Yanming Qu

Increased isoform-specific membrane translocation of conventional and novel protein kinase C in human neuroblastoma SH-SY5Y cells following prolonged hypoxia

Several studies have suggested that protein kinase C (PKC) plays a key role in the mechanism of cerebral ischemic/hypoxic preconditioning (I/HPC). However, detailed information regarding PKC isoforms in response to brain ischemia/hypoxia and their potential role in neuroprotection is unclear. Previous studies in our laboratory have demonstrated that the levels in membrane translocation of conventional PKC (cPKC) betaII, gamma, and novel PKCepsilon (nPKC), but not cPKCalpha, betaI, nPKCdelta, eta, mu, theta, and atypical PKC (aPKC) zeta and iota/lambda, were increased significantly in the hippocampus and cortex of intact mice with hypoxic preconditioning. To further detect cPKC and nPKC isoforms activation following prolonged hypoxia in vitro, we tested the membrane translocation (an indicator of PKC activation) of cPKCalpha, betaI, betaII, and gamma, and nPKCdelta, epsilon, eta, mu, and theta in a human neuroblastoma SH-SY5Y cell line following sustained hypoxic exposure (1% O(2)/5% CO(2)/94% N(2)). Using Western blot and immunocytochemistry methods, we found that the levels of cPKCalpha, betaI, betaII, and nPKCepsilon, but not nPKCdelta, eta, mu, and theta, membrane translocation were increased significantly (P < 0.05, n = 8) in a time-dependent manner (from 0.5 to 24 h) following sustained hypoxic exposure. Similarly, the immunostaining experiment also showed a noticeable translocation of cPKCalpha, betaI, betaII, and nPKCepsilon from the cytosol to the perinuclear or membrane-related areas after 6 h posthypoxic exposure. In addition, no cPKCgamma was detected in this cell line under either a normoxic or hypoxic condition. These results suggested that prolonged hypoxia may induce the activation of cPKCalpha, betaI, betaII, and nPKCepsilon by triggering their membrane translocation in SH-SY5Y cells.

VCAM-1 siRNA reduces neointimal formation after surgical mechanical injury of the rat carotid artery

OBJECTIVE Restenosis is one of several complications following carotid endarterectomy (CEA). The pathogenesis of restenosis may be related to postsurgery inflammation and leukocyte recruitment mediated by cellular adhesion molecules. In this study, we examine the role of vascular cell adhesion molecule-1 (VCAM-1) in carotid neointimal hyperplasia following carotid surgical mechanical de-endothelialization (CSMDE) in a rat model of CEA. METHODS The inhibition of siRNA on VCAM-1 protein expression was determined by using the methods of immunostaining and Western blot. Ultrasound imaging and morphometric analysis were applied to measure the degree of CSMDE-induced carotid artery neointimal hyperplasia of rats. RESULTS We found that a lentivirus-based construct expressing a small interfering RNA (siRNA) against VCAM-1 could effectively (P < .05, n = 10 per group) reduce VCAM-1 protein expression in the carotid arteries of rats undergoing CSMDE (CSMDE+RNAi: 135.0 +/- 27.6%) when compared that of CSMDE with scrambled siRNA (CSMDE+CON: 182.7 +/- 36.4%). Doppler ultrasonography revealed that CSMDE+RNAi was accompanied by a significant reduction in the extent of stenosis demonstrated by increased blood velocity (665.85 +/- 48.37 mm/s) and linear diameter (0.59 +/- 0.77 mm) compared to CSMDE+CON (46.72 +/- 28.67 mm/s with undetectable linear diameter, P < .05, n = 10 per group). In addition, morphometric analysis of hematoxylin and eosin (HE)-stained sections indicated that the intima (innermost layer of media at lesion site)/media area ratio (I/M) was significantly increased (P < .05, n = 10 per group) both in the CSMDE (3.99 +/- 0.65) and CSMDE+CON (4.33 +/- 0.59) groups compared with the SHAM group (0.35 +/- 0.13). However, CSMDE+RNAi resulted in a significant (P < .05, n = 10 per group) decrease in the I/M ratio (1.79 +/- 0.43) compared to CSMDE+CON, whereas there were no significant differences in the total arterial area and medial areas among the groups. CONCLUSION These results suggest that perivascular events mediated by VCAM-1 are likely to play an important role in the pathogenesis of carotid artery neointimal hyperplasia in rats after CSMDE.

