BST2 promotes gastric cancer metastasis under the regulation of HOXD9 and PABPC1.

Gastric cancer (GC) constitutes substantial cancer mortality worldwide. Several cancer types aberrantly express bone marrow stromal cell antigen 2 (BST2), yet its functional and underlying mechanisms in GC progression remain unknown. In our study, RNA sequencing data revealed that BST2 was transcriptionally activated by homeobox D9 (HOXD9). BST2 was significantly upregulated in GC tissues and promoted epithelial-mesenchymal transition and metastasis of GC. BST2 knockdown reversed HOXD9's oncogenic effect on GC metastasis. Moreover, BST2 messenger RNA stability could be enhanced by poly(A) binding protein cytoplasmic 1 (PABPC1) through the interaction between BST2 3'-UTR and PABPC1 in GC cells. PABPC1 promoted GC metastasis, which BST2 silencing attenuated in vitro and in vivo. In addition, positive correlations among HOXD9, BST2, and PABPC1 were established in clinical samples. Taken together, increased expression of BST2 induced by HOXD9 synergizing with PABPC1 promoted GC cell migration and invasion capacity.

What influences newly graduated registered nurses' intention to leave the nursing profession? An integrative review.

BACKGROUND: Newly graduated registered nurses leaving the nursing profession in the early stages of their career have enormous financial and time implications for nursing organizations and affect the quality of nursing care. OBJECTIVE: To identify the factors influencing newly graduated registered nurses' intention to leave the nursing profession over the past 10 years. METHODS: The framework developed by Whittemore and Knafl was used to conduct this integrative review. An electronic search was conducted for English articles to identify research studies published between 2011-2022 using the following databases of PubMed, MEDLINE, CINAHL, PsycINFO, and Scopus. Eligible publications were critically reviewed and scored using the Critical Appraisal Skills Program Checklist and the Center for Evidence-Based Management appraisal. RESULTS: Twenty-one studies were analyzed. The main factors affecting newly graduated registered nurses' intention to leave the nursing profession included demographic factors (age, educational level, year of experience, professional title, employment status, health status, shift, hospital location and size), supervisor and peer support, challenges in the workplace, cognitive and affective response to work, work environment (collegial nurse-physician relations, insufficient staffing level, person-work environment fit), gender stereotypes, autonomous motivation, role models, and resilience. CONCLUSIONS: The factors affecting newly graduated registered nurses' intention to leave the nursing profession are multifaceted and should receive continuous attention from nurse managers. The findings provide more comprehensive for nurse administrators to develop intervention strategies to mitigate newly graduated registered nurses' turnover intention.

Temporal and spatial evolution of net primary productivity in the Three-River Headwaters Region under phenological changes and anthropogenic influence.

Understanding the spatiotemporal changes in net primary productivity (NPP) and the driving factors behind these changes in climate-vulnerable regions is crucial for ecological conservation. This study simulates the actual NPP (NPPA) and climate potential NPP (NPPC) in the Three-River Headwaters Region from 2000 to 2020. The Theil-Sen Median method and Mann-Kendall mutation analyses are employed to explore their spatiotemporal variation patterns, while geographic weighted regression and machine learning are used to investigate the influence of anthropogenic activities and climatic factors on NPPA, the results indicate that the average NPPA across the entire region over multiple years is 382.506 g C m - 2 yr - 1 , which is 0.132 times the average annual NPPC over the past 21 years, showing an overall distribution pattern of low in the northwest and high in the southeast. The annual increase in NPPA from 2000 to 2020 is approximately 1.034 g C m - 2 yr - 1 . The source region of the Yangtze River shows the largest improvement in vegetation, with 74.1% of the area showing improvement. Between 2002 and 2003, the annual NPPA in the Three-River Headwaters Region experienced a sudden change, lagging behind the NPPC change by 1 year, and after 2005, the upward trend in NPPA became more pronounced. The impact of anthropogenic activities on NPPA shifted from positive to negative to positive from 2000 to 2020, with significant impact areas mainly concentrated in the northeast and a few areas in the central and southern parts. The proportion of areas with extremely significant impact increased from 1.9% in 2000 to 3.7% in 2020. Over the past 21 years, the main factors influencing NPPA changes in the Three-River Headwaters Region have been soil moisture and precipitation, with the influence of different climate factors on NPP changing over time. Additionally, NPP is more sensitive to changes in altitude in low-altitude areas. This study can provide more accurate theoretical support for ecological environment assessment and subsequent protection efforts in the Three-River Headwaters Region.

