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Sökning: WFRF:(Magnusson Yvonne)

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1.
  • Stolk, Lisette, et al. (författare)
  • Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways
  • 2012
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 260-268
  • Tidskriftsartikel (refereegranskat)abstract
    • To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.
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2.
  • Allentoft, Morten E., et al. (författare)
  • Population genomics of post-glacial western Eurasia
  • 2024
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7994, s. 301-311
  • Tidskriftsartikel (refereegranskat)abstract
    • Western Eurasia witnessed several large-scale human migrations during the Holocene1–5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes—mainly from the Mesolithic and Neolithic periods—from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a ‘great divide’ genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 bp, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 bp, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a ‘Neolithic steppe’ cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.
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3.
  • Barbabella, Francesco, Dr. 1984-, et al. (författare)
  • Recruitment of Adolescent Young Carers to a Psychosocial Support Intervention Study in Six European Countries : Lessons Learned from the ME-WE Project
  • 2023
  • Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 20:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Young carers provide a substantial amount of care to family members and support to friends, yet their situation has not been actively addressed in research and policy in many European countries or indeed globally. Awareness of their situation by professionals and among children and young carers themselves remains low overall. Thus, young carers remain a largely hidden group within society. This study reports and analyses the recruitment process in a multi-centre intervention study offering psychosocial support to adolescent young carers (AYCs) aged 15–17 years. A cluster-randomised controlled trial was designed, with recruitment taking place in Italy, the Netherlands, Slovenia, Sweden, Switzerland and the United Kingdom exploiting various channels, including partnerships with schools, health and social services and carers organisations. In total, 478 AYCs were recruited and, after screening failures, withdrawals and initial dropouts, 217 were enrolled and started the intervention. Challenges encountered in reaching, recruiting and retaining AYCs included low levels of awareness among AYCs, a low willingness to participate in study activities, uncertainty about the prevalence of AYCs, a limited school capacity to support the recruitment; COVID-19 spreading in 2020–2021 and related restrictions. Based on this experience, recommendations are put forward for how to better engage AYCs in research.
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4.
  • Björk, Yvonne, et al. (författare)
  • Androgens in women after allogeneic hematopoietic cell transplantation : Impact of chronic GvHD and glucocorticoid therapy
  • 2017
  • Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 52:3, s. 431-437
  • Tidskriftsartikel (refereegranskat)abstract
    • Low androgen levels may contribute to sexual dysfunction in women after allogeneic hematopoietic cell transplantation (alloHCT). However, data on serum androgens in women after alloHCT are limited. The aim of this study was to assess androgen levels and their association with chronic GvHD (cGvHD) and glucocorticoid (GC) therapy. Included were 65 allografted women, 33 with cGvHD, and 23 of these were on GC therapy. Controls were 94 healthy, age-matched women. Supportive study groups were women after autologous HCT (autoHCT; n=20) and non-transplanted women on GC therapy (n=26). Compared with controls, free testosterone (free T) and dehydroepiandrosterone sulfate (DHEAS) levels were lower in both the alloHCT group and GC groups; P<0.0001 and P<0.05, respectively. Androgens in the autoHCT group were similar or higher than controls. In the subgroup of alloHCT patients without cGvHD, free T was similar to controls (7.2 vs 8.6 pmol/L; P=0.42), whereas DHEAS levels was lower than controls (1.7 vs 2.5 μmol/L; P=0.008). Compared with controls, cGvHD without GC (n=10) was associated with lower free T and DHEAS; P=0.004 and P=0.0004, respectively). The lowest androgen levels were seen in women with both cGvHD and GC therapy. In conclusion, low serum androgens were associated with cGvHD and GC therapy, prompting for studies assessing a possible association between low androgens and sexual dysfunction and quality of life in allografted women.
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5.
  • Busch, Susann, et al. (författare)
  • TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer
  • 2015
  • Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 34:1, s. 27-38
  • Tidskriftsartikel (refereegranskat)abstract
    • Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-beta family. Data from mouse model experiments demonstrated that loss of Tgfbr2 expression in mammary fibroblasts was linked to tumour initiation and metastasis. Using a randomised tamoxifen trial cohort including in total 564 invasive breast carcinomas, we examined TGFBR2 expression (n = 252) and phosphorylation level of downstream target SMAD2 (pSMAD2) (n = 319) in cancer-associated fibroblasts (CAFs) and assessed links to clinicopathological markers, prognostic and treatment-predictive values. The study revealed that CAF-specific TGFBR2 expression correlated with improved recurrence-free survival. Multivariate analysis confirmed CAF-TGFBR2 to be an independent prognostic marker (multivariate Cox regression, hazard ratio: 0.534, 95% (CI): 0.360-0.793, P = 0.002). CAF-specific pSMAD2 levels, however, did not associate with survival outcome. Experimentally, TGF-beta signalling in fibroblasts was modulated using a TGF-beta ligand and inhibitor or through lentiviral short hairpin RNA-mediated TGFBR2-specific knockdown. To determine the role of fibroblastic TGF-beta pathway on breast cancer cells, we used cell contact-dependent cell growth and clonogenicity assays, which showed that knockdown of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival. Further, in a mouse model transfected CAFs were co-injected with MCF7 and tumour weight and proportion was monitored. We found that mouse xenograft tumours comprising TGFBR2 knockdown fibroblasts were slightly bigger and displayed increased tumour cell capacity. Overall, our data demonstrate that fibroblast-related biomarkers possess clinically relevant information and that fibroblasts confer effects on breast cancer cell growth and survival. Regulation of tumour-stromal cross-talk through fibroblastic TGF-beta pathway may depend on fibroblast phenotype, emphasising the importance to characterise tumour microenvironment subtypes.
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6.
  • Chen, Jie, et al. (författare)
  • Long-term exposure to ambient air pollution and bladder cancer incidence in a pooled European cohort : the ELAPSE project
  • 2022
  • Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 126:10, s. 1499-1507
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The evidence linking ambient air pollution to bladder cancer is limited and mixed.Methods: We assessed the associations of bladder cancer incidence with residential exposure to fine particles (PM2.5), nitrogen dioxide (NO2), black carbon (BC), warm season ozone (O3) and eight PM2.5 elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) in a pooled cohort (N = 302,493). Exposures were primarily assessed based on 2010 measurements and back-extrapolated to the baseline years. We applied Cox proportional hazard models adjusting for individual- and area-level potential confounders.Results: During an average of 18.2 years follow-up, 967 bladder cancer cases occurred. We observed a positive though statistically non-significant association between PM2.5 and bladder cancer incidence. Hazard Ratios (HR) were 1.09 (95% confidence interval (CI): 0.93–1.27) per 5 µg/m3 for 2010 exposure and 1.06 (95% CI: 0.99–1.14) for baseline exposure. Effect estimates for NO2, BC and O3 were close to unity. A positive association was observed with PM2.5 zinc (HR 1.08; 95% CI: 1.00–1.16 per 10 ng/m3).Conclusions: We found suggestive evidence of an association between long-term PM2.5 mass exposure and bladder cancer, strengthening the evidence from the few previous studies. The association with zinc in PM2.5 suggests the importance of industrial emissions.
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7.
  • Chen, Jie, et al. (författare)
  • Long-Term Exposure to Source-Specific Fine Particles and Mortality-A Pooled Analysis of 14 European Cohorts within the ELAPSE Project
  • 2022
  • Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:13, s. 9277-9290
  • Tidskriftsartikel (refereegranskat)abstract
    • We assessed mortality risks associated with sourcespecific fine particles (PM2.5) in a pooled European cohort of 323,782 participants. Cox proportional hazard models were applied to estimate mortality hazard ratios (HRs) for source-specific PM2.5 identified through a source apportionment analysis. Exposure to 2010 annual average concentrations of source-specific PM2.5 components was assessed at baseline residential addresses. The source apportionment resulted in the identification of five sources: traffic, residual oil combustion, soil, biomass and agriculture, and industry. In single-source analysis, all identified sources were significantly positively associated with increased natural mortality risks. In multisource analysis, associations with all sources attenuated but remained statistically significant with traffic, oil, and biomass and agriculture. The highest association per interquartile increase was observed for the traffic component (HR: 1.06; 95% CI: 1.04 and 1.08 per 2.86 mu g/m(3) increase) across five identified sources. On a 1 mu g/m(3) basis, the residual oil-related PM2.5 had the strongest association (HR: 1.13; 95% CI: 1.05 and 1.22), which was substantially higher than that for generic PM2.5 mass, suggesting that past estimates using the generic PM2.5 exposure response function have underestimated the potential clean air health benefits of reducing fossil-fuel combustion. Source-specific associations with cause-specific mortality were in general consistent with findings of natural mortality.
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8.
  • Chiale, P A, et al. (författare)
  • High prevalence of antibodies against beta 1- and beta 2-adrenoceptors in patients with primary electrical cardiac abnormalities.
  • 1995
  • Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 26:4, s. 864-9
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: This study sought to determine the prevalence of autoantibodies directed against the beta-adrenoceptors in patients with primary electrical cardiac abnormalities, including atrial arrhythmias, ventricular arrhythmias and conduction disturbances, in the absence of any other cardiac abnormality. BACKGROUND: Using synthetic peptides corresponding to the predicted sequences for the second extracellular loop of the human beta 1- and beta 2-adrenoceptors as antigenic targets, autoantibodies directed against the beta-adrenoceptors were recently shown to occur in patients with idiopathic dilated cardiomyopathy and Chagas' heart disease. METHODS: Eighty-six patients (57 with primary electrical abnormalities, 29 with idiopathic dilated cardiomyopathy) and 101 healthy and cardiopathic control subjects were studied. Antibodies against the beta 1- and beta 2-peptides were detected with an enzyme immunoassay performed in blinded manner. In nine selected (seropositive) cases, the immunoglobulin G (IgG) fraction was tested for functional effects on the rate of beating of cultured neonatal rat cardiomyocytes. RESULTS: Antibodies recognizing the beta 1- and beta 2-peptides were found in 11 (52.3%) of 21 patients with ventricular arrhythmias (p < 0.01), 5 (35.7%) of 14 patients with conduction disturbances (p < 0.05), 3 (13.6%) of 22 patients with atrial arrhythmias (p > 0.05) and 11 (37.9%) of 29 patients with dilated cardiomyopathy (p < 0.05) compared with 15 (14.8%) of 101 control subjects. A rapid increase in the rate of beating of the cultured cardiomyocytes was induced by IgG from a selected group of patients, suggesting an agonist-like interaction with a functional epitope. This response was mediated by stimulation of both the beta 1- and beta 2-adrenoceptors in the patients with primary ventricular arrhythmias but only the beta 1-adrenoceptors in the patients with idiopathic dilated cardiomyopathy. CONCLUSIONS: Primary ventricular arrhythmias and conduction disturbances, like idiopathic cardiomyopathy, show a high prevalence of antibodies interacting with functional epitopes of the beta-adrenoceptors, suggesting a common or similar abnormal immunoregulatory process.
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9.
  • Drvota, V, et al. (författare)
  • The effect of amiodarone on the beta-adrenergic receptor is due to a downregulation of receptor protein and not to a receptor-ligand interaction.
  • 1999
  • Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 255:2, s. 515-20
  • Tidskriftsartikel (refereegranskat)abstract
    • Downregulation of beta adrenergic receptors (beta-AR) by amiodarone (Am) have been reported in several studies both in vivo and in vitro. The mechanism underlying the antiadrenergic effect of Am is, however, still unclear. The aim of this study was to characterize whether the antiadrenergic effect of amiodarone is due to binding to the beta-AR or to downregulation of the beta-AR receptor protein. All experiments were performed on confluent mouse AT-1 cardiomyocytes cultured for 6 days. In acute experiments, equilibrium binding with [3H]-CGP-12177 to beta-AR was not directly inhibited by Am and the equilibrium binding constant did not change during prolonged exposure up to 72 hours. After Am exposure for 48 hours beta-AR density was decreased by 26% (p<0.005). T3 partially prevented the downregulation elicited by Am (p<0.05). A Western blot analysis with beta1-AR antibodies revealed a decreased signal intensity in cells treated with Am for 48 h as compared to control (p<0.05). Isoproterenol-provoked cAMP response did not change after acute exposure to Am. After incubation for 48 hours with Am there was, however, a 20% decrease in cAMP response as compared to control (p<0.05). This study shows that the effect of Am on beta-AR is due to a downregulation of the beta-AR protein and not to a competitive or non-competitive receptor-ligand interaction. This indicates a new pharmacological mechanism for modulation of beta-AR, which probably is transcriptionally regulated.
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10.
  • Eng, H, et al. (författare)
  • Beta 2-adrenergic receptor antibodies in myasthenia gravis.
  • 1992
  • Ingår i: Journal of autoimmunity. - 0896-8411. ; 5:2, s. 213-27
  • Tidskriftsartikel (refereegranskat)abstract
    • Although autoantibodies against the nicotinic acetylcholine receptor are the characteristic feature of the autoimmune disease myasthenia gravis (MG), no strong correlation is found between the autoantibody titer and the degree of clinical severity. Numerous studies have attempted to detect the presence of other autoantibody populations that might have a role in the pathology of the disease. We report, for the first time, that 18% of the MG patients we screened have antibodies in their serum to a peptide corresponding to the second extracellular loop of the human beta 2-adrenergic receptor (residues 172-197). Affinity purified antibodies to the beta 2-adrenergic receptor peptide 172-197 reacted with the human beta 2-adrenergic receptor protein obtained from transfected E. coli cell membrane extracts, but did not cross-react with the human AChR. Sufficient material was obtained from nine MG patients and it was found that the gamma globulin fraction from these patients immunoprecipitated the receptor, and that affinity purified IgG to peptide 172-197 competed for receptor binding with the beta-antagonist iodo-cyanopindolol. Using truncated peptides or amino acid modification procedures, no immunodominant B-cell epitope could be detected within region 172-197. Thus, a subpopulation of MG patients possesses anti-beta 2-adrenergic receptor antibodies which are a distinct set of autoantibodies with possible pharmacological activity.
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11.
  • Fu, Michael, 1963, et al. (författare)
  • Autoantibodies against cardiac G-protein-coupled receptors define different populations with cardiomyopathies but not with hypertension.
  • 1994
  • Ingår i: Clinical immunology and immunopathology. - 0090-1229. ; 72:1, s. 15-20
  • Tidskriftsartikel (refereegranskat)abstract
    • It was previously shown that the second extracellular loop of cardiovascular G-protein-coupled receptors is an antigenic target for pharmacologically active autoantibodies in patients with idiopathic dilated cardiomyopathy. To extend these observations to cover patients with the same disease from different geographical origins or to patients with other cardiac diseases, peptides corresponding to the sequences of the second extracellular loops of the human M2 muscarinic receptors and beta adrenoceptors were used as antigens in an enzyme immunoassay. Sera from patients from Sweden and Japan with idiopathic dilated cardiomyopathy (DCM, n = 32), hypertrophic cardiomyopathy (HCM, n = 23), malignant essential hypertension (MEH, n = 11), malignant secondary hypertension (MSH, n = 10), and sera from healthy blood donors (HBD, n = 49) were tested. Sera from patients with DCM recognized the muscarinic receptor peptide in 38% of cases and the beta 1 adrenoceptor peptide in 31% of cases. In 50% of the positive patients, autoantibodies against both peptides coexisted as shown by competition experiments using both peptides as inhibitors. In HCM patients, there was a lower frequency of autoantibodies but with a higher but not significant predominance against the M2 peptide. No autoantibodies were detected in sera from patients with MEH or MSH. Autoantibodies against the M2 muscarinic receptors, affinity-purified from positive patients, displayed pharmacological activity as demonstrated by changes in the affinity and number of radioligand binding sites. In contrast, antibodies purified from positive HBD had no effect. These results confirm that autoantibodies displaying pharmacological activity against G-protein-coupled cardiovascular receptors are mainly restricted to patients with idiopathic dilated cardiomyopathy and that different autoantibody populations are responsible for the recognition of the different receptors.
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12.
  • Galanti, Maria Rosaria, et al. (författare)
  • School environment and mental health in early adolescence - a longitudinal study in Sweden (KUPOL)
  • 2016
  • Ingår i: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 16
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Longitudinal studies indicate strong associations between school proficiency and indicators of mental health throughout adulthood, but the mechanisms of such associations are not fully elucidated. The Kupol study is a prospective cohort study in Sweden set up in order to: (i) describe the association of school pedagogic and social environment and its specific dimensions with the risk of mental ill-health and psychiatric disorders in adolescence; (ii) evaluate the direct effects of school pedagogic and social environment on mental health and the effects mediated by the individual's academic achievements; and (iii) assess if school pedagogic and social environment are associated with mental ill-health through epigenetic mechanisms, in particular those involving genes regulating the response to stress.Methods: The Kupol cohort at baseline consists of 3959 children attending the 7th grade of compulsory school (13-14 years old) in 8 regions of central Sweden in the school years 2013-2014 or 2014-2015. Three follow-up surveys in subsequent years are planned. Teachers' and students' perceptions of the culture, climate and ethos of their schools, and students' mental ill-health are assessed at the whole school level by annual questionnaire surveys. In order to conduct epigenetic analyses saliva specimens are collected from a nested sample of students at inception and two years later. Further, class-, family-and child-level information is collected at baseline and during each year of follow-up. Self-reported information is being complemented with register data via record-linkages to national and regional health and administrative registers.Discussion: The topic being investigated is new, and the sample constitutes the largest adolescent cohort in Sweden involved in an ad hoc study. Epigenetic analyses centered on environmental cues to stress response are a thoroughly new approach. Finally a notable feature is the multi-informant and multi-method data collection, with surveys at the school, class, family, and student level. Collaboration and data access: interested investigators should contact the coordinating centre. Additional information is available on the study's website, http://kupolstudien.se/.
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13.
  • Guillet, J G, et al. (författare)
  • Induction of a pharmacologically active clonotypic B cell response directed to an immunogenic region of the human beta 2-adrenergic receptor.
  • 1992
  • Ingår i: Clinical and experimental immunology. - 0009-9104. ; 89:3, s. 461-7
  • Tidskriftsartikel (refereegranskat)abstract
    • It has been reported that autoantibodies against the beta 2-adrenergic receptors are involved in the pathology of allergic disorders and of Chagas' disease. Therefore, the immune response against a peptide (H26Q) corresponding to the putative second extracellular loop of the human beta 2-adrenergic receptor, which could be a target for autoantibody attack, was analysed in view of its possible immunogenicity. The free peptide induced a T cell-mediated humoral response in the context of three different murine MHC haplotypes. The T cell epitope was found to be localized in the N-terminal region of the peptide. Highly specific T helper cells were capable of stimulating B cells with the potential to generate a large antibody repertoire reactive with the loop peptide. MoAbs were screened to analyse this B cell response for antibodies potentially interfering with receptor function and a MoAb was found that impaired ligand binding to the receptor.
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14.
  • Hansdotter, Frida I., et al. (författare)
  • The incidence of acute gastrointestinal illness in Sweden
  • 2015
  • Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 43:5, s. 540-547
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: The aim of this study was to estimate the self-reported domestic incidence of acute gastrointestinal illness in the Swedish population irrespective of route of transmission or type of pathogen causing the disease. Previous studies in Sweden have primarily focused on incidence of acute gastrointestinal illness related to consumption of contaminated food and drinking water. Methods: In May 2009, we sent a questionnaire to 4000 randomly selected persons aged 0-85 years, asking about the number of episodes of stomach disease during the last 12 months. To validate the data on symptoms, we compared the study results with anonymous queries submitted to a Swedish medical website. Results: The response rate was 64%. We estimated that a total number of 2744,778 acute gastrointestinal illness episodes (95% confidence intervals 2475,641-3013,915) occurred between 1 May 2008 and 30 April 2009. Comparing the number of reported episodes with web queries indicated that the low number of episodes during the first 6 months was an effect of seasonality rather than recall bias. Further, the result of the recall bias analysis suggested that the survey captured approximately 65% of the true number of episodes among the respondents. Conclusions: The estimated number of Swedish acute gastrointestinal illness cases in this study is about five times higher than previous estimates. This study provides valuable information on the incidence of gastrointestinal symptoms in Sweden, irrespective of route of transmission, indicating a high burden of acute gastrointestinal illness, especially among children, and large societal costs, primarily due to production losses.
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15.
  • Hanson, Elizabeth, 1961-, et al. (författare)
  • Research and Innovation for and with Adolescent Young Carers to Influence Policy and Practice—The European Union Funded “ME-WE” Project
  • 2022
  • Ingår i: International Journal of Environmental Research and Public Health. - : MDPI. - 1661-7827 .- 1660-4601. ; 19:16
  • Tidskriftsartikel (refereegranskat)abstract
    • Young carers are children and adolescents who provide care to other family members or friends, taking over responsibilities that are usually associated with adulthood. There is emerging but still scarce knowledge worldwide about the phenomenon of young carers and the impact of a caring role on their health, social and personal development spheres. This paper provides an overview of the main results from the ME-WE project, which is the first European research and innovation project dedicated to adolescent young carers (AYCs) (15–17 years). The project methods relied on three main activities: (1) a systematization of knowledge (by means of a survey to AYCs, country case studies, Delphi study, literature review); (2) the co-design, implementation and evaluation of a primary prevention intervention addressing AYCs’ mental health (by means of Blended Learning Networks and a clinical trial in six European countries); (3) the implementation of knowledge translation actions for dissemination, awareness, advocacy and lobbying (by means of national and international stakeholder networks, as well as traditional and new media). Project results substantially contributed to a better understanding of AYCs’ conditions, needs and preferences, defined tailored support intervention (resilient to COVID-19 related restrictions), and significant improvements in national and European policies for AYCs.
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16.
  • Hellgren, I, et al. (författare)
  • Study of the beta1 adrenergic receptor expression in human tissues: immunological approach.
  • 2000
  • Ingår i: Biological & pharmaceutical bulletin. - : Pharmaceutical Society of Japan. - 0918-6158 .- 1347-5215. ; 23:6, s. 700-3
  • Tidskriftsartikel (refereegranskat)abstract
    • Questions exist regarding tissue distribution of the beta1 adrenergic receptor (beta1-AR). The aim of this study was to investigate relative distribution patterns of the beta1-AR at the protein level in a variety of human tissues by Western blot analysis. The specificity of anti-peptide antibodies was confirmed both by Western blot with recombinant beta1-AR expressed as a membrane protein in E. coli and by immunoprecipitation of membranes from Sf9 cells infected with baculovirus to express the human recombinant beta1-AR. beta1-AR was found in all tissues examined. The relative amount of protein varied significantly between the tissues, from highest in lung and testis to very low in liver. beta1-ARs were rather abundant in heart, kidney, placenta, spleen and thyroid. These results reveal unique distribution of beta1-AR protein that suggests its tissue specific role. Moreover, our data demonstrate a high sensitivity of immunological detection that allows direct comparison of beta1-AR subtype expression and could be used for receptor study in biopsies available in limited amounts, such as human heart biopsy.
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17.
  • Jacobsson, B, et al. (författare)
  • Abnormality of adenylate cyclase regulation in human platelet membranes in renal insufficiency.
  • 1985
  • Ingår i: European journal of clinical investigation. - 0014-2972. ; 15:2, s. 75-81
  • Tidskriftsartikel (refereegranskat)abstract
    • Adenylate cyclase in human platelets is under dual control of prostaglandins (PGI2 and PGE1) and catecholamines. The adenylate cyclase complex in membranes of platelets from ten patients with uraemia was investigated. The activation of the platelet cyclase by PGE1 is increased in the uraemic state, Vmax 4436 +/- 607 pmol cAMP mg-1 15 min-1. In the normal state Vmax is 2098 +/- 309 pmol cAMP mg-1 15 min-1. The alpha 2-adrenergic receptor was assayed with 3H-yohimbine binding. The density of receptors was equal in the uraemic (175 fmol mg-1 membrane protein) and the normal (170 fmol mg-1 membrane protein) states. Norepinephrine/3H-yohimbine competition binding revealed that catecholamines were bound with normal affinity in platelets in uraemia. Yet the inhibition of adenylate cyclase through the alpha 2-adrenergic receptor was diminished since Vmax values of adenylate cyclase with PGE1 and PGE2 + norepinephrine did not significantly differ. In the normal state, norepinephrine significantly (P less than 0.05) inhibited the PGE1 stimulated cyclase. It is concluded that platelet adenylate cyclase in the uraemia has an increased capacity for activation which is the result of both a sensitized stimulatory mechanism (prostaglandin mediated) and a deficient inhibitory mechanism (catecholamine mediated). It is suggested that a defect exists in the inhibitory nucleotide binding protein (NI) which is the coupling unit between the adenylate cyclase catalytic subunit (C).
