NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression.

The ubiquitination-mediated protein degradation exerts a vital role in the progression of multiple tumors. NEDD4L, which belongs to the E3 ubiquitin ligase NEDD4 family, is related to tumor genesis, metastasis and drug resistance. However, the anti-tumor role of NEDD4L in esophageal carcinoma, and the potential specific recognition substrate remain unclear. Based on public esophageal carcinoma database and clinical sample data, it was discovered in this study that the expression of NEDD4L in esophageal carcinoma was apparently lower than that in atypical hyperplastic esophageal tissue and esophageal squamous epithelium. Besides, patients with high expression of NEDD4L in esophageal carcinoma tissue had longer progression-free survival than those with low expression. Experiments in vivo and in vitro also verified that NEDD4L suppressed the growth and metastasis of esophageal carcinoma. Based on co-immunoprecipitation and proteome analysis, the NEDD4L ubiquitination-degraded protein ITGB4 was obtained. In terms of the mechanism, the HECT domain of NEDD4L specifically bound to the Galx-ß domain of ITGB4, which modified the K915 site of ITGB4 in an ubiquitination manner, and promoted the ubiquitination degradation of ITGB4, thus suppressing the malignant phenotype of esophageal carcinoma.

The potential health effects associated with electronic-cigarette.

A good old gateway theory that electronic-cigarettes (e-cigarettes) are widely recognized as safer tobacco substitutes. In actuality, demographics also show that vaping cannibalizes smoking, the best explanation of the data is the "common liability". However, the utilization of e-cigarette products remains a controversial topic at present. Currently, there has been a widespread and substantial growth in e-cigarette use worldwide owing to their endless new flavors and customizable characteristics. Furthermore, e-cigarette has grown widespread among smokers as well as non-smokers, including adolescents and young adults. And some studies have shown that e-cigarette users are at greater risk to start using combustible cigarettes while e-cigarettes use was also observed the potential benefits to people who want to quit smoking or not. Although it is true that e-cigarettes generally contain fewer toxic substances than combustible cigarettes, this does not mean that the chemical composition in e-cigarettes aerosols poses absolutely no risks. While concerns about toxic substances in e-cigarettes and their widespread use in the population are reasonable, it is also crucial to consider that e-cigarettes have been associated with the potential for promoting smoking cessation and the clinically relevant improvements in users with smoking-related pathologies. Meanwhile, there is still short of understanding of the health impacts associated with e-cigarette use. Therefore, in this review, we discussed the health impacts of e-cigarette exposure on oral, nasal, pulmonary, cardiovascular systems and brain. We aspire for this review to change people's previous perceptions of e-cigarettes and provide them with a more balanced perspective. Additionally, we suggest appropriate adjustments on regulation and policy for e-cigarette to gain greater public health benefits.

Multi-omics and multi-stages integration identified a novel variant associated with silicosis risk.

Assessing the association between candidate single-nucleotide polymorphisms (SNPs) identified by multi-omics approaches and susceptibility to silicosis. RNA-seq analysis was performed to screen the differentially expressed mRNAs in the fibrotic lung tissues of mice exposed to silica particles. Following this, we integrated the SNPs located in the above human homologenes with the silicosis-related genome-wide association study (GWAS) data to select the candidate SNPs. Then, expression quantitative trait locus (eQTL)-SNPs were identified by the GTEx database. Next, we validated the associations between the functional eQTL-SNPs and silicosis susceptibility by additional case-control study. And the contribution of the identified SNP and its host gene in the fibrosis process was further validated by functional experiments. A total of 12 eQTL-SNPs were identified in the screening stage. The results of the validation stage suggested that the variant T allele of rs419540 located in IL12RB1 significantly increased the risk of developing silicosis [additive model: odds ratio (OR) = 1.78, 95% confidence interval (CI) 1.11-2.85, P = 0.017]. Furthermore, the combination of GWAS and the results of validation stage also indicated that the variant T allele of rs419540 in IL12RB1 was associated with increased silicosis risk (additive model: OR = 2.07, 95% CI 1.38-3.12, P < 0.001). Additionally, after knockdown or overexpression of IL12RB1, the levels of pro-inflammatory factors, such as IL-12, IFN-γ, and other pro-inflammatory factors, were correspondingly decreased or increased. The novel eQTL-SNP, rs419540, might increase the risk of silicosis by modulating the expression levels of IL12RB1.

Integration of apaQTL and eQTL analysis reveals novel SNPs associated with occupational pulmonary fibrosis risk.

To explore the association between apaQTL/eQTL-SNPs and the susceptibility to silicosis. A silicosis-related GWAS was initially conducted to screen for single nucleotide polymorphisms (SNPs) associated with the risk of silicosis. Candidate SNPs with apaQTL and eQTL functions were then obtained from the 3'aQTL-atlas and GTEx databases. Subsequently, additional case-control studies were performed to validate the relationship between the candidate apaQTL/eQTL-SNPs and the risk of silicosis. Finally, experiments were conducted to illustrate APA events occurring at different alleles of the identified apaQTL/eQTL-SNPs. The combined results of the GWAS and iMLDR validations indicate that the variant T allele of the rs2974341 located on SMIM19 (additive model: OR = 0.66, the 95% CI = 0.53-0.84, P = 0.001) and the variant T allele of the rs2390488 located on TMTC4 (additive model: OR = 0.72, 95% CI = 0.57-0.90, P = 0.005) were significantly associated with decreased risk of developing silicosis susceptibility. Furthermore, 3'RACE experiments verified the presence of two poly (A) sites (proximal and distal) in SMIM19, rs2974341 may remotely regulate the binding between miRNA-3646 and SMIM19 with its high LD locus rs2974353 to affect the expression level of SMIM19. The rs2974341 variant T allele may contribute to the generation of the shorter 3'UTR transcript of SMIM19 and affect the binding of miRNA-3646 to the target gene SMIM19. The apaQTL/eQTL-SNPs may provide new perspectives for evaluating the regulatory function of SNPs in the development of silicosis.

The Impact of Customized Short Message Service on High-Risk Behaviors Among MSM in China, a Randomized Controlled Trial Study.

An individual based randomized controlled trial (RCT) was designed to evaluate the impact of a customized short message service (SMS) intervention on HIV-related high-risk behaviors among Men who have sex with men (MSM). In total, 631 HIV-negative MSM were enrolled at baseline and divided into intervention and control groups randomly. Nine months later, the intervention group who received additional customized SMS intervention reported significantly lower rates of multiple partners, unclear partner infection status and condomless anal intercourse compared to the control group who received the routine intervention only. Six months post stopping the SMS intervention, the rates of unclear partner infection status and condomless anal intercourse still remained lower report in the intervention group. Our study shown that the customized SMS interventions can significantly reduce the HIV-related high-risk behaviors among MSM and with sustained effects over a period of time.

Cost-effectiveness analysis of antiretroviral drugs for treatment-naive HIV infection in China.

INTRODUCTION: Dolutegravir (DTG)-based regimen was included in the expanded formulary of China's National Free Antiretroviral Treatment Program at the end of 2021. Yet high price of DTG and lack of health economic evaluation in China present barriers for implementation of the regimen. The study aims to investigate the lifetime cost-effectiveness of DTG-based regimen for treatment-naive HIV infection in China. METHODS: A decision-analytic Markov model was used to obtain the costs and effectiveness of four regimens: Arm A, efavirenz (EFV)-based regimen; Arm B, DTG-based regimen; Arm C, elvitegravir/cobicistat/tenofovir alafenamide/emtricitabine (EVG/c/FTC/TAF) regimen; Arm D, abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) regimen. The potential impact of national centralized drug procurement policy was assessed in scenario analysis. The results were further validated through sensitivity analysis. RESULTS: Compared with other three regimens, DTG-based regimen led to the fewest cumulative adverse reactions, opportunistic infections and deaths. Compared with EFV-based regimen, the base-case ICERs for DTG-based regimen were 13,357 (USD/QALY) and 13,424 (USD/QALY) from the healthcare system and societal perspective respectively. In the policy scenario analysis with the procurement price of DTG equal to that of LPV/r, DTG-based regimen would be dominant. The model results remained robust in sensitivity analyses. CONCLUSIONS: DTG-based regimen for treatment-naive patients is likely to be cost-effective and deserve wider implementation in China. This study strongly suggests the centralized procurement of DTG to minimize cost and maximize cost-effectiveness.

A novel circRNA-SNP may increase susceptibility to silicosis.

In this study, we aimed to reveal the association between circRNA-related single nucleotide polymorphisms (SNPs) with the susceptibility of silicosis. To achieve this goal, a silicosis-related GWAS was constructed to select the candidate SNPs, and circBase database was utilized to select the promising SNPs which may locate on circRNAs. In addition, the eQTL analysis between the SNPs and located genes was performed to select the candidate SNPs. Finally, the association between candidate SNPs with the susceptibility of silicosis was validated. As a result, we firstly selected 10,922 SNPs with P < 1 × 10-3 through the silicosis-related GWAS. Among which, 1,752 SNPs were identified that may locate on 2,660 circRNAs. After the MAF evaluation and the sequences checking, we obtained 94 SNPs and related 105 circRNAs. EQTL analysis indicated that 7 circRNA-SNPs might regulate the expression of located genes. Subsequently, a strong association was found between variant A of rs17115143 and silicosis risk in the validation stage (OR= 1.68, P = 0.032). Combination of the GWAS data and Taqman genotyping data also revealed a strong association between rs17115143 and silicosis risk in both dominant and additive models (dom: OR= 1.96, P = 3.98 × 10-4; add: OR= 1.40, P = 3.06 × 10-4). In conclusion, the variant A allele of circRNA-SNP rs17115143 could be a risk factor in the progression of silicosis. And related 6 circRNAs may function as novel biomarkers for the diagnostic of silicosis. Further researches to explore the biological mechanisms of rs17115143 related 6 circRNAs in the regulation of silicosis are warranted.

Peripheral blood circular RNA hsa_circ_0058493 as a potential novel biomarker for silicosis and idiopathic pulmonary fibrosis.

Existing studies reported that some circular RNAs (circRNAs) play vital roles in the development of pulmonary fibrosis. However, few studies explored the biomarker potential of circRNAs for pulmonary fibrosis based on population data. Therefore, we aimed to identify peripheral blood circRNAs as potential biomarkers for diagnosing silicosis and idiopathic pulmonary fibrosis (IPF). In brief, an RNA-seq screening based on 4 silicosis cases and 4 controls was initially performed. Differentially expressed circRNAs were combined with the human serum circRNA dataset to identify overlapping serum-detectable circRNAs, followed by validation using the GEO dataset (3 IPF cases and 3 controls) and subsequent qRT-PCR, including 84 additional individuals. Following the above steps, 243 differentially expressed circRNAs were identified during the screening stage, with fold changes ≥ 1.5 and P < 0.05. Of note, the human serum circRNA dataset encompassed 28 of 243 circRNAs. GEO (GSE102660) validation revealed two highly expressed circRNAs (P < 0.05) in the IPF case group. Furthermore, at the enlarged sample validation stage, hsa_circ_0058493 was highly expressed in both silicosis and IPF cases (silicosis: P = 1.16 × 10-6; IPF: P = 7.46 × 10-5). Additionally, hsa_circ_0058493 expression was significantly increased in MRC-5 cells upon TGF-ß1 treatment, while hsa_circ_0058493 knockdown inhibited the expression of fibrotic molecules by affecting the epithelial-mesenchymal transition process. These shreds of evidence indicated that hsa_circ_0058493 might serve as a novel biomarker for diagnosing silicosis and IPF.

