Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health.

The challenge posed by opioid overdose has become a significant concern for health systems due to the complexities associated with drug prohibition, widespread clinical use, and potential abuse. In response, healthcare professionals have primarily concentrated on mitigating the hallucinogenic and respiratory depressant consequences of opioid overdose to minimize associated risks. However, it is crucial to acknowledge that most opioids possess the capacity to prolong the QT interval, particularly in cases of overdose, thereby potentially resulting in severe ventricular arrhythmias and even sudden death if timely intervention is not implemented. Consequently, alongside addressing the typical adverse effects of opioids, it is imperative to consider their cardiotoxicity. To enhance comprehension of the correlation between opioids and arrhythmias, identify potential targets for prompt intervention, and mitigate the hazards associated with clinical utilization, an exploration of the interaction between drugs and ion channels, as well as their underlying mechanisms, becomes indispensable. This review primarily concentrates on elucidating the impact of opioid drugs on diverse ion channels, investigating recent advancements in this domain, and attaining a deeper understanding of the mechanisms underlying the prolongation of the QT interval by opioid drugs, along with potential interventions.

Detecting early-warning biomarkers associated with heart-exosome genetic-signature for acute myocardial infarction: A source-tracking study of exosome.

The genetic information of plasma total-exosomes originating from tissues have already proven useful to assess the severity of coronary artery diseases (CAD). However, plasma total-exosomes include multiple sub-populations secreted by various tissues. Only analysing the genetic information of plasma total-exosomes is perturbed by exosomes derived from other organs except the heart. We aim to detect early-warning biomarkers associated with heart-exosome genetic-signatures for acute myocardial infarction (AMI) by a source-tracking analysis of plasma exosome. The source-tracking of AMI plasma total-exosomes was implemented by deconvolution algorithm. The final early-warning biomarkers associated with heart-exosome genetic-signatures for AMI was identified by integration with single-cell sequencing, weighted gene correction network and machine learning analyses. The correlation between biomarkers and clinical indicators was validated in impatient cohort. A nomogram was generated using early-warning biomarkers for predicting the CAD progression. The molecular subtypes landscape of AMI was detected by consensus clustering. A higher fraction of exosomes derived from spleen and blood cells was revealed in plasma exosomes, while a lower fraction of heart-exosomes was detected. The gene ontology revealed that heart-exosomes genetic-signatures was associated with the heart development, cardiac function and cardiac response to stress. We ultimately identified three genes associated with heart-exosomes defining early-warning biomarkers for AMI. The early-warning biomarkers mediated molecular clusters presented heterogeneous metabolism preference in AMI. Our study introduced three early-warning biomarkers associated with heart-exosome genetic-signatures, which reflected the genetic information of heart-exosomes carrying AMI signals and provided new insights for exosomes research in CAD progression and prevention.

A causal relationship between appendicular lean mass and atrial fibrillation: A two sample Mendelian randomization study.

BACKGROUND AND AIM: The relationship between appendicular lean mass (ALM) and most cardiovascular events has been established, but the direct association between ALM and atrial fibrillation (AF) remains uncertain. METHODS AND RESULTS: Herein, we identified 494 single-nucleotide polymorphisms (SNPs) strongly associated with ALM as instrumental variables (P < 5E-8) based on a genome-wide association study (GWAS) with 450,243 European participants. Then, we employed five Mendelian randomization (MR) analysis methods to investigate the causal relationship between ALM and AF. All results indicated a causal relationship between ALM and AF, among Inverse variance weighted (P = 8.44E-15, odds ratio [OR]: 1.16, 95 % confidence interval [CI]: 1.114-1.198). Furthermore, we performed a sensitivity analysis, which revealed no evidence of pleiotropy (egger_intercept = 0.000089, P = 0.965) or heterogeneity (MR Egger, Q Value = 0.980; Inverse variance weighted, Q Value = 0.927). The leave-one-out method demonstrates that individual SNPs have no driven impact on the whole causal relationship. Multivariable MR analysis indicates that, after excluding the influence of hypertension and coronary heart disease, a causal relationship between ALM and AF still exists (P = 7.74E-40, OR 95 %CI: 1.389 (1.323-1.458)). Importantly, the Radial MR framework analysis and Robust Adjusted Profile Score (RAPS) further exhibit the robustness of this causal relationship. CONCLUSION: A strong association between ALM and AF was confirmed, and high ALM is a risk factor for AF.

