Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells

The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells-newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies

Model of fibrolamellar hepatocellular carcinomas reveals striking enrichment in cancer stem cells

The aetiology of human fibrolamellar hepatocellular carcinomas (hFL-HCCs), cancers occurring increasingly in children to young adults, is poorly understood. We present a transplantable tumour line, maintained in immune-compromised mice, and validate it as a bona fide model of hFL-HCCs by multiple methods. RNA-seq analysis confirms the presence of a fusion transcript (DNAJB1-PRKACA) characteristic of hFL-HCC tumours. The hFL-HCC tumour line is highly enriched for cancer stem cells as indicated by limited dilution tumourigenicity assays, spheroid formation and flow cytometry. Immunohistochemistry on the hFL-HCC model, with parallel studies on 27 primary hFL-HCC tumours, provides robust evidence for expression of endodermal stem cell traits. Transcriptomic analyses of the tumour line and of multiple, normal hepatic lineage stages reveal a gene signature for hFL-HCCs closely resembling that of biliary tree stem cells—newly discovered precursors for liver and pancreas. This model offers unprecedented opportunities to investigate mechanisms underlying hFL-HCCs pathogenesis and potential therapies

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Mechanism of anion selectivity and stoichiometry of the Na+/I- symporter (NIS)

I(-) uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na(+)/I(-) symporter (NIS) with an electrogenic 2Na(+):1I(-) stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I(-) transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive. Substitutions at position 93 show that the longer the side chain of the neutral residue at this position, the higher the K(m) for the anion substrates. Unlike WT NIS, which mediates symport of Na(+) and the environmental pollutant perchlorate electroneutrally, G93T/N/Q/E/D NIS, strikingly, do it electrogenically with a 21 stoichiometry. Furthermore, G93E/Q NIS discriminate between anion substrates, a discovery with potential clinical relevance. A 3D homology model of NIS based on the structure of the bacterial Na(+)/galactose transporter identifies G93 as a critical player in the mechanism of the transporter: the changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivo

Actores sociales frente al desafío de la sustentabilidad II : Grupo de Investigación en Tecnologías Ambientales

PROYECTOS CONSOLIDAD 2018-2021. Editores de contenido: Santiago María Reyna, Marta Susana Juliá. Edición de portada y formato: María Florencia Bianco.Este segundo libro del Grupo de Investigación en Tecnologías Ambientales, dirigido por el Dr. Ing. Santiago Reyna, docente e investigador de nuestra Facultad de Ciencias Exactas, Físicas y Naturales de la Universidad Nacional de Córdoba y del Consejo de Investigaciones Científicas y Tecnológicas, avanza decididamente sobre las normativas relacionados con las problemáticas del ambiente. Lo hace, reconociendo al espacio gubernamental como a un actor destacado con obligada capacidad de generar las condiciones necesarias para el desarrollo de las soluciones para que el futuro de un planeta sano, como legado a las generaciones venideras, no sea una utopía o meros discursos de los gobiernos para seducir a potenciales votantes. La criticidad de la tragedia ambiental impone tomas de decisión y el desarrollo de políticas ambientales efectivas y de implementación a corto plazo. Corresponde a las universidades, principalmente a las que se destacan por su volumen y por ser de gestión estatal, estudiar, investigar, desarrollar y generar vías de solución que, dentro del marco legal y de fomento necesarios, se constituyan en acciones y herramientas concretas para la morigeración del impacto de las actividades humanas en el medio en el que ellas se desenvuelven, diseñadas y construidas sobre los conceptos de sostenibilidad.Fil: Reyna, Santiago María. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Juliá, Marta Susana. Universidad Nacional de Córdoba. Facultad de Derecho y Ciencias Sociales; Argentina.Fil: Juliá, Marta Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones Jurídicas y Sociales; Argentina.Fil: Buraschi, Mónica. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Reyna, Teresa M. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Recabarren, Pablo. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: López, Fabián. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: López, Fabián. Gobierno de la provincia de Córdoba. Ministerio de Servicios Públicos; Argentina.Fil: Devalis, Sergio. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Devalis, Sergio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; Argentina.Fil: Delgadino, Francisco A. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Peretti, María Florencia. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Amato, Celina N. Universidad Nacional de Córdoba. Facultad de Ciencias Económicas; Argentina.Fil: Amato, Celina N. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Estudios sobre Cultura y Sociedad; Argentina.Fil: Fulginiti, Fabián. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Bianco, María Florencia. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Lábaque, María. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Bianchi, Rocío. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Neyra, Sofía. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Reyna, Manuel M. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Carro Pérez, Magalí. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Medina, Rocío. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Marini, Lourdes I. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Regali, Agustina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Strauss Bertolini, Federico José. Universidad Nacional de Córdoba. Facultad de Derecho; Argentina.Fil: Gauna, Marco. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Degano, Salvador. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina.Fil: Bertolino, Cecilia. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales; Argentina

Mechanism of anion selectivity and stoichiometry of the Na+/I- symporter (NIS)

I- uptake in the thyroid, the first step in thyroid hormone biosynthesis, is mediated by the Na+/I- symporter (NIS) with an electrogenic 2Na+ : 1I- stoichiometry. We have obtained mechanistic information on NIS by characterizing the congenital I- transport defect-causing NIS mutant G93R. This mutant is targeted to the plasma membrane but is inactive. Substitutions at position 93 show that the longer the side chain of the neutral residue at this position, the higher the Km for the anion substrates. Unlike WT NIS, which mediates symport of Na+ and the environmental pollutant perchlorate electroneutrally, G93T/N/Q/E/D NIS, strikingly, do it electrogenically with a 2∶1 stoichiometry. Furthermore, G93E/Q NIS discriminate between anion substrates, a discovery with potential clinical relevance. A 3D homology model of NIS based on the structure of the bacterial Na+/galactose transporter identifies G93 as a critical player in the mechanism of the transporter: the changes from an outwardly to an inwardly open conformation during the transport cycle use G93 as a pivot