RESUMEN
R-loops are three-stranded nucleic acid structures found abundantly and yet often viewed as by-products of transcription. Studying cells from patients with a motor neuron disease (amyotrophic lateral sclerosis 4 [ALS4]) caused by a mutation in senataxin, we uncovered how R-loops promote transcription. In ALS4 patients, the senataxin mutation depletes R-loops with a consequent effect on gene expression. With fewer R-loops in ALS4 cells, the expression of BAMBI, a negative regulator of transforming growth factor ß (TGF-ß), is reduced; that then leads to the activation of the TGF-ß pathway. We uncovered that genome-wide R-loops influence promoter methylation of over 1,200 human genes. DNA methyl-transferase 1 favors binding to double-stranded DNA over R-loops. Thus, in forming R-loops, nascent RNA blocks DNA methylation and promotes further transcription. Hence, our results show that nucleic acid structures, in addition to sequences, influence the binding and activity of regulatory proteins.
Asunto(s)
Regulación de la Expresión Génica/genética , Regiones Promotoras Genéticas , ARN Helicasas/genética , ARN Helicasas/metabolismo , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , ADN/genética , ADN/ultraestructura , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , ADN Helicasas , Metilación de ADN/genética , Humanos , Proteínas de la Membrana/metabolismo , Enzimas Multifuncionales , Mutación , Regiones Promotoras Genéticas/genética , Procesamiento Proteico-Postraduccional , ARN/genética , ARN/ultraestructura , Motivos de Unión al ARN , Activación Transcripcional/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: Gene therapy by convection-enhanced delivery of type 2 adeno-associated virus-glial cell derived neurotrophic factor (AAV2-GDNF) to the bilateral putamina seeks to increase GDNF gene expression and treat Parkinson's disease (PD). METHODS: A 63-year-old man with advanced PD received AAV2-GDNF in a clinical trial. He died from pneumonia after anterior cervical discectomy and fusion 45 months later. An autopsy included brain examination for GDNF transgene expression. Putaminal catecholamine concentrations were compared to in vivo 18F-Fluorodopa (18F-FDOPA) positron emission tomography (PET) scanning results before and 18 months after AAV2-GDNF infusion. RESULTS: Parkinsonian progression stabilized clinically. Postmortem neuropathology confirmed PD. Bilateral putaminal regions previously infused with AAV2-GDNF expressed the GDNF gene. Total putaminal dopamine was 1% of control, confirming the striatal dopaminergic deficiency suggested by baseline 18F-DOPA-PET scanning. Putaminal regions responded as expected to AAV2-GDNF. CONCLUSION: After AAV2-GDNF infusion, infused putaminal regions showed increased GDNF gene expression, tyrosine hydroxylase immunoreactive sprouting, catechol levels, and 18F-FDOPA-PET signal, suggesting the regenerative potential of AAV2-GDNF in PD.
Asunto(s)
Factor Neurotrófico Derivado de la Línea Celular Glial , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , Putamen , Humanos , Masculino , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Persona de Mediana Edad , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Putamen/metabolismo , Dependovirus/genética , Terapia Genética/métodosRESUMEN
Traumatic microbleeds are small foci of hypointensity seen on T2*-weighted MRI in patients following head trauma that have previously been considered a marker of axonal injury. The linear appearance and location of some traumatic microbleeds suggests a vascular origin. The aims of this study were to: (i) identify and characterize traumatic microbleeds in patients with acute traumatic brain injury; (ii) determine whether appearance of traumatic microbleeds predict clinical outcome; and (iii) describe the pathology underlying traumatic microbleeds in an index patient. Patients presenting to the emergency department following acute head trauma who received a head CT were enrolled within 48 h of injury and received a research MRI. Disability was defined using Glasgow Outcome Scale-Extended ≤6 at follow-up. All magnetic resonance images were interpreted prospectively and were used for subsequent analysis of traumatic microbleeds. Lesions on T2* MRI were stratified based on 'linear' streak-like or 'punctate' petechial-appearing traumatic microbleeds. The brain of an enrolled subject imaged acutely was procured following death for evaluation of traumatic microbleeds using MRI targeted pathology methods. Of the 439 patients enrolled over 78 months, 31% (134/439) had evidence of punctate and/or linear traumatic microbleeds on MRI. Severity of injury, mechanism of injury, and CT findings were associated with traumatic microbleeds on MRI. The presence of traumatic microbleeds was an independent predictor of disability (P < 0.05; odds ratio = 2.5). No differences were found between patients with punctate versus linear appearing microbleeds. Post-mortem imaging and histology revealed traumatic microbleed co-localization with iron-laden macrophages, predominately seen in perivascular space. Evidence of axonal injury was not observed in co-localized histopathological sections. Traumatic microbleeds were prevalent in the population studied and predictive of worse outcome. The source of traumatic microbleed signal on MRI appeared to be iron-laden macrophages in the perivascular space tracking a network of injured vessels. While axonal injury in association with traumatic microbleeds cannot be excluded, recognizing traumatic microbleeds as a form of traumatic vascular injury may aid in identifying patients who could benefit from new therapies targeting the injured vasculature and secondary injury to parenchyma.