Mitoglitazone ameliorates renal ischemia/reperfusion injury by inhibiting ferroptosis via targeting mitoNEET.

Ischemia/reperfusion- (I/R-) induced injury is unavoidable and a major risk factor for graft failure and acute rejection following kidney transplantation. However, few effective interventions are available to improve the outcome due to the complicated mechanisms and lack of appropriate therapeutic targets. Hence, this research aimed to explore the effect of the thiazolidinedione (TZD) compounds on I/R-induced kidney damage. One of the main causes of renal I/R injury is the ferroptosis of renal tubular cells. In this study, compared with the antidiabetic TZD pioglitazone (PGZ), we found its derivative mitoglitazone (MGZ) exerted significantly inhibitory effects on erastin-induced ferroptosis by suppressing mitochondrial membrane potential hyperpolarization and lipid ROS production in HEK293 cells. Moreover, MGZ pretreatment remarkably alleviated I/R-induced renal damages by inhibiting cell death and inflammation, upregulating the expression of glutathione peroxidase 4 (GPX4), and reducing iron-related lipid peroxidation in C57BL/6 N mice. Additionally, MGZ exhibited excellent protection against I/R-induced mitochondrial dysfunction by restoring ATP production, mitochondrial DNA copy numbers, and mitochondrial morphology in kidney tissues. Mechanistically, molecular docking and surface plasmon resonance experiments demonstrated that MGZ exhibited a high binding affinity with the mitochondrial outer membrane protein mitoNEET. Collectively, our findings indicated the renal protective effect of MGZ was closely linked to regulating the mitoNEET-mediated ferroptosis pathway, thus offering potential therapeutic strategies for ameliorating I/R injuries.

Global, regional, and national epidemiology of migraine and tension-type headache in youths and young adults aged 15-39 years from 1990 to 2019: findings from the global burden of disease study 2019.

BACKGROUND: In recent years, headache disorders have garnered significant attention as a pressing global health issue. This concern is especially pronounced in low- to middle-income countries and exhibits a notable increase in prevalence among adolescents and young adults. Such a surge in these disorders has invariably diminished the quality of life for affected individuals. Despite its global impact, comprehensive studies exploring the ramifications of headache disorders in the younger population remain scant. Our study endeavored to quantify the global prevalence of headache disorders in individuals between the ages of 15 and 39, over a three-decade span from 1990 to 2019. METHODS: Our study, conducted from 1990 to 2019, evaluated the impact of headache disorders, specifically migraines and tension-type headaches (TTH), in 204 different countries and territories. This comprehensive assessment included a detailed analysis of incidence rates, prevalence, and disability-adjusted life-years (DALYs) across various demographics such as age, gender, year, geographical location, and Socio-demographic Index (SDI). RESULTS: In 2019, there were an estimated 581,761,847.2 migraine cases globally (95% UI: 488,309,998.1 to 696,291,713.7), marking a 16% increase from 1990. Concurrently, TTH cases numbered at 964,808,567.1 (95% UI: 809,582,531.8 to 1,155,235,337.2), reflecting a 37% rise since 1990. South Asia reported the highest migraine prevalence with 154,490,169.8 cases (95% UI: 130,296,054.6 to 182,464,065.6). High SDI regions exhibited the most substantial migraine prevalence rates both in 1990 (22,429 per 100,000 population) and 2019 (22,606 per 100,000 population). Among the five SDI classifications, the middle SDI region recorded the highest tally of TTH cases in both 1990 (210,136,691.6 cases) and 2019 (287,577,250 cases). Over the past 30 years, East Asia experienced the most pronounced surge in the number of migraine cases. On the whole, there was a discernible positive correlation between the disease burden of migraine and TTH and the SDI. CONCLUSION: Migraine and TTH represent formidable challenges in global health. The intensity of their impact exhibits marked disparities across nations and is distinctly elevated among women, individuals within the 30-39 age bracket, and populations characterized by a high SDI. The results of our research emphasize the imperative of assimilating migraine and TTH management into contemporary healthcare paradigms. Such strategic integration holds the potential to amplify public cognizance regarding pertinent risk factors and the spectrum of therapeutic interventions at hand.

The N6-methyladenosine writer WTAP contributes to the induction of immune tolerance post kidney transplantation by targeting regulatory T cells.

N6-methyladenosine (m6A) modification is involved in diverse immunoregulation, while the relationship between m6A modification and immune tolerance post kidney transplantation remains unclear. Expression of Wilms tumor 1-associating protein (WTAP), an m6A writer, was firstly detected in tolerant kidney transplant recipients (TOL). Then the role of WTAP on regulatory T (Treg) cell differentiation and function in CD4+ T cells from kidney transplant recipients with immune rejection (IR) was investigated. The potential target of WTAP and effect of WTAP on immune tolerance in vivo were subsequently verified. WTAP was upregulated in CD4+ T cells of TOL and positively correlated with Treg cell proportion. In vitro, WTAP overexpression promoted Treg cell differentiation and enhanced Treg cell-mediated suppression toward naïve T cells. Forkhead box other 1 (Foxo1) was identified as a target of WTAP. WTAP enhanced m6A modification of Foxo1 mRNA in coding sequence (CDS) region, leading to up-regulation of Foxo1. Overexpression of m6A demethylase removed the effect of WTAP overexpression, while Foxo1 overexpression reversed these effects. WTAP overexpression alleviated allograft rejection in model mice, as evidenced by reduced inflammatory response and increased Treg population. Our study suggests that WTAP plays a positive role in induction of immune tolerance post kidney transplant by promoting Treg cell differentiation and function.

Optimal Cutoff Concentration of Urinary Cyanoethyl Mercapturic Acid for Differentiating Cigarette Smokers From Nonsmokers.

INTRODUCTION: Cotinine is a widely used biomarker for classifying cigarette smoking status. However, cotinine does not differentiate between the use of combustible and noncombustible tobacco products. The increasing use of noncombustible tobacco drives the need for a complementary biomarker for distinguishing cigarette smokers from users of noncombustible tobacco products. AIMS AND METHODS: We evaluated the urinary acrylonitrile metabolite, 2CyEMA, as a biomarker of exposure to cigarette smoke in the US population-representative data from the National Health and Nutritional Examination Survey (NHANES). Smoking status was categorized based on the recent tobacco use questionnaire. The receiver operating characteristic (ROC) curve analysis was performed to identify optimal cutoff concentrations by maximizing Youden's J index. The area under the curve (AUC) was used to compare 2CyEMA effectiveness with respect to serum cotinine. RESULTS: The overall cutoff concentration for the classification of cigarette smokers from nonsmokers was 7.32 ng/ml with high sensitivity and specificity (≥0.925). When stratified by demographic variables, the cutoff concentrations varied among subgroups based on age, sex, and race/Hispanic origin. Non-Hispanic Blacks had the highest cutoff concentration (15.3 ng/ml), and Hispanics had the lowest (4.63 ng/ml). Females had higher cutoff concentrations (8.80 ng/ml) compared to males (6.10 ng/ml). Among different age groups, the cutoff concentrations varied between 4.63 ng/ml (21-39 years old) and 10.6 ng/ml (for ≥60 years old). We also explored the creatinine adjusted cutoff values. CONCLUSIONS: 2CyEMA is an effective biomarker for distinguishing cigarette smokers from nonsmokers (users of noncombustible tobacco products or nonusers). IMPLICATIONS: Distinguishes smokers from noncombustible tobacco product users.

Cigarette smoking is associated with acrylamide exposure among the U.S. population: NHANES 2011-2016.

