High Syndecan-1 Research Articles

Dynamic changes and prognosis value of plasma syndecan-1 and different microcirculatory parameters in sepsis: A prospective observational study.

Glycocalyx degradation is implicated in endothelial damage and microcirculatory dysfunction in sepsis, whereas the effectiveness of plasma syndecan-1 levels and sublingual microcirculatory parameters in evaluating sepsis's prognosis has not yet been determined. This study aims to track their dynamic changes and investigate the prognostic utility of these indexes in sepsis. In this prospective study conducted at the First Affiliated Hospital of Sun Yat-sen University, blood samples were collected from adult surgical septic patients within 2days after intensive care unit admission measuring plasma syndecan-1 concentrations. Relevant sublingual microcirculatory parameters were also obtained simultaneously. Additionally, capillary refill time and serum lactate levels were recorded. The primary outcome was 30-day mortality. Of the 74 patients enrolled, the 30-day mortality rate was 35.1%. Significantly, higher syndecan-1 levels were observed in nonsurvivors at baseline, day 1, and day 2 (62.43 [37.37 and 103.16] vs. 97.24 [52.95 and 186.40] ng/mL and p=0.035; 62.22 [41.50 and 87.52] vs. 96.71 [60.82 and 176.00] ng/mL and p=0.009; and 56.03 [39.16 and 94.48] vs. 87.69 [72.52 and 159.70] ng/mL and p=0.005, respectively). High syndecan-1 levels (≥121ng/mL) were associated with lower survival rates (p=0.001) and an increase exceeding 8ng/mL within 2days indicated a higher mortality risk (p=0.0075). Syndecan-1 levels displayed satisfactory prognostic capability (AUC: 0.7056), whereas combining syndecan-1 and blood lactate demonstrated the highest predictive ability for 30-day survival (AUC: 0.7726). Plasma syndecan-1 levels effectively predict sepsis prognosis, with higher baseline levels or increasing trends indicating worse outcomes. Combining syndecan-1 with blood lactate enhances predictive accuracy for 30-day mortality in sepsis. This study registered in China on December 31, 2021 at Chinese Clinical Trial Registry (ChiCTR2100055066).

Syndecan-1 Levels in Females with Active Rheumatoid Arthritis.

Background: The relationship between serum glycoprotein syndecan-1 and disease activity in rheumatoid arthritis (RA) is still unknown. This study aimed to evaluate whether serum syndecan-1 concentrations are associated with moderate/severe disease activity. Methods: Study Design: This was a cross-sectional study. Seventy-five adult women with RA were classified into (a) moderate/severe RA based on the disease activity score, using the erythrocyte sedimentation rate (DAS28-ESR ≥ 3.2, n = 50), and (b) RA in remission (DAS28-ESR < 2.6, n = 25). Twenty-five healthy women were taken as the reference group. Syndecan-1 levels were determined using enzyme-linked immunosorbent assay (ELISA). High values of serum syndecan-1 levels (≥24 ng/mL) were used to identify the utility values of this biomarker. Results: The patients with RA had higher levels of syndecan-1 than the controls (p < 0.001). RA patients with active disease had higher syndecan-1 levels than RA patients in remission (57.6 vs. 23.5 ng/mL, respectively; p = 0.002). High syndecan-1 concentrations demonstrated the following utility values for identifying disease activity: sensitivity, 84% (95%CI: 71-93); specificity, 52% (95%CI: 31-72); positive predictive value, 78% (95%CI: 70-84); and negative predictive value, 62% (95%CI: 44-77). Conclusions: High syndecan-1 levels have good sensitivity and positive predictive value for identifying disease activity; however, their specificity is limited. Future prospective studies are needed to assess whether syndecan-1 levels can predict treatment failure in RA.

Peripheral blood syndecan-1 levels after mechanical thrombectomy can predict the clinical prognosis of patients with acute ischemic stroke.

