| 1. |
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| 2. |
- Crous, P. W., et al.
(författare)
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Fungal Planet description sheets : 785-867
- 2018
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Ingår i: Persoonia. - : Naturalis Biodiversity Center. - 0031-5850 .- 1878-9080. ; 41, s. 238-417
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Tidskriftsartikel (refereegranskat)abstract
- Novel species of fungi described in this study include those from various countries as follows: Angola, Gnomoniopsis angolensis and Pseudopithomyces angolensis on unknown host plants. Australia, Dothiora cotymbiae on Corymbia citriodora, Neoeucasphaeria eucalypti (incl. Neoeucasphaeria gen. nov.) on Eucalyptus sp., Fumagopsis stellae on Eucalyptus sp., Fusculina eucalyptorum (incl. Fusculinaceae fam. nov.) on Eucalyptus socialis, Harknessia cotymbiicola on Corymbia maculata, Neocelosporium eucalypti (incl. Neocelosporium gen. nov., Neocelosporiaceae fam. nov. and Neocelosporiales ord. nov.) on Eucalyptus cyanophylla, Neophaeomoniella corymbiae on Corymbia citriodora, Neophaeomoniefia eucalyptigena on Eucalyptus pilularis, Pseudoplagiostoma corymbiicola on Corymbia citriodora, Teratosphaeria gracilis on Eucalyptus gracilis, Zasmidium corymbiae on Corymbia citriodora. Brazil, Calonectria hemileiae on pustules of Hemileia vastatrix formed on leaves of Coffea arabica, Calvatia caatinguensis on soil, Cercospora solani-betacei on Solanum betaceum, Clathrus natalensis on soil, Diaporthe poincianellae on Poincianella pyramidalis, Geastrum piquiriunense on soil, Geosmithia carolliae on wing of Carollia perspicillata, Henningsia resupinata on wood, Penicillium guaibinense from soil, Periconia caespitosa from leaf litter, Pseudocercospora styracina on Styrax sp., Simplicillium filiforme as endophyte from Citrullus lanatus, Thozetella pindobacuensis on leaf litter, Xenosonderhenia coussapoae on Coussapoa floccosa. Canary Islands (Spain), Orbilia amarilla on Euphorbia canariensis, Cape Verde Islands, Xylodon jacobaeus on Eucalyptus camaldulensis. Chile, Colletotrichum arboricola on Fuchsia magellanica. Costa Rica, Lasiosphaeria miniovina on tree branch. Ecuador, Ganoderma chocoense on tree trunk. France, Neofitzroyomyces nerii (incl. Neofitzroyomyces gen. nov.) on Nerium oleander. Ghana, Castanediella tereticornis on Eucalyptus tereticornis, Falcocladium africanum on Eucalyptus brassiana, Rachicladosporium corymbiae on Corymbia citriodora. Hungary, Entoloma silvae-frondosae in Carpinus betulus-Pinus sylvestris mixed forest. Iran, Pseudopyricularia persiana on Cyperus sp. Italy, lnocybe roseascens on soil in mixed forest. Laos, Ophiocordyceps houaynhangensis on Coleoptera larva. Malaysia, Monilochaetes melastomae on Melastoma sp. Mexico, Absidia terrestris from soil. Netherlands, Acaulium pannemaniae, Conioscypha boutwelliae, Fusicolla septimanifiniscientiae, Gibellulopsis simonii, Lasionectria hilhorstii, Lectera nordwiniana, Leptodiscella rintelii, Parasarocladium debruynii and Sarocladium dejongiae (incl. Sarocladiaceae fam. nov.) from soil. New Zealand, Gnomoniopsis rosae on Rosa sp. and Neodevriesia metrosideri on Metrosideros sp. Puerto Rico, Neodevriesia coccolobae on Coccoloba uvifera, Neodevriesia tabebuiae and Alfaria tabebuiae on Tabebuia chrysantha. Russia, Amanita paludosa on bogged soil in mixed deciduous forest, Entoloma tiliae in forest of Tilia x europaea, Kwoniella endophytica on Pyrus communis. South Africa, Coniella diospyri on Diospyros mespiliformis, Neomelanconiella combreti (incl. Neomelanconiellaceae fam. nov. and Neomelanconiella gen. nov.) on Combretum sp., Polyphialoseptoria natalensis on unidentified plant host, Pseudorobillarda bolusanthi on Bolusanthus speciosus, Thelonectria pelargonii on Pelargonium sp. Spain, Vermiculariopsiella lauracearum and Anungitopsis lauri on Laurus novocanariensis, Geosmithia xerotolerans from a darkened wall of a house, Pseudopenidiella gallaica on leaf litter. Thailand, Corynespora thailandica on wood, Lareunionomyces loeiensis on leaf litter, Neocochlearomyces chromolaenae (incl. Neocochlearomyces gen. nov.) on Chromolaena odorata, Neomyrmecridium septatum (incl. Neomyrmecridium gen. nov.), Pararamichloridium caricicola on Carex sp., Xenodactylaria thailandica (incl. Xenodactylariaceae fam. nov. and Xenodactylaria gen. nov.), Neomyrmecridium asiaticum and Cymostachys thailandica from unidentified vine. USA, Carolinigaster bonitoi (incl. Carolinigaster gen. nov.) from soil, Penicillium fortuitum from house dust, Phaeotheca shathenatiana (incl. Phaeothecaceae fam. nov.) from twig and cone litter, Pythium wohlseniorum from stream water, Superstratomyces tardicrescens from human eye, Talaromyces iowaense from office air. Vietnam, Fistulinella olivaceoalba on soil. Morphological and culture characteristics along with DNA barcodes are provided.
