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| 3. |
- Haiman, Christopher A., et al.
(författare)
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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| 4. |
- Menkveld, Albert J., et al.
(författare)
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Nonstandard Errors
- 2024
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Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
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Tidskriftsartikel (refereegranskat)abstract
- In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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| 5. |
- Cornelissen, Johannes H C, et al.
(författare)
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Global negative vegetation feedback to climate warming responses of leaf litter decomposition rates in cold biomes
- 2007
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Ingår i: Ecology Letters. - : Wiley. - 1461-023X .- 1461-0248. ; 10:7, s. 619-627
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Tidskriftsartikel (refereegranskat)abstract
- Whether climate change will turn cold biomes from large long-term carbon sinks into sources is hotly debated because of the great potential for ecosystem-mediated feedbacks to global climate. Critical are the direction, magnitude and generality of climate responses of plant litter decomposition. Here, we present the first quantitative analysis of the major climate-change-related drivers of litter decomposition rates in cold northern biomes worldwide.Leaf litters collected from the predominant species in 33 global change manipulation experiments in circum-arctic-alpine ecosystems were incubated simultaneously in two contrasting arctic life zones. We demonstrate that longer-term, large-scale changes to leaf litter decomposition will be driven primarily by both direct warming effects and concomitant shifts in plant growth form composition, with a much smaller role for changes in litter quality within species. Specifically, the ongoing warming-induced expansion of shrubs with recalcitrant leaf litter across cold biomes would constitute a negative feedback to global warming. Depending on the strength of other (previously reported) positive feedbacks of shrub expansion on soil carbon turnover, this may partly counteract direct warming enhancement of litter decomposition.
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| 8. |
- Mereaux, JL, et al.
(författare)
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Increasing involvement of CAPN1 variants in spastic ataxias and phenotype-genotype correlations
- 2021
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Ingår i: Neurogenetics. - : Springer Science and Business Media LLC. - 1364-6753 .- 1364-6745. ; 22:1, s. 71-79
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Tidskriftsartikel (refereegranskat)abstract
- Spastic ataxias are rare neurogenetic disorders involving spinocerebellar and pyramidal tracts. Many genes are involved. Among them, CAPN1, when mutated, is responsible for a complex inherited form of spastic paraplegia (SPG76). We report the largest published series of 21 novel patients with nine new CAPN1 disease-causing variants and their clinical characteristics from two European university hospitals (Paris and Stockholm). After a formal clinical examination, causative variants were identified by next-generation sequencing and confirmed by Sanger sequencing. CAPN1 variants are a rare cause (~ 1.4%) of young-adult-onset spastic ataxia; however, together with all published cases, they allowed us to better describe the clinical and genetic spectra of this form. Truncating variants are the most frequent, and missense variants lead to earlier age at onset in favor of an additional deleterious effect. Cerebellar ataxia with cerebellar atrophy, dysarthria and lower limb weakness are often associated with spasticity. We also suggest that cognitive impairment and depression should be assessed specifically in the follow-up of SPG76 cases.
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| 9. |
- Freischmidt, Axel, et al.
(författare)
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Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
- 2015
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
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| 15. |
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| 16. |
- Cheng, Q., et al.
(författare)
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Clinical epidemiology of Guillain-Barré syndrome in adults in Sweden 1996-97 : A prospective study
- 2000
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 7:6, s. 685-692
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Tidskriftsartikel (refereegranskat)abstract
- We described clinical manifestations, outcomes, prognostic indicators and clinico-epidemiological subgroups for 53 adult patients with Guillain-Barré syndrome (GBS) in Sweden during the period 1996-97. These patients were identified from a population of 2.8 million inhabitants and prospectively followed up for one year by a network of neurologists. An additional 10 cases, of whom five were adults who had not been prospectively followed up, were not included in the analyses. At 6 months after onset 80% of the patients could walk without aid, while at 1 year 46% were fully recovered, 42% had mild residual signs or symptoms, 4% had moderate and 6% severe disabilities, and 2% had died. Intravenous human immunoglobulin or plasmapheresis were used in 72% of the patients. The sum of the Medical Research Council (MRC) score at nadir was found as the only significant predictor for residual signs at 1 year in a multivariate model. Three subgroups, with different clinico-epidemiological characteristics, were identified by using cluster analysis. In conclusion, GBS in Sweden is frequently preceded by a respiratory infection, is often treated with immunomodulatory therapies, and exhibits a high recovery rate and a low fatality rate.
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| 17. |
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| 18. |
- Frost, Sofia, 1981, et al.
(författare)
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α-Imaging Confirmed Efficient Targeting of CD45-Positive Cells After 211At-Radioimmunotherapy for Hematopoietic Cell Transplantation.
- 2015
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Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 1535-5667. ; 56:11, s. 1766-1773
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Tidskriftsartikel (refereegranskat)abstract
- Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-211 ((211)At)-radioimmunotherapy, extending the analysis to include intra-organ (211)At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining.
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| 19. |
- Green, Damian J, et al.
(författare)
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Astatine-211 conjugated to an anti-CD20 monoclonal antibody eradicates disseminated B-cell lymphoma in a mouse model.
- 2015
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 125:13, s. 2111-9
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Tidskriftsartikel (refereegranskat)abstract
- α-Emitting radionuclides deposit a large amount of energy within a few cell diameters and may be particularly effective for radioimmunotherapy targeting minimal residual disease (MRD). To evaluate this hypothesis, (211)At-labeled 1F5 monoclonal antibody (mAb) (anti-CD20) was studied in both bulky lymphoma tumor xenograft and MRD animal models. Superior treatment responses to (211)At-labeled 1F5 mAb were evident in the MRD setting. Lymphoma xenograft tumor-bearing animals treated with doses of up to 48 µCi of (211)At-labeled anti-CD20 mAb ([(211)At]1F5-B10) experienced modest responses (0% cures but two- to threefold prolongation of survival compared with negative controls). In contrast, 70% of animals in the MRD lymphoma model demonstrated complete eradication of disease when treated with (211)At-B10-1F5 at a radiation dose that was less than one-third (15 µCi) of the highest dose given to xenograft animals. Tumor progression among untreated control animals in both models was uniformly lethal. After 130 days, no significant renal or hepatic toxicity was observed in the cured animals receiving 15 µCi of [(211)At]1F5-B10. These findings suggest that α-emitters are highly efficacious in MRD settings, where isolated cells and small tumor clusters prevail.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Zabriskie, Matthew S., et al.
(författare)
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BCR-ABL1 Compound Mutations Combining Key Kinase Domain Positions Confer Clinical Resistance to Ponatinib in Ph Chromosome-Positive Leukemia
- 2014
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 26:3, s. 428-442
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Tidskriftsartikel (refereegranskat)abstract
- Ponatinib is the only currently approved tyrosine kinase inhibitor (TKI) that suppresses all BCR-ABL1 single mutants in Philadelphia chromosome-positive (Ph+) leukemia, including the recalcitrant BCR-ABL1(T315I) mutant. However, emergence of compound mutations in a BCR-ABL1 allele may confer ponatinib resistance. We found that clinically reported BCR-ABL1 compound mutants center on 12 key positions and confer varying resistance to imatinib, nilotinib, dasatinib, ponatinib, rebastinib, and bosutinib. T315I-inclusive compound mutants confer high-level resistance to TKIs, including ponatinib. In vitro resistance profiling was predictive of treatment outcomes in Ph+ leukemia patients. Structural explanations for compound mutation-based resistance were obtained through molecular dynamics simulations. Our findings demonstrate that BCR-ABL1 compound mutants confer different levels of TKI resistance, necessitating rational treatment selection to optimize clinical outcome.
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| 24. |
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| 25. |
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| 26. |
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| 27. |
- Corcia, Philippe, et al.
(författare)
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Homozygous SMN2 deletion is a protective factor in the Swedish ALS population
- 2012
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 20:5, s. 588-591
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations. European Journal of Human Genetics (2012) 20, 588-591; doi:10.1038/ejhg.2011.255; published online 25 January 2012
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| 28. |
- Cornelissen, C, et al.
(författare)
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Global change and arctic ecosystems : is lichen decline a function of increases in vascular plant biomass?
