Dematin inhibits glioblastoma malignancy through RhoA-mediated CDKs downregulation and cytoskeleton remodeling.

Glioblastoma multiforme (GBM) is well known as a highly aggressive brain tumor subtype. Here, we show that overexpression (OE) of dematin actin-binding protein (DMTN) inhibits GBM proliferation and invasion by affecting cell cycle regulation and actin remodeling, respectively. RT-qPCR, western blotting, and immunohistochemical (IHC) staining demonstrated a significant reduction in DMTN expression in gliomas, especially in high-grade gliomas (HGG) compared with normal brains, which correlates with worse survival in HGG patients. Functional studies revealed inhibitory effects of DMTN on tumor proliferation and migratory capacities. The attenuation in tumor proliferative ability upon DMTN OE was accompanied by RhoA suppression and CDK1, CDK2, CDK4, and cyclin D1 downregulation, while RhoA rescue restored the proliferative phenotype. Meanwhile, overexpression of DMTN produced profoundly disorganized stress fibers, which led to impaired tumor invasion. Furthermore, DMTN overexpression produced substantial suppression of tumor growth upon subcutaneous and intracranial implantation in mice, and this was accompanied by significantly reduced vinculin expression and Ki67 positivity. Taken together, these findings demonstrate the role of DMTN in regulating GBM cell proliferation, actin cytoskeleton, and cell morphology and identify DMTN as a vital tumor suppressor in GBM progression.

Super-resolution of brain tumor MRI images based on deep learning.

INTRODUCTION: To explore and evaluate the performance of MRI-based brain tumor super-resolution generative adversarial network (MRBT-SR-GAN) for improving the MRI image resolution in brain tumors. METHODS: A total of 237 patients from December 2018 and April 2020 with T2-fluid attenuated inversion recovery (FLAIR) MR images (one image per patient) were included in the present research to form the super-resolution MR dataset. The MRBT-SR-GAN was modified from the enhanced super-resolution generative adversarial networks (ESRGAN) architecture, which could effectively recover high-resolution MRI images while retaining the quality of the images. The T2-FLAIR images from the brain tumor segmentation (BRATS) dataset were used to evaluate the performance of MRBT-SR-GAN contributed to the BRATS task. RESULTS: The super-resolution T2-FLAIR images yielded a 0.062 dice ratio improvement from 0.724 to 0.786 compared with the original low-resolution T2-FLAIR images, indicating the robustness of MRBT-SR-GAN in providing more substantial supervision for intensity consistency and texture recovery of the MRI images. The MRBT-SR-GAN was also modified and generalized to perform slice interpolation and other tasks. CONCLUSIONS: MRBT-SR-GAN exhibited great potential in the early detection and accurate evaluation of the recurrence and prognosis of brain tumors, which could be employed in brain tumor surgery planning and navigation. In addition, this technique renders precise radiotherapy possible. The design paradigm of the MRBT-SR-GAN neural network may be applied for medical image super-resolution in other diseases with different modalities as well.

Guideline conformity to the Stupp regimen in patients with newly diagnosed glioblastoma multiforme in China.

Aims: To determine how consistently Chinese glioblastoma multiforme (GBM) patients were treated according to the Stupp regimen. Patients and methods: The proportion of treatments conforming to the Stupp regimen and reasons for nonconformity were evaluated in 202 newly diagnosed GBM patients. Results: Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations were temozolomide dosages >75 mg/m2 (58/120; 48.3%) and treatment durations <42 days (84/120; 70.0%) in the concomitant phase and temozolomide dosages <150 mg/m2 (89/101; 88.1%) in the maintenance phase. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments. Conclusion: Increased conformity to the Stupp regimen is needed for GBM patients in China.

