| 1. |
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| 2. |
- Clark, DW, et al.
(författare)
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Associations of autozygosity with a broad range of human phenotypes
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4957-
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Tidskriftsartikel (refereegranskat)abstract
- In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (FROH) for >1.4 million individuals, we show that FROH is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of all environmental confounding.
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| 3. |
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| 4. |
- Frisoni, G. B., et al.
(författare)
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Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers
- 2017
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Ingår i: Lancet Neurology. - 1474-4422 .- 1474-4465. ; 16:8, s. 661-676
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Tidskriftsartikel (refereegranskat)abstract
- The diagnosis of Alzheimer's disease can be improved by the use of biological measures. Biomarkers of functional impairment, neuronal loss, and protein deposition that can be assessed by neuroimaging (ie, MRI and PET) or CSF analysis are increasingly being used to diagnose Alzheimer's disease in research studies and specialist clinical settings. However, the validation of the clinical usefulness of these biomarkers is incomplete, and that is hampering reimbursement for these tests by health insurance providers, their widespread clinical implementation, and improvements in quality of health care. We have developed a strategic five-phase roadmap to foster the clinical validation of biomarkers in Alzheimer's disease, adapted from the approach for cancer biomarkers. Sufficient evidence of analytical validity (phase 1 of a structured framework adapted from oncology) is available for all biomarkers, but their clinical validity (phases 2 and 3) and clinical utility (phases 4 and 5) are incomplete. To complete these phases, research priorities include the standardisation of the readout of these assays and thresholds for normality, the evaluation of their performance in detecting early disease, the development of diagnostic algorithms comprising combinations of biomarkers, and the development of clinical guidelines for the use of biomarkers in qualified memory clinics.
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| 5. |
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| 6. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 7. |
- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 10. |
- Agrawal, K., et al.
(författare)
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Allergic sensitization impairs lung resident memory CD8 T-cell response and virus clearance
- 2022
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 150:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with asthma often suffer from frequent respiratory viral infections and reduced virus clearance. Lung resident memory T cells provide rapid protection against viral reinfections. Objective: Because the development of resident memory T cells relies on the lung microenvironment, we investigated the impact of allergen sensitization on the development of virus-specific lung resident memory T cells and viral clearance. Methods: Mice were sensitized with house dust mite extract followed by priming with X47 and a subsequent secondary influenza infection. Antiviral memory T-cell response and protection to viral infection was assessed before and after secondary influenza infection, respectively. Gene set variation analysis was performed on data sets from the U-BIOPRED asthma cohort using an IFN-γ–induced epithelial cell signature and a tissue resident memory T-cell signature. Results: Viral loads were higher in lungs of sensitized compared with nonsensitized mice after secondary infection, indicating reduced virus clearance. X47 priming induced fewer antiviral lung resident memory CD8 T cells and resulted in lower pulmonary IFN-γ levels in the lungs of sensitized as compared with nonsensitized mice. Using data from the U-BIOPRED cohort, we found that patients with enrichment of epithelial IFN-γ–induced genes in nasal brushings and bronchial biopsies were also enriched in resident memory T-cell–associated genes, had more epithelial CD8 T cells, and reported significantly fewer exacerbations. Conclusions: The allergen-sensitized lung microenvironment interferes with the formation of antiviral resident memory CD8 T cells in lungs and virus clearance. Defective antiviral memory response might contribute to increased susceptibility of patients with asthma to viral exacerbations.
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| 11. |
- Andersen, Toril, et al.
(författare)
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Chitosan-Based Nanomedicine to Fight Genital Candida Infections : Chitosomes
- 2017
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Ingår i: Marine Drugs. - : MDPI. - 1660-3397. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Vaginal infections are associated with high recurrence, which is often due to a lack of efficient treatment of complex vaginal infections comprised of several types of pathogens, especially fungi and bacteria. Chitosan, a mucoadhesive polymer with known antifungal effect, could offer a great improvement in vaginal therapy; the chitosan-based nanosystem could both provide antifungal effects and simultaneously deliver antibacterial drugs. We prepared chitosan-containing liposomes, chitosomes, where chitosan is both embedded in liposomes and surface-available as a coating layer. For antimicrobial activity, we entrapped metronidazole as a model drug. To prove that mucoadhesivness alone is not sufficient for successful delivery, we used Carbopol-containing liposomes as a control. All vesicles were characterized for their size, zeta potential, entrapment efficiency, and in vitro drug release. Chitosan-containing liposomes were able to assure the prolonged release of metronidazole. Their antifungal activity was evaluated in a C. albicans model; chitosan-containing liposomes exhibited a potent ability to inhibit the growth of C. albicans. The presence of chitosan was crucial for the system's antifungal activity. The antifungal efficacy of chitosomes combined with antibacterial potential of the entrapped metronidazole could offer improved efficacy in the treatment of mixed/complex vaginal infections.
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| 12. |
- Andersson, Karin, et al.
(författare)
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The feasibility of including sustainability in LCA for product development
- 1998
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Ingår i: Journal of Cleaner Production. - 0959-6526 .- 1879-1786. ; 6:3-4, s. 289-98
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Tidskriftsartikel (refereegranskat)abstract
- The feasibility of combining the concept of sustainability principles and the methodology of Life Cycle Assessment (LCA) is examined. The goal is to achieve an operational tool that incorporates sustainability in product development and strategic planning. While the method outlined has the structure of LCA, it emphasises aspects and parameters often omitted from traditional LCA. The analysis and results can be either qualitative or semi-quantitative. Although a qualitative analysis is less time consuming, it can still highlight the important issues. Qualitative information, which is easily lost in a quantitative analysis, can be emphasised. One of the conclusions is that the method is well suited for screening analysis. © 1998 Elsevier Science Ltd. All rights reserved.
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| 13. |
- Arino, I., et al.
(författare)
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On the relation between surface texture and gloss of injection-molded pigmented plastics
- 2005
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Ingår i: Polymer Engineering and Science. - : Wiley. - 0032-3888 .- 1548-2634. ; 45:10, s. 1343-1356
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Tidskriftsartikel (refereegranskat)abstract
- The relation between the surface topography of injection-molded plastic objects with deliberately imposed textures and their gloss, measured by means of a conventional glossmeter at incident angles of 20 degrees, 60 degrees and 85 degrees, was investigated. A modification of the general scalar Kirchhoff approximation, which accounts for geometrical features of the glossmeter, is used to describe the experimental gloss values of the textured surfaces. The agreement between the measured and the calculated values for incidence angles of 20 degrees and 60 degrees confirms the usefulness of the approach, though several of the textured surfaces used here are too rough for the Kirchhoff theory to be strictly valid. A poorer agreement, however, was noted at higher incidence angles (85 degrees in this case). For very smooth surfaces (without any texture), the classical Bennett-Porteus theory could in many cases describe the gloss level with sufficient accuracy. The influence on the measured gloss of the polymer material (in terms of its refractive index) and the color of the injection-molded object is also discussed. Light beige specimens in three different polymeric materials (acrylonitrile-butadiene-styrene, acrylonitrile-butadiene-styrene/polycarbonate blend, and polypropylene) as well as three acrylonitrile-butadiene-styrene products with different colors were used. The refractive index of the polymer had no major influence on the measured gloss. The gloss level increased slightly with increasing lightness of the specimens, which can be associated with an increased contribution from the bulk scattering. However, the surface texture governed most of the gloss variations.
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| 14. |
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| 21. |
- Brailo, V., et al.
(författare)
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World Workshop on Oral Medicine VI: Utilization of Oral Medicine-specific software for support of clinical care, research, and education: current status and strategy for broader implementation
- 2015
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Ingår i: Oral Surgery Oral Medicine Oral Pathology Oral Radiology. - : Elsevier BV. - 2212-4403. ; 120:2, s. 172-184
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. To assess the current scope and status of Oral Medicine-specific software (OMSS) utilized to support clinical care, research, and education in Oral Medicine and to propose a strategy for broader implementation of OMSS within the global Oral Medicine community. Study Design. An invitation letter explaining the objectives was sent to the global Oral Medicine community. Respondents were interviewed to obtain information about different aspects of OMSS functionality. Results. Ten OMSS tools were identified. Four were being used for clinical care, one was being used for research, two were being used for education, and three were multipurpose. Clinical software was being utilized as databases developed to integrate of different type of clinical information. Research software was designed to facilitate multicenter research. Educational software represented interactive, case-orientated technology designed for clinical training in Oral Medicine. Easy access to patient data was the most commonly reported advantage. Difficulty of use and poor integration with other software was the most commonly reported disadvantage. Conclusions. The OMSS presented in this paper demonstrate how information technology (IT) can have an impact on the quality of patient care, research, and education in the field of Oral Medicine. A strategy for broader implementation of OMSS is proposed.
