Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity.

PURPOSE: Recent studies have reported important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). Here, we tested the antitumor activity of a Dopamine receptor D1 (DRD1) agonist, either alone or in combination with temozolomide (TMZ) on GBM cells. METHODS: Immunofluorescence, immunohistochemistry and Western blotting were used to detect dopamine receptor expression in primary human GBM tissues. In addition, clinical data of GBM patients downloaded from The Cancer Genome Atlas (TCGA) were analyzed. Image-based tracking analysis of LC3 using a mCherry-eGFP-LC3 plasmid was utilized to monitor autophagic flux. Transmission electron microscopy (TEM) was used to visualize aggregation of autophagosomes/autolysosomes. Finally, DRD1 agonist (SKF83959)-induced inhibition of GBM growth was assessed in vitro and in vivo. RESULTS: Positive DRD1 expression was observed in human GBM tissues and found to be related with a good clinical outcome. DRD1 activation specifically inhibited GBM cell growth and significantly disrupted autophagic flux, which led to tumor cell death. Moreover, we found that DRD1 agonist treatment inhibited auto-lysosomal degradation in GBM cells and that this process was calcium overload dependent and related to inhibition of mammalian target of rapamycin (mTOR). Finally, we found that DRD1 agonist and TMZ co-treatment yielded a synergistic therapeutic effect both in vivo and in vitro. CONCLUSIONS: From our data we conclude that DRD1 activation inhibits GBM cell growth and may serve as an alternative avenue for the design of future GBM therapies.

Mechanism and modeling of hexavalent chromium interaction with a typical black soil: the importance of the relationship between adsorption and reduction.

Black soils have a significant retention effect on the migration of Cr(vi) towards groundwater, and Cr(vi) adsorption and reduction are both involved in this process. However, the adsorption and reduction of Cr(vi) were always investigated separately in previous studies resulting in an unclear relationship between them. In this study, the adsorption and reduction kinetic processes of Cr(vi) by a typical black soil were separately investigated under different initial Cr(vi) concentrations (40-400 mg L-1) and pH conditions (3.5-7.0) by the means of desorption treatment, and the equilibrium relationship between aqueous and adsorbed Cr(vi) was innovatively established based on the kinetic data. It was found that under pH 5.7 the adsorbed Cr(vi) content on soil particles was linearly correlated with the remaining Cr(vi) concentration in solution with time (R 2 = 0.98), and the reduction rate of Cr(vi) in the reaction system was linearly correlated with the adsorbed Cr(vi) content on soil particles with time (R 2 = 0.99). With pH decreasing from 7.0 to 3.5, the partition of Cr(vi) between solid and aqueous phases turned out to be of a non-linear nature, which can be fitted better by the Freundlich model. The retention of Cr(vi) by black soil was determined to follow the "adsorption-reduction" mechanism, where the Cr(vi) was first rapidly adsorbed onto the soil particles by a reversible adsorption reaction, and then the adsorbed Cr(vi) was gradually reduced into Cr(iii). A two-step kinetic model was developed accordingly, and the experimental data were fitted much better by the two-step adsorption-reduction kinetic model (R 2 = 0.89 on average) compared with the traditional first-order and second-order kinetic models (R 2 = 0.66 and 0.76 on average respectively). This paper highlights the novel two step kinetic model developed based on the proposed "adsorption-reduction" mechanism of Cr(vi) retention by a typical black soil.

Clinical characteristics and epilepsy outcomes following surgery caused by focal cortical dysplasia (type IIa) in 110 adult epileptic patients.

