Transitions to smokeless tobacco use among adult cigarette smokers in the Population Assessment of Tobacco and Health (PATH) Study, Waves 3-5 (2015-2019).

OBJECTIVE: Examine patterns of dual use of cigarettes and smokeless tobacco and complete switching over time among adult current cigarette smokers using data from the Population Assessment of Tobacco and Health Study Wave 3 (2015-2016), Wave 4 (2016-2018) and Wave 5 (2018-2019). METHODS: We examined four tobacco use states among 6834 exclusive smokers and 372 dual users at Wave 3 with two waves of follow-up data: exclusive cigarette use, exclusive smokeless tobacco use, dual use and use of neither product. RESULTS: Among exclusive smokers at Wave 3, only 1.6% (95% CI: 1.3% to 2.1%) transitioned to dual use at Wave 4, and 0.1% (95% CI: 0.07% to 0.2%) switched to exclusive smokeless tobacco use. Among exclusive smokers who switched to dual use, 53.1% (95% CI: 40.9% to 64.9%) returned to exclusive cigarette smoking, 34.3% (95% CI: 23.8% to 46.6%) maintained dual use and 12.6% (95% CI: 7.0% to 21.7%) did not smoke cigarettes after an additional wave of follow-up. Dual users at Wave 3 were likely to maintain their dual use status at Wave 4, 51.2% (95% CI: 46.1% to 56.3%) and Wave 5, 47.9% (95% CI: 40.1% to 55.8%). CONCLUSIONS: Very few cigarette smokers transition to smokeless tobacco use, and among those who do, dual use is more common than exclusive smokeless tobacco use. Further, the majority of exclusive cigarette smokers who transition to dual use at Wave 4 continue smoking cigarettes at Wave 5, either as dual users or as exclusive smokers.

DLGAP1-AS2 promotes human colorectal cancer progression through trans-activation of Myc.

Substantial evidence suggests that non-coding RNA plays a vital role in human cancer, especially long non-coding RNA (lncRNA) with a length greater than 200nt. Herein, we found a lncRNA facilitating human colorectal cancer (CRC) progression. DLGAP1-AS2 was significantly increased in CRC tissues and cell lines. Knockdown of DLGAP1-AS2 inhibited CRC cell proliferation, migration, invasion in vitro, and tumor growth in vivo. The subcellular localization of DLGAP1-AS2 was translocated from the cytoplasm of normal cells to the nucleus of CRC cells due to reduced levels of N6-methyladenosine (m6A) modification. Further, through the screening of a series of signal pathways, we found that Myc pathway was involved in the effect of DLGAP1-AS2. Silencing of DLGAP1-AS2 markedly reduced Myc mRNA and protein levels. Blockade of Myc effectively abolished the enhanced aggressive behaviors of CRC cells caused by DLGAP1-AS2 overexpression. Mechanistically, DLGAP1-AS2 directly bound CTCF, a well-known transcriptional repressor of Myc, resulting in reduced binding of CTCF on Myc promoter and activating Myc transcription. The second hairpin structure of DLGAP1-AS2 was critical for the interaction between DLGAP1-AS2 and CTCF in the nucleus. Taken together, our study reveals the oncogenic regulatory axis of DLGAP1-AS2/CTCF/Myc in CRC, implying a promising targeted therapy for clinical application.

Tobacco Product Use Among Middle and High School Students - United States, 2022.

Tobacco use* is the leading cause of preventable disease, disability, and death among adults in the United States (1). Youth use of tobacco products in any form is unsafe, and nearly all tobacco use begins during youth and young adulthood (2). The Food and Drug Administration (FDA) and CDC analyzed data from the 2022 National Youth Tobacco Survey (NYTS) to estimate current (past 30-day) use of eight tobacco products among U.S. middle (grades 6-8) and high school (grades 9-12) students. In 2022, approximately 11.3% of all students (representing 3.08 million persons) reported currently using any tobacco product, including 16.5% of high school and 4.5% of middle school students (2.51 million and 530,000 persons, respectively). Electronic cigarettes (e-cigarettes) were the most commonly used tobacco product among high school (14.1%; 2.14 million) and middle school (3.3%; 380,000) students. Approximately 3.7% of all students (representing 1 million persons) reported currently smoking any combustible tobacco product. Current use of any tobacco product was higher among certain population groups, including 13.5% of non-Hispanic American Indian or Alaska Native (AI/AN)† students; 16.0% of students identifying as lesbian, gay, or bisexual (LGB); 16.6% of students identifying as transgender; 18.3% of students reporting severe psychological distress; 12.5% of students with low family affluence; and 27.2% of students with low academic achievement. Implementation of comprehensive evidence-based tobacco control strategies, combined with FDA regulation, is important for preventing and reducing youth tobacco product use (1,2).

