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1.
Cancer Cell ; 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-36113475

RESUMO

We present the largest whole-genome sequencing (WGS) study of non-small cell lung cancer (NSCLC) to date among 6,004 individuals of Chinese ancestry, coupled with 23,049 individuals genotyped by SNP array. We construct a high-quality haplotype reference panel for imputation and identify 20 common and low-frequency loci (minor allele frequency [MAF] ≥ 0.5%), including five loci that have never been reported before. For rare loss-of-function (LoF) variants (MAF < 0.5%), we identify BRCA2 and 18 other cancer predisposition genes that affect 5.29% of individuals with NSCLC, and 98.91% (181 of 183) of LoF variants have not been linked previously to NSCLC risk. Promoter variants of BRCA2 also have a substantial effect on NSCLC risk, and their prevalence is comparable with BRCA2 LoF variants. The associations are validated in an independent case-control study including 4,410 individuals and a prospective cohort study including 23,826 individuals. Our findings not only provide a high-quality reference panel for future array-based association studies but depict the whole picture of rare pathogenic variants for NSCLC.

2.
Cancer Biol Med ; 2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36047776

RESUMO

OBJECTIVE: Although our previous genome-wide association study (GWAS) has identified chromosome 2q33.1 as a susceptibility locus for non-small cell lung cancer (NSCLC), the causal variants remain unclear. The aims of this study were to identify the causal variants in 2q33.1 and to explore their biological functions in NSCLC. METHODS: CCK-8, colony formation, EdU incorporation, Transwell, and quantitative real-time polymerase chain reaction assays were applied to examine variant function. The tumor xenograft model was used to examine variant function in vivo. Caspase-8 activity assays, flow cytometry analysis, and co-immunoprecipitation assays were used to explore the molecular mechanism. RESULTS: The missense variant rs3769823 (A > G), which caused the substitution of lysine with arginine at amino acid 14 in caspase-8 (caspase-8K14R), was identified as a potential causal candidate in 2q33.1. Compared with the wild type caspase-8 (caspase-8WT) group, the caspase-8K14R group had higher expression of caspase-8 and cleaved caspase-8. Caspase-8K14R inhibited the proliferation and metastasis of human lung cancer cell lines in vitro. Moreover, caspase-8K14R repressed lung cancer cell growth in vivo. Mechanistically, caspase-8K14R was more sensitive than caspase-8WT to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis and showed higher binding of caspase-8 and FADD. CONCLUSIONS: These results suggested that rs3769823 is the causal variant in chromosome 2q33.1 and is involved in an apoptosis pathway, leading to a decreased risk of NSCLC.

3.
Polymers (Basel) ; 14(17)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36080591

RESUMO

Thermophysical molding (TPM) treatments can significantly improve the surface properties of thick wood veneer. To understand the effects of TPM treatments on the surface properties of thick veneer, the roughness, contact angles, and chemical changes were determined. The results indicated that the roughness of the thick veneer decreased when the temperature and the duration increased. The contact angles decreased when the temperature increased, resulting in better wettability. X-ray photoelectron spectroscopic (XPS) results provided information about the significant chemical changes in the surface with different TPM temperatures of 160-190 °C and durations of 5-11 min. Increases in temperature and duration increased the C content and decreased the O content during the treatment process. The most significant changes in the thick veneer that resulted from increasing the temperature and the duration were the increase in the C1 component and the decrease in the C2 component. Thus, the oxygen to carbon (O/C) ratio decreased and the ratio of aromatic carbon to aliphatic carbon (C1/C2) notably increased with the increasing TPM temperature. The TPM duration slightly affected the O/C ratio, but it had a stronger linear relation with the C1/C2 ratio. Additionally, the C1/C2 ratio and the O/C ratio had a linear statistical relationship with the initial wettability. These findings could provide useful information for the future utilization of thick veneers treated with TPM.

4.
Environ Res ; 215(Pt 2): 114305, 2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36096164

RESUMO

Previous epidemiological studies have reported that prenatal exposure to metals might have influence on fetal growth. Most studies assessed the effect of individual metals, while the investigation on the relationship between multiple metal exposure and fetal growth is sparse. The objective of the present study is to assess the joint impact of metal mixtures on fetal growth during pregnancy. A total of 1275 maternal-infant pairs from the Jiangsu Birth Cohort (JBC) Study were included to investigate the effect of maternal metal exposure on fetal biometry measures at 22-24, 30-32, and 34-36 weeks of gestation. Lead (Pb), arsenic (As), cadmium (Cd), mercury (Hg), chromium (Cr), vanadium(V), thallium (Tl) and barium (Ba) were measured by inductively coupled plasma mass spectrometry (ICP-MS) in maternal urine samples collected in the first trimester. We used general linear models and restricted cubic splines to test dose-response relationships between single metals and fetal growth. The weighted quantile sum (WQS) models were then applied to evaluate the overall effect of all these metals. We observed inverse associations of exposure to Pb, V and Cr with estimated fetal weight (EFW) at 34-36 weeks of gestation. Notably, maternal exposure to metal mixtures was significantly associated with reduced EFW at 34-36 weeks of gestation after adjusting for some covariates and confounders (aß -0.05 [95% CI: 0.09, -0.01], P = 0.023), and this association was mainly driven by Cr (30.41%), Pb (23.92%), and Tl (15.60%). These findings indicated that prenatal exposure to metal mixtures might impose adverse effects on fetal growth.

5.
Drug Dev Res ; 2022 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-36031759

RESUMO

Acute myeloid leukemia (AML) is a hematologic malignancy with increased lethality. We focused on elucidating the role of Neratinib, a tyrosine kinase inhibitor, in the progression of AML and identify the potential mechanisms. Upon the treatment of Neratinib, autophagy suppressor 3-methyladenine (3-MA) and ferroptosis stimulator Erastin, the viability and proliferation of HL-60 cells were evaluated by cell counting kit-8 and 5-Ethynyl-20-Deoxyuridine staining assays. A flow cytometer was to observe cell cycle and apoptosis. Production of reactive oxygen species (ROS) was tested via 2,7-dichlorodihydrofluorescein diacetate  assay. Additionally, malondialdehyde (MDA) content and Fe2+ activity were examined with commercial kits. LC3-II expression was examined by using immunofluoresence staining. Western blot analysis ascertained the expression of proliferation, apoptosis, ferroptosis and autophagy-associated proteins. It was noted that Neratinib notably mitigated cell viability and proliferation, cut down Ki67 and proliferating cell nuclear antigen expression. Moreover, Neratinib hindered cell cycle at G0/G1 phase whereas exacerbated apoptosis. ROS, MDA and Fe2+ activities were elevated by Neratinib, coupled with the reduced glutathione peroxidase 4, ferritin heavy chain 1 expression and enhanced acyl-CoA synthetase long-chain family member 4 expression. Furthermore, Neratinib promoted autophagy of HL-60 cells, evidenced by raised LC3-II, ATG5, Beclin1 expression and lessened p62 expression. Importantly, 3-MA eased the impacts of Neratinib on cell ferroptosis, proliferation and apoptosis, which were offset by further administration of Erastin. To conclude, Neratinib could suppress proliferation and promote apoptosis of HL-60 cells through autophagy-dependent ferroptosis.

6.
Nutrients ; 14(16)2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36014876

RESUMO

(1) Background: The association between metabolic obesity phenotypes and incident lung cancer (LC) remains unclear. (2) Methods: Based on the combination of baseline BMI categories and metabolic health status, participants were categorized into eight groups: metabolically healthy underweight (MHUW), metabolically unhealthy underweight (MUUW), metabolically healthy normal (MHN), metabolically unhealthy normal (MUN), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obesity (MHO), and metabolically unhealthy obesity (MUO). The Cox proportional hazards model and Mendelian randomization (MR) were applied to assess the association between metabolic obesity phenotypes with LC risk. (3) Results: During a median follow-up of 9.1 years, 3654 incident LC patients were confirmed among 450,482 individuals. Compared with participants with MHN, those with MUUW had higher rates of incident LC (hazard ratio (HR) = 3.24, 95% confidence interval (CI) = 1.33-7.87, p = 0.009). MHO and MHOW individuals had a 24% and 18% lower risk of developing LC, respectively (MHO: HR = 0.76, 95% CI = 0.61-0.95, p = 0.02; MHO: HR = 0.82, 95% CI = 0.70-0.96, p = 0.02). No genetic association of metabolic obesity phenotypes and LC risk was observed in MR analysis. (4) Conclusions: In this prospective cohort study, individuals with MHOW and MHO phenotypes were at a lower risk and MUUW were at a higher risk of LC. However, MR failed to reveal any evidence that metabolic obesity phenotypes would be associated with a higher risk of LC.


Assuntos
Neoplasias Pulmonares , Síndrome Metabólica , Obesidade Metabolicamente Benigna , Bancos de Espécimes Biológicos , Índice de Massa Corporal , Humanos , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Síndrome Metabólica/complicações , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Obesidade Metabolicamente Benigna/complicações , Obesidade Metabolicamente Benigna/epidemiologia , Sobrepeso/complicações , Fenótipo , Estudos Prospectivos , Fatores de Risco , Magreza/complicações , Reino Unido/epidemiologia
7.
Gene ; 844: 146824, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-35995117

RESUMO

BACKGROUND: Cervical cancer is one of the major cancers that threaten the health of women. CircRNA is an important factor in the regulation of cancer development and progression. The role of circRNA in cervical cancer is less well studied. The aim of this study was to explore the mechanism of circRNA effects on cervical cancer using circRNA-seq technology to study the expression profile data of 9 pairs of primary cervical cancer and paracancerous tissues. METHOD: DESeq2 was used to analyse differentially expressed circRNA and mRNA in cervical cancer and paracancerous tissues. MiRanda and TargetScan are used to predict miRNAs that interact with circRNAs and mRNAs and to construct circRNA-miRNA-mRNA regulatory networks. KEGG and GO are used for functional annotation of differentially expressed genes. TIDE, TIMER2.0 was used to assess the status of the tumour immune microenvironment in cervical cancer. GEPIA2 was used to validate the results of differential expression analysis. RESULTS: We eventually obtained 22 differentially expressed circRNAs (7 up-regulated and 15 down-regulated) and 1834 differentially expressed genes (613 up-regulated and 1221 down-regulated). The results of the KEGG analysis showed that the differentially expressed genes were mainly enriched in cell cycle and cancer-related signalling pathways. The new circRNA: circZNF208 was identified to promote fibroblast proliferation by interfering with its downstream hsa-miR-324-3p regulating four downstream genes LPHN3. The level of fibroblast infiltration is implicated in the poor prognosis of cervical cancer. CONCLUSION: We have identified a novel circRNA: circZNF208 that can interfere with fibroblast proliferation in cervical cancer through a ceRNA regulatory network, thereby promoting fibroblast proliferation in cervical cancer and affecting the prognosis of cancer patients.


Assuntos
MicroRNAs , Neoplasias do Colo do Útero , Proliferação de Células/genética , Feminino , Fibroblastos/metabolismo , Redes Reguladoras de Genes , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Microambiente Tumoral/genética , Neoplasias do Colo do Útero/genética
8.
Artigo em Inglês | MEDLINE | ID: mdl-35977051

RESUMO

OBJECTIVE: To identify novel metabolic markers for future type 2 diabetes (T2D) in Chinese individuals of Han ethnicity and to determine whether the combined effect of metabolic and genetic markers improves the accuracy of prediction models containing clinical factors. METHODS: A nested case-control study containing 220 incident T2D and 220 age- and sex- matched controls from normoglycemic Chinese individuals of Han ethnicity was conducted within the Wuxi Non-Communicable Disease cohort with a 12-year follow-up. Metabolic profiling detection was performed by high-performance liquid chromatography‒mass spectrometry (HPLC‒MS) by an untargeted strategy. Twenty single nucleotide polymorphisms (SNPs) associated with type 2 diabetes were genotyped using the Iplex Sequenom MassARRAY platform. Machine learning methods were used to identify metabolites associated with future T2D risk. RESULTS: We found that abnormal levels of five metabolites were associated with an increased risk of future type 2 diabetes: riboflavin, cnidioside A, 2-methoxy-5-(1H-1, 2, 4- triazol-5- yl)- 4-(trifluoromethyl) pyridine, 7-methylxanthine and mestranol. The genetic risk score (GRS) based on 20 SNPs was significantly associated with T2D risk (OR = 1.35, 95% CI: 1.08-1.70 per SD). The area under the receiver operating characteristic curve (AUC) was greater for the model containing metabolites, GRS, and clinical traits than for the model containing clinical traits only (0.960 vs. 0.798, P = 7.91×10-16). CONCLUSION: In individuals with normal fasting glucose levels, abnormal levels of 5 metabolites were associated with future T2D. The combination of newly discovered metabolic markers and genetic markers could improve the prediction of incident T2D.

