Proteomic analysis of plasma proteins from patients with cardiac rupture after acute myocardial infarction using TMT-based quantitative proteomics approach.

BACKGROUND: Cardiac rupture (CR) is a rare but catastrophic mechanical complication of acute myocardial infarction (AMI) that seriously threatens human health. However, the reliable biomarkers for clinical diagnosis and the underlying signaling pathways insights of CR has yet to be elucidated. METHODS: In the present study, a quantitative approach with tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectrometry was used to characterize the differential protein expression profiles of patients with CR. Plasma samples were collected from patients with CR (n = 37), patients with AMI (n = 47), and healthy controls (n = 47). Candidate proteins were selected for validation by multiple reaction monitoring (MRM) and enzyme-linked immunosorbent assay (ELISA). RESULTS: In total, 1208 proteins were quantified and 958 differentially expressed proteins (DEPs) were identified. The difference in the expression levels of the DEPs was more noticeable between the CR and Con groups than between the AMI and Con groups. Bioinformatics analysis showed most of the DEPs to be involved in numerous crucial biological processes and signaling pathways, such as RNA transport, ribosome, proteasome, and protein processing in the endoplasmic reticulum, as well as necroptosis and leukocyte transendothelial migration, which might play essential roles in the complex pathological processes associated with CR. MRM analysis confirmed the accuracy of the proteomic analysis results. Four proteins i.e., C-reactive protein (CRP), heat shock protein beta-1 (HSPB1), vinculin (VINC) and growth/differentiation factor 15 (GDF15), were further validated via ELISA. By receiver operating characteristic (ROC) analysis, combinations of these four proteins distinguished CR patients from AMI patients with a high area under the curve (AUC) value (0.895, 95% CI, 0.802-0.988, p < 0.001). CONCLUSIONS: Our study highlights the value of comprehensive proteomic characterization for identifying plasma proteome changes in patients with CR. This pilot study could serve as a valid foundation and initiation point for elucidation of the mechanisms of CR, which might aid in identifying effective diagnostic biomarkers in the future.

A fluorescence-based immunochromatographic assay using quantum dot-encapsulated nanoparticles for the rapid and sensitive detection of fetuin-B.

Coronary artery disease (CAD) is the leading cause of death worldwide. Earlier detection of CAD improves treatment outcomes and secondary prevention. The circulating fetuin-B protein is considered to be a promising biomarker for the early detection of CAD. However, a facile and reliable clinical test for fetuin-B is still lacking. Herein, we describe a reliable fluorescent biosensor for detecting fetuin-B in plasma that combines quantum dots-doped polystyrene nanoparticles with an immunochromatographic assay strip (QNPs-ICAS). The QNPs served as detection signals in the QNPs-ICAS sensor system, which was based on a double-antibody sandwich structure. Under optimum experimental conditions, the biosensor exhibited a broad linear range of 1-200 ng mL-1 and a low detection limit of 0.299 ng mL-1. Furthermore, the proposed immunosensor demonstrated high sensitivity, satisfactory selectivity, good reproducibility, and excellent recovery. Finally, the performance and applicability of our QNPs-based ICAS system were validated in clinical samples using a commercial ELISA kit with excellent correlations (r = 0.98451, n = 116). To conclude, the proposed sensor served as a rapid, sensitive, and accurate method for detecting fetuin-B in actual clinical samples, thereby demonstrating its potential for preliminary CAD screening and diagnosis.

Prevalence of hepatitis B virus infection among pregnant women in the mountainous regions of southern China: A retrospective single-center study.

