A new noninvasive screening tool for colorectal neoplasia detects epigenetic alterations exhibited by gastrointestinal tumor cells shed into stool. There is insufficient existing data to determine temporal associations between colorectal cancer (CRC) progression and aberrant DNA methylation. To evaluate the feasibility of using fecal DNA methylation status to determine CRC progression, we collected stool samples from 14 male SD rats aged six weeks, and administered subcutaneous injections of either 1,2-dimethylhydrazine or saline weekly. p16 DNA methylation statuses in tumorous and normal colon tissue, and from stool samples were determined using methylation-specific PCR. Additionally, p16 methylation was detected in stool DNA from 85.7% of the CRC rats. The earliest change in p16 methylation status in the DMH-treated group stool samples occurred during week nine; repeatabilities were 57.1% in week 19 (p = 0.070) and 85.7% in week 34 (p = 0.005). A temporal correlation was evidenced between progression of CRC and p16 methylation status, as evidenced by DMH-induced rat feces. Using fecal DNA methylation status to determine colorectal tissue methylation status can reveal CRC progression. Our data suggests that p16 promoter methylation is a feasible epigenetic marker for the detection and may be useful for CRC screening.
<p>Supplementary Tables 1-3, Supplementary Figures 1-7. Supplementary Table 1: Oligonucleotide primers used for qRT-PCR analysis. Supplementary Table 2: GSEA enrichment of KEGG functional pathways in lovastatin-regulated genes. Supplementary Table 3: Lovastatin affects expression of genes in glycolysis/gluconeogenesis pathway. Supplementary Figure 1: Daily administration of lovastatin prevents tumor growth in mogp-TAg transgenic mice. Supplementary Figure 2: Body weight and serum levels of cholesterol and triglyceride in mogp-TAg, SKOV3-IP, and OVCAR5 mouse tumor models. Supplementary Figure 3: Atorvastatin treatment delays growth of ovarian tumor xenografts. Supplementary Figure 4: Statin treatment increases transcript levels of LC3A and LC3B. Supplementary Figure 5: Scheme of the mevalonate pathway. Supplementary Figure 6: Applying GGPP or FPP as a single agent does not affect ovarian cancer cell proliferation. Supplementary Figure 7: Real-time qRT-PCR confirms knockdown efficiency of each siRNA.</p>
<p>Supplementary Tables 1-3, Supplementary Figures 1-7. Supplementary Table 1: Oligonucleotide primers used for qRT-PCR analysis. Supplementary Table 2: GSEA enrichment of KEGG functional pathways in lovastatin-regulated genes. Supplementary Table 3: Lovastatin affects expression of genes in glycolysis/gluconeogenesis pathway. Supplementary Figure 1: Daily administration of lovastatin prevents tumor growth in mogp-TAg transgenic mice. Supplementary Figure 2: Body weight and serum levels of cholesterol and triglyceride in mogp-TAg, SKOV3-IP, and OVCAR5 mouse tumor models. Supplementary Figure 3: Atorvastatin treatment delays growth of ovarian tumor xenografts. Supplementary Figure 4: Statin treatment increases transcript levels of LC3A and LC3B. Supplementary Figure 5: Scheme of the mevalonate pathway. Supplementary Figure 6: Applying GGPP or FPP as a single agent does not affect ovarian cancer cell proliferation. Supplementary Figure 7: Real-time qRT-PCR confirms knockdown efficiency of each siRNA.</p>
// Wen-Chih Wu 1, 2 , Po-Chien Hsieh 1 , Fu-Kang Hu 3 , Jen-Chun Kuan 4, 5 , Chi-Ming Chu 1 , Chien-An Sun 6, 7 , Tsan Yang 8 , Sui-Lung Su 1 and Yu-Ching Chou 1 1 School of Public Health, National Defense Medical Center, Taipei, Taiwan 2 Department of Surgery, Suao and Yuanshan branches of Taipei Veterans General Hospital, Yilan, Taiwan 3 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 4 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 5 Department of Biostatistics, Firma Clinical Research, Hunt Valley, MD, USA 6 Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan 7 Big Data Research Center, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan 8 Department of Health Business Administration, Meiho University, Pingtung, Taiwan Correspondence to: Yu-Ching Chou, email: trishow@mail.ndmctsgh.edu.tw Keywords: predictor; chronic kidney disease (CKD); aircrew; early detection; longitudinal study Received: August 02, 2017 Accepted: February 27, 2018 Published: April 13, 2018 ABSTRACT Background: The high incidence and prevalence of chronic kidney disease (CKD) in Taiwan have produced tremendous burdens on health care resources. The work environment of air force special operations personnel engenders high psychological stress, and the resulting increased blood pressure can lead to glomerular hypertension and accelerated glomerular injury in the long term. The aim of the study was to establish the predictive models to define the predictors of CKD. Results: The results indicated that the prevalence of CKD over 4 consecutive years was 3.8%, 9.4%, 9.0%, and 9.4%. The capability of using occult blood in urine to predict the risk of CKD after 1, 2, and 3 years was statistically significant. The age-adjusted odds ratio (OR) and 95% confidence interval (CI) were 7.94 (95% CI: 2.61–24.14), 12.35 (95% CI: 4.02–37.94) and 4.25 (95% CI: 1.32–13.70), respectively. Discussion: The predictive power of occult blood in urine for the risk of CKD in each model was statistically significant. Future investigations can explore the feasibility of implementing simple and accurate urine dipsticks for preliminary testing besides annual aircrew physical examinations to facilitate early detection and treatment. Methods: This study was a longitudinal study, in which air force special operations personnel who received physical examinations at military hospitals between 2004 and 2010 were selected. CKD was determined based on the definition provided by the US National Kidney Foundation. Overall, 212 participants that could be followed continuously for 4 years were analyzed.
