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PTEN white matter

Yang Yuan, Mao Yunhe, Wang Xiang, Liu Yanhui, Liang Ruofei, Luo Jiewen, Mao Qing
BACKGROUND: Tumor location, which serves as a prognostic factor for high-grade gliomas, may reflect the molecular and genetic phenotype of tumor initiate cells and thus predict tumor origin. Therefore, the purpose of this study was to combine radiographic atlases and tumor biomarkers through a voxel-based neuroimaging approach. METHODS: Preoperative MRIs were collected from 65 newly diagnosed patients with histologically confirmed high-grades gliomas. These samples were analyzed for TP53 mutations and MMP-9...
November 2016: Clinical Neurology and Neurosurgery
Rafer Willenberg, Katherine Zukor, Kai Liu, Zhigang He, Oswald Steward
Corticospinal tract (CST) axons from one hemisphere normally extend and terminate predominantly in the contralateral spinal cord. We previously showed that deleting the gene phosphatase and tensin homolog (PTEN) in the sensorimotor cortex enables CST axons to regenerate after spinal cord injury and that some regenerating axons extend along the "wrong" side. Here, we characterize the degree of specificity of regrowth in terms of laterality. PTEN was selectively deleted via cortical adeno-associated virus (AAV)-Cre injections in neonatal PTEN-floxed mice...
September 1, 2016: Journal of Comparative Neurology
Amanda K Tilot, Thomas W Frazier, Charis Eng
Germline mutations in PTEN, which encodes a widely expressed phosphatase, was mapped to 10q23 and identified as the susceptibility gene for Cowden syndrome, characterized by macrocephaly and high risks of breast, thyroid, and other cancers. The phenotypic spectrum of PTEN mutations expanded to include autism with macrocephaly only 10 years ago. Neurological studies of patients with PTEN-associated autism spectrum disorder (ASD) show increases in cortical white matter and a distinctive cognitive profile, including delayed language development with poor working memory and processing speed...
July 2015: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Guohua Wang, Yejie Shi, Xiaoyan Jiang, Rehana K Leak, Xiaoming Hu, Yun Wu, Hongjian Pu, Wei-Wei Li, Bo Tang, Yun Wang, Yanqin Gao, Ping Zheng, Michael V L Bennett, Jun Chen
Severe traumatic brain injury (TBI) elicits destruction of both gray and white matter, which is exacerbated by secondary proinflammatory responses. Although white matter injury (WMI) is strongly correlated with poor neurological status, the maintenance of white matter integrity is poorly understood, and no current therapies protect both gray and white matter. One candidate approach that may fulfill this role is inhibition of class I/II histone deacetylases (HDACs). Here we demonstrate that the HDAC inhibitor Scriptaid protects white matter up to 35 d after TBI, as shown by reductions in abnormally dephosphorylated neurofilament protein, increases in myelin basic protein, anatomic preservation of myelinated axons, and improved nerve conduction...
March 3, 2015: Proceedings of the National Academy of Sciences of the United States of America
Nai-Kui Liu, Xiao-Ming Xu
Acute spinal cord injury initiates a complex cascade of molecular events termed 'secondary injury', which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death, glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury...
September 15, 2012: Neural Regeneration Research
Yuji Ueno, Masato Koike, Yoshiaki Shimada, Hideki Shimura, Kenichiro Hira, Ryota Tanaka, Yasuo Uchiyama, Nobutaka Hattori, Takao Urabe
Chronic cerebral hypoperfusion causes white-matter lesions (WMLs) with oxidative stress and cognitive impairment. However, the biologic mechanisms that regulate axonal plasticity under chronic cerebral hypoperfusion have not been fully investigated. Here, we investigated whether L-carnitine, an antioxidant agent, enhances axonal plasticity and oligodendrocyte expression, and explored the signaling pathways that mediate axonal plasticity in a rat chronic hypoperfusion model. Adult male Wistar rats subjected to ligation of the bilateral common carotid arteries (LBCCA) were treated with or without L-carnitine...