BACKGROUND: Hepatitis B virus (HBV) infection remains a major public health issue worldwide. Moreover, its prevalence varies significantly in different geographic areas of China. The current study aimed to assess the prevalence of HBV infection among Hakka pregnant women in Meizhou, a remote mountainous region in southern China. METHODS: This research was performed between January 2015 and December 2020. In total, 16,727 pregnant women receiving antenatal care at Meizhou People's Hospital were included in the analysis. All pregnant women were screened for serum HBV markers. RESULTS: The prevalence rates of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody positivity among the participants were 11.74% (n = 1964) and 48.00% (n = 8029), respectively. The overall prevalence rates of susceptibility to infection, HBV immunity, previous/occult infection, inactive HBsAg carrier, and active infection were 36.16%, 33.61%, 16.94%, 8.11%, and 2.30%, respectively. According to age distribution, the prevalence rate of HBsAg positivity elevated concomitantly with increasing age (p < 0.001). From 2015 to 2020, the prevalence rate of HBsAg positivity decreased from 14.50% to 8.19% and that of hepatitis B pre-core antigen positivity from 4.42% to 2.31%. In addition, pregnant women with HBsAg-positive status were more likely to present with gestational diabetes, thrombocytopenia, and anemia than those with HBsAg-negative status. CONCLUSION: The HBV infection rate remains high among pregnant women in the indigenous Hakka population in southern China. To prevent vertical transmission, cautious surveillance of maternal HBV infection status should be considered in Hakka pregnant women in Meizhou.

Association of serum laboratory parameters with periprocedural myocardial infarction after a primary percutaneous coronary intervention.

BACKGROUND: Periprocedural myocardial infarction (PMI) is one of the mortality-related complications of percutaneous coronary intervention (PCI) and significantly affects short- and long-term adverse outcomes and immediate cardiovascular events. Our present study aimed to evaluate the association of preprocedural serum laboratory parameters and PMI in patients who received primary PCI and attempted to provide detailed data on the predictors of PCI-related PMI. METHODS: A total of 1184 consecutive coronary artery disease (CAD) patients who received primary and elective PCI between July 2015 and June 2017 were included and divided into control group and PMI group. The data of serum laboratory parameters were collected from the electronic database of Meizhou People's Hospital. RESULTS: The results indicated that preprocedural fasting blood glucose were higher in PMI group compared with the control group (p < .001). Patients with prior hyperlipidemia were more likely to have experienced PCI-related PMI (p = .018) and the preprocedural level of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, apolipoprotein B (Apo B), and LDL-C/high density lipoprotein cholesterol (HDL-C) were significantly enhanced in PMI group (p < .001). Multivariate regression analysis revealed that preprocedural fasting blood glucose > 6.11 mmol/L (p < .001, OR = 1.949, 95% CI: 1.444-2.630) and LDL-C levels ≥130 mg/dL (p = .005, OR = 1.941, 95% CI: 1.217-3.098) independently predicted PCI-related PMI. CONCLUSION: Our results indicated preprocedural fasting blood glucose >6.11 mmol/L and LDL-C levels ≥130 mg/dL may be useful predictors for PCI-related PMI. The study may provide a detailed data on the predictors of PCI-related PMI.

Clinical study of factors associated with pregnancy outcomes in pregnant women with systemic lupus erythematosus in the southern China.

Objectives: This study aims to estimate predicted factors for maternal and fetal outcomes in Hakka pregnant women with systemic lupus erythematosus (SLE) in the southern China. Patients and methods: Between June 2014 and February 2020, we retrospectively analyzed the data of a total of 123 singleton pregnant women with SLE (mean age: 27.1±4.1 years; range, 19 to 39 years) who were referred to our rheumatology clinic. Demographic, clinical, and laboratory data of the patients were recorded. Adverse pregnancy outcomes (APOs) were assessed. Results: Multivariate logistic regression analysis revealed that preeclampsia was associated with the increased odds of APOs (odds ratios [OR]=9.538, 95% confidence interval [CI]: 2.055-44.271, p=0.004), premature birth (OR=14.289, 95% CI: 3.596-56.777, p<0.001) and low birth weight (OR=8.275, 95% CI: 2.117-32.345, p=0.002). Anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody positivity was the predictor of APOs (OR=2.165, 95% CI: 1.034-4.532, p=0.040), premature birth (OR=2.849, 95% CI: 1.220-6.657, p=0.016) and pregnancy loss (OR=3.004, 95% CI: 1.086-8.305, p=0.034). The use of hydroxychloroquine and prednisone was associated with the decreased odds of APOs (OR=0.412, 95% CI: 0.198-0.860, p=0.018) and pregnancy loss (OR=0.304, 95% CI: 0.111-0.831, p=0.020). Conclusion: Our study results indicate that preeclampsia, anti-dsDNA antibody positivity, and the use of hydroxychloroquine and prednisone are independent predictors of pregnancy outcomes.

Plasma Proteome Profiling of Patients With In-stent Restenosis by Tandem Mass Tag-Based Quantitative Proteomics Approach.

Background: Despite the widespread application of new drug-eluting stents, a considerable portion of patients experience in-stent restenosis (ISR). To date, the pathophysiologic mechanisms of ISR remain poorly understood. Methods: In this study, we collected plasma samples from ISR patients (n = 29) and non-ISR patients (n = 36) after drug-eluting stent implantation, as well as from healthy controls (HCs) (n = 32). Our goal was to investigate differences in plasma protein profiles using tandem mass tag (TMT) labeling coupled with liquid chromatography and tandem mass spectrometry. The proteomic data were validated by enzyme-linked immunosorbent assay (ELISA). Bioinformatic analyses were conducted to analyze potential pathways and protein-protein interaction (PPI) involved in ISR. Results: A total of 1,696 proteins were identified, of which 278 differed in protein abundance between non-ISR and HCs, 497 between ISR and HCs, and 387 between ISR and non-ISR, respectively. Bioinformatic analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and PPI, further demonstrated that differentially abundant proteins between ISR and non-ISR are involved in several crucial biological processes and signaling pathways, such as focal adhesion, platelet activation, Rap1 signaling, regulation of actin cytoskeleton, and cholesterol metabolism. Among the identified differentially abundant proteins in ISR, 170 were increased in abundance relative to both non-ISR patients and HCs. Some of these proteins were identified to have critical functions for atherosclerosis development and might be involved in ISR pathology. Among these proteins, 3 proteins with increased abundance including fetuin-B, apolipoprotein C-III (APOC3), and cholesteryl ester transfer protein (CETP) were confirmed by ELISA. Conclusions: This is the first study provided a comprehensive proteomic profile to understand ISR pathology, which may help identify early diagnostic biomarkers and therapeutic targets.

MicroRNA-146a-5p alleviates lipopolysaccharide-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production via the regulation of TRAF6 and IRAK1 in human umbilical vein endothelial cells (HUVECs).

BACKGROUND: Microribonucleic acids (miRNAs) have an evident role in regulating endothelial inflammation and dysfunction, which characterizes the early stages of atherosclerosis. The NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been reported to contribute to the endothelial inflammatory response that promotes atherosclerosis development and progression. This study sought to investigate the effects of miR-146a-5p on lipopolysaccharide (LPS)-induced NLRP3 inflammasome injury and pro-inflammatory cytokine production in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were transfected with a miR-146a-5p mimic, small-interfering RNA (siRNA) (si-TRAF6, and si-IRAK1), and were then stimulated with LPS for 24 h. The messenger (mRNA) and the protein levels of p-NF-κB/NF-κB, NLRP3, Caspase-1, pro-inflammatory cytokine [interleukin (IL)-6, IL-1ß and tumor necrosis factor alpha (TNF-α)] in the HUVECs were analyzed by quantitative real-time polymerase chain reactions (PCRs) and western blot assays, respectively. The secretion of IL-6 from the cells was detected by enzyme-linked immunoassay (ELISA). Bioinformatic and dual-luciferase reporter assays were performed to identify the targets of miR-146a-5p. RESULTS: LPS promoted pro-inflammatory cytokine expression in a dose-dependent manner and significantly increased the expression levels of p-NF-κB/NF-κB p65, NLRP3, and Caspase-1. After transfection with a miR-146a-5p mimic, or si-TRAF6 or si-IRAK1, we observed that the mRNA and protein levels of NF-κB/p-NF-κB, NLRP3, Caspase-1, and pro-inflammatory cytokine in the HUVECs were all down-regulated, and the secretion of IL-6 from cells declined significantly. After transfection with a miR-146-5p mimic, the expression of TRAF6 and IRAK1 in HUVECs were both down-regulated. Dual-luciferase reporter assays confirmed that miR-146-5p directly targets the 3'-untranslated region (3'-UTR) of TRAF6 and IRAK1 to regulate their expression. CONCLUSIONS: As a modulator of TRAF6 and IRAK1, miR-146a-5p negatively regulated LPS-induced NF-κB activation and the NLRP3 inflammasome signaling pathway in HUVECs. Thus, miRNA-146a-5p may serve as a potential therapeutic target for atherosclerosis.

Association between the APOE gene polymorphism and lipid profile and the risk of atrial fibrillation.