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18.
  • Järlskog, Ida, 1991, et al. (författare)
  • Occurrence of tire and bitumen wear microplastics on urban streets and in sweepsand and washwater
  • 2020
  • Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 729
  • Tidskriftsartikel (refereegranskat)abstract
    • Tire and road wear particles have been identified as a potential major source of microplastics in the environment. However, more knowledge of the emissions and their further fate in the environment is needed, and the effectiveness and benefits of potential measures must be investigated to support future risk management efforts. Here the concentrations of tire and bitumen microplastic particles (TBMP) on roads and in nearby in stormwater, sweepsand and washwater were measured for the first time within the same area and time period. The analysis also included plastic, paint and fiber particles. Road dust was sampled on the road surface using a wet dust sampler, before and after street sweeping on two occasions. On each of these occasions, and several occasions during a four-month period with frequent street sweeping, sweepsand and washwater, as well as flow-weighted sampling of stormwater, were collected. TBMP concentrations were operationally defined, using density separation for some samples, followed by analysis by stereo microscopy. Sodium iodide (NaI) was found to be effective for density separation of TBMP. The largest proportion of anthropogenic microplastics detected consisted of tire tread wear and bitumen. The number of TBMP ≥100 μm in the WDS samples was up to 2561 particles/L. Sweepsand and washwater contained high amounts of TBMP ≥100 μm, up to 2170 particles/kg dw and 4500 particles/L, respectively. The results show that the sweeper collects considerable amounts of TBMP, and thus weekly sweeping might prevent further transport of TBMP to the receiving stormwater. In stormwater the number of particles ≥100 μm was up to 3 particles/L and ≥ 20 μm was up to 5900 particles/L showing the importance of analysing smaller microparticle sizes than 100 μm in all samples in future studies. This study also confirms that there is a substantial volume of TBMP generated from traffic that enters the environment.
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19.
  • Järlskog, Ida, 1991, et al. (författare)
  • Traffic-related microplastic particles, metals, and organic pollutants in an urban area under reconstruction
  • 2021
  • Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 774
  • Tidskriftsartikel (refereegranskat)abstract
    • In urban environments, particularly areas under reconstruction, metals, organic pollutants (OP), and microplastics (MP), are released in large amounts due to heavy traffic. Road runoff, a major transport route for urban pollutants, contributes significantly to a deteriorated water quality in receiving waters. This study was conducted in Gothenburg, Sweden, and is unique because it simultaneously investigates the occurrence of OP, metals, and MP on roads and in stormwater from an urban area under reconstruction. Correlations between the various pollutants were also explored. The study was carried out by collecting washwater and sweepsand generated from street sweeping, road surface sampling, and flow-proportional stormwater sampling on several occasions. The liquid and solid samples were analyzed for metals, polycyclic aromatic hydrocarbons (PAH), oxy-PAH, aliphatics, aromatics, phthalates, and MP. The occurrence of OP was also analyzed with a non-target screening method of selected samples. Microplastics, i.e. plastic fragments/fibers, paint fragments, tire wear particles (TWP) and bitumen, were analyzed with a method based on density separation with sodium iodide and identification with a stereo microscope, melt-tests, and tactile identification. MP concentrations amounted to 1500 particles/L in stormwater, 51,000 particles/L in washwater, and 2.6 × 106 particles/kg dw in sweepsand. In stormwater, washwater and sweepsand, MP ≥20 μm were found to be dominated by TWP (38%, 83% and 78%, respectively). The results confirm traffic as an important source to MP, OP, and metal emissions. Concentrations exceeding water and sediment quality guidelines for metals (e.g. Cu and Zn), PAH, phthalates, and aliphatic hydrocarbons in the C16–C35 fraction were found in most samples. The results show that the street sweeper collects large amounts of polluted materials and thereby prevents further spread of the pollutants to the receiving stormwater.
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20.
  • Kanoni, Stavroula, et al. (författare)
  • Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
  • 2022
  • Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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21.
  • Karlén, Jerker, 1971-, et al. (författare)
  • Are children from Crete abandoning a Mediterranean diet?
  • 2008
  • Ingår i: Rural and remote health. - 1445-6354. ; 8:4, s. 1034-
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION:Mediterranean countries such as Greece have experienced rapid social change in the last decade. These community changes affect nutritional habits and there is a tendency for the traditional healthy Mediterranean diet to be abandoned.METHODS:The parents of children from one rural Greek village on Crete (Neapolis), and one rural village in Sweden (Kisa) were invited to their primary health care centers for an interview and to fill in a validated nutrition questionnaire, KidMed.RESULTS:There were no differences (p = 0.48) in total KidMed score between the Cretan and Swedish children, adjusted for gender and age. However, there were some significant differences in scores on certain KidMed questions. Parents of the Cretan children reported significantly higher daily use of olive oil at home and more regular nut consumption, but also more commercially baked goods or pastries for breakfast. The parents of Swedish children reported significantly higher use of cereals, grains or bread for breakfast. The mean BMIs were similar for the Cretan (Neapolis mean 16.8, 95% CI 13.5-23.0) and for the Swedish children (Kisa mean 17.4, 95% CI 13.7-25.5)CONCLUSION:The results suggest the possibility of changing nutritional habits, measurable among young children in rural areas. The study raises the question of whether Cretan children may have abandoned some aspects of the traditional Mediterranean diet. It may also be that Swedish children have changed their diet in favor of a more Mediterranean food choice. The major limitation of the study is the small sample size, and further, larger studies are warranted.
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22.
  • Lagou, Vasiliki, et al. (författare)
  • Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
  • 2021
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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23.
  • Levin, Malin, 1973, et al. (författare)
  • A novel polymorphism in the gene coding for the beta(1)-adrenergic receptor associated with survival in patients with heart failure.
  • 2000
  • Ingår i: European heart journal. - : Oxford University Press (OUP). - 0195-668X. ; 21:22, s. 1853-8
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: The adrenergic nervous system is of major importance in congestive heart failure. No genetic polymorphism has previously been identified in the beta(1)-adrenergic receptor gene. The aim of this study was to find possible mutations in this gene and to relate such findings to morbidity and prognosis in heart failure. METHODS AND RESULTS: Genomic DNA was extracted from blood leukocytes from patients with congestive heart failure (n=184) and from age-matched controls (n=77). The part of the beta(1)-adrenergic receptor gene corresponding to nucleotide 1-255 was amplified by polymerase chain reaction and analysed by automated sequencing. The patients were investigated by echocardiography and followed regarding symptoms and survival for 5 years. A missense mutation was identified at nucleotide position 145 in the beta(1)-adrenergic receptor gene, which predicted an amino acid substitution at position 49 (Ser49Gly). The allele frequency of the Gly49 variant was 0.13 in controls and 0.18 in patients (P=0.19). At the time of the 5-years follow-up, 62% of the patients with the wild type gene and 39% of the patients with the Ser49Gly variant had died or had experienced hospitalization (P=0.005). Patients without the mutation had significantly poorer survival compared to those with the mutation, risk ratio 2.34 (95% CI 1.30-4.20), P=0.003. In a mulivariate analysis, the risk ratio was 2.03 (95% CI 0.99-4.16) P=0.05. CONCLUSION: A novel missense mution in the beta(1)-adrenergic receptor gene was associated with a decreased mortality risk in patients with congestive heart failure. These data suggest that the beta(1)-receptor Ser49Gly variant might be associated with altered receptor function, resulting in myocardial protection in patients with heart failure.
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24.
  • Levin, Malin, 1973, et al. (författare)
  • The myocardium-protective Gly-49 variant of the beta 1-adrenergic receptor exhibits constitutive activity and increased desensitization and down-regulation.