Previously, we revealed noticeable dynamic fluctuations in syndecan-1 levels in the peripheral blood of post-stroke patients. We further investigated the clinical prognostic value of syndecan-1 as a biomarker of glycoprotein damage in patients with acute ischaemic stroke (AIS). We examined 105 patients with acute large vessel occlusion in the anterior circulation, all of whom underwent mechanical thrombectomy (MT). Peripheral blood syndecan-1 levels were measured 1 day after MT, and patients were categorised into favourable and unfavourable prognostic groups based on the 90-day modified Rankin Scale (mRS) score. Additionally, we compared the clinical outcomes between groups with high and low syndecan-1 concentrations. The findings revealed a significantly lower syndecan-1 level in the group with an unfavourable prognosis compared to those with a favourable prognosis (p < 0.01). In the multivariable logistic regression analysis, lower syndecan-1 levels were identified as a predictor of unfavourable prognosis (odds ratio (OR) = 0.965, p = 0.001). Patients displaying low syndecan-1 expression in the peripheral blood (< 29.51 ng/mL) experienced a > twofold increase in the rates of unfavourable prognosis and mortality. Our study demonstrates that syndecan-1, as an emerging, easily detectable stroke biomarker, can predict the clinical outcomes of patients with AIS. After MT, low levels of syndecan-1 in the peripheral blood on the first day emerged as an independent risk factor for an unfavourable prognosis, suggesting that lower syndecan-1 levels might signify worse clinical presentation and outcomes in stroke patients undergoing this procedure.

Circulating Syndecan-1 Levels Are Associated with Chronological Coagulofibrinolytic Responses and the Development of Disseminated Intravascular Coagulation (DIC) after Trauma: A Retrospective Observational Study.

The purpose of this study was to evaluate the association between endotheliopathy represented by high levels of circulating syndecan-1 (SDC-1) and coagulofibrinolytic responses due to trauma, which can lead to disseminated intravascular coagulation (DIC). We retrospectively evaluated 48 eligible trauma patients immediately admitted to our hospital and assessed SDC-1 and coagulofibrinolytic parameters for 7 days after admission. We compared the longitudinal changes of coagulofibrinolytic parameters and SDC-1 levels between two groups (high and low SDC-1) according to median SDC-1 value on admission. The median circulating SDC-1 level was 99.6 (61.1-214.3) ng/mL on admission, and levels remained high until 7 days after admission. Coagulofibrinolytic responses assessed by biomarkers immediately after trauma were correlated with SDC-1 elevation (thrombin-antithrombin complex, TAT: r = 0.352, p = 0.001; antithrombin, AT: r = -0.301, p < 0.001; plasmin-α2-plasmin inhibitor complex, PIC: r = 0.503, p = 0.035; tissue plasminogen activator, tPA: r = 0.630, p < 0.001). Sustained SDC-1 elevation was associated with intense and prolonged coagulation activation, impairment of anticoagulation, and fibrinolytic activation followed by inhibition of fibrinolysis, which are the primary responses associated with development of DIC in the acute phase of trauma. Elevation of circulating SDC-1 level was also associated with consumption coagulopathy and the need for transfusion, which revealed a significant association between high SDC-1 levels and the development of DIC after trauma (area under the curve, AUC = 0.845, cut-off value = 130.38 ng/mL, p = 0.001). High circulating levels of syndecan-1 were associated with intense and prolonged coagulation activation, impairment of anticoagulation, fibrinolytic activation, and consumption coagulopathy after trauma. Endotheliopathy represented by SDC-1 elevation was associated with trauma induced coagulopathy, which can lead to the development of DIC.

Appl1, Sortilin and Syndecan-1 immunohistochemistry on intraductal carcinoma of the prostate provides evidence of retrograde spread

The presence of intraductal carcinoma of the prostate (IDCP) correlates with late-stage disease and poor outcomes for patients with prostatic adenocarcinoma, but the accurate and reliable staging of disease severity remains challenging. Immunohistochemistry (IHC) has been utilised to overcome problems in assessing IDCP morphology, but the current markers have only demonstrated limited utility in characterising the complex biology of this lesion. In a retrospective study of a cohort of patients who had been diagnosed with IDCP, we utilised IHC on radical prostatectomy sections with a biomarker panel of Appl1, Sortilin and Syndecan-1, to interpret different architectural patterns and to explore the theory that IDCP occurs from retrograde spread of high-grade invasive prostatic adenocarcinoma. Cribriform IDCP displayed strong Appl1, Sortilin and Syndecan-1 labelling patterns, while solid IDCP architecture had high intensity Appl1 and Syndecan-1 labelling, but minimal Sortilin labelling. Notably, the expression pattern of the biomarker panel in regions of IDCP was similar to that of adjacent invasive prostatic adenocarcinoma, and also comparable to prostate cancer showing perineural and vascular invasion. The Appl1, Sortilin, and Syndecan-1 biomarker panel in IDCP provides evidence for the model of retrograde spread of invasive prostatic carcinoma into ducts/acini, and supports the inclusion of IDCP into the five-tier Gleason grading system.

ASO Author Reflections: Immediate Postoperative High Syndecan-1 is an Early Biomarker for Morbidity After Robot-Assisted Esophagectomy.

ASO Author Reflections: Immediate Postoperative High Syndecan-1 is an Early Biomarker for Morbidity After Robot-Assisted Esophagectomy.

Syndecan-1 as a marker to predict acute kidney injury after isolated coronary artery bypass graft operations.

Postoperative acute kidney injury is an important problem that can occur after coronary artery bypass graft operations, and it is important to identify risky patient groups preoperatively. This study aimed to investigate the importance of preoperative syndecan-1 levels in predicting acute kidney injury after elective coronary artery bypass graft operations accompanied by cardiopulmonary bypass. Patients who underwent coronary artery bypass graft operation in our clinic between March 1 and May 10, 2022, were included in this prospective study. Patients who did not develop acute kidney injury in the postoperative period were recorded as group 1 and patients who developed it were recorded as group 2. A total of 79 patients undergoing coronary artery bypass graft surgery with cardiopulmonary bypass were included in the study. There were 55 patients in group 1 and 24 patients in group 2. There was no difference between the groups in terms of age, gender, diabetes mellitus, body mass index, smoking, and hyperlipidemia rates. In multivariate logistic regression analysis, increased blood product use (odds ratio 1.634; 95%CI 1.036-2.579; p=0.035), preoperative high creatinine (odds ratio 59.387; 95%CI 3.034-1162.496; p=0.007), and high syndecan-1 (odds ratio 1.015; 95%CI 1.002-1.028; p=0.025) were independent predictors of acute kidney injury. This study revealed that elevated preoperative syndecan-1 is associated with acute kidney injury after isolated coronary artery bypass graft accompanied by cardiopulmonary bypass and has prognostic utility independent of other recognized risk factors.

Association of endothelial glycocalyx shedding and coronary microcirculation assessed by an angiography-derived index of microcirculatory resistance in patients with suspected coronary artery disease.

BackgroundThe endothelial glycocalyx (EG) is essential for maintaining microvascular homeostasis. However, the relationship between the EG and coronary microcirculation remains to be elucidated. One of the main components of EG is syndecan-1, and its shedding has been claimed to represent the state of the EG. In this study, we aimed to analyze the association between syndecan-1 and the coronary microcirculation.MethodsWe enrolled suspected coronary artery disease (CAD) patients who consecutively underwent coronary angiography (CAG) and angiography-based analysis of physiological indices in the left anterior descending artery (LAD). Serum syndecan-1 was measured by enzyme-linked immunosorbent assay (ELISA). The coronary microcirculation was evaluated by the presence of coronary microvascular dysfunction (CMD) and an impaired microvascular vasodilatory capacity (IMVC), which were quantified by an angiography-derived index of microcirculatory resistance (IMRangio) in the maximum hyperemic state (H-IMRangio) induced by adenosine triphosphate and the ratio (RRRangio) of IMRangio in the non-hyperemic phase to H-IMRangio, respectively.ResultsA total of 528 patients were enrolled in this study. There was no difference in epicardial coronary complexity between patients with high syndecan-1 (HSG) and low syndecan-1 (LSG) levels grouped by the median concentration of syndecan-1 (SYNTAX: 7[3, 10] vs. 9[4, 12], P = 0.15). However, H-IMRangio and RRRangio were different between the LSG and HSG groups (H-IMRangio: 23.64 ± 6.28 vs. 27.67 ± 5.59, P < 0.01; RRRangio: 1.74[1.46, 2.08] vs. 1.55[1.34, 1.72], P < 0.01). Patients with CMD (H-IMRangio > 25) and patients with IMVC (RRRangio below the median value) both had higher syndecan-1 levels (CMD: 86.44 ± 54.15 vs. 55.2 ± 43.72, P < 0.01; IMVC: 83.86 ± 55.41 vs. 59.68 ± 45.06, P < 0.01). After adjustment for confounding factors, HSG remained associated with the presence of CMD and IMVC (CMD: odds ratio [OR]: 2.769, P < 0.01; IMVC: OR: 1.908, P < 0.01).ConclusionHigh levels of syndecan-1 are independently associated with the presence of CMD and IMVC among patients with suspected CAD.

Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19

BackgroundWe investigated the feasibility of two biomarkers of endothelial damage (Syndecan-1 and thrombomodulin) in coronavirus disease 2019 (COVID-19), and their association with inflammation, coagulopathy, and mortality.MethodsThe records of 49 COVID-19 patients who were admitted to an intensive care unit (ICU) in Wuhan, China between February and April 2020 were examined. Demographic, clinical, and laboratory data, and outcomes were compared between survivors and non-survivors COVID-19 patients, and between patients with high and low serum Syndecan-1 levels. The dynamics of serum Syndecan-1 levels were also analyzed.ResultsThe levels of Syndecan-1 were significantly higher in non-survivor group compared with survivor group (median 1031.4 versus 504.0 ng/mL, P = 0.002), and the levels of thrombomodulin were not significantly different between these two groups (median 4534.0 versus 3780.0 ng/mL, P = 0.070). Kaplan–Meier survival analysis showed that the group with high Syndecan-1 levels had worse overall survival (log-rank test: P = 0.023). Patients with high Syndecan-1 levels also had significantly higher levels of thrombomodulin, interleukin-6, and tumor necrosis factor-α. Data on the dynamics of Syndecan-1 levels indicated much greater variations in non-survivors than survivors.ConclusionsCOVID-19 patients with high levels of Syndecan-1 develop more serious endothelial damage and inflammatory reactions, and have increased mortality. Syndecan-1 has potential for use as a marker for progression or severity of COVID-19. Protecting the glycocalyx from destruction is a potential treatment for COVID-19.

High Preoperative Serum Syndecan-1, a Marker of Endothelial Glycocalyx Degradation, and Severe Acute Kidney Injury after Valvular Heart Surgery.

Degradation of endothelial glycocalyx (EG) is associated with inflammation and endothelial dysfunction, which may contribute to the development of acute kidney injury (AKI). We investigated the association between a marker of EG degradation and AKI after valvular heart surgery. Serum syndecan-1 concentrations were measured at induction of anesthesia and discontinuation of cardiopulmonary bypass in 250 patients. Severe AKI was defined as Kidney Disease: Improving Global Outcomes Criteria Stage 2 or 3. Severe AKI occurred in 13 patients (5%). Receiver operating characteristic analysis of preoperative syndecan-1 to predict severe AKI showed area under curve of 0.714 (95% confidence interval (CI), 0.575–0.853; p = 0.009). The optimal cut-off value was 90 ng/mL, with a sensitivity of 61.5% and specificity of 78.5%. In multivariable analysis, both preoperative syndecan-1 ≥ 90 ng/mL and Cleveland Clinic Foundation score independently predicted severe AKI. Severe tricuspid regurgitation was more frequent (42.4% vs. 17.8%, p < 0.001), and baseline right ventricular systolic pressure (41 (33–51) mmHg vs. 33 (27–43) mmHg, p = 0.001) and TNF-α (1.85 (1.37–2.43) pg/mL vs. 1.45 (1.14–1.92) pg/mL, p <0.001) were higher in patients with high preoperative syndecan-1. Patients with high preoperative syndecan-1 had longer hospital stay (16 (12–24) days vs. 13 (11–17) days, p = 0.001). In conclusion, a high preoperative syndecan-1 concentration greater than 90 ng/mL was able to predict severe AKI after valvular heart surgery and was associated with prolonged hospitalization.

