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Monique Den L Boer - One of the best experts on this subject based on the ideXlab platform.
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the synergism of mcl1 and glycolysis on pediatric acute lymphoblastic leukemia cell survival and Prednisolone resistance
Haematologica, 2013Co-Authors: Ingrid M Aries, Bo Hansen, Troels Koch, Rosanna Van Den Dungen, William E Evans, Rob Pieters, Monique Den L BoerAbstract:In vitro and in vivo resistance to Prednisolone are predictive for an adverse prognosis in pediatric precursor B-acute lymphoblastic leukemia. Causes of resistance are still poorly understood. In this study, we observed that Prednisolone exposure of Prednisolone-sensitive patients' leukemic cells decreased anti-apoptotic MCL1 protein levels by 2.9-fold, while MCL1 protein expression in Prednisolone-resistant leukemic patients' cells was unaffected (P<0.01). Locked nucleic acid oligonucleotides directed against MCL1 reduced MCL1 protein levels by 82±16% (P<0.05) in leukemic cells, decreased proliferation by 9-fold and sensitized to Prednisolone up to 80.8-fold, compared to a non-silencing-control locked nucleic acid (P<0.05). Remarkably, we discovered that MCL1-silencing up-regulated the glucose consumption of leukemic cells by 2.5-fold (P<0.05), suggesting a potential rescue mechanism mediated by glycolysis. Targeting glycolysis by 2-deoxyglucose synergistically inhibited leukemic survival by 23.2-fold in MCL1-silenced cells (P<0.05). Moreover, 2-deoxyglucose and MCL1 locked nucleic acid concomitantly sensitized leukemic cells to Prednisolone compared to MCL1 locked nucleic acid or 2-deoxyglucose alone (P<0.05). In conclusion, these results indicate the need to target both MCL1 and glycolysis simultaneously to inhibit leukemic survival and sensitize acute leukemia patients towards Prednisolone.
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inhibition of glycolysis modulates Prednisolone resistance in acute lymphoblastic leukemia cells
Blood, 2009Co-Authors: Esther Hulleman, William E Evans, Rob Pieters, Karin M Kazemier, Amy Holleman, David J Vanderweele, Charles M Rudin, Mathilde J C Broekhuis, Monique Den L BoerAbstract:Treatment failure in pediatric acute lymphoblastic leukemia (ALL) is related to cellular resistance to glucocorticoids (eg, Prednisolone). Recently, we demonstrated that genes associated with glucose metabolism are differentially expressed between Prednisolone-sensitive and Prednisolone-resistant precursor B-lineage leukemic patients. Here, we show that Prednisolone resistance is associated with increased glucose consumption and that inhibition of glycolysis sensitizes Prednisolone-resistant ALL cell lines to glucocorticoids. Treatment of Prednisolone-resistant Jurkat and Molt4 cells with 2-deoxy-D-glucose (2-DG), lonidamine (LND), or 3-bromopyruvate (3-BrPA) increased the in vitro sensitivity to glucocorticoids, while treatment of the Prednisolone-sensitive cell lines Tom-1 and RS4; 11 did not influence drug cytotoxicity. This sensitizing effect of the glycolysis inhibitors in glucocorticoid-resistant ALL cells was not found for other classes of antileukemic drugs (ie, vincristine and daunorubicin). Moreover, down-regulation of the expression of GAPDH by RNA interference also sensitized to Prednisolone, comparable with treatment with glycolytic inhibitors. Importantly, the ability of 2-DG to reverse glucocorticoid resistance was not limited to cell lines, but was also observed in isolated primary ALL cells from patients. Together, these findings indicate the importance of the glycolytic pathway in glucocorticoid resistance in ALL and suggest that targeting glycolysis is a viable strategy for modulating Prednisolone resistance in ALL.
Sanjay N Rao - One of the best experts on this subject based on the ideXlab platform.
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treatment of herpes simplex virus stromal keratitis unresponsive to topical Prednisolone 1 with topical cyclosporine 0 05
American Journal of Ophthalmology, 2006Co-Authors: Sanjay N RaoAbstract:Purpose To assess the efficacy of topical cyclosporine 0.05% (Restasis) in patients with herpes simplex virus nonnecrotizing stromal keratitis unresponsive to topical Prednisolone. Design Prospective case series. Methods Patients with herpes simplex virus stromal keratitis (n = 12) that was unresponsive to topical Prednisolone acetate 1% for at least four weeks were evaluated at a single site. Eyes were treated with topical cyclosporine twice a day and begun on a rapid Prednisolone taper. Visual acuity, slit-lamp appearance, intraocular pressure, and corneal sensitivity were evaluated every two weeks for at least three months. Results Stromal keratitis resolved with cyclosporine in 10 of 12 patients after one month. The mean lesion area decreased more with cyclosporine than with Prednisolone (2.0 mm with cyclosporine compared with 0.25 mm with Prednisolone). After stopping cyclosporine therapy, four patients had recurrence of stromal keratitis. Conclusion This series suggests that herpes simplex virus stromal keratitis can be treated effectively with topical cyclosporine, particularly in cases that are not responsive to topical Prednisolone.
Raman Sankar - One of the best experts on this subject based on the ideXlab platform.