Immune-mediated inflammatory diseases and the risk of valvular heart disease: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested that immune-mediated inflammatory diseases (IMIDs) are associated with a higher risk of valvular heart disease (VHD). But the potential causal association is not clear. Therefore, we used Mendelian randomization (MR) analysis to assess the causal association of IMIDs with VHD risk. METHODS: A two-sample MR analysis was performed to confirm the causal association of several common IMIDs (systemic lupus erythematosus, SLE; rheumatoid arthritis, RA; multiple sclerosis, MS; ankylosing spondylitis, AS; psoriasis, PSO; inflammatory bowel disease, IBD) with the risk of VHD. The exposure data is derived from published genome-wide association studies (GWASs) and outcome data come from the FinnGen database (47,003 cases and 182,971 controls). Inverse-variance weighted (IVW), MR-Egger, and weighted median methods were performed to assess the causal association. The study design applied univariable MR and multivariable MR. RESULTS: The MR analysis indicated that several genetically predicted IMIDs increased the risk of VHD, including SLE (odds ratio (OR) = 1.014; 95% confidence interval (CI) = < 1.001,1.028 > ; p = 0.036), RA (OR = 1.017; 95% CI = < 1.002,1.031 > ; p = 0.025), and IBD (OR = 1.018; 95% CI = < 1.002,1.033 > ; p = 0.023). Multivariable MR indicated that the adverse effect of these IMIDs on VHD was dampened to varying degrees after adjusting for smoking, obesity, coronary artery disease, and hypertension. CONCLUSION: Our findings support the first genetic evidence of the causality of genetically predicted IMIDs with the risk of developing into VHD. Our results deliver a viewpoint that further active intervention needs to be explored to mitigate VHD risk in patients with SLE, RA, and IBD. Key Points • Genetically predicted systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) are causally associated with valvular heart disease (VHD). • To reduce the risk of VHD in patients with SLE, RA, and IBD, active interventions should be further explored.

SYNPO2 promotes the development of BLCA by upregulating the infiltration of resting mast cells and increasing the resistance to immunotherapy.

Synaptopodin 2 (SYNPO2) plays a pivotal role in regulating tumor growth, development and progression in bladder urothelial Carcinoma (BLCA). However, the precise biological functions and mechanisms of SYNPO2 in BLCA remain unclear. Based on TCGA database­derived BLCA RNA sequencing data, survival analysis and prognosis analysis indicate that elevated SYNPO2 expression was associated with poor survival outcomes. Notably, exogenous SYNPO2 expression significantly promoted tumor invasion and migration by upregulating vimentin expression in BLCA cell lines. Enrichment analysis revealed the involvement of SYNPO2 in humoral immune responses and the PI3K/AKT signaling pathway. Moreover, increased SYNPO2 levels increased the sensitivity of BLCA to PI3K/AKT pathway­targeted drugs while being resistant to conventional chemotherapy. In in vivo BLCA mouse models, SYNPO2 overexpression increased pulmonary metastasis of 5637 cells. High SYNPO2 expression led to increased infiltration of innate immune cells, particularly mast cells, in both nude mouse model and clinical BLCA samples. Furthermore, tumor immune dysfunction and exclusion score showed that patients with BLCA patients and high SYNPO2 expression exhibited worse clinical outcomes when treated with immune checkpoint inhibitors. Notably, in the IMvigor 210 cohort, SYNPO2 expression was significantly associated with the population of resting mast cells in BLCA tissue following PD1/PDL1 targeted therapy. In conclusion, SYNPO2 may be a promising prognostic factor in BLCA by modulating mast cell infiltration and exacerbating resistance to immune therapy and conventional chemotherapy.