2-carbamoylethyl mercapturic acid (2CaEMA, N-Acetyl-S-carbamoylethyl-L-cysteine) is a urinary metabolite and exposure biomarker of acrylamide, which is a harmful volatile organic compound found in cigarette smoke and in some foods. The goal of this study was to determine the association between cigarette smoking and urinary 2CaEMA concentrations among the U.S. population while considering potential dietary sources of acrylamide intake and demographics. We measured 2CaEMA concentrations in urine specimens collected during the National Health and Nutrition Examination Survey 2011-2012, 2013-2014, and 2015-2016 cycles from eligible participants 18 years and older (n = 5443) using liquid chromatography/tandem mass spectrometry. We developed multiple regression models with urinary 2CaEMA concentrations as the dependent variable and sex, age, race/Hispanic origin, reported primary sources of dietary acrylamide intake, and cigarette smoke exposure as independent variables. This study demonstrates that cigarette smoking is strongly associated with urinary 2CaEMA, suggests that cigarette smoking is likely a primary source of acrylamide exposure, and provides a baseline measure for 2CaEMA in the U.S. population.

Association between dietary theobromine with depression: a population-based study.

OBJECTIVE: The purpose of this study is to investigate the possible link between dietary theobromine intake and symptoms of depression. MATERIALS AND METHODS: These results are based on the responses of 3637 people who took part in the National Health and Nutrition Examination Survey in 2017-2018. Participants' daily theobromine intake was determined using a 24-h food questionnaire from the 2017-2018 cycle. Presence of depression was defined as a score of 5 or above on the Patient Health Questionnaire. Association between theobromine intake and depression was examined using a multivariate logistic regression adjusting for several relevant sociodemographic, lifestyle and health-related factors. RESULTS: A total of 6903 participants were included in the study. The results of multivariate logistic regression showed a correlation between depressive symptoms and theobromine intake (OR:1.17, 95%CI:1.02-1.34). CONCLUSIONS: Our cross-sectional population based study suggests that increased theobromine intake is associated with increased risk for depression. Nevertheless, more investigations are needed to confirm our findings.

The circACTN4 interacts with FUBP1 to promote tumorigenesis and progression of breast cancer by regulating the expression of proto-oncogene MYC.

BACKGROUND: Recent studies have revealed that circular RNAs (circRNAs) play significant roles in the occurrence and development of many kinds of cancers including breast cancer (BC). However, the potential functions of most circRNAs and the molecular mechanisms underlying progression of BC remain elusive. METHOD: Here, Circular RNA microarray was executed in 4 pairs of breast cancer tissues and para-cancer tissues. The expression and prognostic significance of circACTN4 in BC cells and tissues were determined by qRT-PCR and in situ hybridization. Gain-and loss-of-function experiments were implemented to observe the impacts of circACTN4 on the growth, invasion, and metastasis of BC cells in vitro and in vivo. Mechanistically, chromatin immunoprecipitation, luciferase reporter, RNA pulldown, mass spectrum, RNA immunoprecipitation, fluorescence in situ hybridization and co-immunoprecipitation assays were executed. RESULTS: CircACTN4 was significantly upregulated in breast cancer tissues and cells, its expression was correlated with clinical stage and poor prognosis of patients with BC. Ectopic expression of circACTN4 strikingly facilitated the growth, invasion, and metastasis of breast cancer cells in vitro and in vivo. Whereas knockdown of circACTN4 revealed opposite roles. CircACTN4 was mainly distributed in the nucleus. Further mechanistic research proved that circACTN4 could competitively bind to far upstream element binding protein 1 (FUBP1) to prevent the combination between FUBP1 and FIR, thereby activating MYC transcription and facilitating tumor progression of breast cancer. Furthermore, we found that upstream transcription factor 2 (USF2) might promote the biogenesis of circACTN4. CONCLUSION: Our findings uncover a pivotal mechanism that circACTN4 mediated by USF2 might interact with FUBP1 to promote the occurrence and development of breast cancer via enhancing the expression of MYC. CircACTN4 could be a novel potential target for diagnosis and treatment of breast cancer.

Exposure to 1,3-Butadiene in the U.S. Population: National Health and Nutrition Examination Survey 2011-2016.

