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1.	Abbott, Benjamin W., et al. (författare) Biomass offsets little or none of permafrost carbon release from soils, streams, and wildfire : an expert assessment 2016 Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 11:3 Tidskriftsartikel (refereegranskat)abstract As the permafrost region warms, its large organic carbon pool will be increasingly vulnerable to decomposition, combustion, and hydrologic export. Models predict that some portion of this release will be offset by increased production of Arctic and boreal biomass; however, the lack of robust estimates of net carbon balance increases the risk of further overshooting international emissions targets. Precise empirical or model-based assessments of the critical factors driving carbon balance are unlikely in the near future, so to address this gap, we present estimates from 98 permafrost-region experts of the response of biomass, wildfire, and hydrologic carbon flux to climate change. Results suggest that contrary to model projections, total permafrost-region biomass could decrease due to water stress and disturbance, factors that are not adequately incorporated in current models. Assessments indicate that end-of-the-century organic carbon release from Arctic rivers and collapsing coastlines could increase by 75% while carbon loss via burning could increase four-fold. Experts identified water balance, shifts in vegetation community, and permafrost degradation as the key sources of uncertainty in predicting future system response. In combination with previous findings, results suggest the permafrost region will become a carbon source to the atmosphere by 2100 regardless of warming scenario but that 65%-85% of permafrost carbon release can still be avoided if human emissions are actively reduced.
2.	Barrett, Jennifer H., et al. (författare) Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions 2015 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:6, s. 1351-1360 Tidskriftsartikel (refereegranskat)abstract At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the missing heritability. What's new? In genome-wide association studies, researchers identify genetic variants that frequently associate with a particular disease, though the variants identified may not contribute to the molecular cause of the disease. This study took a closer look at 17 regions associated with melanoma, fine mapping the regions both in people with melanoma and in healthy controls. Though single SNPs account for the association in some regions, they found that in a few regions, several SNPs - and possibly multiple genes - contributed to the association signal. These findings illustrate the importance of not overlooking the interaction between multiple genetic markers when conducting such studies.
3.	Chen, Hongjie, et al. (författare) Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals 2021 Ingår i: Human Genetics and Genomics Advances. - : Cell Press. - 2666-2477. ; 2:3 Tidskriftsartikel (refereegranskat)abstract Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
4.	Chen, Zhishan, et al. (författare) Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes 2024 Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1 Tidskriftsartikel (refereegranskat)abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
5.	Davies, John R., et al. (författare) An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study 2014 Ingår i: Pigment Cell & Melanoma Research. - : Wiley. - 1755-148X .- 1755-1471. ; 27:2, s. 234-243 Tidskriftsartikel (refereegranskat)abstract An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization.
6.	Davies, John R, et al. (författare) Inherited variation in the PARP1 gene and survival from melanoma 2014 Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:7, s. 1625-1633 Tidskriftsartikel (refereegranskat)abstract We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiology
7.	Ederle, Joerg, et al. (författare) Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial 2010 Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997 Tidskriftsartikel (refereegranskat)abstract Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
8.	Fernandez-Rozadilla, Ceres, et al. (författare) Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries 2023 Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99 Tidskriftsartikel (refereegranskat)abstract Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
9.	Lindström, Sara, et al. (författare) Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions 2023 Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 115:6, s. 712-732 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.METHODS: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.RESULTS: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.
10.	Lu, Yingchang, et al. (författare) New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk 2016 Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7 Tidskriftsartikel (refereegranskat)abstract To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
11.	Orr, Nick, et al. (författare) Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk 2012 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 44:11, s. 1182-1184 Tidskriftsartikel (refereegranskat)abstract We conducted a genome-wide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B at 14q24.1 was significantly associated with male breast cancer risk (P = 3.02 x 10(-13); odds ratio (OR) = 1.57). We also refine association at 16q12.1 to a SNP within TOX3 (P = 3.87 x 10(-15); OR = 1.50).
12.	Vigliar, Elena, et al. (författare) COVID-19 pandemic impact on cytopathology practice in the post-lockdown period: An international, multicenter study 2022 Ingår i: Cancer Cytopathology. - : WILEY. - 1934-662X .- 1934-6638. ; 130:5, s. 344-351 Tidskriftsartikel (refereegranskat)abstract Background In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 "lockdown" period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow-up worldwide survey collecting data from the post-lockdown period (2020). Methods Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post-lockdown period (2020), which ranged from April 4 to October 31. Differences between the post-lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses. Results A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P < .001) during the same time period. Similar results were obtained if both malignancy and suspicious for malignancy rates were considered together (15,759 [6.58%] vs 16,011 [4.98%]; P < .001). Conclusions The data showed a persistent reduction in the cytological specimen volume during the post-lockdown period (2020). However, the relative increase in the cytological workload in the late part of the post-lockdown is a promising finding of a slow return to normality.
13.	Vigliar, Elena, et al. (författare) Global impact of the COVID-19 pandemic on cytopathology practice: Results from an international survey of laboratories in 23 countries 2020 Ingår i: Cancer Cytopathology. - : WILEY. - 1934-662X .- 1934-6638. ; 128:12, s. 885-894 Tidskriftsartikel (refereegranskat)abstract Background To the authors knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported. Methods Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach. Results Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%). Conclusions The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted.
