| 1. |
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| 2. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 3. |
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| 4. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 5. |
- Yue, Siyao, et al.
(författare)
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Brown carbon from biomass burning imposes strong circum-Arctic warming
- 2022
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Ingår i: ONE EARTH. - : Elsevier BV. - 2590-3330 .- 2590-3322. ; 5:3, s. 293-304
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Tidskriftsartikel (refereegranskat)abstract
- Rapid warming in the Arctic has a huge impact on the global environment. Atmospheric brown carbon (BrC) is one of the least understood and uncertain warming agents due to a scarcity of observations. Here, we performed direct observations of atmospheric BrC and quantified its light-absorbing properties during a 2 month circum-Arctic cruise in summer of 2017. Through observation-constrained modeling, we show that BrC, mainly originated from biomass burning in the mid-to high latitudes of the Northern Hemisphere (similar to 60%), can be a strong warming agent in the Arctic region, especially in the summer, with an average radiative forcing of-90 mW m(-2) (similar to 30% relative to black carbon). As climate change is projected to increase the frequency, intensity, and spread of wildfires, we expect BrC to play an increasing role in Arctic warming in the future.
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| 6. |
- Hyde, K. D., et al.
(författare)
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Global consortium for the classification of fungi and fungus-like taxa
- 2023
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Ingår i: MYCOSPHERE. - : Mushroom Research Foundation. - 2077-7000 .- 2077-7019. ; 14:1, s. 1960-2012
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Tidskriftsartikel (refereegranskat)abstract
- The Global Consortium for the Classification of Fungi and fungus-like taxa is an international initiative of more than 550 mycologists to develop an electronic structure for the classification of these organisms. The members of the Consortium originate from 55 countries/regions worldwide, from a wide range of disciplines, and include senior, mid-career and early-career mycologists and plant pathologists. The Consortium will publish a biannual update of the Outline of Fungi and fungus-like taxa, to act as an international scheme for other scientists. Notes on all newly published taxa at or above the level of species will be prepared and published online on the Outline of Fungi website (https://www.outlineoffungi.org/), and these will be finally published in the biannual edition of the Outline of Fungi and fungus-like taxa. Comments on recent important taxonomic opinions on controversial topics will be included in the biannual outline. For example, 'to promote a more stable taxonomy in Fusarium given the divergences over its generic delimitation', or 'are there too many genera in the Boletales?' and even more importantly, 'what should be done with the tremendously diverse 'dark fungal taxa?' There are undeniable differences in mycologists' perceptions and opinions regarding species classification as well as the establishment of new species. Given the pluralistic nature of fungal taxonomy and its implications for species concepts and the nature of species, this consortium aims to provide a platform to better refine and stabilise fungal classification, taking into consideration views from different parties. In the future, a confidential voting system will be set up to gauge the opinions of all mycologists in the Consortium on important topics. The results of such surveys will be presented to the International Commission on the Taxonomy of Fungi (ICTF) and the Nomenclature Committee for Fungi (NCF) with opinions and percentages of votes for and against. Criticisms based on scientific evidence with regards to nomenclature, classifications, and taxonomic concepts will be welcomed, and any recommendations on specific taxonomic issues will also be encouraged; however, we will encourage professionally and ethically responsible criticisms of others' work. This biannual ongoing project will provide an outlet for advances in various topics of fungal classification, nomenclature, and taxonomic concepts and lead to a community-agreed classification scheme for the fungi and fungus-like taxa. Interested parties should contact the lead author if they would like to be involved in future outlines.
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| 7. |
- Wang, Fang, et al.
(författare)
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Emerging contaminants: A One Health perspective
- 2024
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Ingår i: Innovation. - 2666-6758. ; 5
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Forskningsöversikt (refereegranskat)abstract
- Environmental pollution is escalating due to rapid global development that often prioritizes human needs over planetary health. Despite global efforts to mitigate legacy pollutants, the continuous introduction of new substances remains a major threat to both people and the planet. In response, global initiatives are focusing on risk assessment and regulation of emerging contaminants, as demonstrated by the ongoing efforts to establish the UN's Intergovernmental Science-Policy Panel on Chemicals, Waste, and Pollution Prevention. This review identifies the sources and impacts of emerging contaminants on planetary health, emphasizing the importance of adopting a One Health approach. Strategies for monitoring and addressing these pollutants are discussed, underscoring the need for robust and socially equitable environmental policies at both regional and international levels. Urgent actions are needed to transition toward sustainable pollution management practices to safeguard our planet for future generations.
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| 8. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 9. |
- Ablikim, M., et al.
(författare)
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Measurement of the leptonic decay width of J/psi using initial state radiation
- 2016
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 761, s. 98-103
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Tidskriftsartikel (refereegranskat)abstract
- Using a data set of 2.93 fb(-1) taken at a center-of-mass energy of root s = 3.773 GeV with the BESIII detector at the BEPCII collider, we measure the process e(+) e(-) -> J/psi gamma -> mu(+)mu(-)gamma and determine the product of the branching fraction and the electronic width B-mu mu . Gamma(ee) = (333.4 +/- 2.5(stat) +/- 4.4(sys)) eV. Using the earlier-published BESIII result for B-mu mu = (5.973 +/- 0.007(stat) +/- 0.037(sys))%, we derive the J/psi electronic width Gamma(ee) = (5.58 +/- 0.05(stat) +/- 0.08(sys)) keV. (C) 2016 The Author(s). Published by Elsevier B.V.
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| 10. |
- Ariyawansa, Hiran A., et al.
(författare)
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Fungal diversity notes 111–252—taxonomic and phylogenetic contributions to fungal taxa
- 2015
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Ingår i: Fungal diversity. - : Springer Science and Business Media LLC. - 1560-2745 .- 1878-9129. ; 75, s. 27-274
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Tidskriftsartikel (refereegranskat)abstract
- This paper is a compilation of notes on 142 fungal taxa, including five new families, 20 new genera, and 100 new species, representing a wide taxonomic and geographic range. The new families, Ascocylindricaceae, Caryosporaceae and Wicklowiaceae (Ascomycota) are introduced based on their distinct lineages and unique morphology. The new Dothideomycete genera Pseudomassariosphaeria (Amniculicolaceae), Heracleicola, Neodidymella and P s e u d o m i c ros p h a e r i o p s i s ( D id y m e l l a c e a e ) , P s e u d o p i t h o m y c e s ( D i d y m o s p h a e r i a c e a e ) , Brunneoclavispora, Neolophiostoma and Sulcosporium (Halotthiaceae), Lophiohelichrysum (Lophiostomataceae), G a l l i i c o l a , Popul o c re s c e n t i a a nd Va g i c o l a (Phaeosphaeriaceae), Ascocylindrica (Ascocylindricaceae), E l o n g a t o p e d i c e l l a t a ( R o u s s o e l l a c e a e ) , Pseudoasteromassaria (Latoruaceae) and Pseudomonodictys (Macrodiplodiopsidaceae) are introduced. The newly described species of Dothideomycetes (Ascomycota) are Pseudomassariosphaeria bromicola (Amniculicolaceae), Flammeascoma lignicola (Anteagloniaceae), Ascocylindrica marina (Ascocylindricaceae) , Lembosia xyliae (Asterinaceae), Diplodia crataegicola and Diplodia galiicola ( B o t r yosphae r i a cea e ) , Caryospor a aquat i c a (Caryosporaceae), Heracleicola premilcurensis and Neodi dymell a thai landi cum (Didymellaceae) , Pseudopithomyces palmicola (Didymosphaeriaceae), Floricola viticola (Floricolaceae), Brunneoclavispora bambusae, Neolophiostoma pigmentatum and Sulcosporium thailandica (Halotthiaceae), Pseudoasteromassaria fagi (Latoruaceae), Keissleriella dactylidicola (Lentitheciaceae), Lophiohelichrysum helichrysi (Lophiostomataceae), Aquasubmersa japonica (Lophiotremataceae) , Pseudomonodictys tectonae (Macrodiplodiopsidaceae), Microthyrium buxicola and Tumidispora shoreae (Microthyriaceae), Alloleptosphaeria clematidis, Allophaeosphaer i a c y t i s i , Allophaeosphae r i a subcylindrospora, Dematiopleospora luzulae, Entodesmium artemisiae, Galiicola pseudophaeosphaeria, Loratospora(Basidiomycota) are introduced together with a new genus Neoantrodiella (Neoantrodiellaceae), here based on both morphology coupled with molecular data. In the class Agaricomycetes, Agaricus pseudolangei, Agaricus haematinus, Agaricus atrodiscus and Agaricus exilissimus (Agaricaceae) , Amanita m e l l e i a l b a , Amanita pseudosychnopyramis and Amanita subparvipantherina (Amanitaceae), Entoloma calabrum, Cora barbulata, Dictyonema gomezianum and Inocybe granulosa (Inocybaceae), Xerocomellus sarnarii (Boletaceae), Cantharellus eucalyptorum, Cantharellus nigrescens, Cantharellus tricolor and Cantharellus variabilicolor (Cantharellaceae), Cortinarius alboamarescens, Cortinarius brunneoalbus, Cortinarius ochroamarus, Cortinarius putorius and Cortinarius seidlii (Cortinariaceae), Hymenochaete micropora and Hymenochaete subporioides (Hymenochaetaceae), Xylodon ramicida (Schizoporaceae), Colospora andalasii (Polyporaceae), Russula guangxiensis and Russula hakkae (Russulaceae), Tremella dirinariae, Tremella graphidis and Tremella pyrenulae (Tremellaceae) are introduced. Four new combinations Neoantrodiella gypsea, Neoantrodiella thujae (Neoantrodiellaceae), Punctulariopsis cremeoalbida, Punctulariopsis efibulata (Punctulariaceae) are also introduced here for the division Basidiomycota. Furthermore Absidia caatinguensis, Absidia koreana and Gongronella koreana (Cunninghamellaceae), Mortierella pisiformis and Mortierella formosana (Mortierellaceae) are newly introduced in the Zygomycota, while Neocallimastix cameroonii and Piromyces irregularis (Neocallimastigaceae) ar e i n t roduced i n the Neocallimastigomycota. Reference specimens or changes in classification and notes are provided for Alternaria ethzedia, Cucurbitaria ephedricola, Austropleospora, Austropleospora archidendri, Byssosphaeria rhodomphala, Lophiostoma caulium, Pseudopithomyces maydicus, Massariosphaeria, Neomassariosphaeria and Pestalotiopsis montellica.
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| 11. |
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| 12. |
- Brenner, Darren R, et al.
(författare)
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Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia
- 2015
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 36:11, s. 1314-1326
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale genome-wide association studies (GWAS) have likely uncovered all common variants at the GWAS significance level. Additional variants within the suggestive range (0.0001> P > 5×10−8) are, however, still of interest for identifying causal associations. This analysis aimed to apply novel variant prioritization approaches to identify additional lung cancer variants that may not reach the GWAS level. Effects were combined across studies with a total of 33456 controls and 6756 adenocarcinoma (AC; 13 studies), 5061 squamous cell carcinoma (SCC; 12 studies) and 2216 small cell lung cancer cases (9 studies). Based on prior information such as variant physical properties and functional significance, we applied stratified false discovery rates, hierarchical modeling and Bayesian false discovery probabilities for variant prioritization. We conducted a fine mapping analysis as validation of our methods by examining top-ranking novel variants in six independent populations with a total of 3128 cases and 2966 controls. Three novel loci in the suggestive range were identified based on our Bayesian framework analyses: KCNIP4 at 4p15.2 (rs6448050, P = 4.6×10−7) and MTMR2 at 11q21 (rs10501831, P = 3.1×10−6) with SCC, as well as GAREM at 18q12.1 (rs11662168, P = 3.4×10−7) with AC. Use of our prioritization methods validated two of the top three loci associated with SCC (P = 1.05×10−4 for KCNIP4, represented by rs9799795) and AC (P = 2.16×10−4 for GAREM, represented by rs3786309) in the independent fine mapping populations. This study highlights the utility of using prior functional data for sequence variants in prioritization analyses to search for robust signals in the suggestive range.
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| 13. |
- Chen, Chao, et al.
(författare)
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Epigenome-wide gene-age interaction analysis reveals reversed effects of PRODH DNA methylation on survival between young and elderly early-stage NSCLC patients
- 2020
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 12:11, s. 10642-10662
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation changes during aging, but it remains unclear whether the effect of DNA methylation on lung cancer survival varies with age. Such an effect could decrease prediction accuracy and treatment efficacy. We performed a methylation-age interaction analysis using 1,230 early-stage lung adenocarcinoma patients from five cohorts. A Cox proportional hazards model was used to investigate lung adenocarcinoma and squamous cell carcinoma patients for methylation-age interactions, which were further confirmed in a validation phase. We identified one adenocarcinoma-specific CpG probe, cg14326354PRODH, with effects significantly modified by age (HRinteraction = 0.989; 95% CI: 0.986-0.994; P = 9.18×10-7). The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard (HRyoung = 2.44; 95% CI: 1.26-4.72; P = 8.34×10-3; HRelderly = 0.58; 95% CI: 0.42-0.82; P = 1.67×10-3). Moreover, there was an antagonistic interaction between low cg14326354PRODH methylation and elderly age (HRinteraction = 0.21; 95% CI: 0.11-0.40; P = 2.20×10-6). In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.
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| 14. |
- Chen, Chi-Kuan, et al.
(författare)
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Leukocyte cell-derived chemotaxin 2 antagonizes MET receptor activation to suppress hepatocellular carcinoma vascular invasion by protein tyrosine phosphatase 1B recruitment
- 2014
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Ingår i: Hepatology. - Hoboken : Wiley-Blackwell. - 0270-9139 .- 1527-3350. ; 59:3, s. 974-985
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Leukocyte cell-derived chemotoxin 2 (LECT2) has been shown to act as a tumor suppressor in hepatocellular carcinoma (HCC). However, the underlying mechanism has not yet been completely defined. Here, we employ a LECT2-affinity column plus liquid chromatography coupled with tandem mass spectrometry to identify LECT2-binding proteins and found that MET receptor strongly interacted with LECT2 protein. Despite the presence of hepatocyte growth factor, the LECT2 binding causes an antagonistic effect to MET receptor activation through recruitment of protein tyrosine phosphatase 1B. The antagonistic effect of LECT2 on MET activation also mainly contributes to the blockage of vascular invasion and metastasis of HCC. Furthermore, serial deletions and mutations of LECT2 showed that the HxGxD motif is primarily responsible for MET receptor binding and its antagonistic effects.CONCLUSION: These findings reveal a novel, specific inhibitory function of LECT2 in HCC by the direct binding and inactivation of MET, opening a potential avenue for treating MET-related liver cancer.
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| 15. |
- Chen, Sijie, et al.
(författare)
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Inverse Estimation of Soil Hydraulic Parameters in a Landslide Deposit Based on a DE-MC Approach
- 2022
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Ingår i: Water. - : MDPI AG. - 2073-4441. ; 14:22
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Tidskriftsartikel (refereegranskat)abstract
- Extreme rainfall is a common triggering factor of landslide disasters, for infiltration and pore water pressure propagation can reduce suction stress and shear strength at the slip surface. The subsurface hydrological model is an essential component in the early-warning system of rainfall-triggered landslides, whereas soil moisture and pore water pressure simulated by the Darcy–Richards equation could be significantly affected by uncertainties in soil hydraulic parameters. This study conducted an inverse analysis of in situ measured soil moisture in an earthquake-induced landslide deposit, and the soil hydraulic parameters were optimized with the Differential Evolution Markov chain Monte Carlo method (DE-MC). The DE-MC approach was initially validated with a synthetic numerical experiment to demonstrate its effectiveness in finding the true soil hydraulic parameters. Besides, the soil water characteristic curve (SWCC) and hydraulic conductivity function (HCF) described with optimized soil hydraulic parameter sets had similar shapes despite the fact that soil hydraulic parameters may be different. Such equifinality phenomenon in inversely estimated soil hydraulic parameters, however, did not affect the performance of simulated soil moisture dynamics in the synthetic numerical experiment. The application of DE-MC to a real case study of a landslide deposit also indicated satisfying model performance in terms of accurate match between the in situ measured soil moisture content and ensemble of simulations. In conclusion, based on the satisfying performance of simulated soil moisture and the posterior probability density function (PDF) of parameter sets, the DE-MC approach can significantly reduce uncertainties in specified prior soil hydraulic parameters. This study suggested the integration of the DE-MC approach with the Darcy–Richards equation for an accurate quantification of unsaturated soil hydrology, which can be an essential modeling strategy to support the early-warning of rainfall-triggered landslides.
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| 16. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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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.
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| 17. |
- Chien, Ming-Hsien, et al.
(författare)
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Vascular endothelial growth factor-C (VEGF-C) promotes angiogenesis by induction of COX-2 in leukemic cells via the VEGF-R3/JNK/AP-1 pathway.
- 2009
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 30:12, s. 2005-13
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Tidskriftsartikel (refereegranskat)abstract
- Vascular endothelial growth factor (VEGF)-C is recognized as a tumor lymphangiogenic factor based on the effects of activated VEGF-R3 on lymphatic endothelial cells. Many tumor cells express VEGF-R3 but the function of this receptor in tumor cells is largely unknown. It has been reported that the VEGF-C/VEGF-R3 axis is activated in subsets of leukemia patients. Herein, we have shown that VEGF-C induces angiogenic activity in the tube formation assay invitro and Matrigel plug assay in vivo by upregulating an angiogenic factor, cyclooxygenase-2 (COX-2), through VEGF-R3 in the human acute myeloid leukemia (AML) cell line, THP-1. COX-2 induction by VEGF-C was also observed in other VEGF-R3(+) human AML cell lines (U937 and HL60). Moreover, immunohistochemical analysis of bone marrow specimens of 37 patients diagnosed with AML revealed that VEGF-C expression in specimens was associated with the expression of COX-2 (P < 0.001). The manner by which signaling pathways transduced by VEGF-C is responsible for COX-2 upregulation was further investigated. Blocking the p42/44 mitogen-activated protein kinase (MAPK) pathway with the MAPK kinase inhibitor, PD 98059, failed to inhibit VEGF-C-mediated COX-2 expression. However, VEGF-C-induced COX-2 upregulation was effectively abolished by overexpression of dominant-negative c-Jun N-terminal kinase (JNK) or treatment with the JNK inhibitor, SP 600125. VEGF-C induced JNK-dependent nuclear translocation of c-Jun. Furthermore, chromatin immunoprecipitation and reporter assays revealed that VEGF-C enhanced c-Jun binding to the cyclic adenosine 3',5'-monophosphate-response element of the COX-2 promoter and induced COX-2 expression. In sum, the data herein highlight the pathogenic role of VEGF-C in leukemia via regulation of angiogenesis through upregulation of COX-2.
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| 18. |
- Feng, Dawei, et al.
(författare)
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Stable metal-organic frameworks containing single-molecule traps for enzyme encapsulation
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 5979-
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Tidskriftsartikel (refereegranskat)abstract
- Enzymatic catalytic processes possess great potential in chemical manufacturing, including pharmaceuticals, fuel production and food processing. However, the engineering of enzymes is severely hampered due to their low operational stability and difficulty of reuse. Here, we develop a series of stable metal-organic frameworks with rationally designed ultra-large mesoporous cages as single-molecule traps (SMTs) for enzyme encapsulation. With a high concentration of mesoporous cages as SMTs, PCN-333(Al) encapsulates three enzymes with record-high loadings and recyclability. Immobilized enzymes that most likely undergo single-enzyme encapsulation (SEE) show smaller Km than free enzymes while maintaining comparable catalytic efficiency. Under harsh conditions, the enzyme in SEE exhibits better performance than free enzyme, showing the effectiveness of SEE in preventing enzyme aggregation or denaturation. With extraordinarily large pore size and excellent chemical stability, PCN-333 may be of interest not only for enzyme encapsulation, but also for entrapment of other nanoscaled functional moieties.
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| 19. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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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.
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| 20. |
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| 21. |
- Han, Ning, et al.
(författare)
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Lowering the kinetic barrier via enhancing electrophilicity of surface oxygen to boost acidic oxygen evolution reaction
- 2024
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Ingår i: Matter. - 2590-2393 .- 2590-2385. ; 7:3, s. 1330-1343
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Tidskriftsartikel (refereegranskat)abstract
- The acidic oxygen evolution reaction (OER) is essential for many renewable energy conversion and storage technologies. However, the high energy required to break the strong covalent O-H bond of H2O in acidic media results in sluggish OER kinetics. Here, we report the critical role of iron in a new family of iron-containing yttrium ruthenate (Y2-xFexRu2O7-δ) electrocatalysts in highly increasing the electrophilicity of surface oxygen, leading to a significant reduction of the kinetics barrier by 33%, thus an exceptional OER mass activity of 1,021 A· up to 12.4 and 7.7 times that of Y2Ru2O7-δ and RuO2, respectively. Introducing iron reduces the Mulliken atomic charge on the O sites in the generated Ru-O-Fe structure, thereby facilitating the acid-base nucleophilic assault from H2O and reducing the free energy on the rate-determining step of OER. This work provides an effective strategy to reduce the kinetics barrier to achieve highly efficient and economic OER in acidic conditions.
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| 22. |
- Haycock, Philip C., et al.
(författare)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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Ingår i: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 23. |
- Hua, Kuo-Tai, et al.
(författare)
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N-α-acetyltransferase 10 protein suppresses cancer cell metastasis by binding PIX proteins and inhibiting Cdc42/Rac1 activity
- 2011
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Ingår i: Cancer Cell. - : Cell Press. - 1535-6108 .- 1878-3686. ; 19:2, s. 218-231
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Tidskriftsartikel (refereegranskat)abstract
- N-α-acetyltransferase 10 protein, Naa10p, is an N-acetyltransferase known to be involved in cell cycle control. We found that Naa10p was expressed lower in varieties of malignancies with lymph node metastasis compared with non-lymph node metastasis. Higher Naa10p expression correlates the survival of lung cancer patients. Naa10p significantly suppressed migration, tumor growth, and metastasis independent of its enzymatic activity. Instead, Naa10p binds to the GIT-binding domain of PIX, thereby preventing the formation of the GIT-PIX-Paxillin complex, resulting in reduced intrinsic Cdc42/Rac1 activity and decreased cell migration. Forced expression of PIX in Naa10-transfected tumor cells restored the migration and metastasis ability. We suggest that Naa10p functions as a tumor metastasis suppressor by disrupting the migratory complex, PIX-GIT- Paxillin, in cancer cells.
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| 24. |
- Ji, Xinyu, et al.
(författare)
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Epigenetic–smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients
- 2020
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Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 14:11, s. 2759-2774
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Tidskriftsartikel (refereegranskat)abstract
- Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30–2.09, P = 4.52 × 10−5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87–1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407TRIM27 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49LUAD vs 54.79LUSC, P = 1.03 × 10−19) and included a higher proportion of current smokers than LUAD patients (28.24%LUAD vs 34.09%LUSC, P = 0.037). cg05293407TRIM27 was significantly associated with overall survival only in NSCLC patients with medium–high pack-year of smoking (HR = 1.58, 95% CI: 1.26–1.96, P = 5.25 × 10−5). We conclude that cg05293407TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.
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| 25. |
- Ji, Xuemei, et al.
(författare)
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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
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| 26. |
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| 27. |
- Kuemmerli, Christoph, et al.
(författare)
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Impact of enhanced recovery protocols after pancreatoduodenectomy : meta-analysis
- 2022
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 109:3, s. 256-266
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This individual-patient data meta-analysis investigated the effects of enhanced recovery after surgery (ERAS) protocols compared with conventional care on postoperative outcomes in patients undergoing pancreatoduodenectomy. METHODS: The Cochrane Library, MEDLINE, Embase, Scopus, and Web of Science were searched systematically for articles reporting outcomes of ERAS after pancreatoduodenectomy published up to August 2020. Comparative studies were included. Main outcomes were postoperative functional recovery elements, postoperative morbidity, duration of hospital stay, and readmission. RESULTS: Individual-patient data were obtained from 17 of 31 eligible studies comprising 3108 patients. Time to liquid (mean difference (MD) -3.23 (95 per cent c.i. -4.62 to -1.85) days; P < 0.001) and solid (-3.84 (-5.09 to -2.60) days; P < 0.001) intake, time to passage of first stool (MD -1.38 (-1.82 to -0.94) days; P < 0.001) and time to removal of the nasogastric tube (3.03 (-4.87 to -1.18) days; P = 0.001) were reduced with ERAS. ERAS was associated with lower overall morbidity (risk difference (RD) -0.04, 95 per cent c.i. -0.08 to -0.01; P = 0.015), less delayed gastric emptying (RD -0.11, -0.22 to -0.01; P = 0.039) and a shorter duration of hospital stay (MD -2.33 (-2.98 to -1.69) days; P < 0.001) without a higher readmission rate. CONCLUSION: ERAS improved postoperative outcome after pancreatoduodenectomy. Implementation should be encouraged.
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| 28. |
- Lu, Lu, et al.
(författare)
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Crystal structure of tubulin folding cofactor A from Arabidopsis thaliana and its beta-tubulin binding characterization
- 2010
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Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 584:16, s. 9-3533
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Tidskriftsartikel (refereegranskat)abstract
- Microtubules are composed of polymerized alpha/beta-tubulin heterodimers. Biogenesis of assembly-competent tubulin dimers is a complex multistep process that requires sequential actions of distinct molecular chaperones and cofactors. Tubulin folding cofactor A (TFCA), which captures beta-tubulin during the folding pathway, has been identified in many organisms. Here, we report the crystal structure of Arabidopsis thaliana TFC A (KIESEL, KIS), which forms a monomeric three-helix bundle. The functional binding analysis demonstrated that KIS interacts with beta-tubulin in plant. Furthermore, mutagenesis studies indicated that the alpha-helical regions of KIS participate in beta-tubulin binding. Unlike the budding yeast TFC A, the two loop regions of KIS are not required for this interaction suggesting a distinct binding mechanism of TFC A to beta-tubulin in plants.
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| 29. |
- Pan, Dong, et al.
(författare)
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Dimension Engineering of High-Quality InAs Nanostructures on a Wafer Scale
- 2019
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Ingår i: Nano Letters. - : American Chemical Society (ACS). - 1530-6984 .- 1530-6992. ; 19:3, s. 1632-1642
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Tidskriftsartikel (refereegranskat)abstract
- Low-dimensional narrow-band-gap III-V semiconductors are key building blocks for the next generation of high-performance nanoelectronics, nanophotonics, and quantum devices. Realizing these various applications requires an efficient methodology that enables the material dimensional control during the synthesis process and the mass production of these materials with perfect crystallinity, reproducibility, low cost, and outstanding electronic and optoelectronic properties. Although advances in one- and two-dimensional narrow-band-gap III-V semiconductors synthesis, the progress toward reliable methods that can satisfy all of these requirements has been limited. Here, we demonstrate an approach that provides a precise control of the dimension of InAs from one-dimensional nanowires to wafer-scale free-standing two-dimensional nanosheets, which have a high degree of crystallinity and outstanding electrical and optical properties, using molecular-beam epitaxy by controlling catalyst alloy segregation. In our approach, two-dimensional InAs nanosheets can be obtained directly from one-dimensional InAs nanowires by silver-indium alloy segregation, which is much easier than the previously reported methods, such as the traditional buffering technique and select-area epitaxial growth. Detailed transmission electron microscopy investigations provide solid evidence that the catalyst alloy segregation is the origination of the InAs dimensional transformation from one-dimensional nanowires to two-dimensional nanosheets and even to three-dimensional complex crosses. Using this method, we find that the wafer-scale free-standing InAs nanosheets can be grown on various substrates including Si, MgO, sapphire, GaAs, etc. The InAs nanosheets grown at high temperature are pure-phase single crystals and have a high electron mobility and a long time-resolved terahertz kinetics lifetime. Our work will open up a conceptually new and general technology route toward the effective controlling of the dimension of the low-dimensional III-V semiconductors. It may also enable the low-cost fabrication of free-standing nanosheet-based devices on an industrial scale.
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| 30. |
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| 31. |
- Ren, Hong, et al.
(författare)
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Measurement report: Vertical distribution of biogenic and anthropogenic secondary organic aerosols in the urban boundary layer over Beijing during late summer
- 2021
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Ingår i: ATMOSPHERIC CHEMISTRY AND PHYSICS. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 21:17, s. 12949-12963
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Tidskriftsartikel (refereegranskat)abstract
- Secondary organic aerosol (SOA) plays a significant role in atmospheric chemistry. However, little is known about the vertical profiles of SOA in the urban boundary layer (UBL). This knowledge gap constrains the SOA simulation in chemical transport models. Here, the aerosol samples were synchronously collected at 8, 120, and 260m based on a 325m meteorological tower in Beijing from 15 August to 10 September 2015. Strict emission controls were implemented during this period for the 2015 China Victory Day parade. Here, we observed that the total concentration of biogenic SOA tracers increased with height. The fraction of SOA from isoprene oxidation increased with height, whereas the fractions of SOA from monoterpenes and sesquiterpenes decreased, and 2,3-dihydroxy-4-oxopentanoic acid (DHOPA), a tracer of anthropogenic SOA from toluene oxidation, also increased with height. The complicated vertical profiles of SOA tracers highlighted the need to characterize SOA within the UBL. The mass concentration of estimated secondary organic carbon (SOC) ranged from 341 to 673 ngC m(-3). The increase in the estimated SOC fractions from isoprene and toluene with height was found to be more related to regional transport, whereas the decrease in the estimated SOC from monoterpenes and sesquiterpene with height was more subject to local emissions. Emission controls during the parade reduced SOC by 4 %-35 %, with toluene SOC decreasing more than the other SOC. This study demonstrates that vertical distributions of SOA within the UBL are complex, and the vertical profiles of SOA concentrations and sources should be considered in field and modeling studies in the future.
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| 32. |
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| 33. |
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| 34. |
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| 35. |
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| 36. |
- Tang, Jinfeng, 1984, et al.
(författare)
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Comprehensive evaluation of the effectiveness on metals recovery and decontamination from MSWI fly ash by an integrating hydrometallurgical process in Guangzhou
- 2020
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 728
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Tidskriftsartikel (refereegranskat)abstract
- Municipal solid waste incineration (MSWI) fly ash generally contains substantial toxic elements which can be easily released into the environment, giving rise to serious environmental contaminations. In order to dispose of these harmful fly ashes safely and feasibly, an advanced and reliable strategy is needed. This work presented an integrated method designed for recycling of valuable copper (Cu) and zinc (Zn) through hydrochloric acid leaching and sequential extraction (using LIX 860N-I and Cyanex 572 for Cu and Zn as extractants, respectively) and clean-up of cadmium (Cd) and lead (Pb) in consequential waste effluent by adsorption with a versatile material – bundle-like hydroxyapatite (B-HAP). The method was applied in the pilot scale tests with recovery yields of 95% and 61% for Cu and Zn, respectively. Additionally, satisfied removal efficiencies of Cd and Pb (over 95% for both) were realized, reaching the acceptable emission level for Cd and Pb in China. A scenario based on the latest MSW data in 2018 in Guangzhou was assessed through the integrated pilot experiment. The evaluation demonstrates a reduction of a $ 20.8 million cost; over 48.2 k GJ of energy consumption and 5800 tons of CO2 emission can be reduced in 2018, comparing to that landfilled in hazardous waste sites, which reveals great benefits. The valuable metal recovery in combination with decontamination of toxic elements/substances as a complete and combined process gives a promising fly ash treatment strategy in future.
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| 37. |
- Tang, Jinfeng, 1984, et al.
(författare)
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Highly efficient recovery and clean-up of four heavy metals from MSWI fly ash by integrating leaching, selective extraction and adsorption
- 2019
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Ingår i: Journal of Cleaner Production. - : Elsevier BV. - 0959-6526. ; 234, s. 139-149
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Tidskriftsartikel (refereegranskat)abstract
- Municipal solid waste incineration (MSWI) fly ash contains significant amounts of heavy metals (e.g., Cd, Cu, Pb and Zn) and is therefore considered to be a hazardous waste requiring proper treatment prior to its disposal. In this work, an integrated hydrometallurgical process for treatment of MSWI fly ash was evaluated. Valuable metals, e.g. Cu and Zn, were first recovered by combining leaching and extraction sequentially. In the next step, the t removal of Cd and Pb from the remaining leachate using four types of iron-based adsorbents was evaluated. The leaching was optimized with respect to pH, leaching time and liquid to solid ratio. A test done under optimal conditions gave metal releases of 100% and 80% for Cu and Zn as well as 100% and 85% for Cd and Pb, respectively. The resulting leachate was contacted with organic phases based on kerosene containing the extractants LIX860N–I for Cu extraction and Cyanex 572 for Zn extraction in two consecutive steps. Efficient extractions were achieved, thus demonstrating that the combination of leaching and extraction can be successfully used for the recovery of Cu and Zn. Adsorption of heavy metal ions on various iron based sorbents to detoxify the aqueous effluent from the extraction showed good removal efficiency (more than 95%) for both Cd and Pb. The results of this study show that the proposed integrated process is a promising tool that can be used in the strategy for metal recovery and detoxification of MSWI fly ash.
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| 38. |
- Tang, Ting-Ting, et al.
(författare)
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Impaired thymic export and apoptosis contribute to regulatory T-cell defects in patients with chronic heart failure.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 6:9, s. e24272-
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Tidskriftsartikel (refereegranskat)abstract
- Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients.
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| 39. |
- Thomas, Minta, et al.
(författare)
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Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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| 40. |
- Thomas, Minta, et al.
(författare)
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Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.
- 2020
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Ingår i: American Journal of Human Genetics. - Cambridge : Elsevier BV. - 0002-9297 .- 1537-6605. ; 107:3, s. 432-444
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Tidskriftsartikel (refereegranskat)abstract
- Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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| 41. |
- Thomas, Minta, et al.
(författare)
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Response to Li and Hopper
- 2021
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 108:3, s. 527-529
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Tidskriftsartikel (refereegranskat)
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| 42. |
- Wan, Lu Ming, et al.
(författare)
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Heparanase Facilitates PMA-Induced Megakaryocytic Differentiation in K562 Cells via Interleukin 6/STAT3 Pathway
- 2020
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Ingår i: Thrombosis and Haemostasis. - : GEORG THIEME VERLAG KG. - 0340-6245 .- 2567-689X. ; 120:4, s. 647-657
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Tidskriftsartikel (refereegranskat)abstract
- Heparanase (HPSE) is an endo-beta-D-glucuronidase that cleaves heparan sulfate and hence participates in remodeling of the extracellular matrix, leading to release of cytokines that are immobilized by binding to heparan sulfate proteoglycans (HSPGs), and consequently activating signaling pathways. This function of HPSE is correlated to its expression level that is normally very low in majority of the tissues. Exceptionally, human platelets express high level of HPSE, suggesting a unique physiological role in this cell. Using K562 cell line, we found a progressive increase of HPSE during the megakaryocytic differentiation. Analysis of a series of megakaryocytic differentiation-related heparin-binding proteins (HBPs) in the cell culture medium revealed an exclusive positive correlation between the level of interleukin 6 (IL-6) and HPSE expression. IL-6 modulated megakaryocytic differentiation through activation of STAT3. Further, we demonstrated that overexpression of HPSE potentiates megakaryocytic differentiation, whereas elimination of HPSE led to a delayed differentiation. This function of HPSE is associated with its activity, as overexpression of inactive HPSE had no effect on IL-6 production and megakaryocytic differentiation. The role of HPSE is further supported by the observation in an umbilical cord blood CD34+ cells megakaryocytic differentiation model. Our data propose a novel role for HPSE in platelets production by a HPSE/IL-6/STAT3 positive feedback loop that specifically regulates megakaryocytes maturation.
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| 43. |
- Wang, Yufei, et al.
(författare)
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Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer
- 2014
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 46:7, s. 736-741
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Tidskriftsartikel (refereegranskat)abstract
- We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 x 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 x 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 x 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.
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| 44. |
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| 45. |
- Wei, Runmin, et al.
(författare)
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Metabotypes Related to Meat and Vegetable Intake Reflect Microbial, Lipid and Amino Acid Metabolism in Healthy People
- 2018
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Ingår i: Molecular Nutrition and Food Research. - : Wiley. - 1613-4125 .- 1613-4133. ; 62:21
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Tidskriftsartikel (refereegranskat)abstract
- Scope: The objective of this study is to develop a new methodology to identify the relationship between dietary patterns and metabolites indicative of food intake and metabolism. Methods and results: Plasma and urine samples from healthy Swiss subjects (n = 89) collected over two time points are analyzed for a panel of host–microbial metabolites using GC– and LC–MS. Dietary intake is evaluated using a validated food frequency questionnaire. Dietary pattern clusters and relationships with metabolites are determined using Non-Negative Matrix Factorization (NNMF) and Sparse Generalized Canonical Correlation Analysis (SGCCA). Use of NNMF allows detection of latent diet clusters in this population, which describes a high intake of meat or vegetables. SGCCA associates these clusters to i) diet-host microbial and lipid associated bile acid metabolism, and ii) essential amino acid metabolism. Conclusion: This novel application of NNMF and SGCCA allows detection of distinct metabotypes for meat and vegetable dietary patterns in a heterogeneous population. As many of the metabolites associated with meat or vegetable intake are the result of host–microbiota interactions, the findings support a role for microbiota mediating the metabolic imprinting of different dietary choices.
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| 46. |
- Wei, Xiao-Ping, et al.
(författare)
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Investigations on electronic, Fermi surface, Curie temperature and optical properties of Zr2CoAl
- 2017
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Ingår i: Journal of Solid State Chemistry. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0022-4596 .- 1095-726X. ; 247, s. 97-104
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Tidskriftsartikel (refereegranskat)abstract
- Using full-potential local-orbital minimum-basis along with spin-polarized relativistic Korringa-Kohn-Rostoker methods, we study the electronic, Fermi surface, Curie temperature and optical properties of Zr2CoAl alloy. The alloy with Li2AgSb and Cu2MnAl structures are compared in terms of magnetic properties, and the electronic structures in two structures are also discussed. According to the calculated electronic states, it finds that the Zr2CoAl with Li2AgSb structure is half-metallic ferromagnet with an integral magnetic moment of 2.00 mu(beta), meanwhile we also notice the d-d and p-d hybridizations are responsible for the formation of minority-spin gap, furthermore, the fat-bands are applied to discuss the mixture between d and p electrons in the vicinity of the Fermi level. The Fermi surfaces related to the valence bands are constructed, and it is found that the spin-up valence bands 26, 27 and 28 across the Fermi energy dominate the nature of electrons. By mapping the system onto a Heisenberg Hamiltonian, we obtain the exchange coupling parameters, and observe that the Zr(A)-Co(C) and Zr(A)-Zr(B) interactions provide a major contribution for exchange interactions. Based on the calculated exchange coupling parameters, the Curie temperature is estimated to be 287.86 K at equilibrium, and also the dependence of Curie temperature on lattice constant related to the tunable Curie temperature in Zr2CoAl alloy is studied. Finally, we report the optical properties of Zr2CoAl alloy, and present the photon energy dependence of the absorption, the optical conductivity and the loss function.
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| 47. |
- Wei, Yanfei, et al.
(författare)
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Stalled oligodendrocyte differentiation in IDH-mutant gliomas.
- 2023
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Ingår i: Genome medicine. - 1756-994X. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Roughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized.Using bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers.Genes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas.Our studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas.
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| 48. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 49. |
- Yi, Fan, et al.
(författare)
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Non-Fully Conjugated Dimerized Giant Acceptors with Different Alkyl-Linked Sites for Stable and 19.13 % Efficiency Organic Solar Cells
- 2024
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Ingår i: Angewandte Chemie International Edition. - : WILEY-V C H VERLAG GMBH. - 1433-7851 .- 1521-3773.
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Tidskriftsartikel (refereegranskat)abstract
- Achieving both high power conversion efficiency (PCE) and device stability is a major challenge for the practical development of organic solar cells (OSCs). Herein, three non-fully conjugated dimerized giant acceptors (named 2Y-sites, including wing-site-linked 2Y-wing, core-site-linked 2Y-core, and end-site-linked 2Y-end) are developed. They share the similar monomer precursors but have different alkyl-linked sites, offering the fine-tuned molecular absorption, packing, glass transition temperature, and carrier mobility. Among their binary active layers, D18/2Y-wing has better miscibility, leading to optimized morphology and more efficient charge transfer compared to D18/2Y-core and D18/2Y-end. Therefore, the D18/2Y-wing-based OSCs achieve a superior PCE of 17.73 %, attributed to enhanced photocurrent and fill factor. Furthermore, the D18/2Y-wing-based OSCs exhibit a balance of high PCE and improved stability, distinguishing them within the 2Y-sites. Building on the success of 2Y-wing in binary systems, we extend its application to ternary OSCs by pairing it with the near-infrared absorbing D18/BS3TSe-4F host. Thanks to the complementary absorption within 300-970 nm and further optimized morphology, ternary OSCs obtain a higher PCE of 19.13 %, setting a new efficiency benchmark for the dimer-derived OSCs. This approach of alkyl-linked site engineering for constructing dimerized giant acceptors presents a promising pathway to improve both PCE and stability of OSCs. Three new non-fully conjugated dimerized giant acceptors with different alkyl-linked sites are developed. Among them, wing-sited 2Y-wing has fine-tuned packing and better miscibility with donor, allowing to 19.13 % efficiency (which is the highest value among the devices with giant acceptors) and highly stable organic solar cells. image
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| 50. |
- Zhang, Ruyang, et al.
(författare)
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Independent Validation of Early-Stage Non-Small Cell Lung Cancer Prognostic Scores Incorporating Epigenetic and Transcriptional Biomarkers With Gene-Gene Interactions and Main Effects
- 2020
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Ingår i: Chest. - : Elsevier BV. - 0012-3692. ; 158:2, s. 808-819
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Tidskriftsartikel (refereegranskat)abstract
- Background: DNA methylation and gene expression are promising biomarkers of various cancers, including non-small cell lung cancer (NSCLC). Besides the main effects of biomarkers, the progression of complex diseases is also influenced by gene-gene (G×G) interactions. Research Question: Would screening the functional capacity of biomarkers on the basis of main effects or interactions, using multiomics data, improve the accuracy of cancer prognosis? Study Design and Methods: Biomarker screening and model validation were used to construct and validate a prognostic prediction model. NSCLC prognosis-associated biomarkers were identified on the basis of either their main effects or interactions with two types of omics data. A prognostic score incorporating epigenetic and transcriptional biomarkers, as well as clinical information, was independently validated. Results: Twenty-six pairs of biomarkers with G×G interactions and two biomarkers with main effects were significantly associated with NSCLC survival. Compared with a model using clinical information only, the accuracy of the epigenetic and transcriptional biomarker-based prognostic model, measured by area under the receiver operating characteristic curve (AUC), increased by 35.38% (95% CI, 27.09%-42.17%; P = 5.10 × 10–17) and 34.85% (95% CI, 26.33%-41.87%; P = 2.52 × 10–18) for 3- and 5-year survival, respectively, which exhibited a superior predictive ability for NSCLC survival (AUC3 year, 0.88 [95% CI, 0.83-0.93]; and AUC5 year, 0.89 [95% CI, 0.83-0.93]) in an independent Cancer Genome Atlas population. G×G interactions contributed a 65.2% and 91.3% increase in prediction accuracy for 3- and 5-year survival, respectively. Interpretation: The integration of epigenetic and transcriptional biomarkers with main effects and G×G interactions significantly improves the accuracy of prognostic prediction of early-stage NSCLC survival.
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