Epigenetic inactivation of the NORE1 gene correlates with malignant progression of colorectal tumors

<p>Abstract</p> <p>Background</p> <p>NORE1 (RASSF5) is a newly described member of the RASSF family with Ras effector function. <it>NORE1 </it>expression is frequently inactivated by aberrant promoter hypermethylation in many human cancers, suggesting that NORE1 might be a putative tumor suppressor. However, expression and mutation status of <it>NORE1 </it>and its implication in colorectal tumorigenesis has not been evaluated.</p> <p>Methods</p> <p>Expression, mutation, and methylation status of <it>NORE1A </it>and <it>NORE1B </it>in 10 cancer cell lines and 80 primary tumors were characterized by quantitative PCR, SSCP, and bisulfite DNA sequencing analyses. Effect of NORE1A and NORE1B expression on tumor cell growth was evaluated using cell number counting, flow cytometry, and colony formation assays.</p> <p>Results</p> <p>Expression of <it>NORE1A </it>and <it>NORE1B </it>transcript was easily detectable in all normal colonic epithelial tissues, but substantially decreased in 7 (70%) and 4 (40%) of 10 cancer cell lines and 31 (38.8%) and 25 (31.3%) of 80 primary carcinoma tissues, respectively. Moreover, 46 (57.6%) and 38 (47.5%) of 80 matched tissue sets exhibited tumor-specific reduction of <it>NORE1A </it>and <it>NORE1B</it>, respectively. Abnormal reduction of <it>NORE1 </it>was more commonly observed in advanced stage and high grade tumors compared to early and low grade tumors. While somatic mutations of the gene were not identified, its expression was re-activated in all low expressor cells after treatment with the demethylating agent 5-aza-dC. Bisulfite DNA sequencing analysis of 31 CpG sites within the promoter region demonstrated that abnormal reduction of <it>NORE1A </it>is tightly associated with promoter CpG sites hypermethylation. Moreover, transient expression and siRNA-mediated knockdown assays revealed that both NORE1A and NORE1B decrease cellular growth and colony forming ability of tumor cells and enhance tumor cell response to apoptotic stress.</p> <p><b>Conclusion</b></p> <p>Our data indicate that epigenetic inactivation of <it>NORE1 </it>due to aberrant promoter hypermethylation is a frequent event in colorectal tumorigenesis and might be implicated in the malignant progression of colorectal tumors.</p

Triple-negative, basal-like, and quintuple-negative breast cancers: better prediction model for survival

Background: Triple-negative breast cancers (TNBCs) and basal-like breast cancers (BLBCs) are known as poor outcome subtypes with a lack of targeted therapy. Previous studies have shown conflicting results regarding the difference of prognostic significance between TNBCs and BLBCs. In this study, we aimed to characterize the prognostic features of TNBCs, in view of BLBCs and quintuple-negative breast cancers (QNBC/5NPs). Methods: Using tissue microarray-based immunohistochemical analysis, we categorized 951 primary breast cancers into four or five subtypes according to the expression of ER, PR, HER2, and basal markers (CK5/6, EGFR). Results: The results of this study showed that both TNBCs and BLBCs were associated with high histological and/ or nuclear grades. When the TNBCs are divided into two subtypes by the presence of basal markers, the clinicopathologic characteristics of TNBCs were mainly maintained in the BLBCs. The 5-subgrouping was the better prediction model for both disease free and overall survival in breast cancers than the 4-subgrouping. After multivariate analysis of TNBCs, the BLBCs did not have a worse prognosis than the QNBC/5NPs. Interestingly, the patients with BLBCs showed significant adjuvant chemotherapy benefit. In addition, QNBC/5NPs comprised about 6~8% of breast cancers in publicly available breast cancer datasets Conclusion: The QNBC/5NP subtype is a worse prognostic subgroup of TNBCs, especially in higher stage and this result may be related to adjuvant chemotherapy benefit of BLBCs, calling for caution in the identification of subgroups of patients for therapeutic classification

Effects of maternal education on diet, anemia, and iron deficiency in Korean school-aged children

<p>Abstract</p> <p>Background</p> <p>We investigated the relationship among socioeconomic status factors, the risk of anemia, and iron deficiency among school-aged children in Korea.</p> <p>Methods</p> <p>The sample consisted of fourth-grade students aged 10 y recruited from nine elementary schools in Korean urban areas in 2008 (<it>n </it>= 717). Anthropometric and blood biochemistry data were obtained for this cross-sectional observational study. Anemia was defined as hemoglobin levels lower than 11.5 g/dl. Iron deficiency was defined as serum iron levels lower than 40 ug/dl. We also obtained data on parental education from questionnaires and on children's diets from 3-day food diaries. Parental education was categorized as low or high, with the latter representing an educational level beyond high school.</p> <p>Results</p> <p>Children with more educated mothers were less likely to develop anemia (<it>P </it>= 0.0324) and iron deficiency (<it>P </it>= 0.0577) than were those with less educated mothers. This group consumed more protein (<it>P </it>= 0.0004) and iron (<it>P </it>= 0.0012) from animal sources than did the children of less educated mothers, as reflected by their greater consumption of meat, poultry, and derivatives (<it>P </it>< 0.0001). Logistic regression analysis revealed a significant inverse relationship between maternal education and the prevalence of anemia (odds ratio: 0.52; 95% confidence interval: 0.32, 0.85).</p> <p>Conclusions</p> <p>As a contributor to socioeconomic status, maternal education is important in reducing the risk of anemia and iron deficiency and in increasing children's consumption of animal food sources.</p

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

The 5p15.33 Locus Is Associated with Risk of Lung Adenocarcinoma in Never-Smoking Females in Asia

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10−7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10−11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10−11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10−20, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma