Novel role of the nociceptin system as a regulator of glutamate transporter expression in developing astrocytes.

Our previous results showed that oligodendrocyte development is regulated by both nociceptin and its G-protein coupled receptor, the nociceptin/orphanin FQ receptor (NOR). The present in vitro and in vivo findings show that nociceptin plays a crucial conserved role regulating the levels of the glutamate/aspartate transporter GLAST/EAAT1 in both human and rodent brain astrocytes. This nociceptin-mediated response takes place during a critical developmental window that coincides with the early stages of astrocyte maturation. GLAST/EAAT1 upregulation by nociceptin is mediated by NOR and the downstream participation of a complex signaling cascade that involves the interaction of several kinase systems, including PI-3K/AKT, mTOR, and JAK. Because GLAST is the main glutamate transporter during brain maturation, these novel findings suggest that nociceptin plays a crucial role in regulating the function of early astrocytes and their capacity to support glutamate homeostasis in the developing brain.

m6A mRNA Modifications in Glioblastoma: Emerging Prognostic Biomarkers and Therapeutic Targets.

Glioblastoma, the most common and aggressive primary brain tumor, is highly invasive and neurologically destructive. The mean survival for glioblastoma patients is approximately 15 months and there is no effective therapy to significantly increase survival times to date. The development of effective therapy including mechanism-based therapies is urgently needed. At a molecular biology level, N6-methyladenine (m6A) mRNA modification is the most abundant posttranscriptional RNA modification in mammals. Recent studies have shown that m6A mRNA modifications affect cell survival, cell proliferation, invasion, and immune evasion of glioblastoma. In addition, m6A mRNA modifications are critical for glioblastoma stem cells, which could initiate the tumor and lead to therapy resistance. These findings implicate the function of m6A mRNA modification in tumorigenesis and progression, implicating its value in prognosis and therapies of human glioblastoma. This review focuses on the potential clinical significance of m6A mRNA modifications in prognostic and therapeutics of glioblastoma. With the identification of small-molecule compounds that activate or inhibit components of m6A mRNA modifications, a promising novel approach for glioblastoma therapy is emerging.

A 42-Year-Old Woman With Rapidly Expanding White Matter Lesions: From the National Multiple Sclerosis Society Case Conference Proceedings.

A 42-year-old woman and active cocaine user complained of subacutely worsening blurred vision and imbalance. Examination of the brain MRI showed rapidly expanding white matter lesions. Brain biopsy was consistent with inflammatory demyelination. Given an unusual presentation and a history of cocaine use, a broad differential diagnosis was considered including neurologic toxidromes.

USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5.

BACKGROUND: ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability. METHODS: The contribution of deubiquitinating enzymes (DUB) to the fluctuation of ALKBH5 protein expression was globally profiled with western blot analysis. Mass spectrometry and immunoprecipitation were performed to identify the USP36 and ALKBH5 interaction. The effects of USP36 on the stability of ALKBH5 were detected with in vivo and in vitro ubiquitination assays. Cell proliferation assays, neurosphere formation, limited dilution assay, and intracranial tumor growth assays were implemented to assess the collaborative capacities of USP36 and ALKBH5 in tumorigenesis. RESULTS: Ubiquitin-specific peptidase 36 (USP36), as a potential ALKBH5-activating DUB, played an essential role in stabilization of ALKBH5 and regulation of ALKBH5-mediated gene expression in glioblastoma. The depletion of USP36 drastically impaired cell proliferation deteriorated the self-renewal of GSCs and sensitized GSCs to temozolomide (TMZ) treatment. Furthermore, the deletion of USP36 substantially decreased the in vivo tumor growth when monitored by bioluminescence imaging. Our findings indicate that USP36 regulates the protein degradation and expression of ALKBH5, and the USP36-ALKBH5 axis orchestrates glioma tumorigenesis. CONCLUSION: Our findings identify USP36 as a DUB of ALKBH5 and its role in glioblastoma progression, which may serve as a potential therapeutic target for glioblastoma treatment.

Casein Kinase 2 Mediates HIV- and Opioid-Induced Pathologic Phosphorylation of TAR DNA Binding Protein 43 in the Basal Ganglia.

