Evaluation of the inhibitory effects and the mechanism of terpenoids on Toxoplasma gondii tachyzoites.

BACKGROUND: Currently, symptomatic toxoplasmosis is treated with a combination of sulfadiazine and pyrimethamine. However, significant adverse effects and drug resistance have been reported. Terpenoids are widely found in nature, with numerous studies demonstrating that they have effective inhibitory effects on a variety of parasites. METHODS: In this study, we employed intermediates or derivatives of lindenane sesquiterpenoids to evaluate their intracellular and extracellular inhibitory effects on Toxoplasma gondii tachyzoites and their cytotoxicity on macrophages. RESULTS: We demonstrated that two of these target terpenoids could effectively reduce the number of extracellular tachyzoites, probably by inducing tachyzoite apoptosis through altering tachyzoites mitochondrial membrane potential and calcium homeostasis. In addition, the two target terpenoids were able to promote intracellular tachyzoites elimination, possibly by enhancing macrophage activities. CONCLUSIONS: Two derivatives of lindenane sesquiterpenoids with low cytotoxicity to macrophages demonstrated direct and indirect antitoxoplasma effects.

Asymmetric Total Synthesis of Natural Lindenane Sesquiterpenoid Oligomers via a Triene as a Potential Biosynthetic Intermediate.

A previously proposed triene of the lindenane skeleton was synthesized, characterized, and identified as the common intermediate for the non-enzymatic synthesis of natural lindenane oligomers through linear, [4+2]-type and [6+6]-type homo- and hetero- dimerization under simulated physiological conditions. As a result, the following six natural products were successfully synthesized through thermal head-to-head, head-to-tail, and head-to-back binding modes: shizukaols A and J, cycloshizukaol A, chlorahupetone F, chlotrichene B, and trishizukaol A.

Asymmetric Total Synthesis of Shizukaol J, Trichloranoid C and Trishizukaol A.

The asymmetric total synthesis of three lindenane sesquiterpenoid oligomers, shizukaol J, trichloranoid C and trishizukaol A, has been accomplished concisely in 15, 16 and 18 longest linear steps, respectively. The expeditious construction of molecular architectures was facilitated by Nelson's catalytic asymmetric ketene-aldehyde cycloaddition, a sequence of allylic alkylation/reduction/acidic cyclization to forge a lactone, and a double aldol condensation cascade to construct the 5/6 bicyclic system. Diastereoselective nucleophilic substitution promoted by a phase transfer catalyst constructed the C11 quaternary stereogenic center, thus prompting synthetic efficacy toward shizukaol J. The synthesis of trichloranoid C and trishizukaol A was achieved after a cascade involving furanyl diene formation and a Diels-Alder reaction, as well as a one-pot sequence involving furan oxidation and global deprotection. Furthermore, our biological evaluation revealed that two compounds exhibited unexpected toxicity against tumor cell lines.

A unified strategy toward total syntheses of lindenane sesquiterpenoid [4 + 2] dimers.

The dimeric lindenane sesquiterpenoids are mainly isolated from the plants of Chloranthaceae family. Structurally, they have a crowded molecular scaffold decorated with more than 11 stereogenic centers. Here we report divergent syntheses of eight dimeric lindenane sesquiterpenoids, shizukaols A, C, D, I, chlorajaponilide C, multistalide B, sarcandrolide J and sarglabolide I. In particular, we present a unified dimerization strategy utilizing a base-mediated thermal [4 + 2] cycloaddition between a common furyl diene, generated in situ, and various types of dienophiles. Accordingly, all the three types of lindenane [4 + 2] dimers with versatile biological activities are accessible, which would stimulate future probing of their pharmaceutical potential.

[Application of intraoperative MRI combined with neuronavigation in microsurgical resection for insular glioma].

