| 1. |
- Östgren, Carl Johan, et al.
(författare)
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Prevalence of atherosclerosis in individuals with prediabetes and diabetes compared to normoglycaemic individuals-a Swedish population-based study.
- 2023
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Ingår i: Cardiovascular diabetology. - : BioMed Central (BMC). - 1475-2840. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Patients with type 2 diabetes have an increased risk of death and cardiovascular events and people with diabetes or prediabetes have been found to have increased atherosclerotic burden in the coronary and carotid arteries. This study will estimate the cross-sectional prevalence of atherosclerosis in the coronary and carotid arteries in individuals with prediabetes and diabetes, compared with normoglycaemic individuals in a large population-based cohort.The 30,154 study participants, 50-64years, were categorized according to their fasting glycaemic status or self-reported data as normoglycaemic, prediabetes, and previously undetected or known diabetes. Prevalence of affected coronary artery segments, severity of stenosis and coronary artery calcium score (CACS) were determined by coronary computed tomography angiography. Total atherosclerotic burden was assessed in the 11 clinically most relevant segments using the Segment Involvement Score and as the presence of any coronary atherosclerosis. The presence of atherosclerotic plaque in the carotid arteries was determined by ultrasound examination.Study participants with prediabetes (n=4804, 16.0%) or diabetes (n=2282, 7.6%) had greater coronary artery plaque burden, more coronary stenosis and higher CACS than normoglycaemic participants (all, p<0.01). Among male participants with diabetes 35.3% had CACS≥100 compared to 16.1% among normoglycaemic participants. For women, the corresponding figures were 8.9% vs 6.1%. The prevalence of atherosclerosis in the coronary arteries was higher in participants with previously undetected diabetes than prediabetes, but lower than in patients with known diabetes. The prevalence of any plaque in the carotid arteries was higher in participants with prediabetes or diabetes than in normoglycaemic participants.In this large population-based cohort of currently asymptomatic people, the atherosclerotic burden in the coronary and carotid arteries increased with increasing degree of dysglycaemia. The finding that the atherosclerotic burden in the coronary arteries in the undetected diabetes category was midway between the prediabetes category and patients with known diabetes may have implications for screening strategies and tailored prevention interventions for people with dysglycaemia in the future.
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| 2. |
- Björck, Hanna M., et al.
(författare)
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Characterization of Shear-Sensitive Genes in the NormalRat Aorta Identifies Hand2 as a Major Flow-ResponsiveTranscription Factor
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:12
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Shear forces play a key role in the maintenance of vessel wall integrity. Current understanding regarding shear-dependent gene expression is mainly based on in vitro or in vivo observations with experimentally deranged shear, hence reflecting acute molecular events in relation to flow. Our objective was to determine wall shear stress (WSS) in the rat aorta and study flow-dependent vessel wall biology under physiological conditions.Methods and Results: Animal-specific aortic WSS magnitude and vector direction were estimated using computational fluid dynamic simulation based on aortic geometry and flow information acquired by MRI. Two distinct flow pattern regions were identified in the normal rat aorta; the distal part of the inner curvature being exposed to low WSS and a non-uniform vector direction, and a region along the outer curvature being subjected to markedly higher levels of WSS and a uniform vector direction. Microarray analysis revealed a strong differential expression between the flow regions, particularly associated with transcriptional regulation. In particular, several genes related to Ca2+-signalling, inflammation, proliferation and oxidative stress were among the most highly differentially expressed.Conclusions: Microarray analysis validated the CFD-defined WSS regions in the rat aorta, and several novel flow-dependent genes were identified. The importance of these genes in relation to atherosusceptibility needs further investigation.
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| 3. |
- Corthay, Alexandre, et al.
