Characterization of wnt signaling in tamoxifen resistant breast cancer stem/progenitor cells

175 p.El tamoxifen, un antagonista de ER, es el tratamiento más común empleado para tratar a pacientes que expresan ER. Las células resistentes a tamoxifen están enriquecidas en células madre/progenitoras. La expresión de WNT1 es heterogénea entre los distintos subtipos de cáncer de mama. Además, Wnt-1 activa una señalización independiente de la ¿-catenina y mediada por ATF2 y TCF1 y es, además, potenciada por la expresión de USP6, que regula la degradación y el reciclaje de los receptores FZD. Se ha observado que Wnt-1 incrementa la población de células CD44+CD24-/low y la habilidad de formar esferas en células resistentes a tamoxifen., consistente con el peor pronóstico que presentan los pacientes de cáncer de mama con tumores que expresan ER y han recibido tratamiento con tamoxifen. Se identificó FZD5 como un receptor de Wnt que se correlaciona con un peor pronóstico de pacientes de cáncer de mama tratados con tamoxifen y que capaz de interaccionar con Wnt-1. El bloqueo de la señalización de Wnt-1 evitando su unión a FZD5 podría ser una buena estrategia para prevenir la recurrencia en un grupo determinado de pacientes de cáncer de mama.CICbioGUNE Eusko Jaurlaritz

Characterization of wnt signaling in tamoxifen resistant breast cancer stem/progenitor cells

175 p.El tamoxifen, un antagonista de ER, es el tratamiento más común empleado para tratar a pacientes que expresan ER. Las células resistentes a tamoxifen están enriquecidas en células madre/progenitoras. La expresión de WNT1 es heterogénea entre los distintos subtipos de cáncer de mama. Además, Wnt-1 activa una señalización independiente de la ¿-catenina y mediada por ATF2 y TCF1 y es, además, potenciada por la expresión de USP6, que regula la degradación y el reciclaje de los receptores FZD. Se ha observado que Wnt-1 incrementa la población de células CD44+CD24-/low y la habilidad de formar esferas en células resistentes a tamoxifen., consistente con el peor pronóstico que presentan los pacientes de cáncer de mama con tumores que expresan ER y han recibido tratamiento con tamoxifen. Se identificó FZD5 como un receptor de Wnt que se correlaciona con un peor pronóstico de pacientes de cáncer de mama tratados con tamoxifen y que capaz de interaccionar con Wnt-1. El bloqueo de la señalización de Wnt-1 evitando su unión a FZD5 podría ser una buena estrategia para prevenir la recurrencia en un grupo determinado de pacientes de cáncer de mama.CICbioGUNE Eusko Jaurlaritz

Anti-MOG encephalitis mimicking small vessel CNS vasculitis

Objective: To report 2 patients with anti-myelin oligodendrocyte glycoprotein (MOG)-associated encephalitis who were initially misdiagnosed with small vessel primary CNS vasculitis. Methods: Review of symptoms, MRI and neuropathologic features, and response to treatment. MOG antibodies were determined in serum and CSF using a cell-based assay. Results: Symptoms included fever, headache, and progressive mental status changes and focal neurologic deficits. CSF studies revealed lymphocytic pleocytosis, and both patients had abnormal brain MRIs. Brain biopsy samples showed prominent lymphocytic infiltration of the wall of small vessels; these findings initially suggested small vessel CNS vasculitis, and both patients were treated accordingly. Although 1 patient had a relapsing-remitting course not responsive to cyclophosphamide, the other one (also treated with cyclophosphamide) did not relapse. Retrospective assessment of serum and CSF demonstrated MOG antibodies in both cases, and review of biopsy specimens showed absence of fibrinoid necrosis (a pathologic requirement for small vessel CNS vasculitis). Conclusions: Anti-MOG-associated encephalitis can be mistaken for small vessel CNS vasculitis. This is important because the diagnosis of anti-MOG-associated encephalitis does not require brain biopsy and can be established with a serologic test

Longitudinal evaluation of neuroinflammation and oxidative stress in a mouse model of Alzheimer disease using positron emission tomography

[EN] Background: Validation of new biomarkers of Alzheimer disease (AD) is crucial for the successful development and implementation of treatment strategies. Additional to traditional AT(N) biomarkers, neuroinflammation biomarkers, such as translocator protein (TSPO) and cystine/glutamine antiporter system (x(c)(-)), could be considered when assessing AD progression. Herein, we report the longitudinal investigation of [F-18]DPA-714 and [F-18]FSPG for their ability to detect TSPO and x(c)(-) biomarkers, respectively, in the 5xFAD mouse model for AD. Methods: Expression of TSPO and x(c)(-) system was assessed longitudinally (2-12 months of age) on 5xFAD mice and their respective controls by positron emission tomography (PET) imaging using radioligands [F-18]DPA-714 and [F-18]FSPG. In parallel, in the same mice, amyloid-beta plaque deposition was assessed with the amyloid PET radiotracer [F-18]florbetaben. In vivo findings were correlated to ex vivo immunofluorescence staining of TSPO and x(c)(-) in microglia/macrophages and astrocytes on brain slices. Physiological changes of the brain tissue were assessed by magnetic resonance imaging (MRI) in 12-month-old mice. Results: PET studies showed a significant increase in the uptake of [F-18]DPA-714 and [F-18]FSPG in the cortex, hippocampus, and thalamus in 5xFAD but not in WT mice over time. The results correlate with A beta plaque deposition. Ex vivo staining confirmed higher TSPO overexpression in both, microglia/macrophages and astrocytes, and overexpression of x(c)(-) in non-glial cells of 5xFAD mice. Additionally, the results show that A beta plaques were surrounded by microglia/macrophages overexpressing TSPO. MRI studies showed significant tissue shrinkage and microstructural alterations in 5xFAD mice compared to controls. Conclusions: TSPO and x(c)(-) overexpression can be assessed by [F-18]DPA-714 and [F-18]FSPG, respectively, and correlate with the level of A beta plaque deposition obtained with a PET amyloid tracer. These results position the two tracers as promising imaging tools for the evaluation of disease progression.J.L. and P.R. thank the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033 (PID2020-117656RB-100 and PID2020-118546RBI00, respectively) and the Interreg Atlantic Area Programme (EAPA_791/2018). Abraham Martin acknowledges funding from the Spanish Ministry of Education and Science (RYC-2017-22412, PID2019-107989RB-I00), the Basque Government (BIO18/IC/006), and Fundacio La Marato de TV3 (17/C/2017). Estibaliz Capetillo-Zarate acknowledges funding from the Basque Government (IT120319; ELKARTEK KK-2020/00034) and CIBERNED (CB06/0005/0076). The work was performed under the Maria de Maeztu Units of Excellence Programme -Grant MDM-2017-0720 funded by MCIN/AEI/10.13039/50110001103

The Castilian Spanish version of the Juvenile Arthritis Multidimensional Assessment Report (JAMAR)

The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) is a new parent/patient reported outcome measure that enables a thorough assessment of the disease status in children with juvenile idiopathic arthritis (JIA). We report the results of the cross-cultural adaptation and validation of the parent and patient versions of the JAMAR in the Castilian Spanish language. The reading comprehension of the questionnaire was tested in 10 JIA parents and patients. Each participating centre was asked to collect demographic, clinical data and the JAMAR in 100 consecutive JIA patients or all consecutive patients seen in a 6-month period and to administer the JAMAR to 100 healthy children and their parents. The statistical validation phase explored descriptive statistics and the psychometric issues of the JAMAR: the three Likert assumptions, floor/ceiling effects, internal consistency, Cronbach\u2019s alpha, interscale correlations, test\u2013retest reliability and construct validity (convergent and discriminant validity). A total of 526 JIA patients (8.6% systemic, 49.4% oligoarticular, 18.2% RF negative polyarthritis, 23.8% other categories) and 78 healthy children, were enrolled in six centres. The JAMAR components discriminated well healthy subjects from JIA patients. All JAMAR components revealed good psychometric performances. In conclusion, the Castilian Spanish version of the JAMAR is a valid tool for the assessment of children with JIA and is suitable for use both in routine clinical practise and clinical research

Microglial phagocytosis dysfunction in stroke is driven by energy depletion and induction of autophagy

Microglial phagocytosis of apoptotic debris prevents buildup damage of neighbor neurons and inflammatory responses. Whereas microglia are very competent phagocytes under physiological conditions, we report their dysfunction in mouse and preclinical monkey models of stroke (macaques and marmosets) by transient occlusion of the medial cerebral artery (tMCAo). By analyzing recently published bulk and single cell RNA sequencing databases, we show that the phagocytosis dysfunction was not explained by transcriptional changes. In contrast, we demonstrate that the impairment of both engulfment and degradation was related to energy depletion triggered by oxygen and nutrient deprivation (OND), which led to reduced process motility, lysosomal exhaustion, and the induction of a protective macroautophagy/autophagy response in microglia. Basal autophagy, in charge of removing and recycling intracellular elements, was critical to maintain microglial physiology, including survival and phagocytosis, as we determined both in vivo and in vitro using pharmacological and transgenic approaches. Notably, the autophagy inducer rapamycin partially prevented the phagocytosis impairment induced by tMCAo in vivo but not by OND in vitro, where it even had a detrimental effect on microglia, suggesting that modulating microglial autophagy to optimal levels may be a hard to achieve goal. Nonetheless, our results show that pharmacological interventions, acting directly on microglia or indirectly on the brain environment, have the potential to recover phagocytosis efficiency in the diseased brain. We propose that phagocytosis is a therapeutic target yet to be explored in stroke and other brain disorders and provide evidence that it can be modulated in vivo using rapamycin.Abbreviations: AIF1/IBA1: allograft inflammatory factor 1; AMBRA1: autophagy/beclin 1 regulator 1; ATG4B: autophagy related 4B, cysteine peptidase; ATP: adenosine triphosphate; BECN1: beclin 1, autophagy related; CASP3: caspase 3; CBF: cerebral blood flow; CCA: common carotid artery; CCR2: chemokine (C-C motif) receptor 2; CIR: cranial irradiation; Csf1r/v-fms: colony stimulating factor 1 receptor; CX3CR1: chemokine (C-X3-C motif) receptor 1; DAPI: 4',6-diamidino-2-phenylindole; DG: dentate gyrus; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HI: hypoxia-ischemia; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MCA: medial cerebral artery; MTOR: mechanistic target of rapamycin kinase; OND: oxygen and nutrient deprivation; Ph/A coupling: phagocytosis-apoptosis coupling; Ph capacity: phagocytic capacity; Ph index: phagocytic index; SQSTM1: sequestosome 1; RNA-Seq: RNA sequencing; TEM: transmission electron microscopy; tMCAo: transient medial cerebral artery occlusion; ULK1: unc-51 like kinase 1

Characterization of wnt signaling in tamoxifen resistant breast cancer stem/progenitor cells

175 p.El tamoxifen, un antagonista de ER, es el tratamiento más común empleado para tratar a pacientes que expresan ER. Las células resistentes a tamoxifen están enriquecidas en células madre/progenitoras. La expresión de WNT1 es heterogénea entre los distintos subtipos de cáncer de mama. Además, Wnt-1 activa una señalización independiente de la ¿-catenina y mediada por ATF2 y TCF1 y es, además, potenciada por la expresión de USP6, que regula la degradación y el reciclaje de los receptores FZD. Se ha observado que Wnt-1 incrementa la población de células CD44+CD24-/low y la habilidad de formar esferas en células resistentes a tamoxifen., consistente con el peor pronóstico que presentan los pacientes de cáncer de mama con tumores que expresan ER y han recibido tratamiento con tamoxifen. Se identificó FZD5 como un receptor de Wnt que se correlaciona con un peor pronóstico de pacientes de cáncer de mama tratados con tamoxifen y que capaz de interaccionar con Wnt-1. El bloqueo de la señalización de Wnt-1 evitando su unión a FZD5 podría ser una buena estrategia para prevenir la recurrencia en un grupo determinado de pacientes de cáncer de mama.CICbioGUNE Eusko Jaurlaritz

Revista de psicodidáctica

Resumen tomado de la publicaciónSe propone una aproximación al concepto de escuela innovadora con TIC desde la perspectiva de los factores que facilitan el uso innovador de las TIC. Con este objetivo se ha construido y validado una escala para la identificación de estos factores mediante la participación de 195 docentes de 16 centros educativos considerados por la administración educativa vasca como innovadores en TIC. Los resultados obtenidos informan de la validez y la fiabilidad de la escala, así como de 5 factores clave que condicionan la innovación docente basada en la tecnología. Esta estructura factorial obtenida permite tener una visión holística de la innovación con TIC en el entorno escolar a través de 3 agentes clave: Contexto escolar, el profesorado y la administración educativa.ES

Factores que facilitan el éxito de la innovación educativa con TIC en los centros escolares

[EN]This paper proposes an approach to the concept of ICT-based innovation in schools, from the perspective of the factors that facilitate the innovative use of ICT. To this end, a scale has been developed and validated to identify these factors through the participation of 195 teachers from 16 schools considered by the Basque educational authorities as innovators in ICT. The results obtained attest to the validity and reliability of both the scale and the 5 key factors that influence innovation in technology-based teaching. This factor-based structure enables a holistic view of ICT innovation in schools across 3 key areas: school context, teachers and the education authorities.[ES]El presente artículo propone una aproximación al concepto de escuela innovadora con TIC desde la perspectiva de los factores que facilitan el uso innovador de las TIC. Con este objetivo se ha construido y validado una escala para la identificación de estos factores mediante la participación de 195 docentes de 16 centros educativos considerados por la administración educativa vasca como innovadores en TIC. Los resultados obtenidos informan de la validez y la fiabilidad de la escala, así como de 5 factores clave que condicionan la innovación docente basada en la tecnología. Esta estructura factorial obtenida permite tener una visión holística de la innovación con TIC en el entorno escolar a través de 3 agentes clave: Contexto escolar, el profesorado y la administración educativa