SUMMARY STATEMENT: HIV/HIV-1 Tat and morphine independently increase pathologic phosphorylation of TAR DNA binding protein 43 in the striatum. HIV- and opioid-induced pathologic phosphorylation of TAR DNA binding protein 43 may involve enhanced CK2 activity and protein levels.

The Roles and Regulation of m6A Modification in Glioblastoma Stem Cells and Tumorigenesis.

Glioblastoma is the most common and most lethal primary malignant brain tumor. N6-methyladenosine (m6A) is a widespread and abundant internal messenger RNA (mRNA) modification found in eukaryotes. Accumulated evidence demonstrates that m6A modification is aberrantly activated in human cancers and is critical for tumorigenesis and metastasis. m6A modification is also strongly involved in key signaling pathways and is associated with prognosis in glioblastoma. Here, we briefly outline the functions of m6A and its regulatory proteins, including m6A writers, erasers, and readers of the fate of RNA. We also summarize the latest breakthroughs in this field, describe the underlying molecular mechanisms that contribute to the tumorigenesis and progression, and highlight the inhibitors targeting the factors in m6A modification in glioblastoma. Further studies focusing on the specific pathways of m6A modification could help identify biomarkers and therapeutic targets that might prevent and treat glioblastoma.

Resolution and Re-ossification of Orbital-Wall Langerhans Cell Histiocytosis Following Stereotactic Needle Biopsy.

Introduction Langerhans cell histiocytosis (LCH) is a rare disease that encompasses a spectrum of clinical syndromes. It is characterized by the proliferation and infiltration of white blood cells into organs or organ systems. Reports of management of these lesions have included biopsy, resection, curettage, radiation, and/or chemotherapy. Case Presentation A 40-year-old man presented with a history of right proptosis and retro-orbital pain and was found to have a lytic mass involving the greater wing of the sphenoid extending into the right orbit. A stereotactic needle biopsy using neuronavigation demonstrated this to be LCH. After no further treatment, the mass spontaneously resolved, with virtual normalization of the orbital magnetic resonance imaging at 10 months following the needle biopsy. The bony defect of the temporal bone caused by the mass also re-ossified following the needle biopsy. Discussion This report highlights the potential for an isolated LCH lesion to regress after simple needle biopsy, an outcome only rarely reported previously. Thus, expectant management of such lesions following biopsy or initial debridement should be considered prior to proceeding with additional treatment.

Critical role of lncEPAT in coupling dysregulated EGFR pathway and histone H2A deubiquitination during glioblastoma tumorigenesis.

Histone 2A (H2A) monoubiquitination is a fundamental epigenetics mechanism of gene expression, which plays a critical role in regulating cell fate. However, it is unknown if H2A ubiquitination is involved in EGFR-driven tumorigenesis. In the current study, we have characterized a previously unidentified oncogenic lncRNA (lncEPAT) that mediates the integration of the dysregulated EGFR pathway with H2A deubiquitination in tumorigenesis. LncEPAT was induced by the EGFR pathway, and high-level lncEPAT expression positively correlated with the glioma grade and predicted poor survival of glioma patients. Mass spectrometry analyses revealed that lncEPAT specifically interacted with deubiquitinase USP16. LncEPAT inhibited USP16's recruitment to chromatin, thereby blocking USP16-mediated H2A deubiquitination and repressing target gene expression, including CDKN1A and CLUSTERIN. Depletion of lncEPAT promoted USP16-induced cell cycle arrest and cellular senescence, and then repressed GBM cell tumorigenesis. Thus, the EGFR-lncEPAT-ubH2A coupling represents a previously unidentified mechanism for epigenetic gene regulation and senescence resistance during GBM tumorigenesis.

Aggressive vertebral hemangioma masquerading as neurological disease in a pediatric patient.

Aggressive hemangioma is a rare vertebral lesion in pediatric patients which can present with deteriorating neurological function. It can mimic malignancy on imaging, particularly as it regularly has an extrasosseous soft tissue component. We present a case of a 13-year-old male who presented with a three month history of lower extremity weakness that was found to have an infiltrative mass at T10 with associated cord compression from epidural extension of the lesion. In this report we review the characteristic imaging findings associated with aggressive hemangioma, including its appearance on read-out segmented diffusion-weighted images. It is imperative that radiologists who interpret studies of children be aware that this lesion exists and what it looks like, as it can be associated with massive hemorrhage if encountered unexpectedly during surgery.

