RESUMEN

BACKGROUND: Numerous clinical MRI studies have been published that describe an association between the repeated administration of (linear) gadolinium-based contrast agents and increased signal intensity in certain brain areas. In November 2017, the European Commission suspended the use of some of these contrast agents. OBJECTIVES: The background for this decision, both regulatory and scientific, are presented and discussed. MATERIALS AND METHODS: The regulatory decisions are evaluated and the clinical and preclinical literature is discussed. RESULTS: Differences in the structure and stability of gadolinium-based contrast agent molecules explain the observed increased signal intensities in individual brain regions (e. g. dentate nucleus) after administration of multiple doses of linear contrast agents. This phenomenon was not observed after administration of multiple doses of macrocyclic contrast agents. Preclinical studies have confirmed these results. CONCLUSION: To date, no clinical symptoms have been confirmed to be associated with the increased signal intensity or gadolinium presence in the brain.

Asunto(s)

Medios de Contraste , Gadolinio , Encéfalo , Imagen por Resonancia Magnética , Estudios Retrospectivos

RESUMEN

Metabolic changes are linked to epigenetic reprogramming and play important roles in several tumor types. PGC-1α is a transcriptional coactivator controlling mitochondrial biogenesis and is linked to oxidative phosphorylation. We provide evidence that melanoma models with elevated PGC-1α levels are characteristic of the proliferative phenotype and are sensitive to bromodomain and extra-terminal domain (BET) inhibitor treatment. A super-enhancer region highly occupied by the BET family member BRD4 was identified for the PGC-1α gene. BET inhibitor treatment prevented this interaction, leading to a dramatic reduction of PGC-1α expression. Accordingly, BET inhibition diminished respiration and mitochondrial function in cells. In vivo, melanoma models with high PGC-1α expression strongly responded to BET inhibition by reduction of PGC-1α and impaired tumor growth. Altogether, our findings identify epigenetic regulatory elements that define a subset of melanomas with high sensitivity to BET inhibition, which opens up the opportunity to define melanoma patients most likely to respond to this treatment, depending on their tumor characteristics.

Asunto(s)

Antineoplásicos/farmacología , Elementos de Facilitación Genéticos/genética , Melanoma/genética , Proteínas Nucleares/antagonistas & inhibidores , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Factores de Transcripción/antagonistas & inhibidores , Animales , Antineoplásicos/uso terapéutico , Azepinas/farmacología , Azepinas/uso terapéutico , Benzodiazepinas/farmacología , Benzodiazepinas/uso terapéutico , Proteínas de Ciclo Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Resistencia a Antineoplásicos/genética , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Nucleares/metabolismo , Selección de Paciente , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Unión Proteica/genética , Factores de Transcripción SOXE/genética , Factores de Transcripción SOXE/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Factores de Transcripción/metabolismo , Resultado del Tratamiento , Triazoles/farmacología , Triazoles/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto