The effects of midazolam (MID) on the in vitro growth and differentiation of two murine myeloid leukemia WEHI 3B (JCS) and M1 cells were studied. MID inhibits the proliferation of both Ml and JCS cells in a dose-dependent manner. At the concentration of 10 μg/ml, MID was found to induce both monocytic and granulocytic differentiation of the JCS but not Ml cells. Induction of morphological differentiation of the JCS cells was also associated with the enhanced expression of the differentiation antigens Mac-1, F4/80, and Gr-1 for the cells. Results from mRNA phenotyping experiments also indicated that the expression of tumor necrosis factor (TNF-α) and neutrophil-specific J11d differentiation marker was significantly upregulated in MID-treated JCS cells. In addition, the phagocytic activity of MID-treated JCS cells was increased towards opsonized yeast cells. Results from this investigation suggested that MID may be used as an inducer for further study on the mechanisms of differentiation in these myeloid leukemia cells.
Nasopharyngeal carcinoma (NPC) is a human malignancy that is particularly prevalent in Southern China and Southeast Asia, and is strongly related to Epstein-Barr virus (EBV) infection. Since early detection of NPC will greatly improve the overall survival, screening becomes important for early NPC diagnosis. In this study, the methylation sensitive-high resolution melting (MS-HRM) method was established for detection of promoter DNA methylation using a panel of five tumor suppressor genes (RASSF1A, WIF1, DAPK1, RARβ2, p16), which were top candidates selected from 13 genes that had been tested in seven NPC cell lines and one immortalized NP cell line and which, showed highly different methylation status between cancer and immortalized cells. Biopsy samples from 52 NPC patients showed methylation for individual genes ranging from 30% to 96%. The combination of WIF1-RASSF1A, WIF1-DAPK1, and WIF1-RARβ2 all reached detection rates of 98% or above in biopsy samples, validating the frequent methylation status of these genes in NPC patients. WIF1, an important secreted Wnt inhibitor, is the most frequently methylated gene in our panel, as reported in many other cancers. In addition, the WIF1-RASSF1A combination showed the highest detection rate, reflecting that both early genetic events in chromosome 3p and the Wnt pathway play important roles in NPC development. To develop non-invasive methods for NPC high-risk screening, early diagnosis and prognosis, more NP brushings and cell-free plasma samples from NPC patients and healthy individuals have been tested for their methylation status of these candidate markers. Preliminary data indicate that the sensitivity and specificity reached more than 90% in certain gene combinations with NP brushings from patients of early NPC stage. The detection rate of methylation in cell-free plasma from NPC patients is even higher than the traditional EBV DNA test, which together show great potential for non-invasive high-risk screening for early NPC and early detection of local recurrence after therapy. In conclusion, a MS-HRM panel of multiple methylation markers is proposed as a complementary test for NPC early detection in combination with more established EBV-based markers. Citation Format: Xuesong Yang, Ying Ying Szeto, Yue Cheng, Dora Lai-wan Kwong, Maria Li Lung. Identification of candidate epigenetic markers for early detection of nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3555. doi:10.1158/1538-7445.AM2013-3555
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