DNA damage-induced NF-κB activation in human glioblastoma cells promotes miR-181b expression and cell proliferation.

BACKGROUND: Glioblastoma (GBM) is the most common and most aggressive form of brain cancer. After surgery, radiotherapy is the mainstay of treatment for GBM patients. Unfortunately, the vast majority of GBM patients fail responding to radiotherapy because GBM cells remain highly resistant to radiation. Radiotherapy-induced DNA damage response may correlate with therapeutic resistance. METHODS: Ionizing radiation (IR) was used to induce DNA damage. Cell proliferation and migration were detected by wound-healing, MTT and apoptosis assays. Dual-luciferase assays and Western blot analysis were performed to evaluate NF-κB activation and validate microRNA targets. Real-time PCR was used to study mRNA and microRNA levels. RESULTS: IR-induced DNA damage activated NF-κB in GBM cells which promoted expression of IL-6, IL-8 and Bcl-xL, thereby contributing to cell survival and invasion. Knockdown SENP2 expression enhanced NF-κB essential modulator (NEMO) SUMOylation and NF-κB activity following IR exposure. miR-181b targets SENP2 and positively regulated NF-κB activity. CONCLUSION: NF-κB activation by DNA damage in GBM cells confers resistance to radiation-induced death.

Β-elemene inhibits Hsp90/Raf-1 molecular complex inducing apoptosis of glioblastoma cells.

ß-Elemene, an active component of herb medicine Curcuma wenyujin, has been shown to antagonize glioblastoma cells by inducing apoptosis. However, how ß-elemene induces apoptosis of these cells remains unclear. In this study, we report that ß-elemene disrupted the formation of the Hsp90/Raf-1 complex, a key step in maintaining the conformation stability of Raf-1, and caused deactivation of Raf-1 and inhibition of the ERK pathway, thereby leading to apoptosis of glioblastoma cells. Specifically, treatment of glioblastoma cell lines with ß-elemene attenuated phosphorylation of multiple members of the kinase families in the Ras/Raf/MEK/ERK cascade, including Raf-1 and ERK as well as downstream signaling targets such as Bcl-2. These results suggest that the Hsp90/Raf-1 complex could be a promising molecular target for new drug development for the treatment of glioblastoma.

Clinical characteristics and treatment outcome of children with intraocular retinoblastoma: a report from a Chinese cooperative group.

BACKGROUND: To present the characteristics and treatment outcome of patients with intraocular retinoblastoma in a Chinese cooperative group. PROCEDURE: Between January 2005 and March 2009, 159 eyes of 133 patients with retinoblastoma were included in this retrospective study. The International Classification of Retinoblastoma (ICRB) staging system was noted for each patient. Cases with visible extraocular extension at diagnosis were excluded. The patient data were reviewed for demographic information, clinical findings, and managements. RESULTS: Of 133 cases, there were 83 (62%) male and 50 (38%) female, ranging in age from 2 months to 134 months (median, 23 months; mean, 26 months). There were 26 bilateral cases (20%). One hundred and twenty-four cases (93%) were deemed sporadic and nine cases (7%) were deemed familial. Leukocoria was the most common presenting symptom. One hundred and twenty-three eyes (77%) of 123 patients (92%) had no visual potential. Only 36 eyes (23%) of 30 patients (23%) utilized vision-preserving treatments. The ocular salvage rate was 83% (30/36) for this group. The cumulative probability of survival was 98% (Kaplan-Meier method) at 60 months follow up. CONCLUSIONS: The overall survival rate of this study is in agreement with data from developed countries. In appropriate patients, systemic chemotherapy, and focal ophthalmic therapy are effective and carry little morbidity. Compared with more medically developed countries, there are still many challenges in the management of retinoblastoma in China. Early detection and doctor education should be an important future goal. Pediatr Blood Cancer 2011; 57: 1113-1116. © 2011 Wiley Periodicals, Inc.

[Clinicopathologic features of retinoblastoma and expression of VEGF and Ki-67 after comprehensive treatment].