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Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Evaluación de la Discapacidad , Hemorragias Intracraneales/diagnóstico por imagen , Lesiones del Sistema Vascular/diagnóstico por imagen , Lesiones del Sistema Vascular/patología , Adolescente , Adulto , Autopsia , Axones/patología , Lesiones Traumáticas del Encéfalo/patología , Femenino , Escala de Consecuencias de Glasgow , Humanos , Hemorragias Intracraneales/patología , Hierro/sangre , Macrófagos/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
BACKGROUND: The etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus. OBJECTIVES: The objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors. METHODS: Formalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus. RESULTS: Decreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls. CONCLUSIONS: Our findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. © 2018 International Parkinson and Movement Disorder Society.
Asunto(s)
Colina O-Acetiltransferasa/deficiencia , Neuronas Colinérgicas/patología , Núcleo Tegmental Pedunculopontino/metabolismo , Tortícolis/patología , Acetilcolina , Anciano , Anciano de 80 o más Años , Neuronas Colinérgicas/metabolismo , Imagen de Difusión Tensora , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Núcleo Tegmental Pedunculopontino/diagnóstico por imagen , Tortícolis/diagnóstico por imagen , Ubiquitina , Proteínas tau/metabolismoRESUMEN
BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant nervous system tumor predisposition disorder caused by constitutive inactivation of one of the two copies of NF2. Meningiomas affect about one half of NF2 patients, and are associated with a higher disease burden. Currently, the somatic mutation landscape in NF2-associated meningiomas remains largely unexamined. CASE PRESENTATION: Here, we present an in-depth genomic study of benign and atypical meningiomas, both from a single NF2 patient. While the grade I tumor was asymptomatic, the grade II tumor exhibited an unusually high growth rate: expanding to 335 times its initial volume within one year. The genomes of both tumors were examined by whole-exome sequencing (WES) complemented with spectral karyotyping (SKY) and SNP-array copy-number analyses. To better understand the clonal composition of the atypical meningioma, the tumor was divided in four sections and each section was investigated independently. Both tumors had second copy inactivation of NF2, confirming the central role of the gene in meningioma formation. The genome of the benign tumor closely resembled that of a normal diploid cell and had only one other deleterious mutation (EPHB3). In contrast, the chromosomal architecture of the grade II tumor was highly re-arranged, yet uniform among all analyzed fragments, implying that this large and fast growing tumor was composed of relatively few clones. Besides multiple gains and losses, the grade II meningioma harbored numerous chromosomal translocations. WES analysis of the atypical tumor identified deleterious mutations in two genes: ADAMTSL3 and CAPN5 in all fragments, indicating that the mutations were present in the cell undergoing fast clonal expansion CONCLUSIONS: This is the first WES study of NF2-associated meningiomas. Besides second NF2 copy inactivation, we found low somatic burden in both tumors and high level of genomic instability in the atypical meningioma. Genomic instability resulting in altered gene dosage and compromised structural integrity of multiple genes may be the primary reason of the high growth rate for the grade II tumor. Further study of ADAMTSL3 and CAPN5 may lead to elucidation of their molecular implications in meningioma pathogenesis.
Asunto(s)
Neoplasias de los Nervios Craneales/genética , Genes de la Neurofibromatosis 2 , Genómica/métodos , Neoplasias Meníngeas/genética , Meningioma/genética , Mutación/genética , Adulto , Neoplasias de los Nervios Craneales/patología , Neoplasias de los Nervios Craneales/cirugía , Femenino , Genotipo , Humanos , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/cirugía , Meningioma/patología , Meningioma/cirugía , Clasificación del Tumor , PronósticoRESUMEN
Transcription factors that induce epithelial-mesenchymal transition (EMT) promote invasion, chemoresistance and a stem-cell phenotype in epithelial tumors, but their roles in central nervous system tumors are not well-understood. We hypothesized these transcription factors have a functional impact in grades II-III gliomas. Using the National Cancer Institute (NCI) Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the Cancer Genome Atlas (TCGA) Lower-Grade Glioma (LGG) data, we determined the impact of EMT-promoting transcription factors (EMT-TFs) on overall survival in grades II-III gliomas, compared their expression across common genetic subtypes and subsequently validated these findings in a set of 31 tumors using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Increased expression of the gene coding for the transcriptional repressor Zinc Finger E box-binding Homeobox 1 (ZEB1) was associated with a significant increase in overall survival (OS) on Kaplan-Meier analysis. Genetic subtype analysis revealed that ZEB1 expression was relatively increased in IDH1/2-mutant gliomas, and IDH1/2-mutant gliomas expressed significantly lower levels of many ZEB1 transcriptional targets. Similarly, IDH1/2-mutant tumors expressed significantly higher levels of targets of microRNA 200C (MIR200C), a key regulator of ZEB1. In a validation study, ZEB1 mRNA was significantly increased in IDH1-mutant grades II-III gliomas, and ZEB1 protein expression was more pronounced in these tumors. Our findings demonstrate a novel relationship between IDH1/2 mutations and expression of ZEB1 and its transcriptional targets. Therapy targeting ZEB1-associated pathways may represent a novel therapeutic avenue for this class of tumors.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Glioma/metabolismo , Isocitrato Deshidrogenasa/genética , Mutación/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Bases de Datos Factuales/estadística & datos numéricos , Femenino , Glioma/genética , Glioma/mortalidad , Humanos , Isocitrato Deshidrogenasa/metabolismo , Estimación de Kaplan-Meier , Masculino , ARN Mensajero/metabolismo , Estadística como AsuntoRESUMEN
BACKGROUND: IDH mutations have been demonstrated to confer prolonged survival in patients suffering from gliomas, but the mechanisms underlying the improved prognosis are unclear. While some studies have attributed these observations to an enhanced sensitivity to genotoxic therapies, others have postulated that IDH-mutated gliomas exhibit less aggressive intrinsic biological behavior, including the propensity to invade distant sites. Although most gliomas recur local to the site of initial presentation, some tumors demonstrate distant recurrence, the vast majority of which involve the contralateral hemisphere. Trans-tentorial spread has been described once before, in which a supratentorial glioblastoma was reported to recur infratentorially in the cerebellum. CASE PRESENTATION: We describe a patient who underwent surgical resection, followed by adjuvant radiation and temozolomide of a World Health Organization (WHO) III anaplastic astrocytoma in the right temporal lobe, exhibiting an IDH1 (R132H) mutation. Twenty-two months after surgery, he developed a second lesion, located in the right cerebellum, suspicious for recurrent tumor versus radiation necrosis. A second surgery was performed, and pathology demonstrated recurrent tumor, consistent with IDH1-mutated anaplastic astrocytoma. CONCLUSIONS: This is the first example of trans-tentorial spread in an IDH-mutated glioma, suggesting that despite improved survival, IDH mutations may not preclude gliomas from exhibiting the ability to invade distant sites of the brain.
Asunto(s)
Neoplasias Encefálicas/genética , Glioma/genética , Isocitrato Deshidrogenasa/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Adulto , Neoplasias Encefálicas/patología , Glioma/patología , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , PronósticoRESUMEN
Sporadic pituitary adenomas occur in over 10% of the population. Hormone-secreting adenomas, including those causing Cushing's disease (CD), cause severe morbidity and early mortality. Mechanistic studies of CD are hindered by a lack of in vitro models and control normal human pituitary glands. Here, we surgically annotate adenomas and adjacent normal glands in 25 of 34 patients. Using single-cell RNA sequencing (RNA-seq) analysis of 27594 cells, we identify CD adenoma transcriptomic signatures compared with adjacent normal cells, with validation by bulk RNA-seq, DNA methylation, qRT-PCR, and immunohistochemistry. CD adenoma cells include a subpopulation of proliferating, terminally differentiated corticotrophs. In CD adenomas, we find recurrent promoter hypomethylation and transcriptional upregulation of PMAIP1 (encoding pro-apoptotic BH3-only bcl-2 protein noxa) but paradoxical noxa downregulation. Using primary CD adenoma cell cultures and a corticotroph-enriched mouse cell line, we find that selective proteasomal inhibition with bortezomib stabilizes noxa and induces apoptosis, indicating its utility as an anti-tumor agent.
Asunto(s)
Adenoma , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Neoplasias Hipofisarias , Adenoma/metabolismo , Hormona Adrenocorticotrópica/metabolismo , Animales , Apoptosis , Humanos , Ratones , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/genética , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/patología , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/metabolismo , Neoplasias Hipofisarias/patologíaRESUMEN
Pathological sensations caused by peripheral painful neuropathy occurring in Type 2 diabetes mellitus (T2DM) are often described as 'sharp' and 'burning' and are commonly spontaneous in origin. Proposed etiologies implicate dysfunction of nociceptive sensory neurons in dorsal root ganglia (DRG) induced by generation of reactive oxygen species, microvascular defects, and ongoing axonal degeneration and regeneration. To investigate the molecular mechanisms contributing to diabetic pain, DRGs were acquired postmortem from patients who had been experiencing painful diabetic peripheral neuropathy (DPN) and subjected to transcriptome analyses to identify genes contributing to pathological processes and neuropathic pain. DPN occurs in distal extremities resulting in the characteristic "glove and stocking" pattern. Accordingly, the L4 and L5 DRGs, which contain the perikarya of primary afferent neurons innervating the foot, were analyzed from five DPN patients and compared with seven controls. Transcriptome analyses identified 844 differentially expressed genes. We observed increases in levels of inflammation-associated transcripts from macrophages in DPN patients that may contribute to pain hypersensitivity and, conversely, there were frequent decreases in neuronally-related genes. The elevated inflammatory gene profile and the accompanying downregulation of multiple neuronal genes provide new insights into intraganglionic pathology and mechanisms causing neuropathic pain in DPN patients with T2DM.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Neuralgia , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Neuropatías Diabéticas/genética , Ganglios Espinales , Perfilación de la Expresión Génica , Inflamación/genética , Neuralgia/genética , Células Receptoras Sensoriales , TranscriptomaRESUMEN
The clinical significance of partial chromosome 3 alteration in uveal melanoma is still not clear. Also, the reported frequencies vary considerably in the published literature from 0 to 48%. The aims of the following study were to identify the frequency, molecular pathology and potential clinical significance of partial chromosome 3 alteration in uveal melanoma. We studied 47 uveal melanomas with an average follow-up of 36 months. Of these, 14 had confirmed metastasis. Allelic imbalance/loss of heterozygosity was studied using microsatellite markers on chromosome 3 enriched in markers located in the previously reported smallest regions of deletion overlap. Chromosomal alterations were assessed by conventional cytogenetics or comparative genomic hybridization (CGH) in a subset of patients. Utilizing genotyping, partial chromosome 3 alteration was detected in 14/47 tumors (30%). In the 23 tumors with available cytogenetic/CGH, partial chromosome 3 alteration was detected in 8/23 (38%) and was caused by both gains (4/8) and losses (4/8) of chromosome 3 with high frequency of complex chromosome 3 aberrations detected by cytogenetics. Out of the 14 tumors with confirmed metastasis, only 1 showed partial chromosome 3 alteration and the remaining showed monosomy 3. By limiting the aggressive disease marker to monosomy 3, genotyping showed 93% sensitivity and 67% specificity for detection of aggressive uveal melanoma. In conclusion, partial chromosome 3 alterations are common in uveal melanoma and mostly caused by complex cytogenetic changes leading to partial gains and/or partial losses of chromosome 3. Partial chromosome 3 alteration is not likely to be associated with highly aggressive uveal melanoma that metastasizes within the first 3 years after treatment. Microsatellite-based genotyping of chromosome 3 is highly sensitive for detection of aggressive uveal melanoma.