(författare)
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Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis
- 1998
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Ingår i: European Journal of Immunology. - 1521-4141. ; 28:8, s. 2580-2590
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Tidskriftsartikel (refereegranskat)abstract
- Immunization of mice with type II collagen (CII) leads to collagen-induced arthritis (CIA), a model for rheumatoid arthritis. T cell recognition of CII is believed to be a critical step in CIA development. We have analyzed the T cell determinants on CII and the TCR used for their recognition, using twenty-nine T cell hybridomas derived from C3H.Q and DBA/1 mice immunized with rat CII. All hybridomas were specific for the CII(256-270) segment. However, posttranslational modifications (hydroxylation and variable O-linked glycosylation) of the lysine at position 264 generated five T cell determinants that were specifically recognized by different T cell hybridoma subsets. TCR sequencing indicated that each of the five T cell epitopes selected its own TCR repertoire. The physiological relevance of this observation was shown by in vivo antibody-driven depletion of TCR Valpha2-positive T cells, which resulted in an inhibition of the T cell proliferative response in vitro towards the non-modified CII(256-270), but not towards the glycosylated epitope. Most hybridomas (20/29) specifically recognized CII(256-270) glycosylated with a monosaccharide (beta-D-galactopyranose). We conclude that this glycopeptide is immunodominant in CIA and that posttranslational modifications of CII create new T cell determinants that generate a diverse TCR repertoire.
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| 4. |
- Jackowski, Christian, 1975-, et al.
(författare)
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Quantitative MRI in Isotropic Spatial Resolution for Forensic Soft Tissue Documentation. Why and How?
- 2011
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Ingår i: Journal of Forensic Sciences. - : Blackwell. - 0022-1198 .- 1556-4029. ; 56:1, s. 208-215
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Tidskriftsartikel (refereegranskat)abstract
- A quantification of T1, T2, and PD in high isotropic resolution was performed on corpses. Isotropic and quantified postmortem magnetic resonance (IQpmMR) enables sophisticated 3D postprocessing, such as reformatting and volume rendering. The body tissues can be characterized by the combination of these three values. The values of T1, T2, and PD were given as coordinates in a T1-T2-PD space where similar tissue voxels formed clusters. Implementing in a volume rendering software enabled color encoding of specific tissues and pathologies in 3D models of the corpse similar to computed tomography, but with distinctively more powerful soft tissue discrimination. From IQpmMR data, any image plane at any contrast weighting may be calculated or 3D color-encoded volume rendering may be carried out. The introduced approach will enable future computer-aided diagnosis that, e.g., checks corpses for a hemorrhage distribution based on the knowledge of its T1-T2-PD vector behavior in a high spatial resolution.
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| 5. |
- Luttens, Andreas, et al.
(författare)
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Ultralarge Virtual Screening Identifies SARS-CoV-2 Main Protease Inhibitors with Broad-Spectrum Activity against Coronaviruses
- 2022
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 144:7, s. 2905-2920
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Tidskriftsartikel (refereegranskat)abstract
- Drugs targeting SARS-CoV-2 could have saved millions of lives during the COVID-19 pandemic, and it is now crucial to develop inhibitors of coronavirus replication in preparation for future outbreaks. We explored two virtual screening strategies to find inhibitors of the SARS-CoV-2 main protease in ultralarge chemical libraries. First, structure-based docking was used to screen a diverse library of 235 million virtual compounds against the active site. One hundred top-ranked compounds were tested in binding and enzymatic assays. Second, a fragment discovered by crystallographic screening was optimized guided by docking of millions of elaborated molecules and experimental testing of 93 compounds. Three inhibitors were identified in the first library screen, and five of the selected fragment elaborations showed inhibitory effects. Crystal structures of target-inhibitor complexes confirmed docking predictions and guided hit-to-lead optimization, resulting in a noncovalent main protease inhibitor with nanomolar affinity, a promising in vitro pharmacokinetic profile, and broad-spectrum antiviral effect in infected cells.
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| 6. |
- Raposo, Bruno, et al.
(författare)
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T cells specific for post-translational modifications escape intrathymic tolerance induction
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Establishing effective central tolerance requires the promiscuous expression of tissue-restricted antigens by medullary thymic epithelial cells. However, whether central tolerance also extends to post-translationally modified proteins is not clear. Here we show a mouse model of autoimmunity in which disease development is dependent on post-translational modification (PTM) of the tissue-restricted self-antigen collagen type II. T cells specific for the non-modified antigen undergo efficient central tolerance. By contrast, PTM-reactive T cells escape thymic selection, though the PTM variant constitutes the dominant form in the periphery. This finding implies that the PTM protein is absent in the thymus, or present at concentrations insufficient to induce negative selection of developing thymocytes and explains the lower level of tolerance induction against the PTM antigen. As the majority of self-antigens are post-translationally modified, these data raise the possibility that T cells specific for other self-antigens naturally subjected to PTM may escape central tolerance induction by a similar mechanism.
