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1.
Hum Mol Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600786

RESUMO

We previously identified five SNPs at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5,662 cases and 9,237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF]=0.40) was associated with DLBCL risk (OR=0.83, P=3.62x10-13). rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5,510 cases and 12,817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF=0.45) was also associated with DLBCL risk (OR=1.20, P=2.31x10-12). This SNP is 29,426 bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

2.
Environ Health Perspect ; 127(9): 97001, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31487206

RESUMO

BACKGROUND: Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and cooking. However, the key components of coal that drive lung cancer risk have not been identified. OBJECTIVES: We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer. METHODS: Using a population-based case-control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables. RESULTS: The strongest association with lung cancer was for a cluster of 25 PAHs [odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change], within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide ([Formula: see text]) was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter [Formula: see text] ([Formula: see text]) were associated with lung cancer in the multipollutant models. CONCLUSIONS: To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. https://doi.org/10.1289/EHP4913.

3.
Mater Sci Eng C Mater Biol Appl ; 104: 109942, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499951

RESUMO

Decellularized matrix (dECM) is isolated extracellular matrix of tissues from its original inhabiting cells, which has emerged as a promising natural biomaterial for tissue engineering, aiming at support, replacement or regeneration of damaged tissues. The dECM can be easily obtained from tissues/organs of various species by adequate decellularization methods, and mimics the structure and composition of the native extracellular matrix, providing a favorable cellular environment. In this review, we summarize the recent developments in the preparation of dECM materials, including decellularization, crosslinking and sterilization. Also, we cover the advances in the utilization of dECM biomaterials in regeneration medicine in pre-clinic and clinical trials. Moreover, we highlight those emerging medical benefits of dECM beyond tissue engineering, such as cell transplantation, in vitro/in vivo model and therapeutic cues delivery. With the advances in the preparation and broader application, the dECM biomaterials could become the gold scaffold and pharmaceutical excipients in medical sciences.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31540283

RESUMO

In recent years, the outbreak of many school sports injury accidents aroused widespread public concern about liability determination of accident. Previous studies have examined the legal application of the liability principles from a law perspective, but few kinds of research attempted to analyze the progress of liability determination from the perspective of "law economics". To fill this research gap, we introduce the evolutionary game model, as an important theoretical tool of "law economics", to investigate how various factors influence the strategy selection of the parties, as well as examine what liability principle can effectively treat school sports injury accidents. The results indicate that the strategic selection of the subject of liability is significantly related to the accident compensation cost and the prevention cost of both parties. Moreover, we also find that both strict and proportional liability rules can play key roles in dealing with the issue of liability determination of school sports injury accidents, but the two liability rules have different effects on the strategic selection of parties. More specifically, compared to the strict liability principle, the proportional liability principle can motivate both the school and the students to adopt the active strategy of "appropriate caution" to prevent occurring sports injury accidents in schools.

5.
J Natl Cancer Inst ; 2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31498409

RESUMO

The Monographs produced by the International Agency for Research on Cancer (IARC) apply rigorous procedures for the scientific review and evaluation of carcinogenic hazards by independent experts. The Preamble to the IARC Monographs, which outlines these procedures, was updated in 2019, following recommendations of a 2018 expert Advisory Group. This article presents the key features of the updated Preamble, a major milestone that will enable IARC to take advantage of recent scientific and procedural advances made during the 12 years since the last Preamble amendments. The updated Preamble formalizes important developments already being pioneered in the Monographs Programme. These developments were taken forward in a clarified and strengthened process for identifying, reviewing, evaluating and integrating evidence to identify causes of human cancer. The advancements adopted include strengthening of systematic review methodologies; greater emphasis on mechanistic evidence, based on key characteristics of carcinogens; greater consideration of quality and informativeness in the critical evaluation of epidemiological studies, including their exposure assessment methods; improved harmonization of evaluation criteria for the different evidence streams; and a single-step process of integrating evidence on cancer in humans, cancer in experimental animals and mechanisms for reaching overall evaluations. In all, the updated Preamble underpins a stronger and more transparent method for the identification of carcinogenic hazards, the essential first step in cancer prevention.

