MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

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Antitumor effects of dioscin in A431 cells via adjusting ATM/p53-mediated cell apoptosis,DNA damage and migration

Skin cancer is the deadliest type of malignant disease and causes primary mortality worldwide. Dioscin, which exists in medicinal plants, has potent anticancer effects. However, its effects on skin cancer remain unknown. In the present study, the activity and mechanism of dioscin on the human skin cancer A431 cell line were investigated, MTT, colony formation, Transwell, wound-healing, TUNEL, Comet, immunofluorescence and western blot assays were used to assess the effects of dioscin on A431 cells. The results of MTT, colony formation, Transwell and wound-healing assays revealed that dioscin suppressed proliferation, colony formation and invasion of the cancer cells. TUNEL and comet assays demonstrated that dioscin exhibited significant effects on cell apoptosis and DNA damage. Investigations into the mechanism revealed that the expression levels of phosphorylated Ataxia telangiectasia-mutated (ATM) were considerably activated by dioscin, which significantly upregulated the expression levels of p53 to activate mitochondrial apoptosis signaling. Furthermore, the expression levels of BAX, cleaved caspase-3/9 and cleaved poly (ADP-ribose) polymerase were upregulated, and the expression levels of BCL-2 were downregulated by dioscin. Additionally, dioscin markedly downregulated the expression levels of matrix metalloproteinase 2 (MMP2), MMP9, RHO and cdc42, which are all associated with tumor invasion. In addition, p53-small interfering RNA transfection experiments indicated that dioscin exhibited excellent activity against skin cancer in vitro by decreasing p53 expression. Overall, the present results suggested that dioscin inhibited skin cancer cell proliferation via adjusting ATM/p53-mediated cell apoptosis, migration and DNA damage, which should be considered as a potential option for future treatments of skin cancer.     

An introduction for the special issue on environmental health and genome integrity

Environmental exposures and genome maintenance mechanisms that respond to environmentally-induced genotoxicity have a profound impact on human health. Eight review articles in this Special Issue (SI) titled “Environmental Health and Genome Integrity” describe emerging new mechanisms by which distinct forms of environmentally-induced DNA damage are remediated, and explain how DNA repair pathway choices impact genome integrity and disease propensity. Here, we provide an introduction to reviews from this SI. Our expanding knowledge of how genotoxic exposures impact the genome will allow us to better predict, prevent and treat environmentally-induced human diseases such as cancer and neurodegenerative disorders.     

肥胖相关性高血压患者中心动脉压与靶器官损害相关性分析

【摘要】目的 探讨肥胖相关性高血压患者靶器管损害程度及中心动脉压（CBP）对靶器管损害的影响。方法 纳入徐州市中心医院2014年6月至2019年6月收住入院的高血压患者150例。根据高血压患者体质量指数，将样本分为正常体重高血压组（BMI<24Kg/m2）、超重高血压组(24 Kg/m2≤BMI<28 Kg/m2)、肥胖高血压组（BMI≥28 Kg/m2）。比较三组患者靶器管损害的差异及其与中心动脉压、24小时动态血压的相关性。结果 (1)与正常体重高血压组、超重高血压组比较，肥胖高血压组BMI、腰围、空腹血糖、同型半胱氨酸（HCY）、高密度脂蛋白（HDL-C）、低密度脂蛋白（LDL-c）、颈-股脉搏波传导速度(c-fPWV)、左心室质量（LVM）、左心室质量指数（LVMI）、尿微量白蛋白（mALB）较高（P<0.05）。(2)高血压患者c-fPWV与中心动脉脉压差（CPP）呈正相关（r=0.580，P=0.001）；LVMI与中心动脉收缩压（CSBP）呈正相关（r=0.279，P=0.004）；mALB与CSBP呈正相关（r=0.333，P=0.001）。结论 体重增加可进一步加重高血压患者靶器管损害，中心动脉压较24小时动态血压对高血压患者靶器管损害更为密切。     

Assessment of systemic genetic damage in pediatric inflammatory bowel disease

The etiology of distal site cancers in inflammatory bowel disease (IBD) is not well understood and requires further study. We investigated whether pediatric IBD patients' blood cells exhibit elevated levels of genomic damage by measuring the frequency of mutant phenotype (CD59-/CD55-) reticulocytes (MUT RET) as a reporter of PIG-A mutation, and the frequency of micronucleated reticulocytes (MN-RET) as an indicator of chromosomal damage. IBD patients (n = 18 new-onset disease, 46 established disease) were compared to age-matched controls (constipation or irritable bowel syndrome patients from the same clinic, n = 30) and young healthy adults age 19–24 (n = 25). IBD patients showed no indication of elevated MUT RET relative to controls (mean ± SD = 3.1 ± 2.3 × 10⁻⁶ vs. 3.6 ± 5.6 x 10⁻⁶, respectively). In contrast, 59 IBD patients where %MN-RET measurements were obtained, 10 exceeded the upper bound 90% tolerance interval derived from control subjects (i.e., 0.42%). Furthermore, each of the 10 IBD patients with elevated MN-RET had established disease (10/42), none were new-onset (0/17) (p = .049). Interestingly, each of the subjects with increased chromosomal damage was receiving anti-TNF based monotherapy at the time blood was collected (10/10, 100%), whereas this therapy was less common (20/32, 63%) among patients that exhibited ≤0.42% MN-RET (p = .040). The results clearly indicate the need for further work to understand whether the results presented herein are reproducible and if so, to elucidate the causative factor(s) responsible for elevated MN-RET frequencies in some IBD patients.     

