| 1. |
- Gustafsson, Nina M. S., et al.
(författare)
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Targeting PFKFB3 radiosensitizes cancer cells and suppresses homologous recombination
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The glycolytic PFKFB3 enzyme is widely overexpressed in cancer cells and an emerging anticancer target. Here, we identify PFKFB3 as a critical factor in homologous recombination (HR) repair of DNA double-strand breaks. PFKFB3 rapidly relocates into ionizing radiation (IR)-induced nuclear foci in an MRN-ATM-gamma H2AX-MDC1-dependent manner and co-localizes with DNA damage and HR repair proteins. PFKFB3 relocalization is critical for recruitment of HR proteins, HR activity, and cell survival upon IR. We develop KAN0438757, a small molecule inhibitor that potently targets PFKFB3. Pharmacological PFKFB3 inhibition impairs recruitment of ribonucleotide reductase M2 and deoxynucleotide incorporation upon DNA repair, and reduces dNTP levels. Importantly, KAN0438757 induces radiosensitization in transformed cells while leaving non-transformed cells unaffected. In summary, we identify a key role for PFKFB3 enzymatic activity in HR repair and present KAN0438757, a selective PFKFB3 inhibitor that could potentially be used as a strategy for the treatment of cancer.
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| 2. |
- Myléus, Anna, 1978-, et al.
(författare)
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Celiac disease revealed in 3% of Swedish 12-year-olds born during an epidemic
- 2009
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - New York : Raven P. - 0277-2116 .- 1536-4801. ; 49:2, s. 170-176
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Tidskriftsartikel (refereegranskat)abstract
- Objetive: Sweden experienced a marked epidemic of celiac disease between 1984 and 1996 in children younger than 2 years of age, partly explained by changes in infant feeding. The objective of this study was to determine the prevalence of celiac disease in 12-year-olds born during the epidemic (1993), including both symptomatic and screening detected cases.Patients and methods: All sixth-grade children in participating schools were invited (n = 10,041). Symptomatic and, therefore, previously diagnosed celiac disease cases were ascertained through the National Swedish Childhood Celiac Disease Register and/or medical records. All serum samples were analyzed for antihuman tissue transglutaminase (tTG)-IgA (Celikey), and serum-IgA, and some for tTG-IgG and endomysial antibodies. A small intestinal biopsy was recommended for all children with suspected undiagnosed celiac disease.Results: Participation was accepted by 7567 families (75%). Previously diagnosed celiac disease was found in 67 children; 8.9/1000 (95% confidence interval [CI] 6.7-11). In another 192 children, a small intestinal biopsy was recommended and was performed in 180. Celiac disease was verified in 145 children, 20/1000 (95% CI 17-23). The total prevalence was 29/1000 (95% CI 25-33).Conclusions: The celiac disease prevalence of 29/1000 (3%)-with two thirds of cases undiagnosed before screening-is 3-fold higher than the usually suggested prevalence of 1%. When these 12-year-olds were infants, the prevailing feeding practice was to introduce gluten abruptly, often without ongoing breast-feeding, which might have contributed to this unexpectedly high prevalence.
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| 3. |
- Norström, Albert, et al.
(författare)
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Principles for knowledge co-production in sustainability research
- 2020
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Ingår i: Nature Sustainability. - : Springer Science and Business Media LLC. - 2398-9629. ; 3:3, s. 182-190
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Tidskriftsartikel (refereegranskat)abstract
- Research practice, funding agencies and global science organizations suggest that research aimed at addressing sustainability challenges is most effective when 'co-produced' by academics and non-academics. Co-production promises to address the complex nature of contemporary sustainability challenges better than more traditional scientific approaches. But definitions of knowledge co-production are diverse and often contradictory. We propose a set of four general principles that underlie high-quality knowledge co-production for sustainability research. Using these principles, we offer practical guidance on how to engage in meaningful co-productive practices, and how to evaluate their quality and success. Research addressing sustainability issues is more effective if 'co-produced' by academics and non-academics, but definitions of co-production vary. This Perspective presents four knowledge co-production principles for sustainability research and guides on how to engage in co-productive practices.
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| 4. |
- Webb, Charlotta, et al.