March 2015: Journal of Cerebral Blood Flow and Metabolism
T W Frazier, R Embacher, A K Tilot, K Koenig, J Mester, C Eng
PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14)...
September 2015: Molecular Psychiatry
Gustavo Mendez, Alp Ozpinar, Jeffrey Raskin, Sakir H Gultekin, Donald A Ross
BACKGROUND: Diagnosis of glioblastoma multiforme (GBM) includes a heterogeneous group of tumors. We describe two cases with histopathologically and molecularly similar tumors, but very different outcomes. We attempt to illustrate the need for improved prognostic markers for GBM. CASE DESCRIPTION: Two patients with similar molecular profiles were retrospectively identified. The following markers were assessed: O (6)-methylguanine DNA methyltransferase (MGMT) methylation, isocitrate dehydrogenase (IDH) 1 and 2 status, epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) status, Ki-67, p53, and 1p/19q status...
2014: Surgical Neurology International
Wise Young
Three theories of regeneration dominate neuroscience today, all purporting to explain why the adult central nervous system (CNS) cannot regenerate. One theory proposes that Nogo, a molecule expressed by myelin, prevents axonal growth. The second theory emphasizes the role of glial scars. The third theory proposes that chondroitin sulfate proteoglycans (CSPGs) prevent axon growth. Blockade of Nogo, CSPG, and their receptors indeed can stop axon growth in vitro and improve functional recovery in animal spinal cord injury (SCI) models...
2014: Cell Transplantation
Chandler L Walker, Xiao-Ming Xu
Cervical spinal cord injury (SCI) damages axons and motor neurons responsible for ipsilateral forelimb function and causes demyelination and oligodendrocyte death. Inhibition of the phosphatase and tensin homologue, PTEN, promotes neural cell survival, neuroprotection and regeneration in vivo and in vitro. PTEN inhibition can also promote oligodendrocyte-mediated myelination of axons in vitro likely through Akt activation. We recently demonstrated that acute treatment with phosphatase PTEN inhibitor, bisperoxovanadium (bpV)-pic reduced tissue damage, neuron death, and promoted functional recovery after cervical hemi-contusion SCI...
June 24, 2014: Neuroscience Letters
Cécile L Maire, Shakti Ramkissoon, Marika Hayashi, Sam Haidar, Lori Ramkissoon, Emmanuelle DiTomaso, Keith L Ligon
Therapeutic modulation of phosphatidylinositol 3-kinase (PI3K)/PTEN signaling is currently being explored for multiple neurological indications including brain tumors and seizure disorders associated with cortical malformations. The effects of PI3K/PTEN signaling are highly cell context dependent but the function of this pathway in specific subsets of neural stem/progenitor cells generating oligodendroglial lineage cells has not been fully studied. To address this, we created Olig2-cre:Pten(fl/fl) mice that showed a unique pattern of Pten loss and PI3K activation in Olig2-lineage cells...
January 2014: Stem Cells
Adeline Vanderver, Davide Tonduti, Ilana Kahn, Johanna Schmidt, Livija Medne, Jodie Vento, Kimberly A Chapman, Brendan Lanpher, Phillip Pearl, Andrea Gropman, Charles Lourenco, John-Steven Bamforth, Cynthia Sharpe, Mercédes Pineda, Jens Schallner, Olaf Bodamer, Simona Orcesi, Saskia A J Lesnik Oberstein, Erik A Sistermans, Helger G Yntema, Carsten Bonnemann, Amy T Waldman, Marjo S van der Knaap
We describe an MRI phenotype seen in a series of patients with mutations in PTEN who have clinical features consistent with PTEN hamartoma tumor syndrome (PHTS). Retrospective review of clinical data and MRI was performed in 23 subjects evaluated in four different tertiary care centers with clinical programs in inherited disorders of the white matter. Patients were referred due to abnormal MRI features and abnormal PTEN sequencing was identified. All subjects had significant macrocephaly (on average >4 SD above the mean), developmental delay with or without autism spectrum disorder and uniform MRI features of enlarged perivascular spaces and multifocal periventricular white matter abnormalities...
March 2014: American Journal of Medical Genetics. Part A
Adam M Sonabend, Jonathan Yun, Liang Lei, Richard Leung, Craig Soderquist, Celina Crisman, Brian J Gill, Arthur Carminucci, Julia Sisti, Mike Castelli, Peter A Sims, Jeffrey N Bruce, Peter Canoll
Molecular subtypes of glioblastoma (GBM) with distinct alterations have been identified. There is need for reproducible, versatile preclinical models that resemble specific GBM phenotypes to facilitate preclinical testing of novel therapies. We present a cell line-based murine proneural GBM model and characterize its response to radiation therapy. Proneural gliomas were generated by injecting PDGF-IRES-Cre retrovirus into the subcortical white matter of adult mice that harbor floxed tumor suppressors (Pten and p53) and stop-floxed reporters...
May 2013: Journal of Neuro-oncology
B M Ellingson, A Lai, R J Harris, J M Selfridge, W H Yong, K Das, W B Pope, P L Nghiemphu, H V Vinters, L M Liau, P S Mischel, T F Cloughesy
BACKGROUND AND PURPOSE: Tumor location is a significant prognostic factor in glioblastoma, which may reflect the genetic profile of tumor precursor cells. The purpose of the current study was to construct and analyze probabilistic radiographic atlases reflecting preoperative tumor locations and corresponding demographic, "-omic," and interventional phenotypes to provide insight into potential niche locations of glioblastoma cells of origin. MATERIALS AND METHODS: Preoperative anatomic MR images in 507 patients with de novo glioblastoma were analyzed...
March 2013: AJNR. American Journal of Neuroradiology
Emily P Harrington, Chao Zhao, Stephen P J Fancy, Sovann Kaing, Robin J M Franklin, David H Rowitch
OBJECTIVE: Repair of myelin injury in multiple sclerosis may fail, resulting in chronic demyelination, axonal loss, and disease progression. As cellular pathways regulated by phosphatase and tensin homologue deleted on chromosome 10 (PTEN; eg, phosphatidylinositol-3-kinase [PI-3K]) have been reported to enhance axon regeneration and oligodendrocyte maturation, we investigated potentially beneficial effects of Pten loss of function in the oligodendrocyte lineage on remyelination. METHODS: We characterized oligodendrocyte numbers and myelin sheath thickness in mice with conditional inactivation of Pten in oligodendrocytes, Olig2-cre, Pten(fl/fl) mice...
November 2010: Annals of Neurology
Trina A Johnson, Shigeki Tsutsui, Frank R Jirik
The Pten tumor suppressor gene is critical for normal intrathymic development of T cells; however, its role in mature antigen-activated T cells is less well defined. A genetically crossed mouse line, Pten(fl/fl) GBC, in which Pten gene deletions could be primarily confined to antigen-activated CD8+ T cells, enabled us to evaluate the consequences of Pten loss on the course of experimental autoimmune encephalomyelitis. Compared with Pten(fl/fl) controls, myelin oligodendrocyte glycoprotein (MOG) peptide-immunized Pten(fl/fl) GBC mice developed more severe and protracted disease...
April 2008: American Journal of Pathology
Ty W Abel, Suzanne J Baker, Melissa M Fraser, Tarik Tihan, James S Nelson, Anthony T Yachnis, John-Paul Bouffard, Hernando Mena, Peter C Burger, Charles G Eberhart
Lhermitte-Duclos disease (LDD) is a rare cerebellar tumor associated with Cowden disease (CD) and germline mutations in the PTEN gene. To further define these relationships, we reviewed clinical and pathologic findings in 31 LDD cases and analyzed the status of the PTEN pathway in 11 of them. We hypothesized that the granule cell hypertrophy in LDD is secondary to activation of mammalian target of rapamycin (mTOR), a downstream effector in the PTEN/AKT pathway and a major regulator of cell growth. Histopathologically, in addition to the classical findings of LDD, we observed prominent vascular proliferation and vacuolization of the white matter in many of the lesions...
April 2005: Journal of Neuropathology and Experimental Neurology
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