| 1. |
- Sampson, Joshua N., et al.
(author)
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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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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Journal article (peer-reviewed)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 2. |
- Smedby, Karin E., et al.
(author)
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GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma
- 2011
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:4, s. e1001378-
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Journal article (peer-reviewed)abstract
- Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL-associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, P-combined= 2x10(-21)) located 962 bp away from rs10484561 (r(2)< 0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012: ORadjusted = 0.70, P-adjusted= 4x10(-12); rs10484561: ORadjusted = 1.64, P-adjusted= 5x10(-15)). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL-associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, P-combined = 1.4x10(-7)). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
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| 3. |
- Sun, Jianteng, et al.
(author)
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Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) in biosolids from municipal wastewater treatment plants in China
- 2013
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In: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 90:9, s. 2388-2395
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Journal article (peer-reviewed)abstract
- Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) along with methoxylated polybrominated diphenyl ethers (MeO-PBDEs) have been frequently identified as natural compounds in marine environment and also assumed as metabolites of PBDEs. In the present study, nine OH-PBDE, nine MeO-PBDE and 10 PBDE congeners were studied in the sewage sludge collected from 36 municipal wastewater treatment plants (WWTPs) in 27 cities of China. The results suggest that OH-PBDEs and PBDEs are ubiquitous in sewage sludge in China, however, methoxylated PBDEs were not detectable. Composition profiles of detected OH-PBDE congeners were different depending on the sampling location. ΣOH-PBDEs in WWTPs sludge ranged from 0.04 to 2.24 ng g-1 dry weight (mean: 0.35 ng g-1 dry weight). The total amount of the two most prominent congeners (6-OH-BDE-47+2'-OH-BDE-68) accounted for about 53.3-100% of the sum of all six identified congeners. A significant linear relationship was found between 6-OH-BDE-47 and 2'-OH-BDE-68. A distinct geographical distribution of ΣOH-PBDEs was observed with greater concentrations of OH-PBDEs at coastal areas than inland regions in China.
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| 4. |
- Wang, Longwei, et al.
(author)
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A Molybdenum Disulfide Nanozyme with Charge-Enhanced Activity for Ultrasound-Mediated Cascade-Catalytic Tumor Ferroptosis
- 2023
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In: Angewandte Chemie - International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 62:11
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Journal article (peer-reviewed)abstract
- The deficient catalytic activity of nanozymes and insufficient endogenous H2O2 in the tumor microenvironment (TME) are major obstacles for nanozyme-mediated catalytic tumor therapy. Since electron transfer is the basic essence of catalysis-mediated redox reactions, we explored the contributing factors of enzymatic activity based on positive and negative charges, which are experimentally and theoretically demonstrated to enhance the peroxidase (POD)-like activity of a MoS2 nanozyme. Hence, an acidic tumor microenvironment-responsive and ultrasound-mediated cascade nanocatalyst (BTO/MoS2@CA) is presented that is made from few-layer MoS2 nanosheets grown on the surface of piezoelectric tetragonal barium titanate (T-BTO) and modified with pH-responsive cinnamaldehyde (CA). The integration of pH-responsive CA-mediated H2O2 self-supply, ultrasound-mediated charge-enhanced enzymatic activity, and glutathione (GSH) depletion enables out-of-balance redox homeostasis, leading to effective tumor ferroptosis with minimal side effects.
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| 5. |
- Xu, HT, et al.
(author)
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Abnormal beta-catenin and reduced axin expression are associated with poor differentiation and progression in non-small cell lung cancer
- 2006
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In: American Journal of Clinical Pathology. - 0002-9173 .- 1943-7722. ; 125:4, s. 534-541
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Journal article (peer-reviewed)abstract
- We studied the expression of axin and beta-catenin and their relation to clinicopathologic factors in 100 non-small cell lung cancers (NSCLCs) by immunohistochemical analysis. The mutation in exon 3 of the beta-catenin gene was examined by polymerase chain reaction and direct sequencing. Preserved axin expression was significantly higher in well- and moderately differentiated NSCLC samples than in poorly differentiated ones. Reduced membranous expression of beta-catenin was shown in 80 cases, whereas 26 cases had aberrant nuclear expression. Poor differentiation and lymph node metastasis were associated significantly with reduced beta-catenin expression. Lower axin expression was related significantly to higher nuclear beta-catenin expression. However, this study failed to detect any exon 3 mutation in the beta-catenin gene in the 100 NSCLC samples. We conclude that reduced beta-catenin and axin expression might predict poor differentiation in NSCLC. Reduced axin expression, but not mutation in exon 3, might be an important explanation for the abnormal beta-catenin expression in NSCLC.
