Cumulative inequality in social determinants of health in relation to depression symptom: An analysis of nationwide cross-sectional data from U.S. NHANES 2005-2018.

Social determinants of health (SDoH) have been linked to a higher likelihood of experiencing mental health problems. This study aimed to investigate whether the accumulation of unfavorable SDoH is associated with depression symptom. Data was gathered from a representative population participating in the U.S. National Health and Nutrition Examination Survey spanning from 2005 to 2018. Self-reported SDoH were operationalized according to the criteria outlined in Healthy People 2030, with a cumulative measure of unfavorable SDoH calculated for analysis. The presence of depression symptom was identified using the Patient Health Questionnaire in a representative sample of 30,762 participants (49.2 % males) representing 1,392 million non-institutionalized U.S. adults, with 2,675 (8.7 %) participants showing depression symptom. Unfavorable SDoH were found to be significantly and independently associated with depression symptom. Individuals facing multiple unfavorable SDoHs were more likely to experience depression symptom (P for trend < 0.001). For instance, a positive association was observed in participants exposed to six or more unfavorable SDoHs with depression symptom (AOR = 3.537, 95 % CI: 1.781, 7.075, P-value < 0.001). The findings emphasize that the likelihood of developing depression symptom significantly increases when multiple SDoHs are present, compared to just a single SDoH.

Outdoor gardening activity with different frequency and duration may be associated with reduction of total and cause-specific mortality risk for general U.S. adults: Findings from the NHANES.

BACKGROUND AND AIMS: Engaging in recommended levels of physical activity (PA) is associated with reduced overall and cause-specific mortality rates. Our study aims to examine the relationship between gardening-specific PA and all-cause and cause-specific mortality based on representative U.S. adults. METHODS AND RESULTS: A total of 13,812 adults representing 663.5 million non-institutionalized U.S. adults were included in the National Health and Nutrition Examination Survey. Self-reported gardening activity (GA) was assessed by a validated questionnaire, and outcomes of interest were all-cause mortality and mortality specific to certain causes. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using survey-multivariable Cox proportional hazards models. During a median follow-up period of 16.8 years (Interquartile range = 14.8-18.7), there were 3,476 deaths. After adjusting for potential covariates, we found that participants exposed to GA were more likely to have a lower risk of total mortality [HR (95% CI): 0.76 (0.68, 0.85), P-value < 0.001], cancer-specific mortality [HR (95% CI): 0.81 (0.67, 0.99), P-value < 0.05], cardiovascular disease mortality [HR (95% CI): 0.65 (0.53, 0.80), P-value < 0.001], and respiratory disease mortality [HR (95% CI): 0.66 (0.45, 0.98), P-value < 0.05], compared to those without GA exposure. Furthermore, engaging in GA more frequently and for longer durations was significantly associated with a lower total mortality risk. CONCLUSION: Our study provides evidence that engaging in GA is associated with a decreased risk of overall and cause-specific mortality. However, further longitudinal or interventional studies are needed to investigate the potential benefits of GA.

Human biodistribution and radiation dosimetry for the tau tracer [18F]Florzolotau in healthy subjects.

