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- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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- Augustin, L S A, et al.
(författare)
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Glycemic index, glycemic load and glycemic response: An International Scientific Consensus Summit from the International Carbohydrate Quality Consortium (ICQC).
- 2015
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Ingår i: Nutrition Metabolism and Cardiovascular Diseases. - : Elsevier BV. - 1590-3729 .- 0939-4753. ; 25:9, s. 795-815
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: The positive and negative health effects of dietary carbohydrates are of interest to both researchers and consumers. Methods: International experts on carbohydrate research held a scientific summit in Stresa, Italy, in June 2013 to discuss controversies surrounding the utility of the glycemic index (GI), glycemic load (GL) and glycemic response (GR). Results: The outcome was a scientific consensus statement which recognized the importance of postprandial glycemia in overall health, and the GI as a valid and reproducible method of classifying carbohydrate foods for this purpose. There was consensus that diets low in GI and GL were relevant to the prevention and management of diabetes and coronary heart disease, and probably obesity. Moderate to weak associations were observed for selected cancers. The group affirmed that diets low in GI and GL should always be considered in the context of diets otherwise understood as healthy, complementing additional ways of characterizing carbohydrate foods, such as fiber and whole grain content. Diets of low GI and GL were considered particularly important in individuals with insulin resistance. Conclusions: Given the high prevalence of diabetes and pre-diabetes worldwide and the consistency of the scientific evidence reviewed, the expert panel confirmed an urgent need to communicate information on GI and GL to the general public and health professionals, through channels such as national dietary guidelines, food composition tables and food labels.
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- Livesey, Geoffrey, et al.
(författare)
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Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes : A Systematic Review and Updated Meta-Analyses of Prospective Cohort Studies
- 2019
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 11:6
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Forskningsöversikt (refereegranskat)abstract
- Published meta-analyses indicate significant but inconsistent incident type-2 diabetes(T2D)-dietary glycemic index (GI) and glycemic load (GL) risk ratios or risk relations (RR). It is nowover a decade ago that a published meta-analysis used a predefined standard to identify validstudies. Considering valid studies only, and using random effects dose-response meta-analysis(DRM) while withdrawing spurious results (p < 0.05), we ascertained whether these relationswould support nutrition guidance, specifically for an RR > 1.20 with a lower 95% confidence limit>1.10 across typical intakes (approximately 10th to 90th percentiles of population intakes). Thecombined T2D-GI RR was 1.27 (1.15-1.40) (p < 0.001, n = 10 studies) per 10 units GI, while that forthe T2D-GL RR was 1.26 (1.15-1.37) (p < 0.001, n = 15) per 80 g/d GL in a 2000 kcal (8400 kJ) diet.The corresponding global DRM using restricted cubic splines were 1.87 (1.56-2.25) (p < 0.001, n =10) and 1.89 (1.66-2.16) (p < 0.001, n = 15) from 47.6 to 76.1 units GI and 73 to 257 g/d GL in a 2000kcal diet, respectively. In conclusion, among adults initially in good health, diets higher in GI or GLwere robustly associated with incident T2D. Together with mechanistic and other data, thissupports that consideration should be given to these dietary risk factors in nutrition advice.Concerning the public health relevance at the global level, our evidence indicates that GI and GLare substantial food markers predicting the development of T2D worldwide, for persons ofEuropean ancestry and of East Asian ancestry.
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- Livesey, Geoffrey, et al.
(författare)
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Dietary Glycemic Index and Load and the Risk of Type 2 Diabetes : Assessment of Causal Relations
- 2019
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 11:6
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Forskningsöversikt (refereegranskat)abstract
- While dietary factors are important modifiable risk factors for type 2 diabetes (T2D), the causal role of carbohydrate quality in nutrition remains controversial. Dietary glycemic index (GI) and glycemic load (GL) have been examined in relation to the risk of T2D in multiple prospective cohort studies. Previous meta-analyses indicate significant relations but consideration of causality has been minimal. Here, the results of our recent meta-analyses of prospective cohort studies of 4 to 26-y follow-up are interpreted in the context of the nine Bradford-Hill criteria for causality, that is: (1) Strength of Association, (2) Consistency, (3) Specificity, (4) Temporality, (5) Biological Gradient, (6) Plausibility, (7) Experimental evidence, (8) Analogy, and (9) Coherence. These criteria necessitated referral to a body of literature wider than prospective cohort studies alone, especially in criteria 6 to 9. In this analysis, all nine of the Hill's criteria were met for GI and GL indicating that we can be confident of a role for GI and GL as causal factors contributing to incident T2D. In addition, neither dietary fiber nor cereal fiber nor wholegrain were found to be reliable or effective surrogate measures of GI or GL. Finally, our cost-benefit analysis suggests food and nutrition advice favors lower GI or GL and would produce significant potential cost savings in national healthcare budgets. The high confidence in causal associations for incident T2D is sufficient to consider inclusion of GI and GL in food and nutrient-based recommendations.
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- Boucher, L. M., et al.