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| 6. |
- Yang, Wenxing, et al.
(author)
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Surface-Ligand "Liquid" to "Crystalline" Phase Transition Modulates the Solar H2 Production Quantum Efficiency of CdS Nanorod/Mediator/Hydrogenase Assemblies
- 2020
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In: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 12:31, s. 35614-35625
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Journal article (peer-reviewed)abstract
- This study reports how the length of capping ligands on a nanocrystal surface affects its interfacial electron transfer (ET) with surrounding molecular electron acceptors, and consequently, impact the H-2 production of a biotic-abiotic hybrid artificial photosynthetic system. Specifically, we study how the H-2 production efficiency of a hybrid system, combining CdS nanorods (NRs), [NiFe] hydrogenase, and redox mediators (propyl-bridged 2,2'-bipyridinium, PDQ(2+)), depends on the alkyl chain length of mercaptocarboxylate ligands on the NR surface. We observe a minor decrease of the quantum yield for H-2 production from 54 +/- 6 to 43 +/- 2% when varying the number of methylene units in the ligands from 2 to 7. In contrast, an abrupt decrease of the yield was observed from 43 +/- 2 to 4 +/- 1% when further increasing n from 7 to 11. ET studies reveal that the intrinsic ET rates from the NRs to the electron acceptor PDQ(2+) are all within 10(8) -10(9) s(-1) regardless of the length of the capping ligands. However, the number of adsorbed PDQ(2+) molecules on NR surfaces decreases dramatically when n >= 10, with the saturating number changing from 45 +/- 5 to 0.3 +/- 0.1 for n = 2 and 11, respectively. These results are not consistent with the commonly perceived exponential dependence of ET rates on the ligand length. Instead, they can be explained by the change of the accessibility of NR surfaces to electron acceptors from a disordered "liquid" phase at n < 7 to a more ordered "crystalline" phases at n > similar to 7. These results highlight that the order of capping ligands is an important design parameter for further constructing nanocrystal/molecular assemblies in broad nanocrystal-based applications.
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| 7. |
- Zhang, Haiyan, et al.
(author)
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Polychlorinated naphthalenes in sewage sludge from wastewater treatment plants in China
- 2014
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In: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 490, s. 555-560
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Journal article (peer-reviewed)abstract
- Polychlorinated naphthalenes (PCNs) were nominated as persistent organic pollutants candidate in the Stockholm Convention in 2011. In this study, the profiles, concentrations and spatial distributions of PCNs were analyzed in 30 sewage sludge samples from wastewater treatment plants (WWTPs) in China. Concentrations of Σ75PCNs in sludge samples were in the range of 1.05-10.9 ng/g dry weight (dw) with a mean value of 3.98 ng/g dw. The predominant homologues in the sludge were mono- to tetra-CNs, accounting for approximately 85% of total PCNs. The total toxic equivalent quantities (TEQs) of dioxin-like PCN congeners ranged from 0.04 to 2.28 pg/g dw with a mean value of 0.36 pg/g dw, which were lower than the maximum permissible TEQ concentrations in sludge for land application in China. Levels of PCNs and TEQs in sludge were relatively higher in samples from highly industrialized and developed cities in eastern China, implying a possible link between PCN contamination and the local economic development, but more studies are warranted to corroborate this. Industrial sources might be important contributors of PCNs to sewage sludge in China.
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| 8. |
- Bjurstöm, Helen, et al.
(author)
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GABA, a natural immunomodulator of T lymphocytes.
