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The S100A10 Pathway Mediates an Occult Hyperfibrinolytic Subtype in Trauma Patients.
Gall, LS, Vulliamy, P, Gillespie, S, Jones, TF, Pierre, RSJ, Breukers, SE, Gaarder, C, Juffermans, NP, Maegele, M, Stensballe, J, et al
Annals of surgery. 2019;(6):1184-1191
Abstract
OBJECTIVE To determine the characteristics of trauma patients with low levels of fibrinolysis as detected by viscoelastic hemostatic assay (VHA) and explore the underlying mechanisms of this subtype. BACKGROUND Hyperfibrinolysis is a central component of acute traumatic coagulopathy but a group of patients present with low levels of VHA-detected fibrinolysis. There is concern that these patients may be at risk of thrombosis if empirically administered an antifibrinolytic agent. METHODS A prospective multicenter observational cohort study was conducted at 5 European major trauma centers. Blood was drawn on arrival, within 2 hours of injury, for VHA (rotation thromboelastometry [ROTEM]) and fibrinolysis plasma protein analysis including the fibrinolytic mediator S100A10. An outcomes-based threshold for ROTEM hypofibrinolysis was determined and patients grouped by this and by D-dimer (DD) levels. RESULTS Nine hundred fourteen patients were included in the study. The VHA maximum lysis (ML) lower threshold was determined to be <5%. Heterogeneity existed among patients with low ML, with survivors sharing similar clinical and injury characteristics to patients with normal ML values (5-15%). Those who died were critically injured with a preponderance of traumatic brain injury and had a 7-fold higher DD level (died vs. survived: 103,170 vs. 13,672 ng/mL, P < 0.001). Patients with low ML and high DD demonstrated a hyperfibrinolytic biomarker profile, low tissue plasminogen activator levels but high plasma levels of S100A10. S100A10 was negatively correlated with %ML (r = -0.26, P < 0.001) and caused a significant reduction in %ML when added to whole blood ex-vivo. CONCLUSIONS Patients presenting with low ML and low DD levels have low injury severity and normal outcomes. Conversely, patients with low ML but high DD levels are severely injured, functionally coagulopathic and have poor clinical outcomes. These patients have low tissue plasminogen activator levels and are not detectable by ROTEM. S100A10 is a cell surface plasminogen receptor which may drive the hyperfibrinolysis in these patients and which when shed artificially lowers %ML ex-vivo.
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Association between serum S100A1 level and Global Registry of Acute Coronary Events score in patients with non-ST-segment elevation acute coronary syndrome.
Li, Y, Han, C, Zhang, P, Zang, W, Guo, R
The Journal of international medical research. 2018;(7):2670-2678
Abstract
Objective Acute coronary syndrome (ACS) is associated with several clinical syndromes, one of which is acute non-ST-segment ACS (NSTE-ACS). S100A1 is a calcium-dependent regulator of heart contraction and relaxation. We investigated the association between the serum S100A1 level and the Global Registry of Acute Coronary Events (GRACE) risk score in patients with NSTE-ACS and the potential of using the serum S100A1 level to predict the 30-day prognosis of NSTE-ACS. Methods The clinical characteristics of 162 patients with NSTE-ACS were analyzed to determine the GRACE score. The serum S100A1 concentration was determined using fasting antecubital venous blood. The patients were divided into different groups according to the serum S100A1 level, and the 30-day NSTE-ACS prognosis was evaluated using Kaplan-Meier analysis. Results The serum S100A1 levels differed significantly among the groups. Correlation analysis showed that the serum S100A1 level was positively correlated with the GRACE score. Kaplan-Meier analysis revealed that the number of 30-day cardiac events was significantly higher in patients with an S100A1 level of >3.41 ng/mL. Conclusions S100A1 is a potential biomarker that can predict the progression of NSTE-ACS and aid in its early risk stratification and prognosis.
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Neuron-specific enolase and S-100b in prolonged targeted temperature management after cardiac arrest: A randomised study.