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| 7. |
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| 8. |
- Urbonaviciute, Vilma, et al.
(författare)
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Therapy targeting antigen-specific T cells by a peptide-based tolerizing vaccine against autoimmune arthritis
- 2023
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - Stockholm : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 120:25
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Tidskriftsartikel (refereegranskat)abstract
- A longstanding goal has been to find an antigen-specific preventive therapy, i.e., a vaccine, for autoimmune diseases. It has been difficult to find safe ways to steer the targeting of natural regulatory antigen. Here, we show that the administration of exog-enous mouse major histocompatibility complex class II protein bounding a unique galactosylated collagen type II (COL2) peptide (Aq-galCOL2) directly interacts with the antigen-specific TCR through a positively charged tag. This leads to expanding a VISTA-positive nonconventional regulatory T cells, resulting in a potent dominant suppressive effect and protection against arthritis in mice. The therapeutic effect is dom-inant and tissue specific as the suppression can be transferred with regulatory T cells, which downregulate various autoimmune arthritis models including antibody-induced arthritis. Thus, the tolerogenic approach described here may be a promising dominant antigen-specific therapy for rheumatoid arthritis, and in principle, for autoimmune diseases in general.
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| 9. |
- Abrahamsson, Annelie, et al.
(författare)
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Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo
- 2016
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Ingår i: Oncoimmunology. - : TAYLOR & FRANCIS INC. - 2162-4011 .- 2162-402X. ; 5:10
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n = 20, or entirely fatty breasts (nondense), n = 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1 was decreased in dense breasts. No differences were found in levels of IL-1, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.
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| 10. |
- Andersson, Charlotta, et al.
(författare)
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Phase-contrast MRI volume flow - a comparison of breath held and navigator based acquisitions
- 2016
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Ingår i: BMC Medical Imaging. - : BioMed Central. - 1471-2342 .- 1471-2342. ; 16:26
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Tidskriftsartikel (refereegranskat)abstract
- Background: Magnetic Resonance Imaging (MRI) 2D phase-contrast flow measurement has been regarded as the gold standard in blood flow measurements and can be performed with free breathing or breath held techniques. We hypothesized that the accuracy of flow measurements obtained with segmented phase-contrast during breath holding, and in particular higher number of k-space segments, would be non-inferior compared to navigator phase-contrast. Volumes obtained from anatomic segmentation of cine MRI and Doppler echocardiography were used for additional reference. Methods: Forty patients, five women and 35 men, mean age 65 years (range 53-80), were randomly selected and consented to the study. All underwent EKG-gated cardiac MRI including breath hold cine, navigator based free-breathing phase-contrast MRI and breath hold phase-contrast MRI using k-space segmentation factors 3 and 5, as well as transthoracic echocardiography within 2 days. Results: In navigator based free-breathing phase-contrast flow, mean stroke volume and cardiac output were 79.7 +/- 17.1 ml and 5071 +/- 1192 ml/min, respectively. The duration of the acquisition was 50 +/- 6 s. With k-space segmentation factor 3, the corresponding values were 77.7 ml +/- 17.5 ml and 4979 +/- 1211 ml/min (p = 0.15 vs navigator). The duration of the breath hold was 17 +/- 2 s. K-space segmentation factor 5 gave mean stroke volume 77.9 +/- 16.4 ml, cardiac output 5142 +/- 1197 ml/min (p = 0.33 vs navigator), and breath hold time 11 +/- 1 s. Anatomical segmentation of cine gave mean stroke volume and cardiac output 91.2 +/- 20.8 ml and 5963 +/- 1452 ml/min, respectively. Echocardiography was reliable in 20 of the 40 patients. The mean diameter of the left ventricular outflow tract was 20.7 +/- 1.5 mm, stroke volume 78.3 ml +/- 15.2 ml and cardiac output 5164 +/- 1249 ml/min. Conclusions: In forty consecutive patients with coronary heart disease, breath holding and segmented k-space sampling techniques for phase-contrast flow produced stroke volumes and cardiac outputs similar to those obtained with free-breathing navigator based phase-contrast MRI, using less time. The values obtained agreed fairly well with Doppler echocardiography while there was a larger difference when compared with anatomical volume determinations using SSFP (steady state free precession) cine MRI.
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