| 1. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 2. |
- Johansson, Anders, et al.
(författare)
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Prevalence of systemic immunoreactivity to Aggregatibacter actinomycetemcomitans leukotoxin in relation to the incidence of myocardial infarction
- 2011
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Ingår i: BMC Infectious Diseases. - : BioMed Central. - 1471-2334. ; 11:1, s. 55-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular disease (CVD). The proinflammatory cytokine, interleukin (IL)-1, is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen Aggregatibacter actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1 from macrophages. The aim of the present study was to compare the prevalence of systemic immunoreactivity to A. actinomycetemcomitans leukotoxin in myocardial infarction (MI) cases (n=532) and matched controls (n=1000) in a population-based case and referents study in northern Sweden. Methods: Capacity to neutralize A. actinomycetemcomitans leukotoxin was analyzed in a bioassay with leukocytes, purified leukotoxin, and plasma. Plasma samples that inhibited lactate-dehydrogenase release from leukotoxin-lysed cells by 50 % were classified as positive. Results: Neutralizing capacity against A. actinomycetemcomitans leukotoxin was detected in 53.3% of the plasma samples. The ability to neutralize leukotoxin correlated to increasing age in men (n=1082) but not in women (n=450). There was no correlation between presence of systemic leukotoxin neutralization capacity and the incidence of MI, except for women (n=146). Women with a low neutralizing capacity had a significantly higher incidence of MI than those who had a high neutralizing capacity. Conclusions: Systemic immunoreactivity against A. actinomycetemcomitans leukotoxin was found at a high prevalence in the analyzed population of adults from northern Sweden. The results from the present study do not support the hypothesis that systemic leukotoxin-neutralizing capacity can decrease the risk for MI.
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| 3. |
- Johansson, Anders, et al.
(författare)
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Systemic antibodies to the leukotoxin of the oral pathogen Actinobacillus actinomycetemcomitans correlate negatively with stroke in women
- 2005
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Ingår i: Cerebrovascular Diseases. - Basel : Karger. - 1015-9770 .- 1421-9786. ; 20:4, s. 226-232
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chronic infections and associated inflammatory markers are suggested risk factors for cardiovascular diseases (CVD) and stroke. The proinflammatory cytokine interleukin (IL)-1β is suggested to play a role in the regulation of local inflammatory responses in both CVD and periodontitis. The leukotoxin from the periodontal pathogen Actinobacillus actinomycetemcomitans has recently been shown to cause abundant secretion of IL-1β from macrophages. The aim of the present study was to compare the prevalence of systemic antibodies to A. actinomycetemcomitansleukotoxin in stroke cases (n = 273) and matched controls (n = 546) in an incident case-control study nested within the Northern Sweden MONICA and Västerbotten Intervention cohorts. Methods: Antibodies to A. actinomycetemcomitans leukotoxin were analyzed in a bioassay with HL-60 cells (leukocytes), purified A. actinomycetemcomitans leukotoxin, and plasma. Plasma samples which inhibited lactate dehydrogenase release from leukotoxin-lysed cells by ≥50% were classified as antibody positive. Results: Antibodies to A. actinomycetemcomitans leukotoxin were detected in 18.8% of the women and 15.2% of the men. Women with those antibodies had a significantly decreased risk for stroke (OR = 0.28, 95% CI: 0.13–0.59), but not men (OR = 0.88, 95% CI: 0.52–1.51). Conclusion: The immunoreactivity to A. actinomycetemcomitans leukotoxin correlates negatively with a future stroke in woman, but not in men. Further studies are needed to explain the underlying mechanisms, as well as the biological relevance of this finding.
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| 4. |
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| 5. |
- Adman, Per, et al.
(författare)
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171 forskare: ”Vi vuxna bör också klimatprotestera”
- 2019
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Ingår i: Dagens nyheter (DN debatt). - Stockholm. - 1101-2447.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- DN DEBATT 26/9. Vuxna bör följa uppmaningen från ungdomarna i Fridays for future-rörelsen och protestera eftersom det politiska ledarskapet är otillräckligt. Omfattande och långvariga påtryckningar från hela samhället behövs för att få de politiskt ansvariga att utöva det ledarskap som klimatkrisen kräver, skriver 171 forskare i samhällsvetenskap och humaniora.
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| 6. |
- Bergqvist, Lena, 1958, et al.
(författare)
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Evidence of Construct Validity for the Modified Mental Fatigue Scale When Used in Persons with Cerebral Palsy
- 2020
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Ingår i: Developmental Neurorehabilitation. - : Informa UK Limited. - 1751-8423 .- 1751-8431. ; 23:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Fatigue impacts negatively on everyday activities in individuals with cerebral palsy (CP). More knowledge is needed about how mental fatigue is manifested in this target group. The purpose of this study was to gather evidence about the validity of the modified Mental Fatigue Scale (m-MFS) in adults with CP. Methods: Mixed sequential exploratory design. The respondents were ten persons aged 22-56 with CP (MACS I-II). Results: The respondents perceived the m-MFS as easy to read and understand. Its structure was characterised as straightforward and the text of the rating options was deemed to assist identification with life situations. Very good agreement was seen between the respondents' and the instrument designers' intended meaning for the items in the m-MFS; the weighted kappa was 0.92. Conclusion: This study showed evidence of construct validity, based on response processes and content, for use of the modified MFS in adults with CP.
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| 9. |
- 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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| 10. |
- Johansson, G, et al.
(författare)
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Underreporting of energy intake in repeated 24-hour recalls related to gender, age, weight status, day of interview, educational level, reported food intake, smoking habits and area of living.
- 2001
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Ingår i: Public Health Nutrition. - 1368-9800 .- 1475-2727. ; 4:4, s. 919-927
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aims of the present study were (1) to evaluate the degree to which underreporting of energy intake by repeated 24-hour recalls was related to gender, age, weight status, day of interview, educational level, smoking habits and area of living, and (2) to compare the dietary characteristics of underreporters with those of others. DESIGN: Cross-sectional study. Ten 24-hour recalls were performed during a one-year period. SETTING: The Västerbotten intervention programme of cardiovascular disease and diabetes in Northern Sweden. SUBJECTS: Ninety-four men and 99 women in four age groups: 30, 40, 50 and 60 years. RESULTS: The prevalence of men and women with a food intake level (FIL; reported energy intake divided by estimated basal metabolic rate) below 1.2 was 44% and 47%, respectively. The youngest age group had higher FIL values than the oldest age group for both men (1.5 versus 1.1) and women (1.4 versus 1.1). The prevalence and magnitude of underreporting were directly related to body mass index (BMI; correlation coefficient: -0.47 (men) and -0.55 (women)). Smokers had a lower FIL value (1.1) than non-smokers (1.3). The nutrient density was lower for the group with high FIL values for protein and calcium and higher for fat and sucrose. The upper FIL group often had higher intake frequencies and larger portion sizes than the lower FIL group. CONCLUSIONS: Underreporting of energy intake is prevalent when 24-hour recalls are used, but the prevalence differs between sub-groups in the population. BMI was the main predictor of underreporting but also old age and smoking seem to contribute in this aspect. Socially desirable food items were not underreported to the same extent as socially undesirable food items. The intake frequencies and portion sizes partly explained the differences in FIL.
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