1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature

Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM

Eurocity London: a qualitative comparison of graduate migration from Germany, Italy and Latvia

This paper compares the motivations and characteristics of the recent migration to London of young-adult graduates from Germany, Italy and Latvia. Conceptually the paper links three domains: the theory of core–periphery structures within Europe; the notion of London as both a global city and a ‘Eurocity’; and the trope of ‘crisis’. The dataset analysed consists of 95 in-depth biographical interviews and the paper’s main objective is to tease out the narrative similarities and differences between the three groups interviewed. Each of the three nationalities represents a different geo-economic positioning within Europe. German graduates move from one economically prosperous country to another; they traverse shallow economic and cultural boundaries. Italian graduates migrate from a relatively peripheral Southern European country where, especially in Southern Italy, employment and career prospects have long been difficult, and have become more so in the wake of the financial crisis. They find employment opportunities in London which are unavailable to them in Italy. Latvian graduates are from a different European periphery, the Eastern one, post-socialist and post-Soviet. Like the Italians, their moves are economically driven whereas, for the Germans, migration is more related to lifestyle and life-stage. For all three groups, the chance to live in a large, multicultural, cosmopolitan city is a great attraction. And for all groups, thoughts about the future are marked by uncertainty and ambiguity