OBJECTIVE: To investigate the clinic pathologic features of retinoblastoma (RB) after comprehensive treatment, and study the expression of vascular endothelial growth factor (VEGF) in retinoblastoma treated with chemotherapy prior to enucleation. METHODS: Retrospective analysis was performed on retinoblastoma specimens obtained consecutively between 2006 and 2008 by enucleation, and patients' clinical information and clinic pathologic features were also collected. Immunohistochemical staining and real-time PCR were performed for the expression of VEGF. Immunohistochemical staining was also performed for Ki-67. RESULT: Among the 9 chemotherapy-treated cases, six belonged to group D and three to group E of IIRC. The reasons for enucleation included extensive vitreous seeds, RB recurrence, extensive subretinal fluid/seeds, vitreous hemorrhage and total tractional detachment of the retina. During the comprehensive treatment, the main tumors regressed in all eyes. The main tumors showed a mean decrease of 43.7% in the largest basal diameter and a mean decrease of 57.9% in thickness. The average interval between the end of chemotherapy and enucleation was 5.7 months. The reason for enucleation was the recurrence of main tumor, recurrence of new tumors, recurrent vitreous seed or subretinal seed. Three eyes showed a type 1 regression pattern, one eye showed a type 2 pattern, and the other five eyes showed type 3 clinical regression patterns. The expression of VEGF was lower in eyes that underwent planned enucleation than eyes that suffered from RB recurrence. CONCLUSIONS: The main reason for enucleation was extensive subretinal fluid/seeds after the comprehensive treatment. The type 3 clinical regression patterns were most common. In retinoblastoma, higher expression of VEGF may play an important role in the recurrence of retinoblastoma after comprehensive treatment.

[Clinical analysis of sarcoidosis of ocular adnexa].

OBJECTIVE: To study the diagnosis and treatment of 17 patients with sarcoidosis in ocular adnexa. METHODS: The clinical data of 17 cases with sarcoidosis in ocular adnexa treated during 1993 and 2008 were retrospectively analyzed. All patients underwent surgical treatment, and the diagnosis was proven histopathologically. RESULTS: Among the 17 cases, 4 were male, and 13 were female. The patients' age ranged from 15 to 70 years, with a mean of 46.9 years. The lesions were located at the orbit (8 cases), lacrimal grand (5 cases) and eyelids (4 cases). Fourteen cases complained of the presence of a local mass, 2 cases complained of exophthalmos and 1 swelling of eyelids. Concurrent systemic sarcoidosis was present in 7 cases. Three cases coincided with lung sarcoidosis, 3 cases with uveitis and 1 case with dermatopathy. Angiotensin converting enzyme analysis was performed in 6 cases; 4 of them were elevated. Computer tomography was performed in 12 cases; in 11 cases it presented as moderate density parenchymatous mass, and in the remaining one it presented as hypodensity cystic mass. B scan of 5 cases showed hypoechoic parenchymatous homogeneous mass. None of 14 cases relapsed after 1 to 15 years follow-up. CONCLUSIONS: Ocular adnexal sarcoidosis usually presents as local mass and it should be included in the differential diagnosis of orbital and ocular adnexal lesions. Excision of localized mass alone could achieve satisfactory outcomes for isolated lesions, while for diffuse or systematic lesions, corticosteroid treatment should be prescribed routinely.

Anti-tumor effect of beta-elemene in glioblastoma cells depends on p38 MAPK activation.

beta-Elemene, a natural plant drug extracted from Curcuma wenyujin, has been used as an antitumor drug for different tumors, including glioblastoma. However, the mechanism of its anti-tumor effect is largely unknown. Here we report that anti-proliferation of glioblastoma cells induced by beta-elemene was dependent on p38 MAPK activation. Treatment of glioblastoma cell lines with beta-elemene, led to phosphorylation of p38 MAPK, cell-cycle arrest in G0/G1 phase and inhibition of proliferation of these cells. Inhibition of p38 MAPK reversed beta-elemene-mediated anti-proliferation effect. Furthermore, the growth of glioblastoma cell-transplanted tumors in nude mice was inhibited by intraperitoneal injection of beta-elemene. Taken together, our findings indicate that activation of p38 MAPK is critical for the anti-proliferation effect of beta-elemene and that p38 MAPK might be a putative pharmacological target for glioblastoma therapy.

