No abstract

Combination of sorafenib, cisplatin (80 mg/m(2)) and 5-FU (3000 mg/m(2)) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted.

Keloids exhibit cancer-like properties without spontaneous regression and usually recur post excision. Although photodynamic therapy (PDT) is a promising treatment, details of the mechanisms remain to be elucidated. In this study, we investigated mechanisms involved in 5-Aminolevulinic Acid (5-ALA)–based PDT against keloid. Found that 5-ALA-PDT induced superoxide anion-dependent autophagic cell death. Application of autophagy inhibitor 3-Methyladenine (3-MA) significantly prevented the effect that 5-ALA-PDT induced keloid–derived fibroblasts death, but Z-VAK-FMK (apoptotic inhibitor) did not. Interestingly, 5-ALA-PDT promoted the SIRT3 protein expression and the activity of mitochondrial superoxide dismutase 2 (SOD2), but SIRT1 protein expression level was decreased. SOD2 as a key enzyme can decrease mitochondrial ROS (mROS) level, Deacetylation of SOD2 by SIRT3 regulates SOD2 enzymatic activity has been identified. Then we explored SOD2 acetylation level with immunoprecipitation, found that 5-ALA-PDT significantly increased the acetylation levels of SOD2. In order to confirm deacetylation of SOD2 regulated by SIRT3, 3-TYP (SIRT3 inhibitor) was used. Found that inhibition of SIRT3 by 3-TYP significantly increased the level of SOD2 acetylation level compared with control group or 5-ALA-PDT group. To explore the connection of SIRT1 and SIRT3, cells were treated with EX527(SIRT1 inhibitor) or SRT1720 (SIRT1 activator), and EX527 increased SIRT3 protein level, however, SRT1720 displayed the opposite effect in the present or absence of 5-ALA-PDT. Moreover SIRT1-inhibited cells are more resistant to 5-ALA-PDT and showing decreased ROS accumulation. These results may demonstrate that 5-ALA-PDT induced SIRT1 protein level decreased, which promoted the effect of SIRT3 increased activity of SOD2 that can reduce mROS level, and then compromised 5-ALA-PDT induced autophagic cell death.

Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors. The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown. Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome. We examined the prevalence of CCND1 amplification and its potential as a biomarker for the efficacy of ICI therapy for solid tumors using a local database ( n = 6,536), The Cancer Genome Atlas (TCGA) database ( n = 10,606), and the Memorial Sloan Kettering Cancer Center (MSKCC) database ( n = 10,109). Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs. A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy. Transcriptomic analysis showed various degrees of immune cell exclusion, including cytotoxic cells, T cells, CD8 + T cells, dendritic cells (DCs), and B cells in the TME in a TCGA CCND1 amplification population. The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial–mesenchymal transition, transforming growth factor (TGF)-β signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors. These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.