Aberrant Expression of Syndecan-1 in Cervical Cancers

Syndecan-1, is a transmembrane heparan/chondroitin sulfate proteoglycan necessary for cell-cell and cell-matrix interactions. Its decreased level on the cell surface correlates with poor prognosis in several tumor types. Aberrant stromal localization of syndecan-1 is also considered an unfavorable prognostic factor in various human malignancies. In the presented work the question was addressed if changes in syndecan-1 expression are related to the prognosis of cervical cancer. Immunohistochemistry for syndecan-1 extracellular domain was performed on surgical specimens of primary cervical cancer. To follow the communication between tumor cells and stromal fibroblasts, their mono-and co-cultures were studied, detecting the expression of syndecan-1, smooth muscle actin, vimentin, and desmin. Immunohistochemistry of tumorous specimens revealed that while cell surface syndecan-1 expression was reduced on cancer cells, it appeared on the surface of tumor-associated fibroblasts. Until year 7, the cohort with high cell surface syndecan-1 expression had significantly longer survival. No difference in the same time-period could be detected when stromal syndecan-1 expression was analyzed. In vitro analysis revealed, that tumor cells can induce syndecan-1 expression on fibroblast, and fibroblasts showed that fibroblast-like cells are built by two cell types: (a) syndecan-1 positive, cytokeratin negative real fibroblasts, and (b) syndecan-1 and cytokeratin positive epithelial-mesenchymal transformed tumor cells. Syndecan-1 on the surface of cancer cells appears to be a positive prognostic marker. Although syndecan-1 positive fibroblasts promote tumor cell proliferation in vitro, we failed to detect their cancer promoting effect in vivo.

Effect of Coagulation Factor Concentrates on Markers of Endothelial Cell Damage in Experimental Hemorrhagic Shock.

Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared with crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS. Eighty-four rats were subjected to pressure-controlled (mean arterial pressure (MAP) 30-35 mm Hg) and lab-guided (targeted cutoff: lactate >2.2. mmol/L and base deficit > 5.5 mmol/L) HS. Animals were resuscitated with fresh frozen plasma (FFP), human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of-observation (120 min after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1). Resuscitation with FFP had no effect on sVEGFR1 compared with crystalloid-based resuscitation (FFP: 19.3 ng/mL vs. RL: 15.9 ng/mL; RL+FC: 19.7 ng/mL; RL+PCC: 18.9 ng/mL; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/mL). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/mL vs. end-of-observation: 36 ng/mL). The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential. VExperimental in vivo study.

Endothelial Glycocalyx Shedding Predicts Donor Organ Acceptability and Is Associated With Primary Graft Dysfunction in Lung Transplant Recipients.

The endothelial glycocalyx, a sieve-like structure located on the luminal surface of all blood vessels, has been found to be integral to regulation of capillary permeability and mechanotransduction. Given this, we investigated the role of endothelial glycocalyx breakdown products in organ donors and recipients in terms of acceptability for transplant and risk of primary graft dysfunction (PGD). Endothelial glycocalyx breakdown products were measured in the peripheral blood of 135 intended and actual organ donors. Breakdown product levels were tested for association with donor demographic and clinical data, organ acceptability for transplant along with lung recipient outcomes (n = 35). Liquid chromatography mass spectrometry analysis was performed to confirm glycosaminoglycan levels and sulfation patterns on donor samples (n = 15). In transplant recipients (n = 50), levels were measured pretransplant and daily for 4 days posttransplant. Levels were correlated with PGD severity and intubation time. Decreased hyaluronan levels in peripheral blood independently predicted organ acceptability in intended and actual donors (odds ratio, 0.96; [95% confidence interval, 0.93-0.99] P = 0.026). Furthermore, high donor syndecan-1 levels were associated with PGD in recipients (3142 [1575-4829] versus 6229 [4009-8093] pg/mL; P = 0.045). In recipient blood, levels of syndecan-1 were correlated with severe (grades 2-3) PGD at 72 hours posttransplant (5982 [3016-17191] versus 3060 [2005-4824] pg/mL; P = 0.01). Endothelial glycocalyx breakdown occurs in lung transplant donors and recipients and predicts organ acceptability and development of PGD. Glycocalyx breakdown products may be useful biomarkers in transplantation, and interventions to protect the glycocalyx could improve transplant outcomes.

Tissue microarray analysis delineate potential prognostic role of Annexin A7 in prostate cancer progression.