Asunto(s)
Cromosomas Humanos Par 3/genética , Melanoma/genética , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/patología , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Femenino , Genotipo , Historia del Siglo XVII , Humanos , Estimación de Kaplan-Meier , Cariotipificación , Masculino , Melanoma/mortalidad , Melanoma/patología , Invasividad Neoplásica/genética , Invasividad Neoplásica/patología , Reacción en Cadena de la Polimerasa , Neoplasias de la Úvea/mortalidadRESUMEN
We have previously shown that high expression levels of the lipid kinase sphingosine kinase-1 (SphK1) correlate with poor survival of glioblastoma (GBM) patients. In this study we examined the regulation of SphK1 expression by epidermal growth factor receptor (EGFR) signaling in GBM cells. As the EGFR gene is often overexpressed and mutated in GBM, and EGFR has been shown to regulate SphK1 in some cell types, we examined the effect of EGF signaling and the constitutively active EGFRvIII mutant on SphK1 in GBM cells. Treatment of glioma cell lines with EGF led to increased expression and activity of SphK1. Expression of EGFRvIII in glioma cells also activated and induced SphK1. In addition, siRNA to SphK1 partially inhibited EGFRvIII-induced growth and survival of glioma cells as well as ERK MAP kinase activation. To further evaluate the connection between EGFR and SphK1 in GBM we examined primary neurosphere cells isolated from fresh human GBM tissue. The GBM-derived neurosphere cell line GBM9, which forms GBM-like tumors intracranially in nude mice, maintained expression of EGFRvIII in culture and had high levels of SphK1 activity. EGFR inhibitors modestly decreased SphK1 activity and proliferation of GBM9 cells. More extensive blockage of SphK1 activity by a SphK inhibitor, potently blocked cell proliferation and induced apoptotic cell death of GBM9 cells. Thus, SphK1 activity is necessary for survival of GBM-derived neurosphere cells, and EGFRvIII partially utilizes SphK1 to further enhance cell proliferation.
Asunto(s)
Neoplasias Encefálicas/mortalidad , Proliferación Celular/efectos de los fármacos , Receptores ErbB/metabolismo , Regulación Neoplásica de la Expresión Génica/fisiología , Glioblastoma/mortalidad , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Animales , Anexina A5/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Factor de Crecimiento Epidérmico/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioblastoma/patología , Humanos , Ratones , Ratones Desnudos , Mutación/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , ARN Interferente Pequeño/farmacología , Transducción de Señal/efectos de los fármacos , Factores de TiempoRESUMEN
Hereditary cancer predisposition syndromes (HCS) become more recognizable as the knowledge about them expands, and genetic testing becomes more affordable. In this review, we discussed the known HCS that predispose to central and peripheral nervous system tumors. Different genetic phenomena were highlighted, and the important cellular biological alterations were summarized. Genetic mosaicism and germline mutations are features of HCS, and recently, they were described in normal population and as modifiers for the genetic landscape of sporadic tumors. Description of the tumors arising in these conditions was augmented by representative cases explaining the main pathological findings. Clinical spectrum of the syndromes and diagnostic criteria were tabled to outline their role in defining these disorders. Interestingly, precision medicine has found its way to help these groups of patients by offering targeted preventive measures. Understanding the signaling pathway alteration of mammalian target of rapamycin (mTOR) in tuberous sclerosis helped introducing mTOR inhibitors as a prophylactic treatment in these patients. More research to define the germline genetic alterations and resulting cellular signaling perturbations is needed for effective risk-reducing interventions beyond prophylactic surgeries.
Asunto(s)
Síndromes Neoplásicos Hereditarios , Neoplasias del Sistema Nervioso Periférico , Esclerosis Tuberosa , Predisposición Genética a la Enfermedad/genética , Humanos , Mutación , Síndromes Neoplásicos Hereditarios/genética , Esclerosis Tuberosa/genéticaRESUMEN
Molecular mechanisms of malignant transformation in spinal cord gliomas are not well-understood. Our objective was to investigate genetic causes of malignant transformation in a primary spinal cord glioma. A 32-year-old female patient presented with bilateral lower extremity weakness and was diagnosed with a primary spinal cord glioma from T9 to T12, with a syrinx extending from the craniocervical junction to the conus. She underwent resection in 2006. Pathology showed an abundance of Rosenthal fibers, calcification and degenerative features consistent with a low-grade pilocytic astrocytoma. She presented in 2020 with tumor recurrence and underwent re-resection. Whole exome sequencing, DNA methylation profiling and immunohistochemistry were performed on her initial and recurrent tumor samples. Immunohistochemical profiling of her recurrent tumor showed pleomorphic cells with extensive necrosis consistent with a high-grade glioma. DNA methylation profiling showed that the initial tumor clustered with pilocytic astrocytomas, whereas the recurrent lesion clustered with anaplastic astrocytomas, confirming malignant transformation. Whole-exome sequencing showed interim acquisition of a rare fibroblast growth factor receptor-transforming acidic coiled-coil (FGFR1-TACC1) gene fusion. We report an FGFR1-TACC1 fusion associated with malignant transformation in a primary spinal cord glioma. Our study adds to growing reports of FGFR-TACC fusions, which are amenable to receptor tyrosine kinase inhibition.
RESUMEN
BACKGROUND: Despite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor-treating fields, the median survival of glioblastoma (GBM) patients is less than 15 months. Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric dimethylation of arginine residues and is overexpressed in GBM. Inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. LB100, a first-in-class small molecular inhibitor of protein phosphatase 2A (PP2A), can sensitize therapy-resistant tumor cells. Here, we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition. METHODS: Patient-derived primary GBM neurospheres (GBMNS), transfected with PRMT5 target-specific siRNA, were treated with LB100 and subjected to in vitro assays including PP2A activity and western blot. The intracranial mouse xenograft model was used to test the in vivo antitumor efficacy of combination treatment. RESULTS: We found that PRMT5 depletion increased PP2A activity in GBMNS. LB100 treatment significantly reduced the viability of PRMT5-depleted GBMNS compared to PRMT5-intact GBMNS. LB100 enhanced G1 cell cycle arrest induced by PRMT5 depletion. Combination therapy also increased the expression of phospho-MLKL. Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100, indicating that necroptosis caused the enhanced cytotoxicity of combination therapy. In the in vivo mouse tumor xenograft model, LB100 treatment combined with transient depletion of PRMT5 significantly decreased tumor size and prolonged survival, while LB100 treatment alone had no survival benefit. CONCLUSION: Overall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone.
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Glioblastoma , Animales , Línea Celular Tumoral , Glioblastoma/tratamiento farmacológico , Humanos , Ratones , Piperazinas , Proteína Fosfatasa 2 , Proteína-Arginina N-Metiltransferasas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The glial glutamate transporter EAAT2 (excitatory amino acid transporter 2) is the major mediator of glutamate clearance that terminates glutamate-mediated neurotransmission. Loss of EAAT2 and associated glutamate uptake function has been reported in the brains of patients with Alzheimer's disease (AD). We previously reported that EAAT2 is associated with lipid raft microdomains of the plasma membrane. In the present study, we demonstrated that association of EAAT2 with lipid rafts is disrupted in AD brains. This abnormality is not a consequence of neuron degeneration, oxidative stress, or amyloid beta toxicity. In AD brains, cholesterol 24S-hydroxylase (CYP46), a key enzyme in maintenance of cholesterol homeostasis in the brain, is markedly increased in astrocytes but decreased in neurons. We demonstrated that increased expression of CYP46 in primary astrocytes results in a reduction of membrane cholesterol levels and leads to the dissociation of EAAT2 from lipid rafts and the loss of EAAT2 and associated glutamate uptake function. These results suggest that a disturbance of cholesterol metabolism may contribute to loss of EAAT2 in AD.
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Enfermedad de Alzheimer/metabolismo , Astrocitos/metabolismo , Encéfalo/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Microdominios de Membrana/metabolismo , Esteroide Hidroxilasas/metabolismo , Anciano , Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiopatología , Química Encefálica/fisiología , Colesterol/metabolismo , Colesterol 24-Hidroxilasa , Ácido Glutámico/metabolismo , Humanos , Regulación hacia Arriba/fisiologíaRESUMEN
Biologically, the site of arthrodesis provides a microenvironment replete of growth factors and active remodeling, which is propitious for bone regrowth. There is a theoretical possibility though that this microenvironment would also provide a fertile site for metastatic deposits to occur. Although spinal fusion with various types of instrumentation is commonly used to treat various disorders, development of tumors at the site of spinal arthrodesis has not been previously reported. We present the clinical, radiographic, and pathological features of a case of previously undiagnosed metastatic adenocarcinoma, occurring 1 year following anterior arthrodesis and fusion for cervical spondylotic myelopathy at the C3-C4 level. The patient's initial radiologic presentation suggested an epidural abscess with osteomyelitic destruction of C3 and C4. Our report alerts surgeons to the possibility that metastasis may occur at the site of a previous spinal arthrodesis.
