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Motivation: In the human genome, ‘CpG islands’, CG-rich regions located in or near gene promoters, are normally unmethylated. However, in cancer cells, CpG islands frequently gain methylation, resulting in silencing of growth-limiting tumor suppressor genes. To our knowledge, the potential relationship between CpG island hypermethylation, transcription factor (TF) binding in local promoter regions and transcriptional control has not been previously explored in a genome-wide context. Results: In this study, we utilized bioinformatics tools and TF binding site(TFBs) databases to globally analyze sequences methylated in a laboratory model for the development of drug-resistant cancer. Our results demonstrated that four TFBS were enriched in hypermethylated sequences. More interestingly, overrepresentation of these TFBS was observed in hyper-/hypo-methylated sequences where signi.cant changes in methylation levels were observed in drug-resistant cancer cells. In summary, we believe that these.ndings offer a means to further explore the relationship between DNA methylation and gene expression in drug resistance and tumorigenesis. Contact: sunkim2@indiana.edu; knephew@indiana.edu [ABSTRACT FROM AUTHOR]

Several studies have reported that a high expression ratio of HOXB13 to IL17BR predicts tumor recurrence in node-negative, estrogen receptor (ER) α-positive breast cancer patients treated with tamoxifen. The molecular mechanisms underlying this dysregulation of gene expression remain to be explored. Our epigenetic analysis has found that increased promoter methylation of one of these genes, HOXB13, correlate with the decreased expression of its transcript in breast cancer cell lines (P HOXB13 is suppressed by the activation of estrogen signaling in ERα-positive breast cancer cells. However, treatment with 4-hydroxytamoxifen (4-OHT), an antiestrogen, abrogates the ERα-mediated suppression in cancer cells. The notion that this transcriptional induction of HOXB13 occurs in vitro with simultaneous exposure to both estrogen and 4-OHT may provide a biological explanation for its aberrant expression in many node-negative patients undergoing tamoxifen therapy. Interestingly, promoter hypermethylation of HOXB13 is more frequently observed in ERα-positive patients with increased lymph node metastasis (P = 0.031) and large tumor sizes (>5 cm) (P = 0.008). In addition, this aberrant epigenetic event is associated with shorter disease-free survival (P = 0.029) in cancer patients. These results suggest that hypermethylation of HOXB13 is a late event of breast tumorigenesis and a poor prognostic indicator of node-positive cancer patients. [ABSTRACT FROM AUTHOR]

Background: A review of the literature pertaining to percutaneous transhepatic cholangioscopic lithotomy (PTCSL) showed that more than 50% of reported patients had undergone earlier biliary surgery., Methods: A retrospective study investigated 74 patients undergoing initial PTCSL for hepatolithiasis who had undergone no prior biliary surgery or manipulation. The patients were followed for 1 to 23 years after PTCSL for effective evaluation of the procedure outcome., Results: Complete clearance of hepatolithiasis was achieved for 61 (82%) patients. The incomplete clearance rate was higher for patients with intrahepatic duct stricture (11/37 [30%] vs 2/37 [5%]; p < 0.05), although it showed no relation to the actual lobar distribution of hepatolithiasis (left: 7/41 [17%] vs right: 2/11 [18%] vs bilateral: 4/22 [18%]; p < 0.05). The recurrence rate for hepatolithiasis also was higher for patients with intrahepatic duct stricture (18/26 [69%] vs 13/35 [37%]; p < 0.05), but the recurrence rate showed no relation to the lobar distribution of hepatolithiasis (left: 18/34 [53%] vs right: 4/9 [44%] vs bilateral: 9/18 [50%] p > 0.05) or the presence of gallbladder stones (5/12 [42%] vs 26/49 [53%]; p > 0.05). Patients showing the coexistence of retained or recurrent hepatolithiasis demonstrated a higher incidence of recurrent cholangitis (57% [13/23] vs 14% [7/51]; p < 0.01) or cholangiocarcinoma (17% [4/23]) vs 0% [0/51]; p < 0.01)., Conclusions: The findings show that PTCSL is effective for treating primary hepatolithiasis, and that complete stone clearance is mandatory to diminish the sequelae of hepatolithiasis. Intrahepatic duct stricture was the main factor contributing to incomplete clearance and stone recurrence.