γ were observed at month 1 and 3 during mild/moderate disease, compared to severe COVID-19. IgG persisted at low levels after six months of diagnosis. In conclusion, higher concentrations of IgA, IgM, and IgG, and IL-6, IL-8 and MIP-1β are identified as early predictors of COVID-19 severity, whereas no significant association is found between baseline SARS-COV-2 viral load and COVID-19 severity., This work was supported by the Plan Estatal de I+D+I 2013-2016 and 2017–2020 and cofinanced by the Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación y Fomento de la investigación del Fondo Europeo de Desarrollo Regional (FEDER), Fondo COVID19 of Instituto de Salud Carlos III (COV20/00698), RETICS, Red de Investigación en SIDA [RD16/0025/0026]; and Fundación Biomédica Galicia Sur. E.R-M. was supported by the Spanish Research Council (CSIC) and by the research grant CV20-85418 from the Consejería de Transformación Económica, Industria, Conocimiento y Universidades (Junta de Andalucía). A.P. was supported by the Instituto de Salud Carlos III, Subprograma Rio Hortega (CM20/00243). A.G.-V. was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (CP19/00159). E.M.M. was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), Subprogram PFIS (FI19/00304). C.K. was supported by Fondo COVID19 of Instituto de Salud Carlos III (COV20/00823).
Published: 2021

123. Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease

Author: Antonio Membrives, Elsa Maymó-Masip, Jurga Laurencikiene, Elena Moreno-Caño, Oriol A. Rangel-Zuñiga, Mikael Rydén, Joan Vendrell, José Manuel Fernández-Real, Rocío Guzmán-Ruiz, Julia Sánchez-Ceinos, Sonia Fernández-Veledo, Juan Luis Romero-Cabrera, Raúl M. Luque, María M. Malagón, Jose Lopez-Miranda, Jaime López-Alcalá, Pablo Perez-Martinez, Mercedes del Rio-Moreno, [Sánchez-Ceinos,J, Guzmán-Ruiz,R, López-Alcalá,J, Moreno-Caño,E, Malagón,MM] Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain. [Sánchez-Ceinos,J, Rangel-Zúñiga,OA, Del Río-Moreno,M, Fernández-Real,JM, Luque,RM, López-Miranda,J, Malagón,MM] CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain. [Rangel-Zúñiga,OA, Romero-Cabrera,JL, Pérez-Martínez,P, López-Miranda,J] Lipids and Atherosclerosis Unit, Department of Internal Medicine, IMIBIC, Córdoba, Spain. [Del Río-Moreno,M, Luque,RM] OncObesity and Metabolism Group. Department of Cell Biology, Physiology and Immunology, IMIBIC/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain. [Maymo-Masip,E, Vendrell,J, Fernández-Veledo,S] CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERdem), Instituto de Salud Carlos III, Madrid, Spain. [Maymo-Masip,E, Fernández-Veledo,S] Hospital Universitari de Tarragona Joan XXIII, Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgil, Tarragona, Spain. [Fernández-Real,JM] Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, and Eumetabolism and Health Group, Girona Biomedical Research Institute (IdibGi), Girona, Spain. [Laurencikiene,J, Rydén,M] Lipid Laboratory. Department of Medicine Huddinge/Karolinska Institute (KI)/Karolinska University Hospital, Stockholm, Sweden. [Membrives,A] Unidad de Gestión Clínica de Cirugía General y Digestivo, Sección de Obesidad, Reina Sofia University Hospital, Córdoba, Spain., Ministerio de Ciencia, Innovación y Universidades/FEDER (BFU2013-44229‐R, BFU2016‐76711‐R, BFU2017‐90578‐REDT to MMM, RTI2018-093919-B-I00 to SF-V), Consejería de Salud y Bienestar Social/Junta de Andalucía/FEDER (PI‐0200/2013 to MMM, PI‐0159‐2016 to RG‐R), Instituto de Salud Carlos III (ISCIII)/FEDER (PIE14/00005 to JL‐M and MMM, PI16/00264 to RML, PI17/0153 to JV), Fondo de Investigación Sanitaria/ISCIII/FEDER Miguel Servet tenure-track program (CP10 /00438, CPII16/00008 to SF-V), Research Plan of University of Córdoba (Mod 2.5, 2019 to RG-R), Co-funded by European Regional Development Fund/European Social Fund 'Investing in your future', and and Consejería de Economía, Conocimiento, Empresas y universidad/Junta de Andalucía/FEDER (BIO-0139). CIBEROBN is an initiative of the ISCIII, Spain.
Subjects: Male, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation [Medical Subject Headings], Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Proteostasis Deficiencies [Medical Subject Headings], obesity-related metabolic diseases, RNA splicing, Expansión de tejido, Obesidad, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation::Adipogenesis [Medical Subject Headings], Metabolic disease, Adipose tissue, UPR, ER-proteostasis, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings], Adipocyte, Adipocytes, Biology (General), Adipogenesis, General Neuroscience, Cell Differentiation, General Medicine, Middle Aged, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Reconstructive Surgical Procedures::Tissue Expansion [Medical Subject Headings], Enfermedades metabólicas, Anatomy::Cells::Connective Tissue Cells::Adipocytes [Medical Subject Headings], Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Medicine, Female, Research Article, Human, Adult, preadipocytes, medicine.medical_specialty, Spliceosome, QH301-705.5, mRNA, Science, Biology, Protein degradation, General Biochemistry, Genetics and Molecular Biology, Cell Line, Insulin resistance, Internal medicine, Adipocitos, medicine, Humans, RNA, Messenger, Obesity, Persons::Persons::Age Groups::Adult [Medical Subject Headings], General Immunology and Microbiology, ARN mensajero, Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], Cell Biology, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [Medical Subject Headings], Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases [Medical Subject Headings], ERAD, medicine.disease, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Proteostasis, Endocrinology, Diabetes Mellitus, Type 2, chemistry, Tissue expansion
Abstract: Preadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we aimed at identifying the pathogenic processes underlying impaired adipocyte differentiation in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). We report that down-regulation of a key member of the major spliceosome, PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery of PRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of endoplasmic reticulum (ER)-associated protein degradation (ERAD) hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.
Published: 2021

124. Comorbid autoimmune diseases and burden of diabetes-related complications in patients with type 1 diabetes from a Mediterranean area

Author: Gabriel Gimenez-Perez, Bogdan Vlacho, Elena Navas, Manel Mata-Cases, Jordi Real, Xavier Cos, Josep Franch-Nadal, Didac Mauricio, [Gimenez-Perez G] Endocrinology Section, Department of Medicine, Hospital General de Granollers, Granollers, Spain. School of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain. [Vlacho B] DAP‑Cat group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. Institut de Recerca Hospital de la Santa Creu i Sant Pau (IIBSantPau), Barcelona, Spain. [Navas E] DAP‑Cat group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. [Mata-Cases M] DAP‑Cat group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain. Primary Health Care Center La Mina, Gerència d’Atenció Primària Barcelona Ciutat, Institut Català de la Salut, Sant Adrià de Besòs, Spain. [Real J] DAP‑Cat group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. Primary Health Care Center La Mina, Gerència d’Atenció Primària Barcelona Ciutat, Institut Català de la Salut, Sant Adrià de Besòs, Spain. [Cos X] DAP‑Cat group, Unitat de Suport a la Recerca Barcelona, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Barcelona, Spain. Primary and Hospital Innovation Department, Innovation Office at Institut Català de la Salut, Barcelona, Spain, and Hospital General de Granollers
Subjects: fenómenos del sistema inmunitario::inmunidad::autoinmunidad [FENÓMENOS Y PROCESOS], Diabetis, enfermedades del sistema endocrino::diabetes mellitus::complicaciones de la diabetes [ENFERMEDADES], Autoimmunitat, Immune System Phenomena::Immunity::Autoimmunity [PHENOMENA AND PROCESSES], Endocrine System Diseases::Diabetes Mellitus::Diabetes Complications [DISEASES], Endocrinology, Diabetes and Metabolism, Myocardial Ischemia, Immune System Diseases::Autoimmune Diseases::Diabetes Mellitus, Type 1 [DISEASES], Type 1 diabetes mellitus, Sucre - Control, Autoimmunity, General Medicine, Autoimmune Diseases, Diabetes Complications, Glycemic control, Cross-Sectional Studies, Diabetes Mellitus, Type 1, Logistic Models, Endocrinology, Diabetes complications, enfermedades del sistema inmune::enfermedades autoinmunes::diabetes mellitus tipo I [ENFERMEDADES], Internal Medicine, Humans, Female
Abstract: Autoimmunity; Glycemic control; Type 1 diabetes mellitus; Autoinmunidad; Control Glicémico; Diabetes mellitus tipo 1 Autoimmunitat; Control glucèmic; Diabetis mellitus tipus 1 Aim: To assess the prevalence of autoimmune diseases (AID) in patients with type 1 diabetes (T1D) and to evaluate whether the rate of diabetes-related complications differs depending on the presence of AID. Methods: Cross-sectional analysis of 13,570 T1D patients aged ≥ 18 years registered in the SIDIAP database. The association between AID and diabetes-related complications was assessed by multivariable logistic regression models. Results: The prevalence of AID was 18.3% with thyroid AID being the most common. Patients with T1D and AID were more often female and their current age, age of diabetes onset and diabetes duration were higher. Patients with only thyroid AID experienced a lower risk of peripheral artery disease (odds ratio [OR] = 0.51, 95%; confidence interval [CI] 0.31 to 0.81) and kidney disease (OR = 0.68, 95%; 95% CI 0.54 to 0.85), whereas patients with other AID had an increased risk of ischemic heart disease (OR = 1.48, 95%; 95% CI 1.04 to 2.06). Conclusions: The burden of diabetes-related complications in patients with T1D differs according to the type of additional AID. The presence of diabetes complications is lower in those with autoimmune thyroid disease while the presence of other AID is associated with higher rates of ischemic heart disease.
Published: 2022

125. Lifestyle changes and mental health during the COVID-19 pandemic: A repeated, cross-sectional web survey

Author: Susana Gomes-da-Costa, Cristina Esteban, Beatriz Atienza-Carbonell, Eduard Vieta, Rafael Tabarés-Seisdedos, María Paz García-Portilla, Vicent Balanzá-Martínez, Iñaki Zorrilla, Benedicto Crespo-Facorro, Ana González-Pinto, M. Jose Jaen-Moreno, Raquel Brandini De Boni, Fernando Sarramea, Jose Cervera-Martínez, Teresa Bobes-Bascarán, Jurema Corrêa da Mota, Flávio Kapczinski, [Cervera-Martinez, Jose] Hosp Denia Marina Salud, Alicante, Spain, [Cervera-Martinez, Jose] Univ Valencia, Dept Med, Valencia, Spain, [Atienza-Carbonell, Beatriz] Univ Valencia, Dept Med, Valencia, Spain, [Mota, Jurema C.] Oswaldo Cruz Fdn FIOCRUZ, Inst Sci & Technol Commun & Informat Hlth ICICT, Rio De Janeiro, Brazil, [De Boni, Raquel B.] Oswaldo Cruz Fdn FIOCRUZ, Inst Sci & Technol Commun & Informat Hlth ICICT, Rio De Janeiro, Brazil, [Bobes-Bascaran, Teresa] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Crespo-Facorro, Benedicto] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Paz Garcia-Portilla, Maria] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Gonzalez-Pinto, Ana] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Sarramea, Fernando] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Vieta, Eduard] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Zorrilla, Inaki] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Tabares-Seisdedos, Rafael] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Balanza-Martinez, Vicent] Ctr Invest Biomed Red Salud Mental CIBERSAM, Madrid, Spain, [Bobes-Bascaran, Teresa] Inst Invest Sanitaria Principado Asturias ISPA, Serv Salud Principado Asturias SESPA, Oviedo, Spain, [Paz Garcia-Portilla, Maria] Inst Invest Sanitaria Principado Asturias ISPA, Serv Salud Principado Asturias SESPA, Oviedo, Spain, [Bobes-Bascaran, Teresa] Univ Oviedo, Dept Psychol, Oviedo, Spain, [Crespo-Facorro, Benedicto] Hosp Univ Virgen del Rocio, IBIS, Seville, Spain, [Esteban, Cristina] Hosp Univ Virgen del Rocio, IBIS, Seville, Spain, [Crespo-Facorro, Benedicto] Univ Seville, Seville, Spain, [Paz Garcia-Portilla, Maria] Univ Oviedo, Sch Med, Dept Psychiat, Oviedo, Spain, [Gomes-da-Costa, Susana] Univ Barcelona, Hosp Clin, Inst Neurosci, IDIBAPS, Barcelona, Catalonia, Spain, [Vieta, Eduard] Univ Barcelona, Hosp Clin, Inst Neurosci, IDIBAPS, Barcelona, Catalonia, Spain, [Gonzalez-Pinto, Ana] Univ Basque Country, Hosp Univ Alava BIOARABA, Vitoria, Spain, [Zorrilla, Inaki] Univ Basque Country, Hosp Univ Alava BIOARABA, Vitoria, Spain, [Jaen-Moreno, M. Jose] Inst Maimonides Invest Biomed Cordoba IMIBIC, Cordoba, Spain, [Sarramea, Fernando] Inst Maimonides Invest Biomed Cordoba IMIBIC, Cordoba, Spain, [Jaen-Moreno, M. Jose] Univ Cordoba, Dept Ciencias Morfol & Sociosanitarias, Cordoba, Spain, [Sarramea, Fernando] Univ Cordoba, Hosp Univ Reina Sofia, Cordoba, Spain, [Tabares-Seisdedos, Rafael] Univ Valencia, Dept Med, Teaching Unit Psychiat & Psychol Med, Blasco Ibanez 15, Valencia 46010, Spain, [Balanza-Martinez, Vicent] Univ Valencia, Dept Med, Teaching Unit Psychiat & Psychol Med, Blasco Ibanez 15, Valencia 46010, Spain, [Kapczinski, Flavio] McMaster Univ, Dept Psychiat & Behav Neurosci, Mood Disorders Program, St Josephs Healthcare Hamilton, Hamilton, ON, Canada, [Kapczinski, Flavio] Univ Fed Rio Grande Sul UFRGS, Inst Nacl Ciencia & Tecnol Translac Med INCT TM, Dept Psychiat, Porto Alegre, RS, Brazil, Instituto de Salud Carlos III, ISCIII, Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Spanish Ministry of Science and Innovation, Plan Nacional de I+D+I - Fondo Europeo de Desarrollo Regional (FEDER), Instituto de Salud Carlos III, CIBER of Mental Health (CIBERSAM), Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement, CERCA Programme, and Departament de Salut de la Generalitat de Catalunya for the PERIS grant
Subjects: Web survey, Lifestyle Mental health, Population, Alcohol abuse, Anxiety, External validity, Social support, Self-rated health, Surveys and Questionnaires, Pandemic, Lockdown, medicine, Humans, Life Style, Pandemics, Exercise, Depression (differential diagnoses), Psychiatry, Resilience, business.industry, SARS-CoV-2, Depression, Prevention, COVID-19, General population, medicine.disease, Lifestyle, Mental health, Psychiatry and Mental health, Clinical Psychology, Cross-Sectional Studies, Mental Health, Scale (social sciences), Communicable Disease Control, medicine.symptom, business, Sleep, Demography, Research Paper
Abstract: VBM acknowledges the national grant PI16/01770 from the Instituto de Salud Carlos III, ISCIII (The PROBILIFE study). EV thanks the support of the Spanish Ministry of Science and Innovation (PI15/00283, PI18/00805) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM) (...), Cervera-Martínez, J., Atienza-Carbonell, B., Mota, J.C., Bobes-Bascarán, T., Crespo-Facorro, B., Esteban, C., García-Portilla, M.P., Gomes-da-Costa, S., González-Pinto, A., Jaén-Moreno, M.J., Sarramea, F., Vieta, E., Zorrilla, I., Tabarés-Seisdedos, R., Kapczinski, F., De Boni, R.B., Balanzá-Martínez, V.
Published: 2021