1,3-Butadiene is a volatile organic compound with a gasoline-like odour that is primarily used as a monomer in the production of synthetic rubber. The International Agency for Research on Cancer has classified 1,3-butadiene as a human carcinogen. We assessed 1,3-butadiene exposure in the U.S. population by measuring its urinary metabolites N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (34HBMA), N-acetyl-S-(1-hydroxymethyl-2-propenyl)-L-cysteine (1HMPeMA), N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (2HBeMA), and N-acetyl-S-(4-hydroxy-2-buten-1-yl)-L-cysteine (4HBeMA). Urine samples from the 2011 to 2016 National Health and Nutrition Examination Survey were analysed for 1,3-butadiene metabolites using ultrahigh-performance liquid chromatography/tandem mass spectrometry. 34HBMA and 4HBeMA were detected in >96% of the samples; 1HMPeMA and 2HBeMA were detected in 0.66% and 9.84% of the samples, respectively. We used sample-weighted linear regression models to examine the influence of smoking status (using a combination of self-reporting and serum-cotinine data), demographic variables, and diet on biomarker levels. The median 4HBeMA among exclusive smokers (31.5 µg/g creatinine) was higher than in non-users (4.11 µg/g creatinine). Similarly, the median 34HBMA among exclusive smokers (391 µg/g creatinine) was higher than in non-users (296 µg/g creatinine). Furthermore, smoking 1-10, 11-20, and >20 cigarettes per day (CPD) was associated with 475%, 849%, and 1143% higher 4HBeMA (p < 0.0001), respectively. Additionally, smoking 1-10, 11-20, and >20 CPD was associated with 33%, 44%, and 102% higher 34HBMA (p < 0.0001). These results provide significant baseline data for 1,3-butadiene exposure in the U.S. population, and demonstrate that tobacco smoke is a major exposure source.

Characterization of the association between cigarette smoking intensity and urinary concentrations of 2-hydroxyethyl mercapturic acid among exclusive cigarette smokers in the National Health and Nutrition Examination Survey (NHANES) 2011-2016.

BACKGROUND: 2-Hydroxyethyl mercapturic acid (2HEMA, N-acetyl-S-(2-hydroxyethyl)-L-cysteine) is a urinary metabolite of several volatile organic compounds including acrylonitrile and ethylene oxide, which are found in cigarette smoke. METHODS: We measured 2HEMA concentrations in urine specimens collected during the National Health and Nutrition Examination Survey (2011-2016) from eligible participants aged >12 years (N = 7,416). We developed two multiple linear regression models to characterize the association between cigarette smoking and 2HEMA concentrations wherein the dependent variable was 2HEMA concentrations among participants who exclusively smoked cigarettes at the time of specimen collection and the independent variables included sex, age, race/ethnicity, creatinine, diet, and either cigarettes smoked per day (CPD) or serum cotinine. RESULTS: We detected 2HEMA in 85% of samples tested among exclusive cigarette smokers, and only 40% of specimens from non-smokers. When compared to exclusive cigarette smokers who smoked 1-9 CPD, smoking 10-19 CPD was associated with 36% higher 2HEMA (p < 0.0001) and smoking >19 CPD was associated with 61% higher 2HEMA (p < 0.0001). Additionally, 2HEMA was positively associated with serum cotinine. CONCLUSIONS: This study demonstrates that cigarette smoking intensity is associated with higher urinary 2HEMA concentrations and is likely a major source of acrylonitrile and/or ethylene oxide exposure.

Examination of xylene exposure in the U.S. Population through biomonitoring: NHANES 2005-2006, 2011-2016.

Aim: Xylenes are aromatic hydrocarbons used for industrial applications such as the production of petrochemicals and plastics. Acute xylene exposures can negatively impact health through neurotoxicity and irritation of respiratory and dermal tissues. We quantified urinary biomarkers of xylene exposure [2-methylhippuric acid (2MHA) and a mixture of 3- and 4-methylhippuric acids (34MH)] in a representative sample of the U.S. population. Methods: Spot urine obtained during the National Health and Nutrition Examination Survey 2005-2006 and 2011-2016 was analysed using ultra-high-performance liquid chromatography/tandem mass spectrometry. Exclusive smokers were distinguished from non-users using a combination of self-report and serum cotinine data. Results: The median 2MHA and 34MH levels were higher for exclusive smokers (100 µg/g and 748 µg/g creatinine, respectively) than for non-users (27.4 µg/g and 168 µg/g creatinine, respectively). Participants who smoked cigarettes had significantly higher 2MHA and 34MH levels (p < 0.0001) than unexposed participants. Smoking 1-10, 11-20, and >20 cigarettes per day (CPD) was significantly associated with 181%, 339% and 393% higher 2MHA levels, respectively. For 34MH, smoking 1-10, 11-20, and >20 CPD was significantly associated with 201%, 398%, and 471% higher 34MH levels, respectively. Conclusion: We confirm that tobacco smoke is a significant source of xylene exposure as measured by urinary 2MHA and 34MH levels.

