ABSTRACT
Cancer cells are often aneuploid and frequently display elevated rates of chromosome missegregation in a phenomenon called chromosomal instability (CIN). CIN is commonly caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduces the efficiency of correction of erroneous K-MT attachments. We recently showed that UMK57, a chemical agonist of MCAK (alias KIF2C) improves chromosome segregation fidelity in CIN cancer cells although cells rapidly develop adaptive resistance. To determine the mechanism of resistance we performed unbiased proteomic screens which revealed increased phosphorylation in cells adapted to UMK57 at two Aurora kinase A phosphoacceptor sites on BOD1L1 (alias FAM44A). BOD1L1 depletion or Aurora kinase A inhibition eliminated resistance to UMK57 in CIN cancer cells. BOD1L1 localizes to spindles/kinetochores during mitosis, interacts with the PP2A phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with clinically relevant doses of taxol or Aurora kinase A inhibitor. Thus, an Aurora kinase A -BOD1L1-PP2A axis promotes faithful chromosome segregation during mitosis.
ABSTRACT
The Circadia Study (Circadia) is a novel "direct-to-participant" research study investigating the genetics of circadian rhythm disorders of advanced and delayed sleep phase and non-24 hour rhythms. The goals of the Circadia Study are twofold: (i) to create an easy-to-use toolkit for at-home circadian phase assessment for patients with circadian rhythm disorders through the use of novel in-home based surveys, tests, and collection kits; and (ii) create a richly phenotyped patient resource for genetic studies that will lead to new genetic loci associated with circadian rhythm disorders revealing possible loci of interest to target in the development of therapeutics for circadian rhythm disorders. Through these goals, we aim to broaden our understanding and elucidate the genetics of circadian rhythm disorders across a diverse patient population while increasing accessibility to circadian rhythm disorder diagnostics reducing health disparities through self-directed at-home dim light melatonin onset (DLMO) collections.
ABSTRACT
Background: Gastric adenocarcinomas are a leading cause of global mortality, associated with chronic infection with Helicobacter pylori. The mechanisms by which infection with H. pylori contributes to carcinogenesis are not well understood. Recent studies from subjects with and without gastric cancer have identified significant DNA methylation alterations in normal gastric mucosa associated with H. pylori infection and gastric cancer risk. Here we further investigated DNA methylation alterations in normal gastric mucosa in gastric cancer cases (n = 42) and control subjects (n = 42) with H. pylori infection data. We assessed tissue cell type composition, DNA methylation alterations within cell populations, epigenetic aging, and repetitive element methylation. Results: In normal gastric mucosa of both gastric cancer cases and control subjects, we observed increased epigenetic age acceleration associated with H. pylori infection. We also observed an increased mitotic tick rate associated with H. pylori infection in both gastric cancer cases and controls. Significant differences in immune cell populations associated with H. pylori infection in normal tissue from cancer cases and controls were identified using DNA methylation cell type deconvolution. We also found natural killer cell-specific methylation alterations in normal mucosa from gastric cancer patients with H. pylori infection. Conclusions: Our findings from normal gastric mucosa provide insight into underlying cellular composition and epigenetic aspects of H. pylori associated gastric cancer etiology.
ABSTRACT
BACKGROUND: Over the last decade, health mobile apps have become an increasingly popular tool used by clinicians and researchers to track food consumption and exercise. However, many consumer apps lack the technological features for facilitating the capture of critical food timing details. OBJECTIVE: This study aimed to introduce users to 11 apps from US app stores that recorded both dietary intake and food timing to establish which one would be the most appropriate for clinical research. METHODS: To determine a viable app that recorded both dietary intake and food timing for use in a food timing-related clinical study, we evaluated the time stamp data, usability, privacy policies, the accuracy of nutrient estimates, and general features of 11 mobile apps for dietary assessment that were available on US app stores. The following apps were selected using a keyword search of related terms and reviewed: text entry apps-Cronometer, DiaryNutrition, DietDiary, FoodDiary, Macros, and MyPlate; image entry apps-FoodView and MealLogger; and text plus image entry apps-Bitesnap, myCircadianClock, and MyFitnessPal. RESULTS: Our primary goal was to identify apps that recorded food time stamps, which 8 (73%) of the 11 reviewed apps did. Of the 11 apps, only 4 (36%) allowed users to edit the time stamps. Next, we sought to evaluate the usability of the apps using the System Usability Scale across 2 days, and 82% (9/11) of the apps received favorable scores for usability. To enable use in research and clinical settings, the privacy policies of each app were systematically reviewed using common criteria, with 1 (9%) Health Insurance Portability and Accountability Act-compliant app (Cronometer). Furthermore, protected health information was collected by 9 (82%) of the 11 apps. Finally, to assess the accuracy of the nutrient estimates generated by these apps, we selected 4 sample food items and a 3-day dietary record to input into each app. The caloric and macronutrient estimates of the apps were compared with the nutrient estimates provided by a registered dietitian using the Nutrition Data System for Research database. In terms of the 3-day food record, the apps were found to consistently underestimate daily calories and macronutrients compared with the Nutrition Data System for Research output. CONCLUSIONS: Overall, we found that the Bitesnap app provided flexible dietary and food timing functionality capable of being used in research and clinical settings, whereas most other apps lacked in the necessary food timing functionality or user privacy.
ABSTRACT
Short sleep duration has been linked to negative health effects, but is a complex phenotype with many contributing factors, including genetic. We evaluated 27 common single nucleotide polymorphisms (SNPs) in candidate genes previously reported to be associated with other sleep variables for association with self-reported habitual sleep duration in the UK Biobank in 111 975 individuals of European ancestry. Genetic variation in DAT1 (rs464049) was significantly associated with sleep duration after correction for multiple testing (p = 4.00 × 10-5), whereas SNPs correlated to a previously studied variable number tandem repeat (VNTR) in DAT1 were not significant in this population. We also replicated a previously reported association in DRD2. Independent replication of these associations and a second signal in DRD2 (rs11214607) was observed in an additional 261 870 participants of European ancestry from the UK Biobank. Meta-analysis confirmed genome-wide significant association of DAT1 rs464049 (G, beta [standard error, SE] = -0.96 [0.18] minutes/allele, p = 5.71 × 10-10) and study-wide significant association of DRD2 (rs17601612, C, beta [SE] = -0.66 [0.18] minutes/allele, p = 1.77 × 10-5; rs11214607, C, beta [SE] = 1.08 (0.24) minutes/allele, p = 1.39 × 10-6). Overall, SNPs in two dopamine-related genes were significantly associated with sleep duration, highlighting the important link of the dopamine system with adult sleep duration in humans.