14.	Aguilar, J. A., et al. (författare) Triboelectric backgrounds to radio-based polar ultra-high energy neutrino (UHEN) experiments 2023 Ingår i: Astroparticle physics. - : Elsevier. - 0927-6505 .- 1873-2852. ; 145 Tidskriftsartikel (refereegranskat)abstract In the hopes of observing the highest-energy neutrinos (E> 1 EeV) populating the Universe, both past (RICE, AURA, ANITA) and current (RNO-G, ARIANNA, ARA and TAROGE-M) polar-sited experiments exploit the impulsive radio emission produced by neutrino interactions. In such experiments, rare single event candidates must be unambiguously identified above backgrounds. Background rejection strategies to date primarily target thermal noise fluctuations and also impulsive radio-frequency signals of anthropogenic origin. In this paper, we consider the possibility that 'fake' neutrino signals may also be generated naturally via the `triboelectric effect' This broadly describes any process in which force applied at a boundary layer results in displacement of surface charge, leading to the production of an electrostatic potential difference AV. Wind blowing over granular surfaces such as snow can induce such a potential difference, with subsequent coronal discharge. Discharges over timescales as short as nanoseconds can then lead to radio-frequency emissions at characteristic MHz-GHz frequencies. Using data from various past (RICE, AURA, SATRA, ANITA) and current (RNO G, ARIANNA and ARA) neutrino experiments, we find evidence for such backgrounds, which are generally characterized by: (a) a threshold wind velocity which likely depends on the experimental trigger criteria and layout; for the experiments considered herein, this value is typically O(10 m/s), (b) frequency spectra generally shifted to the low-end of the frequency regime to which current radio experiments are typically sensitive (100-200 MHz), (c) for the strongest background signals, an apparent preference for discharges from above-surface structures, although the presence of more isotropic, lower amplitude triboelectric discharges cannot be excluded.
15.	Ahmad, T, et al. (författare) Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries 2016 Ingår i: British journal of anaesthesia. - : Elsevier BV. - 1471-6771 .- 0007-0912. ; 117:5, s. 601- Tidskriftsartikel (refereegranskat)
16.	Ahmad, T, et al. (författare) In-hospital clinical outcomes after upper gastrointestinal surgery: Data from an international observational study 2017 Ingår i: European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. - : Elsevier BV. - 1532-2157 .- 0748-7983. ; 43:12, s. 2324-2332 Tidskriftsartikel (refereegranskat)
17.	Ahmad, T, et al. (författare) Use of failure-to-rescue to identify international variation in postoperative care in low-, middle- and high-income countries: a 7-day cohort study of elective surgery 2017 Ingår i: British journal of anaesthesia. - : Elsevier BV. - 1471-6771 .- 0007-0912. ; 119:2, s. 258-266 Tidskriftsartikel (refereegranskat)
18.	Archambault, Alexi N., et al. (författare) Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer 2020 Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12 Tidskriftsartikel (refereegranskat)abstract BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
19.	Beaty, D.W, et al. (författare) The potential science and engineering value of samples delivered to Earth by Mars sample return : International MSR Objectives and Samples Team (iMOST) 2019 Ingår i: Meteoritics and Planetary Science. - : John Wiley & Sons. - 1086-9379 .- 1945-5100. ; 54:S1, s. 3-152 Tidskriftsartikel (refereegranskat)abstract Executive Summary: Return of samples from the surface of Mars has been a goal of the international Mars science community for many years. Affirmation by NASA and ESA of the importance of Mars exploration led the agencies to establish the international MSR Objectives and Samples Team (iMOST). The purpose of the team is to re-evaluate and update the sample-related science and engineering objectives of a Mars Sample Return (MSR) campaign. The iMOST team has also undertaken to define the measurements and the types of samples that can best address the objectives. Seven objectives have been defined for MSR, traceable through two decades of previously published international priorities. The first two objectives are further divided into sub-objectives. Within the main part of the report, the importance to science and/or engineering of each objective is described, critical measurements that would address the objectives are specified, and the kinds of samples that would be most likely to carry key information are identified. These seven objectives provide a framework for demonstrating how the first set of returned Martian samples would impact future Martian science and exploration. They also have implications for how analogous investigations might be conducted for samples returned by future missions from other solar system bodies, especially those that may harbor biologically relevant or sensitive material, such as Ocean Worlds (Europa, Enceladus, Titan) and others. Summary of Objectives and Sub-Objectives for MSR Identified by iMOST: Objective 1 Interpret the primary geologic processes and history that formed the Martian geologic record, with an emphasis on the role of water. Intent To investigate the geologic environment(s) represented at the Mars 2020 landing site, provide definitive geologic context for collected samples, and detail any characteristics that might relate to past biologic processesThis objective is divided into five sub-objectives that would apply at different landing sites. 1.1 Characterize the essential stratigraphic, sedimentologic, and facies variations of a sequence of Martian sedimentary rocks. Intent To understand the preserved Martian sedimentary record. Samples A suite of sedimentary rocks that span the range of variation. Importance Basic inputs into the history of water, climate change, and the possibility of life 1.2 Understand an ancient Martian hydrothermal system through study of its mineralization products and morphological expression. Intent To evaluate at least one potentially life-bearing “habitable” environment Samples A suite of rocks formed and/or altered by hydrothermal fluids. Importance Identification of a potentially habitable geochemical environment with high preservation potential. 1.3 Understand the rocks and minerals representative of a deep subsurface groundwater environment. Intent To evaluate definitively the role of water in the subsurface. Samples Suites of rocks/veins representing water/rock interaction in the subsurface. Importance May constitute the longest-lived habitable environments and a key to the hydrologic cycle. 1.4 Understand water/rock/atmosphere interactions at the Martian surface and how they have changed with time. Intent To constrain time-variable factors necessary to preserve records of microbial life. Samples Regolith, paleosols, and evaporites. Importance Subaerial near-surface processes could support and preserve microbial life. 1.5 Determine the petrogenesis of Martian igneous rocks in time and space. Intent To provide definitive characterization of igneous rocks on Mars. Samples Diverse suites of ancient igneous rocks. Importance Thermochemical record of the planet and nature of the interior. Objective 2 Assess and interpret the potential biological history of Mars, including assaying returned samples for the evidence of life. Intent To investigate the nature and extent of Martian habitability, the conditions and processes that supported or challenged life, how different environments might have influenced the preservation of biosignatures and created nonbiological “mimics,” and to look for biosignatures of past or present life.This objective has three sub-objectives: 2.1 Assess and characterize carbon, including possible organic and pre-biotic chemistry. Samples All samples collected as part of Objective 1. Importance Any biologic molecular scaffolding on Mars would likely be carbon-based. 2.2 Assay for the presence of biosignatures of past life at sites that hosted habitable environments and could have preserved any biosignatures. Samples All samples collected as part of Objective 1. Importance Provides the means of discovering ancient life. 2.3 Assess the possibility that any life forms detected are alive, or were recently alive. Samples All samples collected as part of Objective 1. Importance Planetary protection, and arguably the most important scientific discovery possible. Objective 3 Quantitatively determine the evolutionary timeline of Mars. Intent To provide a radioisotope-based time scale for major events, including magmatic, tectonic, fluvial, and impact events, and the formation of major sedimentary deposits and geomorphological features. Samples Ancient igneous rocks that bound critical stratigraphic intervals or correlate with crater-dated surfaces. Importance Quantification of Martian geologic history. Objective 4 Constrain the inventory of Martian volatiles as a function of geologic time and determine the ways in which these volatiles have interacted with Mars as a geologic system. Intent To recognize and quantify the major roles that volatiles (in the atmosphere and in the hydrosphere) play in Martian geologic and possibly biologic evolution. Samples Current atmospheric gas, ancient atmospheric gas trapped in older rocks, and minerals that equilibrated with the ancient atmosphere. Importance Key to understanding climate and environmental evolution. Objective 5 Reconstruct the processes that have affected the origin and modification of the interior, including the crust, mantle, core and the evolution of the Martian dynamo. Intent To quantify processes that have shaped the planet's crust and underlying structure, including planetary differentiation, core segregation and state of the magnetic dynamo, and cratering. Samples Igneous, potentially magnetized rocks (both igneous and sedimentary) and impact-generated samples. Importance Elucidate fundamental processes for comparative planetology. Objective 6 Understand and quantify the potential Martian environmental hazards to future human exploration and the terrestrial biosphere. Intent To define and mitigate an array of health risks related to the Martian environment associated with the potential future human exploration of Mars. Samples Fine-grained dust and regolith samples. Importance Key input to planetary protection planning and astronaut health. Objective 7 Evaluate the type and distribution of in-situ resources to support potential future Mars exploration. Intent To quantify the potential for obtaining Martian resources, including use of Martian materials as a source of water for human consumption, fuel production, building fabrication, and agriculture. Samples Regolith. Importance Production of simulants that will facilitate long-term human presence on Mars. Summary of iMOST Findings: Several specific findings were identified during the iMOST study. While they are not explicit recommendations, we suggest that they should serve as guidelines for future decision making regarding planning of potential future MSR missions. The samples to be collected by the Mars 2020 (M-2020) rover will be of sufficient size and quality to address and solve a wide variety of scientific questions. Samples, by definition, are a statistical representation of a larger entity. Our ability to interpret the source geologic units and processes by studying sample sub sets is highly dependent on the quality of the sample context. In the case of the M-2020 samples, the context is expected to be excellent, and at multiple scales. (A) Regional and planetary context will be established by the on-going work of the multi-agency fleet of Mars orbiters. (B) Local context will be established at field area- to outcrop- to hand sample- to hand lens scale using the instruments carried by M-2020. A significant fraction of the value of the MSR sample collection would come from its organization into sample suites, which are small groupings of samples designed to represent key aspects of geologic or geochemical variation. If the Mars 2020 rover acquires a scientifically well-chosen set of samples, with sufficient geological diversity, and if those samples were returned to Earth, then major progress can be expected on all seven of the objectives proposed in this study, regardless of the final choice of landing site. The specifics of which parts of Objective 1 could be achieved would be different at each of the final three candidate landing sites, but some combination of critically important progress could be made at any of them. An aspect of the search for evidence of life is that we do not know in advance how evidence for Martian life would be preserved in the geologic record. In order for the returned samples to be most useful for both understanding geologic processes (Objective 1) and the search for life (Objective 2), the sample collection should contain BOTH typical and unusual samples from the rock units explored. This consideration should be incorporated into sample selection and the design of the suites. The retrieval missions of a MSR campaign should (1) minimize stray magnetic fields to which the samples would be exposed and carry a magnetic witness plate to record exposure, (2) collect and return atmospheric gas sample(s), and (3) collect additional dust and/or regolith sample mass if possible.
20.	Beral, V, et al. (författare) Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease 2002 Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 87, s. 1234-45 Tidskriftsartikel (refereegranskat)abstract Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58515 women with invasive breast cancer and 95067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19 - 1.45, P < 0.00001) for an intake of 35 - 44 g per day alcohol, and 1.46 (1.33 - 1.61, P < 0.00001) for greater than or equal to 45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1 % per 10 g per day, P < 0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers= 1.03, 95% CI 0.98 - 1.07, and for current smokers=0.99, 0.92 - 1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver. (C) 2002 Cancer Research UK.
21.	Beral, V, et al. (författare) Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies 2012 Ingår i: The Lancet. Oncology. - 1474-5488. ; 13:11, s. 1141-1151 Tidskriftsartikel (refereegranskat)
22.	Bishop, Anusha P., et al. (författare) A machine learning approach to integrating genetic and ecological data in tsetse flies (Glossina pallidipes) for spatially explicit vector control planning 2021 Ingår i: Evolutionary Applications. - : John Wiley & Sons. - 1752-4571. ; 14:7, s. 1762-1777 Tidskriftsartikel (refereegranskat)abstract Vector control is an effective strategy for reducing vector-borne disease transmission, but requires knowledge of vector habitat use and dispersal patterns. Our goal was to improve this knowledge for the tsetse species Glossina pallidipes, a vector of human and animal African trypanosomiasis, which are diseases that pose serious health and socioeconomic burdens across sub-Saharan Africa. We used random forest regression to (i) build and integrate models of G. pallidipes habitat suitability and genetic connectivity across Kenya and northern Tanzania and (ii) provide novel vector control recommendations. Inputs for the models included field survey records from 349 trap locations, genetic data from 11 microsatellite loci from 659 flies and 29 sampling sites, and remotely sensed environmental data. The suitability and connectivity models explained approximately 80% and 67% of the variance in the occurrence and genetic data and exhibited high accuracy based on cross-validation. The bivariate map showed that suitability and connectivity vary independently across the landscape and was used to inform our vector control recommendations. Post hoc analyses show spatial variation in the correlations between the most important environmental predictors from our models and each response variable (e.g., suitability and connectivity) as well as heterogeneity in expected future climatic change of these predictors. The bivariate map suggests that vector control is most likely to be successful in the Lake Victoria Basin and supports the previous recommendation that G. pallidipes from most of eastern Kenya should be managed as a single unit. We further recommend that future monitoring efforts should focus on tracking potential changes in vector presence and dispersal around the Serengeti and the Lake Victoria Basin based on projected local climatic shifts. The strong performance of the spatial models suggests potential for our integrative methodology to be used to understand future impacts of climate change in this and other vector systems.
