Epigenetic Enzyme Mutations: Role in Tumorigenesis and Molecular Inhibitors

Epigenetic modifications, such as DNA methylation and histone modification, result in heritable changes in gene expression without changing the DNA sequence. Epigenetic regulatory enzymes such as DNA methyltransferases, histone methyltransferases, and histone deacetylases are involved in epigenetic modification. Studies have shown that the dysregulation caused by changes in the amino acid sequence of these enzymes is closely correlated with tumor onset and progression. In addition, certain amino acid changes in the metabolic enzyme isocitrate dehydrogenase (IDH) are linked to altered epigenetic modifications in tumors. Some small molecule inhibitors targeting these aberrant enzymes have shown promising anti-cancer efficacy in preclinical and clinical trials. For example, the small molecule inhibitor ivosidenib, which targets IDH1 with a mutation at R132, has been approved by the FDA for the clinical treatment of acute myeloid leukemia. In this review, we summarize the recurrent “hotspot” mutations in these enzymes in various tumors and their role in tumorigenesis. We also describe candidate inhibitors of the mutant enzymes which show potential therapeutic value. In addition, we introduce some previously unreported mutation sites in these enzymes, which may be related to tumor development and provide opportunities for future study

Evaluations of virtual and augmented reality technology-enhanced learning for higher education

Virtual reality (VR) has good potential to promote technology-enhanced learning. Students can benefit from immersive visualization and intuitive interaction in their learning of abstract concepts, complex structures, and dynamic processes. This paper is interested in evaluating the effects of VR learning games in a Virtual and Augmented Reality Technology-Enhanced Learning (VARTeL) environment within an engineering education setting. A VARTeL flipped classroom is established in the HIVE learning hub at Nanyang Technological University (NTU) Singapore for the immersive and interactive learning. Experiments are designed for the university students conducting the learning, with three interactive and immersive VR games related to science, technology, engineering and mathematics (STEM), i.e., virtual cells, a virtual F1 racing car, and vector geometry. These VR games are a part of the VARTeL apps designed in-house at NTU for STEM education. Quantitative and qualitative analyses are performed. A total of 156 students from Mechanical Engineering participated in the experiment. There are 15 participants selected for an interview after the experiment. Pre-tests and post-tests are performed using two different models, the developed VARTeL and the modified Technology-Rich Outcome-Focused Learning Environment Inventory (TROFLEI), in order to measure the efficiency of the VARTeL environment in Higher Education. Significant improvements of about 24.8% are observed for the post-tests over the pre-tests, which illustrate the effectiveness of the VARTeL for Engineering education. Details of the VR simulation games, methods of data collection, data analyses, as well as the experiment results are discussed. It is observed from the results that all the underlying scales of the modified TROFLEI are above the threshold for the ‘Good’ category, indicating that a very reliable questionnaire is designed in this research. The mean ‘Ideal’ values are about 0.7–2.6% higher than the mean ‘Actual’ values. The limitations of the experiment and future works with recommendations are also presented in this paper

Extracellular histones cause intestinal epithelium injury and disrupt its barrier function in vitro and in vivo.

Extracellular histones are cytotoxic to various cells and have been extensively proven a vital mediator of multiple organ injuries. However, the effect of extracellular histones on the intestine remains largely unknown. This study aimed to clarify the effect of extracellular histones on the intestine. IEC-6, a cell line of rat small intestinal epithelial crypt, and C57BL/6 or ICR mice were treated with histones. The IEC-6 cells treated with histones from 20 μg/mL to 200 μg/mL for 0-24 h displayed a decline of cell viability and an increase of cell death in a concentration- and time-dependent manner. Moreover, histones (100 μg/mL) induced IEC-6 apoptosis through activating caspase 3 and necroptosis through up-regulation of receptor-interacting serine/threonine protein kinase 1 and 3 (RIPK1 and RIPK3), phosphorylated mixed-lineage kinase domain-like protein (p-MLKL) along with the decrease of caspase-8. Histones treatment disturbed zonular occludens 1 (ZO-1) expression and increased permeability of IEC-6 cell monolayer. In vivo, histones 50 mg/kg injection caused mice intestinal edema, loss apex of villus, epithelial lifting down the sides of the villi, and increased neutrophil infiltration. Elevation of serum intestinal fatty acid binding protein (I-FABP), d-lactate, or Diamine oxidase (DAO) and loss of tight junction protein, ZO-1, at 3 h and 6 h after histones injection strongly indicated severe intestinal epithelium injury, which led to increased permeability of the intestine. In conclusion, extracellular histones cause intestinal epithelial damage via direct cytotoxicity. Consequently, intestinal epithelial tight junction and barrier integrity are disrupted, which may play pivotal roles in diverse diseases

Hemoconcentration is associated with early faster fluid rate and increased risk of persistent organ failure in acute pancreatitis patients.

