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Abstract Mitochondria serve as the cellular powerhouse, and their distinct DNA makes them a prospective target for gene editing to treat genetic disorders. However, the impact of genome editing on mitochondrial DNA (mtDNA) stability remains a mystery. Our study reveals previously unknown risks of genome editing that both nuclear and mitochondrial editing cause discernible transfer of mitochondrial DNA segments into the nuclear genome in various cell types including human cell lines, primary T cells, and mouse embryos. Furthermore, drug-induced mitochondrial stresses and mtDNA breaks exacerbate this transfer of mtDNA into the nuclear genome. Notably, we observe that mitochondrial editors, including mitoTALEN and recently developed base editor DdCBE, can also enhance crosstalk between mtDNA and the nuclear genome. Moreover, we provide a practical solution by co-expressing TREX1 or TREX2 exonucleases during DdCBE editing. These findings imply genome instability of mitochondria during induced DNA breaks and explain the origins of mitochondrial-nuclear DNA segments.

Anthropomorphized robots are increasingly integrated into human social life, playing vital roles across various fields. This study aimed to elucidate the neural dynamics underlying users’ perceptual and emotional responses to robots with varying levels of anthropomorphism. We investigated event-related potentials (ERPs) and event-related spectral perturbations (ERSPs) elicited while participants viewed, perceived, and rated the affection of robots with low (L-AR), medium (M-AR), and high (H-AR) levels of anthropomorphism. EEG data were recorded from 42 participants. Results revealed that H-AR induced a more negative N1 and increased frontal theta power, but decreased P2 in early time windows. Conversely, M-AR and L-AR elicited larger P2 compared to H-AR. In later time windows, M-AR generated greater late positive potential (LPP) and enhanced parietal-occipital theta oscillations than H-AR and L-AR. These findings suggest distinct neural processing phases: early feature detection and selective attention allocation, followed by later affective appraisal. Early detection of facial form and animacy, with P2 reflecting higher-order visual processing, appeared to correlate with anthropomorphism levels. This research advances the understanding of emotional processing in anthropomorphic robot design and provides valuable insights for robot designers and manufacturers regarding emotional and feature design, evaluation, and promotion of anthropomorphic robots.

Current international optical science research focuses on the non-visual effects of lighting on human cognition, mood, and biological rhythms to enhance overall well-being. Nocturnal roadway lighting, in particular, has a substantial impact on drivers’ physiological and psychological states, influencing behavior and safety. This study investigates the non-visual effects of correlated color temperature (CCT: 3000K vs. 4000K vs. 5000K) and illuminance levels (20 lx vs. 30 lx) of urban motor vehicle road lighting on driver alertness during various driving tasks. Conducted between 19:00 and 20:30, the experiments utilized a human-vehicle-light simulation platform. EEG (β waves), reaction time, and subjective evaluations using the Karolinska Sleepiness Scale (KSS) were measured. The results indicated that the interaction between CCT and illuminance, as well as between CCT and task type, significantly influenced driver alertness. However, no significant effect of CCT and illuminance on reaction time was observed. The findings suggest that higher illuminance (30 lx) combined with medium CCT (4000K) effectively reduces reaction time. This investigation enriches related research, provides valuable reference for future studies, and enhances understanding of the mechanisms of lighting’s influence on driver alertness. Moreover, the findings have significant implications for optimizing the design of urban road lighting.

Abstract Background Zero-profile anchored spacers (ZAS) and plate-cage constructs (PCC) are currently employed when performing anterior cervical discectomy and fusion (ACDF). Nevertheless, the efficacy and safety of both devices in bilevel ACDF remain controversial. The goal of our meta-analysis is to assess the overall long-term efficacy and security among ZAS and PCC in bilevel ACDF. Methods A search of four electronic databases was conducted to identify researches that compared ZAS with PCC for bilevel ACDF. Stata MP 17.0 software was used for this meta-analysis. Results Nine researches with a total of 580 patients were involved. In comparison to PCC, ZAS significantly reduced intraoperative bleeding and postoperative dysphagia rates. No significant differences were found concerning operation time, JOA score, NDI score, cervical Cobb angle, fusion rates, the incidence of adjacent segmental degeneration (ASD) and implant sinking rates at last follow-up. Conclusion Compared to PCC, ZAS achieved similar efficacy and security in bilevel ACDF with respect to operative time, JOA score, NDI score, cervical Cobb angle, fusion rates, implant sinking rates and ASD rates at final follow-up. It is worth noting that ZAS offered considerable benefits over conventional PCC for the reduction of intraoperative bleeding and postoperative dysphagia. Therefore, for patients requiring bilevel ACDF, ZAS seems superior to PCC. Given the limitations of our study, larger prospective randomised controlled trials are needed to establish reliable proof to consolidate our conclusions.

