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1. Breasts as a perceived barrier to physical activity in Mexican women: A cross-sectional study

Author

Gabriela Valles-Verdugo, Ivan Renteria, Julio Gómez-Figueroa, Mario Villarreal-Ángeles, Paulina Ochoa-Martínez, Javier Hall-López, Juan Gallegos-Ramírez, Yamileth Chacón-Araya, and José Moncada-Jiménez

Subjects
Medicine
Abstract

Background: Scarce evidence exists on barriers to physical activity in Mexican women. Despite evidence from other countries, no research has investigated the influence of the breast on PA in this population. Objective: To determine the association between the breast and physical activity in Mexican women. Design: Cross-sectional observational study. Methods: Volunteers were 279 Mexican women from Veracruz, Durango, and Baja California states, who completed a paper survey of their demographics, brassiere characteristics, breast pain, and frequency and amounts of weekly physical activity. Results: The first barrier to physical activity was time constraints, followed by breast-related issues. Breast pain was reported by 47.1% of women, and the breast as a barrier to physical activity participation was reported by 30.6%. Responses, such as “I am embarrassed by excessive breast movement” and “My breasts are too big” were the most frequently reported breast-related barriers to physical activity. Breast pain was associated with the menstrual cycle and exercise. Breast health knowledge and pain intensity were unrelated to moderate- and vigorous-intensity physical activity. The 36.4% and 6.7% of women did not meet weekly moderate- and vigorous-intensity physical activity guidelines, respectively. Weekly moderate- and vigorous-intensity physical activity was similar between women reporting breast pain and those who did not. Conclusions: Because the breast was the second most significant barrier to physical activity, it is imperative to increase breast health knowledge in Mexican women to reduce impediments to physical activity.

Published
2024
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2. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

Author

Anna L Swan, Christine Schütt, Jan Rozman, Maria Del Mar Muñiz Moreno, Stefan Brandmaier, Michelle Simon, Stefanie Leuchtenberger, Mark Griffiths, Robert Brommage, Piia Keskivali-Bond, Harald Grallert, Thomas Werner, Raffaele Teperino, Lore Becker, Gregor Miller, Ala Moshiri, John R Seavitt, Derek D Cissell, Terrence F Meehan, Elif F Acar, Christopher J Lelliott, Ann M Flenniken, Marie-France Champy, Tania Sorg, Abdel Ayadi, Robert E Braun, Heather Cater, Mary E Dickinson, Paul Flicek, Juan Gallegos, Elena J Ghirardello, Jason D Heaney, Sylvie Jacquot, Connor Lally, John G Logan, Lydia Teboul, Jeremy Mason, Nadine Spielmann, Colin McKerlie, Stephen A Murray, Lauryl M J Nutter, Kristian F Odfalk, Helen Parkinson, Jan Prochazka, Corey L Reynolds, Mohammed Selloum, Frantisek Spoutil, Karen L Svenson, Taylor S Vales, Sara E Wells, Jacqueline K White, Radislav Sedlacek, Wolfgang Wurst, K C Kent Lloyd, Peter I Croucher, Helmut Fuchs, Graham R Williams, J H Duncan Bassett, Valerie Gailus-Durner, Yann Herault, Ann-Marie Mallon, Steve D M Brown, Philipp Mayer-Kuckuk, Martin Hrabe de Angelis, and IMPC Consortium

Subjects
Genetics, QH426-470
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Published
2020
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4. ANÁLISIS DE RIESGO CREDITICIO, PROPUESTA DEL MODELO CREDIT SCORING

Author

ALEXI LUDOVIC LEAL FICA, MARCO ANTONIO ARANGUIZ CASANOVA, and JUAN GALLEGOS MARDONES

Subjects
análisis, riesgo de crédito, credit scoring, evaluación y capacidad de pago, Economic history and conditions, HC10-1085, Economics as a science, HB71-74
Abstract

El presente trabajo aplica en una empresa dedicada a la producción, comercialización y distribu- ción de productos derivados del asfalto en la zona sur Chile. La empresa referida, ha preferido no revelar su razón social, para tal efecto hemos denominado a esta, Fantasía S.A. Durante los últimos años Fantasía ha experimentado un crecimiento significativo en sus ventas y con ello, una disminución de su nivel de liquidez y calidad de sus cuentas por cobrar. Sin embargo, este incre- mento en cuentas por cobrar está asociado a un mayor riesgo asumido de cobro, dada su política liberalizadora de cuentas por cobrar. Más aún, Fantasía S.A., no dispone de un sistema de gestión de crédito objetivo que permita una evaluación adecuada de la calidad y capacidad crediticia de sus clientes actuales y potenciales. Por tanto, en este artículo se propone a Fantasía un modelo de evaluación crediticia a sus clientes actuales y potenciales ajustado y ponderado a su realidad, que permite disminuir el riesgo de crédito o incobrables. El presente trabajo considera, una descripción de los modelos de evaluación de créditos y en específico de los modelos de credit scoring. A través de entrevistas a expertos, se definieron variables cuantitativas y cualitativas críticas a considerar en un proceso de gestión de créditos. Respecto de la calidad del modelo de evaluación crediticia propuesto, este muestra que un 81,82% de los créditos otorgados a sus clientes han superado el nivel mínino de evaluación o límite de aprobación por la empresa.

Published
2018

5. Elección de escuela y costos de cambio

Author

Juan Gallegos Mardones, Rómulo Chumacero, and Ricardo Paredes

Subjects
rendimiento académico, elección de escuela, costo de cambio, chile, Economic history and conditions, HC10-1085, Economics as a science, HB71-74
Abstract

Antecedentes: Los sistemas de vales en educación se basan fundamentalmente en la capacidad de los padres para elegir la escuela de sus hijos. Sin embargo, esta capacidad se reduce cuando enfrentan costos de cambio.Método: Se identificaron los datos de los estudiantes que cursaban cuarto grado en 2000 y octavo grado en 2004, y se verificó si estos, habían cambiado de escuela. Además, comparamos la utilidad que reporta la escuela elegida con respecto a otras, no disponibles en 2000, determinando así la existencia de costos de cambio.Resultados: Encontramos que los costos de cambios son estadísticamente significativos y económicamente relevantes, además, afectan la decisión de cambiar de escuela. También mostramos qué cambios marginales en niveles de utilidad no son suficientemente significativos para cambiar de escuela identificando un eventual umbral.Conclusiones: La preocupación natural de los padres con respecto a la capacidad de reacción está condicionada por la existencia de costos de cambio.

Published
2017
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6. Index to degree of adhesion to good practices of corporate governance and their effect on financial performance: evidence for Chilean companies.

Author

Oyarce, José Navarrete, Moraga Flores, Hugo, and Mardones, Juan Gallegos

Subjects
CORPORATE governance, FINANCIAL performance, BEST practices, EMERGING markets, PANEL analysis
Abstract

Over recent decades, numerous financial crises have affected the global economy, which were caused by the lack of ethical values and conflicts of interest amongst the leaders of organisations. To protect organisations and their interest groups, regulators have developed norms to discourage and prohibit unethical practices through promotion of good practices of corporate governance. However, the literature on good corporate governance practices focuses mainly on developed economies without considering the challenges of developing countries. Therefore, this research proposes an index to measure the degree of adherence to good corporate governance practices in an emerging economy, like Chile, and estimate its effect on the financial performance of companies. Through a panel analysis, this research provides evidence that shows the existence of a positive and significant relationship between this index and financial performance of organisations, as well as a persistence of its benefits over time when companies adopt good practices. [ABSTRACT FROM AUTHOR]

Published
2023
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7. Competition Pressures and Academic Performance in Chile

Author

Rómulo A. Chumacero, Juan Gallegos Mardones, and Ricardo D. Paredes

Subjects
Economic history and conditions, HC10-1085, Economics as a science, HB71-74
Abstract

The positive impact that competition has on performance in most industries has been questioned in the education sector. The difficulty to measure competition, the idea that parents don’t rationally choose schools for their children, and that schools do not react to that choice is in the center of the debate. We critically analyze the prevailing methodology in the literature that relates competition and educational performance, and the data used to estimate that impact. We propose a methodology that considers relevant substitutes for each school using various attributes which parents consider when choosing schools, and we apply it to estimate the effect of competition on educational performance in Chile, were more than 90% of the students are covered by a voucher. The evidence supports the hypothesis that competition has a positive, statistically significant, and economically relevant educational impact on private and public schools.

Published
2016

8. Data from SINE Retrotransposons Cause Epigenetic Reprogramming of Adjacent Gene Promoters

Author

Jean-Pierre J. Issa, Shoudan Liang, Yue Lu, Mhair Dekmezian, Juan Gallegos, and Marcos R.H. Estécio

Abstract

Almost half of the human genome and as much as 40% of the mouse genome is composed of repetitive DNA sequences. The majority of these repeats are retrotransposons of the SINE and LINE families, and such repeats are generally repressed by epigenetic mechanisms. It has been proposed that these elements can act as methylation centers from which DNA methylation spreads into gene promoters in cancer. Contradictory to a methylation center function, we have found that retrotransposons are enriched near promoter CpG islands that stay methylation-free in cancer. Clearly, it is important to determine which influence, if any, these repetitive elements have on nearby gene promoters. Using an in vitro system, we confirm here that SINE B1 elements can influence the activity of downstream gene promoters, with acquisition of DNA methylation and loss of activating histone marks, thus resulting in a repressed state. SINE sequences themselves did not immediately acquire DNA methylation but were marked by H3K9me2 and H3K27me3. Moreover, our bisulfite sequencing data did not support that gain of DNA methylation in gene promoters occurred by methylation spreading from SINE B1 repeats. Genome-wide analysis of SINE repeats distribution showed that their enrichment is directly correlated with the presence of USF1, USF2, and CTCF binding, proteins with insulator function. In summary, our work supports the concept that SINE repeats interfere negatively with gene expression and that their presence near gene promoters is counter-selected, except when the promoter is protected by an insulator element. Mol Cancer Res; 10(10); 1332–42. ©2012 AACR.

Published
2023
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10. Index to degree of adhesion to good practices of corporate governance and their effect on financial performance: evidence for Chilean companies

Author

José Navarrete Oyarce, Hugo Moraga Flores, and Juan Gallegos Mardones

Subjects
Economics and Econometrics, Corporate governance, financial performance, Chile, adhesion to good practices
Abstract

Over recent decades, numerous financial crises have affected the global economy, which were caused by the lack of ethical values and conflicts of interest amongst the leaders of organisations. To protect organisations and their interest groups, regulators have developed norms to discourage and prohibit unethical practices through promotion of good practices of corporate governance. However, the literature on good corporate governance practices focuses mainly on developed economies without considering the challenges of developing countries. Therefore, this research proposes an index to measure the degree of adherence to good corporate governance practices in an emerging economy, like Chile, and estimate its effect on the financial performance of companies. Through a panel analysis, this research provides evidence that shows the existence of a positive and significant relationship between this index and financial performance of organisations, as well as a persistence of its benefits over time when companies adopt good practices.

