ABSTRACT
Enchondroma and chondrosarcoma are the most common benign and malignant cartilaginous neoplasms. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are present in the majority of these tumors. We performed RNA-seq analysis on chondrocytes from Col2a1Cre;Idh1LSL/+ animals and found that genes implied in cholesterol synthesis pathway were significantly upregulated in the mutant chondrocytes. We examined the phenotypic effect of inhibiting intracellular cholesterol biosynthesis on enchondroma formation by conditionally deleting SCAP (sterol regulatory element-binding protein cleavage-activating protein), a protein activating intracellular cholesterol synthesis, in IDH1 mutant mice. We found fewer enchondromas in animals lacking SCAP. Furthermore, in chondrosarcomas, pharmacological inhibition of intracellular cholesterol synthesis significantly reduced chondrosarcoma cell viability in vitro and suppressed tumor growth in vivo. Taken together, these data suggest that intracellular cholesterol synthesis is a potential therapeutic target for enchondromas and chondrosarcomas.
Subject(s)
Cholesterol/biosynthesis , Chondroma/metabolism , Chondrosarcoma/metabolism , Genetic Predisposition to Disease/genetics , Animals , Cell Survival , Chondrocytes/metabolism , Chondroma/drug therapy , Chondroma/genetics , Chondroma/pathology , Chondrosarcoma/drug therapy , Chondrosarcoma/genetics , Chondrosarcoma/pathology , Disease Models, Animal , Isocitrate Dehydrogenase/genetics , Lovastatin/pharmacology , Mice , Mice, Knockout , Xenograft Model Antitumor AssaysABSTRACT
Soft-tissue sarcomas (STS) are a rare group of malignant tumors which can affect any age group. For the majority of patients who present with a localized STS, treatment involves a multidisciplinary team decision-making approach ultimately relying on surgical resection with or without adjuvant radiation for successful limb salvage. The goals of treatment are to provide the patient with a functional extremity without local tumor relapse. The purpose of this article is to review the treatment of extremity STS, with a focus on staging, treatment options, and outcomes.
ABSTRACT
BACKGROUND: Procollagen C-proteinase enhancer 1 (PCPE1), a glycoprotein secreted from differentiating osteoblast, enhances the rate-limiting step of collagen type I fibrillar formation. It is expressed and secreted by cells that produce collagen type I and has the potential to be a marker for bone pathologies. METHODS: We developed an assay to quantify PCPE glycopattern based on isoelectric focusing (IEF) and detection with a bio-imaging camera (coefficient of variation within and between assays, 15% and 20%, respectively). RESULTS: PCPE was quantified in 39 serum samples from healthy subjects (17 females and 22 males). The concentration in the serum was 305(274) ng/ml, median(IQR). The level of the PCPE isoforms and their relative distribution were altered in patients with bone disorders. CONCLUSIONS: The data generated by our system, support our hypothesis that combined data on PCPE concentration and isoforms may be useful for the diagnosis and follow-up of bone diseases. Further research, on larger cohorts of both normal subjects and patients, must be done.
Subject(s)
Carbohydrates/chemistry , Extracellular Matrix Proteins/blood , Glycoproteins/blood , Adult , Bone Diseases, Metabolic/blood , Cell Line , Extracellular Matrix Proteins/chemistry , Female , Glycoproteins/chemistry , Humans , Isoelectric Focusing , Male , Middle Aged , Reference Values , Reproducibility of ResultsABSTRACT
INTRODUCTION: Dexrazoxane (Dex), used clinically to protect against anthracycline-induced cardiotoxicity, possesses iron-chelating properties. The present study was designed to examine whether Dex could inhibit the ischemia/reperfusion (I/R) induced damage to the rat heart. MATERIALS AND METHODS: Isolated perfused rat hearts were exposed to global ischemia (37 degrees C) and 60 min reperfusion. Dex was perfused for 10 min prior to the ischemia, or administered intraperitoneally (150 mg) 30 min prior to anesthesia of the rats. I/R caused a significant hemodynamic function decline in control hearts during the reperfusion (e.g., the work index LVDP X HR declined to 42.7+/-10%). Dex (200 microM) applied during the preischemia significantly increased the hemodynamic recovery following reperfusion (LVDP X HR recovered to 55.7+/-8.8%, p<0.05 vs. control). Intraperitoneal Dex, too, significantly increased the hemodynamic recovery of the reperfused hearts. I/R caused an increase in oxidation of cytosolic proteins, while Dex decreased this oxidation. DISCUSSION: The decrease in proteins carbonylation and correlative hemodynamic improvement suggests that Dex decreases I/R free radical formation and reperfusion injury.