Abstract Background Currently, self-locking stand-alone cages (SSC) are commonly applied in anterior cervical discectomy and fusion (ACDF), as are cage-plate constructs (CPC). However, it remains controversial concerning the long-term effectiveness of both apparatuses. Our purpose is to compare long-term effectiveness of SSC with CPC in monosegmental ACDF. Methods Four electronic databases were queried to identify studies comparing SSC versus CPC in monosegmental ACDF. The meta-analysis was carried out with the use of the Stata MP 17.0 software package. Results Ten trials with 979 patients were included. Compared to CPC, SSC significantly reduced operative time, intraoperative blood loss, duration of hospitalisation, cervical Cobb angle at final follow-up, 1-month postoperative dysphagia rate, and incidence of adjacent segment degeneration (ASD) at final follow-up. No significant difference was found regarding 1-month postoperative cervical Cobb angle, JOA scores, NDI scores, fusion rate and cage subsidence rate at final follow-up. Conclusion Both devices achieved similar long-term effectiveness in monosegmental ACDF regarding JOA scores, NDI scores, fusion rate and cage subsidence rate. SSC had significant advantages over CPC in reducing surgical duration, intraoperative bleeding, duration of hospitalisation, as well as rates of dysphagia and ASD after surgery. Therefore, SSC is a better option than CPC in monosegmental ACDF. However, SSC is inferior to CPC in maintaining cervical curvature at long-term follow-up. Whether radiological changes affect clinical symptoms needs confirmation in trials with longer follow-up.

Aims: Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM. Methods and Results: Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson’s trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all p < 0.01 vs the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all p < 0.05). Conclusion: We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.

IntroductionExercise rehabilitation is crucial for neurological recovery in hemiplegia-induced upper limb dysfunction. Technology-assisted cortical activation in sensorimotor areas has shown potential for restoring motor function. This study assessed the feasibility of mobile serious games for stroke patients' motor rehabilitation.MethodsA dedicated mobile application targeted shoulder, elbow, and wrist training. Twelve stroke survivors attempted a motor task under two conditions: serious mobile game-assisted and conventional rehabilitation. Electroencephalography and electromyography measured the therapy effects.ResultsPatients undergoing game-assisted rehabilitation showed stronger event-related desynchronization (ERD) in the contralateral hemisphere's motor perception areas compared to conventional rehabilitation (p

Abstract Non-invasive prediction for KIT/PDGFRA status in GIST is a challenging problem. This study aims to evaluate whether CT based sarcopenia could differentiate KIT/PDGFRA wild-type gastrointestinal stromal tumor (wt-GIST) from the mutant-type GIST (mu-GIST), and to evaluate genetic features of GIST. A total of 174 patients with GIST (wt-GIST = 52) were retrospectively identified between January 2011 to October 2019. A sarcopenia nomogram was constructed by multivariate logistic regression. The performance of the nomogram was evaluated by discrimination, calibration curve, and decision curve. Genomic data was obtained from our own specimens and also from the open databases cBioPortal. Data was analyzed by R version 3.6.1 and clusterProfiler ( http://cbioportal.org/msk-impact ). There were significantly higher incidence (75.0% vs. 48.4%) and more severe sarcopenia in patients with wt-GIST than in patients with mu-GIST. Multivariate logistic regression analysis showed that sarcopenia score (fitted based on age, gender and skeletal muscle index), and muscle fat index were independent predictors for higher risk of wt-GIST (P

Abstract Background Malignant ventricular arrhythmia (VA) is a major contributor to sudden cardiac death (SCD) in patients with pulmonary arterial hypertension (PAH)-induced right heart failure (RHF). Recently, dapagliflozin (DAPA), a sodium/glucose cotransporter-2 inhibitor (SGLT2i), has been found to exhibit cardioprotective effects in patients with left ventricular systolic dysfunction. In this study, we examined the effects of DAPA on VA vulnerability in a rat model of PAH-induced RHF. Methods Rats randomly received monocrotaline (MCT, 60 mg/kg) or vehicle via a single intraperitoneal injection. A day later, MCT-injected rats were randomly treated with placebo, low-dose DAPA (1 mg/kg/day), or high-dose (3 mg/kg/day) DAPA orally for 35 days. Echocardiographic analysis, haemodynamic experiments, and histological assessments were subsequently performed to confirm the presence of PAH-induced RHF. Right ventricle (RV) expression of calcium (Ca2+) handling proteins were detected via Western blotting. RV expression of connexin 43 (Cx43) was determined via immunohistochemical staining. An optical mapping study was performed to assess the electrophysiological characteristics in isolated hearts. Cellular Ca2+ imaging from RV cardiomyocytes (RVCMs) was recorded using Fura-2 AM or Fluo-4 AM. Results High-dose DAPA treatment attenuated RV structural remodelling, improved RV function, alleviated Cx43 remodelling, increased the conduction velocity, restored the expression of key Ca2+ handling proteins, increased the threshold for Ca2+ and action potential duration (APD) alternans, decreased susceptibility to spatially discordant APD alternans and spontaneous Ca2+ events, promoted cellular Ca2+ handling, and reduced VA vulnerability in PAH-induced RHF rats. Low-dose DAPA treatment also showed antiarrhythmic effects in hearts with PAH-induced RHF, although with a lower level of efficacy. Conclusion DAPA administration reduced VA vulnerability in rats with PAH-induced RHF by improving RVCM Ca2+ handling.

Abstract Background Early DNA replication occurs within actively transcribed chromatin compartments in mammalian cells, raising the immediate question of how early DNA replication coordinates with transcription to avoid collisions and DNA damage. Results We develop a high-throughput nucleoside analog incorporation sequencing assay and identify thousands of early replication initiation zones in both mouse and human cells. The identified early replication initiation zones fall in open chromatin compartments and are mutually exclusive with transcription elongation. Of note, early replication initiation zones are mainly located in non-transcribed regions adjacent to transcribed regions. Mechanistically, we find that RNA polymerase II actively redistributes the chromatin-bound mini-chromosome maintenance complex (MCM), but not the origin recognition complex (ORC), to actively restrict early DNA replication initiation outside of transcribed regions. In support of this finding, we detect apparent MCM accumulation and DNA replication initiation in transcribed regions due to anchoring of nuclease-dead Cas9 at transcribed genes, which stalls RNA polymerase II. Finally, we find that the orchestration of early DNA replication initiation by transcription efficiently prevents gross DNA damage. Conclusion RNA polymerase II redistributes MCM complexes, but not the ORC, to prevent early DNA replication from initiating within transcribed regions. This RNA polymerase II-driven MCM redistribution spatially separates transcription and early DNA replication events and avoids the transcription-replication initiation collision, thereby providing a critical regulatory mechanism to preserve genome stability.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a new type of oral hypoglycaemic agent with good cardiovascular protective effects. There are several lines of clinical evidence suggest that SGLT2i can significantly reduce the risks of heart failure, cardiovascular death, and delay the progression of chronic kidney disease. In addition, recent basic and clinical studies have also reported that SGLT2i also has good anti-arrhythmic effects. However, the exact mechanism is poorly understood. The aim of this review is to summarize recent clinical findings, studies of laboratory animals, and related study about this aspect of the antiarrhythmic effects of SGLT2i, to further explore its underlying mechanisms, safety, and prospects for clinical applications of it.

Abstract Background Clear cell renal cell carcinoma is susceptible to ferroptosis, and immunotherapy is recently recommended as a priority for the initial treatment of metastatic clear cell renal carcinoma. Increased ferroptosis and immune activation can synergistically reinforce each other in killing cancer cells. NCOA4 depletion can eliminate iron accumulation and thus weaken ferroptosis. Here, we aim to identify and validate the association between NCOA4 expression, clinicopathologic characteristics, and overall survival in ccRCC by using The Cancer Genome Atlas and Gene Expression Omnibus databases. We further analyze the interacted proteins of NCOA4 and infiltrated immune cells via TIMER and GEPIA databases. Methods NCOA4 expression in clear cell renal carcinoma (ccRCC) tissues and normal adjacent tissues in The Cancer Genome Atlas (TCGA) data were primarily screened, and further validated in another independent cohort from the gene expression omnibus (GEO) database and human protein atlas. The relationships of NCOA4 expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which NCOA4 interacted were also built using the online STRING website. Meanwhile, we use TIMER and GEPIA databases to investigate the relationships between NCOA4 expression and infiltrated immune cells and their corresponding gene marker sets. Results Contrast to normal tissue, NCOA4 expression was lower in ccRCC tumor tissue(p