BACKGROUND: The relationship between the APOE gene polymorphism and lipid profiles and atrial fibrillation (AF) remains controversial. The current study purposed to investigate how the APOE gene SNPs (rs429358 and rs7412) and lipid profile are associated with the risk for AF among the Hakka population in southern China. METHODS: Finally, 1367 patients were enrolled in this study, including 706 participants with AF (41 ~ 98 years old, 58.64 % male) and 661 non-AF subjects (28 ~ 95 years old, 59.46 % male). The collected data included baseline characteristics, medical history, laboratory tests and echocardiography parameters. A general linear model (two-way analysis of variance (ANOVA)) and Tukey post-hoc tests were applied to identify an APOE allele, AF group, and interaction effect on lipid profiles. Logistic regression analysis was performed to identify risk factors for AF. RESULTS: For AF group, the most common genotype was E3/E3 (53.82 %), followed by E3/E4 (28.19 %), E2/E3 (13.60 %), E4/E4 (1.98 %), E2/E4 (1.84 %) and E2/E2 (0.57 %). The two-way ANOVA followed by the Tukey procedure showed the following: the lipid levels depended significantly on AF and APOE allele groups for TG, TC, LDL-C and Apo-B (all P < 0.001), and statistically significant interactions between AF and APOE allele were observed in the above 4 variables (all P < 0.05). Multivariate regression analysis indicated that age ≥ 65years (P < 0.001), high diastolic blood pressure (DBP ≥ 90mm Hg, P = 0.018), a high levels of total cholesterol (TC ≥ 5.2mmol/L, P < 0.001) and triglyceride (TG ≥ 1.7mmol/L, P = 0.028), but not the two SNPs of the APOE gene (rs7412 and rs429358) (OR 1.079, P = 0.683), were significant independent risk factors for AF in the study population. CONCLUSIONS: The principal findings of this study showed that individuals at high risk for AF were those over 65 years of age, higher DBP as well as high levels of TC and TG among the southern China Hakka population. The levels of TG, TC, LDL-C and Apo-B depended significantly on AF and APOE allele groups, and statistically significant interactions between AF and APOE allele were observed in the above 4 variables, although the APOE gene SNPs (rs429358 and rs7412) were no significant risk for AF incidence. Further investigation is needed to elucidate whether other SNPs of the APOE gene have a bearing on AF incidents.

Plasma Metabolomics of Acute Coronary Syndrome Patients Based on Untargeted Liquid Chromatography-Mass Spectrometry.

Background: Acute coronary syndrome (ACS) is the main cause of death and morbidity worldwide. The present study aims to investigate the altered metabolites in plasma from patients with ACS and sought to identify metabolic biomarkers for ACS. Methods: The plasma metabolomics profiles of 284 ACS patients and 130 controls were carried out based on an untargeted liquid chromatography coupled with tandem mass spectrometry (LC-MS) approach. Multivariate statistical methods, pathway enrichment analysis, and univariate receiver operating characteristic (ROC) curve analysis were performed. Results: A total of 328 and 194 features were determined in positive and negative electrospray ionization mode in the LC-MS analysis, respectively. Twenty-eight metabolites were found to be differentially expressed, in ACS patients relative to controls (p < 0.05). Pathway analysis revealed that these metabolites are mainly involved in synthesis and degradation of ketone bodies, phenylalanine metabolism, and arginine and proline metabolism. Furthermore, a diagnostic model was constructed based on the metabolites identified and the areas under the curve (AUC) for 5-oxo-D-proline, creatinine, phosphatidylethanolamine lyso 16:0, and LPC (20:4) range from 0.764 to 0.844. The higher AUC value of 0.905 was obtained for the combined detection of phosphatidylethanolamine lyso 16:0 and LPC (20:4). Conclusions: Differential metabolic profiles may be useful for the effective diagnosis of ACS and may provide additional insight into the molecular mechanisms underlying ACS.

Diagnostic values of MMP-7, MMP-9, MMP-11, TIMP-1, TIMP-2, CEA, and CA19-9 in patients with colorectal cancer.