BACKGROUND: Tau pathology plays a crucial role in neurodegeneration diseases including Alzheimer's disease (AD) and non-AD diseases such as progressive supranuclear palsy. Tau positron emission tomography (PET) is an in-vivo and non-invasive medical imaging technique for detecting and visualizing tau deposition within a human brain. In this work, we aim to investigate the biodistribution of the dosimetry in the whole body and various organs for the [18F]Florzolotau tau-PET tracer. A total of 12 healthy controls (HCs) were enrolled at Chang Gung Memorial Hospital. All subjects were injected with approximately 379.03 ± 7.03 MBq of [18F]Florzolotau intravenously, and a whole-body PET/CT scan was performed for each subject. For image processing, the VOI for each organ was delineated manually by using the PMOD 3.7 software. Then, the time-activity curve of each organ was acquired by optimally fitting an exponential uptake and clearance model using the least squares method implemented in OLINDA/EXM 2.1 software. The absorbed dose for each target organ and the effective dose were finally calculated. RESULTS: From the biodistribution results, the elimination of [18F]Florzolotau is observed mainly from the liver to the intestine and partially through the kidneys. The highest organ-absorbed dose occurred in the right colon wall (255.83 µSv/MBq), and then in the small intestine (218.67 µSv/MBq), gallbladder wall (151.42 µSv/MBq), left colon wall (93.31 µSv/MBq), and liver (84.15 µSv/MBq). Based on the ICRP103, the final computed effective dose was 34.9 µSv/MBq with CV of 10.07%. CONCLUSIONS: The biodistribution study of [18F]Florzolotau demonstrated that the excretion of [18F]Florzolotau are mainly through the hepatobiliary and gastrointestinal pathways. Therefore, a routine injection of 370 MBq or 185 MBq of [18F]Florzolotau leads to an estimated effective dose of 12.92 or 6.46 mSv, and as a result, the radiation exposure to the whole-body and each organ remains within acceptable limits and adheres to established constraints. TRIAL REGISTRATION: Retrospectively Registered at Clinicaltrials.gov (NCT03625128) on 12 July, 2018, https://clinicaltrials.gov/study/NCT03625128 .

Contribution of individual and cumulative social determinants of health underlying gender disparities in periodontitis in a representative US population: A cross-sectional NHANES study.

AIM: To examine the impact of both individual and cumulative social determinants of health (SDoH) on the likelihood of developing periodontitis, while also exploring any gender disparities in this relationship. MATERIALS AND METHODS: Data of self-reported SDoH domains and sub-items based on Healthy People 2030 were obtained from the U.S. National Health and Nutrition Examination Surveys between 1999 and 2014. Logistic regression models, weighted by survey responses, were used to examine the relationship between SDoH (including eight sub-items and the cumulative number of unfavourable SDoH) and periodontitis. The results were further analysed by gender. RESULTS: A total of 18,075 participants (8867 males and 9208 females) were included in the main analysis, of which 5814 (32.2%) had periodontitis. The study found that certain unfavourable SDoH were individually associated with higher odds of periodontitis, and the cumulative number of unfavourable SDoH was positively linked to the odds of developing periodontitis. Furthermore, males exposed to more unfavourable SDoH appeared to be more susceptible to developing periodontitis than females. CONCLUSIONS: The findings suggest that unfavourable SDoH, especially when they accumulate, are associated with an increased odds of periodontitis and contribute to gender disparities within the U.S.

Deficiency of Trex1 leads to spontaneous development of type 1 diabetes.

BACKGROUND: Type 1 diabetes is believed to be an autoimmune condition, characterized by destruction of insulin-producing cells, due to the detrimental inflammation in pancreas. Growing evidences have indicated the important role of type I interferon in the development of type 1 diabetes. METHODS: Trex1-deficient rats were generated by using CRISPR-Cas9. The fasting blood glucose level of rat was measured by a Roche Accuchek blood glucose monitor. The levels of insulin, islet autoantibodies, and interferon-ß were measured using enzyme-linked immunosorbent assay. The inflammatory genes were detected by quantitative PCR and RNA-seq. Hematein-eosin staining was used to detect the pathological changes in pancreas, eye and kidney. The pathological features of kidney were also detected by Masson trichrome and periodic acid-Schiff staining. The distribution of islet cells, immune cells or ssDNA in pancreas was analyzed by immunofluorescent staining. RESULTS: In this study, we established a Trex1-deletion Sprague Dawley rat model, and unexpectedly, we found that the Trex1-/- rats spontaneously develop type 1 diabetes. Similar to human diabetes, the hyperglycemia in rats is accompanied by diabetic complications such as diabetic nephropathy and cataract. Mechanistical investigation revealed the accumulation of ssDNA and the excessive production of proinflammatory cytokines, including IFN-ß, in Trex1 null pancreas. These are likely contributing to the inflammation in pancreas and eventually leading to the decline of pancreatic ß cells. CONCLUSIONS: Our study links the DNA-induced chronic inflammation to the pathogenesis of type 1 diabetes, and also provides an animal model for type 1 diabetes studies.