Knowledge and practice of diabetic foot care and the prevalence of diabetic foot ulcers among diabetic patients of selected hospitals in the Volta Region, Ghana.

Diabetic foot ulcers (DFUs) are a common but serious complication of diabetes mellitus (DM). The factors distressing the worth of diabetic foot care (DFC) are knowledge and practice. Foot ulcers are the main cause of amputation and death in people suffering from DM. This study assessed the knowledge and practice of DFC and the prevalence of DFUs and its associated factors among diabetic patients of selected hospitals in the Volta Region, Ghana. A multihospital-based cross-sectional study was conducted among 473 patients with DM who were recruited using the systematic sampling method. Data were collected using a validated, pretested, and structured questionnaire, while medical variables were obtained from patient folders and analysed using SPSS version 23. All statistically significant parameters in bivariate analysis were incorporated in the multivariate logistic regression analysis. The results showed that 63% of diabetic patients had good knowledge of DFC, while 49% competently practiced it. A negative correlation was found between knowledge and practice levels of DFC (r = -0.15, P = <.01). The prevalence of DFUs was 8.7% among the studied diabetic patients. Male diabetic patients were 3.4 times more likely to develop DFUs than female diabetic patients (crude odd ratio [cOR] = 3.35; 95% confidence interval [CI] = 1.75-6.43; P = <.001). Type 1 diabetic patients were five times more likely to develop DFUs than those who had type 2 diabetes (cOR = 5.00; 95% CI = 2.50-10.00; P = <.001). Diabetic patients who had a family history of diabetes were 4.7 times more likely to develop DFUs than those without family history (adjusted odd ratio [aOR] = 4.66; 95% CI = 1.55-13.89; P = .006). Those who had diabetes for 5 to 10 years were 3.3 times more likely to develop DFUs than those who had diabetes for less than 5 years (aOR = 3.28; 95% CI = 1.40-7.67; P = .006). Diabetic patients who had comorbidity were 3.4 times more likely to develop DFUs than those without comorbidity (cOR = 3.35; 95% CI = 1.74-6.45; P = <.001). The study found that there was good knowledge but poor practices of DFC among patients. Health care providers are expected to better educate patients and emphasise self-care practices to patients. Health care providers should also give more attention to patients with associated risk factors to avoid further complications and reduce the occurrence of DFUs.

Tetrandrine Treatment May Improve Clinical Outcome in Patients with COVID-19.

Background and objectives: The COVID-19 pandemic continues worldwide, and there is no effective treatment to treat it. Chinese medicine is considered the recommended treatment for COVID-19 in China. This study aimed to examine the effectiveness of tetrandrine in treating COVID-19, which is originally derived from Chinese medicine. Materials and Methods: A total of 60 patients, categorized into three types (mild, moderate, severe), from Daye Hospital of Chinese Medicine with a diagnosis of COVID-19 were included in this study. Demographics, medical history, treatment, and results were collected. We defined two main groups according to the clinical outcome between improvement and recovery. All underlying factors including clinical outcomes were assessed in the total number of COVID-19 patients and moderate-type patients. Results: In a total of 60 patients, there were significant differences in the clinical outcome underlying treatment with antibiotics, tetrandrine, and arbidol (p < 0.05). When the comparison was limited to the moderate type, treatment with tetrandrine further increased recovery rate (p = 0.007). However, the difference disappeared, and no association was indicated between the clinical outcome and the treatment with and without antibiotic (p = 0.224) and arbidol (p = 0.318) in the moderate-type patients. In all-type and moderate-type patients, tetrandrine improved the rate of improvement in cough and fatigue on day 7 (p < 0.05). Conclusions: Tetrandrine may improve clinical outcome in COVID-19 patientsand could be a promising potential natural antiviral agent for the prevention and treatment of COVID-19.

Comparison of different obesity indices related with hypertension among different sex and age groups in China.

BACKGROUND AND AIMS: To compare the relationships of five obesity-related routine anthropometric indicators (body mass index (BMI), body adiposity index (BAI), waist circumference (WC), waist-to-hip ratio (WHR), waist-to-height ratio (WHtR)) for hypertension in both sexes and among different age groups of the Chinese population. METHODS AND RESULTS: A total of 12,064 adult participants (5638 males and 6426 females) were included. Odds ratios (OR) and 95% confidence intervals were used with binary logistic regression models to estimate the risk of hypertension for each obesity index. For the males, WHtR had the highest OR value in all age groups. The degrees of correlation between hypertension and the obesity indices for different age groups were different among the females. WC, BMI, and WHtR were the highest in the 18-44, 45-59, and ≥60 years age groups, respectively. Furthermore, we compared the area under the ROC curve (AUC) of each obesity index for the criterion of hypertension under the influence of risk factors. For the males, the AUC of WHtR was the largest (0.814, 0.710, and 0.662). WC (AUC = 0.820), BMI (AUC = 0.765), and WHtR (AUC = 0.668) tended to be the best criteria for hypertension among females in the 18-44, 45-59, and ≥60 years age groups respectively. In addition, BAI, as an obesity indicator proposed in recent years, has a positive association with hypertension except in 18-44 years women, which was not stronger than other obesity indicators. CONCLUSIONS: For males, WHtR appears to be the best obesity index related with hypertension. For young, middle-aged, and elderly women, the best obesity indices related with hypertension are WC, BMI, and WHtR, respectively.

A novel regQTL-SNP and the risk of lung cancer: a multi-dimensional study.

RegQTL, a novel concept, indicates that different genotypes of some SNPs have differential effects on the expression patterns of miRNAs and their target mRNAs. We aimed to identify the association between regQTL-SNPs and lung cancer risk and to explore the underlying mechanisms. The two-stage case-control study included the first stage in a Chinese population (626 lung cancer cases and 667 healthy controls) and the second stage in a European population (18,082 lung cancer cases and 13,780 healthy controls). Functional annotations were conducted based on the GTEx and the TCGA databases. Functional experiments were performed to explore the underlying biological mechanisms in vitro and vivo. After strict screening, five candidate regQTL-SNPs (rs7110737, rs273957, rs6593210, rs3768617, and rs6836432) were selected. Among them, the variant T allele of rs3768617 in LAMC1 was found to significantly increase the risk of lung cancer (first stage: P = 0.044; second stage: P = 0.007). The eQTL analysis showed that LAMC1 expression level was significantly higher in subjects with the variant T allele of rs3768617 (P = 1.10 × 10-14). In TCGA paired database, the regQTL annotation indicated the different expression patterns between LAMC1 and miRNA-548b-3p for the distinct genotypes of rs3768617. Additionally, LAMC1 knockdown significantly inhibited malignant phenotypes in lung cancer cell lines and suppressed tumor growth. A novel regQTL-SNP, rs3768617, might affect lung cancer risk by modulating the expression patterns of miRNA-548b-3p and LAMC1. RegQTL-SNPs could provide a new perspective for evaluating the regulatory function of SNPs in lung cancer development.

The risk to child nutrition during and after COVID-19 pandemic: what to expect and how to respond.

OBJECTIVE: The current study aimed to address the key areas of concern for child nutrition, both during and after the COVID-19 pandemic, and proposes strategic responses to reduce child undernutrition in the short and long term. DESIGN: A descriptive literature review was performed. The search of the literature was conducted through using electronic databases including PubMed, Web of Science, Google Scholar and Cochrane library. SETTING: A wide range of published articles focused on child malnutrition were reviewed. PARTICIPANTS: The study was focused on children especially those under 5 years. RESULTS: The current study proposes strategic responses to reduce child undernutrition. These responses include strengthening access to community-based nutrition services that support the early detection and treatment of undernourished children and emergency food distribution, including fortified foods with vitamins and minerals, to vulnerable households, particularly those with children under 5 years. Moreover, counseling and promotion programmes should be reinforced to revitalise community nutrition education in areas such as gestation, exclusive breast-feeding and complementary feeding, and hygienic practices involving handwashing, proper sanitation and other basic behavioural changes. CONCLUSIONS: The COVID-19 pandemic has affected many countries especially those in the regions of South Asia and sub-Saharan Africa in which there has been an ongoing burden of child undernutrition. However, malnutrition is preventable and can be eliminated through a multisectoral strategic approach. The effective execution of a multisectoral approach towards preventing childhood malnutrition will require not only a financial investment but also the collective efforts from different ministries of the governments, UN-affiliated agencies and non-governmental organisations.

