ABSTRACT
The olfactomedin 4 (OLFM4) gene has been analyzed as a tumor-suppressor gene and a putative biomarker in many cancers. In our study, we analyzed the relationship of OLFM4 expression with clinicopathological features and with CpG site methylation in the OLFM4 gene promoter region in human primary prostate adenocarcinoma. OLFM4 protein expression was significantly reduced in prostate cancer tissue compared to adjacent normal tissue and was further significantly reduced in more advanced cancers. Bioinformatic studies with clinical datasets revealed that primary prostate adenocarcinoma patients with reduced OLFM4 mRNA expression exhibited higher Gleason scores and higher preoperative serum prostate-specific antigen levels, as well as lower recurrence-free survival. Three of the eight CpG sites in the OLFM4 gene promoter region were hypermethylated in cancerous prostate cells compared to adjacent normal cells, and reduced methylation of eight CpG sites was associated with increased OLFM4 mRNA expression in RWPE1 and PC-3 cells. Furthermore, knockdown of OLFM4 gene expression was associated with enhanced epithelial-mesenchymal transition (EMT)-marker expression in RWPE immortalized normal prostate cells. In contrast, restoration of OLFM4 expression in PC-3 and DU145 prostate cancer cells lacking OLFM4 significantly inhibited both EMT-marker expression and tumor cell growth in in vitro and in vivo models, indicating that OLFM4 may play a tumor-suppressor role in inhibiting the EMT program, as well as tumor initiation and growth, in prostate cells. Taken together, these findings suggest that OLFM4 plays an important tumor-suppressor role in prostate cancer progression and might be useful as a novel candidate biomarker for prostate cancer.
Subject(s)
Adenocarcinoma/genetics , Gene Expression Regulation, Neoplastic , Granulocyte Colony-Stimulating Factor/genetics , Prostatic Neoplasms/genetics , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Aged , Animals , Cell Line, Tumor , Cell Proliferation , CpG Islands/genetics , DNA Methylation , Datasets as Topic , Disease Progression , Disease-Free Survival , Down-Regulation , Epithelial-Mesenchymal Transition/genetics , Gene Knockdown Techniques , Granulocyte Colony-Stimulating Factor/metabolism , Humans , Male , Mice , Middle Aged , Promoter Regions, Genetic/genetics , Prostate/pathology , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
Telavancin is approved in the United States, Canada, and Europe (At the time of submission, the telavancin European marketing authorization for nosocomial pneumonia was suspended until Theravance provides evidence of a new European Medicines Agency approved supplier) as an antibiotic to treat certain Gram-positive bacterial skin infections. Telavancin has been shown to prolong plasmatic prothrombin (PT) and activated partial thromboplastin (aPTT) clotting times in clinical diagnostic lab-based assays. In this study, we evaluated the potential for telavancin to prolong whole blood PT/International Normalized Ratio (INR) and aPTT tests on point-of-care (POC) instruments. Whole blood collected from 8 healthy subjects was supplemented with telavancin to final concentrations of 0, 10, 20, and 100 µg/ml. Final concentrations were selected to match trough, twice trough, and peak plasma levels following the approved 10 mg/kg dose. Four widely employed POC coagulation instruments were chosen to be representative of the POC platforms currently in use.. These systems were the Roche Coaguchek XS, the Abbott iSTAT, the ITC Hemochron SIG+, and the Alere INRatio2 POC devices. The PT/INR measured by the Coaguchek XS showed the greatest sensitivity to the presence of telavancin. The PT/INR measured by the Hemochron SIG+ and iSTAT were sensitive to telavancin but to a lesser extent. The INRatio2 was the least sensitive to the presence of telavancin when testing the whole blood PT/INR. Only the Hemochron SIG+ device was capable of measuring aPTT and showed a concentration-dependent increase in aPTT. This study supports the current recommendation that PT and aPTT monitoring be conducted immediately to the next dose of telavancin when coagulation parameters are tested using POC instrumentation.
Subject(s)
Aminoglycosides/administration & dosage , Anti-Bacterial Agents/administration & dosage , Blood Coagulation/drug effects , Prothrombin Time/instrumentation , Prothrombin Time/methods , Adolescent , Adult , Female , Humans , Lipoglycopeptides , Male , Middle Aged , Partial Thromboplastin Time/instrumentation , Partial Thromboplastin Time/methodsABSTRACT
We sought to design dual pharmacology bronchodilators targeting both the M(3) muscarinic acetylcholine and beta-2 adrenergic (ß(2)) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors.