Sexual orientation disparities in the prevalence of suicidal ideation among U.S adults aged 20 to 59 years: Results from NHANES 2005-2016.

Existing studies have been limited in providing nationally representative data on the relationship between sexual orientation and suicidal ideation (SI) among adults in the U.S. particularly in terms of gender and racial differences. To fill this research gap, we conducted a study using data from the NHANES conducted between 2005 and 2016. Survey-weighted logistic regression models were used to investigate the relationship between sexual orientation and SI risk. Additionally, we performed further analysis by stratifying the data based on demographic variables and performed sensitivity analysis to ensure the reliability of our findings. This study included a weighted sample of 16,564 adults, representing a noninstitutionalized U.S population of 840.1 million. The overall age-adjusted prevalence of SI was found to be 3.5 %. After adjusting for relevant covariates, the study revealed that individuals who identified as something else, homosexual, and bisexual had a higher prevalence risk of suicidal ideation (SI) compared to heterosexual participants. Additionally, the study found that heterosexual participants were 74.4 % less likely to experience SI compared to bisexual individuals. These findings highlight the urgent requirement for inclusive and supportive prevention strategies to effectively address SI among adult sexual minorities in the U.S.

Synergistic impact of co-exposures to whole blood metals on chronic kidney disease in general US adults: a cross­sectional study of the National Health and Nutrition Examination Survey 2011-2020.

The impact of exposure to metals on chronic kidney disease (CKD) has only been investigated in two-way or single metal interactions in previous studies. We investigated the associations between five single metals in blood and their mixed exposure and CKD by using the machine learning approach. Relevant data were extracted from the National Health and Nutrition Examination Survey (NHANES 2011-2020), and the level of five metals in blood detected by inductively coupled plasma mass spectrometry was considered as exposures, namely, cadmium (Cd), lead (Pb), total mercury (Hg), manganese (Mn), and selenium (Se). The correlations between individual metal and metal mixtures and CKD were then evaluated by survey-multivariable logistic regression (SMLR), generalized weighted quantile sum (WQS), and Bayesian kernel machine regression (BKMR). Altogether, our study included 12,412 participants representing 572.6 million non-institutionalized US adults. Several single metals with the high quartile of exposure showed a positive association with the CKD ratio including Cd [(AOR = 1.873, 95% CI: 1.537, 2.284), Q4], Pb [(AOR = 1.559, 95% CI: 1.295, 1.880), Q4], and total Hg [(AOR = 1.169, 95% CI: 1.018, 1.343), Q2], while Mn [(AOR = 0.796, 95% CI: 0.684, 0.927), Q2] and Se [(AOR = 0.805, 95% CI: 0.664, 0.976), Q4] were negatively associated with the CKD ratio. In light of the positive fit of the WQS regression model, a significantly positive correlation was found between mixed metals and CKD (AOR = 1.373, 95% CI: 1.224, 1.539) after full covariate adjustment, and a similar finding was also detected in the BKMR model. Our study revealed that each single metal including Cd, Pb, and total Hg might have a positive association with CKD while this association was negative for both Mn and Se. The five metals might have a positive joint effect on CKD.

Whether weekend warrior activity and other leisure-time physical activity pattern reduce the risk of depression symptom in the representative adults? A population-based analysis of NHANES 2007-2020.

