PRIM2: A Marker of MYC-driven Hyper-proliferation, Disease Progression, Tumor Aggressiveness and Poor Survival in Glioma Patients.

BACKGROUND/AIM: Gliomas are the most prevalent brain tumors with metabolic alterations playing a pivotal role in disease progression. However, the precise coordination of metabolic alterations with tumor-promoting cellular mechanisms, leading to tumor initiation, progression, and aggressiveness, resulting in poor outcomes, remains poorly understood in gliomas. MATERIALS AND METHODS: We conducted a metabolism-targeted differential gene expression analysis using glioma patients' expression profiling data from The Cancer Genome Atlas (TCGA) database. In addition, pathway enrichment analysis, gene set enrichment analysis (GSEA), transcription factor prediction, network construction, and correlation analyses were performed. Survival analyses were performed in R. All results were validated using independent GEO expression datasets. RESULTS: Metabolism-targeted analysis identified 5 hits involved in diverse metabolic processes linking them to disease aggressiveness in gliomas. Subsequently, we established that cell cycle progression and hyper-proliferation are key drivers of tumor progression and aggressiveness in gliomas. One of the identified metabolic hits, DNA primase 2 (PRIM2), a gene involved in DNA replication was found directly associated with cell cycle progression in gliomas. Furthermore, our analysis indicated that PRIM2, along with other cell cycle-related genes, is under the control of and regulated by the oncogenic MYC transcription factor in gliomas. In addition, PRIM2 expression alone is enough to predict MYC-driven cell cycle progression and is associated with tumor progression, aggressive disease state, and poor survival in glioma patients. CONCLUSION: Our findings highlight PRIM2 as a marker of MYC-driven cell cycle progression and hyper-proliferation, disease onset and progression, tumor aggressiveness, and poor survival in glioma patients.

Response Activation and Inhibition in Patients With Prolactinomas: An Electrophysiological Study.

Impairment of executive function has been reported in patients with prolactinomas. However, few studies have investigated the electrophysiological mechanisms of response activation and response inhibition in these patients. In this study, we employ an event-related potentials (ERPs) technique to quantitatively assess response activation and inhibition before and after the surgical treatment of prolactinomas. A 64-electrode electroencephalogram (EEG) skullcap was used to record the brain activity in 20 pre-operative patients, 20 follow-up post-operative patients, and 20 healthy controls (HCs) while performing the visual Go/Nogo task. As expected, we identified P300 across all study populations that could reflect response activation and inhibition. Across the three groups, the Nogo stimuli evoked larger frontal-central P300 than the Go stimuli did. In contrast, the Go trials elicited larger parietal P300 than the Nogo trials did. The peak latency of P300 was significantly delayed in both the pre-operative and the post-operative groups compared to the HCs. The amplitude of P300 in both the Go and the Nogo conditions was significantly decreased in the pre-operative patients compared with that of the HCs. At 6 months post-operatively, the prolactinoma patients showed an increase in amplitude of P300 during both the Go and the Nogo tasks. These findings indicate that the prolactinoma patients suffer from deficits in response activation and inhibition, which could be improved by surgical treatment.

Correction: Opposing Effects of PI3K/Akt and Smad-Dependent Signaling Pathways in NAG-1-Induced Glioblastoma Cell Apoptosis.

[This corrects the article DOI: 10.1371/journal.pone.0096283.].

Long non-coding RNA MEG3 regulates proliferation, apoptosis, and autophagy and is associated with prognosis in glioma.

