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- Lopez de Lapuente Portilla, Aitzkoa, et al.
(författare)
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Genome-wide association study on 13,167 individuals identifies regulators of hematopoietic stem and progenitor cell levels in human blood
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Understanding how hematopoietic stem and progenitor cells (HSPCs) are regulated is of central importance for the development of new therapies for blood disorders and stem cell transplantation. To date, HSPC regulation has been extensively studied in vitro and in animal models, but less is known about the mechanisms in vivo in humans. Here, in a genome-wide association study on 13,167 individuals, we identify 9 significant and 2 suggestive DNA sequence variants that influence HSPC (CD34+) levels in human blood. The identified loci associate with blood disorders, harbor known and novel HSPC genes, and affect gene expression in HSPCs. Interestingly, our strongest association maps to the PPM1H gene, encoding an evolutionarily conserved serine/threonine phosphatase never previously implicated in stem cell biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. By functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates a MYB transcription factor binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, rs772557-A selectively increases HSPC subpopulations in which the MYB site is active, and PPM1H shRNA- knockdown increased CD34+ and CD34+90+ cell proportions in umbilical cord blood cultures. Our findings represent the first large-scale association study on a stem cell trait, illuminating HSPC regulation in vivo in humans, and identifying PPM1H as a novel inhibition target that can potentially be utilized clinically to facilitate stem cell harvesting for transplantation.
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- Redfors, B. Björn, et al.
(författare)
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Incidence and prognosis of the takotsubo syndrome compared to acute myocardial infarction
- 2019
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Ingår i: European Journal of Heart Failure. - : John Wiley & Sons. - 1388-9842 .- 1879-0844. ; 21, s. 267-267
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Takotsubo syndrome (TS) is a potentially life-threatening acute cardiac syndrome with a clinical presentation very similar to myocardial infarction (MI) and for which the natural history, management and outcome remain incompletely understood.Purpose: The aims of this study were to assess the relative short- and long-term mortality risk of TS , ST-elevation MI (STEMI) and non STEMI (NSTEMI) and to identify predictors of in-hospital complications and poor prognosis in patients with TS.Methods: Using the nationwide Swedish Angiography and Angioplasty Registry (SCAAR) we identified almost all (n=117,720) patients who underwent coronary angiography due to TS (N=2,898 [2.5%]), STEMI (N=48,493 [41.2%]) or NSTEMI (N=66,329 [56.3%]) in Sweden between January 2009 and February 2018.Results: Patients with TS were more often women as compared with patients with STEMI or NSTEMI. TS was associated with unadjusted and adjusted 30-day mortality risks lower than STEMI (adjusted hazard ratio [adjHR] 0.60, 95% confidence interval [CI]0.48-0.76, p<0.001), but higher than NSTEMI (adjHR 2.70, 95% CI 2.14-3.41, p<0.001). Compared to STEMI, TS was associated with similar risk of acute heart failure (adjHR 1.26, 95% CI 0.91–1.76, p=0.16) but lower risk of cardio-genic shock (adjHR 0.55, 95% CI 0.34–0.89, p=0.02). The relative 30-day mortality risk for TS versus STEMI and NSTEMI was higher for smokers than non-smokers (adjusted pinteractionSTEMI=0.01 and pinteractionNSTEMI=0.01).Conclusion: Thirty-day mortality in TS was higher than in NSTEMI but lower than STEMI, despite a similar risk of acute heart failure in TS and STEMI. Among patients with TS, smoking was an independent predictor of mortality
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