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- den Hollander, J, et al.
(författare)
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Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 116:9, s. 1498-1505
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Tidskriftsartikel (refereegranskat)abstract
- Myc oncoproteins promote continuous cell growth, in part by controlling the transcription of key cell cycle regulators. Here, we report that c-Myc regulates the expression of Aurora A and B kinases (Aurka and Aurkb), and that Aurka and Aurkb transcripts and protein levels are highly elevated in Myc-driven B-cell lymphomas in both mice and humans. The induction of Aurka by Myc is transcriptional and is directly mediated via E-boxes, whereas Aurkb is regulated indirectly. Blocking Aurka/b kinase activity with a selective Aurora kinase inhibitor triggers transient mitotic arrest, polyploidization, and apoptosis of Myc-induced lymphomas. These phenotypes are selectively bypassed by a kinase inhibitor-resistant-Aurkb mutant, demonstrating that Aurkb is the primary therapeutic target in the context of Myc. Importantly, apoptosis provoked by Aurk inhibition was p53 independent, suggesting that Aurka/Aurkb inhibitors will show efficacy in treating primary or relapsed malignancies having Myc involvement and/or loss of p53 function. (Blood. 2010;116(9):1498-1505)
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- Lahtela, J., et al.
(författare)
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Effect of adding dapagliflozin as an adjunct to insulin on urinary albumin-to-creatinine ratio over 52 weeks in adults with type 1 diabetes
- 2019
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Dapagliflozin (DAPA), as an adjunct to insulin, was reported to improve glycaemic control, reduce body weight, and was well tolerated (DEPICT-1 and 2 studies) in adults with inadequately controlled type 1 diabetes (T1D; HbA1c: 58-91 mmol/mol [7.5-10.5%]).Materials and methods: In this pooled post hoc analysis of the DEPICT-1 and -2 studies, the effect of DAPA on urinary albumin-to-creatinine ratio (UACR) was evaluated in individuals with T1D with baseline micro or macroalbuminuria.Results: UACR was recorded at baseline for 548, 565, and 532 individuals treated with DAPA 5 mg, DAPA 10 mg, and placebo, respectively; baseline albuminuria was found in 80, 84, and 87 of these individuals in the respective arms. Of these 251 individuals, baseline renal function measured as estimated glomerular filtration rate (eGFR) was normal (eGFR≥90 ml min-1[1.73 m]-2) in 93, mildly impaired in (eGFR≥60-<90 ml min-1[1.73 m]-2) 131, and moderately impaired in 27 individuals (eGFR <60 ml min-1[1.73 m]-2). Changes in eGFR were similar across the treatment arms (data not shown). Dose-dependent decrease in UACR was observed with DAPA treatment at Weeks 12, 18, 24, and 52 (Figure). At Week 52, the differences in UACR between DAPA 10 mg vs placebo and DAPA 5 mg vs placebo were−31.1% (95% CI:−49.9,−5.2) and−13.3 (95% CI:−37.2, 19.8), respectively.Conclusion: Treatment with DAPA, as an adjunct to insulin, provided a dose-dependent benefit in reducing UACR, suggesting renoprotective effects in individuals with T1D with baseline albuminuria.
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- Mathieu, C., et al.
(författare)
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Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial
- 2020
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 22:9, s. 1516-1526
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Tidskriftsartikel (refereegranskat)abstract
- Aim To investigate the long-term efficacy and safety of dapagliflozin as an adjunct to adjustable insulin in adults with type 1 diabetes (T1D) and inadequate glycaemic control. Materials and Methods Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-2) was a placebo-controlled, double-blind, multicentre, phase III study of adults with T1D (HbA1c 7.5%-10.5%) randomized (1:1:1) to receive dapagliflozin 5, 10 mg, or placebo. The efficacy and safety of dapagliflozin over 52 weeks were exploratory endpoints in this extension to DEPICT-2. Results Of 813 participants randomized, 88.2% completed the study. From baseline to 52 weeks, dapagliflozin 5 and 10 mg were associated with reduction in HbA1c (difference [95% CI] vs. placebo: -0.20% [-0.34, -0.06] and -0.25% [-0.38, -0.11], respectively) and adjusted mean percentage change in body weight (difference [95% CI] vs. placebo: -4.42% [-5.19, -3.64] and -4.86% [-5.63, -4.08], respectively). Serious adverse events were reported in the dapagliflozin 5, 10 mg, and placebo groups (32 [11.8%], 19 [7.0%] and 16 [5.9%], respectively). The proportion of hypoglycaemic events was similar across groups; severe hypoglycaemia was uncommon. More participants with events adjudicated as definite diabetic ketoacidosis (DKA) were in the dapagliflozin 5 and 10 mg groups versus placebo (11 [4.1%], 10 [3.7%] and 1 [0.4%], respectively); the majority of events were mild or moderate in severity and all were resolved with treatment. Conclusions Dapagliflozin led to long-term reductions in HbA1c and body weight in adults with T1D, but increased DKA risk compared with placebo.
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| 7. |
- Phillip, M., et al.
(författare)
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Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and-2 studies
- 2021
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Ingår i: Diabetes Obesity & Metabolism. - : Wiley. - 1462-8902 .- 1463-1326. ; 23:2, s. 549-560
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Tidskriftsartikel (refereegranskat)abstract
- Aim To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). Materials and Methods DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. Results Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. Conclusions Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies.
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