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| 312. |
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| 313. |
- Orrem, Hilde L., et al.
(författare)
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Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction
- 2018
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Ingår i: International Journal of Cardiology. - : Elsevier. - 0167-5273 .- 1874-1754. ; 268, s. 187-192
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Tidskriftsartikel (refereegranskat)abstract
- Background: The inflammatory response following myocardial infarction (MI) is prerequisite for proper healing of infarcted tissue, but can also have detrimental effects on cardiac function. Interleukin (IL)-1 alpha and IL-1 beta are potent inflammatory mediators and their bioactivity is tightly regulated by IL-1 receptor antagonist (IL-1ra) and soluble (s) IL-1 receptors (R). We aimed to examine whether levels of soluble regulators of IL-1 signalling are changed during ST-elevation MI (STEMI) and their associations with parameters of cardiac injury and ventricular remodelling. Methods: Plasma levels of IL-1Ra, sIL-1R1, sIL-1R2 and sIL-1R accessory protein (sIL-1RAcP) were measured by immunoassays in repeated samples from patients with STEMI (n = 255) and compared to healthy controls (n=65). Results: IL-1Ra, sIL-1R1 and sIL-1R2 levels were all significantly elevated after STEMI, while levels of sIL-1RAcP were lower compared to controls. sIL-1R2 levels (at different time points) correlated positively with C-reactive protein, myocardial infarct size and change in indexed left ventricular end-diastolic and end-systolic volume (LVEDVi and LVESVi) measured by cardiac MR acutely and after 4 months, and negatively with LV ejection fraction. Patients with >median levels of sIL-1R2 in the acute phase were more likely to have increased change in LVEDVi and LVESVi. Importantly, sIL-1R2 remained significantly associated with change in LVEDVi and LVESVi also after adjustment for clinical covariates. Conclusion: Levels of sIL-1R2 are independently associated with parameters of LV adverse remodelling following STEMI. (C 18 Elsevier B.V. All rights reserved.
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| 314. |
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| 315. |
- Schuette, Moritz, et al.
(författare)
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Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal carcinoma represents a heterogeneous entity, with only a fraction of the tumours responding to available therapies, requiring a better molecular understanding of the disease in precision oncology. To address this challenge, the OncoTrack consortium recruited 106 CRC patients (stages I-IV) and developed a pre-clinical platform generating a compendium of drug sensitivity data totalling 44,000 assays testing 16 clinical drugs on patient-derived in vivo and in vitro models. This large biobank of 106 tumours, 35 organoids and 59 xenografts, with extensive omics data comparing donor tumours and derived models provides a resource for advancing our understanding of CRC. Models recapitulate many of the genetic and transcriptomic features of the donors, but defined less complex molecular sub-groups because of the loss of human stroma. Linking molecular profiles with drug sensitivity patterns identifies novel biomarkers, including a signature outperforming RAS/RAF mutations in predicting sensitivity to the EGFR inhibitor cetuximab.
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| 316. |
- Shelke, Ganesh V, 1986, et al.
(författare)
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Endosomal signalling via exosome surface TGF beta-1
- 2019
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Ingår i: Journal of Extracellular Vesicles. - : Wiley. - 2001-3078. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles such as exosomes convey biological messages between cells, either by surface-to-surface interaction or by shuttling of bioactive molecules to a recipient cell's cytoplasm. Here we show that exosomes released by mast cells harbour both active and latent transforming growth factor beta-1 (TGF beta-1) on their surfaces. The latent form of TGF beta-1 is associated with the exosomes via heparinase-II and pH-sensitive elements. These vesicles traffic to the endocytic compartment of recipient human mesenchymal stem cells (MSCs) within 60 min of exposure. Further, the exosomes-associated TGF beta-1 is retained within the endosomal compartments at the time of signalling, which results in prolonged cellular signalling compared to free-TGF beta-1. These exosomes induce a migratory phenotype in primary MSCs involving SMAD-dependent pathways. Our results show that mast cell-derived exosomes are decorated with latent TGF beta-1 and are retained in recipient MSC endosomes, influencing recipient cell migratory phenotype. We conclude that exosomes can convey signalling within endosomes by delivering bioactive surface ligands to this intracellular compartment.
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| 317. |
- Streit, Sven, et al.
(författare)
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Burden of cardiovascular disease across 29 countries and GPs' decision to treat hypertension in oldest-old.
- 2018
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Ingår i: Scandinavian Journal of Primary Health Care. - : Taylor & Francis. - 0281-3432 .- 1502-7724. ; 36:1, s. 89-98
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We previously found large variations in general practitioner (GP) hypertension treatment probability in oldest-old (>80 years) between countries. We wanted to explore whether differences in country-specific cardiovascular disease (CVD) burden and life expectancy could explain the differences.DESIGN: This is a survey study using case-vignettes of oldest-old patients with different comorbidities and blood pressure levels. An ecological multilevel model analysis was performed.SETTING: GP respondents from European General Practice Research Network (EGPRN) countries, Brazil and New Zeeland.SUBJECTS: This study included 2543 GPs from 29 countries.MAIN OUTCOME MEASURES: GP treatment probability to start or not start antihypertensive treatment based on responses to case-vignettes; either low (<50% started treatment) or high (≥50% started treatment). CVD burden is defined as ratio of disability-adjusted life years (DALYs) lost due to ischemic heart disease and/or stroke and total DALYs lost per country; life expectancy at age 60 and prevalence of oldest-old per country.RESULTS: Of 1947 GPs (76%) responding to all vignettes, 787 (40%) scored high treatment probability and 1160 (60%) scored low. GPs in high CVD burden countries had higher odds of treatment probability (OR 3.70; 95% confidence interval (CI) 3.00-4.57); in countries with low life expectancy at 60, CVD was associated with high treatment probability (OR 2.18, 95% CI 1.12-4.25); but not in countries with high life expectancy (OR 1.06, 95% CI 0.56-1.98).CONCLUSIONS: GPs' choice to treat/not treat hypertension in oldest-old was explained by differences in country-specific health characteristics. GPs in countries with high CVD burden and low life expectancy at age 60 were most likely to treat hypertension in oldest-old. Key Points • General practitioners (GPs) are in a clinical dilemma when deciding whether (or not) to treat hypertension in the oldest-old (>80 years of age). • In this study including 1947 GPs from 29 countries, we found that a high country-specific cardiovascular disease (CVD) burden (i.e. myocardial infarction and/or stroke) was associated with a higher GP treatment probability in patients aged >80 years. • However, the association was modified by country-specific life expectancy at age 60. While there was a positive association for GPs in countries with a low life expectancy at age 60, there was no association in countries with a high life expectancy at age 60. • These findings help explaining some of the large variation seen in the decision as to whether or not to treat hypertension in the oldest-old.
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| 318. |
- Streit, Sven, et al.
(författare)
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Variation in GP decisions on antihypertensive treatment in oldest-old and frail individuals across 29 countries.
- 2017
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Ingår i: BMC Geriatrics. - : BioMed Central. - 1471-2318. ; 17:1, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.METHODS: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.RESULTS: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs' decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48-0.59; ORs per country 0.11-1.78).CONCLUSIONS: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
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| 319. |
- Suh, Alexander, et al.
(författare)
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Multiple Lineages of Ancient CR1 Retroposons Shaped the Early Genome Evolution of Amniotes
- 2015
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Ingår i: Genome Biology and Evolution. - : Oxford University Press (OUP). - 1759-6653. ; 7:1, s. 205-217
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Tidskriftsartikel (refereegranskat)abstract
- Chicken repeat 1 (CR1) retroposons are long interspersed elements (LINEs) that are ubiquitous within amniote genomes and constitute the most abundant family of transposed elements in birds, crocodilians, turtles, and snakes. They are also present in mammalian genomes, where they reside as numerous relics of ancient retroposition events. Yet, despite their relevance for understanding amniote genome evolution, the diversity and evolution of CR1 elements has never been studied on an amniote-wide level. We reconstruct the temporal and quantitative activity of CR1 subfamilies via presence/absence analyses across crocodilian phylogeny and comparative analyses of 12 crocodilian genomes, revealing relative genomic stasis of retroposition during genome evolution of extant Crocodylia. Our large-scale phylogenetic analysis of amniote CR1 subfamilies suggests the presence of at least seven ancient CR1 lineages in the amniote ancestor; and amniote-wide analyses of CR1 successions and quantities reveal differential retention (presence of ancient relics or recent activity) of these CR1 lineages across amniote genome evolution. Interestingly, birds and lepidosaurs retained the fewest ancient CR1 lineages among amniotes and also exhibit smaller genome sizes. Our study is the first to analyze CR1 evolution in a genome-wide and amniote-wide context and the data strongly suggest that the ancestral amniote genome contained myriad CR1 elements from multiple ancient lineages, and remnants of these are still detectable in the relatively stable genomes of crocodilians and turtles. Early mammalian genome evolution was thus characterized by a drastic shift from CR1 prevalence to dominance and hyperactivity of L2 LINEs in monotremes and L1 LINEs in therians.
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