BACKGROUND: The rapid pace of life nowadays has seen a gradual increase in public involvement in weekend warrior (WW), a physical activity (PA) pattern that allows people to exercise once or twice a week, the recommended moderate-to-vigorous PA per week, since regular PA takes much time. We aim at exploring the effect of WW activity and other PA patterns on depression symptoms in U.S adults. METHODS: The level of PA was measured by self-reporting activity patterns, (inactive, insufficiently active, WW and regularly active). Participants with Patient Health Questionnaire-9 (PHQ-9) scores above 10 are considered to have depression symptoms. RESULTS: A weighted sample of 23,258 participants representing 1049.8 million non-institutionalized U.S adults aged from 20 to 80. Compared with the inactive group, general adults who met the PA guidelines with PA once or twice per week [WW, adjusted odds ratio (AOR) = 0.790, 95%CI: 0.638, 0.987] or more frequent PA [Regularly active, (AOR = 0.761, 95%CI: 0.671, 0.864)], were inversely associated with depression symptoms, while the association has not been observed in adults with insufficiently active PA (AOR = 0.892, 95%CI: 0.783, 1.017). Increase in minutes, sessions and intensity of PA in regularly active and WW groups brought additional benefits for depression symptoms. CONCLUSION: WW and other equivalent PA intensities patterns may be sufficient to reduce the risk of depression symptom. With the same recommended levels of PA, whether spread over the week or done in fewer days, adults may achieve the same benefits.

Joint effect of whole blood metals exposure with dyslipidemia in representative US adults in NHANES 2011-2020.

With little knowledge on the joint effects of metal exposure on dyslipidemia, we aimed to investigate the relationship between exposure to metal and dyslipidemia among US adults based on the National Health and Nutrition Examination Survey (NHANES). Based on the five NHANES waves (2011-2020), we selected five metals in blood as exposure, namely, cadmium (Cd), lead (Pb), total mercury (Hg), manganese (Mn), and selenium (Se), which were detected by inductively coupled plasma mass spectrometry. Survey-multivariable logistic regression, generalized weighted quantile sum (WQS), and Bayesian kernel machine regression (BKMR) were performed to determine whether dyslipidemia was associated with single metals or mixed metals. Our study included 12,526 participants aged from 20 to 80, representing 577.1 million non-institutionalized US adults. We found a positive association between several metals including Pb [adjusted odds ratio (AOR) = 1.332, 95%CI: 1.165, 1.522], total Hg (AOR = 1.264, 95%CI: 1.120, 1.427), Mn (AOR = 1.181, 95%CI: 1.046, 1.334), and Se (AOR = 1.771, 95%CI: 1.576, 1.992) and dyslipidemia. According to the WQS approach, metal mixtures were positively associated with dyslipidemia (AOR: 1.310, 95%CI: 1.216, 1.411) after a full-model adjustment. As is shown in the BKMR model, mixed metals tended to be positively associated with dyslipidemia ratios in a significant manner. Females, non-Hispanic White populations, people aged over 60, and those who did a little physical activity had a greater risk for dyslipidemia. Our findings suggest metals including Cd, Pb, Hg, Mn, and Se and their combinations may adversely affect dyslipidemia among US adults. Due to the cross-sectional nature of the study, it is possible that reverse causation may exist.

Biomarkers of organophosphate insecticides exposure and asthma in general US adults: findings from NHANES 1999-2018 data.

The limited evidence linking exposure to organophosphate insecticides (OPIs) and asthma in the general population prompted us to investigate this association. Our study focused on US adults and utilized representative samples from the National Health and Nutrition Examination Survey (NHANES). From the 7 NHANES waves (1999-2018), we detected OPIs exposure using the urinary concentrations of six metabolites of dialkyl phosphates (DAPs). To evaluate the relationship between these OPIs and asthma, we employed three statistical methods: survey-multivariable logistic regression (SMLR), generalized weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR). Stratified analyses were done based on the relevant variable subgroups, and sensitivity analyses were carried out to evaluate the robustness of findings. A total of 6009 adults aged from 20 to 85 years old, representing the 313.5 million adults in the non-institutionalized US population, were included in our analyses. Among them, 842 participants were determined as asthma patients with an age-adjusted prevalence of 14.2%. Our results showed that dimethyl phosphate (DMP) (adjusted odd ratio (AOR) = 1.471, 95% CI: 1.086, 1.993), diethyl phosphate (DEP) (AOR = 1.453, 95% CI: 1.118, 1.888), dimethyl thiophosphate (DMTP) (AOR = 1.454, 95% CI: 1.071, 1.973), and dimethyl dithiophosphate (DMDTP) (AOR = 1.478, 95% CI: 1.119, 1.953) had a positive correlation with asthma in adults. This association was stronger in females, non-Hispanic White populations and those with a small amount of physical activity. Our study findings indicated that exposure to OPIs may elevate the risk of asthma in US general adults. Specifically, females, individuals from non-Hispanic White backgrounds, and those with lower levels of physical activity are more susceptible to developing asthma when exposed to OPIs.

Findings of indoor air pollution and childhood obesity in a cross-sectional study of Chinese schoolchildren.

BACKGROUND: Air pollution exposures are increasingly suspected to influence the development of childhood adiposity, especially focusing on outdoor exposure, but few studies investigated indoor exposure and childhood obesity. OBJECTIVES: We aimed to examine the association between exposure to multiple indoor air pollutants and childhood obesity in Chinese schoolchildren. METHODS: In 2019, we recruited 6499 children aged 6-12 years from five Chinese elementary schools in Guangzhou, China. We measured age-sex-specific body mass index z score (z-BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) on standard procedures. Four different indoor air pollution (IAP) exposures, including cooking oil fumes (COFs), home decoration, secondhand smoke (SHS), and incense burning, were collected by questionnaire and then converted into an IAP exposure index with four categories. Association between indoor air pollutants and childhood overweight/obesity as well as four obese anthropometric indices were assessed by logistic regression models and multivariable linear regression models, respectively. RESULTS: Children exposed to ≥3 types of indoor air pollutants had higher z-BMI (coefficient [ß]:0.142, 95% confidence interval [CI]:0.011-0.274) and higher risk of overweight/obesity (odd ratio [OR]:1.27, 95%CI:1.01-1.60). And a dose-response relationship was discovered between the IAP exposure index and z-BMI as well as overweight/obesity (pfor trend<0.05). We also found that exposure to SHS and COFs was positively associated with z-BMI and overweight/obesity (p < 0.05). Moreover, there was a significant interaction between SHS exposure and COFs on the higher risk of overweight/obesity among schoolchildren. Boys appear more susceptible to multiple indoor air pollutants than girls. CONCLUSIONS: Indoor air pollution exposures were positively associated with higher obese anthropometric indices and increased odds of overweight/obesity in Chinese schoolchildren. More well-designed cohort studies are needed to verify our results.

Economic burden of cancers in Taiwan: a direct and indirect cost estimate for 2007-2017.

OBJECTIVE: Cancers result in significant economic burdens on patients, health sectors and society. Reliable burden estimates will help guide resource allocation. This study aimed to perform a nationwide cost analysis of the direct and indirect costs of the top ten most costly cancers, and acute coronary syndrome (ACS), as a comparison, in Taiwan. SETTING: A population-based cohort study. PARTICIPANTS: In total, 545 221 patients with newly diagnosed cancer (lung cancer, female breast cancer, colorectal cancer, liver cancer, oral cancer, leukaemia, prostate cancer, non-Hodgkin's lymphoma, gastric cancer and oesophageal cancer) and 170 879 patients with ACS between 2007 and 2014 were identified. PRIMARY AND SECONDARY OUTCOME MEASURES: Direct medical costs were calculated from claims recorded in the National Health Insurance Research Database . Indirect costs, comprising morbidity-associated and mortality-associated productivity losses, were estimated from public life expectancy, average wage and employment data. The costs incurred in the 3 years after diagnosis were assessed. As a comparison, the cost of ACS was also estimated using the same study frame. A cost driver analysis was conducted to identify factors impacting cancer costs. RESULTS: The cancers with the highest mean direct medical costs and total costs were leukaemia (US$28 464) and oesophageal cancer (US$81 775), respectively. Indirect costs accounted for over 50% of the total economic burden of most cancers, except for prostate cancer and female breast cancer. The costs of ACS were lower than those of most cancers. From the cost driver analysis, older age at diagnosis significantly (p<0.05) decreased the total cost of cancer; in contrast, male, tumour metastasis, comorbidities and treatment in medical centres increased the costs. CONCLUSIONS: This study demonstrates the comprehensive economic burden of the top 10 most costly cancers in Taiwan. These results are valuable for optimising healthcare resource allocation.

Acetylation Blocks cGAS Activity and Inhibits Self-DNA-Induced Autoimmunity.

The presence of DNA in the cytoplasm is normally a sign of microbial infections and is quickly detected by cyclic GMP-AMP synthase (cGAS) to elicit anti-infection immune responses. However, chronic activation of cGAS by self-DNA leads to severe autoimmune diseases for which no effective treatment is available yet. Here we report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. We find that cGAS acetylation on either Lys384, Lys394, or Lys414 contributes to keeping cGAS inactive. cGAS is deacetylated in response to DNA challenges. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibit cGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome (AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation and provides a potential therapy for treating DNA-mediated autoimmune diseases.

Genome-Wide Association Study of Susceptibility Loci for Radiation-Induced Brain Injury.

BACKGROUND: Radiation-induced brain injury is a nonnegligible issue in the management of cancer patients treated by partial or whole brain irradiation. In particular, temporal lobe injury (TLI), a deleterious late complication in nasopharyngeal carcinoma, greatly affects the long-term life quality of these patients. Although genome-wide association studies (GWASs) have successfully identified single nucleotide polymorphisms (SNPs) associated with radiation toxicity, genetic variants contributing to the radiation-induced brain injury have not yet been assessed. METHODS: We recruited and performed follow-up for a prospective observational cohort, Genetic Architecture of Radiotherapy Toxicity and Prognosis, using magnetic resonance imaging for TLI diagnosis. We conducted genome-wide association analysis in 1082 patients and validated the top associations in two independent cohorts of 1119 and 741 patients, respectively. All statistical tests were two-sided. RESULTS: We identified a promoter variant rs17111237 (A > G, minor allele frequency [MAF] = 0.14) in CEP128 associated with TLI risk (hazard ratio = 1.45, 95% confidence interval = 1.26 to 1.66, Pcombined=3.18 × 10-7) which is in moderate linkage disequilibrium (LD) with rs162171 (MAF = 0.18, R2 = 0.69), the top signal in CEP128 (hazard ratio = 1.46, 95% confidence interval = 1.29-1.66, Pcombined= 6.17 × 10-9). Combining the clinical variables with the top SNP, we divided the patients into different subgroups with varying risk with 5-year TLI-free rates ranging from 33.7% to 95.5%. CEP128, a key component of mother centriole, tightly interacts with multiple radiation-resistant genes and plays an important role in maintaining the functional cilia, which otherwise will lead to a malfunction of the neural network. We found that A > G alteration at rs17111237 impaired the promoter activity of CEP128 and knockdown of CEP128 decreased the clonogenic cell survival of U87 cells under radiation. Noteworthy, 12.7% (27/212) of the GWAS-based associated genes (P < .001) were enriched in the neurogenesis pathway. CONCLUSIONS: This three-stage study is the first GWAS of radiation-induced brain injury that implicates the genetic susceptibility gene CEP128 involved in TLI development and provides the novel insight into the underlying mechanisms of radiation-induced brain injury.

Natural Variations in BRLF1 Promoter Contribute to the Elevated Reactivation Level of Epstein-Barr Virus in Endemic Areas of Nasopharyngeal Carcinoma.

BACKGROUND: Epstein-Barr virus (EBV) infection is a crucial risk factor for nasopharyngeal carcinoma (NPC), but the mechanism for its elevated activation level in NPC endemic areas remains unclear. This study aims to identify the EBV natural variations contributed to the different reactivation potential between NPC endemic and non-endemic areas. METHODS: 1030 subjects were recruited in China, including 303 healthy individuals from two NPC non-endemic areas, 483 healthy people from three endemic areas and 244 NPC patients. Among which, saliva DNA samples from 244 participants were sequenced for the EBV immediate early (IE) genes of BRLF1 and BZLF1, their promoters were included; the rest 786 subjects were used for the validation of significant variations among three different populations. Haplotype and population structure analysis were conducted. Dual-luciferase assay was used to detect the promoter activity. RESULTS: A total of 246 distinct variations were detected, 29 showed significant difference in the frequencies between healthy people from NPC endemic area and non-endemic area. Population structure analysis clustered EBV strains into 9 subgroups mostly in accordance with the geographical origin of samples. Interestingly, two EBV genotypes, Rp-V1 and Rp-V2, were identified according to the linkage relationship of the variations in BRLF1 promoter (Rp). Rp-V1 has higher frequency in NPC endemic areas than in non-endemic areas (52.38% vs 18.15%, P = 2.07 × 10-14), and was associated with higher oral EBV DNA levels (adjusted OR = 1.64, 95% CI = 1.21-2.24, P = .002), suggesting a more powerful activation ability of Rp-V1 than that of the prototype Rp-of the EBV strain; On the contrary, Rp-V2 has higher frequency in NPC non-endemic areas than in endemic areas (18.48% vs 0.38%, P = 1.17 × 10-7), might represent a reduced activation potential of EBV. Further dual-luciferase assay showed Rp-V1 has higher promoter activity while compared with Rp-V2 (P < .0001). Notably, Rp-V1 impaired the transcription repression effect of YY1 while Rp-V2 strengthened the transcription repression effect of EBF1 on Rp. In addition, significant differences of Rta 393-407 CTL epitope which may influence the recognition of Rta by CD8+ T cells were detected between healthy people from NPC endemic area and non-endemic area. CONCLUSIONS: This study identified natural variations in cis-acting elements (YY1 and EBF1) of EBV Rp altering Rp transcription activities, which may contribute to the elevated EBV activation level in NPC endemic areas than non-endemic areas.

Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis.

The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.

Association of the Asp312Asn and Lys751Gln polymorphisms in the XPD gene with the risk of non-Hodgkin's lymphoma: evidence from a meta-analysis.

Polymorphisms in DNA repair genes may alter DNA repair capacity and, consequently, lead to genetic instability and carcinogenesis. Several studies have investigated the association of the Asp312Asn and Lys751Gln polymorphisms in the xeroderma pigmentosum complementation group D (XPD) gene with the risk of non-Hodgkin's lymphoma (NHL), but the conclusions have been inconsistent. Therefore, we performed this meta-analysis to more precisely estimate these relationships. A systematic literature search was performed using the PubMed, Embase, and Chinese Biomedical (CBM) databases. Ultimately, 6 studies of Asp312Asn, comprising 3,095 cases and 3,306 controls, and 7 studies of Lys751Gln, consisting of 3,249 cases and 3,676 controls, were included. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of each association. Overall, no association was observed between the Asp312Asn polymorphism and NHL risk (homozygous: OR = 1.11, 95% CI = 0.94-1.32; heterozygous: OR = 1.00, 95% CI = 0.89-1.11; recessive: OR = 1.12, 95% CI = 0.95-1.31; dominant: OR = 1.02, 95% CI = 0.92-1.13; and allele comparison: OR = 1.04, 95% CI = 0.96-1.12) or between the Lys751Gln polymorphism and NHL risk (homozygous: OR = 0.97, 95% CI = 0.83-1.15; heterozygous: OR = 0.96, 95% CI = 0.86-1.06; recessive: OR = 1.00, 95% CI = 0.86-1.16; dominant: OR = 0.96, 95% CI = 0.87-1.06; and allele comparison: OR = 0.98, 95% CI = 0.91-1.05). Furthermore, subgroup analyses did not reveal any association between these polymorphisms and ethnicity, the source of the controls, or the NHL subtype. These results indicated that neither the Asp312Asn nor Lys751Gln XPD polymorphism was related to NHL risk. Large and well-designed prospective studies are required to confirm this finding.

The association between the polymorphisms of TNF-α and non-Hodgkin lymphoma: a meta-analysis.

Many genetic variations in the promoter region of tumor necrosis factor alpha (TNF-α) may confer host susceptibility to cancer by influencing TNF-α expression. Nevertheless, the results remain inconclusive. The current meta-analysis was performed to investigate the association between three common TNF-α promoter polymorphisms and the risk of non-Hodgkin lymphoma (NHL). A literature search was conducted mainly from PubMed for all eligible studies. The pooled odds ratios (ORs) and corresponding 95 % confidence intervals (CIs) were used to assess the association of TNF-α polymorphisms with the risk of NHL. TNF-α -308 A allele showed a statistically significant increased risk for NHL under the homozygous (AA vs. GG, OR = 1.51, 95 % CI = 1.26-1.80) and recessive (OR = 1.47, 95 % CI = 1.23-1.75) models, respectively. The stratified analyses showed an increased risk of NHL with the presence of TNF-α -308 A allele among Africans and Caucasians, but a decreased risk among Asians. No association was observed between -238 G/A polymorphism and NHL risk either in the overall analysis or in the stratified analysis. Similarly, pooled analysis did not reveal an altered risk of NHL with -857 C/T polymorphism. Nonetheless, a statistically significant association was observed among Asians when stratified by ethnicity. Among the three genetic variations of interest, TNF-α -308 G/A polymorphism was significantly associated with the risk of NHL; neither -238 G/A nor -857 C/T polymorphism was shown to alter the overall NHL risk; however, stratified analysis by ethnicity observed a statistically significant association between -857 C/T polymorphism and the risk of NHL among Asians.

Association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma susceptibility: evidence from a meta-analysis.

Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism and DNA synthesis. A number of studies have examined the association of MTHFR C677T and A1298C polymorphisms with non-Hodgkin lymphoma (NHL) susceptibility; however, the conclusions were contradictory. We searched available publications assessing the polymorphisms of MTHFR and NHL susceptibility from MEDLINE, EMBASE and CBM. Genotype-based mRNA expression analysis was performed using data from 270 individuals with three different ethnicities. Ultimately, a total of 7448 cases and 11146 controls from 25 studies were included for the C677T polymorphism, 6173 cases and 9725 controls from 19 studies for the A1298C polymorphism. Pooled results indicated that neither C677T nor A1298C polymorphism was associated with NHL susceptibility. However, C677T polymorphism showed a statistically significantly increased risk for Caucasians, but a decreased risk for Asians in the subgroup analysis by ethnicity. The same variants may confer increased susceptibility to develop follicular lymphoma (FL). Moreover, A1298C polymorphism was associated with increased NHL risk for Asians. This meta-analysis indicated that C677T polymorphism was associated with altered NHL susceptibility for Caucasians, Asians and FL. Increased NHL risk was also shown for A1298C among Asians. These findings warrant validation in large and well-designed prospective studies.

Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain.

Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play a major role in physiological and pathological events involving bioactive KP metabolites. To explore this role in greater detail, we generated mice with a targeted genetic disruption of Kmo and present here the first biochemical and neurochemical characterization of these mutant animals. Kmo(-/-) mice lacked KMO activity but showed no obvious abnormalities in the activity of four additional KP enzymes tested. As expected, Kmo(-/-) mice showed substantial reductions in the levels of its enzymatic product, 3-hydroxykynurenine, in liver, brain, and plasma. Compared with wild-type animals, the levels of the downstream metabolite quinolinic acid were also greatly decreased in liver and plasma of the mutant mice but surprisingly were only slightly reduced (by ∼20%) in the brain. The levels of three other KP metabolites: kynurenine, kynurenic acid, and anthranilic acid, were substantially, but differentially, elevated in the liver, brain, and plasma of Kmo(-/-) mice, whereas the liver and brain content of the major end product of the enzymatic cascade, NAD(+), did not differ between Kmo(-/-) and wild-type animals. When assessed by in vivo microdialysis, extracellular kynurenic acid levels were found to be significantly elevated in the brains of Kmo(-/-) mice. Taken together, these results provide further evidence that KMO plays a key regulatory role in the KP and indicate that Kmo(-/-) mice will be useful for studying tissue-specific functions of individual KP metabolites in health and disease.