[Effect of p38 MAPK on elemene-induced cell cycle arrest in C6 glioblastoma cells].

OBJECTIVE: To observe the effect of elemene on cell cycle of rat C6 glioblastoma cells. METHODS: Cell cycle analysis and expression of p38 in C6 glioblastoma cells under elemene treatment were measured by flow cytometry and Western blot. Flow cytometry and MTT assay were used to examine cell cycle and cell proliferation while C6 glioblastoma cells were pretreated with p38 inhibitor and DN-p38 plasmids. RESULTS: The fraction of C6 in the G0/G1 phase increased 11%, 6.95%, 19.57% respectively in the presence of 40, 60 and 80 microg/ml elemene. The level of phosphorylated p38 MAPK was greatly increased in a dose and time-dependent manner. Inhibition of p38 MAPK activation with SB203580 and DN-p38 blocked elemene-induced anti-proliferation effect. CONCLUSION: Elemene could induce G0/G1 cell cycle phase arrest of C6 glioblastoma cells through up-regulation of phosphorylated p38.

[Orbital solitary fibrous tumor: a clinicopathologic analysis].

OBJECTIVE: To study clinicopathologic features, histologic characteristics, differential diagnosis and the treatment of orbital solitary fibrous tumor (SFT). METHODS: Clinical, radiographic and pathologic findings of 6 cases of SFT were retrospectively analyzed. Immunohistochemistry were performed on selected samples. RESULTS: Four patients were males and 2 were females. Patients age ranged from 19- to 57-years-old. The location of the tumor was in the muscle cone (case 1 and case 5), medial (case 3), lateral (case 4), superior (case 2) and inferolateral (case 6) portion of the orbit, respectively. The presenting symptom was proptosis in 3 cases and was mass of subconjunctival or orbit margin in other 3 cases. Image examination: SFT appeared as a round (case 6 showed irregular) and well-circumscribed parenchymatous mass that could be homogenously enhanced by contrast. Histologically, SFT displayed as a mass of spindle cells in an irregular arrangement Sometime, tumor cells could be storiform or sarciniform. Mitotic figures were infrequent and usually there were 0 to 3 mitotic figures per 10 high-power fields. Hyalinization and staghornform blood vessels were frequently observed. SFT was immunoreactive for markers such as Vim, CD34 and CD99. Two cases were recurred. CONCLUSIONS: SFT is a rare orbital tumor and could be confused with other types of orbital tumors. This tumor can be diagnosed by pathological and immunocytochemical studies, these characteristics can be used to differentiate it from other types of orbital tumors.

Claudin-1 correlates with poor prognosis in lung adenocarcinoma.

BACKGROUND: This study was conducted to investigate the clinical significance of claudin-1 (CLDN1) expression in patients with lung adenocarcinoma. METHODS: We examined CLDN1 protein expression by immunohistochemistry in a tissue microarray from 258 patients with lung adenocarcinoma. We investigated messenger ribonucleic acid (mRNA) expression in H358 (formerly bronchioloalveolar carcinoma) and lung adenocarcinoma cell lines (A549) by real-time reverse transcriptase-polymerase chain reaction. RESULTS: Multivariate analysis showed that prognostic factors for lung adenocarcinoma were histologic type, CLDN1, T stage and N stage. Patients with positive CLDN1 expression had a poorer prognosis than patients with negative CLDN1 expression. CLDN1 expression was correlated with Ras and epidermal growth factor receptor (EGFR) expression. Patients with positive expressions of both CLDN1 and Ras/EGFR had a poorer prognosis than patients with CLDN1 (+) Ras/EGFR(-) or CLDN1 (-) Ras/EGFR(+) and patients with negative expressions of both CLDN1 and Ras/EGFR. CLDN1 mRNA expression was lower in the H358 compared with the lung adenocarcinoma cell line (A549). CONCLUSION: The combination of CLDN1 and Ras/EGFR is a valuable independent prognostic predictor for lung adenocarcinoma.