Middle cerebral arterial bifurcation aneurysms are associated with bifurcation angle and high tortuosity.

PURPOSE: To investigate the association of middle cerebral artery (MCA) bifurcation aneurysms with bifurcation morphology. MATERIALS AND METHODS: 205 patients were enrolled, including 61 patients with MCA bifurcation aneurysms and 144 non-aneurysmal subjects. Aneurysmal cases were divided into types C (aneurysm neck on extension of the parent artery centerline) and D (deviating neck). The radius of the parent artery M1 (RP) and bilateral branches (RS and RL, respectively), smaller (φS) and larger (φL) lateral angles, bifurcation angle, and arterial tortuosity from parent vessel to bilateral branches (TS and TL, respectively) were analyzed. Logistic regression and receiver operator characteristic (ROC) curve analysis were performed to identify risk factors and predictive values for MCA aneurysm presence and types. RESULTS: In aneurysmal MCA bifurcations, bifurcating angle, TS, TL and RL were significantly larger (P<0.01), while φS was significantly smaller (P<0.001) than those in controls. The bifurcation angle, TS and LogitP were better morphological parameters for predicting MCA aneurysm presence with the AUC of 0.795, 0.932 and 0.951, respectively. Significant (P<0.05) differences were observed in the bifurcation angle, φL, RP, RL and TL between types C and D aneurysmal bifurcations. TL was an independent factor in discriminating types C from D aneurysms with an AUC of 0.802. CONCLUSIONS: Bifurcation angle and arterial tortuosity from the parent artery to the branch forming a smaller angle with the parent artery have a higher value in distinguishing MCA aneurysmal from non-aneurysmal ones, and the tortuosity from the parent artery to the contralateral branch is the best indicator for distinguishing types C from D aneurysmal bifurcations.

The contribution of smoking-attributable mortality to differences in mortality and life expectancy among US African-American and white adults, 2000-2019.

BACKGROUND: The role of smoking in racial disparities in mortality and life expectancy in the United States has been examined previously, but up-to-date estimates are generally unavailable, even though smoking prevalence has declined in recent decades. OBJECTIVE: We estimate the contribution of smoking-attributable mortality to observed differences in mortality and life expectancy for US African-American and white adults from 2000-2019. METHODS: The indirect Preston-Glei-Wilmoth method was used with national vital statistics and population data and nationally representative never-smoker lung cancer death rates to estimate the smoking-attributable fraction (SAF) of deaths in the United States by sex-race group from 2000-2019. Mortality rates without smoking-attributable mortality were used to estimate life expectancy at age 50 (e 50) by group during the period. RESULTS: African-American men had the highest estimated SAF during the period, beginning at 26.4% (95% CI:25.0%-27.8%) in 2000 and ending at 12.1% (95% CI:11.4%-12.8%) in 2019. The proportion of the difference in e 50 for white and African-American men that was due to smoking decreased from 27.7% to 14.8%. For African-American and white women, the estimated differences in e 50 without smoking-attributable mortality were similar to observed differences. CONCLUSIONS: Smoking continues to contribute to racial disparities in mortality and life expectancy among men in the United States. CONTRIBUTION: We present updated estimates of the contribution of smoking to mortality differences in the United States using nationally representative data sources.

Assessing quality-adjusted years of life lost associated with exclusive cigarette smoking and smokeless tobacco use.

The main purpose of this analysis is to quantify quality adjusted life years (QALYs) lost associated with lifetime exclusive cigarette or smokeless tobacco use among U.S. adults. Multiple waves of National Health Interview Survey (NHIS) data linked to death certificate records were used to define current exclusive cigarette and smokeless tobacco use and associated mortality risks. NHIS data were used to assess health-related quality of life (HRQOL). Regression and Cox proportional hazard modeling were used to adjust HRQOL and mortality risk associated with tobacco use for age, sex, race/ethnicity, body mass index, education, and household poverty level. QALYs were estimated based on adjusted HRQOL and mortality risks. All analyses were initiated in 2019 and completed in 2020. Male current exclusive cigarette smokers, aged 25 to 29 years would lose 8.1 QALYs (SE = 0.09), and male current exclusive smokeless tobacco users aged 25 to 34 would lose 4.1 QALYs (SE = 0.22), compared to never users of tobacco. Current exclusive cigarette or smokeless tobacco use is associated with QALY loss. QALYs lost can be lessened through preventing the initiation of tobacco product use or helping tobacco product users quit as early in life as possible.