Duez, CHV, Grejs, AM, Jeppesen, AN, Schrøder, AD, Søreide, E, Nielsen, JF, Kirkegaard, H
Resuscitation. 2018;:79-86
Abstract
BACKGROUND We aimed to investigate the impact of prolonged targeted temperature management (TTM) in cardiac arrest patients on release of serum levels of NSE and S-100b and their prognostic performances. METHODS This is a substudy of the Targeted Temperature Management for 24 vs 48h trial. NSE and S-100b levels were analysed retrospectively in serum samples collected upon admission, at 24, 48, and 72h after reaching the target temperature of 33±1°C. The primary outcome was biomarker serum concentrations and secondary outcome was the cerebral performance category score after 6 months. RESULTS 115 patients from two centres were analysed. NSE and S-100b levels did not differ between TTM groups at any single time-point. Poor outcome patients had higher biomarker levels at 24, 48, and 72h: NSE: 9.73 (7.2; 10.9) versus 20.40 (12.7; 27.2), 8.86 (6.6; 9.6) versus 17.47 (11.1; 37.3) and 6.23 (5.3; 8.5) versus 31.05 (12.8; 52.5) respectively and S-100b: 0.09 (0.07; 0.11) versus 0.23 (0.19; 0.39), 0.08 (0.07; 0.09) versus 0.18 (0.15; 0.33) and 0.07 (0.06; 0.08) versus 0.13 (0.09; 0.23). The daily changes in NSE from admission to Day 2 after the cardiac arrest (CA) were also related to the outcome (p=0.003 and p=0.02). The best prediction of outcome was found at 72h for NSE and at 24h as well as 48h for S100b. CONCLUSIONS No clinically relevant differences were found in the levels of NSE or S-100b between standard and prolonged TTM. Prognostic reliability of NSE and S-100b was unaltered by prolonged TTM.
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A novel Munc13-4/S100A10/annexin A2 complex promotes Weibel-Palade body exocytosis in endothelial cells.
Chehab, T, Santos, NC, Holthenrich, A, Koerdt, SN, Disse, J, Schuberth, C, Nazmi, AR, Neeft, M, Koch, H, Man, KNM, et al
Molecular biology of the cell. 2017;(12):1688-1700
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Abstract
Endothelial cells respond to blood vessel injury by the acute release of the procoagulant von Willebrand factor, which is stored in unique secretory granules called Weibel-Palade bodies (WPBs). Stimulated WPB exocytosis critically depends on their proper recruitment to the plasma membrane, but factors involved in WPB-plasma membrane tethering are not known. Here we identify Munc13-4, a protein mutated in familial hemophagocytic lymphohistiocytosis 3, as a WPB-tethering factor. Munc13-4 promotes histamine-evoked WPB exocytosis and is present on WPBs, and secretagogue stimulation triggers an increased recruitment of Munc13-4 to WPBs and a clustering of Munc13-4 at sites of WPB-plasma membrane contact. We also identify the S100A10 subunit of the annexin A2 (AnxA2)-S100A10 protein complex as a novel Munc13-4 interactor and show that AnxA2-S100A10 participates in recruiting Munc13-4 to WPB fusion sites. These findings indicate that Munc13-4 supports acute WPB exocytosis by tethering WPBs to the plasma membrane via AnxA2-S100A10.
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S100A1 promotes cell proliferation and migration and is associated with lymph node metastasis in ovarian cancer.
Tian, T, Li, X, Hua, Z, Ma, J, Liu, Z, Chen, H, Cui, Z
Discovery medicine. 2017;(127):235-245
Abstract
S100A1 is a calcium-binding protein belonging to the family of S100 proteins, and is highly expressed in ovarian cancer. However, its role in ovarian cancer has not yet been fully elucidated. In this study, we examined S100A1 expression in ovarian cancer tissues and normal tissue controls and analyzed the correlation between S100A1 expression and clinicopathological parameters. We found that S100A1 expression was significantly upregulated in ovarian cancer tissues compared with fallopian and normal ovarian epithelium tissues and was significantly associated with lymph node metastasis and International Federation of Gynecology and Obstetrics (FIGO) stages and tumor grades. We then investigated the biological functions of S100A1 in ovarian cancer by cell proliferation, fluorescence-activated cell sorting (FACS), and migration and invasion assays. The results indicated that S100A1 enhanced the ovarian cancer cell proliferation and migration. Together, our findings demonstrated that S100A1 plays an important role in the malignancy of ovarian cancer, and serves as a useful marker for the detection of ovarian malignancy.