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| 22. |
- Brieghel, Christian, et al.
(författare)
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Identifying patients with chronic lymphocytic leukemia without need of treatment : End of endless watch and wait?
- 2022
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Ingår i: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609. ; 108:5, s. 369-378
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Early-stage chronic lymphocytic leukemia (CLL) challenges specialized management and follow-up.Methods We developed and validated a prognostic index to identify newly diagnosed patients without need of treatment (CLL-WONT) by a training/validation approach using data on 4708 patients. Composite scores derived from weighted hazards by multivariable analysis defined CLL-WONT risk groups.Results Age (>65 years: 1 point), Binet stage (B: 2 points), lactate dehydrogenase (LDH) (>205 U/L: 1 point), absolute lymphocyte count (15-30 x 10(9)/L: 1 point; >30 x 10(9)/L; 2 points), beta 2-microglobulin (>4 mg/L: 1 point), IGHV mutation status (unmutated: 1 point), and 11q or 17p deletion (1 point) were independently associated with shorter time to first treatment (TTFT). Low-risk patients demonstrated 5-year TTFT of 2% by internal validation, but 7-19% by external validation. Including all patients with complete scores, the 5-year TTFT was 10% for the 756 (39%) CLL-WONT low-risk patients, and the 704 (37%) patients who were both CLL-WONT and CLL-IPI low risk demonstrated even lower 5-year TTFT (8%).Conclusion We have adopted the CLL-WONT at an institution covering 1 800 000 individuals to allow patients with both low-risk CLL-WONT and CLL-IPI to be managed by primary healthcare providers, thereby prioritizing specialized hematology services for patients in dire need.
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| 23. |
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| 26. |
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| 27. |
- Dini, P., et al.
(författare)
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Proceedings - 5th International Conference on Software Engineering Advances, ICSEA 2010 : Preface
- 2010
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Ingår i: International Conference on Software Engineering Advances (ICSEA). - : Institute of Electrical and Electronics Engineers (IEEE). ; , s. xii-xiii
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Konferensbidrag (populärvet., debatt m.m.)abstract
- Presents the introductory welcome message from the conference proceedings. May include the conference officers' congratulations to all involved with the conference event and publication of the proceedings record.
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| 28. |
- Ebefors, Thorbjörn, et al.
(författare)
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A robust micro conveyer realized by arrayed polyimide joint actuators
- 1999
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Ingår i: Proceedings of the 1999 12th IEEE International Conference on Micro Electro Mechanical Systems. - 0780351940 ; , s. 576-581
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Konferensbidrag (refereegranskat)abstract
- A new micromotion system (micro-conveyer) based on arrays of movable robustsilicon legs has been developed and investigated. The motion is achieved by thermal actuation of polyimide joint actuators using electrical heating. Successful experiments on moving flat objects in the millimeter range with high load capacity have been performed. The conveyerconsists of a15×5 mm2 chip with 12 silicon legs each 500 μm long. The maximum load conveyed on the structure was 2000 mg. Conveyance velocities up to 12 mm/s have been measured. Accelerated life-time measurements demonstrate the long-term stability of the actuators. The function of the polyimide joint actuators is unaffected after more than 2×108 load cycles.
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| 29. |
- Ebefors, Thorbjörn, et al.
(författare)
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A robust micro conveyer realized by arrayed polyimide joint actuators
- 2000
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Ingår i: Journal of Micromechanics and Microengineering. - : IOP Publishing. - 0960-1317 .- 1361-6439. ; 10:3, s. 337-349
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Tidskriftsartikel (refereegranskat)abstract
- A new micro-robotic conveyance system based on arrays of movable robust silicon legs has been developed and investigated. Motion is achieved by thermal expansion in polyimide joint actuators using electrical heating. Successful experiments on moving and rotating flat objects in the millimeter range have been performed with high load capacity. The conveyer consists of a 15 x 5 mm(2) chip having 12 silicon legs, each with a length of 500 mu m. The maximum load conveyed on the structure was 3500 mg. Both transverse and rotational movements have been demonstrated experimentally. Conveyance velocities up to 12 mm s(-1) have been measured. Accelerated lifetime measurements demonstrate the long-term stability of the actuators. The functionality of the: polyimide joint actuators is unaffected after more than 2 x 10(8) load cycles.