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| 3. |
- Weiner, D. J., et al.
(författare)
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Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
- 2017
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 49:7
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Tidskriftsartikel (refereegranskat)abstract
- Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
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| 4. |
- Anney, R. J. L., et al.
(författare)
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Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia
- 2017
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Ingår i: Molecular Autism. - : Springer Science and Business Media LLC. - 2040-2392. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) < 1.15). Methods: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P= 9 x10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. Conclusions: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental- related genes such as EXT1, ASTN2, MACROD2, and HDAC4.
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| 5. |
- Coelho, Teresa, et al.
(författare)
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Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy
- 2023
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 330:15, s. 1448-1458
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group.Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P <.001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P <.001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P <.001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.
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| 6. |
- Pellegrino, T, et al.
(författare)
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Moderated Poster Session 3 : Monday 4 May 2015, 10
- 2015
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Ingår i: European Heart Journal Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 16 Suppl 1
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Tidskriftsartikel (refereegranskat)
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| 7. |
- Pinto, Dalila, et al.
(författare)
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Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders.
- 2014
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Ingår i: American journal of human genetics. - : Elsevier BV. - 1537-6605 .- 0002-9297. ; 94:5, s. 677-694
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Tidskriftsartikel (refereegranskat)abstract
- Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0× 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7× 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
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| 8. |
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| 9. |
- Baroni, M. P. M. A., et al.
(författare)
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Optical and morphological properties of porous diamond-like-carbon films deposited by magnetron sputtering
- 2006
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Ingår i: Journal of Non-Crystalline Solids. - : Elsevier BV. - 0022-3093 .- 1873-4812. ; 352:32-35, s. 3734-3738
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Tidskriftsartikel (refereegranskat)abstract
- Porous diamond-like-carbon (PDLC) thin films obtained on silicon substrate by DC low energy magnetron sputtering have been investigated by photoluminescence, transmission and reflection spectroscopy, photoacoustic and spectroscopic ellipsometry. The absorption features observed for these films show similarities with those of porous silicon (PS) as well as in the performed gradient structural pattern classification of the SFM porosity, by means of the computational GPA-flyby environment on PS and PDLC samples. The dielectric function is also calculated for the bulk diamond-like carbon using the full-potential linearized augmented plane wave method within the framework of local density approximation to density functional theory. From the measurement a low real dielectric constant of about 4.5 at 0.8 eV was found whereas the calculated e(1)(0) for the bulk diamond has a value of 5.5.
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| 10. |
- Alisic, S., et al.
(författare)
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Final report on EURAMET comparison on 1 kg stainless steel mass standards
- 2020
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Ingår i: Metrologia. - : Institute of Physics Publishing. - 0026-1394 .- 1681-7575. ; 57:1 A
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Tidskriftsartikel (refereegranskat)abstract
- In order to demonstrate the equivalence in calibration of mass standards among National Metrology Institutes (NMIs) of EURAMET this key comparison (KC) on 1 kg stainless steel mass standards has been carried out under the auspices of EURAMET. The comparison was undertaken with reference to the International Prototype Kilogram (IPK) as the definition of the unit of mass. The overall result shows good consistency among the participants. Main text To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/. The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
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| 11. |
- Bruneau, Anne, et al.