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Salivary psoriasin (S100A7) correlates with diffusion capacity of carbon monoxide in a large cohort of systemic sclerosis patients.
Giusti, L, Sernissi, F, Donadio, E, Ciregia, F, Giacomelli, C, Giannaccini, G, Mazzoni, MR, Lucacchini, A, Bazzichi, L
Journal of translational medicine. 2016;(1):262
Abstract
BACKGROUND Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive fibrosis of the skin and the internal organs. In a previous work we suggested a correlation between levels of salivary psoriasin (S100A7) and pulmonary involvement in SSc patients. The goals of this study are to determine the distribution characteristics of psoriasin in whole saliva (WS) of SSc and healthy donor populations and define its predictive value on diffusion capacity of carbon monoxide (DLCO), along with others clinical parameters. METHODS Salivary level of psoriasin was determined by ELISA kit in 134 SSc patients, 63 Raynaud syndrome patients, 40 patients affected by other connective diseases (non-case) and 74 healthy control subjects. RESULTS A significant increase of salivary psoriasin was observed in SSc patients when compared with other healthy and pathological controls. Moreover, we confirmed the efficacy of salivary psoriasin to correlate with DLCO in a large cohort of SSc patients. CONCLUSIONS Overall our results suggest a rapid, non invasive and low costing method which can help clinicians in the evaluation of SSc pulmonary involvement.
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S100A11 plays a role in homologous recombination and genome maintenance by influencing the persistence of RAD51 in DNA repair foci.
Foertsch, F, Szambowska, A, Weise, A, Zielinski, A, Schlott, B, Kraft, F, Mrasek, K, Borgmann, K, Pospiech, H, Grosse, F, et al
Cell cycle (Georgetown, Tex.). 2016;(20):2766-79
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Abstract
The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is an essential process in maintenance of chromosomal stability. A key player of HR is the strand exchange factor RAD51 whose assembly at sites of DNA damage is tightly regulated. We detected an endogenous complex of RAD51 with the calcium-binding protein S100A11, which is localized at sites of DNA repair in HaCaT cells as well as in normal human epidermal keratinocytes (NHEK) synchronized in S phase. In biochemical assays, we revealed that S100A11 enhanced the RAD51 strand exchange activity. When cells expressing a S100A11 mutant lacking the ability to bind Ca(2+), a prolonged persistence of RAD51 in repair sites and nuclear γH2AX foci was observed suggesting an incomplete DNA repair. The same phenotype became apparent when S100A11 was depleted by RNA interference. Furthermore, down-regulation of S100A11 resulted in both reduced sister chromatid exchange confirming the restriction of the recombination capacity of the cells, and in an increase of chromosomal aberrations reflecting the functional requirement of S100A11 for the maintenance of genomic stability. Our data indicate that S100A11 is involved in homologous recombination by regulating the appearance of RAD51 in DSB repair sites. This function requires the calcium-binding activity of S100A11.
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Calcyclin Binding Protein/Siah-1 Interacting Protein Is a Hsp90 Binding Chaperone.
Góral, A, Bieganowski, P, Prus, W, Krzemień-Ojak, Ł, Kądziołka, B, Fabczak, H, Filipek, A
PloS one. 2016;(6):e0156507
Abstract
The Hsp90 chaperone activity is tightly regulated by interaction with many co-chaperones. Since CacyBP/SIP shares some sequence homology with a known Hsp90 co-chaperone, Sgt1, in this work we performed a set of experiments in order to verify whether CacyBP/SIP can interact with Hsp90. By applying the immunoprecipitation assay we have found that CacyBP/SIP binds to Hsp90 and that the middle (M) domain of Hsp90 is responsible for this binding. Furthermore, the proximity ligation assay (PLA) performed on HEp-2 cells has shown that the CacyBP/SIP-Hsp90 complexes are mainly localized in the cytoplasm of these cells. Using purified proteins and applying an ELISA we have shown that Hsp90 interacts directly with CacyBP/SIP and that the latter protein does not compete with Sgt1 for the binding to Hsp90. Moreover, inhibitors of Hsp90 do not perturb CacyBP/SIP-Hsp90 binding. Luciferase renaturation assay and citrate synthase aggregation assay with the use of recombinant proteins have revealed that CacyBP/SIP exhibits chaperone properties. Also, CacyBP/SIP-3xFLAG expression in HEp-2 cells results in the appearance of more basic Hsp90 forms in 2D electrophoresis, which may indicate that CacyBP/SIP dephosphorylates Hsp90. Altogether, the obtained results suggest that CacyBP/SIP is involved in regulation of the Hsp90 chaperone machinery.
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Impact of S100A4 Expression on Clinicopathological Characteristics and Prognosis in Pancreatic Cancer: A Meta-Analysis.
Huang, S, Zheng, J, Huang, Y, Song, L, Yin, Y, Ou, D, He, S, Chen, X, Ouyang, X
Disease markers. 2016;:8137378
Abstract
BACKGROUND The small Ca(2+)-binding protein S100A4 is identified as a metastasis-associated or metastasis-inducing protein in various types of cancer. The goal of this meta-analysis was to evaluate the relationship between S100A4 expression and clinicopathological characteristics and prognosis of patients with pancreatic cancer. METHODS A comprehensive literature search was carried out in the electronic databases PubMed and Chinese CNKI. Only the studies reporting the correlation between S100A4 expression and clinicopathological characteristics or overall survival (OS) of patients with pancreatic cancer are enrolled. Extracted data was analyzed using the RevMan 5.3 software to calculate the pooled relative risks (95% confidence interval, CI) for statistical analyses. RESULTS Seven studies including a total of 474 patients were enrolled into this meta-analysis. Negative expression of S100A4 was significantly associated with higher 3-year OS rate (RR = 3.92, 95% CI = 2.24-6.87, P < 0.0001), compared to S100A4-positive cases. Moreover, negative expression of S100A4 was also related to N0 stage for lymph node metastasis (RR = 2.15, 95% CI = 1.60-2.88, P < 0.0001). However, S100A4 expression was not significantly correlated with histological types and distant metastasis status. CONCLUSION S100A4 expression represents a potential marker for lymph node metastasis of pancreatic cancer and a potential unfavorable factor for prognosis of patients with this disease.
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Psoriasin (S100A7) promotes stress-induced angiogenesis.
Vegfors, J, Ekman, AK, Stoll, SW, Bivik Eding, C, Enerbäck, C
The British journal of dermatology. 2016;(6):1263-1273
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Abstract
BACKGROUND Vascular modifications occur early in the development of psoriasis, and angiogenesis is one of the key features in the pathogenesis of the disease. OBJECTIVES To identify the role of the S100 protein psoriasin in psoriasis-associated angiogenesis. METHODS The role of psoriasin in mediating angiogenesis was investigated by silencing psoriasin with small interfering RNA (siRNA) and measuring psoriasis-associated angiogenic factors in human epidermal keratinocytes. The secretion of psoriasin and the effect of psoriasin on general regulators of angiogenesis in keratinocytes, and on endothelial cell migration, proliferation, tube formation and production of angiogenic mediators, was evaluated. RESULTS Reactive oxygen species (ROS) and hypoxia induced the expression of psoriasin. Downregulation of psoriasin in keratinocytes using siRNA altered the ROS-induced expression of the psoriasis-associated angiogenic factors vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor-like growth factor, matrix metalloproteinase 1 and thrombospondin 1. Overexpression of psoriasin altered several regulators of angiogenesis and led to the secretion of psoriasin. Treatment with extracellular psoriasin induced proliferation, migration and tube formation in dermal-derived endothelial cells to a similar extent as VEGF and interleukin-17, and induced the expression and release of proangiogenic mediators. These effects were suggested to be mediated by the PI3K and nuclear factor kappa B pathways. CONCLUSIONS These findings suggest that psoriasin expression is promoted by oxidative stress in keratinocytes and amplifies the ROS-induced expression of angiogenic factors relevant to psoriasis. Moreover, extracellularly secreted psoriasin may act on dermal endothelial cells to contribute to key features angiogenesis.