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1.
Int J Cancer ; 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33521941

RESUMO

China has made rapid progress in reducing the incidence of HBV infection in the past three decades, along with a rapidly changing lifestyle and aging population. We aimed to develop and validate an up-to-date liver cancer risk prediction model with routinely available predictors and evaluate its applicability for screening guidance. Using data from the China Kadoorie Biobank, we included 486 285 participants in this analysis. Fifteen risk factors were included in the model. Flexible parametric survival models were used to estimate the 10-year absolute risk of liver cancer. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. A total of 2706 participants occurred liver cancer over the 4 814 320 person-years of follow-up. Excellent discrimination of the model was observed in both development and validation datasets, with c-statistics (95% CI) of 0.80 (0.79-0.81) and 0.80 (0.78-0.82) respectively, as well as excellent calibration of observed and predicted risks. Decision curve analysis revealed that use of the model in selecting participants for screening improved benefit at a threshold of 2% 10-year risk, compared to current guideline of screening all HBsAg carriers. Our model was more sensitive than current guideline for cancer screening (28.17% vs 25.96%). We developed and validated a CKB-PLR (Prediction for Liver cancer Risk Based on the China Kadoorie Biobank Study) model to predict the absolute risk of liver cancer for both HBsAg seropositive and seronegative populations. Application of the model is beneficial for precisely identifying the high-risk groups among the general population.

2.
Compr Rev Food Sci Food Saf ; 20(2): 2015-2039, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33594822

RESUMO

Pectic substances, one of the cell wall polysaccharides, exist widespread in vegetables and fruits. A surge of recent research has revealed that pectic substances can inhibit gut inflammation and relieve inflammatory bowel disease symptoms. However, physiological functions of pectins are strongly structure dependent. Pectic substances are essentially heteropolysaccharides composed of homogalacturonan and rhamnogalacturonan backbones substituted by various neutral sugar sidechains. Subtle changes in the architecture of pectic substances may remarkably influence the nutritional function of gut microbiota and the host homeostasis of immune system. In this context, developing a structure-function understanding of how pectic substances have an impact on an inflammatory bowel is of primary importance for diet therapy and new drugs. Therefore, the present review has summarized the polycomponent nature of pectic substances, the activities of different pectic polymers, the effects of molecular characteristics and the underlying mechanisms of pectic substances. The immunomodulated property of pectic substances depends on not only the chemical composition but also the physical structure characteristics, such as molecular weight (Mw ) and chain conformation. The potential mechanisms by which pectic substances exert their protective effects are mainly reversing the disordered gut microbiota, regulating immune cells, enhancing barrier function, and inhibiting pathogen adhesion. The manipulation of pectic substances on gut health is sophisticated, and the link between structural specificity of pectins and selective regulation needs further exploration.

3.
Biomed Res Int ; 2020: 6739823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879886

RESUMO

BRCA1 and BRCA2 as important DNA repair genes have been thoroughly investigated in abundant studies. The potential relationships of BRCA1/2 pathogenic variants between multicancers have been verified in Caucasians but few in Chinese. In this study, we performed a two-stage study to screen BRCA1/2 pathogenic variants or variants of uncertain significance (VUS) with 7580 cancer cases and 4874 cancer-free controls, consisting of a discovery stage with 70 familial breast cancer cases and a subsequent validation stage with 7510 cases (3217 breast cancer, 1133 cervical cancer, 2044 hepatocellular carcinoma, and 1116 colorectal cancer). 48 variants were obtained from 70 familial breast cancer cases after BRCA1/2 exon detection, and finally, 20 pathogenic variants or VUS were selected for subsequent validation. Four recurrent variants in sporadic cases (BRCA1 c.4801A>T, BRCA1 c.3257del, BRCA1 c.440del, and BRCA2 c.7409dup) were identified and three of them were labeled Class 5 by ENIGMA. Two variants (BRCA1 c.3257del and c.440del) were specific in breast cancer cases, while BRCA2 c.7409dup and c.4307T>C were detected in two hepatocellular carcinoma patients and the BRCA1 c.4801A>T variant in one cervical cancer patient, respectively. Moreover, BRCA1 c.3257del was the most frequent variant observed in Chinese sporadic breast cancer and showed increased proliferation of BRCA1 c.3257del-overexpressing triple-negative breast cancer cell lines (MDA-MB-231) in vitro. In addition to the known founder deleterious mutations, our findings highlight that the recurrently pathogenic variants in breast cancer cases could be taken as candidate genetic screening loci for a more efficient genetic screening of the Chinese population.

