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| 2. |
- Wu, Chuanyan, et al.
(author)
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Elevated circulating follistatin associates with an increased risk of type 2 diabetes
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12, s. 1-10
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Journal article (peer-reviewed)abstract
- The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04-1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09-1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.
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| 3. |
- Tomic, Tajana Tesan, et al.
(author)
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MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
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In: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
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Journal article (peer-reviewed)abstract
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
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| 4. |
- Aupke, Phil, et al.
(author)
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Impact of Clustering Methods on Machine Learning-based Solar Power Prediction Models
- 2022
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In: 2022 IEEE International Smart Cities Conference (ISC2). - : Institute of Electrical and Electronics Engineers (IEEE). - 9781665485616
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Conference paper (peer-reviewed)abstract
- Prediction of solar power generation is important in order to optimize energy exchanges in future micro-grids that integrate a large amount of photovoltaics. However, an accurate prediction is difficult due to the uncertainty of weather phenomena that impact produced power. In this paper, we evaluate the impact of different clustering methods on the forecast accuracy for predicting hourly ahead solar power when using machine learning based prediction approaches trained on weather and generated power features. In particular, we compare clustering methods using clearness index and K-means clustering, where we use both euclidian distance and dynamic time-warping. For evaluating prediction accuracy, we develop and compare different prediction models for each of the clusters using production data from a swedish SmartGrid. We demonstrate that proper tuning of thresholds for the clearness index improves prediction accuracy by 20.19% but results in worse performance than using K-means with all weather features as input to the clustering.
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| 5. |
- Bronge, Mattias, et al.
(author)
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Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis
- 2022
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:17
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Journal article (peer-reviewed)abstract
- Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-gamma responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4(+) and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.
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| 6. |
- Chen, Yihong, et al.
(author)
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Circulating Hepatocyte Growth Factor Reflects Activation of Vascular Repair in Response to Stress
- 2022
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In: JACC: Basic to Translational Science. - : Elsevier BV. - 2452-302X. ; 7:8, s. 747-762
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Journal article (peer-reviewed)abstract
- Hepatocyte growth factor (HGF) is released by stressed human vascular cells and promotes vascular cell repair responses in both autocrine and paracrine ways. Subjects with a low capacity to express HGF in response to systemic stress have an increased cardiovascular risk. Human atherosclerotic plaques with a low content of HGF have a more unstable phenotype. The present study shows that subjects with a low ability to express HGF in response to metabolic stress have an increased risk to suffer myocardial infarction and stroke.
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| 7. |
- Chen, Yihong, et al.
(author)
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Evidence for a protective role of placental growth factor in cardiovascular disease
- 2020
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:572
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Journal article (peer-reviewed)abstract
- Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.
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| 8. |
- Einarsdottir, Sigrun, et al.
(author)
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Deficiency of SARS-CoV-2 T-cell responses after vaccination in long-term allo-HSCT survivors translates into abated humoral immunity.
- 2022
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In: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 6:9, s. 2723-2730
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Journal article (peer-reviewed)abstract
- Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological diseases are at risk of severe disease and death from COVID-19. To determine the safety and immunogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines, samples from 50 infection-naive allo-HSCT recipients (median, 92 months from transplantation, range, 7-340 months) and 39 healthy controls were analyzed for serum immunoglobulin G (IgG) against the receptor binding domain (RBD) within spike 1 (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; anti-RBD-S1 IgG) and for SARS-CoV-2-specific T-cell immunity, reflected by induction of T-cell-derived interferon-γ in whole blood stimulated ex vivo with 15-mer SI-spanning peptides with 11 amino acid overlapS1-spanning peptides. The rate of seroconversion was not significantly lower in allo-transplanted patients than in controls with 24% (12/50) and 6% (3/50) of patients remaining seronegative after the first and second vaccination, respectively. However, 58% of transplanted patients lacked T-cell responses against S1 peptides after 1 vaccination compared with 19% of controls (odds ratio [OR] 0.17; P = .009, Fisher's exact test) with a similar trend after the second vaccination where 28% of patients were devoid of detectable specific T-cell immunity, compared with 6% of controls (OR 0.18; P = .02, Fisher's exact test). Importantly, lack of T-cell reactivity to S1 peptides after vaccination heralded substandard levels (<100 BAU/mL) of anti-RBD-S1 IgG 5 to 6 months after the second vaccine dose (OR 8.2; P = .007, Fisher's exact test). We conclude that although allo-HSCT recipients achieve serum anti-RBD-S1 IgG against SARS-CoV-2 after 2 vaccinations, a deficiency of SARS-CoV-2-specific T-cell immunity may subsequently translate into insufficient humoral responses.
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| 9. |
- Grossmann, Benjamin Achim, et al.
(author)
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Response Letter to the editor
- 2021
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In: Acta Anaesthesiologica Scandinavica. - : Wiley-Blackwell Publishing Inc.. - 0001-5172 .- 1399-6576. ; 65:2, s. 279-280
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Journal article (other academic/artistic)abstract
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| 10. |
- Grossmann, Benjamin, et al.
(author)
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Patient-controlled Sedation During Flexible Bronchoscopy : A Randomized Controlled Trial
- 2020
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In: Journal of Bronchology & Interventional Pulmonology. - : Lippincott Williams & Wilkins. - 1944-6586 .- 1948-8270. ; 27:2, s. 77-85
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Journal article (peer-reviewed)abstract
- Background: Patient-controlled sedation (PCS) is a documented method for endoscopic procedures considered to facilitate early recovery. Limited data have been reported, however, on its use during flexible bronchoscopy (FB).Materials and Methods: This study hypothesized that PCS with propofol during FB would facilitate early recovery, with similar bronchoscopist and patient satisfaction compared with nurse-controlled sedation (NCS) with midazolam. A total of 150 patients were randomized 1:1:1 into a control group (premedication with morphine-scopolamine and NCS with midazolam), PCS-MS group (premedication with morphine-scopolamine and PCS with propofol), and PCS-G group (premedication with glycopyrronium and PCS with propofol).Results: The procedures included transbronchial biopsy, transbronchial needle aspiration, cryotherapy/biopsy, and/or multistation endobronchial ultrasound. FB duration values in median (range) were 40 (10 to 80), 39 (12 to 68), and 44 (10 to 82) minutes for the groups NCS, PCS-MS, and PCS-G, respectively. An overall 81% of the patients in the combined PCS groups were ready for discharge (modified Post Anaesthetic Discharge Scoring System, score 10) 2 hours after bronchoscopy compared with 40% in the control group (P<0.0001). Between PCS groups, 96% of the PCS-G group patients were ready for discharge compared with 65% in the PCS-MS group (P=0.0002) at 2 hours. Bronchoscopists’ and patients’ satisfaction scores were high in all groups. Postdischarge quality scores showed no differences among the groups.Conclusion: PCS with propofol during FB is feasible, as it shortened recovery time without compromising procedure conditions for bronchoscopists or patients. A rapid postsedation stabilization of vital signs facilitates surveillance before the patient leaves the hospital.
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