Ameer Abutaleb

Glucose-6–phosphatase Is a Key Metabolic Regulator of Glioblastoma Invasion

Glioblastoma (GBM) remains the most aggressive primary brain cancer in adults. Similar to other cancers, GBM cells undergo metabolic reprogramming to promote proliferation and survival. Glycolytic inhibition is widely used to target such reprogramming. However, the stability of glycolytic inhibition in GBM remains unclear especially in a hypoxic tumor microenvironment. In this study, it was determined that glucose-6–phosphatase (G6PC/G6Pase) expression is elevated in GBM when compared with normal brain. Human-derived brain tumor–initiating cells (BTIC) use this enzyme to counteract glycolytic inhibition induced by 2-deoxy-d-glucose (2DG) and sustain malignant progression. Downregulation of G6PC renders the majority of these cells unable to survive glycolytic inhibition, and promotes glycogen accumulation through the activation of glycogen synthase (GYS1) and inhibition of glycogen phosphorylase (PYGL). Moreover, BTICs that survive G6PC knockdown are less aggressive (reduced migration, invasion, proliferation, and increased astrocytic differentiation). Collectively, these findings establish G6PC as a key enzyme with promalignant functional consequences that has not been previously reported in GBM and identify it as a potential therapeutic target. Implications: This study is the first to demonstrate a functional relationship between the critical gluconeogenic and glycogenolytic enzyme G6PC with the metabolic adaptations during GBM invasion. Visual Overview: http://mcr.aacrjournals.org/content/12/11/1547/F1.large.jpg. Mol Cancer Res; 12(11); 1547–59. ©2014 AACR. Visual Overview

Safety of computed tomography in patients with cardiac rhythm management devices: Assessment of the U.S. food and drug administration advisory in clinical practice

OBJECTIVES To assess the safety of computed tomography (CT) imaging in patients with cardiac rhythm management (CRM) devices, which was subject to an advisory from the U.S. Food and Drug Administration (FDA) in 2008. BACKGROUND The FDA warned about potential interference of CT imaging with CRM devices and made recommendations for clinical practice despite only limited evidence. METHODS All 516 CT scans that involved direct radiation exposure of CRM devices (332 defibrillators, 184 pacemakers) at 2 large-volume centers between July 2000 and May 2010 were included. The primary outcome was a composite endpoint of death, bradycardia or tachycardia requiring termination of the scan or an immediate intervention, unplanned hospital admission, reprogramming of the device, inappropriate defibrillator shocks, or device replacement/revision thought to be due to CT imaging. Significant changes in device parameters were sought as a secondary outcome (control group 4:1 ratio). RESULTS The main finding was that none of the CTs were associated with the primary outcome. With serial device interrogations, there were no differences in changes in battery voltage or lead parameters between devices exposed to radiation and their controls. Potentially significant changes in device parameters were observed in a small group of devices (both the CT group and control group), but no definitive link to CT was confirmed, and there were no associated clinical consequences. CONCLUSIONS The findings suggest that the presence of CRM devices should not delay or result in cancellation of clinically indicated CT imaging procedures, and provide evidence that would be helpful when the FDA advisory is re-evaluated.

Interacting post-muscarinic receptor signaling pathways potentiate matrix metalloproteinase-1 expression and invasion of human colon cancer cells.

