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Background 27-hydroxycholesterol (27HC) was the first identified endogenous selective estrogen receptor modulator (SERM); 27HC promoted growth and metastasis in experimental models of estrogen receptor-positive mammary cancer. There are no data on prediagnosis circulating 27HC and breast cancer risk in women. Methods We conducted a nested case-control study in the well-characterized Heidelberg, Germany, cohort of the European Investigation into Cancer and Nutrition (EPIC) including 530 incident invasive breast cancer cases, each matched to up to two control participants (n = 1036). Serum 27HC was analyzed by liquid chromatography-mass spectrometry (LC-MS) in blood samples collected at study recruitment. Multivariable conditional logistic regression models were used to quantify the association between circulating 27HC and breast cancer risk overall, by tumor hormone receptor status (ie estrogen and progesterone receptors), and by menopausal status at blood collection. All statistical tests were two-sided. Results 27HC was not associated with breast cancer risk overall (relative risk [RR]Quartile4vsQuartile1 [Q4vsQ1] = 0.90, 95% confidence interval [CI] = 0.66 to 1.22). The association between 27HC and breast cancer risk differed by menopausal status at blood collection (Phet = .02), but not by age at diagnosis (Phet = .78). Among women who were postmenopausal at blood collection, higher serum 27HC levels were associated with lower breast cancer risk (RRQ4vsQ1 = 0.56, 95% CI = 0.36 to 0.87). We observed no association between 27HC and breast cancer risk (RRQ4vsQ1 = 1.33, 95% CI = 0.75 to 2.38) among women who were premenopausal at blood collection. Conclusions In this first prospective study, higher circulating 27HC was associated with lower risk of breast cancer in postmenopausal women. Identification of the first endogenous SERM associated with reduced risk of invasive breast cancer in postmenopausal women may offer novel avenues for breast cancer prevention strategies.

Given that 27-hydroxycholesterol (27HC) is the first identified endogenous selective estrogen receptor modulator, the aim of this study was to investigate the extent to which dietary or lifestyle factors impact circulating 27HC concentrations in a large-scale setting. This cross-sectional analysis included 1,036 women aged 35–65 years who served as controls in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg breast cancer case–control study. Circulating 27HC was quantified in serum using liquid chromatography/tandem mass spectrometry. Generalized linear models were used to investigate the association between 27HC concentrations and dietary habits, and lifestyle, reproductive, and anthropometric factors. Higher concentrations of 27HC were observed among postmenopausal relative to premenopausal women (geometric mean 200.5 vs. 188.4 nM, p = 0.03), whereas women reporting ever full-term pregnancy had lower concentrations of 27HC relative to never (191.4 vs. 198.6; p = 0.03). Significant trends were observed showing higher concentrations with relatively high levels of physical activity (ptrend = 0.03) and alcohol consumption (ptrend = 0.01), and women currently smoking at blood collection (ptrend

Background Circulating oxysterols have been proposed as biological markers of disease risk. However, within-person reproducibility of circulating oxysterols over time is not well established. Methods We evaluated the one-year reproducibility of 11 oxysterols and lanosterol among 30 postmenopausal women with repeat blood samples in the European Prospective Investigation into Cancer and Nutrition (EPIC) - Heidelberg, Germany cohort. Liquid chromatography–mass spectrometry (LC/MS) was performed to quantify serum concentrations of 22R–hydroxycholesterol, 25-hydroxycholesterol, 24S-hydroxycholesterol, 27-hydroxycholesterol, 22S-hydroxycholeterol, 24,25-epoxycholesterol, 5α,6β-dihydroxycholestanol, 7α-hydroxycholesterol, 5β,6β-epoxycholesterol, 5α,6α-epoxycholesterol, 24-dihydrolanosterol, and lanosterol. We evaluated Spearman correlations and intraclass correlation coefficients (ICCs) between quantifiable concentrations measured in repeat samples taken one-year apart to estimate within-person reproducibility. Results Spearman correlations (ICCs) over one year ranged from 0 (ICC = 0.10) for 5β,6β-epoxycholesterol and 0.10 (ICC = 0.20) for 5α,6α-epoxycholesterol, representing low within-person stability, to 0.81 (ICC = 0.75) for 27-hydroxycholesterol and 0.86 (ICC = 0.91) for 24S–hydroxycholesterol, representing relatively high within-person stability. Correlations between oxysterols and lanosterol ranged from 0.01 between 24S-hydroxycholesterol and lanosterol to 0.70 between 5α,6α-epoxycholesterol and 5β,6β-epoxycholesterol. Conclusions Our results demonstrate that for 27-hydroxycholesterol, 24S–hydroxycholesterol, 25-hydroxycholesterol, 7α-hydroxycholesterol and lanosterol, a single serum measurement can reliably estimate average levels over a one-year period. Circulating oxysterols are of increasing interest in epidemiologic studies of chronic disease risk including cancer and cardiovascular disease. Our data suggest that within-person stability of oxysterols differs depending on the individual oxysterol evaluated. We identified four oxysterols and lanosterol as stable over time to inform the use of circulating oxysterols in epidemiologic studies.