Lay abstract In 2005 the European Organization for Research and Treatment of Cancer 26981 study led to US FDA approval for the use of temozolomide in combination with radiotherapy to treat glioblastoma multiforme (GBM). The Stupp regimen consists of fractionated focal irradiation in daily fractions of 2 Gy given 5 days/week for 6 weeks (a total of 60 Gy), plus concomitant daily temozolomide (75 mg/m²/day, 7 days/week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150­200 mg/m²/day for 5 days during each 28-day cycle). In 2012 the Chinese guidelines for the diagnosis and treatment of glioma of the CNS recommended the Stupp regimen as first-line therapy for newly diagnosed GBM. In the present study, compliance of GBM treatments with the Stupp regimen in 28 Chinese centers from 2012­2016 was evaluated. Only 15.8% of GBM patients received treatments compliant with the Stupp regimen. The main deviations related to temozolomide dosages and treatment durations in the concomitant and maintenance phases. Median overall survival (27.09 vs 18.21 months) and progression-free survival (14.27 vs 12.10 months) were longer in patients who received Stupp regimen-compliant treatments.

Chordoid Glioma: A Neoplasm Found in the Anterior Part of the Third Ventricle.

ABSTRACT: Chordoid glioma is a rare low-grade tumor that originates almost exclusively in the anterior part of the third ventricle. The diagnosis and treatment of the tumor remain controversial. In this article, the authors present a novel case of chordoid glioma of the third ventricle. The patient was treated with less invasive microsurgery followed by low-dose gamma knife radiosurgery. Magnetic resonance imaging revealed a decrease in tumor size and necrosis in the central region of the tumor, without significant complications at follow-up 14 months later. Based on these findings, the authors suggest that less invasive microsurgical resection followed by low-dose gamma knife radiosurgery is safe and effective for the treatment of chordoid glioma of the third ventricle.

Upregulated AHIF-mediated radioresistance in glioblastoma.

Long non-coding RNAs (lncRNAs) play vital roles in the pathobiology of glioblastoma multiforme (GBM). Though radiotherapy remains the most effective component of multiple therapies for patients with GBM, lncRNAs conferring GBM radioresistance are less unknown. Here, the present study identified that the antisense transcript of hypoxia-inducible factor-1α (AHIF) was upregulated in GBM cells after radiotherapy. The deregulation of AHIF affected GBM cell clonogenic formation, DNA repair and apoptosis. Notably, knockdown of AHIF inhibited tumorigenesis after radiotherapy in vivo. Further biochemical analysis identified that AHIF regulated proteins associated with apoptosis after radiotherapy. Thus, the present data illustrate that suppression of AHIF increases radiosensitivity in GBM cells, which may be a potential diagnostic and therapeutic target for GBM patients.

Histone methyltransferase SUV39H2 regulates cell growth and chemosensitivity in glioma via regulation of hedgehog signaling.

BACKGROUND: Malignant glioma is one of the essentially incurable tumors with chemoresistance and tumor recurrence. As a histone methyltransferase, SUV39H2 can trimethylate H3K9. SUV39H2 is highly expressed in many types of human tumors, while the function of SUV39H2 in the development and progression of glioma has never been elucidated. METHODS: RT-qPCR and IHC were used to test SUV39H2 levels in glioma tissues and paired normal tissues. The clinical relevance of SUV39H2 in glioma was analyzed in a public database. Colony formation assays, CCK-8 assays, and flow cytometry were conducted to explore the role of SUV39H2 in the growth of glioma cells in vitro. A cell line-derived xenograft model was applied to explore SUV39H2's role in U251 cell proliferation in vivo. Sphere formation assays, RT-qPCR, flow cytometry, and IF were conducted to illustrate the role of SUV39H2 in the stemness and chemosensitivity of glioma. Luciferase reporter assays and WB were applied to determine the function of SUV39H2 in Hh signaling. RESULTS: SUV39H2 was highly expressed in glioma tissues relative to normal tissues. SUV39H2 knockdown inhibited cell proliferation and stemness and promoted the chemosensitivity of glioma cells in vitro. In addition, SUV39H2 knockdown also significantly inhibited glioma cell growth in vivo. Moreover, we further uncovered that SUV39H2 regulated hedgehog signaling by repressing HHIP expression. CONCLUSIONS: Our findings delineate the role of SUV39H2 in glioma cell growth and chemosensitivity as a pivotal regulator of the hedgehog signaling pathway and may support SUV39H2 as a potential target for diagnosis and therapy in glioma management.

Rare Intrasellar Arachnoid Cyst Distinguishing From Other Benign Cystic Lesions and its Surgical Strategies.