PURPOSE: Accumulating evidence indicates that dysregulated long noncoding RNAs (lncRNAs) play critical roles in tumorigenesis and cancer progression. LncRNA-maternally expressed gene 3 (MEG3) has been shown to be involved in the initiation and development of several cancers, including glioma. However, the clinical prognostic value of MEG3 in glioma has not yet been fully elucidated. METHODS: The expression levels of MEG3 were detected in 79 glioma tissues and adjacent normal brain tissues, as well as, glioma cells and normal human astrocytes by qRT-PCR. Kaplan-Meier and Cox regression methods were utilized for the survival analysis. MTT assay, flow cytometry, and immunofluorescence assay were carried out to detect the impact of MEG3 on glioma cell proliferation, apoptosis, and autophagy. RESULT: The current results showed that MEG3 expression was significantly downregulated in glioma tissues and cell line and negatively correlated with WHO grade in glioma patients. Low MEG3 expression was significantly associated with the advanced WHO grade, low Karnofsky performance score (KPS), IDH wild-type, and tumor recurrence. Patients displaying a low expression of MEG3 contributed to poor overall survival. The downregulated level of MEG3, advanced WHO grade, low KPS, IDH wild-type, and tumor recurrence were independent poor prognostic indicators in glioma patients. The in vitro experiments demonstrated that the MEG3 overexpression remarkably suppressed the proliferation while facilitating apoptosis and autophagy in glioma cells. CONCLUSIONS: These findings indicated a critical role of MEG3 in glioma cell proliferation, apoptosis, and autophagy. Also, the gene was found to be significantly associated with the prognosis in glioma patients. Thus, it might provide a new target for predicting prognosis and therapeutic intervention in glioma.

Treatment strategies for traumatic cervico-cranial pseudoaneurysms: A single institution experience.

AIM: Limited clinical and angiographic data exists for patients with traumatic cervico-cerebral pseudoaneurysms. In this paper, we present our limited experience with various management strategies for traumatic cervico-cranial pseudoaneurysms. MATERIALS AND METHODS: We retrospectively analyzed 37 consecutive cases of traumatic pseudoaneurysms involving the cervico-cranial or the cerebral arteries diagnosed at our center from September 2009 to December 2014. The demographic data, etiology, clinical presentation, lesion location, treatment modality, and follow-up outcomes of these patients were reviewed. Among these 37 patients, 5 patients were treated by surgery, while 29 patients were treated by the endovascular approach and 3 received conservative treatment. RESULTS: During the study period, 42 pseudoaneurysms were identified in 37 patients with a history of head or neck injury. Five patients underwent surgical exploration of the lesion with an uneventful postoperative course. Twenty-nine patients were treated by endovascular interventions with various embolization materials including coils, stents, detachable balloons, liquid embolic agents, and a combination of these agents. The angiographic follow-up imaging demonstrated complete exclusion of the aneurysm from the circulation with the patient being free from any additional neurological deficits. CONCLUSION: Proper selection of an appropriate approach is essential to address the management of traumatic cervico-cerebral pseudoaneurysms. The treatment of traumatic cervico-cerebral pseudoaneurysms should be selected according to the location and the clinical features of the pseudoaneurysms. The endovascular treatment is a safe and effective modality and should be the first-line choice for treatment of traumatic pseudoaneurysms.

14-3-3zeta Positive Cells Show More Tumorigenic Characters in Human Glioblastoma.

AIM: Expression of 14-3-3zeta is upregulated in many cancer types and plays an important role in tumorigenesis. Our previous studies have shown that 14-3-3zeta has a positive expression and is associated with a poor prognosis in patients with glioblastoma. In this study, we investigated whether 14-3-3zeta positive cells show more tumorigenic character and stronger chemotherapy resistance. MATERIAL AND METHODS: Six human glioblastoma cells lines were derived from the 6 patients with tumor, and the cells were sorted by 14-3-3zeta expression. The cell viability, invasion, tumorigenic ability and chemotherapy resistance were compared between the 14-3-3 positive and negative expression groups. RESULTS: 14-3-3zeta positive cells displayed oncogenic properties, more tumorigenic character, high invasiveness, tumorsphere formation ability and resistance to temozolomide chemotherapy treatment. CONCLUSION: Cells with 14-3-3zeta positive expression show more tumorigenic character and should be administered other treatments in the future.

GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke.

