RESUMEN
The tyrosine kinase inhibitor imatinib (Gleevec, Novartis Pharmaceuticals Corporation; Basel, Switzerland) is a powerful drug for treatment of chronic myelogenous leukemia (CML) and other malignancies. It selectively targets various tyrosine kinases, thereby leading to growth arrest of respective cancer cells. Given its wide application, it is of high importance to know all related underlying molecular mechanisms. We had previously found that imatinib increases the cellular clearance of intracellular protein aggregates by targeting the abl pathway and thereby upregulating lysosomal activity. Here, we describe that imatinib dose dependently activates the cellular autophagy machinery in mammalian cells, independently of tissue type, species origin or immortalization status of cells. Autophagy is an archetypical cellular degradation mechanism implicated in many physiological and pathophysiological conditions. Our data link for the first time the process of autophagy with the mode of action of imatinib. Induction of autophagy might represent an additional mechanism of imatinib to induce growth arrest, promote apoptosis in cancer cells and eventually even promote tumour regression.
Asunto(s)
Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Piperazinas/farmacología , Pirimidinas/farmacología , Animales , Benzamidas , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Mesilato de Imatinib , Lisosomas/efectos de los fármacos , Ratones , Fagosomas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidoresRESUMEN
OBJECTIVE: With akteonline.de a patient owned Electronic Health Record (EHR) has been implemented that combines both data from clinical information systems and data entered by the patient. In addition the EHR supports information exchange/communication controlled by the user. The EHR thus offers the potential to place the patient into a more empowered position. This impact on patient empowerment and the implementation of additional features is to be investigated. Additionally, the user satisfaction is to be evaluated regarding patients' acceptance and utilization of the system. METHOD: Users were divided into three groups, two of which received different training on the functionalities of akteonline.de. A quantitative study employing an online-questionnaire and considering all registered users was conducted. RESULTS: Users evaluated the internet based system to be feasible and the navigation to be suitable, yet additional training for users regarding particular features seems to be required and also for hospital staff in general. The proposed add-ons were approved of. The study also showed positive effects on patient empowerment.
Asunto(s)
Registros Electrónicos de Salud , Sistemas de Registros Médicos Computarizados , Comunicación , Humanos , Internet , Satisfacción Personal , Encuestas y CuestionariosRESUMEN
Sp3 is a ubiquitous transcription factor closely related to Sp1. Previous analyses showed that, unlike Sp1, Sp3 fails to activate transcription in certain promoter settings. This is due to the presence of an inhibitory domain located between the second glutamine-rich activation domain and the DNA-binding domain. To further analyze the transcriptional properties of Sp3, we have expressed and purified recombinant Sp3 and Sp1 as epitope-tagged proteins from stable transfected insect cells. We found that Sp3 does act as a strong activator similar to Sp1 in an in vitro transcription assay using Sp1/Sp3-depleted HeLa nuclear extract. However, on the same promoter Sp3 is almost inactive when transfected into cells. Mutational studies demonstrate that a single lysine residue is responsible for the low transcriptional activity of Sp3 in vivo. We show that Sp3, but not a mutant of Sp3 that lacks this lysine residue, is highly acetylated in vivo. Our results strongly suggest that the transcriptional activity of Sp3 is regulated by acetylation. The consequences of acetylation for the activity of Sp3 are discussed.