(författare)
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Celiac disease can be predicted by high levels of anti-tissue transglutaminase antibodies in population-based screening
- 2015
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : Lippincott Williams & Wilkins. - 0277-2116 .- 1536-4801. ; 60:6, s. 787-791
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate any potential correlation between anti-tissue transglutaminase antibodies of type immunoglobulin A (tTG-IgA) and the degree of gluten induced enteropathy in children participating in a screening study for celiac disease (CD) and to assess to what extent the revised ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) guidelines cover this group of patients.METHODS: This is a sub-study of a cross-sectional CD screening study, ETICS (Exploring the Iceberg of Celiacs in Sweden), a two-phased study performed during 2005-2006 and 2009-2010. The 13,279 participating children had a blood test obtained and those with positive tTG-IgA were recommended a small intestinal biopsy. The tTG-IgA levels at the time of biopsy were compared with the assessment of the biopsy.RESULTS: There were 267 children included, of whom 230 were diagnosed with CD. Out of all children, 67 children had low tTG-IgA levels (<5 U/mL), whereof 55% had Marsh 3 lesions. All children with tTG-IgA levels exceeding 10 times the upper limit of normal values of 5 U/mL, i.e. 50 U/mL, were diagnosed with CD. Lowering the cut-off to 3 U/mL, all but one child with 30 U/mL got CD diagnosis.CONCLUSION: By adapting the revised ESPGHAN criteria, biopsies could have been omitted in a fourth of all cases. Our results indicate, that the criteria might be useful even on screened children. Further studies are needed to confirm whether the 2012 ESPGHAN guidelines should be revised to also apply to the populations being screened.
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| 5. |
- Webb, Charlotta, et al.
(författare)
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High adherence to a gluten-free diet in adolescents with screening-detected celiac disease
- 2015
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Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : Lippincott Williams & Wilkins. - 0277-2116 .- 1536-4801. ; 60:1, s. 54-59
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate the gluten-free diet (GFD) adherenceafter one year of follow-up in children with screening-detected celiac disease (CD) in a general population. METHODS: A total of 18,325 12 year olds were invited to participate in apopulation-based CD screening (ETICS- Exploring the Iceberg of Celiacs in Sweden), of whom 13,279 participated. In 240 children, CD was detected through elevated anti-tissue transglutaminase antibodies 2 (TG2-IgA) and verified by a small-intestinal biopsy. This sub-study included the 210 children with TG2-IgAevaluated both at the initialbiopsy occasion and at the one-year follow-up. GFD adherence was evaluated by a combination of TG2-IgA measurements and self-reported adherence (n = 193). RESULTS: After one year, 83% (179/210) had normalizedTG2-IgA levels (<5U/mL). Among those who had >50 U/mL at diagnosis,25% (16/63) still had elevated TG2-IgA but for the majority their initial values were more than halved. Most reported a high level ofGFD adherence ('always' 75%(158/193) and 'often' 14%(30/193)), and 75% (145/193) reported always adhereingcombined with normalized TG2-IgA. Although reporting that they were always adherent, 13 (6.7%) had not yet normalized their TG2-IgA levels completely, however, a majority of these initially had the highestTG2-IgA levels. CONCLUSIONS: GFD adherence is high in adolescents with CD detected by screening of the general population of Swedish 12yearolds. Almost all had normalized serology and reported GFD adherenceat the one-year follow-up. However, a few adolescents whoreported GFD adherence still had elevated TG2-IgA levelssuggesting more severe disease and/or non-adherence.
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| 6. |
- Xu, Yiyi, et al.
(författare)
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Serum Half-Lives for Short- and Long-Chain Perfluoroalkyl Acids after Ceasing Exposure from Drinking Water Contaminated by Firefighting Foam
- 2020
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Ingår i: Environmental Health Perspectives. - 1552-9924 .- 0091-6765. ; 128:7, s. 77004-77004
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Firefighting foam-contaminated ground water, which contains high levels of perfluoroalkyl substances (PFAS), is frequently found around airports. In 2018 it was detected that employees at a municipal airport in northern Sweden had been exposed to high levels of short-chain PFAS along with legacy PFAS (i.e., PFOA, PFHxS, and PFOS) through drinking water.OBJECTIVES: In this study, we aimed to describe the PFAS profile in drinking water and biological samples (paired serum and urine) and to estimate serum half-lives of the short-chain PFAS together with legacy PFAS.METHODS: Within 2 weeks after provision of clean water, blood sampling was performed in all 26 airport employees. Seventeen of them were then followed up monthly for 5 months. PFHxA, PFHpA, PFBS, PFPeS, and PFHpS together with legacy PFAS in water and biological samples were quantified using LC/MS/MS. Half-lives were estimated by assuming one compartment, first-order elimination kinetics.RESULTS: The proportions of PFHxA, PFHpA, and PFBS were higher in drinking water than in serum. The opposite was found for PFHxS and PFOS. The legacy PFAS accounted for about 50% of total PFAS in drinking water and 90% in serum. Urinary PFAS levels were very low compared with serum. PFBS showed the shortest half-life {average 44 d [95% confidence interval (CI): 37, 55 d]}, followed by PFHpA [62 d (95% CI: 51, 80 d)]. PFPeS and PFHpS showed average half-lives as 0.63 and 1.46 y, respectively. Branched PFOS isomers had average half-lives ranging from 1.05 to 1.26 y for different isomers. PFOA, PFHxS, and linear PFOS isomers showed average half-lives of 1.77, 2.87, and 2.93 y, respectively.DISCUSSION: A general pattern of increasing half-lives with increasing chain length was observed. Branched PFOS isomers had shorter half-lives than linear PFOS isomers. https://doi.org/10.1289/EHP6785.
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