BACKGROUND: Stroke could lead to serious morbidity, of which ischemic stroke counts for majority of the cases. Inflammation plays an important role in the pathogenesis of ischemic stroke, thus drugs targeting inflammation could be potentially neuroprotective. Estradiol was shown to be neuroprotective as well as anti-inflammatory in animal models of ischemic stroke with unclear mechanism. We hypothesize that the anti-inflammatory and neuroprotective effect of estradiol is mediated by the estradiol receptor G protein-coupled estrogen receptor 1 (GPER) expressed on microglia. METHODS: We have generated the rat global cerebral ischemic model and the primary microglia culture to study the neuroprotective and anti-inflammatory effect of estradiol. We have further used pharmacological methods and siRNA knockdown approach to study the underlying mechanism. RESULTS: We found that estradiol reduced the level of proinflammatory cytokines including IL-1ß and TNF-α, both in vivo and in vitro. We also found that the specific GPER agonist G1 could reduce the level of IL-1ß (P = 0 P = 0.0017, one-way ANOVA and post hoc test) and TNF-α (P < 0.0001) in the primary microglia culture. Moreover, the specific GPER antagonist G15 was able to abolish the anti-inflammatory effect of estradiol. Estradiol failed to reduce the level of IL-1ß (P = 0.4973, unpaired Student's t-test) and TNF-α (P = 0.1627) when GPER was knocked down. CONCLUSIONS: Our studies have suggested that GPER expressed on microglia mediated the anti-inflammatory effect of estradiol after ischemic stroke. Our studies could potentially help to develop more specific drugs to manage inflammation postischemic stroke.

GPER1 mediates estrogen-induced neuroprotection against oxygen-glucose deprivation in the primary hippocampal neurons.

It is well-known that the neuroprotective effects of estrogen have potential in the prevention and amelioration of ischemic and degenerative neurological disorders, while the underlying mechanisms for estrogen actions are undefined. As an important mediator for the non-genomic functions of estrogen, GPER1 (G Protein-coupled Estrogen Receptor 1) has been suggested to involve in the beneficial roles of estrogen in neural cells. Here our studies on primary hippocampal neurons have focused on GPER1 in an in vitro model of ischemia using oxygen-glucose deprivation (OGD). GPER1 expression in the primary hippocampal neurons was stimulated by the OGD treatments. Both E2 (estradiol) and E2-BSA (membrane impermeable estradiol by covalent conjugation of bovine serum albumin) attenuated OGD-induced cell death in primary cultures of hippocampal neurons. Importantly, this membrane-mediated estrogen function requires GPER1 protein. Knocking down of GPER1 diminished, while overexpression of GPER1 potentiated, the protective roles of E2/E2-BSA following OGD. Additionally, the downstream mechanisms employed by membrane-associated estrogen signaling were found to include PI3K/Akt-dependent Ask1 inhibition in the primary hippocampal neurons. Overall, these research results could enhance our understanding of the neuroprotective actions for estrogen, and provide a new therapeutic target for improving stroke outcome and ameliorating degenerative neurological diseases.

Effect of clipping anterior communicating artery aneurysms via pterional approach contralateral to supply of dominant blood: report of 15 patients.

BACKGROUND AND PURPOSE: Anterior communicating artery aneurysm (ACoAA) is a common cerebrovascular disease. This research is to observe the curative effect and safety of clipping anterior communicating artery (ACoA) aneurysms by microsurgery through the pterional approach contralateral to supply of dominant blood. MATERIALS AND METHODS: Before the surgery, three-dimensional-DSA (3D-DSA) was performed to study the regional anatomy of ACoA complexes in all 15 patients with ACoA aneurysms. According to 3D-DSA, the aneurysms and ACoA complexes could be satisfactorily exposed by the microsurgery through the pterional approach contralateral to the supply of dominant blood. And then the microsurgery through the pterional approach contralateral to the supply of dominant blood was performed in 15 patients with ACoA aneurysms. RESULTS: Clipping of ACoA aneurysms were successfully performed in all patients. The aneurysms and ACoA complexes were satisfactorily exposed via 3D-DSA. Among 15 patients with ACoA aneurysms, 14 cases were cured and 1 case need further care. CONCLUSIONS: The ideal side of pterional approach may be cheese via simulation of pterional approach with 3D-DSA. The ACoA complex and aneurysm can be clearly exposed, and the aneurysm may be smoothly clipped safely by the microsurgery through the ideal side pterional approach contralateral to supply of dominant blood in the patients with ACoA aneurysms.

Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1-induced glioblastoma cell apoptosis.

Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) is a divergent member of the transforming growth factor-beta (TGF-ß) superfamily. NAG-1 plays remarkable multifunctional roles in controlling diverse physiological and pathological processes including cancer. Like other TGF-ß family members, NAG-1 can play dual roles during cancer development and progression by negatively or positively modulating cancer cell behaviors. In glioblastoma brain tumors, NAG-1 appears to act as a tumor suppressor gene; however, the precise underlying mechanisms have not been well elucidated. In the present study, we discovered that overexpression of NAG-1 induced apoptosis in U87 MG, U118 MG, U251 MG, and T98G cell lines via the intrinsic mitochondrial pathway, but not in A172 and LN-229 cell lines. NAG-1 could induce the phosphorylation of PI3K/Akt and Smad2/3 in all six tested glioblastoma cell lines, except Smad3 phosphorylation in A172 and LN-229 cell lines. In fact, Smad3 expression and its phosphorylation were almost undetectable in A172 and LN-229 cells. The PI3K inhibitors promoted NAG-1-induced glioblastoma cell apoptosis, while siRNAs to Smad2 and Smad3 decreased the apoptosis rate. NAG-1 also stimulated the direct interaction between Akt and Smad3 in glioblastoma cells. Elevating the level of Smad3 restored the sensitivity to NAG-1-induced apoptosis in A172 and LN-229 cells. In conclusion, our results suggest that PI3K/Akt and Smad-dependent signaling pathways display opposing effects in NAG-1-induced glioblastoma cell apoptosis.

Overexpression of NDRG2 can inhibit neuroblastoma cell proliferation through negative regulation by CYR61.

Several recent studies have showed that the n-myc downstream regulated gene 2 (NDRG2) is a new tumor suppressor gene, and that it plays an important role in tumor suppression in several cancers or cancer cell lines. However, few studies focused on its function in neuroblastoma cells. In the present investigation, we demonstrated that NDRG2 overexpression inhibited their proliferation. Using a cDNA microarray, we found that overexpression of NDRG2 inhibited the expression of cysteine-rich protein 61 (CYR61), a proliferation related gene. From our research, CYR61 may partially hinder NDRG2-mediated inhibition of cell proliferation. Overexpression of NDRG2 resulted in accumulation of cells in the G1 phase, which was accompanied by upregulation of p21 and p27 and downregulation of CDK4 and cyclin D1. Taken together, these data indicate that NDRG2 inhibits the proliferation of neuroblastoma cells partially through suppression of CYR61. Our findings offer novel insights into the physiological roles of NDRG2 in neuroblastoma cell proliferation, and NDRG2 may prove to be effective candidate for the treatment of children with neuroblastoma.

Evaluation of cerebral arteriovenous malformation using 'dual vessel fusion' technology.

AIM: This study explored the value of using a vessel fusion technique for visualizing and evaluating the vessel structure of patients diagnosed with arteriovenous malformations (AVMs). MATERIALS AND: methods 10 patients with AVMs supplied by multiple cerebral arteries were investigated. The three-dimensional structure of the AVM nidus, feeding arteries, and draining veins were reconstructed from rotational angiographic images and then displayed on a single image in a fused manner. RESULTS: In the vessel fusion image, the tangled cluster of vessels surrounding the AVMs could be clearly visualized in three-dimensional space from a selected optimal viewing angle. Each AVM nidus component with its specific feeding arteries and venous drainage could be accurately identified. CONCLUSIONS: The vessel fusion technique offered detailed anatomical information that enabled clinicians to better understand the AVM structure, which helped with treatment planning.

[Endovascular treatment of the pseudoaneurysms of extracranial segment of internal carotid artery].

OBJECTIVE: To discuss the endovascular interventional treatment of pseudoaneurysm of extracranial segment of internal carotid artery. METHOD: The clinical data of 5 cases with traumatic pseudoaneurysm of extracranial segment of internal carotid artery were retrospectively studied. RESULT: All the patients were cured via endovascular interventional treatment, and performed with implanting covered stent into the parent artery. The patients recovered well with patency of the parent artery. CONCLUSION: Endovascular interventional treatment with covered stent implantation was safe and effective in treatment of pseudoaneurysm of extracranial segment of internal carotid artery.

Clinical and radiological observation in a surgical series of 36 cases of fibrous dysplasia of the skull.

OBJECTIVES: To describe the clinical and radiological findings in a consecutive series of patients diagnosed with fibrous dysplasia of the skull. PATIENTS AND METHODS: A retrospective analysis of collected data for 36 patients with histopathologically confirmed fibrous dysplasia involving the skull is presented. The demographic data, clinical presentation, radiographic characteristics, and the management of these patients were reviewed. RESULTS: All 36 patients in this review were diagnosed with fibrous dysplasia involving at least part of the skull. In this study, the most commonly involved area of the skull was the frontal bone (52.78% of patients). The next most common area of skull was the temporal bone (30.56% of patients), followed by the sphenoid bone (25% of patients), the parietal bone (19.44% of patients), and orbital bone (13.89% of patients). The principal clinical presentation included headache, local lump, exophthalmos, visual disorder, cranial nerve paralysis, and facial malformation. These patients were treated by surgical treatment, and several of our patients underwent various degrees of reconstruction to optimize function. CONCLUSIONS: Effective surgical treatment may improve the short-term outcome in these patients, and a "tailored" surgical approach is necessary.

The utility of angiographic CT in the diagnosis and treatment of neurovascular pathologies in the vicinity of cranial base.

This study aims to explore the utility of angiographic computed tomography (CT) in the diagnosis and treatment of neurovascular pathologies in the vicinity of cranial base. Two cases of cranial base dural arteriovenous fistula, one internal carotid pseudoaneurysm and one PICA aneurysm were demonstrated utilizing the angiographic CT for obtaining significant image details on the relative location of the diseases against the neighboring bony structure. An angiography suite outfitted with conventional DSA and rotational volume cone-beam was used, angiographic CT images being concomitantly produced together with the routine angiographic modalities. By virtue of the angiographic CT images integrating the selective angiography and reconstructed cranial base tomography, we succeeded in getting significant information on the relative location of various vascular diseases to the skull base, greatly facilitating the diagnosis and treatment procedures.

Safety, feasibility, and mid-term follow-up of Willis stent graft placement in the treatment of symptomatic complicated intra- or extra-cranial aneurysms: a multicenter experience.

We report the technical success rate and mid-term follow-up results after deploying stent-grafts to treat a cohort of patients with symptomatic complicated intra- or extracranial aneurysms (SCIEAs). This study was a retrospective review of 58 patients (39 male; mean age 40.4 ± 12.3 years) with 60 SCIEAs treated by 67 Willis covered stents at three medical centers in China between April 2005 and January 2010. The locations of the SCIEAs were as follows: Intracranial internal carotid artery (ICA) in 54 patients, extracranial ICA in one, intracranial vertebral artery (VA) in three and extra-cranial VA in two. Surgery was successful in 59 (98.3%) SCIEAs. Total exclusion was immediately achieved in 48 SCIEAs, and minor endoleaks were present in 11. Acute thrombosis occurred in two patients and hemorrhage in one. Follow-up angiography (mean 13.8 ± 8.9 months) revealed that 49 of 52 (94.2%) aneurysms were completely isolated, with mild in-stent stenosis in only two patients and in-stent occlusion in one patient. Willis stent-graft application is an alternative therapy to treat SCIEAs in either intra- or extracranial ICAs or VAs. In the case of a tortuous intracranial ICA or potential side branch coverage, however, it is still not a first choice.

[Biocompatibility of polyurethane-BaFe(12)O(19 ) composite microsphere as a new endovascular embolization material].

OBJECTIVE: To investigate the biocompatibility of polyurethane-BaFe(12)O(19) magnetic composite microsphere as a new endovascular embolization material. METHODS: The biocompatibility of BaFe(12)O(19) particle was evaluated in vitro using Ames test, cell toxicity test, acute and subacute systemic toxicity test, hemolysis test, bleeding time and clotting time test and blood clotting function assay. RESULTS: Ames test showed that the MR values of this particle leaching solution were all less than 2 without mutagenicity. Cell toxicity test showed that leaching solution at different concentrations had grade I toxicity on L929 cells. Acute and subacute systemic toxicity test showed that the experimental animals had good general condition without obvious pathological abnormality. The hemolysis rate of experimental group was 2.43%, which met the ISO standard (no more than 5%). The bleeding time and clotting time in mice were comparable between the experimental group and control group (P>0.05). There were no significant differences in blood clotting function between experimental group and control group (P>0.05). CONCLUSION: The material has no obvious toxicity or mutagenicity, and does not cause hemolysis or hemopexis or affect the bleeding time and clotting time. Polyurethane-BaFe(12)O( 19) particle possesses satisfactory biocompatibility.

