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1. SARS-CoV-2 viral load in nasopharyngeal swabs is not an independent predictor of unfavorable outcome

Author: Sonsoles Salto-Alejandre, Judith Berastegui-Cabrera, Pedro Camacho-Martínez, Carmen Infante-Domínguez, Marta Carretero-Ledesma, Juan Carlos Crespo-Rivas, Eduardo Márquez, José Manuel Lomas, Claudio Bueno, Rosario Amaya, José Antonio Lepe, José Miguel Cisneros, Jerónimo Pachón, Elisa Cordero, Javier Sánchez-Céspedes, The Virgen del Rocío Hospital COVID-19 Working Team, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Junta de Andalucía, Salto-Alejandre, Sonsoles, Camacho-Martínez, Pedro, Sánchez-Céspedes, Javier, Salto-Alejandre, Sonsoles [0000-0002-1280-4810], Camacho-Martínez, Pedro [0000-0002-6331-4600], Sánchez-Céspedes, Javier [0000-0003-2707-1979], The Virgen del Rocío Hospital COVID-19 Working Team, [Salto-Alejandre,S, Berastegui-Cabrera,J, Camacho-Martínez,P, Infante-Domínguez,C, Carretero-Ledesma,M, Crespo-Rivas,JC, Lomas,JM, Lepe,JA, Cisneros,JM, Cordero,E, Sánchez-Céspedes,J] Unit of Infectious Diseases, Microbiology, and Preventive Medicine, Virgen del Rocío University Hospital, Seville, Spain. [Salto-Alejandre,S, Pachón,J, Sánchez-Céspedes,J] Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Seville, Spain. [Márquez,E] Medico Surgical Unit of Respiratory Diseases, Virgen del Rocío University Hospital, Seville, Spain. [Bueno,C] Unit of Emergencies, Virgen del Rocío University Hospital, Seville, Spain. [Amaya,R] Intensive Care Unit, Virgen del Rocío University Hospital, Seville, Spain. [Pachón,J, Cordero,E] Department of Medicine, University of Seville, Seville, Spain., Tis work was supported by National Plan R+D+I 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministry of Economy, Industry, and Competitiveness, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0009], cofnanced by European Develop ment Regional Fund 'A way to achieve Europe', Operative program Intelligent Growth 2014–2020, and supported by Grants from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Proyectos de Investigación sobre el SARS-CoV-2 y la enfermedad COVID-19 [COV20/00370, and COV20/00580]. J.S.C. is a researcher belong ing to the program 'Nicolás Monardes' (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain.
Subjects: 0301 basic medicine, Male, Logistic regression, Severity of Illness Index, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], law.invention, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Patient Admission, Carga Viral, law, Nasopharynx, Clinical endpoint, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings], Aged, 80 and over, Multidisciplinary, Pronóstico, Middle Aged, Viral Load, Prognosis, Intensive care unit, Death, Intensive Care Units, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys::Health Status Indicators::Patient Acuity::Severity of Illness Index [Medical Subject Headings], Muerte, Quartile, COVID-19 Nucleic Acid Testing, RNA, Viral, Medicine, Female, Viral load, Adult, medicine.medical_specialty, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Anatomy::Respiratory System::Pharynx::Nasopharynx [Medical Subject Headings], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Science, 030106 microbiology, Check Tags::Male [Medical Subject Headings], Real-Time Polymerase Chain Reaction, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospital Units::Intensive Care Units [Medical Subject Headings], Article, 03 medical and health sciences, 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], Severity of illness, medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Patient Care::Hospitalization::Patient Admission [Medical Subject Headings], Humans, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, Viral [Medical Subject Headings], Persons::Persons::Age Groups::Adult [Medical Subject Headings], Aged, business.industry, SARS-CoV-2, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Real-Time Polymerase Chain Reaction [Medical Subject Headings], 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], Check Tags::Female [Medical Subject Headings], Risk factors, Persons::Persons::Age Groups::Adult::Aged::Aged, 80 and over [Medical Subject Headings], Viral infection, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Microbiological Techniques::Viral Load [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis [Medical Subject Headings], business, Follow-Up Studies
Abstract: The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at first patient’s hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confirmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n = 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥ 7.35 log10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the final multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age ≥ 70 years, SpO2, neutrophils > 7.5 × 103/µL, lactate dehydrogenase ≥ 300 U/L, and C-reactive protein ≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome., This work was supported by National Plan R+D+I 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministry of Economy, Industry, and Competitiveness, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0009]; cofinanced by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020; and supported by Grants from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Proyectos de Investigación sobre el SARS-CoV-2 y la enfermedad COVID-19 [COV20/00370; COV20/00580]. J.S.C. is a researcher belonging to the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain.
Published: 2021

2. A multi-laboratory benchmark study of isothermal titration calorimetry (ITC) using Ca2+ and Mg2+ binding to EDTA

Author: Huaying Zhao, Adrián Velázquez-Campoy, Di Wu, Eric Ennifar, Shih Chia Tso, Jonas Höring, Louis Bourlon, Grzegorz Piszczek, Chad A. Brautigam, Olga Abian, Sandro Keller, Patrick England, Rafael Claveria-Gimeno, Bárbara Claro, Jonathan B. Chaires, Margarida Bastos, Peter Schuck, Fundação para a Ciência e a Tecnologia (Portugal), Ministerio de Economía y Competitividad (España), Ministerio de Educación y Cultura (España), Instituto de Salud Carlos III, European Commission, Diputación General de Aragón, Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (España), National Institutes of Health (US), National Institute of Biomedical Imaging and Bioengineering (US), Ministério da Saúde (Portugal), Universidade do Porto (Portugal), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Instituto de Investigación Sanitaria de Aragón [Zaragoza] (IIS Aragón), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas (CIBERehd), Liver Unit, Clínica Universitaria, CIBER-EHD, Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID), Universidade do Porto, Instituto Aragonés de Ciencias de la Salud [Zaragoza] (IACS), Technische Universität Kaiserslautern (TU Kaiserslautern), Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Louisville, National Institutes of Health [Bethesda] (NIH), University of Texas Southwestern Medical Center [Dallas], Karl-Franzens-Universität [Graz, Autriche], BioTechMed-Graz, Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität [Graz, Autriche]-Medical University Graz, M.B. acknowledges the financial support from Fundação para a Ciência e Tecnologia (FCT), Portugal, together with FEDER through 'Programa Operacional Competitividade e Internacionalização' (POCI), by COMPETE2020 to Projects POCI-01-0145-FEDER-030579 and UIDB/00081/2020. A.V.C. and O.A. acknowledge financial support from the Spanish Ministry of Economy and Competitiveness and European ERDF Funds (MCIU/AEI/FEDER, EU) (BFU2013-47064-P and BFU2016-78232-P to A.V.C.), the Spanish Ministry of Education and Culture (FPU13/3870 to R.C.G.), Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III and European Union (ERDF/ESF, 'Investing in your future') (PI15/00663 and PI18/00349 to O.A.), Diputación General de Aragón (Protein Targets and Bioactive Compounds Group E45_20R to A.V.C. and Digestive Pathology Group B25_20R to O.A.) and Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd). JBC was supported by NIH Grant GM077422. This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. MB gratefully acknowledges the support of Frederico Silva of the Biochemical and Biophysical Technologies Scientific Platform of the Instituto de Investigação e Inovação em Saúde, I3S, Universidade do Porto. We all thank COST Action CA15126, Working Group 4, for the support to this study., Universidade do Porto = University of Porto, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Karl-Franzens-Universität Graz, Graz University of Technology [Graz] (TU Graz)-Karl-Franzens-Universität Graz-Medical University Graz, University of Graz, and Graz University of Technology [Graz] (TU Graz)-University of Graz-Medical University Graz
Subjects: 0301 basic medicine, 030103 biophysics, Data treatment, Sample preparation, Biophysics, Standard reaction, computer.software_genre, Isothermal Titration Calorimetry (ITC), Standard deviation, Set (abstract data type), 03 medical and health sciences, Software, Benchmark study, Ligand-binding, Mathematics, Protocol (science), business.industry, Isothermal titration calorimetry, General Medicine, 3. Good health, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, 030104 developmental biology, Benchmark (computing), Data mining, business, computer
Abstract: 23 pags., 11 figs., 14 tabs., A small-scale ITC benchmarking study was performed involving 9 biophysics laboratories/facilities, to evaluate inter-laboratory and intra-laboratory basal levels of uncertainty. Our prime goal was to assess a number of important factors that can influence both the data gathered by this technique and the thermodynamic parameter values derived therefrom. In its first part, the study involved 5 laboratories and 13 different instruments, working with centrally prepared samples and the same experimental protocol. The second part involved 4 additional laboratories and 6 more instruments, where the users prepared their own samples according to provided instructions and did the experiments following the same protocol as in the first part. The study design comprised: (1) selecting a minimal set of laboratories; (2) providing very stable samples; (3) providing samples not requiring preparation or manipulation; and (4) providing a well-defined and detailed experimental protocol. Thus, we were able to assess: (i) the variability due to instrument and data analysis performed by each user on centrally prepared samples; (ii) the comparability of data retrieved when using 4 different software packages to analyze the same data, besides the data analysis carried out by the different users on their own experimental results; and (iii) the variability due to local sample preparation (second part of the study). Individual values, as well as averages and standard deviations for the binding parameters for EDTA-cation interaction, were used as metrics for comparing the equilibrium association constant (logK), enthalpy of interaction (ΔH), and the so-called “stoichiometry” (n), a concentration-correction factor., M.B. acknowledges the fnancial support from Fundação para a Ciência e Tecnologia (FCT), Portugal, together with FEDER through “Programa Operacional Competitividade e Internacionalização” (POCI), by COMPETE2020 to Projects POCI-01-0145- FEDER-030579 and UIDB/00081/2020. A.V.C. and O.A. acknowledge fnancial support from the Spanish Ministry of Economy and Competitiveness and European ERDF Funds (MCIU/AEI/FEDER, EU) (BFU2013-47064-P and BFU2016-78232-P to A.V.C.), the Spanish Ministry of Education and Culture (FPU13/3870 to R.C.G.), Fondo de Investigaciones Sanitarias from Instituto de Salud Carlos III and European Union (ERDF/ESF, “Investing in your future”) (PI15/00663 and PI18/00349 to O.A.), Diputación General de Aragón (Protein Targets and Bioactive Compounds Group E45_20R to A.V.C. and Digestive Pathology Group B25_20R to O.A.) and Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd). JBC was supported by NIH Grant GM077422. This work was supported by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. MB gratefully acknowledges the support of Frederico Silva of the Biochemical and Biophysical Technologies Scientifc Platform of the Instituto de Investigação e Inovação em Saúde, I3S, Universidade do Porto. We all thank COST Action CA15126, Working Group 4, for the support to this study
Published: 2021

3. A set of miRNAs predicts T2DM remission in patients with coronary heart disease: from the CORDIOPREV study

Author: Gracia M. Quintana-Navarro, Raúl M. Luque, Jose M. Ordovas, Pablo Perez-Martinez, Oriol A. Rangel-Zuñiga, Juan F. Alcala-Diaz, Yelizaveta Krylova, Francisco Gomez-Delgado, Antonio Camargo, Ana Leon-Acuña, Jose Lopez-Miranda, Javier Delgado-Lista, Cristina Vals-Delgado, Regional Government of Andalusia (España), Centro de Excelencia en Investigación sobre Aceite de Oliva y Salud, Ministerio de Medio Ambiente, Medio Rural y Marino (España), Fundación Patrimonio Comunal Olivarero, Ministerio de Economía y Competitividad (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto de Salud Carlos III, United States Department of Agriculture, Junta de Andalucía, Diputaciones de Jaén, Diputaciones de Jaén y Córdoba, Ministerio de Medio Ambiente, Medio Rural y Marino, Consejería de Innovación, Ciencia y Empresa, European Regional Development Fund (ERDF/FEDER), and Instituto de Salud Carlos III - ISCIII
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Mediterranean diet, Receiver operating characteristic, endocrine system diseases, business.industry, Proportional hazards model, Hazard ratio, lcsh:RM1-950, Area under the curve, Type 2 Diabetes Mellitus, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, lcsh:Therapeutics. Pharmacology, 030220 oncology & carcinogenesis, Internal medicine, Drug Discovery, microRNA, Linear regression, medicine, Molecular Medicine, Original Article, business
Abstract: MicroRNAs (miRNAs) regulate the expression of genes associated with the development of diseases, including type 2 diabetes mellitus (T2DM). However, the use of miRNAs to predict T2DM remission has been poorly studied. Therefore, we aimed to investigate whether circulating miRNAs could be used to predict the probability of T2DM remission in patients with coronary heart disease. We included the newly diagnosed T2DM (n = 190) of the 1,002 patients from the CORDIOPREV study. Seventy-three patients reverted from T2DM after 5 years of dietary intervention with a low-fat or Mediterranean diet. Plasma levels of 56 miRNAs were measured by OpenArray. Generalized linear model, receiver operating characteristic (ROC), Cox regression, and pathway analyses were performed. ROC analysis based on clinical variables showed an area under the curve (AUC) of 0.66. After a linear regression analysis, seven miRNAs were identified as the most important variables in the group’s differentiation. The addition of these miRNAs to clinical variables showed an AUC of 0.79. Cox regression analysis using a T2DM remission score including miRNAs showed that high-score patients have a higher probability of T2DM remission (hazard ratio [HR]low versus high, 4.44). Finally, 26 genes involved in 10 pathways were related to the miRNAs. We have identified miRNAs (hsa-let-7b, hsa-miR-101, hsa-miR-130b-3p, hsa-miR-27a, hsa-miR-30a-5p, hsa-miR-375, and hsa-miR-486) that contribute to the prediction of T2DM remission in patients with coronary heart disease., Graphical Abstract, Type 2 diabetes mellitus (T2DM) is one of the most important health problems worldwide, but this disease may revert by the consumption of healthy diets. Our work suggests the use of seven genetic factors (microRNAs) to predict the probability of T2DM remission in patients with coronary heart disease.
Published: 2021

4. Sophisticated viral quasispecies with a genotype-related pattern of mutations in the hepatitis B X gene of HBeAg-ve chronically infected patients

Author: Marçal Yll, L. Carioti, Mercedes Guerrero-Murillo, Rosa Lopez-Martinez, Rafael Esteban-Mur, Mar Riveiro-Barciela, Cristina Godoy, Carolina González, Ariadna Rando, Josep Gregori, Selene Garcia-Garcia, Francisco Rodriguez-Frias, Maria Francesca Cortese, David Tabernero, Sara Sopena, Beatriz Pacín Ruiz, Rosario Casillas, Josep Quer, Maria Buti, Institut Català de la Salut, [Cortese MF, Casillas R, Sopena S, Yll M] Liver Unit, Liver Disease Laboratory Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Unitat de Patologia Hepàtica, Servei de Bioquímica i Servei de Microbiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [González C, Rando A, Lopez-Martinez R] Unitat de Patologia Hepàtica, Servei de Bioquímica i Servei de Microbiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Gregori J] Liver Unit, Liver Disease Laboratory Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Roche Diagnostics SL, Sant Cugat del Vallès, Spain. [Carioti L] Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy. [Guerrero-Murillo M] Servei de Microbiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Riveiro-Barciela M, Esteban-Mur R, Buti M] Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain. Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Godoy C, Tabernero D, Rodríguez-Frías F] Unitat de Patologia Hepàtica, Servei de Bioquímica i Servei de Microbiologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain. [Quer J] Liver Unit, Liver Disease Laboratory Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto De Salud Carlos III, Madrid, Spain. [Pacín Ruiz B, García-García S] Liver Unit, Liver Disease Laboratory Viral Hepatitis, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Liver Cirrhosis, Male, Genes, Viral, viruses, Virus Replication, 0302 clinical medicine, Genotype, fenómenos genéticos::variación genética::cuasiespecies [FENÓMENOS Y PROCESOS], Sequencing, Hepatitis B e Antigens, Genètica vírica, Virus Diseases::DNA Virus Infections::Hepadnaviridae Infections::Hepatitis B::Hepatitis B, Chronic [DISEASES], Multidisciplinary, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Liver Neoplasms, Hepatitis B, Middle Aged, HBx, HBeAg, Hepatocellular carcinoma, Infectious diseases, Medicine, 030211 gastroenterology & hepatology, Female, Adult, Hepatitis B virus, Genetic Phenomena::Genetic Variation::Quasispecies [PHENOMENA AND PROCESSES], Carcinoma, Hepatocellular, Science, Viremia, Viral quasispecies, Biology, Article, 03 medical and health sciences, Hepatitis B, Chronic, medicine, Other subheadings::Other subheadings::/genetics [Other subheadings], Humans, Aged, Virus de l'hepatitis B, medicine.disease, Virology, virosis::infecciones por virus ADN::infecciones por Hepadnaviridae::hepatitis B::hepatitis B crónica [ENFERMEDADES], digestive system diseases, Quasispecies, 030104 developmental biology, Viral replication, Haplotypes, Mutation, DNA, Viral
Abstract: Haplotipos; Enfermedades infecciosas; Mutación Haplotips; Enfermetats infeccioses; Mutació Haplotypes; Infectious diseases; Mutation Patients with HBeAg-negative chronic infection (CI) have not been extensively studied because of low viremia. The HBx protein, encoded by HBX, has a key role in viral replication. Here, we analyzed the viral quasispecies at the 5′ end of HBX in CI patients and compared it with that of patients in other clinical stages. Fifty-eight HBeAg-negative patients were included: 16 CI, 19 chronic hepatitis B, 16 hepatocellular carcinoma and 6 liver cirrhosis. Quasispecies complexity and conservation were determined in the region between nucleotides 1255 and 1611. Amino acid changes detected were tested in vitro. CI patients showed higher complexity in terms of mutation frequency and nucleotide diversity and higher quasispecies conservation (p
Published: 2021

5. Predictive and prognostic value of total tumor load in sentinel lymph nodes in breast cancer patients after neoadjuvant treatment using one-step nucleic acid amplification: the NEOVATTL study

Author: M. Sancho, Begoña Vieites, M. D. Martín-Salvago, L. Alfaro, María Ángeles López-García, L. López-Vilaró, B. Fernández-Rodriguez, F. Villardell, Octavio Burgues, V. Peg, C.L. Ramirez-Tortosa, R. Rezola, Institut Català de la Salut, [Vieites B] Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain. [López-García MÁ] Department of Pathology, Hospital Universitario Virgen del Rocío, Sevilla, Spain. CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Instituto de Salud Carlos III, Madrid, Spain. [Martín-Salvago MD, Ramirez-Tortosa CL] Department of Pathology, Hospital Universitario Materno-Infantil, Jaén, Spain. [Rezola R] Department of Pathology, Onkologikoa Kutxa Fundazioa, Donostia, Spain. [Sancho M] Department of Pathology, Hospital Universitario de Salamanca, Salamanca, Spain. [Peg V] Servei d’Anatomia Patològica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. CIBERONC (Centro de Investigación Biomédica en Red de Cáncer), Instituto de Salud Carlos III, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Oncology, Cancer Research, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Neoadjuvant systemic therapy, diagnóstico::técnicas y procedimientos diagnósticos::técnicas de laboratorio clínico::técnicas citológicas::citodiagnóstico::biopsia::biopsia del ganglio linfático centinela [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Metastasis, Breast cancer, 0302 clinical medicine, OSNA, Nodes limfàtics - Biòpsia, Lymph node, Otros calificadores::/terapia [Otros calificadores], neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], medicine.diagnostic_test, General Medicine, Prognosis, Neoadjuvant Therapy, Tumor Burden, medicine.anatomical_structure, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Female, Lymph, Sentinel Lymph Node, Nucleic Acid Amplification Techniques, Research Article, medicine.medical_specialty, Prognostic variable, Prognosi, Disease-free survival, Sentinel lymph node, Breast Neoplasms, Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Cytological Techniques::Cytodiagnosis::Biopsy::Sentinel Lymph Node Biopsy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], 03 medical and health sciences, Predictive Value of Tests, Internal medicine, Biopsy, medicine, Humans, Retrospective Studies, Sentinel Lymph Node Biopsy, business.industry, diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Other subheadings::/therapy [Other subheadings], Nomogram, Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], medicine.disease, 030104 developmental biology, Mama - Càncer - Tractament, business, Total tumor load
Abstract: Objective To evaluate the predictive and prognostic value of total tumor load (TTL) in sentinel lymph nodes (SLNs) in patients with infiltrating breast cancer after neoadjuvant systemic therapy (NST). Methods This retrospective multicenter study used data from a Spanish Sentinel Lymph Node database. Patients underwent intraoperative SLN biopsy after NST. TTL was determined from whole nodes using a one-step nucleic acid amplification (OSNA) assay and defined as the total sum of CK19 mRNA copies in all positive SLNs. Cox-regression models identified independent predictive variables, which were incorporated into a nomogram to predict axillary non-SLN metastasis, and identified prognostic variables for incorporation into a disease-free survival (DFS) prognostic score. Results A total of 314 patients were included; most had no lymph node involvement prior to NST (cN0; 75.0% of patients). Most received chemotherapy with or without biologic therapy (91.7%), and 81 patients had a pathologic complete response. TTL was predictive of non-SLN involvement (area under the concentration curve = 0.87), and at a cut-off of 15,000 copies/µL had a negative predictive value of 90.5%. Nomogram parameters included log (TTL + 1), maximum tumor diameter and study-defined NST response. TTL was prognostic of disease recurrence and DFS at a cut-off of 25,000 copies/µL. After a 5-year follow-up, DFS was higher in patients with ≤ 25,000 copies/µL than those with > 25,000 (89.9% vs. 70.0%; p = 0.0017). Conclusions TTL > 15,000 mRNA copies/µL was predictive of non-SLN involvement and TTL > 25,000 mRNA copies/µL was associated with a higher risk of disease recurrence in breast cancer patients who had received NST.
Published: 2021

6. Pharmacokinetics of echinocandins in suspected candida peritonitis: A potential risk for resistance

Author: Jesús Fortún, Pilar Martín-Dávila, Manuel Cuenca-Estrella, Maria Alvarez, Elia Gomez-García de la Pedrosa, Francesca Gioia, Alicia Gomez-Lopez, Santiago Moreno, Instituto de Salud Carlos III, Redes Tematicas de Investigacion Cooperativa en Salud (España), Ministerio de Ciencia, Innovación y Universidades (España), Red Española de Investigación en Patología Infecciosa, European Regional Development Fund, Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III - ISCIII, and European Regional Development Fund (ERDF/FEDER)
Subjects: Male, 0301 basic medicine, Antifungal Agents, Resistance, Candida glabrata, Anidulafungin, Gastroenterology, Echinocandins, chemistry.chemical_compound, 0302 clinical medicine, Caspofungin, Prospective Studies, 030212 general & internal medicine, Candida, biology, Candidiasis, General Medicine, Infectious Diseases, Female, medicine.drug, Adult, Microbiology (medical), medicine.medical_specialty, Echinocandin, Critical Illness, 030106 microbiology, Peritonitis, Microbial Sensitivity Tests, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Internal medicine, medicine, Humans, lcsh:RC109-216, Pharmacokinetics, business.industry, Peritoneal fluid, Micafungin, bacterial infections and mycoses, medicine.disease, biology.organism_classification, chemistry, business
Abstract: Introduction: A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid. Materials/methods: Peritoneal and serum concentrations of caspofungin, micafungin and anidulafungin were analysed in surgical patients with suspected candida peritonitis. After 4 days of starting therapy, serum and peritoneal samples (through peritoneal drainage) were obtained at baseline, 1, 6, 12 and 24 h of drug administration. Micafungin and anidulafungin concentrations were determined using highperformance liquid chromatography (HPLC/F), whereas caspofungin concentrations were established by bioassay. Results: Twenty-three critically ill patients with suspected abdominal fungal infection who were receiving an echinocandin were prospectively recruited. No specific criteria were applied to prescribe one specific echinocandin. No special clinical differences were observed among the three groups of patients. All were receiving antibiotic therapy, 80% required inotropic drugs, and fungal peritonitis was confirmed in 74% of them. The AUC0_24h (mg h/L) obtained in serum and peritoneal fluid were: 126.84 and 34.38, 98.52 and 18.83, and 66.9 and 8.78 for anidulafungin, micafungin and caspofungin, respectively. The median concentration in peritoneal fluid ranged from 0.66 to 1.82mg/mL for anidulafungin, 0.68–0.88mg/mL for micafungin and 0.21–0.46 mg/mL for caspofungin. Conclusion: The results showed moderate penetration of echinocandins into the peritoneal fluid of these patients. These levels are below the threshold of resistance mutant selection published by other authors. This could justify a potential risk of resistance in patients with prolonged treatment with echinocandins and suboptimal control of abdominal infection. The study received funding from the “Fondo de Investigaciones Sanitarias” of the Spanish Ministry of Health (FIS PI 15/1536). The work was supported by Plan Nacional de I + D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16), and co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014-2020. Sí
Published: 2020

7. The value of the continuous genotyping of multi-drug resistant tuberculosis over 20 years in Spain

Author: Iglesias, M.J., Ibarz, D., Cebollada, A., Comín, J., Jiménez, M.S., Vázquez, M.C., Samper, S., Cabezas, T., Reyes, A., Ruiz, I., García, P., López, M.D., Cardeñoso, L., de la Calle, I.J., Ruiz, P., Alados, J.C., Román, J., Villa-Real, R., Saavedra, J., Amores, C., Bermúdez, P., Sánchez, M.A., Montiel, N., Bernal, S., Lepe, J.A., Batista, N., Roldán, E., Torres, L., Navarro, C., Chocarro, P., Aldea, M.J., Viñuelas, J., Vitoria, M.A., Palacios, J.J., Villar, H., Prendes, P., Blanco, M., Vázquez, F., Telenti, M., Sánchez, I., Carbo, L., Escobar, S., Ramírez, A., Gallegos, C., Pérez, M.C., Lecuona, M., Díez, O., Copado, R., Campos, I., Cañas, F., Salas, C., Fernández, C., Roíz, M.P., Barba, I., Manrique, E., Carranza, R., Maroto, A.S., González, A., Rodríguez, E., Martino, V., Sánchez, C., Martínez, C., Robles, P., Simarro, E., Romero, C., López, R., Blanco, M.D., Nebreda, T., Rodríguez, J., Fernández, J.M., Álvarez, E., Jaime, M.L., Tejero, M.D., Alberte, A., Oteda, E., Megías, G., Labayru, C., Ibáñez, R., Campos, A., Carrero, P., Villó, J.M., Sans, T., Pujol, I., Clivillé, X., Castellví, J.B., de Batlle, J., Mariscal, D., Prat, C., García, M., Alcalde, F., Gallén, C., Sauca, G., Cuchi, E., Alonso, C., Corcoy, F., Schmidt, G., Tortola, M.T., Garduño, E., Moreno, J.J., Hernández, P., Montes, I., Roman, J., Alonso, P., Rodríguez, A., Barbeyto, L., Fernández, B., Domínguez, D., Villanueva, R., Iglesias, I., Vasallo, F.J., Sevillano, J., Pascual, A., Pérez del Molino, M.L., Ugalde, E., Dopereiro, R., Cuadros, J.A., Pelayo, I., Cacho, J., Cogollos, R., Páez, M., Prieto, S., Fernández, R., López, P., Domingo, D., Millán, R., Bonilla, I., Merino, P., Toro, C., Ruiz, M.J., Menéndez, M., Romero, P., Tato, M., Simón, M., Urmeneta, A., Delgado, A., García, L., Cobos, J., Merino, J., Aznar, E., Piqueras, J., Navarro, M.D., Artero, J.M., Navascués, A., Gil, A., Leiva, J., Elorduy, L., Urra, E., Idígoras, P., Pérez-Trallero, E., Canut, A., Barrios, J.L., Michans, L., Ayarza, R., García, F., Unzaga, M.J., Navarro, M., Gonzalo, N., Martín, C., Gimeno, A., Elia, M., Sabater, S., Rodríguez, J.C., Santos, M., Bosque, M., López, J., Tabernero, E., Galán, M.I., Instituto de Salud Carlos III - ISCIII, and Instituto de Salud Carlos III
Subjects: Male, 0301 basic medicine, Genotyping Techniques, Extensively Drug-Resistant Tuberculosis, Minisatellite Repeats, 0302 clinical medicine, Drug Resistance, Multiple, Bacterial, Tuberculosis, Multidrug-Resistant, Epidemiology, Cluster Analysis, 030212 general & internal medicine, Child, Phylogeny, media_common, Molecular Epidemiology, Mycobacterium bovis, Multidisciplinary, biology, Multi-drug-resistant tuberculosis, Age Factors, Middle Aged, Phylogenetics, Exact test, Child, Preschool, Population Surveillance, Infectious diseases, Medicine, Female, Microbial genetics, Adult, medicine.medical_specialty, Tuberculosis, Adolescent, Science, Policy and public health in microbiology, Article, Young Adult, 03 medical and health sciences, medicine, Humans, media_common.cataloged_instance, European union, Clinical microbiology, Genotyping, Respiratory tract diseases, Molecular epidemiology, Health care, Infant, Newborn, Infant, Mycobacterium tuberculosis, medicine.disease, biology.organism_classification, 030104 developmental biology, Risk factors, Spain, Demography
Abstract: Molecular epidemiology of circulating clinical isolates is crucial to improve prevention strategies. The Spanish Working Group on multidrug resistant tuberculosis (MDR-TB) is a network that monitors the MDR-TB isolates in Spain since 1998. The aim of this study was to present the study of the MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patterns in Spain using the different recommended genotyping methods over time by a national coordinated system. Based on the proposed genotyping methods in the European Union until 2018, the preservation of one method, MIRU-VNTR, applied to selected clustered strains permitted to maintain our study open for 20 years. The distribution of demographic, clinical and epidemiological characteristics of clustered and non-clustered cases of MDR/XDR tuberculosis with proportion differences as assessed by Pearson's chi-squared or Fisher's exact test was compared. The differences in the quantitative variables using the Student's-t test and the Mann-Whitney U test were evaluated. The results obtained showed a total of 48.4% of the cases grouped in 77 clusters. Younger age groups, having a known TB case contact (10.2% vs 4.7%) and XDR-TB (16.5% vs 1.8%) were significantly associated with clustering. The largest cluster corresponded to a Mycobacterium bovis strain mainly spread during the nineties. A total of 68.4% of the clusters detected were distributed among the different Spanish regions and six clusters involving 104 cases were grouped in 17 and 18 years. Comparison of the genotypes obtained with those European genotypes included in The European Surveillance System (TESSy) showed that 87 cases had become part of 20 European clusters. The continuity of MDR strain genotyping in time has offered a widespread picture of the situation that allows better management of this public health problem. It also shows the advantage of maintaining one genotyping method over time, which allowed the comparison between ancient, present and future samples. The molecular methods applied in this work were supported by the Carlos III Health Institute in the context of two consecutive Grants FIS15/0317 and 18/0336 and JC was awarded a scholarship by the Government of Aragon / European Social Fund, “Building Europe from Aragon”. Sí
Published: 2020

8. Proteomic analysis of plasma proteins of high-flux haemodialysis and on-line haemodiafiltration patients reveals differences in transthyretin levels related with anaemia