- 2001
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Ingår i: Journal of Ecology. - : Wiley. - 0022-0477 .- 1365-2745. ; 89:6, s. 984-994
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Tidskriftsartikel (refereegranskat)abstract
- 1 Macrolichens are important for the functioning and biodiversity of cold northern ecosystems and their reindeer-based cultures and economics. 2 We hypothesized that, in climatically milder parts of the Arctic, where ecosystems have relatively dense plant canopies, climate warming and/or increased nutrient availability leads to decline in macrolichen abundance as a function of increased abundance of vascular plants. In more open high-arctic or arctic-alpine plant communities such a relationship should be absent. To test this, we synthesized cross-continental arctic vegetation data from ecosystem manipulation experiments simulating mostly warming and increased nutrient availability, and compared these with similar data from natural environmental gradients. 3 Regressions between abundance or biomass of macrolichens and vascular plants were consistently negative across the subarctic and mid-arctic experimental studies. Such a pattern did not emerge in the coldest high-arctic or arctic-alpine sites. The slopes of the negative regressions increased across 10 sites as the climate became milder (as indicated by a simple climatic index) or the vegetation denser (greater site above-ground biomass). 4 Seven natural vegetation gradients in the lower-altitude sub- and mid-arctic zone confirmed the patterns seen in the experimental studies, showing consistent negative relationships between abundance of macrolichens and vascular plants. 5 We conclude that the data supported the hypothesis. Macrolichens in climatically milder arctic ecosystems may decline if and where global changes cause vascular plants to increase in abundance. 6 However, a refining of our findings is needed, for instance by integrating other abiotic and biotic effects such as reindeer grazing feedback on the balance between vascular plants and lichens.
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| 29. |
- Frost, Sofia, 1981, et al.
(författare)
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Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models.
- 2015
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.
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| 30. |
- Huang, YM, et al.
(författare)
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Dendritic cells derived from patients with multiple sclerosis show high CD1a and low CD86 expression
- 2001
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Ingår i: Multiple sclerosis (Houndmills, Basingstoke, England). - : SAGE Publications. - 1352-4585 .- 1477-0970. ; 7:2, s. 95-99
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DC) are important antigen presenting cells (APC) and play a major role in initiating and orchestrating immune responses by priming T cells. Little is known about involvement of DC in multiple sclerosis (MS), where auto-aggressive T cells against myelin autoantigens are considered to contribute to inflammation and demyelination in the central nervous system. In this study, we compared phenotype and cytokine secretion of DC from patients with MS, other neurological diseases (OND) and healthy subjects. DC were generated from blood adherent mononuclear cells (MNC) by culture for 7 days with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield and morphology of DC were similar in MS patients and controls. In both, the DC phenotype was that of immature myeloid lineage, comprising CD1a+ and CD11c+. The proportion of CD1a+ DC, being important for presentation of lipid antigens to T cells, was higher in MS patients compared to controls. The proportion of CD86+ DC, a co-stimulatory molecule that is assumed to promote Th2 differentiation, was low in MS. Low proportions of CD86+ DC were only observed in untreated MS patients but not in patients treated with IFN-b. Production of IL-10 and IL-12 p40 by DC did not differ in MS patients and controls. These findings indicate that alterations of functionally important surface molecules on DC are associated with MS.
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| 31. |
- Hytteborn, Håkan, et al.
(författare)
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Century-long tree population dynamics in a deciduous forest stand in central Sweden
- 2017
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Ingår i: Journal of Vegetation Science. - : Wiley. - 1100-9233 .- 1654-1103. ; 28:5, s. 1057-1069
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Tidskriftsartikel (refereegranskat)abstract
- Question: We quantify tree dynamics over a century of free development in a small broadleaved forest dominated by Fraxinus excelsior and Ulmus glabra. What are the internal and external factors driving the changes, and how predictable are they? What were the time scale and effects of the spread of Dutch elm disease (DED)? Location: Vårdsätra, eastern central Sweden.Methods: The survival, growth and recruitment of all trees (≥ 12 cm in girth) were monitored in 1912, 1967, 1988 and 2013 (more often for a part of the forest). Woody species in the field and shrub layers were surveyed in permanent plots in 1976 and 2012. We used transition matrix models to project changes in population sizes and species composition within the century and for 2050.Results: The results indicate that the forest was in a successional development during the first period. The species composition had stabilised by 1967, except for an expansion of Acer platanoides and the drastic effect of DED that struck the forest around 2000. It took only a decade to kill virtually all large elms in the forest, leading to strong decrease in stem density and basal area. The evidence for effects of DED is still weak, but there has been an increase in saplings, notably of Fraxinus, Prunus padus, Ulmus, and of shoots of Corylus avellana. Several species that are abundant in the vicinity and as seeds fail to establish (Picea abies, Betula spp., Quercus robur, Populus tremula). Projections for 2050 based on the third period (1988-2013) are probably unrealistic since also Fraxinus may disappear because of the recent arrival of the ash dieback.Conclusions: Slow dynamics in forests that could follow from climate change will locally probably be overruled by unforeseen catastrophes, such as invasions by forest pathogens. These initiate changes with long lag phases difficult to quantify. Still, a dense deciduous forest can resist invasion of colonist species and of regionally dominant conifers; the reason being unfavourable conditions for establishment rather than dispersal limitation
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| 32. |
- Ingre, Caroline, et al.