Genetic and immunological insights into COVID-19 with acute myocardial infarction: integrated analysis of mendelian randomization, transcriptomics, and clinical samples.

Background: Globally, most deaths result from cardiovascular diseases, particularly ischemic heart disease. COVID-19 affects the heart, worsening existing heart conditions and causing myocardial injury. The mechanistic link between COVID-19 and acute myocardial infarction (AMI) is still being investigated to elucidate the underlying molecular perspectives. Methods: Genetic risk assessment was conducted using two-sample Mendelian randomization (TSMR) to determine the causality between COVID-19 and AMI. Weighted gene co-expression network analysis (WGCNA) and machine learning were used to discover and validate shared hub genes for the two diseases using bulk RNA sequencing (RNA-seq) datasets. Additionally, gene set enrichment analysis (GSEA) and single-cell RNA-seq (scRNA-seq) analyses were performed to characterize immune cell infiltration, communication, and immune correlation of the hub genes. To validate the findings, the expression patterns of hub genes were confirmed in clinical blood samples collected from COVID-19 patients with AMI. Results: TSMR did not find evidence supporting a causal association between COVID-19 or severe COVID-19 and AMI. In the bulk RNA-seq discovery cohorts for both COVID-19 and AMI, WGCNA's intersection analysis and machine learning identified TLR4 and ABCA1 as significant hub genes, demonstrating high diagnostic and predictive value in the RNA-seq validation cohort. Single-gene GSEA and single-sample GSEA (ssGSEA) revealed immune and inflammatory roles for TLR4 and ABCA1, linked to various immune cell infiltrations. Furthermore, scRNA-seq analysis unveiled significant immune dysregulation in COVID-19 patients, characterized by altered immune cell proportions, phenotypic shifts, enhanced cell-cell communication, and elevated TLR4 and ABCA1 in CD16 monocytes. Lastly, the increased expression of TLR4, but not ABCA1, was validated in clinical blood samples from COVID-19 patients with AMI. Conclusion: No genetic causal link between COVID-19 and AMI and dysregulated TLR4 and ABCA1 may be responsible for the development of immune and inflammatory responses in COVID-19 patients with AMI.

Prognostic Value of Endothelial Progenitor Cells in Acute Myocardial Infarction Patients.

Objective: To determine prognostic role of endothelial progenitor cells (EPCs) in intensive care patients with acute myocardial infarction (AMI). Materials and Methods: From December 2018 to July 2021, a total of 91 eligible patients with AMI were consecutively examined in a single intensive care unit (ICU) in China. Patients with a history of acute coronary artery disease were excluded from the study. Samples were collected within 24 hr of onset of symptoms. EPCs, defined as coexpression of CD34+/CD133+ cells or CD133+/CD34+/KDR+, were studied using flow cytometry and categorized by quartiles. Based on the 28-days mortality outcome, the patients were further divided into two groups: death and survival. The study incorporated various variables, including cardiovascular risk factors such as body mass index, hypertension, diabetes, hypercholesterolemia, atherosclerotic burden, and medication history, as well as clinical characteristics such as APACHEⅡscore, central venous-arterial carbon dioxide difference (GAP), homocysteine, creatinine, C-reactive protein, HbAlc, and cardiac index. Cox regression analysis was employed to conduct a multivariate analysis. Results: A total of 91 patients with AMI who were admitted to the ICU were deemed eligible for inclusion in the study. Among these patients, 23 (25.3%) died from various causes during the follow-up period. The counts of EPCs were found to be significantly higher in the survival group compared to the death group (P < 0.05). In the univariate analysis, it was observed that the 28-days mortality rate was associated with the several factors, including the APACHEⅡscore (P=0.00), vasoactive inotropic score (P=0.03), GAP (P=0.00), HCY (P=0.00), creatinine (P=0.00), C-reactive protein (P=0.00), HbAlc (P=0.00), CI (P=0.01), quartiles of CD34+/CD133+ cells (P=0.00), and quartiles of CD34+/CD133+/KDR+ cells (P=0.00). CD34+/CD133+/KDR+ cells retained statistical significance in Cox regression models even after controlling for clinical variables (HR: 6.258 × 10-10 and P=0.001). Nevertheless, no significant correlation was observed between CD34+/CD133+ cells and all-cause mortality. Conclusions: The decreased EPCs levels, especially for CD34+/CD133+/KDR+ cells subsets, were an independent risk factor for 28-days mortality in AMI patients.