Background:Controversies existed surrounding the use of hematocrit to guide early fluid therapy in acute pancreatitis (AP). The association between hematocrit, early fluid therapy, and clinical outcomes in ward AP patients needs to be investigated. Methods:Data from prospectively maintained AP database and retrospectively collected details of fluid therapy were analyzed. Patients were stratified into three groups: Group 1, hematocrit 44% at 24 h; Group 3: hematocrit >44% on admission and decreased thereafter during first 24 h. "Early" means first 24 h after admission. Baseline characteristics, early fluid rates, and clinical outcomes of the three groups were compared. Results:Among the 628 patients, Group 3 had a higher hematocrit level, greater baseline predicted severity, faster fluid rate, and more fluid volume in the first 24 h compared with Group 1 or 2. Group 3 had an increased risk for persistent organ failure (POF; odds ratio 2, 95% confidence interval [1.1-3.8], P = 0.03) compared with Group 1 after adjusting for difference in baseline clinical severity scores, there was no difference between Group 2 and Group 3 or Group 1. Multivariate regression analyses revealed that hemoconcentration and early faster fluid rate were risk factors for POF and mortality (both P < 0.05). Conclusions:Hemoconcentration is associated with faster fluid rate and POF in ward AP patients. Randomized trials comparing standardized early fast and slow fluid management is warranted

ELK4 exerts opposite roles in cytokine/chemokine production and degranulation in activated mast cells

The proliferative potential of mast cells after activation for 3-4h was found to be decreased, which suggests that mast cell degranulation and cell proliferation are differentially regulated. ELK4, a member of the ternary complex factor (TCF) subfamily of Ets transcription factors, is one of the downstream effectors of MAPK signaling that is critical for cell proliferation. And Elk4 has been identified to be vital for macrophage activation in response to zymosan and the transcriptional response to 12-O-tetrade canoyl phorbol-13-acetate (TPA) stimulation in fibroblast. However, the effect of ELK4 on the mast cell transcriptional response to FcϵRI and GPCR mediated activation and its potential functional significance in mast cells remain unclear. Here, we showed that ELK4 expression is downregulated in activated mast cells. Elk4 knockout suppresses cell proliferation and impedes the cell cycle in bone marrow-derived mast cells (BMMCs), which is associated with decreased transcription of cell cycle genes. Additionally, the transcriptional activation of cytokines and chemokines is diminished while mast cell degranulation is enhanced in Elk4 knockout BMMCs. Mechanistically, ELK4 might positively modulate Hdc, Ccl3 and Ccl4 transcription by interacting with MITF and negatively regulate the transcription of degranulation-related genes by complexing with SIRT6. Overall, our study identifies a new physiological role of the transcription factor ELK4 in mast cell proliferation and activation

Early Rapid Fluid Therapy Is Associated with Increased Rate of Noninvasive Positive-Pressure Ventilation in Hemoconcentrated Patients with Severe Acute Pancreatitis

Background/Aims Hematocrit is a widely used biomarker to guide early fluid therapy for patients with acute pancreatitis (AP), but there is controversy over whether early rapid fluid therapy (ERFT) should be used in hemoconcentrated patients. This study investigated the association of hematocrit and ERFT with clinical outcomes of patients with AP. Methods Data from prospectively maintained AP database and retrospectively collected fluid management details were stratified according to actual severity defined by revised Atlanta classification. Hemoconcentration and “early” were defined as hematocrit > 44% and the first 6 h of general ward admission, respectively, and “rapid” fluid rate was defined as ≥ 3 ml/kg/h. Patients were allocated into 4 groups for comparisons: group A, hematocrit ≤ 44% and fluid rate  44% and fluid rate  44% and fluid rate ≥ 3 ml/kg/h. Primary outcome was rate of noninvasive positive-pressure ventilation (NPPV). Results A total of 912 consecutive AP patients were analyzed. ERFT has no impact on clinical outcomes of hemoconcentrated, non-severe or all non-hemoconcentrated AP patients. In hemoconcentrated patients with severe AP (SAP), ERFT was accompanied with increased risk of NPPV (odds ratio 5.96, 95% CI 1.57–22.6). Multivariate regression analyses confirmed ERFT and hemoconcentration were significantly and independently associated with persistent organ failure and mortality in patients with SAP. Conclusions ERFT is associated with increased rate of NPPV in hemoconcentrated patients with SAP

A solar wind-derived water reservoir on the Moon hosted by impact glass beads

The past two decades of lunar exploration have seen the detection of substantial quantities of water on the Moon’s surface. It has been proposed that a hydrated layer exists at depth in lunar soils, buffering a water cycle on the Moon globally. However, a reservoir has yet to be identified for this hydrated layer. Here we report the abundance, hydrogen isotope composition and core-to-rim variations of water measured in impact glass beads extracted from lunar soils returned by the Chang’e-5 mission. The impact glass beads preserve hydration signatures and display water abundance profiles consistent with the inward diffusion of solar wind-derived water. Diffusion modelling estimates diffusion timescales of less than 15 years at a temperature of 360 K. Such short diffusion timescales suggest an efficient water recharge mechanism that could sustain the lunar surface water cycle. We estimate that the amount of water hosted by impact glass beads in lunar soils may reach up to 2.7 × 1014 kg. Our direct measurements of this surface reservoir of lunar water show that impact glass beads can store substantial quantities of solar wind-derived water on the Moon and suggest that impact glass may be water reservoirs on other airless bodies