Osteosarcoma is the most frequent malignant bone tumor affecting mainly adolescents and people older than 50years old. Current treatment involves chemotherapy and surgical removal. Despite efforts... Show moreOsteosarcoma is the most frequent malignant bone tumor affecting mainly adolescents and people older than 50years old. Current treatment involves chemotherapy and surgical removal. Despite efforts to find a cure, there is 70% 5year survival rate. For patients that present metastasis at the moment of diagnosis, the prognosis is worse. Additionally, many do not respond well to chemotherapy. The aim of this research was to find new treatment options for patients with osteosarcoma. I searched for inhibitors that could sensitize osteosarcoma cells to chemotherapy. In this thesis, it is shown that targeting cell cycle regulators, proteins involved in apoptosis inhibition, and cellular pathways involved in survival, proliferation and migration are promising candidates for further research. Show less
Rationale Glucocorticoid hormones facilitate sensitization to repeated administration of psychostimulants, an effect that is mediated by glucocorticoid receptors (GRs). It is still unclear, however... Show moreRationale Glucocorticoid hormones facilitate sensitization to repeated administration of psychostimulants, an effect that is mediated by glucocorticoid receptors (GRs). It is still unclear, however, at which stage of psychomotor sensitization are stress and GR-mediated effects involved.Objectives In the present study, we have tested the hypothesis that GR-mediated effects during the phase of repeated amphetamine injections play a crucial role in the long-term expression of sensitization. For this purpose, we used DBA/2 mice, an inbred strain commonly used for the study of stress effects on psychostimulant sensitization.Methods Animals were treated with the GR antagonist mifepristone (200 mg/kg) at 2.5 h before each daily injection of amphetamine (2.5 mg/kg) or saline in a 5-day protocol. The amphetamine or saline injections were given in the home or a novel context. This was followed by a 2.5-week withdrawal period, without any drug delivery. Following the withdrawal period, two low-dose amphetamine challenges (1.25 mg/kg) were given subsequently, without additional mifepristone.Results The animals receiving amphetamine in the novel context showed a higher expression of sensitization at challenge as compared to those in the home condition. Mifepristone treatment influenced locomotor response to repeated amphetamine injections, but this effect during the initial phase did not affect the expression of sensitization after a withdrawal period.Conclusion Our results indicate that GR-related processes during the initial phase of sensitization are involved in, but not crucial for, the development of long-term sensitization. Show less
Franceschini, A.; Nair, A.; Bele, T.; Maagdenberg, A.M.J.M. van den; Nistri, A.; Fabbretti, E. 2012
For a majority of people worries about upcoming stressful events are a common experience in daily life. The aim of this thesis was to examine the effects of common worries on somatic health. In... Show moreFor a majority of people worries about upcoming stressful events are a common experience in daily life. The aim of this thesis was to examine the effects of common worries on somatic health. In particular, the effects of worry on somatic health complaints, like headache and back pain, and on cardiac activity after stressful events were tested. Furthermore, the mechanisms by which worry was hypothesized to affect somatic health were investigated. The studies in this thesis add to the accumulating number of studies testing the perseverative cognition hypothesis stating that only perseverative cognitive representations of stressful events (worries) lead to prolonged stress-related physiological activity which, in turn, can lead to somatic disease. Taken together, the studies reported in this thesis provide evidence for the perseverative cognition hypothesis, that is, worry predicted adverse somatic health outcomes. In addition, the results of the studies presented in the second part of this thesis yielded several new and more specific hypotheses concerning the mechanisms behind the health effects of worry and the effects of worry on stress management therapies. All in all, evidence from real life and laboratory studies makes clear that worry might play a substantial role in somatic health. Show less