(författare)
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A 50bp deletion in the SOD1 promoter lowers enzyme expression but is not associated with ALS in Sweden
- 2016
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Informa UK Limited. - 2167-8421 .- 2167-9223. ; 17:5-6, s. 452-457
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the superoxide dismutase (SOD1) gene have been linked to amyotrophic lateral sclerosis (ALS). A 50 base pair (bp) deletion of SOD1 has been suggested to reduce transcription and to be associated with later disease onset in ALS. This study was aimed to reveal if the 50bp deletion influenced SOD1 enzymatic activity, occurrence and phenotype of the disease in a Swedish ALS/control cohort. Blood samples from 512 Swedish ALS patients and 354 Swedish controls without coding SOD1 mutations were analysed for the 50bp deletion allele. The enzymatic activity of SOD1 in erythrocytes was analysed and genotype-phenotype correlations were assessed. Results demonstrated that the genotype frequencies of the 50bp deletion were all found to be in Hardy-Weinberg equilibrium. No significant differences were found for age of onset, disease duration or site of onset. SOD1 enzymatic activity showed a statistically significant decreasing trend in the control group, in which the allele was associated with a 5% reduction in SOD1 activity. The results suggest that the 50bp deletion has a moderate reducing effect on SOD1 synthesis. No modulating effects, however, were found on ALS onset, phenotype and survival in the Swedish population.
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| 33. |
- Ingre, Caroline, 1977-, et al.
(författare)
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A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts
- 2013
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Ingår i: Neurobiology of Aging. - New York : Elsevier. - 0197-4580 .- 1558-1497. ; 34:6
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Tidskriftsartikel (refereegranskat)abstract
- Profilin 1 is a central regulator of actin dynamics. Mutations in the gene profilin 1 (PFN1) have veryrecently been shown to be the cause of a subgroup of amyotrophic lateral sclerosis (ALS). Here, weperformed a large screen of US, Nordic, and German familial and sporadic ALS and frontotemporaldementia (FTLD) patients for PFN1 mutations to get further insight into the spectrum and pathogenicrelevance of this gene for the complete ALS/FTLD continuum. Four hundred twelve familial and 260sporadic ALS cases and 16 ALS/FTLD cases from Germany, the Nordic countries, and the United Stateswere screened for PFN1 mutations. Phenotypes of patients carrying PFN1 mutations were studied. Ina German ALS family we identified the novel heterozygous PFN1 mutation p.Thr109Met, which wasabsent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. The recentlydescribed p.Gln117Gly sequence variant was found in another familial ALS patient from the United States.The ALS patients with mutations in PFN1 displayed spinal onset motor neuron disease without overtcognitive involvement. PFN1 mutations were absent in patients with motor neuron disease anddementia, and in patients with only FTLD. We provide further evidence that PFN1 mutations can causeALS as a Mendelian dominant trait. Patients carrying PFN1 mutations reported so far represent the“classic” ALS end of the ALS-FTLD spectrum. The novel p.Thr109Met mutation provides additional proofof-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motorneuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization byphosphorylation of profilin 1 might be necessary for motor neuron survival.
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| 34. |
- Ingre, Caroline, 1977-, et al.
(författare)
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Erythrocyte SOD1 enzyme activity in ALS patients is not modulated by a 50 bp deletion in the alleged SOD1 promotor
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background A known cause of ALS are mutations in the SOD1 gene. There is also evidence that SOD1 may be involved in cases lacking mutations in the gene. A 50 bp deletion located 1684 bp upstream of the start codon of SOD1 has been suggested to reduce transcription of SOD1, affect enzymatic activity and to be associated with later disease onset in ALS patients. The findings have been challenged by a study of Italian ALS patients, and here we examined the 50 bp deletion in Swedish ALS patients and controls. Methods Blood samples from 543 Swedish ALS patients and 356 Swedish controls were analysed for the 50 bp deletion and for SOD1 enzymic activity. The results were related to the disease phenotype of the patients.Results The frequency of the 50 bp deletion was the same in the patient and control cohorts, and both were found to be in Hardy-Weinberg equilibrium regarding the deletion. In relation to the different genotypes, no differences were detected in SOD1 enzymic activity, duration of disease, age of onset or site of onset.Conclusions When interpreting the present results together with previous results from other populations, we find it unlikely that the 50 bp deletion region has any regulatory function for the SOD1 gene, nor any effects on the phenotype of ALS.