(författare)
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Advances in Legume Systematics 14. Classification of Caesalpinioideae. Part 2: Higher-level classification
- 2024
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Ingår i: PhytoKeys. - Sofia : Pensoft Publishers. - 1314-2011 .- 1314-2003. ; 240, s. 1-552
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Tidskriftsartikel (refereegranskat)abstract
- Caesalpinioideae is the second largest subfamily of legumes (Leguminosae) with ca. 4680 species and 163 genera. It is an ecologically and economically important group formed of mostly woody perennials that range from large canopy emergent trees to functionally herbaceous geoxyles, lianas and shrubs, and which has a global distribution, occurring on every continent except Antarctica. Following the recent re-circumscription of 15 Caesalpinioideae genera as presented in Advances in Legume Systematics 14, Part 1, and using as a basis a phylogenomic analysis of 997 nuclear gene sequences for 420 species and all but five of the genera currently recognised in the subfamily, we present a new higher-level classification for the subfamily. The new classification of Caesalpinioideae comprises eleven tribes, all of which are either new, reinstated or re-circumscribed at this rank: Caesalpinieae Rchb. (27 genera / ca. 223 species), Campsiandreae LPWG (2 / 5-22), Cassieae Bronn (7 / 695), Cera-tonieae Rchb. (4 / 6), Dimorphandreae Benth. (4 / 35), Erythrophleeae LPWG (2 /13), Gleditsieae Nakai (3 / 20), Mimoseae Bronn (100 / ca. 3510), Pterogyneae LPWG (1 / 1), Schizolobieae Nakai (8 / 42-43), Sclerolobieae Benth. & Hook. f. (5 / ca. 113). Although many of these lineages have been recognised and named in the past, either as tribes or informal generic groups, their circumscriptions have varied widely and changed over the past decades, such that all the tribes described here differ in generic membership from those previously recognised. Importantly, the approximately 3500 species and 100 genera of the former subfamily Mimosoideae are now placed in the reinstated, but newly circumscribed, tribe Mimoseae. Because of the large size and ecological importance of the tribe, we also provide a clade-based classification system for Mimoseae that includes 17 named lower-level clades. Fourteen of the 100 Mimoseae genera remain unplaced in these lower-level clades: eight are resolved in two grades and six are phylogenetically isolated monogeneric lineages. In addition to the new classification, we provide a key to genera, morphological descriptions and notes for all 163 genera, all tribes, and all named clades. The diversity of growth forms, foliage, flowers and fruits are illustrated for all genera, and for each genus we also provide a distribution map, based on quality-controlled herbarium specimen localities. A glossary for specialised terms used in legume morphology is provided. This new phylogenetically based classification of Caesalpinioideae provides a solid system for communication and a framework for downstream analyses of biogeography, trait evolution and diversification, as well as for taxonomic revision of still understudied genera.
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| 12. |
- Budeus, B., et al.
(författare)
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Human cord blood b cells differ from the adult counterpart by conserved ig repertoires and accelerated response dynamics
- 2021
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 206:12, s. 2839-2851
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Tidskriftsartikel (refereegranskat)abstract
- Neonatal and infant immune responses are characterized by a limited capability to generate protective Ab titers and memory B cells as seen in adults. Multiple studies support an immature or even impaired character of umbilical cord blood (UCB) B cells themselves. In this study, we provide a comprehensive molecular and functional comparison of B cell subsets from UCB and adult peripheral blood. Most UCB B cells have a mature, naive B cell phenotype as seen in adults. The UCB Ig repertoire is highly variable but interindividually conserved, as BCR clonotypes are frequently shared between neonates. Furthermore, UCB B cells show a distinct transcriptional program that confers accelerated responsiveness to stimulation and facilitated IgA class switching. Stimulation drives extensive differentiation into Ab-secreting cells, presumably limiting memory B cell formation. Humanized mice suggest that the distinctness of UCB versus adult B cells is already reflected by the developmental program of hematopoietic precursors, arguing for a layered B-1/B-2 lineage system as in mice, albeit our findings suggest only partial comparability to murine B-1 cells. Our study shows that UCB B cells are not immature or impaired but differ from their adult mature counterpart in a conserved BCR repertoire, efficient IgA class switching, and accelerated, likely transient response dynamics. © 2021 by TheAmericanAssociation of Immunologists, Inc.
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| 13. |
- Coelho, Teresa, et al.
(författare)
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Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy
- 2013
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Ingår i: Journal of Neurology. - : Springer Berlin/Heidelberg. - 0340-5354 .- 1432-1459. ; 260:11, s. 2802-2814
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Tidskriftsartikel (refereegranskat)abstract
- Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.
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| 14. |
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| 15. |
- Coelho, Teresa, et al.