9.
Microb Biotechnol ; 15(9): 2337-2350, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35849816

RESUMO

Pseudomonas sp. strain 166 was isolated from soil samples from Changbai Mountains. A novel bacteriocin PA166 from Pseudomonas sp. 166 was purified using ammonium sulfate, dextran gel chromatography column and Q-Sepharose column chromatography successively. The molecular mass of bacteriocin PA166 was found to be 49.38 kDa by SDS-PAGE and liquid chromatography-mass spectrometry (MS)/MS. Bacteriocin PA166 showed stability at a wide range of pH (2-10), and thermal stability (40, 60, 80 and 100°C). The bacteriocin PA166 antimicrobial activity was slightly inhibited by Ca2+ , K+ and Mg2+ . The minimum bactericidal concentrations of bacteriocin PA166 against five Pasteurella multocida strains ranged from 2 to 8 µg ml-1 . Bacteriocin PA166 showed low cytotoxicity and a higher treatment index (TI = 82.51). Fluorescence spectroscopy indicated that bacteriocin PA166 destroyed the cell membrane to exert antimicrobial activity. In summary, bacteriocin PA166 had strong antibacterial activity, high TI and low toxicity, and hence could serve as a potential clinical therapeutic drug.


Assuntos
Bacteriocinas , Antibacterianos/química , Bacteriocinas/farmacologia , Eletroforese em Gel de Poliacrilamida , Peso Molecular , Pseudomonas
10.
Front Vet Sci ; 9: 945491, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35903134

RESUMO

The Rcs phosphorelay system is present in many members of the Enterobacteriaceae. The aim of this study was to illustrate the possible mechanisms of eugenol on ultimate targets of Klebsiella pneumoniae (K. pneumoniae) Rcs phosphorelay, rcsB, and impact on biofilm formation. The minimum inhibitory concentration (MIC) of eugenol against K. pneumoniae KP1 and KP1 ΔrcsB strain was determined using the 2-fold micro-dilution method. Biofilm was measured by crystal violet staining. Transcriptome sequencing was performed to investigate sub-MIC eugenol on K. pneumoniae, and gene expression at mRNA level was analyzed by RT-qPCR. In vitro biofilm formation test and molecular docking were used to evaluate the effect of eugenol and to predict potential interactions with RcsB. MicroScale Thermophoresis (MST) was conducted for further validation. MIC of eugenol against K. pneumoniae KP1 and KP1 ΔrcsB strain was both 200 µg/ml. Transcriptome sequencing and RT-qPCR results indicated that rpmg, degP, rnpA, and dapD were downregulated, while rcsB, rcsD, rcsA, yiaG, and yiaD were upregulated in the eugenol-treated group. ΔrcsB exhibited a weakened biofilm formation capacity. Additional isopropyl-ß-d-thiogalactoside (IPTG) hinders biofilm formation, while sub-MIC eugenol could promote biofilm formation greatly. Docking analysis revealed that eugenol forms more hydrophobic bonds than hydrogen bonds. MST assay also showed a weak binding affinity between eugenol and RcsB. These results provide significant evidence that rcsB plays a key role in K. pneumoniae biofilm formation. Sub-MIC eugenol facilitates biofilm formation to a large extent instead of inhibiting it. Our findings reveal the potential risk of natural anti-biofilm ingredients at sub-MIC to treat drug-resistance bacteria.

11.
Int J Chron Obstruct Pulmon Dis ; 17: 1601-1612, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35860812

RESUMO

Introduction: Chronic obstructive pulmonary disease (COPD) and lung cancer often coexist, but its pathophysiology and genomics features are still unclear. Methods: In this study, we retrospectively collected lung cancer concomitant COPD (COPD-LC) and non-COPD lung cancer (non-COPD-LC) patients, who performed next generation sequencing (NGS) and had clinicopathological information simultaneously. The COPD-LC data from the TCGA cohort were collected to conduct further analysis. Results: A total of 51 COPD-LC patients and 88 non-COPD-LC patients were included in the study. Clinicopathological analysis showed that proportion of male gender, older age, and smoking patients were all substantially higher in COPD-LC group than in non-COPD-LC group (all P<0.01). Comparing the genomic data of the two groups in our cohort, COPD-LC had higher mutation frequency of LRP1B (43% vs 9%, P = 0.001), EPHA5 (24% vs 1%, P = 0.002), PRKDC (14% vs 1%, P = 0.039), PREX2 (14% vs 0%, P = 0.012), and FAT1 (14% vs 0%, P = 0.012), which had a relationship with improved tumor immunity. Immunotherapy biomarker of PD-L1 positive expression (62.5% vs 52.0%, P = 0.397) and tumor mutation burden (TMB, median TMB: 7.09 vs 2.94, P = 0.004) also were higher in COPD-LC. In addition, RNA data from TCGA further indicated tumor immunity increased in COPD-LC. Whereas, COPD-LC had lower frequency of EGFR mutation (19% vs 50%, P = 0.013) and EGFR mutant COPD-LC treated with EGFR-TKI had worse progression-free survival (PFS) (HR = 3.52, 95% CI: 1.27-9.80, P = 0.01). Conclusion: In this retrospective study, we first explored molecular features of COPD-LC in a Chinese population. Although COPD-LC had lower EGFR mutant frequency and worse PFS with target treatment, high PD-L1 expression and TMB indicated these patients may benefit from immunotherapy.