OBJECTIVE: Colorectal cancer (CRC) is one of the most common and lethal malignancies. The identification of precise and noninvasive biomarkers is urgently needed to aid the early diagnosis and clinical management of CRC. METHODS: A total of 112 patients with CRC and 115 healthy control subjects were included in this study. Serum levels of matrix metalloproteinase (MMP)-7, MMP-9, MMP-11, tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 were analyzed by enzyme-linked immunosorbent assay, and carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 levels were measured using an automatic immunoassay analyzer. RESULTS: MMP-7, MMP-9, MMP-11, TIMP-1, TIMP-2, CEA, and CA19-9 levels were all significantly higher in CRC patients compared with healthy controls. MMP-7, TIMP-1, and CEA levels were also closely related to clinicopathologic features in patients with CRC. The combination of serum CEA, MMP-7, and TIMP-1 significantly improved the diagnostic value compared with any single marker (area under the curve 0.858-0.890). Furthermore, a combined detection model including MMP-7, TIMP-1, and CEA improved both the specificity and sensitivity for detecting CRC. CONCLUSIONS: The results showed that combined detection of CEA, MMP-7, and TIMP-1 in serum could provide a specific and sensitive biomarker for the diagnosis of CRC.

Long non-coding RNA expression profiles in peripheral blood mononuclear cells of patients with coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a leading cause of death and often presents as a complex systemic disease. The aim of the presents study was to determine the expression profiles of long non-coding RNAs (lncRNAs) in peripheral blood mononuclear cells (PBMC) of CAD patients and controls. METHODS: The lncRNA expression profiling of PBMC obtained from 40 CAD patients and 10 non-obstructive coronary atherosclerosis (NOCA) subjects were analyzed using the Illumina Hiseq 4000 sequencer. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the differentially expressed lncRNAs. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of mRNA were conducted to predict biologic functions. RESULTS: Our results indicated that lncRNAs were differentially expressed; 83 were upregulated lncRNAs and 114 were downregulated lncRNAs (P<0.05). A horizontal comparison of lncRNA expression indicated that the change in the expression profile of 48 lncRNAs was consistent with the degree of CAD. Six lncRNAs were validated using qRT-PCR, confirming the accuracy of the RNA sequencing analysis. GO analysis indicated that these dysregulated lncRNA transcripts were related to chromatin organization, cell and cell part, and protein heterodimerization activity. Pathway analysis indicated that these differentially expressed genes mainly included viral carcinogenesis, systemic lupus erythematosus and alcoholism. CONCLUSIONS: Our preliminary findings indicate that lncRNAs could be used as potential biomarkers of subclinical cardiac abnormalities in the PBMC of CAD patients. However, further studies are needed to verify our findings and hypothesis.

Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms.

BACKGROUND: Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to chemotherapy-related adverse events. In the present study, we purposed to assess the impact of DPYD and GSTP1 variants on the toxicity of adjuvant chemotherapy risk among the Hakka population, minimize adverse events, and to maximize therapy outcome for individualized treatment. METHODS: Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drug-based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A, and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed. RESULTS: The data suggest that the incidence of DPYD*5A, DPYD*9A, and GSTP1 c.313A>G variants were 38.4%, 24%, and 32.7%, respectively. DPYD*2A variant was not found. A total of 23 patients (22.1%) suffered severe vomiting and 19 patients (18.3%) suffered severe anemia. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe vomiting and skin ulceration (p = 0.042 and p = 0.018, respectively). Patients with GSTP1 c. 313A>G mutant type contributed to a higher risk for grade severe toxicity compared with wild genotype (p = 0.027). Nevertheless, no significant difference was found between patients with DPYD*2A, *5A, and *9A for chemotherapeutic toxicity. CONCLUSIONS: The results demonstrated that GSTP1 polymorphisms were useful predictors of severe events. Screening of single-nucleotide polymorphisms of GSTP1 in colorectal cancer patients before chemotherapy may help to realize personalized therapy.

Association between apolipoprotein E gene polymorphism and the risk of coronary artery disease in Hakka postmenopausal women in southern China.

