| 1. |
- Dekhuijzen, P. N Richard, et al.
(författare)
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Incidence of oral thrush in patients with COPD prescribed inhaled corticosteroids : Effect of drug, dose, and device
- 2016
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111. ; 120, s. 54-63
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims Little information is available on real-life occurrence of oral thrush in COPD patients treated with ICS. We investigated oral thrush incidence in COPD patients prescribed FDC ICS/LABA therapies and assessed whether it is modulated by the ICS type, dose, and delivery device. Methods We conducted a historical, observational, matched cohort study (one baseline year before and one outcome year after initiation of therapy) using data from the UK Optimum Patient Care Research Database. We assessed oral thrush incidence in patients initiating long-acting bronchodilators or FDC ICS/LABA therapy. We then compared different combination therapies (budesonide/formoterol fumarate dihydrate [BUD/FOR] and fluticasone propionate/salmeterol xinafoate [FP/SAL]) and devices (DPI and pMDI). Results Patients prescribed FDC ICS/LABA had significantly greater odds of experiencing oral thrush than those prescribed long-acting bronchodilators alone (adjusted OR 2.18 [95% CI 1.84–2.59]). Significantly fewer patients prescribed BUD/FOR DPI developed oral thrush compared with FP/SAL DPI (OR 0.77 [0.63–0.94]) when allowing for differences in prescribed doses between the drugs. A significantly smaller proportion of patients developed oral thrush in the FP/SAL pMDI arm than in the FP/SAL DPI arm (OR 0.67 [0.55–0.82]). Additionally, in the FP/SAL cohort (both DPI and pMDI), increased risk of oral thrush was significantly associated with high ICS daily dose (OR 1.97 [1.22–3.17] vs low daily dose). Conclusions ICS use increases oral thrush incidence in COPD and this effect is dose-dependent for FP/SAL therapies. Of the therapies assessed, FP/SAL pMDI and BUD/FOR DPI may be more protective against oral thrush.
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| 2. |
- Fletcher, Nick, et al.
(författare)
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Altered retinoid metabolism in female Long-Evans and Han/Wistar rats following long-term 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-treatment
- 2005
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Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-6080 .- 1096-0929. ; 86:2, s. 264-272
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the effects of long-term low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on retinoid, thyroid hormone, and vitamin D homeostasis in Long-Evans and Han/Wistar rats using a tumor promotion exposure protocol. Female rats (ten/group) were partially hepatectomized, initiated with nitrosodiethylamine (NDEA), and given TCDD once per week by sc injection for 20 weeks at calculated daily doses of 0, 1, 10, 100, or 1000 ng/kg bw/day. Groups of nonhepatectomized/uninitiated rats (five/group) were identically maintained. After 20 weeks, the rats were killed, and apolar retinoid levels were determined in the liver and kidneys. No consistent differences were seen between partially hepatectomized/initiated and nonhepatectomized/uninitiated animals with respect to apolar retinoid levels or hepatic TCDD concentration. Further analyses of polar and apolar retinoid levels in liver, plasma, and kidney, as well as free thyroxine (FT4) and vitamin D (25-OH-D(3)) concentrations were carried out in partially hepatectomized/inititated animals. In Long-Evans rats, TCDD exposure dose-dependently decreased hepatic retinyl ester concentrations at doses of 1-100 ng/kg bw/day. Likewise, hepatic all-trans-retinoic acid (all-trans-RA) concentration was decreased 39 and 54% at 10 and 100 ng/kg bw/day respectively, whereas 9-cis-4-oxo-13,14-dihydro-retinoic acid (9-cis-4-oxo-13,14-dihydro-RA), a recently discovered retinoic acid metabolite, was decreased approximately 60% in the liver at 1 ng/kg bw/day. TCDD dose-dependently increased plasma retinol and kidney retinol concentrations, whereas all-trans-RA concentration was also increased in the plasma and kidney at 10 and 100 ng/kg bw/day. Plasma 9-cis-4-oxo-13,14-dihydro-RA was decreased to below detection limits from doses of 1 ng/kg bw/day TCDD. A qualitatively similar pattern of retinoid disruption was observed in the Han/Wistar rat strain following TCDD exposure. FT4 was decreased to a similar extent in both strains, whereas 25-OH-D(3) was decreased only at 100 ng/kg bw/day in Long-Evans rats. Together these results show that TCDD disrupts both retinoid storage and metabolism of retinoic acid and retinoic acid metabolites in liver, kidney, and plasma from doses as low as 1 ng/kg bw/day. Furthermore, 9-cis-4-oxo-13,14-dihydro-RA was identified as a novel and sensitive indicator of TCDD exposure, in a resistant and sensitive rat strain, thereby extending the database of low-dose TCDD effects.
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| 3. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 4. |
- Pietilä, Riikka, et al.
(författare)
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Molecular anatomy of adult mouse leptomeninges
- 2023
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Ingår i: Neuron. - : Elsevier. - 0896-6273 .- 1097-4199. ; 111:23
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Tidskriftsartikel (refereegranskat)abstract
- Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we iden-tify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arach-noid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.
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| 5. |
- Rothman, Nathaniel, et al.
(författare)
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A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 978-984
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into the mechanisms of carcinogenesis.
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| 6. |
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| 7. |
- Stevens, Kristen N, et al.
(författare)
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19p13.1 is a triple negative-specific breast cancer susceptibility locus
- 2012
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72, s. 1795-
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Tidskriftsartikel (refereegranskat)abstract
- The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 - 1.15, p=3.49 x 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 - 1.31, p=2.22 x 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 - 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 - 1.33, p=3.31 x 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
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