4.
J Agric Food Chem ; 68(32): 8688-8701, 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32633953

RESUMO

Obesity is associated with gut microbiome dysbiosis. Our previous research has shown that highly branched rhamnogalacturonan type I (RG-I)-enriched pectin (WRP, 531.5 kDa, 70.44% RG-I, Rha/(Gal + Ara) = 20) and its oligosaccharide with less branched RG-I [DWRP, 12.1 kDa, 50.29% RG-I, Rha/(Gal + Ara) = 6] are potential prebiotics. The present study is conducted to uncover the impact of the content, molecular size, and branch degrees of RG-I on the inhibiting effect of high-fat diet (HFD)-induced obesity. The commercial pectin (CP, 496.2 kDa, 35.77% RG-I, Rha/(Gal + Ara) = 6), WRP, and DWRP were orally administered to HFD-fed C57BL/6J mice (100 mg kg-1 d-1) to determine their individual effects on obesity. WRP significantly prevented bodyweight gain, insulin resistance, and inflammatory responses in HFD-fed mice. No obvious anti-obesity effect was observed in either CP or DWRP supplementation. A mechanistic study revealed that CP and DWRP could not enhance the diversity of gut microbiota, while WRP treatment positively modulated the gut microbiota of obese mice by increasing the abundance of Butyrivibrio, Roseburia, Barnesiella, Flavonifractor, Acetivibrio, and Clostridium cluster IV. Furthermore, WRP significantly promoted browning of white adipose tissues in HFD-fed mice, while CP and DWRP did not. WRP can attenuate the HFD-induced obesity by modulation of gut microbiota and lipid metabolism. Highly branched RG-I domain enrichment is essential for pectin mitigating against the HFD-induced obesity.

5.
Int J Infect Dis ; 97: 47-53, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32531432

RESUMO

PURPOSE: To explore the molecular genetic mechanisms underlying different responsiveness to Enterovirus 71 (EV71) vaccine. METHODS: We recruited 10,245 healthy children into a phase 3 clinical trial to evaluate the efficacy of EV71 vaccine in 2012. Fifty subjects from the trial were divided into the potent immune response group (20 subjects) and the ineffective immune response group (30 subjects). Whole-exome sequencing was performed for these 50 samples and we conducted bioinformatics analyses based on online public database. RESULTS: A total of 222,180 germline variants were detected across 50 subjects. Single nucleotide variant (SNV)-based screening of the subjects with potent or ineffective immune response allowed the identification of a potentially detrimental heterozygous missense variant (c.3784C>T) in EEA1. We also retained TRIM59 and ABCA7 genes that contain different loss of function (LoF) variants shared in two cases and involved in the immune response process. Then, we conducted high-resolution typing of 9 classical HLA genes, HLA-DRB1*03:01, HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles were frequently (recurrence ≥5) observed only in ineffective immune responders. CONCLUSIONS: Our study is a meaningful attempt on the comparison of genomic profiles between potent and ineffective immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified.


Assuntos
Enterovirus Humano A/imunologia , Vacinas Virais/imunologia , Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Pré-Escolar , China , Feminino , Variação Genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas com Motivo Tripartido/genética , Sequenciamento Completo do Exoma
6.
Int J Cancer ; 147(11): 3075-3084, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32478856

RESUMO

The relationship between hepatitis B virus (HBV) and nonhepatocellular cancers remains inconclusive. This large case-control study aimed to assess the associations between HBV infection status and multiple cancers. Cases (n = 50 392) and controls (n = 11 361) were consecutively recruited from 2008 to 2016 at the First Affiliated Hospital of Nanjing Medical University. Multivariable adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression by adjusting age and gender. A meta-analysis based on published studies was also performed to verify the associations. Of these, 12.1% of cases and 5.5% of controls were hepatitis B surface antigen (HBsAg) seropositive. We observed significant associations between HBsAg seropositivity and esophagus cancer (aOR [95% CI] = 1.32 [1.13-1.54]), stomach cancer (1.46 [1.30-1.65]), hepatocellular carcinoma (HCC; 39.11 [35.08-43.59]), intrahepatic and extrahepatic bile duct carcinoma (ICC and ECC; 3.83 [2.58-5.67] and 1.72 [1.28-2.31]), pancreatic cancer (PaC; 1.37 [1.13-1.65]), non-Hodgkin lymphoma (NHL; 1.88 [1.61-2.20]) and leukemia (11.48 [4.05-32.56]). Additionally, compared to participants with HBsAg-/anti-HBs-/anti-HBc-, participants with HBsAg-/anti-HBs-/anti-HBc+, indicating past HBV-infected, had an increased risk of esophagus cancer (aOR [95% CI] = 1.46 [1.24-1.73]), stomach cancer (1.20 [1.04-1.39]), HCC (4.80 [3.95-5.84]) and leukemia (15.62 [2.05-119.17]). Then the overall meta-analysis also verified that HBsAg seropositivity was significantly associated with stomach cancer (OR [95% CI] = 1.23 [1.14-1.33]), ICC (4.05 [2.78-5.90]), ECC (1.73 [1.30-2.30]), PaC (1.26 [1.09-1.46]), NHL (1.95 [1.55-2.44]) and leukemia (1.54 [1.26-1.88]). In conclusion, both our case-control study and meta-analysis confirmed the significant association of HBsAg seropositivity with stomach cancer, ICC, ECC, PaC, NHL and leukemia. Of note, our findings also suggested that the risk of stomach cancer elevated for people whoever exposed to HBV.

7.
Cancer Med ; 8(6): 3086-3093, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31033235

RESUMO

BACKGROUND: Accompanied by HBV infection, HBV mutations gradually occur because HBV polymerase appears proofread deficiencies. In our previous study, we have identified that EnhII/BCP/PC mutations and genotype C of HBV DNA were associated with hepatocellular carcinoma (HCC) risk. In this study, we extend our research to explore HCC prognosis associated genotype and mutations in EnhII/BCP/PC regions. METHODS: We designed a case-cohort study of 331 HCC patients to evaluate the effects of the HBV genotypes and mutations on HCC survival. Log-rank test and Cox proportional hazard models were used for the analyses. RESULTS: Results showed that genotype C, which was more frequent in HBV-related HCC (77.4%), presented a negative signal with HCC survival. Interestingly, we detected a significant association between EnhII/BCP/PC mutation nt1753 and HCC prognosis (Log-rank P = 0.034). Subgroup analysis revealed that this risk effect was more pronounced in non-B genotype (P = 0.090 for heterogeneity test). We also detected a borderline multiplicative interaction between genotypes of nt1753 and HBV genotype on HCC survival (P for interaction = 0.069). CONCLUSIONS: These findings indicated that, in Chinese population, nt1753 in EnhII/BCP/PC region might be a novel marker for HCC prognosis.


Assuntos
Carcinoma Hepatocelular/etiologia , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Neoplasias Hepáticas/etiologia , Regiões Promotoras Genéticas/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Mutação
8.
Breast Cancer Res Treat ; 175(3): 691-699, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30868394

RESUMO

PURPOSE: To evaluate the prognostic effect of the integration of genomic and transcriptomic profiles in breast cancer. METHODS: Eight hundred and ten samples from the Cancer Genome Atlas (TCGA) data sets were randomly divided into the training set (540 subjects) and validation set (270 subjects). We first selected single-nucleotide polymorphism (SNPs) and genes associated with breast cancer prognosis in the training set to construct the prognostic prediction model, and then replicated the prediction efficiency in the validation set. RESULTS: Four SNPs and three genes associated with the prognosis of breast cancer in the training set were included in the prognostic model. Patients were divided into the high-risk group and low-risk group based on the four SNPs and three genes signature-based genetic prognostic index. High-risk patients showed a significant worse overall survival [Hazard Ratio (HR) 9.43, 95% confidence interval (CI) 3.81-23.33, P < 0.001] than the low-risk group. Compared to the model constructed with only gene expression, the C statistics for the signature-based genetic prognostic index [area under curves (AUC) = 0.79, 95% CI 0.72-0.86] showed a significant increase (P < 0.001). Additionally, we further replicated the prognostic prediction model in the validation set as patients in the high-risk group also showed a significantly worse overall survival (HR 4.55, 95% CI 1.50-13.88, P < 0.001), and the C statistics for the signature-based genetic prognostic index was 0.76 (95% CI 0.65-0.86). The following time-dependent ROC revealed that the mean of AUCs were 0.839 and 0.748 in the training set and the validation set, respectively. CONCLUSIONS: Our findings suggested that integrating genomic and transcriptomic profiles could greatly improve the predictive efficiency of the prognosis of breast cancer patients.


Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica/métodos , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA/métodos , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Análise de Sobrevida
10.
Cancer Epidemiol ; 50(Pt A): 39-45, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28797893

RESUMO

BACKGROUND: Observational studies show an association between telomere length and Hepatocellular carcinoma (HCC) risk, but the relationship is controversial. Particularly, it remains unclear whether the association is due to confounding or biases inherent in conventional epidemiological studies. Here, we applied Mendelian randomization approach to evaluate whether telomere length is causally associated with HCC risk. METHODS: Individual-level data were from HBV-related HCC Genome-wide association studies (1,538 HBV positive HCC patients and 1,465 HBV positive controls). Genetic risk score, as proxy for actual measured telomere length, derived from nine telomere length-associated genetic variants was used to evaluate the effect of telomere length on HCC risk. RESULTS: We observed a significant risk signal between genetically increased telomere length and HBV-related HCC risk (OR=2.09, 95% CI 1.32-3.31, P=0.002). Furthermore, a U-shaped curve was fitted by the restricted cubic spline curve, which indicated that either short or long telomere length would increase HCC risk (P=0.0022 for non-linearity test). Subgroup analysis did not reveal significant heterogeneity between different age, gender, smoking status and drinking status groups. CONCLUSIONS: Our results indicated that a genetic background that favors longer or shorter telomere length may increase HBV-related HCC risk-a U-shaped association.


Assuntos
Carcinoma Hepatocelular/genética , Variação Genética , Hepatite B/complicações , Neoplasias Hepáticas/genética , Análise da Randomização Mendeliana/métodos , Telômero/genética , Carcinoma Hepatocelular/etiologia , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Hepatite B/virologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Humanos , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
11.
Sci Rep ; 6: 20675, 2016 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-26857734

RESUMO

Telomere dysfunction participates in malignant transformation and tumorigenesis. Previous studies have explored the associations between telomere length (TL) and cancer susceptibility; however, the findings are inconclusive. The associations between genetic variants and TL have been verified by quite a few genome-wide association studies (GWAS). Yet, to date, there was no published study on the relationship between TL, related genetic variants and susceptibility to squamous cell carcinoma of the head and neck (SCCHN) in Chinese. Hence, we detected relative telomere length (RTL) by using quantitative PCR and genotyped seven selected single nucleotide polymorphisms by TaqMan allelic discrimination assay in 510 SCCHN cases and 913 controls in southeast Chinese. The results showed that RTL was significantly associated with SCCHN risk [(adjusted odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.08-1.32, P = 0.001]. Furthermore, among seven selected SNPs, only G allele of rs2736100 related to RTL in Caucasians was significantly associated with both the decreased RTL (P = 0.002) and the increased susceptibility to SCCHN in Chinese (additive model: adjusted OR = 1.17, 95%CI = 1.00-1.38, P = 0.049). These findings provide evidence that shortened TL is a risk factor for SCCHN, and genetic variants can contribute to both TL and the susceptibility to SCCHN in southeast Chinese population.


Assuntos
Alelos , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Polimorfismo de Nucleotídeo Único , Homeostase do Telômero , Telômero/genética , Idoso , Grupo com Ancestrais do Continente Asiático , China , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade
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