LncRNA H19 inhibitor represses synovial cell proliferation and apoptosis in rats with rheumatoid arthritis via Notch signaling pathway.

The article "LncRNA H19 inhibitor represses synovial cell proliferation and apoptosis in rats with rheumatoid arthritis via Notch signaling pathway, by L.-Q. Zhi, Q. Zhong, J.-B. Ma, L. Xiao, S.-X. Yao, X. Wang, published in Eur Rev Med Pharmacol Sci 2020; 24 (8): 4088-4094-DOI: 10.26355/eurrev_202004_20985-PMID: 32373945" has been withdrawn from the authors. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/20985.

LncRNA H19 inhibitor represses synovial cell proliferation and apoptosis in rats with rheumatoid arthritis via Notch signaling pathway.

OBJECTIVE: To study the roles and underlying mechanisms of long non-coding ribonucleic acid (lncRNA) H19 in the synovial cell proliferation and apoptosis in rats with rheumatoid arthritis (RA). MATERIALS AND METHODS: A total of 30 Sprague-Dawley rats were randomly divided into Control group and Model group. The rat model of RA was induced by using type II collagen in Model group. The primary synovial cells were isolated from the synovial tissues of the rats and were assigned into Control group, Model group, and lncRNA H19 inhibitor intervention group. 5-Ethynyl-2'-deoxyuridine (EdU) staining was applied to detect cell proliferation in each group. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining was employed to determine the cell apoptosis in each group. Western blotting assay was adopted to measure the expression levels of Notch1 and hairy/enhancer of split-1 (Hes1) in each group of cells. RESULTS: The RA score of the Model group was higher than that of the Control group. Compared to the Control group, the expression of lncRNA H19, Notch, and Hes1 of the synovial cells in the Model group were significantly elevated. Besides, the cell proliferation rate of the Model was also increased, while the cell apoptosis rate was decreased compared with those in the Control group. Moreover, in comparison with Model group, lncRNA H19 inhibitor intervention group exhibited a lowered lncRNA H19 level, remarkably reduced cell proliferation rate and protein levels of Notch1 and Hes1, as well as notably raised cell apoptosis rate. CONCLUSIONS: Our results indicated that lncRNA H19 inhibitor could repress the proliferation and promote the apoptosis of synovial cells in RA rats, which might be attributed to the inhibition of the Notch signaling pathway.

Quantitative evaluation of the radon and lung cancer association in a case control study of Chinese tin miners.

Studies of underground miners have consistently shown an increased risk of lung cancer with cumulative exposure to radon-222 and its decay products. Although the deleterious effects of high radon exposure are clear, questions regarding the shape of the exposure-response relationship, and the effects of time factors such as attained age, time since exposure and early age at first exposure, the effect of exposure rate, and the joint association of radon exposure and tobacco use have not yet been fully clarified. This report considers these questions by fitting various models for the relative odds of disease to 74 male lung cancer cases who were diagnosed between 1981 and 1984 and were alive in 1985 and an equal number of controls. All subjects are current or past employees of the Yunnan Tin Corporation, Gejiu City, China, who reside in the local area. Workers were interviewed to obtain information on work history, from which radon exposure in cumulative working level months and arsenic exposure were estimated, and on tobacco use. Results indicate that excess relative risk increases by 1.7% per cumulative working level month [95% confidence interval (0.5, 5.4)]. The linear exposure response relationship significantly declines with year since last radon exposure (P = 0.02). The risk trend also declines with increasing exposure rate (P = 0.001), indicating that long duration of exposure at a low rate may be more deleterious than short duration of exposure at a high rate. A unique aspect of this study population is the very early ages at first radon exposure for many of the workers, about 37% of the radon-exposed workers were first exposed under the age of 13 years. The analysis shows no modification of the radon lung cancer relationship with age at first exposure. These patterns of risk with radon exposure are generally consistent with those reported in the recent National Academy of Sciences' Biological Effects of Ionizing Radiations IV report. The primary method of tobacco consumption in this area of China is by waterpipe. Lung cancer risk increases with pipe-years of use. The joint analysis of tobacco use and radon exposure supports the Biological Effects of Ionizing Radiations IV conclusion that the most likely model is between additive and multiplicative. The variations of the radon lung cancer relationship by years since last exposure and exposure rate are not affected by adjustment for arsenic exposure.