The study reported a case of an intrasellar arachnoid cyst with visual disturbances as the main symptom. Arachnoid cyst is a common intracranial benign space-occupying lesion, but rarely seen in intrasellar region with less than 100 cases reported available in English language literature. Therefore, it is still controversial about the diagnosis and treatment of such patients. This article reviewed previous literature and discussed the differential diagnosis and surgical strategies of intrasellar arachnoid cyst in combination with our own case.

Palliative Interventional Embolization for Finding of Ectopic Noradrenaline-Secreting Pheochromocytoma in the Nasal Cavity.

A 52-year-old male who had chronic hypertension for several years presented with abrupt epistaxis. The CT scan revealed a 40 mm × 40 mm mass in the nasal cavity intended to the maxillary sinus and the base of skull. Nasal endoscope biopsy and serum/urinary catecholamine detection conformed an ectopic noradrenaline-secreting pheochromocytoma. The present research was to discuss the clinical characteristics of the rare pheochromocytoma and the palliative interventional embolization for it.

Regulation of Gli2 stability by deubiquitinase OTUB2.

The transcription factor Gli2 plays crucial roles in the transduction of Hedgehog (Hh) signals, yet the mechanisms that control Gli2 degradation remain unclear. Here we have identified the eubiquitinating enzyme otubain2 (OTUB2) as a regulator of Gli2 protein degradation. We found that OTUB2 was coimmunoprecipitated with Gli2. Knockdown of OTUB2 decreased Gli2 protein level while the proteasome inhibitor MG-132 treatment restored Gli2 expression. Additionally, OTUB2 overexpression stabilized Gli2 protein in U2OS cells and extended the half-life of Gli2. We also found that knockdown of OTUB2 reduced deubiquitination of Gli2 in vivo. In vitro deubiquitination assay showed that ubiquitinated Gli2 was decreased by wild-type OTUB2 but not OTUB2 mutations. We also found that OTUB2 knockdown suppressed the ALP activity and the expression of the common markers BMP2 and RUNX2 during osteogenesis of MSCs in response to Shh and Smo agonists, which indicated OTUB2 may have effect on osteogenic differentiation by regulating Hh signaling.

Cortical surface area reduction in identification of subjects at high risk for post-traumatic stress disorder: A pilot study.

OBJECTIVE: Victims of motor vehicle accidents often develop post-traumatic stress disorder, which causes significant social function loss. For the difficulty in treating post-traumatic stress disorder, identification of subjects at high risk for post-traumatic stress disorder is essential for providing possible intervention. This paper aims to examine the cortical structural traits related to susceptibility to post-traumatic stress disorder. METHODS: To address this issue, we performed structural magnetic resonance imaging study in motor vehicle accident victims within 48 hours from the accidents. A total of 70 victims, available for both clinical and magnetic resonance imaging data, enrolled in our study. Upon completion of 6-month follow-up, 29 of them developed post-traumatic stress disorder, while 41 of them didn't. At baseline, voxelwise comparisons of cortical thickness, cortical area and cortical volume were conducted between post-traumatic stress disorder group and trauma control group. RESULTS: As expected, several reduced cortical volume within frontal-temporal loop were observed in post-traumatic stress disorder. For cortical thickness, no between-group differences were observed. There were three clusters in left hemisphere and one cluster in right hemisphere showing decreased cortical area in post-traumatic stress disorder patients, compared with trauma controls. Peak voxels of the three clusters in left hemisphere were separately located in superior parietal cortex, insula and rostral anterior cingulate cortex. CONCLUSION: The finding of reduced surface area of left insula and left rostral anterior cingulate cortex suggests that shrinked surface area in motor vehicle accident victims could act as potential biomarker of subjects at high risk for post-traumatic stress disorder.

Anti-Neutrophil Cytoplasmic Antibody-Negative Central Nervous System Granulomatosis With Polyangiitis and Its Clinical Characteristics.

Granulomatosis with polyangiitis (GPA) is a necrotizing granulomatous vasculitis occasionally affecting central nervous system (CNS), and GPA patients with initial CNS symptoms are even rarer, whose diagnosis is further confused by an absence of positive antineutrophil cytoplasmic antibody. The authors described the characteristics of antineutrophil cytoplasmic antibody -negative GPA with CNS onset in a patient and discussed on its management, which may contribute to future diagnosis and treatment of patients with similar conditions.

