Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 466
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33170614

RESUMO

Microporous carbon has been widely known as a probable material to capture greenhouse gases. This work provides a facile synthesis of monodisperse biomass-derived microporous carbon spheres (CSs) for effective CO2 capture. The spheres were synthesized by a novel continuous microfluidic strategy from oil-in-water-in-oil ((O1/W2)/O2) emulsions. O1 nanodroplets could be self-assembled into the cores of micelles, which were formed by chitosan and surfactant F127 in the W2 phase through high-speed liquid-phase shearing. The obtained O1/W2 emulsion can be further sheared into a sphere by the O2 phase. After carbonization, nanodroplet-templated pores shrank to micropores and ultramicropores. The optimal sample showed the developed pore structure with a Brunauer-Emmett-Teller (BET) surface area of 576 m2/g and microporous volume of 0.22 cm3/g. Compared with O1 free CS, the dynamic adsorption capacity of CO2 was improved to 1.20 mmol/g from 0.42 mmol/g. The CO2 capture capacity, cycling stability, isosteric heats, and mass diffusion coefficient of CSs were evaluated as well. The results demonstrate that microporous CSs are promising candidates for CO2 capture with low cost and a green synthesis route, which was achieved via continuous microfluidic strategy using sustainable biomass chitosan as a carbon precursor and droplets as templates.

3.
Bioorg Chem ; 105: 104455, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33197847

RESUMO

Acute kidney injury (AKI) is associated with a strong inflammatory response, and inhibiting the response effectively prevents or ameliorates AKI. A series of novel arylpropionic esters were designed, synthesized and evaluated their biological activity in LPS-stimulated RAW264.7 cells. Novel arylpropionic esters bearing multi-functional groups showed significant anti-inflammatory activity, in which, compound 13b exhibited the most potent activity through dose-dependent inhibiting the production of nitric oxide (NO, IC50 = 3.52 µM), TNF-α and IL-6 (84.1% and 33.6%, respectively), as well as suppressing the expression of iNOS, COX-2 and TLR4 proteins. In C57BL/6 mice with cisplatin-induced AKI, compound 13b improved kidney function, inhibited inflammatory development, and reduced pathological damage of kidney tissues. In brief, this arylpropionic ester scaffold may be developed as anti-inflammatory agents.

4.
BMC Med Genet ; 21(Suppl 1): 176, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33092550

RESUMO

BACKGROUND: Previous studies indicated a strong association between hyperkalemia and lung squamous cell carcinomas (LSCC). However, the underlying mechanism is not fully understood so far. METHODS: Literature-based data mining was conducted to identify genes, molecule, and cell processes linked to both hyperkalemia and LSCC. Pathway analysis was performed to explore the interactive network, common-target network, and common-regulator network for both disorders. Then, a mega-analysis using 11 independent LSCC RNA expression datasets (358 LSCCs and 278 healthy controls) was performed to test the hypothesis that genes influencing hyperkalemia may also play roles in LSCC. RESULTS: There was a significant overlap between the genes implicated with both diseases (20 genes, p-value = 4.98e-15), which counts for 16% of all hyperkalemia genes (125 genes). Network analysis identified 12 molecules as common targets for hyperkalemia and LSCC, and 19 molecules as common regulators. Moreover, 19 molecules were identified within an interactive network, through which hyperkalemia and LSCC could exert influence on each other. In addition, meta-analysis identified one hyperkalemia promoter, SPP1, as a novel contributor for LSCC (LFC = 2.64; p-value = 2.81e-6). MLR analysis suggests geographical region as an influential factor for the expression levels of SPP1 in LSCC patients (p value = 0.036, 0.054). CONCLUSION: Our results showed that there was a common molecular basis for the pathology of both hyperkalemia and LSCC, and that genes promoting hyperkalemia might also play roles in the development of LSCC. However, this study did not suggest hypercalcemia as a casual factor for LSCC.

5.
Macromol Biosci ; : e2000226, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33094556

RESUMO

Biodegradable poly(ε-caprolactone) (PCL) scaffolds with adipose-derived mesenchymal stem cells (ADSCs) have been used in vascular regeneration studies. An evaluation method of the effect of PCL degradation products (DP) on the viability, stemness, and differentiation capacities of ADSCs is established. ADSCs are cultured in medium containing different concentrations of PCL DP before evaluating the effect of PCL DP on the cell apoptosis and proliferation, cell surface antigens, adipogenic and osteogenic differentiation capacities, and capacities to differentiate into endothelial cells and smooth muscle cells. The results demonstrate that PCL DP exceed 0.05 mg mL-1 may change the stemness and differentiation capacities of ADSCs. Therefore, to control the proper concentration of PCL DP is essential for ADSCs in vascular regeneration application.

6.
J Environ Sci (China) ; 97: 169-179, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32933732

RESUMO

Total contents of metals in soil and sediments on the Tibetan Plateau of China have been widely analyzed, but existing information is insufficient to effectively evaluate metal ecological risk because of a lack of metal bioavailability data. In this study, distribution, potential risk, mobility and bioavailability of metals in sediments of Lake Yamdrok Basin in Tibet of China were explored by combined use of total digestion, sequential extraction and the diffusive gradient in thin-films (DGT). Average concentrations of Cr, Ni, Cu, Zn, As, Cd and Pb in surface sediments were 31.25, 30.31, 22.00, 45.04, 31.32, 0.13 and 13.39 mg/kg, respectively. Higher levels of metals were found near the inflowing rivers. Residual form was dominant in Cr, Ni, Zn, Cd and Pb, and reducible form was dominant in As and Cd. Metals in surface sediments showed a low enrichment degree overall, but Cd and As had higher ecological risk levels than the other metals. Furthermore, there was a larger average proportion of exchangeable form of As (20.4%) and Cd (9.0%) than the other metals (1.7%-3.3%), implying their higher mobility and release risk. Average DGT-labile concentrations of Cr, Ni, Cu, Zn, As, Cd and Pb were 0.5, 4.5, 0.7, 25.1, 60.0, 0.22 and 1.0 µg/L, respectively. The DGT-labile As was significantly correlated with extractable As forms (p< 0.01), suggesting that extractable As in sediments acts as a "mobile pool" for bioavailable As. These results suggest potential risks of As and Cd, especially As, deserve further attention in Lake Yamdrok Basin.


Assuntos
Metais Pesados/análise , Poluentes Químicos da Água/análise , Disponibilidade Biológica , China , Monitoramento Ambiental , Sedimentos Geológicos , Lagos , Medição de Risco , Tibet
7.
J Neurochem ; 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32891068

RESUMO

Neuroinflammation is believed to play a primary role in the pathogenesis of most neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and schizophrenia. Currently, suitable in vitro neuroinflammation models for studying cellular interactions and inflammatory mechanisms at the neurovascular unit are still scarce. In this study, we established an experimentally flexible tri-culture neuroinflammation model combining murine microglial cells (N11), mouse neuroblastoma Nuro2A cell lines and brain microvascular endothelial MVEC(B3) cells in a transwell co-culture system stimulated with lipopolysaccharides. Neuroinflammation was induced in this tri-culture model as manifested by activated N11 cells via toll-like receptor 4, resulting in increased release of proinflammatory mediators (nitric oxide, interleukin-6 and tumour necrosis factor-α) through the activation of nuclear factor-κB signalling pathway. The released inflammatory cytokines from N11 in turn, damaged the tight junction in microvascular endothelial MVEC(B3) cells, increased permeability of endothelial barrier, and induced tau phosphorylation and up-regulated caspase-3 expression in mouse neuroblastoma Nuro2A cell lines, leading to neuroinflammation injury. In summary, this tri-culture inflammation model mimics the microenvironment, the cellular crosstalk and the molecular events that take place during neuroinflammation. It provides a robust in vitro model for studying neuroinflammation mechanisms and screening for potential therapeutics to treat various neurodegenerative diseases.

8.
Inorg Chem ; 59(18): 13067-13077, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32870670

RESUMO

Luminescent thermochromic materials with a dramatic shift of emission band under different temperatures are highly desirable in temperature sensing fields. However, the design of the synthesis of such compounds remains a great challenge. In this work, two new luminescent thermochromic silver iodides, (emIm)Ag3I4 (1) and (emIm)Ag2I3 (2) (emIm = 1-ethyl-3-methyl imidazole), have been synthesized under solvothermal conditions. Compound 1 features a [Ag3I4]- anionic layer, while compound 2 possesses an infinite [Ag2I3]- chain structure, both of which are charge balanced by emIm+ cations. Particularly, they display luminescent thermochromism with a significant wavelength shift of emission maximum with temperature change. They represent rare examples of infinite layered or chain silver iodides that show luminescent thermochromism. Furthermore, the results indicate that compounds 1 and 2 are promising wavelength-dependent luminescent thermometers.

9.
Arthritis Rheumatol ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32964675

RESUMO

OBJECTIVES: To understand the association between obesity-related traits and risk of rheumatoid arthritis (RA), we conducted genetic correlation analysis and two-sample Mendelian randomization (MR) study, using genome-wide genetic data based on >850,000 individuals of European ancestry. METHODS: We collected summary statistics from the hitherto largest GWAS conducted for body mass index (BMI, N=806,810), waist-to-hip ratio (WHR, N=697,734), WHR adjusted for BMI (WHRadjBMI, N=694,649) and RA (Ncase =14,361, Ncontrol =43,923). We conducted cross-trait linkage disequilibrium score regression and ρ-HESS to quantify genetic correlation between pairs of traits (causal overlap). For each obesity-related exposure, we utilized independent, genome-wide significant SNPs (p<5×10-9 ) as instruments to perform MR analysis (causal relationship). We interrogated the causal relationship in both the general population and in a sex-specific manner. We also performed sensitivity analyses to validify MR model assumptions. RESULTS: Despite a negligible overall genetic correlation between the three obesity-related traits and RA, we found significant local genetic correlation from several regions on chromosome 6 (positions 28-29M, 30-35M, 50-52M), highlighting a shared genetic basis. We further observed an increased risk of RA per SD increment (4.8 kg/m2 ) in genetically predicted BMI (OR=1.22; 95%CI: 1.09-1.37). The effect was consistent across sensitivity analyses and comparable between sexes (male: OR=1.22, 95% CI: 1.04-1.44; female: OR=1.19, 95%CI: 1.04-1.36). However, we did not find evidence supporting a causal role of either WHR (OR=0.98; 95%CI: 0.84-1.14) or WHRadjBMI (OR=0.90; 95%CI: 0.79-1.04) in RA. CONCLUSIONS: Genetically predicted BMI significantly increases RA risk. Future studies are needed to understand the biological mechanisms underlying such a link.

10.
Anal Chem ; 92(18): 12400-12406, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32794705

RESUMO

Horseradish peroxidase (HRP)-based assays feature particular interests because of the simple colorimetric readout. In these assays, 3,3',5,5'-tetramethylbenzidine (TMB) is the most widely used chromogenic substrates for HRP. The later research in nanozyme and DNAzyme also used TMB (the chosen substrate) because they are both HRP-mimics. It should be noted that the substrate of HRP is not just limited to TMB but, in fact, a broad range of benzidine derivatives. However, except decreased carcinogenicity due to tetrasubstitution of benzidine, the rationale for the chosen substrate TMB is not clear yet. Here, we addressed such a fundamental issue from the chemistry point of view. Nine benzidine derivatives featuring varied properties (different substitution groups and varied number of substitutions) were selected and investigated with four typical TMB-involved chromogenic systems. Among the existing benzidine substrates that are used for peroxidase-based assays, TMB exhibited the highest sensitivity, better color purity of colored products, and reasonable stability of oxidation products. Moreover, two tetrasubstituted benzidine derivatives other than TMB (4OCH3 and 2OCH32CH3) were synthesized for comparison. It turned out that the performances (sensitivity, color purity, and stability of the colored products) of TMB are still superior, thus chemically confirming its status of "the chosen substrate" in colorimetric assays.

11.
Diabetes Care ; 43(10): 2588-2596, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32788283

RESUMO

OBJECTIVE: Coffee may protect against multiple chronic diseases, particularly type 2 diabetes, but the mechanisms remain unclear. RESEARCH DESIGN AND METHODS: Leveraging dietary and metabolomic data in two large cohorts of women (the Nurses' Health Study [NHS] and NHSII), we identified and validated plasma metabolites associated with coffee intake in 1,595 women. We then evaluated the prospective association of coffee-related metabolites with diabetes risk and the added predictivity of these metabolites for diabetes in two nested case-control studies (n = 457 case and 1,371 control subjects). RESULTS: Of 461 metabolites, 34 were identified and validated to be associated with total coffee intake, including 13 positive associations (primarily trigonelline, polyphenol metabolites, and caffeine metabolites) and 21 inverse associations (primarily triacylglycerols [TAGs] and diacylglycerols [DAGs]). These associations were generally consistent for caffeinated and decaffeinated coffee, except for caffeine and its metabolites that were only associated with caffeinated coffee intake. The three cholesteryl esters positively associated with coffee intake showed inverse associations with diabetes risk, whereas the 12 metabolites negatively associated with coffee (5 DAGs and 7 TAGs) showed positive associations with diabetes. Adding the 15 diabetes-associated metabolites to a classical risk factor-based prediction model increased the C-statistic from 0.79 (95% CI 0.76, 0.83) to 0.83 (95% CI 0.80, 0.86) (P < 0.001). Similar improvement was observed in the validation set. CONCLUSIONS: Coffee consumption is associated with widespread metabolic changes, among which lipid metabolites may be critical for the antidiabetes benefit of coffee. Coffee-related metabolites might help improve prediction of diabetes, but further validation studies are needed.

12.
Mol Cell ; 79(6): 978-990.e5, 2020 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-32857953

RESUMO

Processing bodies (PBs) and stress granules (SGs) are prominent examples of subcellular, membraneless compartments that are observed under physiological and stress conditions, respectively. We observe that the trimeric PB protein DCP1A rapidly (within ∼10 s) phase-separates in mammalian cells during hyperosmotic stress and dissolves upon isosmotic rescue (over ∼100 s) with minimal effect on cell viability even after multiple cycles of osmotic perturbation. Strikingly, this rapid intracellular hyperosmotic phase separation (HOPS) correlates with the degree of cell volume compression, distinct from SG assembly, and is exhibited broadly by homo-multimeric (valency ≥ 2) proteins across several cell types. Notably, HOPS sequesters pre-mRNA cleavage factor components from actively transcribing genomic loci, providing a mechanism for hyperosmolarity-induced global impairment of transcription termination. Our data suggest that the multimeric proteome rapidly responds to changes in hydration and molecular crowding, revealing an unexpected mode of globally programmed phase separation and sequestration.


Assuntos
Endorribonucleases/genética , Precursores de RNA/genética , Estresse Fisiológico/genética , Transativadores/genética , Terminação da Transcrição Genética , Animais , Tamanho Celular , Sobrevivência Celular/genética , Humanos , Pressão Osmótica/fisiologia , Proteoma/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-32803594

RESUMO

Post-combustion flue gas desulfurization and denitrification technologies are essential in achieving the full compliance of fine particulate matter (PM2.5, aerodynamic diameter less than 2.5 µm) air quality standards by 2030 in China as sulfur dioxide (SO2) and nitrogen oxides (NOX) are the main precursors of PM2.5. Some studies have addressed the performance evaluation of desulfurization technology, but none included the water-soluble ions (sulfate (SO42-), nitrate (NO3-), etc.) as an indicator nor accounted for uncertainty involved. In this study, we present a multilevel fuzzy method that integrates the analytic hierarchy process with fuzzy theory, defines SO42-concentration as a new environmental indicator, and is supplemented with an uncertainly analysis and apply the method for the techno-economic and environmental evaluation of desulfurization and denitrification technologies in six typical enterprises (including two power plants and three industrial production plants and a waste incineration plant) in Chengdu, China. The evaluation shows that first, the fluctuating desulfurization rate and the dosage leads to changed ranking of the economic and technical secondary evaluation results, with the overall comprehensive evaluation ranks unchanged. Second, from the perspective of environmental protection agency and the public, if the environmental indicators are empowered, the lower the SO42-concentration of an enterprise, the better its evaluation ranking will be and vice versa. Third, if we re-empower from the perspective of the enterprise, under the condition that the technical feasibility is met and the environmental indicators are basically up to standard, the low-cost removing process is more likely to be the tendency of the enterprise. In summary, the findings of the study have led to the conclusions that (1) for the power industry, the integration of desulfurization, denitrification, and dedusting technologies should be promoted rigorously; (2) the non-power industry should continue the end-of-pipe treatment and environmental protection regulatory policies of the power industry; and (3) the energy industry structure should be optimized with enhanced end-of-pipe control technologies to achieve deep reduction of air pollutants.

15.
Huan Jing Ke Xue ; 41(4): 1676-1683, 2020 Apr 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608673

RESUMO

Based on the historical monitoring survey data from 2018 to 2019, the temporal and spatial distribution characteristics and main influencing factors of nitrogen and phosphorus in the overlying water in Daihai Lake were analyzed, and the differences of the temporal and spatial distribution were discussed. The results showed that the content of total nitrogen and total phosphorus in the overlying water was at a high level, especially the total nitrogen content was obviously higher than that in other lakes in China. The content of total nitrogen ranged from 3.29 mg·L-1 to 4.99 mg·L-1, with a mean value of (3.93±0.33) mg·L-1; the content of total phosphorus ranged from 0.063 mg·L-1 to 0.163 mg·L-1, with a mean value of (0.111±0.023) mg·L-1. In spring and summer, the content of total nitrogen and total phosphorus in the overlying deep water from the middle of the lake was significantly higher than that in the surrounding area. In autumn, the contents decreased from east to west, and in winter, the contents in the shallow water of the southern area were higher than that in the northern area. Nitrogen and phosphorus in the overlying water were mainly in the dissolved state, and the proportions of total dissolved nitrogen and phosphorus were 86.62% and 77.84%, respectively. The dissolved nitrogen was dominated by nitrate, whereas dissolved phosphorus was dominated by organic phosphorus. The concentration of lake water and the release of endogenous nutrient salts are the main reasons for the high total nitrogen and phosphorus. To prevent further deterioration of water quality, it is suggested to carry out endogenous treatment and ecological restoration in combination with engineering measures.