Abstract Background: Cancer recurrence and chemoresistance contribute greatly to the high mortality of ovarian cancers; however, molecular players involved in these processes remain under-determined. Several theories have been proposed to account for the development of resistance to chemotherapeutic agents. One of the emerging concepts is tumor heterogeneity, which argues for the presence of different cell subpopulations in bulk tumor with varying degrees of tumor initiating potential and drug sensitivity. The fractions of cells with enhanced tumor initiating potential are referred to as cancer stem-like cells (CSC). These cells have defining “stemness” phenotypes, including unlimited cell division, repopulation by a minimum cell number and resistance to cytotoxic agents and irradiation. New Findings: To identify embryonic stem cell factors that are potentially involved in tumor recurrence and chemoresistance, we have screened expression levels of four of these factors by immunohistochemistry in pairs of matched recurrent and primary tumor tissues from 41 patients. Our data demonstrated that PBX1 is significantly up-regulated in recurrent/chemoresistant ovarian tumors. Moreover, PBX1 overexpression in ascites tumors correlates with shorter overall survival in post-chemotherapy ovarian cancer patients. When PBX1 is ectopically expressed, it promotes cancer stem cell-like phenotypes, including increased side population and ALDH1 activity, enhanced tumorigenicity at low cell density, and increased resistance to platinum-based therapy. In platinum-resistant cell lines that overexpress PBX1, silencing PBX1 expression using RNA interference sensitizes cells to platinum treatment and reduces their stem cell-like phenotypes. Gene expression and chromatin immunoprecipitation analyses identified PBX1 direct target genes involved in multi-drug resistance, stem cell maintenance, immunomodulation, and DNA damage response. In the TCGA ovarian cancer recurrent series, expression of several PBX1 direct target genes, including ABCA1, Nanog, BMP3, and ATM, is tightly associated with PBX1 expression, further supporting the tissue-level transcriptional regulation of these genes by PBX1. Conclusion: The above findings establish PBX1 as an upstream regulator of key functional networks that mediate cancer stem-like and drug resistant phenotypes. Studies on the hematopoietic system have indicated that PBX1 maintains a viable pool of quiescent stem cells. Recently, in a renal cell carcinoma system, chemotherapy has been shown to induce damage signaling and to stimulate cell division and repopulation of quiescent CSCs. We speculate that chemotherapy in ovarian cancer may induce comparable injury responses and trigger PBX1 signaling, which in turn may activate downstream networks that support CSC survival and create a microenvironment niche that is essential for CSC repopulation at the tissue level. Collectively, the association between PBX1 and a cascade of stemness pathways points to a potential Achilles's heel critical to responding to chemotherapy and developing chemoresistance and argues for the development of antagonists of PBX1 signaling as anticancer agents. Citation Format: Jin-Gyoung Jung, Tae-Hoen Kim, Emily Gerry, Jen-Chun Kuan, Ayse Ayhan, Ben Davidson, Ie-Ming Shih, Tian-Li Wang. PBX1, a transcriptional regulator, promotes stemness and chemoresistance in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A32.
Aberrant DNA methylation plays a crucial role in cancer development; however, prospective evidence of an interaction between molecular biomarkers and cancer staging for predicting the prognosis of colorectal cancer (CRC) is still limited. We examined DNA methylation in tumors and adjacent normal tissues from patients who underwent CRC surgical resection, and evaluated the interaction between cancer staging (advanced vs local) and DNA methylation to predict the prognosis of CRC. We recruited 132 patients with CRC from Tri-Service General Hospital in Taiwan and used the candidate gene approach to select 3 tumor suppressor genes involved in carcinogenesis pathways. ORs and 95% CIs were computed using logistic regression analyses while adjusting for potential covariates. Advanced cancer stage was correlated with cancer recurrence (OR 7.22, 95% CI 2.82 to 18.45; p<0.001). In addition, after stratification by promoter methylation in 3 combined genes in the matched normal tissues, we observed a joint effect after adjusting for sex, age at surgery, and adjuvant chemotherapy, yielding a significant OR of 20.35 (95% CI 4.16 to 99.57; p<0.001). DNA methylation status would significantly increase the recurrence risk of CRC with a significant impact on joint effect between DNA methylation and clinical stage, particularly in matched normal tissues. This was attributed to molecular changes that could not be examined on the basis of clinical pathology. Our interaction results may serve as a reference marker for evaluating the risk of recurrence in future studies.
Cognitive impairment develops with pre-diabetes and dementia is a complication of diabetes. Natural products like turmeric and cinnamon may ameliorate the underlying pathogenesis.People ≥ 60 years (n=48) with newly-recognised untreated pre-diabetes were randomised to a double-blind metabolic study of placebo, turmeric (1 g), cinnamon (2 g) or both (1 g & 2 g respectively), ingested at a white bread (119 g) breakfast. Observations were made over 6 hours for pre- and post-working memory (WM), glycaemic and insulin responses and biomarkers of Alzheimer's disease (AD)(0, 2, 4 and 6 hours): amyloid precursor protein (APP), γ-secretase subunits presenilin-1 (PS1), presenilin-2 (PS2), and glycogen synthase kinase (GSK-3β). Differences between natural product users and non-users were determined by Students t and chi square tests; and between pre-test and post-test WM by Wilcoxon signed rank tests. Interaction between turmeric and cinnamon was tested by 2-way ANOVA. Multivariable linear regression (MLR) took account of BMI, glycaemia, insulin and AD biomarkers in the WM responses to turmeric and cinnamon.No interaction between turmeric and cinnamon was detected. WM increased from 2.6 to 2.9 out of 3.0 (p=0.05) with turmeric, but was unchanged with cinnamon. WM improvement was inversely associated with insulin resistance (r=-0.418, p<0.01), but not with AD biomarkers. With MLR, the WM responses to turmeric were best predicted with an R2 of 34.5%; and with significant turmeric, BMI and insulin/glucose AUC beta-coefficients.Co-ingestion of turmeric with white bread increases working memory independent of body fatness, glycaemia, insulin, or AD biomarkers.背景：認知功能失調伴隨糖尿病前期與失智症是糖尿病的併發症之ㄧ。天然食品如薑黃及 肉桂可改善此致病機轉。本研究為評估薑黃肉桂如何影響糖尿病前期患者認知功能之代謝 研究。方法：對象為三軍總醫院參加老人健檢者，納入條件為其空腹血糖介於100-126 mg/dL，共計48 位參與者。經由雙盲性別分層隨機分派至服用口服降血糖藥物或其組合、 薑黃、肉桂或其組合及控制組共4 組，每組12 名，男女各半。參與者須於報到後抽取空 腹血液、實施工作記憶前測及測量基本體位資料。再於8 時服用早餐及受試藥物，各組分 別為安慰劑、薑黃1 克、肉桂2 克、肉桂2 克與薑黃1 克等。隨後每隔2 小時採集血液， 共4 次，於最後1 次抽血完畢後，再測工作記憶分數。利用RT-PCR 技術測得APP、 PS1、PS2、GSK-3βmRNA 表現量。利用t 檢定及卡方檢定比較天然食品使用者及非使用 者平均值之差異；魏克森符號等級檢定工作記憶前測及後測的分數。利用雙因子變異數分 析檢定薑黃與肉桂兩植物成分之交互作用。複迴歸模式分析校正身體質量指數、血糖、胰 島素濃度、阿茲海默症相關之生物標記後，薑黃肉桂對工作記憶之影響。結果：薑黃與肉 桂兩植物成分並無交互作用產生。有服用薑黃者工作記憶平均分數由2.6 增加至2.9 分， 為邊緣性顯著（p=0.05），服用肉桂者工作記憶前後測平均分數沒有顯著差異。工作記憶 分數之改善與胰島素阻抗呈負相關 （r=-0.418, p<0.01），但與阿茲海默症之相關生物標記 無顯著相關。複迴歸分析結果顯示服用薑黃、BMI 及胰島素阻抗為工作記憶分數最佳預測 因子。結論：本研究觀察到的薑黃改善認知效果，可能並非透過假設之降血糖途徑或降低 生物標記基因表現量而來，推測薑黃有其他保護神經元機制。
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