SLC7A11 Overexpression in Glioblastoma Is Associated with Increased Cancer Stem Cell-Like Properties

System x_c^− 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_c^−, 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_c^− 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_c^− 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_C^− in combination with other chemotherapeutics can reduce cancer resistance and recurrence and improve GBM patient survival

Increased Expression of System x_c^- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance

Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system x_c^-, a transporter involved in cysteine import, that modulates glutathione production and glioma growth. However, the role of system x_c^- in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system x_c^- 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 x_c^- in glioma, stable SLC7A11-knockdown and -overexpressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but overexpression did increase anchorage-independent cell growth. Knockdown of SLC7A11 increased basal reactive oxygen species (ROS) and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Overexpression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 overexpression 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

What drives executive stock option backdating?

We study motives for executive stock option backdating, the practice of changing the grant dates of current options to dates in the past using hindsight. We find that smaller, younger, and less profitable firms tend to be heavier involved in backdating. These results are consistent with the retention hypothesis. In line with the incentive hypothesis, we find that backdating occurs more for options that are out-of-the-money. We derive some evidence for the agency hypothesis, in the sense that backdating companies have a larger percentage of inside directors. However, contrary to this hypothesis, we conclude that backdating firms have better protection for minority shareholders compared to firms that do not backdate

How do I Know what you Know? A Novel Theoretical Account of Epistemic Inference

Of the capacities that make us uniquely human—pedagogy, social learning, coop- eration, communication, moral evaluation—all hinge, at least in part, on an under- standing of what others know or believe. Critically, we cannot see mental states: we have access only to the observable behaviors they cause. So, to navigate the social world, we must often infer what others think from observing what they do. While prior work has investigated how children and adults infer preferences, goals, and desires from behavior, little research has investigated how we infer epistemic states (knowledge and beliefs). In this thesis, I expand upon existing accounts of mental state reasoning to formalize a novel theoretical account of epistemic inference. I test whether this account captures adults’ knowledge inferences, and use it to systemati- cally investigate the development of our capacities

Stem Cells and Metastatic Cancer: Fatal Attraction?

Fodde discusses a new study in PLoS ONE, by Aboody and colleagues, who report on the successful eradication of whole-body disseminated metastases in a mouse model of neuroblastoma

When Does Information Asymmetry Affect the Cost of Capital?

This paper examines when information asymmetry among investors affects the cost of capital in excess of standard risk factors. When equity markets are perfectly competitive, information asymmetry has no separate effect on the cost of capital. When markets are imperfect, information asymmetry can have a separate effect on firms’ cost of capital. Consistent with our prediction, we find that information asymmetry has a positive relation with firms’ cost of capital in excess of standard risk factors when markets are imperfect and no relation when markets approximate perfect competition. Overall, our results show that the degree of market competition is an important conditioning variable to consider when examining the relation between information asymmetry and cost of capital

Performance study of reactive routing protocol in wildfire detection using mobile ad-hoc network

The routing protocols play an important role in creating routes and sending packets between sensor nodes. There are many methods in the literature that presented and applied several protocols in various domains. However, there is a lack of using routing protocols in the detection of wildfire. Moreover, most methods have used a single number of sensor nodes, where there is a need to investigate the routing protocol based on different simulation parameters such as the number of sensor nodes. Therefore, in this paper, we propose a type of reactive routing protocol that is named Location Aided Routing (LAR). The simulation of LAR protocol has been conducted based on a various number of sensor nodes in order to deeply study and investigate the LAR protocol in the detection of wildfire. In addition, different performance metrics are used for evaluating the performance of the LAR protocol. In the simulation, the performance of LAR protocol shows promising results in the wildfire detection

From information-seeking actions (and their costs), adults jointly infer both whatothers know, and what they believe they can learn

We face a challenge when inferring what others know. Actions do not transparently reveal epistemic states: ignorantagents routinely ignore information too costly to obtain, and knowledgeable agents often confirm what they already knowwhen its convenient. We hypothesized that epistemic inferences are sensitive both to agents actions, and the underlyingutilities that best explain them. We tested this possibility in a simple task. Adults watched an explorer decide whetherto collect a map before searching an island for treasure. Participants (n=40) were asked to jointly infer how much theexplorer knew about the treasures location, and how much information the explorer believed the map had. Participantjudgments matched a computational model of epistemic inference structured around an expectation that agents rationallytradeoff information gain with information cost (r=0.86; 95%: 0.740.93, p¡.001). Our results suggest that adult Theory ofMind supports nuanced and graded epistemic inferences from observable action

Developing a Reputation for Reticence

A sender who has disclosable information with probability less than one may partially conceal bad news by choosing to withhold information and pooling with uninformed types. The success of this strategy depends on receivers' beliefs about the probability that the sender has disclosable news. In a dynamic context, informed senders try to cultivate a reputation for reticence either by concealing good news along with the bad, or by concealing some good news and disclosing some bad news. A reputation for reticence is valuable because it makes receivers less skeptical of past or future nondisclosures. The model provides insight into the choice by firms such as Google not to disclose quarterly earnings guidance to analysts, as well as Tony Blair's reticence over his son's vaccine record during the measles–mumps–rubella scare in the United Kingdom.State Farm Insurance Companies (Foundation Doctoral Award)Stanford Institute for Economic Policy Research (Taube Scholarship Fund Fellowship

Market and Technology Access Through Firm Acquisitions : Beyond One Size Fits All

Firm acquisitions have been shown to serve as a way to gain access to international markets, technological assets, products or other valuable resources of the target firm. Given this heterogeneity of takeover motivations and the skewness of the distribution of the deal value we show whether and how the importance of different takeover motivations changes along the deal value distribution. Based on a comprehensive dataset of 652 European mergers and acquisitions in the period from 1997 to 2003, we use quantile regressions to decompose the deal value at different points of its distribution. Our results indicate that the importance of technological assets is indeed higher for smaller target firms. The findings support the view on small acquisition targets to complement the acquirer’s technology portfolio while larger acquisition targets tend to be used to gain access to international markets