Food safety knowledge, attitude, and hygiene practices of street-cooked food handlers in North Dayi District, Ghana.

BACKGROUND: Food safety and hygiene are currently a global health apprehension especially in unindustrialized countries as a result of increasing food-borne diseases (FBDs) and accompanying deaths. This study aimed at assessing knowledge, attitude, and hygiene practices (KAP) of food safety among street-cooked food handlers (SCFHs) in North Dayi District, Ghana. METHODS: This was a descriptive cross-sectional study conducted on 407 SCFHs in North Dayi District, Ghana. The World Health Organization's Five Keys to Safer Food for food handlers and a pretested structured questionnaire were adapted for data collection among stationary SCFHs along principal streets. Significant parameters such as educational status, average monthly income, registered SCFHs, and food safety training course were used in bivariate and multivariate logistic regression models to calculate the power of the relationships observed. RESULTS: The majority 84.3% of SCFHs were female and 56.0% had not attended a food safety training course. This study showed that 67.3%, 58.2%, and 62.9% of SCFHs had good levels of KAP of food safety, respectively. About 87.2% showed a good attitude of separating uncooked and prepared meal before storage. Good knowledge of food safety was 2 times higher among registered SCFHs compared to unregistered [cOR=1.64, p=0.032]. SCFHs with secondary education were 4 times good at hygiene practices of food safety likened to no education [aOR=4.06, p=0.003]. Above GHc1500 average monthly income earners were 5 times good at hygiene practices of food safety compared to below GHc500 [aOR=4.89, p=0.006]. Registered SCFHs were 8 times good at hygiene practice of food safety compared to unregistered [aOR=7.50, p<0.001]. The odd for good hygiene practice of food safety was 6 times found among SCFHs who had training on food safety courses likened to those who had not [aOR=5.97, p<0.001]. CONCLUSIONS: Over half of the SCFHs had good levels of KAP of food safety. Registering as SCFH was significantly associated with good knowledge and hygiene practices of food safety. Therefore, our results may present an imperative foundation for design to increase food safety and hygiene practice in the district, region, and beyond.

A Nationwide Spatiotemporal Analysis of Syphilis Over 21 Years and Implications for Prevention and Control in China.

Syphilis control programs have been scaled up due to the substantial burden in China. We analyzed syphilis incidence according to demographic, spatiotemporal, and economic factors. The increasing latent syphilis diagnoses and declining congenital syphilis suggest the effectiveness of scale-up screening. However, primary and secondary cases persist, especially in inland provinces.

Effectiveness of Lifestyle and Drug Intervention on Hypertensive Patients: a Randomized Community Intervention Trial in Rural China.

