SummaryThe effect of propranolol was studied in a double-blind crossover trial in 24 carefully selected hypertensive outpatients. Each patient received propranolol 60 mg/day, 120 mg/day, 240 mg/day, and placebo for four weeks each according to a randomised sequence. Propranolol 60 mg/day was no better than placebo in reducing blood pressure. The effects of propranolol 120 mg/day and 240 mg/day were not significantly different. Both doses reduced lying blood pressure by about 20/10 mm Hg from an initial level of 173/104 mm Hg. No difference was detected between the effects of the different doses of propranolol and placebo on weight or on the occurrence of adverse reactions. IntroductionPropranolol is the most widely used beta-adrenoceptor antagonist in the treatment of hypertension and has been available for 11 years. Nevertheless, the optimum dosage regimen has not been established, and although incremental dosage studies have been carried out we have been unable to trace a within-patient crossover study that compares the effects of different doses in hypertensive patients. We report a controlled assessment of oral propranolol at three doses (60, 120, 240 mg/day) in outpatients with mild hypertension. Because the time of onset of the
Glioblastoma Multiforme (GBM) is the most aggressive form of primary brain tumour, with a median survival of 12–14 months after diagnosis. Although GBM has been extensively characterised on the molecular level during the past decades, many targeted therapies have been proved to be ineffective due to high heterogeneity of GBM. Thus, novel therapies targeting the altered metabolism which is exhibited by all cancer cells have gained more attentions. Our strategy is the therapeutic ketogenic diet (KD), a high fat, low carbohydrate and adequate protein diet, which has been recognized as a treatment for refractory paediatric epilepsy. Recent studies have shown that KD reduces tumour growth and potentiates the effects of radiotherapy in some glioma animal models. However, the underlying mechanism is still unclear. To unravel the mechanism of action, we carried out small-RNA sequencing and chromatin modifying enzyme analysis using brain tumour samples from GBM mice model, fed with either KD or standard diet (SD). Our results highlighted an overall upregulation of tumour suppressor miRNAs and key chromatin modifying enzymes that are typically downregulated in GBM in mice fed with KD compared with those fed with SD. We also observed a corresponding downregulation in target genes of these miRNAs and chromatin modifying enzymes. These genes have been reported as key regulators in tumour growth, tumour invasion and chemo/radio-resistance in previous publications. Therefore, our study indicates that targeting cancer metabolism using the KD alters the epigenetic landscape of GBM and induces changes in key genes that potentiate the effects of chemo/radiotherapy.
We thank the medical director and staff of the United Kingdom Transplant Service and the administrators and medical records officers of the 21 hospitals that cooperated in this study by providing details from patient case records.
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