Graphical AbstractHighlights d Structure-guided design and optimization yield potent FTO inhibitors d mRNA m 6 A acts as the major effector of the inhibitor/FTO axis in AML cells d FTO inhibitor FB23-2 displays therapeutic effects in PDX AML models d Targeting epitranscriptomic RNA methylation holds potential to treat AML SUMMARY FTO, an mRNA N 6 -methyladenosine (m 6 A) demethylase, was reported to promote leukemogenesis. Using structure-based rational design, we have developed two promising FTO inhibitors, namely FB23 and FB23-2, which directly bind to FTO and selectively inhibit FTO's m 6 A demethylase activity. Mimicking FTO depletion, FB23-2 dramatically suppresses proliferation and promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cell line cells and primary blast AML cells in vitro. Moreover, FB23-2 significantly inhibits the progression of human AML cell lines and primary cells in xeno-transplanted mice. Collectively, our data suggest that FTO is a druggable target and that targeting FTO by small-molecule inhibitors holds potential to treat AML. SignificanceAs the most abundant internal mRNA modification, m 6 A impacts various biological processes. As a major m 6 A demethylase, FTO is overexpressed in certain subtypes of AMLs and promotes leukemogenesis. Thus, the development of effective inhibitors to target FTO's aberrant m 6 A demethylase activity is urgently needed for leukemia therapy. Here we report two selective FTO inhibitors that efficiently reverse/suppress FTO-mediated aberrant epitranscriptome in AML cells and significantly inhibit AML progression in vivo. Our studies provide the proof-of-concept evidence demonstrating that small-molecule inhibitors targeting oncogenic FTO represent a promising targeted therapeutic strategy for the effective treatment of AML. Moreover, given the overexpression of FTO in various cancers, our work may have a broad impact on cancer therapy by targeting the FTO-mediated epitranscriptome.

Purpose To accelerate MR parameter mapping (MRPM) using a locally low rank (LLR) constraint, and the combination of parallel imaging (PI) and the LLR constraint. Theory and Methods An LLR method is developed for MRPM and compared with a globally low rank (GLR) method in a multi-echo spin-echo T2 mapping experiment. For acquisition with coil arrays, a combined LLR and PI method is proposed. The proposed method is evaluated in a variable flip angle T1 mapping experiment and compared with the LLR method and PI alone. Results In the multi-echo spin-echo T2 mapping experiment, the LLR method is more accurate than the GLR method for acceleration factors 2 and 3, especially for tissues with high T2 values. Variable flip angle T1 mapping is achieved by acquiring datasets with 10 flip angles, each dataset accelerated by a factor of 6, and reconstructed by the proposed method with a small normalized root mean square error of 0.025. Conclusion The LLR method is likely superior to the GLR method for MRPM. The proposed combined LLR and PI method has better performance than the two methods alone, especially with highly accelerated acquisition.

Introduction Untargeted metabolomics studies for biomarker discovery often have hundreds to thousands of human samples. Data acquisition of large-scale samples has to be divided into several batches and may span from months to as long as several years. The signal drift of metabolites during data acquisition (intra-and inter-batch) is unavoidable and is a major confounding factor for largescale metabolomics studies. Objectives We aim to develop a data normalization method to reduce unwanted variations and integrate multiple batches in large-scale metabolomics studies prior to statistical analyses. Methods We developed a machine learning algorithmbased method, support vector regression (SVR), for largescale metabolomics data normalization and integration. An R package named MetNormalizer was developed and provided for data processing using SVR normalization.Results After SVR normalization, the portion of metabolite ion peaks with relative standard deviations (RSDs) less than 30 % increased to more than 90 % of the total peaks, which is much better than other common normalization methods. The reduction of unwanted analytical variations helps to improve the performance of multivariate statistical analyses, both unsupervised and supervised, in terms of classification and prediction accuracy so that subtle metabolic changes in epidemiological studies can be detected. Conclusion SVR normalization can effectively remove the unwanted intra-and inter-batch variations, and is much better than other common normalization methods.

Introduction Previous metabolomics studies have revealed perturbed metabolic signatures in esophageal squamous cell carcinoma (ESCC) patients, however, most of these studies included mainly late-staged ESCC patients due to the difficulties of collecting the early-staged samples from asymptotic ESCC subjects. Objectives This study aims to explore the early-staged ESCC metabolic signatures and potential of serum metabolomics to diagnose ESCC at early stages. Methods Serum samples of 97 ESCC patients (stage 0, 39 cases; stage I, 17 cases; stage II, 11 cases, stage III, 30 cases) and 105 healthy controls (HC) were enrolled and randomly separated into training data (77 ESCCs, 84 HCs) and validation data (20 ESCCs, 21 HCs). Untargeted metabolomics was performed to identify ESCC-related metabolic signatures. ResultsThe global metabolomics profiles could clearly distinguish ESCC from HC in training data. 16 ascertained metabolites were found to be disturbed in the metabolic pathways characterized by dysregulated fatty acid biosynthesis, glycerophospholipid metabolism, choline metabolism in cancer and linoleic acid metabolism. The AUC value in validation data was 0.895, with sensitivity 85.0 % and specificity 90.5 %. Good diagnostic performances were also achieved for early stage ESCC, with the values of area under the curve (AUC) 0.881 for the ESCC patients in both stage 0 and I-II. In addition, six metabolites were found to discriminate ESCC stages. Among them, three biomarkers, dodecanoic acid, LysoPA(18:1), and LysoPC(14:0), exhibited clear trend for ESCC progression. Conclusion These findings suggest serum metabolomics, performed in a minimally noninvasive and convenient manner, may possess great potential for early diagnosis of ESCC patients.