OBJECTIVE: To evaluate the value of intraoperative magnetic resonance imaging (iMRI) combined with neuronavigation for the resection of insular gliomas.
 Methods: From August 2014 to October 2017 in the First Hospital Affiliated to Sun Yat-sen University, clinical data of 41 patients with insular glioma, who underwent the surgery assisted with 3.0T iMRI and neuronavigation, were analyzed retrospectively, and the resection extent, complications and prognosis were evaluated.
 Results: Subtotal tumor resection was achieved in 21 patients and partial resection was done in 20 after iMRI scanning. After further resection, total tumor resection was achieved in 16 patients, subtotal resection in 18 and partial resection in 7. There was a statistical significant difference in tumor resection between pre-iMRI and post-iMRI according to the Fisher test (P<0.05). In the follow-up from 3 months to 3 years, the symptoms of the 41 patients had improved.
 Conclusion: iMRI corrected the shift of brain. Neuronavigation can accurately and timely assess the degree of resecting tumor. The combination of neuronavigation with surgery can maximally and safely resect insular glioma.

Expression and clinical relevance of SPOPL in medulloblastoma.

Medulloblastoma (MB) is a type of malignant brain tumor in children. Although knowledge of MB is increasing and the survival rate of patients with MB has improved in previous years, the long-term treatment-associated complications remain unfavorable. Early diagnosis and treatment is critical for patients with MB, but effective molecular markers for MB remain elusive. The Speckle-type POZ protein (SPOP) is a member of the MATH-BTB protein family and is a type of joint molecule for Cullin-3. SPOP inhibits tumor growth. However, the SPOP-like (SPOPL) gene, which is a SPOP paralog gene and shares an overall 85% sequence identity with SPOP, has not been explored in cancer studies at present. The results of the present study demonstrate that the SPOPL expression is decreased in MB cells and tissues compared with normal cells and tissues at the protein and mRNA levels. Immunohistochemical analysis revealed decreased expression of SPOPL in 42/56 (75%) paraffin-embedded archival MB biopsies, and SPOPL expression may be associated with the MB differentiation level (P=0.011). Patients with increased SPOPL expression exhibit improved survival rates compared with those with decreased SPOPL expression, and the SPOPL gene may be a potentially valuable molecular marker of MB.

Forkhead Box M1 positively regulates UBE2C and protects glioma cells from autophagic death.

Ubiquitin-conjugating enzyme E2C (UBE2C) is characterized as a crucial molecule in cancer cell growth that plays an essential role in the development of gliomas, but the detailed mechanisms have not been fully elucidated. In this study, we found that Forkhead box transcription factor M1 (FoxM1) overexpression increased UBE2C expression, whereas FoxM1 suppression inhibited UBE2C expression in glioma cells. In addition, high FoxM1/UBE2C expression was significantly correlated with poor prognosis in glioma. We subsequently demonstrated that UBE2C was a direct transcriptional target of FoxM1, and site-directed mutations markedly down-regulated UBE2C promoter activity. Moreover, UBE2C siRNA (si-UBE2C) significantly induced glioma cell autophagy and increased both mCherry-LC3 punctate fluorescence and LC3B-II/LC3-I expression. Notably, the si-UBE2C-induced decrease in cell viability was markedly inhibited by the autophagy inhibitor bafilomycin A1. The silencing of UBE2C resulted in a distinct inhibition of the PI3K-Akt-mTOR pathway, which functions in the negative modulation of autophagy. Collectively, our findings provide clinical and molecular evidence that FoxM1 promotes glioma progression by enhancing UBE2C transcription and that the inhibition of UBE2C partially induces autophagic glioma cell death. Thus, targeting the FoxM1-UBE2C axis has therapeutic potential in the treatment of gliomas.

Metadherin/Astrocyte elevated gene-1 positively regulates the stability and function of forkhead box M1 during tumorigenesis.