  • 2002
  • Ingår i: The Journal of biological chemistry. - 0021-9258. ; 277:34, s. 30429-35
  • Tidskriftsartikel (refereegranskat)abstract
    • The beta(1)-adrenergic receptor (beta(1)AR) is a major mediator of catecholamine effects in human heart. Patients with heart failure who were hetero- or homozygous for the Gly-49 variant of the beta(1)AR (Gly-49-beta(1)AR) showed improved long-term survival as compared with those with the Ser-49 genotype. Here, the functional consequences of this polymorphism were studied in cells expressing either variant. The Gly-49-beta(1)AR demonstrated characteristic features of constitutively active receptors. In cells expressing the Gly-49-beta(1)AR, both basal and agonist-stimulated adenylyl cyclase activities were higher than in cells expressing the Ser-49 variant (Ser-49-beta(1)AR). The Gly-49-beta(1)AR was more sensitive to the inhibitory effect of the inverse agonist metoprolol and displayed increased affinity for agonists. Isoproterenol potency for adenylyl cyclase activation was higher on membranes expressing the Gly-49-beta(1)AR than on those expressing the Ser-49-beta(1)AR. After incubation with saturating concentrations of catecholamines or sustained stimulation, the Gly-49 variant showed a much higher desensitization, which largely prevailed over constitutive activity in terms of cAMP accumulation. The Gly-49-beta(1)AR also displayed a more profound agonist-promoted down-regulation than the Ser-49 variant. The stronger regulation of the Gly-49-beta(1)AR could explain the beneficial effect of the Gly-49 genotypes on survival, further supporting the concept that beta(1)AR desensitization is protective in heart failure.
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25.
  • Lindberg, Erika, 1979, et al. (författare)
  • Impaired activation of IFN-gamma+CD4+ T cells in peripheral blood of patients with dilated cardiomyopathy
  • 2010
  • Ingår i: Cellular Immunology. - San Diego, USA : Elsevier. - 0008-8749 .- 1090-2163. ; 263:2, s. 224-229
  • Tidskriftsartikel (refereegranskat)abstract
    • Viral persistence and autoantibodies are pathogenic components in patients with idiopathic dilated cardiomyopathy (DCM). The aim was to evaluate T-cell function in DCM using different flow cytometry based detection techniques. Following stimulation, the frequency of IFN-gamma-producing CD4+ T cells was significantly lower in patients compared with controls. In contrast, the frequency of IL-4 producing CD4+ T cells was no different. In supernatants of cultured PBMC, IFN-gamma and IL-10 were significantly lower in patients. In addition, lymphocyte proliferation was significantly lower in patients compared with controls, whereas major lymphocyte subsets were not different. IFN-gamma and IL-10 are key cytokines in the ability to mount protective immune responses and to maintain self-tolerance. A reduced activation of T-helper 1 (IFN-gamma producing) cells and a decreased capacity to produce IL-10, found in the present study, could explain parts of the autoimmune features seen in patients with DCM.
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26.
  •  
27.
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28.
  • Locke, Adam E, et al. (författare)
  • Genetic studies of body mass index yield new insights for obesity biology.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
  •  
29.
  • Magnusson, Cecilia, et al. (författare)
  • Acoustic Enrichment of Heterogeneous Circulating Tumor Cells and Clusters from Metastatic Prostate Cancer Patients
  • 2024
  • Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 1520-6882 .- 0003-2700. ; 96:18, s. 6914-6921
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: There are important unmet clinical needs to develop cell enrichment technologies to enable unbiased label-free isolation of both single cell and clusters of circulating tumor cells (CTCs) manifesting heterogeneous lineage specificity. Here, we report a pilot study based on the microfluidic acoustophoresis enrichment of CTCs using the CellSearch CTC assay as a reference modality.METHODS: Acoustophoresis uses an ultrasonic standing wave field to separate cells based on biomechanical properties (size, density, and compressibility), resulting in inherently label-free and epitope-independent cell enrichment. Following red blood cell lysis and paraformaldehyde fixation, 6 mL of whole blood from 12 patients with metastatic prostate cancer and 20 healthy controls were processed with acoustophoresis and subsequent image cytometry.RESULTS: Acoustophoresis enabled enrichment and characterization of phenotypic CTCs (EpCAM +, Cytokeratin +, DAPI +, CD45 -/CD66b -) in all patients with metastatic prostate cancer and detected CTC-clusters composed of only CTCs or heterogeneous aggregates of CTCs clustered with various types of white blood cells in 9 out of 12 patients. By contrast, CellSearch did not detect any CTC clusters, but detected comparable numbers of phenotypic CTCs as acoustophoresis, with trends of finding a higher number of CTCs using acoustophoresis. CONCLUSION: Our preliminary data indicate that acoustophoresis provides excellent possibilities to detect and characterize CTC clusters as a putative marker of metastatic disease and outcomes. Moreover, acoustophoresis enables the sensitive label-free enrichment of cells with epithelial phenotypes in blood and offers opportunities to detect and characterize CTCs undergoing epithelial-to-mesenchymal transitioning and lineage plasticity.
  •  
30.
  • Magnusson, Cecilia, et al. (författare)
  • Acoustic enrichment of heterogenous circulating tumor cells and clusters from patients with metastatic prostate cancer
  • 2023
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • BACKGROUND: There are important unmet clinical needs to develop cell enrichment technologies to enable unbiased label-free isolation of both single cell and clusters of circulating tumor cells (CTCs) manifesting heterogeneous lineage specificity. Here, we report a pilot study based on microfluidic acoustophoresis enrichment of CTCs using the CellSearch CTC assay as a reference modality.METHODS: Acoustophoresis uses an ultrasonic standing wave field to separate cells based on biomechanical properties (size, density, and compressibility) resulting in inherently label-free and epitope-independent cell enrichment. Following red blood cell lysis and paraformaldehyde fixation, 6 mL of whole blood from 12 patients with metastatic prostate cancer and 20 healthy controls were processed with acoustophoresis and subsequent image cytometry.RESULTS: Acoustophoresis enabled enrichment and characterization of phenotypic CTCs (EpCAM + , Cytokeratin + , DAPI + , CD45 - /CD66b - ) in all patients with metastatic prostate cancer and detected CTC-clusters composed of only CTCs or heterogenous aggregates of CTCs clustered with various types of white blood cells in 9 out of 12 patients. By contrast, CellSearch did not detect any CTC-clusters, but detected comparable numbers of phenotypic CTCs as acoustophoresis, with trends of finding higher number of CTCs using acoustophoresis. CONCLUSION: Our preliminary data indicate that acoustophoresis provides excellent possibilities to detect and characterize CTC-clusters as a putative marker of metastatic disease and outcomes. Moreover, acoustophoresis enables sensitive label-free enrichment of cells with epithelial phenotype in blood and offers opportunities to detect and characterize CTCs undergoing epithelial-to-mesenchymal transitioning and lineage plasticity.
  •  
31.
  •  
32.
  • Magnusson, Cecilia, et al. (författare)
  • Clinical-Scale Cell-Surface-Marker Independent Acoustic Microfluidic Enrichment of Tumor Cells from Blood
  • 2017
  • Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 89:22, s. 11954-11961
  • Tidskriftsartikel (refereegranskat)abstract
    • Enumeration of circulating tumor cells (CTCs) predicts overall survival and treatment response in metastatic cancer, but as many commercialized assays isolate CTCs positive for epithelial cell markers alone, CTCs with little or no epithelial cell adhesion molecule (EpCAM) expression stay undetected. Therefore, CTC enrichment and isolation by label-free methods based on biophysical rather than biochemical properties could provide a more representative spectrum of CTCs. Here, we report on a clinical-scale automated acoustic microfluidic platform processing 5 mL of erythrocyte-depleted paraformaldehyde (PFA)-fixed blood (diluted 1:2) at a flow rate of 75 μL/min, recovering 43/50 (86 ± 2.3%) breast cancer cell line cells (MCF7), with 0.11% cancer cell purity and 162-fold enrichment in close to 2 h based on intrinsic biophysical cell properties. Adjustments of the voltage settings aimed at higher cancer cell purity in the central outlet provided 0.72% cancer cell purity and 1445-fold enrichment that resulted in 62 ± 8.7% cancer cell recovery. Similar rates of cancer-cell recovery, cancer-cell purity, and fold-enrichment were seen with both prostate cancer (DU145, PC3) and breast cancer (MCF7) cell line cells. We identified eosinophil granulocytes as the predominant white blood cell (WBC) contaminant (85%) in the enriched cancer-cell fraction. Processing of viable cancer cells in erythrocyte-depleted blood provided slightly reduced results as to fixed cells (77% cancer cells in the enriched cancer cell fraction, with 0.2% WBC contamination). We demonstrate feasibility of enriching either PFA-fixed or viable cancer cells with a clinical-scale acoustic microfluidic platform that can be adjusted to meet requirements for either high cancer-cell recovery or higher purity and can process 5 mL blood samples in close to 2 h.