The aim of the present study was to investigate the effects of surgical intervention of focal cortical dysplasia (FCD) IIa on the outcome of epilepsy, and to evaluate the prognostic factors of seizure freedom. Patient data from epilepsy surgeries were retrospectively reviewed at the Second Affiliated Hospital of Dalian Medical University between 2007 and 2015. A total of 110 patients with a definite pathological diagnosis of FCD IIa were included. Moreover, the clinical characteristics, seizure outcome and quality of life in adults with FCD IIa were evaluated. The Engel seizure outcome achievements were class I in 72, class II in 20, class III in 11 and class IV in 7 patients. In addition, the Engel seizure outcome was relevant with the resection range of the lesions (P=0.028). The assessments of electrocorticography (ECoG) patterns and magnetic resonance imaging (MRI) are relevant to determining the extent of the resection, which may influence the surgery outcome (P=0.001 and P=0.023). Using multivariate regression analyses, the extent of resection, seizure frequency, preoperative ECoG and location of resection were the most important risk factors for seizure recurrence. The results of quality of life in epilepsy-10 scoring revealed that the quality of life improved significantly following surgery (P<0.01). Moreover, surgical intervention, EcoG, MRI positioning and complete resection helped to have improved seizure control, relief of anxiety and quality of life. All these observations strongly recommend an early consideration of epilepsy surgery in FCD IIa patients.

Long-Term Survival of Primary Intracranial Plasmablastic Lymphoma: Case Report and Review of the Literature.

BACKGROUND: Primary intracranial plasmablastic lymphoma (PIPBL) is a rare malignant tumor. CASE DESCRIPTION: We present a case of PIPBL in a 32-year-old man who complained of a progressive growing, painful mass on the right parieto-occipital part of head. Computed tomography and magnetic resonance imaging revealed a homogeneously enhanced mass with partial bone destruction. The patient underwent total resection and cranioplasty in one stage. Histopathologic examination showed large tumor cells with immunoblast-like nuclei. Immunohistochemical staining displayed CD38(+), CD138(+), Mum-1(+), CD20(-), and PAX-5(-). The patient received chemotherapy. The patient has survived more than 3.5 years after operation, with follow-up. We also review the clinical data, molecular pathologic traits, treatment, and prognosis of additional 6 cases with PIPBL in the literature. CONCLUSIONS: This study provides important clinical information for the diagnosis and treatment of PIPBL.

Aberrant Expression of miR-323a-5p in Patients with Refractory Epilepsy Caused by Focal Cortical Dysplasia.

BACKGROUND: Epilepsy remains one of the most common clinical neurological disorders. About a third of patients with epilepsy are refractory to drug treatment, mainly as a result of focal cortical dysplasia (FCD). In this study, we analyzed the aberrant expression of microRNAs (miRNAs) in the cortex and plasma of FCD patients. METHODS: Cortical samples were collected from nine patients with refractory epilepsy caused by FCD who underwent surgery, and from eight volunteers (control group) undergoing emergency surgery for hypertensive cerebral hemorrhage. miRNA expression in the cortex was detected by microarray analysis and miR-323a-5p expression levels in the cortex were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). We also collected plasma samples from 30 patients with refractory epilepsy caused by FCD and from 23 healthy controls, and compared differential expression of miR-323a-5p in the plasma using qRT-PCR. RESULTS: miRNA microarray analysis showed that expression of miR-323a-5p was upregulated in the FCD group compared with the control group, and miR-323a-5p expression levels in the cortex analyzed by qRT-PCR supported those obtained by microarray analysis. Plasma levels of miR-323a-5p were significantly higher in patient plasma compared with the healthy controls, as determined by qRT-PCR. Furthermore, expression of miR-323a-5p was positively correlated with the duration of epilepsy (p = 0.014) and seizure frequency (p = 0.043). The effectiveness of surgery in patients with FCD was significantly poorer in patients with high plasma levels of miR-323a-5p compared with those with low levels. CONCLUSIONS: The expression of miR-323a-5p was significantly elevated in the cortex and plasma of FCD patients. These results suggest that abnormal expression of miR-323a-5p could be used for improving the current diagnosis of FCD and monitoring treatment responses in patients with FCD.

Globose, cystic olfactory ensheathing cell tumor: A case report and literature review.

