Gasdermin B over-expression modulates HER2-targeted therapy resistance by inducing protective autophagy through Rab7 activation

Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors. Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples. GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers. Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome. The online version contains supplementary material available at 10.1186/s13046-022-02497-w

La evaluación colegiada de las competencias básicas en la Comunidad Autónoma de Canarias : hacia un modelo de escuela inclusiva y sostenible

Precede al título: Educación Primaria y Educación Secundaria ObligatoriaLa Ley Orgánica de Educación (LOE) introduce el concepto de «competencias básicas» como eje articulador del currículo, conectando de pleno con las reflexiones y las estrategias que se están desarrollando en otros sistemas educativos internacionales a la luz del informe Delors (1996), el documento DeSeCo (Definición y Selección de Competencias fundamentales) elaborado por la OCDE, de las evaluaciones PISA (Programa para la Evaluación Internacional del Alumnado), etc. Esta propuesta centra el foco en la dimensión formativa de la «evaluación», aspecto inacabado con la LOGSE (Ley Orgánica General del Sistema Educativo), a pesar de los esfuerzos realizados en esa dirección. Trabajar en las aulas para la consecución de las «competencias básicas» lleva ineludiblemente al problema de cómo evaluarlas de forma colegiada —cuando la propia ordenación del sistema educativo fragmenta cada una de las enseñanzas en diferentes áreas o materias— y de cómo emplear la información que proporciona esta labor para hacer valer el sentido formativo y regulador que debe tener la evaluación de las competencias básicas.Consejería de Educación y Universidades. Dirección General de Ordenación, Innovación y Promoción Educativa; Avda. Buenos Aires, 5; 38071 Tenerife; Tel. +34922592592; Fax +34922592570; [email protected]

Optimization of adsorptive removal of α-toluic acid by CaO2 nanoparticles using response surface methodology

The present work addresses the optimization of process parameters for adsorptive removal of α-toluic acid by calcium peroxide (CaO2) nanoparticles using response surface methodology (RSM). CaO2 nanoparticles were synthesized by chemical precipitation method and confirmed by Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis which shows the CaO2 nanoparticles size range of 5–15 nm. A series of batch adsorption experiments were performed using CaO2 nanoparticles to remove α-toluic acid from the aqueous solution. Further, an experimental based central composite design (CCD) was developed to study the interactive effect of CaO2 adsorbent dosage, initial concentration of α-toluic acid, and contact time on α-toluic acid removal efficiency (response) and optimization of the process. Analysis of variance (ANOVA) was performed to determine the significance of the individual and the interactive effects of variables on the response. The model predicted response showed a good agreement with the experimental response, and the coefficient of determination, (R2) was 0.92. Among the variables, the interactive effect of adsorbent dosage and the initial α-toluic acid concentration was found to have more influence on the response than the contact time. Numerical optimization of process by RSM showed the optimal adsorbent dosage, initial concentration of α-toluic acid, and contact time as 0.03 g, 7.06 g/L, and 34 min respectively. The predicted removal efficiency was 99.50%. The experiments performed under these conditions showed α-toluic acid removal efficiency up to 98.05%, which confirmed the adequacy of the model prediction