Radiotherapy is the most successful nonsurgical treatment for nasopharyngeal carcinoma (NPC). Despite this, the prognosis remains poor. Although NPCs initially respond well to a full course of radiation, recurrence is frequent. The cancer stem cell (CSC) hypothesis provides a framework for explaining the discrepancy between the response of NPC to therapy and the poor survival rate. In this study, a stem cell-like subpopulation (PKH26þ) was identified in NPC cell lines using a label-retention technique. PKH26þ cells were enriched for clonogenicity, sphere formation, side-population cells, and resistance to radiotherapy. Using genomic approaches, we show that the proto-oncogene c-MYC (MYC) regulates radiotolerance through transcriptional activation of CHK1 (CHEK1) and CHK2 (CHEK2) checkpoint kinases through direct binding to the CHK1 and CHK2 promoters. Overexpression of c-MYC in the PKH26þ subpopulation leads to increased expression of CHK1 and CHK2 and subsequent activation of the DNA-damage-checkpoint response, resulting in radioresistance. Furthermore, loss of CHK1 and CHK2 expression reverses radioresistance in PKH26þ (c-MYC high expression) cells in vitro and in vivo. This study elucidates the role of the c-MYC-CHK1/CHK2 axis in regulating DNA-damage-checkpoint responses and stem cell characteristics in the PKH26þ subpopulation. Furthermore, these data reveal a potential therapeutic application in reversal of radioresistance through inhibition of the c-MYC-CHK1/CHK2 pathway. Cancer Res; 73(3); 1219-31. Ó2012 AACR.

Raspberries have been reported to contain abundant anthocyanins and other active compounds. To extract anthocyanins from raspberries more efficiently, a novel procedure of ultrasound-assisted deep eutectic solvent extraction (UADESE) was proposed in this paper. The extraction process was optimized by response surface methodology coupled with a genetic algorithm. The optimum extraction parameters to achieve the highest yield of anthocyanins 1.378 ± 0.009 mg/g from raspberry powder via UADESE were obtained at a water content of 29%, ultrasonic power of 210 W, extraction temperature of 51 °C and extraction time of 32 min. The AB-8 macroporous resin combined with the high-speed counter current chromatography (HSCCC) method were further used to isolate and purify the anthocyanins extracts obtained under optimum extraction conditions, and the structure of purified anthocyanins components were identified by UV-Visible spectrophotometer (UV-Vis), high-performance liquid chromatography (HPLC), high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS/MS), 1H nuclear magnetic resonance (NMR) and 13C-NMR spectra. The two anthocyanins (cyanidin-3-glucoside with a purity of 92.25% and cyanidin-3-rutinoside with a purity of 93.07%) identified were consistent with those present in raspberries. These findings provided an effective and feasible method for extraction, isolation and purification of anthocyanins from natural plant resources.

A low prevalence of AD was found in Tibetans from the Qinghai-Tibet plateau. Multivariate analysis might suggest that regular "mind-body" religious meditative activities may be negatively associated with AD in this population, as well as the CLU genotype at rs9331888.

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