BACKGROUND: Strict medication guidance and lifestyle interventions to manage blood pressure (BP) in hypertensive patients are typically difficult to follow. OBJECTIVE: To evaluate the 1-year effectiveness of lifestyle and drug intervention in the management of rural hypertensive patients. DESIGN: Randomized community intervention trial. PARTICIPANTS: The control group comprised 967 patients who received standard antihypertensive drug intervention therapy from two communities, whereas the intervention group comprised 1945 patients who received antihypertensive drug and lifestyle intervention therapies from four communities in rural China. MAIN MEASURES: Data on lifestyle behaviors and BP measurements at baseline and 1-year follow-up were collected. A difference-in-difference logistic regression model was used to assess the effect of the intervention. KEY RESULTS: BP control after the 1-year intervention was better than that at baseline in both groups. The within-group change in BP control of 59.3% in the intervention group was much higher than the 25.2% change in the control group (P < 0.001). Along with the duration of the follow-up period, systolic and diastolic BP decreased rapidly in the early stages and then gradually after 6 months in the intervention group (P < 0.001). In the intervention group, drug therapy adherence was increased by 39.5% (from 48.1% at 1 month to 87.6% at 1 year) (P < 0.001), more in women (45.6%) than in men (31.2%; P < 0.001). The net effect of the lifestyle intervention improved the rate of BP control by 56.1% (70.8% for men and 44.7% for women). For all physiological and biochemical factors, such as body mass index, waist circumference, lipid metabolism, and glucose control, improvements were more significant in the behavioral intervention group than those in the control group (all P < 0.001). CONCLUSION: The addition of lifestyle intervention by physicians or nurses helps control BP effectively and lowers BP better than usual care with antihypertensive drug therapy alone.

miRNA sequencing reveals miRNA-4508 from peripheral blood lymphocytes as potential diagnostic biomarker for silica-related pulmonary fibrosis: A multistage study.

BACKGROUND AND OBJECTIVE: This study aimed to identify miRNA as potential diagnostic biomarkers for silica-related pulmonary fibrosis (SPF). METHODS: We first performed a comprehensive miRNA-seq screening in PBL of eight subjects exposed to silica dust (four individuals with SPF and four healthy controls). The promising miRNA were then evaluated in the first-stage validation using an independent GEO data set (GSE80555) of 6 subjects (3 individuals with SPF and 3 healthy controls), followed by a second-stage validation using 120 subjects exposed to silica dust (60 individuals with SPF and 60 healthy controls). RESULTS: Thirty-five miRNA showed strong expression differences in miRNA-seq screening, while miRNA-4508 (P = 9.52 × 10-3 ) was retained as a candidate after the first-stage validation (GSE80555), which was further confirmed in the second-stage validation with similar and strong effect (P = 9.93 × 10-17 ). ROC analysis showed that miRNA-4508 could distinguish SPF cases from healthy controls with high AUC (0.886), with sensitivity of 81.7% and specificity of 86.7%. In addition, the miRNA-4508 upstream rs6576457 mutant A allele exhibited a strong association with susceptibility to SPF (OR = 1.64, 95% CI = 1.20-2.23, P = 0.002), while eQTL analysis revealed a potential association between different genotypes of rs6576457 and miRNA-4508 expression (P = 0.068) in 60 healthy subjects with silica dust exposure. CONCLUSION: miRNA-4508 may be a potential diagnostic marker for SPF, and rs6576457, a functional variant of miRNA-4508, may affect SPF susceptibility. The detailed mechanism of action of this miRNA remains to be elucidated.

Putative functional variants of PI3K/AKT/mTOR pathway are associated with knee osteoarthritis susceptibility.

BACKGROUND: Osteoarthritis (OA) is a degenerative musculoskeletal disease which causes joint deformity and pain and finally leads to limb dysfunction. Knee osteoarthritis (KOA) has the highest incidence among all kinds of OA. Strong evidence leads to the understanding that P13K/AKT/mTOR signaling is very important in cartilage degeneration. METHODS: This research sought to understand the association between genetic variation of PI3K/AKT/mTOR genes and KOA susceptibility among Chinese population. All the genetic variants of PI3K/AKT/mTOR pathway were graded and selected using RegulomeDB database, and then, an association study including 278 osteoarthritis patients and 289 controls was conducted. RESULTS: Finally, eight SNPs' genotypes' distributions and susceptibility to KOA were presented. AKT1 rs2498789 was associated with KOA susceptibility in dominate genetic model (AA + GA vs GG) after adjusted for BMI, age, and gender: OR = 1.46, 95% CI: 1.03-2.05, P = .03. PIK3CA rs7646409 was also associated with KOA susceptibility (TC vs TT) after adjusted for BMI, age, and gender: OR = 0.58, 95% CI: 0.36-0.93, P = .02. PIK3CA rs7646409 (TC vs TT) with KOA risk was more significant in age < 60 group (P for heterogeneity was .03). Risk score showed significant association with KOA susceptibility after cumulative analysis (OR = 2.45, 95% CI: 1.35-4.45, P = .003). CONCLUSIONS: This study shows that genetic variation of PI3K/AKT/mTOR is associated with KOA susceptibility in Chinese Han population, indicating that PI3K/AKT/mTOR is very important in KOA pathogenesis.

