Regulation of the cancer cell membrane lipid composition by NaCHOleate : Effects on cell signaling and therapeutical relevance in glioma

This review summarizes the cellular bases of the effects of NaCHOleate (2-hydroxyoleic acid; 2OHOA; Minerval) against glioma and other types of tumors. NaCHOleate, activates sphingomyelin synthase (SGMS) increasing the levels of cell membrane sphingomyelin (SM) and diacylglycerol (DAG) together with reductions of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). The increases in the membrane levels of NaCHOleate itself and of DAG induce a translocation and overexpression of protein kinase C (PKC) and subsequent reductions of Cyclin D, cyclin-dependent kinases 4 and 6 (CDKs 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of E2F1 and knockdown of dihydrofolate reductase (DHFR) impairing DNA synthesis. In addition in some cancer cells, the increases in SM are associated with Fas receptor (FasR) capping and ligand-free induction of apoptosis. In glioma cell lines, the increases in SM are associated with the inhibition of the Ras/MAPK and PI3K/Akt pathways, in association with p27Kip1 overexpression. Finally, an analysis of the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database for glioma patient survival shows that the weight of SM-related metabolism gene expression in glioma patients' survival is similar to glioma-related genes. Due to its low toxicity and anti-tumoral effect in cell and animal models its status as an orphan drug for glioma treatment by the European Medicines Agency (EMA) was recently acknowledged and a phase 1/2A open label, non-randomized study was started in patients with advanced solid tumors including malignant glioma. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.     

Epiprofin/Sp6: a new player in the regulation of tooth development

Odontogenesis is governed by a complex network of intercellular signaling events between the dental epithelium and mesenchyme. This network leads to the progressive determination of tooth shape, and to the differentiation of these tissues into enamel-producing ameloblasts and dentin-producing odontoblasts respectively. Among the main signaling pathways involved in the regulation of tooth development, Bone Morphogenetic Protein (BMP), Sonic hedgehog (Shh) and Wingless-type MMTV integration site (Wnt) pathways have been reported to play significant roles. Recently, the phenotype of mice deficient in Epiprofin/Sp6 (Epfn) has been found to present striking dental abnormalities, including a complete lack of differentiated ameloblasts and consequently no enamel, highly altered molar cusp patterns and the formation of multiple supernumerary teeth. In this article, we review the interaction of Epfn with the BMP, Shh and Wnt pathways in the regulation of tooth development, based on the data obtained from the study of several genetically modified mice.     

Involvement of lipid droplets in hepatic responses to lipopolysaccharide treatment in mice

Infection and inflammation induce important changes in lipid metabolism, which result in increased free fatty acids and triacylglycerol in plasma and altered high density lipoprotein (HDL) metabolism. Our aim was to elucidate whether hepatic lipid droplets (LDs) are involved in the adaptations of lipid metabolism to endotoxemia. We characterized the lipid content and several enzymatic activities in subcellular fractions and subpopulations of LDs from livers of mice 24 h after lipopolysaccharide (LPS) treatment and analyzed the expression of key genes involved in lipid management. Endotoxemic mice showed lower lipid content in LDs with decreased molar fraction of cholesteryl ester and higher diacylglycerol/triacylglycerol ratio as compared to their controls. They also showed a decrease in cytosolic triacylglycerol hydrolase activity, specifically in dense LDs, and in microsomal and cytosolic diacylglycerol hydrolase activity; concomitantly neutral lipid biosynthetic capacity and triacylglycerol levels in plasma lipoproteins increased. Together with the overexpression of genes involved in lipogenesis and HDL formation our results suggest that altered hepatic management of LD lipids in LPS-treated mice might be related to the channeled mobilization of triacylglycerol for very low density lipoprotein assembly and to the induction of cholesterol export.     

Multiple phospholipid substrates of phospholipase C/sphingomyelinase HR2 from Pseudomonas aeruginosa

The activity of phospholipase C/sphingomyelinase HR₂ (PlcHR₂) from Pseudomonas aeruginosa was characterized on a variety of substrates. The enzyme was assayed on liposomes (large unilamellar vesicles) composed of PC:SM:Ch:X (1:1:1:1; mol ratio) where X could be PE, PS, PG, or CL. Activity was measured directly as disappearance of substrate after TLC lipid separation. Previous studies had suggested that PlcHR₂ was active only on PC or SM. However we found that, of the various phospholipids tested, only PS was not a substrate for PlcHR₂. All others were degraded, in an order of preference PC > SM > CL > PE > PG. PlcHR₂ activity was sensitive to the overall lipid composition of the bilayer, including non-substrate lipids.     

Adjuvant radiotherapy in malignant tumors of parotid. Experience of the Navarra Hospital Complex

BackgroundThe objective of the study was to review the outcome of patients with parotid cancer treated with postoperative radiotherapy at Complejo Hospitalario de Navarra in the last ten years.Materials and methodsWe retrospectively reviewed patients treated with adjuvant radiotherapy between January 2008 and December 2018. We analyzed demographic data, histopathologic findings, local control (LC) and overall survival (OS).ResultsA total of 40 patients received postoperative radiotherapy during the period mentioned. There were 22 men (55%) and 18 women (45%). Median age was 58 years (19–90). By tumor histology, the most common was squamous cell carcinoma (22.5%) followed by ex-pleomorphic adenoma (15%) and adenoid cystic carcinoma (10%). According to Surgery, 19 patients (47.5%) underwent a total parotidectomy, 20 (50%) partial parotidectomy, and 1 (2.5%) a radical parotidectomy. Twenty-one patients (51.2%) underwent cervical dissection, most of them being supraomohyoid (31.7%). Reasons for adjuvant RT were: R1 resection (35% of the patients), high grade tumors (27.5%) and 17.5% because R1 surgery and R1. Radiation was administered using IMRT in most patients to a total dose of 60 Gy in 30 fractions. The 5-year overall survival (OS) (Kaplan-Meier) was 81% (95% CI: 68.5–96.2%), and 10-years — 64%. The 5-year local control (LC) (Kaplan-Meier) was 82.4% (95% CI: 91.46–73.33%) and the 10-year LC — 72.2% (95% CI: 54.9–96%). To date, only 4 patients (10%) have died due to their parotid tumor.ConclusionThe adjuvant radiotherapy added to surgery, significantly reduces the risk of recurrence in high-risk patients with a very acceptable survival rate.