Olfactory ensheathing cell tumor (OECT) is one of the most rare intracranial, extra-axial tumors located in the anterior cranial fossa. The present study reports a case of a 34-year-old female patient who presented with a history of hyposmia for 1 year, as well as a gradual dizziness and emotional lability for 2 months. Magnetic resonance imaging of the brain revealed a globose, well-defined cystic mass at the midline of the anterior cranial fossa, which was confirmed as an OECT by histology and was completely resected by bifrontal craniotomy. According to the immunostaining results, the tumor was positive for vimentin and S100 protein, and negative for epithelial membrane antigen, glial fibrillary acidic protein and cluster of differentiation 57 (also known as Leu-7). The presentation, imaging findings, histopathological examination and histogenesis of OECT are discussed in the present study, along with a literature review.

Expression of microRNA-129-2-3p and microRNA-935 in plasma and brain tissue of human refractory epilepsy.

OBJECTIVE: Numerous microRNAs (miRNAs) are differentially expressed in specific diseases, suggesting possible use as diagnostic or prognostic biomarkers. The purpose of this study is to investigate the expression levels of miR-129-2-3p and miR-935 in cortical brain tissue and plasma samples from controls and refractory temporal lobe epilepsy (TLE) patients to evaluate the utility of these measures as diagnostic biomarkers. METHODS: The study was divided into three phases. First, cortical brain tissue samples from nine refractory TLE patients and eight controls were screened for differential miRNA expression using the Affymetrix miRNA 4.0 microarray. Second, real-time quantitative PCR (qRT-PCR) was used to verify the microarray results in brain tissue samples from 13 refractory TLE patients and 13 healthy controls (including those studied by microarray analysis). Third, we tested the expression levels of selected miRNAs in plasma samples from 25 refractory TLE patients and 25 healthy volunteers by qRT-PCR. The capacity of miR-129-2-3p and miR-935 expression to distinguish refractory TLE from health controls was tested by receiver operator characteristics (ROC) curve analysis. RESULTS: (1) High-resolution miRNA arrays indicated that miR-129-2-3p and miR-935 were significantly upregulated in the cortical brain tissues of TLE patients compared to controls. (2) qRT-PCR confirmed upregulated miR-129-2-3p expression in the brain tissue(P<0.0001) and plasma samples(P=0.0008) of refractory TLE patients. (3) The expression of miR-935 in epilepsy patients was higher than control group, however, there are no significant statistical differences between them whether in plasma samples(P=0.644) or in tissue samples(P=0.258). (4) ROC analysis of miRNA-129-2-3p showed that the area under the curve (AUC) was 0.929 (95% CI: 0.833-1.000; p=0.000) for brain tissue and 0.778 (95% CI: 0.640-0.915; p=0.001) for plasma. CONCLUSION: Expression of miRNA-129-2-3p was upregulated in cortical brain tissue and plasma samples from patients with refractory TLE, but miR-935 not. Plasma miRNA-129-2-3p has great potential as a non-invasive biomarker for early detection and clinical evaluation of refractory TLE.

Targeting of microRNA-199a-5p protects against pilocarpine-induced status epilepticus and seizure damage via SIRT1-p53 cascade.

OBJECTIVE: MicroRNAs (miRNAs) are noncoding small RNAs that control gene expression at the posttranscriptional level. Some dysregulated miRNAs have been shown to play important roles in epileptogenesis. The aim of this study was to determine if miR-199a-5p regulates seizures and seizure damage by targeting the antiapoptotic protein silent information regulator 1 (SIRT1). METHODS: Hippocampal expression levels of miR-199a-5p, SIRT1, and acetylated p53 were quantified by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting in the acute, latent, and chronic stages of epilepsy in a rat lithium-pilocarpine epilepsy model. Silencing of miR-199a-5p expression in vivo was achieved by intracerebroventricular injection of antagomirs. The effects of targeting miR-199a-5p and SIRT1 protein on seizure and epileptic damage post-status epilepticus were assessed by electroencephalography (EEG) and immunohistochemistry, respectively. RESULTS: miR-199a-5p expression was up-regulated, SIRT1 levels were decreased, and neuron loss and apoptosis were induced in epilepsy model rats compared with normal controls, as determined by up-regulation of acetylated p53 and cleaved caspase-3 expression. In vivo knockdown of miR-199a-5p by an antagomir alleviated the seizure-like EEG findings and protected against neuron damage, in accordance with up-regulation of SIRT1 and subsequent deacetylation of p53. Furthermore, the seizure-suppressing effect of the antagomir was partly SIRT1 dependent. SIGNIFICANCE: The results of this study suggest that silencing of miR-199a-5p exerts a seizure-suppressing effect in rats, and that SIRT1 is a direct target of miR-199a-5p in the hippocampus. The effect of miR-199a-5p on seizures and seizure damage is mediated via down-regulation of SIRT1. The miR-199a-5p/SIRT1 pathway may thus represent a potential target for the prevention and treatment of epilepsy and epileptic damage.