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33.
  • Magnusson, Cecilia, et al. (författare)
  • Regulation of cysteinyl leukotriene receptor 2 expression-a potential anti-tumor mechanism.
  • 2011
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:12
  • Tidskriftsartikel (refereegranskat)abstract
    • The cysteinyl leukotrienes receptors (CysLTRs) are implicated in many different pathological conditions, such as inflammation and cancer. We have previously shown that colon cancer patients with high CysLT(1)R and low CysLT(2)R expression demonstrate poor prognosis. Therefore, we wanted to investigate ways for the transcriptional regulation of CysLT(2)R, which still remains to be poorly understood.
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34.
  • Magnusson, Yvonne, 1957, et al. (författare)
  • Antigenic analysis of the second extra-cellular loop of the human beta-adrenergic receptors.
  • 1989
  • Ingår i: Clinical and experimental immunology. - 0009-9104. ; 78:1, s. 42-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Polyclonal antibodies were raised in rabbits by immunization with free peptides corresponding to positions 197-222 of the human beta 1-adrenergic receptor (beta 1 peptide) and the corresponding sequence (172-197) of the human beta 2-adrenergic receptor (beta 2 peptide). While the beta 2 peptide yielded antibodies that cross-reacted with the beta 1 peptide, the antibodies against the beta 1 peptide did not cross-react with the beta 2 sequence. Cross-reactivity of the anti-beta 2 peptide antibodies and the selectivity of the anti-beta 1 peptide antibodies were also revealed in the recognition by immunoblots of the beta 1- and beta 2-adrenergic receptors of different species or of the receptor gene products expressed in a bacterial vector. These antibodies could be used immunohistochemically to visualize the beta-adrenergic receptors on rabbit heart. The anti-beta 2 peptide antibodies did not show any functional effect on the beta-adrenergic receptors; the anti-beta 1 peptide antibodies were able to displace agonist affinity to higher values. Recognition of truncated peptides by the anti-beta 1 and anti-beta 2 peptide antibodies suggested that the cross-reaction of the anti-beta 2 peptide antibodies was due to the recognition of a common epitope on the C-terminal part of the peptides. The anti-beta 1 peptide antibodies recognized the N-terminal part of the peptide better than the C-terminal part. These results suggest that the second extracellular loop postulated in the structure of the human beta-adrenergic receptor contains the T and B cell epitopes necessary for induction of an immune response. The selectivity and the functional properties of the antibodies raised against that loop in the beta 1 adrenergic receptor could have relevance in induction of auto antibodies in certain cardiomyopathic conditions.
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35.
  • Magnusson, Yvonne, 1957, et al. (författare)
  • Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effect.
  • 1994
  • Ingår i: Circulation. - 0009-7322. ; 89:6, s. 2760-7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Autoantibodies against the beta 1-adrenoceptor have been detected in the sera of patients with idiopathic dilated cardiomyopathy (DCM). The mechanisms by which these autoantibodies can alter normal receptor function are investigated, and the results are interpreted in the light of the beneficial effects of beta 1-blockade in some of these patients. METHODS AND RESULTS: Autoantibodies against the beta 1-adrenoceptor, affinity purified from sera of patients with idiopathic DCM, were analyzed in a functional test system of spontaneously beating neonatal rat heart myocytes. Antibodies from rabbits immunized with peptides derived from the amino acid sequence of this receptor were also analyzed. Autoantibodies, against the second extracellular loop increased the beating frequency of isolated myocytes in a concentration-dependent manner, to approximately 80% of maximal isoproterenol stimulation. Rabbit anti-peptide antibodies against the second extracellular loop increased the beating frequency correspondingly. Autoantibodies and rabbit anti-peptide antibodies against the second extracellular loop were able to immunoprecipitate the unliganded receptor but not the antagonist-occupied receptor. In contrast, rabbit antibodies against the extracellular N-terminal sequence 34-57 of the beta 1-adrenoceptor were able to immunoprecipitate both the unliganded and the antagonist-occupied receptor although with no effect on the beating frequency of myocytes. The positive chronotropic effect of the antibodies was completely neutralized both by the addition of increasing concentrations of the beta 1-selective antagonist bisoprolol and by preincubation with the peptide corresponding to the second extracellular loop. The antibody-induced increase in beating frequency remained unchanged for more than 6 hours. This should be compared with the isoproterenol-stimulated beating frequency, which undergoes desensitization within 60 minutes. Addition of isoproterenol to autoantibody-stimulated myocytes resulted in only a small increase in beating frequency and did not cause desensitization. Antibodies had only a marginal effect on cyclic AMP production of stimulated cardiomyocytes compared with the 10-fold increase obtained after stimulation with isoproterenol. CONCLUSIONS: The second extracellular loop of the beta 1-adrenoceptor is a specific target for antibodies with stimulatory activity detected in patients with idiopathic DCM. The antibodies have a positive chronotropic effect on isolated rat heart myocytes. Autoantibody stimulation does not cause the normal agonist-induced desensitization phenomena of the effector system. These findings could contribute to our understanding of the pathophysiological mechanisms of the autoantibodies and of the beneficial effect of beta 1-blocking agents in the treatment of patients with idiopathic DCM.
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36.
  • Magnusson, Yvonne, 1957, et al. (författare)
  • Beta 1-adrenoceptor autoimmunity in cardiomyopathy.
  • 1996
  • Ingår i: International journal of cardiology. - 0167-5273. ; 54:2, s. 137-41
  • Forskningsöversikt (refereegranskat)abstract
    • A growing body of studies have confirmed that autoantibodies against beta 1-adrenoceptors are present in different types of cardiomyopathy. This suggests that they play a role in the pathophysiology of the disease. This article will review the data indicating the presence of anti-beta 1-adrenoceptor autoantibodies in cardiomyopathy. It will focus upon their structural and functional properties which could explain their possible role in the induction and development of cardiomyopathic diseases.
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37.
  • Magnusson, Yvonne, 1957, et al. (författare)
  • Functional analysis of rabbit anti-peptide antibodies which mimic autoantibodies against the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy.
  • 1991
  • Ingår i: Journal of autoimmunity. - 0896-8411. ; 4:6, s. 893-905
  • Tidskriftsartikel (refereegranskat)abstract
    • A synthetic peptide corresponding to the second extracellular loop of the beta 1-adrenergic receptor was used as an antigen for antibody production in three rabbits. Antibodies of high titers were obtained in all rabbits. Only one rabbit yielded antibodies which decreased radioligand binding on the receptor in a similar way to that described for autoantibodies in patients with dilated cardiomyopathy. These antibodies recognized the receptor protein in immunoblots. Epitope mapping indicated that the N-terminal sequence of the loop used as antigen was the target of the major antigen fraction. Incubation of antibodies with C6 glioma cell membranes or inner membranes of E. coli, which express the human beta 1-adrenergic receptor, resulted in a decrease in number of radioligand binding sites. This decrease was dependent on the concentration of antibody and of Mg++ ions. It was not affected by the GTP analog GppNHp or the beta 1 subtype-specific antagonist metoprolol. The agonist, isoproterenol, also induced a decrease but the effects of antibody and agonist were not additive. These results suggest that the antibodies induce a Mg(++)-dependent, 'active', labile conformation of the receptor, independent from coupling to the GTP regulatory protein, but similar to that induced by the agonist isoproterenol. This interpretation was corroborated by the beta 1-adrenergic receptor agonist-like effect of the antibodies on cardiomyocytes in culture.
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38.
  • Magnusson, Yvonne, 1957, et al. (författare)
  • Mapping of a functional autoimmune epitope on the beta 1-adrenergic receptor in patients with idiopathic dilated cardiomyopathy.