23.	Bishop, Paul, et al. (författare) ‘Bottom-up’ bedrock river response to rock uplift: Unravelling the controls of landscape responses to transience. 2010 Ingår i: <em>British Society for Geomorphology Programme & Abstracts</em>. London, England, Aug 2010.. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Bedrock rivers set the boundary conditions for landscape evolution. Most recent bedrock river research has been in steady-state settings in which rock uplift is matched by landscape lowering driven by bedrock river incision and slope lowering, but more attention is now being paid to bedrock rivers is transient settings (where transience in the fluvial system is triggered by changes in the rate of rock uplift and/or by climatic oscillations). Transient responses in bedrock rivers close to base-level are dominated by ‘bottom-up’ processes. Those processes remain less well understood than the ‘top-down’ processes that are thought to be characteristic of steady state landscapes and are driven by discharges of water and sediment. Key issues in understanding rates of landscape-wide response to transience are (i) rates of knickpoint retreat to transmit a base-level fall signal through the drainage net, and (ii) rates of hillslope response once that base-level fall has passed the foot of a hillslope. Terrestrial cosmogenic nuclide (TCN) data from a transient landscape in southern Spain point to the latter being the rate-limiting control (“fast rivers, slow hillslopes”). In terms of the former, morphometric and TCN data from coastal rivers in Scotland confirm knickpoint retreat in response to glacio-isostatic rebound, whereas TCN data from higher up these rivers, above the reach affected by glacio-isostatic base-level fall, point to more diffusive bedrock channel incision, without knickpoint retreat. Determining why diffusive incision is initiated at a particular locality in those settings is difficult but in at least one case the incision is probably ‘pinned’ on resistant lithologies. A wider and more taxing issue is the relationship between ‘bottom-up’ and ‘top-down’ incisional processes and whether the former must precede, and can evolve into, the latter.
24.	Branstrom, Richard, et al. (författare) Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma 2012 Ingår i: European Journal of Cancer. - : Elsevier BV. - 1879-0852 .- 0959-8049. ; 48:16, s. 3052-3062 Tidskriftsartikel (refereegranskat)abstract Background: Several melanoma susceptibility genes have been identified. As part of the international genetic research programme of the GenoMEL consortiums research on genetic mutations in melanoma families, the aim of this study was to examine family members' views about their risk of melanoma, gene testing and genetic research. Methods: Self-report data were gathered using online and paper-based surveys available in four languages among 312 individuals (62% from Europe, 18% from Australia, 13% from the United States of America (USA) and 7% from Israel). Results: Fifty three percent had been diagnosed with a melanoma, and 12% had a positive susceptibility gene test result. Respondents with many moles and freckles were more likely to perceive themselves at risk for developing melanoma (odds ratio [OR](Freckles) = 2.24 with 95% confidence interval [CI] = 1.18-4.26; ORMany (moles) = 6.92, 95% CI = 2.37-20.23). Respondents who had received a non-informative (negative) genetic test result were much less likely to perceive themselves at increased risk (OR = 0.17, 95% CI = 0.04-0.73). Safe-guards were perceived as important to protect genetic information, but there was also support for the storage and exchange of such information. Overall, respondents were in favour of genetic testing, even if current knowledge about melanoma risk genes is still limited. Contrary to previous studies, participants reported that a non-informative (negative) genetic test result, although not necessarily indicative of lower risk of melanoma, would be likely to reduce their practise of preventive behaviours. Conclusions: Participants were influenced by their phenotype and test results in risk estimations. They expressed positive views on genetic research and towards genetic testing, but reported that a non-informative (negative) test result might be associated with an (erroneous) perception of reduced risk and fewer preventive behaviours. These results highlight the urgency of improving the quality of genetic counselling and increasing the effectiveness of communication regarding genetic test results. (C) 2012 Elsevier Ltd. All rights reserved.
25.	Carreras-Torres, Robert, et al. (författare) Genome-wide interaction study with smoking for colorectal cancer risk identifies novel genetic loci related to tumor suppression, inflammation, and immune response 2023 Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American association for cancer research. - 1055-9965 .- 1538-7755. ; 32:3, s. 315-328 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer.METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia.RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33).CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response.IMPACT: These findings can guide potential prevention treatments.
26.	Castillo, Miguel, et al. (författare) Estimating erosion rates on active bedrock channels using in situ produced 10Be: implications for landscape evolution in small transient rivers. 2010 Ingår i: <em>Geological Society of America Abstract with Programs</em>, 178678. Denver, USA, Oct-Nov 2010.. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract We measured concentrations of 10Be in two small bedrock rivers catchments on the Isle of Jura (western Scotland) in order to obtain erosion rates to test models of the responses of small bedrock rivers to base-level fall. The rivers of Jura experienced an abrupt, glacioisostatic base-level fall ca. 13.5ka, triggering upstream-propagating knickpoints. 10Be concentrations were obtained in the channel bed upstream and downstream of the main knickpoint triggered by that base-level fall. The preliminary results indicate that erosion rates are slightly higher downstream of the knickpoints, reflecting incomplete accommodation of the base-level fall by knickpoint retreat, ongoing glacioisostatic uplift and/or knickpoint rotation.
