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- Duell, Eric J, et al.
(författare)
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Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort
- 2013
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Ingår i: Genes & Nutrition. - : Springer Berlin/Heidelberg. - 1555-8932 .- 1865-3499. ; 8:6, s. 549-560
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Tidskriftsartikel (refereegranskat)abstract
- Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non-cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis.
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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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- Johansson, Roger, et al.
(författare)
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Eye movements play an active role when visuospatial information is recalled from memory
- 2012
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Ingår i: Journal of Vision. ; 12:9
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Konferensbidrag (refereegranskat)abstract
- Abstract in Undetermined Whilst it has been established that spontaneous eye movements occur with visual imagery and that they are comparable with those from an original scene inspection (e.g., Brandt & Stark, 1997; Johansson, Holsanova, & Holmqvist, 2006), the exact purpose of these eye movements has been a hot topic of debate (cf., Ferreira et al., 2008; Richardson et al., 2009). Do they have an active and functional role in memory retrieval or are they merely an epiphenomenon? In a recent study we reported that when eye movements were prohibited for participants who orally described pictures from memory, their recollections became altered and impaired (Johansson, Holsanova, Dewhurst, & Holmqvist, (in press). Journal of Experimental Psychology: Human Perception and Performance). The current study was designed as a follow-up, aiming to uncover exactly how imposing different eye movements on participants affects memory retrieval processes. Eye movements were recorded from participants who recalled properties and spatial arrangements of sets of objects under four different manipulations: (1) free viewing on a blank screen; (2) gazing at a fixation cross; (3) looking at an area which was matched with the original locations of the objects to be recalled; (4) looking at an area which did not match the original locations of the objects to be recalled. By restricting eye movements in different ways during recall, we demonstrate the sensitivity of retrieval performance to specific eye movement manipulations. Results provide evidence that eye movements do have an active and supportive role when visuospatial information is recalled by highlighting the circumstances under which a visual memory is hampered. Additionally, findings suggest that the influence of "eye movements to nothing" is primarily related to the processing and retrieval of spatial information.
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