Background: Forkhead box M1 (FOXM1) is overexpressed and activates numerous oncoproteins in tumors. However, the mechanism by which the FOXM1 protein aberrantly accumulates in human cancer remains uncertain. This study was designed to clarify the upstream signaling pathway(s) that regulate FOXM1 protein stability and transcriptional activity. Methods: Mass spectrometry and immunoprecipitation were performed to identify the FOXM-metadherin (MTDH) interaction. In vivo and in vitro ubiquitination assays were conducted to test the effect of MTDH on FOXM1 stability. Chromatin immunoprecipitation assays were used to determine the involvement of MTDH in FOXM1 transcriptional activity. Cell invasion assays, tube formation assays, and in vivo tumor formation assays were performed to evaluate the cooperative activities of FOXM1 and MTDH during tumorigenesis. Results: MTDH directly interacts with FOXM1 via the N-terminal inhibitory domain of MTDH, and this interaction disrupted the binding of cadherin-1 to FOXM1, thus protecting FOXM1 from subsequent proteasomal degradation. Deleting the MTDH-binding sites of FOXM1 abolished the MTDH overexpression-mediated stabilization of FOXM1. MTDH also bound to FOXM1 target gene promoters and enhanced FOXM1 transcriptional activity. MTDH knockdown destabilized FOXM1 and attenuated its transcriptional activity, consequently inhibiting cell cycle progression, angiogenesis, and cancer cell invasion in vitro and in vivo; these effects were abolished via forced overexpression of a stabilized mutant form of FOXM1. Thus, MTDH stabilized FOXM1 and supported the sustained activation of FOXM1 target genes. Conclusion: These findings highlight a novel MTDH-regulated mechanism of FOXM1 stabilization and provide profound insight into the tumorigenic events simultaneously mediated by FOXM1 and MTDH.

The role of SDF-1/CXCR4 in the vasculogenesis and remodeling of cerebral arteriovenous malformation.

BACKGROUND: Cerebral arteriovenous malformation (AVM) involves the vasculogenesis of cerebral blood vessels and can cause severe intracranial hemorrhage. Stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, are believed to exert multiple physiological functions including angiogenesis. Thus, we investigated the role of SDF-1/CXCR4 in the vasculogenesis of cerebral AVM. METHODS: Brain AVM lesions from surgical resections were analyzed for the expression of SDF-1, CXCR4, VEGF-A, and HIF-1 by using immunohistochemical staining. Flow cytometry was used to quantify the level of circulating endothelial progenitor cells (EPCs). Further, in an animal study, chronic cerebral hypoperfusion model rats were analyzed for the expression of SDF-1 and HIF-1. CXCR4 antagonist, AMD3100, was also used to detect its effects on cerebral vasculogenesis and SDF-1 expression. RESULTS: Large amounts of CXCR4-positive CD45(+) cells were found in brain AVM lesion blood vessel walls, which also have higher SDF-1 expression. Cerebral AVM patients also had higher level of EPCs and SDF-1. In chronic cerebral hypoperfusion rats, SDF-1, HIF-1, and CD45 expressions were elevated. The application of AMD3100 effectively suppressed angiogenesis and infiltration of CXCR4-positive CD45(+) cells in hypoperfusion rats compared to controls. CONCLUSION: The SDF-1/CXCR4 axis plays an important role in the vasculogenesis and migration of inflammatory cells in cerebral AVM lesions, possibly via the recruitment of bone marrow EPCs.

Inhibition of FOXM1 by thiostrepton sensitizes medulloblastoma to the effects of chemotherapy.

Medulloblastoma (MB) is the most common malignant brain tumor in children and is highly invasive and metastatic. Despite recent advances, most MB patients suffer significant therapy-related morbidity, and the survival rate for patients with metastatic MB remains unsatisfactory. Altered expression of FOXM1 has been detected in many types of cancers, and the inhibition of FOXM1 has been studied as a cancer therapy. In the present study, we evaluated the impact of the inhibition of FOXM1 by thiostrepton in Daoy MB cells. Cells were treated with different concentrations of thiostrepton alone or in combination with cisplatin. Cell viability was measured with CCK-8 assays, and cell cycle distribution and apoptosis were assessed by flow cytometric analysis. Changes in protein expression were examined by western blotting. RNAi experiments were performed using siRNA oligonucleotides. The invasion and migration studies were performed using 8-µm Transwell plates. Inhibition of FOXM1 by thiostrepton significantly decreased MB cell proliferation. Cell arrest at the G2/M phase and apoptosis were significantly increased in MB cell lines that were treated with thiostrepton or transfected with siRNA. Thiostrepton decreased the IC50 value of cisplatin for MB treatment by enhancing cisplatin-induced apoptosis. Thiostrepton also decreased cell invasion and migration, which are crucial steps for tumor progression. Our data suggest that targeting FOXM1 with small-molecule inhibitors results in potent antitumor activity and chemosensitizing effects in human medulloblastoma cells.

