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1.
Pediatr Blood Cancer ; : e28047, 2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31736278

RESUMO

PURPOSE: To estimate the absolute number of adult survivors of childhood cancer in the U.S. population who carry a pathogenic or likely pathogenic variant in a cancer predisposition gene. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Program, we estimated the number of childhood cancer survivors on December 31, 2016 for each childhood cancer diagnosis, multiplied this by the proportion of carriers of pathogenic/likely pathogenic variants in the St. Jude Lifetime Cohort (SJLIFE) study, and projected the resulting number onto the U.S. RESULTS: Based on genome sequence data, 11.8% of 2450 SJLIFE participants carry a pathogenic/likely pathogenic variant in one of 156 cancer predisposition genes. Given this information, we estimate that 21 800 adult survivors of childhood cancer in the United States carry a pathogenic/likely pathogenic variant in one of these genes. The highest estimated absolute number of variant carriers are among survivors of central nervous system tumors (n = 4300), particularly astrocytoma (n = 1800) and other gliomas (n = 1700), acute lymphoblastic leukemia (n = 4300), and retinoblastoma (n = 3500). The most frequently mutated genes are RB1 (n = 3000), NF1 (n = 2300), and BRCA2 (n = 800). CONCLUSION: Given the increasing number of childhood cancer survivors in the United States, clinicians should counsel survivors regarding their potential genetic risk, consider referral for genetic counseling and testing, and, as appropriate, implement syndrome-specific cancer surveillance or risk-reducing measures.

2.
J Natl Cancer Inst ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31647544

RESUMO

BACKGROUND: We aimed to systematically evaluate telomere dynamics across a spectrum of pediatric cancers, search for underlying molecular mechanisms, and assess potential prognostic value. METHODS: The fraction of telomeric reads was determined from whole-genome sequencing data for paired tumor/normal samples from 653 patients with 23 cancer types from the Pediatric Cancer Genome Project (PCGP). Telomere dynamics were characterized as the ratio of telomere fractions between tumor and normal samples. Somatic mutations were gathered, RNA sequencing data for 330 patients were analyzed for gene expression, and Cox regression was used to assess the telomere dynamics on patient survival. RESULTS: Telomere lengthening was observed in 28.7% of solid tumors, 10.5% of brain tumors, and 4.3% of hematological cancers. Among 81 samples with telomere lengthening, 26 had somatic mutations in ATRX, corroborated by a low level of ATRX expression in the subset of tumors with RNA sequencing. TERT amplification and/or activation was observed in 10 tumors with telomere lengthening, including 2 leukemias of the E2A-PBX1 subtype. Among hematological cancers, pathway analysis for genes with expressions most negatively correlated with telomere fractions suggest implication of a gene ontology process of antigen presentation by MHC class II. A higher ratio of telomere fractions was statistically significantly associated with poorer survival for patients with brain tumors (hazard ratio = 2.18, 95% confidence interval = 1.37 to 3.46). CONCLUSION: Because telomerase inhibitors are currently being explored as potential agents to treat pediatric cancer, these data are valuable as they identify a subpopulation of patients with reactivation of telomerase who are most likely to benefit from this novel therapeutic option.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31604778

RESUMO

Patients harboring germline pathogenic biallelic variants in genes involved in the recognition and repair of DNA damage are known to have a substantially increased cancer risk. Emerging evidence suggests that individuals harboring heterozygous variants in these same genes may also be at heightened, albeit lesser, risk for cancer. Herein, we sought to determine whether heterozygous variants in RECQL4, the gene encoding an essential DNA helicase that is defective in children with the autosomal recessive cancer-predisposing condition Rothmund-Thomson syndrome (RTS), are associated with increased risk for childhood cancer. To address this question, we interrogated germline sequence data from 4435 pediatric cancer patients at St. Jude Children's Research Hospital and 1127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database and identified 24 (0.43%) who harbored loss-of-function (LOF) RECQL4 variants, including five of 249 (2.0%) with osteosarcoma (OS). These RECQL4 variants were significantly overrepresented in children with OS, the cancer most frequently observed in patients with RTS, as compared to 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = 0.00087, odds ratio [OR] = 7.1, 95% CI, 2.9-17). Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis. Altogether these data expand our understanding of the genetic factors predisposing to childhood cancer and reveal a novel association between heterozygous RECQL4 LOF variants and development of pediatric OS.

4.
Gut ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383772

RESUMO

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10- 8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10- 9) and 4q28.1 (OR=1.14, p=3.33×10- 11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.

