| 1. |
- Panneman, Daan M., et al.
(författare)
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Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis
- 2023
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.
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| 2. |
- Coomans, Emma M., et al.
(författare)
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Performance of a [18F]Flortaucipir PET Visual Read Method Across the Alzheimer Disease Continuum and in Dementia with Lewy Bodies
- 2023
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 101:19, s. 1850-1862
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesRecently, the US Food and Drug Administration approved the tau-binding radiotracer [18F]flortaucipir and an accompanying visual read method to support the diagnostic process in cognitively impaired patients assessed for Alzheimer disease (AD). Studies evaluating this visual read method are limited. In this study, we evaluated the performance of the visual read method in participants along the AD continuum and dementia with Lewy bodies (DLB) by determining its reliability, accordance with semiquantitative analyses, and associations with clinically relevant variables.MethodsWe included participants who underwent tau-PET at Amsterdam University Medical Center. A subset underwent follow-up tau-PET. Two trained nuclear medicine physicians visually assessed all scans. Inter-reader agreement was calculated using Cohen . To examine the concordance of visual read tau positivity with semiquantification, we defined standardized uptake value ratio (SUVr) positivity using different threshold approaches. To evaluate the prognostic value of tau-PET visual read, we performed linear mixed models with longitudinal Mini-Mental State Examination (MMSE).ResultsWe included 263 participants (mean age 68.5 years, 45.6% female), including 147 cognitively unimpaired (CU) participants, 97 amyloid-positive participants with mild cognitive impairment or AD dementia (AD), and 19 participants with DLB. The visual read inter-reader agreement was excellent ( = 0.95, CI 0.91-0.99). None of the amyloid-negative CU participants (0/92 [0%]) and 1 amyloid-negative participant with DLB (1/12 [8.3%]) were tau-positive. Among amyloid-positive participants, 13 CU participants (13/52 [25.0%]), 85 with AD (85/97 [87.6%]), and 3 with DLB (3/7 [42.9%]) were tau-positive. Two-year follow-up visual read status was identical to baseline. Tau-PET visual read corresponded strongly to SUVr status, with up to 90.4% concordance. Visual read tau positivity was associated with a decline on the MMSE in CU participants (β =-0.52, CI-0.74 to-0.30, p < 0.001) and participants with AD (β =-0.30, CI-0.58 to-0.02, p = 0.04).DiscussionThe excellent inter-reader agreement, strong correspondence with SUVr, and longitudinal stability indicate that the visual read method is reliable and robust, supporting clinical application. Furthermore, visual read tau positivity was associated with prospective cognitive decline, highlighting its additional prognostic potential. Future studies in unselected cohorts are needed for a better generalizability to the clinical population.Classification of EvidenceThis study provides Class II evidence that [18F]flortaucipir visual read accurately distinguishes patients with low tau-Tracer binding from those with high tau-Tracer binding and is associated with amyloid positivity and cognitive decline.
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| 3. |
- Nano, Rita, et al.
(författare)
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Heterogeneity of Human Pancreatic Islet Isolation Around Europe : Results of a Survey Study
- 2020
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Ingår i: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 104:1, s. 190-196
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Tidskriftsartikel (refereegranskat)abstract
- Background: Europe is currently the most active region in the field of pancreatic islet transplantation, and many of the leading groups are actually achieving similar good outcomes. Further collaborative advances in the field require the standardization of islet cell product isolation processes, and this work aimed to identify differences in the human pancreatic islet isolation processes within European countries.Methods: A web-based questionnaire about critical steps, including donor selection, pancreas processing, pancreas perfusion and digestion, islet counting and culture, islet quality evaluation, microbiological evaluation, and release criteria of the product, was completed by isolation facilities participating at the Ninth International European Pancreas and Islet Transplant Association (EPITA) Workshop on Islet-Beta Cell Replacement in Milan.Results: Eleven islet isolation facilities completed the questionnaire. The facilities reported 445 and 53 islet isolations per year over the last 3 years from deceased organ donors and pancreatectomized patients, respectively. This activity resulted in 120 and 40 infusions per year in allograft and autograft recipients, respectively. Differences among facilities emerged in donor selection (age, cold ischemia time, intensive care unit length, amylase concentration), pancreas procurement, isolation procedures (brand and concentration of collagenase, additive, maximum acceptable digestion time), quality evaluation, and release criteria for transplantation (glucose-stimulated insulin secretion tests, islet numbers, and purity). Moreover, even when a high concordance about the relevance of one parameter was evident, thresholds for the acceptance were different among facilities.Conclusions: The result highlighted the presence of a heterogeneity in the islet cell product process and product release criteria.
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| 4. |
- Blombach, Fabian, et al.
(författare)
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Archaeal MBF1 binds to 30S and 70S ribosomes via its helix-turn-helix domain
- 2014
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Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 462, s. 373-384
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Tidskriftsartikel (refereegranskat)abstract
- MBF1 (multi-protein bridging factor 1) is a protein containing a conserved HTH (helix-turn-helix) domain in both eukaryotes and archaea. Eukaryotic MBF1 has been reported to function as a transcriptional co-activator that physically bridges transcription regulators with the core transcription initiation machinery of RNA polymerase II. In addition, MBF1 has been found to be associated with polyadenylated mRNA in yeast as well as in mammalian cells. aMBF1 (archaeal MBF1) is very well conserved among most archaeal lineages; however, its function has so far remained elusive. To address this, we have conducted a molecular characterization of this aMBF1. Affinity purification of interacting proteins indicates that aMBF1 binds to ribosomal subunits. On sucrose density gradients, aMBF1 co-fractionates with free 30S ribosomal subunits as well as with 70S ribosomes engaged in translation. Binding of aMBF1 to ribosomes does not inhibit translation. Using NMR spectroscopy, we show that aMBF1 contains a long intrinsically disordered linker connecting the predicted N-terminal zinc-ribbon domain with the C-terminal HTH domain. The HTH domain, which is conserved in all archaeal and eukaryotic MBF1 homologues, is directly involved in the association of aMBF1 with ribosomes. The disordered linker of the ribosome-bound aMBF1 provides the N-terminal domain with high flexibility in the aMBF1 ribosome complex. Overall, our findings suggest a role for aMBF1 in the archaeal translation process.
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| 5. |
- Piemonti, Lorenzo, et al.
(författare)
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US food and drug administration (FDA) panel endorses islet cell treatment for type 1 diabetes : A pyrrhic victory?
- 2021
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Ingår i: Transplant International. - : John Wiley & Sons. - 0934-0874 .- 1432-2277. ; 34:7, s. 1182-1186
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Allogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of continental Europe, and parts of Canada. The United States is now endorsing islet cell treatment for type 1 diabetes, but the FDA has chosen to consider islets as a biologic that requires licensure, making the universal implementation of the procedure in the clinic very challenging and opening the manufacture of islet grafts to private companies. The commercialization of human tissues raises significant legal and ethical issues and ironically leads to a situation where treatments developed as a result of the scientific and economic efforts of academia over several decades become exploited exclusively by for-profit entities.
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