Long-term effect of nitrate on Cr(VI) removal by Fe(0): column studies.

Lab-scale parallel continuous-flow column experiments were performed to assess the long-term effect of nitrate (NO3 (-)) on hexavalent chromium (Cr(VI)) removal by scrap iron (Fe(0)). The first column (L1) was fed with the Cr(VI) solution and the second column (L2) was loaded with the Cr(VI) + NO3 (-) solution. Raman spectroscopy and scanning electron microscopy energy-dispersive X-ray analyses (SEM-EDS) were conducted to investigate the changes of the iron oxides on Fe(0). The results showed that the process of Cr(VI) removal by Fe(0) was divided into three different stages in the presence of NO3 (-): inhibition period (<198 pore volumes (PVs)); promotion period (198∼1025 PVs); and complete passivation period (1025∼1300 PVs). During the 462∼1025 PVs, Cr(VI) removal capacity in L2 was about 2.5 times higher than that in L1, and the longevity of L2 than L1 was 275PVs longer. NO3 (-) exhibited the most dominant effect on the Cr(VI) removal by Fe(0) in the last two stages. New magnetite (Fe3O4) produced by the redox reaction of NO3 (-) and Fe(0) was discovered on the surface of the Fe(0) obtained from L2. The new generated Fe3O4 could directly reduce the Cr(VI) and could also act as an inhibitor for the formation of passive film on the Fe(0) surface as well as an electron mediator that facilitated electron transport from Fe(0) to adsorbed Cr(VI).

Serum MicroRNA-4521 is a Potential Biomarker for Focal Cortical Dysplasia with Refractory Epilepsy.

Early biomarker-based diagnosis of focal cortical dysplasia (FCD) represents a major clinical challenge. The aim of this study was to identify novel brain microRNAs (miRNAs) in patients with refractory epilepsy and FCD as potential biomarkers. We evaluated serum hsa-miR-4521 as a promising novel biomarker in patients with FCD. Tissue for microarray was obtained from nine patients with temporal lobe refractory epilepsy who underwent surgery to remove epileptic foci identified by cortical video electroencephalogram monitoring. Control tissue was collected from eight patients with hypertension who required emergency surgery to remove an intracranial hematoma. The Affymetrix® GeneChip® Command Console® Software (Affymetrix miRNA 4.0) was used to compare miRNA expression in the cerebral cortex of experimental and control patients. Temporal cortex tissue and serum samples were taken from the same patients for verification of hsa-miR-4521 expression by real-time quantitative polymerase chain reaction (RT-qPCR). The experimental and control patients did not differ significantly in terms of age and gender. 19.4 % (148/764) of the total miRNAs were differentially expressed in experimental and control tissue, which is in agreement with the existing literature. We selected miRNA-4521 for further analysis; the fold-change in expression was 14.4707 and the q value was almost 0, which confirmed up-regulation. Significant up-regulation of hsa-miR-4521 was further validated by RT-qPCR. miRNA microarrays can efficiently and conveniently identify differentially expressed miRNAs in epilepsy brain tissue. This is the first study to identify differential expression of hsa-miR-4521 in brain tissue and serum of refractory epilepsy patients and suggests that serum hsa-miR-4521 may represent a potential diagnostic biomarker for FCD with refractory epilepsy.