4-phenylbutyric acid re-trafficking hERG/G572R channel protein by modulating the endoplasmic reticulum stress-associated chaperones and endoplasmic reticulum-associated degradation gene.

Background: Long QT syndrome type 2 (LQT2) is caused by mutations in the KCNH2/human ether-à-go-go-related gene (hERG). Some hERG genetic mutation-associated diseases are alleviated by hERG-specific drug chaperones (glycerol, dimethyl sulfoxide, trimethylamine N-oxide, thapsigargin), delayed rectifier K+ current (IKr) blockers methanesulfonanilide E4031, the antihistamine astemizole, or the prokinetic drug cisapride, and the anti-arrhythmic drug quinidine. Meanwhile, many in vivo and in vitro studies have reported the efficacy of 4-phenylbutyric acid (4-PBA) in diseases with inherited genetic mutations. This study aims to explore potential therapeutic agents for hERG/G572R mutated ion channel. Methods: pcDNA3/hERG [wild type (WT)]-FLAG and pcDNA3/hERG (G572R)-FLAG plasmids were transfected into HEK293 cells. A western blot (WB) experiment was conducted to analyze protein expression. Quantitative real-time polymerase chain reaction (qPCR) was used to analyze the messenger RNA (mRNA) expression levels in the WT/G572R heterozygous HEK293 cell model treated with or without 4-PBA. The interaction between WT/G572R and BIP (GRP78), GRP94, and 3-hydroxy-3-methylglutaryl coenzyme A reductase degradation protein 1 (HRD1) was tested by co-immunoprecipitation (co-IP). To investigate the effect of 4-PBA on the WT/G572R channel current, we used electrophysiological assays (patch-clamp electrophysiological recordings). Results: The results showed that WT/G572R activated the ATF6 pathway in the endoplasmic reticulum stress (ERS), the ERS response markers GRP78, GRP94, and calreticulin (CRT)/calnexin (CNX), and HRD1, which decreased after application of the ERS inhibitor 4-PBA. The results of co-IP confirmed that the ability of hERG interacted with GRP78, GRP94, and HRD1. Moreover, 4-PBA increased the current of WT/G572R and reversed the gating kinetics of the WT/G572R channel. Conclusions: 4-PBA corrects hERG channel transport defects by inhibiting excessive ERS and the endoplasmic reticulum-associated degradation (ERAD)-related gene E3 ubiquitin ligase HRD1. Additionally, 4-PBA improved WT/G572R channel current. 4-PBA is expected to be developed as a new treatment method for LQT2.

Synaptopodin-2: a potential tumor suppressor.

Initially identified as an actin-binding protein containing a PSD95-DLG-ZO1 Domain (PZD domain), Synaptopodin 2 (SYNPO2) has long been considered a structural protein ubiquitously expressed in muscular tissues. However, emerging evidence suggests that SYNPO2 performs diverse functions in cancers in addition to its role in microfilament assembly. In most cancers, high SYNPO2 expression is positively correlated with a good prognosis, suggesting its role as a novel tumor suppressor. Abnormal SYNPO2 expression affects autophagy generation, particularly mitophagy induced by low oxidation or viral infection, as well as chaperone-mediated autophagy triggered by microfilament damage. Mechanically, SYNPO2 regulates tumor growth, metastasis, and invasion via activating the PI3K/AKT/mTOR signal and Hippo signaling pathways. Moreover, the subcellular localization, promoter methylation and single nucleotide polymorphism (SNP) of SYNPO2 have been associated with cancer progression and clinical outcomes, highlighting its potential as a prognostic or diagnostic target for this patient population. This review focuses on the role of SYNPO2 in cancer, including its generation, epigenetic modification, subcellular localization, and biological function.