Assuntos
Neoplasias Pulmonares , Doença Pulmonar Obstrutiva Crônica , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Receptores ErbB/genética , Humanos , Masculino , Mutação , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Estudos Retrospectivos
12.
Int J Cancer ; 2022 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-35904854

RESUMO

Characterization of metabolic perturbation prior to hepatocellular carcinoma (HCC) may deepen the understanding of causal pathways and identify novel biomarkers for early prevention. We conducted two 1:1 matched nested case-control studies (108 and 55 pairs) to examine the association of plasma metabolome (profiled using LC-MS) with the risk of HCC based on two prospective cohorts in China. Differential metabolites were identified by paired t tests and orthogonal partial least-squares discriminant analysis (OPLS-DA). Weighted gene coexpression network analysis (WGCNA) was performed to classify metabolites into modules for identifying biological pathways involved in hepatocarcinogenesis. We assessed the risk predictivity of metabolites using multivariable logistic regression models. Among 612 named metabolites, 44 differential metabolites were identified between cases and controls, including 12 androgenic/progestin steroid hormones, 8 bile acids, 10 amino acids, 6 phospholipids, and 8 others. These metabolites were associated with HCC in the multivariable logistic regression analyses, with odds ratios ranging from 0.19 (95% confidence interval [CI]: 0.11-0.35) to 5.09 (95% CI: 2.73-9.50). WGCNA including 612 metabolites showed 8 significant modules related to HCC risk, including those representing metabolic pathways of androgen and progestin, primary and secondary bile acids, and amino acids. A combination of 18 metabolites of independent effects showed the potential to predict HCC risk, with an AUC of 0.87 (95% CI: 0.82-0.92) and 0.86 (95% CI: 0.80-0.93) in the training and validation sets, respectively. In conclusion, we identified a panel of plasma metabolites that could be implicated in hepatocellular carcinogenesis and have the potential to predict HCC risk.

13.
Front Endocrinol (Lausanne) ; 13: 884851, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35846339

RESUMO

Objectives: Adequate maternal thyroid hormone availability is crucial for fetal neurodevelopment, but the role of maternal mild hypothyroidism is not clear. We aim to investigate the association of maternal mild hypothyroidism with neurodevelopment in infants at 1 year of age among TPOAb-negative women. Methods: The present study was conducted within the Jiangsu Birth Cohort. A total of 793 mother-infant pairs were eligible for the present study. Maternal thyroid function was assessed by measuring serum thyroid-stimulating hormone, free thyroxine, and thyroid peroxidase antibodies. Neurodevelopment of infants was assessed by using the Bayley Scales of Infant and Toddler Development third edition screening test (Bayley-III screening test). Results: In the multivariate adjusted linear regression analyses, infants of women with subclinical hypothyroidism and isolated hypothyroxinemia were associated with decreased receptive communication scores (ß = -0.68, p = 0.034) and decreased gross motor scores (ß = -0.83, p = 0.008), respectively. Moreover, infants of women with high-normal TSH concentrations (3.0-4.0 mIU/L) and low FT4 concentrations were significantly associated with lower gross motor scores (ß = -1.19, p = 0.032), while no differences were observed in infants when the mothers had a high-normal TSH concentration and normal FT4 levels. Conclusions: Maternal subclinical hypothyroidism is associated with decreased receptive communication scores in infants at 1 year of age. In addition, maternal TSH concentration greater than 4.0 mIU/L and maternal isolated hypothyroxinemia are associated with impaired gross motor ability of infants, especially in infants of women with high-normal TSH concentrations (3.0-4.0 mIU/L).