Published
2023

12. Working capital management and business performance: evidence from Latin American companies

Author

Juan Gallegos Mardones

Subjects
non-linear relationship, Economics and Econometrics, Financial performance, Latin Americans, Public economics, Working capital, Economic growth, development, planning, Affect (psychology), financial performance, Regional economics. Space in economics, HT388, working capital, HD72-88, emerging economies, Business, Emerging markets, Empirical evidence
Abstract

Working capital management is one of the most important decisions that affect an organisation’s financial performance. Despite the importance of this topic, the empirical evidence for emerging economies is scarce; therefore, this research attempts to estimate and compare how investment in working capital impacts the financial performance of companies listed on the stock exchanges in Chile, Mexico, Peru, and Brazil for the years 2000 to 2018. This study uses panel data methodology, and the results show the existence of a positive and significant but non-linear relationship between investments in working capital and firm performance. However, there are mixed results for different countries and industries that could be explained by macroeconomic variables that favour access to financing for such investments. Furthermore, the results show that investments in working capital perform better for larger companies than smaller companies.

Published
2021

13. Análisis de riesgo crediticio, propuesta del modelo credit scoring

Author

Alexi Ludovic Leal Fica, Marco Antonio Aranguiz Casanova, and Juan Gallegos Mardones

Subjects
Análisis, riesgo de crédito, credit scoring, evaluación y capacidad de pago, Economic history and conditions, HC10-1085, Economics as a science, HB71-74
Abstract

El presente trabajo aplica en una empresa dedicada a la producción, comercialización y distribución de productos derivados del asfalto en la zona sur Chile. La empresa referida, ha preferido no revelar su razón social, para tal efecto hemos denominado a esta, Fantasía S.A. Durante los últimos años Fantasía ha experimentado un crecimiento significativo en sus ventas y con ello, una disminución de su nivel de liquidez y calidad de sus cuentas por cobrar. Sin embargo, este incremento en cuentas por cobrar está asociado a un mayor riesgo asumido de cobro, dada su política liberalizadora de cuentas por cobrar. Más aún, Fantasía S.A., no dispone de un sistema de gestión de crédito objetivo que permita una evaluación adecuada de la calidad y capacidad crediticia de sus clientes actuales y potenciales. Por tanto, en este artículo se propone a Fantasía un modelo de evaluación crediticia a sus clientes actuales y potenciales ajustado y ponderado a su realidad, que permite disminuir el riesgo de crédito o incobrables. El presente trabajo considera, una descripción de los modelos de evaluación de créditos y en específico de los modelos de credit scoring. A través de entrevistas a expertos, se definieron variables cuantitativas y cualitativas críticas a considerar en un proceso de gestión de créditos. Respecto de la calidad del modelo de evaluación crediticia propuesto, este muestra que un 81,82% de los créditos otorgados a sus clientes han superado el nivel mínino de evaluación o límite de aprobación por la empresa

Published
2017
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16. Can higher education admission be more equitable? Evidence supporting the inclusion of relative ranking in the process

Author

Nelyda Campos-Requena and Juan Gallegos Mardones

Subjects
Economics and Econometrics, Latin Americans, Actuarial science, Higher education, Process (engineering), business.industry, education, academic performance, Equity (finance), Economic growth, development, planning, equity, higher education, ranking, University Selection Test (P.S.U.), S.I.M.C.E, Chile, university selection test (p.s.u.), s.i.m.c.e, chile, Regional economics. Space in economics, Ranking, HT388, HD72-88, Economics, business, Inclusion (education)
Abstract

Many higher education systems require students to take admission exams, which are considered good predictors of academic performance. However, in Latin America, their use has been criticised for promoting socioeconomic segregation and favouring students of higher socioeconomic levels. This research complements the higher education admission process by using alternative measures of relative performance that promote greater equity in the system and allow access to higher education for more vulnerable sectors. A longitudinal study of students in Chile taking the University Selection Test (P.S.U.) and estimations of ordinary least squares (O.L.S.) in two stages were conducted. We found that the use of new measures of performance allows those more vulnerable students from public schools to reach equal and/ or superior levels of relative performance than their peers from private schools. The practical implications of this research relate to recognising that good students can also attend public schools and that those students who have the capability can enter higher education, independent of their economic situations.

Published
2020
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17. Capital structure and performance in Latin American companies

Author

Juan Gallegos Mardones and Gonzalo Ruiz Cuneo

Subjects
Economics and Econometrics, Latin Americans, Financial performance, capital structure, Capital structure, Financial economics, latin america, lcsh:Regional economics. Space in economics, ownership structure, Latin America, lcsh:HD72-88, lcsh:HT388, lcsh:Economic growth, development, planning, financial performance, Quantitative analysis (finance), Economics
Abstract

The purpose of this study is to explain the financial performance of companies in Latin America through the lens of capital structure and ownership structure. We perform a quantitative analysis of companies in Brazil, Chile, Mexico, and Peru using a panel data method. To avoid endogeneity problems, instrumental variables, generalised method of moments models, and panels with random effects are employed. The data cover the period 2000 to 2015. We find a positive relationship between financial performance, growth, and size of the company. However, there are mixed results for short- and long-term financial leverage, as well as for company liquidity. With respect to the ownership structure of Chilean companies, a positive effect is observed for the first major shareholder with financial performance. In general, our results are in line with those of previous studies. However, the existence of mixed results between companies and countries makes for an interesting and novel conclusion.

Published
2020

18. PAND: A Distribution to Identify Functional Linkage from Networks with Preferential Attachment Property.

Author

Hua Li, Pan Tong, Juan Gallegos, Emily Dimmer, Guoshuai Cai, Jeffrey J Molldrem, and Shoudan Liang

Subjects
Medicine, Science
Abstract

Technology advances have immensely accelerated large-scale mapping of biological networks, which necessitates the development of accurate and powerful network-based algorithms to make functional inferences. A prevailing approach is to leverage functions of neighboring nodes to predict unknown molecular function. However, existing neighbor-based algorithms have ignored the scale-free property hidden in many biological networks. By assuming that neighbor sharing is constrained by the preferential attachment property, we developed a Preferential Attachment based common Neighbor Distribution (PAND) to calculate the probability of the neighbor-sharing event between any two nodes in scale-free networks, which nearly perfectly matched the observed probability in simulations. By applying PAND to a human protein-protein interaction (PPI) network, we showed that smaller probabilities represented closer functional linkages between proteins. With the PAND-derive linkages, we were able to build new networks where the links are more functionally reliable than those of the human PPI network. We then applied simple annotation schemes to a PAND-derived network to make reliable functional predictions for proteins. We also developed an R package called PANDA (PAND-derived functional Associations) to implement the methods proposed in this study. In conclusion, PAND is a useful distribution to calculate the probability of the neighbor-sharing events in scale-free networks. With PAND, we are able to extract reliable functional linkages from real biological networks and builds new networks that are better bases for further functional inference.

Published
2015
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19. Working capital management and business performance: evidence from Latin American companies.

Author

Mardones, Juan Gallegos

Subjects
WORKING capital, INDUSTRIAL management, ORGANIZATIONAL performance, PERFORMANCE management, EMERGING markets, FINANCIAL performance, CAPITAL movements
Abstract

Working capital management is one of the most important decisions that affect an organisation's financial performance. Despite the importance of this topic, the empirical evidence for emerging economies is scarce; therefore, this research attempts to estimate and compare how investment in working capital impacts the financial performance of companies listed on the stock exchanges in Chile, Mexico, Peru, and Brazil for the years 2000 to 2018. This study uses panel data methodology, and the results show the existence of a positive and significant but non-linear relationship between investments in working capital and firm performance. However, there are mixed results for different countries and industries that could be explained by macroeconomic variables that favour access to financing for such investments. Furthermore, the results show that investments in working capital perform better for larger companies than smaller companies. [ABSTRACT FROM AUTHOR]

Published
2022
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21. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Author

