The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression

Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with ?-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion

Anales de Edafología y Agrobiología Tomo 41 Número 1-2

Suelos. Mineralización del carbono y del nitrógeno en suelos forestales de Galicia, por R. M. de Anta y F. Díaz-Fierros.-- Características bioclimáticas de interés edafológico de las Sierras de Orce y María, por L J. Alias y J. Martínez Sánchez.-- Factores formadores de los suelos de la cuenca del río Dilar (Sierra Nevada), por R. Delgado Calvo-Flores, E. Barahona y J. Linares.-- Distribución de los suelos de la cuenca alta del río Dilar (Sierra Nevada), por R. Delgado Calvo-Flores, E. Barahona y J. Linares.-- Los mollisoles de la cuenca alta del río Dilar (Sierra Nevada), por R. Delgado Calvo-Flores, E. Barahona, F. Huertas y J. Linares.-- Los inceptisoles de la cuenca alta del río Dilar (Sierra Nevada), por R. Delgado CalvoFlores, E. Barahona, F. Huertas y J. Linares.-- Los entisoles de la cuenca alta del río Dilar (Sierra Nevada), por R. Delgado Calvo-Flores, E. Barahona, F. Huertas y J. Linares.-- Aspectos edafogeoquímicos de la salinidad en la submeseta Sur (Toledo). l. Estudio hidrogeoquímico, por J. Gumuzzio Fernández, J. Astudillo Pastor y J. Batlle Sales.-- Modelo experimental de alteración de oligisto. Aplicación al estudio óptico de minerales opacos, por Hoyos de Castro, A., Remando Costa, J., Remando Massanet, l. y Millán Pérez, R.-- Modelo experimental de alteración de feldespatos. Aplicación de tinción. l. Ortosa. por Hoyos de Castro, A., Hernando Massanet, l. Remando Costa, J. y Yunta, M. V..-- Modelo experimental de alteración de feldespatos. Aplicación al método de tinción. II Labradorita, por Hoyos de Castro, A. Hernando Massanet, I., Hernando Costa, J. y Pisonero Ruiz, L.-- Taxonomía númerica. Su aplicación a la clasificación de los suelos rojos españoles, por L. Alcalá del Olmo, B. y F. Monturiol Rodríguez.-- Propiedades químicas de suelos y niveles de nutrientes inorgánicos en aciculas de A. Pinsapo de Grazalema (Cádiz España), por Paneque, G. y Corral, L.-- Morfología y propiedades químicas de suelos forestales de Granlema (Cádi7., España). l. Suelos bajo Quercus rotundifoliae y Quercus fagineae, por, C. Benírez, J. Mérida, L. Corral y G. Paneque.-- Morfología y propiedades químicas de suelos forestales de Grazalema (Cádiz, España). II. Suelos bajos Quercus suber y A bies pinsapo, por C. Benírez, J. Mérida, L. Corral y G. Paneque.-- Morfología y propiedades químicas de suelos forestales de Grazalema (Cádiz,España). III. Tipovergencia del perfil húmico, por J. Mérida, L. Corral y G. Paneque.-- Fertilidad de Suelos. Q/1 ratio saline soils belongig to Ebro Valley (Spain), por Benigna Elizalde and M. Fernández.-- Fertilidad química de los suelos del valle del río Guadalhorce (Málaga), por S. Bruque, M. Martínez Lara y L. Moreno Real.-- Absorción de K por ryegrass y Trifolium en suelos deficientes, por J. A. Diez.— Nutrición y Fisiología Vegetal. Correlaciones entre bioelementos: Estudio realizado en Trifo/ium subrerraneo L. y A vena saliva L., por Gómez Gutiérrez, J. M. y Hoyos Alonso, C. de.-- Influencia del ácido húmico sobre la nutrición mineral y el desarrollo radicular de plantas de maíz cultivadas en soluciones nutritivas normales y carentes de Fe y Mn, por Fortún, C. y López-Fando, C.-- Notas.-- BibliografíaPeer reviewe

Effectiveness of the combination elvitegravir/cobicistat/tenofovir/emtricitabine (EVG/COB/TFV/FTC) plus darunavir among treatment-experienced patients in clinical practice : A multicentre cohort study

Background: The aim of this study was to investigate the effectiveness and tolerability of the combination elvitegravir/cobicistat/tenofovir/emtricitabine plus darunavir (EVG/COB/TFV/FTC + DRV) in treatment-experienced patients from the cohort of the Spanish HIV/AIDS Research Network (CoRIS). Methods: Treatment-experienced patients starting treatment with EVG/COB/TFV/FTC + DRV during the years 2014-2018 and with more than 24 weeks of follow-up were included. TFV could be administered either as tenofovir disoproxil fumarate or tenofovir alafenamide. We evaluated virological response, defined as viral load (VL) < 50 copies/ml and < 200 copies/ml at 24 and 48 weeks after starting this regimen, stratified by baseline VL (< 50 or ≥ 50 copies/ml at the start of the regimen). Results: We included 39 patients (12.8% women). At baseline, 10 (25.6%) patients had VL < 50 copies/ml and 29 (74.4%) had ≥ 50 copies/ml. Among patients with baseline VL < 50 copies/ml, 85.7% and 80.0% had VL < 50 copies/ml at 24 and 48 weeks, respectively, and 100% had VL < 200 copies/ml at 24 and 48 weeks. Among patients with baseline VL ≥ 50 copies/ml, 42.3% and 40.9% had VL < 50 copies/ml and 69.2% and 68.2% had VL < 200 copies/ml at 24 and 48 weeks. During the first 48 weeks, no patients changed their treatment due to toxicity, and 4 patients (all with baseline VL ≥ 50 copies/ml) changed due to virological failure. Conclusions: EVG/COB/TFV/FTC + DRV was well tolerated and effective in treatment-experienced patients with undetectable viral load as a simplification strategy, allowing once-daily, two-pill regimen with three antiretroviral drug classes. Effectiveness was low in patients with detectable viral loads

γ-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia

Gamma-secretase inhibitors (GSIs) block the activation of oncogenic NOTCH1 in T-cell acute lymphoblastic leukemia (T-ALL). However, limited antileukemic cytotoxicity and severe gastrointestinal toxicity have restricted the clinical application of these targeted drugs. Here we show that combination therapy with GSIs plus glucocorticoids can improve the antileukemic effects of GSIs and reduce their gut toxicity in vivo. Inhibition of NOTCH1 signaling in glucocorticoid-resistant T-ALL restored glucocorticoid receptor auto-up-regulation and induced apoptotic cell death through induction of BIM expression. GSI treatment resulted in cell cycle arrest and accumulation of goblet cells in the gut mediated by upregulation of Klf4, a negative regulator of cell cycle required for goblet cell differentiation. In contrast, glucocorticoid treatment induced transcriptional upregulation of Ccnd2 and protected mice from developing intestinal Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research