126. Effects of the Topical Administration of Semaglutide on Retinal Neuroinflammation and Vascular Leakage in Experimental Diabetes

Author: Olga Simó-Servat, Hugo Ramos, Patricia Bogdanov, Jordi Huerta, Cristina Hernández, Rafael Simó, Institut Català de la Salut, [Simó R, Bogdanov P, Ramos H, Simó-Servat O, Hernández C] Unitat de Recerca en Diabetis i Metabolisme, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain. [Huerta J] Unitat de Recerca en Diabetis i Metabolisme, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, medicine.medical_specialty, retina, QH301-705.5, Medicine (miscellaneous), Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], 030209 endocrinology & metabolism, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Retinal ganglion, Article, General Biochemistry, Genetics and Molecular Biology, Retina, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Diabetic retinopathy, Diabetes mellitus, Internal medicine, medicine, Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Experimental [DISEASES], afecciones patológicas, signos y síntomas::procesos patológicos::inflamación [ENFERMEDADES], Biology (General), Db/db mouse, semaglutide, business.industry, Semaglutide, Retinal, db/db mouse, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [DISEASES], Pharmaceutical Preparations::Solutions::Pharmaceutical Solutions::Ophthalmic Solutions [CHEMICALS AND DRUGS], medicine.disease, Intercellular adhesion molecule, Retinopatia diabètica - Tractament, enfermedades nutricionales y metabólicas::enfermedades metabólicas::trastornos del metabolismo de la glucosa::diabetes mellitus::diabetes mellitus experimental [ENFERMEDADES], Db/db Mouse, diabetic retinopathy, Diabetis - Tractament, 030104 developmental biology, medicine.anatomical_structure, Endocrinology, Farmacologia ocular, preparados farmacéuticos::soluciones::soluciones farmacéuticas::soluciones oftálmicas [COMPUESTOS QUÍMICOS Y DROGAS], chemistry, business
Abstract: Background: An unexpected increase in the rate of severe diabetic retinopathy was observed in the Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN)-6 clinical trial. Although this effect was attributed to a rapid decrease in blood glucose levels, a direct deleterious effect of semaglutide on the retina could not be ruled out. In order to shed light on this issue, we have performed a study aimed at testing the direct effect of semaglutide administered by eye drops on retinal neuroinflammation and microvascular abnormalities using the db/db mouse model. Methods: Eye drops containing semaglutide (0.33 mg/mL, 5 μL once/daily) or vehicle (PBS, 5 μL once daily) were administered for 15 days. Results: We found that semaglutide significantly reduced glial activation, as well as the retinal expression of Nuclear factor kB (NF-κB), proinflammatory cytokines (IL-1β, IL-6, IL-18) and Intercellular Adhesion Molecule (ICAM)-1. In addition, semaglutide prevented the apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway. Finally, a dramatic decrease in vascular leakage was observed in db/db mice treated with semaglutide. All these findings were observed without any change in blood glucose levels and, therefore, can be directly attributed to semaglutide. Conclusions: These experimental findings point to a beneficial rather than a deleterious effect of semaglutide on the retina of subjects with diabetes.
Published: 2021

127. Bisphenol A Modulates Autophagy and Exacerbates Chronic Kidney Damage in Mice

Author: Emilio González Parra, Sebastian Mas, José Luis Morgado-Pascual, Alberto Ruiz Priego, Sandra Rayego-Mateos, Marta Ruiz-Ortega, [Priego,AR, Parra,EG, Mas,S] Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-UAM/IRSIN, Madrid, Spain. [Morgado-Pascual,JL] Cellular Biology, Physiology and Immunology Department, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, Cordoba, Spain. [Ruiz-Ortega,M, Rayego-Mateos,S] Molecular and Cellular Biology in Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid Faculty of Medicine, Madrid, Spain., This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI17/00119, PI20/00140, DTS20/00083, PI16/01298, Red de Investi gación Renal REDINREN: RD16/0009 to M.R-O), Comunidad Autónoma de Madrid FEDER-a way to build Europe (B2017/BMD-3751 NOVELREN-CM to M.R-O), Juan de la Cierva incorporacion grant: IJC2018-035187-I to S.R-M, Juan de la Cierva de Formacion grant: FJC2019-042028-I to J.M-P and Fundacion Conchita Rabago grant to A.R.P, 'Convocatoria Dinamización Europa Investigación 2019' MINECO (EIN2019-103294 to M.R-O and SR-M), and Innovation programme under the Marie Skłodowska-Curie grant of the European Union’s Horizon 2020 (IMProve-PD ID: 812699) to M.R-O and Sociedad Española de Nefrologia to S.R-M
Subjects: Male, 0301 basic medicine, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings], Autophagosome maturation, 030232 urology & nephrology, Riñón, Apoptosis, Anatomy::Urogenital System::Urinary Tract::Kidney::Nephrons::Kidney Tubules [Medical Subject Headings], Kidney, medicine.disease_cause, Diseases::Female Urogenital Diseases and Pregnancy Complications::Female Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Renal Insufficiency, Chronic [Medical Subject Headings], Antioxidants, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Antioxidants [Medical Subject Headings], Mice, 0302 clinical medicine, Bisphenol A, Organisms::Eukaryota::Animals [Medical Subject Headings], oxidative stress, Biology (General), Phenomena and Processes::Metabolic Phenomena::Metabolism::Oxidative Stress [Medical Subject Headings], Spectroscopy, Chemistry, Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney Diseases [Medical Subject Headings], Estrés oxidativo, General Medicine, Computer Science Applications, Kidney Tubules, medicine.anatomical_structure, Female, Kidney Diseases, MAP1LC3B, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, endocrine system, autophagy, QH301-705.5, ATG5, Autofagia, Article, Catalysis, Cell Line, Proinflammatory cytokine, Inorganic Chemistry, 03 medical and health sciences, Phenols, Bisfenol A glicidil metacrilato, Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Phenols [Medical Subject Headings], Internal medicine, medicine, Animals, Humans, Benzhydryl Compounds, Renal Insufficiency, Chronic, Physical and Theoretical Chemistry, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Autophagy [Medical Subject Headings], Molecular Biology, QD1-999, Inflamación, urogenital system, Organic Chemistry, Autophagy, fibrosis, Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Benzhydryl Compounds [Medical Subject Headings], medicine.disease, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death::Apoptosis [Medical Subject Headings], Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Endocrinology, inflammation, Oxidative stress, Kidney disease
Abstract: BACKGROUND: Bisphenol A (BPA) is a ubiquitous environmental toxin that accumulates in chronic kidney disease (CKD). Our aim was to explore the effect of chronic exposition of BPA in healthy and injured kidney investigating potential mechanisms involved. METHODS: In C57Bl/6 mice, administration of BPA (120 mg/kg/day, i.p for 5 days/week) was done for 2 and 5 weeks. To study BPA effect on CKD, a model of subtotal nephrectomy (SNX) combined with BPA administration for 5 weeks was employed. In vitro studies were done in human proximal tubular epithelial cells (HK-2 line). RESULTS: Chronic BPA administration to healthy mice induces inflammatory infiltration in the kidney, tubular injury and renal fibrosis (assessed by increased collagen deposition). Moreover, in SNX mice BPA exposure exacerbates renal lesions, including overexpression of the tubular damage biomarker Hepatitis A virus cellular receptor 1 (Havcr-1/KIM-1). BPA upregulated several proinflammatory genes and increased the antioxidant response [Nuclear factor erythroid 2-related factor 2 (Nrf2), Heme Oxygenase-1 (Ho-1) and NAD(P)H dehydrogenase quinone 1 (Nqo-1)] both in healthy and SNX mice. The autophagy process was modulated by BPA, through elevated autophagy-related gene 5 (Atg5), autophagy-related gene 7 (Atg7), Microtubule-associated proteins 1A/1B light chain 3B (Map1lc3b/Lc3b) and Beclin-1 gene levels and blockaded the autophagosome maturation and flux (p62 levels). This autophagy deregulation was confirmed in vitro. CONCLUSIONS: BPA deregulates autophagy flux and redox protective mechanisms, suggesting a potential mechanism of BPA deleterious effects in the kidney.
Published: 2021
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128. Gut Microbiota: The Missing Link Between Helicobacter pylori Infection and Metabolic Disorders?

Author: Isabel Cornejo-Pareja, Gracia M. Martin-Nuñez, Mercedes Clemente-Postigo, Francisco J. Tinahones, [Martin-Nuñez,GM, Cornejo-Pareja,I, Tinahones,FJ] Unidad de Gestión Clínica de Endocrinología y Nutrición (Hospital Universitario Virgen de la Victoria), Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Martin-Nuñez,GM, Clemente-Postigo,M, Tinahones,FJ] Centro de Investigación Biomédica en Red (CIBER) Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Clemente-Postigo,M] Department of Cell Biology, Physiology and Immunology. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)-Reina Sofia University Hospital, University of Cordoba, Córdoba, Spain., GMM-N was supported by a Juan de la Cierva, Formación contract (FJCI-2017-34349, Ministerio de Ciencia, Innovación y Universidades, and Spain). MC-P was recipient of a postdoctoral
Subjects: 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Antibiotics, Chronic gastritis, Gut flora, metabolic diseases, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Nonalcoholic fatty liver disease, Organisms::Eukaryota::Animals [Medical Subject Headings], Metabolismo, diabetes, biology, Phenomena and Processes::Metabolic Phenomena::Metabolism::Biological Transport::Protein Transport [Medical Subject Headings], Chemicals and Drugs::Carbohydrates::Glycosides::Glucosides [Medical Subject Headings], eradication therapy for Helicobacter pylori, Anti-Bacterial Agents, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Carbohydrate Metabolism [Medical Subject Headings], Enfermedades metabólicas, Protein Transport, Carbohydrate Metabolism, 030211 gastroenterology & hepatology, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Dysbiosis [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [Medical Subject Headings], Peptic Ulcer, Microbioma gastrointestinal, medicine.drug_class, Proton-pump inhibitor, Diseases of the endocrine glands. Clinical endocrinology, Helicobacter Infections, 03 medical and health sciences, Diabetes mellitus, medicine, Animals, Humans, Diseases::Bacterial Infections and Mycoses::Bacterial Infections::Gram-Negative Bacterial Infections::Helicobacter Infections [Medical Subject Headings], Helicobacter pylori, gut microbiota, business.industry, Sequence Analysis, DNA, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases [Medical Subject Headings], RC648-665, medicine.disease, biology.organism_classification, Anatomy::Digestive System::Gastrointestinal Tract::Upper Gastrointestinal Tract::Stomach::Gastric Mucosa [Medical Subject Headings], Gastrointestinal Microbiome, Glucose, 030104 developmental biology, Gastric Mucosa, Immunology, Dysbiosis, business, metabolism, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Hemorrhage::Gastrointestinal Hemorrhage::Peptic Ulcer Hemorrhage [Medical Subject Headings]
Abstract: Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects approximately 4.4 billion individuals worldwide. Although the majority of infected individuals remain asymptomatic, this bacterium colonizes the gastric mucosa causing the development of various clinical conditions as peptic ulcers, chronic gastritis and gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphomas, but complications are not limited to gastric ones. Extradigestive pathologies, including metabolic disturbances such as diabetes, obesity and nonalcoholic fatty liver disease, have also been associated with H. pylori infection. However, the underlying mechanisms connecting H. pylori with extragastric metabolic diseases needs to be clarified. Notably, the latest studies on the topic have confirmed that H. pylori infection modulates gut microbiota in humans. Damage in the gut bacterial community (dysbiosis) has been widely related to metabolic dysregulation by affecting adiposity, host energy balance, carbohydrate metabolism, and hormonal modulation, among others. Taking into account that Type 2 diabetic patients are more prone to be H. pylori positive, gut microbiota emerges as putative key factor responsible for this interaction. In this regard, the therapy of choice for H. pylori eradication, based on proton pump inhibitor combined with two or more antibiotics, also alters gut microbiota composition, but consequences on metabolic health of the patients has been scarcely explored. Recent studies from our group showed that, despite decreasing gut bacterial diversity, conventional H. pylori eradication therapy is related to positive changes in glucose and lipid profiles. The mechanistic insights explaining these effects should also be addressed in future research. This review will deal with the role of gut microbiota as the linking factor between H. pylori infection and metabolic diseases, and discussed the impact that gut bacterial modulation by H. pylori eradication treatment can also have in host’s metabolism. For this purpose, new evidence from the latest human studies published in more recent years will be analyzed.
Published: 2021

129. Selective inhibition of monoacylglycerol lipase is associated with passive coping behavior and attenuation of stress-induced dopamine release in the medial prefrontal cortex