Author: Emilio Camafeita, Alberto Alcázar, Emma Martínez-Alonso, Paula Alcázar, Gloria Ruiz-Roso, Milagros Fernández-Lucas, Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Instituto de Salud Carlos III - ISCIII, and European Regional Development Fund (ERDF/FEDER)
Subjects: 0301 basic medicine, Male, Proteomics, 030232 urology & nephrology, 0302 clinical medicine, Tandem Mass Spectrometry, Prealbumin, chemistry.chemical_classification, Aged, 80 and over, Multidisciplinary, biology, medicine.diagnostic_test, Anemia, Blood Proteins, Middle Aged, Blood proteins, Nephrology, Erythropoiesis, Medicine, Female, Antibody, medicine.drug, Biotechnology, medicine.medical_specialty, Science, Down-Regulation, Hemodiafiltration, Article, Apolipoproteins E, 03 medical and health sciences, Western blot, Renal Dialysis, Internal medicine, medicine, Humans, Erythropoietin, Aged, business.industry, Transthyretin, 030104 developmental biology, Endocrinology, chemistry, Transferrin, biology.protein, Kidney Failure, Chronic, business, Chromatography, Liquid
Abstract: A large proportion of end-stage renal disease (ESRD) patients under long-term haemodialysis, have persistent anaemia and require high doses of recombinant human erythropoietin (rhEPO). However, the underlying mechanisms of renal anaemia have not been fully elucidated in these patients. In this study, we will be focusing on anaemia and plasma proteins in ESRD patients on high-flux haemodialysis (HF) and on-line haemodiafiltration (HDF), to investigate using two proteomic approaches if patients undergoing these treatments develop differences in their plasma protein composition and how this could be related to their anaemia. The demographic and biochemical data revealed that HDF patients had lower anaemia and much lower rhEPO requirements than HF patients. Regarding their plasma proteomes, HDF patients had increased levels of a protein highly similar to serotransferrin, trypsin-1 and immunoglobulin heavy constant chain alpha-1, and lower levels of alpha-1 antitrypsin, transthyretin, apolipoproteins E and C-III, and haptoglobin-related protein. Lower transthyretin levels in HDF patients were further confirmed by transthyretin-peptide quantification and western blot detection. Since ESRD patients have increased transthyretin, a protein that can aggregate and inhibit transferrin endocytosis and erythropoiesis, our finding that HDF patients have lower transthyretin and lower anaemia suggests that the decrease in transthyretin plasma levels would allow an increase in transferrin endocytosis, contributing to erythropoiesis. Thus, transthyretin could be a critical actor for anaemia in ESRD patients and a novel player for haemodialysis adequacy. This work was supported by Grants (to A.A.) from the Instituto de Salud Carlos III and cofinanced by the European Development Regional Fund (FEDER) (PI14/00705 and PI18/00255). E.M-A. is a recipient of a research. Sí
Published: 2020

9. Deletion of the Wilms' Tumor Suppressor Gene in the Cardiac Troponin-T Lineage Reveals Novel Functions of WT1 in Heart Development

Author: Sandra Díaz del Moral, Silvia Barrena, Francisco Hernández-Torres, Amelia Aránega, José Manuel Villaescusa, Juan José Gómez Doblas, Diego Franco, Manuel Jiménez-Navarro, Ramón Muñoz-Chápuli, Rita Carmona, [Díaz del Moral,S, Barrena,S, Muñoz-Chápuli,R, Carmona,R] Department of Animal Biology, University of Málaga, Málaga, Spain. [Hernández-Torres,F] Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, Spain. [Hernández-Torres,F, Aránega,A] Medina Foundation, Technology Park of Health Sciences, Granada, Spain. [Aránega,A, Franco,D] Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, Jaén, Spain. [Villaescusa,JM, Gómez Doblas,JJ, Jiménez-Navarro,M] Heart Area Clinical Management Unit, University Hospìtal Virgen de la Victoria, CIBERCV Enfermedades Cardiovasculares Health Institute Carlos III, Biomedical Research Institute of Malaga (IBIMA), University of Málaga, Málaga, Spain., and This work was supported by: Spanish Ministry of Economy, Industry and Competitivity (BFU2017-83907-P to RM-C and RC and PID2019-107492GB-I00 to AA and DF), Consejería de Salud, Junta de Andalucía (PC0066?2017/PC-0081-2017 to RC, JV, and JG), Instituto de Salud Carlos III-TERCEL network (RD16/0011/0030 to RM-C and RC), Instituto de Salud Carlos III-CIBERCV 'Enfermedades Cardiovasculares' (CB16/11/00360 to MJ-N), and Consejería de Economía yConocimiento, Junta de Andalucía (UMA18-FEDERJA-146 to RM-C and RC and FEDER-UJA to AA and DF).
Subjects: 0301 basic medicine, Pathology, Genes supresores de tumores, TNNT2, cardiac development, Canales de potasio, cardiomyocytes, Genes del tumor de Wilms, 0302 clinical medicine, Calcium homeostasis, Homeostasis, Wilms’ tumor suppressor gene, Atrium (heart), Biology (General), Anatomy::Cardiovascular System::Heart::Pericardium [Medical Subject Headings], Original Research, Cardiomyocytes, Anatomy::Musculoskeletal System::Muscles::Myocardium [Medical Subject Headings], Heart development, calcium homeostasis, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Potassium Channels [Medical Subject Headings], potassium channels, Chemicals and Drugs::Inorganic Chemicals::Elements::Metals, Alkaline Earth::Calcium [Medical Subject Headings], medicine.anatomical_structure, Chemicals and Drugs::Macromolecular Substances::Polymers::Biopolymers::Microfilament Proteins::Troponin::Troponin T [Medical Subject Headings], cardiovascular system, Crecimiento y desarrollo, medicine.medical_specialty, QH301-705.5, Biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings], Pectinate muscles, Potassium channels, 03 medical and health sciences, QRS complex, Cell and Developmental Biology, Calcio, Cardiac development, medicine, Interventricular septum, cardiovascular diseases, Sinus venosus, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Recessive::Genes, Tumor Suppressor [Medical Subject Headings], Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Wilms' tumor, Cell Biology, medicine.disease, Wilms' tumor supressor gene, 030104 developmental biology, Diseases::Neoplasms::Neoplastic Syndromes, Hereditary::Wilms Tumor [Medical Subject Headings], Anatomy::Cardiovascular System::Heart::Myocardium::Myocytes, Cardiac [Medical Subject Headings], Miocitos cardíacos, 030217 neurology & neurosurgery, Developmental Biology
Abstract: This work was supported by: Spanish Ministry of Economy, Industry and Competitivity (BFU2017-83907-P to RM-C and RC and PID2019-107492GB-I00 to AA and DF), Consejeria de Salud, Junta de Andalucia (PC0066?2017/PC-0081-2017 to RC, JV, and JG), Instituto de Salud Carlos III-TERCEL network (RD16/0011/0030 to RM-C and RC), Instituto de Salud Carlos III-CIBERCV "Enfermedades Cardiovasculares" (CB16/11/00360 to MJ-N), and Consejeria de Economia y Conocimiento, Junta de Andalucia (UMA18-FEDERJA-146 to RM-C and RC and FEDER-UJA to AA and DF)., Expression of Wilms’ tumor suppressor transcription factor (WT1) in the embryonic epicardium is essential for cardiac development, but its myocardial expression is little known. We have found that WT1 is expressed at low levels in 20–25% of the embryonic cardiomyocytes. Conditional ablation of WT1 using a cardiac troponin T driver (Tnnt2Cre) caused abnormal sinus venosus and atrium development, lack of pectinate muscles, thin ventricular myocardium and, in some cases, interventricular septum and cardiac wall defects, ventricular diverticula and aneurisms. Coronary development was normal and there was not embryonic lethality, although survival of adult mutant mice was reduced probably due to perinatal mortality. Adult mutant mice showed electrocardiographic anomalies, including increased RR and QRS intervals, and decreased PR intervals. RNASeq analysis identified differential expression of 137 genes in the E13.5 mutant heart as compared to controls. GO functional enrichment analysis suggested that both calcium ion regulation and modulation of potassium channels are deeply altered in the mutant myocardium. In summary, together with its essential function in the embryonic epicardium, myocardial WT1 expression is also required for normal cardiac development., Spanish Ministry of Economy, Industry and Competitivity BFU2017-83907-P PID2019-107492GB-I00, Junta de Andalucia PC0066?2017/PC-0081-2017, Instituto de Salud Carlos III-TERCEL network RD16/0011/0030 Instituto de Salud Carlos III-CIBERCV "Enfermedades Cardiovasculares" CB16/11/00360, Junta de Andalucia UMA18-FEDERJA-146
Published: 2021

10. Use of Different Food Classification Systems to Assess the Association between Ultra-Processed Food Consumption and Cardiometabolic Health in an Elderly Population with Metabolic Syndrome (PREDIMED-Plus Cohort)

Author: Josep Vidal, Jose M. Ordovas, José Alfredo Martínez, Ángel M. Alonso-Gómez, Estefanía Toledo, Nerea Becerra-Tomás, Dolores Corella, Aurora Bueno-Cavanillas, Jessica Vaquero-Luna, María Concepción Barceló-Iglesias, Beatriz Pérez-Sanz, Antonio García Ríos, María Julia Ajejas Bazán, Ramon Estruch, Vicente Martín Sánchez, Rodrigo San-Cristobal, Miguel Ángel Martínez-González, Xavier Pintó, Dora Romaguera, Jesús Vioque, José J. Gaforio, Pilar Matía-Martín, Lluis Serra-Majem, Itziar Abete, Camille Lassale, Júlia Muñoz-Martínez, Jose Lopez-Miranda, Stephanie K. Nishi, José Lapetra, Lidia Daimiel, Anai Moreno-Rodriguez, Clotilde Vázquez, José V. Sorlí, Celia Martinez-Perez, José Manuel Santos-Lozano, Maira Bes-Rastrollo, Julia Wärnberg, Emilio Ros, María Rosa Bernal-López, Pilar Guallar-Castillón, Nancy Babio, Oscar Lecea-Juarez, María Dolores Zomeño, Olga Castañer, Josep A. Tur, Jordi Salas-Salvadó, Francisco J. Tinahones, Olga Portolés, Jadwiga Konieczna, [Martinez-Perez,C, Ordovás,JM, Daimiel,L] Nutritional Genomics and Epigenomics Group, Precision Nutrition and Obesity Program, IMDEA Food, CEI UAM + CSIC, Madrid, Spain. [San-Cristobal,R, Martinez, JA] Cardiometabolic Nutrition Group, Precision Nutrition and Cardiometabolic Health Program, IMDEA Food, CEI UAM + CSIC, Madrid, Spain. [Guallar-Castillon,P] Cardiovascular and Nutritional Epidemiology Group, IMDEA Food, CEI UAM + CSIC, Madrid, Spain. [Guallar-Castillon,P] Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid—IdiPaz Hospital, Madrid, Spain. [Guallar-Castillon,P, Vioque,J, Bueno-Cavanillas,A, Martín Sánchez,V, Gaforio,JJ] Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain. [Guallar-Castillon,P] Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University, Baltimore, USA. [Martínez-González,MA, Salas-Salvadó,J, Corella,D, Castañer,O, Martinez,JA, Alonso-Gómez,AM, Wärnberg,J, Romaguera,D, López-Miranda,J, Estruch,R, Tinahones,FJ, Lapetra,J, Serra-Majem,L, Tur,JA, Pintó,X, Vázquez,C, Ros,E, Bes-Rastrollo,M, Babio,N, Sorlí,JV, Lassale,C, Vaquero-Luna,J, Konieczna,J, García Ríos,A, Santos-Lozano,JM, Toledo,E, Becerra-Tomás,N, Portoles,O, Abete,I, Moreno-Rodriguez,A] Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Martínez-González,MA, Toledo,E] Department of Preventive Medicine and Public Health, University of Navarra, IdiSNA, Pamplona, Spain. [Martínez-González,MA] Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA. [Salas-Salvadó,J, Becerra-Tomás,T, Nishi,SK] Unitat de Nutrició Humana, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Reus, Spain. [Salas-Salvadó,J, Becerra-Tomás,N] Human Nutrition Unit, Institut d’Investigació Sanitària Pere Virgili (IISPV), Reus, Spain. [Corella,D, Portoles,O] Department of Preventive Medicine, University of Valencia, Valencia, Spain. [Castañer,O, Zomeño,MD, Muñoz-Martínez,J] Cardiovascular Risk and Nutrition Research Group (CARIN), Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. [Martinez,JA, Pérez-Sanz,B, Abete,I] Department of Nutrition, Food Sciences and Physiology, University of Navarra, Pamplona, Spain. [Alonso-Gómez,AM, Moreno-Rodriguez,A] Bioaraba Health Research Institute, Osakidetza Basque Health Service, Araba University Hospital, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain. [Wärnberg, Ajejas Bazán,MJ] Department of Nursing, School of Health Sciences, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Málaga, Málaga. [Vioque,J] Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL-UMH), Alicante, Spain. [Romaguera,D, Konieczna,J] Research Group on Nutritional Epidemiology & Cardiovascular Physiopathology (NUTRECOR), Health Research Institute of the Balearic Islands (IdISBa), University Hospital Son Espases (HUSE), Palma de Mallorca, Spain. [López-Miranda,J, García Ríos,A] Lipids and Atherosclerosis Unit, Department of Internal Medicine, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Córdoba, Spain. [Estruch,R] Department of Internal Medicine, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain. [Tinahones,FJ] Department of Endocrinology, Instituto de Investigación Biomédica de Málaga (IBIMA), Virgen de la Victoria Hospital, University of Málaga, Málaga, Spain. [Lapetra,J, Santos-Lozano,JM] Department of Family Medicine, Research Unit, Distrito Sanitario Atención Primaria Sevilla, Sevilla, Spain. [Serra-Majem,L] Research Institute of Biomedical and Health Sciences (IUIBS), University of Las Palmas de Gran Canaria and Service of Preventive Medicine, Complejo Hospitalario Universitario Insular Materno Infantil (CHUIMI), Canary Health Service, Las Palmas de Gran Canaria, Spain. [Bueno-Cavanillas,A] Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain. [Tur,JA] Research Group on Community Nutrition & Oxidative Stress, University of Balearic Islands-IUNICS & IDISBA, Palma de Mallorca, Spain. [Martín Sánchez,V] Institute of Biomedicine (IBIOMED), University of León, León, Spain. [Pintó,X] Lipids and Vascular Risk Unit, Internal Medicine, Hospital Universitario de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain. [Gaforio,JJ] Departamento de Ciencias de la Salud, Centro de Estudios Avanzados en Olivar y Aceites de Oliva, Universidad de Jaén, Jaén, Spain. [Matía-Martín,P] Department of Endocrinology and Nutrition, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Madrid, Spain. [Vidal,J] Biomedical Research Centre for Diabetes and Metabolic Diseases Network (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. [Vidal,J, Ros,E] Endocrinology and Nutrition Service, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain. [Vázquez,C] Department of Endocrinology and Nutrition, Hospital Fundación Jiménez Díaz, Instituto de Investigaciones Biomédicas IISFJD, University Autónoma, Madrid, Spain. [Ajejas Bazán,MJ] Department of Nursing, Faculty of Nursing, Physiotherapy and Podiatry, Universidad Complutense de Madrid, Madrid, Spain. [Barceló-Iglesias,MC] Centro Salud Cabo Huertas, Alicante, Spain. [Bernal-López,MR] Internal Medicine Department, Instituto de Investigación Biomédica de Málaga (IBIMA), Regional University Hospital of Malaga, Malaga, Spain. [Zomeño,MD] School of Health Sciences, Blanquerna-Ramon Llull University, Barcelona, Spain. [Lecea-Juarez,O] Atención Primaria, Osasunbidea, Servicio Navarro de Salud, Pamplona, Spain. [Ordovás,JM] Nutrition and Genomics Laboratory, JM_USDA Human Nutrition Research Center on Aging, Tufts University, Boston, USA., The PREDIMED-Plus trial was supported by the European Research Council (Advanced Research grant 2014–2019, agreement #340918, granted to M.Á.M.-G.), the official Spanish institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigación para la Salud (FIS) which is co-funded by the European Regional Development Fund (coordinated FIS projects led by J.S-S. and J.V., including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332), and the Especial Action Project 'Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus' (J.S.-S.), the Recercaixa (grant number 2013ACUP00194) (J.S.-S.). Moreover, J.S-S. gratefully acknowledges the financial support by ICREA under the ICREA Academia program, the SEMERGEN grant, Department of Health of the Government of Navarra (61/2015), the Fundació La Marató de TV (Ref. 201630.10), the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (D.R.), grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013, PS0358/2016, PI0137/2018), the PROMETEO/2017/017 grant from the Generalitat Valenciana, the SEMERGEN grant, grant of support to research groups 35/2011 (Balearic Islands Government, and FEDER funds) (J.A.T.). R.S.-C. acknowledges financial support from the Juan de la Cierva Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovación y Ministerio de Universidades (FJC2018-038168- I). N.B.-T. acknowledges financial support from the Juan de la Cierva Formación Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovación y Ministerio de Universidades (FJC2018-036016-I). M.R.B.-L. was supported by 'Miguel Servet Type I' program (CP15/00028) from the ISCIII-Madrid (Spain), cofinanced by the Fondo Europeo de Desarrollo Regional-FEDER. S.K.N. acknowledges financial support from the Canadian Institute for Health Research, CIHR Fellowship. J.K. was supported by the ‘FOLIUM’ programme within the FUTURMed project from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands. C.M.-P. was financially supported by a joint grant from the Community of Madrid and the European Social Fund (grant PEJD-2019-POST/SAL-15892). The METHYL-UP project was supported by the Spanish Ministry of Science and Innovation (RTI2018-095569-B-I00, Programa de Proyectos Orientados a los Retos de la Sociedad 'Projects Toward Society Challenges Program').
Subjects: Síndrome metabólico, Male, Food processing, Mediterranean diet, NOVA, Obesidad, Índice de masa corporal, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, ultra-processed food, Medicine, TX341-641, Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight::Overweight [Medical Subject Headings], Body mass index, classification systems, Incidence, IARC, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Questionnaires [Medical Subject Headings], Metabolic syndrome, 3. Good health, Nutrición, Cohort, Manipulación de alimentos, Dieta, Factores de riesgo cardiometabólico, Concordance, UNC, Check Tags::Male [Medical Subject Headings], Clasificación, Classification systems, Diet Surveys, Article, 03 medical and health sciences, food processing, Humans, Diseases::Cardiovascular Diseases [Medical Subject Headings], Aged, 030109 nutrition & dietetics, Health Care::Health Care Economics and Organizations::Organizations::International Agencies [Medical Subject Headings], Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], PREDIMED-Plus, medicine.disease, Obesity, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Blood pressure, Check Tags::Female [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Linear Models, Fast Foods, Older people, 0301 basic medicine, Síndrome metabòlica, Food Handling, Overweight, Diet, Mediterranean, Persones grans, Cohort Studies, cardiometabolic risk, Endocrinología, 030212 general & internal medicine, Persons::Persons::Age Groups::Adult::Aged [Medical Subject Headings], 2. Zero hunger, Metabolic Syndrome, Nutrition and Dietetics, Technology and Food and Beverages::Technology, Industry, and Agriculture::Industry::Food Industry::Food Handling [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Diet, Mediterranean [Medical Subject Headings], Middle Aged, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Health Surveys::Nutrition Surveys::Diet Surveys [Medical Subject Headings], Female, Technology and Food and Beverages::Food and Beverages::Food::Fast Foods [Medical Subject Headings], medicine.symptom, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin Resistance::Metabolic Syndrome X [Medical Subject Headings], Dietética y nutrición, 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], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Data Collection::Vital Statistics::Morbidity::Incidence [Medical Subject Headings], Environmental health, Alimentos ultraprocesados, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Linear Models [Medical Subject Headings], Nutrició, Nutrition, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], business.industry, Nutrition. Foods and food supply, Cardiometabolic Risk Factors, Dieta mediterránea, Cardiometabolic risk, Ultra-processed food, Diet, Spain, IFIC, Sobrepeso, business, diet, Food Science
Abstract: The PREDIMED-Plus trial was supported by the European Research Council (Advanced Research grant 2014–2019; agreement #340918; granted to M.Á.M.-G.); the official Spanish institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII) through the Fondo de Investigación para la Salud (FIS) which is co-funded by the European Regional Development Fund (coordinated FIS projects led by J.S-S. and J.V., including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332), and the Especial Action Project “Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus” (J.S.-S.); the Recercaixa (grant number 2013ACUP00194) (J.S.-S.). Moreover, J.S-S. gratefully acknowledges the financial support by ICREA under the ICREA Academia program; the SEMERGEN grant; Department of Health of the Government of Navarra (61/2015), the Fundació La Marató de TV (Ref. 201630.10); the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (D.R.); grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013; PS0358/2016; PI0137/2018), the PROMETEO/2017/017 grant from the Generalitat Valenciana, the SEMERGEN grant; grant of support to research groups 35/2011 (Balearic Islands Government; FEDER funds) (J.A.T.). R.S.-C. acknowledges financial support from the Juan de la Cierva Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovación y Ministerio de Universidades (FJC2018-038168- I). N.B.-T. acknowledges financial support from the Juan de la Cierva Formación Program Training Grants of the Spanish State Research Agency of the Spanish Ministerio de Ciencia e Innovación y Ministerio de Universidades (FJC2018-036016-I). M.R.B.-L. was supported by “Miguel Servet Type I” program (CP15/00028) from the ISCIII-Madrid (Spain), cofinanced by the Fondo Europeo de Desarrollo Regional-FEDER. S.K.N. acknowledges financial support from the Canadian Institute for Health Research, CIHR Fellowship. J.K. was supported by the ‘FOLIUM’ programme within the FUTURMed project from the Fundación Instituto de Investigación Sanitaria Illes Balears (financed by 2017 annual plan of the sustainable tourism tax and at 50% with charge to the ESF Operational Program 2014–2020 of the Balearic Islands. C.M.-P. was financially supported by a joint grant from the Community of Madrid and the European Social Fund (grant PEJD-2019- POST/SAL-15892). The METHYL-UP project was supported by the Spanish Ministry of Science and Innovation (RTI2018-095569-B-I00, Programa de Proyectos Orientados a los Retos de la Sociedad “Projects Toward Society Challenges Program”)., The association between ultra-processed food (UPF) and risk of cardiometabolic disorders is an ongoing concern. Different food processing-based classification systems have originated discrepancies in the conclusions among studies. To test whether the association between UPF consumption and cardiometabolic markers changes with the classification system, we used baseline data from 5636 participants (48.5% female and 51.5% male, mean age 65.1 4.9) of the PREDIMEDPlus (“PREvention with MEDiterranean DIet”) trial. Subjects presented with overweight or obesity and met at least three metabolic syndrome (MetS) criteria. Food consumption was classified using a 143-item food frequency questionnaire according to four food processing-based classifications: NOVA, International Agency for Research on Cancer (IARC), International Food Information Council (IFIC) and University of North Carolina (UNC). Mean changes in nutritional and cardiometabolic markers were assessed according to quintiles of UPF consumption for each system. The association between UPF consumption and cardiometabolic markers was assessed using linear regression analysis. The concordance of the different classifications was assessed with intra-class correlation coefficients (ICC3, overall = 0.51). The highest UPF consumption was obtained with the IARC classification (45.9%) and the lowest with NOVA (7.9%). Subjects with high UPF consumption showed a poor dietary profile. We detected a direct association between UPF consumption and BMI (p = 0.001) when using the NOVA system, and with systolic (p = 0.018) and diastolic (p = 0.042) blood pressure when using the UNC system. Food classification methodologies markedly influenced the association between UPF consumption and cardiometabolic risk markers., European Research Council (ERC) European Commission #340918, Centro de Investigacion Biomedica en Red-Fisiopatologia de la Obesidad y Nutricion PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441 PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471 PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332
Published: 2021
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11. Gut microbiota signature in treatment-naïve attention-deficit/hyperactivity disorder

Author: Marta Ribasés, Christian Fadeuilhe, Josep Antoni Ramos-Quiroga, Lorena Arribas, Montserrat Corrales, Alejandro Arias-Vasquez, Cristina Sánchez-Mora, Silvia Karina Rosales-Ortiz, María Soler-Artigas, Vanesa Richarte, Estela Camus Garcia, Laura Vilar-Ribó, Institut Català de la Salut, [Richarte V, Corrales M, Fadeuilhe C] Grup de Recerca en Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. Departament de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Sánchez-Mora C, Vilar-Ribó L] Grup de Recerca en Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. Unitat de Genètica Psiquiàtrica, Grup de Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Arribas L] Grup de Recerca en Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Unitat de Genètica Psiquiàtrica, Grup de Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Garcia E] Unitat de Genètica Psiquiàtrica, Grup de Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Rosales-Ortiz SK] Unitat de Genètica Psiquiàtrica, Grup de Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Department of Biomedicine, University of Barcelona, Barcelona, Spain. [Soler-Artigas M, Ribasés M] Grup de Recerca en Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. Unitat de Genètica Psiquiàtrica, Grup de Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Department of Genetics, Microbiology & Statistics, University of Barcelona, Barcelona, Spain. [Ramos-Quiroga JA] Grup de Recerca en Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. Departament de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain. Unitat de Genètica Psiquiàtrica, Grup de Psiquiatria, Salut Mental i Addiccions, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Adult, 0301 basic medicine, fenómenos microbiológicos::microbiota::microbiota intestinal [FENÓMENOS Y PROCESOS], Scientific community, Adolescent, Veillonellaceae, Physiology, Neurosciences. Biological psychiatry. Neuropsychiatry, Gut flora, Article, Body Mass Index, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Mental Disorders::Neurodevelopmental Disorders::Attention Deficit and Disruptive Behavior Disorders::Attention Deficit Disorder with Hyperactivity [PSYCHIATRY AND PSYCHOLOGY], Abundance (ecology), mental disorders, medicine, Humans, ADHD, Attention deficit hyperactivity disorder, Attention, Intestins - Microbiologia, Child, Relative species abundance, Biological Psychiatry, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Microbiological Phenomena::Microbiota::Gastrointestinal Microbiome [PHENOMENA AND PROCESSES], biology, Gastrointestinal Microbiome, medicine.disease, biology.organism_classification, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Trastorn per dèficit d'atenció amb hiperactivitat, Attention Deficit Disorder with Hyperactivity, Neurodevelopmental Disorders, Dialister, trastornos mentales::trastornos del desarrollo neurológico::trastornos conductuales disruptivos y déficit de atención::trastornos de déficit de atención con hiperactividad [PSIQUIATRÍA Y PSICOLOGÍA], Body mass index, 030217 neurology & neurosurgery, RC321-571
Abstract: Compelling evidence supports alterations in gut microbial diversity, bacterial composition, and/or relative abundance of several bacterial taxa in attention-deficit/hyperactivity disorder (ADHD). However, findings for ADHD are inconsistent among studies, and specific gut microbiome signatures for the disorder remain unknown. Given that previous studies have mainly focused on the pediatric form of the disorder and involved small sample sizes, we conducted the largest study to date to compare the gastrointestinal microbiome composition in 100 medication-naïve adults with ADHD and 100 sex-matched healthy controls. We found evidence that ADHD subjects have differences in the relative abundance of several microbial taxa. At the family level, our data support a lower relative abundance of Gracilibacteraceae and higher levels of Selenomonadaceae and Veillonellaceae in adults with ADHD. In addition, the ADHD group showed higher levels of Dialister and Megamonas and lower abundance of Anaerotaenia and Gracilibacter at the genus level. All four selected genera explained 15% of the variance of ADHD, and this microbial signature achieved an overall sensitivity of 74% and a specificity of 71% for distinguishing between ADHD patients and healthy controls. We also tested whether the selected genera correlate with age, body mass index (BMI), or scores of the ADHD rating scale but found no evidence of correlation between genera relative abundance and any of the selected traits. These results are in line with recent studies supporting gut microbiome alterations in neurodevelopment disorders, but further studies are needed to elucidate the role of the gut microbiota on the ADHD across the lifespan and its contribution to the persistence of the disorder from childhood to adulthood.
Published: 2021

12. Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol

Author: Carlos Sanjuan, Fernando Rodríguez de Fonseca, Francisco Javier Pavón, Rubén Tovar, Elena Baixeras, Juan Antonio Navarro, Cristina Rosell-Valle, Alfonso Gutiérrez-Adán, Juan Carlos Ledesma, Dina Medina-Vera, Juan Decara, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Junta de Andalucía, Medina-Vera, D, Navarro, JA, Tovar, R, Rosell-Valle, C, Gutiérrez-Adán, Alfonso, Ledesma, JC, Sanjuan, C, Pavon, FJ, Baixeras, E, de Fonseca, FR, Decara, J, [Medina-Vera,D, Navarro,JA, Tovar,R, Rosell-Valle,C, Ledesma,JC¸ Pavón,FJ, Rodríguez de Fonseca,F, Decara,J] Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Málaga, Spain. [Medina-Vera,D] Facultad de Ciencias, Universidad de Málaga, Málaga, Spain. [Medina-Vera,D, Tovar,R] Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Pavón,FJ] Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), UGC del Corazón, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain. [Gutiérrez-Adan,A] Departamento de Reproducción Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, Spain. [Sanjuan,C] Euronutra S.L. Málaga, Spain. [Baixeras,E] Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Málaga, Málaga, Spain., This work was supported by grants from the following institutions: Ministerio de Economía y Competitividad, Gobierno de España (Grant RTC-2016-4983-1), EU-ERDF-Instituto de Salud Carlos III (Grant PI19/01577), and Consejería de Economía, Conocimiento y Universidad, Junta de Andalucía (Grant P18-TP-5194), Proyecto de Investigación en Salud, Consejería de Salud y Familias (PI-0139-2018). D.M-V. (FI20/00227) holds a 'PFIS' predoctoral contract from the National System of Health, EU-ERDF-Instituto de Salud Carlos III., Medina-Vera, D [0000-0002-0342-1287], Navarro, JA [0000-0003-3089-0983], Tovar, R [0000-0002-4517-8932], Rosell-Valle, C [0000-0001-9545-0976], Gutierrez-Adan, A [0000-0001-9893-9179], Ledesma, JC [0000-0001-6372-2842], Sanjuan, C [0000-0003-3505-0481], Pavon, FJ [0000-0002-5256-8904], Baixeras, E [0000-0001-6955-2434], de Fonseca, FR [0000-0002-4516-5795], and Decara, J [0000-0002-9868-015X]
Subjects: 0301 basic medicine, Blood Glucose, Male, medicine.medical_treatment, Phenomena and Processes::Physiological Phenomena::Pharmacological Phenomena::Drug Resistance::Insulin Resistance [Medical Subject Headings], Administration, Oral, 0302 clinical medicine, insulin resistance, Organisms::Eukaryota::Animals [Medical Subject Headings], Homeostasis, Insulin, TX341-641, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, Wistar [Medical Subject Headings], hypothalamus, Insulin-Like Growth Factor I, Phosphorylation, D-Pinitol, Nutrition and Dietetics, biology, Chemistry, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Administration Routes::Administration, Oral [Medical Subject Headings], Hypothalamus, PI3K/Akt pathway, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Somatomedins::Insulin-Like Growth Factor I [Medical Subject Headings], Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Phosphatidylinositol 3-Kinases::Phosphatidylinositol 3-Kinase [Medical Subject Headings], Signal Transduction, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Pancreatic Hormones::Proglucagon::Glucagon [Medical Subject Headings], medicine.medical_specialty, Resistencia a la insulina, Article, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Enzyme Activation [Medical Subject Headings], 03 medical and health sciences, Ratas, Insulin resistance, Internal medicine, Proteínas proto-oncogénicas c-akt, medicine, Animals, Rats, Wistar, Protein kinase B, PI3K/AKT/mTOR pathway, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Peptide Hormones::Pancreatic Hormones::Insulins [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Alcohols::Sugar Alcohols::Inositol [Medical Subject Headings], Nutrition. Foods and food supply, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Signal Transduction [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain::Limbic System::Hypothalamus [Medical Subject Headings], medicine.disease, Glucagon, Enzyme Activation, Insulin receptor, 030104 developmental biology, Endocrinology, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats [Medical Subject Headings], inositol, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins::Oncogene Proteins::Proto-Oncogene Proteins::Proto-Oncogene Proteins c-akt [Medical Subject Headings], biology.protein, Phenomena and Processes::Chemical Phenomena::Organic Chemistry Phenomena::Organic Chemistry Processes::Phosphorylation [Medical Subject Headings], Phosphatidylinositol 3-Kinase, Phenomena and Processes::Physiological Phenomena::Physiological Processes::Homeostasis [Medical Subject Headings], Proto-Oncogene Proteins c-akt, 030217 neurology & neurosurgery, Hipotálamo, Food Science, Hormone, Fosfatidilinositol 3-quinasas, Chemicals and Drugs::Carbohydrates::Monosaccharides::Hexoses::Glucose::Blood Glucose [Medical Subject Headings]
Abstract: D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor., This work was supported by grants from the following institutions: Ministerio de Economía y Competitividad, Gobierno de España (Grant RTC-2016-4983-1), EU-ERDF-Instituto de Salud Carlos III (Grant PI19/01577), and Consejería de Economía, Conocimiento y Universidad, Junta de Andalucía (Grant P18-TP-5194), Proyecto de Investigación en Salud, Consejería de Salud y Familias (PI-0139-2018). D.M-V. (FI20/00227) holds a “PFIS” predoctoral contract from the National System of Health, EU-ERDF-Instituto de Salud Carlos III
Published: 2021