Assuntos
Hipotireoidismo , Tiroxina , Feminino , Humanos , Hipotireoidismo/complicações , Lactente , Estudos Prospectivos , Testes de Função Tireóidea , Hormônios Tireóideos , Tireotropina
14.
BMC Med ; 20(1): 203, 2022 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-35658861

RESUMO

BACKGROUND: Body mass index (BMI) has been found to be associated with a decreased risk of non-small cell lung cancer (NSCLC); however, the effect of BMI trajectories and potential interactions with genetic variants on NSCLC risk remain unknown. METHODS: Cox proportional hazards regression model was applied to assess the association between BMI trajectory and NSCLC risk in a cohort of 138,110 participants from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. One-sample Mendelian randomization (MR) analysis was further used to access the causality between BMI trajectories and NSCLC risk. Additionally, polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between BMI trajectories and genetic variants in NSCLC risk. RESULTS: Compared with individuals maintaining a stable normal BMI (n = 47,982, 34.74%), BMI trajectories from normal to overweight (n = 64,498, 46.70%), from normal to obese (n = 21,259, 15.39%), and from overweight to obese (n = 4,371, 3.16%) were associated with a decreased risk of NSCLC (hazard ratio [HR] for trend = 0.78, P < 2×10-16). An MR study using BMI trajectory associated with genetic variants revealed no significant association between BMI trajectories and NSCLC risk. Further analysis of PRS showed that a higher GWAS-identified PRS (PRSGWAS) was associated with an increased risk of NSCLC, while the interaction between BMI trajectories and PRSGWAS with the NSCLC risk was not significant (PsPRS= 0.863 and PwPRS= 0.704). In GWIA analysis, four independent susceptibility loci (P < 1×10-6) were found to be associated with BMI trajectories on NSCLC risk, including rs79297227 (12q14.1, located in SLC16A7, Pinteraction = 1.01×10-7), rs2336652 (3p22.3, near CLASP2, Pinteraction = 3.92×10-7), rs16018 (19p13.2, in CACNA1A, Pinteraction = 3.92×10-7), and rs4726760 (7q34, near BRAF, Pinteraction = 9.19×10-7). Functional annotation demonstrated that these loci may be involved in the development of NSCLC by regulating cell growth, differentiation, and inflammation. CONCLUSIONS: Our study has shown an association between BMI trajectories, genetic factors, and NSCLC risk. Interestingly, four novel genetic loci were identified to interact with BMI trajectories on NSCLC risk, providing more support for the aetiology research of NSCLC. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov , NCT01696968 .


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Índice de Massa Corporal , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Estudos de Coortes , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Sobrepeso/complicações , Fatores de Risco
15.
Int J Neurosci ; : 1-9, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35645223

RESUMO

BACKGROUND: Leukoaraiosis (LA) is a disease manifested by demyelination and gliosis in white matter, mainly caused by cerebrovascular diseases. LA is closely related to the expression level of inflammatory factors, oxidative stress, and vascular endothelial dysfunction in patients. Vitamin E may play antioxidant and anti-inflammatory roles in various diseases. We aimed to explore the effects of vitamin E on the patients with LA. METHODS: A total of 160 patients with LA were recruited in this research. Matrix metalloproteinase-9 (MMP-9), MMP-2, C-reactive protein (CRP), complement 3 (C3), C4, nitric oxide (NO), and endothelin (ET) levels were evaluated by ELISA. The Mini-Mental State Examination (MMSE) was used for cognitive impairment assessment. Superoxide dismutase (SOD) and malondialdehyde (MDA) concentrations were analyzed by commercial kits. RESULTS: The levels of CRP, C3, and C4 significantly decreased in the serum of LA patients after the administration of vitamin E. The levels of MMP-2 and MPP-9 showed a significant decrease in the administered group. Vitamin E significantly inhibited the expression of MDA, while significantly upregulated the expression of SOD. Significant increase in NO production and significant downregulation of ET expression occurred in vitamin E groups. MMSE score was significantly increased by vitamin E. CONCLUSION: In conclusion, vitamin E showed effects on the alleviation of inflammatory response, oxidative stress, endothelial damage, and cognitive dysfunction. Thus, vitamin E could be a potential drug for the clinical treatment of LA patients.