16.
BMC Bioinformatics ; 21(1): 298, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32650714

RESUMO

BACKGROUND: Even though we have established a few risk factors for metastatic breast cancer (MBC) through epidemiologic studies, these risk factors have not proven to be effective in predicting an individual's risk of developing metastasis. Therefore, identifying critical risk factors for MBC continues to be a major research imperative, and one which can lead to advances in breast cancer clinical care. The objective of this research is to leverage Bayesian Networks (BN) and information theory to identify key risk factors for breast cancer metastasis from data. METHODS: We develop the Markov Blanket and Interactive risk factor Learner (MBIL) algorithm, which learns single and interactive risk factors having a direct influence on a patient's outcome. We evaluate the effectiveness of MBIL using simulated datasets, and compare MBIL with the BN learning algorithms Fast Greedy Search (FGS), PC algorithm (PC), and CPC algorithm (CPC). We apply MBIL to learn risk factors for 5 year breast cancer metastasis using a clinical dataset we curated. We evaluate the learned risk factors by consulting with breast cancer experts and literature. We further evaluate the effectiveness of MBIL at learning risk factors for breast cancer metastasis by comparing it to the BN learning algorithms Necessary Path Condition (NPC) and Greedy Equivalent Search (GES). RESULTS: The averages of the Jaccard index for the simulated datasets containing 2000 records were 0.705, 0.272, 0.228, and 0.147 for MBIL, FGS, PC, and CPC respectively. MBIL, NPC, and GES all learned that grade and lymph_nodes_positive are direct risk factors for 5 year metastasis. Only MBIL and NPC found that surgical_margins is a direct risk factor. Only NPC found that invasive is a direct risk factor. MBIL learned that HER2 and ER interact to directly affect 5 year metastasis. Neither GES nor NPC learned that HER2 and ER are direct risk factors. DISCUSSION: The results involving simulated datasets indicated that MBIL can learn direct risk factors substantially better than standard Bayesian network learning algorithms. An application of MBIL to a real breast cancer dataset identified both single and interactive risk factors that directly influence breast cancer metastasis, which can be investigated further.


Assuntos
Algoritmos , Neoplasias da Mama/patologia , Teorema de Bayes , Feminino , Humanos , Teoria da Informação , Cadeias de Markov , Metástase Neoplásica , Fatores de Risco
17.
Eur J Med Chem ; 201: 112273, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32569925

RESUMO

Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with δ-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC50 = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (Ki = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis.

18.
Curr Microbiol ; 77(10): 2775-2782, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32533320

RESUMO

Leclercia sp. W6 and W17, which belong to the Enterobacteriaceae, were isolated from a stomach sample from a 78-year-old female gastric cancer patient, and genomic sequencing and analysis were performed. The genome of Leclercia sp. W6 consists of one chromosome with a size of 4,945,486 bp, while that of Leclercia sp. W17 contains one chromosome and two plasmids with a total size of 5,125,645 bp. Average nucleotide identity (ANI) calculations indicated that strains W6 and W17 exhibited similarities < 91.0% to other strains within the Enterobacteriaceae, except for six Leclercia strains. Phylogenomic analysis based on core-genome showed that strains W6 and W17 belong to the genus Leclercia, and phylogenetic analysis based on ANI values revealed that strains W6 and W17 formed an independent clade from those six Leclercia strains. Furthermore, comparative genomic analysis revealed that strains W6 and W17 had 5086 orthologous clusters (OCs) in their pan-genomes, and 59 exclusive OCs which were absent in their closest relatives. Genomic annotations revealed that the genomes of strains W6 and W17 encoded genes related to multidrug resistance clusters, multiple antibiotic resistance loci, and multidrug efflux pumps and had an identical urease gene cluster and a dissimilatory nitrate reduction pathway. Bioinformatic analyses indicated that strains W6 and W17 represented a novel species within the genus Leclercia. Genomic annotations revealed that these strains encoded genes related to multidrug resistance, nitrate reduction, and urease activity, which contribute to gastric malignant transformation. This will broaden our knowledge of the genetic mechanisms of the Enterobacteriaceae and help improve the clinical conditions of gastric cancer patients.