A case of mushroom-shaped anaplastic oligodendroglioma resembling meningioma and arteriovenous malformation: Inadequacies of diagnostic imaging.

Magnetic resonance imaging (MRI) is the most widely discussed and clinically employed method for the differential diagnosis of oligodendrogliomas; however, MRI occasionally produces unclear results that can hinder a definitive oligodendroglioma diagnosis. The present study describes the case of a 34-year-old man that suffered from headache and right upper-extremity weakness for 2 months. Based on the presurgical evaluation, it was suggested that the patient had a World Health Organization (WHO) grade II-II glioma, meningioma or arteriovenous malformation (AVM), with unclear radiological manifestations. Postsurgical pathological assessment confirmed the tumor to be an anaplastic oligodendroglioma (WHO grade III). This case is notable due to the confusing radiological manifestation of a mushroom-shaped anaplastic oligodendroglioma in the parietal-temporal-occipital region, which provided a potential source of misdiagnosis for meningioma and AVM.

Progress on the relationship between miR-125 family and tumorigenesis.

miRNA-125 family, which is a highly conserved miRNA family throughout evolution, is consist of miRNA-125a-3p, miRNA-125a-5p, miRNA-125b-1 and miRNA-125b-2.The aberrant expression of miR-125 familyis tightly related to tumorigenesis and tumor development. The downstream targets of miRNA-125 include transcription factors like STAT3, cytokines like IL-6 and TGF-ß, tumor suppressing protein p53, pro-apoptotic protein Bak1 and RNA binding protein HuR et al. Through regulating these downstream targets miR-125 family is involved in regulating tumorigenesis and tumor development. Nowadays, miR-125b have already became a putative and valuable biomarker for cancer diagnosis, treatment and prognosis. In this review, we mainly summarize the dual function of miRNA-125 family in suppression and promotion of cancer cells and further elaborate its regulatory mechanisms from four facets, proliferation, apoptosis, invasion or metastasis and immune response.

A new method for evaluation of motor injury after acute brain ischemic damage.

PURPOSE: Motor impairment is an important index for assessing the extent of brain injury. The present study uses a new method, the movement capture analysis (MOCA) system, for assessing motor damage after acute ischemia. MATERIALS AND METHODS: Forty rats were divided into four groups: standard ischemia, sham-operated, Dizocilpine (MK-801), and Ginkgo biloba extract (GBE) groups. Brain ischemia was induced using the temporary right middle cerebral artery occlusion model. Longa score and MOCA were used to assess motor injury one day after ischemia. Infarct volume was delineated with 2% 2,3,5-triphenyltetrazolium chloride (TTC) staining. The correlation of infarct volume with Longa score and MOCA data was calculated. RESULTS: Compared with the sham-operated group (0.10 ± 0.31), Longa scores of MK-801 (2.33 ± 0.73), GBE (1.80 ± 0.58), and standard (2.88 ± 0.83) groups showed a statistical difference (p < 0.05); however, it was unable to discern the difference between MK-801 and standard groups. MOCA was able to clearly discern the differences in motor disparity among the four groups, standard (1.00 ± 0.19), sham-operated group (0.17 ± 0.02), MK-801 (0.79 ± 0.08), GBE (0.38 ± 0.05) (p < 0.05). Both MK-801 (18.03 ± 0.96%) and GBE (10.82 ± 1.93%) treatment reduced infarct size compared with the standard ischemia group (25.88 ± 1.16%) (p < 0.05). The MOCA data showed a more significant correlation with infarct size than Longa score (r = 0.85:0.53). CONCLUSIONS: MOCA system proved to be more sensitive than the Longa score. It may potentially be more accurate method for behavioral evaluation in clinical trials.

BRAF overexpression induces rampant glioma proliferation independent of phospho-EGFR expression.

