| 1. |
- Åström, Mats E., 1963-, et al.
(författare)
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Extensive accumulation of rare earth elements in estuarine sediments affected by leaching of acid sulfate soils
- 2020
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Ingår i: Boreal Environment Research. - : Finnish Environmental Inst. - 1239-6095 .- 1797-2469. ; 25, s. 105-120
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Tidskriftsartikel (refereegranskat)abstract
- The concentrations, loads and speciation of rare earth elements (REEs) were studied in a 3.5 m thick mud depositional succession from an estuary in the Gulf of Bothnia. The uppermost 182.5 cm of the mud, estimated to have deposited from the early 1970s to 2011 (sampling year), had very high REE concentrations (596-1456 ppm) and accumulation rates (5.2-28 g m(-2) year(-1)). This was explained by large REE export from acid sulfate soils after they became efficiently drained with modern drainage techniques. Geochemical and synchrotron-based spectroscopic (XANES) analyses showed that the REEs in the mud are relatively firmly bound in non-clastic phases, likely adsorbed by clay minerals and also to some extent by iron oxyhydroxides. Below 182.5 cm, the REE concentrations successively decreased down to background values at the base at 3.5 m, reflecting less efficient drainage and leaching of the acid sulfate soils in previous decades and centuries.
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| 2. |
- Kim, Hyeongju, et al.
(författare)
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A pathogenic proteolysis-resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function
- 2022
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 7:17
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is a late-onset neurological disorder for which therapeutics are not available. Its key pathological mechanism involves the proteolysis of polyglutamine-expanded (polyQ-expanded) mutant huntingtin (mHTT), which generates N-terminal fragments containing polyQ, a key contributor to HD pathogenesis. Interestingly, a naturally occurring spliced form of HTT mRNA with truncated exon 12 encodes an HTT (HTT & UDelta;12) with a deletion near the caspase-6 cleavage site. In this study, we used a multidisciplinary approach to characterize the therapeutic potential of targeting HTT exon 12. We show that HTT & UDelta;12 was resistant to caspase-6 cleavage in both cell-free and tissue lysate assays. However, HTT & UDelta;12 retained overall biochemical and structural properties similar to those of wt-HTT. We generated mice in which HTT exon 12 was truncated and found that the canonical exon 12 was dispensable for the main physiological functions of HTT, including embryonic development and intracellular trafficking. Finally, we pharmacologically induced HTT & UDelta;12 using the antisense oligonucleotide (ASO) QRX-704. QRX-704 showed predictable pharmacology and efficient biodistribution. In addition, it was stable for several months and inhibited pathogenic proteolysis. Furthermore, QRX-704 treatments resulted in a reduction of HTT aggregation and an increase in dendritic spine count. Thus, ASO-induced HTT exon 12 splice switching from HTT may provide an alternative therapeutic strategy for HD.
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| 3. |
- Mateos, Marion K., et al.
(författare)
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Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children
- 2020
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p < 5 × 10−8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p < 1 × 10−6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10−7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10−7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
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| 4. |
- Pipe, Steven W., et al.
(författare)
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Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B
- 2023
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 388:8, s. 706-718
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Tidskriftsartikel (refereegranskat)abstract
- Background: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. Methods: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. Results: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. Conclusions: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile.
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