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| 30. |
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| 31. |
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| 35. |
- Gaillard, R. C., et al.
(författare)
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Overall and cause-specific mortality in GH-deficient adults on GH replacement
- 2012
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 166:6, s. 1069-1077
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Hypopituitarism is associated with an increased mortality rate but the reasons underlying this have not been fully elucidated. The purpose of this study was to evaluate mortality and associated factors within a large GH-replaced population of hypopituitary patients. Design: In KIMS (Pfizer International Metabolic Database) 13 983 GH-deficient patients with 69 056 patient-years of follow-up were available. Methods: This study analysed standardised mortality ratios (SMRs) by Poisson regression. IGF1 SDS was used as an indicator of adequacy of GH replacement. Statistical significance was set to P<0.05. Results: All-cause mortality was 13% higher compared with normal population rates (SMR, 1.13; 95% confidence interval, 1.04-1.24). Significant associations were female gender, younger age at follow-up, underlying diagnosis of Cushing's disease, craniopharyngioma and aggressive tumour and presence of diabetes insipidus. After controlling for confounding factors, there were statistically significant negative associations between IGF1 SDS after 1, 2 and 3 years of GH replacement and SMR. For cause-specific mortality there was a negative association between 1-year IGF1 SDS and SMR for deaths from cardiovascular diseases (P=0.017) and malignancies (P=0.044). Conclusions: GH-replaced patients with hypopituitarism demonstrated a modest increase in mortality rate; this appears lower than that previously published in GH-deficient patients. Factors associated with increased mortality included female gender, younger attained age, aetiology and lower IGF1 SDS during therapy. These data indicate that GH replacement in hypopituitary adults with GH deficiency may be considered a safe treatment.
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| 36. |
- Globisch, Maria A., et al.
(författare)
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Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation
- 2022
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 140:20, s. 2154-2169
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Tidskriftsartikel (refereegranskat)abstract
- Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies, but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA sequencing to investigate the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (Ccm3-iECKO). We found that Ccm3-deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared with wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. We created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3 expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model, this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.
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| 37. |
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| 38. |
- Grube, M, et al.
(författare)
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An exceptional group-I intron-like insertion in the SSU rDNA of lichen mycobionts
- 1999
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Ingår i: CURRENT GENETICS. - : SPRINGER VERLAG. - 0172-8083. ; 35:5, s. 536-541
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- An exceptional group-I intron-like insertion at position 940 of the nuclear small subunit rDNA is found in lichen mycobionts of the families Parmeliaceae and Lecanoraceae. This shared insertion site is exceptional as it follows a G. Although several featu
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| 39. |
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| 40. |
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| 41. |
- Hermansson, Cecilia, et al.
(författare)
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Macrophage CD14 expression in human carotid plaques is associated with complicated lesions, correlates with thrombosis, and is reduced by angiotensin receptor blocker treatment
- 2014
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Ingår i: International Immunopharmacology. - : Elsevier BV. - 1567-5769. ; 22:2, s. 318-323
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Tidskriftsartikel (refereegranskat)abstract
- CD14 is a predictor of inflammation and associated with atherosclerosis. We analyzed 118 carotid plaques from patients with symptomatic carotid artery stenosis for expression of the macrophage markers CD14, CD68 and the angiotensin II type 1 receptor (AT(1)-R). CD14 staining was significantly increased in thrombotic carotid plaques. AT1-R staining was found in macrophage-rich areas, and AT1-R mRNA was detected in plaque macrophages isolated with anti-CD14 immunobeads. In patients treated with an angiotensin receptor blocker, expression of CD14 and CD68 in carotid plaque and serum levels of inflammatory markers were lower than in untreated patients. In vitro, expression of CD14 in human monocyte-derived macrophages was increased by exposure to lipopolysaccharide and decreased by exposure to an angiotensin receptor blocker. Thus, inhibition of the innate immune responsive lipopolysaccharide receptor CD14 in macrophages, rather than AT(1)-R inhibition, may help explain the anti-inflammatory effects of angiotensin receptor blockade. (C) 2014 The Authors. Published by Elsevier B.V.
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| 42. |
- Janelidze, Shorena, et al.
(författare)
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Plasma P-tau181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia
- 2020
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 26, s. 379-386
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Tidskriftsartikel (refereegranskat)abstract
- Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials. Plasma P-tau18 level increased with progression of Alzheimer's disease (AD) and differentiated AD dementia from other neurodegenerative diseases, supporting its further development as a blood-based biomarker for AD.
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| 43. |
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| 44. |
- Johannsson, Gudmundur, 1960, et al.
(författare)
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Long-Term Safety of Growth Hormone in Adults With Growth Hormone Deficiency: Overview of 15 809 GH-Treated Patients
- 2022
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:7, s. 1906-1919
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Tidskriftsartikel (refereegranskat)abstract
- Context Data on long-term safety of growth hormone (GH) replacement in adults with GH deficiency (GHD) are needed. Objective We aimed to evaluate the safety of GH in the full KIMS (Pfizer International Metabolic Database) cohort. Methods The worldwide, observational KIMS study included adults and adolescents with confirmed GHD. Patients were treated with GH (Genotropin [somatropin]; Pfizer, NY) and followed through routine clinical practice. Adverse events (AEs) and clinical characteristics (eg, lipid profile, glucose) were collected. Results A cohort of 15 809 GH-treated patients were analyzed (mean follow-up of 5.3 years). AEs were reported in 51.2% of patients (treatment-related in 18.8%). Crude AE rate was higher in patients who were older, had GHD due to pituitary/hypothalamic tumors, or adult-onset GHD. AE rate analysis adjusted for age, gender, etiology, and follow-up time showed no correlation with GH dose. A total of 606 deaths (3.8%) were reported (146 by neoplasms, 71 by cardiac/vascular disorders, 48 by cerebrovascular disorders). Overall, de novo cancer incidence was comparable to that in the general population (standard incidence ratio 0.92; 95% CI, 0.83-1.01). De novo cancer risk was significantly lower in patients with idiopathic/congenital GHD (0.64; 0.43-0.91), but similar in those with pituitary/hypothalamic tumors or other etiologies versus the general population. Neither adult-onset nor childhood-onset GHD was associated with increased de novo cancer risks. Neutral effects were observed in lipids/fasting blood glucose levels. Conclusion These final KIMS cohort data support the safety of long-term GH replacement in adults with GHD as prescribed in routine clinical practice.
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| 45. |
- Johansson, Bengt, et al.
(författare)
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Functional class, symptoms, medications, arrhythmia devices and quality of life in adults with congenital aortic valve disease. Data from the national registry of congenital heart disease
- 2013
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 34:Supplement: 1, s. 375-375
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Purpose: Despite the relative high prevalence of congenital aorticvalve disease, the outcome in contemporary cohorts of adults is not well established. In the present study, we have analysed data in the National Registry on Adult Congenital Heart Disease in order to elucidate the long-term outcome regarding functional class,symptoms, quality of life, medications and need for arrhythmiadevices in this cohort.Methods: Six hundred fifty-one adult patients with isolated congenitalaortic valve disease met the criteria and were grouped according to: if their first aortic valve intervention was < 18 years (group 1) (n=152), first aortic valve intervention > 18 years (group 2) (n=129) or no aorticvalve intervention (group 0) (n=370).Results: 92% of the patients were in NYHA I. Symptoms were reportedin 12.7% but more commonly in group 2 compared with group 1 (20.7% vs. 9.6%, p = 0.039). The overall quality of life assessed with EQ-VAS was 90% and equal between groups. The use of cardiovascularmedications, anticoagulation excluded, was higher in group 2 than ingroups 0 and 1 (29.1% vs. 9.1% and 11.6%, p = 0.001, p < 0.001). Warfarin was prescribed in 55.3% of the patients in group 2, in 34.5% ingroup 1 and 1.7% in group 0 (p < 0.001 for all comparisons) whichindicates that non-mechanical valve prostheses or other alternatives are common in group 1 and 2. Implanted arrhythmia devices were more common in group 2 compared with group 0 (5.1 vs. 0.6%, p = 0.01).Conclusion: Functional status and quality of life is generally goodand not obviously related to previous interventions. Symptoms, cardiovascular medications, including warfarin, and anti-arrhythmiadevices were more common in patients with their initial valveintervention in adult age. Many patients with a previous intervention have alternatives to mechanical heart valve prostheses and may thus need future re-interventions.
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| 46. |
- Johansson, Per, et al.
(författare)
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Convergence of chromogranin and amyloid metabolism in the brain.
