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.

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.

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.

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.

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.

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.

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.

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.

Pediatric gliomatosis cerebri mimicking acute disseminated encephalomyelitis.

Gliomatosis cerebri (GC) is a diffuse infiltrating glial neoplasm of astrocytic origin. GC in children is rare and difficult to diagnose, often presenting with a variety of signs and symptoms that may mimic encephalitis. We discuss here the presentation and diagnosis of GC in 2 children who were initially suspected to have acute disseminating encephalomyelitis. In this report we underscore the limitations of relying on clinical presentation and neuroimaging as well as the essential role of pathologic evaluation for the diagnosis of GC in children.

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.