Author: Benjamin F. Cravatt, David G. Stouffer, Marisa Roberto, Ilham Polis, Rémi Martin-Fardon, Loren H. Parsons, Antonia Serrano, Francisco Javier Pavón, Fernando Rodríguez de Fonseca, [Pavón,FJ, Polis,IY, Stouffer,DG, Roberto,M, Martin-Fardon,R, Parsons,LH, Serrano,A] Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA. [Pavón,FJ, Rodríguez de Fonseca,F, Serrano,A] Unidad de Gestión Clínica de Salud Mental, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain. [Pavón,FJ] CIBERCV-Instituto de Salud Carlos III and Unidad de Gestión Clínica del Corazón, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain. [Cravatt,BF] Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA., This work was supported by the following funding sources and grants: the National Institute on Alcohol Abuse and Alcoholism (AA020404, AA022249, AA024146 and AA026999 to RMF, AA006420 to RMF and MR, AA017447 and AA015566 to MR), Pearson Center for Alcoholism and Addiction Research, Instituto de Salud Carlos III (ISCIII) and European Regional Development Funds-European Union (ERDF-EU) [Subprograma RETICS Red de Trastornos Adictivos (RD16/0017/0001), Ministerio de Economía y Competitividad (PI16/01953, PI16/01698, PI17/02026, PI19/01577 and PI19/00886)], Ministerio de Sanidad and Delegacion ´ del Gobierno para el Plan Nacional sobre Drogas (PND2017/ 043, PND2018/044 and PND2018/033), and and Junta de Andalucía and ERDF-EU [Consejería de Economía, Innovacion ´ y Ciencia (CTS-433 and CTS-1052) and Servicio Andaluz de Salud (C1-0049-2019)]. AS and FJP hold a 'Miguel Servet' research contract funded by ISCIII and ERDF-EU (CPII19/00031 and CPII19/00022, respectively). This is article number 29846 from The Scripps Research Institute.
Subjects: Mouse, Physiology, Ratones, Dopamine, Microdialysis, 2-Arachidonoylglycerol, Dopamina, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Fatty acid amide hydrolase, Chemicals and Drugs::Biological Factors::Inflammation Mediators::Autacoids::Serotonin [Medical Subject Headings], Original Research Article, JZL184, QP351-495, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], Psychiatry and Psychology::Behavior and Behavior Mechanisms::Adaptation, Psychological [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Carboxylic Ester Hydrolases::Monoacylglycerol Lipases [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immobilization::Restraint, Physical::Hindlimb Suspension [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Central Nervous System Agents::Central Nervous System Depressants::Tranquilizing Agents::Anti-Anxiety Agents [Medical Subject Headings], lipids (amino acids, peptides, and proteins), Anatomy::Nervous System::Central Nervous System::Brain::Prosencephalon::Telencephalon::Cerebrum::Cerebral Cortex::Frontal Lobe::Prefrontal Cortex [Medical Subject Headings], psychological phenomena and processes, RC321-571, Neurophysiology and neuropsychology, medicine.medical_specialty, Neurosciences. Biological psychiatry. Neuropsychiatry, Stress-coping behavior, 03 medical and health sciences, Cellular and Molecular Neuroscience, Internal medicine, medicine, Chemicals and Drugs::Lipids::Fatty Acids::Endocannabinoids [Medical Subject Headings], RC346-429, Psychiatry and Psychology::Behavior and Behavior Mechanisms::Emotions::Anxiety [Medical Subject Headings], Molecular Biology, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Endocrine and Autonomic Systems, Tail suspension test, 030227 psychiatry, Monoacylglycerol lipase, Microdiálisis, chemistry, Neurology. Diseases of the nervous system, 030217 neurology & neurosurgery, JZL195, Behavioural despair test
Abstract: The endocannabinoid system is involved in the regulation of the stress response, but the relative contribution of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their mechanisms have to be elucidated. In this study, we compared the effects of the pharmacological inhibition of the two major endocannabinoid-degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively] on stress-coping [forced swim test (FST) and tail suspension test (TST)] and anxiety-like [elevated-plus maze (EPM) and light-dark test (LDT)] behaviors in wild-type and FAAH knockout mice. In vivo microdialysis estimated the effects of FAAH and MAGL inhibition on dopamine (DA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) during an FST. Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle. Our data showed that PF-3845 increased latency to immobility and decreased total immobility time in FST, but no effects were observed in TST compared with vehicle-treated wild-type mice. By contrast, JZL184 decreased latency and increased immobility in TST and FST. JZL195 in wild-type mice and JZL184 in FAAH knockout mice reproduced the same passive coping behaviors as JZL184 in wild-type mice in TST and FST. In the microdialysis experiment, FST was associated with increased DA and 5-HT levels in the mPFC. However, JZL184-treated wild-type mice displayed a significant attenuation of forced swim stress-induced DA release compared with vehicle-treated wild-type mice and PF-3845-treated wild-type mice. Finally, FAAH and/or MAGL inhibitors induced robust and consistent anxiolytic-like effects in EPM and LDT. These results suggested differences between FAAH and MAGL inhibition in stress-coping behaviors. Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress., Highlights • FAAH and/or MAGL inhibition induce opposite changes in stress-coping behaviors. • MAGL inhibition increases passive stress-coping behaviors in mice. • Passive stress-coping behaviors are regulated by 2-AG rather than AEA signaling. • MAGL inhibition attenuates mPFC dopamine increase in the forced swim test. • FAAH and/or MAGL inhibitors are associated with anxiolytic-like effects.
Published: 2021

130. Stroke-induced immunosuppression: implications for the prevention and prediction of post-stroke infections

Author: Faura, J, Bustamante, A, Miro-Mur, F, Montaner, J, [Faura,J, Montaner,J] Neurovascular Research Laboratory, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain. [Bustamante,A] Stroke Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain. [Miró-Mur,F] Systemic Autoimmune Research Unit, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain. [Montaner,J] Stroke Research Program, Institute of Biomedicine of Seville, IBiS/Hospital Universitario Virgen del Rocío/CSIC/University of Seville & Department of Neurology, Hospital Universitario Virgen de la Macarena, Seville, Spain., and This project received funding from Instituto de Salud Carlos III (ISCIII) [PI17/02130], co-financed by the European Regional Development Fund (FEDER), and from Fundació La Marató de TV3 [201706]. Neurovascular Research La boratory takes part into the Spanish stroke research network INVICTUS+[RD16/0019/0021].
Subjects: Inflammation, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines [Medical Subject Headings], Infecciones, Inflamación, Anatomy::Hemic and Immune Systems::Blood::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes [Medical Subject Headings], Pneumonia, Diseases::Respiratory Tract Diseases::Respiratory Tract Infections::Pneumonia [Medical Subject Headings], Anatomy::Respiratory System::Lung [Medical Subject Headings], Accidente cerebrovascular, Anatomy::Hemic and Immune Systems::Immune System::Phagocytes::Neutrophils [Medical Subject Headings], Terapia de inmunosupresión, Stroke, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Anatomy::Cells::Phagocytes::Monocytes [Medical Subject Headings], Biomarcadores, Diseases::Bacterial Infections and Mycoses::Infection [Medical Subject Headings], Neumonía, Organisms::Eukaryota::Animals [Medical Subject Headings], Diseases::Cardiovascular Diseases::Vascular Diseases::Cerebrovascular Disorders::Stroke [Medical Subject Headings], Infection, Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings], Immunosuppression, Biomarkers
Abstract: Stroke produces a powerful inflammatory cascade in the brain, but also a suppression of the peripheral immune system, which is also called stroke-induced immunosuppression (SIIS). The main processes that lead to SIIS are a shift from a lymphocyte phenotype T-helper (Th) 1 to a Th2 phenotype, a decrease of the lymphocyte counts and NK cells in the blood and spleen, and an impairment of the defense mechanisms of neutrophils and monocytes. The direct clinical consequence of SIIS in stroke patients is an increased susceptibility to stroke-associated infections, which is enhanced by clinical factors like dysphagia. Among these infections, stroke-associated pneumonia (SAP) is the one that accounts for the highest impact on stroke outcome, so research is focused on its early diagnosis and prevention. Biomarkers indicating modifications in SIIS pathways could have an important role in the early prediction of SAP, but currently, there are no individual biomarkers or panels of biomarkers that are accurate enough to be translated to clinical practice. Similarly, there is still no efficient therapy to prevent the onset of SAP, and clinical trials testing prophylactic antibiotic treatment and beta -blockers have failed. However, local immunomodulation could open up a new research opportunity to find a preventive therapy for SAP. Recent studies have focused on the pulmonary immune changes that could be caused by stroke similarly to other acquired brain injuries. Some of the traits observed in animal models of stroke include lung edema and inflammation, as well as inflammation of the bronchoalveolar lavage fluid.
Published: 2021

131. Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming

Author: Julie A. Chowen, Jesús Aranda, Patricia Rivera, Lourdes Sánchez-Salido, Rubén Tovar, Antonio Vargas, Juan Suárez, Laura González-González, Fernando Rodríguez de Fonseca, [Tovar,R, Vargas,A, Aranda,J, Sánchez-Salido,L, González-González,L, Rodríguez de Fonseca,F, Suárez,J, Rivera,P] Instituto de Investigación Biomédica de Málaga-IBIMA, Málaga, Spain. [Tovar,R, Rivera,P] UGC Salud Mental, Hospital Regional Universitario de Málaga, Málaga, Spain. [Tovar,R, Aranda,J] Andalucia Tech, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Chowen,JA] Department of Endocrinology, Instituto de Investigación Biomédica la Princesa, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Madrid, Spain. [Chowen,JA] CIBEROBN (Centro de Investigación Biomédica en Red Sobre Fisiopatología de la Obesidad y Nutrición), Instituto de Salud Carlos III, Madrid, Spain. [Chowen,JA] IMDEA Food Institute, CEI UAM + CSIC, Madrid, Spain. [Suárez,J] Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Universidad de Málaga, Málaga, Spain., This research was funded by European Regional Development Funds-European Union (ERDF-EU) and Instituto de Salud Carlos III (ISCIII), grant numbers CP19/00068 and PI19/00343, and Consejería de Economía, Conocimien to y Universidad, Junta de Andalucía, grant number P18-TP 5194. J.S. (CPII17/00024) holds a 'Miguel Servet II' research contract from the National System of Health, EU-ERDF-ISCIII. P.R. (CP19/00068) holds a 'Miguel Servet I' research contract from the National System of Health, ISCIII (CD19/00068), co-funded by ESF ('Investing in your future').
Subjects: Astrocitos, 0301 basic medicine, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Newborn [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], Energy homeostasis, Metabolismo de los lípidos, 0302 clinical medicine, Phenomena and Processes::Metabolic Phenomena::Metabolism::Lipid Metabolism [Medical Subject Headings], Pregnancy, lipid metabolism, Organisms::Eukaryota::Animals [Medical Subject Headings], Atención perinatal, Gliosis, Biology (General), hypothalamus, endocannabinoid system, Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Reproductive Physiological Processes::Reproduction::Pregnancy [Medical Subject Headings], Spectroscopy, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Caloric Restriction [Medical Subject Headings], chemistry.chemical_classification, Brain, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], General Medicine, Perinatal programming, Endocannabinoid system, Computer Science Applications, Chemistry, Endocannabinoides, Hypothalamus, Gestation, Female, Signal Transduction, medicine.medical_specialty, QH301-705.5, Offspring, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Physical Examination::Body Constitution::Body Weights and Measures::Body Size::Body Weight [Medical Subject Headings], Biology, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Internal medicine, medicine, Animals, RNA, Messenger, Chemicals and Drugs::Lipids::Fatty Acids::Endocannabinoids [Medical Subject Headings], Physical and Theoretical Chemistry, QD1-999, Molecular Biology, Caloric Restriction, Inflammation, Body Weight, Organic Chemistry, Anatomy::Cells::Neuroglia::Astrocytes [Medical Subject Headings], astrocytes, Caloric theory, Lipid metabolism, Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], perinatal programming, Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hypothalamus [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Gliosis [Medical Subject Headings], Rats, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats [Medical Subject Headings], 030104 developmental biology, Enzyme, Endocrinology, Animals, Newborn, Gene Expression Regulation, Check Tags::Female [Medical Subject Headings], chemistry, Astrocytes, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings], Hipotálamo, 030217 neurology & neurosurgery, Endocannabinoids
Abstract: Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.
Published: 2021

132. In-Hospital Coronary Revascularization Rates and Post-Discharge Mortality Risk in Non–ST-Segment Elevation Acute Coronary Syndrome

Author: Stuart J. Pocock, Nicolas Danchin, Stephen W.L. Lee, Yong Huo, Jesús Medina, Héctor Bueno, Xavier Rossello, Frans Van de Werf, Chee Tang Chin, Fundación AstraZeneca, Fundación ProCNIC, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Bristol-Myers Squibb, Novartis, Instituto de Salud Carlos III - ISCIII, and Novartis Farmaceutica S.A.
Subjects: Male, medicine.medical_specialty, Acute coronary syndrome, Time Factors, medicine.medical_treatment, 030204 cardiovascular system & hematology, Risk Assessment, 03 medical and health sciences, Percutaneous Coronary Intervention, 0302 clinical medicine, Internal medicine, Antithrombotic, Humans, Medicine, ST segment, Prospective Studies, 030212 general & internal medicine, Acute Coronary Syndrome, Prospective cohort study, Survival rate, Aged, business.industry, Mortality rate, Percutaneous coronary intervention, Middle Aged, medicine.disease, Patient Discharge, Hospitalization, Survival Rate, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Risk assessment
Abstract: The relationship between in-hospital coronary revascularization rate (CRR) and post-discharge mortality rates in survivors of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) at a system level is unclear. The purpose of this study was to evaluate CRR and 2-year post-discharge mortality rate (2YMR) in NSTE-ACS. CRR and 2YMR were analyzed by hospital rate of CRR (in deciles), by country, and by world region in 11,931 patients with NSTE-ACS who survived to discharge and were enrolled in the EPICOR (long-tErm follow uP of antithrombotic management patterns In acute CORonary syndrome patients) and EPICOR Asia: twin multinational, observational, prospective cohort studies. Significant differences in patient baseline characteristics, medical therapies, CRR, and 2YMR were found. Mean CRR ranged from 0.0% to 96.8% in the first and tenth decile, respectively (p
Published: 2019

133. Short- and medium-term air pollution exposure, plasmatic protein levels and blood pressure in children

Author: Paula de Prado-Bert, Charline Warembourg, Audrius Dedele, Barbara Heude, Eva Borràs, Eduard Sabidó, Gunn Marit Aasvang, Johanna Lepeule, John Wright, Jose Urquiza, Kristine B. Gützkow, Léa Maitre, Leda Chatzi, Maribel Casas, Marina Vafeiadi, Mark J. Nieuwenhuijsen, Montserrat de Castro, Regina Grazuleviciene, Rosemary R.C. McEachan, Xavier Basagaña, Martine Vrijheid, Jordi Sunyer, Mariona Bustamante, Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), CIBER de Epidemiología y Salud Pública (CIBERESP), Universitat Pompeu Fabra [Barcelona] (UPF), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Vytautas Magnus University - Vytauto Didziojo Universitetas (VDU), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Barcelona Institute of Science and Technology (BIST), Norwegian Institute of Public Health [Oslo] (NIPH), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), University of Bradford, University of Crete [Heraklion] (UOC), Keck School of Medicine [Los Angeles], University of Southern California (USC), The study received funding from the European Community's Seventh Framework Programme (FP7/2007–206) (grant agreement no 308333) (HELIX project), the H2020-EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583) (ATHLETE project) and from the European Union’s Horizon 2020 research and innovation programme (grant Agreement number: 733206) (Early Life stressors and Lifecycle Health (LIFECYCLE)). BiB received funding from the Welcome Trust (WT101597MA), from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/1), and the National Institute for Health Research (NIHR) Applied Research Collaboration for Yorkshire and Humber. The EDEN study was supported by Foundation for medical research (FRM), National Agency for Research (ANR), National Institute for Research in Public health (IRESP: TGIR cohorte santé 2008 program), French Ministry of Health (DGS), French Ministry of Research, INSERM Bone and Joint Diseases National Research (PRO-A), and Human Nutrition National Research Programs, Paris-Sud University, Nestlé, French National Institute for Population Health Surveillance (InVS), French National Institute for Health Education (INPES), the European Union FP7 programmes (FP7/2007–2013, HELIX, ESCAPE, ENRIECO, Medall projects), Diabetes National Research Program (through a collaboration with the French Association of Diabetic Patients (AFD)), French Agency for Environmental Health Safety (now ANSES), Mutuelle Générale de l’Education Nationale a complementary health insurance (MGEN), French national agency for food security, French-speaking association for the study of diabetes and metabolism (ALFEDIAM). INMA was supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research. The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV. 2007.1.2.2.2. Project No 211250 Escape, EU FP7-2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV. 2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX), and the Greek Ministry of Health (Program of Prevention of obesity and neurodevelopmental disorders in preschool children, in Heraklion district, Crete, Greece: 2011–2014, and 'Rhea Plus': Primary Prevention Program of Environmental Risk Factors for Reproductive Health, and Child Health: 2012–15). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128). JU is supported by Spanish regional program PERIS (Ref.: SLT017/20/000119) Granted by Departament de Salut de la Generalitat de Catalunya. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013–2016 from the Instituto de Salud Carlos III (ISCIII). Before the start of HELIX, all six cohorts had undergone the required evaluation by national ethics committees and obtained all the required permissions for their cohort recruitment and follow-up visits. The work in HELIX was covered by new ethic approvals in each country and at enrolment in the new follow-up, participants were asked to sign a new informed consent form.
Subjects: Plasmatic proteins, Air Pollutants, Short-term effects, Aire -- Contaminació, [SDV]Life Sciences [q-bio], Nitrogen Dioxide, Blood Pressure, Environmental Exposure, Environment, Pressió sanguínia, Childhood, [SDE.ES]Environmental Sciences/Environmental and Society, Biochemistry, Air Pollution, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Particulate Matter, Child, Infants, Proteïnes, General Environmental Science
Abstract: Exposure to air pollution influences children's health, however, the biological mechanisms underlying these effects are not completely elucidated. We investigated the association between short- and medium-term outdoor air pollution exposure with protein profiles and their link with blood pressure in 1170 HELIX children aged 6-11 years. Different air pollutants (NO2, PM10, PM2.5, and PM2.5abs) were estimated based on residential and school addresses at three different windows of exposure (1-day, 1-week, and 1-year before clinical and molecular assessment). Thirty-six proteins, including adipokines, cytokines, or apolipoproteins, were measured in children's plasma using Luminex. Systolic and diastolic blood pressure (SBP and DBP) were measured following a standardized protocol. We performed an association study for each air pollutant at each location and time window and each outcome, adjusting for potential confounders. After correcting for multiple-testing, hepatocyte growth factor (HGF) and interleukin 8 (IL8) levels were positively associated with 1-week home exposure to some of the pollutants (NO2, PM10, or PM2.5). NO2 1-week home exposure was also related to higher SBP. The mediation study suggested that HGF could explain 19% of the short-term effect of NO2 on blood pressure, but other study designs are needed to prove the causal directionality between HGF and blood pressure. The study received funding from the European Community’s Seventh Framework Programme (FP7/2007–206) (grant agreement no 308333) (HELIX project), the H2020-EU.3.1.2. - Preventing Disease Programme (grant agreement no 874583) (ATHLETE project) and from the European Union’s Horizon 2020 research and innovation programme (grant Agreement number: 733206) (Early Life stressors and Lifecycle Health (LIFECYCLE)). BiB received funding from the Welcome Trust (WT101597MA), from the UK Medical Research Council (MRC) and Economic and Social Science Research Council (ESRC) (MR/N024397/ 1). The study was supported by the European Union FP7 programmes (FP7/ 2007–2013, HELIX, ESCAPE, ENRIECO, Medall projects). INMA was supported by grants from the Instituto de Salud Carlos III, CIBERESP, and the Generalitat de Catalunya-CIRIT. KANC was funded by the grant of the Lithuanian Agency for Science Innovation and Technology (6-04-2014_31V-66). The Rhea project was financially supported by European projects (EU FP6-2003-Food-3-NewGeneris, EU FP6. STREP Hiwate, EU FP7 ENV. 2007.1.2.2.2. Project No 211250 Escape, EU FP7- 2008-ENV-1.2.1.4 Envirogenomarkers, EU FP7-HEALTH-2009- single stage CHICOS, EU FP7 ENV. 2008.1.2.1.6. Proposal No 226285 ENRIECO, EU- FP7- HEALTH-2012 Proposal No 308333 HELIX). MC received funding from Instituto Carlos III (Ministry of Economy and Competitiveness) (CD12/00563 and MS16/00128). JU is supported by Spanish regional program PERIS (Ref.: SLT017/20/ 000119) Granted by Departament de Salut de la Generalitat de Catalunya. The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013–2016 from the Instituto de Salud Carlos III (ISCIII)
Published: 2022

134. Control of Genome Stability by EndoMS/NucS-Mediated Non-Canonical Mismatch Repair

Author: Cebrián-Sastre, Esmeralda, Martín-Blecua, Isabel, Gullón, Sonia, Blázquez, Jesús, Castañeda-García, Alfredo, [Cebrián-Sastre,E, Martín-Blecua,I, Gullón,S, Blázquez,J, Castañeda-García,A] Centro Nacional de Biotecnología, Department of Microbial Biotechnology, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain. [Martín-Blecua,I] Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain., This work was supported by Plan Nacional de I + D + i 2013–2016, SAF2015-72793-EXP from the Spanish Ministry of Science and Competitiveness (MINECO)-FEDER, the Instituto de Salud Carlos III (ISCIII), grant FIS PI17/00159 (ISCIII/FEDER, UE), and JPI-AMR- MTI4MDR-TB funded by the Spanish Ministerio de Ciencia e Innovación, grant PCI2019-103488. E.C.-S. was the recipient of a PFIS predoctoral research fellowship (FI18/00036) co-funded by the Instituto de Salud Carlos III and the European Social Fund. I.M.-B. was funded by the Spanish Network for Research in Infectious Diseases, and grant REIPI RD16/0016/0009, co-financed by the European Development Regional Fund ‘A Way to Achieve Europe’ and by Operative Program Intelligent Growth 2014-2020. A.C.-G. was supported by grant project SEV-2017-0712 (CNB02) funded by Severo Ochoa program.
Subjects: Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Mutación, Antibiotic resistance, Reparación de la incompatibilidad de ADN, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Bacterial Proteins [Medical Subject Headings], Hypermutation, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Genomic Instability [Medical Subject Headings], ADN, EndoMS/NucS, Farmacorresistencia microbiana, Phenomena and Processes::Microbiological Phenomena::Drug Resistance, Microbial [Medical Subject Headings], Mycobacterium tuberculosis, Organisms::Bacteria::Gram-Positive Bacteria::Actinobacteria [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Mutation Rate [Medical Subject Headings], Actinobacteria, Inestabilidad genómica, Non-canonical mismatch repair, Organisms::Bacteria::Gram-Positive Bacteria::Actinobacteria::Actinomycetales::Mycobacteriaceae::Mycobacterium::Mycobacterium tuberculosis [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation::Base Pair Mismatch [Medical Subject Headings], Genome stability, Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Repair::DNA Mismatch Repair [Medical Subject Headings]
Abstract: The DNA repair endonuclease EndoMS/NucS is highly conserved in Archaea and Actinobacteria. This enzyme is able to recognize and cleave dsDNA carrying a mismatched base pair, and its activity is enhanced by the interaction with the sliding clamp of the replisome. Today, EndoMS/NucS has been established as the key protein of a non-canonical mismatch repair (MMR) pathway, acting specifically in the repair of transitions and being essential for maintaining genome stability. Despite having some particularities, such as its lower activity on transversions and the inability to correct indels, EndoMS/NucS meets the main hallmarks of a MMR. Its absence leads to a hypermutator phenotype, a transition-biased mutational spectrum and an increase in homeologous recombination. Interestingly, polymorphic EndoMS/NucS variants with a possible effect in mutation rate have been detected in clinical isolates of the relevant actinobacterial pathogen Mycobacterium tuberculosis. Considering that MMR defects are often associated with the emergence of resistant bacteria, the existence of EndoMS/NucS-defective mutators could have an important role in the acquisition of antibiotic resistance in M. tuberculosis. Therefore, a further understanding of the EndoMS/NucS-mediated non-canonical MMR pathway may reveal new strategies to predict and fight drug resistance. This review is focused on the recent progress in NucS, with special emphasis on its effect on genome stability and evolvability in Actinobacteria. Yes
Published: 2021

135. A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer's Disease, the 5XFAD Mouse

Author: Juan Antonio Navarro, Cristina Rosell-Valle, Antonio J. López-Gambero, Carlos Sanjuan, Patricia Rivera, Antonio Vargas, Juan Suárez, Dina Medina-Vera, Fernando Rodríguez de Fonseca, [López-Gambero,AJ, Rosell-Valle,C, Medina-Vera,D, Navarro,JA, Vargas,A, Rivera,P, Rodríguez de Fonseca,F, Suárez,J] Instituto de investigación Biomédica de Málaga-IBIMA, Málaga, Spain. [López-Gambero,AJ, Rodríguez de Fonseca,F] UGC Salud Mental, Hospital Regional Universitario de Málaga, Málaga, Spain. [López-Gambero,AJ, Medina-Vera,D] Departamento de Biología Celular, Genética y Fisiología, Universidad de Málaga, Andalucia Tech, Málaga, Spain. [Medina-Vera,D, Suárez,J] Facultad de Medicina, Universidad de Málaga, Andalucia Tech, Málaga, Spain. [Medina-Vera,D] UGC Corazón, Hospital Universitario Virgen de la Victoria, Málaga, Spain. [Sanjuan,C] EURONUTRA S.L, Parque Tecnológico de Andalucía, Campanillas, Spain. [Suárez,J] Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Universidad de Málaga, Málaga, Spain, This research was funded by the European Regional Development Funds-European Union (ERDF-EU) and Fatzheimer project EULAC-HEALTH H2020, grant number EULACH16/T010131, Ministerio de Economía, Industria y Competitividad, Gobierno de España, grant number RTC-2016-4983-1, EU-ERDF and Instituto de Salud Carlos III (ISCIII), grant numbers PI19/01577 and PI19/00343, Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas, grant numbers 2019/040 and 2020/048, and Consejería de Transformación Económica, Industria, Conocimiento y Universidades, Junta de Andalucía, grant number P18-TP-5194. J.S. (CPII17/00024) holds a 'Miguel Servet II' research contract from the National System of Health, EU-ERDF-ISCIII. P.R. (CP19/00068) holds a 'Miguel Servet I' research contract from the National System of Health, EU-ERDF-ISCIII. D.M-V. (FI20/00227) holds a 'PFIS' predoctoral contract from the National System of Health, EU-ERDF-ISCIII. A.J.L.-G. (IFI18/00042) holds an 'iPFIS' predoctoral contract from the National System of Health, EU-ERDF-ISCIII.
Subjects: Male, Leptin, medicine.medical_treatment, Plaque, Amyloid, Mice, 0302 clinical medicine, Polipéptido inhibidor gástrico, energy expenditure, Organisms::Eukaryota::Animals [Medical Subject Headings], Insulin, Resistin, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic [Medical Subject Headings], Biology (General), hypothalamus, Metabolismo energético, Spectroscopy, Enfermedades neuroinflamatorias, digestive, oral, and skin physiology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Amyloid::Amyloidogenic Proteins [Medical Subject Headings], Brain, General Medicine, 5xFAD, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Peptide Hormones::Pancreatic Hormones::Insulins [Medical Subject Headings], Ghrelin, Amyloid, medicine.medical_specialty, QH301-705.5, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interleukins::Interleukin-1 [Medical Subject Headings], Hypothalamus, Check Tags::Male [Medical Subject Headings], Resistencia a la insulina, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Adipokines::Resistin [Medical Subject Headings], Article, Inorganic Chemistry, 03 medical and health sciences, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin Resistance [Medical Subject Headings], Leptina, Alzheimer Disease, Diseases::Pathological Conditions, Signs and Symptoms::Pathological Conditions, Anatomical::Plaque, Amyloid [Medical Subject Headings], Ghrelina, Molecular Biology, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Gastric Inhibitory Polypeptide [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Amyloid beta-Peptides [Medical Subject Headings], Body weight, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases [Medical Subject Headings], medicine.disease, Orexin, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Amyloid::Amyloidogenic Proteins::Amyloid beta-Protein Precursor [Medical Subject Headings], 030104 developmental biology, Endocrinology, Resistina, Check Tags::Female [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::TOR Serine-Threonine Kinases [Medical Subject Headings], 030217 neurology & neurosurgery, 0301 basic medicine, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Amyloid [Medical Subject Headings], Orexinas, neuroinflammation, Amyloid beta-Protein Precursor, Neuroinflammation, Glucagon-Like Peptide 1, Enfermedad de Alzheimer, Phenomena and Processes::Digestive System and Oral Physiological Phenomena::Digestive System Physiological Phenomena::Digestive System Processes::Eating [Medical Subject Headings], Gastric inhibitory polypeptide, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Agouti-Related Protein [Medical Subject Headings], Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Gastrointestinal Hormones::Proglucagon::Glucagon-Like Peptides::Glucagon-Like Peptide 1 [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Serine-Threonine Kinases::AMP-Activated Protein Kinases [Medical Subject Headings], Computer Science Applications, Insulin signaling, Chemistry, Female, Factor de transcripción STAT5, Alzheimer’s disease, hormones, hormone substitutes, and hormone antagonists, Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings], Amyloidogenic Proteins, Mice, Transgenic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal::Disease Models, Animal [Medical Subject Headings], Gastric Inhibitory Polypeptide, Catalysis, Proteínas sustrato del receptor de insulina, Insulin resistance, Metabolic Diseases, Internal medicine, medicine, Animals, Physical and Theoretical Chemistry, QD1-999, insulin signaling, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Adipokines::Leptin [Medical Subject Headings], Amyloid beta-Peptides, business.industry, Organic Chemistry, Peso corporal, Phenomena and Processes::Metabolic Phenomena::Metabolism::Energy Metabolism [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Adaptor Proteins, Signal Transducing::STAT Transcription Factors [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hypothalamus [Medical Subject Headings], STAT5 transcription factor, IRS1, Disease Models, Animal, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Ghrelin [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight [Medical Subject Headings], Energy expenditure, Energy Metabolism, business, Hipotálamo
Abstract: Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer’s disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg5xFAD/5xFAD), heterozygous (Tg5xFAD/-), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg5xFAD/- and Tg5xFAD/5xFAD mice and increased expression of IL-1β in Tg5xFAD/5xFAD mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg5xFAD/- and Tg5xFAD/5xFAD mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin, decreased insulin and leptin hypothalamic signaling, dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2), and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.
Published: 2021

136. Quality standards in proteomics research facilities

Author: Paolo Nanni, Teresa Mendes Maia, Mariette Matondo, Eduard Sabidó, Francis Impens, Karl Mechtler, Karel Stejskal, Anna Shevchenko, Damarys Loew, Dominic Helm, Thibaut Douché, Cristina Chiva, Mandy Rettel, Christian Panse, Barcelona Institute of Science and Technology (BIST), Universitat Pompeu Fabra [Barcelona] (UPF), VIB Proteomics Core, Ghent, Belgium, VIB-UGent Center for Medical Biotechnology, Universiteit Gent = Ghent University (UGENT), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne = University of Lausanne (UNIL), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Institute of Molecular Biotechnology (IMBA), Austrian Academy of Sciences (OeAW), Research Institute of Molecular Pathology (IMP), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Spectrométrie de Masse Protéomique, Institut Curie [Paris], European Molecular Biology Laboratory [Heidelberg] (EMBL), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Gregor Mendel Institute (GMI) - Vienna Biocenter (VBC), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, 'Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012- 0208, and 'Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya' (2017SGR595). The VIB Proteomics Core acknowledges support from the VIB Tech Watch Fund and FWO-SBO Project S006617N. Research in the Mechtler lab was supported by the ERA-CAPS I 3686 project of the Austrian Science Fund. We acknowledge support from the European Union's Horizon 2020 research and innovation program under grant agreement No 823839 (EPIC-XS)., European Project: 823839,H2020-INFRAIA-2018-1,EPIC-XS(2019), Universiteit Gent = Ghent University [Belgium] (UGENT), Université de Lausanne (UNIL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)-Universität Zürich [Zürich] = University of Zurich (UZH), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), University of Zurich, Nanni, Paolo, Shevchenko, Anna, and Sabidó, Eduard
Subjects: Proteomics, 1303 Biochemistry, Centres d'investigació, GeneralLiterature_INTRODUCTORYANDSURVEY, media_common.quotation_subject, 610 Medicine & health, 10071 Functional Genomics Center Zurich, Proteòmica, Biochemistry, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, 1311 Genetics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], 1312 Molecular Biology, Genetics, Quality (business), Science & Society, Molecular Biology, 030304 developmental biology, media_common, 0303 health sciences, 3. Good health, Engineering management, ComputingMethodologies_PATTERNRECOGNITION, 570 Life sciences, biology, Business, 030217 neurology & neurosurgery
Abstract: Proteomics research infrastructures and core facilities within the Core for Life alliance advocate for community policies for quality control to ensure high standards in proteomics services. The CRG/UPF Proteomics Unit is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D+i 2013‐2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, “Centro de Excelencia Severo Ochoa 2013‐2017”, SEV‐2012‐ 0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595). The VIB Proteomics Core acknowledges support from the VIB Tech Watch Fund and FWO‐SBO Project S006617N. Research in the Mechtler lab was supported by the ERA‐CAPS I 3686 project of the Austrian Science Fund. We acknowledge support from the European Union's Horizon 2020 research and innovation program under grant agreement No 823839 (EPIC‐XS)
Published: 2021