27.	Castillo, Miguel, et al. (författare) Knickpoint retreat and transient bedrock channel morphology triggered by base-level fall in small bedrock river catchments : The case of the Isle of Jura, Scotland 2013 Ingår i: Geomorphology. - : Elsevier BV. - 0169-555X .- 1872-695X. ; 180, s. 1-9 Tidskriftsartikel (refereegranskat)abstract A sudden drop in river base-level can trigger a knickpoint that propagates throughout the fluvial network causing a transient state in the landscape. Knickpoint retreat has been confirmed in large fluvial settings (drainage areas > 100 km(2)) and field data suggest that the same applies to the case of small bedrock river catchments (drainage areas < 100 km(2)). Nevertheless, knickpoint recession on resistant lithologies with structure that potentially affects the retreat rate needs to be confirmed with field-based data. Moreover, it remains unclear whether small bedrock rivers can absorb base-level fall via knickpoint retreat. Here we evaluate the response of small bedrock rivers to base-level fall on the isle of Jura in western Scotland (UK), where rivers incise into dipping quartzite. The mapping of raised beach deposits and strath terraces, and the analysis of stream long profiles, were used to identify knickpoints that had been triggered by base-level fall. Our results indicate that the distance of knickpoint retreat scales to the drainage area in a power law function irrespective of structural setting. On the other hand, local channel slope and basin size influence the vertical distribution of knickpoints. As well, at low drainage areas (similar to 4 km(2)) rivers are unable to absorb the full amount of base-level fall and channel reach morphology downstream of the knickpoint tends towards convexity. The results obtained here confirm that knickpoint retreat is mostly controlled by stream discharge, as has been observed for other transient landscapes. Local controls, reflecting basin size and channel slope, have an effect on the vertical distribution of knickpoints; such controls are also related to the ability of rivers to absorb the base-level fall.
28.	Conradson, Steven D., et al. (författare) Closure of the Mott gap and formation of a superthermal metal in the Frohlich-type nonequilibrium polaron Bose-Einstein condensate in UO2+x 2017 Ingår i: Physical Review B. - 2469-9950 .- 2469-9969. ; 96:12 Tidskriftsartikel (refereegranskat)abstract Mixed valence O-doped UO2+x. and photoexcited UO2 containing transitory U3+ and U5+ host a coherent polaronic quantum phase (CPQP) that exhibits the characteristics of a Frohlich-type, nonequilibrium, phononcoupled Bose-Einstein condensate whose stability and coherence are amplified by collective, anharmonic motions of atoms and charges. Complementary to the available, detailed, real space information from scattering and EXAFS, an outstanding question is the electronic structure. Mapping the Mott gap in UO2, U4O9, and U3O7 with O XAS and NIXS and UM5 RIXS shows that O doping raises the peak of the U5f states of the valence band by similar to 0.4 eV relative to a calculated value of 0.25 eV. However, it lowers the edge of the conduction band by 1.5 eV vs the calculated 0.6 eV, a difference much larger than the experimental error. This 1.9 eV reduction in the gap width constitutes most of the 2-2.2 eV gap measured by optical absorption. In addition, the XAS spectra show a tail that will intersect the occupied U5f states and give a continuous density-of-states that increases rapidly above its constricted intersection. Femtosecond-resolved photoemission measurements of UO2, coincident with the excitation pulse with 4.7 eV excitation, show the unoccupied U5f states of UO2 and no hot electrons. 3.1 eV excitation, however, complements the O-doping results by giving a continuous population of electrons for several eV above the Fermi level. The CPQP in photoexcited UO2 therefore fulfills the criteria for a nonequilibrium condensate. The electron distributions resulting from both excitations persist for 5-10 ps, indicating that they are the final state that therefore forms without passing through the initial continuous distribution of nonthermal electrons observed for other materials. Three exceptional findings are: (1) the direct formation of both of these long lived (> 3-10 ps) excited states without the short lived nonthermal intermediate; (2) the superthermal metallic state is as or more stable than typical photoinduced metallic phases; and (3) the absence of hot electrons accompanying the insulating UO2 excited state. This heterogeneous, nonequilibrium, Frohlich BEC stabilized by a Fano-Feshbach resonance therefore continues to exhibit unique properties.
29.	Dias, P. Joana, et al. (författare) Establishment of a taxonomic and molecular reference collection to support the identification of species regulated by the Western Australian Prevention List for Introduced Marine Pests 2017 Ingår i: Management of Biological Invasions. - : Regional Euro-Asian Biological Invasions Centre Oy (REABIC). - 1989-8649. ; 8:2, s. 215-225 Tidskriftsartikel (refereegranskat)abstract Introduced Marine Pests (IMP, = non-indigenous marine species) prevention, early detection and risk-based management strategies have become the priority for biosecurity operations worldwide, in recognition of the fact that, once established, the effective management of marine pests can rapidly become cost prohibitive or impractical. In Western Australia (WA), biosecurity management is guided by the Western Australian Prevention List for Introduced Marine Pests which is a policy tool that details species or genera as being of high risk to the region. This list forms the basis of management efforts to prevent introduction of these species, monitoring efforts to detect them at an early stage, and rapid response should they be detected. It is therefore essential that the species listed can be rapid and confidently identified and discriminated from native species by a range of government and industry stakeholders. Recognising that identification of these species requires very specialist expertise which may be in short supply and not readily accessible in a regulatory environment, and the fact that much publicly available data is not verifiable or suitable for regulatory enforcement, the WA government commissioned the current project to collate a reference collection of these marine pest specimens. In this work, we thus established collaboration with researchers worldwide in order to source representative specimens of the species listed. Our main objective was to build a reference collection of taxonomically vouchered specimens and subsequently to generate species-specific DNA barcodes suited to supporting their future identification. To date, we were able to obtain specimens of 75 species (representative of all but four of the pests listed) which have been identified by experts and placed with the WA Government Department of Fisheries and, where possible, in accessible museums and institutions in Australasia. The reference collection supports the fast and reliable taxonomic and molecular identification of marine pests in WA and constitutes a valuable resource for training of stakeholders with interest in IMP recognition in Australia. The reference collection is also useful in supporting the development of a variety of DNA-based detection strategies such as real-time PCR and metabarcoding of complex environmental samples (e.g. biofouling communities). The Prevention List is under regular review to ensure its continued relevance and that it remains evidence and risk-based. Similarly, its associated reference collection also remains to some extent a work in progress. In recognition of this fact, this report seeks to provide details of this continually evolving information repository publicly available to the biosecurity management community worldwide.
