Apolipoprotein E Polymorphism Impacts White Matter Injury Through Microglial Phagocytosis After Experimental Subarachnoid Hemorrhage.

Apolipoprotein E (apoE, protein; APOE, gene), divided into three alleles of E2, E3 and E4 in humans, is associated with the progression of white matter lesion load. However, mechanism evidence has not been reported regarding the APOE genotype in early white matter injury (WMI) under subarachnoid hemorrhage (SAH) conditions. In the present study, we investigated the effects of APOE gene polymorphisms, by constructing microglial APOE3 and APOE4-specific overexpression, on WMI and underlying mechanisms of microglia phagocytosis in a mice model of SAH. A total of 167 male C57BL/6J mice (weight 22-26 g) were used. SAH and bleeding environment were induced by endovascular perforation in vivo and oxyHb in vitro, respectively. Multi-technology approaches, including immunohistochemistry, high throughput sequencing, gene editing for adeno-associated viruses, and several molecular biotechnologies were used to validate the effects of APOE polymorphisms on microglial phagocytosis and WMI after SAH. Our results revealed that APOE4 significantly aggravated the WMI and decreased neurobehavioral function by impairing microglial phagocytosis after SAH. Indicators negatively associated with microglial phagocytosis increased like CD16, CD86 and the ratio of CD16/CD206, while the indicators positively associated with microglial phagocytosis decreased like Arg-1 and CD206. The increased ROS and aggravating mitochondrial damage demonstrated that the damaging effects of APOE4 in SAH may be associated with microglial oxidative stress-dependent mitochondrial damage. Inhibiting mitochondrial oxidative stress by Mitoquinone (mitoQ) can enhance the phagocytic function of microglia. In conclusion, anti-oxidative stress and phagocytosis protection may serve as promising treatments in the management of SAH.

Transcription factor YY1 mediates self-renewal of glioblastoma stem cells through regulation of the SENP1/METTL3/MYC axis.

Glioma is a primary brain tumor with limited treatment approaches and glioblastoma stem cells (GSCs) are manifested with the self-renewal capability and high tumorigenic capacity. This study was performed to investigate the regulatory effect of the SUMO-specific protease 1 (SENP1)/methyltransferase-like 3 (METTL3)/MYC axis on the self-renewal of GSCs mediated by transcription factor Yin Yang 1 (YY1). Following bioinformatics analysis and clinical and cellular experiments, we found that YY1 was highly expressed in GBM tissues and cells, while silencing its expression reduced the self-renewal ability of GSCs. Functionally, YY1 promoted the transcriptional expression of SENP1 by binding to the promoter region of SENP1, while the deSUMOase SENP1 facilitated the methylase activity of m6A through deSUMOylation of the methylase METTL3, thereby promoting the m6A modification of MYC mRNA via METL3 and promoting the expression of MYC. A nude mouse xenograft model of GBM was also constructed to examine the tumorigenicity of GSCs. The obtained findings demonstrated that YY1 promoted tumorigenicity of GSCs by promoting the expression of MYC in vivo. Conclusively, YY1 can transcriptionally upregulate the SUMOylase SENP1 and enhance the methylase activity of METTL3, resulting in the increased m6A modification level of MYC mRNA, thereby promoting the self-renewal of GSCs.

Prevalence of Venous Thromboembolism in Intensive Care Units: A Meta-Analysis.

OBJECTIVE: Venous thromboembolism (VTE) is a life threating complication in intensive care units (ICUs). This study aimed to pool the prevalence of VTE and examined the risk factors of VTE in intensive care patients worldwide. METHODS: A systematic search in PubMed, EMBASE and Web of Science databases was performed. Studies reported that the data on the prevalence of VTE or relevant information were synthesized using a random-effects model. RESULTS: A total of 42 studies reporting on 27,344 patients were included. The pooled prevalence of VTE was 10.0% (95% CI: 7.0-14.0%). Subgroup and metaregression analyses found that thromboprophylaxis strategy, simplified acute physiology score (SAPS II), age, study quality, sample size, malignancy, sex, spinal cord injury and injury severity score (ISS) moderated the prevalence of VTE in intensive care patients. CONCLUSIONS: The present meta-analysis revealed a high prevalence of VTE in critically ill patients. The risk factors of VTE included thromboprophylaxis strategy, SAPS II, age, malignancy, sex, spinal cord injury and ISS. Therefore, we need to pay more attention to high-risk populations of VTE in intensive care patients.

TDO2 and tryptophan metabolites promote kynurenine/AhR signals to facilitate glioma progression and immunosuppression.

Tumor cells exhibit enhanced uptake and processing of nutrients to fulfill the demands of rapid growth of tumor tissues. Tryptophan metabolizing dioxygenases are frequently up-regulated in several tumor types, which has been recognized as a crucial determinant in accelerated tumor progression. In our study, we explored the specific role of tryptophan 2,3-dioxygenase 2 (TDO2) in glioma progression. Analysis of mRNA profiles in 325 glioma patients based on the rich set of CCGA database was performed, which revealed that high TDO2 expression was tightly correlated with poor prognosis in glioma patients. TDO2 increased intracellular levels of tryptophan metabolism in the kynurenine (Kyn) pathway in vitro and in vivo, resulting in sustained glioma cell proliferation. Mechanistically, overexpression of TDO2 promoted the secretion of Kyn, which in turn stimulated the activation of the aryl hydrocarbon receptor (AhR)/AKT signaling pathway, resulting in heightened proliferative properties and tumorigenic potential in glioma cells. Meanwhile, Kyn produced by tumor cells further suppressed the proliferation of functional T cells, thereby resulting in immunosuppression and enhanced tumor growth in glioma. Our study showed that TDO2-induced increase in tryptophan metabolite Kyn played a pivotal role in glioma development via the AhR/AKT pro-survival signals and immunosuppressive effects, suggesting that the use of TDO2 inhibitors in combination with chemotherapy may be a novel strategy to effectively and synergistically eliminate glioma cells.

Preclinical anti-angiogenic and anti-cancer activities of BAY1143269 in glioblastoma via targeting oncogenic protein expression.

Glioblastoma angiogenesis is critical for tumor growth, making it an appealing target for treatment development. BAY1143269 is a novel inhibitor of mitogen-activated protein kinase interacting serine/threonine-protein kinase 1 (MKN1) and has potent anti-cancer activity. We identified BAY1143269 as an angiogenesis inhibitor, by in vitro and in vivo glioblastoma angiogenesis models. BAY1143269 inhibited the capillary network formation of glioblastoma microvascular endothelial cells (GMECs), particularly the early stage of tubular structure formation. It also inhibited migration and proliferation, and induced apoptosis of GMECs isolated from glioblastoma patients. We found that BAY1143269 acted on GMECs by suppressing the eukaryotic translation initiation factor 4E (eIF4E) and eIF4E-mediated expression of oncogenic proteins, including those involved in cell cycle, epithelial-mesenchymal transition (EMT), and pro-survival. In addition, BAY1143269 suppressed eIF4E phosphorylation, inhibited proliferation, and induced apoptosis of glioblastoma cells. Interestingly, it reduced vascular endothelial growth factor (VEGF) level in tumor cells and culturing medium, demonstrating the inhibitory effect of BAY1143269 on tumor proangiogenic microenvironment. We finally challenged BAY1143269 on the glioblastoma xenograft mice model and observed a significant tumor growth reduction without toxicity in mice receiving oral BAY1143269. Immunoblotting analysis demonstrated significantly less phosphorylated-eIF4E (p-eIF4E), cluster of differentiation 31 (CD31) (microvascular endothelial cell marker), and VEGF in tumors from drug-treated mice. In summary, the inhibition of glioblastoma angiogenesis with BAY1143269 may provide an alternative approach for anti-glioblastoma therapy.

