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- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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- Nikpay, Majid, et al.
(författare)
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:10, s. 1121-1121
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Tidskriftsartikel (refereegranskat)abstract
- Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of similar to 185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
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- Snygg-Martin, Ulrika, 1965, et al.
(författare)
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Cerebrovascular complications in patients with left-sided infective endocarditis are common: a prospective study using magnetic resonance imaging and neurochemical brain damage markers.
- 2008
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Ingår i: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 47:1, s. 23-30
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Tidskriftsartikel (refereegranskat)abstract
- Background. @nbsp; Cerebrovascular complications (CVCs) have remained a major therapeutic and prognostic challenge associated with infective endocarditis, and definite risk factors have not been fully elucidated. This prospective study was designed to the evaluate the total incidence of CVC associated with infective endocarditis and major risk factors. Methods. @nbsp; During 2 study periods, from June 1998 through April 2001 and from September 2002 through January 2005, patients were prospectively enrolled in the study regardless of neurological symptoms. Study patients underwent neurological examinations and magnetic resonance imaging of the brain, and cerebrospinal fluid analyses of inflammatory and neurochemical markers of brain damage (neurofilament protein and glial fibrillary acidic protein) were performed. Results. @nbsp; Sixty patients who experienced episodes of left-sided infective endocarditis were evaluated; 35% of these patients experienced a symptomatic CVC. Silent cerebral complications were detected in another 30% of the patients, and the total CVC rate was 65% (95% confidence interval, 58%-72%). Five percent of patients experienced their first neurological symptom after the initiation of antibiotic treatment without prior surgery. No new symptomatic CVCs were detected after 10 days of antibiotic treatment. No neurological deterioration was observed after surgery in patients who were established to have a symptomatic CVC preoperatively. A larger heart valvular vegetation size was a risk factor for both symptomatic and silent CVCs; Staphylococcus aureus etiology conferred a higher risk for symptomatic cerebral complication only. Conclusions. @nbsp; The use of sensitive methods of detection indicates that the incidence of CVC associated with infective endocarditis is high, but the risk for neurological deterioration during cardiac surgery after a CVC is lower than previously assumed. The major mechanism behind cerebral complications associated with infective endocarditis is cerebral embolization, although the dominant neurological symptoms vary considerably.
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- Strawbridge, Rona J., et al.
(författare)
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Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
- 2017
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 266, s. 196-204
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.
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- Wernersson, Lars-Erik, et al.
(författare)
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Epitaxially overgrown, stable W-GaAs Schottky contacts with sizes down to 50 nm
- 2002
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Ingår i: Journal of Vacuum Science and Technology B. - : American Vacuum Society. - 1520-8567. ; 20:2, s. 580-589
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Tidskriftsartikel (refereegranskat)abstract
- A processing scheme for the fabrication of embedded W-GaAs contacts has been established and the resulting contact characteristics have been evaluated. The main advantage of these contacts is that they are stable during high-temperature epitaxial overgrowth. The fabrication scheme is based on a liftoff process with electron beam evaporation of tungsten and subsequent epitaxial overgrowth using metalorganic vapor phase epitaxy. Various methods were used to characterize the buried contacts. First, the structural properties of GaAs surrounding embedded W features, with widths down to 50 nm, were characterized by high-resolution transmission electron microscopy. Measurements of the conductivity in individual, buried wires were performed in order to study the influence of the overgrowth process on the properties of the tungsten. We also evaluated the current-voltage characteristics for macroscopic contacts, which revealed a clear dependence on processing parameters. Optimized processing conditions could thus be established under which limited contact degradation occurred during overgrowth. Finally, we used the overgrowth technique to perform a detailed investigation of the electrical and optical properties of floating-potential embedded nano-Schottky contacts by space-charge spectroscopy.
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- Annika, Hagenbjörk-Gustafsson, et al.
(författare)
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Spatial variation of ground level ozone and the relation between ozone and NO2/NOx in two Swedish cities
- 2013
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Konferensbidrag (refereegranskat)abstract
- Background Ozone is a pollutant known to cause adverse effects on human health. It is formed by reactions between nitrogen oxides (NOx) and hydrocarbons under the influence of sunlight. In urban areas ozone is consumed oxidating nitrogen oxide (NO) to nitrogen dioxide (NO2). Despite the potential to cause adverse health effects, the local spatial distribution of ozone and the relationship between ozone, NO2 and NOx in different environments is poorly studied.Aims Our aim was to study the concentrations and spatial distribution of ozone in two cities, Malmö in the south of Sweden and Umeå in the north of Sweden, since the contribution of ozone from other parts of Europe decreases with higher latitude. We also wanted to investigate differences in the ozone/NO2 and the ozone/NOx ratios between the cities and between different environments.Methods Ozone, NO2 and NOx concentrations were measured with Ogawa diffusive samplers during three one-week campaigns in April, May/June and in August 2012. Measurements were conducted simultaneously at 20 sites in each city outside preschools, distributed at traffic sites, urban background sites and regional background (rural) sites. Results The average concentration of ozone in Malmö and Umeå were 67,5 µg/m3 and 50,6 µg/m3, respectively. The mean ozone/NOx ratio was of equal magnitude in Malmö and in Umeå, and in both cities the ratio was highest at rural sites and lowest at traffic sites. In Umeå there was a clear trend with highest ozone concentrations at rural sites and lowest concentrations at traffic sites, a trend that was not as obvious in Malmö. In Umeå the ozone/NO2 ratio at rural sites was about three times larger compared to Malmö.Conclusions There is a clear local variation of ozone, with stronger gradients in northern (Umeå) Sweden in comparison to southern Sweden (Malmö). This can partly be explained by less long-range transport of ozone and larger impact of local NO emissions that reduce ozone in northern Sweden.
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