Plasma S100A12 Research Articles

Human Plasma Transcriptome Implicates Dysregulated S100A12 Expression: A Strong, Early-Stage Prognostic Factor in ST-Segment Elevated Myocardial Infarction: Bioinformatics Analysis and Experimental Verification.

The ability of blood transcriptome analysis to identify dysregulated pathways and outcome-related genes following myocardial infarction remains unknown. Two gene expression datasets (GSE60993 and GSE61144) were downloaded from Gene Expression Omnibus (GEO) Datasets to identify altered plasma transcriptomes in patients with ST-segment elevated myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. GEO2R, Gene Ontology/Kyoto Encyclopedia of Genes and Genomes annotations, protein–protein interaction analysis, etc., were adopted to determine functional roles and regulatory networks of differentially expressed genes (DEGs). Dysregulated expressomes were verified at transcriptional and translational levels by analyzing the GSE49925 dataset and our own samples, respectively. A total of 91 DEGs were identified in the discovery phase, consisting of 15 downregulated genes and 76 upregulated genes. Two hub modules consisting of 12 hub genes were identified. In the verification phase, six of the 12 hub genes exhibited the same variation patterns at the transcriptional level in the GSE49925 dataset. Among them, S100A12 was shown to have the best discriminative performance for predicting in-hospital mortality and to be the only independent predictor of death during follow-up. Validation of 223 samples from our center showed that S100A12 protein level in plasma was significantly lower among patients who survived to discharge, but it was not an independent predictor of survival to discharge or recurrent major adverse cardiovascular events after discharge. In conclusion, the dysregulated expression of plasma S100A12 at the transcriptional level is a robust early prognostic factor in patients with STEMI, while the discrimination power of the protein level in plasma needs to be further verified by large-scale, prospective, international, multicenter studies.

Increased Production of Interleukin-10 and Tumor Necrosis Factor-Alpha in Stimulated Peripheral Blood Mononuclear Cells after Inhibition of S100A12.

Sepsis may induce immunosuppression and result in death. S100A12 can bind to the receptor for advanced glycation end-products (RAGE) and Toll-like receptor (TLR)4 following induction of various inflammatory responses. It is unclear whether S100A12 significantly influences the immune system, which may be associated with sepsis-related mortality. We measured plasma S100A12 levels and cytokine responses (mean ± standard error mean) of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) after S100A12 inhibition in healthy controls and patients with sepsis on days one and seven. Day one plasma soluble RAGE (sRAGE) and S100A12 levels in patients with sepsis were significantly higher than those in controls (2481.3 ± 295.0 vs. 1273.0 ± 108.2 pg/mL, p < 0.001; 530.3 ± 18.2 vs. 310.1 ± 28.1 pg/mL, p < 0.001, respectively). Day seven plasma S100A12 levels in non-survivors were significantly higher than those in survivors (593.1 ± 12.7 vs. 499.3 ± 23.8 pg/mL, p = 0.002, respectively). In survivors, plasma sRAGE levels were significantly decreased after 6 days (2297.3 ± 320.3 vs. 1530.1 ± 219.1 pg/mL, p = 0.009, respectively), but not in non-survivors. Inhibiting S100A12 increased the production of tumor necrosis factor (TNF)-α and interleukin (IL)-10 in stimulated PBMCs for both controls and patients. Therefore, S100A12 plays an important role in sepsis pathogenesis. S100A12 may competitively bind to TLR4 and RAGE, resulting in decreased IL-10 and TNF-α production.

Utility of S100A12 as an Early Biomarker in Patients With ST-Segment Elevation Myocardial Infarction.