[Formation and hemodynamics of pseudoaneurysm after rupture and bleeding of aneurysm: an experiment with dogs].

OBJECTIVE: To study the process and mechanism of the formation of pseudoaneurysm after the rupture of aneurysm. METHODS: A model of aneurysm (AN) of the left common carotid artery (CCA) was made in 20 dogs. One to 2 weeks after the formation of AN, a localized hematoma connected with the AN was formed as a model of pseudoaneurysm after the rupture of true aneurysm (false aneurysm caused by the ruptured true aneurysm, T + F) was established. The models were examined by using color Doppler, magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and digital subtraction angiographies (DSA) 1, 2, 3, 4, and 8 weeks after the operation in all the animals. By the end of experiment the models of AN were taken out to undergo pathological examination by light and electron microscopy. The blood flow velocity, pressure on the walls and shear stress in the true and false aneurysm were analyzed by simulation of computational fluid dynamics (CFD) on these animal models. RESULTS: Experimental models of T + F were successfully created in the 11 dogs. CCA was successfully occluded in 3 dogs, true aneurysm was occluded in 2, and true aneurysms without pseudoaneurysm were produced in 4. The blood flow in the pseudoaneurysm was very slow. The pressure and shear stress were very high in the ends distal to the aneurysms and not high around the boundary between the true and false aneurysms. CONCLUSION: The formation and growth of pseudoaneurysm are probably correlated with the pressure within the vessels. T + F should be positively and definitely treated by surgery to prevent them from rupture and bleeding.

Study on intraluminal embolization with microcoils treating traumatic pseudoaneurysms in common carotid artery in rabbits.

OBJECTIVE: To evaluate the long-term effect of endovascular occlusion with microcoils on traumatic pseudoaneurysms (TPAs) in the common carotid artery in rabbits. METHODS: TPAs in the right common carotid artery were surgically made in 16 rabbits. At 3-4 weeks after operation, the survived 12 models were randomly divided into a control group (n=3) with no treatment and an experimental group (n=9), in which TPAs were intraluminally embolized with microcoils and corresponding therapy was given. Three months after embolization, the TPAs were examined with digital subtraction angiography and pathology. RESULTS: The 3 rabbits in the control group all died of rupture of TPA. Among the 9 TPAs occluded with microcoils, 4 were completely occluded, 4 were partially occluded, and 1 was excluded due to the microcoils migrating into the parent artery. Three months after embolization, the 4 TPAs which were completely occluded remained obliterated as determined by digital subtraction angiographic findings. The parent artery remained unobstructed and the structure of the TPAs were replaced by a mass of scar tissues. The 4 TPAs which were partially occluded remained unruptured and the microcoils were compressed. CONCLUSIONS: The lumen in TPA can be completely occluded by microcoils and the parent artery is unblocked. Partial occlusion of the lumen can also prevent the rupture of TPA.

[Intravertebral canals vascular malformations treated by superselective embolization].

OBJECTIVE: To assess the feasibility superselective embolization using microcatheters in treatment of intravertebral canal vascular malformation. METHODS: In 128 patients with intravertebral canals vascular malformation, their AVMS or fistulae were treated with silk thread, Ivalon microspheres or tungsten microcoils. RESULTS: In the 128 patients, 120 fistulae disappeared completely, but 8 were embolized 60% - 80%. Symptoms were improved in 113 patients. Improved muscular strength from grade I to IV was obtained in 8 patients, from grade II to III in 32, from grade III to IV in 32, and from grade IV to V in 41. The symptoms did not change in 15 patients. CONCLUSION: Superselective embolization through microcatheter is effective in the treatment of intraspinal canal vascular malformations.