M3 muscarinic receptor (M3R) expression is increased in colon cancer; M3R activation stimulates colon cancer cell invasion via cross-talk with epidermal growth factor receptors (EGFR), post-EGFR activation of mitogen-activated protein kinase (MAPK) extracellular signal-related kinase 1/2 (ERK1/2), and induction of matrix metalloproteinase-1 (MMP1) expression. MMP1 expression is strongly associated with tumor metastasis and adverse outcomes. Here, we asked whether other MAPKs regulate M3R agonist-induced MMP1 expression. In addition to activating ERK1/2, we found that treating colon cancer cells with acetylcholine (ACh) stimulated robust time- and dose-dependent phosphorylation of p38 MAPK. Unlike ERK1/2 activation, ACh-induced p38 phosphorylation was EGFR-independent and blocked by inhibiting protein kinase C-α (PKC-α). Inhibiting activation of PKC-α, EGFR, ERK1/2, or p38-α/β alone attenuated, but did not abolish ACh-induced MMP1 expression, a finding that predicted potentiating interactions between these pathways. Indeed, ACh-induced MMP1 expression was abolished by incubating cells with either an EGFR or MEK/ERK1/2 inhibitor combined with a p38-α/β inhibitor. Activating PKC-α and EGFR directly with the combination of phorbol 12-myristate 13-acetate (PMA) and EGF potentiated MMP1 gene and protein expression, and cell invasion. PMA- and ACh-induced MMP1 expression were strongly diminished by inhibiting Src and abolished by concurrently inhibiting both p38-α/β and Src, indicating that Src mediates the cross-talk between PKC-α and EGFR signaling. Using siRNA knockdown, we identified p38-α as the relevant p38 isoform. Collectively, these studies uncover novel functional interactions between post-muscarinic receptor signaling pathways that augment MMP1 expression and drive colon cancer cell invasion; targeting these potentiating interactions has therapeutic potential.

Mechanisms of neuropathogenesis in HIV and HCV: similarities, differences, and unknowns

HIV and hepatitis C virus (HCV) have both been associated with cognitive impairment. Combination antiretroviral therapy (cART) has dramatically changed the nature of cognitive impairment in HIV-infected persons, while the role of direct-acting antivirals (DAA) in neurocognition of HCV-infected individuals remains unclear. Also, whether HIV and HCV interact to promote neurocognitive decline or whether they each contribute an individual effect continues to be an open question. In this work, we review the virally mediated mechanisms of HIV- and HCV-mediated neuropathogenesis, with an emphasis on the role of dual infection, and discuss observed changes with HIV viral suppression and HCV functional cure on neurocognitive impairments.

Age Modifies the Association Between Depressive Symptoms and Adherence to Self-Testing With Telemedicine in Patients With Inflammatory Bowel Disease

Background Depression is common in patients with inflammatory bowel disease (IBD) and is known to be associated with poor adherence in the usual care setting. In the last decade, there has been an increase in the use of information technology (IT) for the delivery of IBD care, but the association between depressive symptoms (DS) and adherence to self-testing in this context is not known. We aimed to investigate this association among IBD patients managed via a text messaging-based telemedicine system. Methods This was a prospective study of participants in the 2 intervention arms of the Telemedicine for Patients with IBD (TELE-IBD) trial. Depressive symptoms were measured at baseline, and then participants received periodic text messages to initiate IBD-specific self-testing. Treatment plans were similarly conveyed, and adherence to self-testing was evaluated at the end of 1 year. Regression analyses were performed, and age-stratified models were constructed to evaluate for effect modification. Results Of the 193 study participants, 48% had DS at baseline. Overall, there was no significant association between DS and adherence to self-testing. However, upon stratification by age, adherence increased with depressive symptoms in those that were 40 years and younger (P = 0.02), but there was no association between depressive symptoms and adherence in the older group (P = 0.53). Conclusions Younger IBD patients with DS have high adherence when managed in a text messaging-based telemedicine program. Telemedicine interventions have the potential to improve health outcomes in this demographic-a group that is often thought to be difficult to manage due to nonadherence.

A changing paradigm: management and treatment of the HCV/HIV-co-infected patient

Hepatitis C virus (HCV) treatment in HIV/HCV co-infected individuals has renewed relevance given the ongoing opioid crisis and rise of new HIV and HCV infections associated with injection drug use. Patients co-infected with HIV and HCV demonstrate increased rates of hepatic fibrosis, progression to liver failure, and liver-related mortality. HIV co-infection does not impact outcomes of current HCV treatments, and patients should be treated the same as HCV mono-infected persons, though attention to drug:drug interactions is required. In this review, we discuss the mechanisms mediating injury to the liver in HIV mono-infection and HIV/HCV co-infection, and present the landmark trials of HCV treatment in HIV-infected individuals.