Paul Flicek, Raffaele Teperino, Lydia Teboul, Thomas Werner, Marie-France Champy, Christopher J. Lelliott, Graham R. Williams, Jacqueline K. White, Gregor Miller, Mary E. Dickinson, Ann M Flenniken, Radislav Sedlacek, Martin Hrabé de Angelis, John R. Seavitt, Peter I. Croucher, Maria del Mar Muniz Moreno, Sara Wells, Jan Rozman, Terrence F. Meehan, Kristian F Odfalk, Juan Gallegos, J. H. Duncan Bassett, Mohammed Selloum, John G. Logan, Sylvie Jacquot, Elena J. Ghirardello, Robert Braun, Frantisek Spoutil, Kevin C K Lloyd, Lore Becker, Stephen A. Murray, Jan Prochazka, Elif F. Acar, Taylor S Vales, Michelle Simon, Helmut Fuchs, Nadine Spielmann, Mark Griffiths, Piia Keskivali-Bond, Valerie Gailus-Durner, Tania Sorg, Christine Schütt, Jeremy Mason, Helen Parkinson, Karen L. Svenson, Abdel Ayadi, Anna L Swan, Jason D. Heaney, Colin McKerlie, Wolfgang Wurst, Ann-Marie Mallon, Heather Cater, Stefanie Leuchtenberger, Harald Grallert, Steve D.M. Brown, Stefan Brandmaier, Yann Herault, Philipp Mayer-Kuckuk, Corey L. Reynolds, Ala Moshiri, Robert Brommage, Derek D. Cissell, Lauryl M J Nutter, Connor Lally, MRC Harwell Institute [UK], German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Helmholtz-Zentrum München (HZM), The Wellcome Trust Sanger Institute [Cambridge], University of Michigan [Ann Arbor], University of Michigan System, University of California [Davis] (UC Davis), University of California, Baylor College of Medicine (BCM), Baylor University, European Molecular Biology Laboratory [Hinxton], University of Toronto, University of Manitoba [Winnipeg], Lunenfeld-Tanenbaum Research Institute [Toronto, Canada], French National Infrastructure for Mouse Phenogenomics (PHENOMIN), The Jackson Laboratory [Bar Harbor] (JAX), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, Imperial College London, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Garvan Institute of Medical Research [Sydney, Australia], St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW), Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia], Mundlos, Stefan, Wellcome Trust, Commission of the European Communities, European Commission, Herault, Yann, Helmholtz Zentrum München = German Research Center for Environmental Health, University of California (UC), Garvan Institute of medical research, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Technische Universität München [München] (TUM), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Swan, Anna L [0000-0003-1810-3756], Rozman, Jan [0000-0002-8035-8904], Del Mar Muñiz Moreno, Maria [0000-0002-2662-890X], Leuchtenberger, Stefanie [0000-0003-2475-0810], Brommage, Robert [0000-0002-9947-3822], Grallert, Harald [0000-0002-6876-9655], Werner, Thomas [0000-0003-0402-4539], Teperino, Raffaele [0000-0001-8815-1409], Becker, Lore [0000-0002-6890-4984], Miller, Gregor [0000-0002-4281-4905], Seavitt, John R [0000-0003-3209-3187], Cissell, Derek D [0000-0002-6450-422X], Acar, Elif F [0000-0003-2908-7691], Lelliott, Christopher J [0000-0001-8087-4530], Braun, Robert E [0000-0003-3856-9465], Cater, Heather [0000-0002-8696-6070], Flicek, Paul [0000-0002-3897-7955], Ghirardello, Elena J [0000-0002-1100-9217], Heaney, Jason D [0000-0001-8475-8828], Lally, Connor [0000-0002-3801-1966], Logan, John G [0000-0003-2801-700X], Mason, Jeremy [0000-0002-2796-5123], Nutter, Lauryl MJ [0000-0001-9619-146X], Odfalk, Kristian F [0000-0003-4152-4583], Prochazka, Jan [0000-0003-4675-8995], Selloum, Mohammed [0000-0003-4057-3519], Spoutil, Frantisek [0000-0002-7310-3487], Svenson, Karen L [0000-0002-7928-1911], Vales, Taylor S [0000-0001-9751-5681], Wells, Sara E [0000-0002-0572-0600], White, Jacqueline K [0000-0001-6268-2826], Sedlacek, Radislav [0000-0002-3352-392X], Wurst, Wolfgang [0000-0003-4422-7410], Lloyd, KC Kent [0000-0002-5318-4144], Williams, Graham R [0000-0002-8555-8219], Herault, Yann [0000-0001-7049-6900], Brown, Steve DM [0000-0002-0617-4824], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
Male, Osteoporosis, genetics [Gene Expression Regulation], Transgenic, Transcriptome, Mice, 0302 clinical medicine, Animal Cells, Aetiology, Musculoskeletal System, Connective Tissue Cells, Genetics & Heredity, 0303 health sciences, Genomics, 3. Good health, Cellular Types, musculoskeletal diseases, Genotype, In silico, 1.1 Normal biological development and functioning, 03 medical and health sciences, genetics [Osteoporosis], Rheumatology, pathology [Osteoblasts], Genetic, Genome-Wide Association Studies, Genetics, GENOME-WIDE ASSOCIATION, Molecular Biology, Skeleton, Ecology, Evolution, Behavior and Systematics, METAANALYSIS, metabolism [Osteoblasts], 0604 Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, Osteoblasts, IDENTIFICATION, Biology and Life Sciences, Computational Biology, medicine.disease, COLLAGEN, Biological Tissue, OSTEOGENESIS IMPERFECTA, DISCOVERY, IMPC Consortium, Mutation, Animal Studies, Developmental Biology, Candidate gene, Cancer Research, Bone density, Gene Expression, Osteoclasts, [SDV.GEN] Life Sciences [q-bio]/Genetics, QH426-470, Bone remodeling, Bone Density, Medicine and Health Sciences, 2.1 Biological and endogenous factors, Protein Interaction Maps, Connective Tissue Diseases, Promoter Regions, Genetic, Genetics (clinical), Bone mineral, Sex Characteristics, genetics [Bone Density], metabolism [Osteoclasts], Genetic Pleiotropy, Animal Models, pathology [Osteoclasts], Phenotype, DIFFERENTIATION, Experimental Organism Systems, ANIMAL-MODELS, Connective Tissue, SEX, Female, Anatomy, Technology Platforms, Life Sciences & Biomedicine, Research Article, metabolism [Osteoporosis], Mouse Models, 030209 endocrinology & metabolism, Mice, Transgenic, Biology, Research and Analysis Methods, Promoter Regions, Model Organisms, Underpinning research, medicine, Animals, ddc:610, Bone, 030304 developmental biology, Human Genetics, Cell Biology, Genome Analysis, Gene Ontology, Gene Expression Regulation, Musculoskeletal, Genome-Wide Association Study
Abstract

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease., Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.

Published
2021
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22. Soft windowing application to improve analysis of high-throughput phenotyping data

Author

Alexandr Bezginov, Paul Flicek, Masaru Tamura, Masuya Hiroshi, Mohammed Selloum, Yeon Kyung Kang, Herault Yann, Rodney C. Samaco, Ann-Marie Mallon, Helen Parkinson, Soo Young Cho, Ghina Bou About, Nadine Spielmann, Arturo Garza, Glauco P. Tocchini-Valentini, Gregor Miller, Obata Yuichi, John R. Seavitt, Surabi Veeraragavan, Jennie R. Green, Ewan Straiton, Marie-France Champy, Ann M Flenniken, Je Kyung Seong, Kyung Dong Soo, Isabel Lorenzo, Kevin C K Lloyd, Terrence F. Meehan, Vivek Kumar, Lillian Garrett, Damian Smedley, Elif F. Acar, Hamid Meziane, Ritu Bohat, Lore Becker, Sophie Leblanc, Denise G. Lanza, Angelina Gaspero, Audrey E. Christianson, Juan Gallegos, Wurst Wolfgang, Chih-Wei Hsu, Hamed Haselimashhadi, Colin McKerlie, Ruairidh King, Stephen D.M. Brown, Dave Clary, Nobuhiko Tanaka, Tania Sorg, Helmut Fuchs, Jason D. Heaney, Jacqui White, Jeremy Mason, Martin Hrabé de Angelis, Federico López-Gómez, Laurent Vasseur, Valerie Gailus-Durner, Holger Maier, Corey L. Reynolds, Violeta Muñoz-Fuentes, Mary E Dickinson, K. O. Babalola, Patrick T. Reilly, Jong Kyoung Kim, Schwartz, Russell, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Statistics and Probability, Computer science, Bioinformatics, Pipeline (computing), [SDV]Life Sciences [q-bio], Disease, computer.software_genre, 01 natural sciences, Biochemistry, Article, Mathematical Sciences, Set (abstract data type), Reduction (complexity), 010104 statistics & probability, 03 medical and health sciences, Mice, 0302 clinical medicine, Resampling, Information and Computing Sciences, False positive paradox, Genetics, Animals, Humans, 0101 mathematics, Molecular Biology, Throughput (business), ComputingMilieux_MISCELLANEOUS, Genetic Association Studies, 030304 developmental biology, Linkage (software), 0303 health sciences, Population Health, Biological Sciences, Computer Science Applications, Computational Mathematics, Phenotype, Computational Theory and Mathematics, Data mining, computer, 030217 neurology & neurosurgery, Software
Abstract

Motivation High-throughput phenomic projects generate complex data from small treatment and large control groups that increase the power of the analyses but introduce variation over time. A method is needed to utlize a set of temporally local controls that maximizes analytic power while minimizing noise from unspecified environmental factors. Results Here we introduce ‘soft windowing’, a methodological approach that selects a window of time that includes the most appropriate controls for analysis. Using phenotype data from the International Mouse Phenotyping Consortium (IMPC), adaptive windows were applied such that control data collected proximally to mutants were assigned the maximal weight, while data collected earlier or later had less weight. We applied this method to IMPC data and compared the results with those obtained from a standard non-windowed approach. Validation was performed using a resampling approach in which we demonstrate a 10% reduction of false positives from 2.5 million analyses. We applied the method to our production analysis pipeline that establishes genotype–phenotype associations by comparing mutant versus control data. We report an increase of 30% in significant P-values, as well as linkage to 106 versus 99 disease models via phenotype overlap with the soft-windowed and non-windowed approaches, respectively, from a set of 2082 mutant mouse lines. Our method is generalizable and can benefit large-scale human phenomic projects such as the UK Biobank and the All of Us resources. Availability and implementation The method is freely available in the R package SmoothWin, available on CRAN http://CRAN.R-project.org/package=SmoothWin. Supplementary information Supplementary data are available at Bioinformatics online.

Published
2020
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24. ANÁLISIS DE RIESGO CREDITICIO, PROPUESTA DEL MODELO CREDIT SCORING

Author

Marco Antonio Aranguiz Casanova, Alexi Ludovic Leal Fica, and Juan Gallegos Mardones

Subjects
credit scoring, Economics as a science, análisis, Economic history and conditions, General Medicine, HC10-1085, riesgo de crédito, evaluación y capacidad de pago, HB71-74
Abstract

El presente trabajo aplica en una empresa dedicada a la producción, comercialización y distribu- ción de productos derivados del asfalto en la zona sur Chile. La empresa referida, ha preferido no revelar su razón social, para tal efecto hemos denominado a esta, Fantasía S.A. Durante los últimos años Fantasía ha experimentado un crecimiento significativo en sus ventas y con ello, una disminución de su nivel de liquidez y calidad de sus cuentas por cobrar. Sin embargo, este incre- mento en cuentas por cobrar está asociado a un mayor riesgo asumido de cobro, dada su política liberalizadora de cuentas por cobrar. Más aún, Fantasía S.A., no dispone de un sistema de gestión de crédito objetivo que permita una evaluación adecuada de la calidad y capacidad crediticia de sus clientes actuales y potenciales. Por tanto, en este artículo se propone a Fantasía un modelo de evaluación crediticia a sus clientes actuales y potenciales ajustado y ponderado a su realidad, que permite disminuir el riesgo de crédito o incobrables. El presente trabajo considera, una descripción de los modelos de evaluación de créditos y en específico de los modelos de credit scoring. A través de entrevistas a expertos, se definieron variables cuantitativas y cualitativas críticas a considerar en un proceso de gestión de créditos. Respecto de la calidad del modelo de evaluación crediticia propuesto, este muestra que un 81,82% de los créditos otorgados a sus clientes han superado el nivel mínino de evaluación o límite de aprobación por la empresa.

Published
2018

25. Neuro-fuzzy System with Particle Swarm Optimization for Classification of Physical Fitness in School Children

Author

Gonzalo Luna-Luza, Jose Sulla-Torres, Doris Ccama-Yana, Juan Gallegos-Valdivia, and Marco Cossio-Bolaños

Subjects
0303 health sciences, Adaptive neuro fuzzy inference system, General Computer Science, Artificial neural network, Neuro-fuzzy, 030306 microbiology, Computer science, business.industry, Physical fitness, Particle swarm optimization, Flexibility (personality), 02 engineering and technology, Fuzzy logic, 03 medical and health sciences, 0202 electrical engineering, electronic engineering, information engineering, 020201 artificial intelligence & image processing, Artificial intelligence, business
Abstract

Physical fitness is widely known to be one of the critical elements of a healthy life. The sedentary attitude of school children is related to some health problems due to physical inactivity. The following article aims to classify the physical fitness in school children, using a database of 1813 children of both sexes, in a range that goes from six to twelve years. The physical tests were flexibility, horizontal jump, and agility that served to classify the physical fitness using neural networks and fuzzy logic. For this, the ANFIS (adaptive network fuzzy inference system) model was used, which was optimized using the Particle Swarm Optimization algorithm. The experimental tests carried out showed an RMSE error of 3.41, after performing 500 interactions of the PSO algorithm. This result is considered acceptable within the conditions of this investigation.

