Search

Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer, which is usually preceded by a potentially malignant disorder histologically diagnosed as dysplasia. We and others have provided evidence for the pro-carcinogenic role of the Wnt/β-catenin pathway in this context, in which Wnt ligands stabilize and allow relocalization of β-catenin to the nucleus for transcription of pro-survival and pro-proliferation genes. However, the contribution of Porcupine (PORCN), an O-acyltransferase that catalyzes the palmitoylation of Wnt ligands, to OSCC carcinogenesis is not known. Moreover, the effectiveness of LGK974, a novel PORCN inhibitor remains to be elucidated. By using different ex vivo, in vivo and in vitro OSCC carcinogenesis models, we show that PORCN expression is significantly increased in high-grade dysplasia as well as moderately/poorly- differentiated OSCC. Consistent with these observations, expression of key proteins involved in the Wnt/β-catenin pathway are elevated as well. Importantly, the treatment with LGK974, a chemical PORCN inhibitor, reduced the number and size of oral lesions in mice treated with 4-Nitroquinoline 1-oxide (4NQO), a tobacco smoke surrogate. These results highlight the role of PORCN during OSCC carcinogenesis.

Nearly 90% of oral cancers are characterized as oral squamous cell carcinoma (OSCC), representing the sixth most common type of cancer. OSCC usually evolves from oral potentially malignant disorders that, in some cases, are histologically consistent with a oral dysplasia. The levels of 1α,25 dihydroxyvitamin D3 (1,25-(OH)2D3; calcitriol), the active form of vitamin D3, have been shown to be decreased in patients with oral dysplasia and OSCC. Moreover, treatment with 1,25-(OH)2D3 has been proven beneficial in OSCC by inhibiting the Wnt/β-catenin pathway, a signaling route that promotes cell migration, proliferation, and viability. However, whether this inhibition mechanism occurs in oral dysplasia is unknown. To approach this question, we used dysplastic oral keratinocyte cultures and oral explants (ex vivo model of oral dysplasia) treated with 1,25-(OH)2D3 for 48 h. Following treatment with 1,25-(OH)2D3, both in vitro and ex vivo models of oral dysplasia showed decreased levels of nuclear β-catenin by immunofluorescence (IF) and immunohistochemistry (IHC). Consistently, reduced protein and mRNA levels of the Wnt/β-catenin target gene survivin were observed after treatment with 1,25-(OH)2D3. Moreover, 1,25-(OH)2D3 promoted membranous localization of E-cadherin and nuclear localization of vitamin D receptor (VDR). Functionally, DOK cells treated with 1,25-(OH)2D3 displayed diminished cell migration and viability in vitro.

El artículo tiene por objetivo analizar las percepciones sobre autonomía y las condiciones extramediáticas del ejercicio profesional en periodistas de medios nativos digitales en México y Cuba. La investigación parte de una perspectiva cualitativa y es de tipo exploratoria. Se asumió como técnica fundamental la entrevista en profundidad. Se concluye que las percepciones sobre autonomía de los y las profesionales de los medios estudiados se materializan en una identificación de integración orgánica entre intereses propios y de las organizaciones de pertenencia. Al mismo tiempo, las percepciones sobre las condiciones extramediáticas se materializan en términos de determinación de incidencia variable, autorreconocimiento y distinción. Las entrevistadas y los entrevistados destacaron como condiciones externas del ejercicio profesional los discursos y el accionar político hostil, la resistencia de las fuentes de información gubernamentales a colaborar y, en algunas respuestas, la incidencia indirecta de las fuentes de financiamiento sobre la agenda de uno de los medios.

Abstract Spry2 is a molecular modulator of tyrosine kinase receptor signaling pathways that has cancer-type-specific effects. Mammalian Spry2 protein undergoes tyrosine and serine phosphorylation in response to growth factor stimulation. Spry2 expression is distinctly altered in various cancer types. Inhibition of the proteasome functionality results in reduced intracellular Spry2 degradation. Using in vitro and in vivo assays, we show that protein kinase D (PKD) phosphorylates Spry2 at serine 112 and interacts in vivo with the C-terminal half of this protein. Importantly, missense mutation of Ser112 decreases the rate of Spry2 intracellular protein degradation. Either knocking down the expression of all three mammalian PKD isoforms or blocking their kinase activity with a specific inhibitor contributes to the stabilization of Spry2 wild-type protein. Downregulation of CSN3, a component of the COP9/Signalosome that binds PKD, significantly increases the half-life of Spry2 wild-type protein but does not affect the stability of a Spry2 after mutating Ser112 to the non-phosphorylatable residue alanine. Our data demonstrate that both PKD and the COP9/Signalosome play a significant role in control of Spry2 intracellular stability and support the consideration of the PKD/COP9 complex as a potential therapeutic target in tumors where Spry2 expression is reduced.