137. ΔNp73, TAp73 and Δ133p53 Extracellular Vesicle Cargo as Early Diagnosis Markers in Colorectal Cancer

Author: Mª. Isabel Prieto, Héctor Peinado, Daniel Pastor-Morate, Carmen Poves, Javier Rodríguez-Cobos, D. Viñal, Nuria Rodríguez-Salas, Gemma Domínguez, Rodrigo Barderas, María Jesús Fernández-Aceñero, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Regional Development Fund (ERDF/FEDER), UAM. Departamento de Bioquímica, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), and Instituto de Salud Carlos III - ISCIII
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Ap73, colorectal cancer, Disease, Extracellular vesicles, Article, 03 medical and health sciences, 0302 clinical medicine, Premalignant lesions, Internal medicine, ΔNp73, Screening programs, Medicine, Liquid biopsy, ∆Np73, RC254-282, ∆133p53, liquid biopsy, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biomarkers, Extracellular vesicle, Δ133p53, Biología y Biomedicina / Biología, medicine.disease, Early diagnosis, 030104 developmental biology, 030220 oncology & carcinogenesis, Biomarker (medicine), screening programs, TAp73, business, Premalignant lesion, extracellular vesicles, Biomarkers, premalignant lesions, early diagnosis
Abstract: © 2021 by the authors., The early diagnosis of colorectal cancer is a key factor in the overall survival of the patients. The actual screening programs include different approaches with significant limitations such as unspecificity, high invasiveness, and detection at late stages of the disease. The specific content of extracellular vesicles derived from malignant cells may represent a non-invasive technique for the early detection of colorectal cancer. Here, we studied the mRNA levels of ΔNp73, TAp73, and Δ133p53 in plasma-derived extracellular vesicles from healthy subjects (n = 29), individuals with premalignant lesions (n = 49), and colorectal cancer patients (n = 42). Extracellular vesicles’ ΔNp73 levels were already significantly high in subjects with premalignant lesions. Δ133p53 levels were statistically increased in colorectal cancer patients compared to the other two groups and were associated with patients’ survival. Remarkably, TAp73 mRNA was not detected in any of the individuals. The evaluation of ΔNp73, Δ133p53 and CEA sensitivity, specificity and AUC values supports ΔNp73 as a better early diagnosis biomarker and CEA as the best to identify advanced stages. Thus, low levels of CEA and a high content of ΔNp73 may identify in screening programs those individuals at higher risk of presenting a premalignant lesion. In addition, Δ133p53 emerges as a potential prognosis biomarker in colorectal cancer., This work was supported by PI18/00473 (ISCIII, Ministry of Economy and Competitiveness and co-funded with FEDER funds) and PI17CIII/00045 research project from AES-ISCIII.
Published: 2021
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138. Native α-Synuclein, 3-Nitrotyrosine Proteins, and Patterns of Nitro-α-Synuclein-Immunoreactive Inclusions in Saliva and Submandibulary Gland in Parkinson’s Disease

Author: Fernando Rodríguez de Fonseca, Emilio Fernández-Espejo, Joan Berenguer, Juan Suárez, Dolores Vilas, Iban Aldecoa, Eduardo Tolosa, Fátima Damas-Hermoso, [Fernández-Espejo,E] Reial Acadèmia de Medicina de Catalunya, Barcelona, Spain. [Fernández-Espejo,E] Red Andaluza de Investigación Clínica y Traslacional en Neurología (Neuro-RECA), Laboratorio de Medicina Regenerativa, Hospital Regional Universitario, Málaga, Spain. [Rodríguez de Fonseca,F] Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Málaga, Spain. [Suárez,J] Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, IBIMA, Universidad de Málaga, Málaga, Spain. [Tolosa,E] Unidad de Parkinson y movimientos anormales, Servicio de Neurología, Hospital Clínic, Barcelona. [Tolosa,E] Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. [Tolosa,E] Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain. [Vilas,D] Servicio de Neurología, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. [Aldecoa,I] Centro de Diagnóstico Biomédico, Departamento de Patología, Hospital Clinic de Barcelona, Universitat de Barcelona, Barcelona, Spain. [Aldecoa,I] Banco de Tejidos Neurológicos del Biobanco, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. [Berenguer,J] Servicio de Radiología, Hospital Clínic, Barcelona, Spain. [Damas-Hermoso.F] Servicio de Neurología, Hospital Universitario de Valme, Sevilla, Spain, This work was supported by grants to E.F.-E. from Junta de Andalucía, Consejería de Economía, Conocimiento, Empresas y Universidad, Spain (ref. BIO127, PAIDI), and Sociedad Andaluza de Neurología (ref. SUBAIA2015/006), to F.R.d.F. from European Regional Development Funds-European Union (ERDF-EU) and EULAC-HEALTH H2020 FATZHEIMER Project (EULACH16/T010131), RETICS Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación, and ERDF-EU (RD16/0017/0001), and ISCIII, ERDF-EU (PI19/01577), and as well as to J.S. from Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas (PND 2019/040). J.S. (CPII17/00024) holds 'Miguel Servet II' research contracts from the National System of Health, ISCIII, ERDF-EU.
Subjects: 0301 basic medicine, Saliva, Pathology, Physiology, Clinical Biochemistry, Enfermedad de parkinson, Anatomy::Cells::Cellular Structures::Intracellular Space::Cytoplasm [Medical Subject Headings], Biochemistry, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Diseases::Nervous System Diseases::Neurodegenerative Diseases::Lewy Body Disease [Medical Subject Headings], 0302 clinical medicine, Alfa-sinucleína, nitrative stress, Parkinson, biology, medicine.diagnostic_test, Chemistry, Estrés oxidativo, nitration, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nerve Tissue Proteins::Synucleins::alpha-Synuclein [Medical Subject Headings], medicine.anatomical_structure, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Immunologic Techniques::Immunoassay::Immunoenzyme Techniques::Enzyme-Linked Immunosorbent Assay [Medical Subject Headings], Biomarker (medicine), Immunohistochemistry, Anatomy::Tissues::Connective Tissue [Medical Subject Headings], Antibody, Connective tissue, Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological [Medical Subject Headings], medicine.medical_specialty, Nitration, RM1-950, Article, Tejido conectivo, 03 medical and health sciences, α-synuclein, Biopsy, medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy [Medical Subject Headings], lewy-type, Molecular Biology, 3-nitrotyrosine, saliva, Lewy-type, Cell Biology, 030104 developmental biology, Anatomy::Fluids and Secretions::Bodily Secretions::Saliva [Medical Subject Headings], Cytoplasm, parkinson, biology.protein, Therapeutics. Pharmacology, Enfermedad por cuerpos de Lewy, Nitrative stress, Diseases::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Basal Ganglia Diseases::Parkinsonian Disorders::Parkinson Disease [Medical Subject Headings], 030217 neurology & neurosurgery, Immunostaining
Abstract: Background. Salivary α-synuclein (aSyn) and its nitrated form, or 3-nitrotyrosine-α-synuclein (3-NT-αSyn), hold promise as biomarkers for idiopathic Parkinson’s disease (IPD). Nitrative stress that is characterized by an excess of 3-nitrotyrosine proteins (3-NT-proteins) has been proposed as a pathogenic mechanism in IPD. The objective is to study the pathological role of native αSyn, 3-NT-αSyn, and 3-NT-proteins in the saliva and submandibulary glands of patients with IPD. Methods. The salivary and serum αSyn and 3-NT-proteins concentration is evaluated with ELISA in patients and controls. Correlations of αSyn and 3-NT-proteins content with clinical features of the disease are examined. Immunohistochemical 3-NT-αSyn expression in submandibulary gland sections is analyzed. Results. (a) Salivary concentration and saliva/serum ratios of native αSyn and 3-NT-proteins are similar in patients and controls, (b) salivary αSyn and 3-NT-proteins do not correlate with any clinical feature, and (c) three patterns of 3-NT-αSyn-positive inclusions are observed on histological sections: rounded “Lewy-type” aggregates of 10–25 µm in diameter, coarse deposits with varied morphology, and spheroid inclusions or bodies of 3–5 µm in diameter. “Lewy-type” and coarse inclusions are observed in the interlobular connective tissue of the gland, and small-sized bodies are located within the cytoplasm of duct cells. “Lewy-type” inclusions are only observed in patients, and the remaining patterns of inclusions are observed in both the patients and controls. Conclusions. The patients’ saliva presents a similar concentration of native αSyn and 3-nitrotyrosine-proteins than that of the controls, and no correlations with clinical features are found. These findings preclude the utility of native αSyn in the saliva as a biomarker, and they indicate the absence of nitrative stress in the saliva and serum of patients. As regards nitrated αSyn, “Lewy-type” inclusions expressing 3-NT-αSyn are observed in the patients, not the controls—a novel finding that suggests that a biopsy of the submandibulary gland, if proven safe, could be a useful technique for diagnosing IPD. Finally, to our knowledge, this is also the first description of 3-NT-αSyn-immunoreactive intracytoplasmic bodies in cells that are located outside the nervous system. These intracytoplasmic bodies are present in duct cells of submandibulary gland sections from all subjects regardless of their pathology, and they can represent an aging or involutional change. Further immunostaining studies with different antibodies and larger samples are needed to validate the data.
Published: 2021

139. Generation of three human iPSC lines from PLAN (PLA2G6-associated neurodegeneration) patients

Author: José Antonio Sánchez-Alcázar, Carmen Espinós, Alejandra Darling, Irene Villalón-García, Slaven Erceg, Belén Pérez-Dueñas, Candela Machuca, Deyanira García-Navas, Marta Correa-Vela, Institut Català de la Salut, [Machuca C] Unit of Rare Neurodegenerative Diseases, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. Rare Diseases Joint Units, CIPF-IIS La Fe & INCLIVA, Valencia, Spain. Stem Cells Therapies in Neurodegenerative Diseases Lab, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain. [Correa-Vela M] Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [García-Navas D] Department of Pediatric Neurology. Hospital Universitario San Pedro de Alcántara, Cáceres, Spain. [Darling A] Unit of Pediatric Movement Disorders, Hospital Sant Joan de Déu, Barcelona, Spain. [Villalón-García I, Sánchez-Alcázar JA] Centro Andaluz de Biología del Desarrollo (CABD-CSIC), Universidad Pablo de Olavide, Seville, Spain. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Pérez-Dueñas B] Servei de Neurologia Pediàtrica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Instituto de Salud Carlos III, and Generalitat Valenciana
Subjects: 0301 basic medicine, QH301-705.5, Cellular differentiation, Induced Pluripotent Stem Cells, Neuroaxonal Dystrophies, Cells::Stem Cells::Adult Stem Cells::Induced Pluripotent Stem Cells [ANATOMY], Biology, medicine.disease_cause, células::células madre::células madre adultas::células madre pluripotentes inducidas [ANATOMÍA], Sistema nerviós - Degeneració, Cell Line, Dermal fibroblast, Group VI Phospholipases A2, 03 medical and health sciences, Kruppel-Like Factor 4, 0302 clinical medicine, SOX2, medicine, Humans, enfermedades del sistema nervioso::enfermedades neurodegenerativas [ENFERMEDADES], Biology (General), Induced pluripotent stem cell, Mutation, Neurodegeneration, Cell Differentiation, Cell Biology, General Medicine, medicine.disease, Cellular Reprogramming, 030104 developmental biology, KLF4, Nervous System Diseases::Neurodegenerative Diseases [DISEASES], Cancer research, Malalties rares, Reprogramming, 030217 neurology & neurosurgery, Genètica, Developmental Biology
Abstract: © 2021 The Authors., The human iPSC cell lines, PLANFiPS1-Sv4F-1 (RCPFi004-A), PLANFiPS2-Sv4F-1 (RCPFi005-A), PLANFiPS3-Sv4F-1 RCPFi006-A), derived from dermal fibroblast from three patients suffering PLAN (PLA2G6-associated neurodegeneration; MIM 256600) caused by mutations in the PLA2G6 gene, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors. The pluripotency was assessed by immunocytochemistry and RT-PCR. Differentiation capacity was verified in vitro. This iPSC line can be further differentiated toward affected cells to better understand molecular mechanisms of disease and pathophysiology., This work was supported by the Instituto de Salud Carlos III (ISCIII) - Subdireccion ´ General de Evaluacion ´ y Fomento de la Investigacion ´ [PI18/00147to CE and PI18/01319 to BPD], and by the Generalitat Valenciana [PROMETEO/2018/135], within the framework of the National R + D + I Plan co-funded with ERDF funds. CM has a CIPF-PhD fellowship [P.I.06/2017]. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014–2020).
Published: 2021

140. Genetic Variants in Cytosolic Phospholipase A2 Associated With Nonsteroidal Anti-Inflammatory Drug-Induced Acute Urticaria/Angioedema