Artemisinin attenuated ischemic stroke induced cell apoptosis through activation of ERK1/2/CREB/BCL-2 signaling pathway in vitro and in vivo.

Ischemic stroke is characterized by the presence of both brain ischemic and reperfusion-induced injuries in the brain, leading to neuronal dysfunction and death. Artemisinin, an FDA-approved antimalarial drug, has been reported to have neuroprotective properties. However, the effect of artemisinin on ischemic stroke is not known. In the present study, we investigated the effect of artemisinin on ischemic stroke using an oxygen-glucose deprivation/reperfusion (OGD/RP) cellular model and a mouse middle cerebral artery occlusion (MCAO) animal model and examined the underlying mechanisms. The obtained results revealed that a subclinical antimalarial concentration of artemisinin increased cell viability and decreased LDH release and cell apoptosis. Artemisinin also attenuated the production of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential (Δψm). Importantly, artemisinin attenuated the infarction volume and the brain water content in the MCAO animal model. Artemisinin also improved neurological and behavioural outcomes and restored grasp strength and the recovery of motor function in MCAO animals. Furthermore, artemisinin treatment significantly inhibited the molecular indices of apoptosis, oxidative stress and neuroinflammation and activated the ERK1/2/CREB/BCL-2 signaling pathway. Further validation of the involved signaling pathway by the ERK1/2 inhibitor PD98059 revealed that inhibiting the ERK1/2 signaling pathway or silencing ERK1/2 reversed the neuroprotective effects of artemisinin. These results indicate that artemisinin provides neuroprotection against ischemic stroke via the ERK1/2/CREB/BCL-2 signaling pathway. Our study suggests that artemisinin may play an important role in the prevention and treatment of stroke.

HOXA-AS2 contributes to regulatory T cell proliferation and immune tolerance in glioma through the miR-302a/KDM2A/JAG1 axis.

Long non-coding RNAs (lncRNAs) have been manifested to manipulate diverse biological processes, including tumor-induced immune tolerance. Thus, we aimed in this study to identify the expression pattern of lncRNA homeobox A cluster antisense RNA 2 (HOXA-AS2) in glioma and decipher its role in immune tolerance and glioma progression. We found aberrant upregulation of lncRNA HOXA-AS2, lysine demethylase 2A (KDM2A), and jagged 1 (JAG1) and a downregulation of microRNA-302a (miR-302a) in glioma specimens. Next, RNA immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter gene assay demonstrated that lncRNA HOXA-AS2 upregulated KDM2A expression by preventing miR-302a from binding to its 3'untranslated region. The functional experiments suggested that lncRNA HOXA-AS2 could promote regulatory T (Treg) cell proliferation and immune tolerance, which might be achieved through inhibition of miR-302a and activation of KDM2A/JAG1 axis. These findings were validated in a tumor xenograft mouse model. To conclude, lncRNA HOXA-AS2 facilitates KDM2A/JAG1 expression to promote Treg cell proliferation and immune tolerance in glioma by binding to miR-302a. These findings may aid in the development of novel antitumor targets.

Circular RNA circPHKA2 Relieves OGD-Induced Human Brain Microvascular Endothelial Cell Injuries through Competitively Binding miR-574-5p to Modulate SOD2.