30.	Dimou, Niki L, et al. (författare) Circulating adipokine concentrations and risk of five obesity-related cancers : A Mendelian randomization study. 2021 Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 148:7, s. 1625-1636 Tidskriftsartikel (refereegranskat)abstract Obesity is considered a chronic inflammatory state characterized by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines (adiponectin, leptin, soluble leptin receptor [sOB-R] and plasminogen activator inhibitor-1 [PAI-1]) with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma [RCC], ovarian and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin and 4 for both sOB-R and PAI-1 (P value for inclusion<5 × 10-8 ). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer (odds ratio per 1 μg/mL increment in adiponectin concentration: 0.90 [95% confidence interval = 0.84-0.97]; P = .01); but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, RCC, ovarian cancer and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R and PAI-1 concentrations on the development of five obesity-related cancers.
31.	Ebert, Karin, 1976- (författare) Cenozoic landscape evolution in northern Sweden : Geomorphological interpretation within a GIS-framework 2009 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The large-scale bedrock landscape in northern Sweden has a complex evolution history of planation, uplift, transgression, burial, weathering, and erosion. The aim of this thesis is to examine the long-term development of the area. Terms for base-level surfaces in the area are defined. A combination of GIS-analyses of digital elevation models and field work is used to explore landform characteristics and formation. Inselbergs east of the northern Scandes in northern Sweden are used as a basis for describing landscape development. In total, 794 inselbergs are identified in the study area. The inselbergs are classified according to their degree of glacial erosion. The Parkajoki area, with low glacially modified inselbergs, tors, boulder fields and saprolites, has been shown to have largely escaped Quaternary glacial erosion and is taken as a type area to describe the late-Neogene landscape development prior to glaciation. The removal of Neogene saprolite mantles at the inselberg feet in areas of glacial erosion increased inselberg relief during the Quaternary by 10-20 m. For landscape evolution further back in time, beyond the Neogene, the hypsography of the study areas shows at least two palaeosurface generations in the northern Scandes and at least four palaeosurface generations on the inselberg plains. The distribution of inselbergs in relation to palaeosurface generations in the same elevation intervals suggests land uplift with a tilt towards the SE-ESE. Eocene marine diatom findings at 260 m a.s.l. in Finland, 200 km east of the study area, indicate a pre-Eocene age of the inselberg plains above this elevation. The development of today’s inselberg plains likely started in the late Mesozoic, with a sub-Mesozic etch surface that was subjected to land uplift at the late Mesozoic-Paleocene transition during breakup of the Atlantic. The great antiquity of the northern Swedish bedrock landscape stands as an analogy for shield areas in for example Australia and Africa.
32.	Figueroa, Jonine D., et al. (författare) 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 Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214 Tidskriftsartikel (refereegranskat)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.
33.	Freitag, Daniel F., et al. (författare) Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis 2015 Ingår i: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253 Tidskriftsartikel (refereegranskat)abstract Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
34.	Guo, Xingyi, et al. (författare) Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects 2020 Ingår i: Gastroenterology. - : Elsevier. - 0016-5085 .- 1528-0012. ; 160:4, s. 1164-1178 Tidskriftsartikel (refereegranskat)abstract Background and Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
35.	Howick, Jeremy, et al. (författare) Effects of changing practitioner empathy and patient expectations in healthcare consultations 2015 Ingår i: Cochrane Database of Systematic Reviews. - : John Wiley & Sons. - 1469-493X. Tidskriftsartikel (refereegranskat)
36.	Howick, Jeremy, et al. (författare) Effects of empathic and positive communication in healthcare consultations: a systematic review and meta-analysis 2018 Ingår i: Journal of the Royal Society of Medicine. - : Sage Publications. - 0141-0768 .- 1758-1095. ; 111:7, s. 240-252 Tidskriftsartikel (refereegranskat)abstract BackgroundPractitioners who enhance how they express empathy and create positive expectations of benefit could improve patient outcomes. However, the evidence in this area has not been recently synthesised.ObjectiveTo estimate the effects of empathy and expectations interventions for any clinical condition.DesignSystematic review and meta-analysis of randomised trials.Data sourceSix databases from inception to August 2017.Study selectionRandomised trials of empathy or expectations interventions in any clinical setting with patients aged 12 years or older.Review methodsTwo reviewers independently screened citations, extracted data, assessed risk of bias and graded quality of evidence using GRADE. Random effects model was used for meta-analysis.ResultsWe identified 28 eligible (n = 6017). In seven trials, empathic consultations improved pain, anxiety and satisfaction by a small amount (standardised mean difference −0.18 [95% confidence interval −0.32 to −0.03]). Twenty-two trials tested the effects of positive expectations. Eighteen of these (n = 2014) reported psychological outcomes (mostly pain) and showed a modest benefit (standardised mean difference −0.43 [95% confidence interval −0.65 to −0.21]); 11 (n = 1790) reported physical outcomes (including bronchial function/ length of hospital stay) and showed a small benefit (standardised mean difference −0.18 [95% confidence interval −0.32 to −0.05]). Within 11 trials (n = 2706) assessing harms, there was no evidence of adverse effects (odds ratio 1.04; 95% confidence interval 0.67 to 1.63). The risk of bias was low. The main limitations were difficulties in blinding and high heterogeneity for some comparisons.ConclusionGreater practitioner empathy or communication of positive messages can have small patient benefits for a range of clinical conditions, especially pain.Protocol registrationCochrane Database of Systematic Reviews (protocol) DOI: 10.1002/14651858.CD011934.pub2.