AURKA governs self-renewal capacity in glioma-initiating cells via stabilization/activation of ß-catenin/Wnt signaling.

UNLABELLED: Glioma-initiating cells (GIC), which are characterized by their self-renewal capacity and tumorigenicity, were recently identified as a highly tumorigenic subpopulation of glioblastoma multiforme and are considered responsible for glioblastoma recurrence and chemo/radiation resistance. Previously, it was revealed that Wnt signaling activation is critical to the self-renewal of GICs. However, the molecular mechanism underlying the high expression of ß-catenin, the key transcription factor of the Wnt signaling pathway, remains elusive. In this investigation, it was determined that aurora kinase A (AURKA) regulates the self-renewal and tumorigenicity of GICs by stabilizing ß-catenin. In GICs, AURKA directly interacts with AXIN and disrupts the AXIN/GSK3ß/ß-catenin destruction complex and stabilizes ß-catenin, thereby activating Wnt signaling to promote self-renewal. Stable knockdown of AURKA destabilizes ß-catenin by increasing phosphorylated ß-catenin bound to AXIN and suppresses Wnt signaling, which inhibits the ability of GICs to self-renew. This effect is rescued by expression of an AURKA kinase dead mutant, D274A, which lacks the ability to phosphorylate GSK3ß, indicating that stabilization of ß-catenin by AURKA in GICs is independent from phosphorylation of GSK3ß. Functional experiments confirm that inhibition of AUKRA in GICs could suppress their "stemness," self-renewal ability, and tumorigenicity both in vitro and in vivo, and these effects could be rescued by stabilized ß-catenin mutant. These findings indicate that AURKA competes away the binding of AXIN from ß-catenin, induces ß-catenin stabilization, and activates Wnt signaling in GICs. IMPLICATIONS: AURKA kinase inhibition could effectively attenuate Wnt signaling, thereby inhibiting the self-renewal and tumorigenicity of GICs, and may be a novel target for glioblastoma treatment strategies.

Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1.

Phosphoglycerate dehydrogenase (PHGDH) is the first enzyme branching from glycolysis in the three-step serine biosynthetic pathway. Recent evidence has shown that PHGDH is amplified in human breast cancer and melanoma and plays a key role in cancer metabolism. However, PHGDH expression in glioma and a potential non-metabolic role in tumorigenesis have not been reported. We analyzed PHGDH levels in specimens from glioma patients and found that PHGDH, although negative in normal brain tissues, was highly expressed in astrocytic tumors and increasingly expressed in more aggressive cancer types. Inhibition of PHGDH expression in glioma cells downregulated the expression of VEGF, MMP-2, CHK2 and cyclin D1 and reduced glioma cell proliferation, invasion and tumorigenicity in vitro and in vivo. Interestingly, we found that the oncogenic transcription factor FOXM1 was also downregulated in PHDGH-silenced glioma cells. Using LC/LC MS analysis, we identified PHGDH as a novel binding partner of FOXM1. PHGDH interacted with and stabilized FOXM1 at the protein level, promoting the proliferation, invasion and tumorigenicity of glioma cells. Our data identified PHGDH as a potential prognostic marker of glial brain tumors and identified a non-metabolic role for PHGDH in glioma tumorigenesis, providing a novel angle of targeting the PHGDH-FOXM1 axis in future brain tumor therapy.

FoxM1 inhibition sensitizes resistant glioblastoma cells to temozolomide by downregulating the expression of DNA-repair gene Rad51.

PURPOSE: Recurrent glioblastoma multiforme (GBM) is characterized by resistance to radiotherapy and chemotherapy and a poor clinical prognosis. In this study, we investigated the role of the oncogenic transcription factor FoxM1 in GBM cells' resistance to alkylator temozolomide (TMZ) and its potential molecular mechanism. EXPERIMENTAL DESIGN: FoxM1 expression levels were measured by immunohistochemical analysis in 38 pairs of primary and recurrent GBM tumor samples. Expression levels were also measured in primary recurrent GBM cell lines, and their responses to TMZ were characterized. In a mechanistic study, an siRNA array was used to identify downstream genes, and a chromatin immunoprecipitation assay was used to confirm transcriptional regulation. RESULTS: Recurrent tumors that were TMZ resistant expressed higher levels of FoxM1 than did primary tumors. Recurrent GBM cell lines expressed higher levels of FoxM1 and the DNA damage repair gene Rad51 and were resistant to TMZ. TMZ treatment led to increased FoxM1 and Rad51 expression. FoxM1 knockdown inhibited Rad51 expression and sensitized recurrent GBM cells to TMZ cytotoxicity. FoxM1 directly regulated Rad51 expression through 2 FoxM1-specific binding sites in its promoter. Rad51 reexpression partially rescued TMZ resistance in FoxM1-knockdown recurrent GBM cells. A direct correlation between FoxM1 expression and Rad51 expression was evident in recurrent GBM tumor samples. CONCLUSION: Targeting the FoxM1-Rad51 axis may be an effective method to reverse TMZ resistance in recurrent GBM.

Susceptible gene single nucleotide polymorphism and hemorrhage risk in patients with brain arteriovenous malformation.

The relationship between single nucleotide polymorphism (SNP) of interleukin-17 (IL-17A), transforming growth factor ß (TGF-ß), as well as its receptor (TGFR-ß2) and susceptibility to intracerebral hemorrhage in patients with brain arteriovenous malformation (BAVM) was investigated in the present study. A total of 53 patients with BAVM and 120 healthy controls were recruited, all of whom were Han Chinese from South China. There were no statistically significant differences in the IL-17A-197 guanine/adenine (G/A) or TGF-ß1-509 cytosine/thymine (C/T) genotypes or gene frequencies between BAVM patients and controls (p>0.05), but the gene frequency of the TGFR-ß2-875 A/G genotype in patients with BAVM was significantly higher (p<0.05). Furthermore, the frequencies of the G allele of IL-17A-197 G/A and TGFR-ß2-875 A/G in BAVM patients with hemorrhage were higher than those without hemorrhage. TGFR-ß2-875 G/G genotype is a risk factor for BAVM, and the IL-17A-197 G/A and TGFR-ß2-875 A/G genotype is closely related to hemorrhage risk for patients with BAVM.

IKBKE is over-expressed in glioma and contributes to resistance of glioma cells to apoptosis via activating NF-κB.

IκB kinase-ε (IKBKE), a member of the IκB kinase (IKK) family, has been identified as an oncogenic protein and found to be up-regulated in breast cancer, ovarian cancer and prostate cancer. Nonetheless, the expression status and functional significance of IKBKE in human glioma remain unexplored. For the first time, we have demonstrated that mRNA and protein levels of IKBKE were robustly up-regulated in glioma cell lines and human primary glioma tissues. Immunohistochemistry analysis revealed that 53.5% (38/71) paraffin-embedded archived glioma specimens exhibited high levels of IKBKE expression. Intriguingly, there was no significant difference in IKBKE expression among different grades of glioma. To understand the biological function of IKBKE in the development and progression of human glioma, glioma cells lines ectopically over-expressing IKBKE were established and tested for their responsiveness to apoptotic inducers. Our data showed that IKBKE over-expression inhibited cell apoptosis induced by UV irradiation or adriamycin and, in contrast, shRNAi-mediated suppression of IKBKE increased the sensitivity of glioma cells to the apoptotic inducers. Importantly, we found that up-regulated IKBKE could induce the expression of Bcl-2 through activating NF-κB signalling, and that, specifically, we identified IκB as a critical component for this signalling cascade. The current study suggests that up-regulation of IKBKE may represent an important molecular hallmark that is biologically and clinically relevant to the development and progression, as well as the chemo- and radio-resistance, of the disease.