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| 35. |
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| 36. |
- Ingre, Caroline, 1977-, et al.
(författare)
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No association between VAPB mutations and familial or sporadic ALS in Sweden, Portugal and Iceland
- 2013
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Ingår i: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION. - : Informa Healthcare. - 2167-8421 .- 2167-9223. ; 14:7-8, s. 620-627
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Tidskriftsartikel (refereegranskat)abstract
- Linkage analysis in Brazilian families with amyotrophic lateral sclerosis (ALS) revealed that a missense mutation p. Pro56Ser in a conserved gene VAMP-associated protein type B and C (VAPB) cosegregates with disease. Blood samples were studied from 973 Swedish, 126 Portuguese and 19 Icelandic ALS patients, and from 644 control subjects. We identified five VAPB mutations, two of which are novel, in 14 Swedish ALS patients and in nine control individuals from Sweden and Portugal. The 14 patients with VAPB mutations all carried a diagnosis of sporadic ALS. Mutations were also found in healthy adult relatives. The p. Asp130Glu VAPB mutation was also found in two patients from an Icelandic ALS family, but the mutation did not cosegregate with disease. All patients were instead found to be heterozygous for a p.Gly93Ser SOD1 mutation. There were no clinical differences between them, suggesting that the p. Asp130Glu VAPB mutation is unrelated to the disease process. less thanbrgreater than less thanbrgreater thanIn conclusion, the VAPB mutations were as frequent in control individuals as in patients. This observation, in combination with the finding of several healthy relatives carrying the VAPB mutations and no ancestors with ALS disease, suggests that it is unlikely that these VAPB mutations are pathogenic.
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| 37. |
- Ingre, Caroline, 1977-
(författare)
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On the aetiology of ALS : a comprehensive genetic study
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Amyotrophic lateral sclerosis (ALS) is a deadly, progressive neuromuscular disease that affects individuals all over the world. About 10% of the patients have a familial predisposition (FALS) while the remainder of cases are isolated or sporadic (SALS) and of unknown cause. To date, the principal recognized risk factors for ALS are higher age, male gender, slim figure (BMI<23) and a family history of ALS. In 1993, Rosen et al. observed that some FALS cases were associated with mutations in the gene encoding the CuZn superoxide dismutase enzyme (SOD1). Since then, several mutations in the SOD1 gene have been discovered, and mutations in more than 18 other genes have been associated with causing ALS. The aim of this thesis was to identify new mutations associated with ALS pathogenesis, and by comparing patients from different countries, were we also able to identify population-specific genetic variations. The studies are referred to as I–V.Methods: With written informed consent and adhering to the tenets of the Declaration of Helsinki, through a national network of ALS clinicians´, venous blood samples were collected from ALS patients and healthy subjects in Europe and the USA. The patients were diagnosed according to the El Escorial criteria, and as having FALS according to the criteria of Byrne et al. (2011). The DNA variations were amplified by various PCR techniques. (I, III and IV) The amplicons of ataxin 2 (ATXN2), profilin 1 (PFN1), and vesicle-associated membrane protein type B (VAPB) were characterised by direct sequencing. (II) After quantitative PCR, a genotype-phenotype correlation was performed to assess whether the survival motor neuron gene (SMN) modulates the phenotype of ALS. (V) The amplicons of the 50 base pair deletion in the SOD1 promotor (50 bp) were separated by electrophoresis on agarose.Results: (I) We observed a significant association between CAG expansions in the ATXN2 gene and ALS in a European cohort. (II) Abnormal copy number of the SMN1 gene was identified as a risk factor in France, but not in Sweden. Homozygosity of the SMN2 deletion prolonged survival among Swedish ALS patients, compared to French patients. (III) We identified two mutations in the PFN1 gene, the novel p.Thr109Met mutation and the p.Gln117Gly mutation, in two unrelated FALS patients. (IV) In our cohort, we identified five VAPB mutations p.Asp130Glu, p.Ser160del, p.Asp162Glu, p.Met170Ile, and p.Arg184Trp, two of which are novel. (V) The 50 bp deletion upstream of the SOD1 gene was found in equal frequencies in both the patient and control cohorts. The 50 bp deletion did not affect SOD1 enzymatic activity. Furthermore, we found no differences in age of onset or disease duration in relation to the 50 bp deletion genotype.VIConclusions: (I) Our findings indicate that ATXN2 plays an important role in the pathogenesis of ALS, and that CAG expansions in ATXN2 are a significant risk factor for the disease. (II) We suggest that abnormal SMN1 gene copynumber cannot be considered a universal genetic susceptibility factor for ALS. We also propose that the effect of abnormal SMN2 gene copy number on ALS phenotype may differ between populations. (III) This work provides evidence that PFN1 mutations can cause ALS as a Mendelian dominant trait. The novel p.Thr109Met mutation also shows that disturbance of actin dynamics can cause motor neuron degeneration. (IV) We find it unlikely that the VAPB mutations cause ALS in our cohorts. (V) We find it unlikely that the 50 bp region contains important regulatory elements for SOD1 expression. This thesis supports the theory that ALS is a multigenetic disease, but there appears to be great genetic variation among apparently identical populations. These studies emphasise the importance of continuous genetic screening, to identify further mutations and genes involved in ALS disease, but it also highlights the importance of cooperation and comparison between countries.
