Activation of JNK and p38 MAPK Mediated by ZDHHC17 Drives Glioblastoma Multiforme Development and Malignant Progression.

Rationale: Glioblastoma multiforme (GBM) almost invariably gain invasive phenotype with limited therapeutic strategy and ill-defined mechanism. By studying the aberrant expression landscape of gliomas, we find significant up-regulation of p-MAPK level in GBM and a potent independent prognostic marker for overall survival. DHHC family was generally expressed in glioma and closely related to the activation of MAPK signaling pathway, but its role and clinical significance in GBM development and malignant progression are yet to be determined. Method: Bioinformatics analysis, western blotting and immunohistochemistry (IHC) were performed to detect the expression of ZDHHC17 in GBM. The biological function of ZDHHC17 was demonstrated by a series of in vitro and in vivo experiments. Pharmacological treatment, flow cytometry, Transwell migration assay, Co- Immunoprecipitation and GST pulldown were carried out to demonstrate the potential mechanisms of ZDHHC17. Results: ZDHHC17 is up-regulated and coordinated with MAPK activation in GBM. Mechanistically, ZDHHC17 interacts with MAP2K4 and p38/JNK to build a signaling module for MAPK activation and malignant progression. Notably, the ZDHHC17-MAP2K4-JNK/p38 signaling module contributes to GBM development and malignant progression by promoting GBM cell tumorigenicity and glioma stem cell (GSC) self-renewal. Moreover, we identify a small molecule, genistein, as a specific inhibitor to disrupt ZDHHC17-MAP2K4 complex formation for GBM cell proliferation and GSC self-renewal. Moreover, genistein, identified herein as a lead candidate for ZDHHC17-MAP2K4 inhibition, demonstrated potential therapeutic effect in patients with ZDHHC17-expressing GBM. Conclusions: Our study identified disruption of a previously unrecognized signaling module as a target strategy for GBM treatment, and provided direct evidence of the efficacy of its inhibition in glioma using a specific inhibitor.

Sequential chemoradiotherapy with gemcitabine and cisplatin for locoregionally advanced nasopharyngeal carcinoma.

We investigated a new chemoradiotherapy (CRT) regimen for locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 240 patients were randomly assigned to three different CRT regimens: sequential CRT [1 cycle chemotherapy + Phase I radiotherapy (RT) + 1 cycle chemotherapy + Phase II RT + 2 cycles chemotherapy] with a cisplatin-gemcitabine (GC) regimen (800 mg/m(2) gemcitabine on Days 1 and 8 and 20 mg/m(2) cisplatin on Days 1-5, every 4 weeks) (sGC-RT); sequential chemoradiotherapy with a cisplatin-fluorouracil (PF) regimen (20 mg/m(2) DDP and 500 mg/m(2) 5-FU on Days 1-5, every 4 weeks) (sPF-RT) and cisplatin-based concurrent chemoradiotherapy plus adjuvant PF chemotherapy (Con-RT + PF). The complete response rate was higher in the sGC + RT group than in the other two groups (98.75% vs. 92.50%, p < 0.01). The 3-year overall survival (OS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) rates in the sGC-RT group were significantly higher than those observed in the Con-RT group (OS, 95.0% vs. 76.3%, p < 0.001; DFS, 89.9% vs. 67.5%, p < 0.001; DMFS, 92.5% vs. 76.0%, p = 0.004) and in the sPF + RT group (OS, 95.0% vs. 73.6%, p < 0.001; DFS, 89.9% vs. 63.3%, p < 0.001; DMFS, 92.5% vs. 74.7%, p = 0.002). There were no significant differences in 3-year OS, DFS and MFS rates between the Con-RT and the sPF-RT groups. The GC-RT group experienced more hematologic toxicity, constipation and rash; however, there were no differences in late RT toxicity between the groups. These results demonstrate that a sGC-RT regimen is effective and well tolerated in patients with locoregionally advanced NPC.

Adverse reactions and their management in the treatment of malignant tumors using cytokine-induced killer cells.

OBJECTIVE: To identify the causes and the corresponding management of adverse reactions during the treatment of malignant tumors using cytokine-induced killer cells. METHODS: From January 2012 to December 2012, 441 patients received a total of 1,393 autologous cytokine-induced killer cell transfusion cycles in our department. The adverse reactions after the procedures were observed (assessed using the National Cancer Institute Common Toxicity version 2.0), and targeted care and health education were delivered by nurses. RESULTS: All treatment sessions were successfully completed, and the following adverse reactions were found: grade 1/3 fever in 1.36% (19/1,393) patients; grade 2/3 fever in 0.86% (12/1,393) patients; grade 2/3 chills in 0.65% (9/1,393) patients; and grade 1/3 dizziness in 0.29% (4/1,393) patients. CONCLUSIONS: After timely intervention of the adverse reactions, all patients were treated successfully. The best timing of the CIK cell therapy for cancer patients is when the tumor burden, or the number of tumor cells, reaches the minimal level after the end of surgery, chemotherapy and radiation therapy.

Item selection in the development of quality of life scale for nasopharyngeal carcinoma patients.

BACKGROUND AND OBJECTIVE: At present, the quality of life (QOL) of nasopharyngeal carcinoma (NPC) patients is assessed with the QOL scales for cancer patients or head and neck cancer patients (QLQ-C30, QLQ-H&N35, and so on), and SF-36 scale, but they are not specific scales for NPC patients. The specific scale for NPC patients (Scale of Quality of Life for Nasopharyngeal Carcinoma, SQOL-NPC) has not been updated. This study was to develop a QOL scale (Quality of Life for Nasopharyngeal Carcinoma, QOL-NPC) for NPC patients in China. METHODS: The pilot scale was formed according to the definition of QOL from WHO and based on interviews with some experts and patients. The data were collected from 433 NPC patients treated in Cancer Center of Sun Yat-sen University from January to February, 2007. The items were preliminarily screened, evaluated, and modified, then selected by the methods of coefficient of variation, correlation analysis, factor analysis, and reliability analysis (the internal consistency Cronbach's coefficients). RESULTS: QOL-NPC was developed and evaluated. The scale included 30 items in four domains: physical function (PH), psychological function (PS), social function (SF), and side effect (SE). CONCLUSION: The QOL-NPC scale might be an effective scale for NPC patients because it is consistent with the WHO definition and connotation of QOL, and contains common issues of NPC patients as well.

[Influence of vacuum bag on direct measurement of depth for isocentric posterior oblique field].

BACKGROUND & OBJECTIVE: In order to improve quality assurance (QA) and quality control (QC) of radiotherapy, individualized vacuum bag is used in the localization of radiation treatment, gradually becoming one of the important steps for the QA and QC in the many departments of radiation oncology. It is controversial whether localization with vacuum bags under the simulator influences the precision of direct measurement for tumor depth in the isocentric posterior oblique field in the patients with thoracic and abdominal tumors. This study was designed to explore the influence of vacuum bag on the direct measurement METHODS: Twenty-nine patients with thoracic and abdominal carcinoma who had to need isocentric irradiation in the supine position were immobilized using vacuum bag. The irradiation depths of 45 posterior oblique fields were determined by CT-simulator and conventional simulator, respectively; then the absolute value for the difference of both depths was regarded as error value. RESULTS: There were 37 fields (82.2%) with error value of smaller than 5 mm; 8 fields (17.8%), more than 5 mm. In the latter, 5 field were belonged to be repositioned in the phase II of radiotherapy because of light leaking air into the vacuum bag in the phase I of radiotherapy. CONCLUSION: Vacuum bag has a slight influence on direct measurement for depths of isocentric posterior oblique field.