Importance: S100A12 is a calcium binding protein which is involved in inflammation and progression of atherosclerosis.Objective: We sought to investigate the utility of S100A12 as a biomarker for the early diagnosis and prognostication of patients presenting with ST-segment elevation myocardial infarction (STEMI).Design, Setting, and Participants: S100A12 was measured in 1023 patients presenting to the emergency department with acute chest pain between June 2012 and November 2015. An independent cohort of 398 patients enrolled at 3 different hospitals served as a validation cohort.Main Outcomes and Measures: The primary clinical endpoint of interest was major adverse cardiac and cerebral events (MACCE) defined as a composite of all-cause death, MI, stroke, or hospitalization for heart failure.Results: A total of 438/1023 patients (42.8%) in the diagnosis cohort were adjudicated as STEMI, among whom plasma S100A12 levels increased within 30 min and peaked 1–2 h after symptom onset. Compared with high-sensitivity cardiac troponin T and creatine kinase-MB isoenzyme, S100A12 more accurately identified STEMI, especially within the first 2 h after symptom onset (area under the curve 0.963 compared with 0.860 for hscTnT and 0.711 for CK-MB, both P < 0.05). These results were consistent in the 243-patient validation cohort. The 1-year rate of MACCE was greatest in patients in the highest peak S100A12 tertile, intermediate in the middle tertile and least in the lowest tertile (9.3 vs. 5.7 vs. 3.0% respectively, Ptrend = 0.0006). By multivariable analysis the peak plasma concentration of S100A12 was an independent predictor of MACCE within 1 year after STEMI (HR, 1.001, 95%CI, 1.000–1.002; P = 0.0104).Conclusions and Relevance: S100A12 rapidly identified patients with STEMI, more accurately than other cardiac biomarkers, especially within the first 2 h after symptom onset. The peak plasma S100A12 level was a strong predictor of 1-year prognosis after STEMI.

A Specific Blood Signature Reveals Higher Levels of S100A12: A Potential Bladder Cancer Diagnostic Biomarker Along With Urinary Engrailed-2 Protein Detection.

Urothelial carcinoma of the urinary bladder (UCB) or bladder cancer remains a major health problem with high morbidity and mortality rates, especially in the western world. UCB is also associated with the highest cost per patient. In recent years numerous markers have been evaluated for suitability in UCB detection and surveillance. However, to date none of these markers can replace or even reduce the use of routine tools (cytology and cystoscopy). Our current study described UCB's extensive expression profile and highlighted the variations with normal bladder tissue. Our data revealed that JUP, PTGDR, KLRF1, MT-TC, and RNU6-135P are associated with prognosis in patients with UCB. The microarray expression data identified also S100A12, S100A8, and NAMPT as potential UCB biomarkers. Pathway analysis revealed that natural killer cell mediated cytotoxicity is the most involved pathway. Our analysis showed that S100A12 protein may be useful as a biomarker for early UCB detection. Plasma S100A12 has been observed in patients with UCB with an overall sensitivity of 90.5% and a specificity of 75%. S100A12 is highly expressed preferably in high-grade and high-stage UCB. Furthermore, using a panel of more than hundred urine samples, a prototype lateral flow test for the transcription factor Engrailed-2 (EN2) also showed reasonable sensitivity (85%) and specificity (71%). Such findings provide confidence to further improve and refine the EN2 rapid test for use in clinical practice. In conclusion, S100A12 and EN2 have shown potential value as biomarker candidates for UCB patients. These results can speed up the discovery of biomarkers, improving diagnostic accuracy and may help the management of UCB.

Comparison of pressure- and volume-controlled ventilation during laparoscopic colectomy in patients with colorectal cancer

This study investigated the differences in airway mechanics and postoperative respiratory complications using two mechanical ventilation modalities and the relationship between biomarkers and postoperative respiratory complications in patients with colorectal cancer who underwent laparoscopic colectomy. Forty-six patients with colorectal cancer scheduled for laparoscopic colectomy were randomly allocated to receive mechanical ventilation using either volume-controlled ventilation (VCV) (n = 23) or pressure-controlled ventilation (PCV) (n = 23). Respiratory parameters were measured and plasma sRAGE and S100A12 were collected 20 minutes after the induction of anesthesia in the supine position without pneumoperitoneum (T1), 40 minutes after 30° Trendelenburg position with pneumoperitoneum (T2), at skin closure in the supine position (T3), and 24 hours after the operation (T4). The peak airway pressure (Ppeak) at T2 was lower in the PCV group than in the VCV group. The plateau airway pressures (Pplat) at T2 and T3 were higher in the VCV group than in the PCV group. Plasma levels of sRAGE at T2 and T3 were 1.6- and 1.4-fold higher in the VCV group than in the PCV group, while plasma S100A12 levels were 2.6- and 2.2-fold higher in the VCV group than in the PCV group, respectively. There were significant correlations between Ppeak and sRAGE, and between Ppeak and S100A12. There were also correlations between Pplat and sRAGE, and between Pplat and S100A12. sRAGE and S100A12 levels at T2 and T3 showed high sensitivity and specificity for postoperative respiratory complications. Postoperative respiratory complications were 3-fold higher in the VCV group than in the PCV group. In conclusion, during laparoscopic colectomy in patients with colorectal cancer, the peak airway pressure, the incidence of postoperative respiratory complications, and plasma sRAGE and S100A12 levels were lower in the PCV group than in the VCV group. Intra- and postoperative plasma sRAGE and S100A12 were useful for predicting the development of postoperative respiratory complications.