(författare)
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Expanding conceptualizations of harm reduction: results from a qualitative community-based participatory research study with people who inject drugs
- 2017
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Ingår i: Harm Reduction Journal. - : Springer Science and Business Media LLC. - 1477-7517. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: The perspectives of people who use drugs are critical in understanding why people choose to reduce harm in relation to drug use, what practices are considered or preferred in conceptualizations of harm reduction, and which environmental factors interfere with or support the use of harm reduction strategies. This study explores how people who inject drugs (PWID) think about harm reduction and considers the critical imperative of equity in health and social services delivery for this community. Methods: This community-based participatory research study was conducted in a Canadian urban centre. Using a peer-based recruitment and interviewing strategy, semi-structured qualitative interviews were conducted by and with PWID. The Vidaview Life Story Board, an innovative tool where interviewers and participant co-construct a visual "life-scape" using a board, markers, and customized picture magnets, was used to facilitate the interviews. The topics explored included injection drug use and harm reduction histories, facilitators and barriers to using harm reduction strategies, and suggestions for improving services and supports. Results: Twenty-three interviews with PWID (14 men and 9 women) were analysed, with a median age of 50. Results highlighted an expanded conceptualization of harm reduction from the perspectives of PWID, including motivations for adopting harm reduction strategies and a description of harm reduction practices that went beyond conventional health-focused concerns. The most common personal practices that PWID used included working toward moderation, employing various cognitive strategies, and engaging in community activities. The importance of social or peer support and improving self-efficacy was also evident. Further, there was a call for less rigid eligibility criteria and procedures in health and social services, and the need to more adequately address the stigmatization of drug users. Conclusions: These findings demonstrated that PWID incorporate many personal harm reduction practices in their daily lives to improve their well-being, and these practices highlight the importance of agency, self-care, and community building. Health and social services are needed to better support these practices because the many socio-structural barriers this community faces often interfere with harm reduction efforts. Finally, "one size does not fit all" when it comes to harm reduction, and more personalized or de-medicalized conceptualizations are recommended.
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- Haridass, Isha N., et al.
(författare)
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Cellular metabolism and pore lifetime of human skin following microprojection array mediation
- 2019
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Ingår i: Journal of Controlled Release. - : ELSEVIER SCIENCE BV. - 0168-3659 .- 1873-4995. ; 306, s. 59-68
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Tidskriftsartikel (refereegranskat)abstract
- Skin-targeting microscale medical devices are becoming popular for therapeutic delivery and diagnosis. We used cryo-SEM, fluorescence lifetime imaging microscopy (FLIM), autofluorescence imaging microscopy and inflammatory response to study the puncturing and recovery of human skin ex vivo and in vivo after discretised puncturing by a microneedle array (Nanopatch (R)). Pores induced by the microprojections were found to close by similar to 25% in diameter within the first 30 min, and almost completely close by similar to 6 h. FLIM images of ex vivo viable epidermis showed a stable fluorescence lifetime for unpatched areas of similar to 1000 ps up to 24 h. Only the cells in the immediate puncture zones (in direct contact with projections) showed a reduction in the observed fluorescence lifetimes to between similar to 518-583 ps. The ratio of free-bound NAD(P)H (alpha 1/alpha 2) in unaffected areas of the viable epidermis was similar to 2.5-3.0, whereas the ratio at puncture holes was almost double at similar to 4.2-4.6. An exploratory pilot in vivo study also suggested similar closure rate with histamine administration to the forearms of human volunteers after Nanopatch (R) treatment, although a prolonged inflammation was observed with Tissue Viability Imaging. Overall, this work shows that the pores created by the microneedle-type medical device, Nanopatch (R), are transient, with the skin recovering rapidly within 1-2 days in the epidermis after application.
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| 15. |
- Stender, Joshua D, et al.
(författare)
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Structural and Molecular Mechanisms of Cytokine-Mediated Endocrine Resistance in Human Breast Cancer Cells
- 2017
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Ingår i: Molecular Cell. - Cambridge, United States : Cell Press. - 1097-2765 .- 1097-4164. ; 65:6, s. 1122-1135.e5
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Tidskriftsartikel (refereegranskat)abstract
- Human breast cancers that exhibit high proportions of immune cells and elevated levels of pro-inflammatory cytokines predict poor prognosis. Here, we demonstrate that treatment of human MCF-7 breast cancer cells with pro-inflammatory cytokines results in ERα-dependent activation of gene expression and proliferation, in the absence of ligand or presence of 4OH-tamoxifen (TOT). Cytokine activation of ERα and endocrine resistance is dependent on phosphorylation of ERα at S305 in the hinge domain. Phosphorylation of S305 by IKKβ establishes an ERα cistrome that substantially overlaps with the estradiol (E2)-dependent ERα cistrome. Structural analyses suggest that S305-P forms a charge-linked bridge with the C-terminal F domain of ERα that enables inter-domain communication and constitutive activity from the N-terminal coactivator-binding site, revealing the structural basis of endocrine resistance. ERα therefore functions as a transcriptional effector of cytokine-induced IKKβ signaling, suggesting a mechanism through which the tumor microenvironment controls tumor progression and endocrine resistance.
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