See A.P.,Brigham and Women's Hospital |
Parker J.J.,University of Colorado at Denver |
Waziri A.,Inova Neuroscience Institute
Journal of Neuro-Oncology | Year: 2015
Cell-mediated suppression of anti-tumor immunity is multifactorial in patients with cancer, and recent studies have focused on several distinct cellular agents that are associated with this phenomenon. This review will focus on the potential role of regulatory T cells (Tregs) and microglia in the suppression of cellular immunity observed in patients with glioblastoma. We discuss the ontogeny, basic biology, evidence for activity, and potential clinical options for targeting Tregs and microglia as part of immunotherapy in affected patients. © 2015, Springer Science+Business Media New York.
Griesinger A.M.,University of Colorado at Denver |
Griesinger A.M.,Childrens Hospital Colorado |
Birks D.K.,Childrens Hospital Colorado |
Birks D.K.,University of Colorado at Denver |
And 13 more authors.
Journal of Immunology | Year: 2013
Despite increasing evidence that antitumor immune control exists in the pediatric brain, these findings have yet to be exploited successfully in the clinic. A barrier to development of immunotherapeutic strategies in pediatric brain tumors is that the immunophenotype of these tumors' microenvironment has not been defined. To address this, the current study used multicolor FACS of disaggregated tumor to systematically characterize the frequency and phenotype of infiltrating immune cells in the most common pediatric brain tumor types. The initial study cohort consisted of 7 pilocytic astrocytoma (PA), 19 ependymoma (EPN), 5 glioblastoma (GBM), 6 medulloblastoma (MED), and 5 nontumor brain (NT) control samples obtained from epilepsy surgery. Immune cell types analyzed included both myeloid and T cell lineages and respective markers of activated or suppressed functional phenotypes. Immune parameters that distinguished each of the tumor types were identified. PA and EPN demonstrated significantly higher infiltrating myeloid and lymphoid cells compared with GBM, MED, or NT. Additionally, PA and EPN conveyed a comparatively activated/classically activated myeloid cell-skewed functional phenotype denoted in particular by HLA-DR and CD64 expression. In contrast, GBM and MED contained progressively fewer infiltrating leukocytes and more muted functional phenotypes similar to that of NT. These findings were recapitulated using whole tumor expression of corresponding immune marker genes in a large gene expression microarray cohort of pediatric brain tumors. The results of this crosstumor comparative analysis demonstrate that different pediatric brain tumor types exhibit distinct immunophenotypes, implying that specific immunotherapeutic approaches may be most effective for each tumor type. Copyright © 2013 by The American Association of Immunologists, Inc.
Xu K.,Yale University |
Lipsky R.H.,Inova Neuroscience Institute |
Lipsky R.H.,George Mason University
Experimental Biology and Medicine | Year: 2015
For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. © 2014 by the Society for Experimental Biology and Medicine.
Lipsky R.H.,Inova Neuroscience Institute |
Lipsky R.H.,George Mason University
International Journal of Developmental Neuroscience | Year: 2013
A balance between rapid, short lived, neuronal responses and prolonged ones fulfill the biochemical and cellular requirements for creating a molecular memory. I provide an overview of epigenetic mechanisms in the brain and discuss their impact on synaptic plasticity, cognitive functions, and discuss a recent example of how they can contribute to neurodegeneration and the cognitive decline associated with Alzheimer's disease. © 2012 ISDN.
Rahme R.,Inova Neuroscience Institute |
Vyas N.A.,Inova Neuroscience Institute |
Hamilton J.F.,Inova Neuroscience Institute
World Neurosurgery | Year: 2016
Background: Ischemic stroke is being increasingly recognized as a possible cause of spontaneous isolated convexity subarachnoid hemorrhage (SAH). However, it is a much less established cause of cisternal, aneurysmal-like SAH. Only 3 case reports of concomitant cisternal SAH and perforator infarcts exist in the literature, raising the possibility of perforating artery rupture as a potential mechanism. In contrast, embolic stroke is not recognized as a cause of aneurysmal-like SAH. Case Description: In 2 patients with embolic cerebral infarctions mimicking intracranial aneurysm rupture, diagnosis was confirmed by magnetic resonance imaging with diffusion-weighted imaging after cerebral angiography failed to reveal an underlying vascular lesion. Extracranial atherosclerosis was identified as the source of emboli in each case. One patient was started on antiplatelet therapy, and the other underwent surgical revascularization. Both patients had a favorable hospital course, with no recurrent hemorrhage or ischemia. Conclusions: Based on these observations, embolic stroke should be included in the differential diagnosis of angiogram-negative SAH. Therefore, brain magnetic resonance imaging and vascular imaging of the neck should be part of the routine work-up of this relatively common entity. © 2016 Elsevier Inc.