A causal relationship between irritability and cardiovascular diseases: a Mendelian randomization study.

Background: Observational studies have suggested that irritability is associated with a higher risk of cardiovascular disease (CVD). However, the potential causal association is not clear. Therefore, we used Mendelian randomization (MR) analysis to assess the causal association of irritability with CVD risk. Methods: A two-sample MR analysis was performed to confirm the causal association of irritability with the risk of several common CVDs. The exposure data were derived from the UK biobank involving 90,282 cases and 232,386 controls, and outcome data were collected from the published genome-wide association studies (GWAS) and FinnGen database. Inverse-variance weighted (IVW), MR-Egger, and weighted median methods were performed to assess the causal association. Furthermore, the mediating effect of smoking, insomnia, and depressed affect was explored by using a two-step MR. Results: The MR analysis indicated that genetically predicted irritability increased the risk of CVD, including coronary artery disease (CAD) (Odds ratio, OR: 2.989; 95% confidence interval, CI: 1.521-5.874, p = 0.001), myocardial infarction (MI) (OR: 2.329, 95% CI: 1.145-4.737, p = 0.020), coronary angioplasty (OR: 5.989, 95% CI: 1.696-21.153, p = 0.005), atrial fibrillation (AF) (OR: 4.646, 95% CI: 1.268-17.026, p = 0.02), hypertensive heart disease (HHD) (OR: 8.203; 95% CI: 1.614-41.698, p = 0.011), non-ischemic cardiomyopathy (NIC) (OR: 5.186; 95% CI: 1.994-13.487, p = 0.001), heart failure (HF) (OR: 2.253; 95% CI: 1.327-3.828, p = 0.003), stroke (OR: 2.334; 95% CI: 1.270-4.292, p = 0.006), ischemic stroke (IS) (OR: 2.249; 95% CI: 1.156-4.374, p = 0.017), and ischemic stroke of large-artery atherosclerosis ISla (OR: 14.326; 95% CI: 2.750-74.540, p = 0.002). The analysis also indicated that smoking, insomnia, and depressed affect play an important role in the process of irritability leading to cardiovascular disease. Conclusion: Our findings support the first genetic evidence of the causality of genetically predicted irritability with the risk of developing into CVDs. Our results deliver a viewpoint that more early active interventions to manage an individual's anger and related unhealthy lifestyle habits are needed to prevent the occurrence of adverse cardiovascular events.

Deciphering HERG mutation in long QT syndrome type 2 using antisense oligonucleotide-mediated techniques: Lessons from cystic fibrosis.

Long QT syndrome type 2 (LQT2) is a genetic disorder caused by mutations in the KCNH2 gene, also known as the human ether-a-go-go-related gene (HERG). More than 30% of HERG mutations result in a premature termination codon that triggers a process called nonsense-mediated messenger RNA (mRNA) decay (NMD), where the mRNA transcript is degraded. NMD is a quality control mechanism that removes faulty mRNA to prevent the translation of truncated proteins. Recent advances in antisense oligonucleotide (ASO) technology in the field of cystic fibrosis (CF) have yielded significant progress, including the ASO-mediated comprehensive characterization of key NMD factors and exon-skipping therapy. These advances have contributed to our understanding of the role of premature termination codon-containing mutations in disease phenotypes and have also led to the development of potentially useful therapeutic strategies. Historically, studies of CF have provided valuable insights for the research on LQT2, particularly concerning increasing the expression of HERG. In this article, we outline the current state of knowledge regarding ASO, NMD, and HERG and discuss the introduction of ASO technology in the CF to elucidate the pathogenic mechanisms through targeting NMD. We also discuss the potential clinical therapeutic benefits and limitations of ASO for the management of LQT2. By drawing on lessons learned from CF research, we explore the potential translational values of these advances into LQT2 studies.