BackgroundAnnexin A7 (ANXA7) is a member of the multifunctional calcium or phospholipid-binding annexin gene family. While low levels of ANXA7 are associated with aggressive types of cancer, the clinical impact of ANXA7 in prostate cancer remains unclear. Tissue microarrays (TMA) have revealed several new molecular markers in human tumors. Herein, we have identified the prognostic impact of ANXA7 in a prostate cancer using a tissue microarray containing 637 different specimens.MethodsThe patients were diagnosed with prostate cancer and long-term follow-up information on progression (median 5.3 years), tumor-specific and overall survival data (median 5.9 years) were available. Expression of Ki67, Bcl-2, p53, CD-10 (neutral endopeptidase), syndecan-1 (CD-138) and ANXA7 were analyzed by immunohistochemistry.ResultsA bimodal distribution of ANXA7 was observed. Tumors expressing either high or no ANXA7 were found to be associated with poor prognosis. However, ANXA7 at an optimal level, in between high and no ANXA7 expression, had a better prognosis. This correlated with low Ki67, Bcl-2, p53 and high syndecan-1 which are known predictors of early recurrence. At Gleason grade 3, ANXA7 is an independent predictor of poor overall survival with a p-value of 0.003. Neoadjuvant hormonal therapy, which is known to be associated with overexpression of Bcl-2 and inhibition of Ki67 LI and CD-10, was found to be associated with under-expression of ANXA7.ConclusionsThe results of this TMA study identified ANXA7 as a new prognostic factor and indicates a bimodal correlation to tumor progression.

Circulating syndecan-1 is associated with chemotherapy-resistance in castration-resistant prostate cancer

ObjectivesDocetaxel chemotherapy is a standard treatment for castration-resistant prostate cancer (CRPC). Rapidly expanding treatment options for CRPC provide reasonable alternatives for those who are resistant to docetaxel. Therefore, prediction of docetaxel resistance has become of great clinical importance. Syndecan-1 (SDC1) has been currently shown to be involved in chemotherapy resistance in various malignancies including prostate cancer. The predicting value of serum SDC1 level has not been evaluated yet. Patients and methodsWe assessed the baseline levels of SDC1 in serum samples of 75 patients with CRPC who received docetaxel therapy until the appearance of therapy resistance. In one patient who was treated with three treatment series, we assessed also 6 additional serum samples collected during a 1-year treatment period. Serum SDC1 levels were correlated with clinical outcomes as well as with serum levels of MMP7. ResultsPretreatment SDC1 serum levels were not associated with patients’ age, the presence of bone or visceral metastases. In univariable analyses, patients’ performance status, the presence of bone or visceral metastases, high pretreatment prostate specific antigen and SDC1 levels were significantly associated with cancer-specific survival. In multivariable analysis patients’ performance status (P = 0.005), presence of bone or visceral metastases (P = 0.013) and high SDC1 level (P = 0.045) remained independent predictors of patients’ survival. In the patient with available follow-up samples serum SDC1 level increased from 50 to 300ng/ml at radiographic progression. Serum concentrations of SDC1 were correlated with those of MMP7 (r = 0.420, P = 0.006). ConclusionsOur present results together with currently published data suggest a role for SDC1 shedding in chemotherapy resistance. Determination of serum SDC1 may contribute to the prediction of docetaxel resistance and therefore may help to facilitate clinical decision-making regarding the type and timing of therapy for patients with CRPC.

Syndecan-1 inhibits early stages of liver fibrogenesis by interfering with TGFβ1 action and upregulating MMP14