Prospective detection of preclinical lung cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression.

The United States lung cancer epidemic has not yet been controlled by present prevention and treatment strategies. Overexpression of a Mr 31,000 protein, heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, had shown promise as a marker of lung cancer. In a pilot study of archived preneoplastic sputum specimens, hnRNP A2/B1 overexpression more accurately detected preclinical lung cancer than standard cytomorphology. In separate, ongoing prospective studies, sputum is collected annually from stage I resected non-small cell lung cancer patients at high risk of developing a second primary lung cancer and Yunnan tin miners at high risk of primary lung cancer. After the first year of follow-up, preclinical detection of lung cancer by routine cytology was compared with hnRNP A2/B1 overexpression as measured by quantitative densitometry of immunostained slides. Up-regulation of hnRNP A2/B1 in sputum specimens accurately predicted the outcome in 32 of 40 primary lung cancer and control patients within 12 months, whereas cytological change suggestive of lung cancer was found in only 1 patient. In the primary lung cancer study, overexpressed hnRNP A2/B1 accurately predicted the outcome in 69 of 94 primary lung cancer and control miners, whereas only 10 with primary lung cancer were diagnosed cytologically. These two prospective studies accurately predicted that 67 and 69% of those with hnRNP A2/B1 up-regulation in their sputum would develop lung cancer in the first year of follow-up, compared with background lung cancer risks of 2.2 and 0.9% (35- and 76-fold increase, respectively). Using sputum cells to monitor hnRNP A2/B1 expression may greatly improve the accuracy of preclinical lung cancer detection.

A case-cohort study of an early biomarker of lung cancer in a screening cohort of Yunnan tin miners in China.

We initiated the present study to evaluate the accuracy of a new epithelial biomarker of early lung cancer. We tested the hypothesis that expression of a tumor-associated antigen by exfoliated sputum epithelial cells has greater accuracy (sensitivity and specificity) for the detection of preclinical, localized lung cancer than do routine clinical detection methods. Monoclonal antibody (MAb) 703D4 recognizes heterogeneous nuclear ribonuclear protein (hnRNP) A2/B1. We compared the accuracy of hnRNP up-regulation with cytology and radiographic screening for lung cancer detection in miners who were highly exposed to tobacco smoke, radon, and arsenic in southwestern China. The results showed that MAb 703D4 detection of hnRNP expression by sputum epithelial cells had greater accuracy for the detection of lung cancer than did routine screening methods, particularly for early (localized) disease. Among 57 cases and 76 noncases at the first screening, overall MAb detection of hnRNP was more sensitive (74 versus 21% for cytology and 42% for chest x-ray) but had lower specificity (70 versus 100% for cytology and 90% for chest x-ray) than standard methods. Recognizing hnRNP up-regulation resulted in detection of approximately one-third more early cases than did the combination of X-ray and cytology. Detection of hnRNP A2/B1 expression appears to be a good initial screening test for lung carcinogenesis, as it identified 74% of those who developed subsequent clinical lung cancer. Future studies might separate individuals with high lung cancer risk by MAb detection, confirming the positives with markers having greater specificity (e.g., clinical studies that become positive later in the morphological progression).

Polymorphisms of the DNA repair gene XRCC1 and lung cancer risk.

We explored the association between polymorphisms of the DNA repair gene XRCC1 (codons 194, 280, and 399) and lung cancer risk in a case-control study nested within a cohort of tin miners. Cases were those diagnosed with lung cancer over 6 years of follow-up (n = 108). Two controls, matched on age and sex, were selected for each case by incidence density sampling. Of the three polymorphisms, only the XRCC1 Arg280His allele was associated with increased lung cancer risk (odds ratio, 1.8; 95% confidence interval, 1.0-3.4) after adjustment for radon and tobacco exposure. In addition, individuals with the variant Arg280His allele who were alcohol drinkers seemed to be at higher risk for lung cancer compared with those with the homozygous wild-type genotype. Conversely, individuals with the variant Arg194Trp allele who were alcohol drinkers seemed to be at lower risk for lung cancer compared with those with the homozygous wild-type genotype. Polymorphisms of XRCC1 appear to influence risk of lung cancer and may modify risk attributable to environmental exposures.

Risk factors and early detection of lung cancer in a cohort of Chinese tin miners.

PURPOSE: To examine risk factors and establish a biologic specimen and data bank for the study of early markers of lung cancer. METHODS: We designed a dynamic cohort using an ongoing lung cancer screening program among radon- and arsenic-exposed tin miners in Yunnan China. Through the first four years of the study, 8,346 miners aged 40 years and older with over 10 years of occupational exposure have been enrolled, risk factors have been assessed, annual sputum and chest radiographs have been obtained, and numerous biologic specimens have been collected. RESULTS: A total of 243 new lung cancer cases have been identified through 1995. Radon and arsenic exposures are the predominant risk factors, but lung cancer risk is also associated with chronic bronchitis and silicosis, as well as a number of exposure to tobacco smoke, including early age of first use, duration, and cumulative exposure. Tumor and sputum samples are being examined for early markers of lung cancer. CONCLUSION: A cohort of occupationally-exposed tin miners with an extensive biologic specimen repository has been successfully established to simultaneously study the etiology and early detection of lung cancer.

The effect of dietary intake of fruits and vegetables on the odds ratio of lung cancer among Yunnan tin miners.

All newly diagnosed cases of lung cancer (N = 183) among male tin miners of Yunnan Province, China and age-sex matched occupational controls (N = 183 aged 45-79 years) were interviewed within 3 months following cancer diagnosis. The questionnaire included information about usual adult diet as well as employment and smoking histories. Over 95% of cases and controls were current smokers. The 27-item food frequency questionnaire included 11 fruits and vegetables rich in vitamin A and/or carotenoids. The effect of dietary intake of fruits and vegetables on risk of lung cancer was examined with adjustment for exposures to radon, arsenic, and smoking as previously documented risk factors for lung cancer. Tin miners with reduced intake of yellow and light green vegetables had statistically significant increased odds ratios (OR) of lung cancer (OR = 2.26 and OR = 2.39 for the lowest two quartiles of intake; P value for trend = 0.02) among cases compared with controls after multiple logistic regression adjustment for covariates; and this relationship was monotonic. Tin miners with reduced intake of tomatoes had statistically significant increased adjusted OR of lung cancer (OR = 2.64, OR = 3.09, OR = 2.36 for the three lowest quartiles of intake; P value for trend = 0.04). This is the first study to demonstrate a protective effect of vegetable intake versus the strong effects of smoking and occupational exposures on lung cancer risk.

Exposure to radon progeny, tobacco use and lung cancer in a case-control study in southern China.

A case-control study of lung cancer in underground tin miners in southern China was conducted to examine the interplay between exposure to radon progeny and tobacco use. A total of 460 incident cases and 1,043 controls were evaluated. Among the exposed, mean radon progeny exposures were 600 and 427 working level months (WLM) for cases and controls, respectively. The excess relative risk per WLM (ERR/WLM) was 0.28% overall, with a 95% confidence interval of 0.1-0.6%, similar to the estimate from a cohort study in a related population of underground miners. The established patterns of lung cancer associated with radon were seen; the ERR/WLM decreased with attained age and time since last exposure. Conditional on total exposure, risk was highest for exposures delivered at a low rate. The ERR/WLM did not differ significantly among current and former smokers or within categories of time since last exposure. The relative risk relationship between exposure to radon progeny and tobacco use was consistent with a multiplicative model, but the best-fitting model was intermediate between additive and multiplicative; an additive association was rejected. Adjustment for exposure to inorganic arsenic, a known lung carcinogen, reduced the estimate of the ERR/WLM from 0.86% to 0.28%. The ERR/WLM estimate was homogeneous across subgroups defined by workers not exposed to arsenic and quartiles of cumulative arsenic exposure. Although squamous cell carcinoma was the predominant cell type, small cell and adenocarcinoma histologies appeared more strongly associated with exposure to radon progeny. The finding of a stronger trend with exposure with small cell carcinomas and adenocarcinomas, compared to squamous cell carcinomas, occurred primarily at younger ages at diagnosis. Finally, the risk of lung cancer was higher if exposure to radon progeny and tobacco use occurred together than if the exposure to radon progeny entirely preceded tobacco use.

Estimating lung cancer mortality from residential radon using data for low exposures of miners.

Some recent estimates of lung cancer risk from exposure to radon progeny in homes have been based on models developed from a pooled analysis of 11 cohorts of underground miners exposed to radon. While some miners were exposed to over 10,000 working level months (WLM), mean exposure among exposed miners was 162 WLM, about 10 times the exposure from lifetime residence in an average house and about three times the exposure from lifetime residence at the "action level" suggested by the U.S. Environmental Protection Agency. The extrapolation of lung cancer risk from the higher exposures in the miners to the generally lower exposures in the home is a substantial source of uncertainty in the assessment of the risk of indoor radon. Using the pooled data for the miners, analyses of lung cancer risk were carried out on data restricted to lower exposures, either <50 WLM or <100 WLM. In the pooled data, there were 115 lung cancer cases among workers with no occupational WLM exposure and 2,674 among exposed miners, with 353 and 562 lung cancer cases in miners with <50 WLM and <100 WLM, respectively. Relative risks (RRs) for categories of WLM based on deciles exhibited a statistically significant increasing trend with exposure in each of the restricted data sets. In the restricted data, there was little evidence of departures from a linear excess relative risk model in cumulative exposure, although power to assess alternative exposure-response trends was limited. The general patterns of declining excess RR per WLM with attained age, time since exposure and exposure rate seen in the unrestricted data were similar to the patterns found in the restricted data. Risk models based on the unrestricted data for miners provided an excellent fit to the restricted data, suggesting substantial internal validity in the projection of risk from miners with high exposures to those with low exposures. Estimates of attributable risk for lung cancer (10-14%) in the U.S. from residential radon based on models from the unrestricted data were similar to estimates based on the data for miners receiving low exposures.

Two new non-steroidal constituents from Dioscorea futschauensis R. Kunth.

Dioscorone A (1) and a new isocoumarin derivative (2) were isolated from the rhizome of Dioscorea futschauensis R. Kunth. The structures of 1 and 2 were elucidated on the basis of detailed analysis of NMR spectra. Their anti-fungal activity against Pyricularia oryzae and cytotoxic activity on K562 and HCT-15 cell lines were evaluated in vitro.

Feasibility of conducting a lung-cancer chemoprevention trial among tin miners in Yunnan, P. R. China.

Tin miners in Yunnan Province in southern China have an extremely high rate of lung cancer, more than one percent per year among those at 'high risk' (40+ years old, with 10+ years of underground mining and/or smelting experience). The extraordinary lung cancer rates result from combined exposure to radon, arsenic, and tobacco smoking (cigarettes and/or bamboo water pipe). A study to determine the feasibility of conducting a large-scale, lung-cancer chemoprevention trial was conducted in 1986 among currently employed or retired miners from the Yunnan Tin Corporation in the city of Gejiu. The study was designed to answer four questions: (i) Could potentially eligible miners be identified and recruited? (ii) Could intervention agents be shipped successfully from the United States to the study area and be appropriately distributed? (iii) Would miners adequately adhere to the study protocol and comply with the intervention regimen? (iv) Could potential adverse effects be monitored and documented? The six-month feasibility study yielded affirmative answers to each of these questions. A roster of over 7,000 high-risk miners was compiled. Four agents (vitamin A, 25,000 IU; beta-carotene, 50 mg; vitamin E, 800 IU; and selenium, 400 micrograms) were administered daily with placebos to 350 miners according to a 2(4) factorial design. Adherence, assessed by pill counts and serum micronutrient levels, was approximately 90 percent. The findings from this preliminary study indicate that a full-scale, lung-cancer chemoprevention trial in this population is feasible.

Serum tocopherols, selenium and lung cancer risk among tin miners in China.

