Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.

BACKGROUND AND AIMS: Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis. METHODS: Apolipoprotein-E deficient (ApoE-/-) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia-reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. RESULTS: In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically recruited monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP potentially slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A gene levels. CONCLUSIONS: The findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients.

Preoperative contributing factors and the remission of diabetes after metabolic surgery: the mediating role of preoperative triglyceride.

BACKGROUND AND OBJECTIVE: Limited understanding exists regarding the factors affecting the prognosis of surgical treatment for type 2 diabetes mellitus (T2DM), particularly in Chinese patients. In this study, we examined a cohort of early and intermediate obese T2DM patients to explore the potential impact of preoperative lipid metabolism in metabolic surgery on the postoperative remission of T2DM. METHODS: Participants with T2DM and obesity underwent metabolic surgery. Clinical data, including baseline body mass index, percentage of excess weight loss, and preoperative biochemical indicators, were collected and analyzed. A multidisciplinary team conducted patient follow-up. Remission was defined as sub-diabetic hyperglycemia (HbA1c < 48 mmol/mol, fasting glucose 100-125 mg/dl) without pharmacological intervention for at least 12 months. RESULTS: Over a median follow-up of 27 months, 96 T2DM patients with metabolic surgery were studied, with no laparotomies required. Among these patients, 61 (63.5%) achieved complete remission, and 85 (88.5%) experienced remission. In multivariable analysis models, preoperative fasting blood glucose (FBG) significantly correlated with all postoperative outcomes. Furthermore, mediation analysis indicated that preoperative triglycerides (TG) mediated 26.31% of the association between preoperative FBG and postoperative remission. Both preoperative FBG and TG were negatively associated with the postoperative remission of T2DM. CONCLUSION: In summary, our findings suggest that lower preoperative fasting glucose levels enhance the likelihood of postoperative T2DM remission. Moreover, preoperative TG could potentially play a mediating role in the postoperative remission of T2DM. Therefore, evaluating and managing fasting glucose and lipids before the procedure may aid in assessing the prognosis of metabolic surgery. Level of evidence Level III, designed cohort.

Long non coding RNA COX10-DT promotes the progression of breast cancer via the COX10-DT/miR-206/BDNF axis.

Long noncoding RNAs (lncRNAs) are emerging as critical regulators in the biological development of breast cancer. In this study, we aimed to determine the roles and mechanisms of the lncRNA COX10 divergent transcript (COX10-DT) in breast cancer progression. The relative expression level of COX10-DT was calculated in matched breast cancer tissues and adjacent normal tissues using quantitative real-time PCR. Gain-of-function and loss-of-function approaches further revealed the functions and mechanisms of COX10-DT in breast cancer cells. Clinically, we found that the lncRNA COX10-DT was commonly overexpressed in breast cancer tissues compared to paired peritumoural tissues. Functionally, the lncRNA COX10-DT might promote the proliferation and migration of breast cancer cells. Mechanistically, the lncRNA COX10-DT did not play a role by regulating the expression of its divergent gene COX10 but acted as a competitive endogenous RNA (ceRNA) by directly sponging miR-206, which further regulated the expression of brain-derived neurotrophic factor (BDNF). Taken together, our results proved that the lncRNA COX10-DT could function via the COX10-DT/miR-206/BDNF axis, thereby promoting the development of breast cancer. These findings indicated that the lncRNA COX10-DT might be a potential biomarker and therapeutic target for breast cancer.

Hyperlipidemia inhibits the protective effect of lisinopril after myocardial infarction via activation of dendritic cells.

