Cognitive Impairment and Mossy Fiber Sprouting in a Rat Model of Drug-resistant Epilepsy Induced by Lithium-pilocarpine.

BACKGROUND: The mossy fiber sprouting (MFS) in the dentate gyrus is a common pathological change of epilepsy. Previous studies suggested that it is associated with drug-resistant epilepsy, and mossy cells control spontaneous seizures and spatial memory. METHODS: We investigated the correlations among cognitive impairment, MFS, seizure frequency and drug resistance in a rat model of epilepsy induced by lithium-pilocarpine. Phenytoin and phenobarbital were used to screen drug resistance. Cognitive function and MFS were detected through the novel object recognition (NOR) test, Morris water maze (MWM) test and Timm staining. RESULTS: The results showed that object memory and spatial memory functions were both significantly impaired in rats with epilepsy, and only spatial memory impairment was more severe in rats with drug-resistant epilepsy. More frequent spontaneous seizures and more obvious MFS were observed in the drug-resistant rats. The seizure frequency was significantly associated with the MWM performance but not with the NOR performance in rats with epilepsy. The degree of MFS was significantly associated with seizure frequency and spatial memory function. CONCLUSION: Taken together, these correlations among drug resistance, seizure frequency, spatial memory impairment and MFS suggested the possibility of a common pathological mechanism. More studies are needed to clarify the underlying mechanism behind these correlations and the detailed role of MFS in epilepsy. The mechanism of mossy cell change may be an important target for the treatment of seizures, drug resistance and cognitive dysfunction in patients with epilepsy.

PPARγ activation suppresses the expression of MMP9 by downregulating NF-κB post intracerebral hemorrhage.

Peroxisome proliferator-activated receptor-gamma (PPARγ) is critical in protecting against inflammatory and oxidative stresses post brain injury. We have previously reported that rosiglitazone, an agonist of PPARγ, was effective to prevent microglia from apoptosis and ameliorate neuronal injuries post intracerebral hemorrhage (ICH) with suppression of matrix metalloproteinase-9 (MMP9) expression. However, molecular mechanisms linking how PPARγ decreases MMP9 remain unknown. Here, we hypothesize that PPARγ downregulates MMP9 expression post hemorrhage by inhibiting nuclear factor kappa B (NF-κB), an upstream regulator of MMPs gene and also key transcription factor involved in the control of immune and neuroinflammatory responses. We found both in vivo and in vitro that PPARγ was significantly downregulated post ICH with prominent increases of NF-κB and MMP9. Activation of PPARγ using rosiglitazone decreased the expression of both NF-κB and MMP9, while reversed effects were observed when administrating the PPARγ antagonist GW9662. Besides, inhibiting NF-κB by JSH-23 also suppressed the expression of MMP9, with only limited effect on PPARγ. Further studies revealed prominent colocalizations of NF-κB with PPARγ and MMP9, respectively. Finally, direct interactions of NF-κB with PPARγ and MMP9 gene were also confirmed, respectively, by protein and chromatin immunoprecipitations. These results suggested a role of NF-κB in mediating the reduction of MMP9 by PPARγ, potentially providing a new therapeutic target for brain hemorrhage.

Co-Inhibition of GLUT-1 Expression and the PI3K/Akt Signaling Pathway to Enhance the Radiosensitivity of Laryngeal Carcinoma Xenografts In Vivo.

In the present study, we investigated the role of GLUT-1 and PI3K/Akt signaling in radioresistance of laryngeal carcinoma xenografts. Volume, weight, radiosensitization, and the rate of inhibition of tumor growth in the xenografts were evaluated in different groups. Apoptosis was evaluated by TUNEL assay. In addition, mRNA and protein levels of GLUT-1, p-Akt, and PI3K in the xenografts were measured. Treatment with LY294002, wortmannin, wortmannin plus GLUT-1 AS-ODN, and LY294002 plus GLUT-1 AS-ODN after X-ray irradiation significantly reduced the size and weight of the tumors, rate of tumor growth, and apoptosis in tumors compared to that observed in the 10-Gy group (p<0.05). In addition, mRNA and protein expression of GLUT-1, p-Akt, and PI3K was downregulated. The E/O values of LY294002, LY294002 plus GLUT-1 AS-ODN, wortmannin, and wortmannin plus GLUT-1 AS-ODN were 2.7, 1.1, 1.8, and 1.8, respectively. Taken together, these data indicate that GLUT-1 AS-ODN as well as the inhibitors of PI3K/Akt signaling may act as radiosensitizers of laryngeal carcinoma in vivo.

Effect of antisense oligodeoxynucleotides glucose transporter-1 on enhancement of radiosensitivity of laryngeal carcinoma.

PURPOSE: Laryngeal carcinomas always resist to radiotherapy. Hypoxia is an important factor in radioresistance of laryngeal carcinoma. Glucose transporter-1 (GLUT-1) is considered to be a possible intrinsic marker of hypoxia in malignant tumors. We speculated that the inhibition of GLUT-1 expression might improve the radiosensitivity of laryngeal carcinoma. METHODS: We assessed the effect of GLUT-1 expression on radioresistance of laryngeal carcinoma and the effect of GLUT-1 expressions by antisense oligodeoxynucleotides (AS-ODNs) on the radiosensitivity of laryngeal carcinoma in vitro and in vivo. RESULTS: After transfection of GLUT-1 AS-ODNs: MTS assay showed the survival rates of radiation groups were reduced with the prolongation of culture time (p<0.05); Cell survival rates were significantly reduced along with the increasing of radiation dose (p<0.05). There was significant difference in the expression of GLUT-1mRNA and protein in the same X-ray dose between before and after X-ray radiation (p<0.05). In vivo, the expressions of GLUT-1 mRNA and protein after 8Gy radiation plus transfection of GLUT-1 AS-ODNs were significant decreased compared to 8Gy radiation alone (p<0.001). CONCLUSION: Radioresistance of laryngeal carcinoma may be associated with increased expression of GLUT-1 mRNA and protein. GLUT-1 AS-ODNs may enhance the radiosensitivity of laryngeal carcinoma mainly by inhibiting the expression of GLUT-1.

Recurrent prognostic factors and expression of GLUT-1, PI3K and p-Akt in adenoid cystic carcinomas of the head and neck: Clinicopathological features and biomarkers of adenoid cystic carcinoma.

The purpose of this study was to explore the factors associated with the recurrence of adenoid cystic carcinomas (ACCs). We examined the recurrence values of clinicopathological variables and GLUT-1, p-Akt and PI3K expression in 42 patients with ACC. Of the 42 patients, 17 developed recurrence following initial surgery. The positive rates of GLUT-1, PI3K and p-Akt protein expression in ACC were 38.1, 38.1 and 50.0%, respectively. The expression of GLUT-1, p-Akt or PI3K protein in ACC was higher than that in inflammatory lesions or benign tumors. Our study demonstrated that T stage, a positive resection margin, perineural invasion, surgery without postoperative radiotherapy and the expression of GLUT-1, PI3K and p-Akt were factors predictive of recurrence by univariate analyses. In multivariate analyses, perineural invasion, a positive resection margin and p-Akt were significant predictors of recurrence. Initial surgery is very significant in the recurrence of ACC. Overexpression of GLUT-1, PI3K and p-Akt may also play a role in its development and recurrence.

¹8F-fluorodeoxyglucose positron emission tomography/computed tomography as an effective diagnostic workup in cervical metastasis of carcinoma from an unknown primary tumor.

PURPOSE: The purpose of this study is to assess the potential of ¹8F-fluorodeoxyglucose (¹8FDG) positron emission tomography/computed tomography (PET/CT) imaging for the diagnosis of cervical metastasis of carcinoma of an unknown primary tumor (CUP) and to determine whether the maximum standardized uptake value (SUV(max)) is a prognostic factor. METHODS: Twenty-five consecutive patients with cervical metastasis of CUP were retrospectively analyzed by PET/CT between July 2007 and July 2011. RESULTS: FDG PET/CT suggested a primary tumor in 21 out of 25 patients (84.0%). The sensitivity of FDG PET/CT in detecting the primary tumor was 73.3% (11 of 15), and the positive predictive value was 52.4% (11 of 21). The median follow-up duration of survival patients was 10.4 months (range: 0-30 months). The estimated 2-year overall survival rate of all patients was 50.0%. Univariate analyses did not reveal a significant difference in overall survival between the group of 11 patients identified by pathology and the 14 patients not identified by pathology (overall survival was 57.1% and 49.1%, respectively; p=0.468). The median SUV(max) was 7.6. In the log-rank test, patients with a low SUV(max) (≤ 7.0) in cervical lymph nodes had a significantly higher survival rate at 2 years (87.5% vs. 21.2%; p=0.007) than patients with a high SUV(max) (>7.0). CONCLUSIONS: Although our study was inconclusive due to the small sample size, our results suggest that FDG PET/CT may be an effective diagnostic workup in the cervical metastasis of carcinoma from an unknown primary tumor (UPT). In the present study, SUV(max) of PET/CT in the cervical lymph node may serve as a prognostic factor of cervical metastasis of carcinoma from a UPT based on the limited number of patients. Further studies are needed to confirm these findings.

Etiology analysis and computed tomography imaging of a tonsillar inflammatory myofibroblastic tumor: report of an immunocompetent patient and brief review.

OBJECTIVES: The etiology of Inflammatory myofibroblastic tumor(IMT) is contentious. In this study, we used computed tomography (CT) to examine tonsillar IMT and further analyzed the etiology of this entity. METHODOLOGY: We presented CT features of left tonsillar IMT and reviewed the English-language literature published between 1984 and 2011. RESULTS: To our knowledge, there are only six published cases of tonsillar IMT including the present case. Two patients were asymptomatic at initial presentation. Two patients were taking immunosuppressants, and one was pregnant and in an immunomodulated state. CT of our patient revealed a 2.6 × 1.8 cm irregular soft tissue mass between the left tonsil and the base of the tongue. It did not invade surrounding structures and was not enhanced on contrast-enhanced imaging. CONCLUSIONS: Tonsillar IMT may be a benign tumor. We suggest that preoperative recognition of tonsillar IMT by CT may be important to avoid unnecessary expanded surgery.