5.
Genome Res ; 29(9): 1555-1565, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31439692

RESUMO

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

6.
Clin Cancer Res ; 25(22): 6700-6708, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31462438

RESUMO

PURPOSE: To identify genetic factors associated with risk of stroke among survivors of childhood cancer treated with cranial radiotherapy (CRT). EXPERIMENTAL DESIGN: We analyzed whole-genome sequencing (36.8-fold) data of 686 childhood cancer survivors of European ancestry [median (range), 40.4 (12.4-64.7) years old; 54% male] from the St. Jude Lifetime Cohort study treated with CRT, of whom 116 (17%) had clinically diagnosed stroke. Association analyses (single-variant and Burden/SKAT tests) were performed, adjusting for demographic characteristics and childhood cancer treatment exposures. RESULTS: We identified a genome-wide significant association between 5p15.33 locus and stroke [rs112896372: HR = 2.55; P = 1.42 × 10-8], with a stronger association (HR = 3.68) among survivors treated with CRT dose 25-50 Gray (Gy) and weaker associations among those treated with CRT doses <20 or 20-25 or >50 Gy (HRs = 2.14, 2.40, and 2.28). The association was replicated in 90 CRT-exposed African survivors (HR = 3.05; P = 0.034). In CRT-exposed Europeans, rs112896372 significantly (P < 0.001) improved predictive ability (AUC = 0.717) for determining stroke risk than nongenetic factors alone (AUC = 0.663) at 30 years since diagnosis, with significant improvement among African survivors (P = 0.047). SNP rs112896372 was further evaluated in three independent datasets including 1,641 European (HR = 1.54; P = 0.055) and 316 African survivors (HR = 1.88; P = 0.283) not treated with CRT, and 166,988 males in the UK Biobank (OR = 1.0012; P = 0.042). CONCLUSIONS: A novel locus 5p15.33 is associated with stroke risk among childhood cancer survivors, with a possible CRT dose-specific effect. The locus is of potential clinical utility in characterizing individuals who may benefit from surveillance and intervention strategies.

8.
Genomics ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31306748

RESUMO

We investigated whether genetic susceptibility to tuberculosis (TB) influences lung adenocarcinoma development among never-smokers using TB genome-wide association study (GWAS) results within the Female Lung Cancer Consortium in Asia. Pathway analysis with the adaptive rank truncated product method was used to assess the association between a TB-related gene-set and lung adenocarcinoma using GWAS data from 5512 lung adenocarcinoma cases and 6277 controls. The gene-set consisted of 31 genes containing known/suggestive associations with genetic variants from previous TB-GWAS. Subsequently, we followed-up with Mendelian Randomization to evaluate the association between TB and lung adenocarcinoma using three genome-wide significant variants from previous TB-GWAS in East Asians. The TB-related gene-set was associated with lung adenocarcinoma (p = 0.016). Additionally, the Mendelian Randomization showed an association between TB and lung adenocarcinoma (OR = 1.31, 95% CI: 1.03, 1.66, p = 0.027). Our findings support TB as a causal risk factor for lung cancer development among never-smoking Asian women.

9.
Eur J Hum Genet ; 27(10): 1589-1598, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31231134

RESUMO

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

10.
ACS Appl Mater Interfaces ; 11(26): 23361-23371, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31180630

RESUMO

Recently, many researchers have focused on tetrahedrite-based compounds due to their intrinsic low thermal conductivity; however, their thermoelectric performance is limited by the lower power factor. In this case, using Ge doping on Sb sites, the power factor is obviously enhanced due to an increment in carrier concentration and density of states; simultaneously, the thermal conductivity is substantially suppressed by atomic defects. Also, ZnO nanoparticles are introduced in the Ge-doped compounds to further weaken the thermal conductivity. As a result, the maximum dimensionless figure of merit (ZT) of ∼1.0 is obtained for the Cu12Sb3.96Ge0.04S13-0.5 wt % ZnO sample at 750 K, which is ∼72% larger than that of Cu12Sb4S13. All results indicate that suitable elemental doping combined with the incorporation of the nanophase is a very promising approach for Cu12Sb4S13 tetrahedrites to improve the thermoelectric performance.

11.
Appl Opt ; 58(14): 3902-3907, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-31158207

RESUMO

Quantum key distribution (QKD) has undergone significant development in recent decades, particularly with respect to free-space (air) and optical fiber channels. Here, we report a proof-of-principle experiment for the BB84 protocol QKD over a water channel. First, we demonstrate again the polarization preservation properties of the water channel in optical transmission according to the measured Mueller matrix, which is close to the unit matrix. The reason for the polarization preservation, revealed by Monte Carlo simulation, is that almost all the received photons are unscattered. Then, we performed the first polarization encoding BB84 protocol QKD over a 2.37 m water channel. The results show that QKD can be performed with a low quantum bit error rate, less than 3.5%, with different attenuation coefficients.

12.
J Clin Oncol ; 37(19): 1647-1656, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075046

RESUMO

PURPOSE: Anthracycline-associated risk for subsequent breast cancer in childhood cancer survivors is hypothesized to be mediated by TP53 mutation-related gene-environment interactions. We characterized treatment/genetic risks and the impact of screening for breast cancer in the St Jude Lifetime Cohort. PATIENTS AND METHODS: Female participants underwent risk-based assessments, prior health event validation, chest radiation dosimetry, and whole genome sequencing. Breast biopsy reports were reviewed. A subgroup (n = 139) underwent both breast magnetic resonance imaging and mammography. Multivariable regression was used to calculate hazard ratios (HRs) and 95% CIs. RESULTS: Among 1,467 women, 56 developed 68 breast cancers at a median age 38.6 (range, 24.5 to 53.0) years. Cumulative incidences at age 35 years were 1% (no chest radiation) and 8% (≥ 10 Gy of chest radiation). In adjusted models, breast cancer was associated with 20 Gy or more of chest radiation versus none (HR, 7.6; 95% CI, 2.9 to 20.4), anthracycline exposure versus none (1 to 249 mg/m2: HR, 2.6; 95% CI, 1.1 to 6.2; ≥ 250 mg/m2: HR, 13.4, 95% CI, 5.5 to 32.5), and having a breast cancer predisposition gene mutation (HR, 23.0; 95% CI, 7.3 to 72.2). Anthracyclines 250 mg/m2 or greater remained significantly associated with increased risk of breast cancer in models excluding survivors with cancer predisposition gene mutations, chest radiation 10 Gy or greater, or both. Sensitivity/specificity were 53.8%/96.3% for mammography, 69.2%/91.4% for magnetic resonance imaging, and 85.8%/99.7% for dual imaging. Breast cancers detected by imaging and/or prophylactic mastectomy compared with physical findings were more likely to be in situ carcinomas, smaller, without lymph node involvement, and treated without chemotherapy. CONCLUSION: Higher doses of anthracyclines are associated with increased risk of breast cancer independent of mutations in known cancer predisposition genes. Surveillance imaging identifies breast cancers less likely to require chemotherapy than those detected by physical findings.

14.
Genome Biol ; 20(1): 50, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30867008

RESUMO

BACKGROUND: Sequencing errors are key confounding factors for detecting low-frequency genetic variants that are important for cancer molecular diagnosis, treatment, and surveillance using deep next-generation sequencing (NGS). However, there is a lack of comprehensive understanding of errors introduced at various steps of a conventional NGS workflow, such as sample handling, library preparation, PCR enrichment, and sequencing. In this study, we use current NGS technology to systematically investigate these questions. RESULTS: By evaluating read-specific error distributions, we discover that the substitution error rate can be computationally suppressed to 10-5 to 10-4, which is 10- to 100-fold lower than generally considered achievable (10-3) in the current literature. We then quantify substitution errors attributable to sample handling, library preparation, enrichment PCR, and sequencing by using multiple deep sequencing datasets. We find that error rates differ by nucleotide substitution types, ranging from 10-5 for A>C/T>G, C>A/G>T, and C>G/G>C changes to 10-4 for A>G/T>C changes. Furthermore, C>T/G>A errors exhibit strong sequence context dependency, sample-specific effects dominate elevated C>A/G>T errors, and target-enrichment PCR led to ~ 6-fold increase of overall error rate. We also find that more than 70% of hotspot variants can be detected at 0.1 ~ 0.01% frequency with the current NGS technology by applying in silico error suppression. CONCLUSIONS: We present the first comprehensive analysis of sequencing error sources in conventional NGS workflows. The error profiles revealed by our study highlight new directions for further improving NGS analysis accuracy both experimentally and computationally, ultimately enhancing the precision of deep sequencing.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/normas , Neoplasias/genética , Reação em Cadeia da Polimerase/normas , Análise de Sequência de DNA/normas , Software , Estudos de Casos e Controles , Humanos , Mutação , Controle de Qualidade
15.
J Opt Soc Am A Opt Image Sci Vis ; 36(3): 397-402, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30874176

RESUMO

We carry out a detailed study on underwater ghost imaging (GI) in oceanic turbulence. We set up a physical model of GI through oceanic turbulence, which includes light-field transmission, and interaction between light field and oceanic turbulence without considering the effects of water absorption and scattering of light. We obtain theoretical expressions for the impulse response function and the visibility of GI in oceanic turbulence based on the power spectrum of the turbulence and the extended Huygens-Fresnel integral. The results show that the quality of GI under the effects of oceanic turbulence is related to the intensity of turbulence and the propagation distance of light. The quality of GI could be maintained at a relatively small distance in strong oceanic turbulence, whereas the quality is degraded dramatically at a relatively long distance in strong oceanic turbulence. We further analyze the quality of GI under various turbulence conditions and over different propagation distances by numerical calculation. Our results provide guidance for the realization of adaptive underwater optical GI over different length scales under the effect of oceanic turbulence.

16.
Food Chem ; 288: 405-412, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30902311

RESUMO

The effects of malondialdehyde (MDA) as a byproduct of lipid oxidation on myoglobin and myofibrillar proteins (MP) oxidations in muscle homogenates containing components native to rabbit muscle were investigated. For myoglobin, MDA could lead to increase in metmyoglobin percentage. For MP, MDA could promote protein carbonylation and loss of tryptophan fluorescence. In addition, MDA could affect reactive oxygen species (ROS)-generating system by promoting the formation of hypervalent myoglobin species and release of non-heme iron. The result of MDA-MP adducts fluorescence intensity indicated that ROS-generating systems may be the main reason for protein carbonylation at the later of incubation treatment. SDS-PAGE analysis revealed that the ability of ROS-generating systems to facilitate protein oxidation was enhanced with MDA, which was responsible for the formation of protein cross-linking throughout incubation treatment. Taken together, the ability of MDA on promoting the oxidation of MP in rabbit muscle homogenates may be relied on both adduct reactions and the influence on ROS-generating system.


Assuntos
Peroxidação de Lipídeos , Malondialdeído/química , Carne/análise , Proteínas Musculares/química , Animais , Metamioglobina/química , Metamioglobina/metabolismo , Mioglobina/química , Mioglobina/metabolismo , Oxirredução , Carbonilação Proteica , Coelhos , Espécies Reativas de Oxigênio/química , Espectrometria de Fluorescência
17.
Nutr Cancer ; 71(4): 569-574, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30596268

RESUMO

To analyze the clinical characteristics and prognostic value of prognostic nutritional index (PNI) for diffuse large B-cell lymphoma (DLBCL) treated in the rituximab era, baseline clinical and disease characteristics were recorded in our hospital. Concentration of T-helper cell type (Th1/Th2/Th17) cytokine profiles were measured by flow cytometry. DLBCL patients were classified into low and high PNI group based on the cutoff value as previously reported. Clinical features and survivals were compared between high and low group. In all, 114 (37%) out of 309 patients were classified as low PNI group. The low group had lower levels of albumin, hemoglobin and lymphocyte counts, and older age, and high lactate dehydroxygenase (LDH), and high frequencies of advanced stage, poor performance status, B symptoms, extranodal involvement, and higher level of interferon gamma (INF-γ). Low PNI was associated with poor overall survival (OS) in univariate analyses. But these significances did not stand in the paired patients matched by the well-established prognostic factors. In parallel, there was no significance between survival and PNI in the multivariate analyses. PNI was closely correlated with the well-established prognostic factors for DLBCL patients and was not an independent prognostic factor in our study.

18.
PLoS Med ; 16(1): e1002724, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30605491

RESUMO

BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.


Assuntos
Carcinoma de Células Renais/etiologia , Neoplasias Renais/etiologia , Obesidade/complicações , Glicemia/análise , Pressão Sanguínea , Índice de Massa Corporal , Carcinoma de Células Renais/genética , Diabetes Mellitus Tipo 2/complicações , Feminino , Marcadores Genéticos , Estudo de Associação Genômica Ampla , Humanos , Insulina/sangue , Neoplasias Renais/genética , Lipídeos/sangue , Masculino , Análise da Randomização Mendeliana , Obesidade/genética , Fatores de Risco
19.
Meat Sci ; 150: 14-22, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30562639

RESUMO

This work investigated protein oxidation, proteolysis and their interrelationship during the manufacturing process of low-sodium Chinese traditional bacon. The bacons were prepared by four different salting treatments: substituting sodium chloride (NaCl) using 0, 30, 50, and 70% of potassium chloride (KCl). Protein oxidation was evaluated by total carbonylation, thiol oxidation, and tryptophan fluorescence changes. Proteolysis was detected by non-protein nitrogen, free amino acid, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In the manufacturing process of low-sodium Chinese bacon, protein oxidation and protein proteolysis were simultaneously observed. Electrophoresis pattern showed that 70% substitution of KCl could promote proteolysis, meanwhile, protein oxidation possibly facilitated by 70% KCl replacement resulted in reduced tryptophan fluorescence and increased total carbonyl content. Additionally, a good correlation between protein oxidation and proteolysis was observed.


Assuntos
Produtos da Carne/análise , Cloreto de Potássio/química , Proteínas/química , Proteólise , Cloreto de Sódio/química , Animais , Manipulação de Alimentos/métodos , Oxirredução , Sus scrofa
20.
J Natl Cancer Inst ; 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30541042

RESUMO

Background: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. Methods: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. Results: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. Conclusion: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

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