Overexpression of FoxO3a is associated with glioblastoma progression and predicts poor patient prognosis.

Forkhead transcription factor FoxO3a has been reported to have ambiguous functions and distinct mechanisms in various solid tumors, including glioblastoma (GBM). Although a preliminary analysis of a small sample of patients indicated that FoxO3a aberrations in glioma might be related to aggressive clinical behavior, the clinical significance of FoxO3a in glioblastoma remains unclear. We investigated the expression of FoxO3a in a cohort of 91 glioblastoma specimens and analyzed the correlations of protein expression with patient prognosis. Furthermore, the functional impact of FoxO3a on GBM progression and the underlying mechanisms of FoxO3a regulation were explored in a series of in vitro and in vivo assays. FoxO3a expression was elevated in glioblastoma tissues, and high nuclear FoxO3a expression in human GBM tissues was associated with poor prognosis. Moreover, knockdown of FoxO3a significantly reduced the colony formation and invasion ability of GBM cells, whereas overexpression of FoxO3a promoted the colony formation and invasion ability. The results of in vivo GBM models further confirmed that FoxO3a knockdown inhibited GBM progression. More, the pro-oncogenic effects of FoxO3a in GBM were mediated by the activation of c-Myc, microtubule-associated protein 1 light chain 3 beta (LC3B) and Beclin1 in a mixed-lineage leukemia 2 (MLL2)-dependent manner. These findings suggest that high FoxO3a expression is associated with glioblastoma progression and that FoxO3a independently indicates poor prognosis in patients. FoxO3a might be a novel prognostic biomarker or a potential therapeutic target in glioblastoma.

Bundling potent natural toxin cantharidin within platinum (IV) prodrugs for liposome drug delivery and effective malignant neuroblastoma treatment.

Neuroblastoma (NB) is one of the most commonly seen malignancies in childhood and infancy. Cantharidin is a highly potent natural toxin that possesses potent anti-tumor properties on various cancers including NB. However, exposure to cantharidin can cause severe chemical burns and application of cantharidin for cancer therapy is limited. Here we report a strategy of bundling cantharidin within a hybrid platinum (IV) prodrug conjugate. This hydrophobic drug conjugate, ie, CanPt can be further formulated into liposome for drug delivery to minimize the exposure of cantharidin to normal cells for efficient chemotherapeutic agent against NB.

Neurocutaneous Melanosis Presenting as Cavernous Hemangioma Persistent Abdominal Pain.

Neurocutaneous melanosis (NCM) is a rare congenital syndrome characterized by the presence of multiple congenital melanocytic nevi and the proliferation of melanocytes in the central nervous system. The authors present a 9-year-old Chinese boy whose clinical manifestations are intermittent headache for 2 months and persistent abdominal pain for 10 days. 3D-reconstruction computed tomography angiography image, digital subtraction angiography, and magnetic resonance imaging plus angiography (MRI+MRA) examinations results suggested that cavernoma at left frontal lobe potentially associated with hemorrhage. In addition, miliary abnormal signals were widely scattered on MRA image so that other malignant metastatic diseases cannot be ruled out. GI physical examination had not any abnormal findings, antispasmodic drugs were ineffective but antiepilepsy drugs were effective to abdominal pain. In surgery, no cavernoma was noticed but an accumulation of densely melanocytic mass located at the lesion on radiology images. The lesions spread along with perivascular of sylvian veins and leptomeningeal. Pathology investigation demonstrated brain metastatic malignant melanoma associated with hemosiderosis. The lesion of brain parenchyma was totally removed but the spread lesions could not be treated with surgery. Adjuvant radiotherapy was performed but failed to control the malignant development, still the patient died in 3 months postinitial operation. The authors conclude that abdominal pain was a manifestation of epilepsy related to the frontal lobe lesion. Neurocutaneous melanosis is a rare disease, brain metastases result in abdominal pain is rare even more, and it is worth the attention of clinicians.

The Management for Intracranial Metastatic Neuroendocrine Tumor With Lung Origin.