  • 1990
  • Ingår i: The Journal of clinical investigation. - 0021-9738. ; 86:5, s. 1658-63
  • Tidskriftsartikel (refereegranskat)abstract
    • The presence and properties of serum autoantibodies against beta-adrenergic receptors in patients with idiopathic dilated cardiomyopathy were studied using synthetic peptides derived from the predicted sequences of the human beta-adrenergic receptors. Peptides corresponding to the sequences of the second extracellular loop of the human beta 1- and beta 2-adrenergic receptors were used as antigens in an enzyme immunoassay to screen sera from patients with dilated cardiomyopathy (n = 42), ischemic heart disease (n = 17), or healthy blood donors (n = 34). The sera of thirteen dilated cardiomyopathy patients, none of the ischemic heart disease patients, and four of the healthy controls monospecifically recognized the beta 1-peptide. Only affinity-purified antibodies of these patients had a inhibitory effect on radioligand binding to the beta 1 receptor of C6 rat glioma cells. They recognized the receptor protein by immunoblot and bound in situ to human myocardial tissue. We conclude that a subgroup of patients with idiopathic dilated cardiomyopathy have in their sera autoantibodies specifically directed against the second extracellular loop of the beta 1-adrenergic receptor. These antibodies could serve as a marker of an autoimmune response with physiological and/or pathological implications.
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39.
  • Magnusson, Yvonne, 1957, et al. (författare)
  • Ser49Gly of beta1-adrenergic receptor is associated with effective beta-blocker dose in dilated cardiomyopathy.
  • 2005
  • Ingår i: Clinical pharmacology and therapeutics. - : Springer Science and Business Media LLC. - 0009-9236. ; 78:3, s. 221-31
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Our objective was to evaluate the influence of polymorphisms at codons 49 and 389 of the beta1-adrenergic receptor (beta1-AR) on the response to beta-blockers and outcome in patients with dilated cardiomyopathy. METHODS: We genotyped both codons of the beta1-AR in 375 patients with dilated cardiomyopathy and 492 control subjects. RESULTS: Neither of the polymorphisms was associated with susceptibility for dilated cardiomyopathy. In a retrospective analysis of patients receiving beta-blockers, there was a significant association between long-term survival rate and codon 49 (P = .014) but not codon 389 (P = .08). Despite a similar mean heart rate (69 beats/min), patients with the Ser49 genotype tended to have higher doses of beta-blockade compared with Gly49 carriers (P = .065). In patients receiving a low dose of beta-blockade (< or = 50% of targeted full dose), the 5-year mortality rate was lower among Gly49 carriers than Ser49 patients (risk ratio [RR], 0.24; 95% confidence interval [CI], 0.07-0.80; P = .020). In patients receiving high doses of beta-blockers, there was no significant difference in outcome between genotypes (P = .20), which was attributable to a better outcome for Ser49 patients treated with a high dose of beta-blockade as compared with a low dose. Gly49 carriers had a similar survival rate with different doses of beta-blockers. With low-dose beta-blockers, both codon 49 (RR, 0.26; 95% CI, 0.08-0.89; P = .029) and codon 389 (RR, 2.42; 95% CI, 1.04-5.63, P = .039) were related to 5-year mortality rate. CONCLUSION: In patients with heart failure, the influence of codon 49 on the outcome and effect of beta-blockers appeared to be more pronounced than that of codon 389. The more common Ser49Ser genotype responded less beneficially to beta-blockade and would motivate genotyping to promote higher doses for the best outcome effect.
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40.
  • Margaryan, Ashot, et al. (författare)
  • Population genomics of the Viking world
  • 2020
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 585:7825, s. 390-396
  • Tidskriftsartikel (refereegranskat)abstract
    • The maritime expansion of Scandinavian populations during the Viking Age (about ad750–1050) was a far-flung transformation in world history1,2. Here we sequenced the genomes of 442humans from archaeological sites across Europe and Greenland (to a median depth of about 1×) to understand the global influence of this expansion. We find the Viking period involved gene flow into Scandinavia from the south and east. We observe genetic structure within Scandinavia, with diversity hotspots in the south and restricted gene flow within Scandinavia. We find evidence for a major influx of Danish ancestry into England; a Swedish influx into the Baltic; and Norwegian influx into Ireland, Iceland and Greenland. Additionally, we see substantial ancestry from elsewhere in Europe entering Scandinavia during the Viking Age. Our ancient DNA analysis also revealed that a Viking expedition included close family members. By comparing with modern populations, we find that pigmentation-associated loci have undergone strong population differentiation during the past millennium, and trace positively selected loci—including the lactase-persistence allele of LCT and alleles of ANKA that are associated with the immune response—in detail. We conclude that the Viking diaspora was characterized by substantial transregional engagement: distinct populations influenced the genomic makeup of different regions of Europe, and Scandinavia experienced increased contact with the rest of the continent.
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41.
  • Mobini, Reza, 1965, et al. (författare)
  • A monoclonal antibody directed against an autoimmune epitope on the human beta1-adrenergic receptor recognized in idiopathic dilated cardiomyopathy.
  • 2000
  • Ingår i: Hybridoma. - : Mary Ann Liebert Inc. - 0272-457X. ; 19:2, s. 135-42
  • Tidskriftsartikel (refereegranskat)abstract
    • A monoclonal antibody (MAb M16) was obtained by immunizing Balb/C mice with free peptide H26R, corresponding to the second extracellular loop of the human beta1-adrenergic receptor (beta1AR), against which functional autoantibodies have been detected in patients with idiopathic dilated cardiomyopathy. The MAb was found to be of IgG2b type and directed against a conformational epitope, encompassing the sequence recognized by the human autoantibodies. BIAcore measurements yielded an equilibrium constant of 6.5 X 10(7) M1 with an association rate constant (kon) of 6.5 X 10(4) M(-1) sec(-1) and a dissociation rate constant (koff) of 1.0 X 10(-3) sec(-1). It immunoprecipitated only poorly the solubilized beta1AR of Sf9 cell membranes. Functionally, the MAb was capable of not only reducing the number of the maximal binding sites to the beta1-adrenergic receptor of transfected Sf9 cell membranes, but also of displaying a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These properties, which the MAb shares with the human autoantibodies, makes it an interesting tool for passive transfer studies in mice.
  •  
42.
  • Mobini, Reza, 1965, et al. (författare)
  • Probing the immunological properties of the extracellular domains of the human beta(1)-adrenoceptor.
  • 1999
  • Ingår i: Journal of autoimmunity. - : Elsevier BV. - 0896-8411. ; 13:2, s. 179-86
  • Tidskriftsartikel (refereegranskat)abstract
    • The human beta(1)-adrenoceptor is an immune target for autoantibodies with functional activity in cardiovascular diseases. Different epitopes on the extracellular domains of the receptor are involved. To study the immunological and pharmacological properties of these epitopes, rabbits were immunized with peptides corresponding to a large domain in the N-terminal part of the receptor and to its first and second extracellular loops. In contrast to the two other peptides, the first extracellular loop did not have immunogenic properties but acted as a hapten. Antibodies affinity-purified with the three synthetic peptides were able to significantly immunoprecipitate the solubilized receptor, confirming that they recognized the target receptor. While antibodies against the N-terminal domain did not inhibit the binding of a radiolabelled antagonist to the receptor, those against the first and second extracellular loop showed non-competitive inhibition. Similarly, only the two latter antibodies exerted a specific agonist-like effect on the receptor, as assessed on neonatal rat cardiomyocytes in culture. Our results are in accordance with those found for human anti-receptor autoantibodies with functional effects. We conclude that not all extracellular epitopes give rise to functional autoantibodies with potential physiopathological relevance in cardiac diseases with an autoimmune component.
  •  
43.
