Glioblastoma multiforme (GBM) is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells up-regulate the expression of xCT (SLC7A11), the catalytic subunit of system xc−, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system xc− in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system xc− with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system xc− in glioma, stable SLC7A11 knock-down and over-expressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but over-expression did increase anchorage-independent cell growth. Knock-down of SLC7A11 increased basal ROS and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Over-expression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 over-expression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation and ATP generation. These results suggest that expression of SLC7A11 in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy. Implications: SLC7A11, in addition to redox modulation, appears to be associated with increased cellular metabolism and is a mediator of temozolomide resistance in human glioma, thus making system xC− a potential therapeutic target in GBM.

System x is a sodium-independent electroneutral transporter, comprising a catalytic subunit xCT (SLC7A11), which is involved in importing cystine. Certain cancers such as gliomas upregulate the expression of system x, which confers a survival advantage against the detrimental effects of reactive oxygen species (ROS) by increasing generation of the antioxidant glutathione. However, ROS have also been shown to function as targeted, intracellular second messengers in an array of physiological processes such as proliferation. Several studies have implicated ROS in important cancer features such as migration, invasion, and contribution to a cancer stem cell (CSC)-like phenotype. The role of system x in regulating these ROS-sensitive processes in glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor in adults, remains unknown. Stable SLC7A11 knockdown and overexpressing U251 glioma cells were generated and characterized to understand the role of redox and system x in glioma progression. SLC7A11 knockdown resulted in higher endogenous ROS levels and enhanced invasive properties. On the contrary, overexpression of SLC7A11 resulted in decreased endogenous ROS levels as well as decreased migration and invasion. However, SLC7A11-overexpressing cells displayed actin cytoskeleton changes reminiscent of epithelial-like cells and exhibited an increased CSC-like phenotype. The enhanced CSC-like phenotype may contribute to increased chemoresistance and suggests that overexpression of SLC7A11 in the context of GBM may contribute to tumor progression. These findings have important implications for cancer management where targeting system x in combination with other chemotherapeutics can reduce cancer resistance and recurrence and improve GBM patient survival.

Background: Mucormycosis portends a poor prognosis with mortality rates ranging from 50% to 70% in pulmonary mucormycosis (PM) and up to 95% in disseminated disease. However, detailed outcomes data have been lacking. It remains unknown how to identify patients who would benefit from surgical resection. Objectives:We present our experience with patients undergoing surgical resection for PM, including an analysis of factors affecting postoperative survival. We also describe a thoracic surgeon's approach through illustrative cases. Patients/Methods: We conducted a single-centre retrospective study of all adult patients with PM who received antifungal therapy and underwent surgical resection or who Results: Twelve patients received antifungal therapy and underwent surgical resection and 13 patients received antifungal therapy alone. From infection onset to death (or right-censoring if still alive), patients who underwent surgical resection had a median survival of 406 days (mean, 561.3; range, 22-2510), and patients who received antifungal therapy alone had a median survival of 28 days (mean, 66.7; range, 8-447).In patients who underwent surgical resection, median postoperative survival time was 154 days (range, 11-2495), in-hospital mortality was 16.7%, and 1-year mortality was 50.0%. Age, primary disease, ASA status, extrapulmonary dissemination, laterality, multilobar involvement, number of lesions, largest lesion size, platelet count, surgical approach, type of resection or extent of resection were not significantly associated with postoperative survival. Conclusions:Surgical resection significantly increases survival and should be strongly considered for selected patients with PM.