Functional variant of the carboxypeptidase M (CPM) gene may affect silica-related pneumoconiosis susceptibility by its expression: a multistage case-control study.

OBJECTIVES: In a genome-wide association study, we discovered chromosome 12q15 (defined as rs73329476) as a silica-related pneumoconiosis susceptibility region. However, the causal variants in this region have not yet been reported. METHODS: We systematically screened eight potentially functional single-neucleotide polymorphism (SNPs) in the genes near rs73329476 (carboxypeptidase M (CPM) and cleavage and polyadenylation specific factor 6 (CPSF6)) in a case-control study including 177 cases with silicosis and 204 healthy controls, matched to cases with years of silica dust exposure. We evaluated the associations between these eight SNPs and the development of silicosis. Luciferase reporter gene assays were performed to test the effects of selected SNP on the activity of CPM in the promoter. In addition, a two-stage case-control study was performed to investigate the expression differences of the two genes in peripheral blood leucocytes from a total of 64 cases with silicosis and 64 healthy controls with similar years of silica dust exposure as the cases. RESULTS: We found a strong association between the mutant rs12812500 G allele and the susceptibility of silicosis (OR=1.45, 95% CI 1.03 to 2.04, p=0.034), while luciferase reporter gene assays indicated that the mutant G allele of rs12812500 is strongly associated with increased luciferase levels compared with the wild-type C allele (p<0.01). Moreover, the mRNA (peripheral blood leucocytes) expression of the CPM gene was significantly higher in subjects with silicosis compared with healthy controls. CONCLUSIONS: The rs12812500 variant of the CPM gene may increase silicosis susceptibility by affecting the expression of CPM, which may contribute to silicosis susceptibility with biological plausibility.

Association between CYP2E1 and GOT2 gene polymorphisms and susceptibility and low-dose N,N-dimethylformamide occupational exposure-induced liver injury.

OBJECTIVE: To investigate the effects of the interactions between the CYP2E1 and GOT2 gene polymorphisms and N,N-dimethylformamide (DMF) on liver injury. METHODS: A total of 672 DMF-exposed workers were randomly selected from two synthetic leather enterprises in Suzhou, China, for follow-up in a cohort study. Information on exposure to DMF in the air was collected through a fixed-point air sampler in the worker's breathing zone. The subjects were assessed every year during the period of 2010-2015, they underwent occupational health examinations. Alanine aminotransferase and aspartate aminotransferase levels were measured. Peripheral blood was collected and DNA was extracted. The genotypes rs2031920, rs3813867 and rs6413432 of the CYP2E1 gene and rs7204324 of the GOT2 gene were detected by PCR, and analyzed using the Chi-square test and logistic regression analysis. RESULTS: Workers exposed to a high cumulative dose of DMF were significantly more likely than low-exposed workers to develop liver injury. No association was observed between rs2031920, rs3813867 and rs6413432 of the CYP2E1 gene and DMF-induced liver damage. However, the A allele of rs7204324 on the GOT2 gene may be a risk factor for susceptibility to DMF-induced liver injury. CONCLUSION: Polymorphisms of rs7204324 on GOT2 may play an important role in susceptibility to liver injury following exposure to DMF.