BACKGROUND: Apolipoprotein E (APOE) is involved in the pathogenesis of atherosclerosis and conveys a higher risk of coronary artery disease (CAD). The aim of the present study was to investigate the possible association between APOE gene polymorphism and the risk of CAD in postmenopausal Hakka women in southern China. METHODS: The APOE genotypes of 653 CAD patients and 646 control participants were determined by the polymerase chain reaction (PCR) and hybridization to a Sinochip. RESULTS: The prevalence of each APOE genotype differed between CAD patients and control participants (P = 0.011). The E3/E3 genotype was the most common and the E2/E2 genotype was the least common in the study sample. Moreover, the presence of ε4 allele was associated with higher serum concentrations of triglycerides (TG), total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C), and lower concentration of high-density lipoprotein-cholesterol (HDL-C). Multiple logistic regression analysis revealed that participants with ε4 allele have a significantly higher risk of CAD after adjustment for the presence of diabetes mellitus and hypertension, and their serum uric acid, TC, and LDL-C concentrations (adjusted odds ratio (OR) 1.50, 95% confidence interval (CI) 1.10-2.05, P = 0.010). CONCLUSIONS: The present results suggest that APOE polymorphism is associated with a higher risk of CAD in postmenopausal Hakka women in southern China.

The role of MTHFR C677T and ALDH2 Glu504Lys polymorphism in acute coronary syndrome in a Hakka population in southern China.

BACKGROUND: Acute coronary syndrome (ACS) is the most serious type of coronary heart disease and is a global medical burden. The pathogenesis of ACS is very complex and still poorly understood. Epidemiologic studies have revealed that the manifestation of ACS are the results of the interactions between multiple environmental and genetic factors. The present study aimed to investigate the role of polymorphisms of MTHFR C677T and ALDH2 Glu504Lys as risk factors for ACS in a Hakka population in southern China. METHODS: Between September 1, 2015 and October 31, 2017, a total of 1957 individuals, including 860 ACS patients and 1097 controls were recruited. Blood samples were collected and genotypes were determined by DNA microarray chip method and direct sequencing method. RESULTS: For the MTHFR C677T polymorphism, frequencies of CC, CT, and TT genotypes were 53.60% versus 55.33, 39.53% versus 38.65 and 6.86% versus 6.02% in patients with ACS versus controls, respectively(p > 0.05). The differences in genotype frequencies between the ACS patients and controls in the three genetic model were not statistically significant. For the ALDH2 Glu504Lys polymorphism, the frequencies of ALDH2*1*1, ALDH2*1*2, and ALDH2*2*2 genotypes were 48.72, 42.67 and 8.6% in the ACS patients, respectively, while these were 53.33, 39.11 and 7.57% in the controls, respectively, showing no significant difference in the distribution of the ALDH2 genotype between the groups. Using the wild genotype ALDH2*1*1 as reference, relative risk analysis revealed a slightly increased risk for ACS in individuals with the ALDH2*1*2 plus ALDH2*2*2 genotypes (odds ratio (OR) = 1.203, 95% confidence interval (CI) = 1.006-1.438, p = 0.043). In a multivariate logistic regression model, even after adjusting for potential covariates, the association between ALDH2 *2 allele and ACS remained significant (OR = 1.242, 95% CI = 1.045-1.561, p = 0.038). CONCLUSIONS: We present findings regarding the possible clinical impact of the ALDH2*2 variant on ACS patients in a Hakka population in southern China and our findings might help to stratify the high-risk ACS patients and implement appropriate strategies for this genetic subpopulation to ultimately guide the precision preventive procedures in the future.

Association Between the Polymorphism of Aldehyde Dehydrogenase 2 Gene and Cerebral Infarction in a Hakka Population in Southern China.

Genetic factors play an important role in determining the susceptibility to ischemic stroke. Herein, we examined the association of an aldehyde dehydrogenase 2 (ALDH2) gene polymorphism with cerebral infarction. Patients with cerebral infarction (n = 963) and healthy controls (n = 921) were included. Genotyping was performed using gene chip platform analysis, and Sanger sequencing was used to confirm ALDH2 genotypes. The risk prediction of ALDH2 polymorphisms for cerebral infarction was examined under three genetic modes of inheritance. For males, ALDH2*2/*2 genotype was a significant risk factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 1.514, 95% CI 1.005-2.282, p = 0.047) and the recessive model (age-, smoking-, and drinking-adjusted OR 1.601, 95% CI 1.078-2.379, p = 0.020). However, for females, ALDH2*2/*2 genotype was a protective factor for cerebral infarction in the co-dominant model (age-, smoking-, and drinking-adjusted OR 0.450 95% CI 0.215-0.941, p = 0.034) and the recessive model (age-, smoking-, and drinking-adjusted OR 0.440, 95% CI 0.214-0.903, p = 0.025). Further, logistic regression analysis revealed that age, smoking, hypertension, hyperlipidemia, and hypercholesterolemia were significant risks for the presence of cerebral infarction. In conclusion, these findings support an association of ALDH2 gene polymorphisms with ischemic stroke in a Chinese Hakka population. In particular, homozygote ALDH2*2/*2 may be a risk factor for cerebral infarction in males, but contribute to reduced risk for cerebral infarction in females.