19.
Arthritis Res Ther ; 22(1): 154, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571398

RESUMO

Rheumatoid arthritis (RA) is a multifactorial chronic autoimmune disease, which involves a complex interplay of environmental triggers and genetic components in its etiology. It has been shown that genetics only explain about half of the liability to develop RA, leaving a large room for non-genetic factors. Indeed, several environmental exposures including smoking, drinking, obesity, and dietary patterns (and more) have been identified to be associated with RA risk, yet the observational nature of conventional epidemiological investigation hampers causal inference, as the validity of results could be plagued by measurement error, confounding, and/or reverse causality. Mendelian randomization (MR) is a novel statistical approach that uses genetic variants as instrumental variables (IV) to make causal inferences from observational data. The current genetic discoveries in the many heritable and modifiable human complex traits have provided an exceptional opportunity to evaluate a putative causal relationship between exposure and outcome in the absence of high-quality experimental or intervention studies, through a MR design. In the current review, we detail the contribution of MR studies hitherto conducted for modifiable environmental exposures with the risk of RA to understand the role of these factors in RA pathogenesis. We start with a brief introduction of each study, follow by a summarization of shortcomings and conclude by highlighting future directions. The application of MR design in the field of rheumatology remains limited. Only a few MR studies have examined the causal roles of vitamin D, cigarette smoking, alcohol consumption, coffee consumption, and levels of education in RA, where, no consistent evidence for a causal relationship has been found. Most studies lacked sensitivity analyses to verify MR model assumptions and to guarantee the validity of results. Almost all studies are likely to bias the strength of association towards a null value, since they used IVs from earlier GWAS(s) of exposures with a small sample size (i.e., few genetic markers). As the magnitudes of GWAS expand rapidly, additional trait-associated loci have been discovered. Incorporating these loci would greatly improve the strength of genetic instruments, as well as both the accuracy and precision of MR estimates. To conclude, there is a need for an update and a huge space for improvement of future MR studies in RA.

20.
Cancer Genet ; 245: 35-41, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32585585

RESUMO

BACKGROUND: Alcohol consumption has been found to increase the risk of breast cancer in observation studies, yet it remains unknown if alcohol is related to other hormone-dependent cancers such as ovarian cancer. No Mendelian randomization (MR) studies have been performed to assess a potential causal relationship between alcohol use and risk of breast and ovarian cancer. METHODS: We aim to determine if alcohol consumption is causally associated with the risk of female hormone-dependent cancers, by using summary level genetic data from the hitherto largest genome-wide association studies (GWAS) conducted on alcohol consumption (N=~1.5 million individuals), breast (Ncase=122,977) and ovarian cancer (Ncase=25,509). We examined three different alcohol intake exposures, drinks per week (drinks/week), alcohol use disorder (AUD) and age-adjusted alcohol use disorder identification test (AUDIT-C), to reflect the general and harmful drinking behavior. We constructed updated and stronger instruments using ninety-nine drinks/week-related SNPs, nine AUD-related SNPs and thirteen AUDIT-C-related SNPs and estimated the causal relationship applying several two-sample MR methods. RESULTS: We did not find any evidence to support for a causal association between alcohol consumption and risk of breast cancer [ORdrinks/week=1.01 (0.85-1.21), P=0.89; ORAUD=1.04 (95%CI: 0.89-1.21), P=0.62; ORAUDIT-C=1.07 (0.90-1.28), P=0.44]; neither with its subtypes including ER-positive and ER-negative breast cancer, using any of the three alcohol-related exposures. For ovarian cancer, however, we identified a reduced risk with alcohol consumption, where a borderline significance was found for AUDIT-C but not for drinks/week or AUC [ORdrinks/week=0.83 (0.63-1.10), P=0.19; ORAUD=0.92 (0.83-1.01), P=0.08; ORAUDIT-C=0.83 (0.71-0.97), P=0.02]. The effect attenuated to null excluding SNPs associated with potential confounders [ORdrinks/week=0.81(0.53-1.21), P=0.31; ORAUD=0.96(0.78-1.18), P=0.68; ORAUDIT-C=0.89(0.68-1.16), P=0.38]. CONCLUSION: We do not find any compelling evidence in support for a causal relationship between genetically predicted alcohol consumption and risk of breast or ovarian cancer, consistent across three different alcohol-related exposures. Future MR studies validating our findings are needed, when large-scale alcohol consumption GWAS results become available.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA