Overexpression of oncostatin M receptor regulates local immune response in glioblastoma.

Glioblastoma (GBM) is the most lethal cancer in central nervous system. It is urgently needed to look for novel therapeutics for GBM. Oncostatin M receptor (OSMR) is a cytokine receptor gene of IL-6 family and has been reported to be involved in regulating GBM tumorigenesis. However, the role of OSMR regulating the disrupted immune response in GBM need to be further investigated. Three gene expression profiles, Chinese Glioma Genome Atlas (CGGA), The Cancer Genome Atlas (TCGA), and Gene Expression Omnibus (GEO) data set (GSE16011), were enrolled in our study and used for OSMR expression and survival analysis. The expression of OSMR was further verified with immunohistochemistry and western blot analysis in glioma tissues. Microenvironment cell populations-counter (MCP-counter) was applied for analyzing the relationship between OSMR expression and nontumor cells. The functions of OSMR in GBM was investigated by Gene Ontology, Gene set enrichment analysis (GSEA), gene set variation analysis and so on. The analysis of cytokine receptor activity-related genes in glioma identifies OSMR as a gene with an independent predictive factor for progressive malignancy in GBM. Furthermore, OSMR expression is a prognostic marker in the response prediction to radiotherapy and chemotherapy. OSMR contributes to the regulation of local immune response and extracellular matrix process in GBM. Our findings define an important role of OSMR in the regulation of local immune response in GBM, which may suggest OSMR as a possible biomarker in developing new therapeutic immune strategies in GBM.

Identification of two novel critical mutations in PCNT gene resulting in microcephalic osteodysplastic primordial dwarfism type II associated with multiple intracranial aneurysms.

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a highly detrimental human autosomal inherited recessive disorder. The hallmark characteristics of this disease are intrauterine and postnatal growth restrictions, with some patients also having cerebrovascular problems such as cerebral aneurysms. The genomic basis behind most clinical features of MOPD II remains largely unclear. The aim of this work was to identify the genetic defects in a Chinese family with MOPD II associated with multiple intracranial aneurysms. The patient had typical MOPD II syndrome, with subarachnoid hemorrhage and multiple intracranial aneurysms. We identified three novel mutations in the PCNT gene, including one single base alteration (9842A>C in exon 45) and two deletions (Del-C in exon 30 and Del-16 in exon 41). The deletions were co-segregated with the affected individual in the family and were not present in the control population. Computer modeling demonstrated that the deletions may cause drastic changes on the secondary and tertiary structures, affecting the hydrophilicity and hydrophobicity of the mutant proteins. In conclusion, we identified two novel mutations in the PCNT gene associated with MOPD II and intracranial aneurysms, and the mutations were expected to alter the stability and functioning of the protein by computer modeling.

[Prospective study on associations between levels of total cholesterol, triglyceride and risk of ischemic and hemorrhagic strokes].

OBJECTIVE: To explore associations between levels of total cholesterol (TC), triglyceride (TG) and incidence of ischemic and hemorrhagic strokes in populations. METHODS: Baseline investigations on stroke-related risk factors and physical examinations were performed in 10 093 (> 35 years) stroke-free urban community residents from 5 cities in China during May to July in 1987, follow-up investigations on stroke events were made during 1998 to 2000. The hazard ratios and 95% confidence intervals (CI) of ischemic and hemorrhagic strokes in middle, high tertiles of baseline TC or TG levels were compared with low baseline tertile residents using the Cox regression model. RESULTS: There were 491 first strokes during the 8-years cohort follow-up. Compared with the low tertile, risk of ischemic stroke in the middle and high tertiles of TC level was increased by 61% (HR: 1.61, 95%CI: 1.14-2.27) and 58% (HR: 1.58, 95%CI: 1.12-2.22) after adjustments for DBP, age, sex and other variables in the Cox proportional hazards model. Compared with the low tertile, risk of ischemic stroke in the high tertile of TG level was increased by 43% (HR: 1.43, 95%CI: 1.02-2.00). However, risk of hemorrhagic stroke in the middle and high tertiles of TC level decreased by 12% (HR: 0.88, 95%CI: 0.64-1.22) and 33% (HR: 0.67, 95%CI: 0.48-0.95) compared with the low tertile. CONCLUSIONS: Elevated serum TC and TG are independent risk factors for risk of ischemic stroke. However, low TC was related with increased risk of hemorrhagic stroke.