Human blood PIG-A mutation and micronucleated reticulocyte flow cytometric assays: Method optimization and evaluation of intra- and inter-subject variation

We previously described flow cytometry-based methods for scoring the incidence of micronucleated reticulocytes (MN-RET) and PIG-A mutant phenotype reticulocytes (MUT RET) in rodent and human blood samples. The current report describes important methodological improvements for human blood analyses, including immunomagnetic enrichment of CD71-positive reticulocytes prior to MN-RET scoring, and procedures for storing frozen blood for later PIG-A analysis. Technical replicate variability in MN-RET and MUT RET frequencies based on blood specimens from 14 subjects, intra-subject variability based on serial blood draws from 6 subjects, and inter-subject variation based on up to 344 subjects age 0 to 73 years were quantified. Inter-subject variation explained most of the variability observed for both endpoints (≥77%), with much lower intra-subject and technical replicate variability. The relatively large degree of inter-subject variation is apparent from mean and standard deviation values for MN-RET (0.15 ± 0.10%) and MUT RET (4.7 ± 5.0 per million, after omission of two extreme outliers). The influences of age and sex on inter-subject variation were investigated, and neither factor affected MN-RET whereas both influenced MUT RET frequency. The lowest MUT RET values were observed for subjects <11 years old, and males had moderately higher frequencies than females. These results indicate that MN-RET and MUT RET are automation-compatible biomarkers of genotoxicity that bridge species of toxicological interest to include human populations. These data will be useful for appropriately designing future human studies that include these biomarkers of genotoxicity, and highlight the need for additional work aimed at identifying the sources of inter-individual variability reported herein.     

The impact of frost-damage on the quality and quantity of the secreted antigen-specific IgG repertoire

Freezing of alum-based vaccines drastically alters their colloidal composition and leads to irreversible cluster formation. The loss of stability is well described, but the impact of frost damage on the functionality of the induced and secreted antibody repertoire has not been studied in detail. We therefore applied our single-cell measurement platform to extract the frequencies of Immunoglobulin G-secreting cells in combination with individual secretion rates and affinities. We showed that, frost-damaged or not, the tested vaccine was able to generate similar frequencies of total and antigen-affine IgG-secreting cells. Additionally, the frost-damaged vaccine stimulated a similar T-cell cytokine secretion pattern when compared to the regularly stored vaccine. However, frost-damaged vaccines induced no efficient affinity maturation and a complete collapse of the affinity distribution was observed. This study unveiled the impact of frost-damage to alum-based vaccines on the induced secreted antibody repertoire, and illustrated the power of functional single-antibody analysis.     

In vivo quantification of 3D displacement in sacral soft tissues under compression: Relevance of 2D US-based measurements for pressure ulcer risk assessment

Objective2D Ultrasound (US) imaging has been recently investigated as a more accessible alternative to 3D Magnetic Resonance Imaging (MRI) for the estimation of soft issue motion under external mechanical loading. In the context of pressure ulcer prevention, the aim of this pilot MRI study was to design an experiment to characterize the sacral soft tissue motion under a controlled mechanical loading. Such an experiment targeted the estimation of the discrepancy between tissue motion assessed using a 2D imaging modality (echography) versus tissue motion assessed using a (reference) 3D imaging modality (MRI).MethodsOne healthy male volunteer participated in the study. An MRI-compatible custom-made setup was designed and used to load the top region of the sacrum with a 3D-printed copy of the US transducer. Five MR images were collected, one in the unloaded and four in the different loaded configurations (400–1200 [g]). Then, a 3D displacement field for each loading configuration was extracted based on the results of digital volume correlation. Tissue motion was separated into the X, Y, Z directions of the MRI coordinate system and the ratios between the out-of-plane and in-plane components were assessed for each voxel of the selected region of interest.ResultsRatios between the out-of-plane and in-plane displacement components were higher than 0.6 for more than half of the voxels in the region of interest for all load cases and higher than 1 for at least quarter of the voxels when loads of 400–800 [g] were used.ConclusionThe out-of-ultrasound-plane tissue displacement was not negligible, therefore 2D US imaging should be used with caution for the evaluation of the tissue motion in the sacrum region. The 3D US modality should be further investigated for this application.