13. 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

14. Prevalence and Risk Factors for Multidrug-Resistant Organisms Colonization in Long-Term Care Facilities Around the World: A Review

Author: Juan Carlos Crespo-Rivas, Germán Peñalva, Cecilia Martín-Gandul, Ana Belén Guisado-Gil, María Eugenia Pachón-Ibáñez, José Antonio Lepe, Ángel Rodríguez-Villodres, José Miguel Cisneros, Universidad de Sevilla. Departamento de Microbiología, Universidad de Sevilla. Departamento de Medicina, European Development Regional Fund 'A way to achieve Europe' ERDF, Spanish Network for the Research in Infectious Diseases, REIPI RD16/0016/0009, European Development Regional Fund 'A way to achieve Europe', European Development Regional Fund 'A way to achieve Europe', Operative program Intelligent Growth 2014-2020, Instituto de Salud Carlos III, PI17-02195, Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases, REIPI RD16/0016/0001, Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de InvestigacionCooperativa, Ministry of Economy, Industry and Competitiveness, Spanish Network for Research in Infectious Diseases, REIPI RD16/0016/0001, RD16/0016/0009, Instituto de Salud Carlos III, the Spanish Ministry of Economy, Industry, and Competitiveness, PI17-02195, Plan Nacional de I+D+i 2013-2016, Servicio Andaluz de Salud, Junta de Andalucia, Spain, C1-0038-2019, and Subprograma Rio Hortega, Instituto de Salud Carlos III, Subdireccion General de Redes y Centros de Investigacion Cooperativa, Ministerio de Ciencia, Innovacion y Universidades, Spain
Subjects: 0301 basic medicine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, prevalence, Review, RM1-950, nursing homes, medicine.disease_cause, Biochemistry, Microbiology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Antimicrobial stewardship, risk factors, Pharmacology (medical), Colonization, 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, Chronic care, biology, business.industry, Pseudomonas aeruginosa, multidrug-resistant organism, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, Acinetobacter baumannii, Multiple drug resistance, Long-term care, antimicrobial stewardship, Infectious Diseases, Increased risk, long term care facilities, Therapeutics. Pharmacology, business
Abstract: Elderly people confined to chronic care facilities face an increased risk of acquiring infections by multidrug-resistant organisms (MDROs). This review presents the current knowledge of the prevalence and risk factors for colonization by MDROs in long-term care facilities (LTCF), thereby providing a useful reference to establish objectives for implementing successful antimicrobial stewardship programs (ASPs). We searched in PubMed and Scopus for studies examining the prevalence of MDROs and/or risk factors for the acquisition of MDROs in LTCF. One hundred and thirty-four studies published from 1987 to 2020 were included. The prevalence of MDROs in LTCF varies between the different continents, where Asia reported the highest prevalence of extended-spectrum ß-lactamase (ESBL) Enterobacterales (71.6%), carbapenem resistant (CR) Enterobacterales (6.9%) and methicillin-resistant Staphylococcus aureus (MRSA) (25.6%) and North America the highest prevalence to MDR Pseudomonas aeruginosa (5.4%), MDR Acinetobacter baumannii (15.0%), vancomycin-resistant Enterococcus spp. (VRE) (4.0%), and Clostridioides difficile (26.1%). Furthermore, MDRO prevalence has experienced changes over time, with increases in MDR P. aeruginosa and extended spectrum ß-lactamase producing Enterobacterales observed starting in 2015 and decreases of CR Enterobacterales, MDR A. baumannii, VRE, MRSA and C. difficile. Several risk factors have been found, such as male sex, chronic wounds, the use of medical devices, and previous antibiotic use. The last of these aspects represents one of the most important modifiable factors for reducing colonization with MDROs through implementing ASPs in LTCF.
Published: 2021

15. Use of IP-10 detection in dried plasma spots for latent tuberculosis infection diagnosis in contacts via mail

Author: Josep Domínguez, Adela Cantos, Esther García-García, J. Ruiz-Manzano, Maria Angeles Jimenez, M. L. De Souza-Galvão, Raquel Villar-Hernández, Morten Ruhwald, Israel Molina-Pinargote, Irene Latorre, Beatriz Muriel-Moreno, J. Pilarte, Cristina Prat, Yoel Gonzalez-Diaz, N. Altet, Joan Pau Millet, Institut Català de la Salut, [Villar-Hernández R, Latorre I] Servei de Microbiología, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Institut d'Investigació Germans Trias i Pujol, Badalona, Spain. CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain. Universitat Autònoma de Barcelona, Badalona, Spain. [De Souza-Galvão ML, Jiménez MA] Unitat de Tuberculosi Vall d'Hebron-Drassanes, Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Ruiz-Manzano J] CIBER Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain. Universitat Autònoma de Barcelona, Badalona, Spain. Servei de Pneumologia, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. [Pilarte J, Cantos A] Unitat de Tuberculosi Vall d'Hebron-Drassanes, Hospital Universitari Vall d'Hebron, Barcelona, Spain. [Altet N] Unitat de Tuberculosi Vall d'Hebron-Drassanes, Hospital Universitari Vall d'Hebron, Barcelona, Spain. Unidad Clínica de Tratamiento Directamente Observado 'Serveis Clinics', Barcelona, Spain. CIBER de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Badalona, Spain., and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Adult, Male, Tuberculosis, aminoácidos, péptidos y proteínas::péptidos::péptidos y proteínas de señalización intercelular::citocinas::quimiocinas::quimiocinas CXC::quimiocina CXCL10 [COMPUESTOS QUÍMICOS Y DROGAS], Otros calificadores::/diagnóstico [Otros calificadores], Tuberculosi - Diagnòstic, lcsh:Medicine, Enzyme-Linked Immunosorbent Assay, Sensitivity and Specificity, Article, QuantiFERON, 03 medical and health sciences, 0302 clinical medicine, Latent Tuberculosis, Other subheadings::/diagnosis [Other subheadings], medicine, Humans, Postal Service, Bacterial Infections and Mycoses::Bacterial Infections::Gram-Positive Bacterial Infections::Actinomycetales Infections::Mycobacterium Infections::Tuberculosis::Latent Tuberculosis [DISEASES], lcsh:Science, Whole blood, Multidisciplinary, Chromatography, Latent tuberculosis, Filter paper, Spots, business.industry, infecciones bacterianas y micosis::infecciones bacterianas::infecciones por bacterias grampositivas::infecciones por Actinomycetales::micobacteriosis::tuberculosis::tuberculosis latente [ENFERMEDADES], técnicas de investigación::métodos epidemiológicos::rastreo de contactos [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], lcsh:R, Infection diagnosis, Plasma, medicine.disease, Quimiocines, Chemokine CXCL10, 030104 developmental biology, Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Chemokines::Chemokines, CXC::Chemokine CXCL10 [CHEMICALS AND DRUGS], ROC Curve, Cytokines, Female, lcsh:Q, Dried Blood Spot Testing, Investigative Techniques::Epidemiologic Methods::Contact Tracing [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES AND EQUIPMENT], Contact Tracing, business, 030217 neurology & neurosurgery, Interferon-gamma Release Tests
Abstract: The aim of this study was to test the use of IP-10 detection in dried plasma from contact studies individuals (contacts of smear positive patients), by comparing it with IP-10 and IFN-γ detection in direct plasma, to establish IP-10 detection in DPS as a useful assay for LTBI diagnosis. Whole blood samples were collected from 80 subjects: 12 with active tuberculosis (TB), and 68 from contact studies. The amount of IFN-γ produced by sensitized T cells was determined in direct plasma by QuantiFERON Gold In-Tube test. IP-10 levels were determined in direct and dried plasma by an in-house ELISA. For dried plasma IP-10 determination, two 25 µl plasma drops were dried in Whatman903 filter paper and sent by mail to the laboratory. Regarding TB patients, 100.0%, 91.7% and 75.0% were positive for IFN-γ detection and IP-10 detection in direct and dried plasma, respectively. In contacts, 69.1%, 60.3% and 48.5% had positive results after IFN-γ and IP-10 in direct and dried plasma, respectively. The agreement among in vitro tests was substantial and IP-10 levels in direct and dried plasma were strongly correlated (r = 0.897). In conclusion, IP-10 detection in dried plasma is a simple and safe method that would help improve LTBI management.
Published: 2019

16. Impact of an Antimicrobial Stewardship Program on the Incidence of Carbapenem Resistant Gram-Negative Bacilli: An Interrupted Time-Series Analysis

Author: Elena Pérez-Nadales, Julián Torre-Cisneros, José Ramón del Prado, Luis Martínez-Martínez, Lucrecia García-Martinez, Germán Peñalva, Angela Cano, Elena García-Martinez, José Miguel Cisneros, Inmaculada Salcedo, Manuel Recio, Juan José Castón, Teresa López-Viñau, José Rumbao Aguirre, Irene Gracia-Ahufinger, Montserrat Muñoz-Rosa, Carmen de la Fuente, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Red Española de Investigación en Patología Infecciosa, European Commission, [López-Viñau,T, García-Martínez,L, Del Prado,JR] Pharmacy Unit, Reina Sofia University Hospital, Cordoba, Spain. [López-Viñau,T, Castón,JJ, Cano,Á, Recio,M, Pérez-Nadales,E, Torre-Cisneros,J] Infectious Diseases Unit, Reina Sofia University Hospital, Maimonides, Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba (UCO), Cordoba, Spain. [Peñalva,G, Cisneros,JM] Department of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville, Virgen del Rocio University Hospital, Seville, Spain. [Muñoz-Rosa,M, Martínez-Martínez,L, Gracia-Ahufinger,I] Microbiology Unit, Reina Sofia University Hospital, IMIBIC, Department of Agricultural Chemistry, Edafology and Microbiology, University of Cordoba, Cordoba, Spain. [Rumbao Aguirre,J, García-Martínez,E] Hospital Management, Reina Sofia University Hospital, Cordoba, Spain. [Salcedo,I] Preventive Medicine Unit, Reina Sofia University Hospital, Cordoba, Spain. [de la Fuente,C] Intensive Care Unit, Reina Sofia University Hospital, Cordoba, Spain., This research was funded by the Plan Nacional de I + D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0008, and RD16/0016/0009) co-financed by European Development Regional Fund ‘A way to achieve Europe’ and Operative program intelligent Growth 2014–2020, which did not participate in the development of the program or the analysis of its results.
Subjects: 0301 basic medicine, Carbapenem, Carbapenem-resistant enterobacteriaceae, Antimicrobial resistance, Biochemistry, Carbapenémicos, Interrupted Time Series Analysis, 0302 clinical medicine, Information Science::Information Science::Data Collection::Vital Statistics::Morbidity::Incidence [Medical Subject Headings], Health Care::Environment and Public Health::Public Health [Medical Subject Headings], polycyclic compounds, Medicine, Antimicrobial stewardship, Pharmacology (medical), 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, Health Care::Health Care Facilities, Manpower, and Services::Health Facilities::Hospitals [Medical Subject Headings], Incidence (epidemiology), Mortality rate, Carbapenemases, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Escherichia::Escherichia coli [Medical Subject Headings], Klebsiella pneumoniae, Infectious Diseases, carbapenem-resistant Enterobacteriaceae, carbapenems, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Klebsiella::Klebsiella pneumoniae [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Amides::Lactams::beta-Lactams::Carbapenems [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents [Medical Subject Headings], medicine.drug, Microbiology (medical), medicine.medical_specialty, carbapenemases, 030106 microbiology, Farmacorresistencia microbiana, RM1-950, Microbiology, Article, 03 medical and health sciences, Antibiotic resistance, Carbapenem resistant Enterobacteriaceae, Internal medicine, Enterobacterias resistentes a carbapenémicos, Antimicrobial stewardship program, antimicrobial resistance, Health Care::Health Care Quality, Access, and Evaluation::Quality of Health Care::Health Care Evaluation Mechanisms::Statistics as Topic::Regression Analysis [Medical Subject Headings], Programas de optimización del uso de los antimicrobianos, antimicrobial stewardship program, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Quinolines [Medical Subject Headings], business.industry, Gram negative bacilli, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, Chemicals and Drugs::Organic Chemicals::Amides::Lactams::beta-Lactams::Cephalosporins [Medical Subject Headings], Carbapenem-resistant Enterobacteriaceae, Carbapenems, Therapeutics. Pharmacology, business
Abstract: This article belongs to the Section Antibiotics Use and Antimicrobial Stewardship., Carbapenem-resistant Gram-negative bacilli (CR-GNB) are a critical public health threat, and carbapenem use contributes to their spread. Antimicrobial stewardship programs (ASPs) have proven successful in reducing antimicrobial use. However, evidence on the impact of carbapenem resistance remains unclear. We evaluated the impact of a multifaceted ASP on carbapenem use and incidence of CR-GNB in a high-endemic hospital. An interrupted time-series analysis was conducted one year before and two years after starting the ASP to assess carbapenem consumption, CR-GNB incidence, death rates of sentinel events, and other variables potentially related to CR-GNB incidence. An intense reduction in carbapenem consumption occurred after starting the intervention and was sustained two years later (relative effect −83.51%; 95% CI −87.23 to −79.79). The incidence density of CR-GNB decreased by −0.915 cases per 1000 occupied bed days (95% CI −1.743 to −0.087). This effect was especially marked in CR-Klebsiella pneumoniae and CR-Escherichia coli, reversing the pre-intervention upward trend and leading to a relative reduction of −91.15% (95% CI −105.53 to −76.76) and −89.93% (95% CI −107.03 to −72.83), respectively, two years after starting the program. Death rates did not change. This ASP contributed to decreasing CR-GNB incidence through a sustained reduction in antibiotic use without increasing mortality rates., This research was funded by the Plan Nacional de I + D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0008; RD16/0016/0009) co-financed by European Development Regional Fund ‘A way to achieve Europe’ and Operative program intelligent Growth 2014–2020, which did not participate in the development of the program or the analysis of its results.
Published: 2021
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17. 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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18. 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

19. 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

20. Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

Author: Zhu, Yinggang, Monsel, Antoine, Roberts, Jason A, Pontikis, Konstantinos, Mimoz, Olivier, Rello, Jordi, Qu, Jieming, Rouby, Jean-Jacques, European Investigator Network for Nebulized Antibiotics in Ventilator-Associated Pneumonia (ENAVAP), Laterre, Pierre-François, UCL - SSS/IREC/MEDA - Pôle de médecine aiguë, UCL - (SLuc) Service de soins intensifs, Fudan University [Shanghai], Service d'Anesthésie réanimation [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d’Investigation Clinique intégré en Biothérapies et immunologie [AP-HP pitié-salpêtrière, Paris] (CIC-BTi), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], University of Queensland [Brisbane], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), National and Kapodistrian University of Athens (NKUA), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III [Madrid] (ISC), Vall d’Hebron Research Institute (VHIR), Shanghai Jiao Tong University [Shanghai], Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut Català de la Salut, [Zhu Y] Department of Pulmonary and Critical Care Medicine, Hua-Dong Hospital, Fudan University, Shanghai 200433, China. [Monsel A] Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Medicine Sorbonne University, 75012 Paris, France. Unité Mixte de Recherche (UMR)-S 959, Immunology-Immunopathology-Immunotherapy (I3), Institut National de la Santé et de la Recherche Médicale (INSERM), 75012 Paris, France. Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France. [Roberts JA] Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France. University of Queensland Centre for Clinical Research, Faculty of Medicine The University of Queensland, 4006 Brisbane, Australia. Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women’s Hospital, 4006 Brisbane, Australia. Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, 30029 Nîmes, France. [Pontikis K] Intensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, 15772 Athens, Greece. [Mimoz O] Anaesthesiology and Intensive Care Department, University Hospital of Poitiers, University of Poitiers, 86000 Poitiers, France. [Rello J] Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28029 Madrid, Spain. Recerca Clínica/Innovació en la Pneumònia i Sèpsia (CRIPS), Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Clinical Research, CHU Nîmes, Université Montpellier-Nîmes, 30029 Nîmes, France, Vall d'Hebron Barcelona Hospital Campus, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Saint-Antoine [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Antibiotics, Review, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Gastroenterology, 0302 clinical medicine, Tracheobronchitis, Medicine and Health Sciences, Medicaments antibacterians - Ús terapèutic, Medicine, NOSOCOMIAL PNEUMONIA, 030212 general & internal medicine, colistin, multidrug resistant gram-negative bacteria, Biology (General), nebulized polymyxin, Pneumònia - Tractament, Ventilator-associated pneumonia, ventilator-associated tracheobronchitis, 3. Good health, medicine.anatomical_structure, RESISTANT ACINETOBACTER-BAUMANNII, Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents [CHEMICALS AND DRUGS], Other subheadings::Other subheadings::/administration & dosage [Other subheadings], CRITICALLY-ILL PATIENTS, Malalties bacterianes gramnegatives - Tractament, medicine.drug, Microbiology (medical), INHALED COLISTIMETHATE SODIUM, medicine.medical_specialty, infecciones bacterianas y micosis::infección::infección hospitalaria::neumonía asociada al ventilador [ENFERMEDADES], AEROSOLIZED COLISTIN, QH301-705.5, POLYMYXIN-B HEMOPERFUSION, medicine.drug_class, 030106 microbiology, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], phramacokinetic, acciones y usos químicos::acciones farmacológicas::usos terapéuticos::antiinfecciosos::antibacterianos [COMPUESTOS QUÍMICOS Y DROGAS], Microbiology, 03 medical and health sciences, ventilator-associated pneumonia, Pharmacokinetics, Virology, Internal medicine, pharmacodynamics, SYSTEMIC PHARMACOKINETICS, Bacterial Infections and Mycoses::Infection::Cross Infection::Pneumonia, Ventilator-Associated [DISEASES], Otros calificadores::Otros calificadores::/administración & dosificación [Otros calificadores], PLUS INTRAVENOUS COLISTIN, Lung, nebulized colistimethate sodium, business.industry, Septic shock, SEPTIC SHOCK, PSEUDOMONAS-AERUGINOSA, polylyxin resistance, medicine.disease, Pneumonia, technique of nebulization, Colistin, business
Abstract: Colistin; Phramacokinetic; Technique of nebulization Colistina; Farmacocinètica; Tècnica de nebulització Colistina; Farmacocinético; Técnica de nebulización Clinical evidence suggests that nebulized colistimethate sodium (CMS) has benefits for treating lower respiratory tract infections caused by multidrug-resistant Gram-negative bacteria (GNB). Colistin is positively charged, while CMS is negatively charged, and both have a high molecular mass and are hydrophilic. These physico-chemical characteristics impair crossing of the alveolo-capillary membrane but enable the disruption of the bacterial wall of GNB and the aggregation of the circulating lipopolysaccharide. Intravenous CMS is rapidly cleared by glomerular filtration and tubular excretion, and 20–25% is spontaneously hydrolyzed to colistin. Urine colistin is substantially reabsorbed by tubular cells and eliminated by biliary excretion. Colistin is a concentration-dependent antibiotic with post-antibiotic and inoculum effects. As CMS conversion to colistin is slower than its renal clearance, intravenous administration can lead to low plasma and lung colistin concentrations that risk treatment failure. Following nebulization of high doses, colistin (200,000 international units/24h) lung tissue concentrations are > five times minimum inhibitory concentration (MIC) of GNB in regions with multiple foci of bronchopneumonia and in the range of MIC breakpoints in regions with confluent pneumonia. Future research should include: (1) experimental studies using lung microdialysis to assess the PK/PD in the interstitial fluid of the lung following nebulization of high doses of colistin; (2) superiority multicenter randomized controlled trials comparing nebulized and intravenous CMS in patients with pandrug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis; (3) non-inferiority multicenter randomized controlled trials comparing nebulized CMS to intravenous new cephalosporines/ß-lactamase inhibitors in patients with extensive drug-resistant GNB ventilator-associated pneumonia and ventilator-associated tracheobronchitis. This research received no external funding.
Published: 2021

21. Causal effects of lifetime smoking on breast and colorectal cancer risk:Mendelian randomization study

Author: Marc J. Gunter, Inger T. Gram, Elisabete Weiderpass, Hilary A. Tindle, Sun-Seog Kweon, Renée T. Fortner, Rudolf Kaaks, Sarah J Lewis, James Yarmolinsky, Stephen B. Gruber, Marije F. Bakker, Li Hsu, Yi Lin, Neil Murphy, Polly A. Newcomb, Konstantinos K. Tsilidis, Noralane M. Lindor, Rosario Tumino, Gianluca Severi, Hermann Brenner, Emmanouil Bouras, Jane C. Figueiredo, Niki Dimou, Richard M. Martin, Bethany Van Guelpen, María-José Sánchez-Pérez, 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, Cancerfonden Cancer Research Foundation in Northern Sweden Deutsche Krebshilfe Vetenskapsrådet, VR Australian Lions Childhood Cancer Research Foundation, ALCCRF Knut och Alice Wallenbergs Stiftelse State of Maryland Vetenskapsrådet, VR: VR 2017-00650 Centers for Disease Control and Prevention, CDC Institut National Du Cancer, INCa National Institutes of Health, NIH National Cancer Institute, NCI: P30 CA015704 Centre Hospitalier Universitaire de Nantes, CHU de Nantes Conseil Régional des Pays de la Loire Association Anne de Bretagne Genetique Centre Hospitalier Universitaire de Nantes, CHU de Nantes U.S. Public Health Service, USPHS: HHSN261201500005C U.S. Department of Health and Human Services, HHS National Institutes of Health, NIH National Cancer Institute, NCI National Institute on Aging, NIA: U01 AG18033 Institut National Du Cancer, INCa: P30 CA006973, U01 CA86308 American Institute for Cancer Research, AICR European Commission, EC National Institutes of Health, NIH: R01 CA189184, 2P30CA015704-40, R01 CA207371, U01 CA206110 Matthias Lackas-Stiftung Johns Hopkins University, JHU: HHSN268201200008I National Cancer Institute, NCI National Institutes of Health, NIH: R01 CA143247, R01 CA81488, U01 CA122839, U19 CA148107, U01 CA167551 National Institutes of Health, NIH National Institute of Environmental Health Sciences, NIEHS: T32 ES013678 National Cancer Institute, NCI U.S. Department of Health and Human Services, HHS: R01 CA197350, R01 CA81488, R01 CA201407, P01 CA196569, U19 CA148107, P30 CA014089 Österreichische Forschungsförderungsgesellschaft, FFG: 829675 Instituto de Salud Carlos III, ISCIII European Regional Development Fund, ERDF: PI14-613, PI09-1286 Xarxa de Bancs de Tumors de Catalunya, XBTC: PT13/0010/0013 Generalitat de Catalunya: 2017SGR723 Junta de Castilla y León: LE22A10-2 Agència de Gestió d'Ajuts Universitaris i de Recerca, AGAUR Ministerstvo Zdravotnictví Ceské Republiky, MZCR: AZV 17-30920A, AZV 15-27580A Grantová Agentura České Republiky, GA ČR: CZ GA CR: GAP304/10/1286, 1585 Deutsche Forschungsgemeinschaft, DFG: HO 5117/2-1, BR 1704/6-1, KL 2354/3-1, BR 1704/6-4, BR 1704/6-3, CH 117/1-1, HE 5998/2-1, RO 2270/8-1, BR1704/17-1 Bundesministerium für Bildung und Forschung, BMBF: 01ER0814, 01KH0404, 01ER0815, 01ER1505A, 01ER1505B U01 CA 84968-06 National Cancer Institute, NCI University of Maryland School of Public Health, SPH NIHR Imperial Biomedical Research Centre, BRC Imperial College London NIHR Imperial Biomedical Research Centre, BRC Centre International de Recherche sur le Cancer, CIRC Ministerie van Volksgezondheid, Welzijn en Sport, VWS Deutsche Krebshilfe Cancer Research UK, CRUK: C8221/A29017 Ministerie van Volksgezondheid, Welzijn en Sport, VWS Vetenskapsrådet, VR Ligue Contre le Cancer Bundesministerium für Bildung und Forschung, BMBF Bundesministerium für Bildung und Forschung, BMBF Kræftens Bekæmpelse, DCS Associazione Italiana per la Ricerca sul Cancro, AIRC Instituto de Salud Carlos III, ISCIII Deutsches Krebsforschungszentrum, DKFZ Institut National de la Santé et de la Recherche Médicale, Inserm National Research Council, NRC Institut Gustave-Roussy Deutsches Krebsforschungszentrum, DKFZ Cancerfonden World Cancer Research Fund, WCRF Medical Research Council, MRC: MR/M012190/1 Generalitat de Catalunya: 2017SGR653, 2014SGR135, 2014SGR255, 2017SGR21 SAF2014-54453R, SAF07-64873, SAF 2010-19273 Xunta de Galicia: PGIDIT07PXIB9101209PR Instituto de Salud Carlos III, ISCIII European Regional Development Fund, ERDF: PS09/02368, PI14/00230, 17/00878, PI08/1276, PI17/00509, PI08/0024, PI11/00681, P111/00219, PI14/00173 Xarxa de Bancs de Tumors de Catalunya, XBTC: SLT002/ 16/00398 GCB13131592CAST European Cooperation in Science and Technology, COST: CA17118, BM1206 Deutsche Krebshilfe National Institutes of Health, NIH: K07 CA190673, P01 CA055075, K07CA190673, R35CA197735, U01 CA167552, UM1 CA167552, R01 CA042182, P01 CA087969, R01 CA151993, P50 CA127003, UM1 CA186107, R35 CA197735, R01 CA137178 HCRI15011-1 National Cancer Institute, NCI: R01CA136726 Damon Runyon Cancer Research Foundation, DRCRF: CI-8 Food Standards Agency, FSA Cancer Research UK, CRUK: C588/A19167 VicHealth Cancer Council Victoria National Health and Medical Research Council, NHMRC: 251553, 209057, 509348, 504711 National Institutes of Health, NIH U.S. Department of Health and Human Services, HHS: R01 CA81488 Florida Department of Health: 09BN-13 National Institutes of Health, NIH: R01 CA189184, P30 CA076292 National Institutes of Health, NIH: P30 DK034987, R01 CA66635 18226, 18223 Canadian Institutes of Health Research, CIHR: CRT 43821 National Institutes of Health, NIH U.S. Department of Health and Human Services, HHS: U01 CA74783 Cancerfonden Cancer Research Foundation, CRF Vetenskapsrådet, VR Australian Lions Childhood Cancer Research Foundation, ALCCRF Canadian Cancer Society National Institutes of Health, NIH: U01/ U24 CA074783, U01 CA167551 Pelotonia CA16058, CA67941 Canadian Institutes of Health Research, CIHR: 112746 Ontario Research Foundation, ORF: GL201-043 National Cancer Institute, NCI U.S. Department of Health and Human Services, HHS: U01 HG004446, GEI U01 HG 004438, Z01 CP 010200 Division of Cancer Epidemiology and Genetics, National Cancer Institute, DCEG Institut National Du Cancer, INCa National Institutes of Health, NIH Division of Cancer Prevention, National Cancer Institute, DCP, NCI National Institutes of Health, NIH: U24 CA074794, U01 CA074794, R01 CA076366, U01 CA167551 National Cancer Institute, NCI National Institutes of Health, NIH: UM1 CA182883, U10 CA37429 National Cancer Institute, NCI Institut National Du Cancer, INCa: R03 CA153323, P01 CA074184, K05 CA152715, R01 CA097325 National Institutes of Health, NIH: KL2 TR000421 National Center for Advancing Translational Sciences, NCATS Stockholms Läns Landsting Vetenskapsrådet, VR: K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2 Karolinska Institutet, KI National Institutes of Health, NIH: K05 CA154337 Swedish Cancer Foundation National Heart, Lung, and Blood Institute, NHLBI National Institutes of Health, NIH U.S. Department of Health and Human Services, HHS: HHSN268201100004C, HHSN268201100003C, HHSN268201100001C, HHSN271201100004C, HHSN268201100046C, HHSN268201100002C, R.M. Martin reports grants from Cancer Research UK during the conduct of the study. R.T. Fortner reports that grants from German Cancer Aid and from German Ministry of Education and Research supported the conduct of EPIC Heidelberg. S.B. Gruber reports other from Brogent International LLC outside the submitted work. B. van Guelpen reports grants from Swedish Research Council, Swedish Cancer Society, Knut and Alice Wallenberg Foundation, Lion’s Cancer Research Foundation at Umea° University, and Cancer Research Foundation in Northern Sweden during the conduct of the study. No disclosures were reported by the other authors., CLUE: We appreciate the continued efforts of the staff members at the Johns Hopkins George W. Comstock Center for Public Health Research and Prevention in the conduct of the CLUE II study. We thank the participants in CLUE. Cancer incidence data for CLUE were provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Maryland Department of Health, 201 W. Preston Street, Room 400, Baltimore, MD 21201, http://phpa.dhmh.maryland.gov/cancer, 410-767-4055. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries of the Centers for Disease Control and Prevention for the funds that support the collection and availability of the cancer registry data., CPS-II: The authors thank the CPS-II participants and Study Management Group for their invaluable contributions to this research. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program., NSHDS investigators thank the Biobank Research Unit at Umea° University, the V€asterbotten Intervention Programme, the Northern Sweden MONICA study and Region V€asterbotten for providing data and samples and acknowledge the contribution from Biobank Sweden, supported by the Swedish Research Council (VR 2017-00650)., Cancer incidence data have been provided by the District of Columbia Cancer Registry, Georgia Cancer Registry, Hawaii Cancer Registry, Minnesota Cancer Surveillance System, Missouri Cancer Registry, Nevada Central Cancer Registry, Pennsylvania Cancer Registry, Texas Cancer Registry, Virginia Cancer Registry, and Wisconsin Cancer Reporting System. All are supported in part by funds from the Center for Disease Control and Prevention, National Program for Central Registries, local states or by the National Cancer Institute, Surveillance, Epidemiology, and End Results program. The results reported here and the conclusions derived are the sole responsibility of the authors., Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088, R01 CA059045, R01CA201407). This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA015704., ASTERISK: a Hospital Clinical Research Program (PHRC-BRD09/C) from the University Hospital Center of Nantes (CHU de Nantes) and supported by the Regional Council of Pays de la Loire, the Groupement des EntreprisesFranc¸aises dans la Luttecontre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue RégionaleContre le Cancer (LRCC)., The ATBC Study is supported by the Intramural Research Program of the U.S. National Cancer Institute, National Institutes of Health, and by U.S. Public Health Service contract HHSN261201500005C from the National Cancer Institute, Department of Health and Human Services., CLUE funding was from the National Cancer Institute (U01 CA86308, Early Detection Research Network, and P30 CA006973), National Institute on Aging (U01 AG18033), and the American Institute for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. COLO2&3: NIH (R01 CA60987).
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Epidemiology, medicine.drug_class, Colorectal cancer, Breast Neoplasms, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, Mendelian randomization, Genetic predisposition, Humans, Medicine, Risk factor, 11 Medical and Health Sciences, business.industry, Smoking, Odds ratio, Mendelian Randomization Analysis, medicine.disease, Confidence interval, 3. Good health, Causality, 030104 developmental biology, Estrogen, 030220 oncology & carcinogenesis, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, ICEP, Colorectal Neoplasms, business, Genome-Wide Association Study
Abstract: Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer. Methods: Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking (n = 126 variants) and ever having smoked regularly (n = 112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls). Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00–1.26; P = 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor–positive and estrogen receptor–negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer (OR per 1-SD increment, 1.21; 95% CI, 1.04–1.40; P = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11–1.55; P < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07–1.73; P = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90–1.14; P = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86–1.10; P = 0.68). Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer. Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.
Published: 2021