Author: Raquel Jurado-Escobar, Inmaculada Doña, José Triano-Cornejo, James R. Perkins, Natalia Pérez-Sánchez, Almudena Testera-Montes, Marina Labella, Joan Bartra, José J. Laguna, Miguel Estravís, José A. G. Agúndez, María J. Torres, José A. Cornejo-García, [Jurado-Escobar,R, Doña,I, Triano-Cornejo,J, Torres,MJ, Cornejo-García,JA] Allergy Research Group, Instituto De Investigación Biomédica De Málaga-IBIMA, Malaga, Spain. [Jurado-Escobar,R, Torres,MJ] Departamento De Medicina, Universidad De Málaga, Malaga, Spain. [Doña,I, Pérez-Sánchez,N, Testera-Montes,A, Labella,M, Torres,MJ] Allergy Unit, Hospital Regional Universitario De Málaga, Malaga, Spain. [Doña,I, Bartra,J, Laguna,JJ, Estravis,M, Agúndez,JAG, Cornejo-García,JA] ARADyAL Network, Instituto De Salud Carlos III, Madrid, Spain. [Perkins,JR] Department of Molecular Biology and Biochemistry, University of Malaga, Malaga, Spain. [Perkins,JR] CIBER De Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain. [Perkins,JR] The Biomedical Research Institute of Malaga (IBIMA), Malaga, Spain. [Bartra,J] Allergy Section, Pneumology Department, Hospital Clinic, Universitat De Barcelona, Barcelona, Spain. [Laguna,JJ] Allergy Unit, Allergo-Anaesthesia Unit, Hospital Central De La Cruz Roja, Faculty of Medicine, Alfonso X El Sabio University, Madrid, Spain. [Estravis,M] Instituto De Investigación Biomédica De Salamanca (IBSAL), Salamanca, Spain. [Agúndez,JAG] Institute of Molecular Pathology Biomarkers, UEx, Cáceres, Spain. [Torres,MJ] Nanostructures for Diagnosing and Treatment of Allergic Diseases Laboratory, Andalusian Center for Nanomedicine and Biotechnology-BIONAND, Malaga, Spain., and This work was supported by Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Science and Innovation), co-founded by Fondo Europeo de Desarrollo Regional-FEDER for Research Projects (PI17/ 01593, PI18/00540, and PI20/01540), GR18145 from Junta de Extremadura, the Thematic Networks and Co-operative Research
Subjects: 0301 basic medicine, Polimorfismo Genético, Single-nucleotide polymorphism, RM1-950, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antirheumatic Agents [Medical Subject Headings], 03 medical and health sciences, 0302 clinical medicine, Phospholipase A2, Cytosolic phospholipase A2, Genetic variation, arachidomic acid, medicine, Pharmacology (medical), Phenomena and Processes::Chemical Phenomena::Chemical Processes::Hydrolysis [Medical Subject Headings], cytosolic phospholipase A2, skin and connective tissue diseases, Gene, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Multienzyme Complexes::Prostaglandin-Endoperoxide Synthases [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Carboxylic Ester Hydrolases::Phospholipases::Phospholipases A::Phospholipases A2 [Medical Subject Headings], Ácido araquidónico, Original Research, Pharmacology, Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], biology, Angioedema, business.industry, urticaria/angioedema, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Arachidonic Acids::Arachidonic Acid [Medical Subject Headings], Diseases::Cardiovascular Diseases::Vascular Diseases::Angioedema [Medical Subject Headings], Angioneurotic oedema, NSAID cross-hypersensitivity, PLA2G4A, 030104 developmental biology, Arachidomic acid, 030220 oncology & carcinogenesis, Immunology, Fosfolipasas A2 grupo IV, biology.protein, Cyclooxygenase, Therapeutics. Pharmacology, medicine.symptom, Urticaria/angioedema, business, polymorphisms, Polymorphisms
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the main triggers of drug hypersensitivity reactions, probably due to their high consumption worldwide. The most frequent type of NSAID hypersensitivity is NSAID cross-hypersensitivity, in which patients react to NSAIDs from different chemical groups in the absence of a specific immunological response. The underlying mechanism of NSAID cross-hypersensitivity has been linked to cyclooxygenase (COX)-1 inhibition causing an imbalance in the arachidonic acid pathway. Despite NSAID-induced acute urticaria/angioedema (NIUA) being the most frequent clinical phenotype, most studies have focused on NSAID-exacerbated respiratory disease. As NSAID cross-hypersensitivity reactions are idiosyncratic, only appearing in some subjects, it is believed that individual susceptibility is under the influence of genetic factors. Although associations with polymorphisms in genes from the AA pathway have been described, no previous study has evaluated the potential role of cytosolic phospholipase A2 (cPLA2) variants. This enzyme catalyzes the initial hydrolysis of membrane phospholipids to release AA, which can be subsequently metabolized into eicosanoids. Here, we analyzed for the first time the overall genetic variation in the cPLA2 gene (PLA2G4A) in NIUA patients. For this purpose, a set of tagging single nucleotide polymorphisms (tagSNPs) in PLA2G4A were selected using data from Europeans subjects in the 1,000 Genomes Project, and genotyped with the iPlex Sequenom MassArray technology. Two independent populations, each comprising NIUA patients and NSAID-tolerant controls, were recruited in Spain, for the purposes of discovery and replication, comprising a total of 1,128 individuals. Fifty-eight tagSNPs were successfully genotyped in the discovery cohort, of which four were significantly associated with NIUA after Bonferroni correction (rs2049963, rs2064471, rs12088010, and rs12746200). These polymorphisms were then genotyped in the replication cohort: rs2049963 was associated with increased risk for NIUA after Bonferroni correction under the dominant and additive models, whereas rs12088010 and rs12746200 were protective under these two inheritance models. Our results suggest a role for PLA2G4A polymorphisms in NIUA. However, further studies are required to replicate our findings, elucidate the mechanistic role, and evaluate the participation of PLA2G4A variants in other phenotypes induced by NSAID cross-hypersensitivity.
Published: 2021

141. Non-Coding RNAs in Kidney Diseases: The Long and Short of Them

Author: Melania Guerrero-Hue, Valérie Metzinger-Le Meuth, Eya Hamza, Cristina García-Caballero, Sandra Rayego-Mateos, Juan Antonio Moreno, Laurent Metzinger, Mercedes Vallejo-Mudarra, UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), [Moreno,JA, Guerrero-Hue,M, García-Caballero,C, Vallejo-Mudarra,M] Maimonides Biomedical Research Institute of Cordoba (IMIBIC), UGC Nephrology, Hospital Universitario Reina Sofía, Córdoba, Spain. [Moreno,JA] Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), Madrid, Spain. [Moreno,JA] Department of Cell Biology, Physiology and Immunology, University of Cordoba, Cordoba, Spain. [Hamza,E, Metzinger,L, Metzinger-Le Meuth,V] HEMATIM UR 4666, C.U.R.S, Université de Picardie Jules Verne (UPJV), CEDEX 1, Amiens, France. [Rayego-Mateos,S] Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain. [Metzinger-Le Meuth,V] INSERM UMRS 1148, Laboratory for Vascular Translational Science (LVTS), UFR SMBH, Université Sorbonne Paris Nord, CEDEX, Bobigny, France., This research was funded by SFNDT, Vifor. (L.M., V.M.-L.M. and E.H.), Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130 and PI20/00375), Spanish Biomedical Research Centre in Cardiovascular Diseases (CIBERCV), Spanish Ministry of Science and Innovation (RYC-2017-22369), and Spanish Society of Nephrology (SEN). The 'PFIS' and 'Sara Borrell' training program of the ISCIII supported the salary of MGH (FI18/00310) and SR-M (CD19/00021)., Hospital Universitario Reina Sofia [Cordoue, Espagne], Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares [Spain] (CIBERCV), Universidad de Córdoba = University of Córdoba [Córdoba], HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad Autónoma de Madrid (UAM), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, UFR Santé, Médecine et Biologie Humaine (UFR SMBH), Université Sorbonne Paris Nord, and DESSAIVRE, Louise
Subjects: [SDV]Life Sciences [q-bio], Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::Oligonucleotides, Antisense [Medical Subject Headings], non-coding RNA, Review, Genome, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Chronic kidney disease, Acute kidney disease, Organisms::Eukaryota::Animals [Medical Subject Headings], Insuficiencia renal crónica, Biology (General), Spectroscopy, Regulation of gene expression, MicroARNs, Kidney, Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Renal Insufficiency, Chronic [Medical Subject Headings], long non-coding RNA, microRNA, Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney Diseases [Medical Subject Headings], General Medicine, IgA nephropathy, Non-coding RNA, Long non-coding RNA, Computer Science Applications, [SDV] Life Sciences [q-bio], Chemistry, medicine.anatomical_structure, Diseases::Female Urogenital Diseases and Pregnancy Complications::Female Urogenital Diseases::Urologic Diseases::Kidney Diseases [Medical Subject Headings], RNA, Long Noncoding, acute kidney disease, ARN largo no codificante, Glomerulonefritis por IgA, ARN no traducido, Medicina, QH301-705.5, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Untranslated::RNA, Long Noncoding [Medical Subject Headings], Computational biology, Biology, Catalysis, Inorganic Chemistry, Enfermedades renales, Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], medicine, Animals, Humans, RNA, Messenger, Physical and Theoretical Chemistry, Renal Insufficiency, Chronic, QD1-999, Molecular Biology, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::DNA, Intergenic [Medical Subject Headings], Organic Chemistry, RNA, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Messenger [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology::Genomics [Medical Subject Headings], Noncoding DNA, Gene regulation, MicroRNAs, Regulación de la expresión génica, Gene Expression Regulation, gene regulation, chronic kidney disease
Abstract: Recent progress in genomic research has highlighted the genome to be much more transcribed than expected. The formerly so-called junk DNA encodes a miscellaneous group of largely unknown RNA transcripts, which contain the long non-coding RNAs (lncRNAs) family. lncRNAs are instrumental in gene regulation. Moreover, understanding their biological roles in the physiopathology of many diseases, including renal, is a new challenge. lncRNAs regulate the effects of microRNAs (miRNA) on mRNA expression. Understanding the complex crosstalk between lncRNA– miRNA–mRNA is one of the main challenges of modern molecular biology. This review aims to summarize the role of lncRNA on kidney diseases, the molecular mechanisms involved, and their function as emerging prognostic biomarkers for both acute and chronic kidney diseases. Finally, we will also outline new therapeutic opportunities to diminish renal injury by targeting lncRNA with antisense oligonucleotides., This research was funded by SFNDT, Vifor. (L.M., V.M.-L.M. and E.H.), Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130 and PI20/00375), Spanish Biomedical Research Centre in Cardiovascular Diseases (CIBERCV), Spanish Ministry of Science and Innovation (RYC-2017-22369), and Spanish Society of Nephrology (SEN). The “PFIS” and “Sara Borrell” training program of the ISCIII supported the salary of MGH (FI18/00310) and SR-M (CD19/00021). Córdoba University supported the salary of C.G.C.
Published: 2021

142. Nanomedicine to Overcome Multidrug Resistance Mechanisms in Colon and Pancreatic Cancer: Recent Progress

Author: Ortíz, Raúl, Quiñonero, Francisco, García-Pinel, Beatriz, Fuel, Marco, Mesas, Cristina, Cabeza, Laura, Melguizo, Consolación, Prados, Jose, [Ortíz,R, Quiñonero,F, García-Pinel,B, Fuel,M, Mesas,C, Cabeza,L, Melguizo,C, Prados,J] Institute of Biopathology and Regenerative Medicine (IBIMER), Center of Biomedical Research (CIBM), University of Granada, Granada, Spain. [Ortíz,R, Prados,J] Department of Anatomy and Embriology, Faculty of Medicine, University of Granada, Granada, Spain. [Ortíz,R, Prados,J] Instituto Biosanitario de Granada (ibs.GRANADA), Granada, Spain., and This work was funded by the Consejería de Salud de la Junta de Andalucía (projects PI-0102-2017 and P18-HO-3882) and by the CTS-107 Group. This research was partially supported by a grant from the Instituto de Salud Carlos III (ISCIII) (Project PI19/01478) (FEDER).
Subjects: Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Repair [Medical Subject Headings], Anatomy::Cells::Stem Cells::Neoplastic Stem Cells [Medical Subject Headings], Anatomy::Digestive System::Gastrointestinal Tract::Intestines::Intestine, Large::Colon [Medical Subject Headings], Resistencia a medicamentos, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome::Treatment Failure [Medical Subject Headings], PARP, Microambiente tumoral, Disciplines and Occupations::Natural Science Disciplines::Nanotechnology::Nanomedicine [Medical Subject Headings], Neoplasias del colon, Chemicals and Drugs::Macromolecular Substances::Micelles [Medical Subject Headings], Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance [Medical Subject Headings], Technology and Food and Beverages::Technology, Industry, and Agriculture::Manufactured Materials::Nanostructures::Nanoparticles [Medical Subject Headings], miRNA, MicroARNs, Neoplasias pancreáticas, Poli(ADP-Ribosa) polimerasas, Pancreatic cancer, Colon cancer, Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Pancreatic Neoplasms [Medical Subject Headings], Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAs [Medical Subject Headings], Nanomedicine, Tumor microenvironment, Drug resistance, Nanomedicina, Chemicals and Drugs::Macromolecular Substances::Polymers::Dendrimers [Medical Subject Headings], Chemicals and Drugs::Biomedical and Dental Materials::Membranes, Artificial::Liposomes [Medical Subject Headings]
Abstract: The development of drug resistance is one of the main causes of cancer treatment failure. This phenomenon occurs very frequently in different types of cancer, including colon and pancreatic cancers. However, the underlying molecular mechanisms are not fully understood. In recent years, nanomedicine has improved the delivery and efficacy of drugs, and has decreased their side effects. In addition, it has allowed to design drugs capable of avoiding certain resistance mechanisms of tumors. In this article, we review the main resistance mechanisms in colon and pancreatic cancers, along with the most relevant strategies offered by nanodrugs to overcome this obstacle. These strategies include the inhibition of efflux pumps, the use of specific targets, the development of nanomedicines affecting the environment of cancer-specific tissues, the modulation of DNA repair mechanisms or RNA (miRNA), and specific approaches to damage cancer stem cells, among others. This review aims to illustrate how advanced nanoformulations, including polymeric conjugates, micelles, dendrimers, liposomes, metallic and carbon-based nanoparticles, are allowing to overcome one of the main limitations in the treatment of colon and pancreatic cancers. The future development of nanomedicine opens new horizons for cancer treatment. Yes
Published: 2021

143. Key Chagas disease missing knowledge among at-risk population in Spain affecting diagnosis and treatment

Author: Teresa Blasco-Hernández, Teresa Boquete, Agustín Benito, Laura Iglesias-Rus, María Romay-Barja, Instituto de Salud Carlos III, Red de Investigación Cooperativa en Enfermedades Tropicales (España), and Instituto de Salud Carlos III - ISCIII
Subjects: Male, Chagas disease, medicine.medical_specialty, Barrier, Population, Disease, Infectious and parasitic diseases, RC109-216, Non-endemic country, Logistic regression, Diagnosis, Risk Factors, Environmental health, parasitic diseases, Prevalence, medicine, Humans, Blood test, education, At-Risk Population, education.field_of_study, medicine.diagnostic_test, business.industry, Transmission (medicine), Public health, Public Health, Environmental and Occupational Health, General Medicine, medicine.disease, Treatment, Cross-Sectional Studies, Infectious Diseases, Knowledge, Spain, Female, Public aspects of medicine, RA1-1270, business, Research Article
Abstract: Background Chagas disease is endemic in Latin America and, over the last few decades, due to population movements, the disease has spread to other continents. Early diagnosis and treatment are critical in terms of improving outcomes for those living with Chagas disease. However, poor knowledge and awareness is one of barriers that affects access to Chagas disease diagnosis and treatment for the population at risk. Information regarding immigrants’ knowledge concerning Chagas disease control and prevention is insufficient in non-endemic countries and, therefore, this study sought to assess Chagas disease knowledge and awareness within the Bolivian community residing in Madrid. Methods This cross-sectional study was carried out in March–August 2017. A total of 376 Bolivians answered a structured questionnaire. A knowledge index was created based on respondents’ knowledge about transmission, symptoms, diagnosis, and place to seek treatment. Multivariate logistic regressions analyses were performed to assess the factors associated with respondents’ knowledge of Chagas disease. Results A total 159 (42.4%) of Bolivians interviewed about their knowledge of Chagas disease were men and 217 (57.6%) were women. Vinchuca was mentioned as mode of transmission by 71% of the Bolivians surveyed, while only 9% mentioned vertical transmission. Almost half of the Bolivians did not know any symptom of Chagas disease and only 47% knew that a specific blood test is necessary for diagnosis. Most of Bolivians were aware of the severity of Chagas disease, but 45% of Bolivians said that there is no cure for Chagas and 96% did not know any treatment. Based on the index of knowledge generated, only 34% of Bolivians had a good knowledge about Chagas disease transmission, symptoms, diagnosis and treatment. According to the multiple logistic regression analysis, knowledge regarding Chagas disease, diagnosis and treatment was significantly higher amongst older Bolivians who had secondary education at least, as well as amongst those who had already been tested for Chagas disease. Conclusions This study found that most of the Bolivian population living in Spain had poor knowledge about Chagas disease transmission, symptoms, diagnostic methods and treatment. A poor understanding of the disease transmission and management is one of the most important barriers when it comes to searching for early diagnosis and appropriate care.
Published: 2021

