Cdc20 and securin overexpression predict short-term breast cancer survival.

BACKGROUND: Cdc20 is an essential component of cell division and responsible for anaphase initiation regulated by securin degradation. Cdc20 function is strongly regulated by the spindle assembly checkpoint to ensure the timely separation of sister chromatids and integrity of the genome. We present the first results on Cdc20 in a large clinical breast cancer material. METHODS: The study was based on 445 breast cancer patients with up to 20 years of follow-up (mean 10.0 years). DNA content was determined by image cytometry on cell imprints, and Cdc20 and securin immunohistochemistry on tissue microarrays of breast cancer tissue. RESULTS: In our results, high Cdc20 and securin expression was associated with aneuploid DNA content. In prognostic analyses, high Cdc20 immunoexpression alone and in combination with high securin immunoexpression indicated aggressive course of disease and up to 6.8-fold (P<0.001) risk of breast cancer death. Particularly, high Cdc20 and securin immunoexpression identified a patient subgroup with extremely short, on average 2.4 years, breast cancer survival and triple-negative breast cancer (TNBC) subtype. CONCLUSIONS: We report for the first time the association of high Cdc20 and securin immunoexpression with extremely poor outcome of breast cancer patients. Our experience indicates that Cdc20 and securin are promising candidates for clinical applications in breast cancer prognostication, especially in the challenging prognostic decisions of TNBC.

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models.

Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα(12/13) and Gα(i) were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα(12/13) signalling, regulating cell motility and invasion versus epithelial maturation.

Control of chemical risks during the treatment of soil contaminated with chlorophenol, creosote and copper-chrome-arsenic-wood preservatives.

BACKGROUND: Exposure to chemicals in polluted soil was studied during the remediation of four polluted sites. They are sawmill areas contaminated with chlorophenols and polychlorinated dibenzo-p-dioxins and furanes (PCDD/F), wood impregnating plants contaminated with polycyclic aromatic hydrocarbons (PAH) from creosote oil, old gas works area contaminated with PAH, and a wood impregnation plant contaminated with copper-chromium-arsenic (CCA) preservative. METHODS: The exposure levels were determined by both air and biological monitoring. RESULTS: Air monitoring showed that the exposure levels were generally well below the current occupational exposure limits. The calculations indicated, however, that the lowest acceptable daily intake value recommended for PCDD/F by the U.S. Environmental Protection Agency was exceeded. Chlorophenol exposure was generally low. Exposure to volatile PAH was 0.038-0.884 mg/m(3) and that to particulate PAH was 0.004-0.183 mg/m(3). The biomonitoring results (urinary 1-pyrenol) suggested that some exposure occurs, probably through the contamination of hands or skin absorption. At the sites contaminated with CCA salts, no exposure limits were exceeded. CONCLUSIONS: The results generally suggest that the exposure of cleanup workers is generally below the current occupational exposure limits but that short-term high exposure cannot be excluded. There was also some indication of poor skin protection, which should be improved when soil contaminated with PAH and creosote oil is handled.

FIOH external quality assurance scheme for organic solvent metabolites.

The scheme consists of analyses for phenol,2,5-hexanedione, and mandelic, trichloroacetic and methylhippuric acids in urine. The present participants are 31 laboratories from 14 countries. Samples are prepared by pooling urine obtained from occupationally exposed workers or by spiking with appropriate pure metabolites. Four sets of samples at two concentration levels for each analyte are distributed annually. The report includes information on the arithmetic means, standard deviations and CVs for overall results and separately for different methods. During the last three years, the CVs have varied rather non systematically, being 21-31% for mandelic acid, 24-26% for trichloroacetic acid, 24-35% for phenol, 55-110% for 2,5-hexanedione and 44-50% for methylhippuric acid.

Biological monitoring of isopropyl nitrate.

Four healthy men were exposed to an isopropyl nitrate (IPN) concentration of 45.8 mg/m3 for 60 min. The IPN in the expired air, blood and urine of volunteers was analysed by gas chromatography. The longest elimination half-time of IPN by the respiratory route was 98 min. Within 6 h post-exposure 0.02% of the estimated intake was excreted in the urine. A preliminary field test of the methods was carried out during the starting and refueling of Dragen jet fighters. Urinary monitoring was found to be the most promising method for simple sampling and sensitive analyses.

2,5-Hexanedione excretion after occupational exposure to n-hexane.

The urinary excretion of the n-hexane metabolite 2,5-hexanedione (HD) was determined in four shoe factory workers during four workingdays that were preceded by four free days and followed by two free days. The correlation between excretion of HD and the n-hexane concentrations in the workroom air was evaluated. The air concentrations of n-hexane and those of acetone, toluene, and other organic solvents were monitored with charcoal tubes. All the urine from each worker was collected at freely chosen intervals during the experimental period and the following two free days. The samples were analysed by gas chromatography. The relative excretion of HD increased as the exposure to n-hexane increased, although it seemed that HD accumulated progressively in the body at the highest n-hexane concentrations and at higher total solvent concentrations.