22. 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

23. Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis

Author: L. Francisco Lorenzo-Martín, Eugenio Santos, Carmen Segrelles, Xosé R. Bustelo, Rocío Fuentes-Mateos, Natalia Fernández-Parejo, Cynthia Mucientes-Valdivieso, Rósula García-Navas, Jesús M. Paramio, Fernando C. Baltanás, Nuria Calzada, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, La Caixa HR20-00164, Fundación Ramón Areces CIVP19A5942, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) SAF2015-66015-R, PID2019-110758RB-I00, Instituto de Salud Carlos III CB16/12/00228, CB16/12/00352, FIS PI19/00934, Gobierno regional de Castilla y León CSI252P18, CSI145P20, CLC-2017-01, SA264P18-UIC 076, Fundación Memoria de D. Samuel Solorzano Barruso FS/32-2020, Asociación Española Contra el Cáncer GC16173472GARC, Ministerio de Ciencia e Innovación (MICIN). España RTI2018-096481-B-100, Ministerio de Universidades FPU13/02923, FPU17/03912, Instituto de Salud Carlos III, Junta de Castilla y León, Fundación Ramón Areces, Fundación Memoria de D. Samuel Solorzano Barruso, European Commission, Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundación 'la Caixa', and Asociación Española Contra el Cáncer
Subjects: 0301 basic medicine, keratinocytes, Cancer Research, Population, Biology, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, medicine, Transcriptional regulation, Sos1, GEF, education, Protein kinase B, Sos2, RC254-282, Ras signaling, Epidermal stem cell homeostasis, education.field_of_study, Cell growth, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, KO, Cell biology, 030104 developmental biology, Oncology, skin homeostasis, 030220 oncology & carcinogenesis, Stem cell, Carcinogenesis, Homeostasis
Abstract: © 2021 by the authors., Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis., The E.S. group was supported by grants from ISCIII-MCUI (FIS PI19/00934), JCyL (SA264P18-UIC 076), Areces Foundation (CIVP19A5942), Solorzano-Barruso Foundation (FS/32-2020), and by ISCIII-CIBERONC (group CB16/12/00352). Research was co-financed by FEDER funds. The J.M.P. lab is co-funded by European Regional Development Fund (FEDER) grants from Science and Innovation (SAF2015-66015-R and PID2019-110758RB-I00 to J.M.P.) and Instituto de Salud Carlos III (CIBERONC no. CB16/12/00228 to J.M.P.). The XRB lab is funded by “la Caixa” Banking Foundation (HR20-00164), the Castilla-León autonomous government (CSI252P18, CSI145P20, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (RTI2018-096481-B-100), and the Spanish Association against Cancer (GC16173472GARC). The CIC is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01). L.F.L.-M. and N.F.-P. contracts have been supported by funding from the Spanish Ministry of Universities (FPU13/02923, FPU17/03912) and, in the case of L.F.L.M., by CLC-2017-01 grant.
Published: 2021
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24. Citric Acid Cycle Metabolites Predict Infarct Size in Pigs Submitted to Transient Coronary Artery Occlusion and Treated with Succinate Dehydrogenase Inhibitors or Remote Ischemic Perconditioning

Author: Begoña Benito, Marisol Ruiz-Meana, Javier Inserte, Norberto Núñez, Marta Consegal, Ignacio Ferreira-González, Antonio Rodríguez-Sinovas, Ignasi Barba, Institut Català de la Salut, [Consegal M, Benito B, Ruiz-Meana M, Inserte J, Rodríguez-Sinovas A] Grup de Recerca en Malalties Cardiovasculars, Servei de Cardiologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain. [Núñez N] Unitat d'Alta Tecnologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Barba I] Grup de Recerca en Malalties Cardiovasculars, Servei de Cardiologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Faculty of Medicine, University of Vic-Central University of Catalonia (UVicUCC), Can Baumann. Ctra. de Roda, 70, 08500 Vic, Spain. [Ferreira-González I] Grup de Recerca en Malalties Cardiovasculars, Servei de Cardiologia, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. Centro de Investigación Biomédica en Red (CIBER) de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, 28029 Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Swine, Endogeny, 030204 cardiovascular system & hematology, Pharmacology, ischemia-reperfusion, Cardiovascular Diseases::Heart Diseases::Myocardial Ischemia::Myocardial Infarction [DISEASES], chemistry.chemical_compound, 0302 clinical medicine, hemic and lymphatic diseases, Dicarboxylic Acids, Myocardial infarction, Biology (General), Enzyme Inhibitors, Ischemic Preconditioning, Spectroscopy, remote ischemic conditioning, biology, Àcid cítric - Metabolisme, Chemistry, Succinate dehydrogenase, Ischemia-reperfusion, metabolismo::metabolismo energético::metabolismo::ciclo del ácido cítrico [FENÓMENOS Y PROCESOS], Remote ischemic conditioning, Heart, General Medicine, enfermedades cardiovasculares::enfermedades cardíacas::isquemia miocárdica::infarto de miocardio [ENFERMEDADES], Computer Science Applications, Malonate, myocardial infarction, Other subheadings::Other subheadings::/administration & dosage [Other subheadings], sustancias macromoleculares::complejos multiproteicos::complejos multienzimáticos::succinato citocromo c oxidorreductasa::complejo II de transporte de electrones::succinato deshidrogenasa [COMPUESTOS QUÍMICOS Y DROGAS], QH301-705.5, Sodium, Citric Acid Cycle, chemistry.chemical_element, Catalysis, Great cardiac vein, Article, Inorganic Chemistry, 03 medical and health sciences, Metabolism::Energy Metabolism::Metabolism::Citric Acid Cycle [PHENOMENA AND PROCESSES], medicine, Animals, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, Macromolecular Substances::Multiprotein Complexes::Multienzyme Complexes::Succinate Cytochrome c Oxidoreductase::Electron Transport Complex II::Succinate Dehydrogenase [CHEMICALS AND DRUGS], Otros calificadores::Otros calificadores::/administración & dosificación [Otros calificadores], Myocardium, Organic Chemistry, medicine.disease, succinate dehydrogenase, malonate, Citric acid cycle, Infart de miocardi, 030104 developmental biology, Coronary Occlusion, Inhibidors enzimàtics, Coronary occlusion, biology.protein, Biomarkers
Abstract: Succinate dehydrogenase (SDH) inhibition with malonate during reperfusion reduced myocardial infarction in animals, whereas its endogenous substrate, succinate, is detected in plasma from STEMI patients. We investigated whether protection by SDH inhibition is additive to that of remote ischemic perconditioning (RIC) in pigs submitted to transient coronary artery occlusion, and whether protective maneuvers influence plasma levels of citric acid cycle metabolites. Forty pigs were submitted to 40 min coronary occlusion and reperfusion, and allocated to four groups (controls, sodium malonate 10 mmol/L, RIC, and malonate + RIC). Plasma was obtained from femoral and great cardiac veins and analyzed by LC-MS/MS. Malonate, RIC, and malonate + RIC reduced infarct size (24.67 ± 5.98, 25.29 ± 3.92 and 29.83 ± 4.62% vs. 46.47 ± 4.49% in controls, p &lt, 0.05), but no additive effects were detected. Enhanced concentrations of succinate, fumarate, malate and citrate were observed in controls during initial reperfusion in the great cardiac vein, and most were reduced by cardioprotective maneuvers. Concentrations of succinate, fumarate, and malate significantly correlated with infarct size. In conclusion, despite the combination of SDH inhibition during reperfusion and RIC did not result in additive protection, plasma concentrations of selected citric acid cycle metabolites are attenuated by protective maneuvers, correlate with irreversible injury, and might become a prognosis tool in STEMI patients.
Published: 2021

25. Extra virgin olive oil improved body weight and insulin sensitivity in high fat diet-induced obese LDLr−/−.Leiden mice without attenuation of steatohepatitis

Author: Manuel Romero-Gómez, Lourdes M. Varela, Anabel Rojas, Amparo Luque Sierra, Alejandro Martin-Montalvo, Javier López-Beas, Abdelkrim Hmadcha, Eloísa Andújar, Leticia Álvarez-Amor, Franz Martín, Genoveva Berná, Mónica Pérez-Alegre, Antonio Cárdenas, Robert Kleemann, Rocío Gallego-Durán, Lucía López-Bermudo, Mª José Robles-Frías, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Junta de Andalucía, Instituto de Salud Carlos III, European Commission, [Álvarez-Amor,L, Sierra,AL, Cárdenas,A, López-Bermudo,L, López-Beas,J, Andújar,E, Pérez-Alegre,M, Varela,LM, Martin-Montalvo,A, Berná,G, Rojas,A, Martín,F] Andalusian Center of Molecular Biology and Regenerative Medicine CABIMER, University Pablo Olavide-University of Seville-CSIC, Seville, Spain. [Álvarez-Amor,L, Hmadcha,A, Martín,F] Biomedical Research Network On Diabetes and Related Metabolic Diseases CIBERDEM, Instituto de Salud Carlos III, Madrid, Spain. [Gallego-Durán,R, Romero-Gómez,M] Hospital Universitario Virgen del Rocío de Sevilla, Instituto de Biomedicina de Sevilla, Universidad de Sevilla, Sevilla, Spain. [Gallego-Durán,R, Romero-Gómez,M] Biomedical Research Network On Hepatic and Digestive Diseases CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain. [Robles-Frías,MJ] Compared Pathology Unit, Hospital Universitario Virgen del Rocío Intituto de Biomedicina de Sevilla Biobank Node, Andalucia Health Public System Biobank, Sevilla, Spain. [Kleemann,R] Department of Metabolic Health Research, Netherlands Organisation for Applied Scientifc Research-TNO, Leiden, The Netherlands. [Kleemann,R] Department of Vascular Surgery, Leiden University Medical Centre, Leiden, The Netherlands., and This work was supported by the grants AGL2014-54585-R, AGL-2017-86927-R, CP14/ 00105, PI18/01590 (Ministerio de Economía y Competitividad), PAI-BIO311 (Junta de Andalucía), CB07/08/0006 (Instituto de Salud Carlos III) and by the TNO research programs 'Body Brain Interactions ERP 020' and 'Functional Biomarkers PMC13'.
Subjects: 0301 basic medicine, Anatomy::Digestive System::Liver [Medical Subject Headings], Mice, Obese, Diet, Mediterranean, Mice, chemistry.chemical_compound, 0302 clinical medicine, Phenomena and Processes::Metabolic Phenomena::Metabolism::Lipid Metabolism [Medical Subject Headings], Non-alcoholic Fatty Liver Disease, Extra virgin olive oil, Organisms::Eukaryota::Animals [Medical Subject Headings], Glucose homeostasis, Non-alcoholic steatohepatitis, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, Chemistry, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Nutrition Therapy::Diet Therapy::Diet, Mediterranean [Medical Subject Headings], Fatty liver, Lipoproteínas LDL, food and beverages, Type 2 diabetes, Insulin sensitivity, Aceite de oliva, Liver, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Lipoprotein::Receptors, LDL [Medical Subject Headings], Medicine, Female, 030211 gastroenterology & hepatology, lipids (amino acids, peptides, and proteins), medicine.symptom, medicine.medical_specialty, Science, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Obese [Medical Subject Headings], steatohepatitis, Diet, High-Fat, Resistencia a la insulina, Article, Transaminase, LDL, 03 medical and health sciences, Insulin resistance, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet::Diet, High-Fat [Medical Subject Headings], Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin Resistance [Medical Subject Headings], Internal medicine, medicine, Animals, Obesity, Olive Oil, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Fatty acid metabolism, Body Weight, Diet, high-fat, Hígado graso, nutritional and metabolic diseases, Peso corporal, Body weight, Lipid Metabolism, medicine.disease, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], 030104 developmental biology, Endocrinology, Dieta alta en grasa, Receptors, LDL, Check Tags::Female [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Signs and Symptoms::Body Weight [Medical Subject Headings], Insulin Resistance, Steatohepatitis, Lipid profile, Weight gain, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Knockout [Medical Subject Headings]
Abstract: Dietary fatty acids play a role in the pathogenesis of obesity-associated non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance (IR). Fatty acid composition is critical for IR and subsequent NAFLD development. Extra-virgin olive oil (EVOO) is the main source of monounsaturated fatty acids (MUFA) in Mediterranean diets. This study examined whether EVOO-containing high fat diets may prevent diet-induced NAFLD using Ldlr−/−. Leiden mice. In female Ldlr−/−.Leiden mice, the effects of the following high fat diets (HFDs) were examined: a lard-based HFD (HFD-L); an EVOO-based HFD (HFD-EVOO); a phenolic compounds-rich EVOO HFD (HFD-OL). We studied changes in body weight (BW), lipid profile, transaminases, glucose homeostasis, liver pathology and transcriptome. Both EVOO diets reduced body weight (BW) and improved insulin sensitivity. The EVOOs did not improve transaminase values and increased LDL-cholesterol and liver collagen content. EVOOs and HFD-L groups had comparable liver steatosis. The profibrotic effects were substantiated by an up-regulation of gene transcripts related to glutathione metabolism, chemokine signaling and NF-kappa-B activation and down-regulation of genes relevant for fatty acid metabolism. Collectivelly, EVOO intake improved weight gain and insulin sensitivity but not liver inflammation and fibrosis, which was supported by changes in hepatic genes expression., This work was supported by the grants AGL2014-54585-R, AGL-2017-86927-R, CP14/ 00105, PI18/01590 (Ministerio de Economía y Competitividad), PAI-BIO311 (Junta de Andalucía), CB07/08/0006 (Instituto de Salud Carlos III) and by the TNO research programs “Body Brain Interactions ERP 020” and “Functional Biomarkers PMC13”.
Published: 2021

26. 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

27. Periprosthetic Joint Infection Prophylaxis in the Elderly after Hip Hemiarthroplasty in Proximal Femur Fractures: Insights and Challenges

Author: Carles Pigrau, P. Corona, Benito Almirante, Júlia Sellarès-Nadal, Laura Escolà-Vergé, Dolors Rodríguez-Pardo, Institut Català de la Salut, [Rodríguez-Pardo D] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003), Instituto de Salud Carlos III, 28029 Madrid, Spain. Study Group on Osteoarticular Infections of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIO-SEIMC), 28003 Madrid, Spain. Medicina Interna, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Escolà-Vergé L, Pigrau C] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003), Instituto de Salud Carlos III, 28029 Madrid, Spain. Study Group on Osteoarticular Infections of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIO-SEIMC), 28003 Madrid, Spain. [Sellarès-Nadal J] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Study Group on Osteoarticular Infections of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIO-SEIMC), 28003 Madrid, Spain. Medicina Interna, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Corona PS] Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003), Instituto de Salud Carlos III, 28029 Madrid, Spain. Study Group on Osteoarticular Infections of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIO-SEIMC), 28003 Madrid, Spain. Medicina Interna, Universitat Autònoma de Barcelona, Bellaterra, Spain. Unitat de Cirurgia Sèptica i Reconstructiva (UCSO), Servei de Cirurgia Ortopèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Almirante B] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003), Instituto de Salud Carlos III, 28029 Madrid, Spain. Medicina Interna, Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Infeccions quirúrgiques, Antibiotics, Cefazolin, Periprosthetic, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Otros calificadores::Otros calificadores::/efectos adversos [Otros calificadores], Biochemistry, 0302 clinical medicine, Decolonization, Periprosthetic joint infection, Pharmacology (medical), 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, Antibiotic prophylaxis, periprosthetic joint infection, antibiotic prophylaxis, intervenciones quirúrgicas::procedimientos ortopédicos::artroplastia::artroplastia de sustitución::hemiartroplastia [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Articulacions artificials, Antimicrobial, Glycopeptide, Infectious Diseases, Perspective, medicine.drug, Microbiology (medical), medicine.medical_specialty, medicine.drug_class, 030106 microbiology, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Proximal femur fracture, Microbiology, 03 medical and health sciences, Internal medicine, medicine, Malalties bacterianes - Tractament, Bacterial Infections and Mycoses::Infection::Prosthesis-Related Infections [DISEASES], Other subheadings::Other subheadings::/adverse effects [Other subheadings], business.industry, proximal femur fracture, Hip hemiarthroplasty, lcsh:RM1-950, infecciones bacterianas y micosis::infección::infecciones relacionadas con prótesis [ENFERMEDADES], Clindamycin, Surgical Procedures, Operative::Orthopedic Procedures::Arthroplasty::Arthroplasty, Replacement::Hemiarthroplasty [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], lcsh:Therapeutics. Pharmacology, hip hemiarthroplasty, decolonization, business
Abstract: Profilaxi antibiòtica; Hemiartroplàstia de maluc; Infecció periprotèsica de l'articulació Profilaxis antibiótica; Hemiartroplastia de cadera; Infección de la articulación periprotésica Antibiotic prophylaxis; Hip hemiarthroplasty; Periprosthetic joint infection We review antibiotic and other prophylactic measures to prevent periprosthetic joint infection (PJI) after hip hemiarthroplasty (HHA) surgery in proximal femoral fractures (PFFs). In the absence of specific guidelines, those applied to these individuals are general prophylaxis guidelines. Cefazolin is the most widely used agent and is replaced by clindamycin or a glycopeptide in beta-lactam allergies. A personalized antibiotic scheme may be considered when colonization by a multidrug-resistant microorganism (MDRO) is suspected. Particularly in methicillin-resistant Staphylococcus aureus (MRSA) colonization or a high prevalence of MRSA-caused PJIs a glycopeptide with cefazolin is recommended. Strategies such as cutaneous decolonization of MDROs, mainly MRSA, or preoperative asymptomatic bacteriuria treatment have also been addressed with debatable results. Some areas of research are early detection protocols in MDRO colonizations by polymerase-chain-reaction (PCR), the use of alternative antimicrobial prophylaxis, and antibiotic-impregnated bone cement in HHA. Given that published evidence addressing PJI prophylactic strategies in PFFs requiring HHA is scarce, PJIs can be reduced by combining different prevention strategies after identifying individuals who will benefit from personalized prophylaxis. This work was supported by the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación, through the project PI15/02161 and by the Plan Nacional de I+D+i 2013-016 and ISCIIII, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economia, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003)-co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020.
Published: 2021

28. Candida Periprosthetic Joint Infection: Is It Curable?

Author: Dolors Rodríguez-Pardo, P. Corona, Carles Pigrau, Laura Escolà-Vergé, Institut Català de la Salut, [Escolà-Vergé L, Rodríguez-Pardo D, Pigrau C] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003), Instituto de Salud Carlos III, 28029 Madrid, Spain. Study Group on Osteoarticular Infections of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIO-SEIMC), 28003 Madrid, Spain. [Corona PS] Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003), Instituto de Salud Carlos III, 28029 Madrid, Spain. Study Group on Osteoarticular Infections of the Spanish Society of Clinical Microbiology and Infectious Diseases (GEIO-SEIMC), 28003 Madrid, Spain. Unitat de Cirurgia Sèptica i Reconstructiva, Servei de Cirurgia Ortopèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Microbiology (medical), Antifungal, medicine.medical_specialty, medicine.drug_class, Candida spp, 030106 microbiology, Cement spacer, Periprosthetic, Candidiasi - Tractament, Two-stage exchange surgery, RM1-950, antifungal-loaded cement spacer, Biochemistry, Microbiology, biofilm, 03 medical and health sciences, 0302 clinical medicine, Antifungal-loaded cement spacer, two-stage exchange surgery, Antibiotic therapy, Bacterial Infections and Mycoses::Mycoses::Candidiasis [DISEASES], Pròtesis - Complicacions, Periprosthetic joint infection, Bacterial Infections and Mycoses::Infection::Prosthesis-Related Infections [DISEASES], Medicine, Pharmacology (medical), General Pharmacology, Toxicology and Pharmaceutics, Intensive care medicine, Otros calificadores::/terapia [Otros calificadores], Fungus, 030222 orthopedics, Surgical approach, periprosthetic joint infection, business.industry, Biofilm, fungus, infecciones bacterianas y micosis::infección::infecciones relacionadas con prótesis [ENFERMEDADES], infecciones bacterianas y micosis::micosis::candidiasis [ENFERMEDADES], Other subheadings::/therapy [Other subheadings], Chronic infection, Infectious Diseases, Perspective, Therapeutics. Pharmacology, business
Abstract: Fong; Infecció articular periprotèsica; Cirurgia d'intercanvi en dues etapes Hongo; Infección de la articulación periprotésica; Cirugía de recambio en dos etapas Fungus; Periprosthetic joint infection; Two-stage exchange surgery Candida periprosthetic joint infection (CPJI) is a rare and very difficult to treat infection, and high-quality evidence regarding the best management is scarce. Candida spp. adhere to medical devices and grow forming biofilms, which contribute to the persistence and relapse of this infection. Typically, CPJI presents as a chronic infection in a patient with multiple previous surgeries and long courses of antibiotic therapy. In a retrospective series of cases, the surgical approach with higher rates of success consists of a two-stage exchange surgery, but the best antifungal treatment and duration of antifungal treatment are still unclear, and the efficacy of using an antifungal agent-loaded cement spacer is still controversial. Until more evidence is available, focusing on prevention and identifying patients at risk of CPJI seems more than reasonable. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Published: 2021

29. HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV/HCV-coinfected patients

Author: Brochado Kith, Óscar, Martínez, Isidoro, Berenguer, Juan, Medrano, Luz María, González-García, Juan, Jiménez-Sousa, María Ángeles, Carrero, Ana, Hontañón Antoñana, Víctor, Navarro, Jordi, Guardiola Tey, Jose Maria, Fernández-Rodríguez, Amanda, Resino, Salvador, Miralles, P., López, J.C., Parras, F., Padilla, B., Aldámiz-Echevarría, T, Tejerina, F., Díez, C., Pérez-Latorre, L., Fanciulli, C., Gutiérrez, I., Ramírez, M., Carretero, S., Bellón, J.M., Bermejo, Javier, Arribas, J. R., Montes, M.L., Bernardino, I., Pascual, J.F., Zamora, Francisco, Peña, J.M., Arnalich, F., Díaz, M., Domingo, Pere, Van den Eynde, E., Pérez, M., Ribera, E., Crespo, M., Casado, J.L., Dronda, F., Moreno, A., Pérez-Elías, M.J., Sanfrutos, M.A., Moreno, S., Quereda, C., Arranz, A., Casas, E., de Miguel, J., Schroeder, S., Sanz, J., Santos, I., Bustinduy, M.J., Iribarren, J.A., Rodríguez-Arrondo, F., Von-Wichmann, M.A., Vergas, J., Téllez, M.J., Vinuesa, D., Muñoz, L., Hernández-Quero, J., Ferrer, A., Galindo, M.J., Ortiz, L., Ortega, E., Montero, M., Blanes, M., Cuellar, S., Lacruz, J., Salavert, M., López-Aldeguer, J., Pérez, G., Gaspar, G., Yllescas, M., Crespo, P., Aznar, E., Esteban, H., Instituto de Salud Carlos III, European Regional Development Fund (ERDF/FEDER), Ministerio de Ciencia e Innovación, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Ministerio de Ciencia e Innovación (España), Institut Català de la Salut, [Brochado Ó, Martínez I, Medrano L, Jiménez-Sousa MÁ] Unidad de Infección Viral E Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Madrid, Spain. [Berenguer J] Unidad de Enfermedades Infecciosas/VIH, Hospital General Universitario 'Gregorio Marañón', Madrid, Spain. Instituto de Investigación Sanitaria del Gregorio Marañón, Madrid, Spain. [González-García J] Unidad de VIH, Servicio de Medicina Interna, Hospital Universitario 'La Paz', Madrid, Spain. Instituto de Investigacion Sanitaria La Paz (IdiPAZ), Madrid, Spain. [Navarro J] Servei de Malalties Infeccioses, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Male, 0301 basic medicine, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, lcsh:Medicine, Gene Expression, HIV Infections, Hepacivirus, medicine.disease_cause, 0302 clinical medicine, Interferon, Medicine, Pharmacology (medical), Other subheadings::/therapeutic use [Other subheadings], Interferon therapy, Coinfection, virus diseases, Genetic Phenomena::Gene Expression [PHENOMENA AND PROCESSES], General Medicine, Hepatitis C, Middle Aged, Interferó - Ús terapèutic, Hepatocellular carcinoma, Female, 030211 gastroenterology & hepatology, medicine.drug, Adult, Hepatitis C virus, Peripheral blood mononuclear cell, Virus, HCV clearance, aminoácidos, péptidos y proteínas::péptidos::péptidos y proteínas de señalización intercelular::citocinas::interferones [COMPUESTOS QUÍMICOS Y DROGAS], 03 medical and health sciences, Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Interferons [CHEMICALS AND DRUGS], Immune system, Humans, Molecular Biology, Virus Diseases::Coinfection [DISEASES], Otros calificadores::/uso terapéutico [Otros calificadores], business.industry, virosis::coinfección [ENFERMEDADES], Research, lcsh:R, Biochemistry (medical), HIV, Cell Biology, medicine.disease, Expressió gènica, HIV/HCV coinfection, 030104 developmental biology, Virosis, PBMCs, Immunology, Leukocytes, Mononuclear, Gene expression, Interferons, business, fenómenos genéticos::expresión génica [FENÓMENOS Y PROCESOS]
Abstract: Coinfecció pel VIH/VHC; Sistema immunitari; Teràpia amb interferó Coinfección por VIH/VHC; Sistema inmunitario; Terapia con interferón HIV/HCV coinfection; Immune system; Interferon therapy Objective To evaluate the impact of hepatitis C virus (HCV) elimination via interferon (IFN)-based therapy on gene expression profiles related to the immune system in HIV/HCV-coinfected patients. Methods We conducted a prospective study in 28 HIV/HCV-coinfected patients receiving IFN-based therapy at baseline (HIV/HCV-b) and week 24 after sustained virological response (HIV/HCV-f). Twenty-seven HIV-monoinfected patients (HIV-mono) were included as a control. RNA-seq analysis was performed on peripheral blood mononuclear cells (PBMCs). Genes with a fold-change (FC) ≥ 1.5 (in either direction) and false discovery rate (FDR) ≤ 0.05 were identified as significantly differentially expressed (SDE). Results HIV/HCV-b showed six SDE genes compared to HIV-mono group, but no significantly enriched pathways were observed. For HIV/HCV-f vs. HIV/HCV-b, we found 58 SDE genes, 34 upregulated and 24 downregulated in the HIV/HCV-f group. Of these, the most overexpressed were CXCL2, PDCD6IP, ATP5B, IGSF9, RAB26, and CSRNP1, and the most downregulated were IFI44 and IFI44L. These 58 SDE genes revealed two significantly enriched pathways (FDR
Published: 2021

30. Population Pharmacokinetics of Piperacillin in Non-Critically Ill Patients with Bacteremia Caused by Enterobacteriaceae

Author: Adoración Valiente-Mendez, Álvaro Pascual, Mercedes Delgado-Valverde, Jesús Rodríguez-Baño, Manuel Camean, William W. Hope, Vicente Merino-Bohórquez, Fernando Docobo-Pérez, Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad (España), Red Española de Investigación en Patología Infecciosa, European Commission, Universidad de Sevilla. Departamento de Farmacología, Pediatría y Radiología, Universidad de Sevilla. Departamento de Microbiología, Universidad de Sevilla. Departamento de Medicina, [Merino-Bohórquez,V, Cameán,M] Unidad de Gestión de Farmacia Hospitalaria, Hospital Universitario Virgen Macarena, Sevilla, Spain. [Merino-Bohórquez,V] Departamento de Farmacología, Universidad de Sevilla, Sevilla, Spain. [Docobo-Pérez,F, Pascual,Á] Departamento de Microbiología, Universidad de Sevilla, Sevilla, Spain. [Docobo-Pérez,F, Valiente-Méndez,A, Delgado-Valverde,M, Pascual,Á, Rodríguez-Baño,J] Instituto de Biomedicina de Sevilla IBIS, Hospital Universitario Virgen Macarena/CSIC/Universidad de Sevilla, Sevilla, Spain. [Docobo-Pérez,F, Rodríguez-Baño,J] Red Española de Investigación en Patología Infecciosa (REIPI RD16/0016), Instituto de Salud Carlos III, Madrid, Spain. [Valiente-Méndez,A, Rodríguez-Baño,J] Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Sevilla, Spain. [Hope,WW] Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK. [Hope,WW] Royal Liverpool and Broadgreen University Hospital Trust, Liverpool, UK. [Rodríguez-Baño,J] Departamento de Medicina, Universidad de Sevilla, Sevilla, Spain., and This study was funded by Plan Nacional de I+D+i 2013–2016, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001) and PI10/02021, cofunded by European Development Regional Fund 'A way toachieve Europe', Operative Programme Intelligent Growth 2014–2020.
Subjects: 0301 basic medicine, piperacillin–tazobactam, Biochemistry, Gastroenterology, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, neurotoxicity, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Monte Carlo Method [Medical Subject Headings], Medicine, Pharmacology (medical), 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Diagnostic Techniques, Urological::Kidney Function Tests::Glomerular Filtration Rate [Medical Subject Headings], Diseases::Bacterial Infections and Mycoses::Infection::Sepsis [Medical Subject Headings], Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae [Medical Subject Headings], education.field_of_study, Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Renal Insufficiency, Chronic [Medical Subject Headings], Combinación de piperacilina y tazobactam, nephrotoxicity, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability [Medical Subject Headings], Infectious Diseases, Piperacillin/tazobactam, pharmacokinetics, medicine.drug, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, Renal function, bloodstream infection, Microbiology, Loading dose, Article, Nephrotoxicity, 03 medical and health sciences, Pharmacokinetics, Enterobacteriaceae, Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 2-Ring::Bicyclo Compounds, Heterocyclic::Penicillins::Penicillin G::Ampicillin::Piperacillin [Medical Subject Headings], Sepsis, Internal medicine, education, Síndromes de neurotoxicidad, business.industry, lcsh:RM1-950, renal function, medicine.disease, lcsh:Therapeutics. Pharmacology, Farmacocinética, Pruebas de función renal, business, Kidney disease, Piperacillin
Abstract: This study analyzes the pharmacokinetic variability of piperacillin in non-critically ill patients with Enterobacteriaceae bloodstream infections (EBSI) and explores predicted clinical outcomes and piperacillin-related neurotoxicity under different renal conditions. Hospitalized, non-critically ill patients treated with piperacillin–tazobactam for EBSI were included. Four serum samples per patient were collected and analyzed. A population pharmacokinetic model was developed using the Pmetrics package for R. Monte Carlo simulations of various dosage regimens of 4 g piperacillin, administered q8 h or q12 h by short (0.5 h) or long (4 h) infusion, following the different glomerular filtration rate (GFR) categories used to classify chronic kidney disease (Kidney Disease: Improving Global Outcomes, KDIGO) to determine the probability of target attainment (PTA) using a free drug concentrations above the minimal inhibitory concentration (fT &gt, MIC) of 50% for efficacy and targets for piperacillin-associated neurotoxicity. Twenty-seven patients (102 samples) were included. Extended piperacillin infusions reached a PTA &gt, 90% (50%fT &gt, MIC) within the susceptibility range, although a loading dose did not greatly improve the expected outcome. Long infusions reduced the expected toxicity in patients with severe renal impairment. The study supports the use of extended infusions of piperacillin in non-critically ill patients with EBSI. No benefits of a loading dose were expected in our population. Finally, extended infusions may reduce the risk of toxicity in patients with severe renal impairment.
Published: 2021

31. Integrative Clinical, Molecular, and Computational Analysis Identify Novel Biomarkers and Differential Profiles of Anti-TNF Response in Rheumatoid Arthritis