Neuroform stent-assisted coil embolization: a new treatment strategy for complex intracranial aneurysms. Results of medium length follow-up.

BACKGROUND AND PURPOSE: We present detailed results of using Neuroform stent-assisted coil embolization to treat complex cerebral aneurysms over a three-year period. MATERIAL AND METHODS: Only patients who underwent Neuroform stent-assisted coil embolization were included in this study. We assessed patients' history, aneurysm morphology, indications for stenting, and technical details of the procedures, as well as complications and the midterm follow-up data. RESULTS: This study included 26 patients with 39 aneurysms. A total of 32 of 39 aneurysms were treated by Neuroform stent-assisted embolization (SAC), whereas 3 aneurysms were stented without coiling, 2 aneurysms coiled without stenting and 2 aneurysms surgically clipped. The indications for use of stent included broad-neck aneurysms (n = 28), giant or large aneurysms (n = 6), and fusiform aneurysms (n = 5). Of the 32 aneurysms treated with Neuroform SAC, we achieved complete (100%) and near complete (> 95%) occlusion in 27 aneurysms, and partial (< 95%) occlusion in 5 aneurysms. Follow-up angiographic data available in 22 of 32 aneurysms treated with Neuroform SAC (68.7%) demonstrated recanalization in 3 aneurysms (13.6%), and stable occlusion in 19 aneurysms (86.4%). There was no delayed progressive embolization or in-stent stenosis. CONCLUSIONS: Direct and midterm follow-up results confirmed that Neuroform stent-assisted coil embolization was a safe and effective technique in the treatment of complex cerebral aneurysms. Although clinically significant complications were uncommon and the evaluation at midterm follow-up is encouraging, further studies need to assess the long-term stability and durability of the stent.

Prognostic significance of integrin-linked kinase1 overexpression in astrocytoma.

Integrin-linked kinase 1 (ILK1), a member of the serine/threonine kinases, has been demonstrated to be associated with numerous biological and pathological processes. However, the clinical and functional significance of ILK1 expression has not been characterized previously in human astrocytoma. In this study, we found that ILK1 was overexpressed, at both mRNA and protein levels, in astrocytoma cell lines as compared with normal human astrocytes. The ILK1 mRNA and protein were significantly increased up to 5.6-fold and 10.1-fold, respectively, in primary astrocytoma in comparison with the paired adjacent noncancerous brain tissues obtained from the same patient. Furthermore, immunohistochemical analysis revealed that ILK1 protein was positive in 208 of 228 (91.2%) paraffin-embedded archival astrocytoma specimens. Statistical analysis suggested that the upregulation of ILK1 was significantly correlated with the histological grading of astrocytoma (p = 0.000), and that patients with high ILK1 level exhibited shorter survival time (p < 0.001). Multivariate analysis revealed that ILK1 upregulation might be an independent prognostic indicator for the survival of patients with astrocytoma. Taken together, our results suggest that ILK1 might represent a novel and useful prognostic marker for astrocytoma and play a role during the development and progression of the disease.

Combined covered stent and onyx treatment for complex dural arteriovenous fistula involving the clivus and cavernous sinus.

BACKGROUND: Complex DAVFs involving both the clivus and cavernous sinus are rare, especially when associated with brainstem compression from a large varix. In this report, we describe the use of a covered stent in combination with a liquid embolic agent to cure a complex clival-cavernous DAVF. METHODS: A 46-year-old man presented with 6 months of dizziness, dysphagia, and progressive dysarthria. Magnetic resonance imaging showed tortuous and enlarged right cavernous and preclival flow voids. There were also bilateral prepontine varices compressing the ventral pons, which led to marked dorsal pontine edema. A cerebral angiogram revealed a clival DAVF supplied by multiple branches of the right ECA, as well as the MHT of the right ICA. RESULTS: An endovascular cure was achieved by deploying a covered stent in the right cavernous ICA, followed by transarterial embolization of the feeding arteries originating from the ECA with Onyx (ev3, Irvine, Calif). This combined approach resulted in complete occlusion of the fistula. His 1-month follow-up angiogram confirmed persistent occlusion of the fistula and preserved patency of the right ICA. The patient made a full recovery without any new symptoms, and he remained neurologically intact at 18-month follow-up. CONCLUSION: The combined technique of covered stent placement and Onyx transarterial embolization is valuable for the management of complex DAVFs supplied by branches of both the external and internal carotid arteries.

[Therapeutic effect of embolization of brain arteriovenous malformation with non-adhesive liquid embolic agent].

OBJECTIVE: To observe the clinical and pathological characteristics of brain arteriovenous malformations (BAVM) embolized with the non-adhesive aqueous embolic agent Onyx and evaluate its application in comprehensive treatment of BAVM. METHODS: Thirty-four patients underwent BAVM embolization using Onyx, and their clinical manifestations, architecture of the malformed vessels, emblization procedure, and complications associated with the procedures were recorded. The resected tissues after embolization with Onyx were observed with electron microscope, and the prognosis of the patients was estimated with modified Rankin Score (mRS). RESULTS: These patients included 21 male and 13 female patients with a mean age of 30.45-/+11.81 years and an estimated mean size of the nidus of 3.98-/+1.43 cm. The patients received a total of 52 endovascular treatment procedures with Onyx to embolize 86 feeding pedicals, which resulted in an average estimated size reduction of the nidus of (72.35-/+21.26)%. Complications associated with the procedure occurred in 7 patients, and 23 patients received surgical resection or radiosurgery after embolization. Follow-up of the patients for 6 months to 4 years showed that the mRS was below 3 in 32 cases and > or =3 in 2 cases. Vasodilatation, brain tissue edema surrounding the nidus, and inflammatory cell infiltration were observed in the resected tissues after embolization. In some major feeding pedicals, thrombus recanalization was observed after embolization with Onyx (diameter> or =3 mm). CONCLUSION: Endovascular treatment of BAVM with Onyx can achieve high occlusion rate, enhance the safety of operation and radiosurgery, and improve the clinical prognosis of the patients.

[Study on inhibitory effect of arsenic trioxide on growth of rat C6 glioma cells].

OBJECTIVE: To explore the inhibitory effect of arsenic trioxide (A(s2)O3) on the growth of rat C6 glioma cells (C6 cells) as well as finding out the feasibility of using As2O3 as chemotherapy of gliomas. METHOD: C6 cells were treated by different dose of As2O3 (1, 2, 4, 6 and 8 micromol L(-1)). MTT assay and staining for PCNA were used for cell proliferation. Cell apoptosis was determined by TUNEL method and Bcl-2 expression was studied by Western blot. Parental rat C6 cells (5 x 10(5)/15 microL) were implanted into right caudate nucleus of male SD rats as control group. Rats bearing cerebral C6 gliomas as treated group were treated with 1 mmol x L(-1) As2O3. The general manifestation, survival time, MRI dynamic scanning and histopathological changes of all rats were observed. RESULT: All the treated cells showed decreased proliferation in vitro as detected by MTT method (P < 0.01) and staining for PCNA. In situ labeling apoptotic DNA fragment of the treated cells demonatrated that the cell apoptosis significantly increased following treatment with As2O3 (P < 0.01). Western blot showed that the expression of Bcl-2 protein was decreased. All rats in control group died of cerebral gliomas within 3 weeks after implantation of C6 cells (17.8 +/- 0.92) d. Eight out of 10 rats in treated group died within 24-36 days (32.1 +/- 1.35) d and other 2 ones kept alive beyond 120 days with one treated rat being totally disappear of the tumor foci and another having a little residue of tumor. CONCLUSION: The result demonstrates the potential efficacy of As2O3 in the treatment of gliomas. It also suggests that As2O3 may be a good candidate for chemotherapy of human gliomas.