RESUMEN
A child was admitted to our hospital for repair of a ventricular septal defect (VSD) characterized by a predominantly right-to-left shunt and a severe stenosis of the right ventricular outflow tract (Tetralogy of Fallot). Severe congenital anemia (hemoglobin 72 g/L), thrombocytopenia (42×G/L) and profound platelet dysfunction led a stem cell defect to be suspected. X-linked thrombocytopenia (GATA-1 mutation) was diagnosed. GATA-1 defect may complicate medical interventions due to excessive bleeding and partial or complete bone marrow failure. Maintaining a platelet count of 100 G/L and a maximal clot firmness (EXTEM-MCF) >50 mm allowed repair of the congenital heart defect without bleeding or hematological complications. Anemia and thrombocytopenia persisted after cardiac surgery, while the spontaneous bleeding tendency improved.
Asunto(s)
Anemia Diseritropoyética Congénita/complicaciones , Anemia Diseritropoyética Congénita/genética , Factor de Transcripción GATA1/genética , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Tetralogía de Fallot/complicaciones , Tetralogía de Fallot/genética , Tetralogía de Fallot/cirugía , Trombocitopenia/complicaciones , Trombocitopenia/genética , Transcripción Genética/genética , Austria , Biopsia con Aguja , Médula Ósea/patología , Niño , Estudios de Seguimiento , Hemostasis Quirúrgica/métodos , Humanos , Masculino , Turismo Médico , Agujas , Pruebas de Función Plaquetaria , Cuidados PosoperatoriosRESUMEN
Novel drugs like Abiraterone or Enzalutamide, which target androgen receptor (AR) signaling to improve androgen deprivation therapy (ADT), have been developed during the past years. However, the application of these drugs is limited because of occurrence of inherent or acquired therapy resistances during the treatment. Thus, identification of new molecular targets is urgently required to improve current therapeutic prostate cancer (PCa) treatment strategies. PIAS1 (protein inhibitor of activated STAT1 (signal transducer and activator of transcription-1)) is known to be an important cell cycle regulator and PIAS1-mediated SUMOylation is essential for DNA repair. In this context, elevated PIAS1 expression has already been associated with cancer initiation. Thus, in the present study, we addressed the question of whether PIAS1 targeting can be used as a basis for an improved PCa therapy in combination with anti-androgens. We show that PIAS1 significantly correlates with AR expression in PCa tissue and in cell lines and demonstrate that high PIAS1 levels predict shorter relapse-free survival. Our patient data are complemented by mechanistic and functional in vitro experiments that identify PIAS1 as an androgen-responsive gene and a crucial factor for AR signaling via prevention of AR degradation. Furthermore, PIAS1 knockdown is sufficient to decrease cell proliferation as well as cell viability. Strikingly, Abiraterone or Enzalutamide treatment in combination with PIAS1 depletion is even more effective than single-drug treatment in multiple PCa cell models, rendering PIAS1 as a promising target protein for a combined treatment approach to improve future PCa therapies.
Asunto(s)
Retroalimentación Fisiológica , Neoplasias de la Próstata/patología , Proteínas Inhibidoras de STAT Activados/metabolismo , Receptores Androgénicos/metabolismo , Transducción de Señal , Andrógenos/farmacología , Androstenos/farmacología , Benzamidas , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Retroalimentación Fisiológica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Inhibidoras de STAT Activados/deficiencia , Proteínas Inhibidoras de STAT Activados/genética , Estabilidad Proteica/efectos de los fármacos , Proteolisis/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Androgénicos/genética , Transducción de Señal/efectos de los fármacos , Análisis de Supervivencia , Transcripción Genética/efectos de los fármacosRESUMEN
The rapid kinetics of D-glucose uptake into membrane vesicles, prepared from the renal cortex of the rat, were measured. A vacuum manifold apparatus for the filtration of suspensions containing membrane vesicles and radiolabelled sugars was constructed to permit measurements of D-glucose accumulation within the vesicles at 8-s intervals. The rate of Na+-independent accumulation of D-glucose was nearly constant for the first 24 s while the rate for Na+-dependent uptake was always changing. While a linear relationship between Na+-dependent D-glucose accumulation and time could not be established for a time period as short as 8 s, the time for half maximum Na+-dependent D-glucose uptake could be estimated. A value of 4 s for half maximum accumulation D-glucose into membrane vesicles in the presence of sodium was obtained.