Author: Alejandra M. Patiño-Trives, Chary López-Pedrera, José Luis Marenco, Rafaela Ortega-Castro, Carlos Perez-Sanchez, M. Romero-Gómez, Iván Arias de la Rosa, Alejandro Escudero-Contreras, Eduardo Collantes-Estevez, Natalia Mena-Vázquez, Nuria Barbarroja, Pilar Font, Antonio Fernández-Nebro, J.J. Pérez-Venegas, Desiree Ruiz-Vilchez, Carmen Dominguez, M. D. C. Abalos-Aguilera, C.M. Romero-Barco, Juan Antonio Marin-Sanz, M. Angeles Aguirre, Carlos Rodriguez-Escalera, Mª Dolores Ruiz-Montesinos, Julia Uceda-Montañez, María Luque-Tévar, Mª Dolores Toledo-Coello, Clementina López-Medina, [Luque-Tévar,M, Perez-Sanchez,C, Patiño-Trives,AM, Barbarroja,N, Arias de la Rosa,I, Abalos-Aguilera,MC, Marin-Sanz,JA, Ruiz-Vilchez,D, Ortega-Castro,R, Font,P, Lopez-Medina,C, Romero-Gomez,M, Aguirre,MA, Escudero-Contreras,A, Collantes-Estevez,E, Lopez-Pedrera,C] Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Reina Sofia, Universidad de Cordoba, Córdoba, Spain. [Rodriguez-Escalera,C] Hospital Universitario de Jaen, Jaén, Spain. [Perez-Venegas,J, Ruiz-Montesinos,MD, Dominguez,C] Hospital Universitario Virgen Macarena, Sevilla, Spain. [Romero-Barco,C] Hospital Clínico Universitario, Malaga, Spain. [Fernandez-Nebro,A, Mena-Vazquez,N] Hospital Regional Universitario de Malaga, Malaga, Spain. [Marenco,JL, Uceda-Montañez,J] Hospital Universitario Virgen de Valme, Sevilla, Spain. [Toledo-Coello,MD] Hospital Universitario de Jerez de la Frontera, Cádiz, Spain., and This study was supported by grants from the Instituto de Salud Carlos III (PI18/00837), cofinanciado por el Fondo Europeo de Desarrollo Regional de la Unión Europea Una manera de hacer Europa, Spain, the Spanish Inflammatory and Rheumatic Diseases Network (RIER), Instituto de Salud Carlos III (RD16/0012/0015) and the Andalusian Regional Health System (ref. PI-0285-2017). CL-P was supported by a contract from the Spanish Junta de Andalucía (Nicolas Monardes program).
Subjects: Male, 0301 basic medicine, Oncology, rheumatoid arthritis, Longitudinal study, Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings], Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines::Tumor Necrosis Factors [Medical Subject Headings], efficacy, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing [Medical Subject Headings], Logistic regression, Extracellular Traps, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Arthritis, Rheumatoid, 0302 clinical medicine, Cluster Analysis, Immunology and Allergy, Longitudinal Studies, Prospective Studies, Computational analysis, Phenomena and Processes::Metabolic Phenomena::Metabolism::Oxidative Stress [Medical Subject Headings], Original Research, MicroARNs, Estrés oxidativo, Anti-TNF agents, Middle Aged, Phenotype, Aprendizaje automático, microRNAs, Diseases::Musculoskeletal Diseases::Rheumatic Diseases::Arthritis, Rheumatoid [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Research Design::Sensitivity and Specificity::Predictive Value of Tests [Medical Subject Headings], Treatment Outcome, machine learning, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Models, Statistical::Logistic Models [Medical Subject Headings], Eficacia, Antirheumatic Agents, Rheumatoid arthritis, Cohort, Female, Tumor necrosis factor alpha, anti-TNF agents, medicine.symptom, Fenotipo, Chemicals and Drugs::Biological Factors::Biological Markers::Biomarkers, Pharmacological [Medical Subject Headings], Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Phenomena and Processes::Mathematical Concepts::Algorithms [Medical Subject Headings], Efficacy, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies::Prospective Studies [Medical Subject Headings], Immunology, Check Tags::Male [Medical Subject Headings], Inflammation, Artritis reumatoide, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Cluster Analysis [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antirheumatic Agents [Medical Subject Headings], NEtosis, 03 medical and health sciences, Predictive Value of Tests, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies::Longitudinal Studies [Medical Subject Headings], Internal medicine, Machine learning, medicine, Humans, Persons::Persons::Age Groups::Adult [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], 030203 arthritis & rheumatology, Inflamación, Predictors, business.industry, Inhibidores del factor de necrosis tumoral, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Area Under Curve [Medical Subject Headings], Persons::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings], medicine.disease, Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Antisense Elements (Genetics)::RNA, Antisense::MicroRNAs [Medical Subject Headings], MicroRNAs, Oxidative Stress, Biomarcadores, predictors, 030104 developmental biology, Check Tags::Female [Medical Subject Headings], Oxidative stress, inflammation, Tumor Necrosis Factor Inhibitors, business, lcsh:RC581-607, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings], Biomarkers
Abstract: Background: This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients.Methods: A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions.Results: Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort.Conclusions: Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.
Published: 2021
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32. Repurposing of the Tamoxifen Metabolites to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli

Author: Jerónimo Pachón, Manuel E. Jiménez-Mejías, Andrea Miró-Canturri, Andrea Vila-Domínguez, Rafael Ayerbe-Algaba, Younes Smani, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Red Española de Investigación en Patología Infecciosa, European Commission, Ministerio de Economía y Competitividad (España), Universidad de Sevilla. Departamento de Medicina, Instituto de Biomedicina de Sevilla (IBIS). Grupo de Investigación: CTS-203 Estudio de las Enfermedades Infecciosas, [Miró-Canturri,A, Ayerbe-Algaba,R, Vila-Domínguez,A, Jiménez-Mejías,ME, Smani,Y] Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocío, Seville, Spain. [Miró-Canturri,A, Pachón,J, Smani,Y] Institute of Biomedicine of Seville (IBiS), University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain. [Pachón,J] Department of Medicine, University of Seville, Seville, Spain., and This study was supported by the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (grants PI16/01378 and PI19/01453) and by Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009)—co-financed by European Development Regional Fund 'A way to achieve Europe', Operative program Intelligent Growth 2014–2020. Younes Smani is supported by the Subprograma Miguel Servet Tipo I from the Ministerio de Economía y Competitividad of Spain (CP15/00132).
Subjects: 0301 basic medicine, Terapéutica, medicine.disease_cause, Biochemistry, Organisms::Eukaryota::Animals [Medical Subject Headings], Pharmacology (medical), Tamoxifeno, General Pharmacology, Toxicology and Pharmaceutics, bacteria, Diseases::Bacterial Infections and Mycoses::Infection::Sepsis [Medical Subject Headings], biology, tamoxifen, treatment, Antimicrobial, Tamoxifen metabolite, Acinetobacter baumannii, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Facultatively Anaerobic Rods::Enterobacteriaceae::Escherichia::Escherichia coli [Medical Subject Headings], Infectious Diseases, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Clinical Laboratory Techniques::Microbiological Techniques::Microbial Sensitivity Tests [Medical Subject Headings], Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents [Medical Subject Headings], Bacterias, Infection, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Drug Discovery::Drug Repositioning [Medical Subject Headings], medicine.drug, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents [Medical Subject Headings], Microbiology (medical), Membrane permeability, 030106 microbiology, tamoxifen metabolite, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins [Medical Subject Headings], Microbiology, Article, 03 medical and health sciences, Minimum inhibitory concentration, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Aerobic Bacteria::Gram-Negative Aerobic Rods and Cocci::Moraxellaceae::Acinetobacter::Acinetobacter baumannii [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Clinical Laboratory Techniques::Microbiological Techniques::Bacteriological Techniques::Bacterial Load [Medical Subject Headings], Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Cyclic::Hydrocarbons, Aromatic::Benzene Derivatives::Benzylidene Compounds::Stilbenes::Tamoxifen [Medical Subject Headings], medicine, Infección, Escherichia coli, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Bacteria, Pseudomonas aeruginosa, lcsh:RM1-950, Organisms::Bacteria::Gram-Negative Bacteria::Gram-Negative Aerobic Bacteria::Gram-Negative Aerobic Rods and Cocci::Pseudomonadaceae::Pseudomonas::Pseudomonas aeruginosa [Medical Subject Headings], Anatomy::Hemic and Immune Systems::Immune System [Medical Subject Headings], biology.organism_classification, Phenomena and Processes::Chemical Phenomena::Permeability [Medical Subject Headings], infection, Multiple drug resistance, Treatment, Tamoxifen, lcsh:Therapeutics. Pharmacology, 030104 developmental biology
Abstract: This article belongs to the Special Issue The Quest for Novel Antimicrobials: From Chemical Synthesis and Discovery to Mechanisms of Action and Resistance., The development of new strategic antimicrobial therapeutic approaches, such as drug repurposing, has become an urgent need. Previously, we reported that tamoxifen presents therapeutic efficacy against multidrug-resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli in experimental infection models by modulating innate immune system cell traffic. The main objective of this study was to analyze the activity of N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen, three major metabolites of tamoxifen, against these pathogens. We showed that immunosuppressed mice infected with A. baumannii, P. aeruginosa, or E. coli in peritoneal sepsis models and treated with tamoxifen at 80 mg/kg/d for three days still reduced the bacterial load in tissues and blood. Moreover, it increased mice survival to 66.7% (for A. baumannii and E. coli) and 16.7% (for P. aeruginosa) when compared with immunocompetent mice. Further, susceptibility and time-kill assays showed that N-desmethyltamoxifen, 4-hydroxytamoxifen, and endoxifen exhibited minimum inhibitory concentration of the 90% of the isolates (MIC90) values of 16 mg/L, and were bactericidal against clinical isolates of A. baumannii and E. coli. This antimicrobial activity of tamoxifen metabolites paralleled an increased membrane permeability of A. baumannii and E. coli without affecting their outer membrane proteins profiles. Together, these data showed that tamoxifen metabolites presented antibacterial activity against MDR A. baumannii and E. coli, and may be a potential alternative for the treatment of infections caused by these two pathogens., This study was supported by the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (grants PI16/01378 and PI19/01453) and by Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009)—co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020. Younes Smani is supported by the Subprograma Miguel Servet Tipo I from the Ministerio de Economía y Competitividad of Spain (CP15/00132).
Published: 2021
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33. The Association between Portion Sizes from High-Energy-Dense Foods and Body Composition in European Adolescents: The HELENA Study

Author: Jean Dallongeville, Yannis Manios, Anthony Kafatos, Stefaan De Henauw, Laura Censi, Luis A Moreno, Ascensión Marcos, Kurt Widhalm, Marcela González-Gross, Cristina Molina-Hidalgo, Frédéric Gottrand, Dénes Molnár, Inge Huybrechts, Peter Stehle, Sondos M Flieh, María L Miguel-Berges, Esther M. González-Gil, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Instituto Agroalimentario de Aragón (IA2), University of Zaragoza - Universidad de Zaragoza [Zaragoza]-Centro de Investigación y Tecnología Agroalimentaria de Aragón (CITA), Instituto de Investigación Sanitaria de Aragón [Zaragoza] (IIS Aragón), Universidad de Granada = University of Granada (UGR), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Consiglio per la Ricerca in Agricoltura e l’analisi dell’economia agraria = Council for Agricultural Research and Economics (CREA), Medizinische Universität Wien = Medical University of Vienna, Harokopio University of Athens, Hellenic Mediterranean University, Greece, University of Crete [Heraklion] (UOC), University of Pecs, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Universität Bonn = University of Bonn, Instituto de Salud Carlos III [Madrid] (ISC), Universidad Politécnica de Madrid (UPM), Spanish National Research Council (CSIC), Universiteit Gent = Ghent University (UGENT), 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), Inserm, Université de Lille, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, Institute for Translational Research in Inflammation - U 1286 [INFINITE (Ex-Liric)], Lille Inflammation Research International Center (LIRIC) - U995, University of Crete [Heraklion] [UOC], Rheinische Friedrich-Wilhelms-Universität Bonn, Instituto de Salud Carlos III [Madrid] [ISC], Spanish National Research Council [CSIC], Universiteit Gent = Ghent University [UGENT], and Universidad de Granada = University of Granada [UGR]
Subjects: 0301 basic medicine, Agriculture and Food Sciences, Male, Pediatric Obesity, obesity, [SDV]Life Sciences [q-bio], CHILDHOOD, Social Sciences, CHILDREN, Portion size, energy dense food, 0302 clinical medicine, Medicine and Health Sciences, Medicine, Prospective cohort study, Child, Nutrition and Dietetics, Europe, food portion size, body mass index, fat mass index, adolescent, Body Composition, Composition (visual arts), NUTRITION, lcsh:Nutrition. Foods and food supply, 030209 endocrinology & metabolism, lcsh:TX341-641, Article, 03 medical and health sciences, BMI, Humans, Association (psychology), Socioeconomic status, Exercise, 030109 nutrition & dietetics, OVERWEIGHT, business.industry, Portion Size, HEALTHY LIFE-STYLE, CONSUMPTION, medicine.disease, Obesity, Cross-Sectional Studies, Socioeconomic Factors, Food, Ordered logit, business, Energy Intake, Body mass index, Food Science, Demography
Abstract: Obesity prevalence has been simultaneously increasing with high consumption of large food portion sizes (PS). However, there is scarce information on PS of energy-dense (ED) foods as a potential risk factor of obesity in adolescents. In the present study, we investigate the association between the PS of the most ED foods and body composition. A sample of 1889 adolescents (54.4% females) from the Healthy Lifestyle in Europe by Nutrition in Adolescence cross-sectional multicenter study (HELENA–CSS) study were included. Most ED foods (e.g., cheese) were selected according to higher fat and/or sugar content and low fiber and water. Linear and ordinal logistic regression models were adjusted for age, physical activity, total energy intake (TEI), and socioeconomic status (SES). Analysis was performed both in those adolescents reporting plausible energy intake according to the approach of Goldberg et al. and in the whole sample. In male plausible reporters, PS from “breakfast cereals” showed a significant and positive association with BMI (β = 0.012, 0.048). PS from “carbonated soft drinks” in males (OR = 1.001, 95% CI 1.000, 1.002) and “bread and rolls” in females (OR = 1.002, 1.004) were associated with higher probability of having obesity, while “sweet bakery products” were associated with lower probability of having obesity (OR = 0.996, 95% CI 0.991, 0.999) in females. The present study suggests association between PS of ED foods and obesity in European adolescents. Prospective studies are needed to examine the effect of prolonged exposure to large PS and obesity development.
Published: 2021
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34. Antimicrobial resistance research in a post-pandemic world: Insights on antimicrobial resistance research in the COVID-19 pandemic

Author: Margo Warren, Birgitta Henriques-Normark, Ramanan Laxminarayan, Ghada Zoubiane, Gian Maria Rossolini, Till T. Bachmann, Adam P. Roberts, Alison Holmes, Sabiha Y. Essack, Benedikt Huttner, Steven J. Hoffman, Charu Kaushic, Herman Goossens, Norio Ohmagari, Srinivas Murthy, Evelina Tacconelli, Jesús Rodríguez-Baño, Shawon Lahiri, Laura Plant, Patriq Fagerstedt, Rafael Cantón, Cornelius J. Clancy, Constance Schultsz, [Rodríguez-Baño,J] Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain. [Rodríguez-Baño,J] Departamento de Medicina, Universidad de Sevilla, Seville, Spain. [Rodríguez-Baño,J] Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain. [Rossolini,GM] Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. [Rossolini,GM] Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy. [Schultsz,C] Department of Global Health–AIGHD Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. [Tacconelli,E] Division of Infectious Diseases, Department of Diagnostic and Public Health, University of Verona, Verona, Italy. [Murthy,S] BC Children’s Hospital, University of British Columbia, Vancouver, Canada. [Ohmagari,N] Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan. [Holmes,A] Department of Medicine, Faculty of Medicine, Imperial College London, London, UK. [Bachmann,T] The University of Edinburgh, Edinburgh Medical School, Division of Infection and Pathway Medicine, The Chancellor’s Building, Edinburgh, UK. [Goossens,H] Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute, University of Antwerp, Antwerp, Belgium. [Canton,R] Servicio de Microbiología, Hospital Universitario Ramón y Cajal and Instituto Ramón y Cajal de Investigación Sanitaria, Madrid, Spain. [Canton,R] Red Española de Investigación en Patología Infecciosa (REIPI), Instituto de Salud Carlos III, Madrid, Spain. [Roberts,AP] Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK. [Henriques-Normark,B] Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. [Henriques-Normark,B] Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden. [Clancy,CJ] University of Pittsburgh, Pittsburgh, PA, USA. [Huttner,B] Division of Infectious Diseases, Geneva University Hospitals, Faculty of Medicine, University of Geneva, Geneva, Switzerland. [Fagerstedt,P, Lahiri,S] JPIAMR Secretariat, Swedish Research Council, Stockholm, Sweden. [Kaushic,C, Plant,L] Institute of Infection and Immunity, Canadian Institutes of Health Research, Canada. [Kaushic,C] McMaster Immunology Research Center, Department Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. [Hoffman,SJ] Global Strategy Lab, Dahdaleh Institute for Global Health Research, School of Global Health and Osgoode Hall Law School, York University, Toronto, Canada. [Warren,M] Access to Medicine Foundation, Amsterdam, The Netherlands. [Zoubiane,G, Essack,S] International Centre for Antimicrobial Resistance Solutions (ICARS), Copenhagen, Denmark. [Essack,S] Antimicrobial Research Unit, University of KwaZulu-Natal, Durban, South Africa. [Laxminarayan,R] Center for Disease Dynamics, Economics & Policy, New Delhi, India. [Rodríguez-Baño,J] Red Española de Investigación en Patología Infecciosa (REIPI), Instituto de Salud Carlos III. Madrid, Spain., APR would like to acknowledge funding from the AMR CrossCouncil Initiative through a grant from the Medical Research Council, a Council of UK Research and Innovation [grant number MR/S004793/1], the National Institute for Health Research [grant number NIHR200632] and the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via the Medical Research Council in the UK [grant number MR/S037640/1]. JRB and RC acknowledge funding on AMR from Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0001 and RD16/0016/ 0011], co-financed by the European Regional Development Fund ‘A way to achieve Europe’, Operative Program Intelligence Growth 2014–2020. JRB also acknowledges the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via Instituto de Salud Carlos III [grant number AC16/00076]. ET acknowledges funding on AMR from the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via the German Federal Ministry of Education and Research (BMBF) [grant number 01KI1830], Innovative Medicines Initiative 1 and 2 Joint Undertaking [grants number 115737,115523 and820755] and the Global Antibiotic Research and Development Partnership (GARDP). LP, PF and SL would like to acknowledge funding to the JPIAMR from the European Commission (EXEDRA, JPI-EC-AMR and JPIAMR-ACTION)., Medical Research Council (UK), UK Research and Innovation, National Institute for Health Research (UK), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Red Española de Investigación en Patología Infecciosa, European Commission, Federal Ministry of Education and Research (Germany), Innovative Medicines Initiative, Global Health, AII - Infectious diseases, and APH - Global Health
Subjects: 0301 basic medicine, Vulnerability, Antimicrobial stewardship, Antimicrobial resistance, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Pandemic, wc_505, Immunology and Allergy, Phenomena and Processes::Microbiological Phenomena::Bacterial Physiological Phenomena::Drug Resistance, Bacterial [Medical Subject Headings], 030212 general & internal medicine, wb_330, Surveillance, Transmission (medicine), Pharmacology. Therapy, QR1-502, Anti-Bacterial Agents, Investigación, qw_160, Healthcare system, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Infective Agents::Anti-Bacterial Agents [Medical Subject Headings], Microbiology (medical), medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Infecciones por coronavirus, 030106 microbiology, Immunology, Microbiology, Article, qw_45, Health Care::Environment and Public Health::Public Health::Epidemiologic Methods::Data Collection::Health Surveys::Population Surveillance::Public Health Surveillance [Medical Subject Headings], 03 medical and health sciences, Antibiotic resistance, Stewardship, covid-19, research, surveillance, Drug Resistance, Bacterial, medicine, Humans, Intensive care medicine, Pandemics, Programas de optimización del uso de los antimicrobianos, Pandemia, business.industry, SARS-CoV-2, Research, COVID-19, Health Care::Environment and Public Health::Public Health::Disease Outbreaks::Epidemics::Pandemics [Medical Subject Headings], Diseases::Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [Medical Subject Headings], Infectious disease (medical specialty), wc_518, Clinical Microbiology and Infection, Human medicine, Disciplines and Occupations::Health Occupations::Medicine::Public Health::Epidemiology [Medical Subject Headings], business
Abstract: Antimicrobial resistance must be recognised as a global societal priority - even in the face of the worldwide challenge of the COVID-19 pandemic. COVID-19 has illustrated the vulnerability of our healthcare systems in co-managing multiple infectious disease threats as resources for monitoring and detecting, and conducting research on antimicrobial resistance have been compromised during the pandemic. The increased awareness of the importance of infectious diseases, clinical microbiology and infection control and lessons learnt during the COVID-19 pandemic should be exploited to ensure that emergence of future infectious disease threats, including those related to AMR, are minimised. Harnessing the public understanding of the relevance of infectious diseases towards the long-term pandemic of AMR could have major implications for promoting good practices about the control of AMR transmission., APR would like to acknowledge funding from the AMR Cross-Council Initiative through a grant from the Medical Research Council, a Council of UK Research and Innovation [grant number MR/S004793/1], the National Institute for Health Research [grant number NIHR200632] and the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via the Medical Research Council in the UK [grant number MR/S037640/1]. JRB and RC acknowledge funding on AMR from Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases [REIPI RD16/0016/0001 and RD16/0016/0011], co-financed by the European Regional Development Fund ‘A way to achieve Europe’, Operative Program Intelligence Growth 2014–2020. JRB also acknowledges the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via Instituto de Salud Carlos III [grant number AC16/00076]. ET acknowledges funding on AMR from the Joint Programming Initiative for Antimicrobial Resistance (JPIAMR) via the German Federal Ministry of Education and Research (BMBF) [grant number 01KI1830], Innovative Medicines Initiative 1 and 2 Joint Undertaking [grants number 115737, 115523 and820755] and the Global Antibiotic Research and Development Partnership (GARDP). LP, PF and SL would like to acknowledge funding to the JPIAMR from the European Commission (EXEDRA, JPI-EC-AMR and JPIAMR-ACTION).
Published: 2021

35. 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

36. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Coignard, Juliette, Lush, Michael, Beesley, Jonathan, O’Mara, Tracy A., Dennis, Joe, Tyrer, Jonathan P., Barnes, Daniel R., McGuffog, Lesley, Leslie, Goska, Bolla, Manjeet K., Adank, Muriel A., Agata, Simona, Ahearn, Thomas, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Arnold, Norbert, Aronson, Kristan J., Arun, Banu K., Augustinsson, Annelie, Azzollini, Jacopo, Barrowdale, Daniel, Baynes, Caroline, Becher, Heko, Bermisheva, Marina, Bernstein, Leslie, Białkowska, Katarzyna, Blomqvist, Carl, Bojesen, Stig E., Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Campa, Daniele, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., Bertrand, Ophélie, Caputo, Sandrine, Dupré, Anaïs, le Mentec, Marine, Belotti, Muriel, Birot, Anne-Marie, Buecher, Bruno, Fourme, Emmanuelle, Gauthier-Villars, Marion, Golmard, Lisa, Houdayer, Claude, Moncoutier, Virginie, de Pauw, Antoine, Saule, Claire, Sinilnikova, Olga, Mazoyer, Sylvie, Damiola, Francesca, Barjhoux, Laure, Verny-Pierre, Carole, Léone, M. lanie, Boutry-Kryza, Nadia, Calender, Alain, Giraud, Sophie, Caron, Olivier, Guillaud-Bataille, Marine, Bressac-de-Paillerets, Brigitte, Bignon, Yves- Jean, Uhrhammer, Nancy, Lasset, Christine, Bonadona, Valérie, Berthet, Pascaline, Vaur, Dominique, Castera, Laurent, Noguchi, Tetsuro, Popovici, Cornel, Sobol, Hagay, Bourdon, Violaine, Remenieras, Audrey, Noguès, Catherine, Coupier, Isabelle, Pujol, Pascal, Dumont, Aurélie, Révillion, Françoise, Adenis, Claude, Muller, Danièle, Barouk-Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Leroux, Dominique, Dreyfus, H. lène, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Baurand, Amandine, Jacquot, Caroline, Bertolone, Geoffrey, Lizard, Sarab, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Mari, V. ronique, Vénat-Bouvet, Laurence, Delnatte, Capucine, Bézieau, Stéphane, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Warcoin, Mathilde, Sokolowska, Johanna, Bronner, Myriam, Collonge-Rame, Marie-Agnès, Damette, Alexandre, Gesta, Paul, Lallaoui, Hakima, Chiesa, Jean, Molina-Gomes, Denise, Ingster, Olivier, Gregory, Helen, Miedzybrodzka, Zosia, Morrison, Patrick J., Ong, Kai-ren, Donaldson, Alan, Rogers, Mark T., Kennedy, M. John, Porteous, Mary E., Brewer, Carole, Davidson, Rosemarie, Izatt, Louise, Brady, Angela, Barwell, Julian, Adlard, Julian, Foo, Claire, Lalloo, Fiona, Side, Lucy E., Eason, Jacqueline, Henderson, Alex, Walker, Lisa, Eeles, Rosalind A., Cook, Jackie, Snape, Katie, Eccles, Diana, Murray, Alex, McCann, Emma, Collée, J. Margriet, Conroy, Don M., Czene, Kamila, Daly, Mary B., Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M., Dörk, Thilo, dos-Santos-Silva, Isabel, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Eliassen, A. Heather, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M., Garber, Judy, Garcia-Barberan, Vanesa, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Gayther, Simon A., Gehrig, Andrea, Georgoulias, Vassilios, Giles, Graham G., Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., He, Wei, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hopper, John L., Horcasitas, Darling J., Hulick, Peter J., Hunter, David J., Imyanitov, Evgeny N., Fox, Stephen, Campbell, Ian, Spurdle, Amanda, Webb, Penny, de Fazio, Anna, Tassell, Margaret, Kirk, Judy, Lindeman, Geoff, Price, Melanie, Southey, Melissa, Milne, Roger, Deb, Sid, Bowtell, David, van der Hout, Annemieke H., van den Ouweland, Ans M. W., Mensenkamp, Arjen R., van Deurzen, Carolien H. M., Kets, Carolien M., Seynaeve, Caroline, van Asperen, Christi J., Aalfs, Cora M., Gómez Garcia, Encarna B., van Leeuwen, Flora E., de Bock, G. H., Meijers-Heijboer, Hanne E. J., Obdeijn, Inge M., Gille, J. J. P., Oosterwijk, Jan C., Wijnen, Juul T., van der Kolk, Lizet E., Hooning, Maartje J., Ausems, Margreet G. E. M., Mourits, Marian J. E., Blok, Marinus J., Rookus, Matti A., van der Luijt, Rob B., van Cronenburg, T. C. T. E. F., van der Pol, Carmen C., Russell, Nicola S., Siesling, Sabine, Overbeek, Lucy, Wijnands, R., de Lange, Judith L., Clarke, Christine, Graham, Dinny, Sachchithananthan, Mythily, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Jager, Agnes, Jakubowska, Anna, James, Paul A., Jensen, Uffe Birk, John, Esther M., Jones, Michael E., Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y., Keeman, Renske, Khusnutdinova, Elza, Kiiski, Johanna I., Ko, Yon-Dschun, Kosma, Veli-Matti, Kraft, Peter, Kurian, Allison W., Laitman, Yael, Lambrechts, Diether, le Marchand, Loic, Lester, Jenny, Lesueur, Fabienne, Lindstrom, Tricia, Lopez-Fernández, Adria, Loud, Jennifer T., Luccarini, Craig, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Milne, Roger L., Montagna, Marco, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nielsen, Finn C., O’Brien, Katie M., Olopade, Olufunmilayo I., Olson, Janet E., Olsson, H. kan, Osorio, Ana, Ottini, Laura, Park-Simon, Tjoung-Won, Parsons, Michael T., Pedersen, Inge Sokilde, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul D. P., Phillips, Kelly-Anne, Polley, Eric C., Poppe, Bruce, Presneau, Nadege, Pujana, Miquel Angel, Punie, Kevin, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sandler, Dale P., Santella, Regina, Scheuner, Maren T., Schmidt, Marjanka K., Schmidt, Gunnar, Scott, Christopher, Sharma, Priyanka, Soucy, Penny, Southey, Melissa C., Spinelli, John J., Steinsnyder, Zoe, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Swerdlow, Anthony, Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Terry, Mary Beth, Teulé, Alex, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Trainer, Alison H., Truong, Thérèse, Tung, Nadine, Vachon, Celine M., Vega, Ana, Vijai, Joseph, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R., Weitzel, Jeffrey N., Wendt, Camilla, Wolk, Alicja, Yadav, Siddhartha, Yang, Xiaohong R., Yannoukakos, Drakoulis, Zheng, Wei, Ziogas, Argyrios, Zorn, Kristin K., Park, Sue K., Thomassen, Mads, Offit, Kenneth, Schmutzler, Rita K., Couch, Fergus J., Simard, Jacques, Chenevix-Trench, Georgia, Easton, Douglas F., Andrieu, Nadine, Antoniou, Antonis C., German Cancer Research Center, National Health and Medical Research Council (Australia), United States of Department of Health & Human Services, National Institute for Health Research (Reino Unido), French National Cancer Institute, Ligue Nationale Contre le Cancer (Francia), Cancer Research UK (Reino Unido), Unión Europea. Comisión Europea, Canadian Institutes of Health Research, Cancer Council New South Wales (Australia), KWF Kankerbestrijding, Instituto de Salud Carlos III, Xunta de Galicia (España), Ministerio de Sanidad, Política Social e Igualdad (España), Helmholtz Association, California Breast Cancer Research Program, Federal Ministry of Education & Research (Alemania), Government of Netherlands, Russian Foundation for Basic Research, O’Mara, Tracy A. [0000-0002-5436-3232], Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan P. [0000-0003-3724-4757], Barnes, Daniel R. [0000-0002-3781-7570], Leslie, Goska [0000-0001-5756-6222], Ahearn, Thomas [0000-0003-0771-7752], Andrulis, Irene L. [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Azzollini, Jacopo [0000-0002-9364-9778], Barrowdale, Daniel [0000-0003-1661-3939], Becher, Heko [0000-0002-8808-6667], Bernstein, Leslie [0000-0002-7692-6518], Bojesen, Stig E. [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Caldés, Trinidad [0000-0002-1038-5392], Chanock, Stephen J. [0000-0002-2324-3393], Chung, Wendy K. [0000-0003-3438-5685], Claes, Kathleen B. M. [0000-0003-0841-7372], Collée, J. Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dunning, Alison M. [0000-0001-6651-7166], Dwek, Miriam [0000-0001-7184-2932], Eliassen, A. Heather [0000-0002-3961-6609], Fritschi, Lin [0000-0002-7692-3560], García-Closas, Montserrat [0000-0003-1033-2650], García-Sáenz, José A. [0000-0001-6880-0301], Gayther, Simon A. [0000-0001-7937-5443], Giles, Graham G. [0000-0003-4946-9099], Greene, Mark H. [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Håkansson, Niclas [0000-0001-7673-5554], Hart, Steven N. [0000-0001-7714-2734], He, Wei [0000-0003-0161-3274], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J. [0000-0001-8397-4078], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A. [0000-0002-4361-4657], Jensen, Uffe Birk [0000-0002-6205-6355], Jones, Michael E. [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Kraft, Peter [0000-0002-4472-8103], Kurian, Allison W. [0000-0002-6175-9470], Lambrechts, Diether [0000-0002-3429-302X], Lesueur, Fabienne [0000-0001-7404-4549], Martens, John W. M. [0000-0002-3428-3366], Miller, Austin [0000-0001-9739-8462], Milne, Roger L. [0000-0001-5764-7268], Nathanson, Katherine L. [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I. [0000-0002-9936-1599], Olson, Janet E. [0000-0003-4944-7789], Ottini, Laura [0000-0001-8030-0449], Parsons, Michael T. [0000-0003-3242-8477], Pedersen, Inge Sokilde [0000-0002-9902-8040], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Pharoah, Paul D. P. [0000-0001-8494-732X], Punie, Kevin [0000-0002-1162-7963], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Sandler, Dale P. [0000-0002-6776-0018], Schmidt, Marjanka K. [0000-0002-2228-429X], Scott, Christopher [0000-0003-1340-0647], Stone, Jennifer [0000-0001-5077-0124], Toland, Amanda E. [0000-0002-0271-1792], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M. [0000-0002-1962-9322], Vega, Ana [0000-0002-7416-5137], Vijai, Joseph [0000-0002-7933-151X], Weitzel, Jeffrey N. [0000-0001-6714-092X], Wolk, Alicja [0000-0001-7387-6845], Yadav, Siddhartha [0000-0003-4630-9903], Yannoukakos, Drakoulis [0000-0001-7509-3510], Ziogas, Argyrios [0000-0003-4529-3727], Zorn, Kristin K. [0000-0003-2143-8979], Park, Sue K. [0000-0001-5002-9707], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F. [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Becher, Heiko [0000-0002-8808-6667], RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, German Cancer Research Center (DKFZ), National Health and Medical Research Council of Australia, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, National Institute for Health Research (NIHR), Institut National du Cancer (INCA) France, Ligue nationale contre le cancer, Cancer Research UK, European Commision, Canadian Institutes of Health Research (CIHR), Cancer Council New South Wales, Accion Estrategica de Salud del Instituto de Salud Carlos III FIS Intrasalud, Xunta de Galicia, Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain, Fondo de Investigacion Sanitario, California Breast Cancer Research Fund, Federal Ministry of Education & Research (BMBF), Netherlands Government, Russian Foundation for Basic Research (RFBR), O'Mara, Tracy A [0000-0002-5436-3232], Tyrer, Jonathan P [0000-0003-3724-4757], Barnes, Daniel R [0000-0002-3781-7570], Andrulis, Irene L [0000-0002-4226-6435], Bojesen, Stig E [0000-0002-4061-4133], Chanock, Stephen J [0000-0002-2324-3393], Chung, Wendy K [0000-0003-3438-5685], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Dunning, Alison M [0000-0001-6651-7166], Eliassen, A Heather [0000-0002-3961-6609], García-Sáenz, José A [0000-0001-6880-0301], Gayther, Simon A [0000-0001-7937-5443], Giles, Graham G [0000-0003-4946-9099], Greene, Mark H [0000-0003-1852-9239], Hart, Steven N [0000-0001-7714-2734], Hulick, Peter J [0000-0001-8397-4078], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kurian, Allison W [0000-0002-6175-9470], Martens, John WM [0000-0002-3428-3366], Milne, Roger L [0000-0001-5764-7268], Nathanson, Katherine L [0000-0002-6740-0901], Olopade, Olufunmilayo I [0000-0002-9936-1599], Olson, Janet E [0000-0003-4944-7789], Parsons, Michael T [0000-0003-3242-8477], Pharoah, Paul DP [0000-0001-8494-732X], Sandler, Dale P [0000-0002-6776-0018], Schmidt, Marjanka K [0000-0002-2228-429X], Toland, Amanda E [0000-0002-0271-1792], Vachon, Celine M [0000-0002-1962-9322], Weitzel, Jeffrey N [0000-0001-6714-092X], Zorn, Kristin K [0000-0003-2143-8979], Park, Sue K [0000-0001-5002-9707], Easton, Douglas F [0000-0003-2444-3247], HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Institut Català de la Salut, [Coignard J] Genetic Epidemiology of Cancer team, Inserm, U900, Paris, France. Institut Curie Paris, Paris, France. Mines ParisTech Fontainebleau, Paris, France. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. PSL University Paris, Paris, France. Paris Sud University, Orsay, France. [Lush M, Dennis J] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Beesley J, O'Mara TA] Department of Genetics and Computational Biology QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. [Tyrer JP] Centre for Cancer Genetic Epidemiology, Department of Oncology University of Cambridge, Cambridge, UK. [Diez O] Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Àrea de Genètica Clínica i Molecular, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Lopez-Fernández A] High Risk and Cancer Prevention Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Life Course Epidemiology (LCE), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Human Genetics, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Cancer biology and immunology, Clinical Genetics, Medical Oncology, Pathology, and Radiology & Nuclear Medicine
Subjects: 0301 basic medicine, Linkage disequilibrium, endocrine system diseases, Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], 45/43, General Physics and Astronomy, Genome-wide association study, Linkage Disequilibrium, Breast cancer, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Risk Factors, Genotype, breast neoplasms, Medicine and Health Sciences, 631/208/68, skin and connective tissue diseases, Cancer genetics, adult, alleles, BRCA1 protein, BRCA2 protein, female, genetic predisposition to disease, genome-wide association study, genotype, humans, linkage disequilibrium, middle aged, mutation, quantitative trait loci, risk factors, polymorphism, single nucleotide, HEBON Investigators, Genetics, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, Otros calificadores::Otros calificadores::/genética [Otros calificadores], BRCA1 Protein, Genetic Predisposition to Disease/genetics, article, Single Nucleotide, Middle Aged, BRCA2 Protein/genetics, 3. Good health, Mama - Càncer - Factors de risc, 030220 oncology & carcinogenesis, Mutation (genetic algorithm), Genome-Wide Association Study/methods, Medical genetics, Female, Medical Genetics, 692/499, Adult, medicine.medical_specialty, 45/61, Science, 3122 Cancers, Population, Quantitative Trait Loci, Genetic Phenomena::Genetic Variation::Mutation [PHENOMENA AND PROCESSES], ABCTB Investigators, 631/67/2324, Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Càncer de mama, GEMO Study Collaborators, 03 medical and health sciences, Cancer epidemiology, SDG 3 - Good Health and Well-being, Other subheadings::Other subheadings::/genetics [Other subheadings], medicine, Humans, Genetic Predisposition to Disease, Allele, Polymorphism, education, EMBRACE Collaborators, fenómenos genéticos::variación genética::mutación [FENÓMENOS Y PROCESOS], Alleles, Medicinsk genetik, BRCA2 Protein, Mutació (Biologia), General Chemistry, 631/67/1347, Genotype frequency, 030104 developmental biology, Mutation, Mama - Càncer - Aspectes genètics, BRCA1 Protein/genetics, 3111 Biomedicine, KConFab Investigators, Quantitative Trait Loci/genetics, Genètica, Genome-Wide Association Study
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P, Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
Published: 2021

