MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma

BACKGROUND: Through negative regulation of gene expression, microRNAs (miRNAs) can function in cancers as oncosuppressors, and they can show altered expression in various tumor types. Here we have investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many cell-fate-determining stages. MBs occur bimodally, with the peak incidence seen between 3-4 years and 8-9 years of age, although it can also occur in adults. Notch regulates a subset of the MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulated these phenomena, and can be used in anti-cancer therapies. METHODOLOGY/PRINCIPAL FINDINGS: In a screening of MB cell lines, the miRNA miR-199b-5p was seen to be a regulator of the Notch pathway through its targeting of the transcription factor HES1. Down-regulation of HES1 expression by miR-199b-5p negatively regulates the proliferation rate and anchorage-independent growth of MB cells. MiR-199b-5p over-expression blocks expression of several cancer stem-cell genes, impairs the engrafting potential of MB cells in the cerebellum of athymic/nude mice, and of particular interest, decreases the MB stem-cell-like (CD133+) subpopulation of cells. In our analysis of 61 patients with MB, the expression of miR-199b-5p in the non-metastatic cases was significantly higher than in the metastatic cases (P = 0.001). Correlation with survival for these patients with high levels of miR-199b expression showed a positive trend to better overall survival than for the low-expressing patients. These data showing the down-regulation of miR-199b-5p in metastatic MBs suggest a potential silencing mechanism through epigenetic or genetic alterations. Upon induction of de-methylation using 5-aza-deoxycytidine, lower miR-199b-5p expression was seen in a panel of MB cell lines, supported an epigenetic mechanism of regulation. Furthermore, two cell lines (Med8a and UW228) showed significant up-regulation of miR-199b-5p upon treatment. Infection with MB cells in an induced xenograft model in the mouse cerebellum and the use of an adenovirus carrying miR-199b-5p indicate a clinical benefit through this negative influence of miR-199b-5p on tumor growth and on the subset of MB stem-cell-like cells, providing further proof of concept. CONCLUSIONS/SIGNIFICANCE: Despite advances in our understanding of the pathogenesis of MB, one-third of these patients remain incurable and current treatments can significantly damage long-term survivors. Here we show that miR-199b-5p expression correlates with metastasis spread, identifying a new molecular marker for a poor-risk class in patients with MB. We further show that in a xenograft model, MB tumor burden can be reduced, indicating the use of miR199b-5p as an adjuvant therapy after surgery, in combination with radiation and chemotherapy, for the improvement of anti-cancer MB therapies and patient quality of life. To date, this is the first report that expression of a miRNA can deplete the tumor stem cells, indicating an interesting therapeutic approach for the targeting of these cells in brain tumors

La teoría de la relevancia y la estrategia humorística de la incongruencia-resolución

En la teoría de la Relevancia Sperber y Wilson proponen un modelo cognitivo de la interpretación humana basado en el interés del receptor por adquirir, en cada estadio de la conversación, la información más relevante Esta elección está influida, en última instancia, por un equilibrio entre interés y esfuerzo. En el presente artículo se propone una posible aplicación de esta teoría a la estrategia humorística de la "disonancia cognitiva", concretamente la estrategia de incongruencia-resolución, de tal modo que podemos encontrar una explicación de cómo el emisor consigue el efecto humorístico deseado.In Relevance theory Sperber and Wilson propose a cognitive model of human interpretation based on the addressee's willingness to grasp, in every step of the conversation the most relevant information. This choice is influenced, eventually, by a balance of interest and effort. In the present article we propose an application of this theory to the humorous strategy of "cognitive dissonance", specifically the strategy of incongruence-resolution, in such a way that we can find an explanation of how the addresser manages to get the desired humorous effect

ESCAP Expert Paper: New developments in the diagnosis and treatment of adolescent anorexia nervosa-a European perspective

Anorexia nervosa is a potentially life-threatening disorder with a typical onset in adolescence and high rates of medical complications and psychiatric comorbidity. This article summarizes issues relating to classification in DSM-5 and presents a narrative review of key evidence-based medical and behavioral interventions for adolescent AN and subthreshold restricting eating disorders, mainly, but not exclusively published between 2012 and 2014. In addition, it systematically compares the clinical guidelines of four European countries (Germany, Spain, The Netherlands, and United Kingdom) and outlines common clinical practice, in relation to treatment settings, nutritional rehabilitation, family-oriented and individual psychotherapy, and psychopharmacological treatment. With the exception of family-based treatment, which is mainly evaluated and practiced in Anglo-American countries, the evidence base is weak, especially for medical interventions such as refeeding and pharmacological intervention. There is a need for common European research efforts, to improve the available evidence base and resulting clinical guidance