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    • This study has several limitations First only papers publish

    2018-10-25

    This study has several limitations. First, only papers published in English were included. Publications in languages other than English were excluded due to insufficient information, which may lead to selection bias. Second, this study involved largely Asians and Caucasians; other ethnic subgroups (e.g., Africans) were lacking. In addition, several of the studies were based on a small Caucasian population. In the future, additional studies with large Caucasian and African populations are necessary. Third, further prospective studies using quantitative detection methodologies (i.e., pyrosequencing, MethyLight, methylation-sensitive high resolution melting, etc.) are needed to confirm the role of RASSF1A promoter methylation as a biomarker for the diagnosis of NPC. Finally, the correlation between RASSF1A promoter methylation and the clinicopathological characteristics of NPC patients requires further validation because of the limited sample size.
    Conclusions The findings from this study suggest that RASSF1A promoter methylation is more common in NPC than in non-tumor tissue, brushing, and blood samples. Furthermore, RASSF1A promoter methylation was higher in later stage than in early stage patients, higher in patients with lymph node metastasis than without, higher in patients with distant metastasis than those without, and higher in patients with T3–4 classification than in patients with T1–2 classification. In addition, RASSF1A promoter methylation may be a diagnostic biomarker in tissue and brushing samples that could be used for the clinical diagnosis of NPC. In the future, well-matched prospective studies are essential for determining the prognostic and diagnostic significance of RASSF1A promoter methylation in patients with NPC. The following are the supplementary data related to this article.
    Funding This research was supported by grants from the Natural Science Foundation of Zhejiang Province (LY16H160005), the Ningbo Natural Science Foundation (2014A610235), and the Project of the Scientific Innovation Team of Ningbo (2015B11050). The sponsor had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
    Conflicts of Interest
    Authors\' Contributions
    Ethical Review from Patients
    Introduction Multiple myeloma (MM) is a plasma cell neoplasm. Four active PD 0332991 of drugs including glucocorticoids, DNA alkylators (melphalan), proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide), combined with or without autologous stem cell transplantation (ASCT) have led to complete remissions (CRs) in the large majority of newly diagnosed patients with MM (Alexanian et al., 2014; Fu et al., 2013; Terpos et al., 2014; Wang et al., 2014; Sonneveld et al., 2013; Gay et al., 2013; Liu et al., 2013; Bergsagel, 2014). These treatments have greatly improved patient progression-free and overall survival. However, there are at least three major problems limiting the administration of these agents: 1. All these drugs target both tumor and non-tumor cells; 2. Increased hematologic toxicity has been identifined by combining alkylators with either immunomodulatory drugs (IMIDs) (Bergsagel, 2014); and 3. High doses of the DNA alkalating agent, such as melphalan, have strong cytotoxicity on gut epithelial cells and hematopoietic stem cells (Shaw et al., 2014). One way to deal with non-selective toxicity of high dose melphalan is to combine it with another agent which very specifically targets tumor cells and therefore decreasing melphalan dosing without loss of efficacy. In the 1970s, Cameron and Pauling reported that high doses of vitamin C increased survival of patients with cancer (Cameron and Pauling, 1976, 1978). Recently, reports have shown that pharmacologically dosed ascorbic acid (PAA) 50–100g (Chen et al., 2008; Padayatty et al., 2004; Hoffer et al., 2008; Padayatty et al., 2006; Welsh et al., 2013), administered intravenously, has potent anti-cancer activity and its role as anti-cancer therapy is being studied at the University of Iowa and in other centers (Du et al., 2012; Ma et al., 2014). In the presence of catalytic metal ions like iron, PAA administered intravenously exerts pro-oxidant effects leading to the formation of highly reactive oxygen species (ROS), resulting in cell death (Yun et al., 2015; Ma et al., 2014; Du et al., 2012; Chen et al., 2007, 2005). In a previous study, we have reported that the labile iron pool (LIP) is significantly elevated in MM cells (Gu et al., 2015), suggesting that PAA treatment should target MM cells quite selectively. The higher LIP is the direct result of the low expression of the only known mammalian cellular iron exporter, Ferroportin 1 (Fpn1), in MM as demonstrated by our group (Gu et al., 2015). These findings led us to the hypothesis that PAA might specifically target MM cells with high iron content and may also act synergistically in combination with commonly used MM therapies.