37. A versatile workflow to integrate RNA-seq genomic and transcriptomic data into mechanistic models of signaling pathways

Author: Francisco M. Ortuño, Daniel Lopez-Lopez, Joaquín Dopazo, Eduardo Muñoz, Maria Peña-Chilet, Martín Garrido-Rodríguez, Marco A. Calzado, [Garrido-Rodriguez,M, Lopez-Lopez,D, Ortuno,FM, Peña-Chilet,M, Dopazo,J] Clinical Bioinformatics Area, Fundación Progreso y Salud (FPS), Hospital Virgen del Rocío, Sevilla, Spain. [Garrido-Rodriguez,M, Calzado,MA] Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain. [Garrido-Rodriguez,M, Muñoz,E, Calzado,MA] Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain. [Garrido-Rodriguez,M, Calzado.MA] Hospital Universitario Reina Sofía, Córdoba, Spain. [Lopez-Lopez.D: Ortuno,FM, Dopazo,J] Computational Systems Medicine, Institute of Biomedicine of Seville (IBIS), Sevilla, Spain. [Peña-Chilet,M, Dopazo,J] Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), FPS, Hospital Virgen del Rocío, Sevilla, Spain. [Dopazo,J] FPS/ELIXIR-es, Hospital Virgen del Rocío, Sevilla, Spain, JD has received these grants: SAF2017- 88908-R from the Ministerio de Economı´a y Competitividad and PT17/0009/0006 from the Instituto de Salud Carlos III, as well as an FP7 People Marie-Curie Actions 813533 and and Horizon 2020 Framework Programme 676559. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, and European Commission
Subjects: 0301 basic medicine, Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor [Medical Subject Headings], Signaling pathways, Databases, Factual, Computer science, Gene Expression, RNA-Seq, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Sequence Analysis::High-Throughput Nucleotide Sequencing [Medical Subject Headings], Workflow, Transcriptome, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical [Medical Subject Headings], Sequencing techniques, Mathematical and Statistical Techniques, 0302 clinical medicine, Cell Signaling, Information Science::Information Science::Computing Methodologies::Software [Medical Subject Headings], Biology (General), Information Science::Information Science::Systems Analysis::Workflow [Medical Subject Headings], Ecology, High-Throughput Nucleotide Sequencing, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Signal Transduction [Medical Subject Headings], RNA sequencing, Genomics, Functional Genomics, 3. Good health, Computational Theory and Mathematics, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], Modeling and Simulation, Information Science::Information Science::Information Storage and Retrieval::Databases as Topic::Databases, Factual [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics [Medical Subject Headings], Signal transduction, Genomic Signal Processing, Transcriptome Analysis, Functional genomics, Algorithms, Research Article, Signal Transduction, Phenomena and Processes::Mathematical Concepts::Algorithms [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Mutation [Medical Subject Headings], QH301-705.5, Process (engineering), RNA massive sequencing, Computational biology, Secuenciación de escopeta completa del transcriptoma, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Expression Profiling [Medical Subject Headings], Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Transcription, Genetic::Transcriptome [Medical Subject Headings], 03 medical and health sciences, Cellular and Molecular Neuroscience, Cell Line, Tumor, Fish Genomics, Exome Sequencing, Genetics, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Gene Expression Profiling, Flujo de trabajo, Biology and Life Sciences, Computational Biology, Cell Biology, Models, Theoretical, Genome Analysis, Research and analysis methods, Transcriptoma, Molecular biology techniques, 030104 developmental biology, Animal Genomics, Mutation, Functional profiling, ComputingMethodologies_GENERAL, RNA-seq, Functional Analysis, Software, 030217 neurology & neurosurgery
Abstract: This is a PLOS Computational Biology Software paper., [Abstract] MIGNON is a workflow for the analysis of RNA-Seq experiments, which not only efficiently manages the estimation of gene expression levels from raw sequencing reads, but also calls genomic variants present in the transcripts analyzed. Moreover, this is the first workflow that provides a framework for the integration of transcriptomic and genomic data based on a mechanistic model of signaling pathway activities that allows a detailed biological interpretation of the results, including a comprehensive functional profiling of cell activity. MIGNON covers the whole process, from reads to signaling circuit activity estimations, using state-of-the-art tools, it is easy to use and it is deployable in different computational environments, allowing an optimized use of the resources available., [Author summary] Currently, RNA massive sequencing RNA-seq is the most extensively used technique for gene expression profiling in a single assay. The output of RNA-seq experiments contains millions of sequences, generated from cDNA libraries produced by the retro-transcription of RNA samples, that need to be processed by computational methods to be transformed into meaningful biological information. Thus, a number of bioinformatic workflows and pipelines have been proposed to produce different types of gene expression measurements, including in some cases, functional annotations to facilitate biological interpretation. While most pipelines focus exclusively on transcriptional data, the ultimate activity of the resulting gene product also depends critically on its integrity. Although traditional hybridization-based transcriptomics methodologies (microarrays) miss this information, RNA-seq data also contains information on variants present in the transcripts that can affect the function of the gene product, which is systematically ignored by current RNA-seq pipelines. MIGNON is the first workflow able to perform an integrative analysis of transcriptomic and genomic data in the proper functional context, provided by a mechanistic model of signaling pathway activity, making thus the most of the information contained in RNA-Seq data. MIGNON is easy to use and to deploy and may become a valuable asset in fields such as personalized medicine., JD has received these grants: SAF2017-88908-R from the Ministerio de Economía y Competitividad and PT17/0009/0006 from the Instituto de Salud Carlos III, as well as an FP7 People Marie-Curie Actions 813533 and and Horizon 2020 Framework Programme 676559.
Published: 2021

38. In Patients With Obesity, the Number of Adipose Tissue Mast Cells Is Significantly Lower in Subjects With Type 2 Diabetes

Author: David Lopez-Perez, Anaïs Redruello-Romero, Jesús Garcia-Rubio, Carlos Arana, Luis A. Garcia-Escudero, Francisco Tamayo, Jose D. Puentes-Pardo, Sara Moreno-SanJuan, Javier Salmeron, Armando Blanco, Julio Galvez, Josefa Leon, Ángel Carazo, [Lopez-Perez,D, Puentes-Pardo,JD, Galvez,J] Department of Pharmacology, Faculty of Pharmacy, University of Granada, Granada, Spain. [Lopez-Perez,D, Redruello-Romero,A, Galvez,J, Leon,J, Carazo,A] Research Unit, Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. [Garcia-Rubio,J, Tamayo,F] Surgery Unit, San Cecilio University Hospital, Granada, Spain. [Arana,C] Endocrinology and Nutrition Unit, Virgen de las Nieves University Hospital, Granada, Spain. [García-Escuder,LA] Department of Statistics and Operative Research, Faculty of Sciences, University of Valladolid, Valladolid, Spain. [Moreno-SanJuan,S] Cytometry and Microscopy Research Service, Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. [Salmeron,J] Gastroenterology Unit, San Cecilio University Hospital, Granada, Spain. [Blanco,A] Department of Computer Science and Artificial Intelligence, University of Granada, Granada, Spain. [Galvez,J] Centro de Investigación Biomédica En Red para Enfermedades Hepáticas y Digestivas (CIBER-EHD), Center for Biomedical Research, University of Granada, Granada, Spain. [Leon,J, Carazo,A] Clinical Management Unit of Digestive Disease, San Cecilio University Hospital, Granada, Spain., and Instituto de Salud Carlos III (grant PI18/01947). Instituto de Salud Carlos III is a research institution from the Spanish government that funds biomedical research. Instituto de Salud Carlos III funded all the experiments.
Subjects: 0301 basic medicine, obesity, endocrine system diseases, Angiogenesis, Obesidad, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation::Adipogenesis [Medical Subject Headings], Mastocitos, Adipose tissue, Cell Count, White adipose tissue, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], angiogenesis, 0302 clinical medicine, Phenomena and Processes::Circulatory and Respiratory Physiological Phenomena::Cardiovascular Physiological Phenomena::Cardiovascular Physiological Processes::Neovascularization, Physiologic [Medical Subject Headings], Immunology and Allergy, T2D, Flow cytometry, Mast Cells, Intestinal Mucosa, Original Research, education.field_of_study, Adipogenesis, food and beverages, Mast cell, Anatomy::Tissues::Connective Tissue::Adipose Tissue [Medical Subject Headings], adipose tissue, medicine.anatomical_structure, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2 [Medical Subject Headings], Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Diagnostic Techniques and Procedures::Clinical Laboratory Techniques::Immunologic Tests::Immunophenotyping [Medical Subject Headings], lipids (amino acids, peptides, and proteins), medicine.symptom, hormones, hormone substitutes, and hormone antagonists, Tejido adiposo, medicine.medical_specialty, Adipose Tissue, White, Population, Immunology, Neovascularization, Physiologic, 030209 endocrinology & metabolism, Inflammation, Anatomy::Cells::Connective Tissue Cells::Mast Cells [Medical Subject Headings], Immunophenotyping, 03 medical and health sciences, Internal medicine, Chemicals and Drugs::Biological Factors::Biological Markers [Medical Subject Headings], medicine, Humans, Obesity, Progenitor cell, education, Inflamación, business.industry, flow cytometry, nutritional and metabolic diseases, RC581-607, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Anatomy::Tissues::Connective Tissue::Adipose Tissue::Adipose Tissue, White [Medical Subject Headings], 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, inflammation, Immunologic diseases. Allergy, Citometría de flujo, business, mast cell, Anatomy::Digestive System::Gastrointestinal Tract::Intestines::Intestinal Mucosa [Medical Subject Headings], Biomarkers
Abstract: This work was supported by Instituto de Salud Carlos III (grant PI15/01361), Spain; and MINECO (grant DPI2017-84439-R), Madrid and FEDER. DL-P is a predoctoral fellow ("Programa de doctorado en Bioquimica y Biologia Molecular", B16.56.1) funded by the Spanish Ministry of Science and Innovation (" Formacion de profesorado universitario" grant FPU18/ 04432). DL-P participated in this work thanks to a grant from University of Granada ("Becas de iniciacion a la investigacion del plan propio de la UGR")., Type 2 diabetes (T2D) is a rising global health problem mainly caused by obesity and a sedentary lifestyle. In healthy individuals, white adipose tissue (WAT) has a relevant homeostatic role in glucose metabolism, energy storage, and endocrine signaling. Mast cells contribute to these functions promoting WAT angiogenesis and adipogenesis. In patients with T2D, inflammation dramatically impacts WAT functioning, which results in the recruitment of several leukocytes, including monocytes, that enhance this inflammation. Accordingly, the macrophages population rises as the WAT inflammation increases during the T2D status worsening. Since mast cell progenitors cannot arrive at WAT, the amount of WAT mast cells depends on how the new microenvironment affects progenitor and differentiated mast cells. Here, we employed a flow cytometry-based approach to analyze the number of mast cells from omental white adipose tissue (o-WAT) and subcutaneous white adipose tissue (s-WAT) in a cohort of 100 patients with obesity. Additionally, we measured the number of mast cell progenitors in a subcohort of 15 patients. The cohort was divided in three groups: non-T2D, pre-T2D, and T2D. Importantly, patients with T2D have a mild condition (HbA1c, Instituto de Salud Carlos III PI15/01361, MINECO, Madrid DPI2017-84439-R, European Commission, Spanish Ministry of Science and Innovation (" Formacion de profesorado universitario" grant) FPU18/04432 B16.56.1, University of Granada ("Becas de iniciacion a la investigacion del plan propio de la UGR")
Published: 2021

39. Transitioning From Preclinical Evidence to Advanced Therapy Medicinal Product: A Spanish Experience

Author: Paloma Gastelurrutia, Cristina Prat-Vidal, Joaquim Vives, Ruth Coll, Antoni Bayes-Genis, Carolina Gálvez-Montón, Institut Català de la Salut, [Gastelurrutia P, Prat-Vidal C] Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, L'Hospitalet de Llobregat, Spain. Insuficiencia Cardíaca y Regeneración Cardíaca Research Program, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain. Centro de Investigación Biomédica en Red Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain. [Vives J] Servei de Teràpia Cel·lular, Banc de Sang i Teixits, Barcelona, Spain. Grup d’Enginyeria tissular musculoesquelètica, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Coll R] Servei de Teràpia Cel·lular, Banc de Sang i Teixits, Barcelona, Spain. [Bayes-Genis A] Insuficiencia Cardíaca y Regeneración Cardíaca Research Program, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain. Centro de Investigación Biomédica en Red Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain. Hospital Universitari Germans Trias i Pujol, Badalona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Gálvez-Montón C] Insuficiencia Cardíaca y Regeneración Cardíaca Research Program, Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain. Centro de Investigación Biomédica en Red Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Therapeutics::Therapies, Investigational [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], 0301 basic medicine, regulatory agency, lcsh:Diseases of the circulatory (Cardiovascular) system, medicine.medical_specialty, terapéutica::tratamientos en investigación [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], media_common.quotation_subject, Cellular therapy, Investigació mèdica, Cardiovascular Medicine, 030204 cardiovascular system & hematology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Policy and Practice Reviews, Medicine research, medicine, Quality (business), Medical physics, Product (category theory), media_common, Medicaments - Desenvolupament, investigational medicinal product dossier (IMPD), localizaciones geográficas::Europa (continente)::España [DENOMINACIONES GEOGRÁFICAS], translational (regulation), Medicina basada en l'evidència, business.industry, Teràpia cel·lular, Medicina - Investigació - Espanya, Geographic Locations::Europe::Spain [GEOGRAPHICALS], 030104 developmental biology, investigational medicinal product, chemistry, Natural Science Disciplines::Science::Research::Biomedical Research::Translational Medical Research [DISCIPLINES AND OCCUPATIONS], lcsh:RC666-701, New product development, disciplinas de las ciencias naturales::ciencia::investigación::investigación biomédica::investigación médica traslacional [DISCIPLINAS Y OCUPACIONES], advanced therapy medicinal product, Regulatory agency, ATMP, Cardiology and Cardiovascular Medicine, business
Abstract: Medicament de teràpia avançada; Medicament en investigació; Translacional (regulació) Medicamento de terapia avanzada; Medicamento en investigación; Traslacional (regulación) Advanced therapy medicinal product; Investigational medicinal product; Translational (regulation) A systematic and ordered product development program, in compliance with current quality and regulatory standards, increases the likelihood of yielding a successful advanced therapy medicinal product (ATMP) for clinical use as safe and effective therapy. As this is a novel field, little accurate information is available regarding the steps to be followed, and the information to be produced to support the development and use of an ATMP. Notably, successful clinical translation can be somewhat cumbersome for academic researchers. In this article, we have provided a summary of the available information, supported by our experience in Spain throughout the development of an ATMP for myocardial infarction, from the pre-clinical stage to phase I clinical trial approval. This work was supported by the Spanish Cell Therapy Network (TerCel) [RD16/0011/0006 and RD16/0011/0028]; and CIBER Cardiovascular [CB16/11/00403] projects, as a part of the National R&D&I Plan, and was co-funded by the ISCIII-Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund (ERDF); the Government of Catalonia: Agency for Management of University and Research Grants (AGAUR) [2017-SGR-483 and 2017-SGR-719], PERIS Program (Health Department) [SLT002/16/00234 and SLT002/16/00209] and CERCA Program; La Caixa Banking Foundation; grants from the Spanish Ministry of Science, Innovation and Universities (MICINN) [SAF2017-84324-C2-1-R]; Institute of Health Carlos III (ISCIII) [PI18/00256, PIC18/00014, ICI19/00039, and PI19/01788], and cofunded by European Union (ERDF/ESF) - A way to build Europe. This work has also been funded by the Sociedad Española de Cardiología and by the Call for Expression of Interest (EoI) for Collaborative Projects on Regenerative Medicine 2019 of Center for Regenerative Medicine of Barcelona (CMR[B]). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.
Published: 2021

40. High-fructose feeding does not induce steatosis or non-alcoholic fatty liver disease in pigs

Author: Julián Albarrán-Juárez, Nikolaj Schmidt, Jacob F. Bentzon, Søren K. Moestrup, Pia Svendsen, Novo Nordisk Foundation, Danish National Research Foundation, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Fundación ProCNIC, Danish National Resarch Foundation (ATLAS center), and Instituto de Salud Carlos III - ISCIII
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, food.ingredient, Science, Sus scrofa, Adipose tissue, Connective tissue, Fructose, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, food, Downregulation and upregulation, Species Specificity, Non-alcoholic Fatty Liver Disease, Internal medicine, Genetics research, medicine, Dietary Carbohydrates, Animals, Humans, Acute inflammation, Multidisciplinary, business.industry, Lipogenesis, Fatty liver, medicine.disease, Corn syrup, Experimental models of disease, Disease Models, Animal, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, chemistry, Adipose Tissue, Liver, Medicine, 030211 gastroenterology & hepatology, Steatosis, business
Abstract: Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition that has been linked to high-fructose corn syrup consumption with induction of hepatic de novo lipogenesis (DNL) as the suggested central mechanism. Feeding diets very high in fructose (> 60%) rapidly induce several features of NAFLD in rodents, but similar diets have not yet been applied in larger animals, such as pigs. With the aim to develop a large animal NAFLD model, we analysed the effects of feeding a high-fructose (HF, 60% w/w) diet for four weeks to castrated male Danish Landrace-York-Duroc pigs. HF feeding upregulated expression of hepatic DNL proteins, but levels were low compared with adipose tissue. No steatosis or hepatocellular ballooning was seen on histopathological examination, and plasma levels of transaminases were similar between groups. Inflammatory infiltrates and the amount of connective tissue was slightly elevated in liver sections from fructose-fed pigs, which was corroborated by up-regulation of macrophage marker expression in liver homogenates. Supported by RNA-profiling, quantitative protein analysis, histopathological examination, and biochemistry, our data suggest that pigs, contrary to rodents and humans, are protected against fructose-induced steatosis by relying on adipose tissue rather than liver for DNL. The study was supported by a Synergy Grant from the Novo Nordisk Foundation (NNF14OC0011537) and by the Danish National Resarch Foundation (ATLAS center). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Sí
Published: 2021

41. Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Author: Rósula García-Navas, Fernando C. Baltanás, P. Liceras-Boillos, Nuria Calzada, José M. Cuezva, Eugenio Santos, Carmela Gómez, Cristina Nuevo-Tapioles, UAM. Departamento de Biología Molecular, Instituto de Salud Carlos III, Junta de Castilla y León, Fundación Ramón Areces, European Commission, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER), Instituto de Salud Carlos III FIS PI19/00934, CIBERONC-CB16/12/00352, Gobierno regional de Castilla y Leon SA264P18-UIC 076, and Fundación Ramon Areces CIVP19A5942
Subjects: 0301 basic medicine, Cancer Research, Fission, Molecular biology, Activation, Endogeny, Oxidative phosphorylation, Mitochondrion, Biology, medicine.disease_cause, Mitochondrial Dynamics, Article, Induction, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Homeostasis, Glycolysis, Fusion, Pathways, Cancer, Cell-Proliferation, Superoxide, Metabolism, Oncogenes, Mass, Biología y Biomedicina / Biología, Electron transport chain, Cell biology, Oxidative Stress, 030104 developmental biology, 030220 oncology & carcinogenesis, ras Guanine Nucleotide Exchange Factors, Oxidative stress, Intracellular, Cell signalling
Abstract: © The Author(s) 2021., SOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function., This work was supported by grants from ISCIII-MCUI (FIS PI19/00934 and CIBERONCCB16/12/00352), Junta de Castilla y Leon (SA264P18-UIC 076), and Ramon Areces Foundation (CIVP19A5942). The research was co-financed by FEDER funds.
Published: 2021

42. Mediterranean diet, screen-time-based sedentary behavior and their interaction effect on adiposity in european adolescents: the helena study

Author: Luis A Moreno, Kurt Widhalm, Yannis Manios, Cristina Molina-Hidalgo, Marcela González-Gross, Miguel Seral-Cortes, Luis M. Esteban, Pilar De Miguel-Etayo, Anthony Kafatos, Frédéric Gottrand, Alexandro Bailo-Aysa, Dénes Molnár, Stefaan De Henauw, Sergio Sabroso-Lasa, Christina Mavrogianni, Jean Dallongeville, Laura Censi, Idoia Labayen, University of Zaragoza - Universidad de Zaragoza [Zaragoza], Centro Nacional de Investigaciones Oncologicas / Spanish National Cancer Research Centre [Madrid, Espagne] (CNIO), Universität Bonn = University of Bonn, Universidad Politécnica de Madrid (UPM), Instituto de Salud Carlos III [Madrid] (ISC), University of Pecs, Consiglio per la Ricerca in Agricoltura e l’analisi dell’economia agraria = Council for Agricultural Research and Economics (CREA), Universidad de Granada = University of Granada (UGR), CHU Lille, Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universiteit Gent = Ghent University (UGENT), Harokopio University of Athens, Medizinische Universität Wien = Medical University of Vienna, University of Crete [Heraklion] (UOC), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Universidad Pública de Navarra [Espagne] = Public University of Navarra (UPNA), Université de Lille, LillOA, University of Bonn, Inserm, Université de Lille, Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167, Centro Nacional de Investigaciones Oncologicas / Spanish National Cancer Research Centre [Madrid, Espagne] [CNIO], Universidad Politécnica de Madrid [UPM], Instituto de Salud Carlos III [Madrid] [ISC], Consiglio per la Ricerca in Agricoltura e l’analisi dell’economia agraria = Council for Agricultural Research and Economics [CREA], Lille Inflammation Research International Center (LIRIC) - U995, Universiteit Gent = Ghent University [UGENT], University of Crete [Heraklion] [UOC], and Universidad Pública de Navarra [Espagne] = Public University of Navarra [UPNA]
Subjects: 0301 basic medicine, Male, Mediterranean diet, [SDV]Life Sciences [q-bio], Adolescents, Diet, Mediterranean, Body Mass Index, Eating, 0302 clinical medicine, Surveys and Questionnaires, Medicine and Health Sciences, adolescents, Child, Adiposity, 2. Zero hunger, adiposity, Nutrition and Dietetics, gender and, Sedentary behavior, Sedentary time, [SDV] Life Sciences [q-bio], Europe, Female, lcsh:Nutrition. Foods and food supply, Waist, Adolescent, sedentary time, 030209 endocrinology & metabolism, lcsh:TX341-641, Interaction, Childhood obesity, Article, gender and HELENA, Screen Time, 03 medical and health sciences, Screen time, Sex Factors, HELENA, medicine, Humans, 030109 nutrition & dietetics, Gender and HELENA, business.industry, medicine.disease, Cross-Sectional Studies, Socioeconomic Factors, Linear Models, Sedentary Behavior, business, Body mass index, Food Science, Demography
Abstract: Childhood obesity is a worldwide epidemic. Mediterranean diet (MD) is inversely associated with childhood obesity, but the interaction with other environmental factors, such screen time, might influence the health benefits of a highMD adherence in adolescents. The aimof the present studywas to assess whether an association between MD and screen time exists in European adolescents. Moreover, we also explored whether sedentary time has a modulatory effect on the association between MD and adiposity. Adherence to the MD (24 h recalls), screen time (questionnaire), pubertal development, body mass index (BMI), fat mass index (FMI) and waist circumference (WC) were evaluated in 2053 adolescents (54.7% females), aged 12.5–17.5 years. In females, MD adherence was associated with lower BMI and FMI only when they were exposed to less than 338 min/day of screen time (81.8% of females);MD adherence was also associated with lowerWC only when females were exposed to less than 143 min/day of screen time (31.5% of females). No significantMD-screen time interaction was observed in males. In conclusion, screen-time-based sedentary behaviours had a modulatory effect in the association between MD adherence and adiposity in European female adolescents., Iberus Talent Pre-doctoral fellowships 2018, under the European Union's H2020 research and innovation programme under Marie Sklodowska-Curie grant 801586, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, CIBERObn ISCIII-CB15/00043, European Commission FOOD-CT-2005-007034, HELENA project, Spanish Ministry of Economy and Competitiveness RYC-2010-05957 RYC-2011-09011, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn)
Published: 2021

43. Toll-Like Receptors in Acute Kidney Injury

Author: Sandra Rayego-Mateos, Mercedes Vallejo-Mudarra, Isabel Cortegano, María Luisa Gaspar, Carmen Herencia-Bellido, Lucas Opazo-Ríos, Melania Guerrero-Hue, Cristina Vázquez-Carballo, José Luis Morgado-Pascual, Cristina García-Caballero, Juan Antonio Moreno, Belén de Andrés, Jesús Egido, [Vázquez-Carballo,C, Rayego-Mateos,S, Opazo-Ríos,L, Herencia-Bellido,C, Egido,J] Renal, Vascular and Diabetes Research Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain. [Guerrero-Hue,M, García-Caballero,C, Morgado-Pascual,JL, Vallejo-Mudarra,M, Moreno,JA] Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Hospital Universitario Reina Sofía, Córdoba, Spain. [Opazo-Ríos,L, Egido,J] Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. [Cortegano,I, Gaspar,ML, de Andrés,B] Immunobiology Department, Carlos III Health Institute, Majadahonda (Madrid), 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, The authors work has been supported by grants from Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130, PI17/01495, PI20/00375, PI20/00487), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Cardiovascular (CIBERCV), Spanish Ministry of Science and Innovation (RTI2018-099114-B-100, RTI2018-098788-B-100, DTS19/00093, RYC-2017-22369), and Spanish Societies of Cardiology (SEC), Nephrology (SEN) and Atherosclerosis (SEA). The 'PFIS' and 'Sara Borrell' training program of the ISCIII supported the salary of MGH (FI18/00310), SR-M (CD19/00021) and CH-B (CP16/00017). Córdoba University supported the salary of C.G.C. No other relevant affiliations or financial involvement exist with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties., Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), Sociedad Española de Cardiología, Sociedad Española de Nefrología, Sociedad Española de Arteriosclerosis, University of Córdoba (España), UAM. Departamento de Farmacología, UAM. Departamento de Medicina, Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), and Universidad de Córdoba
Subjects: 0301 basic medicine, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Pattern Recognition::Toll-Like Receptors::Toll-Like Receptor 4 [Medical Subject Headings], Anatomy::Urogenital System::Urinary Tract::Kidney [Medical Subject Headings], Nefrología y urología, medicine.medical_treatment, Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Acute Kidney Injury [Medical Subject Headings], Review, Bioinformatics, urologic and male genital diseases, Kidney, drugs, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings], Lesión renal aguda, lcsh:Chemistry, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Risk Factors, Chronic kidney disease, Epidemiology, Organisms::Eukaryota::Animals [Medical Subject Headings], Insuficiencia renal crónica, Receptor, lcsh:QH301-705.5, Spectroscopy, Diseases::Male Urogenital Diseases::Urologic Diseases::Kidney Diseases::Renal Insufficiency::Renal Insufficiency, Chronic [Medical Subject Headings], Toll-Like Receptors, Acute kidney injury, Drugs, General Medicine, Acute Kidney Injury, female genital diseases and pregnancy complications, Computer Science Applications, Renal Replacement Therapy, Terapia, 030220 oncology & carcinogenesis, Disease Progression, Medicamentos, Persons::Persons::Patients::Survivors [Medical Subject Headings], medicine.symptom, Factores de riesgo, medicine.medical_specialty, Medicina, Receptores toll-like, Inflammation, Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Inflammatory Agents [Medical Subject Headings], Catalysis, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Renal Replacement Therapy [Medical Subject Headings], Inorganic Chemistry, 03 medical and health sciences, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Internationality::International Cooperation::Developing Countries [Medical Subject Headings], medicine, Animals, Humans, Renal replacement therapy, Physical and Theoretical Chemistry, Renal Insufficiency, Chronic, Molecular Biology, Pathological, Diseases::Cardiovascular Diseases [Medical Subject Headings], therapy, Inflamación, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Progression [Medical Subject Headings], business.industry, urogenital system, Organic Chemistry, and therapy, medicine.disease, Toll-like receptors, Toll-Like Receptor 4, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Risk factors, inflammation, TLR4, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Receptors, Pattern Recognition::Toll-Like Receptors [Medical Subject Headings], Therapy, business, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings], Kidney disease
Abstract: Acute kidney injury (AKI) is an important health problem, affecting 13.3 million individuals/year. It is associated with increased mortality, mainly in low- and middle-income countries, where renal replacement therapy is limited. Moreover, survivors show adverse long-term outcomes, including increased risk of developing recurrent AKI bouts, cardiovascular events, and chronic kidney disease. However, there are no specific treatments to decrease the adverse consequences of AKI. Epidemiological and preclinical studies show the pathological role of inflammation in AKI, not only at the acute phase but also in the progression to chronic kidney disease. Toll-like receptors (TLRs) are key regulators of the inflammatory response and have been associated to many cellular processes activated during AKI. For that reason, a number of anti-inflammatory agents targeting TLRs have been analyzed in preclinical studies to decrease renal damage during AKI. In this review, we updated recent knowledge about the role of TLRs, mainly TLR4, in the initiation and development of AKI as well as novel compounds targeting these molecules to diminish kidney injury associated to this pathological condition, The authors work has been supported by grants from Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130, PI17/01495, PI20/00375, PI20/00487), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Cardiovascular (CIBERCV), Spanish Ministry of Science and Innovation (RTI2018-099114-B-100, RTI2018-098788-B-100, DTS19/00093, RYC-2017-22369), and Spanish Societies of Cardiology (SEC), Nephrology (SEN) and Atherosclerosis (SEA). The “PFIS” and “Sara Borrell” training program of the ISCIII supported the salary of MGH (FI18/00310), SR-M (CD19/00021) and CH-B (CP16/00017). Córdoba University supported the salary of C.G.C.
Published: 2021

44. Genetic association study of childhood aggression across raters, instruments, and age

Author: Nicholas G. Martin, S. Alexandra Burt, Louise Arseneault, Fazil Aliev, Luke M. Evans, Hill F. Ip, Beate St Pourcain, Michel G. Nivard, William E. Copeland, Rebecca K. Vinding, Scott Gordon, Koen Bolhuis, Christian J. Hopfer, Gun Peggy Knudsen, Stefan Johansson, Avshalom Caspi, Richard Border, Chandra A. Reynolds, Pål R. Njølstad, Liisa Keltikangas-Järvinen, Dorret I. Boomsma, Klaus Bønnelykke, Teemu Palviainen, Marta Ribasés, Alina Rodriguez, Catharina A. Hartman, Ilkka Seppälä, Christel M. Middeldorp, Rosa Bosch, Jan Haavik, Gail M. Williams, Andrea G. Allegrini, Ruth Ks, John R. B. Perry, Hadi Zafarmand, Chang Jiang, Elizabeth J. Costello, Camiel M. van der Laan, Olli T. Raitakari, Miquel Casas, Isabell Brikell, William G. Iacono, Jaakko Kaprio, John K. Hewitt, Andrew C. Heath, Eero Vuoksimaa, Xiaoran Tong, Gemma Español, Erik A. Ehli, Richie Poulton, Gareth E. Davies, Albertine J. Oldehinkel, Hans Bisgaard, Naomi R. Wray, Ted Reichborn-Kjennerud, Robert Plomin, Michael C. Stallings, Qing Lu, Jackob M. Najman, Daniel E. Adkins, Yi Lu, Harold Snieder, Sally J. Wadsworth, Alexander Neumann, Alexandra Havdahl, Karen Sugden, Kelly L. Klump, Andrew Smolen, Henrik Larsson, Toos C. E. M. van Beijsterveldt, Kenneth Krauter, Tarunveer S. Ahluwalia, Tellervo Korhonen, Andrey A. Shabalin, Joachim Heinrich, Anke R. Hammerschlag, Shelby Marrington, Lærke Sass, Pamela A. F. Madden, Henning Tiemeier, Tanja Vrijkotte, Paul Lichtenstein, Terho Lehtimäki, Ville Karhunen, Cristina Sánchez-Mora, Robin P. Corley, Anna A. E. Vinkhuyzen, Richard J. Rose, Per Magnus, Sabrina Llop, Ilja M. Nolte, S.A. Brown, Christian Hakulinen, Anjali K. Henders, Marie Standl, Silvia Alemany, Gretchen R.B. Saunders, Jouke-Jan Hottenga, Eveline L. de Zeeuw, Meike Bartels, Elisabeth Thiering, José J. Morosoli, Fiona A. Hagenbeek, Laura Pulkki-Råback, Frank C. Verhulst, Martin A. Kennedy, Craig E. Pennell, Eva Krapohl, Kaili Rimfeld, Tetyana Zayats, Lucía Colodro-Conde, Judith B.M. Ensink, André G. Uitterlinden, Natalia Vilor-Tejedor, Felix R. Day, Jennifer R. Harris, George Davey Smith, Qi Chen, Sebastian Lundström, Marjo-Riitta Järvelin, Alyce M. Whipp, Katrina L. Grasby, L. John Horwood, John Pearson, Judy L. Silberg, Paula Rovira, Hermine H. Maes, Carol A. Wang, Roseann E. Peterson, Tamara L. Wall, Andrew J. O. Whitehouse, Maria-Jose Lopez-Espinosa, Najaf Amin, Jess Tyrrell, Danielle M. Dick, Sarah E. Medland, Allison L. Miller, Øyvind Helgeland, Josep Antoni Ramos Quiroga, Joseph M. Boden, Abdullah Mamun, James Scott, María Soler Artigas, Joseph A. Prinz, Lindon J. Eaves, Terrie E. Moffitt, Matt McGue, Jordi Sunyer, Joanna Martin, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Apollo-University Of Cambridge Repository, Ip, Hill F [0000-0003-1991-5019], Sánchez-Mora, Cristina [0000-0003-4211-1107], Nolte, Ilja M [0000-0001-5047-4077], St Pourcain, Beate [0000-0002-4680-3517], Palviainen, Teemu [0000-0002-7847-8384], Colodro-Conde, Lucía [0000-0002-9004-364X], Gordon, Scott [0000-0001-7623-328X], Aliev, Fazil [0000-0001-8357-4699], Karhunen, Ville [0000-0001-6064-1588], Border, Richard [0000-0002-6293-2968], Ahluwalia, Tarunveer S [0000-0002-7464-3354], Day, Felix R [0000-0003-3789-7651], Hottenga, Jouke-Jan [0000-0002-5668-2368], Rimfeld, Kaili [0000-0001-5139-065X], Lu, Yi [0000-0001-9933-3654], Soler Artigas, María [0000-0002-3213-1107], Bosch, Rosa [0000-0002-7596-183X], Ramos Quiroga, Josep Antoni [0000-0003-1622-0350], Neumann, Alexander [0000-0001-6653-3203], Grasby, Katrina [0000-0001-8539-0228], Middeldorp, Christel [0000-0002-6218-0428], Evans, Luke M [0000-0002-7458-1720], Alemany, Silvia [0000-0002-7925-6767], Sass, Lærke [0000-0002-5217-7014], Ruth, Kate [0000-0003-4966-9170], Ehli, Erik A [0000-0002-7865-3015], Hagenbeek, Fiona A [0000-0002-8773-0430], Snieder, Harold [0000-0003-1949-2298], Uitterlinden, André G [0000-0002-7276-3387], Haavik, Jan [0000-0001-7865-2808], Johansson, Stefan [0000-0002-2298-7008], Knudsen, Gun Peggy S [0000-0002-6193-4291], Njolstad, Pal Rasmus [0000-0003-0304-6728], Rodriguez, Alina [0000-0003-1209-8802], Brown, Sandy [0000-0001-8780-0323], Miller, Allison [0000-0003-3816-2251], Keltikangas-Järvinen, Liisa [0000-0002-7977-3852], Havdahl, Alexandra [0000-0002-9268-0423], Perry, John RB [0000-0001-6483-3771], Lehtimäki, Terho [0000-0002-2555-4427], Arseneault, Louise [0000-0002-2938-2191], Boden, Joseph [0000-0003-1502-1608], Pearson, John [0000-0001-5607-4517], Kennedy, Martin [0000-0002-6445-8526], Poulton, Richie [0000-0002-1052-4583], Copeland, William E [0000-0002-1348-7781], Wray, Naomi [0000-0001-7421-3357], Järvelin, Marjo-Riitta [0000-0002-2149-0630], McGue, Matt [0000-0002-5580-1433], Pennell, Craig E [0000-0002-0937-6165], Dick, Danielle M [0000-0002-1636-893X], Martin, Nicholas G [0000-0003-4069-8020], Medland, Sarah E [0000-0003-1382-380X], Kaprio, Jaakko [0000-0002-3716-2455], Tiemeier, Henning [0000-0002-4395-1397], Davey Smith, George [0000-0002-1407-8314], Oldehinkel, Albertine J [0000-0003-3925-3913], Ribasés, Marta [0000-0003-1039-1116], Lichtenstein, Paul [0000-0003-3037-5287], Plomin, Robert [0000-0002-0756-3629], Bartels, Meike [0000-0002-9667-7555], Nivard, Michel G [0000-0003-2015-1888], Boomsma, Dorret I [0000-0002-7099-7972], Apollo - University of Cambridge Repository, Life Course Epidemiology (LCE), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Child and Adolescent Psychiatry / Psychology, Epidemiology, Internal Medicine, Institute for Molecular Medicine Finland, Genetic Epidemiology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Tellervo Korhonen / Principal Investigator, Cognitive and Brain Aging, Faculty Common Matters (Faculty of Medicine), Medicum, Doctoral Programme in Cognition, Learning, Instruction and Communication, Department of Psychology and Logopedics, Helsinki Inequality Initiative (INEQ), Faculty Common Matters (Faculty of Education), Psychosocial factors and health, Behavioural Sciences, Department of Public Health, Adult Psychiatry, Epidemiology and Data Science, APH - Aging & Later Life, APH - Methodology, ARD - Amsterdam Reproduction and Development, Graduate School, Child Psychiatry, ACS - Pulmonary hypertension & thrombosis, ANS - Cellular & Molecular Mechanisms, ANS - Compulsivity, Impulsivity & Attention, Public and occupational health, APH - Health Behaviors & Chronic Diseases, Institut Català de la Salut, [Ip HF] Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. [van der Laan CM] Department of Biological Psychology, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. Netherlands Institute for the Study of Crime and Law Enforcement, Amsterdam, The Netherlands. [Krapohl EML] Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK. [Brikell I] Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. [Sánchez-Mora C, Soler Artigas M, Rovira P, Ribasés M] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Unitat de Genètica Psiquiàtrica, Grup de Recerca en Psiquiatria, Salut Mental i Addicció, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Nolte IM] Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. [Bosch R] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Servei de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Español G] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Ramos Quiroga JA, Ribasés M] Servei de Psiquiatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Barcelona, Spain. Unitat de Genètica Psiquiàtrica, Grup de Recerca en Psiquiatria, Salut Mental i Addicció, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Servei de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Biological Psychology, APH - Personalized Medicine, APH - Mental Health, Amsterdam Reproduction & Development, Perry, John R B [0000-0001-6483-3771], Ip, Hill F. [0000-0003-1991-5019], Nolte, Ilja M. [0000-0001-5047-4077], Ahluwalia, Tarunveer S. [0000-0002-7464-3354], Day, Felix R. [0000-0003-3789-7651], Evans, Luke M. [0000-0002-7458-1720], Ehli, Erik A. [0000-0002-7865-3015], Hagenbeek, Fiona A. [0000-0002-8773-0430], Uitterlinden, André G. [0000-0002-7276-3387], Knudsen, Gun Peggy S. [0000-0002-6193-4291], Perry, John R. B. [0000-0001-6483-3771], Copeland, William E. [0000-0002-1348-7781], Pennell, Craig E. [0000-0002-0937-6165], Dick, Danielle M. [0000-0002-1636-893X], Martin, Nicholas G. [0000-0003-4069-8020], Medland, Sarah E. [0000-0003-1382-380X], Oldehinkel, Albertine J. [0000-0003-3925-3913], Nivard, Michel G. [0000-0003-2015-1888], and Boomsma, Dorret I. [0000-0002-7099-7972]
Subjects: 0301 basic medicine, DISORDER, 45/43, Genome-wide association study, 3124 Neurology and psychiatry, 0302 clinical medicine, Child, Psychiatry, 0303 health sciences, trastornos mentales [PSIQUIATRÍA Y PSICOLOGÍA], HERITABILITY, Mental Disorders, Cognition, Genomics, Explained variation, Justice and Strong Institutions, Aggression, Psychiatry and Mental health, Meta-analysis, ADOLESCENCE, Child, Preschool, conducta y mecanismos de la conducta::conducta::síntomas conductuales::agresión [PSIQUIATRÍA Y PSICOLOGÍA], 631/208/212, Female, Biological psychiatry, medicine.symptom, Life Sciences & Biomedicine, Investigative Techniques::Genetic Techniques::Genetic Association Studies [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], BEHAVIOR, RC321-571, Childhood aggression, Clinical psychology, SDG 16 - Peace, Adolescent, Mental Disorders [PSYCHIATRY AND PSYCHOLOGY], Neurosciences. Biological psychiatry. Neuropsychiatry, Single-nucleotide polymorphism, Biology, 3121 Internal medicine, Malalties mentals - Aspectes genètics, Genetic correlation, Article, 1117 Public Health and Health Services, Cellular and Molecular Neuroscience, 03 medical and health sciences, 631/477/2811, SDG 3 - Good Health and Well-being, Human behaviour, medicine, SNP, Humans, GENOME-WIDE ASSOCIATION, Biological Psychiatry, Genetic Association Studies, 030304 developmental biology, Genetic association, Retrospective Studies, técnicas de investigación::técnicas genéticas::estudios de asociación genética [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Science & Technology, SDG 16 - Peace, Justice and Strong Institutions, Infant, Behavior and Behavior Mechanisms::Behavior::Behavioral Symptoms::Aggression [PSYCHIATRY AND PSYCHOLOGY], 1103 Clinical Sciences, Agressivitat en els infants, Heritability, 030104 developmental biology, 1701 Psychology, ORIGINS, Research Programm of Donders Centre for Neuroscience, 3111 Biomedicine, TRAJECTORIES, 030217 neurology & neurosurgery, Demography, Genome-Wide Association Study
Abstract: Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
Published: 2021

45. Palmitoleoylethanolamide Is an Efficient Anti-Obesity Endogenous Compound: Comparison with Oleylethanolamide in Diet-Induced Obesity

Author: Antonio Vargas, Fernando Rodríguez de Fonseca, Juan Decara, Laura Soverchia, Laura Hernandez-Folgado, Nadine Jagerovic, Roberto Ciccocioppo, Ana Luisa Gavito, Rubén Tovar, Elena Baixeras, Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia e Innovación (España), Ministerio de Economía, Industria y Competitividad (España), Hernandez-Folgado, Laura [0000-0001-8670-6941], Jagerovic, Nadine [0000-0003-2642-6969], Hernandez-Folgado, Laura, Jagerovic, Nadine, [Tovar,R, Gavito,AL, Vargas,A, Rodríguez de Fonseca,F, Decara,J] Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UGC Salud Mental, Avda. Carlos Haya, Pabellón de Gobierno, Málaga, Spain. [Tovar,R] Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Soverchia,L, Ciccocioppo,R, Decara,J] Pharmacology Unit, School of Pharmacy, University of Camerino, Camerino, Italy. [Hernandez-Folgado,L, Jagerovic,N] Instituto de Química Médica, CSIC, Madrid, Spain. [Baixeras,E] Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Málaga, Málaga, Spain., and This work was supported by grants from the following institutions: Grant for international postdoctoral stay. Jose Castillejo Program (Grant CAS15/00257), Ministerio de Educación Cultura y Deporte. Gobierno de España. Proyecto de Investigación en Salud, Consejería de Salud y Familias (Grant PI-0139-2018). EU-ERDF-Instituto de Salud Carlos III (Grant PI19/01577). Proyectos de desarrollo tecnológico, Ministerio de Ciencia e Innovación (Grant DTS19/00125). Ministerio de Economía, Industria y Competitividad (Grant RTC-2019-007329-1).
Subjects: 0301 basic medicine, Male, Anatomy::Digestive System::Liver [Medical Subject Headings], Obesidad, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Rats::Rats, Sprague-Dawley [Medical Subject Headings], Endogeny, Oleic Acids, PPAR alfa, Receptores de cannabinoides, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Fatty Acids, Monounsaturated, Rats, Sprague-Dawley, Oleoylethanolamide, chemistry.chemical_compound, Chemicals and Drugs::Chemical Actions and Uses::Toxic Actions::Noxae::Carcinogens::Peroxisome Proliferators [Medical Subject Headings], 0302 clinical medicine, N-Acylethanolamine, Phenomena and Processes::Digestive System and Oral Physiological Phenomena::Digestive System Physiological Phenomena::Digestive System Processes::Eating [Medical Subject Headings], Organisms::Eukaryota::Animals [Medical Subject Headings], Palmitoleic acid, hypercaloric cafeteria diet, TX341-641, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::DNA-Binding Proteins::Receptors, Cytoplasmic and Nuclear::Peroxisome Proliferator-Activated Receptors::PPAR alpha [Medical Subject Headings], Receptor, Nutrition and Dietetics, Fatty Acids, monounsaturated fatty acids, Ingestión de energía, Citocinas, Chemicals and Drugs::Lipids::Fatty Acids [Medical Subject Headings], Ácidos grasos monoinsaturados, Liver, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Monounsaturated::Oleic Acids [Medical Subject Headings], Ethanolamines, Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Fatty Acids, Monounsaturated [Medical Subject Headings], Cytokines, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Demography::Health Status [Medical Subject Headings], medicine.symptom, oleylethanolamide, palmitoleic acid, Chemicals and Drugs::Organic Chemicals::Alcohols::Amino Alcohols::Ethanolamines [Medical Subject Headings], medicine.medical_specialty, 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], Diseases::Digestive System Diseases::Liver Diseases::Fatty Liver [Medical Subject Headings], Check Tags::Male [Medical Subject Headings], Alpha (ethology), Inflammation, Phenomena and Processes::Physiological Phenomena::Nutritional Physiological Phenomena::Diet [Medical Subject Headings], Resistencia a la insulina, Article, Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Biochemical Processes::Lipogenesis [Medical Subject Headings], 03 medical and health sciences, Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Hyperinsulinism::Insulin Resistance [Medical Subject Headings], Internal medicine, medicine, Animals, Humans, Chemicals and Drugs::Lipids::Fatty Acids::Endocannabinoids [Medical Subject Headings], Obesity, Ácido oléico, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines [Medical Subject Headings], palmitoleylethanolamide, Inflamación, business.industry, Nutrition. Foods and food supply, Lipogenesis, Body Weight, N-acylethanolamine, cannabinoid receptors type 1, Peso corporal, medicine.disease, Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::Obesity [Medical Subject Headings], Diet, Rats, Fatty Liver, 030104 developmental biology, Endocrinology, chemistry, oleic acid, Insulin Resistance, business, 030217 neurology & neurosurgery, peroxisome proliferator receptor alpha, Chemicals and Drugs::Biological Factors::Inflammation Mediators [Medical Subject Headings], Food Science, Endocannabinoids
Abstract: This work was supported by grants from the following institutions: Grant for international postdoctoral stay. Jose Castillejo Program (Grant CAS15/00257), Ministerio de Educación Cultura y Deporte. Gobierno de España. Proyecto de Investigación en Salud, Consejería de Salud y Familias (Grant PI-0139-2018). EU-ERDF-Instituto de Salud Carlos III (Grant PI19/01577). Proyectos dedesarrollo tecnológico, Ministerio de Ciencia e Innovación (Grant DTS19/00125). Ministerio de Economía, Industria y Competitividad (Grant RTC-2019-007329-1).
Published: 2021

46. Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Author: Jesús Rodríguez-Baño, Jerónimo Pachón, Jordi Carratalà, Pablo Ryan, Inmaculada Jarrín, María Yllescas, José Ramón Arribas, Juan Berenguer, Esther Aznar Muñoz, Pedro Gil Divasson, Patricia González Muñiz, Clara Muñoz Aguirre, Marta Díaz Menéndez, Fernando de la Calle Prieto, Marta Arsuaga Vicente, Elena Trigo Esteban, Ignacio Pérez Valero, Rosa de Miguel Buckley, Julen Cadiñaños Loidi, Beatriz Diaz Pollan, Luz Martín Carbonero, Juan Carlos Ramos Ramos, Belén Loeches Yagüe, Rocío Montejano Sánchez, Juan González García, Julio García Rodríguez, Margarita Ramírez, Isabel Gutiérrez, Francisco Tejerina, Teresa Aldámiz-Echevarría, Cristina Díez, Chiara Fanciulli, Leire Pérez-Latorre, Blanca Pinilla, Juan Carlos López, Ana Such Diaz, Elena Álvaro Alonso, Juan Torres Macho, Guillermo Cuevas Tascon, Eva Jiménez González de Buitrago, Fátima Brañas Baztán, Jorge Valencia de la Rosa, Mario Pérez Butragueño, Inés Fernández Jiménez, Gemma Muñiz Nicolás, Antonia Sepúlveda Berrocal, Alberto Gato Díez, María Pilar Toledano Sierra, María Paz García Butenegro, Ana Isabel Peláez Ballesta, Elena Morcillo Rodríguez, Isidoro Fernández Romero, Cristina Peláez Ballesta, María Isabel Guirado Torrecillas, Josune Goikoetxea Agirre, Elena Bereciartua Bastarrica, Laura Guio Carrión, Regino Rodríguez Álvarez, Marta Ibarrola Hierro, Isabel A. Pérez Hernández, Inés Pérez Zapata, Sergio Román Soto, Mohamed Kallouchi, Juan Ramón Domínguez Vicent, Rafae Silvariño Fernández, Jon Ugalde Espiñeira, Ainhoa Sanjuan López, Silvia García Martínez, Mikel Temprano Gogenola, Víctor Asensi, Silvia Suárez, Lucia Suárez, Carmen Yllera, María Rivas-Carmenado, Alberto Romero-Palacios, Jesús Ruiz Aragón, Patricia Jiménez Aguilar, Ma Luisa Fernández Ávila, Rosario Castilla Ortiz, Vanesa Alende Castro, Cristina Pérez García, Marta Fernández Morales, María Lorena María Valle Feijoo Begoña Rodríguez Ferreira, Joan Gómez-Junyent, Judit Villar-García, Inmaculada López-Montesinos, Itziar Arrieta-Aldea, Abora Rial-Villavecchia, Elisa García Vázquez, Aychel Elena Roura Piloto, Encarnación Moral Escudero, Alicia Hernández Torres, Helena Albendín Iglesias, David Vinuesa García, Clara Martínez Montes, Francisco Javier De la Hera Fernández, Francisco Anguita Santos, Andrés Ruiz Sancho, Vicens Díaz de Brito Fernández, Montserrat Sanmarti Vilamala, Sergio España Cueto, Daniel Molina Morant, Araceli González-Cuevas, Joel Elías Chara Cervantes, Guillem Policarpo Torres, Meritxell Ortega Montoliu, Mònica Angerri Nadal, Ariadna De Genover Gil, Eleni Patera, Rita Godoy Lorenzo, Evangelia Anna María Zioga, Virginia Isern Fernández, Carlos Enrique Sabbagh Fajardo, Ana Ferrer Ribera, Carlos Bea Serrano, Rosa Oltra Sempere, Sara Vela Bernal, Paloma Albiol Viñals, Miguel Pedromingo Kus, María Ángeles Garcinuño, Silvana Fiorante, Sergio Pérez Pinto, Alexandra de la Vega, María Carmen Fariñas Álvarez, Claudia González Rico, Francisco Arnaiz de las Revillas, Teresa Giménez, Jorge Calvo, Yolanda Meije Castillo, Alejandra Duarte Borges, Júlia Pareja Coca, Mercedes Clemente Presas, Xavier Sanz Salvador, Ma Teresa Pérez Rodríguez, Adrián Sousa, Alexandre Pérez González, Rebeca Longueira, Alejandro Araujo, Blanca Alonso Martínez, Laura García Escudero, Sara Lidia Kamel Rey, David Roa Alonso, Juan Pablo Avilés Parra, Iván Pelegrín Senent, Rosana Rouco Esteves Marques, Laia Raich Montiu, Jessica Souto Higueras, Manuel Alejandro Gálvez Bobadilla, Jorge Parra Ruiz, Violeta Ramos Sesma, Sara Velasco Fuentes, Laura García Pereña, Alfonso Lluna Carrascosa, Sergio Gilaberte Reyzábal, Mónica Liébana Gómez, Juan Salillas Hernando, Alberto Serrano Martínez, Miguel Torralba González de Suso, Patricia Martínez Martín, Isabel Rábago Lorite, Patricia González-Ruano Pérez, Beatriz Pérez-Monte Mínguez, Ángeles García Flores, Pere Comas Casanova, Andrea Martín Plata, Sergio Manuel Santana Báez, Oscar Sanz Peláez, Karim Mohamed Ramírez, José María Robaina Bordón, Helem Haydeé Vílchez Rueda, Melchor Riera Jaume, Gemma Mut Ramon, Meritxell Gavalda Manso, Lluis Planas Bibiloni, Laura Castelo Corral, Lucía Ramos Merino, Efrén Sánchez Vidal, María Rodríguez Mayo, Enrique Míguez Rey, José M. García de Lomas Guerrero, Javier De la Torre Lima, Ana Correa Ruiz, Fernando Fernández Sánchez, Nicolás Jiménez-García, José Luis Sierra-Monzón, Borja Gracia-Tello, María Hernández-Bonaga, Galadriel Pellejero, Marta Asín-Corrochano, Lucia Boix Palop, Esther Calbo, Cristina Badía, Beatriz Dietl, Gómez Lucía, Ángel Domínguez-Castellano, María José Ríos-Villegas, María D. del Toro, Zaira R. Palacios Baena, Elena Salamanca-Rivera, Elena Marín, Virginia Almadana, Salvador Pérez-Galera, Luisa González-Iglesias, Gabriela Abelenda-Alonso, Claudia Álvarez-Pouso, Francesc Escrihuela, Carlota Gudiol, Laia Lorenzo-Esteller, Jordi Niubó, Daniel Podzamczer, Miquel Pujol, Alexander Rombauts, Miguel Salvert Lletí, Ricardo Gil Sánchez, Marta Jiménez Escrig, Laura Parra Gómez, Mariona Tasias Pitarch, Marta Navarro Vilasaró, María Luisa Machado Sicilia, Aina Gomila Grange, Sonia Calzado Isbert, Nerea Carrasco Antón, Elizabet Petkova-Saiz, Alfonso Cabello Úbeda, Miguel Górgolas Hernández-Mora, Olga Sánchez-Pernaute, Carlos Dueñas Gutiérrez, Javier Martin Guerra, José Javier Castrodeza Sanz, Virginia Fernández Espinilla, Laura Rodríguez Fernández, Juan González-Moreno, Aroa Villoslada Gelabert, María Antonia Ribot Sanso, María Victoria Fernández-Baca, Almudena Hernández Milian, Miguel Ángel Morán Rodríguez, Zuriñe Ortiz de Zárate Ibarra, José Joaquin Portu Zapirain, Ester Saez de Adana Arroniz, Juan Carlos Gainzarain Arana, Olga Meca Birlanga, Ma Jesús del Amor Espín, Montserrat Viqueira González, Josefina García García, Onofre Martínez Madrid, Enrique Bernal Morell, Antonia Alcaraz, Ángeles Muñoz, Ignacio Pina, Vicente de la Rosa, Tamara Caínzos Romero, Sabela Sánchez Trigo, Ana Isabel Mariño Callejo, Hortensia Álvarez Díaz, Nieves Valcarce Pardeiro, Adriana Sánchez Serrano, Diana Piñar Cabezos, Eva Pilar García Villalba, Carmen Aguayo Jiménez, María Ruíz Campuzano, Virginia Naranjo Velasco, Marta Santos Peña, Juan Mora Delgado, Israel Sevilla Moreno, Cristina Lojo Cruz, Xabier Kortajarena Urkola, José Antonio Iribarren Loyarte, María Jesús Bustinduy Odriozola, Maialen Ibarguren Pinilla, Ignacio Álvarez Rodríguez, Francisco Javier Martínez Marcos, Francisco Javier Rodríguez Gómez, Isabel Asschert Agüero, Francisco Muñoz Beamud, Antonio José Ruiz Reina, Jara Llenas-García, Inmaculada González-Cuello, Elena Hellín-Valiente, Esther Martínez Birlanga, José Manuel Tafalla Torres, Jorge Calderón Parra, Gabriela Escudero López, Isabel Gutiérrez Martín, Ane Andrés Eisenhofer, Sonia García Prieto, Raquel Álvarez Franco, Daniel Roger Zapata, Blanca Martínez Cifre, Elena Aranda Rife, Irene Martín Rubio, André Barbosa Ventura, Javier Garrido, Concepción Gonzalo, Iván Piñero, Nieves de la Cruz Felipe, Eva Talavera García, Marta Lamata Subero, Paula Mendoza Roy, María Soledad García de Carlos, Justo Lajusticia Aisa, Lorea Arteche Eguizabal, Ainhoa Urrutia Losada, Saioa Domingo Echaburu, Pedro Ángel Cuadros Tito, Gurutz Orbe Narváez, Ma del Carmen Liébana Martos, Carolina Roldán Fontana, Carmen Herrero Rodríguez, Gaspar Duro Ruiz, Santiago Pérez Parra, Arantzazu Mera Fidalgo, Miquel Hortos Alsina, Ana Alberich Conesa, Lourdes Bladé Vidal, Nicolás Merchante Gutiérrez, Eva León Jiménez, Reinaldo Espíndola Gómez, María Erostarbe Gallardo, Pedro Martínez Pérez-Crespo, José Miguel Cisneros, Manuela Aguilar-Guisado, Teresa Aldabó, Claudio Bueno, Elisa Cordero-Matía, Ana Escoresca, Carmen Infante, Martín Guillermo, Sonsoles Salto, Francesca Gioia, Pilar Vizcarra, Jesús Fortún Abete, Pilar Martín Dávila, Santiago Moreno Guillén, José A. Oteo Revuelta, Concepción García-García, Paula Santibañez Sáenz, Cristina Cervera Acedo, José M. Azcona Gutiérrez, José María Reguera Iglesias, Antonio Plata Ciezar, Lucia Valiente de Santis, Beatriz Sobrino Diaz, Juan Diego Ruiz Mesa, Ministerio de Ciencia e Innovación, Fundación SEIMC/GeSIDA, Instituto de Salud Carlos III - ISCIII, European Regional Development Fund (ERDF/FEDER), Red Española de Investigación en SIDA, Red Española de Investigación en Patología Infecciosa, UAM. Departamento de Medicina, UAM. Departamento de Medicina Preventiva y Salud Pública y Microbiología, Universidad de Cantabria, SAM-COVID Study Group, [Rodríguez-Baño,J] Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Sevilla, Spain. [Rodríguez-Baño,J, Pachón,J] Departamento de Medicina, Universidad de Sevilla, Spain. [Rodríguez-Baño,J, Pachón,J] Instituto de Biomedicina de Sevilla (IBiS), Seville, Spain. [Pachón,J] Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen del Rocío, Sevilla, Spain. [Carratalà,J] Servei de Malalties Infeccioses, Hospital Universitari de Bellvitge, Barcelona, Spain. [Carratalà,J] Instituto de Investigación Biomédica de Bellvitge (IDIBELL), Barcelona, Spain. [Carratalà,J] Universitat de Barcelona, Barcelona, Spain. [Ryan,P] Servicio de Medicina Interna, Hospital Universitario Infanta Leonor, Madrid, Spain. [Jarrín,I] Centro Nacional de Epidemiología, Instituto de Salud Carlos III, Madrid, Spain. [Yllescas,M] Fundación SEIMC/GeSIDA, Madrid, Spain. [Arribas,JR] Unidad de Enfermedades Infecciosas, Servicio de Medicina Interna, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. [Arribas,JR] Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain. [Berenguer,J] Servicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Madrid, Spain. [Berenguer,J] Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain., Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Red de Investigación Cooperativa en Investigación en Sida (España), Red de Investigación Cooperativa en Investigación en Patología Infecciosa (España), Gilead Sciences, ViiV Healthcare, AbbVie Pharmaceuticals, Merck & Co, Janssen Biotech, Teva Pharmaceutical Industries, Ministerio de Ciencia, Innovación y Universidades (España), European Commission, Universidad de Sevilla. Departamento de Medicina, Instituto Carlos III (España), and Unión Europea
Subjects: 0301 basic medicine, Male, law.invention, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], chemistry.chemical_compound, 0302 clinical medicine, Organisms::Viruses::RNA Viruses::Nidovirales::Coronaviridae [Medical Subject Headings], Randomized controlled trial, law, Adrenal Cortex Hormones, Clinical endpoint, Medicine, 030212 general & internal medicine, Hospital Mortality, Health Care::Environment and Public Health::Public Health::Epidemiologic Measurements::Demography::Vital Statistics::Mortality [Medical Subject Headings], Adrenocortical hormones, Hazard ratio, General Medicine, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Intubation::Intubation, Intratracheal [Medical Subject Headings], Middle Aged, Tocilizumab, Hospitalization, Infectious Diseases, Treatment Outcome, Diseases::Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections [Medical Subject Headings], Drug Therapy, Combination, Female, Cohort study, Microbiology (medical), medicine.medical_specialty, Diseases::Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections::Severe Acute Respiratory Syndrome [Medical Subject Headings], Combination therapy, Medicina, Hyperinflammatory state, 030106 microbiology, Estudios de cohortes, Antibodies, Monoclonal, Humanized, Article, 03 medical and health sciences, 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], Intubation, Intratracheal, Mortalitat, Humans, Corticosteroids, Mortality, Corticoesteroides, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis::Treatment Outcome [Medical Subject Headings], Aged, Proportional Hazards Models, Retrospective Studies, Geographical Locations::Geographic Locations::Europe::Spain [Medical Subject Headings], Inflammation, business.industry, SARS-CoV-2, COVID-19, Odds ratio, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones::Adrenal Cortex Hormones [Medical Subject Headings], Corticosteroides, COVID-19 Drug Treatment, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Propensity Score [Medical Subject Headings], chemistry, Spain, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Cohort Studies [Medical Subject Headings], Propensity score matching, Mortalidad, Monoclonal antibodies, business, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings], Anticossos monoclonals
Abstract: © 2020 The Author(s)., [Objectives]: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters., [Methods]: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs)., [Results]: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22–0.47; p < 0.001) for tocilizumab, 0.82 (0.71–1.30; p 0.82) for IHDC, 0.61 (0.43–0.86; p 0.006) for PDC, and 1.17 (0.86–1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02–0.17; p < 0.001)., [Conclusions]: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situation., IJ has received honoraria for participating in an advisory board from Gilead Sciences, and for educational activities from ViiV. JB has received research grants from AbbVie, Gilead Sciences, Merck, and ViiV, and honoraria for being a speaker or advisory board participation from AbbVie, Gilead Sciences, Janssen, Merck, and ViiV. JRA received fees for participating in an advisory board, being a speaker, and research grant support from Viiv, Janssen, Gilead, MSD, Teva, Alexa and Serono. PR is involved as speaker or advisory board participant for Gilead Sciences, AbbVie and ViiV. JR-B, JP, JC and MY have no conflicts of interest to declare. SAM-COVID was funded by Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (COV20/01031) co-funded by European Union (ERDF/ESF, “Investing in your future”) and Fundación SEIMC/GeSIDA. In addition, Juan Berenguer, Jesús Rodríguez-Baño, Inmaculada Jarrín, Jordi Carratalá, Jerónimo Pachón, and José R Arribas received funding for research from Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades – co- financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020 through the networks: Spanish AIDS Research Network (RIS) [RD16/0025/0017 (JB), RD16/0025/0018 (JRA), RD16/0025/00XX (IJ)] and Spanish Network for Research in Infectious Diseases (REIPI)[RD16/0016/0001 (JRB), RD16/0016/0005 (JC), and RD16/0016/0009 (JP).
Published: 2021

