Downregulating DNA methyltransferase 3B by suppressing the PI3K/Akt signaling pathway enhances the chemosensitivity of glioblastoma to temozolomide.

Glioblastoma (GBM) is the most common malignant brain tumor and has the poorest prognosis attributed to its chemoresistance to temozolomide (TMZ), the first-line drug for treating GBM. TMZ resistance represents a significant obstacle to successful GBM treatment, necessitating the development of new strategies to overcome this resistance and augment the chemosensitivity of GBM cells to TMZ. This study established a TMZ-resistant U251 (U251-TMZ) cell line by exposing it to increasing doses of TMZ in vitro. We focused on the DNA methyltransferase 3B (DNMT3B) gene, phosphorylated Akt (p-Akt), total Akt (t-Akt), phosphorylated PI3K (p-PI3K), and total PI3K (t-PI3K) protein expression. Results showed that the DNMT3B gene was significantly upregulated in the U251-TMZ cell line. The p-Akt and p-PI3K protein expression in U251-TMZ cells was also significantly elevated. Moreover, we found that DNMT3B downregulation was correlated with the increased chemosensitivity of GBM cells to TMZ. LY294002 suppressed the PI3K/Akt signaling pathway, leading to a notable inhibition of PI3K phosphorylation and a significant decrease in DNMT3B expression in U251-TMZ cells. Given that DNMT3B expression is mediated by the PI3K/Akt signaling pathway, its downregulation further increased the chemosensitivity of GBM cells to TMZ and therefore is a promising therapeutic for GBM treatment. Our results suggested that DNMT3B downregulation can inhibit the proliferation of GBM cells and induce GBM cell apoptosis in vitro. In addition, the PI3K/Akt signaling pathway plays an important role in the chemosensitivity of GBM cells to TMZ by regulating DNMT3B expression.

Overexpression miR-486-3p Promoted by Allicin Enhances Temozolomide Sensitivity in Glioblastoma Via Targeting MGMT.

Glioblastoma is the most common primary tumor of the central nervous system that develops chemotherapy resistance. Previous studies showed that Allicin could inhibit multiple cancer cells including glioblastoma, but the function of Allicin in glioblastoma is still unclear. Our work aimed to investigate the underlying molecular mechanism. The results showed that miR-486-3p levels were greatly increased in glioblastoma during Allicin treatment. Overexpression of miR-486-3p increased chemosensitivity to temozolomide (TMZ) in vitro and in vivo. O6-methylguanine-DNA methyltransferase (MGMT) was identified as a direct target of miR-486-3p, and miR-486-3p overexpression prevented the protein translation of MGMT. Moreover, overexpression of MGMT restored miR-486-3p-induced chemosensitivity to TMZ. Taken together, our studies revealed that Allicin could upregulate miR-486-3p and enhance TMZ sensitivity in glioblastoma. The results suggested that in the future, Allicin can be used as an adjuvant therapy with TMZ to improve the prognosis of patients, and miR-486-3p may be a potential target for glioblastoma treatment to improve the curative effects.

Analysis of related factors affecting prognosis of shunt surgery in patients with secondary normal pressure hydrocephalus.

OBJECTIVE: The management of secondary normal pressure hydrocephalus (sNPH) is controversial. Many factors may affect the surgery effect. The purpose of this study was to identify the possible factors influencing prognosis and provide theoretical basis for clinical treatment of sNPH. METHODS: A retrospective study was carried out to investigate the results of 31 patients with sNPH who underwent ventriculoperitoneal shunt surgery from January 2007 to December 2011. We processed the potential influencing factors by univariate analysis and the result further by multivariate logistic regression analysis. RESULTS: Factors including age, disease duration and Glasgow coma scale (GCS) score before surgery significantly influenced the prognosis of sNPH (P less than 0.05). Further logistic regression analysis showed that all the three factors are independent influencing factors. CONCLUSION: Age, disease duration and GCS score before surgery have positive predictive value in estimating favorable response to surgical treatment for sNPH.

Zero drift of intraventricular and subdural intracranial pressure monitoring systems.

OBJECTIVE: To assess zero drift of intraventricular and subdural intracranial pressure (ICP) monitoring systems. METHODS: A prospective study was conducted in patients who received Codman ICP monitoring in the neurosurgical department from January 2010 to December 2011. According to the location of sensors, the patients were categorized into two groups: intraventricular group and subdural group. Zero drift between the two groups and its association with the duration of ICP monitor were analyzed. RESULTS: Totally, 22 patients undergoing intraventricular ICP monitoring and 27 receiving subdural ICP monitoring were enrolled. There was no significant difference in duration of ICP monitoring, zero drift value and its absolute value between intraventricular and subdural groups (5.38 d+/-2.58 d vs 4.58 d+/-2.24 d, 0.77 mm Hg+/-2.18 mm Hg vs 1.03 mm Hg+/-2.06 mm Hg, 1.68 mm Hg+/-1.55 mm Hg vs 1.70 mm Hg+/-1.53 mm Hg, respectively; all P larger than 0.05). Absolute value of zero drift in both groups significantly rose with the increased duration of ICP monitoring (P less than 0.05) while zero drift value did not. Moreover, daily absolute value in the intraventricular group was significantly smaller than that in the subdural group (0.27 mm Hg+/-0.32 mm Hg vs 0.29 mm Hg+/-0.18 mm Hg, P less than 0.05). CONCLUSION: This study demonstrates that absolute value of zero drift significantly correlates with duration of both intraventricular and subdural ICP monitoring. Due to the smaller daily absolute value, ICP values recorded from intraventricular system may be more reliable than those from subdural system.

Which side of lateral ventricles to choose during external ventricular drainage in patients with intraventricular hemorrhage: ipsilateral or contralateral?

BACKGROUND: We attempted to investigate the effect of external ventricular drainage (EVD) plus intraventricular fibrinolysis from ipsilateral or contralateral ventricle on clinical outcomes in patients with intraventricular hemorrhage. METHODS: We undertook a prospective controlled study. Patients with acute obstructive hydrocephalus after intraventricular hemorrhage were randomized to receive EVD from ipsilateral ventricle (ipsilateral group [IG]) or contralateral ventricle (contralateral group [CG]). They received intracranial pressure (ICP) monitoring and intraventricular injection of urokinase after surgery. We compared clinical outcomes and complications between groups. RESULTS: A total of 45 patients were enrolled, with a mean age of 55.4 years. We assigned 28 patients assigned to the IG and 17 patients to the CG. Patients in the IG showed significantly faster clot clearance in the third and fourth ventricles on computed tomography than those in the CG (3.3 ± 1.0 d versus 3.9 ± 0.8 d; P = 0.042). Analysis of ICP data showed that initial ICP in the IG was significantly higher than in the CG (20.4 ± 7.2 mm Hg versus 16.5 ± 4.4 mm Hg; P = 0.039), as was the average daily ICP on the following 3 d. The percentage of ICP readings over 20 mm Hg in the IG was also significantly larger than that in the CG (18.0% versus 10.9%; P < 0.001). There was no significant difference in the incidence of complications regarding rebleeding, infection, epilepsy, or communicating hydrocephalus. Neither 30-d mortality rate nor Glasgow Outcome Scale score revealed significant differences between the two groups. CONCLUSIONS: External ventricular drainage plus EVT from the ipsilateral or contralateral ventricle has similar short-term outcomes and complications in patients with intraventricular hemorrhage. Faster clot clearance in the third and fourth ventricles but higher ICP levels at the early stage may be expected in patients with EVD from the ipsilateral ventricle, compared with those from with EVD from the contralateral ventricle.