Assessment of Serum Concentrations of 12 Aldehydes in the U.S. Population from the 2013-2014 National Health and Nutrition Examination Survey.

Aldehydes are known carcinogens and irritants that can negatively impact health. They are present in tobacco smoke, the environment, and food. The prevalence of aldehyde exposure and potential health impact warrants a population-wide study of serum aldehydes as exposure biomarkers. We analyzed 12 aldehydes in sera collected from 1843 participants aged 12 years or older in the 2013-2014 National Health and Nutrition Examination Survey. Several aldehydes were detected at high rates, such as isopentanaldehyde (99.2%) and propanaldehyde (88.3%). We used multiple linear regression models to examine the impact of tobacco smoke and dietary variables on serum concentrations of isopentanaldehyde and propanaldehyde. Although 12 serum aldehydes were analyzed and compared to tobacco smoke exposure, only isopentanaldehyde and propanaldehyde showed any significant association with tobacco smoke exposure. Survey participants who smoked 1-10 cigarettes per day (CPD) had 168% higher serum isopentanaldehyde and 28% higher propanaldehyde compared with nonusers. Study participants who smoked 11-20 CPD had higher serum isopentanaldehyde (323%) and propanaldehyde (70%). Similarly, study participants who smoked >20 CPD had 399% higher serum isopentanaldehyde and 110% higher serum propanaldehyde than nonexposed nonusers. The method could not, however, differentiate between nonexposed nonusers and nonusers exposed to secondhand smoke for either of these two aldehydes. No dietary variables were consistently predictive of serum isopentanaldehyde and propanaldehyde concentrations. This report defines baseline concentrations of serum aldehydes in the U.S. population and provides a foundation for future research into the potential health effects of aldehydes. In addition, this study suggests that tobacco smoke is a significant source of exposure to some aldehydes such as isopentanaldehyde and propanaldehyde.

The circRNA circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer.

BACKGROUND: Increasing studies have shown that circRNA is closely related to the carcinogenesis and development of many cancers. However, biological functions and the underlying molecular mechanism of circRNAs in triple-negative breast cancer (TNBC) remain largely unclear so far. METHODS: Here, we investigated the expression pattern of circRNAs in four pairs of TNBC tissues and paracancerous normal tissues using RNA-sequencing. The expression and prognostic significance of circSEPT9 were evaluated with qRT-PCR and in situ hybridization in two TNBC cohorts. The survival curves were drawn by the Kaplan-Meier method, and statistical significance was estimated with the log-rank test. A series of in vitro and in vivo functional experiments were executed to investigate the role of circSEPT9 in the carcinogenesis and development of TNBC. Mechanistically, we explored the potential regulatory effects of E2F1 and EIF4A3 on biogenesis of circSEPT9 with chromatin immunoprecipitation (ChIP), luciferase reporter and RNA immunoprecipitation (RIP) assays. Furthermore, fluorescent in situ hybridization (FISH), luciferase reporter and biotin-coupled RNA pull-down assays were implemented to verify the relationship between the circSEPT9 and miR-637 in TNBC. RESULTS: Increased expression of circSEPT9 was found in TNBC tissues, which was positively correlated with advanced clinical stage and poor prognosis. Knockdown of circSEPT9 significantly suppressed the proliferation, migration and invasion of TNBC cells, induced apoptosis and autophagy in TNBC cells as well as inhibited tumor growth and metastasis in vivo. Whereas up-regulation of circSEPT9 exerted opposite effects. Further mechanism research demonstrated that circSEPT9 could regulate the expression of Leukemia Inhibitory Factor (LIF) via sponging miR-637 and activate LIF/Stat3 signaling pathway involved in progression of TNBC. More importantly, we discovered that E2F1 and EIF4A3 might promote the biogenesis of circSEPT9. CONCLUSIONS: Our data reveal that the circSEPT9 mediated by E2F1 and EIF4A3 facilitates the carcinogenesis and development of triple-negative breast cancer through circSEPT9/miR-637/LIF axis. Therefore, circSEPT9 could be used as a potential prognostic marker and therapeutical target for TNBC.