Background Several distributions of country-specific blood pressure (BP) percentiles by sex, age and height for children and adolescents have been established worldwide. However, there are no globally unified BP references for defining elevated BP in children and adolescents, which limit international comparisons of prevalence of pediatric elevated BP. We aimed to establish international BP references for children and adolescents using seven nationally representative data (China, India, Iran, Korea, Poland, Tunisia and USA). Methods and Results Data on BP for 52,636 non-overweight children and adolescents aged 6–19 years were obtained from seven large nationally representative cross-sectional surveys in China, India, Iran, Korea, Poland, Tunisia, and USA. BP values were obtained with certified mercury sphygmomanometers in all seven countries, using standard procedures for BP measurement. Smoothed BP percentiles (50th, 90th, 95th and 99th) by age and height were estimated using the Generalized Additive Model for Location Scale and Shape (GAMLSS) model. BP values were similar between males and females until the age of 13 years and were higher in males than females thereafter. Compared to BP level of the 90th and 95th percentiles of the U.S. Fourth Report at median height, systolic BP of the corresponding percentiles of these international references was lower while diastolic BP was similar. Conclusions These international BP references will be a useful tool for international comparison of the prevalence of elevated BP in children and adolescents and may help identify hypertensive youths in diverse populations.

Post-operative IMRT following narrow-margin hepatectomy may be a favourable therapy for both its safety profile and clinical benefit in patients with HCC located close to the major vessels.

BACKGROUND AND OBJECTIVE: Previous studies have shown that the prevalence of abdominal obesity among US children and adolescents increased significantly between 1988 to 1994 and 2003 to 2004. However, little is known about time trends in abdominal obesity since 2003 to 2004. This study was designed to provide updated national estimates of childhood abdominal obesity and examine the trends in childhood abdominal obesity from 2003 to 2012. METHODS: Data were from the National Health and Nutrition Examination Survey (NHANES), conducted during 5 time periods (2003–2004, 2005–2006, 2007–2008, 2009–2010, and 2011–2012). A total of 16 547 US children and adolescents aged 2 to 18 years were included. Abdominal obesity is defined as a waist circumference (WC) greater than or equal to the gender- and age-specific 90th percentile based on data from NHANES III (1988–1994) or a waist/height ratio (WHtR) ≥0.5 RESULTS: In 2011 to 2012, 18.87% of children and adolescents aged 2 to 18 years were abdominally obese as defined by WC; 33.29% of those aged 6 to 18 years were abdominally obese as defined by WHtR. Mean WC and WHtR and the prevalence of abdominal obesity remained stable between 2003 to 2004 and 2011 to 2012, independent of gender, age, and race or ethnicity. However, abdominal obesity decreased across survey years among non-Hispanic white children. CONCLUSIONS: The prevalence of abdominal obesity leveled off among US children and adolescents between 2003 to 2004 and 2011 to 2012.

Rationale: Previous EWASs (Epigenome-Wide Association Studies) suggest that obesity may be the cause, not a consequence, of changes in DNA methylation (DNAm). However, longitudinal observations are lacking. Objective: To identify 5′—cytosine—phosphate—guanine—3′ in DNA (CpG) sites associated with body mass index (BMI) and examine the temporal relationship between dynamic changes in DNAm and BMI in a longitudinal cohort. Methods and Results: Race-specific EWASs were performed in 995 whites and 490 blacks from the Bogalusa Heart Study. Suggestive CpG sites were further replicated in 252 whites and 228 blacks from the Georgia Stress and Heart Study. Cross-lagged panel analysis was used to examine the temporal relationship between DNAm and BMI in 439 whites and 201 blacks who were examined twice 6.2 years apart. In discovery and replication samples, 349 CpG sites (266 novel) in whites and 36 (21 novel) in blacks were identified to be robustly associated with BMI, with 8 (1 novel) CpG sites overlapping between the 2 races. Cross-lagged panel analyses showed significant unidirectional paths (P FDR <0.05) from baseline BMI to follow-up DNAm at 18 CpG sites in whites and 7 in blacks; no CpG sites showed significant paths from DNAm at baseline to BMI at follow-up. Baseline BMI was associated with a DNAm score (calculated from DNAm levels at the associated CpG sites) at follow-up ( P <0.001 both in blacks and in whites). Conclusions: The findings provide strong evidence that obesity is the cause, not a consequence, of changes in DNAm over time.