Impact of chrono-radiotherapy on the prognosis and treatment-related toxicity in patients with locally advanced nasopharyngeal carcinoma: A multicenter propensity-matched study.

The timing of radiotherapy (RT) delivery has been reported to affect both cancer survival and treatment toxicity. However, the association among the timing of RT delivery, survival, and toxicity in locally advanced nasopharyngeal carcinoma (LA-NPC) has not been investigated. We retrospectively reviewed patients diagnosed with LA-NPC who received definitive RT at multiple institutions. The median RT delivery daytime was categorized as morning (DAY) and night (NIGHT). Seasonal variations were classified into the darker half of the year (WINTER) and brighter half (SUMMER) according to the sunshine duration. Cohorts were balanced according to baseline characteristics using propensity score matching (PSM). Survival and toxicity outcomes were evaluated using Cox regression models. A total of 355 patients were included, with 194/161 in DAY/NIGHT and 187/168 in WINTER/SUMMER groups. RT delivered during the daytime prolonged the 5-year overall survival (OS) (90.6% vs. 80.0%, p = 0.009). However, the significance of the trend was lost after PSM (p = 0.068). After PSM analysis, the DAY cohort derived a greater benefit in 5-year progression-free survival (PFS) (85.6% vs. 73.4%, p = 0.021) and distant metastasis-free survival (DMFS) (89.2% vs. 80.8%, p = 0.051) in comparison with the NIGHT subgroup. Moreover, multivariate analysis showed that daytime RT was an independent prognostic factor for OS, PFS, and DMFS. Furthermore, daytime RT delivery was associated with an increase in the incidence of leukopenia and radiation dermatitis. RT delivery in SUMMER influenced only the OS significantly (before PSM: p = 0.051; after PSM: p = 0.034). There was no association between toxicity and the timing of RT delivery by season. In LA-NPC, the daytime of radical RT served as an independent prognostic factor. Furthermore, RT administered in the morning resulted in more severe toxic side effects than that at night, which needs to be confirmed in a future study.

Therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development through HSPA5/NFκB/CD55 pathway in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is endemic in Southern China and Southeast Asia. Hyperthermia is widely used in combination with chemotherapy and radiotherapy to enhance therapeutic efficacy in NPC treatment, but the underlying anti-tumor mechanisms of hyperthermia remain unclear. Complement C3 has been reported to participate in the activation of immune system in the tumor microenvironment, leading to tumor growth inhibition. In this study, we aimed to explore the effect and mechanisms of hyperthermia and investigate the functional role of complement C3 in NPC hyperthermia therapy (HT). The serum levels of complement C3 before and after hyperthermia therapy in patients with NPC were analyzed. NPC cell lines SUNE1 and HONE1 were used for in vitro experiment to evaluate the function of complement C3 and HT on cell proliferation and apoptosis. SUNE1 xenograft mouse model was established and tumor-bearing mice were treated in water bath at a constant temperature of 43°C. Tumor samples were collected at different time points to verify the expression of complement C3 by immunohistochemical staining and western blot. The differential expressed genes after hyperthermia were analyzed by using RNA sequencing. We found that complement could enhance hyperthermia effect on suppressing proliferation and promoting apoptosis of tumor cells in NPC. Hyperthermia decreased the mRNA expression of complement C3 in tumor cells, but promoted the aggregation and activation circulating C3 in NPC tumor tissue. By using in vitro hyperthermia-treated NPC cell lines and SUNE1 xenograft tumor-bearing mice, we found that the expression of heat shock protein 5 (HSPA5) was significantly upregulated. Knockdown of HSPA5 abrogated the anti-tumor effect of hyperthermia. Moreover, we demonstrated that hyperthermia downregulated CD55 expression via HSPA5/NFκB (P65) signaling and activated complement cascade. Our findings suggest that therapeutic hyperthermia regulates complement C3 activation and suppresses tumor development via HSPA5/NFκB/CD55 pathway in NPC.

Sodium valproate prevents radiation-induced injury in hippocampal neurons via activation of the Nrf2/HO-1 pathway.

PURPOSE: To investigate the neuroprotective role of sodium valproate (VPA) in a hippocampal neuronal cell line (HT22) and the hippocampus of zebrafish after exposure to radiation. METHODS: We investigated whether VPA could protect HT22 hippocampal neurons and the hippocampus of zebrafish from radiation-induced injury. We measured the generation of reactive oxygen species (ROS), the mitochondrial membrane potential, the levels of glutathione (GSH) and malondialdehyde (MDA), and the activity of superoxide dismutase (SOD). The expression of nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was also measured. The cognitive behavior of the zebrafish was evaluated 1month after radiation exposure. RESULTS: VPA treatment improved the survival rate (300 mg/kg body weight (BW) VPA: 76.67%; 100 mg/kg BW VPA: 56.7%) of zebrafish 1 month after exposure to a lethal dose of whole-body irradiation (P<0.01). VPA treatment decreased the ROS generation (P<0.01), decreased the MDA levels (P<0.01), increased the GSH levels (P<0.01) and increased the SOD activity (P<0.01). VPA treatment activated the Nrf2/HO-1 pathway, increased the nuclear translocation of Nrf2 and increased the mRNA (P<0.01) and protein expression of HO-1 to prevent radiation-induced neuronal injury. SiRNA knockdown of the Nrf2 gene prevented the VPA-induced attenuation of radiation injury in the HT22 neuronal cells that was found in the control cells (40.09±1.76% vs. 41.14±1.09%, P>0.05). VPA also improved the zebrafish cognitive behavior after radiation-induced neuronal injury as measured by the exploration test (control 5.74±1.42min vs. radiation therapy 16.39±4.03min vs. radiation therapy plus VPA 7.18±1.79min, P<0.05). CONCLUSIONS: ROS generation after radiation exposure contributes to DNA damage in the zebrafish brain. VPA inhibits ROS generation by activating the Nrf2/HO-1 pathway, which improves cognitive behavior following radiation-induced neuronal injury.

Protective effect of tanshinone IIA against radiation-induced ototoxicity in HEI-OC1 cells.

Radiotherapy is a highly efficient treatment method for nasopharyngeal carcinoma that is often accompanied by significant ototoxic side-effects. The inner ear hair cells are particularly prone to serious injury following radiotherapy. Tanshinone IIA is a transcription factor inhibitor that is extracted from the traditional herbal medicine, Salvia miltiorrhiza Bunge. The present study investigated the effects of tanshinone IIA treatment on radiation-induced toxicity in the HEI-OC1 hair cell line. Using an MTT assay and flow cytometry, the radiation-induced weakening of the cells was observed to be alleviated when the cells were pre-treated with tanshinone IIA. Radiation exposure promoted p65/nuclear factor (NF)-κB nuclear translocation and activated the p53/p21 pathway, two processes which play a significant role in radiation-induced cell apoptosis. However, pre-treatment of the cells with tanshinone IIA inhibited p65/NF-κB nuclear translocation and p53/p21 pathway activation. These results demonstrate that tanshinone IIA is capable of protecting cochlear cells from radiation-induced injury through the suppression of p65/NF-κB nuclear translocation and the p53/p21 signaling pathway.