Asunto(s)
Adenocarcinoma/secundario , Artrodesis/efectos adversos , Neoplasias Pulmonares/patología , Fusión Vertebral/efectos adversos , Neoplasias de la Columna Vertebral/secundario , Espondilosis/cirugía , Adenocarcinoma/cirugía , Regeneración Ósea/fisiología , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/patología , Vértebras Cervicales/cirugía , Quimiotaxis/fisiología , Descompresión Quirúrgica , Progresión de la Enfermedad , Discectomía/efectos adversos , Resultado Fatal , Humanos , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Desplazamiento del Disco Intervertebral/diagnóstico por imagen , Desplazamiento del Disco Intervertebral/patología , Desplazamiento del Disco Intervertebral/cirugía , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/fisiopatología , Metástasis de la Neoplasia/prevención & control , Procedimientos Neuroquirúrgicos , Osteogénesis/fisiología , Radiografía , Reoperación , Compresión de la Médula Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/patología , Compresión de la Médula Espinal/cirugía , Fusión Vertebral/métodos , Neoplasias de la Columna Vertebral/cirugía , Estenosis Espinal/diagnóstico por imagen , Estenosis Espinal/patología , Estenosis Espinal/cirugía , Espondilosis/diagnóstico por imagen , Espondilosis/patología , Resultado del TratamientoRESUMEN
Metastases are the most common intracranial tumors in adults. Lung cancer, melanoma, renal cell carcinoma, and breast cancer are the most common primary tumors that metastasize to the brain. Improved detection of small metastases by MRI, and improved systemic therapy for primary tumors, resulted in increased incidence of brain metastasis. Advances in neuroanesthesia and neurosurgery have significantly improved the safety of surgical resection of brain metastases. Surgical approach and active management have become applicable for many patients. Subsequently, brain metastases diagnosis no longer equals palliative treatment. Moreover, the demand for diagnosing brain masses has increased with its associated challenges.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/patología , Encéfalo/patología , Humanos , Carcinomatosis Meníngea/diagnóstico , Carcinomatosis Meníngea/patologíaRESUMEN
OBJECTIVE: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS). BACKGROUND: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies. DESIGN/METHODS: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B. RESULTS: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results. INTERPRETATION: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies.
Asunto(s)
Epilepsia Refractaria , Epilepsia del Lóbulo Temporal , Herpesvirus Humano 6/patogenicidad , Hipocampo/patología , Adulto , Lobectomía Temporal Anterior , ADN Viral/aislamiento & purificación , Epilepsia Refractaria/etiología , Epilepsia Refractaria/patología , Epilepsia Refractaria/cirugía , Epilepsia Refractaria/virología , Epilepsia del Lóbulo Temporal/etiología , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/cirugía , Epilepsia del Lóbulo Temporal/virología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Esclerosis/patología , Método Simple CiegoRESUMEN
Neurofibromatosis type 2 (NF2) is an autosomal dominant Mendelian tumor predisposition disorder caused by germline pathogenic variants in the tumor suppressor NF2. Meningiomas are the second most common neoplasm in NF2, often occurring in multiple intracranial and spinal locations within the same patient. In this prospective longitudinal study, we assessed volumes and growth rates of ten spinal and ten cranial benign meningiomas in seven NF2 patients that concluded with surgical resection and performed whole-exome sequencing and copy-number variant (CNV) analysis of the tumors. Our comparison of the volume and the growth rate of NF2-associated spinal and cranial meningiomas point to the differences in timing of tumor initiation and/or to the differences in tumor progression (e.g., non-linear, saltatory growth) at these two anatomical locations. Genomic investigation of these tumors revealed that somatic inactivation of NF2 is the principal and perhaps the only driver of tumor initiation; and that tumor progression likely occurs via accumulation of CNVs, rather than point mutations. Results of this study contribute to a better understanding of NF2-associated meningiomas clinical behavior and their genetic underpinnings.