Integrated analysis of the voltage-gated potassium channel-associated gene KCNH2 across cancers.

KCNH2 encodes the human ether-a-go-go-related gene (hERG) potassium channel and is an important repolarization reserve for regulating cardiac electrical activity. Increasing evidence suggests that it is involved in the development of various tumours, yet a thorough analysis of the underlying process has not been performed. Here, we have comprehensively examined the role of KCNH2 in multiple cancers by assessing KCNH2 gene expression, diagnostic and prognostic value, genetic alterations, immune infiltration correlations, RNA modifications, mutations, clinical correlations, interacting proteins, and associated signalling pathways. KCNH2 is differentially expressed in over 30 cancers and has a high diagnostic value for 10 tumours. Survival analysis showed that high expression of KCNH2 was associated with a poor prognosis in glioblastoma multiforme (GBM) and hepatocellular carcinoma (LIHC). Mutations and RNA methylation modifications (especially m6A) of KCNH2 are associated with its expression in multiple tumours. KCNH2 expression is correlated with tumour mutation burden, microsatellite instability, neoantigen load, and mutant-allele tumour heterogeneity. In addition, KCNH2 expression is associated with the tumour immune microenvironment and its immunosuppressive phenotype. KEGG signalling pathway enrichment analysis revealed that KCNH2 and its interacting molecules are involved in a variety of pathways related to carcinogenesis and signal regulation, such as the PI3K/Akt and focal adhesion pathways. Overall, we found that KCNH2 and its interaction molecular are expected to be immune-related biomarkers for cancer diagnosis and prognosis evaluation, and are potential regulatory targets of singalling pathways for tumour development due to their significant role in cancers.

The Advantages, Challenges, and Future of Human-Induced Pluripotent Stem Cell Lines in Type 2 Long QT Syndrome.

Type 2 long QT syndrome (LQT2) is the second most common subtype of long QT syndrome and is caused by mutations in KCHN2 encoding the rapidly activating delayed rectifier potassium channel vital for ventricular repolarization. Sudden cardiac death is a sentinel event of LQT2. Preclinical diagnosis by genetic testing is potentially life-saving.Traditional LQT2 models cannot wholly recapitulate genetic and phenotypic features; therefore, there is a demand for a reliable experimental model. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) meet this challenge. This review introduces the advantages of the hiPSC-CM model over the traditional model and discusses how hiPSC-CM and gene editing are used to decipher mechanisms of LQT2, screen for cardiotoxicity, and identify therapeutic strategies, thus promoting the realization of precision medicine for LQT2 patients.

Chronic Administration of COVID-19 Drugs Fluvoxamine and Lopinavir Shortens Action Potential Duration by Inhibiting the Human Ether-à-go-go-Related Gene and Cav1.2.

Background: Old drugs for new indications in the novel coronavirus disease of 2019 (COVID-19) pandemic have raised concerns regarding cardiotoxicity, especially the development of drug-induced QT prolongation. The acute blocking of the cardiac hERG potassium channel is conventionally thought to be the primary mechanism of QT prolongation induced by COVID-19 drugs fluvoxamine (FLV) and lopinavir (LPV). The chronic impact of these medications on the hERG expression has yet to be determined. Methods: To investigate the effect of long-term incubation of FLV and LPV on the hERG channel, we used electrophysiological assays and molecular experiments, such as Western blot, RT-qPCR, and immunofluorescence, in HEK-293 cells stably expressing hERG and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Results: Compared to the acute effects, chronic incubation for FLV and LPV generated much lower half-maximal inhibitory concentration (IC50) values, along with a left-shifted activation curve and retarded channel activation. Inconsistent with the reduction in current, we unexpectedly found that the chronic effects of drugs promoted the maturation of hERG proteins, accompanied by the high expression of Hsp70 and low expression of Hsp90. Targeting Hsp70 using siRNA was able to reverse the effects of these drugs on hERG proteins. In addition, FLV and LPV resulted in a significant reduction of APD90 and triggered the early after-depolarizations (EADs), as well as inhibited the protein level of the L-type voltage-operated calcium channel (L-VOCC) in hiPSC-CMs. Conclusion: Chronic incubation with FLV and LPV produced more severe channel-blocking effects and contributed to altered channel gating and shortened action potential duration by inhibiting hERG and Cav1.2.

