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- Chauhan, S., et al.
(författare)
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Cdk2 catalytic activity is essential for meiotic cell division in vivo
- 2016
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Ingår i: Biochemical Journal. - : Portland Press Ltd.. - 0264-6021 .- 1470-8728. ; 473, s. 2783-2798
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Tidskriftsartikel (refereegranskat)abstract
- Cyclin-dependent kinases (Cdks) control the eukaryotic cell cycle by phosphorylating serine and threonine residues in key regulatory proteins, but some Cdk family members may exert kinase-independent functions that cannot easily be assessed using gene knockout approaches. While Cdk2-deficient mice display near-normal mitotic cell proliferation due to the compensatory activities of Cdk1 and Cdk4, they are unable to undergo meiotic generation of gametes and are consequently sterile. To investigate whether Cdk2 regulates meiosis via protein phosphorylation or by alternative kinase-independent mechanisms, we generated two different knockin mouse strains in which Cdk2 point mutations ablated enzyme activity without altering protein expression levels. Mice homozygous for the mutations Cdk2(D145N/D145N) or Cdk2(T160A/T160A) expressed only 'kinase-dead' variants of Cdk2 under the control of the endogenous promoter, and despite exhibiting normal expression of cell cycle regulatory proteins and complexes, both mutations rendered mice sterile. Mouse cells that expressed only 'kinase-dead' variants of Cdk2 displayed normal mitotic cell cycle progression and proliferation both in vitro and in vivo, indicating that loss of Cdk2 kinase activity exerted little effect on this mode of cell division. In contrast, the reproductive organs of Cdk2 mutant mice exhibited abnormal morphology and impaired function associated with defective meiotic cell division and inability to produce gametes. Cdk2 mutant animals were therefore comparable to gene knockout mice, which completely lack the Cdk2 protein. Together, our data indicate that the essential meiotic functions of Cdk2 depend on its kinase activity, without which the generation of haploid cells is disrupted, resulting in sterility of otherwise healthy animals.
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- Christiansen, O., et al.
(författare)
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Predictors of upgrading from low-grade cancer at prostatectomy in men with biparametric magnetic resonance imaging
- 2022
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Ingår i: Central European Journal of Urology. - : Polish Urological Association. - 2080-4806 .- 2080-4873. ; 75:1, s. 35-40
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Prostate-specific antigen (PSA) density has previously been identified as a predictor of histological upgrading at radical prostatectomy, but how information from pre-treatment biparametric magnetic resonance imaging (bpMRI) contributes needs further clarification. The objective of this register-based study was to identify predictors of upgrading at prostatectomy in men with Grade group (GG) 1 and pre-treatment bpMRI. Material and methods This single-center study included men with GG 1 cancer on prediagnostic biopsy, who underwent bpMRI and robotic-assisted radical prostatectomy (RARP) between March 2014 and September 2019. We estimated logistic regression models to explore predictors for upgrading. The explored potential predictors were age, PSA density, tumor stage and Prostate Imaging Reporting and Data System (PI-RADS) score (dichotomised 1-3 versus 4-5). Results Upgrading was observed in 56% (73/130) of the men. PSA density was the only significant predictor for upgrading (unadjusted OR = 1.7, 95% CI 1.2; 2.4 adjusted OR = 1.7, 95% CI 1.2; 2.5). The probability of upgrading was lower for men with a PIRADS 1-3 than for PIRADS 4-5, but the difference was not statistically significant (adjusted OR 0.4, 95% CI 0.2; 1.1, p = 0.082). Among men with PI-RADS 1-3, the probability increased with increasing PSA density (p = 0.036). With PI-RADS 4-5 the probability of upgrading was high over the entire PSA density range. Conclusions PSA density is a clinically important factor to predict upgrading from GG1 when bpMRI shows PI-RADS 1-3. In men with PI-RADS 4-5 on bpMRI, the probability of an undetected GG 2-5 cancer is high regardless of the PSA density.
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- Okada, Yukinori, et al.
(författare)
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Genetics of rheumatoid arthritis contributes to biology and drug discovery
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 506:7488, s. 376-381
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)(1). Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating similar to 10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2-4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation(5), cis-acting expression quantitative trait loci(6) and pathway analyses(7-9)-as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes-to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.
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