The Relationship between Plasma Soluble Receptor for Advanced Glycation End Products and Coronary Artery Disease.

Background Inflammation is involved in the development and progression of coronary artery disease (CAD). The role of the receptor for advanced glycation end products (RAGE) in the development of CAD has been recognized. The expression of sRAGE and S100A12 in patients with coronary artery disease from different studies was inconsistent. We attempted to determine the expression of sRAGE and S100A12 and their relationship in the subjects with different severity levels of CAD. Methods A total of 259 patients undergoing coronary angiography were enrolled from the Department of Geriatric Cardiology in the First Affiliated Hospital of Nanjing Medical University from January 2014 to December 2016. Groups were divided as follows: normal coronary artery (control group), nonobstructive coronary atherosclerosis (<50% stenosis in all coronary vessels, NOCA group), stable angina (SAP group), and acute coronary syndrome (ACS group). During CAG or PCI, peripheral arterial blood was collected from all the patients. Plasma sRAGE and S100A12 levels were measured by ELISA. We calculated the SYNTAX score of each patient with CAD according to the result of CAG. Results The levels of sRAGE were significantly elevated in the ACS group compared with those in the control group, the NOCA group, and the SAP group. sRAGE levels were similar among the control group, the NOCA group, and the SAP group. Plasma S100A12 levels were significantly higher in the ACS group than in the control group and the NOCA group. Baseline correlations between plasma levels of sRAGE and plasma S100A12 in the ACS group were significant. Plasma sRAGE concentration was increasing in patients with ACS and was significantly positively correlated with the increasing SYNTAX score. ROC curve analysis revealed that the combination of sRAGE and S100A12 had a good performance in the prediction of high-risk CAD patients. Conclusion The plasma levels of sRAGE and S100A12 can be increased in patients with ACS. The elevated sRAGE concentration may be independently associated with the severity of CAD and the inflammatory process. sRAGE combined with S100A12 may be used as a predictor of severe coronary heart disease.

Increased Plasma Levels of S100A8, S100A9, and S100A12 in Chronic Spontaneous Urticaria.

Background:Chronic spontaneous urticaria (CSU) is a skin disorder with an important immunologic profile. S100A8, S100A9, and S100A12 are the members of S100 family that have been reported to play important role in autoimmune diseases, but the characteristics of these three S100 members have not been defined in CSU.Aims:This study was performed to investigate the levels of these three S100s in patients with CSU and to study whether they were associated with the severity and clinical characteristics of CSU.Materials and Methods:The levels of plasma S100A8, S100A9, and S100A12 were measured in 51 CSU patients and 20 healthy controls using enzyme linked immunosorbent assay kits. The values in the patient group and that of the healthy controls were statistically compared. The relationships between the different markers were evaluated by correlation analysis.Results:The plasma levels of S100A8, S100A9, and S100A12 were significantly higher in CSU patients than those in controls. Interestingly, the level of S100A12 was significantly correlated with S100A8 and S100A9 in CSU patients (P < 0.05 and P < 0.001, respectively). In addition, S100A8, S100A9, and S100A12 were all significantly inversely correlated with blood basophil percentage.Conclusions:Plasma S100A8, S100A9, and S100A12 levels were elevated in CSU patients. They might be useful biomarkers of CSU, with the potential role in the pathogenesis of CSU.

S100A12 and S100A8/9 proteins are biomarkers of articular disease activity in Blau syndrome.

To identify biomarkers of articular and ocular disease activity in patients with Blau syndrome (BS). Multiplex plasma protein arrays were performed in five BS patients and eight normal healthy volunteers (NHVs). Plasma S100A12 and S100A8/9 were subsequently measured by ELISA at baseline and 1-year follow-up in all patients from a prospective multicentre cohort study. CRP was measured using Meso Scale Discovery immunoassay. Active joint counts, standardization uveitis nomenclature for anterior uveitis cells and vitreous haze by Nussenblatt scale were the clinical parameters. Multiplex Luminex arrays identified S100A12 as the most significantly elevated protein in five selected BS vs eight NHVs and this was confirmed by ELISA on additional samples from the same five BS patients. In the patient cohort, S100A12 (n = 39) and S100A8/9 (n = 33) were significantly higher compared with NHVs (n = 44 for S100A12, n = 40 for S100A8/9) (P = 0.0000004 and P = 0.0003, respectively). Positive correlations between active joint counts and S100 levels were significant for S100A12 (P = 0.0008) and S100A8/9 (P = 0.015). CRP levels did not correlate with active joint count. Subgroup analysis showed significant association of S100 proteins with active arthritis (S100A12 P = 0.01, S100A8/9 P = 0.008). Active uveitis was not associated with increased S100 levels. S100 proteins are biomarkers of articular disease activity in BS and potential outcome measures in future clinical trials. As secreted neutrophil and macrophage products, S100 proteins may reflect the burden of granulomatous tissue in BS.

Associations between Soluble Receptor for Advanced Glycation End Products (sRAGE) and S100A12 (EN-RAGE) with Mortality in Long-term Hemodialysis Patients.

Hemodialysis (HD) patients experience vascular calcification, ultimately leading to high mortality rates. Previously, we reported associations between soluble receptor for advanced glycation end products (sRAGEs) and extracellular newly identified RAGE-binding protein S100A12 (EN-RAGE) and vascular calcification. Here, we extended our observations, investigating whether these biomarkers may be useful for predicting cardiovascular morbidity and mortality in these subjects. Thus, we evaluated the relationship between sRAGE and S100A12 and mortality in long-term HD patients. This was a prospective observational cohort study in 199 HD patients from an extended analysis of our previous study. Plasma sRAGE, S100A12, comorbidities, and other traditional risk factors were investigated. The cumulative incidences for death using Cox proportional hazards regression were evaluated in multivariable analyses. The observation period was 44 months. During the observation period, 27 (13.6%) patients died. Univariate analysis demonstrated that S100A12 was correlated with diabetes (P = 0.040) and high-sensitivity C-reactive protein (hsCRP) (P = 0.006). In multivariable analyses, plasma sRAGE (hazard ratio [HR] = 1.155; 95% confidence interval [CI] = 0.612–2.183; P = 0.656) and S100A12 (HR = 0.960; 95% CI = 0.566–1.630; P = 0.881) were not associated with mortality in HD patients, although traditional predictors of mortality, including age, history of cardiovascular diseases (CVDs), and serum levels of albumin and hsCRP were related to mortality. Powerful predictors of mortality were age, CVD, and albumin levels. Plasma sRAGE and S100A12 may be weak surrogate markers for predicting all-cause mortality in patients undergoing HD, although S100A12 was partly related to diabetes and inflammation.

Elevated Circulating S100A12 Associates with Vascular Disease and Worse Clinical Outcome in Peritoneal Dialysis Patients.

♦ The pro-inflammatory receptor of advanced glycation end-products (RAGE)-ligand S100A12 is thought to promote, whereas anti-inflammatory soluble RAGE (sRAGE) may protect against, vascular disease. We evaluated circulating S100A12 and sRAGE in relation to vascular disease, inflammation, nutritional status, and mortality risk in peritoneal dialysis (PD) patients. ♦ Plasma S100A12 and sRAGE, biomarkers of inflammation, nutritional status, and comorbidities were analyzed in 82 prevalent PD patients (median age 65 years; 70% men; median vintage 12 months) and, for comparative analysis, also in 190 hemodialysis (HD) patients and 50 control subjects. Associations between mortality risk and concentrations of S100A12 and sRAGE were assessed in PD and HD patients after a mean follow-up period of 31 and 29 months respectively using a competing risk Cox regression model. ♦ In PD patients, median S100A12, sRAGE and S100A12/sRAGE were markedly higher than in controls, and S100A12 was 1.9 times higher and median sRAGE 14% lower compared with HD patients. In PD patients, S100A12 associated with C-reactive protein (ρ = 0.46; p < 0.001) and interleukin-6 (ρ = 0.38; p < 0.001), and, negatively, with s-albumin (ρ = -0.27; p < 0.05) whereas sRAGE associated negatively with body mass index (ρ = -0.37; p < 0.001), fat body mass index (ρ = -0.34; p < 0.001), and lean body mass index (ρ = -0.36; p < 0.001). Peripheral vascular disease or cerebrovascular disease (PCVD) was present in 28% of PD patients and, in multivariate analysis, associated mainly with high S100A12 (odds ratio [OR] 3.52, p = 0.04). In both PD and HD patients, the highest versus other tertiles of S100A12 associated with increased mortality. In contrast, sRAGE did not associate with PCVD or mortality in PD and HD patients. ♦ Plasma S100A12 and sRAGE are markedly elevated in PD patients. Soluble RAGE was inversely related to body mass indices while S100A12 associated with increased inflammation, PCVD, and mortality, suggesting that S100A12 may identify PD patients at high risk for vascular disease and increased mortality.

The Receptor for Advanced Glycation End Products (Rage) and Its Ligands in Plasma and Infrainguinal Bypass Vein

The aim was to investigate whether RAGE and its ligands are associated with infrainguinal bypass outcome in patients with and without diabetes. This was a prospective observational cohort. Patients (n = 68) with (n = 38) and without (n = 30) diabetes undergoing infrainguinal vein bypass for peripheral arterial disease were followed for 3 years. Endosecretory RAGE (esRAGE), S100A12, advanced glycation end products, and carboxymethyl-lysine (CML) were determined in plasma using ELISA. The influence of plasma levels on the main outcome (amputation free survival) was evaluated using Cox proportional hazard analysis. Plasma esRAGE, CML, and S100A12 in healthy controls (n = 30) without cardiovascular disease matched for sex and age were compared with patients, using the Mann—Whitney U test. Veins from bypass surgery procedures were stained and S100A12, RAGE, AGE, and CML were determined using immunohistochemistry. Forty-six patients survived with an intact leg during follow up. Seventeen died (median survival time 702 days, IQR 188-899 day), and six had amputations. High plasma S100A12 was associated with reduced amputation free survival (hazard ratio [HR] 2.99; 95% CI 1.24-7.24) when comparing levels above the 75th percentile with levels below. The increased risk was unchanged adjusting for age, sex, and diabetes. Diabetic patients had higher plasma S100A12 (11.75 ng/mL; 95% CI 8.12-15.38 ng/mL) than non-diabetic patients (5.0141 ng/mL; 95% CI 3.62-6.41 ng/mL), whereas plasma CML, esRAGE, and AGE were similar. Plasma CML and S100A12 were higher in patients than in controls (1.25 μg/mL, 95% CI 1.18-1.32 μg/mL vs 0.8925 μg/mL, 95% CI 0.82-0.96 μg/mL; and 8.7 μg/mL, 95% CI 6.52-10.95 μg/mL vs 3.47 μg/mL, 95% CI 2.95-3.99 μg/mL, respectively). The proportion of vein tissue stained for AGE (21%), RAGE (5%), CML (9%) and S100A12 (3%), were similar in patients with and without diabetes. Plasma S100A12 and CML are elevated in peripheral arterial disease and markers of RAGE and its ligands are found in vein used for bypass. This indicates a role for S100A12, CML, and RAGE in peripheral arterial disease complications by activation of the RAGE system.

The Receptor for Advanced Glycation End Products (Rage) and Its Ligands in Plasma and Infrainguinal Bypass Vein

The aim was to investigate whether RAGE and its ligands are associated with infrainguinal bypass outcome in patients with and without diabetes. This was a prospective observational cohort. Patients (n = 68) with (n = 38) and without (n = 30) diabetes undergoing infrainguinal vein bypass for peripheral arterial disease were followed for 3 years. Endosecretory RAGE (esRAGE), S100A12, advanced glycation end products, and carboxymethyl-lysine (CML) were determined in plasma using ELISA. The influence of plasma levels on the main outcome (amputation free survival) was evaluated using Cox proportional hazard analysis. Plasma esRAGE, CML, and S100A12 in healthy controls (n = 30) without cardiovascular disease matched for sex and age were compared with patients, using the Mann-Whitney U test. Veins from bypass surgery procedures were stained and S100A12, RAGE, AGE, and CML were determined using immunohistochemistry. Forty-six patients survived with an intact leg during follow up. Seventeen died (median survival time 702 days, IQR 188-899 day), and six had amputations. High plasma S100A12 was associated with reduced amputation free survival (hazard ratio [HR] 2.99; 95% CI 1.24-7.24) when comparing levels above the 75th percentile with levels below. The increased risk was unchanged adjusting for age, sex, and diabetes. Diabetic patients had higher plasma S100A12 (11.75 ng/mL; 95% CI 8.12-15.38 ng/mL) than non-diabetic patients (5.0141 ng/mL; 95% CI 3.62-6.41 ng/mL), whereas plasma CML, esRAGE, and AGE were similar. Plasma CML and S100A12 were higher in patients than in controls (1.25 μg/mL, 95% CI 1.18-1.32 μg/mL vs. 0.8925 μg/mL, 95% CI 0.82-0.96 μg/mL; and 8.7 μg/mL, 95% CI 6.52-10.95 μg/mL vs. 3.47 μg/mL, 95% CI 2.95-3.99 μg/mL, respectively). The proportion of vein tissue stained for AGE (21%), RAGE (5%), CML (9%) and S100A12 (3%), were similar in patients with and without diabetes. Plasma S100A12 and CML are elevated in peripheral arterial disease and markers of RAGE and its ligands are found in vein used for bypass. This indicates a role for S100A12, CML, and RAGE in peripheral arterial disease complications by activation of the RAGE system.

Advanced glycation end products are elevated in cystic fibrosis-related diabetes and correlate with worse lung function

BackgroundThe onset of cystic fibrosis-related diabetes (CFRD) exacerbates lung function decline and increases mortality. One pathway that may worsen the lung dysfunction associated with CFRD is that of the receptor for advanced glycation end products (RAGE) and its ligands. MethodsHuman plasma was obtained from age-matched healthy, CF and CFRD patients. Plasma RAGE ligands (i.e. advanced glycation end products, S100A12, and high-mobility group protein B1) and soluble RAGE (sRAGE) levels were measured. ResultsCFRD patients had elevated plasma levels of AGEs and S100A12. Soluble RAGE, a RAGE ligand decoy receptor, was not significantly different between groups. Plasma AGE levels and S100A12 levels had significantly negative correlations with FEV1. ConclusionsAGEs are significantly elevated in CFRD and correlate negatively with FEV1. CFRD patients did not have significant increases in the decoy sRAGE, suggesting there may be heightened binding and activation of RAGE in CFRD exacerbating activation of proinflammatory pathways.

Increased Plasma S100A12 Levels Are Associated With Diabetic Retinopathy and Prognostic Biomarkers of Macrovascular Events in Type 2 Diabetic Patients.

To explore the association between plasma S100A12 levels and the presence of diabetic retinopathy (DR) and disease outcomes. Fasting venous blood samples were collected from 372 subjects (264 relatively healthy subjects with type 2 diabetes and 108 nondiabetic subjects). The plasma CRP, pentosidine, soluble form of the receptor for advanced glycation end products (sRAGE), and S100A12 levels were analyzed in all of the patients and controls. In total, 264 patients with diabetes were followed through office visits and medical records for an average of 17.6 ± 1.5 months to determine the occurrence of major adverse disease end points. An increase in the plasma levels of S100A12, pentosidine, sRAGE, and hs-CRP from healthy to T2DM to T2DM with DR was observed. Multivariate logistic regression revealed that plasma S100A12 levels were independently associated with the presence of DR in the patients with T2DM (odds ratio, 1.421; 95% confidence interval [CI], 1.036-2.531; P = 0.033). The receiver operating characteristic (ROC) curves for developing DR using the Log S100A12, Log pentosidine, Log sRAGE, and Log hs-CRP values revealed that the area under the receiver operating characteristic curves (AUC) were 0.822 (P < 0.001), 0.561 (P = 0.092), 0.572 (P = 0.051), and 0.566 (P = 0.068), respectively. Increased plasma S100A12 levels might be predictive of future major adverse disease end points in DR patients without a previous diagnosis of macrovascular disease. The plasma levels of S100A12 are closely associated with the presence of DR and might be a better biomarker for DR and the prediction of future macrovascular events.

Do elevated plasma S100A12 levels predict atherosclerosis in peritoneal dialysis patients?

Aim: Atherosclerotic cardiovascular disease is one of the major causes of mortality and morbidity in peritoneal dialysis (PD) patients. S100A12 is an endogenous receptor ligand of advanced glycation end-products. It was shown to contribute to the development of atherosclerosis in animal models. The aim of this study was to evaluate the relationship between S100A12 levels and carotid atherosclerosis in PD patients. Methods: A cross-sectional study was performed in 56 PD patients and 20 control subjects. Plasma S100A12 levels were measured from all participants beside routine laboratory evaluation. All subjects underwent high-resolution B-mode ultrasonography to determine carotid intima media thickness (CIMT). S100A12 levels were compared between patient and control groups. Correlation analyses of S100A12 with other laboratory values and CIMT were also performed. Results: Plasma S100A12 levels were higher in PD patients compared with control subjects (129.5 ± 167.2 ng/mL vs. 48.5 ± 30.3 ng/mL, respectively, p < 0.001). In the patient group, CIMT was found to be positively correlated with age (r = 0.354; p = 0.007), CRP level (r = 0.269; p = 0.045), and S100A12 (r = 0.293; p = 0.028) level while it was found to be negatively correlated with hemoglobin concentration (r = −0.264; p = 0.049). In the linear regression analysis, the model, including CRP, S100A12, age, and Hgb, was found to be significant (F: 4.177, p: 0.005). When the parameters are analyzed age and S100A12 were found to be independent determinants of CIMT (β = 0.308, p = 0.018 and β = 0.248, p = 0.049, respectively). Conclusions: This study suggests that an elevated plasma S100A12 level was closely associated with atherosclerosis. With aging elevated plasma S100A12 may show a powerful proatherogenic potential in patients undergoing PD.

Usefulness of S100A12 as a prognostic biomarker for adverse events in patients with heart failure

ObjectivesS100A12 has been proposed as a novel pivotal factor in inflammation produced by granulocytes. The purpose of this study was to investigate the relationship between S100A12 and chronic heart failure (CHF). Design and methodsOne hundred and seventy-seven patients with CHF and 66 subjects without CHF were included in this study. Plasma levels of S100A12 and high-sensitivity C-reactive protein (hs-CRP) were measured in all participants. After a follow-up period of 18months for CHF patients, major cardiovascular events (MCE), including cardiac death and rehospitalization for heart failure, were recorded. ResultsPlasma levels of S100A12 were significantly higher in CHF patients than in control subjects (P<0.001) and positively correlated with hs-CRP (r=0.316, P<0.001). S100A12 levels were also higher in MCE patients than in MCE-free patients. The occurrence of MCE increased with advancing plasma S100A12 levels by stratification according to quartiles (Q4 vs Q1, P=0.015). Cox proportional hazards regression analysis revealed that S100A12 was an independent risk factor for MCE in CHF patients (P=0.009). ConclusionsS100A12 is a potential biomarker of CHF that may provide important information regarding the prediction of MCE in patients with CHF.

Plasma levels of the pro-inflammatory protein S100A12 (EN-RAGE) are associated with muscle and fat mass in hemodialysis patients: a cross-sectional study.

BackgroundMalnutrition is highly prevalent and contributes to mortality in hemodialysis (HD) patients. Although the receptor for advanced glycation end products (RAGE) system also contributes to the morbidity and mortality of these patients, the role that the RAGE system plays in determining nutritional status is currently unknown.MethodsA cross-sectional study examining 79 HD patients was performed. The plasma concentrations of the soluble RAGE (sRAGE) and S100A12 (also known as EN-RAGE) were studied to evaluate their association with nutritional status, which was assessed by measuring the mid-thigh muscle mass and subcutaneous fat mass with computed tomography.ResultsPlasma S100A12 concentrations were shown to be significantly and negatively correlated with muscle mass and with fat mass (r = −0.237, P < 0.05 and r = −0.261, P < 0.05, respectively). In contrast, sRAGE was not shown to significantly correlate with either of these factors. Multiple regression analyses demonstrated that S100A12 is a significant independent predictor of both muscle mass and fat mass (P < 0.01 and P < 0.05, respectively).ConclusionsOur findings suggest that plasma S100A12 levels could play an important role in determining muscle mass and fat mass in HD patients.Trial registrationStudy number; UMIN000012341.

Studying the association of plasma S100A12 and noninfectious pulmonary complication in infants and young children following cardiopulmonary bypass (HUM1P.305)

Abstract Objective To examine the kinetics of plasma S100A12 and sRAGE in infants and young children with CPB, and to investigate whether they could predict the occurrence of noninfectious pulmonary complication (NPC) after cardiac surgery. Methods 20 patients were in NPC group, which included pleural effusion, chylothorax, partial lung collapse, pulmonary hypertensive crisis, airway disorders, pneumothorax, pneumomediastinum, and phrenic nerve palsy, and 40 patients in no-NPC group. Plasma S100A12 and sRAGE were measured at 6 perioperative time points. Results S100A12 and sRAGE increased immediately after CPB (P&amp;lt;0.001). SRAGE dropped to lower than baseline level (P&amp;lt;0.05), while S100A12 was still at high level 24h after operation (P&amp;lt;0.001). S100A12 and sRAGE immediately after CPB in NPC group were significantly higher than no-NPC group (P&amp;lt;0.05). S100A12 were still higher in NPC group than no-NPC at 24h after operation (P&amp;lt;0.01). S100A12 immediately after CPB was a predictor for postoperative NPC (OR=1.042, 95% CI: 1.010-1.076, P=0.011). S100A12 immediately after CPB were positively associated with MV time (r=0.47, P&amp;lt;0.001), duration of surgical Intensive Care Unit (r=0.407, P=0.002) and hospital stay (r=0.421, P=0.001). Conclusions Plasma S100A12 and sRAGE were significantly increased immediately after CPB; The elevated S100A12 immediately after CPB served as an early reliable biomarker of the occurrence and the prognosis of NPC after CPB in infants and young children.

Plasma S100A12 is associated with functional outcome after ischemic stroke: Research for Biomarkers in Ischemic Stroke

BackgroundIschemic stroke is accompanied by an inflammatory response, which exacerbates brain injury and deteriorates functional outcome. S100A12 is expressed abundantly in granulocytes, and has been implicated to play an important role on inflammatory reactions in various disease states. We aimed to determine the association between plasma S100A12 levels and a functional outcome in patients with acute ischemic stroke. MethodsWe prospectively included 171 patients with acute ischemic stroke within 24h after onset in this study. Plasma samples were collected for the measurement of S100A12 levels. Poor functional outcome was defined as a modified Rankin Scale of 2–6 at day 90 after stroke onset. ResultsOf 171 patients, 74 (43.3%) had a poor functional outcome at day 90 after stroke onset. Plasma S100A12 levels on admission were significantly higher in patients with a poor functional outcome (2.1 [1.2–5.1] ng/mL, median [interquartile]) than in those with a favorable outcome (1.1 [0.5–2.0] ng/mL; p<0.001). Multivariate analysis showed that the highest quartile of plasma S100A12 levels on admission showed a significantly higher risk for a poor functional outcome (odds ratio, 4.01; 95% confidence interval, 1.09–16.10; p=0.03) than the lowest quartile. ConclusionsHigh plasma S100A12 levels on admission are associated with a poor functional outcome in patients with acute ischemic stroke.

Prognostic utility of plasma S100A12 levels to establish a novel scoring system for predicting mortality in maintenance hemodialysis patients: a two-year prospective observational study in Japan

BackgroundS100A12 protein is an endogenous receptor ligand for advanced glycation end products. In this study, the plasma S100A12 level was assessed as an independent predictor of mortality, and its utility in clinical settings was examined.MethodsIn a previous cross-sectional study, plasma S100A12 levels were measured in 550 maintenance hemodialysis patients to determine the association between S100A12 and the prevalence of cardiovascular diseases (CVD). In this prospective study, the risk of mortality within a two-year period was determined. An integer scoring system was developed to predict mortality on the basis of the plasma S100A12 levels.ResultsHigher plasma S100A12 levels (≥18.79 ng/mL) were more closely associated with higher all-cause mortality than lower plasma S100A12 levels (<18.79 ng/mL; P = 0.001). Multivariate Cox proportional hazards analysis revealed higher plasma S100A12 levels [hazard ratio (HR), 2.267; 95% confidence interval (CI), 1.195–4.302; P = 0.012], age ≥65 years (HR, 1.961; 95%CI, 1.017–3.781; P = 0.044), serum albumin levels <3.5 g/dL (HR, 2.198; 95%CI, 1.218–3.968; P = 0.012), and history of CVD (HR, 2.068; 95%CI, 1.146–3.732; P = 0.016) to be independent predictors of two-year all-cause mortality. The integer score was derived by assigning points to these factors and determining total scores. The scoring system revealed trends across increasing scores for predicting the all-cause mortality [c-statistic = 0.730 (0.656–0.804)]. The resulting model demonstrated good discriminative power for distinguishing the validation population of 303 hemodialysis patients [c-statistic = 0.721 (0.627–0.815)].ConclusionThe results indicate that plasma S100A12 level is an independent predictor for two-year all-cause mortality. A simple integer scoring system was therefore established for predicting mortality on the basis of plasma S100A12 levels.