Long non-coding RNA TP73-AS1 contributes to glioma tumorigenesis by sponging the miR-103a/GALNT7 pathway.

Glioma is the most aggressive, commonly occurring brain tumor in adults. Long non-coding RNAs (lncRNAs) are among the gene expression regulators in cancer development. Previous research posited that the up-regulation of LncRNA TP73-AS1 (TP73-AS1) in glioma is linked to low survival rates. However, the precise LncRNA TP73-AS1 mechanism in glioma remains unknown. Herein, we found that TP73-AS1 was up-regulated in glioma and was associated with a dismal prognosis. The silencing of TP73-AS1 repressed the multiplication of glioma cells and caused cell death. Mechanistically, we identified that TP73-AS1 in glioma acts as a ceRNA by sequestering miR-103a from GALNT7. Further, the results of this study revealed a reciprocal expression between TP73-AS1 and miR-103a, and a positive regulation between TP73-AS1 and GALNT7, validating the identified mechanism. Besides, luciferase reporter assay identified miR-103a as the direct binding site of both TP73-AS1 and GALNT7. Moreover, the findings of CCK-8 and colony-formation assays indicated that exogenous expression of GALNT7 reversed TP73-AS1-induced division inhibition of glioma cells. Altogether, our results established that TP73-AS1 facilitates the progression of glioma through competing for endogenous RNA (ceRNA) in a TP73-AS1/miR-103a/GALNT7 loop.

The Chinese version of the SLEQOL is a reliable assessment of health-related quality of life in Han Chinese patients with systemic lupus erythematosus.

To assess the health-related quality of life (HRQOL) of Han Chinese people with systemic lupus erythematosus (SLE) using a Chinese version of the Systemic Lupus Erythematosus-Specific Quality of Life Questionnaire (SLEQOL-C) and explore the factors influencing HRQOL of people with SLE. Participants were Han Chinese people with SLE. The SLEQOL-C and 36-item Short Form Health Survey (SF-36) were used to estimate the HRQOL. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Participant factors included age, gender, educational background, disease duration, erythrocyte sedimentation rate (ESR), and complement C3 and C4 levels. The results showed that higher SLEQQL-C scores correlated with lower SF-36 both measures are essential for HRQQL prediction. The SLEQOL-C scores were correlated with educational level,age, FACIT-F score, SLEDAI score, and ESR, which suggests that poor educational background, old-age, and increased fatigue, disease activity, and ESR might represent poor HRQOL. Although disease duration did not significantly correlate with the scores on the SLEQOL-C; those whose disease duration was 12-24 months had higher SLEQOL-C summary scores and physical functioning, symptoms, and treatment subscale scores than did those whose duration was less than 6 months. The FACIT-F score, education level, age, disease duration, SLEDAI score, and ESR contributed to SLEQOL-C scores. The SLEQOL-C is reliable for assessing HRQOL of Han Chinese people with SLE. Fatigue, educational level, age, disease duration, ESR, and disease activity mainly influenced HRQOL of SLE patients.

Identifying survival-associated modules from the dysregulated triplet network in glioblastoma multiforme.

BACKGROUND: Long noncoding RNAs (lncRNAs) can act as competitive endogenous RNAs (ceRNAs) to compete with mRNAs for binding miroRNAs (miRNAs). The dysregulated triplets, composed by mRNAs, lncRNAs, and miRNAs, contributed to the development and progression of diseases, such as cancer. However, the roles played by triplet biomarkers are not fully understand in glioblastoma multiforme (GBM) patient survival. OBJECTIVES: Here, we constructed a differential triplet interaction network (TriNet) between GBM and normal tissues and identified GBM survival related triplets. METHODS: Four significantly dysregulated modules, enriched differentially expressed molecules, were identified by integrating affinity propagation method and hypergeometric method. Furthermore, knockdown of TP73-AS1 was implemented by siRNA and the expression of RFX1 was examined in U87 cells by qRT-PCR. The apoptosis of U87 cells was investigated using MTT assay and Acridine orange/Ethidium bromide (AO/EB) assay. RESULTS: We randomly split GBM samples into training and testing sets, and found that these four modules can robustly and significantly distinguish low- and high-survival patients in both two sets. By manually curated literatures for triplets mediated by core interactions, we found that members involved tumor invasion, proliferation, and migration. The dysregulated triplets may cause the poor survival of GBM patients. We finally experimentally verified that knockdown of TP73-AS1, an lncRNA of one triplet, could not only reduce the expression of RFX1, an mRNA of this triplet, but also induce apoptosis in U87 cells. CONCLUSIONS: These results can provide further insights to understand the functions of triplet biomarkers that associated with GBM prognosis.

Corpus callosum atrophy associated with the degree of cognitive decline in patients with Alzheimer's dementia or mild cognitive impairment: a meta-analysis of the region of interest structural imaging studies.

Individual structural neuroimaging studies of the corpus callosum (CC) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) with the region of interest (ROI) analysis have yielded inconsistent findings. The aim of this study was to conduct a meta-analysis of structural imaging studies using ROI technique to measure the CC midsagittal area changes in patients with AD or MCI. Databases of PubMed, the Cochrane Library, the ISI Web of Science, and Science Direct from inception to June 2014 were searched with key words "corpus callosum" or "callosal", plus "Alzheimer's disease" or "mild cognitive impairment". Twenty-three studies with 603 patients with AD, 146 with MCI, and 638 healthy controls were included in this meta-analysis. Effect size was used to measure the difference between patients with AD or MCI and healthy controls. Significant callosal atrophy was found in MCI patients with an effect size of -0.36 (95% CI, -0.57 to -0.14; P = 0.001). The degree of the CC atrophy in mild AD was less severe than that in moderate AD with a mean effect size -0.69 (95% CI, -0.89 to -0.49) versus -0.92 (95% CI, -1.16 to -0.69), respectively. Comparing with healthy controls, patients with MCI had atrophy in the anterior portion of the CC (i.e., rostrum and genu). In contrast, patients with AD had atrophy in both anterior and posterior portions (i.e., splenium). These results suggest that callosal atrophy may be related to the degree of cognitive decline in patients with MCI and AD, and it may be used as a biomarker for patients with cognitive deficit even before meeting the criteria for AD.

Blockage of potassium channel inhibits proliferation of glioma cells via increasing reactive oxygen species.

The potassium (K(+)) channel plays an important role in the cell cycle and proliferation of tumor cells, while its role in brain glioma cells and the signaling pathways remains unclear. We used tetraethylammonium (TEA), a nonselective antagonist of big conductance K(+) channels, to block K(+) channels in glioma cells, and antioxidant N-acetyl-l-cysteine (NAC) to inhibit production of intracellular reactive oxygen species (ROS). TEA showed an antiproliferation effect on C6 and U87 glioma cells in a time-dependent manner, which was accompanied by an increased intracellular ROS level. Antioxidant NAC pretreatment reversed TEA-mediated antiproliferation and restored ROS level. TEA treatment also caused significant increases in mRNA and protein levels of tumor-suppressor proteins p53 and p21, and the upregulation was attenuated by pretreatment of NAC. Our results suggest that K(+) channel activity significantly contributes to brain glioma cell proliferation via increasing ROS, and it might be an upstream factor triggering the activation of the p53/p21(Cip1)-dependent signaling pathway, consequently leading to glioma cell cycle arrest.

Stereotactic aspiration and thrombolysis of spontaneous intracerebellar hemorrhage.

BACKGROUND: Spontaneous intracerebellar hemorrhage (SCH) accounts for 10% of intracerebral hemorrhages. Up to now stereotactic aspiration and thrombolysis of SCH was less reported. The aim of this study was to assess the effect and feasibility of the method, and to refine the clinical protocol. METHODS: Eighteen patients with SCH were treated by stereotactic aspiration and thrombolysis and reviewed in this report. The 3-mm axial stereotactic computed tomography slices throughout the hematoma were obtained. Those images were then transferred to the workstation. The trajectory of catheter was designed to go through the main axis of the hematoma. Under local anesthesia a catheter was directed stereotactically into the hematoma through a burr hole. Hematoma thrombolysis and clot drainage was followed by instillation of urokinase (10,000 U) every 12 hours. The catheter was removed when the majority of hematoma was evacuated. RESULTS: Initial SCH volume was reduced by an average of 86% and the average final hematoma volume was 2.8 ml. At 3-month follow-up, 13 patients (72%) had achieved good recovery. At 6-month follow-up, 12 patients (67%) had achieved good recovery. CONCLUSION: Stereotactic aspiration and thrombolysis of SCH was a simple, feasible and effective method to treat moderate and some benign SCH that less respond to medical treatment.

Stereotactic localization and visualization of the subthalamic nucleus.

BACKGROUND: The subthalamic nucleus (STN) is widely recognized as one of the most important and commonly targeted nuclei in stereotactic and functional neurosurgery. The success of STN surgery depends on accuracy in target determination. Construction of a digitalized atlas of STN based on stereotactic MRI will play an instrumental role in the accuracy of anatomical localization. The aim of this study was to investigate the three-dimensional (3D) target location of STN in stereotactic space and construct a digitalized atlas of STN to accomplish the visualization of the STN on stereotactic MRI, thus providing clinical guidance on the precise anatomical localization of STN. METHODS: One hundred and twenty healthy people volunteered to be scanned by 1.5 Tesla MRI scanning with 1-mm-thick slice in the standard stereotactic space between 2005 and 2006. One adult male was selected for 3D reconstruction of STN. The process of 3D reconstruction included identification, manual segmentation, extraction, conservation and reconstruction. RESULTS: There was a significant correlation between the coordinates and age (P < 0.05). The volume of left STN was significantly larger than the right STN, and there was a significant negative correlation between volume and age (P < 0.05). The surface of the STN nucleus after 3D reconstruction appeared smooth, natural and realistic. The morphological feature of STN on the individual brain could be visualized directly in 3D. The 3D reconstructed STN could be rotated, zoomed and displayed at any direction in the stereotactic space. The anteroposterior diameter of the STN nucleus was longer than the vertical and transverse diameters in 3D space. The 3D reconstruction of STN manifested typical structure of the "dual lens". CONCLUSIONS: The visualization of individual brain atlas based on stereotactic MRI is feasible. However, software for automated segmentation, extraction and registration of MR images need to be further developed.

[Microstructural observation of epileptic neurons in vitro by atomic force microscopy].

OBJECTIVE: To observe the microstructure of the cell membrane of epileptic neurons using atomic force microscopy (AFM). METHODS: Model of epileptic neurons was established by subjecting the neurons culture for 14 days in vitro to magnesium-free media treatment for 3 h. Patch clamp technique was applied to record the electrophysiological activity of the epileptic neurons. AFM was performed to observe and measure the microstructure of the cell membrane of the epileptic neuron. RESULTS: After a 3-hour treatment with magnesium-free media, the epileptic neurons displayed sustained epileptiform discharge, which continued after the neurons were returned to normal medium culture on day 14. Under AFM scanning size of 80 microm x 80 microm and 2 microm x 2 microm, no obvious difference in the morphology of the cell membrane was noted between epileptic and normal neurons; under the scanning size of 500 nm x 500 nm, small pits occurred in the cell membrane in both groups, but no significant difference was found in the dimension of the pits between the two groups (the diameter and depth of the pits was 114.86-/+9.33 nm and 5.71-/+0.69 nm in epileptic neurons, and 116.4-/+9.13 nm and 5.69-/+0.71 nm in the control neurons, respectively, P>0.05). CONCLUSION: AFM provides a new method for observing neuronal membrane microstructure at nanometer resolutions. No significant alterations occur in the membrane of the neurons after a 3-hour magnesium-free media treatment.