OBJECTIVE: To evaluate the association of prediagnostic serum antioxidants and lung cancer risk we conducted a case-control study nested in an occupational cohort of tin miners. METHODS: Male workers free of cancer enrolled in the cohort. During up to 6 years of follow-up, 339 lung cancer cases were diagnosed and, among these cases, those who donated blood prospectively (n = 108) were eligible for this study. For each case, two controls alive and free of cancer at the time of case diagnosis were matched on age and date of blood collection. RESULTS: Overall, we observed no association between serum alpha-tocopherol, gamma-tocopherol or selenium levels and lung cancer risk. However, a significant gradient of decreasing lung cancer risk with increasing serum alpha-tocopherol was apparent for men less than 60 years old (odds ratio by tertile: 1.0, 0.9, 0.2; trend p = 0.002). Alpha-tocopherol was also protective in men who reported no alcohol drinking (OR by tertile: 1.0, 0.6, 0.3; trend p = 0.008). CONCLUSION: Although there were no significant overall associations between prospectively collected serum alpha-tocopherol, gamma-tocopherol or selenium and incidence of lung cancer, results from this study suggest that higher alpha-tocopherol levels may be protective in men less than 60 years old and in those who do not drink alcohol.

Relation of radon exposure and tobacco use to lung cancer among tin miners in Yunnan Province, China.

We studied the relation of radon exposure and tobacco use to lung cancer among tin miners in Yunnan Province in the People's Republic of China. Interviews were conducted in 1985 with 107 living tin miners with lung cancer and an equal number of age-matched controls from among tin miners without lung cancer to obtain information on lung cancer risk factors including a detailed history of employment and tobacco use. Occupational history was combined with extensive industrial hygiene data to estimate cumulative working level months (WLM) of radon daughter exposure. Similar data were also used to estimate arsenic exposure for control in the analysis. Results indicate an increased risk of lung cancer for water pipe smoking, a traditional form of tobacco use practiced in 91% of cases and 85% of controls. Ever use of water pipes was associated with a twofold elevation in risk when compared with tobacco abstainers, and a dose-response relation was observed with increasing categories of pipe-year (dose times duration) usage. Estimated WLM of radon exposure varied from 0 to 1,761 among subjects but averaged 515 in cases versus only 244 in controls. Analyses indicated that the persons in the highest quarter of the radon exposure distribution had an odds ratio (OR) = 9.5 (95% confidence interval = 2.7-33.1) compared to persons without radon exposure after controlling for arsenic exposure and other potential confounders. Examination of duration and rate of radon exposure indicated higher risk associated with long duration as opposed to high rate of exposure. Cross-categorizations of radon exposure and tobacco use suggest greater risk associated with radon exposure than tobacco in these workers.

Relation of arsenic exposure to lung cancer among tin miners in Yunnan Province, China.

The relation of mining and smelting exposure to arsenic and lung cancer was studied among tin miners in Yunnan Province in the People's Republic of China. Interviews were conducted in 1985 with 107 living tin miners who had lung cancer and an equal number of age matched controls from among tin miners without lung cancer to obtain information on risk factors for lung cancer including detailed history of employment and tobacco use. Occupational history was combined with industrial hygiene data to estimate cumulative arsenic exposure. Similar methods were also used to estimate radon exposure for simultaneous evaluation in this analysis. The results indicate that subjects in the highest quarter of cumulative arsenic exposure have a relative risk of 22.6 compared with subjects without exposure after adjusting for tobacco and radon exposure, and a positive dose response relation was observed. Simultaneous evaluation of arsenic and tobacco exposure indicates a greater risk for arsenic, whereas simultaneous assessment of arsenic and radon exposure suggests radon to be the greater risk. There is no evidence of synergism between arsenic and tobacco exposure. Among arsenic exposed individuals, cases of lung cancer have longer duration but lower average intensity of arsenic exposure than controls, indicating that duration of exposure to arsenic may be more important than intensity in the aetiology of lung cancer. Finally, risk of lung cancer among workers exposed to arsenic only in mining is only slightly less than for miners whose exposure to arsenic was limited to smelting, although risks are highest when workers were exposed to both mining and smelting.

Dietary determinants of lung-cancer risk: results from a case-control study in Yunnan Province, China.