37.	Huyghe, Jeroen R., et al. (författare) Discovery of common and rare genetic risk variants for colorectal cancer 2019 Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76- Tidskriftsartikel (refereegranskat)abstract To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
38.	Huyghe, Jeroen R, et al. (författare) Genetic architectures of proximal and distal colorectal cancer are partly distinct 2021 Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334 Tidskriftsartikel (refereegranskat)abstract Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
39.	Ioannidis, John P A, et al. (författare) A road map for efficient and reliable human genome epidemiology 2006 Ingår i: Nature Genetics. - 1061-4036. ; 38:1, s. 3-5 Tidskriftsartikel (refereegranskat)
40.	Jansen, John D., et al. (författare) Does decreasing paraglacial sediment supply slow knickpoint retreat? 2011 Ingår i: Geology. - 0091-7613 .- 1943-2682. ; 39:6, s. 543-546 Tidskriftsartikel (refereegranskat)abstract In four rivers in western Scotland for which there is a well-constrained record of relative base-level fall, the rate of postglacial bedrock erosion is quantified by measuring the concentration of in situ cosmogenic (10)Be on strath terraces downstream of headward-retreating knickpoints. Along-channel gradients in (10)Be exposure age show two distinct trends: upstream younging and constant age, which we interpret as diagnostic of knickpoint retreat and diffusive transport-limited incision, respectively. We show that bedrock channel incision and regional formation of strath terraces began shortly after deglaciation (ca. 11.5 ka), and that knickpoint retreat rates peaked in the early to mid-Holocene. Erosion rates have since decreased by two orders of magnitude, converging in the late Holocene to low rates independent of stream power per unit channel area. We infer this regional slowing in postglacial knickpoint retreat to be the result of the depletion of paraglacial sediment supply over the Holocene, leading to a deficiency in tools for bedrock erosion. Our results imply that episodes of major fluvial erosion may be in tune with glacial cycles, and that sediment depletion following glacial-interglacial transitions may be an important cause of bedrock erosion rate variations in rivers draining glaciated landscapes.
41.	Jansen, John, 1967-, et al. (författare) Scale Dependence of Lithological Control on Topography : Bedrock Channel Geometry and Catchment Morphometry in Western Scotland 2010 Ingår i: The Journal of geology. - Chicago : The University of Chicago. - 0022-1376 .- 1537-5269. ; 118:3, s. 223-246 Tidskriftsartikel (refereegranskat)abstract We propose that a scale-dependent topographic signature of erodibility arises due to fluvial and glacial erosion acting on different parts of the landscape at different times. For 14 catchments in western Scotland, we define three levels of substrate erodibility in order of decreasing resistance: quartzite rocks, non-quartzite rocks, and zones of fault-related fracture. Then, using digital topographic and planimetric data coupled with field measurements, we identify regression-based scaling relationships between substrate erodibility and morphometric parameters at two spatial scales. Catchment-scale morphometry shows a weak to variable relationship with substrate metrics overall. Erodibility can be inferred from catchment steepness indices (i.e., channel steepness index and relief ratio), but the existence of multiple exceptions could confound a more general application of this approach. Nonetheless, major valley troughs trace fault zones and non-quartzite rocks, leaving much of the higher and steeper ground formed in quartzite. At the reach-scale, bedrock channel slope is far more sensitive to substrate erodibility than is channel width. Quartzite outcrops steepen bedrock channels by a factor of 1.5 to 6.0 and, in terms of unit stream power, channels increase their erosional capacity by a factor of 2.7 to 3.5. Yet only 4 to 13% of this increase is due to channel narrowing. Based on a large dataset of bedrock channel width (n=5825) from 4 rivers, we find that width scales with drainage area (in m2) as W=0.01 A0.28. Our results are consistent with the view that width-area scaling is similar in all single-thread rivers subject to transport-limited conditions, but for increasingly sediment supply-limited settings erosional thresholds at the channel boundary are the key determinants of bedrock channel width.
42.	Morrison, Kathleen D., et al. (författare) Mapping past human land use using archaeological data : A new classification for global land use synthesis and data harmonization 2021 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 16:4 Tidskriftsartikel (refereegranskat)abstract In the 12,000 years preceding the Industrial Revolution, human activities led to significant changes in land cover, plant and animal distributions, surface hydrology, and biochemical cycles. Earth system models suggest that this anthropogenic land cover change influenced regional and global climate. However, the representation of past land use in earth system models is currently oversimplified. As a result, there are large uncertainties in the current understanding of the past and current state of the earth system. In order to improve representation of the variety and scale of impacts that past land use had on the earth system, a global effort is underway to aggregate and synthesize archaeological and historical evidence of land use systems. Here we present a simple, hierarchical classification of land use systems designed to be used with archaeological and historical data at a global scale and a schema of codes that identify land use practices common to a range of systems, both implemented in a geospatial database. The classification scheme and database resulted from an extensive process of consultation with researchers worldwide. Our scheme is designed to deliver consistent, empirically robust data for the improvement of land use models, while simultaneously allowing for a comparative, detailed mapping of land use relevant to the needs of historical scholars. To illustrate the benefits of the classification scheme and methods for mapping historical land use, we apply it to Mesopotamia and Arabia at 6 kya (c. 4000 BCE). The scheme will be used to describe land use by the Past Global Changes (PAGES) LandCover6k working group, an international project comprised of archaeologists, historians, geographers, paleoecologists, and modelers. Beyond this, the scheme has a wide utility for creating a common language between research and policy communities, linking archaeologists with climate modelers, biodiversity conservation workers and initiatives.
