Browsing by Author "Mitchell, Dana"

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    Common Molecular Alterations in Canine Oligodendroglioma and Human Malignant Gliomas and Potential Novel Therapeutic Targets
    (Frontiers, 2019-08-14) Mitchell, Dana; Chintala, Sreenivasulu; Fetcko, Kaleigh; Henriquez, Mario; Tewari, Brij N.; Ahmed, Atique; Bentley, R. Timothy; Dey, Mahua; Neurological Surgery, School of Medicine
    Spontaneous canine (Canis lupus) oligodendroglioma (ODG) holds tremendous potential as an immunocompetent large animal model of human malignant gliomas (MG). However, the feasibility of utilizing this model in pre-clinical studies depends on a thorough understanding of the similarities and differences of the molecular pathways associated with gliomas between the two species. We have previously shown that canine ODG has an immune landscape and expression pattern of commonly described oncogenes similar to that of human MG. In the current study, we performed a comprehensive analysis of canine ODG RNAseq data from 4 dogs with ODG and 2 normal controls to identify highly dysregulated genes in canine tumors. We then evaluated the expression of these genes in human MG using Xena Browser, a publicly available database. STRING-database inquiry was used in order to determine the suggested protein associations of these differentially expressed genes as well as the dysregulated pathways commonly enriched by the protein products of these genes in both canine ODG and human MG. Our results revealed that 3,712 (23%) of the 15,895 differentially expressed genes demonstrated significant up- or downregulation (log2-fold change > 2.0). Of the 3,712 altered genes, ~50% were upregulated (n = 1858) and ~50% were downregulated (n = 1854). Most of these genes were also found to have altered expression in human MG. Protein association and pathway analysis revealed common pathways enriched by members of the up- and downregulated gene categories in both species. In summary, we demonstrate that a similar pattern of gene dysregulation characterizes both human MG and canine ODG and provide additional support for the use of the canine model in order to therapeutically target these common genes. The results of such therapeutic targeting in the canine model can serve to more accurately predict the efficacy of anti-glioma therapies in human patients.
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    Neuroinflammation in Autoimmune Disease and Primary Brain Tumors: The Quest for Striking the Right Balance
    (Frontiers Media, 2021-08-13) Mitchell, Dana; Shireman, Jack; Potchanant, Elizabeth A. Sierra; Lara-Velazquez, Montserrat; Dey, Mahua; Pediatrics, School of Medicine
    According to classical dogma, the central nervous system (CNS) is defined as an immune privileged space. The basis of this theory was rooted in an incomplete understanding of the CNS microenvironment, however, recent advances such as the identification of resident dendritic cells (DC) in the brain and the presence of CNS lymphatics have deepened our understanding of the neuro-immune axis and revolutionized the field of neuroimmunology. It is now understood that many pathological conditions induce an immune response in the CNS, and that in many ways, the CNS is an immunologically distinct organ. Hyperactivity of neuro-immune axis can lead to primary neuroinflammatory diseases such as multiple sclerosis and antibody-mediated encephalitis, whereas immunosuppressive mechanisms promote the development and survival of primary brain tumors. On the therapeutic front, attempts are being made to target CNS pathologies using various forms of immunotherapy. One of the most actively investigated areas of CNS immunotherapy is for the treatment of glioblastoma (GBM), the most common primary brain tumor in adults. In this review, we provide an up to date overview of the neuro-immune axis in steady state and discuss the mechanisms underlying neuroinflammation in autoimmune neuroinflammatory disease as well as in the development and progression of brain tumors. In addition, we detail the current understanding of the interactions that characterize the primary brain tumor microenvironment and the implications of the neuro-immune axis on the development of successful therapeutic strategies for the treatment of CNS malignancies.
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    Surgical Neuro-Oncology: Management of Glioma
    (Elsevier, 2022) Mitchell, Dana; Shireman, Jack M.; Dey, Mahua; Pediatrics, School of Medicine
    Gliomas are the most common intrinsic brain tumor in adults. Although maximal tumor resection improves survival, this must be balanced with preservation of neurologic function. Technological advancements have greatly expanded our ability to safely maximize tumor resection and design innovative therapeutic trials that take advantage of intracavitary delivery of therapeutic agents after resection. In this article, we review the role of surgical intervention for both low-grade and high-grade gliomas and the innovations that are driving and expanding the role of surgery in this therapeutically challenging group of malignancies.