| 1. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 2. |
- Naik, Shalini, et al.
(författare)
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Economic evaluation of caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia in Sweden
- 2011
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Ingår i: Scandinavian Journal of Infectious Diseases. - : Informa UK Limited. - 0036-5548 .- 1651-1980. ; 43:6-7, s. 504-514
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To evaluate the cost-effectiveness of caspofungin versus liposomal amphotericin B (L-AmB) for empirical antifungal therapy in patients with persistent fever and neutropenia in Sweden. Methods: With a decision-analytic model, the expected direct costs, life-years lost and quality adjusted life-years lost were estimated for an average patient in Sweden. Efficacy/tolerability data were obtained from analysis of a randomized, double-blind multinational trial. Life expectancy, medical resource use and unit costs data were gathered from the literature and expert opinion. Probabilistic sensitivity analysis was used to evaluate the impact of uncertainty in data on outcomes. Results: The direct cost with caspofungin amounted to 233,851 SEK (95% uncertainty interval 225,091-242,210) and with L-AmB to 271,921 SEK (262,935-281,363), a difference of 38,070 SEK (31,745-44,811) favouring caspofungin. Treatment with caspofungin resulted in 0.25 (0.01-0.55) quality-adjusted life-years (QALYs) saved in comparison to L-AmB. Given the uncertainty in the estimates there is a >95% probability that caspofungin is economically dominant over L-AmB, i.e. cost-saving and QALY-saving. Conclusion: Given the underlying assumptions and data used, caspofungin is expected to be cost-effective with at least comparable outcomes compared to L-AmB for the empirical treatment of patients with suspected fungal infections in Sweden.
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| 3. |
- Nejadnik, M. Reza, et al.
(författare)
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Self-healing Hybrid Nanocomposites consisting of Bisphosphonated Hyaluronan and Calcium Phosphate Nanoparticles
- 2014
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Ingår i: Biomaterials. - : Elsevier BV. - 0142-9612 .- 1878-5905. ; 35:25, s. 6918-6929
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Tidskriftsartikel (refereegranskat)abstract
- Non-covalent interactions are often regarded as insufficient to construct macroscopic materials of substantial integrity and cohesion. However, the low binding energy of such reversible interactions can be compensated by increasing their number to work in concert to create strong materials. Here we present the successful development of an injectable, cohesive nanocomposite hydrogel based on reversible bonds between calcium phosphate nanoparticles and bisphosphonate-functionalized hyaluronic acid. These nanocomposites display a capacity for self-healing as well as adhesiveness to mineral surfaces such as enamel and hydroxyapatite. Most importantly, these non-covalently cross-linked composites are surprisingly robust yet biodegradable upon extensive in vitro and in vivo testing and show bone interactive capacity evidenced by bone ingrowth into material remnants. The herein presented method provides a new methodology for constructing nanoscale composites for biomedical applications, which owe their integrity to reversible bonds.
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| 4. |
- van Karnebeek, Clara D. M., et al.
(författare)
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CIAO1 and MMS19 de fi ciency : A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders
- 2024
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Ingår i: Genetics in Medicine. - : Elsevier. - 1098-3600 .- 1530-0366. ; 26:6
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome. Studies in patient-derived skin fibroblasts and zebrafish models were performed to investigate the biochemical and cellular consequences.Results: Metabolic analysis showed elevated uracil and thymine levels in body fluids but no pathogenic variants in DPYD, encoding dihydropyrimidine dehydrogenase. Genome sequencing identified compound heterozygosity in 2 patients for missense variants in CIAO1, encoding cytosolic iron-sulfur assembly component 1, and homozygosity for an in-frame 3-nucleotide deletion in MMS19, encoding the MMS19 homolog, cytosolic iron-sulfur assembly component, in the third patient. Profound alterations in the proteome, metabolome, and lipidome were observed in patient-derived fibroblasts. We confirmed the detrimental effect of deficiencies in CIAO1 and MMS19 in zebrafish models.Conclusion: A general failure of cytosolic and nuclear iron-sulfur protein maturation caused pleiotropic effects. The critical function of the cytosolic iron-sulfur protein assembly machinery for antiviral host defense may well explain the recurrent severe infections occurring in our patients. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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