BACKGROUND: Circular RNA phosphorylase kinase regulatory subunit alpha 2 (circPHKA2; hsa_circ_0090002) has a significantly, specifically different expression in acute ischemic stroke (AIS) patients' blood. Here, we intended to investigate the role and mechanism of circPHKA2 in oxygen-glucose deprivation- (OGD-) induced stoke model in human brain microvascular endothelial cells (HBMEC). METHODS: Expression of circPHKA2, microRNA- (miR-) 574-5p, and superoxide dismutase-2 (SOD2) was detected by quantitative PCR and western blotting. Cell injury was measured by detecting cell proliferation (EdU assay and CCK-8 assay), migration (transwell assay), neovascularization (tube formation assay), apoptosis (flow cytometry and western blotting), endoplasmic reticulum stress (western blotting), and oxidative stress (assay kits). Direct intermolecular interaction was determined by bioinformatics algorithms, dual-luciferase reporter assay, biotin-labelled miRNA capture, and argonaute 2 RNA immunoprecipitation. RESULTS: circPHKA2 was downregulated in AIS patients' blood in SOD2-correlated manner. Reexpressing circPHKA2 rescued EdU incorporation, cell viability and migration, tube formation, B cell lymphoma-2 (Bcl-2) expression, and SOD activity of OGD-induced HBMEC and alleviate apoptotic rate and levels of Bcl-2-associated protein (Bax), glucose-regulated protein 78 kD (GRP78), C/EBP-homologous protein (CHOP), caspase-12, reactive oxygen species (ROS), and malondialdehyde (MDA). Additionally, blocking SOD2 partially attenuated these roles of circPHKA2 overexpression. Molecularly, circPHKA2 upregulated SOD2 expression via interacting with miR-574-5p, and miR-574-5p could target SOD2. Similarly, allied to neurovascular protection of circPHKA2 was the downregulation of miR-574-5p. CONCLUSION: circPHKA2 could protect HBMEC against OGD-induced cerebral stroke model via the miR-574-5p/SOD2 axis, suggesting circPHKA2 as a novel and promising candidate in ischemic brain injury.

Histone demethylase JMJD1C promotes the polarization of M1 macrophages to prevent glioma by upregulating miR-302a.

Glioma is regarded as an aggressive lethal primary brain tumor. Jumonji domain containing 1C (JMJD1C) is a H3K9 demethylase which participates in the progression of various tumors, but its specific function and underlying mechanism in glioma development remain undefined, which is the purpose of our work. We initially assessed JMJD1C expression in glioma tissues and cells using the assays of RT-qPCR and immunohistochemistry. Meanwhile, the H3K9 level at the microRNA (miR)-302a promoter region was measured by chromatin immunoprecipitation assay, while luciferase-based reporter assay was performed for validation of the binding affinity between miR-302a and methyltransferase-like 3 (METTL3). The effect of METTL3 on suppressor of cytokine signaling 2 (SOCS2) was subsequently analyzed by MeRIP-RT-qPCR. Finally, a xenograft tumor model was established in nude mice, followed by measurement of tumor-associated macrophages using flow cytometry. JMJD1C was poorly expressed in glioma tissues. Furthermore, JMJD1C increased miR-302a expression through promoting H3K9me1 demethylation at the miR-302a promoter region. miR-302a was identified to target METTL3, which could inhibit SOCS2 expression via m6A modification. JMJD1C promoted M1 macrophage polarization and suppressed the growth of glioma xenografts through the miR-302a/METTL3/SOCS2 axis both in vivo and in vitro. In conclusion, JMJD1C could enhance M1 macrophage polarization to inhibit the onset of glioma, bringing a new insight into the contribution of JMJD1C to the pathobiology of glioma, with possible implications for targeted therapeutic method.

Matrix stiffness promotes glioma cell stemness by activating BCL9L/Wnt/ß-catenin signaling.

Matrix stiffness is a key physical characteristic of the tumor microenvironment and correlates tightly with tumor progression. Here, we explored the association between matrix stiffness and glioma development. Using atomic force microscopy, we observed higher matrix stiffness in highly malignant glioma tissues than in low-grade/innocent tissues. In vitro and in vivo analyses revealed that culturing glioma cells on stiff polyacrylamide hydrogels enhanced their proliferation, tumorigenesis and CD133 expression. Greater matrix stiffness could obviously up-regulated the expression of BCL9L, thereby promoting the activation of Wnt/ß-catenin signaling and ultimately increasing the stemness of glioma cells. Inhibiting Wnt/ß-catenin signaling using gigantol consistently improved the anticancer effects of chemotherapy and radiotherapy in mice with subcutaneous glioma tumors. These findings demonstrate that a stiffer matrix increases the stemness of glioma cells by activating BCL9L/Wnt/ß-catenin signaling. Moreover, we have provided a potential strategy for clinical glioma treatment by demonstrating that gigantol can improve the effectiveness of traditional chemotherapy/radiotherapy by suppressing Wnt/ß-catenin signaling.

Remodeling cancer stemness by collagen/fibronectin via the AKT and CDC42 signaling pathway crosstalk in glioma.

Cancer development is a complex set of proliferative progression, which arises in most cases via multistep pathways associated with various factors, including the tumor microenvironment and extracellular matrix. However, the underlying mechanisms of cancer development remain unclear and this study aimed to explore the role of extracellular matrix in glioma progression. Methods: The expression of type I collagen and fibronectin in tumor tissues from glioma patients was examined by immunofluorescence staining. The correlations between collagen/fibronectin and glioma progression were then analyzed. A 3D collagen/fibronectin cultured system was established for tumor cells culture in vitro. Quantitative, real-time PCR and western blot were used to detect PI3K/ATK and CDC42 signals associated proteins expression in glioma. We used in vitro Cell Counting Kit-8, colony formation, and tumorigenesis assays to investigate the function of PI3K/AKT and CDC42 signals associated proteins. A xenograft glioma mice model was also used to study the anticancer effects of integrin inhibitor in vivo. Results: Our study demonstrated that type I collagen and fibronectin collaborate to regulate glioma cell stemness and tumor growth. In a 3D collagen/fibronectin culture model, glioma cells acquired tumorigenic potential and revealed strengthened proliferative characteristics. More significantly, collagen/fibronectin could facilitate the activation of PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways via integrin αvß3, eliciting sustained tumor growth and cancer relapse. Combination of the integrin signaling pathway inhibitor and the chemotherapeutic agent efficiently suppressed glioma cell proliferation and tumorigenic ability. Conclusion: We demonstrated that type I collagen and fibronectin could collaborate to promote glioma progression through PI3K/AKT/SOX2 and CDC42/YAP-1/NUPR1/Nestin signaling pathways. Blockade of the upstream molecular integrin αvß3 revealed improved outcome in glioma therapy, which provide new insights for eradicating tumors and reducing glioma cancer relapse.

Monensin inhibits glioblastoma angiogenesis via targeting multiple growth factor receptor signaling.

Glioblastoma is characterized by the extensive vascularization with poor prognosis. Targeting both tumor cell and angiogenesis may present an effective therapeutic strategy for glioblastoma. Monensin, a polyether ionophore antibiotic, has been recently recognized as promising anticancer drug candidate due to its potent and selective anti-tumor activities. However, little is known on the effects of monensin on tumor angiogenesis. In this work, we investigated the effects and underlying mechanisms of monensin on glioblastoma angiogenesis and growth. We show that monensin at nanomolar concentrations inhibits early stages of capillary network formation of glioblastoma endothelial cell. Monensin inhibited multiple endothelial cellular events, including migration, growth and survival, without affecting adhesion to Matrigel. We further demonstrate that monensin acts on endothelial cells via suppressing VEGFR- and EGFR-mediated signaling pathways. Monensin also inhibits proliferation and induces apoptosis in a panel of glioblastoma cells. However, monensin is more effective in targeting endothelial cells than tumor cells. Using glioblastoma growth xenograft mice model, we show that monensin at tolerable dose effectively inhibits glioblastoma growth. Of note, there is a significant decreased tumor vascularization from monensin-treated mice. Our work clearly demonstrates the anti-angiogenic activity of monensin and its ability in suppressing multiple tyrosine kinase receptor-mediated pathways. Our findings suggest that is a useful addition to the treatment armamentarium for glioblastoma.

The role of FOXOs and autophagy in cancer and metastasis-Implications in therapeutic development.

Autophagy is a highly conserved intracellular degradation process that plays a crucial role in cell survival and stress reactions as well as in cancer development and metastasis. Autophagy process involves several steps including sequestration, fusion of autophagosomes with lysosomes and degradation. Forkhead box O (FOXO) transcription factors regulate the expression of genes involved in cellular metabolic activity and signaling pathways of cancer growth and metastasis. Recent evidence suggests that FOXO proteins are also involved in autophagy regulation. The relationship among FOXOs, autophagy, and cancer has been drawing attention of many who work in the field. This study summarizes the role of FOXO proteins and autophagy in cancer growth and metastasis and analyzes their potential roles in cancer disease management.

Pristimerin-induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway.

Uveal melanoma (UM) is a highly invasive intraocular malignancy with high mortality. Presently, there is no FDA-approved standard for the treatment of metastatic UM. Pristimerin is a natural quinine methide triterpenoid compound with anti-angiogenic, anti-cancer and anti-inflammatory activities. However, Pristimerin potential cytotoxic effect on UM was poorly investigated. In the present study, we found the migration and invasion of UM-1 cells were inhibited by Pristimerin which also caused a rapid increase of ROS, decreased mitochondrial membrane potential, induced the accumulation of cells in G0/G1 phase, ending with apoptotic cell death. Pristimerin inhibited Akt and FoxO3a phosphorylation and induced nuclear accumulation of FoxO3a in UM-1 cells, increased the expression of pro-apoptotic proteins Bim、p27Kip1 , cleaved caspase-3, PARP and Bax, and decreased the expression of Cyclin D1 and Bcl-2. LY294002 or Akt-siRNA inhibited the PI3K/Akt/FoxO3a pathway and promoted the Pristimerin-induced apoptosis, while Pristimerin effects were partially abolished in FoxO3a knockdown UM-1 cell cultures. Taken together, present results showed that Pristimerin induced apoptotic cell death through inhibition of PI3K/Akt/FoxO3a pathway in UM-1 cells. These findings indicate that Pristimerin may be considered as a potential chemotherapeutic agent for patients with UM.

LIM and SH3 protein 1 induces glioma growth and invasion through PI3K/AKT signaling and epithelial-mesenchymal transition.

PURPOSE: This study investigated the underlying mechanism of LIM and SH3 protein 1 (LASP1)-induced malignant glioma growth and invasion. MATERIALS AND METHODS: We compared the expression of LASP1 in malignant glioma tumor tissues and low-grade glioma tissues by immunohistochemistry. We also compared LASP1 overexpression and LASP1 knockout glioma cell proliferation and invasion in vitro and in vivo. We detected activation of the PI3K/AKT signaling pathway and epithelial-mesenchymal transition (EMT) process in tumor cells by western blotting or immunofluorescence. Glioma-bearing mice were used to investigate the anticancer effects of PI3K/AKT inhibitors in combination with temozolomide. RESULTS: We observed the enhanced expression of LASP1 in malignant glioma tumor tissues compared to low-grade glioma tissues, and LASP1 overexpression in glioma cells revealed an elevated capability of proliferation and invasion in vitro and in vivo. LASP1 overexpression also facilitated PI3K/AKT signaling and the EMT process through the downstream transcription factor Snail, which resulted in the intensive invasion of cancer cells. We combined PI3K/AKT inhibitors and temozolomide to block the LASP1/PI3K/AKT/Snail signaling pathway, which dramatically enhanced tumor suppression and provides an innovative approach for clinical glioma treatment. CONCLUSION: LASP1 is upregulated in malignant glioma and facilitates glioma cell proliferation and invasion by activation the PI3K/AKT/Snail signaling pathway. Blockade of the PI3K/AKT signal efficiently enhanced the anticancer effects of chemotherapeutic agents, which provides an innovative target in glioma treatment.

LIM and SH3 protein 1 regulates cell growth and chemosensitivity of human glioblastoma via the PI3K/AKT pathway.

BACKGROUND: LIM and SH3 protein 1 (LASP1) is upregulated in several types of human cancer and implicated in cancer progression. However, the expression and intrinsic function of LASP1 in glioblastoma (GBM) remains unclear. METHOD: Oncomine and The Cancer Genome Atlas (TCGA) database was analyzed for the expression and clinical significance of LASP1 in GBM. LASP1 mRNA and protein level were measured by qRT-PCR and western blotting. The effect of LASP1 on GBM proliferation was examined by MTT assay and colony formation assay, the effect of LASP1 on sensitivity of Temozolomide was measured by flow cytometry and subcutaneous tumor model. The association between LASP1 and PI3K/AKT signaling was assessed by western blotting. RESULTS: Oncomine GBM dataset analysis indicated LASP1 is significantly upregulated in GBM tissues compared to normal tissues. GBM dataset from The Cancer Genome Atlas (TCGA) revealed that high LASP1 expression is related to poor overall survival. LASP1 mRNA and protein in clinical specimens and tumor cell lines are frequently overexpressed. LASP1 knockdown dramatically suppressed U87 and U251 cell proliferation. Silencing LASP1 potentiated cell chemosensitivity to temozolomide in vitro, LASP1 knockdown inhibited tumor growth and enhanced the therapeutic effect of temozolomide in vivo. TCGA dataset analysis indicated LASP1 was correlated with PI3K/AKT signaling pathway, and LASP1 deletion inhibited this pathway. Combination treatment with PI3K/AKT pathway inhibitor LY294002 dramatically accelerated the suppression effect of temozolomide. CONCLUSION: LASP1 may function as an oncogene in GBM and regulate cell proliferation and chemosensitivity in a PI3K/AKT-dependent mechanism. Thus, the LASP1/PI3K/AKT axis is a promising target and therapeutic strategy for GBM treatment.

Impact of hypertension and smoking on the rupture of intracranial aneurysms and their joint effect.

BACKGROUND: In general population, the prevalence of intracranial aneurysm reaches as high as three percent. The goal of the study was to analyze retrospectively the independent risk factors for the rupture of intracranial aneurysms and their joint effect. METHODS: The records and angiographies of continuous 519 intracranial aneurysm patients treated at our center between February 2013 and July 2014 were retrospectively analyzed. Ruptured group and unruptured group were included in the study according to their clinical and imaging information. Univariate analysis and multivariate logistic regression analysis was used to identified independent risk factors for the rupture of intracranial aneurysms. We assessed the joint effect of independent risk factors for the rupture of intracranial aneurysms with an additional logistic regression analysis. RESULTS: The results of multivariate analysis show that hypertension (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.05-2.18) and smoking (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.06-2.33) were independent risk factors for rupture of intracranial aneurysms. The joint risk of hypertension and smoking was higher (OR, 2.28; 95% CI, 1.29-4.02) than the risks of hypertension (OR, 1.74; 95% CI, 1.11-2.72) and smoking (OR, 1.86; 95% CI, 1.05-3.29) independently. CONCLUSIONS: Hypertension and smoking increase of the rupture risk of intracranial aneurysms. And the joint risk of hypertension and smoking was higher than the risks of hypertension and smoking independently.

[Pathophysiological roles of matrix metalloproteinases and nitric oxide synthase in cerebral aneurysm].

OBJECTIVE: To explore the expressions of matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9) and inducible nitric oxide synthase (iNOS) in cerebral aneurysms, compare them with normal brain vessels tissue so as to gain a better understanding of the pathogenesis of cerebral aneurysms. METHODS: Twelve samples of cerebral aneurysms were obtained during operations and 10 cortical arteries as controls during surgery for temporal lobe epilepsy from 2009 to 2012 at Inner Mongolia People's Hospital and Beijing Tiantan Hospital. The activities of MMP-2, MMP-9 and iNOS in specimens were detected with spectrophotometry and substrate gel zymography. RESULTS: The MMP-2 and MMP-9 levels in cerebral aneurysm group were (199 598 ± 125 288) gray scale area × mg⁻¹ × L⁻¹ and (719 253 ± 376 519) gray scale area × mg⁻¹ × L⁻¹. Both in cerebral aneurysm group were significantly higher than that in control group (P < 0.05) . The TNOS and iNOS levels in cerebral aneurysm group were (23.6 ± 6.6) and (11.4 ± 2.6) U/mgprot. The difference of TNOS level was not significant between aneurysm and control groups (P > 0.05) while the levels of iNOS and iNOS/TNOS in cerebral aneurysm group were significantly higher than that in control group (P < 0.05). CONCLUSION: MMP-2, MMP-9 and iNOS are closely correlated with cerebral aneurysm.

Onyx embolization of cavernous sinus dural arteriovenous fistulas via direct transorbital puncture under the guidance of three-dimensional reconstructed skull image (reports of six cases).

BACKGROUND: Because of complex angioarchitecture, the transarterial or venous pathway is not feasible for some cavernous sinus dural arteriovenous fistulas (CS DAVFs). We present six cases in which onyx embolization of a CS DAVFs was made possible through direct transorbital puncture. METHODS: In the present study, all patients were penetrated through one third of the medial-lateral of the inferior orbital rim under the guidance of fluoroscopy superimposed on the three-dimensional reconstructed skull image to complete embolization (onyx with or without coils). The records of patient demographics, clinical manifestation, fistula features, procedures, clinical outcome and angiographic outcome were reviewed and analyzed. RESULTS: In our series of six patients, the immediate angiographic result showed complete occlusion in all patients. The six patients experienced retrobulbarhematoma and eye swelling right after embolization, while the swelling significantly subsided after 3-5 days of conservative treatment. During the postoperative angiography and clinical follow-up (4-10 months), one of the patients had decreased visual acuity; the other five patients did not have neurological dysfunction. CONCLUSIONS: Onyx embolization via direct transorbital puncture provides a method to be considered to treat CS DAVFs when the conventional transvenous approaches are inaccessible.

Clinical effectiveness of preoperative embolization for cerebellar hemangioblastoma.

The cerebellar hemangioblastoma (CHB) has an abundant blood supply and deep anatomical location. Complete surgical resection is generally very difficult. This study investigated the safety and effectiveness of preoperative embolization followed by surgical resection of CHB in a large cohort of patients. A database of 125 CHB patients with surgical resection in Beijing Tiantan Hospital between July 2006 and July 2012 was reviewed. Of those, 46 cases (experimental group) received preoperative embolization, 79 cases (control group) underwent surgery without embolization. Patient demographics, tumor size, duration of surgery, blood loss, blood transfusion, complications and follow-up results were collected and analyzed retrospectively. In the experimental group, the Kamofsky score (KS) was 80-100 in 40 cases (86.9%), 40-70 in 4 cases (8.7%), and below 40 in 2 cases (4.3%). Among 31 cases with follow-up, KS was 80-100 in 27 cases (87.1%), 40-70 in 2 cases (6.5%), and 0 in 2 cases (6.5%). In control group, KS was 80 -100 in 65 cases (82.2%), 40-70 in 6 cases (7.6%), 10-30 in 3 cases (3.8%), and 0 in 3 cases (3.8%). Among 53 cases with follow-up, KS was 80-100 in 44 cases (83.0%), 40-70 in 4 cases (7.5%), 10-30 in 1 case (1.9%), and 0 in 4 cases (7.5%). There were statistically significant differences between the experimental and control groups in tumor size, duration of surgery, amount of intraoperative blood loss and transfusion (p <0.01). However, complications (p = 0.31) and follow-up results (p = 0.76) showed no significant differences between groups. Selective preoperative embolization of those CHB patients with richer blood supply, higher hemorrhage risk, is safe and effective, and is a reliable adjuvant therapy for complete surgical resection of CHB.