(författare)
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Tafamidis for transthyretin familial amyloid polyneuropathy : A randomized, controlled trial
- 2012
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Ingår i: Neurology. - Philadelphia : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 79:8, s. 785-792
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the efficacy and safety of 18 months of tafamidis treatment in patients with early-stage V30M transthyretin familial amyloid polyneuropathy (TTR-FAP). Methods: In this randomized, double-blind trial, patients received tafamidis 20 mg QD or placebo. Coprimary endpoints were the Neuropathy Impairment Score-Lower Limbs (NIS-LL) responder analysis (<2-point worsening) and treatment-group difference in the mean change from baseline in Norfolk Quality of Life-Diabetic Neuropathy total score (TQOL) in the intent-to-treat (ITT) population (n = 125). These endpoints were also evaluated in the efficacy-evaluable (EE; n = 87) population. Secondary endpoints, including changes in neurologic function, nutritional status, and TTR stabilization, were analyzed in the ITT population. Results: There was a higher-than-anticipated liver transplantation dropout rate. No differences were observed between the tafamidis and placebo groups for the coprimary endpoints, NIS-LL responder analysis (45.3% vs 29.5% responders; p = 0.068) and change in TQOL (2.0 vs 7.2; p = 0.116) in the ITT population. In the EE population, significantly more tafamidis patients than placebo patients were NIS-LL responders (60.0% vs 38.1%; p = 0.041), and tafamidis patients had better-preserved TQOL (0.1 vs 8.9; p = 0.045). Significant differences in most secondary endpoints favored tafamidis. TTR was stabilized in 98% of tafamidis and 0% of placebo patients (p < 0.0001). Adverse events were similar between groups. Conclusions: Although the coprimary endpoints were not met in the ITT population, tafamidis was associated with no trend toward more NIS-LL responders and a significant reduction in worsening of most neurologic variables, supporting the hypothesis that preventing TTR dissociation can delay peripheral neurologic impairment. Classification of evidence: This study provides Class II evidence that 20 mg tafamidis QD was associated with no difference in clinical progression in patients with TTR-FAP, as measured by the NIS-LL and the Norfolk QOL-DN score. Secondary outcomes demonstrated a significant delay in peripheral neurologic impairment with tafamidis, which was well tolerated over 18 months. Neurology (R) 2012;79:785-792
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| 16. |
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| 17. |
- Gupta, Dhanu, et al.
(författare)
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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
- 2021
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Ingår i: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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| 18. |
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| 19. |
- Stephan, Astrid, et al.
(författare)
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Barriers and facilitators to the access to and use of formal dementia care : findings of a focus group study with people with dementia, informal carers and health and social care professionals in eight European countries
- 2018
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Ingår i: BMC Geriatrics. - : BioMed Central. - 1471-2318. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: People with dementia and informal carers often access formal care late in the process of dementia. The barriers and facilitators to service use from the perspectives of different stakeholders involved are not well understood. Thus, we aimed to explore the barriers and facilitators of access to and utilisation of formal care from the perspectives of people with dementia, their informal carers and health and social care professionals.METHOD: Focus groups with people with dementia, informal carers and professionals were conducted in eight European countries. Recruitment targeted people with dementia, informal carers with experience of formal care and professionals involved in providing (access to) formal care. Qualitative content analysis using open coding was used on a national level. Cross-national synthesis was based on the translated national reports.RESULTS: Overall, 55 focus groups with 261 participants were conducted, involving 51 people with dementia, 96 informal carers and 114 professionals. Sixteen categories describing barriers and facilitators were identified, referring to three global themes: Aspects related to 1) individuals involved, 2) the system or 3) overarching aspects. The attitudes and beliefs of people with dementia and their carers may have a major impact, and they often serve as barriers. Formal care was perceived as a threat to the individual independence of people with dementia and was thus avoided as long as possible. A healthcare professional serving as a constant key contact person could be an essential facilitator to overcome these barriers. Contact should be initiated proactively, as early as possible, and a trusting and consistent relationship needs to be established. Beyond that, the findings largely confirm former research and show that barriers to accessing and using formal care still exist across Europe despite a number of national and European initiatives.CONCLUSION: Further investigations are needed to elaborate how the concept of a key contact person could be integrated with existing case management approaches and how the independence and autonomy of people with dementia can be strengthened when formal care needs to be accessed and used. These may be meaningful facilitators regarding enhanced access to formal care for people with dementia and their families.
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| 20. |
- Suhr, Ole B., et al.
(författare)
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Efficacy and safety of patisiran for familial amyloidotic polyneuropathy : a phase II multi-dose study
- 2015
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Ingår i: Orphanet Journal of Rare Diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development.
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