NLRP3 inflammasomes in macrophages drive colorectal cancer metastasis to the liver.

Inflammation and immunity are important determinants of cancer initiation, promotion, and progression to cancer equilibrium or suppression. The NOD-like receptor family pyrin domain containing 3 (NLRP3) is an oligomeric intracellular immune receptor, and the main component of inflammasome. As a widely distributed effector of innate immunity, NLRP3 inflammasome affects development of many cancer types, but its exact role in colorectal cancer (CRC) is controversial. We found that cells with the macrophage (MΦ) marker CD68 and strong NLRP3 expression densely surrounded CRC tissue. The NLRP3 inflammasome was activated in MΦs by MΦ-CRC cell crosstalk; it resulted in faster migration of CRC cells, whereas blocking NLRP3 signaling suppressed CRC cell migration in vitro, and metastatic ability in vivo. NLRP3 signaling activation in MΦs can contribute to CRC cell migration and invasion.

Dexmedetomidine Attenuates Acute Lung Injury Induced by Heatstroke and Improve Outcome.

INTRODUCTION: Dexmedetomidine (DEX) has been demonstrated to inhibit inflammatory response and protect against multiorgan injury in various scenarios. The objectives of the present study were to ascertain whether DEX is able to attenuate acute lung injury (ALI) under heatstroke (HS), and to explore the underlying mechanism. METHODS: Male C57BL/6 mice were exposed to ambient temperature of 39.5 ±â€Š0.2°C until core temperature reach 43°C. DEX or 0.9% saline was injected i.p. immediately. At the end of the experiment, bronchoalveolar lavage fluid (BALF) and lung tissue were harvested. RESULTS: HS induce ALI and pulmonary dysfunction, while DEX treatment could significantly inhibit lung injury and improve respiratory dysfunction under HS. The overall effect was beneficial and improved the 72 h cumulative survival rate of mice with HS. Furthermore, HS significantly elevated the levels of cytokines in BALF, as well as increased the activity of toll-like receptor 4 (TLR4)/MyD88/nuclear factor-κB (NFκB) signaling pathway in lung tissue, while DEX treatment could inhibit such effects. Finally, DEX could upregulate the expression of caveolin 1 downregulated by HS, which may contribute to the inhibition of TLR4/MyD88/NFκB signaling pathway. DISCUSSION: In conclusion, the present results indicated that DEX may protect against lung inflammatory response and injury under HS via TLR4/MyD88/NFκB signaling pathway, and caveolin-1 may participate in the effects.

Measurement of urinary matrix metalloproteinase-7 for early diagnosis of acute kidney injury based on an ultrasensitive immunomagnetic microparticle-based time-resolved fluoroimmunoassay.

The morbidity and mortality associated with acute kidney injury (AKI) remain obstinately high. Early diagnosis is urgently required and should be pursued in at-risk populations. Recently, a newly validated biomarker, matrix metalloproteinase-7 (MMP-7), was reported as a novel indicator for early AKI prediction and a noninvasive surrogate biomarker of kidney function. Monitoring urinary MMP-7 (uMMP-7) levels fills the gaps in early diagnosis of AKI at early onset. However, the lack of available reagents for its rapid detection limits its use. Herein, we established an ultrasensitive and rapid immunomagnetic microparticles-based time-resolved fluoroimmunoassay to measure urinary MMP-7 in AKI patients. The assay time is 30 min. The calibration curve showed high linear correlation (r = 0.9998) with a linearity of detection of 0.063-150 ng mL-1 and lower limit of detection of 0.039 ng mL-1. The coefficient variation of the intra- and inter-assay lower than 5.17%, and the analytical recovery was 99.06%-105.60%. Testing of clinical samples using the proposed assay and a DUOSET@ ELISA kit showed good correlations in the comparison of uMMP-7 levels (r = 0.9541) and uMMP-7/uCreatinine (r = 0.9595). The proposed assay has satisfactory analytical performance and may serve as a promising tool for early diagnosis of AKI.