Nicotinamide N-methyltransferase decreases 5-fluorouracil sensitivity in human esophageal squamous cell carcinoma through metabolic reprogramming and promoting the Warburg effect.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with poor prognosis. And different individuals respond to the same drug differently. Increasing evidence has confirmed that metabolism reprogramming was involved in the drug sensitivity of tumor cells. However, the potential molecular mechanism of 5-fluorouracil (5-FU) sensitivity remains to be elucidated in ESCC cells. In this study, we found that the 5-FU sensitivity of TE1 cells was lower than that of EC1 and Eca109 cells. Gas chromatography-mass spectrometry analysis results showed that nicotinate and nicotinamide metabolism and tricarboxylic acid cycle were significantly different in these three cell lines. Nicotinamide N-methyltransferase (NNMT), a key enzyme of nicotinate and nicotinamide metabolism, was significantly higher expressed in TE1 cells than that in EC1 and Eca109 cells. Therefore, the function of NNMT on 5-FU sensitivity was analyzed in vitro and in vivo. NNMT downregulation significantly increased 5-FU sensitivity in TE1 cells. Meanwhile, the glucose consumption and lactate production were decreased, and the expression of glycolysis-related enzymes hexokinase 2, lactate dehydrogenase A, and phosphoglycerate mutase 1 were downregulated in NNMT knockdown TE1 cells. Besides, overexpression of NNMT in EC1 and Eca109 cells caused the opposite effects. Moreover, when glycolysis was inhibited by 2-deoxyglucose, the roles of NNMT on 5-FU sensitivity was weakened. In vivo experiments showed that NNMT knockdown significantly increased the sensitivity of xenografts to 5-FU and suppressed the Warburg effect. Overall, these results demonstrated that NNMT decreases 5-FU sensitivity in human ESCC cells through promoting the Warburg effect, suggesting that NNMT may contribute to predict the treatment effects of the clinical chemotherapy in ESCC.

MiR-1231 decrease the risk of cancer-related mortality in patients combined with non-small cell lung cancer and diabetes mellitus.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a deadly human malignancy, and previous studies support the contribution of microRNAs (miRNAs) to cancer assessment. It has been reported that miR-1231 can be used as a biomarker to assess prognosis in different cancers. However, the prognostic value of miR-1231 in NSCLC patients with comorbid diabetes mellitus (DM) remains unclear. The present study evaluated the risk factors for NSCLC with DM and developed a predictive model for it. METHODS: A real-world study was conducted, including data from 108 patients with NSCLC combined with DM from April 1, 2010, to June 1, 2015. MiR-1231 was recorded during hospital admission. Cox-proportional hazards model was applied for survival analysis of risk factors for cancer-related mortality and to create nomograms for prediction. The accuracy of the model was evaluated by C-index and calibration curves. RESULTS: The mortality rate in the high miR-1231 level (≥ 1.775) group was 57.4%. On the basis of univariate analysis, we put factors (P < 0.05) into multivariate regression models, and high miR-1231 levels (P < 0.001, HR = 0.57), surgery (P < 0.001, HR = 0.37) and KPS score > 80 (P = 0.01, HR = 0.47) had a better prognosis and were considered as independent protective factors. These independently relevant factors were used to create nomograms to predict long-term patient survival. Nomogram showed good accuracy in risk estimation with a guide-corrected C-index of 0.691. CONCLUSION: MiR-1231 reduced the risk of cancer-related death in patients with combined NSCLC and DM. Nomogram based on multivariate analysis showed good accuracy in estimating the overall risk of death.

The topological key lncRNA H2k2 from the ceRNA network promotes mesangial cell proliferation in diabetic nephropathy via the miR-449a/b/Trim11/Mek signaling pathway.