Glycopattern Alteration of Glycoproteins in Gastrointestinal Cancer Cell Lines and Their Cell-Derived Exosomes.

Gastrointestinal (GI) cancers constitute the largest portion of all human cancers, and the most prevalent GI cancers in China are colorectal cancer (CRC), gastric cancer (GC), and hepatocellular carcinoma (HCC). Exosomes are nanosized vesicles containing proteins, lipids, glycans, and nucleic acid, which play important roles in the tumor microenvironment and progression. Aberrant glycosylation is closely associated with GI cancers; however, little is known about the glycopattern of the exosomes from GI cancer cells. In this study, glycopatterns of HCC, CRC, and GC cell lines and their exosomes were detected using lectin microarrays. For all exosomes, (GlcNAcß1-4)n and Galß1-4GlcNAc (DSA) were the most abundant glycans, but αGalNAc and αGal (GSL-II and SBA) were the least. Different cancers had various characteristic glycans in either cells or exosomes. Glycans altered in cell-derived exosomes were not always consistent with the host cells in the same cancer. However, Fucα1-6GlcNAc (core fucose) and Fucα1-3(Galß1-4)GlcNAc (AAL) were altered consistently in cells and exosomes although they were decreased in HCC and CRC but increased in GC. The study drew the full-scale glycan fingerprint of cells and exosomes related to GI cancer, which may provide useful information for finding specific biomarkers and exploring the underlying mechanism of glycosylation in exosomes.

Deciphering Common Long QT Syndrome Using CRISPR/Cas9 in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

From carrying potentially pathogenic genes to severe clinical phenotypes, the basic research in the inherited cardiac ion channel disease such as long QT syndrome (LQTS) has been a significant challenge in explaining gene-phenotype heterogeneity. These have opened up new pathways following the parallel development and successful application of stem cell and genome editing technologies. Stem cell-derived cardiomyocytes and subsequent genome editing have allowed researchers to introduce desired genes into cells in a dish to replicate the disease features of LQTS or replace causative genes to normalize the cellular phenotype. Importantly, this has made it possible to elucidate potential genetic modifiers contributing to clinical heterogeneity and hierarchically manage newly identified variants of uncertain significance (VUS) and more therapeutic options to be tested in vitro. In this paper, we focus on and summarize the recent advanced application of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9 (CRISPR/Cas9) in the interpretation for the gene-phenotype relationship of the common LQTS and presence challenges, increasing our understanding of the effects of mutations and the physiopathological mechanisms in the field of cardiac arrhythmias.

A Predictive Model for Prognosis and Therapeutic Response in Hepatocellular Carcinoma Based on a Panel of Three MED8-Related Immunomodulators.