Neuroendocrine tumor (NET) is not a common source of brain metastasis and the standard management of intracranial metastatic NET with lung origin remains unclear as a result of its rarity. We aimed to generalize some applicable protocols from our current 2 cases and relevant literature.

Suppression of Glutamate Carboxypeptidase II Ameliorates Neuronal Apoptosis from Ischemic Brain Injury.

BACKGROUND: Ischemia stroke is a destructive cerebrovascular disease and a major cause of death and lifelong neurological disability. N-Acetyl-l-aspartyl-l-glutamate (NAAG) is a neurotransmitter in the mammalian brain and involves a variety of physiological and pathological functions including ischemia brain injury. Full understanding of the functions of NAAG peptidase (GCPII) in the pathogenesis of ischemia brain injury is extremely valuable for effective therapies to ischemia stroke. METHODS: The expressions of GCPII and NAAG agonist metabotropic glutamate receptor (mGluR3) and TGFb1 were examined by real-time polymerase chain reaction and western blot. Moreover, GCPII knockdown cells were constructed using lentivirus-mediated transfection. Function and molecular mechanisms of GCPII knockdown on apoptosis induced from hypoxic-ischemic-induced injury in neuronal cells were analyzed. RESULTS: In this study, we found that the expressions of GCPII and mGluR3 were upregulated in CoCl2-induced hypoxia environment in neuronal cells. Moreover, knockdown of GCPII in neuronal cells ameliorated apoptosis from hypoxic-ischemic-induced injury through suppressing expressions of caspase 3 and caspase 9. CONCLUSIONS: Our results highlighted the roles of GCPII in the ischemia brain injury, and might provide an important target in therapeutic implications.

MiR-26a enhances the radiosensitivity of glioblastoma multiforme cells through targeting of ataxia-telangiectasia mutated.

Glioblastoma multiforme (GBM) is notoriously resistant to radiation, and consequently, new radiosensitizers are urgently needed. MicroRNAs are a class of endogenous gene modulators with emerging roles in DNA repair. We found that overexpression of miR-26a can enhance radiosensitivity and reduce the DNA repair ability of U87 cells. However, knockdown miR-26a in U87 cells could act the converse manner. Mechanistically, this effect is mediated by direct targeting of miR-26a to the 3'UTR of ATM, which leads to reduced ATM levels and consequent inhibition of the homologous recombination repair pathway. These results suggest that miR-26a may act as a new radiosensitizer of GBM.

5'-adenosine monophosphate-induced hypothermia attenuates brain ischemia/reperfusion injury in a rat model by inhibiting the inflammatory response.

Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5'-adenosine monophosphate (5'-AMP), a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5'-AMP-induced hypothermia (AIH) may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO) model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9), interleukin-1 receptor (IL-1R), tumor necrosis factor receptor (TNFR), and Toll-like receptor (TLR) protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL-) positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5'-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia.

Residual hemifacial spasm after microvascular decompression: prognostic factors with emphasis on preoperative psychological state.

Residual hemifacial spasm (HFS) after microvascular decompression (MVD) is common, and the factors associated with residual HFS are still controversial. In the present study, we analyzed the outcome of 212 patients with hemifacial spasm after a single microvascular decompression and evaluated the prognostic factors involved in residual hemifacial spasm. Based on our study, possible prognostic factors included indentation of the root exit zone (REZ), preoperative illness duration, and preoperative psychological state. We suggest that MVD should be performed as early as possible for it may decrease the rate of residual HFS. Preoperative assessment of psychological state in HFS patients is a timely intervention that should be implemented to minimize the residual HFS.

Early-stage hemangioblastoma presenting as a small lesion with significant edema in the cerebellum.

Hemangioblastomas are benign tumors that are frequently associated with peritumoral cysts; however, their early characteristics before cyst formation remain unclear. In this article, the authors present a novel case of a cerebellar hemangioblastoma presenting as a small solid lesion with significant edema. Surgery was performed to resect the tumor, and a follow-up magnetic resonance imaging scan revealed complete excision of the mass and resolution of the cerebellar edema. Histological examination confirmed that the lesion was a hemangioblastoma. This is the only report in the literature to describe the imaging and histopathologic characteristics of an initial hemangioblastoma in the cerebellum.