Objective. Clopidogrel is widely used for preventing ischemic complications related to cardiovascular diseases. However, many patients experience clopidogrel resistance (CR). The polymorphisms of CYP2C19 have been implicated in CR, but CYP2C19 polymorphism considerably varies with both ethnic group and geographical location. This study aimed to investigate the association between CYP2C19 polymorphisms and clopidogrel resistance (CR) in patients with coronary heart disease and ischemic stroke among Han and Tibetan populations in Qinghai Province, China. Methods. From June 2019 to January 2020, patients who were diagnosed with coronary heart disease or cerebral infarction in internal medicine of Qinghai Provincial People’s Hospital and had taken dual antiplatelet drugs were included in this study. Blood was collected and routine items were completed. Whole exome sequencing was performed for CYP2C19 genetic polymorphisms of CYP2C19∗2 (rs4244285), CYP2C19∗3 (rs4986893), and CYP2C19∗17 (rs12248560). Results. A total of 91 patients with coronary heart disease or cerebral infarction (67 Han people (65.99 ± 12.25 years old) and 24 Tibetan (63.6324 Tib years old)) including 52 cases with CR and 39 cases with non-CR were enrolled in this study. For the Han population, the differences in age, glycosylated hemoglobin, activated partial thromboplastin time (APTT), gender, aspirin resistance, and diabetes were significant between the CR and non-CR groups. For the Tibetan population, the two groups showed no significant difference in all indicators. There was no significant difference between CR and non-CR groups for all genotypes (CYP2C19 ∗2, ∗3, and ∗17) in either Han or Tibetan populations. For the Han populations, age, APTT, and aspirin resistance were significantly correlated with CR. Conclusion. The present study indicated that CYP2C19∗2, CYP2C19∗3, and CYP2C19∗17 alleles were not correlated with CR for both Han and Tibetan populations in Qinghai Province, while age, APTT, and aspirin resistance were independent risk factors of CR in this region.

Background: Regulatory T (Treg) cells are a class of anti-inflammatory lymphocyte subpopulations with a potential protective effect against atherosclerosis, whereas T helper 17 (Th17) cells have been reported to possess proatherogenic activity. It was believed that disturbed circulating Treg/Th17 balance was associated with the onset and progression of atherosclerosis. This study is designed to probe the regulative action of serum Nod-like receptor protein 3 (NLRP3) on the Treg/Th17 balance in patients with atherosclerosis. Methods: Fifty-two patients with coronary atherosclerosis and stenosis degrees of more than 50% were assigned to the coronary artery disease (CAD) group, and an equal number of people without coronary atherosclerosis were assigned to the control group (assessed by coronary angiography). Peripheral blood mononuclear cells (PBMCs) from two group patients were extracted and cultivated. The calculation of the Treg/Th17 ratio and quantitative analysis of the Treg and Th17 cell frequencies were performed through flow cytometry. Real-time fluorescence quantitative polymerase chain reaction (RT-PCR) was executed for the quantitative mRNA detection of the fork head-winged helix transcription factor (Foxp3) and the retinoic acid-related orphan nuclear receptor C (RORC) in PBMCs. Enzyme-linked immunosorbent assays were applied to measure the serum level of NLRP3, interleukin (IL)-10, IL-1β, IL-17A, IL-23, and transforming growth factor (TGF)-β1. Additionally, the connection between serum Treg/Th17 ratio and NLRP3 levels was analyzed using the Pearson correlation coefficient. Results: The baseline parameters, including sex, age, or blood biochemical indices had no difference in both groups (p > 0.05). The CAD group showed higher Th17 cell frequency, lower Treg cell frequency, and a lower Treg/Th17 ratio when compared to the control (p < 0.05). Consistent with the variation in the T-cell subset ratio, in patients with atherosclerosis, the Th17-cell-related transcription factor RORC showed a markedly higher mRNA level (p < 0.05), conversely, the mRNA expression of the Treg cell-related transcription factor Foxp3 was notably reduced (p < 0.05). Similarly, the serum levels of NLRP3, IL-17A, IL-1, and IL-23 were significantly enhanced in CAD group but IL-10 and TGF-β1 were reduced (p < 0.05). Additionally, a negative correlation was found between NLRP3 and the Treg/Th17 ratio (r = –0.69, p < 0.001). Conclusions: Due to the potential impact on the serum Treg/Th17 ratio, NLRP3 may act as an aggravator in the onset and progression of atherosclerotic disease.

Sarcoma or sarcomatoid malignancies are a set of mesenchymal-origin malignancies with vast heterogeneity in clinical and molecular characteristics. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase oncoprotein expressed by several tumors, including sarcomas. Crizotinib is an effective ALK inhibitor. In this review paper, we summarized findings from the literature regarding the use of crizotinib for the treatment of sarcoma and sarcomatoid malignancies harboring ALK fusions with definitive partners (with the given gene(s) name) from the years 2010 to 2021.One hundred and four articles were retrieved and after exclusion, 28 studies containing 33 patients were finally selected. All 33 patients were treated with crizotinib. Among the 33 cases, 19 were adult patients, 11 were pediatric patients, and 3 cases did not have data on age and/or gender. Most cases had a primary abdominal lesion (16/30), followed by thoracic (10/30), trunk (3/30), retroperitoneal (1/30), and one case of right medial thigh (case 7). Stage IV disease was reported in 76.7% (23/30) of patients. The objective response rate and disease control rate was 86.7% (26/30) and 96.7% (29/30), respectively, which were assessed on average of 8 weeks after crizotinib initiation. Rapid improvement of symptoms was observed within one to two weeks in some cases including patients with extensive diseases or poor performance. There was no difference in crizotinib response between pediatrics and adult cases. Crizotinib is effective; however, surgery remains the mainstay of therapy, with newer evidence showing concurrent crizotinib with surgery conferring long-term overall survival. However, we should still be cognizant of the heterogeneous landscape of crizotinib efficacy and its associated fatal adverse events.

Objective: The diagnostic performance of soluble suppression of tumorigenicity (sST2) in heart failure (HF) had been investigated in multiple studies, but the results were inconsistent. This meta-analysis evaluated the diagnostic value of sST2 in HF.Methods: Pubmed, Web of Science, Embase, and Cochrane Library databases were searched until March 2021. Cohort studies or case-control studies relevant to the diagnostic value of sST2 in HF were screened, and true positive (TP), false positive (FP), false negative (FN), and true negative (TN) data were extracted for calculating sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC). The quality of the included studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS), the threshold effect was determined by calculating Spearman correlation coefficients and summary receiver operating characteristic (SROC) curve patterns, the heterogeneity was evaluated using the I2 statistic and the Galbraith radial plot, and sensitivity analysis was also performed. Deeks' test was used to assess publication bias.Results: A total of 11 studies from 10 articles were included in this meta-analysis. The Spearman correlation coefficient was 0.114, p = 0.739, and the SROC curve did not show a “shoulder-arm” shape, which suggests that there was no threshold effect, but study heterogeneity existed because of non-threshold effects. The combined sensitivity was 0.72 [95% confidence interval (CI): 0.65–0.78], specificity was 0.65 (95% CI: 0.45–0.81), PLR was 1.75 (95% CI: 1.33–2.31), NLR was 0.48 (95% CI: 0.37–0.63), DOR was 3.63 (95% CI: 2.29–5.74), and AUC was 0.75. The Deeks' test suggested no significant publication bias in the included studies (P = 0.94).Conclusion: sST has some diagnostic value in HF, but this should be further evaluated in additional studies with rigorous design and high homogeneity.

Morphogenesis of tissue sheets is well studied, but mechanisms that shape bulk tissues are unclear. Here, the authors show that mesenchymal cells intercalate in 3D to shape the mouse branchial arch, with cortical forces driving intercalations in a Wnt5a-, Yap/Taz- and Piezo1-dependent manner.

Abstract Ferroptosis is a novel type of cell death with distinct properties and recognizing functions involved in physical conditions or various diseases including cancers. The fast-growing studies of ferroptosis in cancer have boosted a perspective for its usage in cancer therapeutics. Here, we review the current findings of ferroptosis regulation and especially focus on the function of ncRNAs in mediating the process of cell ferroptotic death and on how ferroptosis was in relation to other regulated cell deaths. Aberrant ferroptosis in diverse cancer types and tissues were summarized, and we elaborated recent data about the novel actors of some “conventional” drugs or natural compounds as ferroptosis inducers in cancer. Finally, we deliberate future orientation for ferroptosis in cancer cells and current unsettled issues, which may forward the speed of clinical use of ferroptosis induction in cancer treatment.

Background: Clear cell renal cell carcinoma (ccRCC) is characteristics of resistance to chemotherapy and radiotherapy. The prognosis of ccRCC was dismay with immense diversity. Iron metabolism disturbance is a common phenomenon in ccRCC. The purpose of our study is to identify and validate the candidate prognostic gene signature of iron metabolism and methylation closely related to the poor prognosis of ccRCC through comprehensive bioinformatics analysis in The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases.Methods: The prognostic iron metabolism-related genes were screened according to the overlapping differentially expressed genes (DEGs) from the TCGA database. We built a prognostic model using risk score method to predict OS, each ccRCC patient's risk score was calculated, and the resulting score can divide these patients into two categories according to the cut-point risk score. The prognostic significance of the hub genes was further evaluated with the Kaplan-Meier (KM) survival and Receiver Operating Characteristic (ROC) curve analysis. Univariate and multivariate Cox regression analysis was implemented to evaluate the impact of each variable on OS. Furthermore, the prediction power of the 25 gene signatures has been validated using an independent ccRCC cohort from the GEO database. The Gene Set Enrichment Analysis (GSEA) identified the characteristics of hub related oncogenes. Finally, we utilize Weighted Gene Co-expression Network Analysis (WGCNA) to investigate the co-expression network based on these DEGs.Results: In this study, we identified and validated 25 iron metabolism-related and methylated genes as the prognostic signatures, which differentiated ccRCC patients into high and low risk subgroups. The KM analysis showed that the survival rate of the high-risk patients was significantly lower than that of the low-risk patients. The risk score calculated with 25 gene signatures could largely predict OS and DFS for 1, 3, and 5 years in patients with ccRCC.Conclusions: Taken together, we identified the key iron metabolism-related and methylated genes for ccRCC through a comprehensive bioinformatics analysis. This study provides a reliable and robust gene signature for the prognostic predictor of ccRCC patients and maybe provides a promising treatment strategy for this lethal disease.

Background: Long-term β-adrenergic receptor (β-AR) activation can impair myocardial structure and function. Dapagliflozin (DAPA) has been reported to improve clinical prognosis in heart failure patients, whereas the exact mechanism remains unclear. Here, we investigated the effects of DAPA against β-AR overactivation toxicity and explored the underlying mechanism. Methods and Results: Rats were randomized to receive saline + placebo, isoproterenol (ISO, 5 mg/kg/day, intraperitoneally) + placebo, or ISO + DAPA (1 mg/kg/day, intragastrically) for 2-week. DAPA treatment improved cardiac function, alleviated myocardial fibrosis, prevented cardiomyocytes (CMs) apoptosis, and decreased the expression of ER stress-mediated apoptosis markers in ISO-treated hearts. In isolated CMs, 2-week ISO stimulation resulted in deteriorated kinetics of cellular contraction and relaxation, increased diastolic intracellular Ca2+ level and decay time constant of Ca2+ transient (CaT) but decreased CaT amplitude and sarcoplasmic reticulum (SR) Ca2+ level. However, DAPA treatment prevented abnormal Ca2+ handling and contractile dysfunction in CMs from ISO-treated hearts. Consistently, DAPA treatment upregulated the expression of SR Ca2+-ATPase protein and ryanodine receptor 2 (RyR2) but reduced the expression of phosphorylated-RyR2, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and phosphorylated-CaMKII in ventricles from ISO-treated rats. Conclusion: DAPA prevented myocardial remodeling and cardiac dysfunction in rats with β-AR overactivation via restoring calcium handling and suppressing ER stress-related CMs apoptosis. [ABSTRACT FROM AUTHOR]