Published
2020
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26. Creation of a Robotically Assisted Terminal Jejunogastrostomy Is Safe and Effective in Regaining Antegrade Enteral Bile Duct Access After Live Donor Liver Transplant With Roux Limb

Author

Tuan Pham, Terry Box, Gilbert Pan, Jeffrey Campsen, Juan Gallegos, Eryberto Martinez, Mariah Goodale, Robin D. Kim, Ryan O'Hara, Michael Sossenheimer, and George Rofaiel

Subjects
Transplantation, medicine.medical_specialty, medicine.anatomical_structure, Terminal (electronics), business.industry, Live donor, Bile duct, Medicine, business, Enteral administration, Surgery, Liver Transplantation
Published
2019

27. Can higher education admission be more equitable? Evidence supporting the inclusion of relative ranking in the process.

Author

Mardones, Juan Gallegos and Campos-Requena, Nelyda

Subjects
HIGHER education, HIGHER education research, UNIVERSITY & college admission, ACADEMIC achievement, PRIVATE schools, RIGHT to education
Abstract

Many higher education systems require students to take admission exams, which are considered good predictors of academic performance. However, in Latin America, their use has been criticised for promoting socioeconomic segregation and favouring students of higher socioeconomic levels. This research complements the higher education admission process by using alternative measures of relative performance that promote greater equity in the system and allow access to higher education for more vulnerable sectors. A longitudinal study of students in Chile taking the University Selection Test (P.S.U.) and estimations of ordinary least squares (O.L.S.) in two stages were conducted. We found that the use of new measures of performance allows those more vulnerable students from public schools to reach equal and/or superior levels of relative performance than their peers from private schools. The practical implications of this research relate to recognising that good students can also attend public schools and that those students who have the capability can enter higher education, independent of their economic situations. [ABSTRACT FROM AUTHOR]

Published
2021
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28. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Author

