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Purpose To investigate the associations of anion gap (AG) levels before and 1-day after hemodialysis as well as anion gap changes with the mortality in critically ill patients receiving renal replacement therapy (RRT). Methods Totally, 637 patients from MIMIC-III were included in this cohort study. The associations between AG (T0), AG (T1), or ∆AG [AG (T0) − AG (T1)], and the risk of 30-day or 1-year mortality were examined by Cox restricted cubic spline regression models. Univariate and multivariate Cox proportional-hazards model was applied to assess the associations between AG (T0), AG (T1), ∆AG with 30-day and 1-year mortality, respectively. Results The median follow-up time was 18.60 (8.53, 38.16) days and 263 (41.3%) patients were survived. There was a linear relationship between AG (T0), AG (T1) or ∆AG and the risk of 30-day or 1-year mortality, respectively. The risk of 30-day mortality was higher in AG (T0) > 21 group (HR = 1.723, 95% CI 1.263–2.350), and AG (T1) > 22.3 group (HR = 2.011, 95% CI 1.417–2.853), while lower in AG > 0 group (HR = 0.664, 95% CI 0.486–0.907). The risk of 1-year mortality was increased in AG (T0) > 21 group (HR = 1.666, 95% CI 1.310–2.119), and AG (T1) > 22.3 group (HR = 1.546, 95% CI 1.159–2.064), while decreased in AG > 0 group (HR = 0.765, 95% CI 0.596–0.981). Patients with AG (T0) ≤ 21 had higher 30-day and 1-year survival probability than those with AG (T0) > 21. Conclusion AG before and after dialysis as well as the changes of AG were important factors associated with the risk of 30-day and 1-year mortality in critically ill patients receiving RRT.

Background: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. Methods: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high–throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell–derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. Results: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer–promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell–derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell–derived cardiomyocytes induced a distinct gain of enhancer–promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell–derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca 2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. Conclusions: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer–promoter connectome to drive DCM pathogenesis.

Acute myocardial infarction (AMI) is one of the most serious cardiovascular diseases with high morbidity and mortality. Numerous studies have indicated that S100A12 may has an essential role in the occurrence and development of AMI, and in-depth studies are currently lacking. The purpose of this study is to investigate the effect of S100A12 on inflammation and oxidative stress and to determine its clinical applicability in AMI. Here, AMI datasets used to explore the expression pattern of S100A12 in AMI were derived from the Gene Expression Omnibus (GEO) database. The pooled standard average deviation (SMD) was calculated to further determine S100A12 expression. The overlapping differentially expressed genes (DEGs) contained in all included datasets were recognized by the GEO2R tool. Then, functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were carried out to determine the molecular function of overlapping DEGs. Gene set enrichment analysis (GSEA) was conducted to determine unrevealed mechanisms of S100A12. Summary receiver operating characteristic (SROC) curve analysis and receiver operating characteristic (ROC) curve analysis were carried out to identify the diagnostic capabilities of S100A12. Moreover, we screened miRNAs targeting S100A12 using three online databases (miRWalk, TargetScan, and miRDB). In addition, by comprehensively using enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (RT–qPCR), Western blotting (WB) methods, etc., we used the AC16 cells to validate the expression and underlying mechanism of S100A12. In our study, five datasets related to AMI, GSE24519, GSE60993, GSE66360, GSE97320, and GSE48060 were included; 412 overlapping DEGs were identified. Protein-protein interaction (PPI) network and functional analyses showed that S100A12 was a pivotal gene related to inflammation and oxidative stress. Then, S100A12 overexpression was identified based on the included datasets. The pooled standard average deviation (SMD) also showed that S100A12 was upregulated in AMI ( SMD = 1.36 , 95% CI: 0.70-2.03, p = 0.024 ). The SROC curve analysis result suggested that S100A12 had remarkable diagnostic ability in AMI ( AUC = 0.90 , 95% CI: 0.87-0.92). And nine miRNAs targeting S100A12 were also identified. Additionally, the overexpression of S100A12 was further confirmed that it maybe promote inflammation and oxidative stress in AMI through comprehensive in vitro experiments. In summary, our study suggests that overexpressed S100A12 may be a latent diagnostic biomarker and therapeutic target of AMI that induces excessive inflammation and oxidative stress. Nine miRNAs targeting S100A12 may play a crucial role in AMI, but further studies are still needed. Our work provides a positive inspiration for the in-depth study of S100A12 in AMI.

Patients with gastric cancer (GC) have a poor prognosis, which is mainly due to the low rate of early diagnosis. The present study aimed to evaluate whether circulating microRNA-130b (miR-130b) and blood routine parameters [neutrophil count (N#), lymphocyte count (L#), monocyte count (M#), neutrophil percentage (N%), lymphocyte percentage (L%), monocyte percentage (M%), hemoglobin (Hb) level, hematocrit (Hct), red blood cell distribution width (RDW), platelet count, platelet distribution width (PDW), mean platelet volume (MPV), MPV to platelet count ratio (MPV/PC), monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR)] are useful biomarkers for GC, early stage GC (EGC) and precancerous lesion (Pre) detection, and to identify more effective diagnostic models by combining circulating blood markers. Circulating levels of M#, M%, RDW-coefficient of variation (RDW-CV), MPV, PDW, MLR and NLR were significantly higher, and the levels of Hb and L% were significantly lower in patients with GC and Pre compared with those in healthy controls (NCs) (all P

BackgroundIschemia/reperfusion-mediated myocardial infarction (MIRI) is a major pathological factor implicated in the progression of ischemic heart disease, but the key factors dysregulated during MIRI have not been fully elucidated, especially those essential non-coding factors required for cardiovascular development.MethodsA murine MIRI model and RNA sequencing (RNA-seq) were used to identify key lncRNAs after myocardial infarction. qRT-PCR was used to validate expression in cardiac muscle tissues and myocardial cells. The role of Gm18840 in HL-1 cell growth was determined by flow cytometry experiments in vitro. Full-length Gm18840 was identified by using a rapid amplification of cDNA ends (RACE) assay. The subcellular distribution of Gm18840 was examined by nuclear/cytoplasmic RNA fractionation and qRT-PCR. RNA pulldown and RNA immunoprecipitation (RIP)-qPCR assays were performed to identify Gm18840-interacting proteins. Chromatin isolation by RNA purification (ChIRP)-seq (chromatin isolation by RNA purification) was used to identify the genome-wide binding of Gm18840 to chromatin. The regulatory activity of Gm18840 in transcriptional regulation was examined by a luciferase reporter assay and qRT-PCR.ResultsGm18840 was upregulated after myocardial infarction in both in vivo and in vitro MIRI models. Gm18840 was 1,471 nt in length and localized in both the cytoplasm and the nucleus of HL-1 cells. Functional studies showed that the knockdown of Gm18840 promoted the apoptosis of HL-1 cells. Gm18840 directly interacts with histones, including H2B, highlighting a potential function in transcriptional regulation. Further ChIRP-seq and RNA-seq analyses showed that Gm18840 is directly bound to the cis-regulatory regions of genes involved in developmental processes, such as Junb, Rras2, and Bcl3.ConclusionGm18840, a novel transcriptional regulator, promoted the apoptosis of myocardial cells via direct transcriptional regulation of essential genes and might serve as a novel therapeutic target for MIRI.

To investigate the influence of bleomycin (BLM) on the proliferation and apoptosis of brain glioma cells through transforming growth factor-β (TGF-β)/Smads signaling pathway.The U87 brain glioma cells were cultured in vitro and reacted with different concentrations of BLM (5 and 10 mU/mL), and the cell growth status of each group was observed under a microscope. The cell proliferation activity was detected using Cell Counting Kit-8 (CCK-8) assay, the percentage of 5-Ethynyl-2'-deoxyuridine (EdU)-positive cells in each group was determined via EdU staining, and the apoptosis of U87 cells was tested by means of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to measure the messenger ribonucleic acid (mRNA) levels of genes related to proliferation, apoptosis and the TGF-β/Smads signaling pathway. Finally, western blotting assay was performed to analyze the expression of the TGF-β/Smads signaling pathway.In the 5 mU/mL BLM group, the glioma cells were in a poor growth status, with a low density, while the 10 mU/mL BLM group exhibited the poorest growth status and the lowest density, and the morphological structure trended toward normal. It was discovered via CCK-8 assay and EdU staining that the number of cells and proliferation activity were decreased markedly in the 10 mU/mL BLM group. According to TUNEL staining, 10 mU/mL BLM group had remarkably increased apoptotic cells, while negative control (NC) group had fewer apoptotic cells. The gene assay results revealed that the gene expressions of Bcl-2 and TGF-β1 declined notably in the 10 mU/mL BLM group but rose in the NC group, and the gene expression trends of Caspase-3 and Smad4 were the opposite. The protein assay results manifested that the expressions of TGF-β1 was obviously reduced, while that of Smad4 was evidently raised in the 10 mU/mL BLM group.BLM at an appropriate concentration can inhibit the proliferation and promote apoptosis of brain glioma cells by repressing the TGF-β/Smads signaling pathway, thus ameliorating and treating brain glioma and other related diseases.

Objective MicroRNA (miR)-421 plays a key role in cancer progression. It has been reported that circulating miR-421may be a potential tumor marker for the diagnosis of several cancers. However, the role of miR-421 in plasma as a potential biomarker in the diagnosis of precancerous gastric lesions (Pre) and early-stage gastric cancer (GC) remains poorly understood. In this study, we investigated miR-421 in plasma as a novel potential biomarker for the detection of precancerous gastric lesions and early-stage (GC). Materials & Methods The miRNA content was determined by quantitative real-time polymerase chain reaction (qRT-PCR). MiR-421 content in all subjects was normalized by endogenous miRNA (miR-16). The diagnostic value of miR-421 for Pre and GC was assessed by comparing receiver operating characteristic (ROC) analysis with traditional tumor markers, including CEA, CA125, CA153, CA211 and CA50. The correlation between the expression of miR-421 and the pathological characteristics of Pre and GC was analyzed. Results Elevated expression of miR-421 in plasma can robustly distinguish the normal population from Pre and GC cases, especially in the early stages of gastric cancer cases (all p p p p Conclusions Overexpression of plasma miR-421 is a novel biomarker for the detection of precancerous lesions and early gastric cancer.

IntroductionOur previous study showed that naringin (NRG) protects cardiomyocytes against high glucose (HG)-induced injuries by inhibiting p38 mitogen-activated protein kinase (MAPK). Leptin induces hypertrophy in rat cardiomyocytes via p38/MAPK activation. The present study aimed to test the hypothesis that leptin-Janus kinase 2 (JAK2)/signal transducers and activators of transcription 3 (STAT3), which are responsible for leptin’s functions, are involved in HG-induced injuries and cardioprotective effects of NRG in cardiomyocytes.Material and methodsH9c2 cells were exposed to HG for 24 h to establish a cardiomyocyte injury model. Cells were pretreated with NRG and other drugs before exposure to HG. Protein expression was measured by western blot analysis. Cell viability was detected by Cell Counting Kit-8 assay. Apoptotic cells were assessed by Hoechst 33258 staining assay. Intracellular reactive oxygen species levels were determined by dichlorofluorescein diacetate staining. Mitochondrial membrane potential was evaluated using JC-1. An enzyme-linked immunosorbent assay was performed to determine the inflammatory cytokines.ResultsNRG significantly attenuated HG-induced increases in leptin and Ob-R expression. Pretreatment with either a leptin antagonist (LA) or NRG markedly ameliorated HG-induced elevation of phosphorylated (p)-JAK2 and p-STAT3, respectively. Pretreatment with NRG, LA, Ob-R antagonist, or AG490 clearly alleviated HG-induced injuries and inflammation.ConclusionsThis study provides new evidence of the NRG protective effects of H9c2 cells against HG-induced injuries possibly via modulation of the leptin-JAK2/STAT3 pathway.

The present study determined the levels of plasma biomarkers in patients with gastric carcinoma (GC) and investigated their clinical significance and diagnostic value. Between April 2014 and December 2018, 90 patients with GC, 90 patients with precancerous lesions (Pre) and 45 healthy controls (NC) were recruited from the Affiliated Liutie Central Hospital of Guangxi Medical University. Five markers were measured: microRNA-650 (miRNA-650; using reverse transcription-quantitative polymerase chain reaction), and carcinoembryonic antigen (CEA), carbohydrate antigen (CA)125, CA211 and CA50 using electrochemiluminescence. Circulating markers were all upregulated in patients with GC (P

ObjectivesN-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is an unfavourable factor responsible for poor outcomes in the cardiovascular diseases. Nevertheless, the prognostic role of NT-pro-BNP in type B aortic dissection (TBAD) remains unclear. The aim of the current study was to investigate the relationship between NT-pro-BNP levels and in-hospital and long-term adverse prognosis in patients with TBAD.DesignA retrospective multicentre study.SettingLiutie Central Hospital, Nanfang Hospital and Huiyang Hospital in China.ParticipantsA total of 657 consecutive patients with TBAD were enrolled in the study. NT-pro-BNP was measured at admission and included patients were divided into three groups according to the tertiles of NT-pro-BNP (pg/mL): 312 (n=219).Primary and secondary outcome measuresLong-term mortality and in-hospital major adverse clinical events.ResultsOverall, in-hospital death occurred in 27 patients (4.1%), which was significantly higher in upper tertiles of NT-pro-BNP (0.5% vs 4.1% vs 7.8%, p210 pg/mL had 81.5% sensitivity and 58.6% specificity for predicting in-hospital death (area under the curve= 0.774, 95% CI 0.692 to 0.855; p210 pg/mL compared with patients with NT-pro-BNP ≤210 pg/mL (log-rank=26.92, p210 pg/mL was independently associated with long-term death (adjusted HR 2.47, 95% CI 1.45 to 4.22, p=0.001).ConclusionsNT-pro-BNP resulted as an independent predictor of adverse prognosis in patients with TBAD, thus could be used as a potential risk-stratification tool.