16.
Clin Chem ; 68(8): 1094-1107, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35708664

RESUMO

BACKGROUND: The roles of individual and co-regulated lipid molecular species in the development of type 2 diabetes (T2D) and mediation from metabolic risk factors remain unknown. METHODS: We conducted profiling of 166 plasma lipid species in 2 nested case-control studies within 2 independent cohorts of Chinese adults, the Dongfeng-Tongji and the Jiangsu non-communicable disease cohorts. After 4.61 (0.15) and 7.57 (1.13) years' follow-up, 1039 and 520 eligible participants developed T2D in these 2 cohorts, respectively, and controls were 1:1 matched to cases by age and sex. RESULTS: We found 27 lipid species, including 10 novel ones, consistently associated with T2D risk in the 2 cohorts. Differential correlation network analysis revealed significant correlations of triacylglycerol (TAG) 50:3, containing at least one oleyl chain, with 6 TAGs, at least 3 of which contain the palmitoyl chain, all downregulated within cases relative to controls among the 27 lipids in both cohorts, while the networks also both identified the oleyl chain-containing TAG 50:3 as the central hub. We further found that 13 of the 27 lipids consistently mediated the association between adiposity indicators (body mass index, waist circumference, and waist-to-height ratio) and diabetes risk in both cohorts (all P < 0.05; proportion mediated: 20.00%, 17.70%, and 17.71%, and 32.50%, 28.73%, and 33.86%, respectively). CONCLUSIONS: Our findings suggested notable perturbed co-regulation, inferred from differential correlation networks, between oleyl chain- and palmitoyl chain-containing TAGs before diabetes onset, with the oleyl chain-containing TAG 50:3 at the center, and provided novel etiological insight regarding lipid dysregulation in the progression from adiposity to overt T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Lipidômica , Adiposidade , Adulto , China , Humanos , Obesidade , Estudos Prospectivos , Fatores de Risco , Triglicerídeos
17.
Biol Reprod ; 107(1): 358-367, 2022 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-35686808

RESUMO

Well-designed birth cohorts are able to estimate prevalence/distribution of various health events/outcomes, and to link early-life origins with adult health and function. The past two decades have seen a surge in the establishment of new birth cohorts and their accompanying research. We discussed distinct designs of current birth cohort studies, reviewed their achievements, and highlighted insights obtained from birth cohort studies, as well as challenges we are facing. Birth cohort studies are providing increasing opportunities to identify determining factors for short- and long-term health, yielding substantial evidence to uncover biological mechanisms of diseases and phenotypes, and providing further insights for public health. Dynamic monitoring, accurate measurements, long-term follow-ups, and collaborative efforts are warranted in new birth cohorts to elucidate the nature of life course relationships in contemporary generation.


Assuntos
Coorte de Nascimento , Estudos de Coortes , Humanos
18.
Cancer Commun (Lond) ; 42(7): 609-626, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35730068

RESUMO

BACKGROUND: Epigenetic alterations have been shown to contribute immensely to human carcinogenesis. Dynamic and reversible N6-methyladenosine (m6A) RNA modification regulates gene expression and cell fate. However, the reasons for activation of KIAA1429 (also known as VIRMA, an RNA methyltransferase) and its underlying mechanism in lung adenocarcinoma (LUAD) remain largely unexplored. In this study, we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD. METHODS: Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase. The in vitro and in vivo functions of KIAA1429 were investigated. Transcriptome sequencing, methylated RNA immunoprecipitation sequencing (MeRIP-seq), m6A dot blot assays and RNA immunoprecipitation (RIP) were performed to confirm the modified gene mediated by KIAA1429. RNA stability assays were used to detect the half-life of the target gene. RESULTS: Copy number amplification drove higher expression of KIAA1429 in LUAD, which was correlated with poor overall survival. Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD. Mechanistically, the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays. We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner. Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA, leading to enhanced YTH m6A RNA binding protein 2 (YTHDF2, the m6A "reader")-dependent BTG2 mRNA stability and promoted the expression of BTG2; thus, participating in the tumorigenesis of LUAD. CONCLUSIONS: Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis, which may provide a novel view on the targeted molecular therapy of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Proteínas Imediatamente Precoces , Neoplasias Pulmonares , Proteínas de Ligação a RNA , Proteínas Supressoras de Tumor , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Carcinogênese/genética , Amplificação de Genes , Humanos , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Metiltransferases/genética , Metiltransferases/metabolismo , Prognóstico , RNA , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
19.
Am J Obstet Gynecol ; 2022 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-35667419