Evidence has shown that long noncoding RNAs (lncRNAs) in the competing endogenous RNA (ceRNA) network are involved in various diseases. However, there is a lack of studies of the ceRNA network in diabetic nephropathy (DN). In this study, we investigated the effect of lncRNAs on mesangial cell (MC) proliferation in DN-related ceRNA networks. Differences in lncRNA and mRNA expression between DN and normal mouse kidney tissues were detected with RNA-seq, and DN-related lncRNA/mRNA/microRNA (miRNA) ceRNA networks were constructed by R3.4.3. Computational analysis was performed, and expression and interactions between the topological RNAs were detected by bioinformatics methods, real-time quantitative PCR (qPCR), and luciferase assay. Cell proliferation ability was measured by 5-ethynyl-2'-deoxyuridine (EdU) in MCs cultured under high- or low-glucose conditions. Moreover, the effect of the topological key lncRNA histocompatibility 2 K region locus 2 (H2k2) H2k2 on MC proliferation via the miRNA (miR)-449a/b/triplet motif 11 (Trim11)/Mek signaling pathway was examined by EdU, flow cytometry analysis, and Western blot. In total, 153 lncRNAs, 428 mRNAs, and 2242 interactions were included in the constructed DN-related ceRNA network. There were 15 RNAs in the top 5% of degree and betweenness. The expression of lncRNA H2k2 and mRNA Trim11 in MCs was increased in DN, which is consistent with the results of RNA-seq and real-time qPCR invivo and in vitro. miR-449a and miR-449b, which were down-regulated in MCs cultured with high glucose, were selected for further analysis. The results of real-time qPCR and luciferase assay revealed the lncRNA H2k2-miR-449a/b-Trim11 interaction in MCs. In addition, the data showed that H2k2 regulates MC proliferation via the miR-449ab/Trim11/Mek signaling pathway. Taken together, these results provide new insight into the association between the topological key lncRNA H2k2 in the DN-related ceRNA network and the miR-449a/b/Trim11/Mek signaling pathway during MC proliferation in DN.-Chen, W., Peng, R., Sun, Y., Liu, H., Zhang, L., Peng, H., Zhang, Z. The topological key lncRNA H2k2 from the ceRNA network promotes mesangial cell proliferation in diabetic nephropathy via the miR-449a/b/Trim11/Mek signaling pathway.

Correction to: Downregulation of nicotinamide N-methyltransferase inhibits migration and epithelial-mesenchymal transition of esophageal squamous cell carcinoma via Wnt/ß-catenin pathway.

Fig. 2C has been published incorrectly in the original article. The correct version of the Fig. 6 is provided in this erratum.

Isoprene Exposure in the United States Based on Urinary IPM3: NHANES 2015-2016.

Isoprene is the 2-methyl analog of 1,3-butadiene and is a possible human carcinogen (IARC Group 2B). We assessed isoprene exposure in the general US population by measuring its urinary metabolite, N-acetyl-S-(4-hydroxy-2-methyl-2-buten-1-yl)-l-cysteine (IPM3) in participants (≥3 year old) from the 2015-2016 National Health and Nutrition Examination Survey. Spot urine samples were analyzed for IPM3 using ultrahigh-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. Exclusive tobacco smokers were distinguished from non-users using a combination of self-reporting and serum cotinine data. IPM3 was detected in 80.2% of samples. The median IPM3 level was higher for exclusive cigarette smokers (39.8 µg/g creatinine) than for non-users (3.05 µg/g creatinine). Sample weighted regression analysis, controlling for creatinine, sex, age, race, body mass index, and diet, showed that IPM3 was positively and significantly associated with serum cotinine. Smoking 1-10 cigarettes per day (CPD, 0.5 pack) was significantly associated with an IPM3 increase of 596% (p < .0001), and smoking >20 CPD (>1 pack) was significantly associated with an IPM3 increase of 1640% (p < .0001), controlling for confounding variables. Drinking beer/ale at median and 90th percentile levels (compared to zero consumption) was associated (p < 0.05) with 0 and 2.9% increase in IPM3 in non-users, respectively. We conclude that tobacco smoke is a major source of isoprene exposure in the US population. This study provides important public health biomonitoring data on isoprene exposure in the general US population.