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treatment of infantile spasms with very high dose Prednisolone before high dose adrenocorticotropic hormone
Epilepsia, 2014Co-Authors: Shaun A Hussain, Shlomo Shinnar, Grace Kwong, Jason T Lerner, Joyce H Matsumoto, Donald W Shields, Raman SankarAbstract:SummaryPurpose This study investigated the short-term response to a standardized hormonal therapy protocol for treatment of infantile spasms. Methods Twenty-seven children with video electroencephalography (EEG)–confirmed infantile spasms received very high dose (8 mg/kg/day, max 60 mg/day) oral Prednisolone for 2 weeks. Response (absence of both hypsarrhythmia and spasms) to Prednisolone was ascertained by repeat overnight video-EEG. Responders were tapered over 2 weeks and nonresponders were immediately transitioned to high dose (150 IU/m2/day) intramuscular adrenocorticotropic hormone (ACTH) for two additional weeks. Response was again determined by overnight video-EEG after ACTH therapy. Key Findings Sixty-three percent (17/27) of patients responded completely to Prednisolone. Subsequently, 40% (4/10) of Prednisolone nonresponders exhibited a complete response after an additional 2-week course with ACTH. Among 27 subjects with median follow-up of 13.5 months (interquartile range [IQR] 4.8–25.9), 12% (2/17) of Prednisolone responders and 50% (2/4) of ACTH responders experienced a relapse between 2 and 9 months after initial response. Significance Very high dose Prednisolone demonstrated significantly higher efficacy than previously reported for lower doses in prior studies. High dose ACTH may be superior to very high dose Prednisolone, and in lieu of a definitive clinical trial, the choice between Prednisolone and ACTH for initial treatment of infantile spasms remains controversial.
Julie A Anderson - One of the best experts on this subject based on the ideXlab platform.
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Prednisolone response in patients with chronic obstructive pulmonary disease results from the isolde study
Thorax, 2003Co-Authors: P S Burge, P M A Calverley, Paul W Jones, Sally Spencer, Julie A AndersonAbstract:Background: A trial of corticosteroids has been recommended for all patients with chronic obstructive pulmonary disease (COPD), with the subsequent "response" determining the treatment selected. This approach assumes that patients can be reliably divided into responder and non-responder groups. We have assessed whether such a separation is statistically valid, which factors influence the change in forced expiratory volume in 1 second (FEV1) after Prednisolone, and whether the Prednisolone response predicts 3 year changes in FEV1, health status, or number of exacerbations during placebo or fluticasone propionate treatment. Methods: Oral Prednisolone 0.6 mg/kg was given for 14 days to 524 patients with COPD before randomised treatment for 3 years with fluticasone propionate or placebo. Factors relating to change in FEV1 after Prednisolone were investigated using multiple regression. The response to Prednisolone was entered into separate mixed effects models of decline in FEV1 and health status during the 3 years of the study. Results: The post-bronchodilator FEV1 increased by a mean 60 ml (CI 46 to 74) after Prednisolone with a wide unimodal distribution. Current smoking was the factor most strongly associated with the change in FEV1 after Prednisolone, with an increase of 35 ml in current smokers and 74 ml in confirmed ex-smokers (p<0.001). There was no relationship between the change in FEV1 after Prednisolone and the response to inhaled bronchodilators, baseline FEV1, atopic status, age, or sex. The response to Prednisolone, however expressed, was unrelated to the subsequent change in FEV1 over the following 3 years on either placebo or fluticasone propionate. Regression to the mean effects explained much of the apparent Prednisolone response. The significant effect of treatment on decline in health status was not predicted by the Prednisolone response. Conclusion: Patients with COPD cannot be separated into discrete groups of corticosteroid responders and non-responders. Current smoking reduces the FEV1 response to Prednisolone. Prednisolone testing is an unreliable predictor of the benefit from inhaled fluticasone propionate in individual patients.
Pierre Duroux - One of the best experts on this subject based on the ideXlab platform.
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comparison of nebulized budesonide and oral Prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease a randomized controlled trial
American Journal of Respiratory and Critical Care Medicine, 2002Co-Authors: Francois Maltais, Juliette Ostinelli, Jean Bourbeau, Andre Bernard Tonnel, Nadine Jacquemet, Jennifer Haddon, Michel Rouleau, Mohamed Boukhana, Jean Benoit Martinot, Pierre DurouxAbstract:Nebulized budesonide has been used successfully to treat acute asthma exacerbation, and we hypothesized that it could also be effective for exacerbations of chronic obstructive pulmonary disease (COPD). In this multicenter, double-blind, randomized, placebo-controlled trial, the efficacy of nebulized budesonide (Pulmicort Respules/Nebuamp), oral Prednisolone, and placebo was compared in 199 patients with acute exacerbations of COPD requiring hospitalization. Patients received from randomization (H(0)) to 72 h (H(72)), 2 mg of budesonide every 6 h (n = 71), 30 mg of oral Prednisolone every 12 h (n = 62), or placebo (n = 66). All received standard treatment, including nebulized beta(2)-agonists, ipratropium bromide, oral antibiotics, and supplemental oxygen. The mean change (95% confidence interval) in postbronchodilator FEV(1) from H(0) to H(72) was greater with active treatments than with placebo: budesonide versus placebo, 0.10 L (0.02 to 0.18 L); Prednisolone versus placebo, 0.16 L (0.08 to 0.24 L). The difference in FEV(1) between budesonide and Prednisolone was not significant, -0.06 L (-0.14 to 0.02 L). The occurrence of serious adverse events was similar for all groups. Budesonide had less systemic activity than Prednisolone as indicated by a higher incidence of hyperglycemia observed with Prednisolone. Both budesonide and Prednisolone improved airflow in COPD patients with acute exacerbations when compared with placebo. Nebulized budesonide may be an alternative to oral Prednisolone in the treatment of nonacidotic exacerbations of COPD but further studies should be done to evaluate its long-term impact on clinical outcomes after an initial episode of COPD exacerbation.