Modeling mortality risk effects of cigarettes and smokeless tobacco: results from the National Health Interview Survey Linked Mortality File Data.

BACKGROUND: Cigarettes and smokeless tobacco (SLT) products are among a wide range of tobacco products that are addictive and pose a significant health risk. In this study, we estimated smoking- and SLT use-related mortality hazard ratios (HRs) among U.S. adults by sex, age group, and cause of death, for nine mutually exclusive categories of smoking and/or SLT use. METHODS: We used data from the public-use National Health Interview Survey Linked Mortality with mortality follow-up through 2015. We used Cox proportional hazard models to estimate mortality HRs, adjusted by race/ethnicity, education, poverty level, body mass index, and tobacco-use status. RESULTS: With never users as reference group, HRs for smoking-related diseases for male exclusive current smokers aged 35-64 and 65+ were 2.18 (95% confidence interval [CI]: 1.79-2.65), and 2.45 (95% CI: 2.14-2.79), respectively. Similar significant HR estimates were found for females and for all-cause mortality (ACM) and other-cause mortality (OCM) outcomes. HRs for exclusive current SLT users were only significant for males aged 35-64 for ACM (HR: 2.04, 95% CI: 1.27-3.27) and OCM (HR: 2.80, 95% CI: 1.50-5.25). HRs for users who switched from cigarettes to SLT products were significant for males aged 65+ for smoking-related diseases (HR: 2.06, 95% CI: 1.47-2.88), SLT-related diseases (HR: 1.99, 95% CI: 1.36-2.89), and ACM (HR: 1.63, 95% CI: 1.21-2.19). CONCLUSIONS: Male exclusive current SLT users aged 35-64 had a significant HR for ACM and OCM outcomes, suggesting that deaths not attributed to SLT use could be contributing to the ACM elevated HR for exclusive current SLT users.

Circular RNA hsa_circ_0001178 facilitates the invasion and metastasis of colorectal cancer through upregulating ZEB1 via sponging multiple miRNAs.

Metastasis is the main cause of increasing cancer morbidity and mortality. However, the underlying mechanism of cancer metastasis remains largely unknown. In the present study, we identified one circular RNA (circRNA) closely related to the metastasis of colorectal cancer (CRC), namely hsa_circ_0001178. CRC patients with high hsa_circ_0001178 were more prone to have metastatic clinical features, advanced TNM stage and adverse prognosis. Stable knockdown of hsa_circ_0001178 significantly weakened CRC cell migratory and invasive capabilities in vitro as well as lung and liver metastases in vivo. Mechanistic study revealed that hsa_circ_0001178 acted as a competing endogenous RNA (ceRNA) for miR-382/587/616 to upregulate ZEB1 (a key trigger of epithelial-to-mesenchymal transition), thereby promoting CRC metastatic dissemination. Of note, ZEB1 could also increase hsa_circ_0001178 expression via physically binding to hsa_circ_0001178 promoter region. Collectively, our data uncover the crucial role of hsa_circ_0001178 in CRC metastasis, and targeted therapy based on this positive feedback ceRNA axis may be a promising treatment for metastatic CRC patients.

E-cigarette Use Among Middle and High School Students - United States, 2020.

The use of any tobacco product by youths is unsafe, including electronic cigarettes (e-cigarettes) (1). Most e-cigarettes contain nicotine, which is highly addictive, can harm the developing adolescent brain, and can increase risk for future addiction to other drugs (1). E-cigarette use has increased considerably among U.S. youths since 2011 (1,2). Multiple factors have contributed to this increase, including youth-appealing flavors and product innovations (1-3). Amid the widespread use of e-cigarettes and popularity of certain products among youths, on February 6, 2020, the Food and Drug Administration (FDA) implemented a policy prioritizing enforcement against the manufacture, distribution, and sale of certain unauthorized flavored prefilled pod or cartridge-based e-cigarettes (excluding tobacco or menthol).

Tobacco Product Use Among Middle and High School Students - United States, 2020.

