TY - JOUR A1 - Litovkin, Kirill A1 - Van Eynde, Aleyde A1 - Joniau, Steven A1 - Lerut, Evelyne A1 - Laenen, Annouschka A1 - Gevaert, Thomas A1 - Gevaert, Olivier A1 - Spahn, Martin A1 - Kneitz, Burkhard A1 - Gramme, Pierre A1 - Helleputte, Thibault A1 - Isebaert, Sofie A1 - Haustermans, Karin A1 - Bollen, Mathieu T1 - DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer JF - PLoS ONE N2 - Background Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients. Methods A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation. Results Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95% CI, 1.03 to 17.72) as well as in the combined cohort ( HR, 2.74; 95% CI, 1.42 to 5.27) in multivariate analysis. Conclusions Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients. KW - CpG island hypermethylation KW - radical prostatectomy KW - promoter methylation KW - receptor beta KW - gene KW - GSTP1 KW - biomarkers KW - diagnosis KW - recurrence KW - reveals Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151705 VL - 10 IS - 6 ER - TY - JOUR A1 - Wehrle, Esther A1 - Liedert, Astrid A1 - Heilmann, Aline A1 - Wehner, Tim A1 - Bindl, Ronny A1 - Fischer, Lena A1 - Haffner-Luntzer, Melanie A1 - Jakob, Franz A1 - Schinke, Thorsten A1 - Amling, Michael A1 - Ignatius, Anita T1 - The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice JF - Disease Models & Mechanisms N2 - Fracture healing is impaired in aged and osteoporotic individuals. Because adequate mechanical stimuli are able to increase bone formation, one therapeutical approach to treat poorly healing fractures could be the application of whole-body vibration, including low-magnitude high-frequency vibration (LMHFV). We investigated the effects of LMHFV on fracture healing in aged osteoporotic mice. Female C57BL/6NCrl mice (n=96) were either ovariectomised (OVX) or sham operated (non-OVX) at age 41 weeks. When aged to 49 weeks, all mice received a femur osteotomy that was stabilised using an external fixator. The mice received whole-body vibrations (20 minutes/day) with 0.3 g peak-to-peak acceleration and a frequency of 45 Hz. After 10 and 21 days, the osteotomised femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, micro-computed tomography (mu CT), histology and gene expression analyses. LMHFV disturbed fracture healing in aged non-OVX mice, with significantly reduced flexural rigidity (-81%) and bone formation (-80%) in the callus. Gene expression analyses demonstrated increased oestrogen receptor β (ERβ, encoded by Esr2) and Sost expression in the callus of the vibrated animals, but decreased β-catenin, suggesting that ERβ might mediate these negative effects through inhibition of osteoanabolic Wnt/β-catenin signalling. In contrast, in OVX mice, LMHFV significantly improved callus properties, with increased flexural rigidity (+ 1398%) and bone formation (+637%), which could be abolished by subcutaneous oestrogen application (0.025 mg oestrogen administered in a 90-day-release pellet). On a molecular level, we found an upregulation of ER alpha in the callus of the vibrated OVX mice, whereas ERβ was unaffected, indicating that ERa might mediate the osteoanabolic response. Our results indicate a major role for oestrogen in the mechanostimulation of fracture healing and imply that LMHFV might only be safe and effective in confined target populations. KW - level mechanical vibrations KW - ovariectomized rats KW - bone formation KW - LMHFV KW - whole body vibration KW - receptor beta KW - replacement therapy KW - osteoblastic cells KW - early stage KW - alpha KW - Wnt KW - fracture healing KW - oestrogen receptor signalling KW - Wnt signalling Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144700 VL - 8 ER -