47. Expression of DDX11 and DNM1L at the 12p11 Locus Modulates Systemic Lupus Erythematosus Susceptibility

Author: Laura Muñoz-Barrera, Eduardo Collantes Estévez, Chary López-Pedrera, Maria Angeles Aguirre, A. M. Patiño-Trives, Alejandro Ibáñez-Costa, Mohammad Saeed, [Saeed,M] ImmunoCure, Karachi, Pakistan. [Ibáñez-Costa,A, Patiño-Trives,AM, Muñoz-Barrera,L, Collantes Estévez,E, Aguirre,MA, López-Pedrera,C] Rheumatology Service, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Reina Sofia Hospital, University of Cordoba, Cordoba, Spain., and This study was supported by grants from the Instituto de Salud Carlos III (PI18/00837), cofinanciado por el Fondo Europeo de Desarrollo Regional de la Unión Europea 'Una manera de hacer Europa,' Spain, and the Spanish Inflammatory and Rheumatic Diseases Network (RIER), Instituto de Salud Carlos III (RD16/0012/0015). C.L.-P. was supported by a contract from the Spanish Junta de Andalucía ('Nicolas Monardes' program). A.I.-C. was supported by a 'Sara Borrell' contract (CD19/00255).
Subjects: 0301 basic medicine, Chemicals and Drugs::Hormones, Hormone Substitutes, and Hormone Antagonists::Hormones [Medical Subject Headings], DDX11, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology::Systems Biology [Medical Subject Headings], DNM1L, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Genomic Instability [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Structures::Chromosomes::Chromosomes, Mammalian::Chromosomes, Human::Chromosomes, Human, 6-12 and X::Chromosomes, Human, Pair 12 [Medical Subject Headings], Gene Expression, Genome-wide association study, medicine.disease_cause, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression [Medical Subject Headings], Monocytes, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], DEAD-box RNA Helicases, 0302 clinical medicine, Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Monocytes [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility [Medical Subject Headings], Databases, Genetic, Gene expression, Lupus Erythematosus, Systemic, Biology (General), skin and connective tissue diseases, Spectroscopy, Genetics, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Epidemiologic Study Characteristics as Topic::Epidemiologic Studies::Case-Control Studies [Medical Subject Headings], Diseases::Immune System Diseases::Autoimmune Diseases::Lupus Erythematosus, Systemic [Medical Subject Headings], OASIS, General Medicine, Computer Science Applications, Chemistry, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Acid Anhydride Hydrolases::GTP Phosphohydrolases::Dynamins [Medical Subject Headings], Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Genetics::Genomics [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genotype [Medical Subject Headings], Disease Susceptibility, KRAS, Signal Transduction, Dynamins, Monocitos, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Acid Anhydride Hydrolases::Adenosine Triphosphatases::DNA Helicases [Medical Subject Headings], Genotype, QH301-705.5, Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression::Transcription, Genetic::Transcriptome [Medical Subject Headings], Quantitative Trait Loci, Lupus, Locus (genetics), Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Expression Profiling [Medical Subject Headings], Biology, Polymorphism, Single Nucleotide, Article, Catalysis, Inorganic Chemistry, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [Medical Subject Headings], 03 medical and health sciences, Systemic lupus erythematosus, Information Science::Information Science::Information Storage and Retrieval::Databases as Topic::Databases, Factual::Databases, Genetic [Medical Subject Headings], Lupus eritematoso sistémico, medicine, Humans, SNP, Genetic Predisposition to Disease, Physical and Theoretical Chemistry, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle::Cell Division::Cytokinesis [Medical Subject Headings], QD1-999, Molecular Biology, Gene, Genetic association, 030203 arthritis & rheumatology, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::RNA Nucleotidyltransferases::RNA Helicases [Medical Subject Headings], Phenomena and Processes::Genetic Phenomena::Genetic Variation::Polymorphism, Genetic::Polymorphism, Single Nucleotide [Medical Subject Headings], Chromosomes, Human, Pair 12, Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::RNA Nucleotidyltransferases::RNA Helicases::DEAD-box RNA Helicases [Medical Subject Headings], Gene Expression Profiling, Organic Chemistry, Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Signal Transduction [Medical Subject Headings], DNA Helicases, Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genetic Loci::Quantitative Trait Loci [Medical Subject Headings], lupus, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Molecular Epidemiology::Genome-Wide Association Study [Medical Subject Headings], 030104 developmental biology, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intracellular Signaling Peptides and Proteins::Monomeric GTP-Binding Proteins::ras Proteins::Proto-Oncogene Proteins p21(ras) [Medical Subject Headings], Case-Control Studies, Expression quantitative trait loci, Transcriptome, Genotipo, Expresión génica, Genome-Wide Association Study
Abstract: Objectives: This study employed genetic and functional analyses using OASIS meta-analysis of multiple existing GWAS and gene-expression datasets to identify novel SLE genes. Methods: Four hundred and ten genes were mapped using SNIPPER to 30 SLE GWAS loci and investigated for expression in three SLE GEO-datasets and the Cordoba GSE50395-dataset. Blood eQTL for significant SNPs in SLE loci and STRING for functional pathways of differentially expressed genes were used. Confirmatory qPCR on SLE monocytes was performed. The entire 12p11 locus was investigated for genetic association using two additional GWAS. Expression of 150 genes at this locus was assessed. Based on this significance, qPCRs for DNM1L and KRAS were performed. Results: Fifty genes were differentially expressed in at least two SLE GEO-datasets, with all probes directionally aligned. DDX11, an RNA helicase involved in genome stability, was downregulated in both GEO and Cordoba datasets. The most significant SNP, rs3741869 in OASIS locus 12p11.21, containing DDX11, was a cis-eQTL regulating DDX11 expression. DDX11 was found repressed. The entire 12p11 locus showed three association peaks. Gene expression in GEO datasets identified DNM1L and KRAS, besides DDX11. Confirmatory qPCR validated DNM1L as an SLE susceptibility gene. DDX11, DNM1L and KRAS interact with each other and multiple known SLE genes including STAT1/STAT4 and major components of IFN-dependent gene expression, and are responsible for signal transduction of cytokines, hormones, and growth-factors, deregulation of which is involved in SLE-development. Conclusion: A genomic convergence approach with OASIS analysis of multiple GWAS and expression datasets identified DDX11 and DNM1L as novel SLE-genes, the expression of which is altered in monocytes from SLE patients. This study lays the foundation for understanding the pathogenic involvement of DDX11 and DNM1L in SLE by identifying them using a systems-biology approach, while the 12p11 locus harboring these genes was previously missed by four independent GWAS.
Published: 2021

48. Probiotic and Functional Properties of Limosilactobacillus reuteri INIA P572

Author: Margarita Medina, Patricia Diez-Echave, Arjan Narbad, Ana García-Lafuente, Melinda J. Mayer, José Garrido-Mesa, José María Landete, Julio Gálvez, Juan Luis Arqués, Laura Hidalgo-García, Teresa Vezza, Alba Rodríguez-Nogales, María Elena Rodríguez-Cabezas, Francesca Algieri, Izaskun Martín-Cabrejas, Susana Langa, [Diez-Echave,P, Garrido-Mesa,J, Vezza,T, Hidalgo-García,L, Algieri,F, Rodríguez-Nogales,A, Rodríguez-Cabezas,ME, Gálvez,J] Centro de Investigaciones Biomédicas en Red–Enfermedades Hepáticas y Digestivas (CIBER-EHD), Department of Pharmacology, Center for Biomedical Research (CIBM), University of Granada, Granada, Spain. [Diez-Echave,P, Gálvez,J] Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. [Martín-Cabrejas,I, Langa,S, Landete,JM, Medina,M, Arqués,JL] Departamento Tecnología de Alimentos, INIA-CSIC, Madrid, Spain. [Mayer,MJ, Narbad,A] Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich, UK. [García-Lafuente,A] Centro para la Calidad de los Alimentos, INIA-CISC, Soria, Spain., This work was supported by project no. RTA2017-00002-00-00 from the Spanish Ministry of Science and Innovation, by the Junta de Andalucía (CTS 164) and Instituto de Salud Carlos III (PI19/01058) with funds from the European Union., Ministerio de Ciencia e Innovación (España), Junta de Andalucía, Instituto de Salud Carlos III, European Commission, Diez-Echave, Patricia (0000-0003-4493-3091), Martín-Cabrejas, Izaskun (0000-0002-7913-0291), Garrido-Mesa, José (0000-0001-6420-9055), Langa, Susana (0000-0003-2729-219X), Vezza, Teresa (0000-0002-9780-0180), Landete, José M (0000-0002-5147-3989), Hidalgo-García, Laura (0000-0002-5529-171X), Algieri, Francesca (0000-0002-0262-4867), Mayer, Melinda J (0000-0002-8764-2836), Narbad, Arjan (0000-0003-2968-7558), García-Lafuente, Ana (0000-0002-5147-3145), Medina, Margarita (0000-0001-9692-4977), Rodríguez-Nogales, Alba (0000-0003-1927-0628), Rodríguez-Cabezas, María Elena (0000-0001-9085-8147), Gálvez, Julio (0000-0001-6876-3782), and Arqués, Juan L (0000-0002-8548-0183)
Subjects: Male, 0301 basic medicine, Limosilactobacillus reuteri, Colonic model, Probiotic, Organisms::Bacteria::Gram-Positive Bacteria::Lactobacillales::Lactobacillaceae::Lactobacillus::Lactobacillus reuteri [Medical Subject Headings], law.invention, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, Anatomy::Cells::Cells, Cultured::Cell Line [Medical Subject Headings], law, Inmunomodulación, Chemicals and Drugs::Organic Chemicals::Aldehydes::Glyceraldehyde [Medical Subject Headings], Organisms::Eukaryota::Animals [Medical Subject Headings], Technology and Food and Beverages::Food and Beverages::Food::Dairy Products [Medical Subject Headings], TX341-641, Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons, Acyclic::Alkanes::Propane [Medical Subject Headings], Chemicals and Drugs::Carbohydrates::Polysaccharides::Glucans::Dextrans::Dextran Sulfate [Medical Subject Headings], Nutrition and Dietetics, Strain (chemistry), In vitro toxicology, Antimicrobial compound, Reuterin, Anatomy::Cells::Myeloid Cells::Macrophages [Medical Subject Headings], Sulfato de Dextran, Línea Celular, Technology and Food and Beverages::Food and Beverages::Food::Dietary Supplements::Probiotics [Medical Subject Headings], Sodium, 030106 microbiology, Lactobacillus reuteri, chemistry.chemical_element, Check Tags::Male [Medical Subject Headings], In Vitro Techniques, Protectores contra radiación, Glyceraldehyde, Microbiology, Protective effect, Immunomodulation, Propane, 03 medical and health sciences, In vivo, Animals, Humans, Macrófagos, Inflammation, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Nutrition. Foods and food supply, Macrophages, Probiotics, Probióticos, Dextran sulphate sodium, In vitro, Diseases::Animal Diseases::Disease Models, Animal [Medical Subject Headings], Gastrointestinal Tract, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, chemistry, Dextran sulphate, DSS-induced colitic model, Anatomy::Digestive System::Gastrointestinal Tract [Medical Subject Headings], Organisms::Eukaryota::Animals::Animal Population Groups::Animals, Laboratory::Animals, Inbred Strains::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings], Cell line, Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings], Food Science
Abstract: 18 Pág. Departamento de Tecnología de Alimentos, Limosilactobacillus reuteri INIA P572 is a strain able to produce the antimicrobial compound reuterin in dairy products, exhibiting a protective effect against some food-borne pathogens. In this study, we investigated some probiotic properties of this strain such as resistance to gastrointestinal passage or to colonic conditions, reuterin production in a colonic environment, and immunomodulatory activity, using different in vitro and in vivo models. The results showed a high resistance of this strain to gastrointestinal conditions, as well as capacity to grow and produce reuterin in a human colonic model. Although the in vitro assays using the RAW 264.7 macrophage cell line did not demonstrate direct immunomodulatory properties, the in vivo assays using a Dextran Sulphate Sodium (DSS)-induced colitic mice model showed clear immunomodulatory and protective effects of this strain., This work was supported by project no. RTA2017-00002-00-00 from the Spanish Ministry of Science and Innovation, by the Junta de Andalucía (CTS 164) and Instituto de Salud Carlos III (PI19/01058) with funds from the European Union
Published: 2021
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49. ARMCX3 Mediates Susceptibility to Hepatic Tumorigenesis Promoted by Dietary Lipotoxicity

Author: José María Balibrea, Roman Serrat, Carmen Berasain, Monica Higuera, Aleix Gavaldà-Navarro, Eduardo Soriano, Matías A. Avila, Iker Uriarte, María Teresa Salcedo, Francesc Villarroya, Eva Santamaría, Beatriz Minguez, Yasmina Manso, Serena Mirra, Ferran Burgaya, Institut Català de la Salut, [Mirra S, Manso Y, Serrat R] Department of Cell Biology, Physiology and Immunology, University of Barcelona, 08007 Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28029 Madrid, Spain. [Gavaldà-Navarro A] Department of Biochemistry and Molecular Biomedicine and Institute of Biomedicine, University of Barcelona, 08028 Barcelona, Spain. Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029 Madrid, Spain. [Higuera M] Grup de Recerca en Malalties Hepàtiques, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Salcedo MT] Servei de Patologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. [Balibrea JM] Unitat de Cirurgia Endocrina, Metabòlica i Bariàtrica, Servei de Cirurgia General, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Mínguez B] Grup de Recerca en Malalties Hepàtiques, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain. Unitat del Fetge, Servei de Medicina Interna, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: 0301 basic medicine, Cancer Research, obesity, neoplasias::neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias hepáticas::carcinoma hepatocelular [ENFERMEDADES], Otros calificadores::Otros calificadores::/inducido químicamente [Otros calificadores], SOX9, Biology, medicine.disease_cause, lcsh:RC254-282, Article, Fetge - Càncer - Tractament, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, NAFLD, medicine, Obesity, HCC, Gene knockdown, lipotoxicity, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, 030104 developmental biology, Neoplasms::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Liver Neoplasms::Carcinoma, Hepatocellular [DISEASES], Oncology, Lipotoxicity, Cell culture, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Other subheadings::Other subheadings::/chemically induced [Other subheadings], Hepatic stellate cell, Cancer research, Alex3, Carcinogenesis
Abstract: Simple Summary An excess fat in the liver enhances the susceptibility to hepatic cancer. We found that Armcx3, a protein only known to date to play a role in neural development, is strongly increased in mouse liver in response to lipid availability and proliferation-inducing insults. In patients, the levels of hepatic Armcx3 are also increased in conditions of high exposure of the liver to fat. We wanted to determine the role of Armcx3 in the hepatocarcinogenesis favored by a high-fat diet. We generated mice with genetically driven suppression of Armcx3, and we found that they were protected against experimentally induced hepatic cancer, especially in conditions of a high-fat diet. Armcx3 was also found to promote hepatic cell proliferation through the interaction with Sox9, a known proliferation factor in hepatocellular carcinoma. Armcx3 is identified as a novel factor in meditating propensity to liver cancer in conditions of high hepatic lipid insults. Abstract ARMCX3 is encoded by a member of the Armcx gene family and is known to be involved in nervous system development and function. We found that ARMCX3 is markedly upregulated in mouse liver in response to high lipid availability, and that hepatic ARMCX3 is upregulated in patients with NAFLD and hepatocellular carcinoma (HCC). Mice were subjected to ARMCX3 invalidation (inducible ARMCX3 knockout) and then exposed to a high-fat diet and diethylnitrosamine-induced hepatocarcinogenesis. The effects of experimental ARMCX3 knockdown or overexpression in HCC cell lines were also analyzed. ARMCX3 invalidation protected mice against high-fat-diet-induced NAFLD and chemically induced hepatocarcinogenesis. ARMCX3 invalidation promoted apoptotic cell death and macrophage infiltration in livers of diethylnitrosamine-treated mice maintained on a high-fat diet. ARMCX3 downregulation reduced the viability, clonality and migration of HCC cell lines, whereas ARMCX3 overexpression caused the reciprocal effects. SOX9 was found to mediate the effects of ARMCX3 in hepatic cells, with the SOX9 interaction required for the effects of ARMCX3 on hepatic cell proliferation. In conclusion, ARMCX3 is identified as a novel molecular actor in liver physiopathology and carcinogenesis. ARMCX3 downregulation appears to protect against hepatocarcinogenesis, especially under conditions of high dietary lipid-mediated hepatic insult.
Published: 2021

50. Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

Author: José Luis Trillo-Contreras, Pedro Gómez-Gálvez, Luis M. Escudero, Nieves Lara-Ureña, Andrea S. Bullones-Bolanos, Javier Vitorica, Miriam Echevarría, Rosana March-Díaz, Miguel Marchena, Jose Carlos Davila, Ana C. Sanchez-Hidalgo, Eloisa Herrera, Fernando de Castro, Jakob Körbelin, Antonia Gutierrez, Rocio González-Martínez, Alicia E. Rosales-Nieves, Raquel del Toro, Clara Ortega-de San Luis, Maria I. Alvarez-Vergara, Alberto Pascual, Pablo Vicente-Munuera, Manuel A. Sanchez-Garcia, Guiomar Rodriguez-Perinan, Martin Trepel, Francisco G. Scholl, Alberto Rábano, Javier Villadiego, Miguel Martin-Bornez, Beatriz Fernández-Gómez, Universidad de Sevilla. Departamento de Biología Celular, Instituto de Salud Carlos III PI18/01556, PI18/01557, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas CB06/05/ 0094, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, European Commission, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Fundació La Marató de TV3, Junta de Andalucía, Fundación Domingo Martínez, [Alvarez-Vergara,MI, Rosales-Nieves,AE, March-Diaz,R, Rodriguez-Perinan,G, Lara-Ureña,N, Ortega-de San Luis,C, Sanchez-Garcia,MA, Martin-Bornez,M, Gómez-Gálvez,P, Vicente-Munuera,P, Bullones-Bolanos,AS, Trillo-Contreras,JL, Sanchez-Hidalgo,AC, del Toro,R, Scholl,FG, Escudero,LM, Villadiego,J, Echevarria,M, Vitorica,J, Pascual,A] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Seville, Spain. [Gómez-Gálvez,P, Escudero,LM] Department of Biología Celular, Universidad de Sevilla. Seville, Spain. [Gómez-Gálvez,P, Davila,JC, Gutierrez,A, Vitorica,J] Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Fernandez-Gomez,B, Marchena,MA, de Castro,F] Grupo de Neurobiología del Desarrollo-GNDe, Instituto Cajal-CSIC, Madrid, Spain. [Marchena,MA] Departamento de Medicina, Facultad de Ciencias, Biomédicas y de la Salud, Universidad Europea de Madrid, Villaviciosa de Odón, Spain. [Davila,JC, Gutierrez,A] Department of Biologia Celular, Genetica y Fisiologia, Facultad de Ciencias, Instituto de Investigacion Biomedica de Malaga (IBIMA), Universidad de Malaga, Malaga, Spain. [Gonzalez-Martinez,R, Herrera,E] 7 Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández (CSIC-UMH), Alicante, Spain. [Trillo-Contreras,JL, Echevarria,M] Department of Fisiología Médica y Biofisica, Universidad de Sevilla, Seville, Spain. [del Toro,R] Centro de Investigacion Biomedica en Red de Enfermedades Cardiovasculares (CIBER-CV), Madrid, Spain. [Trepel,M] Augsburg Medical Center, Department of Hematology and Oncology, Augsburg, Germany. [Körbelin,J] Section of Pneumology, Department of Oncology, Hematology and Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [Rabano,A] Fundacion CIEN, Madrid, Spain. [Vitorica,J] Department of Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain. [Ortega-de San Luis,L] Present address: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College of Dublin, Dublin, Ireland. [Sanchez-Garcia,MA] Present address: Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK. [Alvarez-Vergara,MI, Rosales-Nieves,AE] These authors contributed equally: Maria I. Alvarez-Vergara, Alicia E. Rosales-Nieves., A.E.R.-N. was the recipient of a JdlC-F fellowship from the Spanish Ministry of Economy, Industry, and Competitiveness (MINEICO) (FJCI-2015-23708), M.I.A.-V., N.L.-U., and C.O.-d.S.L. were the recipient of an FPU fellowship from Spanish Ministry of Education, Culture, and Sport (respectively, FPU15/02898, FPU14-02115, and AP2010‐1598), and R.M.-D. was the recipient of a 'Sara Borrell' fellowship from ISCIII (CD09/0007). Work was supported by grants to A.P. by the Spanish MINEICO, ISCIII, and FEDER (SAF2012‐33816, SAF2015‐64111‐R, RTI2018-096629-B-100, SAF2017-90794-REDT, and PIE13/0004), by the regional Government of Andalusia ('Proyectos de Excelencia', P12‐CTS‐2138 and P12‐CTS‐2232) co-funded by CEC and FEDER funds, and by the 'Ayuda de Biomedicina 2018', Fundación Domingo Martínez, J.Vitorica: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union (PI18/01556) by La Marató-TV3 Foundation grant 20141431, by CIBERNED (CB06/05/0094), and by Junta de Andalucia Consejería de Economía y Conocimiento through grant US-1262734, A.G.: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grant PI18/01557, and by Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 and P18-RT-2233 co-financed by Programa Operativo FEDER 2014-2020. The authors thank Maria Llorens-Martin (CBM-Severo Ochoa, Madrid, Spain) for the generous gift of the human samples, Ralf H. Adams and Jose L. de la Pompa for providing the Cdh5-Cre, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
Subjects: 0301 basic medicine, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred C57BL [Medical Subject Headings], Cerebrovascular disorders, Angiogenesis, Malformaciones vasculares, Endothelial cells, General Physics and Astronomy, Plaque, Amyloid, Molecular neuroscience, Neovascularization, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], 0302 clinical medicine, Blood vessels, Péptidos beta-amiloides, Enfermedad de Alzheimer, Organisms::Eukaryota::Animals [Medical Subject Headings], Anatomy::Cells::Epithelial Cells::Endothelial Cells [Medical Subject Headings], Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Metaplasia::Neovascularization, Pathologic [Medical Subject Headings], Mice, Knockout, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Presenilins [Medical Subject Headings], Multidisciplinary, Microglia, Neovascularization, Pathologic, Reverse Transcriptase Polymerase Chain Reaction, Placa amiloide, Presenilins, Brain, Alzheimer's disease, Cell biology, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Reverse Transcriptase Polymerase Chain Reaction [Medical Subject Headings], medicine.anatomical_structure, Vasos sanguíneos, Anatomy::Cardiovascular System::Blood Vessels::Microvessels [Medical Subject Headings], Encéfalo, Female, medicine.symptom, Alzheimer disease, Blood vessel, Diseases::Nervous System Diseases::Neurodegenerative Diseases::Tauopathies::Alzheimer Disease [Medical Subject Headings], Phagocytosis, Science, Vascular malformations, Presenilinas, Diseases::Skin and Connective Tissue Diseases::Skin Diseases::Skin Abnormalities [Medical Subject Headings], Mice, Transgenic, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Expression Profiling [Medical Subject Headings], Biology, General Biochemistry, Genetics and Molecular Biology, Presenilin, Article, Plaque, amyloid, 03 medical and health sciences, Alzheimer Disease, Diseases::Pathological Conditions, Signs and Symptoms::Pathological Conditions, Anatomical::Plaque, Amyloid [Medical Subject Headings], medicine, Extracellular, Animals, Humans, ddc:610, Anatomy::Cardiovascular System::Blood Vessels [Medical Subject Headings], Amyloid beta-Peptides, Gene Expression Profiling, Células endoteliales, Endothelial Cells, General Chemistry, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Amyloid beta-Peptides [Medical Subject Headings], Anatomy::Nervous System::Central Nervous System::Brain [Medical Subject Headings], Diseases::Animal Diseases::Disease Models, Animal [Medical Subject Headings], Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Check Tags::Female [Medical Subject Headings], Blood Vessels, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Transgenic [Medical Subject Headings], 030217 neurology & neurosurgery, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Mutant Strains::Mice, Knockout [Medical Subject Headings]
Abstract: The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD., A.E.R.-N. was the recipient of a JdlC-F fellowship from the Spanish Ministry of Economy, Industry, and Competitiveness (MINEICO) (FJCI-2015-23708), M.I.A.-V., N.L.-U., and C.O.-d.S.L. were the recipient of an FPU fellowship from Spanish Ministry of Education, Culture, and Sport (respectively, FPU15/02898, FPU14-02115, and AP2010‐1598), and R.M.-D. was the recipient of a “Sara Borrell” fellowship from ISCIII (CD09/0007). Work was supported by grants to A.P. by the Spanish MINEICO, ISCIII, and FEDER (SAF2012‐33816, SAF2015‐64111‐R, RTI2018-096629-B-100, SAF2017-90794-REDT, and PIE13/0004), by the regional Government of Andalusia (“Proyectos de Excelencia”, P12‐CTS‐2138 and P12‐CTS‐2232) co-funded by CEC and FEDER funds, and by the “Ayuda de Biomedicina 2018”, Fundación Domingo Martínez; J.Vitorica: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union (PI18/01556) by La Marató-TV3 Foundation grant 20141431; by CIBERNED (CB06/05/0094); and by Junta de Andalucia Consejería de Economía y Conocimiento through grant US-1262734; A.G.: Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grant PI18/01557; and by Junta de Andalucia Consejería de Economía y Conocimiento through grants UMA18-FEDERJA-211 and P18-RT-2233 co-financed by Programa Operativo FEDER 2014-2020.
Published: 2021

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