It is known that microRNA-219 (miR-219) expression is downregulated in medulloblastoma. In the present study, we investigated the expression, targets and functional effects of miR-219 in D283-MED medulloblastoma cells. We first demonstrated that miR-219 not only inhibits proliferation, but also suppresses the invasion and migration of D283-MED cells. Moreover, the knockdown of miR-219 promoted the proliferation, migration and invasion of the D283-MED cells. Secondly, we predicted that miR-219 targets the 3' untranslated region (3'UTR) of CD164 and orthodenticle homeobox 2 (OTX2) and then confirmed that it significantly downregulated the protein expression of CD164 and OTX2 in D283-MED cells. Finally, we demonstrated that the proliferation, invasion and migration of D283-MED cells were promoted by theectopic expression of CD164. These results indicate that miR-219 suppresses the proliferation, migration and invasion of medulloblastoma cells by targeting CD164. The results also suggest that miR-219 may serve as a potential therapeutic agent for medulloblastoma.

High expression of estrogen receptor α (ERα) is associated with a poor prognosis that correlates closely with cellular proliferation in breast cancer. However, the exact molecular mechanism by which ERα controls breast cancer cell proliferation is not clear. Here we report that ERα regulates the cell cycle by suppressing p53/p21 and up-regulating proliferating cell nuclear antigen (PCNA) and proliferation-related Ki-67 antigen (Ki-67) to promote proliferation of MCF-7 cells. In addition, 17-β-estradiol (E2) enhances ERα-induced proliferation of MCF-7 cells by stimulating expression of PCNA and Ki-67. Knockdown of ERα significantly affects PCNA/Ki-67 and p53/p21 expression. Furthermore, ERα inhibits the transcriptional activity of p53/p21 in an estrogen response element-dependent manner. More importantly, we provide new evidence that ERα mediates proliferation of MCF-7 cells by up-regulating miR-17 to silence the expression of p21. Thus, these data provide new insights into the underlying effect of ERα on breast cancer proliferation.

The pouring concrete dam construction program decision-making, decision-makers preference program attributes should be considered in addition to consider the objective attributes of the options. In this paper, on the basis of traditional ordered weighted geometric average operator (OWGA), considering the preference attributes analysis, establish OWGA operator multiple attribute decision making model. The model is applied to the dam concrete construction program decisions of hydropower project to verify the feasibility and reasonableness of the model.

At present, the treatment effect evaluation is mostly used to evaluate the result of dangerous reservoirs reinforcement which belongs to the post-evaluation. Due to the large quantity, difficult treatment, and limited funds of dangerous reservoirs in our country, this paper proposes the priority evaluation model of dangerous reservoirs treatment which belongs to the pre-evaluation. And in the paper the endangering degree index is added into the previous technology-based evaluation system to make it more close to reality. The information entropy theory is used to determine the weights of index system, and the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) method is used to confirm the order of dangerous reservoirs treatment in a range. At last a case study is given to verify the feasibility and practicability of the model. It provides scientific basis for program decision-making.

Myocardin is frequently repressed during human malignant transformation, and restoration of myocardin expression in sarcoma cells contributes to the inhibition of malignant growth. However, its role in breast carcinoma has barely been addressed. Here, we reported that myocardin could inhibit the proliferation of MCF-7 cells. Notably, we show that myocardin inhibited ERα-mediated proliferation of breast cancer MCF-7 via impairing ER-dependent transcriptional activation, mainly through the inhibition of the activity of ERα. Importantly, the molecular mechanism for the inhibition of the ERα-mediated proliferation is that myocardin inhibited the transcription and expression of ERα-induced PCNA, Ki-67, and E2F1 to impair ERα-mediated proliferation of breast cancer MCF-7. Interestingly, myocardin significantly enhanced the transcription and expression of miR-885 depending on the CArG box in miR-885 promoter, and miR-885 targeted the 3' untranslated regions (UTR) of E2F1 to silence the expression of E2F1. Thus, our data provided important and novel insights into how myocardin may deeply influence ERα-mediated breast cancer proliferation. In conclusion, myocardin could be seen as a breast cancer tumor suppressor so that it will provide new ideas for the treatment of breast cancer. © 2016 IUBMB Life, 68(6):477-487, 2016.

microRNA-96 (miR-96) is known to be downregulated in pancreatic cancer. The overexpression of miR-96 in MIA PaCa-2 pancreatic cancer cells has been shown to inhibit cell proliferation, migration and invasion; however, the mechanisms involved have not yet been fully elucidated. Novel (nua) kinase family 1 (NUAK1) functions as an oncogene in non‑small cell lung cancer (NSCLC), melanoma, glioma, breast cancer, hepatocellular carcinoma and pancreatic cancer. In this study, firstly, we demonstrate that NUAK1 expression is specifically upregulated in pancreatic cancer and that it promotes the proliferation, migration and invasion of MIA PaCa-2 pancreatic cancer cells. Secondly, we performed an analysis of potential microRNA (miRNA) target sites using three commonly used prediction algorithms: miRanda, TargetScan and PicTar. All three algorithms predicted that miR-96 targets the 3' untranslated region (3' UTR) of NUAK1. Further experiments confirmed this prediction, namely that miR-96 suppresses the expression of NUAK1 by targeting its 3' UTR. Finally, we demonstrate that the introduction of NUAK1 cDNA lacking predicted sites of the 3' UTR abrogates miR-96 cellular function.