The relation between diet and lung cancer was studied among male residents of a mining community in Yunnan Province. After obtaining food frequency data from subjects or proxies, we compared diets of 428 cases, aged 35-74 years, and 1,011 age-matched controls. Cases tended to consume slightly more rice, but less protein-rich foods (i.e., bean curd, meat, eggs) and vegetables than did controls. The relative risks of lung cancer across increasing quartiles of meat (i.e., pork) consumption, for example, were 1.00, 0.67, 0.72 and 0.46 (p for trend less than 0.01). The relative risks of lung cancer across increasing quartiles of consumption of dark-green, leafy vegetables were 1.00, 0.62, 0.52 and 0.41 (p for trend less than 0.01). Although specific dietary constituent(s) responsible for the protective effect of vegetable consumption could not be identified, carotenoids other than beta-carotene, or compounds in cruciferous or Allium vegetables, are possibilities.

Serum carotenoids are associated with increased lung cancer risk among alcohol drinkers, but not among non-drinkers in a cohort of tin miners.

To examine the association between pre-diagnostic serum carotenoid levels and lung cancer risk and the effects of alcohol intake on the carotenoid-lung cancer relationship, we conducted a case-control study in an occupational cohort from the Yunnan Tin Corporation in China. During 6 years of follow-up, 339 cases of confirmed lung cancer were diagnosed. Among these cases, those who donated pre-diagnostic blood (n = 108) were eligible for this study. For each case, two individuals alive and free of cancer at the time of case diagnosis, matched on age, sex, and date of blood collection, were selected as controls. Serum beta-carotene (odds ratios (ORs) for tertiles: 1, 1.3, 2.0) and beta-cryptoxanthin (ORs for tertiles: 1, 1.8, 2.9) levels were positively associated with lung cancer risk after adjustment for tobacco use and radon exposure. Among alcohol drinkers, higher serum carotenoid levels were significantly associated with increased lung cancer risk (alpha-carotene OR 2.2, 95% confidence interval (CI) 1.1-4.4, beta-carotene OR 7.6, 95% CI 3.1-18.6, lutein/zeaxanthin OR 2.3, 95% CI 1.2-6.6 and beta-cryptoxanthin OR 7.6, 95% CI 2.7-21.5). Conversely, risk estimates among non-drinkers suggest a possible protective association for higher carotenoid levels.

Relative validity of a food frequency questionnaire among tin miners in China: 1992/93 and 1995/96 diet validation studies.

OBJECTIVE: Diet validation research was conducted to compare the respondents' reporting of dietary intake in a food frequency questionnaire (FFQ) with intake reported in food recalls. Because the population received annual salary increments that could modify food intake, diet validation studies (DVSs) were conducted during two time intervals. DESIGN: A 99-item FFQ was administered by an interviewer twice in a 1-year interval, and responses to each FFQ item were compared with 28 days of interviewer-administered food recalls that were collected in four 1-week intervals during each season of 1992/93. The second validation study in 1995/96 had a similar design to the earlier one. SETTING: A prospective cohort study of lung cancer among tin miners in China was initiated in 1992, with dietary and other risk factors updated annually. SUBJECTS: Among a cohort of high risk tin miners for lung cancer, two different samples (n = 141 in 1992/93, and n = 113 in 1995/96) for each diet validation study were randomly selected from four mine units, that were representative of all worker units. RESULTS: Miners reported a significantly higher average frequency of intake of foods in the food recalls than the FFQ, with few exceptions. Deattenuated Pearson correlation coefficients of the frequency of food intake between the FFQ and food recalls were in the range of -0.40 to 0.72 in both studies, with higher positive correlations for beverages and cereal staples than for animal protein sources, vegetables, fruits and legumes. The percentage of individuals with exact agreement in the extreme quartiles of intake in the food recalls and FFQ ranged from 0 to 100% in both studies. CONCLUSIONS: Among Chinese miners, the range in correlations between the food recalls and the FFQ were due to: (i) market availability of foods during the food recall weeks compared to their annual reported intake in the FFQ; (ii) cultural perception of time; and (iii) differences in how the intake of mixed dishes and their multi-ingredient foods were reported in the recalls vs. the FFQ. The range in the percentage of agreement in the same quartiles and the changes in food intake over time may have implications for the analysis of the diet-disease relationship in this cohort.