To investigate the prevention of cardiac remodelling and inflammatory immune response after myocardial infarction (MI) via ACEI regulating dendritic cells (DCs), we explored whether the protective effect of ACEI was repressed under hyperlipidemic environment. In vivo, the survival rate and left ventricular function of the mice were recorded on day 7 after MI. Tissue samples of the myocardium, spleen, bone marrow and peripheral blood were assessed for Ang II concentration, inflammatory cytokines and DCs expression. In vitro, DCs were treated with ox-LDL + Ang II, simulating the internal environment of MI in ApoE-/- mice to explore the mechanism involved in the DCs maturation and inflammation. Under hyperlipidemic circumstances, we found that the cardioprotective effect of ACEI was attenuated through regulating DCs maturation and inflammation after MI, affecting survival rate and left ventricular function. Effects of lisinopril on the release of spleen-derived DCs and myocardial infiltration were also reduced under hyperlipidemic conditions. In vitro, immune maturation and inflammation of DCs were further induced by ox-LDL on the basis of Ang II treatment, as indicated by the upregulation of CD83, CD86, and the expressions of cytokines and chemokines. Furthermore, ox-LDL could activate TLR4-MyD88 signalling pathway, promoting IRAK-4 and NF-κB. The present study demonstrated that ACEI reduced the recruitment of DCs to the infarct site, leading to a higher survival rate and improved function. However, this effect was inhibited under hyperlipidemic environment. TLR4-MyD88 signalling pathway may be responsible for the molecular mechanism involved in the immune maturation and inflammation of DCs induced by ox-LDL.

Incidence, survival, and prognostic nomogram of patients with small intestinal neuroendocrine tumors: A SEER population-based study.

Small intestinal neuroendocrine tumors (SI-NETs) are a group of rare and significantly heterogeneous tumors with limited research currently available. This study aimed to investigate the incidence, survival, and prognostic factors of SI-NETs. We selected data from the surveillance, epidemiology, and end results (SEER) database between 2000 and 2019 and evaluated the incidence trend of SI-NETs during this period. We utilized the Kaplan-Meier method to examine the association between clinical variables and survival rates. Based on the multivariable Cox regression analysis results, we developed a nomogram to predict the 1-, 2-, and 3-year cancer-specific survival (CSS) of SI-NETs patients. We evaluated the consistency, accuracy, and clinical utility of the nomogram by drawing calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA) curves. The incidence of SI-NETs showed an upward trend in recent years. Age, grade, T stage, M stage, and primary tumor surgery were independent risk factors for CSS in SI-NETs patients. The nomogram model based on these risk factors showed high accuracy and clinical benefit. SI-NETs are rare tumors with an increasing incidence rate. The nomogram model is expected to be an effective tool for personalized prognosis prediction in SI-NETs patients, which may benefit clinical decision-making.

Survival and Prognosis for Patients with Rectal Melanomas in the United States: A SEER-Based Study.

PURPOSE: Limited attention was paid to focus on rectal melanomas (RM). This study aimed to evaluate the survival rate and prognostic factors of RM. METHODS: The data for patients with RM from Surveillance, Epidemiology, and End Results (SEER) database were used to analyze tumor survival. Kaplan-Meier method and log-rank test were employed to estimate cancer-specific survival (CSS) and overall survival (OS). A nomogram was established based on the risk factors of survival by the forest plot for multivariate Cox regression analysis. Receiver operating characteristic (ROC) and calibration curve were conducted for validation. RESULTS: A total of 187 patients with RM were selected to perform survival analyses. The median survival time of OS was 12 months (range: 0-146 months), and the median survival time of CSS was 12 months (range: 0-74 months). Patients' age, tumor size, stage, the number of nodes examined, surgery, and radiation were identified as prognostic indicators for CSS by the forest plot for multivariate Cox regression analysis. The nomogram was validated as a reliable model for CSS. CONCLUSION: Clinicopathologic relevance with tumor prognosis was confirmed in this study. Our nomogram can provide a relatively accurate prediction of the survival rate of patients with RM.

Comprehensive characterization of FBXW7 mutational and clinicopathological profiles in human colorectal cancers.