Autophagy is an intracellular degradation mechanism that allows recycling of organelles and macromolecules. Autophagic function increases metabolite availability modulating metabolic pathways, differentiation and cell survival. The oral environment is composed of several structures, including mineralized and soft tissues, which are formed by complex interactions between epithelial and mesenchymal cells. With aging, increased prevalence of oral diseases such as periodontitis, oral cancer and periapical lesions are observed in humans. These aging-related oral diseases are chronic conditions that alter the epithelial-mesenchymal homeostasis, disrupting the oral tissue architecture affecting the quality of life of the patients. Given that autophagy levels are reduced with age, the purpose of this review is to discuss the link between autophagy and age-related oral diseases.

gdpc is an R package for the computation of the generalized dynamic principal components proposed in Peña and Yohai (2016). In this paper, we briefly introduce the problem of dynamical principal components, propose a solution based on a reconstruction criteria and present an automatic procedure to compute the optimal reconstruction. This solution can be applied to the non-stationary case, where the components need not be a linear combination of the observations, as is the case in the proposal of Brillinger (1981). This article discusses some new features that are included in the package and that were not considered in Peña and Yohai (2016). The most important one is an automatic procedure for the identification of both the number of lags to be used in the generalized dynamic principal components as well as the number of components required for a given reconstruction accuracy. These tools make it easy to use the proposed procedure in large data sets. The procedure can also be used when the number of series is larger than the number of observations. We describe an iterative algorithm and present an example of the use of the package with real data.

Objetivo: La artritis indiferenciada es una artropatía inflamatoria que no cumple con los criterios de enfermedades reumatológicas específicas y cuyos síntomas persisten durante un año. Estos individuos pueden remitir espontáneamente o evolucionar a otra artropatía definida, especialmente artritis reumatoide. El objetivo de este estudio fue describir las características clínicas y de laboratorio, tanto basales como de seguimiento, de pacientes con artritis indiferenciada en un centro de referencia.Materiales y métodos: Se realizó un estudio descriptivo retrospectivo con pacientes con artritis indiferenciada por criterio de reumatólogo. Se analizaron variables sociodemográficas, clínicas y terapéuticas. Las variables cualitativas se expresaron como frecuencias absolutas y relativas, y las cuantitativas con mediana y rango intercuartílico.Resultados: Se incluyeron 66 pacientes; la mediana de edad fue 46,3 años (RIC: 37,5-51,8); diez (15,2 %) sujetos tenían antecedente familiar de artritis reumatoide. Cuarenta (60,6 %) individuos tuvieron compromiso articular en interfalángicas proximales; el principal síntoma fue la rigidez matinal en 29 pacientes (44 %). El compromiso extraarticular más frecuente fue el cutáneo (n=14; 21,2 %). Los antiinflamatorios no esteroideos (n=18; 27,2 %) y los esteroides (n=15; 22,7 %) fueron los tratamientos más frecuentes. De 43 pacientes, 22 (51,2 %) permanecieron con diagnóstico de artritis indiferenciada, 18 (41,9 %) progresaron a otras enfermedades, siendo la más frecuente artritis reumatoide, y en tres (7 %) hubo remisión.Conclusiones: En una cohorte de pacientes con artritis indiferenciada del noroccidente colombiano, luego de 12 meses, la mayoría, persiste con este diagnóstico; fue llamativa la frecuencia importante de antecedente familiar de artritis reumatoide y de baja remisión espontánea.

Oral squamous cell carcinoma, the most common type of oral cancer, affects more than 275,000 people per year worldwide. Oral squamous cell carcinoma is very aggressive, as most patients die after 3 to 5 years post-diagnosis. The initiation and progression of oral squamous cell carcinoma are multifactorial: smoking, alcohol consumption, and human papilloma virus infection are among the causes that promote its development. Although oral squamous cell carcinoma involves abnormal growth and migration of oral epithelial cells, other cell types such as fibroblasts and immune cells form the carcinoma niche. An underlying inflammatory state within the oral tissue promotes differential stress-related responses that favor oral squamous cell carcinoma. Autophagy is an intracellular degradation process that allows cancer cells to survive under stress conditions. Autophagy degrades cellular components by sequestering them in vesicles called autophagosomes, which ultimately fuse with lysosomes. Although several autophagy markers have been associated with oral squamous cell carcinoma, it remains unclear whether up- or down-regulation of autophagy favors its progression. Autophagy levels during oral squamous cell carcinoma are both timing- and cell-specific. Here we discuss how autophagy is required to establish a new cellular microenvironment in oral squamous cell carcinoma and how autophagy drives the phenotypic change of oral squamous cell carcinoma cells by promoting crosstalk between carcinoma cells, fibroblasts, and immune cells.