6.
Ann Work Expo Health ; 63(8): 842-855, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31504127

RESUMO

OBJECTIVES: Occupational exposures in population-based case-control studies are increasingly being assessed using decision rules that link participants' responses to occupational questionnaires to exposure estimates. We used a hierarchical process that incorporated decision rules and job-by-job expert review to assign occupational benzene exposure estimates in a US population-based case-control study of non-Hodgkin lymphoma. METHODS: We conducted a literature review to identify scenarios in which occupational benzene exposure has occurred, which we grouped into 12 categories of benzene exposure sources. For each source category, we then developed decision rules for assessing probability (ordinal scale based on the likelihood of exposure > 0.02 ppm), frequency (proportion of work time exposed), and intensity of exposure (in ppm). The rules used the participants' occupational history responses and, for a subset of jobs, responses to job- and industry-specific modules. For probability and frequency, we used a hierarchical assignment procedure that prioritized subject-specific module information when available. Next, we derived job-group medians from the module responses to assign estimates to jobs with only occupational history responses. Last, we used job-by-job expert review to assign estimates when job-group medians were not available or when the decision rules identified possible heterogeneous or rare exposure scenarios. For intensity, we developed separate estimates for each benzene source category that were based on published measurement data whenever possible. Frequency and intensity annual source-specific estimates were assigned only for those jobs assigned ≥75% probability of exposure. Annual source-specific concentrations (intensity × frequency) were summed to obtain a total annual benzene concentration for each job. RESULTS: Of the 8827 jobs reported by participants, 8% required expert review for one or more source categories. Overall, 287 (3.3%) jobs were assigned ≥75% probability of exposure from any benzene source category. The source categories most commonly assigned ≥75% probability of exposure were gasoline and degreasing. The median total annual benzene concentration among jobs assigned ≥75% probability was 0.11 ppm (interquartile range: 0.06-0.55). The highest source-specific median annual concentrations were observed for ink and printing (2.3 and 1.2 ppm, respectively). CONCLUSIONS: The applied framework captures some subject-specific variability in work tasks, provides transparency to the exposure decision process, and facilitates future sensitivity analyses. The developed decision rules can be used as a starting point by other researchers to assess occupational benzene exposure in future population-based studies.

7.
Int J Cancer ; 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31523805

RESUMO

Elevated prediagnostic serum levels of the immune activation markers sCD27 and sCD30 have been associated with non-Hodgkin lymphoma (NHL). However, the use of a single sample per participant in these studies has limited etiologic inferences. We report findings, overall and by NHL subtype, from a case-control analysis (422 cases, 434 controls) within the Janus Serum Bank with two samples per subject collected on average 5 years apart. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was associated with elevated sCD27 in the later, but not earlier, prediagnostic sample (odds ratio [OR] 4.2, 95% confidence interval [CI] 1.5-11.6 and 1.7, 0.7-4.7 per log increase, respectively) in analyses adjusting for both analytes, while follicular lymphoma (FL) was associated with elevated sCD30 in both the later and earlier samples (OR 2.9, 95% CI 1.4-4.4 and 2.3, 1.2-4.4, respectively). CLL/SLL cases were significantly more likely than controls to have higher sCD27 in the later vs. earlier sample (OR 1.4, 95% CI 1.1-1.9 per standard deviation increase); no such difference in sCD30 was apparent for FL. In a joint analysis, NHL cases were more likely than controls to have below-median sCD27 in the earlier sample and above-median sCD27 in the later sample (OR 1.5, 95% CI 1.0-2.3). For sCD30, the association between sCD30 and FL was confined to subjects with above-median analyte levels in both samples (OR 2.5, 95% CI 1.1-5.9). Our findings are compatible with elevated sCD27 representing a disease-induced effect and sCD30 representing a marker of increased FL susceptibility.

8.
Eur Cytokine Netw ; 30(2): 59-66, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31486397

RESUMO

Recent studies have demonstrated that nicotine exhibited anti-inflammatory and neuroprotective properties by interacting with the alpha 7 nicotinic acetylcholine receptor (α7nAChR). However, the role of nicotine in regeneration during peripheral nerve injury has not been elucidated. The aim of this study was to investigate whether nicotine down-regulated production of proinflammatory cytokines and promoted peripheral nerve regeneration in rats. Rats challenged with sciatic nerve crush injury were treated with nicotine (1.5 mg/kg), three times per day. The expression of the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin (IL-1ß), pinch test results, growth-associated protein 43 (GAP-43) expression, morphometric analyses, and the sciatic functional indexes were determined in sciatic nerves. Treatment with nicotine decreased local levels of TNF-α and IL-1ß, and increased the expression of GAP-43. Nicotine also improved nerve regeneration and functional recovery. The overall protective effects of nicotine were reversed by concomitant treatment with α7nACHR antagonist methyllycaconitine, indicating that nicotine exerted its specific anti-inflammatory and neuroprotective effects through the α7nAChR. These findings show that nicotine administration can provide a potential therapeutic pathway for the treatment of peripheral nerve injury, by a direct protective effect through the α7nAChR-mediated cholinergic anti-inflammatory pathway.

9.
JAMA Netw Open ; 2(9): e1911970, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31539079

RESUMO

Importance: Chinese women have the highest rate of lung cancer among female never-smokers in the world, and the etiology is poorly understood. Objective: To assess the association between metabolomics and lung cancer risk among never-smoking women. Design, Setting, and Participants: This nested case-control study included 275 never-smoking female patients with lung cancer and 289 never-smoking cancer-free control participants from the prospective Shanghai Women's Health Study recruited from December 28, 1996, to May 23, 2000. Validated food frequency questionnaires were used for the collection of dietary information. Metabolomic analysis was conducted from November 13, 2015, to January 6, 2016. Data analysis was conducted from January 6, 2016, to November 29, 2018. Exposures: Untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance metabolomic profiles were characterized using prediagnosis urine samples. A total of 39 416 metabolites were measured. Main Outcomes and Measures: Incident lung cancer. Results: Among the 564 women, those who developed lung cancer (275 participants; median [interquartile range] age, 61.0 [52-65] years) and those who did not develop lung cancer (289 participants; median [interquartile range] age, 62.0 [53-66] years) at follow-up (median [interquartile range] follow-up, 10.9 [9.0-11.7] years) were similar in terms of their secondhand smoke exposure, history of respiratory diseases, and body mass index. A peak metabolite, identified as 5-methyl-2-furoic acid, was significantly associated with lower lung cancer risk (odds ratio, 0.57 [95% CI, 0.46-0.72]; P < .001; false discovery rate = 0.039). Furthermore, this peak was weakly correlated with self-reported dietary soy intake (ρ = 0.21; P < .001). Increasing tertiles of this metabolite were associated with lower lung cancer risk (in comparison with first tertile, odds ratio for second tertile, 0.52 [95% CI, 0.34-0.80]; and odds ratio for third tertile, 0.46 [95% CI, 0.30-0.70]), and the association was consistent across different histological subtypes and follow-up times. Additionally, metabolic pathway analysis found several systemic biological alterations that were associated with lung cancer risk, including 1-carbon metabolism, nucleotide metabolism, oxidative stress, and inflammation. Conclusions and Relevance: This prospective study of the untargeted urinary metabolome and lung cancer among never-smoking women in China provides support for the hypothesis that soy-based metabolites are associated with lower lung cancer risk in never-smoking women and suggests that biological processes linked to air pollution may be associated with higher lung cancer risk in this population.

10.
Transplantation ; 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31365475

RESUMO

BACKGROUND: Islet transplantation is a promising option for the treatment of type 1 diabetes. However, the current lack of practical techniques for the isolated islets preservation still hampers the advancement of life-saving islet transplantation. Islet suffers from internal or external stimuli induced oxidative stress and subsequent inflammation during preservation, which leads to disappointing outcomes regarding islet yield, survival and function. ROS overproduction is the primary cause of oxidative stress that induces islet loss and dysfunction. Thus, in this paper, we hypothesized that an endogenous antioxidant, bilirubin, that could efficiently scavenge ROS and inhibit inflammatory reactions could be beneficial for islet preservation. METHODS: Herein, we studied the effect of bilirubin on the hypothermic preserved (4°C) islets, and evaluate the islets viability, insulin secretory function, oxidative stress levels, and in vivo transplantation performance. RESULTS: Bilirubin could prevent cellular damages during short-term preservation, and maintain the co-cultured islets viability and function. The protective role of bilirubin is associated with its antioxidative ability, which dramatically increased the activities of antioxidant enzymes (SOD and GSH-Px), and decreased the levels of ROS and MDA. Diabetic mice transplanted with bilirubin preserved islets were normoglycemic for 28 days, even overmatched the diabetic mouse transplanted with fresh islets. Mice receiving bilirubin co-cultured islets required the least time to achieve normoglycemia among all groups and exhibited minimum inflammatory responses during the early transplantation stage. CONCLUSIONS: By utilizing bilirubin, we achieved highly viable and functional islets after hypothermic preservation to reverse diabetes in mice.

11.
Zhongguo Fei Ai Za Zhi ; 22(8): 477-487, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31451137

RESUMO

BACKGROUND: Lung cancer rates among women in rural Xuanwei and Fuyuan counties in eastern Yunnan province, China, are among the highest in the world, even though almost all women are non-smokers, and they tend to develop lung cancer at a younger age than other locations by roughly 5 yr-10 yr. This study investigated the survival of lung cancer patients among female never-smokers. METHODS: The female never-smokers, who had lived for many years in Xuanwei and Fuyuan counties, with lung cancer newly-diagnosed between July 2006 to March 2010, were followed up through the end of 2016. Age-standardized relative survival for all cases was calculated using local life table. The Kaplan-Meier method and Log-rank test were used to analyze the relationship between the variables and the prognosis in univariate analysis. Cox regression analysis was employed in the multivariate analysis. RESULTS: Among 1,250 total subjects, 1,075 died and the remaining 175 were censored during the follow-up, with a median follow-up period of 69 months (95%CI: 61.9-76.0). Overall, the mean age was (54.8 ±10.9) yr, with variable clinical stages: 3.5% of cases were stage I, 8.7% stage II, 20.7% stage III, 29.7% stage IV, and 37.4% stage unknown. The 645 patients(51.6%) with cyto-histological diagnosis contains 303 with Squamous cell carcinoma, and 231 with adenocarcinoma, 24 with small cell, 43 with other specified type and 39 with unknown histological type. Only 215 (17.2%) patients received surgery, 487 (39.0%) were treated without surgery, and 548 (43.8%) did not receive any specific anticancer therapy. The 5-year observed survival rate and age-standardized relative survival were 8.9% (95%CI: 7.0-10.6), and 10.1% (95%CI: 3.7-20.5) respectively, with a median survival of 13.2 months. The 5-year survival rates were 41.1% for stage I, 22.4% for stage II, 5.3% for stage III, 1.3% for stage IV, 11.2% for missing stage, 17.9% for adenocarcinoma, and 5.6% for squamous cell carcinoma respectively. Surgery significantly improved 5-year survival rate compared with non-surgery (34.8% vs 3.2%, P<0.001). The patients with non-treatment, aged 65 years and older, living in rural areas and farmer with low socioeconomic status had poorer survival, whereas the patients treated in provincial hospitals and chest X-ray screening had better survival. Cox multivariate analysis further showed that stage of tumor-node-metastasis (TNM), treatment status, hospital-level, and X-ray screening were factors correlated with survival. CONCLUSIONS: Patients with lung cancer among female never-smokers in Xuanwei and Fuyuan experience poorer survival, because they are less likely to be diagnosed at early stage, as well as less likely to receive surgery and comprehensive treatment. Furthermore low socioeconomic status and poor health security are also responsible for the low survival.

12.
Zhongguo Fei Ai Za Zhi ; 22(8): 512-519, 2019 Aug 20.
Artigo em Chinês | MEDLINE | ID: mdl-31451142

RESUMO

Brain is the most frequent site for distant metastases of non-small cell lung cancer (NSCLC). Brain metastasis (BM) is also the leading cause of disabilities and death in advanced NSCLC. In recent years, the application and effectiveness of small-molecule tyrosine kinase inhibitors has formed the basis for the treatment of NSCLC brain metastases with driver gene mutations. With the development of programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) inhibitors and relevant combination therapies, immunotherapy has become an important choice for non-classic oncogene addicted NSCLC BM patients. Also, the roles of relevant biomarkers are increasingly standing out. By reason of the particular immunopathological features of NSCLC brain metastases and its microenvironment, the aim of this review is to summarize relevant research progresses and provide more references for combination strategies of different therapeutic methods as well as the development of novel immunotherapies.
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13.
Int J Epidemiol ; 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31377785

RESUMO

BACKGROUND: Lifetime use of bituminous ('smoky') coal is associated with nearly a 100-fold higher risk of lung cancer mortality compared with anthracite ('smokeless') coal use in rural Xuanwei, China, among women. Risk of mortality from ischaemic heart disease (IHD) and stroke for these coal types has not been evaluated. METHODS: A cohort of 16 323 non-smoking women in Xuanwei, who were lifetime users of either smoky or smokeless coal, were followed up from 1976 to 2011. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) to evaluate lifetime use of coal types and stoves in the home in relation to risk of IHD and stroke mortality. RESULTS: Among lifetime users of smokeless coal, higher average exposure intensity (≥4 tons/year vs <2.5 tons/year, HR = 7.9, 95% CI = 3.5-17.8; Ptrend =<0.0001) and cumulative exposure (>64 ton-years vs ≤28 ton-years, HR = 6.5, 95% CI = 1.5-28.3; Ptrend =0.003) during follow-up and over their lifetime was associated with increased IHD mortality, and ventilated stove use dramatically reduced this risk (HR = 0.2, 95% CI 0.1-0.5). Higher cumulative exposure to smoky coal during follow-up showed positive associations with IHD mortality, but the evidence for other metrics was less consistent compared with associations with smokeless coal use. CONCLUSIONS: Higher use of smokeless coal, which is burned throughout China and is generally regarded to be a cleaner fuel type, is associated with IHD mortality. Use of cleaner fuels or stove interventions may be effective in reducing the increasing burden of IHD in developing regions that currently rely on smokeless coal for cooking and heating.

14.
Cancer Epidemiol Biomarkers Prev ; 28(10): 1712-1719, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387968

RESUMO

BACKGROUND: No epidemiologic studies have directly assessed the association between dietary and urinary isoflavonoids and risk of liver cancer in humans. METHODS: A nested case-control study, including 217 incident cases of liver cancer and 427 individually matched control subjects, was conducted in Shanghai, China. Dietary isoflavonoid intakes were assessed through a validated food-frequency questionnaire and the Chinese Food Composition Tables. Urinary excretion levels of four major isoflavonoids were measured by the reversed-phase high-performance liquid chromatography. ORs and 95% confidence intervals (CI) were derived using conditional logistic regression models. RESULTS: The adjusted ORs (95% CIs) for liver cancer across increasing quartiles of urinary genistein levels were 1.00 (reference), 0.55 (95% CI, 0.22-1.36), 0.57 (95% CI, 0.23-1.43), and 0.19 (95% CI, 0.06-0.59) (P trend = 0.008) in women and 1.00 (reference), 1.22 (0.52-2.86), 1.17(0.47-2.90), and 1.23 (0.55-2.76) in men, respectively. These associations were consistent by limiting the cases to primary malignant neoplasm of liver or malignant neoplasms of the intrahepatic bile ducts, or among participants without self-reported liver disease or cirrhosis at the baseline survey. No associations were found between dietary isoflavonoids and liver cancer risk. CONCLUSIONS: Our study suggests for the first time that urinary excretion of genistein may be associated with reduced risk of liver cancer in women. IMPACT: In this nested case-control study in China, we found that urinary excretion of genistein was associated with lower risk of liver cancer in women, and not in men.

15.
Int J Cancer ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276202

RESUMO

Cell-mediated immune suppression may play an important role in lung carcinogenesis. We investigated the associations for circulating levels of tryptophan, kynurenine, kynurenine:tryptophan ratio (KTR), quinolinic acid (QA) and neopterin as markers of immune regulation and inflammation with lung cancer risk in 5,364 smoking-matched case-control pairs from 20 prospective cohorts included in the international Lung Cancer Cohort Consortium. All biomarkers were quantified by mass spectrometry-based methods in serum/plasma samples collected on average 6 years before lung cancer diagnosis. Odds ratios (ORs) and 95% confidence intervals (CIs) for lung cancer associated with individual biomarkers were calculated using conditional logistic regression with adjustment for circulating cotinine. Compared to the lowest quintile, the highest quintiles of kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk, and tryptophan with a 15% lower risk of lung cancer (all ptrend < 0.05). The strongest associations were seen for current smokers, where the adjusted ORs (95% CIs) of lung cancer for the highest quintile of KTR, QA and neopterin were 1.42 (1.15-1.75), 1.42 (1.14-1.76) and 1.45 (1.13-1.86), respectively. A stronger association was also seen for KTR and QA with risk of lung squamous cell carcinoma followed by adenocarcinoma, and for lung cancer diagnosed within the first 2 years after blood draw. This study demonstrated that components of the tryptophan-kynurenine pathway with immunomodulatory effects are associated with risk of lung cancer overall, especially for current smokers. Further research is needed to evaluate the role of these biomarkers in lung carcinogenesis and progression.

16.
Cell Biol Int ; 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31329338

RESUMO

To investigate the roles of tripartite motif containing 52 (TRIM52) in human hepatic fibrosis in vitro, human hepatic stellate cell line LX-2 cells were transfected with hepatitis B virus (HBV) replicon to establish HBV-induced fibrosis in LX-2 cells, and then treated with small interfering RNA-mediated knockdown of TRIM52 (siTRIM52). LX-2 cells without HBV replicon transfection were treated with lentiviruses-mediated overexpression of TRIM52 and phosphatase magnesium dependent 1A (PPM1A). Fibrosis response of LX-2 cells were assessed by the production of hydroxyproline (Hyp) and collagen I/III, as well as protein levels of α-smooth muscle actin (α-SMA). PPM1A and phosphorylated (p)-Smad2/3 were measured to assess the mechanism. The correlation between TRIM52 and PPM1A was determined using co-immunoprecipitation, and whether and how TRIM52 regulated the degradation of PPM1A were determined by ubiquitination assay. Our data confirmed HBV-induced fibrogenesis of LX-2 cells, as evidenced by significant increase in Hyp and collagen I/III and α-SMA, which was associated with reduction of PPM1A and elevation of transforming growth factor-ß (TGF-ß), p-Smad2/3, and p-Smad3L. However, those changes induced by HBV were significantly attenuated with additional siTRIM52 treatment. Similar to HBV, overexpression of TRIM52 exerted promoted effect in the fibrosis of LX-2 cells. Interestingly, TRIM52 induced the fibrogenesis of LX-2 cells and the activation of TGF-ß/Smad pathway were significantly reversed by PPM1A overexpression. Furthermore, our data confirmed TRIM52 as a deubiquitinase that influenced the accumulation of PPM1A protein, and subsequently regulated the fibrogenesis of LX-2 cells. TRIM52 was a fibrosis promoter in hepatic fibrosis in vitro, likely through PPM1A-mediated TGF-ß/Smad pathway.

17.
Org Lett ; 21(15): 6145-6148, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31335156

RESUMO

Structurally unique thiopyranodipyridine alkaloids xylaridines C (1) and D (2) were isolated from the fungus Xylaria longipes. Their structures were established by comprehensive spectroscopic analysis combined with single-crystal X-ray diffraction and electron-capture detection (ECD) calculations. Compound 1 possesses two piperidine moieties fused with a centered thiopyran ring, while compound 2 is a dimer of 1. Compound 1 was resoluted into optical pure enatiomers (+)-1 and (-)-1 by chiral HPLC. Moreover, compound 2 was resoluted into an optically pure compound (+)-2 and a mixture of (-)-2 and meso-2. Plausible biosynthetic pathways of compounds 1 and 2 are proposed.

18.
Nat Commun ; 10(1): 3319, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31346162

RESUMO

Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy.

19.
Int J Cancer ; 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31351006

RESUMO

Ghrelin is a hormone produced in the oxyntic glands of the stomach. Previous work by our group has suggested that serum ghrelin concentrations are inversely associated with gastric and esophageal cancer risk. We measured ghrelin concentrations in the Linxian General Population Nutrition Intervention Trial (NIT), and the Shanghai Women's Health Study (SWHS). In NIT, we analyzed serum samples from 298 esophageal squamous cell carcinoma (ESCC) cases, 518 gastric cardia adenocarcinoma (GCA) cases, 258 gastric noncardia adenocarcinoma (GNCA) cases and 770 subcohort controls (case-cohort). In SWHS, we measured ghrelin in plasma samples from 249 GNCA cases and 498 matched controls (nested case-control). Ghrelin was measured using radioimmunoassay. In NIT and SWHS, low ghrelin concentrations were associated with an increased risk of developing GNCA and GCA. The hazard ratio (HR Q1:Q4 ) for GNCA in NIT was 1.35 (95% CI: 0.89-2.05; p-trend = 0.02); the odds ratio in SWHS was 1.66 (95% CI: 1.02-2.70; p-trend = 0.06). Low ghrelin was associated with a twofold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45-2.77; p-trend<0.001). In contrast, a lower risk of ESCC (NIT ESCC HR Q1:Q4 = 0.65, 95% CI: 0.45-0.92; p-trend = 0.02) was found in NIT. Low baseline ghrelin concentrations were associated with an increased risk for GNCA and GCA in the NIT and the SWHS. In contrast, low ghrelin concentrations at baseline were associated with a reduced risk of developing ESCC in the NIT. Ghrelin may be an early marker of future cancer risk for developing upper gastrointestinal cancer in regions of high incidence.

20.
Artigo em Inglês | MEDLINE | ID: mdl-31161417

RESUMO

OBJECTIVES: The objective of our study was to evaluate the association between occupational exposure to trichloroethylene (TCE), a suspected lymphomagen, and serum levels of miRNAs in a cross-sectional molecular epidemiology study of TCE-exposed workers and comparable unexposed controls in China. METHODS: Serum levels of 40 miRNAs were compared in 74 workers exposed to TCE (median: 12 ppm) and 90 unexposed control workers. Linear regression models were used to test for differences in serum miRNA levels between exposed and unexposed workers and to evaluate exposure-response relationships across TCE exposure categories using a three-level ordinal variable [i.e., unexposed, < 12 ppm, the median value among workers exposed to TCE) and ≥ 12 ppm)]. Models were adjusted for sex, age, current smoking, current alcohol use, and recent infection. RESULTS: Seven miRNAs showed significant differences between exposed and unexposed workers at FDR (false discovery rate) < 0.20. miR-150-5p and let-7b-5p also showed significant inverse exposure-response associations with TCE exposure (Ptrend= 0.002 and 0.03, respectively). The % differences in serum levels of miR-150-5p relative to unexposed controls were - 13% and - 20% among workers exposed to < 12 ppm and ≥ 12 ppm TCE, respectively. CONCLUSIONS: miR-150-5p is involved in B cell receptor pathways and let-7b-5p plays a role in the innate immune response processes that are potentially important in the etiology of non-Hodgkin lymphoma (NHL). Further studies are needed to replicate these findings and to directly test the association between serum levels of these miRNAs and risk of NHL in prospective studies.

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