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| 38. |
- Kim, Haesook T., et al.
(författare)
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Prognostic Score and Cytogenetic Risk Classification for Chronic Lymphocytic Leukemia Patients : Center for International Blood and Marrow Transplant Research Report
- 2019
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Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 25:16, s. 5143-5155
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT).Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research.Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or >= 5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years).Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.
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- Longinetti, Elisa, et al.
(författare)
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The Swedish motor neuron disease quality registry
- 2018
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Ingår i: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis. - 2167-8421 .- 2167-9223. ; 19:7-8, s. 528-537
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We set up the Swedish Motor Neuron Disease (MND) Quality Registry to assure early diagnosis and high-quality health care for all MND patients (mainly amyotrophic lateral sclerosis, ALS), and to create a research base by prospectively following the entire MND population in Sweden. Methods: Since 2015, the MND Quality Registry continuously collects information about a wide range of clinical measures, biological samples, and quality of life outcomes from all MND patients recruited at the time of MND diagnosis in Sweden and followed at each clinic visit approximately every 12 weeks. The Registry includes an Internet based patient own reporting portal that involves patients in the registration of their current symptoms and health status. Results: As of 20th January 2017, the MND Quality Registry included 99% of the MND patients of the Stockholm area (N = 194), consisting mostly of ALS patients (N = 153, 78.9%), followed by patients labeled as MND due to a neurophysiology finding but not fulfilling the criteria for ALS (N = 20, 10.3%), primary lateral sclerosis (N = 13, 6.7%), and progressive spinal muscular atrophy patients (N = 8, 4.1%). A higher proportion of these patients were women (N = 100, 52%), and women and men had a similar age at symptoms onset (59 years). Conclusions: Main strengths of the MND Quality Registry are its clinical, quantitative, qualitative, and prospective nature, providing the researchers potential means of identifying appropriate candidates for clinical trials and other research projects, as well as assuring to the patients an effective and adequate time spent on-site with the healthcare professionals.
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- Pagel, John M, et al.
(författare)
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Anti-CD45 pretargeted radioimmunotherapy using bismuth-213: high rates of complete remission and long-term survival in a mouse myeloid leukemia xenograft model.
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:3, s. 703-11
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Tidskriftsartikel (refereegranskat)abstract
- Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with acute myeloid leukemia. Accordingly, we have used (213)Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of (213)Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5% ± 1.1% of the injected dose of (213)Bi was delivered per gram of tumor. α-imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after (213)Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide ((90)Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of (213)Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of (213)Bi- or (90)Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for more than 100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of acute myeloid leukemia.
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- Piehl, F., et al.
(författare)
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Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis The RINOMAX Randomized Clinical Trial
- 2022
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157.
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown. OBJECTIVE To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG. DESIGN, SETTING, AND PARTICIPANTS This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids. INTERVENTIONS Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo. MAIN OUTCOMES AND MEASURES Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment. RESULTS Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event. CONCLUSIONS AND RELEVANCE A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment.
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