22 research outputs found
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Recurrent non-canonical histone H3 mutations in spinal cord diffuse gliomas.
Amiloride Improves Locomotor Recovery after Spinal Cord Injury
Amiloride is a drug approved by the United States Food and Drug Administration, which has shown neuroprotective effects in different neuropathological conditions, including brain injury or brain ischemia, but has not been tested in spinal cord injury (SCI). We tested amiloride's therapeutic potential in a clinically relevant rat model of contusion SCI inflicted at the thoracic segment T10. Rats receiving daily administration of amiloride from 24 h to 35 days after SCI exhibited a significant improvement in hindlimb locomotor ability at 21, 28, and 35 days after injury, when compared to vehicle-treated SCI rats. Rats receiving amiloride treatment also exhibited a significant increase in myelin oligodendrocyte glycoprotein (MOG) levels 35 days after SCI at the site of injury (T10) when compared to vehicle-treated controls, which indicated a partial reverse in the decrease of MOG observed with injury. Our data indicate that higher levels of MOG correlate with improved locomotor recovery after SCI, and that this may explain the beneficial effects of amiloride after SCI. Given that amiloride treatment after SCI caused a significant preservation of myelin levels, and improved locomotor recovery, it should be considered as a possible therapeutic intervention after SCI
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DNA methylation profiling demonstrates superior diagnostic classification to RNA-sequencing in a case of metastatic meningioma.
Meningiomas are the most common primary intracranial tumors, but meningioma metastases are rare. Accordingly, the clinical workup, diagnostic testing, and molecular classification of metastatic meningioma is incompletely understood. Here, we present a case report of multiply recurrent meningioma complicated by liver metastasis. We discuss the patient presentation, imaging findings, and conventional histopathologic characterization of both the intracranial lesion and the metastatic focus. Further, we perform multiplatform molecular profiling, comprised of DNA methylation arrays and RNA-sequencing, of six stereotactically-guided samples from the intracranial meningioma and a single ultrasound-guided liver metastasis biopsy. Our results show that DNA methylation clusters distinguish the liver metastasis from the intracranial meningioma samples, and identify a small focus of hepatocyte contamination with the liver biopsy. Nonetheless, DNA methylation-based classification accurately identifies the liver metastasis as a meningioma with high confidence. We also find that clustering of RNA-sequencing results distinguishes the liver metastasis from the intracranial meningiomas samples, but that differential gene expression classification is confounded by hepatocyte-specific gene expression programs in the liver metastasis. In sum, this case report sheds light on the comparative biology of intracranial and metastatic meningioma. Furthermore, our results support methylation-based classification as a robust method of diagnosing metastatic lesions, underscore the broad utility of DNA methylation array profiling in diagnostic pathology, and caution against the routine use of bulk RNA-sequencing for identifying tumor signatures in heterogeneous metastatic lesions
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DNA methylation profiling demonstrates superior diagnostic classification to RNA-sequencing in a case of metastatic meningioma.
Meningiomas are the most common primary intracranial tumors, but meningioma metastases are rare. Accordingly, the clinical workup, diagnostic testing, and molecular classification of metastatic meningioma is incompletely understood. Here, we present a case report of multiply recurrent meningioma complicated by liver metastasis. We discuss the patient presentation, imaging findings, and conventional histopathologic characterization of both the intracranial lesion and the metastatic focus. Further, we perform multiplatform molecular profiling, comprised of DNA methylation arrays and RNA-sequencing, of six stereotactically-guided samples from the intracranial meningioma and a single ultrasound-guided liver metastasis biopsy. Our results show that DNA methylation clusters distinguish the liver metastasis from the intracranial meningioma samples, and identify a small focus of hepatocyte contamination with the liver biopsy. Nonetheless, DNA methylation-based classification accurately identifies the liver metastasis as a meningioma with high confidence. We also find that clustering of RNA-sequencing results distinguishes the liver metastasis from the intracranial meningiomas samples, but that differential gene expression classification is confounded by hepatocyte-specific gene expression programs in the liver metastasis. In sum, this case report sheds light on the comparative biology of intracranial and metastatic meningioma. Furthermore, our results support methylation-based classification as a robust method of diagnosing metastatic lesions, underscore the broad utility of DNA methylation array profiling in diagnostic pathology, and caution against the routine use of bulk RNA-sequencing for identifying tumor signatures in heterogeneous metastatic lesions
Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy
Summary: Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin’s E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder
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Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma.
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Recurrent KBTBD4 small in-frame insertions and absence of DROSHA deletion or DICER1 mutation differentiate pineal parenchymal tumor of intermediate differentiation (PPTID) from pineoblastoma.
High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis.
High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features