T-type calcium channel inhibition restores sensitivity to MAPK inhibitors in de-differentiated and adaptive melanoma cells.

BACKGROUND: Drug resistance remains as one of the major challenges in melanoma therapy. It is well known that tumour cells undergo phenotypic switching during melanoma progression, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). METHODS: We investigated the melanoma phenotype switching using a partial reprogramming model to de-differentiate murine melanoma cells and target melanoma therapy adaptation against MAPKi. RESULTS: Here, we show that partially reprogrammed cells are a less proliferative and more de-differentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate adaptation to MAPKi, cells were exposed to B-Raf Proto-Oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors. De-differentiated cells became less sensitive to MAPKi, showed increased cell viability and decreased apoptosis. Furthermore, T-type calcium channels expression increased in adaptive murine cells and in human adaptive melanoma cells. Treatment with the calcium channel blocker mibefradil induced cell death, differentiation and susceptibility to MAPKi in vitro and in vivo. CONCLUSION: In summary, we show that partial reprogramming of melanoma cells induces de-differentiation and adaptation to MAPKi. Moreover, we postulated a calcium channel blocker such as mibefradil, as a potential candidate to restore sensitivity to MAPKi in adaptive melanoma cells.

Environmental Regulation of Heterosis in the Allopolyploid Arabidopsis suecica.

Allopolyploids are organisms possessing more than two complete sets of chromosomes from two or more species and are frequently more vigorous than their progenitors. To address the question why allopolyploids display hybrid vigor, we compared the natural allopolyploid Arabidopsis suecica to its progenitor species Arabidopsis thaliana and Arabidopsis arenosa. We measured chlorophyll content, CO2 assimilation, and carbohydrate production under varying light conditions and found that the allopolyploid assimilates more CO2 per unit chlorophyll than either of the two progenitor species in high intensity light. The increased carbon assimilation corresponds with greater starch accumulation, but only in strong light, suggesting that the strength of hybrid vigor is dependent on environmental conditions. In weaker light A. suecica tends to produce as much primary metabolites as the better progenitor. We found that gene expression of LIMIT DEXTRINASE1, a debranching enzyme that cleaves branch points within starch molecules, is at the same level in the allopolyploid as in the maternal progenitor A. thaliana and significantly more expressed than in the paternal progenitor A. arenosa. However, expression differences of ß-amylases and GLUCAN-WATER DIKINASE1 were not statistically significantly elevated in the allopolyploid over progenitor expression levels. In contrast to allopolyploids, autopolyploid A. thaliana showed the same photosynthetic rate as diploids, indicating that polyploidization alone is likely not the reason for enhanced vigor in the allopolyploid. Taken together, our data suggest that the magnitude of heterosis in A. suecica is environmentally regulated, arises from more efficient photosynthesis, and, under specific conditions, leads to greater starch accumulation than in its progenitor species.

Cambios en la marcha asociados con demencia por cuerpos de Lewy: una revisión narrativa de la literatura / Gait changes associated with Lewy body dementia: a narrative review of the literature

RESUMEN INTRODUCCIÓN: La demencia por cuerpos de Lewy (DCL) es una enfermedad neurodegenerativa con alta prevalencia y a menudo subdiagnosticada. En las demencias pueden presentarse alteraciones en la marcha que potencialmente permitan identificar su subtipo y dar una orientación clínica, diagnóstica y terapéutica temprana. Esta revisión narrativa de la literatura busca revisar los cambios de la marcha que se han descrito asociados con DCL. MATERIALES Y MÉTODOS: Se realizó una revisión de la literatura sobre la relación de las alteraciones de la marcha con la DCL. Se seleccionaron los siguientes parámetros de búsqueda mediante el buscador Scopus: ((falls and dementia and gait and (evaluation or analysis))). Los datos se ordenaron según relevancia y se obtuvieron 267 resultados. Igualmente, se hizo una búsqueda en PubMed, para a la que se introdujeron los términos (gait and lewy-body-disease), y no se utilizaron otros filtros; se obtuvieron 139 resultados. Se hizo una selección no sistemática de los artículos para llevar a cabo una revisión narrativa acerca de los cambios en la marcha asociados con DCL. RESULTADOS: Las alteraciones en la marcha pueden tener un valor predictor importante en la DCL. Los pacientes con demencias no debido a EA o causas vasculares muestran un deterioro de la funcionalidad física más rápido comparado con pacientes con EA y sin problemas cognitivos. La priorización incorrecta de las tareas, evidenciada en la EP, también es observable en los pacientes con DCL, y se asocia con el paradigma de doble tarea en el paciente con trastorno neurocognitivo mayor. El congelamiento de la marcha, también conocido como bloqueo de la marcha, se ha asociado con mayor progresión de la alteración cognitiva. Los pacientes con DCL también presentan un mayor compromiso en el tiempo de balanceo y la variabilidad de duración de la zancada, como también peor desempeño en ritmo y variabilidad de la marcha, e inestabilidad de la marcha, con posturas inadecuadas. CONCLUSIONES: Existe una relación entre la DCL y las caídas en el adulto mayor. En este grupo de edad, los cambios en la marcha y en las pruebas de desempeño podrían tener una utilidad clínica como factores asociados a con DCL, así como con las caídas. Al parecer, existe una variación característica entre los parámetros de la marcha y los subtipos de demencias que puede tener un valor como marcador diagnóstico. Se requieren más estudios con respecto a este tema puesto que hay escasa evidencia disponible hasta el momento, lo cual impide definir con mayor precisión las alteraciones más sensibles de cada dominio de la marcha que permitan diferenciar el envejecimiento normal del patológico.

ABSTRACT INTRODUCTION: Lewy body dementia is a highly prevalent neurodegenerative disease and often goes unnoticed due to little knowledge about it. In dementias there may be gait alterations that potentially allow the identification of its subtype and provide early clinical, diagnostic, and therapeutic guidance. This narrative review of the literature aims to review gait changes that have been described as associated with Lewy body dementia. MATERIALS AND METHODS: A literature review was carried out on the relationship of gait disturbances and LBD. The following search parameters were selected using the Scopus search engine: ((falls and dementia and gait and (evaluation or analysis))). The data were ordered according to relevance, obtaining 267 results. Likewise, a search was made in PubMed, using the terms (gait and lewy-body-disease), and no other filters were used, obtaining 139 results. A non-systematic selection of literature was made to carry out a narrative review about the changes in gait associated with LBD. RESULTS: We found that gait disturbances may have an important predictive value in LBD. Patients with dementias not due to AD or vascular causes have a faster deterioration of physical function compared to patients with AD and without cognitive problems. The incorrect prioritization of tasks evidenced in PD is also observable in patients with LBD and is associated with the "dual-task" paradigm in patients with major neurocognitive disorder. Freezing of gait, also known as motor block or "freezing of gait" has been associated with a greater progression of cognitive impairment. Patients with LBD also show greater compromise in swing time, stride duration variability, poorer performance in gait pace and variability, and gait instability with inappropriate postures. CONCLUSIONS: We observe that there is a relationship between LBD and falls in the elderly. Changes in gait and performance tests could have clinical utility as factors associated with LBD as well as falls in the elderly. There appears to be a characteristic variation between gait parameters and dementia subtypes that may have value as a diagnostic marker. More studies are required on this subject since there is little evidence available to date, which makes it impossible to define with greater precision the most sensitive alterations in each domain of gait that make it possible to differentiate normal from pathological aging.