The current tumor-node-metastasis (TNM) system is limited in predicting the survival and guiding the treatment of hepatocellular carcinoma (HCC) patients since the TNM system only focuses on the anatomical factors, regardless of the intratumoral molecule heterogeneity. Besides, the landscape of intratumoral immune genes has emerged as a prognostic indicator. The mediator complex subunit 8 (MED8) is a major polymerase regulator and has been described as an oncogene in renal cell carcinoma, but its pathophysiological significance of HCC and its contribution to the prognosis of HCC remain unclear. Here, we aimed to discuss the expression profile and clinical correlation of MED8 in HCC and construct a predictive model based on MED8-related immunomodulators as a supplement to the TNM system. According to our analyses, MED8 was overexpressed in HCC tissues and increased expression of MED8 was an indicator of poor outcome in HCC. The knockdown of MED8 weakened the proliferation, colony forming, and migration of HepG2 and Huh7 cells. Subsequently, a predictive model was identified based on a panel of three MED8-related immunomodulators using The Cancer Genome Atlas (TCGA) database and further validated in International Cancer Genome Consortium (ICGC) database. The combination of the predictive model and the TNM system could improve the performance in predicting the survival of HCC patients. High-risk patients had poor overall survival in TCGA and ICGC databases, as well as in subgroup analysis with early clinicopathology classification. It was also found that high-risk patients had a higher probability of recurrence in TCGA cohort. Furthermore, low-risk score indicated a better response to immunotherapy and drug therapy. This predictive model can be served as a supplement to the TNM system and may have implications in prognosis stratification and therapeutic guidance for HCC.

Skp2 regulates DNA damage repair and apoptosis via interaction with Ku70.

PURPOSE: Skp2, an oncoprotein, regulates tumor proliferation, invasion and metastasis. Ku70 is a critical component of the non-homologous end-joining (NHEJ) process. Both Skp2 and Ku70 are positively associated in multiple cancers. However, there is no report about the relationship between Skp2 and Ku70 proteins. METHODS: In this study, we carried out Bioinformatics and molecular biological methods to investigate the relationship between Skp2 and Ku70 proteins. RESULTS: We first observed Skp2 and Ku70 mRNAs were significantly increased in cervical cancer tissues. And we identified Ku70 as a Skp2-binding protein and the binding site located in the C-terminal of Ku70 protein. We further found that Skp2 knockdown decreased the Ku70 protein level in cells, and increase the cellular apoptosis and DNA damage, suggesting Skp2 mediates the Ku70 protein stability and function via post-translational modification. CONCLUSION: The direct interaction between Skp2 and Ku70 proteins mediates the DNA damage repair and cellular apoptosis by regulating Ku70 stability and function via post-translational modification. The molecular mechanisms how Skp2 stabilize Ku70 would be clarified in our following research work.

Brother of regulator of imprinted sites inhibits cisplatin-induced DNA damage in non-small cell lung cancer.

Cisplatin (DDP) chemotherapy is the primary modality of treatment for non-small cell lung cancer (NSCLC). However, due to the occurrence of DDP resistance, only a limited number of patients benefit from this treatment regimen. Brother of Regulator of Imprinted Sites (BORIS) is expressed elevated in NSCLC. Whether BORIS is involved in the DDP resistance of NSCLC is currently undetermined. The association between BORIS expression and overall survival rate of 156 patients with NSCLC who received DDP chemotherapy was analyzed in the present study. In order to investigate the function of BORIS in DDP chemotherapy, BORIS was silenced or overexpressed in four NSCLC cell lines. The cell viabilities, apoptosis and DNA damage induced by DDP were evaluated in these cell lines. In addition, the regulations of DNA repair genes were assessed, including POLH, ERCC1, BRCA1, MSH6 and XPA. The present study demonstrated that high BORIS expression was associated with decreased overall survival rate in patients with NSCLC who received DDP chemotherapy. The patients who benefited and went into remission following DDP therapy expressed a relatively low level of BORIS, suggesting the potential function of BORIS in DDP resistance. Cell experiments revealed that NSCLC cells that had a higher proliferation rate and resisted DDP treatment expressed a relatively higher level of BORIS. Knockdown of BORIS in NSCLC cells induced DNA damage; inhibiting cell proliferation and sensitizing cells to DDP treatment. In contrast, BORIS overexpression suppressed DDP-induced DNA damage. Notably, the mismatch repair factor mutS homolog 6 (MSH6) was regulated by BORIS, indicating its association with BORIS-associated DDP resistance in NSCLC. The findings of the present study suggest that BORIS suppresses DNA damage and promotes the progression of NSCLC and DDP resistance. The present study indicates the potential application of BORIS in NSCLC therapy and prognosis.