Vedroprevir in the management of hepatitis C virus infection

ABSTRACT Introduction: Hepatitis C Virus (HCV) is a chronic infection of the liver and the leading cause of liver failure and liver transplantation worldwide. While prior HCV therapies were prolonged and had variable success rates, the advent of direct-acting antivirals (DAAs) has dramatically improved HCV therapy with minimal side effects, shorter treatment durations, and higher cure rates. Areas covered: In this paper, we review the literature discussing the use of Vedroprevir (GS-9451) in treatment of HCV in a variety of patient populations. Articles accessible on MEDLINE/PubMed were reviewed to provide context on chemistry, pharmacology, and efficacy of Vedroprevir in HCV treatment. Expert opinion: Vedroprevir is highly effective in reducing treatment duration in combination with other DAAs without compromising treatment success rates. GS-9451 is insufficient as HCV monotherapy due to low threshold for development of high level of resistance and must be combined with other DAAs to achieve sustained virologic response (SVR).

Abstract 5422: Human GBM-derived brain tumor stem cells resist glycolysis inhibition through Glucose 6 phosphatase: a potential clinical implication in the treatment of recurrent brain tumors.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Glioblastomas (GBMs) are characterized by a very aggressive behavior and a heterogeneous presentation that includes proliferative, invasive, and necrotic areas. The rapid expansion of GBMs frequently outgrowths the blood supply, originating hypoxic and necrotic regions, which induces metabolic changes in the tumor cells. In a survival adaptation response, tumor cells adjust their glucose metabolism to an anaerobic glycolysis, even in the presence of oxygen. This is known as the Warburg effect and it is enhanced in Brain Tumor Stem Cells (BTSCs), the cellular sub-population considered to be responsible for the tumor origin and recurrence. Glycolysis inhibition can be achieved using glucose analogues like 2-deoxyglucose (2DG). We have previously demonstrated that 2DG treatment of BTSCs induces a decrease in cell proliferation and an increase in cell death and neuronal differentiation. Nevertheless, some BTSC cells are able to survive glycolysis inhibition and recover their aggressive phenotype which might be related to brain tumor recurrence. Here we studied the tumorigenic behavior of human GBM-derived primary BTSCs after recovery from glycolysis inhibition. We observed that cells which were pretreated with 2DG and subsequently allowed to recover for 72h in glucose-containing media, exhibited a more aggressive phenotype; including an increased migration, invasion, and proliferation capability; as well as MMP2 and nestin overexpression. Some of these features recapitulate what occurs in recurrent brain tumors. In studying the potential molecular mechanisms responsible for this behavior, we observed an increased expression of glucose-6-phosphatase isoform α (G6PC) in our primary GBM cells when compared to normal brain. Moreover, 2DG treatment induced an increase in the expression of this isoform. G6PC is a key glucose homeostasis enzyme not previously reported in brain tissue. In addition, when G6PC was inhibited, either pharmacologically (with chlorogenic acid) or genetically (with shRNA), we observed that the recovery capacity of GBM cells was significantly reduced. This was evident by a decrease in their proliferation, migration, and invasion ability, as well as by a decrease in HIF1α, pSTAT3 protein, MMP2 gene expression. In summary, we report for the first time the expression of G6PC in GBM cells. This specific isoform is not expressed in normal brain parenchyma, which makes it a very attractive target for anticancer therapy. Our results suggest a role of G6PC in promoting a mechanism of GBM cell recovery from glycolysis inhibition. By unraveling these mechanisms we describe an important therapeutic target that could impact the recurrence ability of brain tumors. Citation Format: Sara Abbadi, Hugo Guerrero-Cazares, Ameer Abutaleb, Chris L. Smith, William Ruff, Jennifer Schiller, Andre Levchenko, Alfredo Quinones-Hinojosa. Human GBM-derived brain tumor stem cells resist glycolysis inhibition through Glucose 6 phosphatase: a potential clinical implication in the treatment of recurrent brain tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2013-5422