Dystrophic muscle distribution in late-stage muscular dystrophy.

There is scant information about the comprehensive distribution of dystrophic muscles in muscular dystrophy. Despite different clinical presentations of muscular dystrophy, a recent multi-center study concluded that phenotypic distribution of dystrophic muscles is independent of clinical phenotype and suggested that there is a common pattern of involved muscles. To evaluate this possibility, the present case report used cadaveric dissection to determine the whole-body distribution of fat-infiltrated, dystrophic muscles from a 72-year-old white male cadaver with adult-onset, late-stage muscular dystrophy. Severely dystrophic muscles occupied the pectoral, gluteal and pelvic regions, as well as the arm, thigh and posterior leg. In contrast, muscles of the head, neck, hands and feet largely appeared unaffected. Histopathology and a CT-scan supported these observations. This pattern of dystrophic muscles generally conformed with that described in the multi-center study, and provides prognostic insight for patients and the physicians treating them.

Lynch syndrome-associated ultra-hypermutated pediatric glioblastoma mimicking a constitutional mismatch repair deficiency syndrome.

Pediatric glioblastoma multiforme (GBM) has a poor prognosis as a result of recurrence after treatment of surgery and radiochemotherapy. A small subset of pediatric GBMs presenting with an ultra-high tumor mutational burden (TMB) may be sensitive to immune checkpoint inhibition. Here we report a 16-yr-old male with an ultra-hypermutated GBM. After incomplete surgical resection, molecular analysis of the tumor identified unusually high numbers of mutations and intratumor heterogeneity by a hotspot next-generation sequencing (NGS) panel. Further comprehensive molecular profiling identified a TMB of 343 mutations/Mb. An ultra-hypermutation genotype in pediatric GBMs is suggestive of a constitutive mismatch repair deficiency syndrome (CMMRD), which often acquires additional somatic driver mutations in replicating DNA polymerase genes. Tumor sequencing identified two MSH6 nonsense variants, a hotspot POLE mutation and a mutational signature supportive of a germline MMR deficiency with a somatic POLE mutation. However, constitutional testing identified only one nonsense MSH6 variant consistent with a Lynch syndrome diagnosis. This case represents the first confirmed Lynch syndrome case mimicking CMMRD by manifesting as an ultra-hypermutated pediatric GBM, following somatic mutations in MSH6 and POLE These findings permitted the patient's enrollment in an anti-PD-1 clinical trial for children with ultra-hypermutated GBM. Immunotherapy response has resulted in the patient's stable condition for over more than 1 year postdiagnosis.

Multiple extraspinal recurrences of ependymoma 13 years after spinal cordectomy: case report.

Ependymomas of the spinal cord remain confined to the CNS and vary in presentation, depending on WHO grade. Higher-grade lesions usually cannot be surgically removed due to their infiltrative growth pattern. Spinal cordectomy has been proposed as a rescue treatment to improve survival in patients with high-grade as well as recurrent lesions. This report details an instructive and unique case of long-term follow-up of a patient who underwent cordectomy from T-4 through S-5 for what was initially diagnosed as a high-grade glial neoplasm of the spinal cord in 1993. The patient lived symptom free for 13 years after spinal cord resection and then presented with numerous bilateral extraspinal (intraabdominal and intrathoracic) tumors, which eventually led to her death 15 years after the cordectomy. In this case, spinal cordectomy was effective in preventing the ascending spread of the neoplasm, but ultimately not effective in preventing recurrence in the plicated distal dural sac.

An unusual case of schwannomatosis with bilateral maxillary sinus schwannomas and a novel SMARCB1 gene mutation.

Schwannomas are benign tumors that arise from Schwann cells in the peripheral nervous system. Patients with multiple schwannomas without signs and symptoms of neurofibromatosis Type 1 or 2 have the rare disease schwannomatosis. Tumors in these patients occur along peripheral nerves throughout the body. Mutations of the SMARCB1 gene have been described as one of the predisposing genetic factors in the development of this disease. This report describes a patient who was observed for 6 years after having undergone removal of 7 schwannomas, including bilateral maxillary sinus schwannomas, a tumor that has not been previously reported. Genetic analysis revealed a novel mutation of c.93G>A in exon 1 of the SMARCB1 gene.

