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- Eron, Joseph J., et al.
(författare)
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Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1
- 2019
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Ingår i: Antiviral Research. - : Elsevier BV. - 0166-3542 .- 1872-9096. ; 170
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Tidskriftsartikel (refereegranskat)abstract
- © 2019 The Authors Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52–96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF.
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- Koerkamp, M. G., et al.
(författare)
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Dissection of transient oxidative stress response in Saccharomyces cerevisiae by using DNA microarrays
- 2002
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Ingår i: Molecular Biology of the Cell. - 1059-1524 .- 1939-4586. ; 13:8, s. 2783-2794
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Tidskriftsartikel (refereegranskat)abstract
- Yeast cells were grown in glucose-limited chemostat cultures and forced to switch to a new carbon source, the fatty acid oleate. Alterations in gene expression were monitored using DNA microarrays combined with bioinformatics tools, among which was included the recently developed algorithm REDUCE. Immediately after the switch to oleate, a transient and very specific stress response was observed, followed by the up-regulation of genes encoding peroxisomal enzymes required for fatty acid metabolism. The stress response included up-regulation of genes coding for enzymes to keep thioredoxin and glutathione reduced, as well as enzymes required for the detoxification of reactive oxygen species. Among the genes coding for various isoenzymes involved in these processes, only a specific subset was expressed. Not the general stress transcription factors Msn2 and Msn4, but rather the specific factor Yap1p seemed to be the main regulator of the stress response. We ascribe the initiation of the oxidative stress response to a combination of poor redox flux and fatty acid-induced uncoupling of the respiratory chain during the metabolic reprogramming phase.
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- Raj, K, et al.
(författare)
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Comparison of outcomes for HLA-matched sibling and haplo-identical donors in Myelodysplastic syndromes: report from the chronic malignancies working party of EBMT
- 2022
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Ingår i: Blood cancer journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 12:9, s. 140-
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Tidskriftsartikel (refereegranskat)abstract
- Myelodysplastic syndromes (MDS) are the second common indication for an Allo-HCT. We compared the outcomes of 1414 matched sibling (MSD) with 415 haplo-identical donors (HD) transplanted with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis between 2014 and 2017. The median age at transplant with MSD was 58 and 61 years for HD. The median time to neutrophil engraftment was longer for HD being 20 vs 16 days for MSD (p < 0.001). Two-year overall survival (OS) and PFS (progression free survival) with MSD were significantly better at 58% compared with 50%, p ≤ 0.001, and 51% vs 47%, p = 0.029, with a HD. Relapse at 2 years was lower with a HD 23% than with MSD 29% (p = 0.016). Non relapse mortality (NRM) was higher with HD in the first 6 months post-transplant [HR 2.59 (1.5–4.48) p < 0.001] and was also higher at 2 years being 30% for HD and 20% for MSD, p ≤ 0.001. The incidence of acute GVHD grade II-IV and III–IV at 100 days was comparable for MSD and HD, however, chronic GVHD at 2 years was significantly higher with MSD being 44% vs 32% for HD (p < 0.001). After multivariable analysis, OS and primary graft failure were significantly worse for HD particularly before 6 months [HR 1.93(1.24–3.0)], and HR [3.5(1.5–8.1)]. The median age of HD 37 (IQR 30–47) years was significantly lower than sibling donors 56 (IQR 49–62 years) p < 0.001. However, there was no effect on NRM, relapse or PFS. This data set suggests that a MSD donor remains the preferred choice in MDS over a haplo donor. Transplants with haploidentical donors result in satisfactory long-term outcome, justifying it’s use when no better donor is available.
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