- 2008
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In: Journal of Neuroimmunology. - : Elsevier BV. - 1872-8421 .- 0165-5728. ; 205:1-2, s. 44-50
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Journal article (peer-reviewed)abstract
- gamma-aminobutyric acid (GABA) is the main neuroinhibitory transmitter in the brain. Here we show that GABA in the extracellular space may affect the fate of pathogenic T lymphocytes entering the brain. We examined in encephalitogenic T cells if they expressed functional GABA channels that could be activated by the low (nM-1 microM), physiological concentrations of GABA present around neurons in the brain. The cells expressed the alpha1, alpha4, beta2, beta3, gamma1 and delta GABAA channel subunits and formed functional, extrasynaptic-like GABA channels that were activated by 1 microM GABA. 100 nM and higher GABA concentrations decreased T cell proliferation. The results are consistent with GABA being immunomodulatory.
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| 9. |
- Cao, Huiming, et al.
(author)
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Effect of Enterohepatic Circulation on the Accumulation of Per- and Polyfluoroalkyl Substances : Evidence from Experimental and Computational Studies
- 2022
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:5, s. 3214-3224
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Journal article (peer-reviewed)abstract
- The pharmacokinetic characteristics of per- and polyfluoroalkyl substances (PFAS) affect their distribution and bioaccumulation in biological systems. The enterohepatic circulation leads to reabsorption of certain chemicals from bile back into blood and the liver and thus influences their elimination, yet its influence on PFAS bioaccumulation remains unclear. We explored the role of enterohepatic circulation in PFAS bioaccumulation by examining tissue distribution of various PFAS in wild fish and a rat model. Computational models were used to determine the reabsorbed fractions of PFAS by calculating binding affinities of PFAS for key transporter proteins of enterohepatic circulation. The results indicated that higher concentrations were observed in blood, the liver, and bile compared to other tissues for some PFAS in fish. Furthermore, exposure to a PFAS mixture on the rat model showed that the reabsorption phenomenon appeared during 8-12 h for most long-chain PFAS. Molecular docking calculations suggest that PFAS can bind to key transporter proteins via electrostatic and hydrophobic interactions. Further regression analysis adds support to the hypothesis that binding affinity of the apical sodium-dependent bile acid transporter is the most important variable to predict the human half-lives of PFAS. This study demonstrated the critical role of enterohepatic circulation in reabsorption, distribution, and accumulation of PFAS.
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| 10. |
- Cao, Huiming, et al.
(author)
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Screening of Potential PFOS Alternatives To Decrease Liver Bioaccumulation : Experimental and Computational Approaches
- 2019
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In: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 53:5, s. 2811-2819
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Journal article (peer-reviewed)abstract
- Perfluorooctanesulfonate (PFOS) is a persistent organic pollutant with significant bioaccumulation potential in liver tissues. Exposure to PFOS could cause increase of liver weight, induce adenomas of the liver, and cause hepatomegaly. Alternatives of PFOS might be designed and synthesized that have significantly lower liver bioaccumulation. In this study, we conducted animal exposure experiments to investigate tissue accumulations of 14 per- and polyfluoroalkyl substances. Correlation analysis demonstrated that accumulation of the compounds in rat liver had strong correlations with their binding affinities of liver fatty acid binding protein (LFABP). Thus, we combined a quantitative structure-activity relationship model with molecular dynamics (MD) simulations to develop computational models to predict the LFABP binding affinities of two newly synthesized alternatives, perfluorodecalin-2-sulfonic acid and N-diperfluorobutanoic acid. The binding characteristics of the PFOS alternatives for LFABP were elaborated to explore how the different structural modifications of molecules influenced the underlying binding mechanisms. Subsequent animal experiments demonstrated that the binding free energy calculations based on the MD simulations provided a good indicator to reflect the relative degree of liver accumulation of the PFOS alternatives in the same exposure doses and durations. Our findings from the combination of experimental exposure and computational model can provide helpful information to design potential alternatives of PFOS with weak LFABP binding capability and low liver accumulation.
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