Background: FBXW7 is recognized as a critical tumor suppressor gene and a component of the ubiquitin-proteasome system, mediating the degradation of multiple oncogenic proteins, including c-MYC, Cyclin E, c-Jun, Notch, p53. Around 16% of colorectal cancer (CRC) patients carried FBXW7 somatic mutations, while a comprehensive characterization of FBXW7 somatic mutations in CRC is still lacking. Methods: Colorectal cancer patients with tumor samples and matching white blood cell samples in the past five years were screened and DNA sequenced. DNA sequencing data of MSK MetTropism cohort and RNA sequencing data of TCGA COAD cohort were analyzed. Results: We discovered that the FBXW7 mutations were associated with higher tumor mutation burden (TMB), higher microsatellite instability (MSI) score, and lower chromosomal instability (CIN) score. Patients with FBXW7 mutations showed better overall survival (HR: 0.67; 95%CI: 0.55-0.80, P < 0.001). However, patients with FBXW7 R465C mutation displayed worse overall survival in multi-variate cox analysis when compared with patients carrying other FBXW7 mutations (HR: 1.6; 95%CI: 1.13-3.1, P = 0.015), and with all other patients (HR: 1.87; 95%CI: 0.99-2.5, P = 0.053). Moreover, in MSI patients, the FBXW7 mutated group showed higher M1 macrophage, CD8+ T cell, and regulatory T cell (Tregs) infiltration rates, and significant enrichment of multiple immune-related gene sets, including interferon-gamma response, interferon-alpha response, IL6 JAK STAT3 signaling, p53 pathway. Conclusion: This analysis comprehensively identified FBXW7 alterations in colorectal cancer patients and uncovered the molecular, clinicopathological, and immune-related patterns of FBXW7-altered CRC patients.

Incidence, survival, and prognostic factors for patients with gastrointestinal mixed neuroendocrine non-neuroendocrine neoplasms: a SEER population-based study.

BACKGROUND: Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are a group of rare tumors with limited research currently available. This study aimed to analyze the incidence, survival, and prognostic factors of gastrointestinal MiNENs. METHODS: We included data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019. We compared the clinicopathologic characteristics and survival rates between MiNENs and neuroendocrine tumors (NETs), and calculated the incidence of MiNENs. We utilized univariate and multivariate Cox analysis to assess independent factors of prognosis and established a nomogram to predict 1-, 2-, and 3-year cancer-specific survival (CSS). Calibration and receiver operating characteristic (ROC) curves were drawn to validate the accuracy and reliability of the model. Decision curve analysis (DCA) was used to assess the clinical utility of the model. RESULTS: Patients with gastrointestinal MiNENs had a poorer prognosis than those with NETs. The overall incidence of gastrointestinal MiNENs has been increasing annually. Multivariate Cox regression analysis revealed that tumor size, lymph node metastasis, distant metastasis, and surgery were independent risk factors for CSS in MiNENs patients. Based on these risk factors, the 1-, 2-, and 3-year CSS nomogram model for MiNENs patients was established. Calibration, ROC, and DCA curves of the training and validation sets demonstrated that this model had good accuracy and clinical utility. CONCLUSION: Gastrointestinal MiNENs are rare tumors with an increasing incidence rate. The nomogram model is expected to be an effective tool for personalized prognosis prediction in MiNENs patients, which may benefit clinical decision-making.

Oncolytic vaccinia virus acts synergistically with anti-PD-L1 antibody to enhance the killing of colon cancer cells by CD8+ T cells.

Both oncolytic vaccinia virus (OVV) and anti-PD-L1 antibody hold promise in cancer immunotherapy. Herein, we aimed to explore the possible synergistic effects of OVV and anti-PD-L1 on the growth and metastasis of colon cancer (CC) in mouse models. Microarray profiling of CC-related genes was first conducted. Expression of PD-L1 in CC tissues was predicted by TCGA and verified by flow cytometry and RT-qPCR. Then, mouse CC cell lines stably carrying luciferase MC38-luc and CT26-luc were infected with recombinant double-deleted vaccinia virus (vvDD) to evaluate the effect of vvDD on cell viability. The data indicated that PD-L1 was highly expressed in CC tissues and cells following vvDD infection. MC38-luc cells were inoculated into mice to construct CC-bearing mouse models, which were treated with vvDD or combined with anti-PD-L1, with tumor growth, metastasis, survival, and the immune environment analyzed. It was found that OVV combined with anti-PD-L1 antibody led to lower tumor burden and growth and higher survival rates than individual treatment in CC-bearing mice. In addition, this combination exerted a remote effect on the untreated subcutaneous tumors in the lateral abdomen, thus suppressing the tumor metastasis. Furthermore, combined therapy of OVV with anti-PD-L1 antibody activated CD8+ T cells, reduced exhaustion of CD8+ T cells, and enhanced their immune response, strengthening the killing of CC cells and inhibiting tumor growth and metastasis. In conclusion, our findings provide mechanistic insights into the action and efficacy of OVV as an immunomodulatory agent combined with the anti-PD-L1 antibody for the treatment of CC.

A novel tapered guide extension catheter facilitated successful completion of complex percutaneous coronary intervention.

BACKGROUND: Guide extension catheters (GEC) are widely applied to cope with insufficient backup support in complex percutaneous coronary intervention (PCI). In the study, we aim to evaluate the feasibility and safety with a novel 5-4F tapered GEC used in complex lesion. METHODS: The single-center retrospective study enrolled a total of 615 patients, in whom the 5F or 5-4F Expressman GEC was used to facilitate PCI procedure. Demographic and procedural data were collected. RESULTS: 5F GEC was used in 295 patients and 5-4F tapered GEC in 320 patients. The average age was 63.6 ± 11.0 years and 81.6% of the patients were male. Severe calcification and chronic total occlusion (CTO) were the commonest indication for the GEC use. The 5-4F tapered GEC was frequently used in active greeting technique (AGT) during CTO intervention procedure than 5F GEC (6.1% vs. 13.1%, p < 0.001). The average depth of intubation was 41.5 ± 19.6 mm for the 5-4F tapered GEC and 24.4 ± 15.1 mm for 5F GEC (p < 0.001). The rate of successful device delivery with 5-4F GEC was higher than 5F GEC (95.6% vs. 98.4%, p = 0.037). Pressure damping with 5F GEC occurred frequently than 5-4F GEC (7.4% vs. 2.5%, p < 0.05). Similarly, the incidence of intraoperative hypotension was higher in 5F GEC than 5-4F GEC (4.7% vs.1.9%, p < 0.05). CONCLUSIONS: The novel 5-4F tapered GEC was superior to the 5F GEC in facilitating successful completion of PCI in the majority of patients with complex lesions via transradial approach.

Soluble interleukin-2 receptor predicts acute kidney injury and in-hospital mortality in patients with acute myocardial infarction.

BACKGROUND: Acute kidney injury (AKI) is the most common and critical complication in patients with acute myocardial infarction (AMI). This study aims to evaluate the significance of elevated soluble interleukin 2 receptor (sIL-2R) levels in predicting AKI and mortality. METHODS: A total of 446 patients with AMI were enrolled between January 2020 and July 2022, including 58 patients with AKI and 388 without AKI. The sIL-2R levels were measured using a commercially available chemiluminescence enzyme immunoassay. Logistic regression analysis was used to examine the risk factors for AKI. Discrimination was assessed based on the area under the receiver operating characteristic curve. The model was internally validated using 10-fold cross-validation. RESULTS: During hospitalization, 13% of patients developed AKI following AMI, with higher sIL-2R levels (0.61 ± 0.27 U/L vs. 0.42 ± 0.19 U/L, p = 0.003) and in-hospital all-cause mortality (12.1% vs. 2.6%, P < 0.001). The sIL-2R levels emerged as an independent risk factor for both AKI (OR = 5.08, 95% CI (1.04-24.84, p < 0.045) and in-hospital all-cause mortality (OR = 73.57,95% CI 10.24-528.41, p < 0.001) in AMI patients. The sIL-2R levels were found to be useful biomarkers in prediction of AKI and in-hospital all-cause mortality in patients with AMI (AUC: 0.771 and 0.894, respectively). The respective cutoff values for sIL-2R levels in predicting AKI and in-hospital all-cause mortality were determined to be 0.423 U/L and 0.615 U/L. CONCLUSIONS: The level of sIL-2R was an independent risk factor and predictor for both AKI and in-hospital all-cause mortality in patients with AMI. These findings highlight the potential of sIL-2R as a valuable tool for identifying high-risk patients regarding AKI and in-hospital mortality.

The Application of Sensitive Nano-Confined Nanoparticle System Using siRNA Targeting Extracellular Signal-Regulated Kinase (ERK)/Mitogen-Activated Protein Kinase (MAPK) Pathway in Gastrointestinal Cancer.

In this study we tried to develop a Sensitive Nano-Confined Nanoparticles (S-NCN) system using siRNA against Programmed death-ligand 1 (PDL-1) and Polo Like Kinase 1 (Plk1) to treat gastrointestinal cancer. In this regard, we first synthesized the corresponding materials, prepared the S-NCN system, and verified its functionality. Subsequently, we demonstrated in vitro that S-NCN delivery of siPlk1 could effectively downregulate the expression of Plk1 gene in GC1436 cells and lead to significant apoptosis of tumor cells. Xenografted gastrointestinal cancer model mice were used to evaluate the in vivo efficacy of the nanoparticle. We have demonstrated that the developed S-NCN system can efficiently bind siRNA and deliver it into target tumor cells, solving the main obstacle of siRNA delivery in vivo and effectively silencing target genes with a very potential delivery option.

Integrated Analysis of Angiogenesis Related lncRNA-miRNA-mRNA in Patients With Coronary Chronic Total Occlusion Disease.

Background: Coronary chronic total occlusion (CTO) disease is common and its specific characteristic is collateral formation. The Integrated analysis of angiogenesis related lncRNA-miRNA-mRNA network remains unclear and might provide target for future studies. Methods: A total of five coronary artery disease (control group) and five CTO (CTO group) patients were selected for deep RNA and miRNA sequencing. The expression profiles of lncRNAs, mRNAs circRNA and miRNAs were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were then performed. The expression of a 14q32 miRNA gene cluster, including miRNA-494, miRNA-495 and miRNA-329, were selected to be determined in another larger patient cohort. Analysis of the lncRNA-miRNA495-mRNA network was constructed to find potential targets for future studies. Results: A total of 871 lncRNAs, 1,080 mRNAs, 138 circRNAs and 56 miRNAs were determined as differentially expressed (DE) in CTO patients compared with control patients. GO and KEGG analyses revealed that the top terms included MAPK signaling pathway, HIF-1 signaling pathway, EGFR tyrosine kinase inhibitor resistance, embryonic organ development, wound healing, MAPK signaling pathway and JAK-STAT signaling pathway, which are related to angiogenesis. The expression of miRNA-494, miRNA-495 and miRNA-329 were all significantly down-regulated in CTO patients and they were confirmed to be down-regulated in another cohort of 68 patients. Then we divided the CTO patients into two groups according to CC grade (poor CC group, CC = 0 or one; good CC group, CC = 2). MiRNA-494, miRNA-495 and miRNA-329 were found to be down-regulated in good CC group compared with poor CC group. Analysis of the lncRNA-miRNA495-mRNA network showed 3 DE lncRNA sponges (NONHSAG008675, NONHSAG020957 and NONHSAG010989), 4 DE lncRNA targets (NONHSAT079547.2, NONHSAT081776.2, NONHSAT148555.1 and NONHSAT150928.1) and 2 DE mRNA targets (RAD54L2 and ZC3H4) of miRNA495. Conclusion: This study revealed that the lncRNA-miRNA-mRNA network might play a critical role in angiogenesis in CTO patients.

The Integrative Analysis of Competitive Endogenous RNA Regulatory Networks in Coronary Artery Disease.

Background: Coronary artery disease (CAD) is the leading cause of cardiovascular death. The competitive endogenous RNAs (ceRNAs) hypothesis is a new theory that explains the relationship between lncRNAs and miRNAs. The mechanism of ceRNAs in the pathological process of CAD has not been fully elucidated. The objective of this study was to explore the ceRNA mechanism in CAD using the integrative bioinformatics analysis and provide new research ideas for the occurrence and development of CAD. Methods: The GSE113079 dataset was downloaded, and differentially expressed lncRNAs (DElncRNAs) and genes (DEGs) were identified using the limma package in the R language. Weighted gene correlation network analysis (WGCNA) was performed on DElncRNAs and DEGs to explore lncRNAs and genes associated with CAD. Functional enrichment analysis was performed on hub genes in the significant module identified via WGCNA. Four online databases, including TargetScan, miRDB, miRTarBase, and Starbase, combined with an online tool, miRWalk, were used to construct ceRNA regulatory networks. Results: DEGs were clustered into ten co-expression modules with different colors using WGCNA. The brown module was identified as the key module with the highest correlation coefficient. 188 hub genes were identified in the brown module for functional enrichment analysis. DElncRNAs were clustered into sixteen modules, including seven modules related to CAD with the correlation coefficient more than 0.5. Three ceRNA networks were identified, including OIP5-AS1-miR-204-5p/miR-211-5p-SMOC1, OIP5-AS1-miR-92b-3p-DKK3, and OIP5-AS1-miR-25-3p-TMEM184B. Conclusion: Three ceRNA regulatory networks identified in this study may play crucial roles in the occurrence and development of CAD, which provide novel insights into the ceRNA mechanism in CAD.

Plasma Heat Shock Protein 70 Is Associated With the Onset of Acute Myocardial Infarction and Total Occlusion in Target Vessels.

Background: Whether the role of plasma heat shock protein 70 (HSP70) in acute myocardial infarction (AMI) is protective or detrimental remains debated, and the relationship between HSP70 and total occlusion remains elusive. Methods: A total of 112 patients with primary diagnosis of AMI and 52 patients with chronic coronary syndrome (CCS) were enrolled into the study. Plasma HSP70 level was determined by ELISA on day 1 and day 7 after the onset of AMI and was examined before angiography in patients with CCS. Peak NT-proBNP, high-sensitivity C-reactive protein (CRP), troponin T (cTnT), and left ventricular ejection fraction were measured. Results: Plasma HSP70 was significantly higher in CCS than AMI (P < 0.0001), and it showed a significant decrease from day 1 to day 7 after AMI (P < 0.01). Elevated HSP70 was associated with decreased levels of LDL-C (P < 0.05), peak cTnT (R = -0.3578, P < 0.0001), peak NT-proBNP (R = -0.3583, P < 0.0001), and peak CRP (R = -0.3539, P < 0.0001) and a lower diagnosis of AMI (R = -0.4016, P < 0.0001) and STEMI (R = -0.3675, P < 0.0001), but a higher diagnosis of total occlusion in target vessels (R = 0.1702, P < 0.05). HSP70 may provide certain predictive value for the diagnosis of AMI, STEMI, and total occlusion in target vessels, and the area under the receiver operating characteristic curves were 0.7660, 0.7152, and 0.5984, respectively. HSP70 was also negatively associated with in-hospital stay (P < 0.001) and positively correlated with left ventricular ejection fraction (LVEF) at 1-year follow-up (P < 0.05), despite no association with in-hospital major adverse cardiovascular events (MACE). Conclusion: Plasma HSP70 level was found to decrease from day 1 to day 7 post-AMI, but the overall level of patients with AMI was lower than that of patients with CCS. However, the ability of HSP70 to identify clinically significant AMI and STEMI was moderate, and the predictive value to total occlusion was slight.

NLRC5, a valuable marker for the diagnosis and prognostic assessment of hepatocellular carcinoma.

BACKGROUND: NLR family CARD domain containing 5 (NLRC5) is involved the initiation and progression of several cancers. However, its role in hepatocellular carcinoma (HCC) is still unclear. This study aimed to explore the expression, clinical significance, and regulated gene sets of NLRC5 in HCC. METHODS: Data related to NLRC5 was extracted from The Cancer Genome Atlas (TCGA) database and analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to verify the NLRC5 mRNA expression in HCC. Immunohistochemistry (IHC) and western blot were performed to detect the NLRC5 protein level in HCC. The clinical significance of NLRC5 was investigated after separating patients into NLRC5-positive and NLRC5-negative groups based on the IHC results. Gene set enrichment analysis (GSEA) was performed to detect gene sets regulated by NLRC5 in HCC. RESULTS: Increased NLRC5 mRNA and protein expression were found in HCC tissues compared to paracancerous tissues. Moreover, enhanced NLRC5 protein expression was associated with a higher presence rate of cirrhosis, a higher TNM stage, and a shorter 3-year overall survival (OS) of HCC participants. Finally, gene sets related to cancer metastasis were up-regulated in the NLRC5 high phenotype. CONCLUSIONS: NLRC5 is a potential marker for the diagnosis and prognostic assessment of HCC.

D-dimer level predicts in-hospital adverse outcomes after primary PCI for ST-segment elevation myocardial infarction.

BACKGROUND: Use of D-dimer for prognostication of patients with ST-segment elevation myocardial infarction (STEMI) remains controversial and undefined among those with angiographically evident thrombus or no-reflow phenomenon. METHODS: We retrospectively analyzed consecutive STEMI patients who received primary percutaneous coronary intervention (PCI) at Zhongshan Hospital Fudan University from January 2008 to December 2018. Outcomes were in-hospital major adverse cardiovascular events (MACE: cardiac death, non-fatal acute myocardial infarction, re-vascularization and stroke), peak troponin T and NT-proBNP levels, left ventricular ejection fraction (LVEF) and hospitalization duration. RESULTS: Among 1165 patients, those with increased (≥0.8 mg/L, n = 224, 19.2%) vs. normal (n = 941, 80.8%) D-dimer level were older; more often women and non-smokers. Increased D-dimer group had similar frequency of AET (58.7% vs. 62.1%, P = .353), more frequently no-reflow phenomenon (13.1% vs. 18.8%, P = .028), higher peak values of troponin T (3.5 [0.9-7.0] vs. 4.5 [1.8-8.7], P = .001) and NT-proBNP (903.3 [532.3-2098.5] vs. 2070.0 [859.1-4378.0], p < .001). In increased D-dimer group, LVEF (53.3 ± 8.3 vs. 48.8 ± 9.8, P < .001) was lower, hospitalization was longer (8.0 ± 4.9 vs. 10.5 ± 6.9 days, P < .001) and risk of developing in-hospital MACE (1.5% vs. 12.1%, P < .001) was greater. D-dimer level was an independent risk factor for MACE (OR 8.408, 95%CI 4.065-17.392, P < .001), including the angiographically evident thrombus (OR 6.939, 95% CI 2.944-16.355, P < .001) and the no-reflow (OR 8.114, 95% CI 1.598-41.196, P = .012) subgroups. CONCLUSIONS: Increased D-dimer level was an independent risk factor for in-hospital MACE in STEMI patients undergoing primary PCI, including those with angiographically evident thrombus and no-reflow phenomenon. D-dimer was not associated to no-reflow phenomenon in STEMI patients.

Roles of Exosomes Derived From Immune Cells in Cardiovascular Diseases.

Therapies aimed at minimizing adverse remodeling in cardiovascular diseases on a molecular and cellular basis are urgently needed. Exosomes are nanosized lipid vesicles released from various cells that are able to mediate intercellular signaling and communication via their cargos. It has been increasingly demonstrated that exosomes from cardiomyocytes or stem/progenitor cells can promote cardiac repair and regeneration, but their mechanism has not been fully explained. Immune responses mediated by immune cells also play important and complicated roles in the progression of various cardiovascular diseases such as myocardial infarction and atherosclerosis. Exosomes derived from immune cells have shown pleiotropic effects on these pathological states, whether similar to or different from their parent cells. However, the underlying mechanism remains obscure. In this review, we first describe the biological characteristics and biogenesis of exosomes. Then we critically examine the emerging roles of exosomes in cardiovascular disease; the exosomes we focus on are derived from immune cells such as dendritic cells, macrophages, B cells, T cells, as well as neutrophils and mast cells. Among the cardiovascular diseases we discuss, we mainly focus on myocardial infarction and atherosclerosis. As active intercellular communicators, exosomes from immune cells may offer prospective diagnostic and therapeutic value in cardiovascular disease.

Dendritic cell exosome­shuttled miRNA146a regulates exosome­induced endothelial cell inflammation by inhibiting IRAK­1: A feedback control mechanism.

Activation of endothelial cells is the first step of atherosclerosis. The current authors have previously reported that exosomes from mature dendritic cells (mDC­exo) participate in endothelial inflammation and atherosclerosis through membrane tumor necrosis factor­α mediated the nuclear factor (NF)­κB signaling pathway. However, whether mDC­exo shuttled microRNAs (miRNAs/miRs) play a role in endothelial inflammation remains unknown. In this study, mDC­exo were co­cultured with human umbilical vein endothelial cells (HUVECs) and the expression of adhesion molecules, such as vascular cell adhesion molecule­1, intercellular adhesion molecule­1 and E­Selectin was investigated. Then the expression of miRNAs in DC­exo was explored and the role of miR­146a in endothelial inflammation was investigated. mDC­exos were first demonstrated to increase endothelial expression of adhesion molecules through a quick activation of the NF­κB signaling pathway. Then it was demonstrated that HUVECs resistant to a second stimulation after the first stimulation by mDC­exo. A set of miRNAs were targeted and their expression in HUVECs stimulated with mDC­exo was measured. Finally, it was confirmed that mDC­exo shuttles miR­146a into HUVECs and the shuttled miR­146a contributes to protect HUVECs from a second stimulation through inhibiting interleukin­1 receptor­associated kinase. These data suggest a negative feedback loop of inflammation regulation by DC­exo.

Effect of combined testing of ceramides with high-sensitive troponin T on the detection of acute coronary syndrome in patients with chest pain in China: a prospective observational study.

OBJECTIVE: Ceramides are associated with coronary plaque vulnerability. We aim to investigate the potential diagnostic value of ceramides for acute coronary syndrome (ACS) in Chinese patients with chest pain. DESIGN: Prospective observational survey. SETTING: Shanghai, China, 2016-2017. PARTICIPANTS: A total of 2773 patients with chest pain from four hospitals in Shanghai, China, between August 2016 and October 2017. MAIN OUTCOME MEASURES: Performance of metabolites model in detection of ACS cases including ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina. RESULTS: Plasma levels of 12 ceramide molecules and corresponding ratios were compared between patients diagnosed with ACS and those without. Cer(d18:1/24:1(15Z))/Cer(d18:1/24:0) ratio, Cer(d18:1/14:0) and Cer(d18:1/22:0) were independent predictors of ACS after adjustment of traditional risk factors and high-sensitivecardiac troponin T. Receiver operating characteristic curve analysis showed a significant improvement in detecting ACS in the multivariable model with ceramides compared with that without (0.865 (0.840 to 0.889) vs 0.808 (0.776 to 0.841), p<0.001). CONCLUSION: Distinct plasma ceramides are independent diagnostic predictors of ACS among patients with chest pain. Ceramides together with high-sensitive troponin and traditional factors showed great potential in identifying ACS among patients with chest pain.