43.	Nounu, Aayah, et al. (författare) A combined proteomics and mendelian randomization approach to investigate the effects of aspirin-targeted proteins on colorectal cancer 2021 Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : Elsevier. - 1055-9965 .- 1538-7755. ; 30:3, s. 564-575 Tidskriftsartikel (refereegranskat)abstract Background: Evidence for aspirin’s chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N ¼ 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N ¼ 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively).Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin’s reduction of metastasis.Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
44.	Nounu, Aayah, et al. (författare) Salicylic Acid and Risk of Colorectal Cancer : A Two-Sample Mendelian Randomization Study 2021 Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 13:11 Tidskriftsartikel (refereegranskat)abstract Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes' coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84-1.27 and OR: 1.08, 95% CI: 0.86-1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
45.	Papadimitriou, Nikos, et al. (författare) Physical activity and risks of breast and colorectal cancer : a Mendelian randomisation analysis 2020 Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value=0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value=0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers. Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
46.	Pastorino, Silvia, et al. (författare) Heterogeneity of Associations between Total and Types of Fish Intake and the Incidence of Type 2 Diabetes : Federated Meta-Analysis of 28 Prospective Studies Including 956,122 Participants 2021 Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 13:4 Tidskriftsartikel (refereegranskat)abstract The association between fish consumption and new-onset type 2 diabetes is inconsistent and differs according to geographical location. We examined the association between the total and types of fish consumption and type 2 diabetes using individual participant data from 28 prospective cohort studies from the Americas (6), Europe (15), the Western Pacific (6), and the Eastern Mediterranean (1) comprising 956,122 participants and 48,084 cases of incident type 2 diabetes. Incidence rate ratios (IRRs) for associations of total fish, shellfish, fatty, lean, fried, freshwater, and saltwater fish intake and type 2 diabetes were derived for each study, adjusting for a consistent set of confounders and combined across studies using random-effects meta-analysis. We stratified all analyses by sex due to observed interaction (p = 0.002) on the association between fish and type 2 diabetes. In women, for each 100 g/week higher intake the IRRs (95% CIs) of type 2 diabetes were 1.02 (1.01–1.03, I2 = 61%) for total fish, 1.04 (1.01–1.07, I2 = 46%) for fatty fish, and 1.02 (1.00–1.04, I2 = 33%) for lean fish. In men, all associations were null. In women, we observed variation by geographical location: IRRs for total fish were 1.03 (1.02–1.04, I2 = 0%) in the Americas and null in other regions. In conclusion, we found evidence of a neutral association between total fish intake and type 2 diabetes in men, but there was a modest positive association among women with heterogeneity across studies, which was partly explained by geographical location and types of fish intake. Future research should investigate the role of cooking methods, accompanying foods and environmental pollutants, but meanwhile, existing dietary regional, national, or international guidelines should continue to guide fish consumption within overall healthy dietary patterns.
47.	Pearce, Matthew, et al. (författare) Associations of Total Legume, Pulse, and Soy Consumption with Incident Type 2 Diabetes : Federated Meta-Analysis of 27 Studies from Diverse World Regions 2021 Ingår i: Journal of Nutrition. - : Elsevier. - 0022-3166 .- 1541-6100. ; 151:5, s. 1231-1240 Tidskriftsartikel (refereegranskat)abstract BackgroundThe consumption of legumes is promoted as part of a healthy diet in many countries but associations of total and types of legume consumption with type 2 diabetes (T2D) are not well established. Analyses across diverse populations are lacking despite the availability of unpublished legume consumption data in prospective cohort studies.ObjectiveTo examine the prospective associations of total and types of legume intake with the risk of incident T2D.MethodsMeta-analyses of associations between total legume, pulse, and soy consumption and T2D were conducted using a federated approach without physical data-pooling. Prospective cohorts were included if legume exposure and T2D outcome data were available and the cohort investigators agreed to participate. We estimated incidence rate ratios (IRRs) and CIs of associations using individual participant data including ≤42,473 incident cases among 807,785 adults without diabetes in 27 cohorts across the Americas, Eastern Mediterranean, Europe, and Western Pacific. Random-effects meta-analysis was used to combine effect estimates and estimate heterogeneity.ResultsMedian total legume intake ranged from 0–140 g/d across cohorts. We observed a weak positive association between total legume consumption and T2D (IRR = 1.02, 95% CI: 1.01 to 1.04) per 20 g/d higher intake, with moderately high heterogeneity (I2 = 74%). Analysis by region showed no evidence of associations in the Americas, Eastern Mediterranean, and Western Pacific. The positive association in Europe (IRR = 1.05, 95% CI: 1.01 to 1.10, I2 = 82%) was mainly driven by studies from Germany, UK, and Sweden. No evidence of associations was observed for the consumption of pulses or soy.ConclusionsThese findings suggest no evidence of an association of legume intakes with T2D in several world regions. The positive association observed in some European studies warrants further investigation relating to overall dietary contexts in which legumes are consumed, including accompanying foods which may be positively associated with T2D.
48.	Rothman, Nathaniel, et al. (författare) A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci 2010 Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 978-984 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.
49.	Seminara, Daniela, et al. (författare) The emergence of networks in human genome epidemiology: challenges and opportunities. 2007 Ingår i: Epidemiology. - : Ovid Technologies (Wolters Kluwer Health). - 1044-3983. ; 18:1, s. 1-8 Tidskriftsartikel (refereegranskat)
50.	Su, Yu-Ru, et al. (författare) Validation of a genetic-enhanced risk prediction model for colorectal cancer in a large community-based cohort 2023 Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American association for cancer research. - 1055-9965 .- 1538-7755. ; 32:3, s. 353-362 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Polygenic risk scores (PRS) which summarize individuals' genetic risk profile may enhance targeted colorectal cancer screening. A critical step towards clinical implementation is rigorous external validations in large community-based cohorts. This study externally validated a PRS-enhanced colorectal cancer risk model comprising 140 known colorectal cancer loci to provide a comprehensive assessment on prediction performance.METHODS: The model was developed using 20,338 individuals and externally validated in a community-based cohort (n = 85,221). We validated predicted 5-year absolute colorectal cancer risk, including calibration using expected-to-observed case ratios (E/O) and calibration plots, and discriminatory accuracy using time-dependent AUC. The PRS-related improvement in AUC, sensitivity and specificity were assessed in individuals of age 45 to 74 years (screening-eligible age group) and 40 to 49 years with no endoscopy history (younger-age group).RESULTS: In European-ancestral individuals, the predicted 5-year risk calibrated well [E/O = 1.01; 95% confidence interval (CI), 0.91-1.13] and had high discriminatory accuracy (AUC = 0.73; 95% CI, 0.71-0.76). Adding the PRS to a model with age, sex, family and endoscopy history improved the 5-year AUC by 0.06 (P < 0.001) and 0.14 (P = 0.05) in the screening-eligible age and younger-age groups, respectively. Using a risk-threshold of 5-year SEER colorectal cancer incidence rate at age 50 years, adding the PRS had a similar sensitivity but improved the specificity by 11% (P < 0.001) in the screening-eligible age group. In the younger-age group it improved the sensitivity by 27% (P = 0.04) with similar specificity.CONCLUSIONS: The proposed PRS-enhanced model provides a well-calibrated 5-year colorectal cancer risk prediction and improves discriminatory accuracy in the external cohort.IMPACT: The proposed model has potential utility in risk-stratified colorectal cancer prevention.

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