Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment. The novel mechanism of action of 2OHOA is associated with important changes in membrane-lipid composition, primarily a recovery of sphingomyelin (SM) levels, which is markedly low in glioma cells before treatment. Parallel to membrane-lipid regulation, treatment with 2OHOA induced a dramatic translocation of Ras from the membrane to the cytoplasm, which inhibited the MAP kinase pathway, reduced activity of the PI3K/Akt pathway, and downregulated Cyclin D-CDK4/6 proteins followed by hypophosphorylation of the retinoblastoma protein (RB). These regulatory effects were associated with induction of glioma cell differentiation into mature glial cells followed by autophagic cell death. Given its high efficacy, low toxicity, ease of oral administration, and good distribution to the brain, 2OHOA constitutes a new and potentially valuable therapeutic tool for glioma patients.fatty acids | sphingomyelin synthase | cancer drug target | glioma biomarker C ancer cells of undifferentiated phenotype (e.g., glioma) have a poor prognosis and limited treatment options. Primary brain tumors, of which glioma is the most common, are generally associated with very high rates of mortality (ca. 90%), being the median survival of patients about 1 y (1, 2). Chemotherapy provides only modest benefits to radiotherapy and surgery being the alkylating agent temozolomide (TMZ) the reference drug; however, tumor relapse is usually observed, and TMZ only increases the patients' life expectancy about 2.5 m (from 12.1 to 14.6 m: ref.3). The present study was designed to investigate the efficacy of 2OHOA against glioma and its molecular mechanisms of action. 2OHOA exhibited a greater efficacy than TMZ in the treatment of glioma, and there was no relapse after long-term treatment with 2OHOA. This efficacy and lack of toxicity at therapeutic doses has been acknowledged recently by the European Medicines Agency (EMA) to designate 2OHOA orphan drug for the treatment of glioma. In previous studies, we showed that this compound induces cell cycle arrest of lung cancer cells (4-6). Here, we showed that 2OHOA reversed the altered lipid profile of glioma cells and how this modification regulated cell signaling to induce autophagy specifically in glioma but not normal cells.Moreover, in the present study we demonstrated that the changes induced by 2OHOA were specific to cancer cells with no significant effects observed in normal cells and no adverse effects in treated animals, features not shared by most anticancer drugs. The efficacy of this compound in the absence ...

Most drugs currently used for human therapy interact with proteins, altering their activity to modulate the pathological cell physiology. In contrast, 2-hydroxy-9-cis-octadecenoic acid (Minerval) was designed to modify the lipid organization of the membrane. Its structure was deduced following the guidelines of the mechanism of action previously proposed by us for certain antitumor drugs. The antiproliferative activity of Minerval supports the above-mentioned hypothesis. This molecule augments the propensity of membrane lipids to organize into nonlamellar (hexagonal H II ) phases, promoting the subsequent recruitment of protein kinase C (PKC) to the cell membrane. The binding of the enzyme to membranes was marked and significantly elevated by Minerval in model (liposomes) and cell (A549) membranes and in heart membranes from animals treated with this drug. In addition, Minerval induced increased PKC␣ expression (mRNA and protein levels) in A549 cells. This drug also induced PKC activation, which led to a p53-independent increase in p21 CIP expression, followed by a decrease in the cellular concentrations of cyclins A, B, and D3 and cdk2. These molecular changes impaired the cell cycle progression of A549 cells. At the cellular and physiological level, administration of Minerval inhibited the growth of cancer cells and exerted antitumor effects in animal models of cancer without apparent histological toxicity. The present results support the potential use of Minerval and related compounds in the treatment of tumor pathologies.

We recommend adding the low-grade neoplasm ES-H to the large list of cutaneous vascular proliferations. Dermatologists should be aware of this low-grade cutaneous vascular tumor.

Imiquimod is an immunomodifier recently approved for the treatment of superficial basal cell carcinomas (sBCC). Although local adverse events (AEs) are the most commonly reported, systemic AEs have also been described. We present the case of a 60-year-old woman who, after the application of two sachets of imiquimod cream per day for 5 days/week to two large sBCCs, developed pemphigus-like lesions both at and distant from the application site. Histological examination of a skin biopsy found intraepidermal acantholytic blistering but results of direct immunofluorescence examination were negative. The lesions resolved after cessation of imiquimod. Two previous cases of imiquimod-induced pemphigus have been reported, but this is the first case with lesions distant from the site of application. We suggest that systemic absorption of the drug or greatly increased synthesis of cytokines could explain this reaction and recommend the use of low doses of imiquimod in the treatment of large or multiple sBCCs.

The late development of symmetrical, ascending telangiectasias over an extensive area of the skin with no associated systemic manifestations is a common presentation of generalized essential telangiectasia (GET). It was recently suggested that cutaneous collagenous vasculopathy (CCV) is clinically identical to GET but that the 2 conditions can be distinguished by their distinctive histopathologic findings. We present 2 patients, both women, with multiple telangiectasias and describe the histopathologic findings that led to the diagnoses of GET and CCV. Dermoscopic findings in both cases were similar, except that the older telangiectasias in the patient with CCV were violaceous and distributed in a tortuous, serpentine pattern. During follow-up 12 years for the woman with GET and 42 years for the woman with CCV we saw that in GET the lesions remained stable in appearance whereas in CCV there was progressive darkening and morphological changes eventually resulting in superficial varicose veins.

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