144. Delivery of oligonucleotide‐based therapeutics: challenges and opportunities

Author: Annemieke Aartsma-Rus, Marisol Montolio, Gisela Gaina, Camilla Foged, Suzan M. Hammond, Alejandro Garanto, David R. Jones, Lourdes R. Desviat, Giuseppina Covello, Sabine Krause, Magdalena Guzowska, Virginia Arechavala-Gomeza, Sven Even F. Borgos, Willeke M. C. van Roon-Mom, Taavi Lehto, Sandra Alves, Ronald A.M. Buijsen, Michela A. Denti, Aurélie Goyenvalle, Rob W.J. Collin, Irina Holodnuka, Lucia Echevarria, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), DFF-4184-00422 20577, 446002002 Foundation Fighting Blindness, FFB: PPA-0517-0717-RAD Fundación Ramón Areces Horizon 2020 Framework Programme, H2020: 721058, 761104 Muscular Dystrophy UK, MDUK Medical Research Council, MRC Institut National de la Santé et de la Recherche Médicale, Inserm Eesti Teadusagentuur, ETAg: PSG226 Ikerbasque, Basque Foundation for Science Prinses Beatrix Spierfonds Instituto de Salud Carlos III, ISCIII: CPII17/00004 Ministerio de Ciencia e Innovación, MICINN: PID2019-105344RB-I00 Duchenne Parent Project Hersenstichting: DR-2018-00253 Friedrich-Baur-Stiftung European Regional Development Fund, ERDF Algemene Nederlandse Vereniging ter voorkoming van Blindheid, ANVVB Landelijke Stichting voor Blinden en Slechtzienden, LSBS Stichting Retina Fonds: 2015-31, 2018-21 Stichting Blinden-Penning Ministerul Cercetării şi Inovării, MCI: 31N/2016/PN 16.22.02.05, PTDC/BBB-BMD/6301/2014, This work was supported by funding from Cooperation of Science and Technology (COST) Action CA17103 (networking grant to V.A-G). V.A-G holds a Miguel Servet Fellowship from the ISCIII [grant reference CPII17/00004] that is part-funded by the European Regional Development Fund (ERDF/FEDER) and also acknowledges funding from Ikerbasque (Basque Foundation for Science). S.M.H is funded by the Medical Research Council and Muscular Dystrophy UK. A.A-R receives funding from amongst others the Duchenne Parent Project, Spieren voor Spieren, the Prinses Beatrix Spierfonds, Duchenne UK and through Horizon2020 project BIND. A.G and R.W.J.C are supported by several foundations including the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Stichting Blinden-Penning, Landelijke Stichting voor Blinden en Slechtzienden, Stichting Oogfonds Nederland, Stichting Macula Degeneratie Fonds, and Stichting Retina Nederland Fonds (who contributed through UitZicht 2015-31 and 2018-21), together with the Rotterdamse Stichting Blindenbelangen, Stichting Blindenhulp, Stichting tot Verbetering van het Lot der Blinden, Stichting voor Ooglijders, and Stichting Dowilvo, as well as the Foundation Fighting Blindness USA, grant no. PPA-0517-0717-RAD. R.A.M.B is supported by Hersenstichting Nederland Grant DR-2018-00253. G.G. is supported by Ministry of Research and Innovation in Romania/National Program 31N/2016/PN 16.22.02.05. S.A is supported by Project PTDC/BBB-BMD/6301/2014 (Funda??o para a Ci?ncia e a Tecnologia?MCTES, Portugal). L.R.D. is supported by Fundaci?n Ram?n Areces Grant XVII CN and Spanish Ministry of Science and Innovation (MICINN, grant PID2019-105344RB-I00). T.L is supported by Estonian Research Council grant PSG226. S.K is supported by the Friedrich-Baur-Stiftung. C.F is funded by The Danish Council for Independent Research, Technology and Production Sciences (grant number DFF-4184-00422). W.vRM is supported by ZonMw Programme Translational Research 2 [Project number 446002002], Campaign Team Huntington and AFM Telethon [Project number 20577]. S.E.B is supported by the H2020 projects B-SMART, Grant number 721058, and REFINE, Grant number 761104. A.T.G is supported by the Institut National de la sant? et la recherche m?dicale (INSERM) and the Association Monegasque contre les myopathies (AMM). L.E. is founded by the Association Monegasque contre les myopathies (AMM)., UAM. Departamento de Biología Molecular, Ministerio de Ciencia y Tecnología (España), Instituto de Salud Carlos III, Ikerbasque Basque Foundation for Science, Medical Research Council (UK), Duchenne UK, Foundation Fighting Blindness, Netherlands Brain Foundation, Ministerio de Ciencia e Innovación (España), Fundação para a Ciência e a Tecnologia (Portugal), and Fundación Ramón Areces
Subjects: safety, 0301 basic medicine, Medicine (General), Computer science, [SDV]Life Sciences [q-bio], Aptamer, Gene Expression, Review, Computational biology, QH426-470, Small Interfering, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 03 medical and health sciences, R5-920, 0302 clinical medicine, Chemical Biology, Marketed products, Genetics, Cost of goods, Antisense, RNA, Small Interfering, Genetica Humana, Antisense Oligonucleotides, oligonucleotides, Oligonucleotide, RNA therapeutics, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Oligonucleotides, Antisense, Biología y Biomedicina / Biología, RNA Biology, preclinical models, Doenças Genéticas, 3. Good health, 030104 developmental biology, delivery, Nanoparticles, Oligonucleotides, Antisense oligonucleotides, RNA, Molecular Medicine, Synthetic Biology & Biotechnology, 030217 neurology & neurosurgery
Abstract: Nucleic acid‐based therapeutics that regulate gene expression have been developed towards clinical use at a steady pace for several decades, but in recent years the field has been accelerating. To date, there are 11 marketed products based on antisense oligonucleotides, aptamers and small interfering RNAs, and many others are in the pipeline for both academia and industry. A major technology trigger for this development has been progress in oligonucleotide chemistry to improve the drug properties and reduce cost of goods, but the main hurdle for the application to a wider range of disorders is delivery to target tissues. The adoption of delivery technologies, such as conjugates or nanoparticles, has been a game changer for many therapeutic indications, but many others are still awaiting their eureka moment. Here, we cover the variety of methods developed to deliver nucleic acid‐based therapeutics across biological barriers and the model systems used to test them. We discuss important safety considerations and regulatory requirements for synthetic oligonucleotide chemistries and the hurdles for translating laboratory breakthroughs to the clinic. Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics., Recent advances in the delivery of nucleic acid‐based therapeutics and in the development of model systems, as well as safety considerations and regulatory requirements for synthetic oligonucleotide chemistries are discussed in this review on oligonucleotide‐based therapeutics.
Published: 2021

145. Molecular Characterisation of Cryptosporidium spp. in Mozambican Children Younger than 5 Years Enrolled in a Matched Case-Control Study on the Aetiology of Diarrhoeal Disease

Author: Myron M. Levine, Pedro L. Alonso, Tacilta Nhampossa, Sergio Massora, Inacio Mandomando, Karen L. Kotloff, David Carmena, Pamela C. Köster, Quique Bassat, Augusto Messa, Anelsio Cossa, Marcelino Garrine, Bill & Melinda Gates Foundation, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministry of Science and Technology (Mozambique), USAID Country Office of Mozambique, and Instituto de Salud Carlos III - ISCIII
Subjects: Microbiology (medical), medicine.medical_specialty, Genotyping, prevalence, Cryptosporidium, lcsh:Medicine, molecular epidemiology, Article, children, Genotype, Epidemiology, parasitic diseases, medicine, Prevalence, Immunology and Allergy, Genetic variability, Molecular Biology, Children, Mozambique, ssu rRNA, General Immunology and Microbiology, biology, Molecular epidemiology, lcsh:R, Case-control study, gp60, biology.organism_classification, Virology, Diarrhoea, diarrhoea, Infectious Diseases, genotyping, Etiology, GEMS
Abstract: Cryptosporidium is a leading cause of childhood diarrhoea and associated physical and cognitive impairment in low-resource settings. Cryptosporidium-positive faecal samples (n = 190) from children aged ≤ 5 years enrolled in the Global Enteric Multicenter Study (GEMS) in Mozambique detected by ELISA (11.5%, 430/3754) were successfully PCR-amplified and sequenced at the gp60 or ssu rRNA loci for species determination and genotyping. Three Cryptosporidium species including C. hominis (72.6%, 138/190), C. parvum (22.6%, 43/190), and C. meleagridis (4.2%, 8/190) were detected. Children ≤ 23 months were more exposed to Cryptosporidium spp. infections than older children. Both C. hominis and C. parvum were more prevalent among children with diarrhoeal disease compared to those children without it (47.6% vs. 33.3%, p = 0.007 and 23.7% vs. 11.8%, p = 0.014, respectively). A high intra-species genetic variability was observed within C. hominis (subtype families Ia, Ib, Id, Ie, and If) and C. parvum (subtype families IIb, IIc, IIe, and IIi) but not within C. meleagridis (subtype family IIIb). No association between Cryptosporidium species/genotypes and child's age was demonstrated. The predominance of C. hominis and C. parvum IIc suggests that most of the Cryptosporidium infections were anthroponotically transmitted, although zoonotic transmission events also occurred at an unknown rate. The role of livestock, poultry, and other domestic animal species as sources of environmental contamination and human cryptosporidiosis should be investigated in further molecular epidemiological studies in Mozambique. This research was funded by the Bill and Melinda Gates Foundation through the Center for Vaccine Development at the University of Maryland, School of Medicine who coordinated GEMS, grant number 38874 (GEMS) and OPP1033572 (GEMS1A). Additional funding was obtained from the Health Institute Carlos III (ISCIII), Ministry of Economy and Competitiveness (Spain), grant number PI16CIII/00024, from the Fundo Nacional de Investigacão, Ministry of Science and Technology (Mozambique), grant number 245-INV, and from the USAID Country Office of Mozambique, grant number AID-656-F-16-00002. No
Published: 2021

146. Population Disequilibrium as Promoter of Adaptive Explorations in Hepatitis C Virus

Author: Lucía Vázquez-Sirvent, Rebeca Lobo-Vega, Brenda Martínez-González, Celia Perales, María Eugenia Soria, Josep Quer, Ana Isabel de Ávila, Carlos Briones, Esteban Domingo, Jordi Gómez, Josep Gregori, Isabel Gallego, Elena Moreno, Carlos García-Crespo, Institut Català de la Salut, [García-Crespo C, Ávila AI] Centro de Biología Molecular 'Severo Ochoa' (CBMSO) (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain. [Gallego I] Centro de Biología Molecular 'Severo Ochoa' (CBMSO) (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain. [Soria ME] Centro de Biología Molecular 'Severo Ochoa' (CBMSO) (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, 28049 Madrid, Spain. Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain. [Martínez-González B, Vázquez-Sirvent L] Department of Clinical Microbiology, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain. [Gregori J] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain. Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Roche Diagnostics, S.L., Sant Cugat del Vallés, 08174 Barcelona, Spain. [Quer J] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) del Instituto de Salud Carlos III, 28029 Madrid, Spain. Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Unidad de Excelencia Científica María de Maeztu Centro de Astrobiología del Instituto Nacional de Técnica Aeroespacial y CSIC, MDM-2017-0737, García Crespo, C. [0000-0001-6561-5389], Martínez González, B. [0000-0002-4482-5181], Moreno, E. [0000-0002-2301-4558], Briones, C. [0000-0003-2213-8353], Quer, J. [0000-0003-0014-084X], Banco Santander, Fundación Ramón Areces, Instituto de Salud Carlos III (ISCIII), Agencia Estatal de Investigación (AEI), Ministerio de Economía y Competitividad (MINECO), Ministerio de Ciencia, SAF2017-87846-R and BFU2017-91384-EXP Innovación y Universidades (MCIU), Miguel Servet program of the Instituto de Salud Carlos III, CPII19/00001, Instituto de Salud Carlos III, PI18/00210, European Regional Development Fund (ERDF), PI19/00301, Centro para el Desarrollo Tecnológico Industrial (CDTI), IDI-20200297, Predoctoral contract MCIU, PRE2018-083422, Predoctoral contract PFIS Instituto de Salud Carlos III, FI19/00119, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, European Commission, Global Virus Network, CSIC-INTA - Centro de Astrobiología (CAB), Fundación Banco Santander, and Agencia Estatal de Investigación (España)
Subjects: hepatitis C virus, viruses, lcsh:QR1-502, Residue conservation, Hepacivirus, Review, Viral Nonstructural Proteins, medicine.disease_cause, Virus Replication, Antiviral drug resistance, lcsh:Microbiology, Viral quasispecies, Genetics, Mutation, education.field_of_study, Hepatitis C virus, antiviral drug resistance, virosis::hepatitis viral humana::hepatitis C [ENFERMEDADES], Virus Diseases::Hepatitis, Viral, Human::Hepatitis C [DISEASES], Hepatitis C, Microbiological Phenomena::Virus Physiological Phenomena::Virus Replication [PHENOMENA AND PROCESSES], Infectious Diseases, sequence space, residue conservation, RNA, Viral, Sequence Analysis, Mutational waves, fenómenos microbiológicos::farmacorresistencia microbiana::farmacorresistencia viral [FENÓMENOS Y PROCESOS], Population, Other subheadings::Other subheadings::Other subheadings::/virology [Other subheadings], Biology, Favipiravir, Antiviral Agents, Virus, Cell Line, universal vaccines, Virology, Drug Resistance, Viral, Ribavirin, medicine, Microbiological Phenomena::Drug Resistance, Microbial::Drug Resistance, Viral [PHENOMENA AND PROCESSES], Humans, Sequence space, education, Resistència als medicaments, NS3, Otros calificadores::Otros calificadores::Otros calificadores::/virología [Otros calificadores], mutational waves, Virus - Reproducció, fenómenos microbiológicos::fenómenos fisiológicos de los virus::replicación viral [FENÓMENOS Y PROCESOS], COVID-19, Universal vaccines, Viral replication, Covis 19, Virus de l'hepatitis C, viral quasispecies
Abstract: Replication of RNA viruses is characterized by exploration of sequence space which facilitates their adaptation to changing environments. It is generally accepted that such exploration takes place mainly in response to positive selection, and that further diversification is boosted by modifications of virus population size, particularly bottleneck events. Our recent results with hepatitis C virus (HCV) have shown that the expansion in sequence space of a viral clone continues despite prolonged replication in a stable cell culture environment. Diagnosis of the expansion was based on the quantification of diversity indices, the occurrence of intra-population mutational waves (variations in mutant frequencies), and greater individual residue variations in mutant spectra than those anticipated from sequence alignments in data banks. In the present report, we review our previous results, and show additionally that mutational waves in amplicons from the NS5A-NS5B-coding region are equally prominent during HCV passage in the absence or presence of the mutagenic nucleotide analogues favipiravir or ribavirin. In addition, by extending our previous analysis to amplicons of the NS3- and NS5A-coding region, we provide further evidence of the incongruence between amino acid conservation scores in mutant spectra from infected patients and in the Los Alamos National Laboratory HCV data banks. We hypothesize that these observations have as a common origin a permanent state of HCV population disequilibrium even upon extensive viral replication in the absence of external selective constraints or changes in population size. Such a persistent disequilibrium¿revealed by the changing composition of the mutant spectrum¿may facilitate finding alternative mutational pathways for HCV antiviral resistance. The possible significance of our model for other genetically variable viruses is discussed., The work at CBMSO was supported by grants SAF2014-52400-R from Ministerio de Economía y Competitividad (MINECO), SAF2017-87846-R and BFU2017-91384-EXP from Ministerio de Ciencia, Innovación y Universidades (MCIU), PI18/00210 from Instituto de Salud Carlos III, S2013/ABI-2906 (PLATESA from Comunidad de Madrid/FEDER), and S2018/BAA-4370 (PLATESA2 from Comunidad de Madrid/FEDER). C.P. is supported by the Miguel Servet program of the Instituto de Salud Carlos III (CPII19/00001), cofinanced by the European Regional Development Fund (ERDF). CIBERehd (Centro de Investigación en Red de Enfermedades Hepáticas y Digestivas) is funded by Instituto de Salud Carlos III. Institutional grants from the Fundación Ramón Areces and Banco Santander to the CBMSO are also acknowledged. The team at CBMSO belongs to the Global Virus Network (GVN). The work in Barcelona was supported by Instituto de Salud Carlos III, cofinanced by the European Regional Development Fund (ERDF) Grant No. PI19/00301 and by the Centro para el Desarrollo Tecnológico Industrial (CDTI) from the MICIU, Grant No. IDI-20200297. Work at CAB was supported by MINECO grant BIO2016-79618R and PID2019-104903RB-I00 (funded by the EU under the FEDER program) and by the Spanish State research agency (AEI) through project number MDM-2017-0737 Unidad de Excelencia “María de Maeztu”-Centro de Astrobiología (CSIC-INTA). C.G.-C. is supported by predoctoral contract PRE2018-083422 from MCIU. B.M.-G. is supported by predoctoral contract PFIS FI19/00119 from Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo), cofinanced by Fondo Social Europeo (FSE).
Published: 2021

