| 1. |
- Sampson, Joshua N., et al.
(author)
-
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
-
In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
-
Journal article (peer-reviewed)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
|
|
| 2. |
|
|
| 3. |
- Boyd, Roslyn N., et al.
(author)
-
REACH : study protocol of a randomised trial of rehabilitation very early in congenital hemiplegia
- 2017
-
In: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 7:9
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: Congenital hemiplegia is the most common form of cerebral palsy (CP). Children with unilateral CP show signs of upper limb asymmetry by 8 months corrected age (ca) but are frequently not referred to therapy until after 12 months ca. This study compares the efficacy of infant-friendly modified constraint-induced movement therapy (Baby mCIMT) to infant friendly bimanual therapy (Baby BIM) on upper limb, cognitive and neuroplasticity outcomes in a multisite randomised comparison trial.METHODS AND ANALYSIS: 150 infants (75 in each group), aged between 3 and 6 months ca, with asymmetric brain injury and clinical signs of upper extremity asymmetry will be recruited. Children will be randomised centrally to receive equal doses of either Baby mCIMT or Baby BIM. Baby mCIMT comprises restraint of the unimpaired hand using a simple restraint (eg, glove, sock), combined with intensive parent implemented practice focusing on active use of the impaired hand in a play-based context. In contrast, Baby BIM promotes active play requiring both hands in a play-based context. Both interventions will be delivered by parents at home with monthly home visits and interim telecommunication support by study therapists. Assessments will be conducted at study entry; at 6, 12 months ca immediately postintervention (primary outcome) and 24 months ca (retention). The primary outcome will be the Mini-Assisting Hand Assessment. Secondary outcomes include the Bayley Scale for Infant and Toddler Development (cognitive and motor domains) and the Hand Assessment of Infants. A subset of children will undertake MRI scans at 24 months ca to evaluate brain lesion severity and brain (re)organisation after intervention.ETHICS AND DISSEMINATION: Full ethical approvals for this study have been obtained from the relevant sites. The findings will be disseminated in peer-reviewed publications.TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry: ACTRN12615000180516, Pre results.
|
|
| 4. |
- Brandelius, Angelica, et al.
(author)
-
dsRNA-induced expression of thymic stromal lymphopoietin (TSLP) in asthmatic epithelial cells is inhibited by a small airway relaxant.
- 2011
-
In: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 24, s. 59-66
-
Journal article (peer-reviewed)abstract
- RATIONALE: Thymic Stromal Lymphopoietin (TSLP) is considered a hub cytokine that activates dendritic cells and T-cells producing asthma-like Th(2)-inflammation. Viral stimuli, a major cause of asthma exacerbations, have been shown to induce overexpression of TSLP in asthmatic epithelium. Capsazepine has multiple effects and is of interest because it relaxes human small airways. Here we have explored effects of capsazepine on viral surrogate (dsRNA)-induced TSLP and other cytokines (TNF-alpha, IL-8) in human bronchial epithelial cells (HBEC) from healthy and asthmatic donors. METHODS: HBEC obtained from healthy and asthmatic subjects were grown and stimulated with dsRNA. Cells pre-treated with capsazepine (3-30μM), dexamethasone (0.1-10μM) or an IkappaB-kinase inhibitor (PS1145, 30μM) were also exposed to dsRNA (10μg/ml). Cells and supernatants were harvested for analyses of gene expression (RT-qPCR) and protein production (ELISA,Western blot). RESULTS: dsRNA-induced TSLP, TNF-alpha, and IL-8 in asthmatic and non-asthmatic HBEC. Dexamethasone attenuated gene expression and protein release whereas capsazepine dose-dependently, and similar to a non-relaxant NFkB inhibitor (PS1145), completely inhibited dsRNA-induced TSLP and TNF-alpha in both healthy and asthmatic HBEC. Capsazepine reduced dsRNA-induced IL-8 and it prevented dsRNA-induced loss of the NF-κB repressor protein IkBα. CONCLUSION: Additional to its human small airway relaxant effects we now demonstrate that capsazepine has potent anti-inflammatory effects on viral stimulus-induced cytokines in HBEC from healthy as well as asthmatic donors. Based on these data we suggest that exploration of structure-activity amongst the multifaceted capsazepinoids is warranted in search for compounds of therapeutic value in viral-induced, steroid-resistant asthma.
|
|
| 5. |
- Brandelius, Angelica, et al.
(author)
-
Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.
- 2012
-
In: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188.