RESUMO

BACKGROUND: It has been well recognized that antenatal administration of dexamethasone to pregnant women at risk of preterm delivery may markedly accelerate fetal maturation and reduce the risk of adverse perinatal outcomes in their preterm infants, particularly for births before 34 weeks of gestation. Since 2015, antenatal corticosteroid administration has been extended beyond 34 weeks of gestation by clinical guidelines, as it might have beneficial effects on fetal maturation and perinatal outcomes. However, concerns regarding the potential influence of antenatal corticosteroid treatment on offspring neurodevelopment have been raised. OBJECTIVE: This study aimed to investigate whether maternal antenatal corticosteroid administration was associated with neurodevelopment in infants at 1 year of age. STUDY DESIGN: In this prospective and longitudinal birth cohort study, women were followed up throughout gestation, and their infants underwent a Bayley Scales of Infant and Toddler Development, Third Edition, screening test at 1 year of age between December 2018 and September 2020. Finally, 1609 pregnant women and 1759 infants were included in the current study. Using a generalized linear mixed model, we examined the association between antenatal corticosteroid exposure and infant neurodevelopment in cognitive, receptive communication, expressive communication, fine motor, and gross motor functions. RESULTS: Of the 1759 infants eligible for this study, 1453 (82.6%) were singletons. A total of 710 infants were exposed to antenatal corticosteroids, among whom 415 were dexamethasone exposed and 483 were prednisone exposed. Dexamethasone was prescribed most often in late pregnancy, whereas prednisone was often used before 8 weeks of gestation among women who conceived through assisted reproductive technology. Compared with those who had no exposure, antenatal corticosteroid exposure was associated with an increased risk of infants being noncompetent in the cognitive development domain after adjusting for conventional risk factors (adjusted risk ratio, 1.53; 95% confidence interval, 1.08-2.18; P=.017). For medication-specific exposure, those exposed vs not exposed to antenatal dexamethasone were 1.62-fold (95% confidence interval, 1.10-2.38; P=.014) more likely to be noncompetent in the cognitive development domain at 1 year. The association did not vary markedly between preterm and term infants, singletons and twins, or assisted reproductive technology-conceived and spontaneously conceived infants (all P>.05 for heterogeneity). In contrast, a null association was observed for the risk of being noncompetent in any domain of neurodevelopment with antenatal prednisone exposure at early pregnancy. CONCLUSION: Here, antenatal corticosteroid, particularly dexamethasone exposure, was markedly associated with an increased risk of infants being noncompetent in the cognitive development domain at 1 year of age. These findings may provide new information when weighing the benefits and potential risks of maternal antenatal corticosteroid administration.

20.
Sci Total Environ ; 842: 156778, 2022 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-35724775

RESUMO

Emerging data have suggested the potential role of prenatal PM2.5 exposure as a neurotoxin for offspring. However, the existing results are equivocal, and no study has examined the effects of complex chemical constituents of the particular matter on offspring neurodevelopment. Therefore, in a prospective birth cohort study conducted in Jiangsu, China, we aimed to investigate the association between prenatal exposure to PM2.5 and the neurodevelopment in infants, and further assess the effects of specific chemical constituents of PM2.5. A total of 1531 children who had available data on daily prenatal PM2.5 exposure and completed assessment on neurodevelopment at 1 year old were enrolled. We used the high-performance machine-learning model to estimate daily PM2.5 exposure concentrations at 1 km × 1 km spatial resolution. The combined geospatial-statistical model was applied to evaluate average concentrations of six chemical constituents [organic matter (OM), black carbon (BC), sulfate (SO42-), nitrate (NO3-), ammonium (NH4+), and soil dust (Dust)]. The neurodevelopment of children was assessed using Bayley-III Screening Test. After adjusting for confounding factors, the risk of non-optimal gross motor development increased by 31 % for every 10 µg/m3 increase in average PM2.5 exposure during gestation (aRR: 1.31; 95 % CI: 1.04, 1.64). Further analysis of PM2.5 constituents showed that prenatally exposed to high SO42- was associated with the risk of non-optimal gross motor development (aRR: 1.40; 95 % CI: 1.08, 1.81). Null associations were observed for the rest four neurodevelopment domains. Collectively, our study suggested that prenatal exposure to PM2.5, particularly with high SO42- concentration, was associated with children's non-optimal gross motor development at 1 year old. The short- and long-term influences of perinatal PM2.5 exposure on children's neurodevelopment warrant further investigation.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Efeitos Tardios da Exposição Pré-Natal , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Coorte de Nascimento , Criança , China , Estudos de Coortes , Poeira/análise , Exposição Ambiental/análise , Feminino , Humanos , Lactente , Exposição Materna , Material Particulado/análise , Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estudos Prospectivos
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