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BackgroundMinimally invasive cardiac surgery offers numerous advantages that patients and surgeons desire. This surgical platform encompasses cannulation strategies for cardiopulmonary bypass, optimal surgical access points, and high-quality visualization techniques. Traditional peripheral cannulation methods, though convenient, possess inherent limitations and carry the potential for complications such as retrograde dissection, stroke, or neurologic sequelae. Conversely, central cannulation may be ideally suited to circumvent the disadvantages above. Fully video-assisted thoracoscopy cardiac surgery represents a state-of-the-art platform, offering surgeons an unparalleled surgical view. This analysis aimed to delineate the efficacy and safety of transthoracic central cannulation strategies and the surgical platform during fully video-assisted thoracoscopy cardiac surgery.MethodsBetween October 2022 and February 2024, we identified a cohort of 85 consecutive patients with cardiopulmonary bypass undergoing fully video-assisted thoracoscopy cardiac surgery at our institutions. The patients' mean age was 41.09 ± 14.01 years, ranging from 18 to 75 years. The mean weight was 64.34 ± 10.59 kg (ranging from 49 to 103 kg). Congenital heart disease repair accounted for the highest proportion, with 43 cases (50.59%). Mitral valve surgery and left atrium Myxoma resections accounted for 29.41%. Specifically, this included 14 mitral valve repairs, five mitral valve replacements, and six left atrium myxoma resections. Aortic valve replacements constitute 20% of all cases.ResultsA total of 85 adult patients underwent fully video-assisted thoracoscopy cardiac surgery. The average CPB time was 83.26 ± 28.26 min, while the aortic cross-clamp time averaged 51.87 ± 23.91 min. The total operation time (skin to skin) averaged 173.8 ± 37.08 min. The mean duration of mechanical ventilation was 5.58 ± 3.43 h, ICU stay was 20.04 ± 2.83 h (ranging from 15.5 to 34 h), and postoperative hospital stay was 5.55 ± 0.87 days. No patients required conversion to thoracotomy and unplanned reoperations due to various reasons. There were no in-hospital deaths, strokes, myocardial infarctions, aortic dissections, or renal failure. No patient developed wound soft tissue infection.ConclusionsFully video-assisted thoracoscopy cardiac surgery utilizing central cannulation strategies is a reliable, cost-effective platform with a low risk of complications and a potential solution for patients facing contraindications for peripheral cannulation.

Purpose: Age-related macular degeneration (AMD) is a chronic and progressive macular degenerative disease that culminates in a gradual deterioration of central vision. Despite its prevalence, the key biomarkers for AMD have not yet been fully elucidated. In this study, we aimed to efficiently identify biomarkers crucial for diagnosing AMD.Methods: Three datasets pertaining to retinal pigment epithelium (RPE)/choroid tissues associated with AMD were selected from the GEO database. The GSE50195 dataset was utilized to conduct weighted gene co-expression network analysis (WGCNA) for identifying module genes linked to AMD. KEGG and GO enrichment analyses were subsequently conducted on these module genes. GSE29801 and GSE135092 datasets were subjected to differential expression analysis to pinpoint the DEGs intersecting with the module genes. Subsequently, wet AMD (wAMD) and dry AMD (dAMD) mouse models were developed, from which RPE/choroid tissues were harvested to validate the hub genes via RT-qPCR and Western blot.Results: Using the WGCNA, we selected the “antiquewhite4” module (r = 0.91 and p = 7e-07), which contains a total of 325 genes. Through the intersection of module genes with DEGs, nine hub genes were identified. Pathways involved in complement and coagulation cascades, ECM–receptor interactions, unsaturated fatty acid biosynthesis, and fatty acid elongation play important roles in AMD. Notably, CDH18 demonstrated notable variance across all three datasets. Post validation using RT-qPCR experiments revealed a significant downregulation of CDH18 in both dAMD and wAMD. EGLN3 was expressed at low levels in wAMD. In dAMD, EYA2, LTB, and PODXL were significantly downregulated, whereas APOC1 was notably upregulated. Western blot confirmed that CDH18 was lowly expressed in dAMD and wAMD mouse models.Conclusion: CDH18 was identified as the key gene involved in the pathogenesis of AMD. An imbalance of the complement and coagulation cascades is a potential mechanism of AMD. This study provides a novel idea for diagnosing and treating AMD in the future.

Abstract The great saphenous vein is the most commonly used vessel for coronary artery bypass grafting (CABG), but its use has been associated with a high restenosis rate at 10-year follow-up. This study sought to determine the key genes associated with vein graft restenosis that could serve as novel therapeutic targets. A total of 3075 upregulated and 1404 downregulated genes were identified after transcriptome sequencing of three pairs of restenosed vein grafts and intraoperative spare great saphenous veins. Weighted gene co-expression network analysis showed that the floralwhite module had the highest correlation with vein graft restenosis. The intersection of the floralwhite module gene set and the upregulated gene set contained 615 upregulated genes strongly correlated with vein graft restenosis. Protein–protein interaction network analysis identified six hub genes (ITGAM, PTPRC, TLR4, TYROBP, ITGB2 and CD4), which were obtained using the STRING database and CytoHubba. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses showed that the common hub genes were mainly involved in the composition of the cell membrane; in biological processes such as neutrophil degranulation, receptor binding and intercellular adhesion, innate immune deficiency; and other signaling pathways. Finally, ITGB2 was selected as the target gene, and its expression was verified in tissues. The results showed that ITGB2 was significantly overexpressed in occluded vein grafts. To study the function of ITGB2 in HVSMCs, primary HVSMCs were cultured and successfully identified. EdU incorporation, wound healing and transwell assays showed that ITGB2 silencing significantly inhibited the proliferation and migration of HVSMCs stimulated by PDGF-BB. Overall, our study provides a basis for future studies on preventing restenosis following CABG.

Abstract Background Atherosclerosis (AS), a significant contributor to cardiovascular disease (CVD), is steadily rising with the aging of the global population. Pyroptosis and apoptosis, both caspase-mediated cell death mechanisms, play an essential role in the occurrence and progression of AS. The human pineal gland primarily produces melatonin (MT), an indoleamine hormone with powerful anti-oxidative, anti-pyroptotic, and anti-apoptotic properties. This study examined MT’s anti-oxidative stress and anti-pyroptotic effects on human THP-1 macrophages treated with nicotine. Methods In vitro, THP-1 macrophages were induced by 1 µM nicotine to form a pyroptosis model and performed 30 mM MT for treatment. In vivo, ApoE-/- mice were administered 0.1 mg/mL nicotine solution as drinking water, and 1 mg/mL MT solution was intragastric administrated at 10 mg/kg/day. The changes in pyroptosis, apoptosis, and oxidative stress were detected. Results MT downregulated pyroptosis, whose changes were paralleled by a reduction in reactive oxygen species (ROS) production, reversal of sirtuin3 (SIRT3), and Forkhead box O3 (FOXO3α) upregulation. MT also inhibited apoptosis, mainly caused by the interaction of caspase-1 and caspase-3 proteins. Vivo studies confirmed that nicotine could accelerate plaque formation. Moreover, mice treated with MT showed a reduction in AS lesion area. Conclusions MT alleviates pyroptosis by regulating the SIRT3/FOXO3α/ROS axis and interacting with apoptosis. Importantly, our understanding of the inhibitory pathways for macrophage pyroptosis will allow us to identify other novel therapeutic targets that will help treat, prevent, and reduce AS-associated mortality.

AbstractContext Metformin (Met) has a protective effect against cardiac ischemia and reperfusion (I/R) injury.Objective This study uncovered the Met effect on ferroptosis in cardiac I/R.Materials and methods Sprague-Dawley rats underwent cardiac I/R treatment (ischaemia 30 min; reperfusion 24 h) (I/R group), and administered intravenously with Met (200 mg/kg) (I/R + Met group). Haematoxylin–eosin staining, Prussian blue staining, immunohistochemistry and transmission electron microscope were conducted on cardiac tissues. H9c2 cells underwent oxygen-glucose deprivation/reoxygenation (OGD/R group) and treated by Met (0.1 mM) (OGD/R + Met group). Adenosine monophosphate-activated protein kinase α (AMPKα) siRNA was transfected into OGD/R-induced H9c2 cells. Cell counting kit-8 (CCK-8) assay, dichloro-dihydro-fluorescein diacetate (DCFH-DA) and JC-1 staining were conducted on H9c2 cells. Ferroptosis-related indicators and gene expression were detected by enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot.Results In cardiac I/R rat, Met decreased heart and serum MDA, cardiac and serum non-heme iron, and serum CK-MB and LDH (inhibition rate: 50.0%, 48.8%, 47.6%, 29.5%, 30.6% and 34.7%, respectively), relieved cardiac tissue ferroptosis and mitochondria damage, increased fraction shortening and ejection fraction (157.5% and 146.2% on day 28, respectively), up-regulated AMPKα and down-regulated NOX4 in cardiac tissues. In OGD/R-induced H9c2 cells, Met (0.1 mM) increased cell viability (promotion rate: 170.0%), decreased non-heme iron and MDA (inhibition rate: 30.1% and 47.9%, respectively), relieved ferroptosis, up-regulated AMPKα and down-regulated NOX4. AMPKα silencing abrogated these effects of Met on the OGD/R-induced H9c2 cells.Discussion and conclusions Met shows effectiveness in relieving ferroptosis in cardiac I/R. In the future, Met may be an effective drug for relieving ferroptosis in cardiac I/R patients clinically.

Abstract Background Bud sport is a kind of somatic mutation that usually occurred in apple. ‘Red Delicious’ is considered to be a special plant material of bud sport, whereas the genetic basis of plant mutants is still unknown. In this study, we used whole-genome resequencing and transcriptome sequencing to identify genes related to spur-type and skin-color in the ‘Red Delicious’ (G0) and its four generation mutants including ‘Starking Red’ (G1), ‘Starkrimson’ (G2), ‘Campbell Redchief’ (G3) and ‘Vallee Spur’ (G4). Results The number of single nucleotide polymorphisms (SNPs), insertions and deletions (InDels) and structural variations (SVs) were decreased in four generation mutants compared to G0, and the number of unique SNPs and InDels were over 9-fold and 4-fold higher in G1 versus (vs.) G2 and G2 vs. G3, respectively. Chromosomes 2, 5, 11 and 15 carried the most SNPs, InDels and SVs, while chromosomes 1 and 6 carried the least. Meanwhile, we identified 4,356 variation genes by whole-genome resequencing and transcriptome, and obtained 13 and 16 differentially expressed genes (DEGs) related to spur-type and skin-color by gene expression levels. Among them, DELLA and 4CL7 were the potential genes that regulate the difference of spur-type and skin-color characters, respectively. Conclusions Our study identified potential genes associated with spur-type and skin-color differences in ‘Red Delicious’ and its four generation mutants, which provides a theoretical foundation for the mechanism of the apple bud sport.

Abstract Background Lipid‐lowering therapy is of utmost importance in both primary and secondary prevention of atherosclerotic cardio vascular disease (ASCVD). However, the presence of residual risk allows cardiovascular events to occur even when low‐density lipoprotein cholesterol (LDL‐C) levels are very low. A large number of clinical studies have provided evidence confirming the association between elevated plasma Lp(a) and the development of ASCVD. Clinical studies have also suggested that reducing Lp(a) may help decrease the occurrence of cardiovascular events. Main Lp(a) consists of LDL‐like particles, apo(a) and OxPL. The level of Lp(a) in thehuman body is predominantly determined by genetics, with external factorshaving minimal impact. Additionally, Lp(a) levels have been found to vary among different ethnicities. There is a notable correlation between elevated levels of Lp(a) and coronary artery disease (CAD), which is independent of other lipoproteins. Furthermore, there exists a linear relationship between Lp(a) levels and the risk of developing ASCVD. It is now wildly believed that Lp(a) primarily contributes to the development of cardiovascular events through pro‐inflammation, pro‐thrombosis and pro‐atherosclerosis. From the perspective of Lp(a) influencing inflammation, it primarily promotes the release of inflammatoryfactors. This, in turn, increases levels of vascular inflammation and facilitates the recruitment of monocytes‐macrophages. Moreover, it also affects the function of endothelial cells during the development process of atherosclerosis. All these aspects complement each other and contribute to the progression of at herosclerosis. Currently, the lipid‐lowering treatment used inclinical practice can partially reduce the levels of Lp(a), but its impact on inflammation is not significant. Conclusion Lp(a) is an independent risk factor for CAD, as it promotes inflammation in the body and accelerates theprogression of atherosclerosis. Further research on effective methods to reduce Lp(a) levels can provide new insights for the treatment of atherosclerosis.

BACKGROUND: Hyponatremia is common in hospitalized patients with heart failure (HF) and predicts a poor prognosis after discharge. In general, hyponatremia can be divided into two types: dilutional or depletional. OBJECTIVE: Assess the impact of hyponatremia type on short-term outcomes. DESIGN: Retrospective cohort SETTINGS: Single center in China PATIENTS AND METHODS: We sorted patients by hyponatremia into two types: dilutional hyponatremia (DiH, with hematocrit

Abstract Histone deacetylase enzymes (HDACs) regulate protein acetylation. HDAC1 is known to enhance ischemia/reperfusion (I/R) injury, but its underlying mechanism(s) of action have not been defined. Here, in vivo mouse models of myocardial I/R were used to investigate the role of HDAC1 during I/R myocardial injury. We show that HDAC1 enhances the inflammatory responses of I/R mice. Using a constructed macrophage H/R (hypoxia/ regeneration) injury model (Raw264.7 cells), we identified Nur77 as a HDAC1 target in macrophages. Nur77 deficient macrophages failed to downregulate IDH1 (isocitrate dehydrogenase 1) and accumulated succinic acid and other tricarboxylic acid (TCA) cycle-derived metabolites in a glutamine-independent manner. These data show that the inhibition of HDAC1 ameliorates H/R-inflammation in macrophages through the regulation of Nur77 and the TCA cycle.

Chimeric antigen receptor T cell therapy has become an important immunotherapeutic tool for overcoming cancers. However, the efficacy of CAR-T cell therapy in solid tumors is relatively poor due to the complexity of the tumor microenvironment and inhibitory immune checkpoints. TIGIT on the surface of T cells acts as an immune checkpoint by binding to CD155 on the tumor cells’ surface, thereby inhibiting tumor cell killing. Blocking TIGIT/CD155 interactions is a promising approach in cancer immunotherapy. In this study, we generated anti-MLSN CAR-T cells in combination with anti-α-TIGIT for solid tumors treatment. The anti-α-TIGIT effectively enhanced the efficacy of anti-MLSN CAR-T cells on the killing of target cells in vitro. In addition, we genetically engineered anti-MSLN CAR-T cells with the capacity to constitutively produce TIGIT-blocking single-chain variable fragments. Our study demonstrated that blocking TIGIT significantly promoted cytokine release to augment the tumor-killing effect of MT CAR-T cells. Moreover, the self-delivery of TIGIT-blocking scFvs enhanced the infiltration and activation of MT CAR-T cells in the tumor microenvironments to achieve better tumor regression in vivo. These results suggest that blocking TIGIT effectively enhances the anti-tumor effect of CAR-T cells and suggest a promising strategy of combining CAR-T with immune checkpoints blockade in the treatment of solid tumors.

Abstract Cardiomyocyte injury is a common complication during cardiac surgery with cardiopulmonary bypass (CPB). Studies have shown that circulating small extracellular vesicles (sEVs) are involved in the pathological process of cardiovascular diseases via delivering signaling molecules. This study aims to investigate the relationship between circulating sEV-encapsulated long noncoding RNAs (lncRNAs) and cardiac injury after CPB. Here, we found that the expression of sEV SEMA5A-IT1 in serum samples of patients after CPB was higher than that of pre-CPB serum samples. Moreover, serum-derived sEV SEMA5A-IT1 levels were negatively correlated with creatine kinase-MB (CK-MB) levels in patients who underwent CPB operation. Notably, circulating sEVs packaged with SEMA5A-IT1 could be uptaken by cardiomyocyte-like cells AC16 and increased SEMA5A-IT1 expression in AC16 cells. Upregulated SEMA5A-IT1 protected cardiomyocytes against hypoxia/reoxygenation injury, confirmed by increased cell viability, reduced cell apoptosis, and inhibited ferroptosis in AC16 cells. Mechanistically, SEMA5A-IT1 regulated the expression of B-cell CLL/lymphoma 2 (BCL2) and solute carrier family 7 member 11 (SLC7A11) through sponging miR-143-3p. Transfection of miR-143-3p mimics, BCL2, or SLC7A11 knockdown could attenuate the protective effect of SEMA5A-IT1 on cardiomyocytes. In conclusion, we propose that SEMA5A-IT1, which is transported to cardiomyocytes through circulating sEVs, is an important regulatory molecule that protects cardiomyocytes from ischemia–reperfusion injury, providing a target for the prevention and treatment of myocardial ischemia–reperfusion injury.

Abstract Rheumatoid arthritis (RA) is a chronic and inflammatory autoimmune disease. Macrophage pyroptosis, a proinflammatory form of cell death, is critically important in RA; however, the detailed mechanism underlying pyroptosis induction is not yet well understood. Here, we report that DNA polymerase β (Pol β), a key enzyme in base excision repair, plays a pivotal role in RA pathogenesis. Our data shows that Pol β expression is significantly decreased in peripheral blood mononuclear cells (PBMCs) from active RA patients and collagen-induced arthritis (CIA) mice, and Pol β deficiency increases the incidence of RA, macrophage infiltration, and bone destruction in CIA mouse models. In vitro, experiments showed that Pol β deficiency exacerbated macrophage pyroptosis induced by LPS plus ATP, while overexpression of Pol β inhibited macrophage pyroptosis. Further characterization revealed that Pol β knockout resulted in DNA damage accumulation and cytosolic dsDNA leakage, which activated the cGAS-STING-NF-κB signaling pathway and upregulated the expression of NLRP3, IL-1 β, and IL-18. In conclusion, our findings clarify the influence of Pol β on the development of RA and provide a detailed explanation for the STING-NF-κB pathway to induce macrophage pyroptosis.

ObjectiveThis study was aimed to analyze the research status and development trend of cutaneous squamous cell carcinoma (CSCC), focusing on the field of programmed cell death of CSCC, and providing suggestions for the research of CSCC.MethodsThe publications related to CSCC and CSCC programmed cell death were searched in the Web of Science Core Collection (WOSCC) database, and timespan was set from 2012 to middle 2022. Research trends, authors, major country collaborations, research institutions, representative journals, publishers, and keywords were analyzed with CiteSpace and VOSviewer.ResultsAfter screening, a total of 3656 publications on CSCC and 156 publications on CSCC cell programmed death were obtained. The number of published articles increased gradually with the years. The United States ranked first in terms of the number of published papers. Research in this field had focused on dermatology. Most of the institutions in both regions were from European and American countries. Harvard University was the most prolific institution. Wiley was the most prolific publisher. The popular keywords for programmed cell death in CSCC were cutaneous squamous cell carcinoma, diagnosis, pd 1, head, nivolumab and risk. Keywords in CSCC field were divided into 7 clusters: cutaneous squamous cell carcinoma, sentinel lymph node biopsy, skin cancer, B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) inhibitor and human Papillomaviruses, and P63 expression. Squamous cell carcinoma, cancer, head and expression were the most popular keywords. The popular keywords for programmed cell death in CSCC were cutaneous squamous cell carcinoma, diagnosis, pd 1, head, nivolumab and risk.ConclusionThis study analyzed the research status of cutaneous squamous cell carcinoma and programmed cell death from 2012 to middle 2022. Understanding research status and hotspots can help scholars, countries and policymakers to better understand the background and research frontier of CSCC, and guide further research directions.

Abstract Background Atherosclerosis (AS), the main pathological basis of life‐threatening cardiovascular disease, is essentially caused by chronic macrophage inflammation. Overexpression of proline/serine‐rich coiled‐coil protein 1 (PSRC1) reduces macrophage inflammatory responses and delays AS development. However, the exact mechanism of PSRC1 is unclear. Methods Proteins interacting with PSRC1 were screened by proteomics in RAW264.7 cells, followed by RT‒qPCR, immunoprecipitation and immunofluorescence to explore the specific mechanistic pathways affecting inflammation. CRISPR‒Cas9 constructs for PSRC1−/−ApoE−/−(DKO) mice and high‐fat diet‐fed ApoE−/− and DKO mice were used for AS models for in vivo experiments. Upstream transcription factors of PSRC1 were predicted by ATAC‐seq, ChIP‐seq and UCSC, and the regulatory mechanism was verified by ChIP‒qPCR and dual luciferase assays. Peripheral blood serum and monocytes were collected from coronary artery disease (CAD) patients and non‐CAD patients. Results Increased binding of ANXA2 to PSRC1 in macrophages under oxidized low‐density lipoprotein stimulation and decreased release of ANXA2 to the extracellular compartment were observed. Knockdown of ANXA2 in AS model mice delayed AS progression. Knockdown of ANXA2 in DKO mice reversed the AS‐promoting effect of PSRC1 knockdown. Mechanistically, ANXA2 promotes STAT3 phosphorylation, which in turn promotes inflammatory responses. In addition, SP1 is a PSRC1 upstream repressive transcription factor, and the SP1 inhibitor mithramycin (Mith) elevated PSRC1 expression and exerted anti‐AS effects in AS model mice. Patients with CAD had considerably greater serum levels of ANXA2 than those without CAD, and Mith reduced the secretion of ANXA2 in peripheral blood monocytes of CAD patients. Conclusion In macrophages, PSRC1 can interact with ANXA2 to inhibit its extracellular release and delay AS development. SP1 is an upstream transcription factor of PSRC1 and inhibits the transcription of PSRC1. The SP1 inhibitor Mith can elevate PSRC1 levels and slow AS progression while reducing ANXA2 release from monocytes in CAD patients. Mith is expected to be a new agent for AS treatment.

BackgroundOur goal was to create a prediction model for in-hospital death in Chinese patients with acute type A aortic dissection (ATAAD).MethodsA retrospective derivation cohort was made up of 340 patients with ATAAD from Tianjin, and the retrospective validation cohort was made up of 153 patients with ATAAD from Nanjing. For variable selection, we used least absolute shrinkage and selection operator analysis, and for risk scoring, we used logistic regression coefficients. We categorized the patients into low-, middle-, and high-risk groups and looked into the correlation with in-hospital fatalities. We established a risk classifier based on independent baseline data using a multivariable logistic model. The prediction performance was determined based on the receiver operating characteristic curve (ROC). Individualized clinical decision-making was conducted by weighing the net benefit in each patient by decision curve analysis (DCA).ResultsWe created a risk prediction model using risk scores weighted by five preoperatively chosen variables [AUC: 0.7039 (95% CI, 0.643–0.765)]: serum creatinine (Scr), D-dimer, white blood cell (WBC) count, coronary heart disease (CHD), and blood urea nitrogen (BUN). Following that, we categorized the cohort's patients as low-, intermediate-, and high-risk groups. The intermediate- and high-risk groups significantly increased hospital death rates compared to the low-risk group [adjusted OR: 3.973 (95% CI, 1.496–10.552), P < 0.01; 8.280 (95% CI, 3.054–22.448), P < 0.01, respectively). The risk score classifier exhibited better prediction ability than the triple-risk categories classifier [AUC: 0.7039 (95% CI, 0.6425–0.7652) vs. 0.6605 (95% CI, 0.6013–0.7197); P = 0.0022]. The DCA showed relatively good performance for the model in terms of clinical application if the threshold probability in the clinical decision was more than 10%.ConclusionA risk classifier is an effective strategy for predicting in-hospital death in patients with ATAAD, but it might be affected by the small number of participants.

Summary: Ovarian granulosa cells (GCs) in the follicle are the important mediator of steroidogenesis and foster oocyte maturation. Evidences suggested that the function of GCs could be regulated by S-palmitoylation. However, the role of S-palmitoylation of GCs in ovarian hyperandrogenism remains elusive. Here, we demonstrated that the protein from GCs in ovarian hyperandrogenism phenotype mouse group exhibits lower palmitoylation level compared with that in the control group. Using S-palmitoylation-enriched quantitative proteomics, we identified heat shock protein isoform α (HSP90α) with lower S-palmitoylation levels in ovarian hyperandrogenism phenotype group. Mechanistically, S-palmitoylation of HSP90α modulates the conversion of androgen to estrogens via the androgen receptor (AR) signalling pathway, and its level is regulated by PPT1. Targeting AR signaling by using dipyridamole attenuated ovarian hyperandrogenism symptoms. Our data help elucidate ovarian hyperandrogenism from perspective of protein modification and provide new evidence showing that HSP90α S-palmitoylation modification might be a potential pharmacological target for ovarian hyperandrogenism treatment.

Immunotherapy is a hot area in cancer treatment, and one of the keys to this therapy is the identification of the right tumour-associated or tumour-specific antigen. Cluster of differentiation 24 (CD24) is an emerging tumour-associated antigen that is commonly and highly expressed in various tumours. In addition, CD24 is associated with several cancer-related signalling pathways and closely interacts with other molecules and immune cells to influence tumour progression. Monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, and CAR-NK cell therapy are currently available for the treatment of CD24. In this review, we summarise the existing therapeutic approaches and possible future directions targeting CD24.

Abstract Background Perioperative coronary artery spasm (CAS) following coronary artery bypass grafting (CABG) is a severe or lethal condition that is rarely reported. In addition, rare cases with CAS following CABG in the non-manipulated coronary artery are angiographically documented in the perioperative period. We aimed to report our experiences on the diagnosis and treatment of a case with CAS following off-pump CABG in the non-manipulated coronary artery. Methods A 57-year old male with coronary heart disease and unstable angina willing to undergo CABG was admitted to our department. CABG was recommended as he showed 90% stenosis in distal left anterior descending artery, 90% stenosis in intermediate branch, 90% stenosis in left circumflex coronary artery, as well as 50% stenosis in proximal right coronary artery (RCA). Results After CABG, the patient showed Adams–Stokes syndrome and ST-segment elevation. Then CPR was conducted and coronary angiography indicated perioperative CAS in the non-manipulated posterior descending artery. For the treatment, the patient received nitroglycerin injection into the coronary artery by catheter and pumping of diltiazem. Finally, the patient was discharged on day 7 after surgery. A comprehensive literature search was conducted to summarize the studies focused on the diagnosis and treatment of such condition, which indicated that all of the CAS cases occurred in the manipulated vessels, except one study showing CAS in the untouched native coronary artery which was similar with our case. Conclusions Perioperative CAS in the non-manipulated coronary artery following CABG is a severe or lethal condition that is rarely reported, which deserves close attention by the clinicians in clinical practice.

Abstract Background Data on the clinical characteristics, electrocardiogram (ECG) findings and outcomes of patients with acute myocardial infarction (AMI) due to total unprotected left main (ULM) artery occlusion is limited. Methods Between 2009 and 2021, 44 patients with AMI due to total ULM occlusion underwent primary percutaneous coronary intervention (PCI) at our institution. The ECG, collateral circulation, clinical and procedural characteristics, and in-hospital mortality were retrospectively evaluated. Results Twenty five patients presented with shock and 18 patients had in-hospital mortality. Nineteen patients presented with ST-segment elevation myocardial infarction (STEMI), while 25 presented with non-ST-segment elevation myocardial infarction (NSTEMI). ST-segment elevation (STE) in I and STEMI were associated with the absence of collateral circulation, while STE in aVR was associated with its presence. In the NSTEMI group, patients with STE in both aVR and aVL showed more collateral filling of the left anterior descending coronary artery (LAD) territory, while patients with STE in aVR showed more collateral filling of the LAD and the left circumflex artery territory. Compared with total ULM occlusion, patients with partial ULM obstruction presented with more STE in aVR, less STE in aVR and aVL, and less STEMI. Shock, post-PCI TIMI 0–2 flow, non-STE in aVR, STEMI, and STE in I predicted in-hospital mortality. STEMI and the absence of collateral flow were significantly associated with shock. Conclusions STE in the precordial leads predicted the absence of collateral circulation while STE in aVR and STE in both aVR and aVL predicted different collateral filling territories in ULM occlusion. STE in I, non-STE in aVR, and STEMI predicted in-hospital mortality in these patients.

Maladaptive inflammatory and immune responses are responsible for intestinal barrier integrity and function dysregulation. Proline/serine-rich coiled-coil protein 1 (PSRC1) critically contributes to the immune system, but direct data on the gut microbiota and the microbial metabolite trimethylamine N-oxide (TMAO) are lacking. Here, we investigated the impact of PSRC1 deletion on TMAO generation and atherosclerosis. We first found that PSRC1 deletion in apoE−/− mice accelerated atherosclerotic plaque formation, and then the gut microbiota and metabolites were detected using metagenomics and untargeted metabolomics. Our results showed that PSRC1 deficiency enriched trimethylamine (TMA)-producing bacteria and functional potential for TMA synthesis and accordingly enhanced plasma betaine and TMAO production. Furthermore, PSRC1 deficiency resulted in a proinflammatory colonic phenotype that was significantly associated with the dysregulated bacteria. Unexpectedly, hepatic RNA-seq indicated upregulated flavin monooxygenase 3 (FMO3) expression following PSRC1 knockout. Mechanistically, PSRC1 overexpression inhibited FMO3 expression in vitro, while an ERα inhibitor rescued the downregulation. Consistently, PSRC1-knockout mice exhibited higher plasma TMAO levels with a choline-supplemented diet, which was gut microbiota dependent, as evidenced by antibiotic treatment. To investigate the role of dysbiosis induced by PSRC1 deletion in atherogenesis, apoE−/− mice were transplanted with the fecal microbiota from either apoE−/− or PSRC1−/−apoE−/− donor mice. Mice that received PSRC1-knockout mouse feces showed an elevation in TMAO levels, as well as plaque lipid deposition and macrophage accumulation, which were accompanied by increased plasma lipid levels and impaired hepatic cholesterol transport. Overall, we identified PSRC1 as an atherosclerosis-protective factor, at least in part, attributable to its regulation of TMAO generation via a multistep pathway. Thus, PSRC1 holds great potential for manipulating the gut microbiome and alleviating atherosclerosis.

Abstract Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell dysfunction is a significant event in the progression of atherosclerosis. Even Myricetin (Myr) has been exhibited strong antioxidant potency, the effect on atherosclerosis is still elusive. HUVECs were subjected to ox-LDL, before which cells were preconditioned with Myr. Cell Counting Kit-8 assay, flow cytometry, quantitative real-time polymerase chain reaction and Western blot were carried out to assess the impacts of ox-LDL and Myr on HUVECs. The expression of EndMT markers was determined by Western blot analysis and immunocytochemistry. In addition, the relationship of GAS5 and miR-29a-3p was evaluated by RNA Fluorescent in Situ Hybridization and RNA immunoprecipitation assay. Myr preconditioning prevented ox-LDL-induced apoptosis, inflammatory response, and EndMT. GAS5 was upregulated in response to ox-LDL while it was down-regulated by Myr preconditioning. GAS5 over-expression attenuates Myr protective effects against ox-LDL–mediated HUVEC injury. Besides, miR-29a-3p is a target of GAS5 and down-regulated miR-29a-3p could further reduce the effects of GAS5 in ox-LDL–mediated HUVEC. Furthermore, Myr inactivated the TLR4/NF-κB signalling pathway in ox-LDL-treated HUVEC by down-regulating GAS5 or upregulating miR-26a-5p. Myr possessed an anti-inflammatory and anti-EndMT function against ox-LDL-induced HUVEC injury by regulating the GAS5/miR-29a-3p, indicating that Myr may have an important therapeutic function for atherosclerosis.

Abstract Chimeric antigen receptor T-cell (CAR-T) therapy has shown tremendous success in eradicating hematologic malignancies. However, this success has not yet been extrapolated to solid tumors due to the limited infiltration and persistence of CAR-T cells in the tumor microenvironment (TME). In this study, we screened a novel anti-CD70 scFv and generated CD70 CAR-T cells that showed effective antitumor functions against CD70+ renal carcinoma cells (RCCs) both in vitro and in vivo. We further evaluated the effect and explored the molecular mechanism of a PARP inhibitor (PARPi) in CAR-T cell immunotherapy by administering the PARPi to mouse xenografts model derived from human RCC cells. Treatment with the PARPi promoted CAR-T cell infiltration by stimulating a chemokine milieu that promoted CAR-T cell recruitment and the modulation of immunosuppression in the TME. Moreover, our data demonstrate that PARPi modulates the TME by activating the cGAS-STING pathway, thereby altering the balance of immunostimulatory signaling and enabling low-dose CAR-T cell treatment to induce effective tumor regression. These data demonstrate the application of CD70 CAR-T cell therapeutic strategies for RCC and the cross-talk between targeting DNA damage responses and antitumor CAR-T cell therapy. These findings provide insight into the mechanisms of PARPis in CAR-T cell therapy for RCC and suggest a promising adjuvant therapeutic strategy for CAR-T cell therapy in solid tumors.

BackgroundAcute coronary syndrome (ACS) is the most time-sensitive acute cardiac event that requires rapid dispatching and response. The medical priority dispatch system (MPDS), one of the most extensively used types of emergency dispatch systems, is hypothesized to provide better-quality prehospital emergency treatment. However, few studies have revealed the impact of MPDS use on the process of ACS care. ObjectiveThis study aimed to investigate whether the use of MPDS was associated with higher prehospital diagnosis accuracy and shorter prehospital delay for patients with ACS transferred by an emergency medical service (EMS), using a national database in China. MethodsThis retrospective analysis was based on an integrated database of China’s MPDS and hospital registry. From January 1, 2016, to December 31, 2020, EMS-treated ACS cases were divided into before MPDS and after MPDS groups in accordance with the MPDS launch time at each EMS center. The primary outcomes included diagnosis consistency between hospital admission and discharge, and prehospital delay. Multivariable logistic regression and propensity score–matching analysis were performed to compare outcomes between the 2 groups for total ACS and subtypes. ResultsA total of 9806 ACS cases (3561 before MPDS and 6245 after MPDS) treated by 43 EMS centers were included. The overall diagnosis consistency of the after MPDS group (Cohen κ=0.918, P

The expression of O-GlcNAc transferase (OGT) and its catalytic product, O-GlcNAcylation (O-GlcNAc), are elevated in many types of cancers, including prostate cancer (PC). Inhibition of OGT serves as a potential strategy for PC treatment alone or combinational therapy. PC is the second common cancer type in male worldwide, for which chemotherapy is still the first-line treatment. However, the function of inhibition of OGT on chemotherapeutic response in PC cells is still unknown. In this study, we show that inhibition of OGT by genetic knockdown using shRNA or by chemical inhibition using OGT inhibitors sensitize PC cells to docetaxel, which is the most common chemotherapeutic agent in PC chemotherapy. Furthermore, we identified that microRNA-140 (miR-140) directly binds to OGT mRNA 3′ untranslated region and inhibits OGT expression. Moreover, docetaxel treatment stimulates miR-140 expression, whereas represses OGT expression in PC cells. Overexpression of miR-140 enhanced the drug sensitivity of PC cells to docetaxel, which could be reversed by overexpression of OGT. Overall, this study demonstrates miR-140/OGT axis as therapeutic target in PC treatment and provides a promising adjuvant therapeutic strategy for PC therapy.

ObjectiveDifferent forms of full coverage policy of essential medicines (FCPEMs) have been adopted worldwide to lower medication expenditure and improve adherence. This study aims to analyse the effect of FCPEMs on patients' medication adherence in Taizhou city, China.MethodsThis study was a quasi-experimental study and set treatment and control groups. We extracted Electronic Health Records (EHRs) for hypertension and diabetes 1 year before and after FCPEMs implementation and their medication adherence level assessed by physicians. We applied the propensity score matching (PSM) method to balance the bias between the two groups. Then, the descriptive analysis was used to compare the differences in the reported medication adherence. Using the Difference-In-Differences (DIDs) method, the fixed-effect model with the logistic regression was built to analyse the effects of FCPEMs.Results225,081 eligible patients were identified from the original database. In the baseline year, FCPEM covered 39,251 patients. After PSM, 6,587 patients in the treatment group and 10,672 patients in the control group remained. We found that the proportion of patients with high adherence in the treatment group increased by 9.1% (60.8 to 69.9%, P < 0.001) and that in the control group increased by 2.6% (62.5 to 65.2%, P < 0.001). The regression results showed that FCPEMs significantly increased patients' medication adherence (OR = 2.546, P < 0.001).ConclusionFCPEMs significantly improved medication adherence. Socially disadvantaged individuals might benefit more from continuing FCPEM efforts. Expanding the coverage of FCPEMs to other medicines commonly used in patients with chronic diseases may be a promising strategy to manage chronic diseases and promote patient outcomes.

BackgroundThis study aimed to define changes in the metabolic and protein profiles of patients with calcific aortic valve disease (CAVD).Methods and resultsWe analyzed cardiac valve samples of patients with and without (control) CAVD (n = 24 per group) using untargeted metabolomics and tandem mass tag-based quantitative proteomics. Significantly different metabolites and proteins between the CAVD and control groups were screened; then, functional enrichment was analyzed. We analyzed co-expressed differential metabolites and proteins, and constructed a metabolite-protein-pathway network. The expression of key proteins was validated using western blotting. Differential analysis identified 229 metabolites in CAVD among which, 2-aminophenol, hydroxykynurenine, erythritol, carnosine, and choline were the top five. Proteomic analysis identified 549 differentially expressed proteins in CAVD, most of which were localized in the nuclear, cytoplasmic, extracellular, and plasma membranes. Levels of selenium binding protein 1 (SELENBP1) positively correlated with multiple metabolites. Adenosine triphosphate-binding cassette transporters, starch and sucrose metabolism, hypoxia-inducible factor 1 (HIF-1) signaling, and purine metabolism were key pathways in the network. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), calcium2+/calmodulin-dependent protein kinase II delta (CAMK2D), and ATP binding cassette subfamily a member 8 (ABCA8) were identified as hub proteins in the metabolite-protein-pathway network as they interacted with ADP, glucose 6-phosphate, choline, and other proteins. Western blotting confirmed that ENPP1 was upregulated, whereas ABCA8 and CAMK2D were downregulated in CAVD samples.ConclusionThe metabolic and protein profiles of cardiac valves from patients with CAVD significantly changed. The present findings provide a holistic view of the molecular mechanisms underlying CAVD that may lead to the development of novel diagnostic biomarkers and therapeutic targets to treat CAVD.

In recent years, the mechanism of cell death has become a hotspot in research on the pathogenesis and treatment of cardiovascular disease (CVD). Different cell death modes, including autophagy, apoptosis, and pyroptosis, are mosaic with each other and collaboratively regulate the process of CVD. This review summarizes the interaction and crosstalk of key pathways or proteins which play a critical role in the entire process of CVD and explores the specific mechanisms. Furthermore, this paper assesses the interrelationships among these three cell deaths and reviews how they regulate the pathogenesis of CVD. By understanding how these three cell death modes go together we can learn about the pathogenesis of CVD, which will enable us to identify new targets for preventing, controlling, and treating CVD. It will not only reduce mortality but also improve the quality of life.

Moving packed bed heat exchanger has been key equipment in the waste energy recovery and concentrated solar power. However, the effect of tube arrangement still deserve investigation to optimize heat transfer. In the present paper, the flow and heat transfer of gravity-driven particles flowing around the tube bank are numerically studied by the discrete element method. It was found that the stagnation zone of the staggered tubes is less than 45° and the cavity zone is in the range of 160° - 180°. The stagnation zone of the aligned tubes is in the range of 0° - 65° and 125° - 180°, and there is no cavity zone below the aligned tubes. The heat transfer performance of the staggered tubes is better than that of the aligned tubes. The best heat transfer region of the staggered tubes is at the top of the tube, and that of the aligned tubes is at the side of the tube. The bottom of the tube has the worst heat transfer in both the staggered and aligned tubes. It is necessary to improve the performance of the staggered tubes by optimizing the particle flow in the range 0° - 45° and 160° - 180°. Reducing the vertical tube spacing may be an effective option for the aligned tubes.

Abstract Insulin resistance (IR) plays an important role in the development of hypertension. Triglyceride and glucose index (TyG index), and triglyceride to high‐density lipoprotein cholesterol ratio (TG/HDL‐c) as effective IR surrogate indexes have been verified in numerous studies. Therefore, the authors conducted a large cross‐sectional study to explore the association of TyG index and TG/HDL‐c with prehypertension and hypertension in the same normoglycemic subjects from Tianjin, China. A total of 32 124 adults were eligible for this study. According to the level of blood pressure, the enrolled individuals were divided into three groups, which were normotension, prehypertension, and hypertension. In multiple logistic regression analysis, there was associated with prehypertension and hypertension when comparing the highest TyG index to the lowest TyG index and corresponding ORs were 1.795 (1.638, 1.968) and 2.439 (2.205, 2.698), respectively. For TG/HDL‐c, the corresponding ORs were 1.514 (1.382, 1.658) and 1.934 (1.751, 2.137), respectively. Furthermore, when comparing the fourth quartile to the first quartile of TyG index and TG/HDL‐c, respectively, both corresponding ORs of hypertension were higher than prehypertension. Elevated TyG index and TG/HDL‐c levels were associated with prehypertension and hypertension in normoglycemic individuals. Moreover, the TyG index was more significant than TG/HDL‐c in distinguishing hypertension. They have the potential to become cost‐effective monitors in the hierarchical management of prehypertension and hypertension.

BackgroundPrediction of left main artery (LM) occlusion may contribute to the administration of early reperfusion. We sought to identify electrocardiographic (ECG) features associated with acute total LM occlusion and explore the relationship between ECG features and collateral circulation.MethodsWe retrospectively studied ECGs in 84 consecutive patients with LM occlusion between January 2001 and April 2022. The ECG findings in these patients were compared with those in 468 consecutive patients with LM subtotal occlusion and non-LM occlusion.ResultsThree main ECG patterns were described according to the characteristics of ST elevation (STE) in LM occlusion: ST-segment elevation myocardial infarction (STEMI), STE in aVR with diffuse ST depression, and STE in both aVR and aVL. These ECG patterns were associated with different collateral filling territories. One-third STEMI in LM occlusion showed STE in the precordial leads including V1, while 2/3 STEMI showed STE in the precordial leads from V2 to V5 without STE in V1. The following ECG characteristics predicted LM occlusion: STE in both aVR and aVL; STE in I, aVL, and V2–V5 without V1; left anterior fascicular block (LAFB); right bundle branch block (RBBB) + LAFB; and prolongation of the QRS interval. The incidences of STE in aVR and STE in aVR and V1 were higher in LM subtotal occlusion than in LM occlusion. The combination of two different STE criteria (STE in aVR and aVL and STE in I, aVL, V2-V5 without V1) predicted LM occlusion with 62% sensitivity and 95% specificity. The combination of the STE criteria and fascicular block criteria (LAFB and LAFB + RBBB) further improved the specificity to 99% but reduced the sensitivity to 39%.ConclusionThe combination of STE criteria predicted LM occlusion with high specificity and moderate sensitivity, and the addition of fascicular block criteria further improved the specificity with some loss of sensitivity.

ObjectivesTo undertake a systematic review and meta-analysis of cohort studies to compare the patency and adverse outcomes of sequential and individual saphenous vein grafts (SVGs) in coronary artery bypass grafting (CABG).MethodsWe searched PubMed, Embase, and the Cochrane Library for cohort studies. Endpoints for vein graft failure, perioperative and follow-up adverse events were extracted as risk ratio (RR) with 95% confidence intervals (95% CI). Statistical heterogeneity across the studies was examined using the I2 statistic. Potential of publication bias was evaluated quantitatively by the Egger's test. Sensitivity analysis was also performed to assess the robustness of our outcomes.ResultsThe 15 studies were analyzed, including 22,004 patients, 4,580 grafts, and seven different adverse events under individual or sequential CABG. The sequential group had inferior graft failure (RR = 0.68; 95% CI, 0.60–0.77) and long-term mortality (RR = 0.76; 95%CI, 0.61–0.95), but with an increased risk of perioperative repeat revascularization (RR = 1.58; 95%CI, 1.16–2.14) than the individual group.ConclusionTaken together, our analysis of the aggregated evidence comparing the sequential and individual saphenous vein grafts for coronary heart disease patients showed that the use of the sequential graft was associated with inferior graft failure and long-term mortality respectively, but with an increased risk of perioperative repeat revascularization. According to our study, both surgical techniques have their own advantages in efficacy and safety, and the selection of surgical techniques should be based on patients and surgeons. Sequential saphenous vein grafts should be more recommended to experienced surgeons in order to both reduce perioperative adverse events and improve long-term patency.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022326992.

As one of the most important enteric viruses, sapovirus (SaV) can infect humans and a variety of animals. Until now, 19 SaV genogroups have been identified, among which 4 from human (GI, GII, GIV, and GV) and 8 from swine (GIII, GV–GXI). Porcine sapovirus (PoSaV) GIII has been prevalent in China; however, the status of PoSaV infection in Yunnan province remains unknown. In this study, 202 fecal samples were collected from piglets associated with outbreaks of acute diarrhea in Yunnan between January and May 2020. PoSaV detection revealed that the total PoSaV infection rate in Yunnan was 35.2%, with 21 PoSaV strains determined and phylogenetically analyzed. The phylogenetic tree analyses demonstrated that twenty PoSaV strains belonged to GIII and fell into five genotypes, whereas one PoSaV strain (YNQB) belonged to GV. Sequence alignments revealed deletions in VP2 region in 10 of the 20 GIII strains, as well as deletions and insertions in VP1 region of the GV strain (YNQB). Furthermore, genomic recombination analyses showed that two GIII strains (YNAN and YNJD) were recombinants, closely related to reference sequences MK965898 and LC215880, MK965898 and FJ387164, respectively. In summary, PoSaV-GIII strains were identified in Yunnan in 2020, and for the first time, a PoSaV-GV strain was identified from China, whereas the comprehensive analyses illustrated high genetic diversity of Yunnan PoSaV strains. This study may shed new light on the current PoSaV infections in Yunnan and pave the way toward further control of the PoSaV infections in China.

Coronary atherosclerotic heart disease (CAD) is a chronic inflammatory cardiovascular disease with high morbidity and mortality. Growing data indicate that many immune cells are involved in the development of atherosclerosis. However, the immunological roles of γδ T cells in the initiation and progression of CAD are not fully understood. Here, we used flow cytometry to determine phenotypical changes of γδ T cells and their subpopulations in peripheral blood samples collected from 37 CAD patients. The Pearson correlation coefficient was used to analyze the relationship between the clinical parameter (serum LDL-C level) and the changes of immunophenotypes of γδ T cells. Our results demonstrated that the frequencies and absolute numbers of total γδ T cells and Vδ2+ T cells were significantly decreased in CAD patients when compared to healthy individuals. However, the proportion of Vδ1+ T cells was much lower in CAD patients than that of healthy individuals. Most importantly, a significant alteration of the Vδ1/Vδ2 ratio was found in CAD patients. In addition, a series of surface markers that are associated with costimulatory signals (CD28, CD40L, CD80, CD86), activation levels (CD69, CD25, HLA-DR), activating NK cell receptors (NKp30, NKp46, NKG2D) and inhibitory receptors (PD-1, CTLA-4, PD-1, Tim-3) were determined and then analyzed in the total γδ T cells, Vδ2+T cells and Vδ2-T cells of CAD patients and healthy individuals. The data demonstrated that immunological activities of total γδ T cells, Vδ2+T cells, and Vδ2-T cells of CAD patients were much lower than those in healthy individuals. Moreover, we found that there were positive correlations between the serum LDL-C levels and frequencies of CD3+γδ+ T cells, CD69+Vδ2+T cells, NKG2D+Vδ2+T cells, and NKp46+Vδ2+T cells. By contrast, there was an inverse correlation between the levels of serum LDL-C and the frequencies of CD69+Vδ2-T cells and NKp46+Vδ2-T cells. Accordingly, these findings could help us to better understand the roles of γδ T cells in the CAD, and shed light on the development of novel diagnostic techniques and therapeutic strategies by targeting γδ T cells for CAD patients.

Abstract Apurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

Methyltransferase-like 3 (METTL3) and N6-methyladenosine (m6A) are involved in many types of biological and pathological processes, including DNA repair. However, the function and mechanism of METTL3 in DNA repair and chemotherapeutic response remain largely unknown. In present study, we identified that METTL3 participates in the regulation of homologous recombination repair (HR), which further influences chemotherapeutic response in both MCF-7 and MDA-MB-231 breast cancer (BC) cells. Knockdown of METTL3 sensitized these BC cells to Adriamycin (ADR; also named as doxorubicin) treatment and increased accumulation of DNA damage. Mechanically, we demonstrated that inhibition of METTL3 impaired HR efficiency and increased ADR-induced DNA damage by regulating m6A modification of EGF/RAD51 axis. METTL3 promoted EGF expression through m6A modification, which further upregulated RAD51 expression, resulting in enhanced HR activity. We further demonstrated that the m6A ‘reader,’ YTHDC1, bound to the m6A modified EGF transcript and promoted EGF synthesis, which enhanced HR and cell survival during ADR treatment in BC. Our findings reveal a pivotal mechanism of METTL3-mediated HR and chemotherapeutic drug response, which may contribute to cancer therapy.

Abstract Background To analyze the risk factors for hypertension in different age groups of urban and rural residents in Tianjin. Methods A total of 33,997 people (35–75 years old) from 13 community health service centers and primary hospitals in Tianjin participated in this study. They were divided into the youth group (≤ 40 years old), middle-aged group (41–65 years old), and elderly group (> 65 years old). Then, a questionnaire survey was administered, followed by physical and blood biochemical examinations. The demographic characteristics and prevalence were recorded and counted. Subsequently, risk factors were analyzed using univariate and stepwise multivariate logistic regression analysis. Results In the youth, middle-aged, and elderly groups, the prevalence rate of hypertension was 18.65, 51.80, and 76.61%, respectively. Logistic regression analysis showed that obesity(OR: 3.263, 95% CI: 1.039–1.656), men (OR: 2.117, 95% CI: 1.691–2.651), diabetes (OR: 1.978, 95% CI: 1.398–2.799), high triglycerides(OR 1.968 95% CI: 1.590–2.434) and family history of stroke (OR: 1.936, 95% CI: 1.287–2.911) are the five factors in youth. In middle-aged group, the significantly associating factors were obesity (OR: 2.478, 95% CI: 2.330–2.636), diabetes (OR: 2.173, 95% CI: 1.398–2.799), family history of stroke (OR: 1.808, 95% CI: 1.619–2.020), maleness (OR: 1.507, 95% CI: 1.412–1.609),Hypertriglyceridemia (OR 1.490 95% CI: 1.409–1.577),family history of cardiovascular disease (OR: 1.484, 95% CI: 1.307–1.684),Hypercholesterolemia (OR 1.228 95% CI: 1.160–1.299). In the elderly group, obesity (OR: 2.104, 95% CI: 1.830–2.418), family history of strokes (OR: 1.688, 95% CI: 1.243–2.292), diabetes mellitus (OR: 1.544, 95% CI: 1.345–1.773), family history of cardiovascular disease (OR: 1.470, 95% CI: 1.061–2.036), hypertriglyceridemia (OR: 1.348, 95% CI: 1.192–1.524) increased the risk for hypertension. Waist circumference (WC) and waist-to-height ratio (WHtR) increased with age, and the value of these two measures for predicting hypertension was better than BMI in middle-aged group. Conclusion Obesity is the most important risk factor for hypertension in all age groups. Diabetes, family history of strokes and high triglyceride were also significant risk factors for all age groups. There was a gender difference between the young and middle-aged groups, with men more likely to hypertension. Waist circumference (WC) and waist-to-height ratio (WHtR) were better predictors of hypertension than BMI in middle-aged group.

As an important pre-processing step in clinical applications, automatic and accurate 3D cardiovascular image segmentation has attracted more and more attention. However, cardiovascular structures are often with high diversity, blood pool and myocardium shapes are also with large variability, and ambiguous cardiac borders make the segmentation task very challenging. In this paper, a novel deep neural network to segment the blood pool and myocardium from three dimensional cardiovascular images is introduced by fully exploiting the global context and complementary information encoded in different feature extraction layers, referred to as GCEFG-R2Net briefly. In order to semantically locate the two kinds of regions in a global manner, we design a global context pooling module which can effectively learn context information in a global manner from the deep features extracted from the last two deep layers. Instead of directly using or combining different levels of deep features, we develop an interactive feature aggregation strategy to enhance different levels of deep features by embedding a series of interactive feature aggregation modules. By using the enhanced features, a residual feature refining branch is designed for refining the side outputs in a top-down stream with the guidance of global context features. Finally, the refined side outputs of different layers and the enhanced deep features are combined to generate the final segmentation result by using a feature fusion module. Extensive experiments on two challenge datasets are conducted to demonstrate that the proposed GCEFG-R2Net can obtain appealing segmentation results for the blood pool and myocardium and performs better than other state-of-the-art methods.

Abstract Background Circadian rhythm disruption impacts a wide range of physiological processes, including fertility. However, the effect of circadian disruption on male spermatogenesis and fertility, and treatments for these effects have been largely unexplored at the molecular level. Methods In this study, we examined the effects of genipin on improving the reproductive health problems caused by circadian disruption. Three groups of animals were fed under different conditions: control group (normal T cycle with saline), group of shortened T cycles (Light/Dark = 4 hours/4 hours) with saline, and a group of shortened T cycles with genipin by oral gavage. The male fertility was evaluated by fertility study and pups parameters analysis after successful sexual behavior and mating with female mice. We sacrificed the treated animals after 5 or 10 weeks and collected the testis, sperm and serum for histological analysis, sperm motility assay, and serum hormone detection, respectively. Furthermore, the effect of genipin was assessed by detection of progesterone secretion and steroidogenic key proteins expression, including StAR and CYP11A1, in mouse Leydig tumor MLTC-1 cells. Results Male mice exposed to shortened light-dark cycles, much shorter than 24 hours, had reduced fertility with decreased sperm concentrations and sperm motility. Male mice under circadian disruption have reduced testis size and abnormal morphology, leading to lower fertility rates, reduced litter size and pup body weight. Treatment with exogenous genipin, a natural plant-derived compound, alleviated circadian disruption-induced damage to fertility and spermatogenesis and normalized testosterone, dihydrotestosterone (DHT), and androstenedione (ASD) levels in the male mice. The levels of key proteins involved in steroidogenesis, StAR and CYP11A1, were reduced in mouse testes after the circadian disruption, but genipin treatment restored the reduction. The mRNA expression of SRD5A1, which encodes an androgen synthesis enzyme, was also upregulated by genipin treatment. Furthermore, genipin treatment showed a positive effect on steroidogenesis in MLTC-1 cells, resulting in an increase in hormone secretion and the upregulation of StAR and CYP11A1. Conclusions Our results showed an association between circadian disruption and reproductive health problems in male mice and indicated that treatments with genipin have positive effects on the reproductive health of male mice with circadian rhythm disorders.

Reactive oxygen species (ROS) are a group of highly oxidative molecules that induce DNA damage, affecting DNA damage response (DDR) and gene expression. It is now recognized that DNA base excision repair (BER) is one of the important pathways responsible for sensing oxidative stress to eliminate DNA damage, in which FEN1 plays an important role in this process. However, the regulation of FEN1 under oxidative stress is still unclear. Here, we identified a novel RNA G-quadruplex (rG4) sequence in the 5′untranslated region (5′UTR) of FEN1 mRNA. Under oxidative stress, the G bases in the G4-forming sequence can be oxidized by ROS, resulting in structural disruption of the G-quadruplex. ROS or TMPyP4, a G4-structural ligand, disrupted the formation of G4 structure and affected the expression of FEN1. Furthermore, pull-down experiments identified a novel FEN1 rG4-binding protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), and cellular studies have shown that hnRNPA1 plays an important role in regulating FEN1 expression. This work demonstrates that rG4 acts as a ROS sensor in the 5′UTR of FEN1 mRNA. Taken together, these results suggest a novel role for rG4 in translational control under oxidative stress.

Short-term starvation (STS) during chemotherapy can block the nutrient supply to tumors and make tumor cells much more sensitive to chemotherapeutic drugs than normal cells. However, because of the diversity of starvation methods and the heterogeneity of tumors, this method’s specific effects and mechanisms for chemotherapy are still poorly understood. In this study, we used HeLa cells as a model for short-term starvation and etoposide (ETO) combined treatment, and we also mimicked the short-term starvation effect by knocking down the glycolytic enzyme GAPDH to explore the exact molecular mechanism. In addition, our study demonstrated that short-term starvation protects cancer cells against the chemotherapeutic agent ETO by reducing DNA damage and apoptosis due to the STS-induced cell cycle G1 phase block and S phase reduction, thereby diminishing the effect of ETO. Furthermore, these results suggest that starvation therapy in combination with cell cycle-specific chemotherapeutic agents must be carefully considered.

Atherosclerosis is a complex metabolic disease characterized by the dysfunction of lipid metabolism and chronic inflammation in the intimal space of the vessel. As the most abundant innate immune cells, monocyte-derived macrophages play a pivotal role in the inflammatory response, cholesterol metabolism, and foam cell formation. In recent decades, it has been demonstrated that monocytes and macrophages can establish innate immune memory (also termed trained immunity) via endogenous and exogenous atherogenic stimuli and exhibit a long-lasting proinflammatory phenotype. The important cellular metabolism processes, including glycolysis, oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and cholesterol synthesis, are reprogrammed. Trained monocytes/macrophages with innate immune memory can be persistently hyperactivated and can undergo extensive epigenetic rewiring, which contributes to the pathophysiological development of atherosclerosis via increased proinflammatory cytokine production and lipid accumulation. Here, we provide an overview of the regulation of cellular metabolic processes and epigenetic modifications of innate immune memory in monocytes/macrophages as well as the potential endogenous and exogenous stimulations involved in the progression of atherosclerosis that have been reported recently. These elucidations might be beneficial for further understanding innate immune memory and the development of therapeutic strategies for inflammatory diseases and atherosclerosis.

Abstract Glioma causes significant mortality across the world and the most aggressive type of brain cancer. The incidence of glioma is believed to increase in the next few decades and hence more efficient treatment strategies need to be developed for management of glioma. Herein, we examined the anticancer effects of Indirubin against a panel of human glioma cells and attempted to explore the underlying mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay showed that Indirubin could inhibit the growth of all the glioma cells but the lowest IC50 of 12.5 µM was observed against the U87 and U118 glioma cells. Additionally, the cytotoxic effects of Indirubin were comparatively negligible against the normal astrocytes with an IC50 of > 100 µM. Investigation of mechanism of action, revealed that Indirubin exerts growth inhibitory effects on the U87 and U118 glioma cells by autophagic and apoptotic cell death. Annexin V/PI staining assay showed that apoptotic cell percentage increased dose dependently. Apoptosis was associated with increase in Bax decrease in Bcl-2 expressions. Additionally, the expression of autophagic proteins such as LC3II, ATG12, ATG15 and Beclin 1 was also increased. Wound heal assay showed that Indirubin caused remarkable decrease in the migration of the U87 and U118 cells indicative of anti-metastatic potential of Indirubin. Taken together, these results suggest that Indirubin exerts potent anticancer effects on glioma cells and may prove essential in the management of glioma.

The full coverage policy for essential medicines (FCPEMs) was proposed and implemented in Taizhou city of Zhejiang Province, China, to promote equal access and adherence to medicines. This study aimed to examine the effects of FCPEMs on the income-related inequality in medication adherence among local patients with hypertension or diabetes. We collected electronic health records of patients with hypertension or diabetes of three districts of Taizhou from 2011 to 2016. As the implementation schedule of the FCPEMs varied across districts, we applied a retrospective longitudinal study design and assigned records from 1 year before to 3 years following the implementation of FCPEMs as baseline and follow-up data. We thus generated a dataset with 4-year longitudinal data. The concentration index (CI) and its decomposition method were employed to measure factors contributing to inequality in medication adherence and the role played by FCPEMs. The sample size rose from 264,836 at the baseline to 315,677, 340,512, and 355,676 by each follow-up year, and the proportion of patients taking free medicines rose from 17.6 to 25.0 and 29.8% after FCPEMs implementation. The proportion of patients with high adherence increased from 39.9% at baseline to 51.6, 57.2, and 60.5%, while CI decreased from 0.073 to −0.011, −0.029, and −0.035. The contribution of FCPEMs ranked at 2nd/13, 7th/13, and 2nd/13 after the implementation of FCPEMs. Changes in CI of medication adherence for every 2 years were −0.084, −0.018, and −0.006, and the contribution of FCPEMs was −0.006, 0.006, and 0.007, ranking at 2nd/13, 2nd/13, and 1st/13, respectively. Most changes in CI of medication adherence can be attributed to FCPEMs. The medication adherence of patients with hypertension or diabetes improved after the implementation FCPEMs in Taizhou, although inequality did not improve consistently. In general, FCPEMs could be a protective factor against income-related inequalities in access and adherence to medicines. Future research is needed to investigate the change mechanism and the optimal design of similar interventions.

BackgroundThe relationship between galectin-3 (Gal-3) and coronary artery disease (CAD) has not been fully elucidated.AimThis study aimed to determine the relationship between the presence and severity of CAD and serum Gal-3 levels.Patients and MethodsThree-hundred thirty-one consecutive CAD patients were enrolled as the study group. An additional 62 patients without CAD were enrolled as the control group. Serum Gal-3 levels were separately compared between the non-CAD and CAD groups, among the stable CAD and Acute coronary syndrome (ACS) groups, and between CAD patients with low and high SYNTAX scores (SSs). The 1-year cumulative rate of major adverse cardiac events (MACEs) was also compared among ACS patients by Gal-3 levels.ResultsSerum Gal-3 was significantly higher in the CAD group than in the non-CAD group 3.89 (0.16–63.67) vs. 2.07 (0.23–9.38) ng/ml, P < 0.001. Furthermore, serum Gal-3 was significantly higher in the non-ST-segment elevation ACS (NSTE-ACS) group than that in the stable CAD group, 4.72 (1.0–16.14) vs. 2.23 (0.65–23.8) ng/ml, P = 0.04 and higher in the ST-segment elevation myocardial infarction (STEMI) group than that in the stable CAD group 7.87 (0.59–63.67) vs. 2.23 (0.65–23.8) ng/ml, P < 0.001. Serum Gal-3 level was an independent predictor of ACS compared with stable CAD group (OR = 1.131, 95% CI: 1.051–1.217, P = 0.001) as well as high SS (OR = 1.030, 95% CI: 1.021–1.047, P = 0.038) after adjust other confounding risk factors. Acute coronary syndrome patients with Gal-3 levels above the median (gal-3 = 4.78 ng/ml) showed a higher cumulative MACE rate than those with Gal-3 levels below the median. After adjusting other confounding risk factors, Gal-3 remained an independent risk factor for the cumulative rate of MACEs in ACS patients (6% higher rate of MACEs incidence per 1 ng/ml increment of Gal-3).ConclusionGalectin-3 correlated with the presence of CAD as well as coronary stability and complexity. Galectin-3 may be valuable in predicting mid-term prognosis in ACS patients.

Background. This study is aimed at effectively investigating the role of coagulation factor II thrombin receptor like 2 (F2RL2) in myocardial infarction (MI) as well as the upstream regulatory miRNA and lncRNA. Methods. Regulatory genes of F2RL2 were analyzed using StarBase and verified by dual-luciferase reporter assay. The MI mouse model was established. The left ventricular ejection fraction (EF) and fractional shortening (FS) were examined by echocardiography. The infarct area, pathological changes, and cell apoptosis in mouse myocardial tissue were evaluated using triphenyltetrazolium chloride and Evans blue, hematoxylin-eosin, and TUNEL staining assays. Oxygen-glucose deprivation- (OGD-) induced human cardiac myocytes (HCMs) were cultured and transfected. The cell viability, proliferation, and apoptosis were determined by CCK-8, EdU staining, and flow cytometry assays. The expressions of F2RL2, miR-582-5p, and nuclear paraspeckle assembly transcript 1 (NEAT1) in myocardial tissues and HCMs were quantified by qRT-PCR or Western blot. Results. NEAT1 sponged miR-582-5p which targeted F2RL2. NEAT1 and F2RL2 were highly expressed while miR-582-5p was lowly expressed in MI mice. F2RL2 downregulation prevented the reduction in EF and SF and the elevation in infarct area and cell apoptosis of MI mice. Both F2RL2 and NEAT1 downregulations reversely modulated the decreased viability and proliferation and the increased apoptosis of OGD-induced HCMs, while miR-582-5p inhibitor did oppositely. NEAT1 silencing upregulated miR-582-5p level but downregulated F2RL2 level. miR-582-5p inhibitor upregulated the F2RL2 level. The role of NEAT1 silencing in OGD-induced HCMs was reversed by miR-582-5p inhibitor whose effect was further offset by F2RL2 downregulation. Conclusion. NEAT1 downregulation ameliorates MI by regulating the miR-582-5p/F2RL2 axis, providing novel biomarkers for MI treatment.

Abstract Background Cervical cancer is one of the most common causes of cancer‐associated mortality among affected women in the world. At present, treatment with weekly cisplatin plus ionizing radiation (IR) therapy is the standard regimen for cervical cancer, especially for locally advanced cervical cancer. The purpose of this study is to determine whether FEN1 inhibitors could enhance the therapeutic effect of IR therapy. Methods Western blot was applied to determine the expression of FEN1‐ and apoptosis‐related proteins. Cell growth inhibition assay and colony formation assay were used to determine the effects of FEN1 inhibitor and IR exposure for Hela cells in vitro. CRISPR technology was used to knockdown FEN1 expression level of 293T cells, and tumor xenograft in nude mice was employed to determine the effects of FEN1 inhibitor and IR exposure on tumor growth in vivo. Results Our data revealed that FEN1 is overexpressed in HeLa cell and can be upregulated further by IR. We also demonstrated that FEN1 inhibitor enhances IR sensitivity of cervical cancer in vitro and in vivo. Conclusion FEN1 inhibitor SC13 could sensitize radiotherapy of cervical cancer cell.

The aim of this study was to test the preventive effects of nano liposomes against contrast-induced nephropathy (CIN) in New Zealand rabbits. Sixty New Zealand rabbits were randomly divided into four groups, with 15 rabbits in each group: control group, contrast group, hydration group and nano liposome group. Serum creatinine (Scr) and Blood Urea Nitrogen (BUN) were measured before and after injection of the contrast agent iopromide. Oxidative stress markers, such as superoxide dismutase (SOD) and malondialdehyde (MDA), and apoptosis markers, such as Bcl2-Associated X (Bax) and B-cell lymphoma-2 (Bcl-2), were measured by enzyme-linked immunosorbent assay (ELISA). Rabbits were killed 24 h after injection of the contrast medium and both kidneys were removed. Real-time Polymerase Chain Reaction (RT-PCR) and Western blot assays were performed in kidney tissue. Pathological changes were analyzed under the optical and electron microscope. Compared with the hydration group, the nano liposome group showed improved protection of renal function, with significantly different Scr and BUN levels, incidence of CIN, apoptosis index, RT-PCR and Western blot protein expression patterns. Under the optical and electron microscope, the renal injury in the nano liposome group was less than in the hydration group. However, based on SOD and MDA, there was no significant difference in oxidative stress when compared with the hydration group. Apoptosis is an important mechanism in CIN. Nano liposomes can prevent the occurrence of CIN by decreasing apoptosis, reducing damage to the kidney by the contrast agent.