-
Journal article (peer-reviewed)abstract
- Background and purpose: Statin treatment may ameliorate viral infection-induced exacerbations of chronic obstructive pulmonary disease (COPD), which exhibit Th2-type bronchial inflammation. Thymic stromal lymphopoietin (TSLP), a hub cytokine switching on Th2-inflammation, is overproduced in viral and dsRNA-stimulated bronchial epithelial cells from COPD donors. Hence, TSLP may be causally involved in exacerbations. This study tests our hypothesis that simvastatin may inhibit dsRNA-induced TSLP. Experimental approach: Epithelial cells, obtained by bronchoscopy from COPD (n=7) and smoker control (n=8) donors, were grown and stimulated with viral infection and danger signal surrogate, dsRNA (10 µg·mL(-1) ). Cells were treated with simvastatin (0.2-5 µg·mL(-1) ), with or without mevalonate (13-26 µg·mL(-1) ), or dexamethasone (1 µg·mL(-1) ) prior to dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-κB) activation were determined. Key results: dsRNA induced TSLP, TNFα, CXCL8, and IFNβ. TSLP was overproduced in dsRNA-exposed COPD cells compared to control. Simvastatin, concentration-dependently, but not dexamethasone, inhibited dsRNA-induced TSLP. Unexpectedly, simvastatin acted independent of mevalonate and did not affect dsRNA-induced NF-κB activation nor did it reduce production of TNFα and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFNβ. Conclusions and implications: Independent of mevalonate and NF-κB, previously acknowledged anti-inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA-induced IRF3 activation and production of TSLP and IFNβ in COPD epithelium. These data provide novel insight into epithelial generation of TSLP and suggest paths to be exploited in drug discovery aimed at inhibiting TSLP-induced pulmonary immunopathology.
|
|
| 6. |
- Broekman, Maarten J. E., et al.
(author)
-
Evaluating expert-based habitat suitability information of terrestrial mammals with GPS-tracking data
- 2022
-
In: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 31:8, s. 1526-1541
-
Journal article (peer-reviewed)abstract
- Aim: Macroecological studies that require habitat suitability data for many species often derive this information from expert opinion. However, expert-based information is inherently subjective and thus prone to errors. The increasing availability of GPS tracking data offers opportunities to evaluate and supplement expert-based information with detailed empirical evidence. Here, we compared expert-based habitat suitability information from the International Union for Conservation of Nature (IUCN) with habitat suitability information derived from GPS-tracking data of 1,498 individuals from 49 mammal species.Location: Worldwide.Time period: 1998-2021.Major taxa studied: Forty-nine terrestrial mammal species.Methods: Using GPS data, we estimated two measures of habitat suitability for each individual animal: proportional habitat use (proportion of GPS locations within a habitat type), and selection ratio (habitat use relative to its availability). For each individual we then evaluated whether the GPS-based habitat suitability measures were in agreement with the IUCN data. To that end, we calculated the probability that the ranking of empirical habitat suitability measures was in agreement with IUCN's classification into suitable, marginal and unsuitable habitat types.Results: IUCN habitat suitability data were in accordance with the GPS data (> 95% probability of agreement) for 33 out of 49 species based on proportional habitat use estimates and for 25 out of 49 species based on selection ratios. In addition, 37 and 34 species had a > 50% probability of agreement based on proportional habitat use and selection ratios, respectively.Main conclusions: We show how GPS-tracking data can be used to evaluate IUCN habitat suitability data. Our findings indicate that for the majority of species included in this study, it is appropriate to use IUCN habitat suitability data in macroecological studies. Furthermore, we show that GPS-tracking data can be used to identify and prioritize species and habitat types for re-evaluation of IUCN habitat suitability data.
|
|
| 7. |
- Figueroa, Jonine D., et al.
(author)
-
Genome-wide association study identifies multiple loci associated with bladder cancer risk
- 2014
-
In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 23:5, s. 1387-1398
-
Journal article (peer-reviewed)abstract
- andidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10−5 was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10−9) and rs907611 on 11p15.5 (P = 4.11 × 10−8). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10−7) and rs4510656 on 6p22.3 (P = 6.98 × 10−7); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
|
|
| 8. |
- Figueroa, Jonine D., et al.
(author)
-
Genome-wide interaction study of smoking and bladder cancer risk
- 2014
-
In: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 35:8, s. 1737-1744
-
Journal article (peer-reviewed)abstract
- Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 x 10(-5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 x 10(-7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 x 10-7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
|
|
| 9. |
- Figueroa, Jonine D., et al.
(author)
-
Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
-
In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
-
Journal article (peer-reviewed)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
|
|
| 10. |
- Fröling, Morgan, 1966-, et al.
(author)
-
Appearances of Ecosystem Services in Environmental Impact Assessment - learnings from two Swedish case studies
- 2016
-
In: Proceedings of Linnaeus Eco-Tech 2016.
-
Conference paper (other academic/artistic)abstract
- Ecosystem Services is an increasingly used concept to understand and describe the dependencies of socio-technical systems on the ecosystems in which they exist. We have studied to what extent ecosystem services are appearing in Environmental Impact Assessments (EIA) in two Swedish cases, the improvement of ecological status in a river used for small scale hydropower and the mining operations of the MM mine. In neither of the two cases ecosystem services have been intentionally included in the work with the EIAs. The goal of the studies has been to examine to what extent ecosystem services are appearing anyway in the EIAs, to what extent data in the EIAs are sufficient to perform more structured ecosystem service assessments, and if the use of a more structured ecosystem services review during the EIA process could have contributed positively to the EIA work. Both EIAs in this study holds some information on impacts on ecosystem services, and more information on affected ecosystem functions that could be translated into ecosystems services and probably to full ecosystem service reviews with additional data gathering. Cases of ecosystem functions and services impacting other ecosystem functions and services, sometimes in several stages, were found, indicating that such functions or services could be of special importance to protect and / or support.
|
|
