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- Arber, C., et al.
(författare)
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Familial Alzheimer’s disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta
- 2020
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 25:11, s. 2919-2931
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Tidskriftsartikel (refereegranskat)abstract
- Familial Alzheimer’s disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD. © 2019, Springer Nature Limited.
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| 2. |
- Arber, C., et al.
(författare)
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Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
- 2019
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme gamma-secretase, cause familial Alzheimer's disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predominantly through gain or loss of function. To address this question, we generated an isogenic allelic series for the PSEN1 mutation intron 4 deletion; represented by control, heterozygous and homozygous mutant induced pluripotent stem cells in addition to a presenilin-1 knockout line. Induced pluripotent stem cell-derived cortical neurons reveal reduced, yet detectable amyloid-beta levels in the presenilin-1 knockout line, and a mutant gene dosage-dependent defect in amyloid precursor protein processing in PSEN1 intron 4 deletion lines, consistent with reduced processivity of gamma-secretase. The different effects of presenilin-1 knockout and the PSEN1 intron 4 deletion mutation on amyloid precursor protein-C99 fragment accumulation, nicastrin maturation and amyloid-beta peptide generation support distinct consequences of familial Alzheimer's disease-associated mutations and knockout of presenilin-1 on the function of gamma-secretase.
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| 5. |
- Arber, N, et al.
(författare)
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Sporadic adenomatous polyp regression with exisulind is effective but toxic : A randomised, double blind, placebo controlled, dose-response study
- 2006
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 55:3, s. 367-373
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: A 12 month, multicentre, randomised, double blind, placebo controlled, phase 3, dose-response study was carried out. Exisulind inhibits tumour growth by induction of apoptosis. The aim of our study was to investigate if exisulind induces regression of sporadic colonic adenomas. Patients and methods: A 12 month multicentre randomised double blind placebo controlled phase 3 dose response study was carried out. At baseline colonoscopy, left sided polyps (3-10 mm) were tattooed, measured, and left in place. Subjects received exisulind 200 or 400 mg, or placebo daily. Follow up sigmoidoscopy was performed after six months, and removal of any remaining polyps at the 12 month colonoscopy. The primary efficacy variable was change in polyp size from baseline. Results: A total of 281 patients were enrolled and randomised, 155 (55%) fulfilled the criteria for the intention to treat (ITT) analysis and 114 (41%) fulfilled the criteria for the efficacy evaluation analysis (patients who underwent the 12 month colonoscopy). The decrease in median polyp size was significantly greater (p = 0.03) in patients who received exisulind 400 mg (-10 mm2) compared with those who received placebo (-4 mm2). Complete or partial response was significantly higher in the exisulind 400 mg group (54.6%) compared with the placebo group (30.2%), and disease progression was significantly lower (6.1% v 27.9%) (p = 0.04 and 0.02, respectively). Increased liver enzymes (8.4%) and abdominal pain (14.7%) were also reported at a greater frequency in the exisulind 400 mg group. Conclusion: Exisulind caused significant regression of sporadic adenomatous polyps but was associated with more toxicity. This model of polyp regression, short in its term and involving a comparatively small patient sample size, may be the best available tool to assess a therapeutic regimen before launching into large preventive clinical studies.
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| 8. |
- Leguit, R. J., et al.
(författare)
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EAHP 2020 workshop proceedings, pediatric myeloid neoplasms
- 2022
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 481:4, s. 621-646
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Forskningsöversikt (refereegranskat)abstract
- The first section of the bone marrow workshop of the European Association of Haematopathology 2020 Virtual Meeting was dedicated to pediatric myeloid neoplasms. The section covered the whole spectrum of myeloid neoplasms, including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN), and acute myeloid leukemia. The workshop cases are hereby presented, preceded by an introduction on these overall rare diseases in this age group. Very rare entities such as primary myelofibrosis, pediatric MDS with fibrosis, and MDS/MPN with JMML-like features and t(4;17)(q12;q21); FIP1L1::RARA fusion, are described in more detail.
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| 9. |
- Mikus, Maria, et al.
(författare)
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Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury
- 2016
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Ingår i: Liver international. - : John Wiley & Sons. - 1478-3223 .- 1478-3231. ; 37:1, s. 132-140
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. Methods: An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. Results: We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. Conclusions: These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.
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