147. Low Sensitivity of Conventional Fungal Agars in Fungemia by Rhodotorula Mucilaginosa: Description of Two Cases

Author: María Dolores Moragues, Sara María Quevedo, Jorge Ligero, Carmen Alicia Garcia-Gutiérrez, María José Buitrago, María Soledad Cuétara-García, Instituto de Salud Carlos III, Basque Government (España), Instituto de Salud Carlos III - ISCIII, and Gobierno Vasco
Subjects: Male, Microbiological Techniques, Microbiology (medical), medicine.medical_specialty, Antifungal Agents, Antigens, Fungal, specific culture media, lcsh:QR1-502, Case Report, Drug resistance, lcsh:Microbiology, Rhodotorula mucilaginosa, lcsh:Infectious and parasitic diseases, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Medical microbiology, Humans, Medicine, rhodotorula mucilaginosa, risk factors, lcsh:RC109-216, 030212 general & internal medicine, Pathogen, Fungemia, Aged, 80 and over, 0303 health sciences, Rapid diagnostic test, fungemia, 030306 microbiology, business.industry, lcsh:RM1-950, Fungi, Rhodotorula, General Medicine, Middle Aged, medicine.disease, Culture Media, lcsh:Therapeutics. Pharmacology, Infectious Diseases, Mycoses, Parasitology, Blood Culture, Candida spp, business
Abstract: Background Although most bloodstream yeast infections are caused by Candida spp., infections by rare or less common species have increased in recent years. Diagnosis of infections caused by these species is difficult due to the lack of specific symptoms and adequate diagnostic tools. Cases presentation We describe two cases of fungemia by Rhodotorula mucilaginosa within a few months of each other, in a secondary Spanish hospital. In both cases, diagnosis was challenging. Blood subcultures in conventional fungal media were persistently negatives and the use of non-conventional fungal media was essential for isolating the yeasts and achieving a correct diagnosis. 1–3 beta-d-glucan detection and a panfungal PCR assay were helpful techniques to confirm the diagnosis Conclusion It is highly important to establish an early diagnosis for fungemia. The process is challenging because often non-specific symptoms are presents. When yeasts grow in blood cultures other genera than Candida spp. could be the cause of infection. Patient risk factors should be assessed to incorporate alternative culture media and the available rapid diagnostic test, in order to provide an early recognition of the pathogen.
Published: 2021

148. Recombinant IGF-1 Induces Sex-Specific Changes in Bone Composition and Remodeling in Adult Mice with

Author: Rubén Tovar, Leticia Rubio, Juan Suárez, Julian K. Christians, Jesús Argente, Antonio Vargas, Fernando Rodríguez de Fonseca, Antonio J. López-Gambero, Patricia Rivera, Stella Martin-de-las-Heras, Julie A. Chowen, [Rubio,L, Martín-de-las-Heras,S, Suárez,J] Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain. [Vargas,A, Rivera,P, López-Gambero,AJ, Tovar,R, Rodríguez de Fonseca,F, Suárez,J] Unidad de Gestión Clínica de Salud Mental, IBIMA, Hospital Regional Universitario de Málaga, Málaga, Spain. [Christians,JK] Department of Biological Sciences, Simon Fraser University, Burnaby, Canada. [Chowen,JA, Argente,J] Department of Endocrinology, Instituto de Investigación Biomédica la Princesa, Hospital Infantil Universitario Niño Jesús, Madrid, Spain. [Chowen,JA, Argente,J] Centro de Investigación Biomédica en Red Fisiología de la Obesidad y Nutrición (CIBEROBN), Madrid, Spain. [Chowen,JA, Argente,J] IMDEA Food Institute, Campus of International Excellence (CEI) UAM + CSIC, Madrid, Spain. [Argente,J] Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain., This research was funded by Instituto de Salud Carlos III (ISCIII), Ministerio de Economía y Competitividad (MINECO) and European Regional Development Funds-European Union (ERDF-EU), grant number PI16/01374 and PI19/00343 (J.S.), PI16/00485 and PI19/00166 (J.A.), and BFU2017– 82565-C2-1-R (J.A.C.), and NSERC (Canada) Discovery Grant, grant number, 2016-04047 (J.K.C.). J.S. (CPII17/00024) and P.R. (CP19/00068) hold 'Miguel Servet' research contracts and A.J.L.-G. holds a i-PFIS research contract (IFI18/00042), all of them from the National System of Health, ISCIII, ERDF-EU.
Subjects: collagen, 0301 basic medicine, IGFBP3, bone, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Pregnancy Proteins::Pregnancy-Associated Plasma Protein-A [Medical Subject Headings], Bone remodeling, law.invention, lcsh:Chemistry, Hueso, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Características sexuales, law, Bone Density, Osteogenesis, Gene expression, Organisms::Eukaryota::Animals [Medical Subject Headings], Apatita, Pappa2 deficiency, Pregnancy-Associated Plasma Protein-A, IGFBP, Osteopontin, Insulin-Like Growth Factor I, lcsh:QH301-705.5, pappalysin, Spectroscopy, Mice, Knockout, Sex Characteristics, biology, Chemistry, Gene Expression Regulation, Developmental, General Medicine, 3. Good health, Computer Science Applications, Resorption, Proteína plasmática asociada al embarazo, Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Genetically Modified::Mice, Transgenic::Mice, Knockout [Medical Subject Headings], Osteocalcin, Recombinant DNA, Bone Remodeling, medicine.medical_specialty, Phenomena and Processes::Reproductive and Urinary Physiological Phenomena::Reproductive Physiological Phenomena::Sex Characteristics [Medical Subject Headings], growth, sex difference, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Calcium-Binding Proteins::Osteocalcin [Medical Subject Headings], 030209 endocrinology & metabolism, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins [Medical Subject Headings], Crecimiento, Article, Catalysis, Bone resorption, Collagen Type I, Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Cytokines::Osteopontin [Medical Subject Headings], Inorganic Chemistry, 03 medical and health sciences, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Insulin-Like Growth Factor Binding Proteins::Insulin-Like Growth Factor Binding Protein 3 [Medical Subject Headings], Internal medicine, medicine, Animals, Humans, Proteínas de unión a factor de crecimiento similar a la insulina, Physical and Theoretical Chemistry, Bone Resorption, Molecular Biology, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Bone Density [Medical Subject Headings], Organic Chemistry, Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Bone Remodeling [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Intercellular Signaling Peptides and Proteins::Somatomedins::Insulin-Like Growth Factor I [Medical Subject Headings], Collagen Type I, alpha 1 Chain, 030104 developmental biology, Endocrinology, Insulin-Like Growth Factor Binding Protein 3, lcsh:Biology (General), lcsh:QD1-999, apatite, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Scleroproteins::Extracellular Matrix Proteins::Collagen::Fibrillar Collagens::Collagen Type I [Medical Subject Headings], Phenomena and Processes::Musculoskeletal and Neural Physiological Phenomena::Musculoskeletal Physiological Phenomena::Musculoskeletal Physiological Processes::Musculoskeletal Development::Bone Development::Osteogenesis [Medical Subject Headings], biology.protein, Colágeno, Carrier Proteins
Abstract: Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive Pappa2 knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. Pappa2ko/ko mice (both sexes) had reduced body and bone length. Male Pappa2ko/ko mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in Igfbp3, osteopontin (resorption) and osteocalcin (formation) characterized the bone of Pappa2ko/ko females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in Pappa2ko/ko mice (both sexes). rmIGF-1 treatment in Pappa2ko/ko females also increased collagen maturity, and Igfbp3, Igfbp5, Col1a1 and osteopontin expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with Pappa2 deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.
Published: 2021

149. Combination immunotherapy using G-CSF and oncolytic virotherapy reduces tumor growth in osteosarcoma

Author: Stefano Gambera, Javier García-Castro, Angela Leo, Alvaro Morales-Molina, Asociación Pablo Ugarte contra el cáncer infantil, Asociación de Familias de Niños con Cáncer de Castilla-La Mancha, Instituto de Salud Carlos III, Comunidad de Madrid (España), Fundación Oncohematología Infantil, Asociación Pablo Ugarte, AFANION, Instituto de Salud Carlos III - ISCIII, Comunidad de Madrid, and Fundación Oncohematología Infantil Asociación Pablo Ugarte
Subjects: lymphocytes, Cancer Research, medicine.medical_treatment, T-Lymphocytes, Immunomodulating Agents, Cytopathogenic Effect, Viral, Databases, Genetic, Granulocyte Colony-Stimulating Factor, Tumor Microenvironment, Immunology and Allergy, Lymphocytes, Oncolytic virotherapy, oncolytic virotherapy, RC254-282, Mice, Inbred BALB C, Osteosarcoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Combined Modality Therapy, Oncolytic Viruses, medicine.anatomical_structure, Oncology, Molecular Medicine, immunotherapy, Immunotherapy, T cell, Immunology, Bone Neoplasms, Mesenchymal Stem Cell Transplantation, programmed cell death 1 receptor, Adenoviridae, Immune system, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, medicine, Animals, Humans, Virotherapy, t-lymphocytes, Pharmacology, business.industry, Mesenchymal stem cell, Programmed cell death 1 receptor, Mesenchymal Stem Cells, tumor-infiltrating, medicine.disease, Oncolytic virus, Oncolytic and Local Immunotherapy, Cancer cell, Cancer research, Tumor-infiltrating, business
Abstract: Factor de impacto: 13,751 Q1 Osteosarcoma is the most common malignant solid tumor that affects bones, however, survival rates of patients with relapsed osteosarcoma have not improved in the last 30 years. Oncolytic virotherapy, which uses viruses designed to selectively replicate in cancer cells, has emerged as a promising treatment for solid tumors. Our group uses mesenchymal stem cells (MSCs) to transport oncolytic adenoviruses (OAds) to the tumor site, a therapeutic strategy called Celyvir. This treatment has been already applied in human patients, canine patients and different mouse models. In parallel, previous results have probed that administration of granulocyte-colony stimulating factor (G-CSF) increased immune infiltration in tumors. We then hypothesized that the mobilization of immune cells by G-CSF may increase the antitumor efficacy of Celyvir treatment by increasing the immune infiltration into the tumors. In this study, we use a murine version of Celyvir consisting in murine MSCs carrying the murine OAd dlE102-here called OAd-MSCs-in an immunocompetent model of osteosarcoma. We tested the antitumoral efficacy of the combination of OAd-MSCs plus G-CSF. Our results show that treatment with OAd-MSCs or the union of OAd-MSCs with G-CSF (Combination) significantly reduced tumor growth of osteosarcoma in vivo. Moreover, treated tumors presented higher tumor infiltration of immune cells-especially tumor-infiltrating lymphocytes-and reduced T cell exhaustion, which seems to be enhanced in tumors treated with the Combination. The comparison of our results to those obtained from a cohort of pediatric osteosarcoma patients showed that the virotherapy induces immunological changes similar to those observed in patients with good prognosis. The results open the possibility of using cellular virotherapy for the treatment of bone cancers. Indeed, its combination with G-CSF may be considered for the improvement of the therapy. This study was funded by the Instituto de Salud Carlos III of Spain (grant numbers PI14CIII/00005 and PI17CIII/00013), Consejería de Educación, Juventud y Deporte of Comunidad de Madrid (grant number P2017/BMD-3692), Fundación Oncohematología Infantil, Asociación Pablo Ugarte and AFANION, whose support we gratefully acknowledge. Sí
Published: 2021

150. Rolipram Prevents the Formation of Abdominal Aortic Aneurysm (AAA) in Mice: PDE4B as a Target in AAA

Author: José Martínez-González, María Galán, Laia Cañes, Saray Varona, Mercedes Camacho, Marc Sirvent, Cristina Rodríguez, Vicente Andrés, Mar Orriols, Silvia Aguiló, Lídia Puertas, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Sociedad Española de Arteriosclerosis, Sociedad Española de Cardiología, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Fundación ProCNIC, Agencia de Gestio d'Ajuts Universitaris i de Recerca, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Generalitat de Catalunya, European Commission, Centro Nacional de Investigaciones Cardiovasculares (España), Instituto de Salud Carlos III - ISCIII, and European Regional Development Fund (ERDF/FEDER)
Subjects: 0301 basic medicine, PDE4B, Physiology, Clinical Biochemistry, Inflammation, 030204 cardiovascular system & hematology, Pharmacology, medicine.disease_cause, Biochemistry, Article, Vascular remodelling in the embryo, 03 medical and health sciences, 0302 clinical medicine, abdominal aortic aneurysm, medicine, cardiovascular diseases, Molecular Biology, Rolipram, reactive oxygen species, biology, rolipram, business.industry, lcsh:RM1-950, Cell Biology, medicine.disease, Angiotensin II, Abdominal aortic aneurysm, 030104 developmental biology, lcsh:Therapeutics. Pharmacology, biology.protein, cardiovascular system, medicine.symptom, business, Elastin, Oxidative stress, medicine.drug
Abstract: Abdominal aortic aneurysm (AAA) is a common life-threatening condition characterized by exacerbated inflammation and the generation of reactive oxygen species. Pharmacological treatments to slow AAA progression or to prevent its rupture remain a challenge. Targeting phosphodiesterase 4 (PDE4) has been verified as an effective therapeutic strategy for an array of inflammatory conditions; however, no studies have assessed yet PDE4 in AAA. Here, we used angiotensin II (AngII)-infused apolipoprotein E deficient mice to study the involvement of the PDE4 subfamily in aneurysmal disease. PDE4B but not PDE4D was upregulated in inflammatory cells from both experimental and human AAA. The administration of the PDE4 selective inhibitor rolipram (3 mg/kg/day) to AngII-challenged mice (1000 ng/kg bodyweight/min) protected against AAA formation, limiting the progressive increase in the aortic diameter without affecting the blood pressure. The drug strongly attenuated the rise in vascular oxidative stress (superoxide anion) induced by AngII, and decreased the expression of inflammatory markers, as well as the recruitment of macrophages (MAC3+), lymphocytes (CD3+), and neutrophils (ELANE+) into the vessel wall. Rolipram also normalized the vascular MMP2 expression and MMP activity, preserving the elastin integrity and improving the vascular remodelling. These results point to PDE4B as a new therapeutic target for AAA., This work was supported by Instituto de Salud Carlos III (ISCIII) [PI18/0919], the Spanish Ministerio de Ciencia e Innovación (MICINN) [RTI2018-094727-B-100 and PID2019-108489RB-100], the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) [2017-SGR-00333], Sociedad Española de Arteriosclerosis [Beca FEA 2020 Investigación Básica], and Sociedad Española de Cardiología [SEC/FEC-INV-BAS 20/005]. The study was co-founded by Fondo Europeo de Desarrollo Regional (FEDER), “A way to make Europe”. L.C. was supported by a FI (AGAUR). The CNIC is supported by MICINN, ISCIII, and the Pro-CNIC Foundation.
Published: 2021

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