Muscle atrophy involves a massive catabolism of intracellular components leading to a significant reduction in cellular and tissue volume. In this regard, autophagy, an intracellular mechanism that degrades proteins and organelles, has been implicated with muscle breakdown. Recently, it has shown that polycystin-2 (PC2), a membrane protein that belongs to the transient receptor potential (TRP) family, is required for the maintenance of cellular proteostasis, by regulating autophagy in several cell types. The role of PC2 in the control of atrophy and autophagy in skeletal muscle remains unknown. Here, we show that PC2 is required for the induction of atrophy in C2C12 myotubes caused by nutrient deprivation or rapamycin exposure. Consistently, overexpression of PC2 induces atrophy in C2C12 myotubes as indicated by decreasing of the myogenic proteins myogenin and caveolin-3. In addition, we show that inhibition of mTORC1, by starvation or rapamycin is inhibited in cells when PC2 is silenced. Importantly, even if PC2 regulates mTORC1, our results show that the regulation of atrophy by PC2 is independent of autophagy. This study provides novel evidence regarding the role of PC2 in skeletal muscle cell atrophy.

Chronic consumption of high fat diets (HFDs), rich in saturated fatty acids (SatFAs) like palmitic acid (PA), is associated with the development of obesity and obesity-related metabolic diseases such as type II diabetes mellitus (T2DM). Previous studies indicate that PA accumulates in the hypothalamus following consumption of HFDs; in addition, HFDs consumption inhibits autophagy and reduces insulin sensitivity. Whether malfunction of autophagy specifically in hypothalamic neurons decreases insulin sensitivity remains unknown. PA does activate the Free Fatty Acid Receptor 1 (FFAR1), also known as G protein-coupled receptor 40 (GPR40); however, whether FFAR1 mediates the effects of PA on hypothalamic autophagy and insulin sensitivity has not been shown. Here, we demonstrate that exposure to PA inhibits the autophagic flux and reduces insulin sensitivity in a cellular model of hypothalamic neurons (N43/5 cells). Furthermore, we show that inhibition of autophagy and the autophagic flux reduces insulin sensitivity in hypothalamic neuronal cells. Interestingly, the inhibition of the autophagic flux, and the reduction in insulin sensitivity are prevented by pharmacological inhibition of FFAR1. Our findings show that dysregulation of autophagy reduces insulin sensitivity in hypothalamic neuronal cells. In addition, our data suggest FFAR1 mediates the ability of PA to inhibit autophagic flux and reduce insulin sensitivity in hypothalamic neuronal cells. These results reveal a novel cellular mechanism linking PA-rich diets to decreased insulin sensitivity in the hypothalamus and suggest that hypothalamic autophagy might represent a target for future T2DM therapies.

This short insight covers some of the recent topics relevant to the field of cadherin–catenin adhesion in mediating connections between different cell types, so-called heterotypic or heterocellular connections, in both homeostasis and cancer. These scientific discoveries are increasing our understanding of how multiple cells residing in complex tissues can be instructed by cadherin adhesion receptors to regulate tissue architecture and function and how these cadherin-mediated heterocellular connections spur tumor growth and the acquisition of malignant characteristics in tumor cells. Overall, the findings that have emerged over the past few years are elucidating the complexity of the functional roles of the cadherin–catenin complexes. Future exciting research lies ahead in order to understand the physical basis of these heterotypic interactions and their influence on the behavior of heterogeneous cellular populations as well as their roles in mediating phenotypic and genetic changes as cells evolve through complex environments during morphogenesis and cancer.

Se presenta un método original para controlar suavidad cuando se estiman tasas de mortalidad en un contexto bidimensional (por edades y años) con una perspectiva de P-splines. El analista puede elegir el porcentaje de suavidad deseado, ya sea en la dimensión de edad, de años o de ambas, con el objetivo de obtener tendencias suavizadas de tasas de mortalidad que sean comparables. Para ello se proponen unos índices que relacionan la suavidad deseada con los parámetros que controlan el suavizamiento. También se establecen algunos resultados teóricos que brindan soporte a los índices de suavidad y se tocan algunos aspectos de carácter numérico. Con fines ilustrativos, el método propuesto se aplica a datos de estadísticas vitales para México y a datos del Continuous Mortality Investigation Bureau del Reino Unido.