- 2010
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5279 .- 1552-5260. ; 6:4, s. 511-511
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Konferensbidrag (refereegranskat)abstract
- Background: Much is unknown regarding the regulation of amyloid precursor protein (APP) processing in the human central nervous system. It has been hypothesized that amyloidogenic APP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of APP-derived molecules in CSF with chromogranin (Cg) derived peptides, representing the regulated secretion. Methods: Patients with Alzheimer's disease (AD, N = 32), multiple sclerosis (MS, N = 50) and healthy controls (N = 70) were enrolled. CSF was analyzed for the amyloid peptides Aβ1-42, Aβx-42, Aβx-40, Aβx-38, α-cleaved soluble APP (α-sAPP), β-cleaved soluble APP (β-sAPP), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes APP into Aβ, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. Results: CSF Cg levels correlated to sAPP and Aβ peptides in AD, MS and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. Conclusions: These results suggest that a large part of APP in the human central nervous system is processed in the regulated secretory pathway of neurons.
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| 47. |
- Joshi, Peter K, et al.
(författare)
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Directional dominance on stature and cognition in diverse human populations
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 523:7561, s. 459-462
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Tidskriftsartikel (refereegranskat)abstract
- Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.
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| 48. |
- Kater, Arnon P., et al.
(författare)
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Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION) : primary analysis of an open-label, randomised, phase 2 trial
- 2022
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Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 23:6, s. 818-828
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Tidskriftsartikel (refereegranskat)abstract
- Background Targeted time-limited treatment options are needed for patients with relapsed or refractory chronic lymphocytic leukaemia. The aim of this study was to investigate the efficacy of minimal residual disease (MRD)-guided, time-limited ibrutinib plus venetoclax treatment in this patient group. Methods HOVON141/VISION was an open-label, randomised, phase 2 trial conducted in 47 hospitals in Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden. Eligible participants were aged 18 years or older with previously treated chronic lymphocytic leukaemia with or without TP53 aberrations; had not been exposed to Bruton tyrosine-kinase inhibitors or BCL2 inhibitors; had a creatinine clearance rate of 30 mL/min or more; and required treatment according to International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. Participants with undetectable MRD (< 10(-4); less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes) in peripheral blood and bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (weekly ramp-up 20 mg, 50 mg, 100 mg, 200 mg, up to 400 mg once daily) were randomly assigned (1:2) to ibrutinib maintenance or treatment cessation. Patients who were MRD positive continued to receive ibrutinib monotherapy. Patients who became MRD (> 10(-2)) during observation reinitiated treatment with ibrutinib plus venetoclax. The primary endpoint was progression-free survival at 12 months after random assignment in the treatment cessation group. Progression-free survival was analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety assessment. The study is registered at ClinicalTrials.gov, NCT03226301, and is active but not recruiting. Findings Between July 12, 2017, and Jan 21, 2019, 230 patients were enrolled, 225 of whom were eligible. 188 (84%) of 225 completed treatment with ibrutinib plus venetoclax and were tested for MRD at cycle 15. After cycle 15, 78 (35%) patients had undetectable MRD and 72 (32%) were randomly assigned to a treatment group (24 to ibrutinib maintenance and 48 to treatment cessation). The remaining 153 patients were not randomly assigned and continued with ibrutinib monotherapy. Median follow-up of 208 patients still alive and not lost to follow-up at data cutoff on June 22, 2021, was 34middot4 months (IQR 30.6-37.9). Progression-free survival after 12 months in the treatment cessation group was 98% (95% CI 89-100). Infections (in 130 [58%] of 225 patients), neutropenia (in 91 [40%] patients), and gastrointestinal adverse events (in 53 [24%] patients) were the most frequently reported; no new safety signals were detected. Serious adverse events were reported in 46 (40%) of 116 patients who were not randomly assigned and who continued ibrutinib maintenance after cycle 15, eight (33%) of 24 patients in the ibrutinib maintenance group, and four (8%) of 48 patients in the treatment cessation group. One patient who was not randomly assigned had a fatal adverse event (bleeding) deemed possibly related to ibrutinib. Interpretation These data point to a favourable benefit-risk profile of MRD-guided, time-limited treatment with ibrutinib plus venetoclax for patients with relapsed or refractory chronic lymphocytic leukaemia, suggesting that MRD-guided cessation and reinitiation is feasible in this patient population. Copyright (C) 2022 Elsevier Ltd. All rights reserved.
