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

Exercising Metabolic, Ventilatory, and Cardiovascular Responses to Isometric Whole Body Vibration Exercise

Purpose: To determine if metabolic, ventilatory, or cardiovascular response to isometric squats with or without external load was enhanced by the addition of a whole body vibration (WBV). Methods: Fifteen subjects (28.4±6.5y; 173.7±8.6 cm; 75.5±20.8 kg) underwent four exercise sessions with three days’ rest between sessions. The sample included 7 males and 8 females. Subject performed 10-sets of one-minute isometrics squats with 45 degrees of knee flexion standing on a WBV platform under four conditions: Unloaded, Unloaded Vibration, Loaded, and Loaded Vibration. Each condition was performed on a separate day; the session order was presented at random. One-minute recovery was given between sets. During the vibration conditions, the plate vibrated at 4mm peak-to-peak displacement and 30Hz. Loaded sessions were performed with a barbell equal to 30% body weight across the subjects shoulder. Oxygen consumption (VO2) and ventilation (VE) were measured using a metabolic cart and heart rate was obtained using polar chest straps. A 2x2 ANOVA was used to evaluate main effects for vibration (vibration vs. no vibration), load (loaded vs. unloaded), and interactions. Results: There were significant vibration (p = 0.02) and load (p = 0.003) main effects for VO2. VO2 during vibration (9.2±3.3 mL.kg-1.min-1) was significantly greater than no vibration (7.9±1.2 mL.kg-1.min-1); VO2 was also greater during the loaded (9.6 ± 3.1 mL . kg-1 . min-1) condition compared to unloaded (7.5±1.1 mL.kg-1.min-1). There were significant vibration (p=0.01) and load (p=0.01) main effects for VE. VE during vibration (20.8±10.0 L.min-1) was greater than no vibration (17.8±4.8 L.min-1); VE was greater during loaded (21.5±9.4 L.min-1) conditions compared to unloaded (17.7±5.5 L.min-1). There were significant vibration (p=0.02) and load (p=0.008) main effects for HR. HR during vibration (97.0±20.3 beats . min-1) was greater than no vibration (86.8 ± 25.7 beats . min-1); HR was also greater during loaded (101.3±20.8 beats . min-1) conditions compared to unloaded (90.8±12.6 beats.min-1). No interaction effects were detected for VO2 (p= 0.16), VE (p=0.14), or HR (p=0.84). Conclusion: Significant differences were observed in VO2, VE, and HR while exercising with WBV. Differences were similar across loaded and unloaded conditions. It is unclear if these small differences would be sufficient to induce enhanced long-term training adaptations. Future research should investigate similar physiological responses during dynamic exercise with a range of loads. Further, research is also needed to determine if these responses are enhanced or diminished by the amplitude, frequency, or duration of the vibration stimulus

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

Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes

Chromatin states must be maintained during cell proliferation to uphold cellular identity and genome integrity. Inheritance of histone modifications is central in this process. However, the histone modification landscape is challenged by incorporation of new unmodified histones during each cell cycle, and the principles governing heritability remain unclear. We take a quantitative computational modeling approach to describe propagation of histone H3K27 and H3K36 methylation states. We measure combinatorial H3K27 and H3K36 methylation patterns by quantitative mass spectrometry on subsequent generations of histones. Using model comparison, we reject active global demethylation and invoke the existence of domains defined by distinct methylation endpoints. We find that H3K27me3 on pre-existing histones stimulates the rate of de novo H3K27me3 establishment, supporting a read-write mechanism in timely chromatin restoration. Finally, we provide a detailed quantitative picture of the mutual antagonism between H3K27 and H3K36 methylation and propose that it stabilizes epigenetic states across cell division

Review Essay

Spurred by the 9/11 terrorist attacks, the poor analysis of Iraq’s weapons of mass destruction programs, and numerous studies, the Intelligence Reform and Ter- rorism Prevention Act of 2004 created the Office of Director of National Intelli- gence (ODNI). Run by former ambassador John Negroponte, ODNI is an independent agency meant to oversee U.S. government intelligence activities and to transform the American intelligence commu- nity

Human anatomical dissection takes a compulsory break during Covid-19 pandemic

The outbreak of the coronavirus effects on people’s daily lives. Like nothing most people have experienced before. One of the many affected sectors is education  In response to Covid-19  pandemic, medical education faculty have quickly transitioned the curriculum to online formats. But no matter the quality of the online resource, do not provide the same level of understanding of complex anatomical relationships as studying human bodies. Under restriction of social isolation because of Covid-19 pandemic, human anatomical dissection takes a compulsory break. Afterward students will come back to their essential training  in dissection room

Shaping the Security Environment

Newport Paper No. 29, Shaping the Security Environment, edited by Derek S. Reveron, makes an important contribution to an unfolding debate on the global role of U.S. military forces in an era of transnational terrorism, failed or failing states, and globalization. Reveron, professor of national security decision making at the Naval War College, looks beyond the current conflicts in which the United States is involved to raise fundamental questions concerning the regional diplomatic roles of America’s combatant commanders (COCOMs) and, more generally, the entire array of non-warfighting functions that have become an increasingly important part of the day-to-day life of the American military as it engages a variety of partners or potential partners around the world.https://digital-commons.usnwc.edu/usnwc-newport-papers/1027/thumbnail.jp