Tobacco use is the leading cause of preventable disease and death in the United States; nearly all tobacco product use begins during youth and young adulthood (1,2). CDC and the Food and Drug Administration (FDA) analyzed data from the 2019 and 2020 National Youth Tobacco Surveys (NYTS) to determine changes in the current (past 30-day) use of seven tobacco products among U.S. middle (grades 6-8) and high (grades 9-12) school students. In 2020, current use of any tobacco product was reported by 16.2% (4.47 million) of all students, including 23.6% (3.65 million) of high school and 6.7% (800,000) of middle school students. Electronic cigarettes (e-cigarettes) were the most commonly used tobacco product among high school (19.6%; 3.02 million) and middle school (4.7%; 550,000) students. From 2019 to 2020, decreases in current use of any tobacco product, any combustible tobacco product, multiple tobacco products, e-cigarettes, cigars, and smokeless tobacco occurred among high school and middle school students; these declines resulted in an estimated 1.73 million fewer current youth tobacco product users in 2020 than in 2019 (6.20 million) (3). From 2019 to 2020, no significant change occurred in the use of cigarettes, hookahs, pipe tobacco, or heated tobacco products. The comprehensive and sustained implementation of evidence-based tobacco control strategies at the national, state, and local levels, combined with tobacco product regulation by FDA, is warranted to help sustain this progress and to prevent and reduce all forms of tobacco product use among U.S. youths (1,2).

Oxidized low-density lipoprotein promotes osteoclast differentiation from CD68 positive mononuclear cells by regulating HMGB1 release.

Patients with ankylosing spondylitis (AS) have an increased risk for cardiovascular mortality. The circulating ox-LDL/LDL ratio is associated with subclinical atherosclerosis in patients with systemic lupus erythematosus. In this study, we found that the ox-LDL/LDL ratio was increased in AS patients. The levels of serum RANKL and HMGB1 were also elevated in AS patients, and the number of CD68+/RANK+ cells was increased in peripheral blood from AS patients. 0.03% ox-LDL in LDL, similar to the ox-LDL/LDL ratio in peripheral blood from AS patients, promoted cytoplasmic translocation and release of HMGB1 as well as RANK expression. Further investigation evidenced that ox-LDL-induced EGR1 expression contributed to the cytoplasmic translocation of HMGB1 and CD68 assisted the secretion of HMGB1 from cytoplasm to extracellular matrix. Extracellular HMGB1 induced RANK expression in CD68+ mononuclear cells, forming osteoclast precursors that were differentiated to osteoclasts in response to RANKL. Taken together, these results suggested that the changes, including ox-LDL/LDL ratio, CD68+/RANK+ cells number, and the levels of RANKL and HMGB1 in AS patients, favored osteoclastogenesis.

Longitudinal latent variable models given incompletely observed biomarkers and covariates.

In this paper, we analyze a two-level latent variable model for longitudinal data from the National Growth and Health Study where surrogate outcomes or biomarkers and covariates are subject to missingness at any of the levels. A conventional method for efficient handling of missing data is to re-express the desired model as a joint distribution of variables, including the biomarkers, that are subject to missingness conditional on all of the covariates that are completely observed, and estimate the joint model by maximum likelihood, which is then transformed to the desired model. The joint model, however, identifies more parameters than desired, in general. We show that the over-identified joint model produces biased estimation of the latent variable model and describe how to impose constraints on the joint model so that it has a one-to-one correspondence with the desired model for unbiased estimation. The constrained joint model handles missing data efficiently under the assumption of ignorable missing data and is estimated by a modified application of the expectation-maximization algorithm. Copyright © 2016 John Wiley & Sons, Ltd.

A Generalized Sequential Bonferroni Procedure for GWAS in Admixed Populations Incorporating Admixture Mapping Information into Association Tests.

OBJECTIVE: To develop effective methods for GWAS in admixed populations such as African Americans. METHODS: We show that, when testing the null hypothesis that the test SNP is not in background linkage disequilibrium with the causal variants, several existing methods cannot control well the family-wise error rate (FWER) in the strong sense in GWAS. These existing methods include association tests adjusting for global ancestry and joint association tests that combine statistics from admixture mapping tests and association tests that correct for local ancestry. Furthermore, we describe a generalized sequential Bonferroni (smooth-GSB) procedure for GWAS that incorporates smoothed weights calculated from admixture mapping tests into association tests that correct for local ancestry. We have applied the smooth-GSB procedure to analyses of GWAS data on American Africans from the Atherosclerosis Risk in Communities (ARIC) Study. RESULTS: Our simulation studies indicate that the smooth-GSB procedure not only control the FWER, but also improves statistical power compared with association tests correcting for local ancestry. CONCLUSION: The smooth-GSB procedure can result in a better performance than several existing methods for GWAS in admixed populations.

MicroRNA-26b inhibits metastasis of osteosarcoma via targeting CTGF and Smad1.