Waziri A.,Inova Neuroscience Institute |
Curry W.T.,Harvard University
Journal of Neuro-Oncology | Year: 2014
Over the 30 years since the formation of the AANS/CNS Section on Tumors, the breadth and scope of our activities have continued to expand. An initial focus on education and collaboration between those members of the neurosurgical community dedicated to the care of patients with neurological tumors has broadened to include development of international relationships, participation in clinical trials and efforts to define standards of care and quality metrics. As we navigate the rapidly changing environment of health care, the Section on Tumors will occupy a central role in promoting advocacy, establishing collaboration, providing education, and supporting research for the community of neurosurgeons dedicated to the care of patients with neurological tumors. This article will provide an update and status report on the development of the Section on Tumors, followed by a brief discussion of the challenges and opportunities emerging at the onset of our fourth decade of service. © 2014, Springer Science+Business Media New York.
Lipsky R.H.,Inova Neuroscience Institute
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience | Year: 2013
A balance between rapid, short lived, neuronal responses and prolonged ones fulfill the biochemical and cellular requirements for creating a molecular memory. I provide an overview of epigenetic mechanisms in the brain and discuss their impact on synaptic plasticity, cognitive functions, and discuss a recent example of how they can contribute to neurodegeneration and the cognitive decline associated with Alzheimer's disease. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.
Sippel T.R.,Aurora University |
Shimizu T.,Aurora University |
Strnad F.,Aurora University |
Traystman R.J.,Aurora University |
And 3 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2015
Transient suppression of peripheral immunity is a major source of complication for patients suffering from ischemic stroke. The release of Arginase I (ArgI) from activated neutrophils has recently been associated with T-cell dysfunction in a number of pathologies. However, this pathway has not been previously explored in ischemic stroke. Using the murine model of transient middle cerebral artery occlusion, we explored effects of stroke on peripheral T-cell function and evaluated the role of neutrophils and ArgI. Stimulation of splenic T cells from post-stroke animals with anti-CD3/CD28 resulted in decreased proliferation and interferon-γ production when compared with sham-surgery controls. Flow cytometric analysis of intrasplenic leukocytes exposed the presence of a transient population of activated neutrophils that correlated quantitatively with elevated ArgI levels in culture media. In vitro activation of purified resting neutrophils from unmanipulated controls confirmed the capacity for murine neutrophils to release ArgI from preformed granules. We observed decreased expression of the L-arg-sensitive CD3ζ on T cells, consistent with decreased functional activity. Critically, L-arg supplementation restored the functional response of post-stroke T cells to mitogenic stimulation. Together, these data outline a novel mechanism of reversible, neutrophil-mediated peripheral immunosuppression related to ArgI release following ischemic stroke. © 2015 ISCBFM.
PubMed | Inova Neuroscience Institute
Type: Journal Article | Journal: International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience | Year: 2013
A balance between rapid, short lived, neuronal responses and prolonged ones fulfill the biochemical and cellular requirements for creating a molecular memory. I provide an overview of epigenetic mechanisms in the brain and discuss their impact on synaptic plasticity, cognitive functions, and discuss a recent example of how they can contribute to neurodegeneration and the cognitive decline associated with Alzheimers disease.
PubMed | University of Nice Sophia Antipolis, Uniformed Services University of the Health Sciences, Michigan State University, King Saud University and Inova Neuroscience Institute
Type: | Journal: BioMed research international | Year: 2015
Alpha-linolenic acid (ALA) is plant-based essential omega-3 polyunsaturated fatty acids that must be obtained through the diet. This could explain in part why the severe deficiency in omega-3 intake pointed by numerous epidemiologic studies may increase the brains vulnerability representing an important risk factor in the development and/or deterioration of certain cardio- and neuropathologies. The roles of ALA in neurological disorders remain unclear, especially in stroke that is a leading cause of death. We and others have identified ALA as a potential nutraceutical to protect the brain from stroke, characterized by its pleiotropic effects in neuroprotection, vasodilation of brain arteries, and neuroplasticity. This review highlights how chronic administration of ALA protects against rodent models of hypoxic-ischemic injury and exerts an anti-depressant-like activity, effects that likely involve multiple mechanisms in brain, and may be applied in stroke prevention. One major effect may be through an increase in mature brain-derived neurotrophic factor (BDNF), a widely expressed protein in brain that plays critical roles in neuronal maintenance, and learning and memory. Understanding the precise roles of ALA in neurological disorders will provide the underpinnings for the development of new therapies for patients and families who could be devastated by these disorders.