Congenital oligodendroglioma: clinicopathologic and molecular assessment with review of the literature.

Oligodendroglioma is an infiltrating glial neoplasm frequently seen in adults. Pediatric oligodendrogliomas are rare, with very few cases presenting in infancy and only rare congenital examples. In contrast to adult oligodendrogliomas, pediatric cases typically lack 1p/19q codeletion. Herein we report a case of WHO grade II oligodendroglioma diagnosed in a 7-month-old male infant. The patient initially presented at 3 months of age with symptoms suspicious for seizure. Initial workup including electroencephalography (EEG), electrocardiogram (EKG), and computed tomography (CT) of the head was negative. His symptoms persisted, and subsequent magnetic resonance imaging (MRI) performed at age of 7 months revealed a 2 cm contrast-enhancing left temporal lobe mass. The mass was excised and the microscopic appearance was that of a classic low grade oligodendroglioma composed of cells with uniformly round nuclei, perinuclear halos, delicate branching capillaries, and an absence of high grade features. Mutant specific (R132H) isocitrate dehydrogenase-1 (IDH1) immunohistochemistry was negative, and the tumor lacked detectable 1p or 19q deletions by fluorescent in situ hybridization (FISH). The onset of neurological symptoms in early infancy followed by the positive MRI findings suggests that this case represents a rare example of congenital oligodendroglioma.

Dystrophic muscle distribution in late-stage muscular dystrophy

There is scant information about the comprehensive distribution of dystrophic muscles in muscular dystrophy. Despite different clinical presentations of muscular dystrophy, a recent multi-center study concluded that phenotypic distribution of dystrophic muscles is independent of clinical phenotype and suggested that there is a common pattern of involved muscles. To evaluate this possibility, the present case report used cadaveric dissection to determine the whole-body distribution of fat-infiltrated, dystrophic muscles from a 72-year-old white male cadaver with adult-onset, late-stage muscular dystrophy. Severely dystrophic muscles occupied the pectoral, gluteal and pelvic regions, as well as the arm, thigh and posterior leg. In contrast, muscles of the head, neck, hands and feet largely appeared unaffected. Histopathology and a CT-scan supported these observations. This pattern of dystrophic muscles generally conformed with that described in the multi-center study, and provides prognostic insight for patients and the physicians treating them.

Acid resistance in Escherichia coli.

To colonize and cause disease, enteric pathogens must overcome environmental challenges that include acid stress in the host's stomach as well as short-chain fatty acid stress in the intestine of the host and reservoir. Three known inducible systems have evolved for stationary phase acid resistance in E. coli. These systems each provide a different level of protection with different requirements and induction conditions. Acid resistance system 1 (AR1) is acid induced in stationary phase, requires the presence of RpoS, and provides the least level of protection at pH 2.5. Acid resistance system 2 (AR2) is glutamate dependent and stationary phase induced, requires the presence of glutamate decarboxylase and a putative glutamate:GABA antiporter, and provides the highest level of protection. Acid resistance system 3 (AR3) is arginine dependent and acid induced under anaerobic conditions, requires the presence of arginine decarboxylase (AdiA), and provides only a modest level of protection. These three systems along with log phase acid tolerance protect cells from the acid stresses in both the reservoir and host, which can range from pH 2 to 4.5. They also protect against acid stress involved in food processing and facilitate the low infectious dose characteristic of E. coli, significantly contributing to the pathogenesis of this organism.

Gliomatosis cerebri: report of 3 cases.

Gliomatosis cerebri is an uncommon glial neoplasm that is exceedingly rare in children and difficult to diagnose. The authors describe the presentation and diagnosis of GC in 3 children ages 12, 14, and 16 years. These children exhibited signs and symptoms of increased intracranial pressure as well as other vague or site specific neurological signs. Because clinical presentation, CSF analysis, and neuroimaging were nonspecific, a stereotactic biopsy to obtain tissue for pathological review was ultimately necessary to confirm the diagnosis. These pediatric cases underscore the limitations of relying solely on clinical presentation and neuroimaging and call to attention the essential role of neurosurgical intervention. The authors emphasize the need to maintain gliomatosis cerebri in the differential diagnosis of children presenting with diffuse neurological signs and MR imaging evidence of widespread, infiltrative lesions.