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| 49. |
- Konstantopoulou, Christina, et al.
(författare)
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Dust depletion of metals from local to distant galaxies : II. Cosmic dust-to-metal ratio and dust composition
- 2024
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 681
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of cosmic dust content and the cycle between metals and dust in the interstellar medium (ISM) play a fundamental role in galaxy evolution. The chemical enrichment of the Universe can be traced through the evolution of the dust-to-metal ratio (DTM) and the dust-to-gas ratio (DTG) with metallicity. The physical processes through which dust is created and eventually destroyed remain to be elucidated. We use a novel method to determine mass estimates of the DTM, DTG, and dust composition in terms of the fraction of dust mass contributed by element X ( fMX ) based on our previous measurements of the depletion of metals in different environments (the Milky Way, the Magellanic Clouds, and damped Lyman-α absorbers (DLAs) towards quasars (QSOs) and towards gamma-ray bursts (GRBs)), which were calculated from the relative abundances of metals in the ISM through absorption-line spectroscopy column densities observed mainly from VLT/UVES and X-shooter, and HST/STIS. We also derive the dust extinction from the estimated dust depletion (AV,depl) for GRB-DLAs, the Magellanic Clouds, and the Milky Way, and compare it with the AV estimated from extinction (AV,ext). We find that the DTM and DTG ratios increase with metallicity and with the dust tracer [Zn/Fe]. This suggests that grain growth in the ISM is the dominant process of dust production, at least in the metallicity range (-2 ≤ [M/H]tot . 0.5) and redshift range (0.6 < z < 6.3) that we are studying. The increasing trend in the DTM and DTG with metallicity is in good agreement with a dust production and evolution hydrodynamical model. Our data suggest that the stellar dust yield is much lower (about 1%) than the metal yield and thus that the overall amount of dust in the warm neutral medium that is produced by stars is much lower than previously estimated. The global neutral gas metallicity is decreasing over cosmic time and is traced similarly by quasar-DLAs and GRB-DLAs. We find that, overall, AV,depl is lower than AV,ext for the Milky Way and in a few lines of sight for the Magellanic Clouds, a discrepancy that is likely related to the presence of carbonaceous dust associated with dense clumps of cold neutral gas. For the other environments studied here, we find good agreement overall between the AV,ext and AV,depl.We show that the main elements ( fMX > 1%) that contribute to the dust composition, by mass, are O, Fe, Si, Mg, C, S, Ni, and Al for all the environments, with Si, Mg, and C being equivalent contributors. There are nevertheless variations in the dust composition depending on the overall amount of dust. The abundances measured at low dust regimes in quasar- and GRB-DLAs suggest the presence of pyroxene and metallic iron in dust. These results give important information on the dust and metal content of galaxies across cosmic times, from the Milky Way up to z = 6.3.
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| 50. |
- Li, Lu, 1964, et al.
(författare)
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The Importance of GLUT3 for De Novo Lipogenesis in Hypoxia-Induced Lipid Loading of Human Macrophages
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:8
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic lesions are characterized by lipid-loaded macrophages (foam cells) and hypoxic regions. Although it is well established that foam cells are produced by uptake of cholesterol from oxidized LDL, we previously showed that hypoxia also promotes foam cell formation even in the absence of exogenous lipids. The hypoxia-induced lipid accumulation results from increased triglyceride biosynthesis but the exact mechanism is unknown. Our aim was to investigate the importance of glucose in promoting hypoxia-induced de novo lipid synthesis in human macrophages. In the absence of exogenous lipids, extracellular glucose promoted the accumulation of Oil Red O-stained lipid droplets in human monocyte-derived macrophages in a concentration-dependent manner. Lipid droplet accumulation was higher in macrophages exposed to hypoxia at all assessed concentrations of glucose. Importantly, triglyceride synthesis from glucose was increased in hypoxic macrophages. GLUT3 was highly expressed in macrophage-rich and hypoxic regions of human carotid atherosclerotic plaques and in macrophages isolated from these plaques. In human monocyte-derived macrophages, hypoxia increased expression of both GLUT3 mRNA and protein, and knockdown of GLUT3 with siRNA significantly reduced both glucose uptake and lipid droplet accumulation. In conclusion, we have shown that hypoxia-induced increases in glucose uptake through GLUT3 are important for lipid synthesis in macrophages, and may contribute to foam cell formation in hypoxic regions of atherosclerotic lesions.
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