Endometrial Cancer and Hypermethylation: Regulation of DNA and MicroRNA by Epigenetics

Endometrial cancer is the seventh most common cancer in women worldwide. Therefore elucidation of the pathogenesis and development of effective treatment for endometrial cancer are important. However, several aspects of the mechanism of carcinogenesis in the endometrium remain unclear. Associations with genetic variation and mutations of cancer-related genes have been shown, but these do not provide a complete explanation. Therefore, in recent years, epigenetic mechanisms that do not involve changes in DNA sequences have been examined. Studies aimed at detection of aberrant DNA hypermethylation in cancer cells present in microscopic amounts in vivo and application of the results to cancer diagnosis have also started. Breakdown of the DNA mismatch repair mechanism is thought to play a large role in the development of endometrial cancer, with changes in the expression of the hMLH1 gene being particularly important. Silencing of genes such as APC and CHFR, Sprouty 2, RASSF1A, GPR54, CDH1, and RSK4 by DNA hypermethylation, onset of Lynch syndrome due to hereditary epimutation of hMLH1 and hMSH2 mismatch repair genes, and regulation of gene expression by microRNAs may also underlie the carcinogenic mechanisms of endometrial cancer. Further understanding of these issues may permit development of new therapies

Relationship between DNA Mismatch Repair Deficiency and Endometrial Cancer

Some cases of endometrial cancer are associated with a familial tumor and are referred to as hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). Lynch syndrome is thought to be induced by germline mutation of the DNA mismatch repair (MMR) gene. An aberration in the MMR gene prevents accurate repair of base mismatches produced during DNA replication. This phenomenon can lead to an increased frequency of errors in target genes involved in carcinogenesis, resulting in cancerization of the cell. On the other hand, aberrant DNA methylation is thought to play a key role in sporadic endometrial carcinogenesis. Hypermethylation of unmethylated CpG islands in the promoter regions of cancer-related genes associated with DNA repair leads to the cell becoming cancerous. Thus, both genetic and epigenetic changes are intricately involved in the process through which cells become cancerous. In this review, we introduce the latest findings on the DNA mismatch repair pathway in endometrial cancer

Risk factors for severity of colonic diverticular hemorrhage

Background/AimsColonic diverticular hemorrhage (DH) was a rare disease until the 1990s, and its incidence has increased rapidly since 2000 in Japan. In recent years, colonic DH has been the most frequent cause of lower gastrointestinal bleeding (LGIB). Nearly all cases of DH are mild, with the bleeding often stopping spontaneously. Some cases, however, require surgery or arterial embolization. In this study, using a cohort at Fukuoka University Chikushi Hospital, we investigated factors associated with severe colonic DH.MethodsAmong patients with LGIB who underwent colonoscopy at our hospital between 1995 and 2013, DH was identified in 273 patients. Among them, 62 patients (22.7%) were defined as having severe colonic DH according to recurrence of bleeding in a short period, and/or the necessity of transfusion, arterial embolization, or surgery. We then evaluated risk factors for severe DH among DH patients in this retrospective cohort.ResultsAmong the 273 patients with DH, use of non-steroidal anti-inflammatory drugs (NSAIDs) (odds ratio [OR], 2.801; 95% confidence interval [CI], 1.164–6.742), Charlson Risk Index (CRI) ≥2 (OR, 3.336; 95% CI, 1.154–7.353), right-sided colonic DH (OR, 3.873; 95% CI, 1.554–9.653), and symptoms of cerebral hypoperfusion (such as light-headedness, dizziness, or syncope) (OR, 2.926; 95% CI, 1.310–6.535) showed an increased risk of severe DH even after controlling for other factors.ConclusionsSevere DH occurred in 23% of DH patients, and NSAID use, CRI ≥2, right-sided colonic DH, and symptoms of cerebral hypoperfusion are suggested to be predictors of severe DH

An Introduction to SGTPPR: Sparse Geochemical Tectono‐Magmatic Setting Probabilistic MembershiP DiscriminatoR

Abstract We present a new and easy‐to‐use geochemical tectono‐magmatic setting discriminator to calculate the probability of membership (the Sparse Geochemical Tectono‐magmatic setting Probabilistic membershiP discriminatoR, SGTPPR) that runs in Excel. It outputs the probability of membership for eight different tectono‐magmatic settings (mid‐ocean ridge, oceanic island, oceanic plateau, continental flood basalt province, intra‐oceanic arc, continental arc, island arc, and back‐arc basin) for a given volcanic rock sample based on major and selected trace element contents (SiO2, TiO2, Al2O3, Fe2O3, MgO, CaO, K2O, Na2O, Rb, Sr, Y, Zr, Nb, and Ba). We consider all possible ratios and multiplications of these contents, in addition to the contents themselves, which improves the discrimination accuracy. We use a statistical method called sparse multinomial logistic regression to construct a robust and predictive discrimination model. By imposing the sparsity, only a small number of essential variables are included in the model. The variables are objectively extracted from 287 possible geochemical variables, including all possible ratios and multiplications of the major and trace element contents. The constructed model exhibits a high classification ability, indicating that tectonic discrimination using major and selected trace elements yields a high classification ability when ratios and multiplications are considered. The system outputs the relative weights of the variables (i.e., contents, and ratios and multiplications of contents) of the input geochemical data to the calculated membership probabilities. This information can be used to evaluate and interpret the results. We apply the model to multiple samples of a geological unit, to determine the tectonic setting