Fluid-fluid level in cystic vestibular schwannoma: a predictor of peritumoral adhesion

OBJECT The aim of this study was to evaluate the clinical results and surgical outcomes of cystic vestibular schwannomas (VSs) with fluid-fluid levels. METHODS Forty-five patients with cystic VSs and 86 with solid VSs were enrolled in the study. The patients in the cystic VSs were further divided into those with and without fluid-fluid levels. The clinical and neuroimaging features, intraoperative findings, and surgical outcomes of the 3 groups were retrospectively compared. RESULTS Peritumoral adhesion was significantly greater in the fluid-level group (70.8%) than in the nonfluid-level group (28.6%) and the solid group (25.6%; p < 0.0001). Complete removal of the VS occurred significantly less in the fluid-level group (45.8%, 11/24) than in the nonfluid-level group (76.2%, 16/21) and the solid group (75.6%, 65/86; p = 0.015). Postoperative facial nerve function in the fluid-level group was less favorable than in the other 2 groups; good/satisfactory facial nerve function 1 year after surgery was noted in 50.0% cases in the fluid-level group compared with 83.3% cases in the nonfluid-level group (p = 0.038). CONCLUSIONS Cystic VSs with fluid-fluid levels more frequently adhered to surrounding neurovascular structures and had a less favorable surgical outcome. A possible mechanism of peritumoral adhesion is intratumoral hemorrhage and consequent inflammatory reactions that lead to destruction of the tumor-nerve barrier. These findings may be useful in predicting surgical outcome and planning surgical strategy preoperatively.

Localization of transverse-sigmoid sinus junction using preoperative 3D computed tomography: application in retrosigmoid craniotomy.

In retrosigmoid craniotomy, neurosurgeons usually depend on surface landmarks and their experience to evaluate the position of transverse-sigmoid sinus junction (TSSJ) and place an appropriate initial burr-hole, which is not accurate each time because of variability in different craniums. The authors introduce a simple procedure based on 3D computed tomography (CT) to localize the TSSJ in retrosigmoid craniotomy. Eighteen patients who underwent retrosigmoid craniotomy were analyzed. On the internal view of skull in 3D CT image, a simulative burr-hole was placed on the margin of transverse-sigmoid sinus groove junction. Then, on the external view of skull in 3D CT image, the center of the simulative burr-hole was marked and a coordinate system was established based on a line connected the digastric point and the asterion. Then the coordinate of the burr-hole’s center was measured in this coordinate system. In operation, the burr-hole was placed according to the coordinate measured previously and craniotomy was performed. The margin of TSSJ was exposed in each case. No damage of venous sinus was encountered. Post-operative skull base CT demonstrated a good match between the actual and predicted burr-hole and bone defects only existed along the cut line. This simple method could help in localizing the TSSJ and avoiding the risk of sinus injury and reducing the bone defect. It is sufficiently precise for practical application at surgical planning.

Downregulation of β-arrestin 1 suppresses glioblastoma cell malignant progression vis inhibition of Src signaling

ABSTRACT Glioblastoma multiforme (GBM) is one of the most common brain malignancies worldwide and is typically associated with a dismal prognosis, yet the mechanisms underlying its aggressiveness remain unclear. Here, we revealed that &bgr;‐arrestin 1 was overexpressed in GBM and contributed to poorer outcome. Knockdown of &bgr;‐arrestin 1 suppressed the proliferation, invasiveness and glycolysis of GBM cells, and also enhanced temozolomide efficacy. Further, we discovered that knockdown of &bgr;‐arrestin 1 decreased the activity of Src, and suppression of Src signaling was critically involved in &bgr;‐arrestin 1 silencing‐mediated suppression of GBM malignancies. Finally, we investigated the effect of &bgr;‐arrestin 1 knockdown on the tumor growth and survival of xenograft models, and found that sh&bgr;‐arrestin 1 apparently inhibited GBM growth in vivo and resulted in better survival of mice. Taken together, our findings suggest that knockdown of &bgr;‐arrestin 1 can suppress GBM cell proliferation, invasion and glycolysis by inhibiting Src signaling. Thus, targeting &bgr;‐arrestin 1 may be a potential therapeutic strategy for GBM treatment. HighlightsExpression of &bgr;‐arrestin 1 was upregulated in GBM and contributed to poor outcome.Knockdown of &bgr;‐arrestin 1 inhibited the proliferation and glycolysis of GBM cells.Knockdown of &bgr;‐arrestin 1 decreased the activity of Src signaling and expressions of malignancy‐related factors.Knockdown of &bgr;‐arrestin 1 suppressed GBM growth in vivo.

Sellar and Suprasellar Granular Cell Tumor of Neurohypophysis

IntroductIon Granular cell tumor (GCT) of neurohypophysis was first reported by Boyce and Beadles in 1983.[1] In 2016 WHO classification of central nervous system (CNS) tumors, GCT of neurohypophysis was defined as a distinct diagnosis.[2] Here, we reported two cases of GCT of neurohypophysis misdiagnosed as pituitary adenoma and craniopharyngioma. One of the cases was a very rare fully described neurohypophysial GCT which invaded into the right cavernous sinus [Figure 1a and 1b], indicating that the benign tumor might possess aggressive features.

Targeting hyperactivated DNA-PKcs by KU0060648 inhibits glioma progression and enhances temozolomide therapy via suppression of AKT signaling

The overall survival remains undesirable in clinical glioma treatment. Inhibition of DNA-PKcs activity by its inhibitors suppresses tumor growth and enhances chemosensitivity of several tumors to chemotherapy. However, whether DNA-PKcs could be a potential target in glioma therapy remains unknown. In this study, we reported that the hyperactivated DNA-PKcs was profoundly correlated with glioma malignancy and observe a significant association between DNA-PKcs activation and survival of the glioma patients. Our data also found that inhibition of DNA-PKcs by its inhibitor KU0060648 sensitized glioma cells to TMZ in vitro. Specifically, we demonstrated that KU0060648 interrupted the formation of DNA-PKcs/AKT complex, leading to suppression of AKT signaling and resultantly enhanced TMZ efficacy. Combination of KU0060648 and TMZ substantially inhibited downstream effectors of AKT. The in vivo results were similar to those obtained in vitro. In conclusion, this study indicated that inhibition of DNA-PKcs activity could suppress glioma malignancies and increase TMZ efficacy, which was mainly through regulation of the of AKT signaling. Therefore, DNA-PKcs/AKT axis may be a promising target for improving current glioma therapy.

A Case of Tentorial Mesenchymal Chondrosarcoma With Bone Metastases

Intracranial mesenchymal chondrosarcoma (MC) with distant metastasis is rare. We present a case of tentorial MC with bone metastases. A 28-year-old Chinese female presented with headaches and double visual failure. Magnetic resonance imaging showed a large mass in the right temporal region with a wide base attached on the upper side of tentorium with intense enhancement. The patient presented with right occipital headache and poor balance. Four years after the first operation, magnetic resonance imaging revealed that the tumor recurred. The patient experienced lower back pain 7 months after the second operation. Multiple metastatic foci on vertebrae, hip bones, and femurs were revealed by bone scan (SPECT). The patient underwent craniotomies twice and whole-brain radiotherapy with a dose of 56 Gy after the second operation. Radiotherapy of the lumbar and pelvic regions was performed with a dose of 40 Gy when evidence of bone metastases was found. Intracranial MC is an extremely rare neoplasm. For complete treatment, it is important to totally remove the tumor and additionally administer postoperative adjuvant radiation therapy. The prognosis of MC is poor, and the tumor has significant potential for local recurrence and distant metastasis.