BACKGROUND: The prognosis for gliomas is still dismal when treated with traditional approaches. Molecular targeted therapy has become a trend in treating tumors, including gliomas. However, molecular characteristics vary among different kinds of tumors and ethnic groups. OBJECTIVES: The aim of the research was to study the expression characteristics of key components in the EGFR pathway of gliomas in order to contribute new data for the molecular targeted treatment of gliomas. MATERIAL AND METHODS: EGFR, KRAS, BRAF, PI3K, phospho-EGFR and Ki67 expression were detected with immunohistochemistry in 82 glioma specimens. RESULTS: The expression of EGFR was positively correlated with the patients' age. There were no significant differences in clinicopathological characteristics between gliomas with and without phospho-EGFR expression. EGFR overexpression was significantly correlated with phospho-EGFR expression. In gliomas with EGFR activation, overexpressions of EGFR, BRAF and PI3K were significantly correlated with proliferation. However, in gliomas without phospho-EGFR expression, only BRAF overexpression was significantly related to the proliferation of tumor cells. CONCLUSIONS: BRAF overexpression could be an independent factor causing tumorigenesis in gliomas regardless of phospho-EGFR expression. The molecular characteristics can vary with the increasing age of glioma patients.

Serotonin transporter (5-HTT) gene polymorphisms and susceptibility to epilepsy: a meta-analysis and meta-regression.

AIMS: Serotonin transporter (5-HTT) plays a central role in the regulation of serotonin (5-hydroxytryptamine [5-HT]) synaptic function. Disturbances in 5-HT transmission are the most frequently reported neurobiological substrates of suicidal behavior. Emerging evidence has shown that the common polymorphisms in the 5-HTT gene may contribute to the risk of epilepsy, but individually published studies showed inconclusive results. This meta-analysis aimed to derive a more precise estimation of the associations between 5-HTT gene polymorphisms and susceptibility to epilepsy. METHODS: A literature search of PubMed, Embase, Web of Science, and China BioMedicine (CBM) databases was conducted on articles published before June 1st, 2013. Crude odds ratios with 95% confidence intervals were calculated. RESULTS: Seven studies were assessed with a total 1303 epilepsy patients and 1288 healthy controls. The meta-analysis results indicated that there was no significant relationship between 5-HTT gene polymorphisms and an increased risk of epilepsy. Further subgroup analysis based on ethnicity also found no significant association between 5-HTT gene polymorphisms and epilepsy risk among both Caucasian and Asian populations. In addition, there was also no significant association between 5-HTT gene polymorphisms and the risk of psychiatric comorbidity in patients with epilepsy. CONCLUSION: In conclusion, the current meta-analysis indicates that 5-HTT gene polymorphisms might not be the primary determinants of epilepsy susceptibility. 5-HTT genes might be expected to interact with other genes in different signaling pathways to initiate and promote the epileptogenic process.

Triple pathology in patients with temporal lobe epilepsy: A case report and review of the literature.

The coexistence of three intracranial lesions related to epileptic pathogenesis is known as 'triple pathology' and has rarely been reported. In this study we report a case of temporal lobe epilepsy (TLE) with the coexistence of hippocampal sclerosis (HS), focal cortical dysplasia (FCD) and ganglioglioma in the temporal lobe. A 29-year-old male who had experienced recurrent seizures for four years was admitted to hospital. Cerebral magnetic resonance imaging (MRI) was conducted and T2-weighted and fluid-attenuated inversion recovery sequence (FLAIR) images revealed a reduced hippocampal volume with an increased FLAIR signal on the right side and a slightly enlarged temporal horn, which are typical imaging findings for HS and FCD. The patient underwent resectioning of the right anterior temporal lobe, hippocampus and amygdala, in addition to the lesion located in the medial temporal lobe. Immunohistochemical analysis of the medial temporal lobe lesion confirmed a ganglioglioma (WHO grade I) in the medial temporal lobe. During the first eight months following surgery, the patient's seizures were controlled with zonisamide and phenytoin. Electroencephalogram (EEG) assessment post-surgery confirmed the absence of epileptic discharges. Based on a literature review and a detailed review of this case, we postulate two possible explanations for the pathogenesis of 'triple pathology': i) 'triple pathology' is a combination of pathological progression and occasionality; and ii) 'triple pathology' lesions have similar pathological origins.