JC Virus T-Antigen Regulates Glucose Metabolic Pathways in Brain Tumor Cells

Recent studies have reported the detection of the human neurotropic virus, JCV, in a significant population of brain tumors, including medulloblastomas. Accordingly, expression of the JCV early protein, T-antigen, which has transforming activity in cell culture and in transgenic mice, results in the development of a broad range of tumors of neural crest and glial origin. Evidently, the association of T-antigen with a range of tumor-suppressor proteins, including p53 and pRb, and signaling molecules, such as β-catenin and IRS-1, plays a role in the oncogenic function of JCV T-antigen. We demonstrate that T-antigen expression is suppressed by glucose deprivation in medulloblastoma cells and in glioblastoma xenografts that both endogenously express T-antigen. Mechanistic studies indicate that glucose deprivation-mediated suppression of T-antigen is partly influenced by 5′-activated AMP kinase (AMPK), an important sensor of the AMP/ATP ratio in cells. In addition, glucose deprivation-induced cell cycle arrest in the G1 phase is blocked with AMPK inhibition, which also prevents T-antigen downregulation. Furthermore, T-antigen prevents G1 arrest and sustains cells in the G2 phase during glucose deprivation. On a functional level, T-antigen downregulation is partially dependent on reactive oxygen species (ROS) production during glucose deprivation, and T-antigen prevents ROS induction, loss of ATP production, and cytotoxicity induced by glucose deprivation. Additionally, we have found that T-antigen is downregulated by the glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), and the pentose phosphate inhibitors, 6-aminonicotinamide and oxythiamine, and that T-antigen modulates expression of the glycolytic enzyme, hexokinase 2 (HK2), and the pentose phosphate enzyme, transaldolase-1 (TALDO1), indicating a potential link between T-antigen and metabolic regulation. These studies point to the possible involvement of JCV T-antigen in medulloblastoma proliferation and the metabolic phenotype and may enhance our understanding of the role of viral proteins in glycolytic tumor metabolism, thus providing useful targets for the treatment of virus-induced tumors

Equitable representation in councils: theory and an application to the United Nations Security Council

We analyze democratic equity in council voting games (CVGs). In a CVG, a voting body containing all members delegates decision-making to a (time-varying) subset of its members, as describes, e.g., the relationship between the United Nations General Assembly and the United Nations Security Council (UNSC). We develop a theoretical framework for analyzing democratic equitability in CVGs at both the country and region levels, and for different assumptions regarding preference correlation. We apply the framework to evaluate the equitability of the UNSC, and the claims of those who seek to reform it. We find that the individual permanent members are overrepresented by between 21.3 times (United Kingdom) and 3.8 times (China) from a country-level perspective, while from a region perspective Eastern Europe is the most heavily overrepresented region with more than twice its equitable representation, and Africa the most heavily underrepresented. Our equity measures do not preclude some UNSC members from exercising veto rights, however

Early reduction of the splicing factor2/alternative splicing factor: a cellular inhibitor of the JC polyomavirus in natalizumab-treated MS patients long before developing progressive multifocal leukoencephalopathy

Natalizumab is effective against relapsing-remitting multiple sclerosis (MS) but increases the risk of progressive multifocal leukoencephalopathy (PML), which is caused by the activation of the JCV polyomavirus. SF2/ASF (splicing factor2/alternative splicing factor) is a potent cellular inhibitor of JCV replication and large T-antigen (T-Ag) expression. We reported that SF2/ASF levels in blood cells increase during the first year of natalizumab therapy and decrease thereafter, inversely related to T-Ag expression, and suggested a correlation with JCV reactivation. Here, we report SF2/ASF levels of longitudinal blood samples of two patients undergoing natalizumab therapy, who developed PML while monitored, in comparison to natalizumab-treated controls and to one-off PML samples. After 6 months of therapy, SF2/ASF levels of the two cases were reduced, instead of increased, and their overall SF2/ASF levels were lower than those from natalizumab controls. Since SF2/ASF inhibits JCV, its early reduction might have a role in subsequent PML. We are aware of the limitations of the study, but the uniqueness of serial blood samples collected before and after PML onset in natalizumab-treated patients must be stressed. If confirmed in other patients, SF2/ASF evaluation could be a new and early biomarker of natalizumab-associated PML risk, allowing an 18-24-month interval before PML onset (presently ~ 5 months), in which clinicians could evaluate other risk factors and change therapy

Effect of chronic treatment with lacidipine or lisinopril on intracellular partitioning of glucose metabolism in type 2 diabetes mellitus

Antihypertensive treatment is frequently needed in type 2 diabetes. In this study we measured the rates of total, oxidative, and nonoxidative glucose disposal, glycogen synthesis, glycolysis, endogenous glucose production, and lipid oxidation using a 4-h euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 300 pmol/L) clamp in combination with a dual glucose tracer infusion ([3-(3)H]- and [U-14C] D-glucose) and indirect calorimetry in 40 nonobese subjects with type 2 diabetes. Subjects were studied twice: after a 4-week run-in period and after a 16-week period of double blind, randomized treatment with 4-6 mg/day lacidipine, a calcium channel blocker (n = 19), or 10-20 mg/day lisinopril, an angiotensin-converting enzyme inhibitor (n = 21). Antihypertensive treatment resulted in a significant increase in total glucose disposal during insulin clamp as well as in basal and insulin-stimulated nonoxidative glucose disposal rates. On the contrary, oxidative glucose disposal was significantly decreased by antihypertensive treatment, mainly in the basal state. The changes in glucose disposal rates were not significantly different in subjects treated with lacidipine and in those treated with lisinopril. The suppression of endogenous glucose production during insulin clamp was significantly greater after lacidipine than after lisinopril. These results suggest that treatment of subjects with type 2 diabetes with either lacidipine or lisinopril has no adverse effect on glucose metabolism. Conversely, both drugs seem to improve insulin sensitivity

Effect of chronic treatment with lacidipine or lisinopril on intracellular partitioning of glucose metabolism in type 2 diabetes mellitus

Antihypertensive treatment is frequently needed in type 2 diabetes. In this study we measured the rates of total, oxidative, and nonoxidative glucose disposal, glycogen synthesis, glycolysis, endogenous glucose production, and lipid oxidation using a 4-h euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 300 pmol/L) clamp in combination with a dual glucose tracer infusion ([3-(3)H]- and [U-14C] D-glucose) and indirect calorimetry in 40 nonobese subjects with type 2 diabetes. Subjects were studied twice: after a 4-week run-in period and after a 16-week period of double blind, randomized treatment with 4-6 mg/day lacidipine, a calcium channel blocker (n = 19), or 10-20 mg/day lisinopril, an angiotensin-converting enzyme inhibitor (n = 21). Antihypertensive treatment resulted in a significant increase in total glucose disposal during insulin clamp as well as in basal and insulin-stimulated nonoxidative glucose disposal rates. On the contrary, oxidative glucose disposal was significantly decreased by antihypertensive treatment, mainly in the basal state. The changes in glucose disposal rates were not significantly different in subjects treated with lacidipine and in those treated with lisinopril. The suppression of endogenous glucose production during insulin clamp was significantly greater after lacidipine than after lisinopril. These results suggest that treatment of subjects with type 2 diabetes with either lacidipine or lisinopril has no adverse effect on glucose metabolism. Conversely, both drugs seem to improve insulin sensitivity