RESUMEN
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RESUMEN
Multiple myeloma is a mostly incurable malignancy characterized by the expansion of a malignant plasma cell (PC) clone in the human bone marrow (BM). Myeloma cells closely interact with the BM stroma, which secretes soluble factors that foster myeloma progression and therapy resistance. Growth arrest-specific gene 6 (Gas6) is produced by BM-derived stroma cells and can promote malignancy. However, the role of Gas6 and its receptors Axl, Tyro3 and Mer (TAM receptors) in myeloma is unknown. We therefore investigated their expression in myeloma cell lines and in the BM of myeloma patients and healthy donors. Gas6 showed increased expression in sorted BMPCs of myeloma patients compared with healthy controls. The fraction of Mer(+) BMPCs was increased in myeloma patients in comparison with healthy controls whereas Axl and Tyro3 were not expressed by BMPCs in the majority of patients. Downregulation of Gas6 and Mer inhibited the proliferation of different myeloma cell lines, whereas knocking down Axl or Tyro3 had no effect. Inhibition of the Gas6 receptor Mer or therapeutic targeting of Gas6 by warfarin reduced myeloma burden and improved survival in a systemic model of myeloma. Thus, the Gas6-Mer axis represents a novel candidate for therapeutic intervention in this incurable malignancy.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intercelular/genética , Mieloma Múltiple/genética , Células Plasmáticas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Animales , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Endogámicos NOD , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Trasplante de Neoplasias , Células Plasmáticas/patología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Células del Estroma/metabolismo , Células del Estroma/patología , Análisis de Supervivencia , Warfarina/farmacología , Tirosina Quinasa c-Mer , Tirosina Quinasa del Receptor AxlRESUMEN
The aim of this work was to analyse the furan concentrations in coffee products targeted to adolescents and to estimate the health risk for those consumers by using the consumption data of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study (DONALD). Three different kinds of coffee beverages were analysed: 'coffee ready to drink' (i.e. industrially manufactured and packaged products available in cans or plastic cups), 'coffee instant' (i.e. soluble coffee in powder form) and 'coffee from coffee chains' (i.e. freshly prepared coffee sampled on-site). Furan was analysed according to the US Food and Drug Administration (USFDA) method using headspace-GC-MS and quantification with standard addition. The lowest furan concentrations were found within the category 'coffee instant', with an average of 4.6 µg kg(-1), followed by the category 'coffee ready to drink', with an average of 41.3 µg kg(-1), while the products from the coffee chains showed the highest concentrations, on average 100.5 µg kg(-1). According to the obtained furan contents, it seems that the highest furan exposure for adolescents is generally given in the consumption of products within the category 'coffee from coffee chains', while the lowest is given in the category 'coffee instant'. Risk assessment based on the margin of exposure (MOE) approach showed that in different consumption scenarios except for consumers of instant coffee, the MOE lay below 10,000, a range that is judged to be of public health relevance. The lowest MOE was found for consumers in the age group 10-12 years (especially females) and for both sexes in the age group 16-18 years.