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- 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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| 2. |
- Randler, C., et al.
(författare)
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Animal welfare attitudes : Effects of gender and diet in university samples from 22 countries
- 2021
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Ingår i: Animals. - : MDPI AG. - 2076-2615. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Animal Welfare Attitudes (AWA) are defined as human attitudes towards the welfare of animals in different dimensions and settings. Demographic factors, such as age and gender are associated with AWA. The aim of this study was to assess gender differences among university students in a large convenience sample from twenty-two nations in AWA. A total of 7914 people participated in the study (5155 women, 2711 men, 48 diverse). Participants completed a questionnaire that collected demographic data, typical diet and responses to the Composite Respect for Animals Scale Short version (CRAS-S). In addition, we used a measure of gender empowerment from the Human Development Report. The largest variance in AWA was explained by diet, followed by country and gender. In terms of diet, 6385 participants reported to be omnivores, 296 as pescatarian, 637 ate a vegetarian diet and 434 were vegans (n = 162 without answer). Diet was related with CRAS-S scores; people with a vegan diet scored higher in AWA than omnivores. Women scored significantly higher on AWA than men. Furthermore, gender differences in AWA increased as gender inequality decreased. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 6. |
- Bost, J. P., et al.
(författare)
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Delivery of Oligonucleotide Therapeutics: Chemical Modifications, Lipid Nanoparticles, and Extracellular Vesicles
- 2021
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Ingår i: Acs Nano. - : American Chemical Society (ACS). - 1936-0851 .- 1936-086X. ; 15:9, s. 13993-14021
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Tidskriftsartikel (refereegranskat)abstract
- Oligonucleotides (ONs) comprise a rapidly growing class of therapeutics. In recent years, the list of FDA-approved ON therapies has rapidly expanded. ONs are small (15-30 bp) nucleotide-based therapeutics which are capable of targeting DNA and RNA as well as other biomolecules. ONs can be subdivided into several classes based on their chemical modifications and on the mechanisms of their target interactions. Historically, the largest hindrance to the widespread usage of ON therapeutics has been their inability to effectively internalize into cells and escape from endosomes to reach their molecular targets in the cytosol or nucleus. While cell uptake has been improved, "endosomal escape" remains a significant problem. There are a range of approaches to overcome this, and in this review, we focus on three: altering the chemical structure of the ONs, formulating synthetic, lipid-based nanoparticles to encapsulate the ONs, or biologically loading the ONs into extracellular vesicles. This review provides a background to the design and mode of action of existing FDA-approved ONs. It presents the most common ON classifications and chemical modifications from a fundamental scientific perspective and provides a roadmap of the cellular uptake pathways by which ONs are trafficked. Finally, this review delves into each of the above-mentioned approaches to ON delivery, highlighting the scientific principles behind each and covering recent advances.
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| 7. |
- Bost, Jeremy P., et al.
(författare)
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Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides
- 2022
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs.
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| 9. |
- De Bacquer, D, et al.
(författare)
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Prediction of recurrent event in patients with coronary heart disease: the EUROASPIRE Risk Model
- 2022
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Ingår i: European journal of preventive cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 29:2, s. 328-339
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Tidskriftsartikel (refereegranskat)abstract
- AimsMost patients with established atherosclerotic cardiovascular disease (CVD) are at very high risk for developing recurrent events. Since this risk varies a lot between patients there is a need to identify those in whom an even more intensive secondary prevention strategy should be envisaged. Using data from the EUROASPIRE IV and V cohorts of coronary heart disease (CHD) patients from 27 European countries, we aimed at developing and internally and externally validating a risk model predicting recurrent CVD events in patients aged < 75 years.Methods and resultsProspective data were available for 12 484 patients after a median follow-up time of 1.7 years. The primary endpoint, a composite of fatal CVD or new hospitalizations for non-fatal myocardial infarction (MI), stroke, heart failure, coronary artery bypass graft, or percutaneous coronary intervention (PCI), occurred in 1424 patients. The model was developed based on data from 8000 randomly selected patients in whom the association between potential risk factors and the incidence of the primary endpoint was investigated. This model was then validated in the remaining 4484 patients. The final multivariate model revealed a higher risk for the primary endpoint with increasing age, a previous hospitalization for stroke, heart failure or PCI, a previous diagnosis of peripheral artery disease, self-reported diabetes and its glycaemic control, higher non-high-density lipoprotein cholesterol, reduced renal function, symptoms of depression and anxiety and living in a higher risk country. The model demonstrated excellent internal validity and proved very adequate in the validation cohort. Regarding external validity, the model demonstrated good discriminative ability in 20 148 MI patients participating in the SWEDEHEART register. Finally, we developed a risk calculator to estimate risks at 1 and 2 years for patients with stable CHD.ConclusionIn patients with CHD, fatal and non-fatal rates of recurrent CVD events are high. However, there are still opportunities to optimize their management in order to prevent further disease or death. The EUROASPIRE Risk Calculator may be of help to reach this goal.
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