Zobair M Younossi, Vlad Ratziu, Rohit Loomba, Mary Rinella, Quentin M Anstee, Zachary Goodman, Pierre Bedossa, Andreas Geier, Susanne Beckebaum, Philip N Newsome, David Sheridan, Muhammad Y Sheikh, James Trotter, Whitfield Knapple, Eric Lawitz, Manal F Abdelmalek, Kris V Kowdley, Aldo J Montano-Loza, Jerome Boursier, Philippe Mathurin, Elisabetta Bugianesi, Giuseppe Mazzella, Antonio Olveira, Helena Cortez-Pinto, Isabel Graupera, David Orr, Lise Lotte Gluud, Jean-Francois Dufour, David Shapiro, Jason Campagna, Luna Zaru, Leigh MacConell, Reshma Shringarpure, Stephen Harrison, Arun J Sanyal, Manal Abdelmalek, Gary Abrams, Humberto Aguilar, Aijaz Ahmed, Elmar Aigner, Guruprasad Aithal, Aftab Ala, William Alazawi, Agustin Albillos, Michael Allison, Sfa Al-Shamma, Raul Andrade, Pietro Andreone, Mario Angelico, Victor Ankoma-Sey, Quentin Anstee, Rodolphe Anty, Victor Araya, Juan Ignacio Arenas Ruiz, Perttu Arkkila, Marty Arora, Tarik Asselah, Jennifer Au, Oyekoya Ayonrinde, Robert James Bailey, Maya Balakrishnan, Kiran Bambha, Meena Bansal, Sidney Barritt, John Bate, Jorge Beato, Jaideep Behari, Pablo Bellot, Ziv Ben Ari, Michael Bennett, Marina Berenguer, Benedetta Terziroli Beretta-Piccoli, Thomas Berg, Maurizio Bonacini, Lucia Bonet, Brian Borg, Marc Bourliere, William Bowman, David Bradley, Marija Brankovic, Marius Braun, Jean-Pierre Bronowicki, Savino Bruno, Cindy Cai, Amy Calderon, José Luis Calleja Panero, Elizabeth Carey, Michal Carmiel, Jose Antonio Carrión, Matthew Cave, Cristina Chagas, Tawfik Chami, Alan Chang, Allan Coates, Jeremy Cobbold, Charlote Costentin, Kathleen Corey, Lynsey Corless, Javier Crespo, Oscar Cruz Pereira, Victor de Ledinghen, Andrew deLemos, Moises Diago, Mamie Dong, Jean-François Dufour, Predrag Dugalic, Winston Dunn, Magby Elkhashab, Michael Epstein, Maria Desamparados Escudero-Garcia, Ohad Etzion, Larry Evans, Robert Falcone, Conrado Fernandez, Jose Ferreira, Scott Fink, Kevin Finnegan, Roberto Firpi-Morell, Annarosa Floreani, Thierry Fontanges, Ryan Ford, Ewan Forrest, Andrew Fowell, Anna Ludovica Fracanzani, Sven Francque, Bradley Freilich, Juan Frias, Michael Fuchs, Javier Fuentes, Michael Galambos, Juan Gallegos, Anja Geerts, Jacob George, Maged Ghali, Reem Ghalib, Pierre Gholam, Pere Gines, Norman Gitlin, Tobias Goeser, John Goff, Stuart Gordon, Frederic Gordon, Odile Goria, Shaun Greer, Alla Grigorian, Henning Gronbaek, Maeva Guillaume, Naresh Gunaratnam, Dina Halegoua-De Marzio, Bilal Hameed, Stephanie Hametner, James Hamilton, Marek Hartleb, Tarek Hassanein, Dieter Häussinger, Paul Hellstern, Robert Herring, Eva Heurich, Christophe Hezode, Holger Hinrichsen, Peter Holland Fischer, Yves Horsmans, Jonathan Huang, Hyder Hussaini, Antoine Jakiche, Lennox Jeffers, Blake Jones, Rosa Jorge, Francisco Jorquera, Shoba Joshi, Alisan Kahraman, Kelly Kaita, Nicholas Karyotakis, Zeid Kayali, Stergios Kechagias, Thomas Kepczyk, Mandana Khalili, Hicham Khallafi, Johannes Kluwe, Anita Kohli, Kevin Korenblat, Kris Kowdley, Aleksander Krag, Richard Krause, Andreas Kremer, Karen Krok, Miodrag Krstic, Marcelo Kugelmas, Sonal Kumar, Scott Kuwada, Damien Labarriere, Michelle Lai, Wim Laleman, Pietro Lampertico, Alice Lee, Vincent Leroy, Steven Lidofsky, Tina Huey Lim, Joseph Lim, Donald Lipkis, Ester Little, Amadeo Lonardo, Michelle Long, Velimir Anthony Christopher Luketic, Yoav Lurie, Guilherme Macedo, Joana Magalhaes, Mihály Makara, Benedict Maliakkal, Michael Manns, Pinelopi Manousou, Parvez Mantry, Giulio Marchesini, Carla Marinho, Paul Marotta, Hanns-Ulrich Marschall, Linda Martinez, Marlyn Mayo, Mark McCullen, William McLaughlin, Uta Merle, Raphael Merriman, Apurva Modi, Esther Molina, Aldo Montano-Loza, Carlos Monteverde, Amilcar Morales Cardona, Sulleman Moreea, Christophe Moreno, Filomena Morisco, Abdullah Mubarak, Beat Muellhaupt, Sandeep Mukherjee, Tobias Müller, Aleksandar Nagorni, Jahnavi Naik, Guy Neff, Moises Nevah, Philip Newsome, Eric Nguyen-Khac, Mazen Noureddin, Jude Oben, Hans Orlent, James Orr, Grisell Ortiz-Lasanta, Violaine Ozenne, Prashant Pandya, Angelo Paredes, James Park, Joykumar Patel, Keyur Patel, Sonali Paul, Heather Patton, Markus Peck-Radosavljevic, Salvatore Petta, Stephen Pianko, Anna Piekarska, Neville Pimstone, Joseph Pisegna, Paul Pockros, Stanislas Pol, Michael Porayko, John Poulos, David Pound, Joe Pouzar, Jose Presa Ramos, Nikolaos Pyrsopoulos, Nila Rafiq, Kate Muller, Alnoor Ramji, Ravi Ravinuthala, Chakradhar Reddy, Gautham Reddy K G, K. Rajender Reddy K R, Frederic Regenstein, Robert Reindollar, Justin Reynolds, Andres Riera, Jose Rivera Acosta, Geert Robaeys, Stuart Roberts, Federico Rodriguez-Perez, Sandor Romero, Manuel Romero-Gomez, Raymond Rubin, Mariagrazia Rumi, Simon Rushbrook, Christian Rust, Michael Ryan, Rifaat Safadi, Adnan Said, Kimmo Salminen, Didier Samuel, John Santoro, Arun Sanyal, Souvik Sarkar, Cynthia Schaeffer, Jörn Schattenberg, Ingolf Schiefke, Eugene Schiff, Wolfgang Schmidt, Jeffrey Schneider, Jeoffrey Schouten, Michael Schultz, Giada Sebastiani, David Semela, Thomas Sepe, Aasim Sheikh, Muhammad Sheikh, Kenneth Sherman, Oren Shibolet, Mitchell Shiffman, Asma Siddique, Cyril Sieberhagen, Samuel Sigal, Katarzyna Sikorska, Krzysztof Simon, Marie Sinclair, Richard Skoien, Joel Solis, Siddharth Sood, Bob Souder, James Spivey, Per Stal, Laura Stinton, Simone Strasser, Petar Svorcan, Gyongzi Szabo, Andrew Talal, Edward Tam, Brent Tetri, Paul Thuluvath, Hillel Tobias, Krzysztof Tomasiewicz, Dawn Torres, Albert Tran, Michael Trauner, Christian Trautwein, Emanuel Tsochatzis, Esther Unitt, Victor Vargas, Istvan Varkonyi, Ella Veitsman, Umberto Vespasiani Gentilucci, David Victor, John Vierling, Catherine Vincent, Aron Vincze, Manfred von der Ohe, Natasha Von Roenn, Raj Vuppalanchi, Michael Waters, Kymberly Watt, Julia Wattacheril, Martin Weltman, Amanda Wieland, Gregory Wiener, Alonzo Williams A, Jeffrey Williams J, Jason Wilson, Maria Yataco, Eric Yoshida, Ziad Younes, Liyun Yuan, Adam Zivony, Donald Zogg, Heinz Zoller, Fabien Zoulim, Eli Zuckerman, Massimo Zuin, Younossi Z.M., Ratziu V., Loomba R., Rinella M., Anstee Q.M., Goodman Z., Bedossa P., Geier A., Beckebaum S., Newsome P.N., Sheridan D., Sheikh M.Y., Trotter J., Knapple W., Lawitz E., Abdelmalek M.F., Kowdley K.V., Montano-Loza A.J., Boursier J., Mathurin P., Bugianesi E., Mazzella G., Olveira A., Cortez-Pinto H., Graupera I., Orr D., Gluud L.L., Dufour J.-F., Shapiro D., Campagna J., Zaru L., MacConell L., Shringarpure R., Harrison S., Sanyal A.J., Abdelmalek M., Abrams G., Aguilar H., Ahmed A., Aigner E., Aithal G., Ala A., Alazawi W., Albillos A., Allison M., Al-Shamma S., Andrade R., Andreone P., Angelico M., Ankoma-Sey V., Anstee Q., Anty R., Araya V., Arenas Ruiz J.I., Arkkila P., Arora M., Asselah T., Au J., Ayonrinde O., Bailey R.J., Balakrishnan M., Bambha K., Bansal M., Barritt S., Bate J., Beato J., Behari J., Bellot P., Ben Ari Z., Bennett M., Berenguer M., Beretta-Piccoli B.T., Berg T., Bonacini M., Bonet L., Borg B., Bourliere M., Bowman W., Bradley D., Brankovic M., Braun M., Bronowicki J.-P., Bruno S., Cai C., Calleja Panero J.L., Carey E., Carmiel M., Carrion J.A., Cave M., Chagas C., Chami T., Chang A., Coates A., Cobbold J., Corey K., Corless L., Crespo J., Cruz Pereira O., de Ledinghen V., deLemos A., Diago M., Dugalic P., Dunn W., Elkhashab M., Epstein M., Escudero-Garcia M.D., Etzion O., Evans L., Falcone R., Fernandez C., Ferreira J., Fink S., Finnegan K., Firpi-Morell R., Floreani A., Fontanges T., Ford R., Forrest E., Fowell A., Fracanzani A.L., Francque S., Freilich B., Frias J., Fuchs M., Fuentes J., Galambos M., Gallegos J., Geerts A., George J., Ghali M., Ghalib R., Gholam P., Gines P., Gitlin N., Goeser T., Goff J., Gordon S., Gordon F., Goria O., Greer S., Grigorian A., Gronbaek H., Guillaume M., Gunaratnam N., Halegoua-De Marzio D., Hameed B., Hametner S., Hamilton J., Hartleb M., Hassanein T., Haussinger D., Hellstern P., Herring R., Heurich E., Hezode C., Hinrichsen H., Holland Fischer P., Horsmans Y., Huang J., Jakiche A., Jeffers L., Jones B., Jorge R., Jorquera F., Kahraman A., Kaita K., Karyotakis N., Kayali Z., Kechagias S., Kepczyk T., Khalili M., Khallafi H., Kluwe J., Kohli A., Korenblat K., Kowdley K., Krag A., Krause R., Kremer A., Krok K., Krstic M., Kugelmas M., Kumar S., Labarriere D., Lai M., Lampertico P., Lee A., Leroy V., Lidofsky S., Lim T.H., Lim J., Lipkis D., Little E., Lonardo A., Long M., Lurie Y., Macedo G., Makara M., Maliakkal B., Manns M., Manousou P., Mantry P., Marchesini G., Marinho C., Marotta P., Marschall H.-U., Mayo M., McCullen M., McLaughlin W., Merriman R., Modi A., Molina E., Montano-Loza A., Monteverde C., Moreea S., Moreno C., Morisco F., Mubarak A., Muellhaupt B., Mukherjee S., Muller T., Nagorni A., Naik J., Neff G., Nevah M., Newsome P., Nguyen-Khac E., Noureddin M., Oben J., Orlent H., Orr J., Ortiz-Lasanta G., Ozenne V., Pandya P., Paredes A., Park J., Patel J., Patel K., Uta M., Patton H., Peck-Radosavljevic M., Petta S., Pianko S., Piekarska A., Pimstone N., Pockros P., Pol S., Porayko M., Poulos J., Pound D., Pouzar J., Presa Ramos J., Pyrsopoulos N., Rafiq N., Muller K., Ramji A., Ravinuthala R., Reddy C., Reddy K G G., Reddy K R K.R., Regenstein F., Reindollar R., Riera A., Rivera Acosta J., Robaeys G., Roberts S., Rodriguez-Perez F., Romero-Gomez M., Rubin R., Rumi M., Rushbrook S., Rust C., Ryan M., Safadi R., Said A., Salminen K., Samuel D., Santoro J., Sanyal A., Sarkar S., Schaeffer C., Schattenberg J., Schiefke I., Schiff E., Schmidt W., Schneider J., Schouten J., Schultz M., Sebastiani G., Semela D., Sepe T., Sheikh A., Sheikh M., Sherman K., Shibolet O., Shiffman M., Siddique A., Sieberhagen C., Sigal S., Sikorska K., Simon K., Sinclair M., Skoien R., Solis J., Sood S., Souder B., Spivey J., Stal P., Stinton L., Strasser S., Svorcan P., Szabo G., Talal A., Tam E., Tetri B., Thuluvath P., Tobias H., Tomasiewicz K., Torres D., Trauner M., Trautwein C., Tsochatzis E., Unitt E., Vargas V., Varkonyi I., Veitsman E., Vespasiani Gentilucci U., Victor D., Vierling J., Vincent C., Vincze A., von der Ohe M., Von Roenn N., Vuppalanchi R., Waters M., Watt K., Weltman M., Wieland A., Wiener G., Williams A A., Williams J J., Wilson J., Yataco M., Yoshida E., Younes Z., Yuan L., Zivony A., Zogg D., Zoller H., Zoulim F., Zuckerman E., Zuin M., Repositório da Universidade de Lisboa, Younossi, Z. M., Ratziu, V., Loomba, R., Rinella, M., Anstee, Q. M., Goodman, Z., Bedossa, P., Geier, A., Beckebaum, S., Newsome, P. N., Sheridan, D., Sheikh, M. Y., Trotter, J., Knapple, W., Lawitz, E., Abdelmalek, M. F., Kowdley, K. V., Montano-Loza, A. J., Boursier, J., Mathurin, P., Bugianesi, E., Mazzella, G., Olveira, A., Cortez-Pinto, H., Graupera, I., Orr, D., Gluud, L. L., Dufour, J. -F., Shapiro, D., Campagna, J., Zaru, L., Macconell, L., Shringarpure, R., Harrison, S., Sanyal, A. J., Abdelmalek, M., Abrams, G., Aguilar, H., Ahmed, A., Aigner, E., Aithal, G., Ala, A., Alazawi, W., Albillos, A., Allison, M., Al-Shamma, S., Andrade, R., Andreone, P., Angelico, M., Ankoma-Sey, V., Anstee, Q., Anty, R., Araya, V., Arenas Ruiz, J. I., Arkkila, P., Arora, M., Asselah, T., Au, J., Ayonrinde, O., Bailey, R. J., Balakrishnan, M., Bambha, K., Bansal, M., Barritt, S., Bate, J., Beato, J., Behari, J., Bellot, P., Ben Ari, Z., Bennett, M., Berenguer, M., Beretta-Piccoli, B. T., Berg, T., Bonacini, M., Bonet, L., Borg, B., Bourliere, M., Bowman, W., Bradley, D., Brankovic, M., Braun, M., Bronowicki, J. -P., Bruno, S., Cai, C., Calleja Panero, J. L., Carey, E., Carmiel, M., Carrion, J. A., Cave, M., Chagas, C., Chami, T., Chang, A., Coates, A., Cobbold, J., Corey, K., Corless, L., Crespo, J., Cruz Pereira, O., de Ledinghen, V., Delemos, A., Diago, M., Dugalic, P., Dunn, W., Elkhashab, M., Epstein, M., Escudero-Garcia, M. D., Etzion, O., Evans, L., Falcone, R., Fernandez, C., Ferreira, J., Fink, S., Finnegan, K., Firpi-Morell, R., Floreani, A., Fontanges, T., Ford, R., Forrest, E., Fowell, A., Fracanzani, A. L., Francque, S., Freilich, B., Frias, J., Fuchs, M., Fuentes, J., Galambos, M., Gallegos, J., Geerts, A., George, J., Ghali, M., Ghalib, R., Gholam, P., Gines, P., Gitlin, N., Goeser, T., Goff, J., Gordon, S., Gordon, F., Goria, O., Greer, S., Grigorian, A., Gronbaek, H., Guillaume, M., Gunaratnam, N., Halegoua-De Marzio, D., Hameed, B., Hametner, S., Hamilton, J., Hartleb, M., Hassanein, T., Haussinger, D., Hellstern, P., Herring, R., Heurich, E., Hezode, C., Hinrichsen, H., Holland Fischer, P., Horsmans, Y., Huang, J., Jakiche, A., Jeffers, L., Jones, B., Jorge, R., Jorquera, F., Kahraman, A., Kaita, K., Karyotakis, N., Kayali, Z., Kechagias, S., Kepczyk, T., Khalili, M., Khallafi, H., Kluwe, J., Kohli, A., Korenblat, K., Kowdley, K., Krag, A., Krause, R., Kremer, A., Krok, K., Krstic, M., Kugelmas, M., Kumar, S., Labarriere, D., Lai, M., Lampertico, P., Lee, A., Leroy, V., Lidofsky, S., Lim, T. H., Lim, J., Lipkis, D., Little, E., Lonardo, A., Long, M., Lurie, Y., Macedo, G., Makara, M., Maliakkal, B., Manns, M., Manousou, P., Mantry, P., Marchesini, G., Marinho, C., Marotta, P., Marschall, H. -U., Mayo, M., Mccullen, M., Mclaughlin, W., Merriman, R., Modi, A., Molina, E., Montano-Loza, A., Monteverde, C., Moreea, S., Moreno, C., Morisco, F., Mubarak, A., Muellhaupt, B., Mukherjee, S., Muller, T., Nagorni, A., Naik, J., Neff, G., Nevah, M., Newsome, P., Nguyen-Khac, E., Noureddin, M., Oben, J., Orlent, H., Orr, J., Ortiz-Lasanta, G., Ozenne, V., Pandya, P., Paredes, A., Park, J., Patel, J., Patel, K., Uta, M., Patton, H., Peck-Radosavljevic, M., Petta, S., Pianko, S., Piekarska, A., Pimstone, N., Pockros, P., Pol, S., Porayko, M., Poulos, J., Pound, D., Pouzar, J., Presa Ramos, J., Pyrsopoulos, N., Rafiq, N., Muller, K., Ramji, A., Ravinuthala, R., Reddy, C., Reddy K G, G., Reddy K R, K. R., Regenstein, F., Reindollar, R., Riera, A., Rivera Acosta, J., Robaeys, G., Roberts, S., Rodriguez-Perez, F., Romero-Gomez, M., Rubin, R., Rumi, M., Rushbrook, S., Rust, C., Ryan, M., Safadi, R., Said, A., Salminen, K., Samuel, D., Santoro, J., Sanyal, A., Sarkar, S., Schaeffer, C., Schattenberg, J., Schiefke, I., Schiff, E., Schmidt, W., Schneider, J., Schouten, J., Schultz, M., Sebastiani, G., Semela, D., Sepe, T., Sheikh, A., Sheikh, M., Sherman, K., Shibolet, O., Shiffman, M., Siddique, A., Sieberhagen, C., Sigal, S., Sikorska, K., Simon, K., Sinclair, M., Skoien, R., Solis, J., Sood, S., Souder, B., Spivey, J., Stal, P., Stinton, L., Strasser, S., Svorcan, P., Szabo, G., Talal, A., Tam, E., Tetri, B., Thuluvath, P., Tobias, H., Tomasiewicz, K., Torres, D., Trauner, M., Trautwein, C., Tsochatzis, E., Unitt, E., Vargas, V., Varkonyi, I., Veitsman, E., Vespasiani Gentilucci, U., Victor, D., Vierling, J., Vincent, C., Vincze, A., von der Ohe, M., Von Roenn, N., Vuppalanchi, R., Waters, M., Watt, K., Weltman, M., Wieland, A., Wiener, G., Williams A, A., Williams J, J., Wilson, J., Yataco, M., Yoshida, E., Younes, Z., Yuan, L., Zivony, A., Zogg, D., Zoller, H., Zoulim, F., Zuckerman, E., Zuin, M., Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andrea, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, Jame, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francoi, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert Jame, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thoma, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Mariu, Bronowicki, Jean-Pierre, Bruno, Savino, Cai, Cindy, Calleja Panero, José Lui, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Corey, Kathleen, Corless, Lynsey, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moise, Dufour, Jean-Françoi, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparado, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Goeser, Tobia, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, Jame, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yve, Huang, Jonathan, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nichola, Kayali, Zeid, Kechagias, Stergio, Kepczyk, Thoma, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johanne, Kohli, Anita, Korenblat, Kevin, Kowdley, Kri, Krag, Aleksander, Krause, Richard, Kremer, Andrea, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Labarriere, Damien, Lai, Michelle, Lampertico, Pietro, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Lurie, Yoav, Macedo, Guilherme, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Mayo, Marlyn, McCullen, Mark, McLaughlin, William, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlo, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobia, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moise, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Orlent, Han, Orr, Jame, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, Jame, Patel, Joykumar, Patel, Keyur, Uta, Merle, Patton, Heather, Peck-Radosavljevic, Marku, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pockros, Paul, Pol, Stanisla, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolao, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Riera, Andre, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thoma, Sheikh, Aasim, Sheikh, Muhammad, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, Jame, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Trauner, Michael, Trautwein, Christian, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, Zuin, Massimo, and REGENERATE Study Investigators