  • Moraes Holst, Luiza, et al. (författare)
  • Fecal Luminal Factors from Patients with Gastrointestinal Diseases Alter Gene Expression Profiles in Caco-2 Cells and Colonoids
  • 2022
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 23:24
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous in vitro studies have shown that the intestinal luminal content, including metabolites, possibly regulates epithelial layer responses to harmful stimuli and promotes disease. Therefore, we aimed to test the hypothesis that fecal supernatants from patients with colon cancer (CC), ulcerative colitis (UC) and irritable bowel syndrome (IBS) contain distinct metabolite profiles and establish their effects on Caco-2 cells and human-derived colon organoids (colonoids). The metabolite profiles of fecal supernatants were analyzed by liquid chromatography-mass spectrometry and distinguished patients with CC (n = 6), UC (n = 6), IBS (n = 6) and healthy subjects (n = 6). Caco-2 monolayers and human apical-out colonoids underwent stimulation with fecal supernatants from different patient groups and healthy subjects. Their addition did not impair monolayer integrity, as measured by transepithelial electrical resistance; however, fecal supernatants from different patient groups and healthy subjects altered the gene expression of Caco-2 monolayers, as well as colonoid cultures. In conclusion, the stimulation of Caco-2 cells and colonoids with fecal supernatants derived from CC, UC and IBS patients altered gene expression profiles, potentially reflecting the luminal microenvironment of the fecal sample donor. This experimental approach allows for investigating the crosstalk at the gut barrier and the effects of the gut microenvironment in the pathogenesis of intestinal diseases.
  •  
44.
  • Mühlemann, Barbara, et al. (författare)
  • Diverse variola virus (smallpox) strains were widespread in northern Europe in the Viking Age
  • 2020
  • Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 369:6502
  • Tidskriftsartikel (refereegranskat)abstract
    • Smallpox, one of the most devastating human diseases, killed between 300 million and 500 million people in the 20th century alone. We recovered viral sequences from 13 northern European individuals, including 11 dated to ~600-1050 CE, overlapping the Viking Age, and reconstructed near-complete variola virus genomes for four of them. The samples predate the earliest confirmed smallpox cases by ~1000 years, and the sequences reveal a now-extinct sister clade of the modern variola viruses that were in circulation before the eradication of smallpox. We date the most recent common ancestor of variola virus to ~1700 years ago. Distinct patterns of gene inactivation in the four near-complete sequences show that different evolutionary paths of genotypic host adaptation resulted in variola viruses that circulated widely among humans.
  •  
45.
  • Palmer, Nicholette D, et al. (författare)
  • A genome-wide association search for type 2 diabetes genes in African Americans.
  • 2012
  • Ingår i: PloS one. - San Francisco : Public Library of Science (PLoS). - 1932-6203. ; 7:1, s. e29202-
  • Tidskriftsartikel (refereegranskat)abstract
    • African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.
  •  
46.
  • Scharin Täng, Margareta, 1962, et al. (författare)
  • Cardiac reserve in the transplanted heart: effect of a graft polymorphism in the beta1-adrenoceptor
  • 2007
  • Ingår i: The Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498. ; 26:9, s. 915-20
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Polymorphism of the beta1-adrenoceptor (beta1-AR) affects outcome and beta-blocker efficacy in patients with heart failure. We studied the influence of the beta1-AR Ser49Gly polymorphism on cardiac reserve in transplanted hearts. METHODS: Beta1-AR polymorphism was determined by allelic discrimination analysis. Patients were divided into two groups: either homozygous for Ser49 (n = 15) or with Gly49 in one or both alleles (Gly49; n = 5). Patients underwent a maximal bicycle exercise test and echocardiographic evaluation at rest and during low-dose dobutamine stress. RESULTS: Patients with Gly49 grafts had better physical endurance (144 +/- 26 vs 112 +/- 31 W, p = 0.03), a trend toward better chronotropic reserve (deltaHR 64 +/- 13 vs 47 +/- 16 bpm, p = 0.056) during exercise, and lower resting heart rate (82 +/- 7 vs 90 +/- 7 bpm, p = 0.04) than those homozygous for Ser49. There were no significant differences in left ventricular ejection fraction (LVEF), with the exception of a decrease in cardiac reserve in patients with the Gly49 variants at the lowest dose of dobutamine (deltaLVEF -4.4 +/- 1.5 vs 2.2 +/- 5.8%, p = 0.04). Doppler myocardial tissue velocities of early relaxation were increased in patients with the Gly49 variants compared with patients homozygous for Ser49, both at rest (14.5 +/- 3.2 vs 10.4 +/- 2.0 cm/s, p = 0.03) and during the lowest dose of dobutamine (15.0 +/- 3.7 vs 10.9 +/- 2.5 cm/s, p = 0.04). CONCLUSIONS: Heart transplant patients with the beta1-AR Gly49 variants had a lower heart rate, and better stress endurance and diastolic function compared with patients homozygous for Ser49. They also showed a trend toward better chronotropic reserve. These results provide a possible explanation for differences in cardiac reserve among patients with heart transplants.
  •  
47.
  • Shungin, Dmitry, et al. (författare)
  • New genetic loci link adipose and insulin biology to body fat distribution.
  • 2015
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
  • Tidskriftsartikel (refereegranskat)abstract
    • Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
  •  
48.
  • Tate, K, et al. (författare)
  • Epitope analysis of T- and B-cell response against the human beta 1-adrenoceptor.
  • 1994
  • Ingår i: Biochimie. - 0300-9084. ; 76:2, s. 159-64
  • Tidskriftsartikel (refereegranskat)abstract
    • Several reports have recently raised the possible significance of the presence of autoantibodies against the beta 1-adrenoceptor in patients with idiopathic dilated cardiomyopathy. An investigation was thus initiated to study the immune response against this receptor at the T-cell and the B-cell level. Using membranes of E coli transfected with the human beta 1-adrenoceptor gene as immunogen, T-helper cells of the immunized mice were stimulated with synthetic peptides derived from the receptor and predicted to be immunogenic to assess the T-cell immunodominant regions of the receptor. Three peptides derived from the second transmembrane region, from the second extracellular loop and from the C-terminal domain were shown to be stimulatory. Synthetic peptides, derived from two domains of the receptor which could be potential targets for autoantibodies, yielded an antibody response after immunization with the free peptides. The peptide derived from the N-terminal region yielded antibodies which recognized the receptor in immunoblot and by immunoprecipitation but they had no functional effect on the receptor. The peptide derived from the second extracellular loop yielded antibodies which recognized the receptor in immunoblot and by immunoprecipitation of the free receptor and which had a pharmacological effect on the receptor. The second extracellular loop thus contains T- and B-cell epitopes which could be involved in the autoimmune process.
  •  
49.
  • Undvall Anand, Eva, et al. (författare)
  • Two-Step Acoustophoresis Separation of Live Tumor Cells from Whole Blood
  • 2021
  • Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 1520-6882 .- 0003-2700. ; 93:51, s. 17076-17085
  • Tidskriftsartikel (refereegranskat)abstract
    • There is an unmet clinical need to extract living circulating tumor cells (CTCs) for functional studies and in vitro expansion to enable drug testing and predict responses to therapy in metastatic cancer. Here, we present a novel two-step acoustophoresis (A2) method for isolation of unfixed, viable cancer cells from red blood cell (RBC) lysed whole blood. The A2 method uses an initial acoustofluidic preseparation step to separate cells based on their acoustic mobility. This acoustofluidic step enriches viable cancer cells in a central outlet, but a significant number of white blood cells (WBCs) remain in the central outlet fraction due to overlapping acoustophysical properties of these viable cells. A subsequent purging step was employed to remove contaminating WBCs through negative selection acoustophoresis with anti-CD45-functionalized negative acoustic contrast particles. We processed 1 mL samples of 1:1 diluted RBC lysed whole blood mixed with 10 000 DU145 cells through the A2 method. Additional experiments were performed using 1000 DU145 cells spiked into 1.5 × 106 WBCs in 1 mL of buffer to further elucidate the dynamic range of the method. Using samples with 10 000 DU145 cells, we obtained 459 ± 188-fold depletion of WBC and 42% recovery of viable cancer cells. Based on spiked samples with 1000 DU145 cells, our cancer cell recovery was 28% with 247 ± 156-fold WBC depletion corresponding to a depletion efficacy of ≥99.5%. The novel A2 method provides extensive elimination of WBCs combined with the gentle recovery of viable cancer cells suitable for downstream functional analyses and in vitro culture.
  •  
50.
  • van der Laan, Sander W., et al. (författare)
  • Cystatin C and Cardiovascular Disease : A Mendelian Randomization Study
  • 2016
  • Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 68:9, s. 934-945
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 x 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 x 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence fora causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0,994), which was statistically different from the observational estimate (p = 1.6 x 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
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