Downregulation of miR-26b has been found in various cancers, but it has never been investigated in osteosarcoma. In this study, we demonstrated downregulation of miR-26b in osteosarcoma tissues, negatively correlated with the expression of connective tissue growth factor (CTGF) and Smad1. Luciferase reporter assay confirmed the interaction of miR-26b with the 3' untranslated regions (UTRs) of CTGF and Smad1. Transfection of miR-26b in osteosarcoma cells suppressed the expression of CTGF and Smad1, suggesting CTGF and Smad1 as direct targets of miR-26b. Overexpression of miR-26b inhibited the migration of osteosarcoma cells, which was reversed by overexpression of CTGF or Smad1. Knockdown of CTGF by small interfering RNA (siRNA) interference blocked the activation of Smad1, ERK1/2, and MMP2, which was opposite to the overexpression of CTGF. Differently, Smad1 did not significantly affect CTGF level, but mediated ERK1/2 phosphorylation and MMP2 activation. Furthermore, miR-26b inhibited lung metastasis of osteosarcoma in vivo. Our data indicated that downregulation of miR-26b in osteosarcoma elevated the levels of CTGF and Smad1, facilitating osteosarcoma metastasis.

Endothelialization of PTFE-covered stents for aneurysms and arteriovenous fistulas created in canine carotid arteries.

To investigate the endothelialization of covered and bare stents deployed in the canine carotid arteries and subclavian arteries for treating experimental aneurysms and arteriovenous fistulas, twenty aneurysms were created in 10 dogs, and 20 fistulas in another 10 dogs. The Willis balloon-expandable covered stent and a self-expandable covered stent were used to treat these lesions, and a self-expandable bare stent was deployed in the subclavian artery for comparison. Followed up for up to 12 months, the gross observation, pathological staining, and scanning electronic microscopic data were analyzed. Two weeks after creation of animal model, thirty self-expandable covered stents and ten balloon-expandable covered stents were deployed. Fifteen bare stents were deployed within the left subclavian arteries. Twenty days after stenting, the aneurysm significantly shrank. At 6 months, the thrombi within the aneurysm cavity were organized. Three to 12 months later, most covered and bare stents were covered by a thin transparent or white layer of endothelial intima. Layers of intima or pseudomembrane were formed on the stent 20-40 days after stent deployment. Over three months, the pseudomembrane became organized, thinner, and merged into the vascular wall. Under scanning electronic microscopy, the surface of covered and bare stents had only deposition of collagen fibers and rare endothelial cells 20-40 days after stenting. From three to ten months, the endothelial cells on the internal surface of stent became mature, with spindle, stripe-like or quasi round morphology along the blood flow direction. Over time, the endothelial cells became mature. In conclusion, three months after deployment in canines' arteries, the self-expandable bare and covered stents have mostly been covered by endothelial cells which become maturer over time, whereas the balloon-expandable covered stents do not have complete coverage of endothelial cells at three months, especially for protruding stent struts and areas. Over time, the endothelialization will become mature.

Knockdown of Galectin-9 alleviates rheumatoid arthritis through suppressing TNF-α-induced activation of fibroblast-like synoviocytes.

The role of Galectin-9 (Gal-9) in the pathogenesis of rheumatoid arthritis (RA) remains unclear. This study aimed to investigate the mechanism of action and therapeutic potential of Gal-9 in RA. We detected Gal-9 expression in clinical samples, explored the mechanism of function of Gal-9 by knockdown and overexpression in fibroblast-like synoviocytes (FLSs), and further verified it in collagen-induced arthritis (CIA) model. We found that the levels of Gal-9 were considerably elevated in RA synovium than in osteoarthritis (OA) patients. A substantial decrease of Gal-9 was demonstrated after tumor necrosis factor (TNF-α) inhibitor treatment in the plasma of patients with RA. Additionally, transcriptome sequencing revealed that Gal-9 was involved in the regulation of the TNF-α pathway. Gal-9 was considerably upregulated after TNF-α stimulation in FLSs, and knockdown of Gal-9 substantially inhibited TNF-α activated proliferation, migration and inflammatory response. According to cell transcriptome sequencing results, we further confirmed that Gal-9 could achieve these effects by interacting with MAFB and affecting PI3K/AKT/mTOR pathway. Finally, we knocked down Gal-9 on the CIA model and found that it could alleviate the progression of arthritis. In conclusion, our study revealed that the knockdown of Gal-9 could inhibited TNF-α induced activation in RA through MAFB, PI3K/AKT/mTOR.