Subjects
Male, Biopsy, Clinical Trial, Phase III, Administration, Oral, 030204 cardiovascular system & hematology, Chronic liver disease, Settore MED/04, Biomarkers/analysis, Gastroenterology, chemistry.chemical_compound, 0302 clinical medicine, Liver Function Tests, Non-alcoholic Fatty Liver Disease, Clinical endpoint, Medicine, 030212 general & internal medicine, 610 Medicine & health, Chenodeoxycholic Acid/administration & dosage, education.field_of_study, Liver Function Test, Research Support, Non-U.S. Gov't, Fatty liver, Obeticholic acid, NASH, OBETICHOLIC ACID, General Medicine, Middle Aged, Multicenter Study, Randomized Controlled Trial, Administration, Female, Biomarkers, Chenodeoxycholic Acid, Double-Blind Method, Humans, Human, Oral, medicine.medical_specialty, Population, Placebo, 03 medical and health sciences, Research Support, N.I.H., Extramural, Internal medicine, Journal Article, education, Intention-to-treat analysis, business.industry, Biomarker, Interim analysis, medicine.disease, Non-alcoholic Fatty Liver Disease/drug therapy, chemistry, Human medicine, business
Abstract

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Published
2019
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30. Corrigendum: High-throughput discovery of novel developmental phenotypes

Author

Mary E, Dickinson, Ann M, Flenniken, Xiao, Ji, Lydia, Teboul, Michael D, Wong, Jacqueline K, White, Terrence F, Meehan, Wolfgang J, Weninger, Henrik, Westerberg, Hibret, Adissu, Candice N, Baker, Lynette, Bower, James M, Brown, L Brianna, Caddle, Francesco, Chiani, Dave, Clary, James, Cleak, Mark J, Daly, James M, Denegre, Brendan, Doe, Mary E, Dolan, Sarah M, Edie Helmut Fuchs, Valerie, Gailus-Durner, Antonella, Galli, Alessia, Gambadoro, Juan, Gallegos, Shiying, Guo, Neil R, Horner, Chih-Wei, Hsu, Sara J, Johnson, Sowmya, Kalaga, Lance C, Keith, Louise, Lanoue, Thomas N, Lawson, Monkol, Lek, Manuel, Mark, Susan, Marschall, Jeremy, Mason, Melissa L, McElwee, Susan Newbigging Lauryl M J, Nutter, Kevin A, Peterson, Ramiro, Ramirez-Solis, Douglas J, Rowland, Edward, Ryder, Kaitlin E, Samocha, John R, Seavitt, Mohammed, Selloum, Zsombor, Szoke-Kovacs, Masaru, Tamura, Amanda G, Trainor, Ilinca, Tudose, Shigeharu, Wakana, Jonathan, Warren, Olivia, Wendling, David B, West, Leeyean, Wong, Atsushi, Yoshiki, Wolfgang, Wurst, Daniel G, MacArthur, Glauco P, Tocchini-Valentini, Xiang, Gao, Paul, Flicek, Allan, Bradley, William C, Skarnes, Monica J, Justice, Helen E, Parkinson, Mark, Moore, Sara, Wells, Robert E, Braun, Karen L, Svenson, Martin Hrabe, de Angelis, Yann, Herault, Tim, Mohun, Ann-Marie, Mallon, R Mark, Henkelman, Steve D M, Brown, David J, Adams, K C Kent, Lloyd, Colin, McKerlie, Arthur L, Beaudet, and Maja Bućan Stephen A, Murray

Subjects
IMPC, KOMP, EUCOMM, knockout, embryonic lethal, Article, mouse
Abstract

Approximately one third of all mammalian genes are essential for life. Phenotypes resulting from mouse knockouts of these genes have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5000 knockout mouse lines, we have identified 410 lethal genes during the production of the first 1751 unique gene knockouts. Using a standardised phenotyping platform that incorporates high-resolution 3D imaging, we identified novel phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes identified in our screen, thus providing a novel dataset that facilitates prioritization and validation of mutations identified in clinical sequencing efforts.

Published
2017

31. Capital structure and performance in Latin American companies.

Author

Mardones, Juan Gallegos and Cuneo, Gonzalo Ruiz

Subjects
CAPITAL structure, FINANCIAL leverage, FINANCIAL performance, PANEL analysis, MOMENTS method (Statistics)
Abstract

The purpose of this study is to explain the financial performance of companies in Latin America through the lens of capital structure and ownership structure. We perform a quantitative analysis of companies in Brazil, Chile, Mexico, and Peru using a panel data method. To avoid endogeneity problems, instrumental variables, generalised method of moments models, and panels with random effects are employed. The data cover the period 2000 to 2015. We find a positive relationship between financial performance, growth, and size of the company. However, there are mixed results for short- and long-term financial leverage, as well as for company liquidity. With respect to the ownership structure of Chilean companies, a positive effect is observed for the first major shareholder with financial performance. In general, our results are in line with those of previous studies. However, the existence of mixed results between companies and countries makes for an interesting and novel conclusion. [ABSTRACT FROM AUTHOR]

Published
2020
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32. Competition Pressures and Academic Performance in Chile

Author

Juan Gallegos Mardones, Ricardo D. Paredes, and Rómulo A. Chumacero

Subjects
Economics and Econometrics, Economic growth, Public economics, lcsh:HB71-74, 05 social sciences, 050301 education, lcsh:Economics as a science, L1, lcsh:Economic history and conditions, Voucher, Competition (economics), Economics, ddc:330, Educational impact, lcsh:HC10-1085, 0501 psychology and cognitive sciences, Vouchers, I21, 0503 education, competition, performance, 050104 developmental & child psychology
Abstract

The positive impact that competition has on performance in most industries has been questioned in the education sector. The difficulty to measure competition, the idea that parents don't rationally choose schools for their children, and that schools do not react to that choice is in the center of the debate. We critically analyze the prevailing methodology in the literature that relates competition and educational performance, and the data used to estimate that impact. We propose a methodology that considers relevant substitutes for each school using various attributes which parents consider when choosing schools, and we apply it to estimate the effect of competition on educational performance in Chile, were more than 90% of the students are covered by a voucher. The evidence supports the hypothesis that competition has a positive, statistically significant, and economically relevant educational impact on private and public schools., El efecto positivo que la competencia suele tener en el desempeño en la mayoría de las industrias ha sido cuestionado en el sector educativo. La dificultad en medir competencia y la idea que los padres pueden no ser racionales al momento de elegir escuelas para sus hijos, además que las escuelas no respondan a estas elecciones, son componentes esenciales del debate. Se realiza una evaluación crítica de la metodología prevalente para medir la relación entre competencia y desempeño. Se propone una metodología que considera a sustitutos relevantes de cada escuela, tomando en cuenta los atributos utilizados por los padres en la elección de escuela. La evidencia favorece la hipótesis que la competencia tiene un efecto positivo, significativo y económicamente relevante en el desempeño de las escuelas.

Published
2016

33. Genome architecture marked by retrotransposons modulates predisposition to DNA methylation in cancer

Author

Woonbok Chung, Peter D. Aplan, Lanlan Shen, Ryan J. Castoro, Juan Gallegos, Marcos R. Estecio, Jaroslav Jelinek, Céline Vallot, Helge Hartung, Bogdan Czerniak, Yutaka Kondo, Jean Pierre J. Issa, Shoudan Liang, Shinji Maegawa, and Yasuhiro Oki

Subjects
Epigenomics, Genetics, Retroelements, Genome, Human, Research, Retrotransposon, Promoter, DNA Methylation, Biology, Gene Expression Regulation, Neoplastic, Leukemia, Myeloid, Acute, Epigenetics of physical exercise, Urinary Bladder Neoplasms, Cell Line, Tumor, Neoplasms, DNA methylation, Tumor Cells, Cultured, Humans, Gene Silencing, Cancer epigenetics, Epigenetics, Gene, Genetics (clinical)
Abstract

Epigenetic silencing plays an important role in cancer development. An attractive hypothesis is that local DNA features may participate in differential predisposition to gene hypermethylation. We found that, compared with methylation-resistant genes, methylation-prone genes have a lower frequency of SINE and LINE retrotransposons near their transcription start site. In several large testing sets, this distribution was highly predictive of promoter methylation. Genome-wide analysis showed that 22% of human genes were predicted to be methylation-prone in cancer; these tended to be genes that are down-regulated in cancer and that function in developmental processes. Moreover, retrotransposon distribution marks a larger fraction of methylation-prone genes compared to Polycomb group protein (PcG) marking in embryonic stem cells; indeed, PcG marking and our predictive model based on retrotransposon frequency appear to be correlated but also complementary. In summary, our data indicate that retrotransposon elements, which are widespread in our genome, are strongly associated with gene promoter DNA methylation in cancer and may in fact play a role in influencing epigenetic regulation in normal and abnormal physiological states.

Published
2010
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34. Severe radiation therapy-related soft tissue toxicity in a patient with porphyria cutanea tarda: A literature review

Author

Juan Gallegos, Csilla K. Hallberg, Karl E. Anderson, A.J. Patel, G. Brandon Gunn, Giuseppe Sanguineti, Sandra S. Hatch, and Gagan Sood

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Pathology, business.industry, medicine.medical_treatment, nutritional and metabolic diseases, Cancer, Soft tissue, medicine.disease, Dermatology, Ionizing radiation, Radiation therapy, Porphyria, Otorhinolaryngology, Toxicity, medicine, Porphyria cutanea tarda, skin and connective tissue diseases, Phototoxicity, business
Abstract

Background Some porphyrias are associated with cutaneous phototoxicity due to photoactivation of porphyrins, but whether ionizing radiation can have an additive effect is not clear. We report a case of severe radiation therapy-related toxicity in a patient with porphyria cutanea tarda and review the literature.