Translationally controlled tumor protein affects colorectal cancer metastasis through the high mobility group box 1-dependent pathway.

Recently, accumulating evidence from clinical and experimental researches have suggested that translationally controlled tumor protein (TCTP) and high mobility group box 1 (HMGB1) are implicated in colorectal cancer (CRC) metastasis. However, whether there is an interconnection between these two tumor-promoting proteins and how they affect CRC metastasis remain to be fully elucidated. In the present study, the expression level of TCTP in CRC tissues was assessed by immunohistochemical staining and immunoblotting, and the serum concentration of HMGB1 in patients with CRC was detected by enzyme-linked immunosorbent assay. In vitro, following the modulation of TCTP expression in colon cancer LoVo cells, the translocation behavior of HMGB1 was observed by immunofluorescence assay. Furthermore, the activity of nuclear factor-κB (NF-κB) in LoVo cells was evaluated by immunoblotting and luciferase assay, and the invasion ability of LoVo cells after different treatments was determined using cell invasion assay. In vivo, xenograft tumor model was established and the correlation of TCTP and HMGB1 expression in xenografted tumors was studied by immunohistochemical examination. The results revealed that the expression level of TCTP in CRC tissue and the serum concentration of HMGB1 in patients with CRC were significantly increased, and there was a strong positive correlation between them. In vitro experiments showed that the overexpression of TCTP on LoVo cells resulted in the release of HMGB1 from the nucleus to the cytoplasm and into the extracellular space. In addition, the overexpression of TCTP led to the activation of NF-κB in LoVo cells, and this effect was reversed by treatment with antibodies targeting HMGB1 or to its receptors Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products advanced glycation end products (RAGE). Furthermore, inhibition of the HMGB1-TLR4/RAGE-NF-κB pathway significantly inhibited the TCTP-stimulated invasion of LoVo cells. In vivo experiments demonstrated that the overexpression of TCTP in nude mice promoted the development and spread of xenografted tumors, and concurrently enhanced the expression of HMGB1 in tumor tissues. Collectively, these findings suggested that TCTP promotes CRC metastasis through regulating the behaviors of HMGB1 and the downstream activation of the NF-κB signaling pathway.

Oncogene mutational analysis in Chinese gastrointestinal stromal tumor patients.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors and exhibit a high frequency of oncogenic KIT or PDGFRA mutations. Tyrosine kinase inhibitors (TKIs) have been mainly used in the treatment of GISTs bearing KIT/PDGFRA mutations. However, other mutation profiles have been found to affect the sensitivity to and effectiveness of TKIs in the treatment of GISTs. PURPOSE: The aim of the present study was to describe the mutational status of multiple genes in GIST samples and to provide information for finding potential predictive markers of therapeutic targets in Chinese GIST patients. PATIENTS AND METHODS: MassARRAY spectrometry was used to test 40 Chinese GIST patients for 238 mutations affecting 19 oncogenes. RESULTS: A total of 14 oncogenes with 43 mutations were detected in 38 samples, with a mutation frequency of 95%. Among these mutation samples, 26 GISTs were found for KIT or PDGFRA mutations, while 12 were KIT/PDGFRA wild-type. Approximately half of the GIST samples harbored multiple mutations. The most frequent mutations were found in KIT (62.5%), CDK4 (17.5%), NRAS (15%) and EGFR (12.5%). Other mutations included PIK3CA and AKT1 (10%), BRAF and ABL1 (7.5%), PDGFRA, ERBB2 and HRAS (5%), and AKT2, FLT3 and KRAS (2.5%). New mutated genes (CDK4, AKT2, FLT3, ERBB2, ABL1 and AKT1), a higher BRAF mutation frequency (7.5%) and new BRAF mutation sites (G464E) were found in Chinese GIST patients. CONCLUSION: This study demonstrated useful mutations in a small fraction of Chinese GIST, but targeted therapeutics on these potential predictive markers need to be investigated in depth especially in Oriental populations.