Increased expression of syndecan-1 is a characteristic feature of human liver cirrhosis. However, no data are available on the significance of this alteration. To address this question we designed a transgenic mouse strain that driven by albumin promoter, expresses human syndecan-1 in the hepatocytes. Liver cirrhosis was induced by thioacetamide in wild type and hSDC1+/+ mice of the identical strain. The process of fibrogenesis, changes in signal transduction and proteoglycan expression were followed. In an in vitro experiment, the effect of syndecan-1 overexpression on the action of TGFβ1 was determined. Human syndecan-1 and TGFβ1 levels were measured by ELISA in the circulation. Without challenge, no morphological differences were observed between wild type and transgenic mice livers, although significant upregulation of phospho-Akt and FAK was observed in the latter. Fibrogenesis in the transgenic livers, characterized by picrosirius staining, collagen type I, and SMA levels, lagged behind that of control in the first and second months. Changes in signal transduction involved in the process of fibrogenesis, as SMAD, MAPK, Akt and GSK, pointed to the decreased effect of TGFβ1, and this was corroborated by the decreased mRNA expression of TIEG and the growth factor itself. In vitro experiments exposing the LX2 hepatic stellate cell line to conditioned media of wild type and syndecan-1 transfected Hep3B cell lines proved that medium with high syndecan-1 content inhibits TGFβ1-induced upregulation of SMA, TIEG, collagen type I and thrombospondin-1 expression. Detection of liver proteoglycans and heparan sulfate level revealed that their amounts are much higher in control transgenic liver, than that in the wild type. However, it decreases dramatically as a result of shedding after hepatic injury. Shedding is likely promoted by the upregulation of MMP14. As syndecan-1 can bind thrombospondin-1, and as our result demonstrated that the same is true for TGFβ1, shed syndecan-1 can remove the growth factor and its activator together into the systemic circulation.Taking together, our results indicate that the effect of syndecan-1 is accomplished on two levels: a, the shedded syndecan can bind, inhibit and remove TGFβ1; b, interferes with the activation of TGFβ1 by downregulation and binding thrombospondin-1, the activator of the growth factor. However, by the end of the fourth month the protective effect was lost, which is explained by the considerable decrease of syndecan-1 and the almost complete loss of heparan sulfate from the surface of hepatocytes.

Clinicopathological and prognostic significance of SDC1 overexpression in breast cancer.

BackgroundBreast cancer is the leading cause of cancer death among global women, and its early diagnosis and treatment are very urgent. Syndecan-1 (SDC1) is a heparin sulfate proteoglycan, which has been linked with the prognosis and treatment response in a various tumor type. To investigate whether SDC1 can serve as a prognostic indictor in breast cancer, bioinformatic analyses were performed in the present study.MethodsSDC1 expression was assessed using Oncomine analysis. Kaplan-Meier Plotter and bc-GenExMiner were performed to identify the prognostic roles of SDC1 in breast cancer. COSMIC analysis and cBioPortal database were performed to analysis the mutations of SDC1. The heat map and methylation status of SDC1 were identified by performing the UCSC.ResultsWe found that SDC1 was more frequently overexpressed in breast cancer than their normal tissues and its expression might be negatively related with some CpG sites. Meanwhile, pooled data suggested that SDC1 mRNA expression is associated worse prognosis of breast cancer. Following data mining in multiple big databases confirmed a positive correlation between SDC1 mRNA expression and PLAU mRNA expression in breast cancer tissues. In addition, high SDC1 expression is associated with increased risked of age, nodal, HER2 and higher SBR grade status.ConclusionOur findings suggest that overexpressed SDC1 was identified in breast cancer than in matched normal tissues and is associated with methylation status of SDC1 promoter. Additionally, SDC1 is positively associated with PLAU and might act as a potential prognostic indicator for breast cancer.

Sympathoadrenal activation and endotheliopathy are drivers of hypocoagulability and hyperfibrinolysis in trauma: A prospective observational study of 404 severely injured patients.

One third of severely injured patients present with a laboratory-based diagnosis of coagulopathy. This study investigated clinical and biomarker profile of patients with rapid thrombelastography (rTEG) coagulopathy, hypothesizing that sympathoadrenal activation and endothelial damage were drivers of this condition. Prospective observational study of 404 trauma patients admitted to a Level 1 US Trauma Center. Patients with admission rTEG and plasma measurements of catecholamines (adrenaline, noradrenaline) and biomarkers reflecting endothelial activation/damage (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin, nucleosomes) were included. Demography, injury type/severity, physiology, treatment, and inhospital mortality were recorded. Patients had a median Injury Severity Score (ISS) of 17, 73% from blunt injury. One third (35%) of the patients had rTEG coagulopathy, which was associated with higher plasma adrenaline, syndecan-1, and nucleosomes (all <0.05), higher transfusion requirements and higher early (<24 hours, 9.3% vs. 2.5%) and late (28 days, 23.8% vs. 13.4%) mortality. By adjusted linear regression analyses, high plasma adrenaline, sVE-cadherin, and syndecan-1 (reflecting sympathoadrenal activation and endothelial cell junction and glycocalyx damage) along with male sex, high ISS, low platelet count and prehospital red blood cell transfusion were independently associated with hypocoagulable rTEG, whereas prehospital plasma and sE-selectin (reflecting endothelial activation) were independently associated with more hypercoagulable rTEG. In this cohort of severely injured trauma patients, rTEG coagulopathy was associated with sympathoadrenal activation, endotheliopathy, and excess mortality. High adrenaline and biomarkers reflecting endothelial cell junction and glycocalyx damage were independently associated with hypocoagulability and hyperfibrinolysis. These findings support that sympathoadrenal activation and endotheliopathy contribute to trauma-induced coagulopathy and warrants further studies of endothelial repair management. Prognostic, Level III.

385 Plasma Syndecan-1 Levels Identify a Cohort of Patients With Severe Sepsis at a High Risk of Intubation Following Large Volume Intravenous Fluid Resuscitation

Sepsis damages the endothelium and extracellular matrix (ECM), contributing to fluid extravasation, acute organ injury, and death. Biomarker-based risk stratification holds promise in identifying those patients who may benefit from restrictive fluid resuscitation strategies. We sought to determine if plasma syndecan–1 levels can predict a cohort at particularly high risk of respiratory failure following intravenous fluid (IVF) administration. Syndecan-1 levels were measured in plasma samples at the time of enrollment. The primary outcome was the difference in syndecan-1 levels in patients intubated versus those not requiring intubation, while secondary outcomes were differences in syndecan-1 based on in-hospital mortality and development of acute kidney injury. A cutoff for high versus low syndecan-1 levels was developed using an ROC curve, and logistic regression was performed to evaluate the risk of intubation associated with administration of IV fluids. Syndecan-1 levels were measured in 175 patients. Fifty two patients (22%) met the primary outcome of intubation, 34 (21%) died, and 100 (57%) developed kidney injury. Levels of syndecan-1 were non-significantly higher in patients who were intubated, and significantly higher in non-survivors and those with kidney injury. High syndecan-1 levels were defined as >240 ng/mL. Median IVF volume administered was 4.0 L (IQR 2.0, 5.3) and was not significantly different between high and low syndecan-1 groups. IVF volume was not associated with risk of intubation in patients with a low syndecan-1 level (p = 0.99), but demonstrated a significant linear relationship with the risk of intubation in patients with high syndecan-1 levels (p < 0.05). These data are represented in Figure 1 as Lowess smoothing plots. Syndecan-1 levels are significantly elevated in ED sepsis non-survivors and non-significantly higher among those requiring intubation. Patients with high syndecan-1 levels may represent a cohort at particular risk for intubation following large volume fluid administration. Further studies to validate these findings in a prospective cohort are indicated.

Plasma syndecan-1 levels identify a cohort of patients with severe sepsis at high risk for intubation after large-volume intravenous fluid resuscitation

PurposeSepsis damages the endothelial glycocalyx, contributing to fluid extravasation, organ injury, and death. Our goal was to determine if syndecan-1 level is associated with the risk of intubation and modifying effect of intravenous fluids (IVFs) in these patients. MethodsSyndecan-1 was measured at enrollment in patients underdoing protocolized resuscitation for severe sepsis or septic shock. The primary outcome was difference in syndecan-1 based on subsequent intubation status, with in-hospital mortality and acute kidney injury serving as secondary outcomes. Logistic regression was performed to evaluate the effect of IVF volume on each outcome. ResultsSyndecan-1 was measured in 175 patients. Twenty-two percent met the primary outcome, 21% died, and 57% developed kidney injury. Syndecan-1 was nonsignificantly higher in intubated patients and was significantly higher in nonsurvivors and those with kidney injury. High syndecan-1 was defined as >240 ng/mL. The IVFs did not differ significantly between high and low syndecan-1 groups. Fluid volume was not associated with intubation in patients with a low syndecan-1 level but was associated with intubation in those with high syndecan-1 levels. ConclusionsSyndecan-1 is elevated in emergency department sepsis nonsurvivors. Patients with high syndecan-1 may represent a cohort at particular risk for intubation after large-volume fluid administration.