Published
2009
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35. High-throughput discovery of novel developmental phenotypes

Author

Henrik Westerberg, Yann Herault, Colin McKerlie, Candice N. Baker, Dave Clary, William C. Skarnes, Hibret A. Adissu, Thomas N. Lawson, Monica J. Justice, R. Mark Henkelman, Monkol Lek, Helen Parkinson, Timothy J. Mohun, Sarah M. Edie, Paul Flicek, Francesco Chiani, Steve D.M. Brown, Martin Hrabé de Angelis, Mary E. Dolan, Chih-Wei Hsu, L. Brianna Caddle, Sara Wells, John R. Seavitt, Wolfgang Weninger, James M. Brown, Neil R. Horner, Zsombor Szoke-Kovacs, Louise Lanoue, Jacqueline K. White, Lauryl M. J. Nutter, Shiying Guo, Allan Bradley, Jonathan Warren, Ann M. Flenniken, Manuel Mark, Kevin A. Peterson, Kaitlin E. Samocha, Douglas J. Rowland, Daniel G. MacArthur, Ann-Marie Mallon, Maja Bucan, Amanda G. Trainor, Susan Newbigging, Ramiro Ramirez-Solis, Glauco P. Tocchini-Valentini, Shigeharu Wakana, Ilinca Tudose, Olivia Wendling, Edward Ryder, Lydia Teboul, Melissa L. McElwee, Kevin C K Lloyd, Terrence F. Meehan, David B. West, Stephen A. Murray, Valerie Gailus-Durner, Lance C. Keith, Mark J. Daly, Lynette Bower, Juan Gallegos, Masaru Tamura, Helmut Fuchs, Susan Marschall, Mark W. Moore, Karen L. Svenson, Sara Johnson, David J. Adams, Xiang Gao, Robert E. Braun, Mohammed Selloum, Xiao Ji, Michael D. Wong, Atsushi Yoshiki, Alessia Gambadoro, James M. Denegre, Leeyean Wong, Jeremy Mason, Antonella Galli, Sowmya Kalaga, Arthur L. Beaudet, James Cleak, Brendan Doe, and Mary E. Dickinson

Subjects
0301 basic medicine, Mouse, Mammalian embryology, Sequence Homology, Genome-wide association study, Penetrance, Development, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Mice, Imaging, Three-Dimensional, medicine, Lethal allele, Animals, Humans, Disease, Gene, Gene knockout, Conserved Sequence, Genetics, Mice, Knockout, Mutation, Multidisciplinary, Genes, Essential, Embryo, Mammalian, Phenotype, High-Throughput Screening Assays, Mice, Inbred C57BL, 030104 developmental biology, Mutagenesis, Genes, Lethal, Genome-Wide Association Study
Abstract

Approximately one-third of all mammalian genes are essential for life. Phenotypes resulting from knockouts of these genes in mice have provided tremendous insight into gene function and congenital disorders. As part of the International Mouse Phenotyping Consortium effort to generate and phenotypically characterize 5,000 knockout mouse lines, here we identify 410 lethal genes during the production of the first 1,751 unique gene knockouts. Using a standardized phenotyping platform that incorporates high-resolution 3D imaging, we identify phenotypes at multiple time points for previously uncharacterized genes and additional phenotypes for genes with previously reported mutant phenotypes. Unexpectedly, our analysis reveals that incomplete penetrance and variable expressivity are common even on a defined genetic background. In addition, we show that human disease genes are enriched for essential genes, thus providing a dataset that facilitates the prioritization and validation of mutations identified in clinical sequencing efforts.

Published
2015
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36. Principles and application of LIMS in mouse clinics

Author

Juan Gallegos, Kimio Kobayashi, Mark Griffiths, Tomohiro Suzuki, Navis Pretheeba Raj, Helmut Fuchs, Holger Maier, Sophie Leblanc, Martin Hrabě de Angelis, David S. Richardson, Rafael Alcantara, Laurent Vasseur, S. Holroyd, Arthur Evans, Shigeharu Wakana, Neha Agrawal, Christine Schütt, Valerie Gailus-Durner, Christian Kipp, Elida Schneltzer, Dave Clary, Ralph Steinkamp, David Melvin, Nobuhiko Tanaka, Christoph Lengger, Hiroshi Masuya, Alison Walling, Philipp Gormanns, David Gannon, and Anja Hurt

Subjects
Decision support system, Biomedical Research, animal structures, 040301 veterinary sciences, Data management, Automatic identification and data capture, Biology, Bioinformatics, Article, Domain (software engineering), 0403 veterinary science, 03 medical and health sciences, Mice, Genetics, Animals, 030304 developmental biology, 0303 health sciences, business.industry, 04 agricultural and veterinary sciences, Schedule (project management), Business process modeling, Management information systems, Major conclusion, Software engineering, business, Clinical Laboratory Information Systems, Software
Abstract

Large-scale systemic mouse phenotyping, as performed by mouse clinics for more than a decade, requires thousands of mice from a multitude of different mutant lines to be bred, individually tracked and subjected to phenotyping procedures according to a standardised schedule. All these efforts are typically organised in overlapping projects, running in parallel. In terms of logistics, data capture, data analysis, result visualisation and reporting, new challenges have emerged from such projects. These challenges could hardly be met with traditional methods such as pen & paper colony management, spreadsheet-based data management and manual data analysis. Hence, different Laboratory Information Management Systems (LIMS) have been developed in mouse clinics to facilitate or even enable mouse and data management in the described order of magnitude. This review shows that general principles of LIMS can be empirically deduced from LIMS used by different mouse clinics, although these have evolved differently. Supported by LIMS descriptions and lessons learned from seven mouse clinics, this review also shows that the unique LIMS environment in a particular facility strongly influences strategic LIMS decisions and LIMS development. As a major conclusion, this review states that there is no universal LIMS for the mouse research domain that fits all requirements. Still, empirically deduced general LIMS principles can serve as a master decision support template, which is provided as a hands-on tool for mouse research facilities looking for a LIMS. Electronic supplementary material The online version of this article (doi:10.1007/s00335-015-9586-7) contains supplementary material, which is available to authorized users.

Published
2015

37. Erratum: Corrigendum: High-throughput discovery of novel developmental phenotypes

Author

Steve D.M. Brown, L. Brianna Caddle, Valerie Gailus-Durner, Xiao Ji, Sowmya Kalaga, Mark J. Daly, Kevin C K Lloyd, Susan Newbigging Lauryl M. J. Nutter, Jeremy Mason, Martin Hrabé de Angelis, Ann-Marie Mallon, Helen Parkinson, Paul Flicek, Timothy J. Mohun, Lynette Bower, Shiying Guo, Edward Ryder, Ramiro Ramirez-Solis, Ilinca Tudose, William C. Skarnes, Hibret A. Adissu, Francesco Chiani, Lance C. Keith, Maja Bućan Stephen A. Murray, Susan Marschall, John R. Seavitt, Henrik Westerberg, Chih-Wei Hsu, Terrence F. Meehan, David B. West, Ann M. Flenniken, Mohammed Selloum, Karen L. Svenson, Daniel G. MacArthur, Allan Bradley, Zsombor Szoke-Kovacs, Alessia Gambadoro, Glauco P. Tocchini-Valentini, James M. Denegre, Leeyean Wong, Neil R. Horner, Amanda G. Trainor, Mary E. Dickinson, James M. Brown, Shigeharu Wakana, Kevin A. Peterson, Lydia Teboul, Michael D. Wong, Atsushi Yoshiki, Robert Braun, Mark W. Moore, Masaru Tamura, Jacqueline K. White, Mary E. Dolan, Manuel Mark, David J. Adams, Kaitlin E. Samocha, Thomas N. Lawson, Monica J. Justice, Candice N. Baker, Wolfgang Weninger, Melissa L. McElwee, Sara Wells, Olivia Wendling, Douglas J. Rowland, R. Mark Henkelman, Juan Gallegos, Sara Johnson, Colin McKerlie, Wolfgang Wurst, Dave Clary, Xiang Gao, Louise Lanoue, Monkol Lek, Sarah M. Edie Helmut Fuchs, Jonathan Warren, Yann Herault, Arthur L. Beaudet, James Cleak, Brendan Doe, and Antonella Galli

Subjects
0301 basic medicine, German, 03 medical and health sciences, 030104 developmental biology, Multidisciplinary, Developmental genetics, language, Library science, Sociology, language.human_language
Abstract

Nature 537, 508–514 (2016); doi:10.1038/nature19356 In this Article, the author Wolfgang Wurst was erroneously omitted from the author list. They are associated with the affiliations: HelmholtzZentrum Munich, Institute of Developmental Genetics, 85764 Munich-Neuherberg, Germany; Technical Universityof Munich, Chair of Developmental Genetics, 85764 Munich-Neuherberg, Germany; German Center for Neurodegenerative Diseases (DZNE) Site Munich, 81377 Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany.

Published
2017
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38. SINE Retrotransposons Cause Epigenetic Reprogramming of Adjacent Gene Promoters

Author

Yue Lu, Jean Pierre J. Issa, Mhair Dekmezian, Marcos R. Estecio, Shoudan Liang, and Juan Gallegos

Subjects
Cancer Research, Transcription, Genetic, Bisulfite sequencing, Retrotransposon, Biology, Article, Epigenesis, Genetic, Mice, Epigenetics of physical exercise, Alu Elements, Antigens, CD, Tumor Suppressor Protein p14ARF, Animals, Humans, Epigenetics, Gene Silencing, Cyclin-Dependent Kinase Inhibitor p19, Promoter Regions, Genetic, Molecular Biology, RNA-Directed DNA Methylation, Adaptor Proteins, Signal Transducing, Short Interspersed Nucleotide Elements, Genetics, Nuclear Proteins, Methylation, DNA Methylation, Cadherins, Cellular Reprogramming, Chromatin, Long Interspersed Nucleotide Elements, Oncology, Genes, DNA methylation, NIH 3T3 Cells, Human genome, Insulator Elements, Transcription Initiation Site, MutL Protein Homolog 1, Protein Binding
Abstract

Almost half of the human genome and as much as 40% of the mouse genome is composed of repetitive DNA sequences. The majority of these repeats are retrotransposons of the SINE and LINE families, and such repeats are generally repressed by epigenetic mechanisms. It has been proposed that these elements can act as methylation centers from which DNA methylation spreads into gene promoters in cancer. Contradictory to a methylation center function, we have found that retrotransposons are enriched near promoter CpG islands that stay methylation-free in cancer. Clearly, it is important to determine which influence, if any, these repetitive elements have on nearby gene promoters. Using an in vitro system, we confirm here that SINE B1 elements can influence the activity of downstream gene promoters, with acquisition of DNA methylation and loss of activating histone marks, thus resulting in a repressed state. SINE sequences themselves did not immediately acquire DNA methylation but were marked by H3K9me2 and H3K27me3. Moreover, our bisulfite sequencing data did not support that gain of DNA methylation in gene promoters occurred by methylation spreading from SINE B1 repeats. Genome-wide analysis of SINE repeats distribution showed that their enrichment is directly correlated with the presence of USF1, USF2, and CTCF binding, proteins with insulator function. In summary, our work supports the concept that SINE repeats interfere negatively with gene expression and that their presence near gene promoters is counter-selected, except when the promoter is protected by an insulator element. Mol Cancer Res; 10(10); 1332–42. ©2012 AACR.

Published
2012

39. Nonsteroidal Anti-Inflammatory Drugs and Gastrocolic Fistula

Author

Raul Martínez, Ramón Carmona-Sánchez, Jorge Suazo-Barahona, Guillermo Robles-Díaz, and Juan Gallegos

Subjects
Gastric Fistula, Drug, medicine.medical_specialty, medicine.drug_class, Fistula, media_common.quotation_subject, Gastrocolic fistula, Gastroenterology, Anti-inflammatory, Arthritis, Rheumatoid, Colonic Diseases, chemistry.chemical_compound, Internal medicine, Intestinal Fistula, Humans, Medicine, Stomach Ulcer, Glucocorticoids, Colonic disease, media_common, Nonsteroidal, Aspirin, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Middle Aged, medicine.disease, Surgery, Barium meal, chemistry, Prednisone, Female, business, Gastrocolic reflex
Published
1998
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40. Competition Pressures and Academic Performance in Chile.

Author

CHUMACERO, RÓMULO A., MARDONES, JUAN GALLEGOS, and PAREDES, RICARDO D.

Subjects
*ACADEMIC achievement, *EDUCATION, *SCHOOL choice, *PARENT-school relationships, *ECONOMIC competition, *PRIVATE schools, *PUBLIC schools
Abstract

The positive impact that competition has on performance in most industries has been questioned in the education sector. The difficulty to measure competition, the idea that parents don't rationally choose schools for their children, and that schools do not react to that choice is in the center of the debate. We critically analyze the prevailing methodology in the literature that relates competition and educational performance, and the data used to estimate that impact. We propose a methodology that considers relevant substitutes for each school using various attributes which parents consider when choosing schools, and we apply it to estimate the effect o f competition on educational performance in Chile, were more than 90% of the students are covered by a voucher. The evidence supports the hypothesis that competition has a positive, statistically significant, and economically relevant educational impact on private and public schools. [ABSTRACT FROM AUTHOR]

Published
2016

41. Adequacy and Findings of Digital Rectal Examination for Prostate Cancer Screening at the Time of Colonoscopy

Author

Kathryn R. Byrne, Ashok K. Tuteja, Kathryn A. Peterson, Juan Gallegos, Jewel Samadder, John F. Valentine, Randall W. Burt, John H. Bowers, John C. Fang, Kathleen K. Boynton, Douglas G. Adler, and Brian So

Subjects
medicine.medical_specialty, Prostate cancer screening, Hepatology, medicine.diagnostic_test, business.industry, Gastroenterology, Medicine, Colonoscopy, Rectal examination, Radiology, business
Published
2013
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42. dsPIG: a tool to predict imprinted genes from the deep sequencing of whole transcriptomes

Author

Shoudan Liang, Yue Lu, Hua Li, Xiao Su, Juan Gallegos, Yuan Ji, and Jeffrey J. Molldrem

Subjects
Sequence analysis, Gene Expression, Biology, Allelic Imbalance, lcsh:Computer applications to medicine. Medical informatics, Biochemistry, Genome, Polymorphism, Single Nucleotide, Genomic Imprinting, Gene Frequency, Structural Biology, Humans, RNA, Messenger, Molecular Biology, Allele frequency, Gene, lcsh:QH301-705.5, Alleles, Analysis of allelic expression, Genetics, mRNA-Seq, Base Sequence, Models, Genetic, Genome, Human, Applied Mathematics, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Bayes Theorem, Sequence Analysis, DNA, Computer Science Applications, Minor allele frequency, Gene expression profiling, Prediction of imprinted genes, lcsh:Biology (General), Bayesian model, Transcriptome deep sequencing, lcsh:R858-859.7, DNA microarray, Genomic imprinting, Transcriptome, Research Article
Abstract

Background Dysregulation of imprinted genes, which are expressed in a parent-of-origin-specific manner, plays an important role in various human diseases, such as cancer and behavioral disorder. To date, however, fewer than 100 imprinted genes have been identified in the human genome. The recent availability of high-throughput technology makes it possible to have large-scale prediction of imprinted genes. Here we propose a Bayesian model (dsPIG) to predict imprinted genes on the basis of allelic expression observed in mRNA-Seq data of independent human tissues. Results Our model (dsPIG) was capable of identifying imprinted genes with high sensitivity and specificity and a low false discovery rate when the number of sequenced tissue samples was fairly large, according to simulations. By applying dsPIG to the mRNA-Seq data, we predicted 94 imprinted genes in 20 cerebellum samples and 57 imprinted genes in 9 diverse tissue samples with expected low false discovery rates. We also assessed dsPIG using previously validated imprinted and non-imprinted genes. With simulations, we further analyzed how imbalanced allelic expression of non-imprinted genes or different minor allele frequencies affected the predictions of dsPIG. Interestingly, we found that, among biallelically expressed genes, at least 18 genes expressed significantly more transcripts from one allele than the other among different individuals and tissues. Conclusion With the prevalence of the mRNA-Seq technology, dsPIG has become a useful tool for analysis of allelic expression and large-scale prediction of imprinted genes. For ease of use, we have set up a web service and also provided an R package for dsPIG at http://www.shoudanliang.com/dsPIG/.

Published
2012

43. Abstract 2791: SINE retrotransposons cause epigenetic reprogramming of adjacent gene promoters

Author

Shoudan Liang, Juan Gallegos, Mhair Dekmezian, Marcos R. Estecio, and Jean Pierre J. Issa

Subjects
Genetics, Cancer Research, Alu element, Retrotransposon, Promoter, Biology, behavioral disciplines and activities, Genome, Oncology, CpG site, DNA methylation, Human genome, Gene, psychological phenomena and processes
Abstract

Retrotransposons of SINE and LINE classes have been extremely successful in colonizing mammalian genomes. Almost half of the human genome and as much as 40% of the mouse genome is composed of repetitive DNA sequences. The comparison of human and mouse genomes revealed a spatial concordance in positioning of SINE but not LINE repeats, indicating evolutionary pressure to maintain and/or exclude these repeats from orthologous regions. We hypothesized that this phenomenon is due to a negative influence of SINE repeats on gene expression and counter selection over evolution, resulting in exclusion of these repeats from vulnerable genomic environments. To test the capacity of SINE B1 elements in promoting gene silencing, we generated a system where the luciferase gene is under the control of three different mouse gene promoters (cdkn2a, p14arf and mlh1), and we inserted two and four copies of SINE B1 elements upstream to these promoters. Using this in vitro system, we found that SINE B1 elements can influence the activity of downstream gene promoters, with acquisition of DNA methylation and loss of activating histone marks, thus resulting in a repressed state. Interestingly, SINE sequences themselves do not immediately acquired DNA methylation, but became marked by H3K9me2 and H3K27me3. Moreover, gain of DNA methylation depended on cryptic genomic methylation centers rather than spreading from SINE B1 repeats. Since mouse SINE B1 elements caused transcriptional repression, we sought to investigate whether human SINE Alu repeats could have the same effect. The human E-cadherin gene has three SINE Alus adjacent to the 3’ region of its CpG island, and in reporter assays the removal of these repeats resulted in higher, stable promoter activity. Genome-wide analysis of SINE repeats distribution in the human and mouse genomes showed that they are excluded from proximal promoters and their enrichment is directly correlated with the presence of USF1, USF2 and CTCF binding, proteins with insulator function. In conclusion, our work supports the concept that SINE repeats interfere negatively with gene expression and that their presence near gene promoters is dependent on, and co-evolved with the presence of insulator elements. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2791. doi:10.1158/1538-7445.AM2011-2791

Published
2011
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44. Persistence of Hepatitis C Virus in Peripheral Blood Mononuclear Cells of Sustained Viral Responders to Pegylated Interferon and Ribavirin Therapy.

Author

Juan Gallegos-Orozco, Jorge Rakela, Marianne Rosati, Hugo Vargas, and Vijayan Balan

Subjects
*HEPATITIS C virus, *BLOOD cells, *CELL adhesion, *RIBAVIRIN, *IMMUNOSUPPRESSION, *MEDICAL care
Abstract

Abstract  The aim of this paper was to assess the persistence of hepatitis C virus (HCV) among patients successfully treated with peginterferon and ribavirin. The persistence of viral RNA was evaluated in the serum and peripheral blood mononuclear cells (PBMCs) of 25 chronic hepatitis C patients with sustained viral response to peginterferon and ribavirin treatment up to 56 months after the completion of therapy. Viral RNA was detected in the peripheral blood mononuclear cell cultures of five patients (20%), but none had detectable serum HCV RNA. At present, the clinical relevance of this finding is unclear. It is possible that viral persistence and, specifically, the presence of HCV RNA in PBMCs may lead to HCV reactivation under special circumstances, such as immunosuppression. [ABSTRACT FROM AUTHOR]

Published
2008
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45. Isoxsuprine in primary dysmenorrhoea. Its effectiveness in premenstrual tension

Author

Juan Gallegos-Torres and Francisco Flores-Mercado

Subjects
Adult, medicine.medical_specialty, Adolescent, Biochemistry, Premenstrual Tension, Premenstrual Syndrome, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Double-Blind Method, Dysmenorrhea, Internal medicine, Caffeine, Isoxsuprine, Medicine, Humans, 030212 general & internal medicine, Acetaminophen, 030219 obstetrics & reproductive medicine, business.industry, Biochemistry (medical), Primary dysmenorrhoea, Cell Biology, General Medicine, Drug Combinations, chemistry, Total dose, Female, business, medicine.drug
Abstract

The drug combination including isoxsuprine 10 mg, acetaminophen 250 mg and caffeine 30 mg was administered to 80 patients divided into two groups, 40 with premenstrual tension and 40 with clinically diagnosed primary dysmenorrhoea. The study was carried out by the double-blind method and the patients were distributed at random. The results obtained show an excellent or very good response in 95% of cases of premenstrual tension and in 92·5% of cases of dysmenorrhoea. When the overall effectiveness of the compound in both conditions is considered, we find it to be 93·75%. A general discussion of the findings is presented in relation to age, civil status, time of appearance of dysmenorrhoea, nature of pain, accompanying symptoms, previous treatment, other non-drug therapies, results obtained, time within which symptoms were alleviated, total dose of the drug and side-effects. It is concluded that the orally-administered therapeutic combination is effective in both dysmenorrhoea and premenstrual tension.

Published
1975

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