Soluble Syndecan-1 Research Articles

Serum Soluble Syndecan-1 (ssCD138) Can Contribute to the Discrimination of Lenalidomide Resistant Multiple Myeloma (MM) Patients

Background Lenalidomide resistance is one of the main emerging therapeutical concerns in MM. SsCD138 levels were shown of prognostic significance in MM at diagnosis while their contribution during disease course has not been evaluated. Aims To evaluate ssCD138 possible prognostic contribution in MM patients treated with Lenalidomide. Patients and methods : Sixty-nine patients treated with Lenalidomide were included in the study. All received dexamethasone (RD) but one maintenance. Medical records were reviewed and frozen sera samples were tested after patient's informed consent. SsCD138 levels were determined by ELISA (Diaclone Research) according to the manufacturer's instructions. Median age of patients was 67 years with 50% women. Immunoglobulin type was IgG in 67% patients, IgA in 22%, Light-Chain in 10% and IgD in 1%. ISS 1, 2 and 3 were 37%, 24% and 39% respectively. ssCD138 were measured at RD initiation, best response and relapse. Median value was used as cut off and any concentrations above median were defined as "High". Median PostLenOS was 27mo, median time to next treatment (TNT) was 12,5mo. Time from RD initiation to the second relapse after RD (LenPFS2) was 24,5mo. Median number of previous treatment lines was 3. Forty healthy individuals were also tested. Statistical analysis was performed using SPSS software v.25. Results: Median ssCD138 was 234 ng/ml (15-841) at RD initiation, 97 ng/ml(12-1500) at plateau and 247(51-395) at relapse while it was 52 ng/ml (21-1070) in Healthy Individuals. Patients achieving VgPR and better had more than 50% reduction in ssynd-1 levels from treatment initiation to plateau (r=0,344, p=0,05). Patients with High ssynd-1 levels at RD initiation presented shorter LenPFS 2 (p=0,011) and TNT (p=0,018). Factors measured at RD initiation impacting on LenPFS2 were ssCD138 levels (HR:2 .p=0,025), abnormal LDH (HR:4,47 ,p=0,0001), ISS (HR=1,54, p=0,008) and b2-microglobulin>5.5mg/L(HR: 2,23, p=0,009), Bone Marrow Infiltration (BMINF)>60% (HR : 2,39, p=0,048), albumin<3.5g/dl (HR: 2,72, p=0,12). In univariate analysis for TNT predictors, ssCD138 levels (HR:2,32, p=0,009), ISS (HR:1,46, p=0,001), b2-microglobulin>5.55mg/L (HR:1,76, p=0,008) and Free Light Chain Ratio(FLCR)>100 (HR:2,08, p=0,000), albumin<3.5 g/dl (HR: 1,75, p=0,031) BMINF>60% (HR : 2,18, p=0,01), Hb<10 g/dl (ΗR:3,3, p=0,001) were significant. Variables of importance for PostLenOS were ISS (HR:1,4 , p=0,004) b2-microglobulin>5.5mg/L (HR:1.61 ,p= 0,031), FLCR>100 (HR:2,8 , p=0,0001) levels, albumin<3.5 g/dl (HR: 2,45, p=0,001), BMINF>60% (HR : 2,8, p=0,002). Based on the independent variables patients were assigned a score of 1 with both FLCR>100 and elevated ssCD138 levels and 0 with both these values normal. Patients with 1 point presented an estimated TNT of 4 Vs 14 months (p=0,001) and shorter LenPFS of 11 Vs 28 months (p=0,001). The estimated PostLenOS was 15 Vs 33 months in patients with 1 and 0 point respectively (p=0,005). Conclusion SsCD138 levels in MM patients treated with RD were significantly associated with LenPFS2 and TNT. A Prognostic score based on ssCD138 and FLCR>100 was shown effective for the prediction of PostLenOS, LenPFS2 and TNT. These results suggest that soluble syndecan-1 levels can discriminate patients at risk to the lenalidomide resistant early. Indeed validation in larger cohort is necessary. Disclosures Panayiotidis: ASH: Honoraria; Phizer: Honoraria; Roche: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria, Research Funding; Genesis: Honoraria, Research Funding; Janssen: Honoraria; Gilead: Honoraria. Kyrtsonis:Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Soluble Syndecan-1 Levels Are Associated with Survival in Platinum-Treated Bladder Cancer Patients.

Cisplatin-containing chemotherapy represents the first-line treatment for patients with locally advanced or metastatic muscle-invasive bladder cancer. Recently, novel therapies have become available for cisplatin-ineligible or -resistant patients. Therefore, prediction of cisplatin response is required to optimize therapy decisions. Syndecan-1 (SDC1) tissue expression and serum concentration may be associated with cisplatin resistance. Thus, pre-treatment serum levels of SDC1 and its expression in chemo-naïve tissues were assessed in 121 muscle-invasive bladder cancer patients who underwent postoperative platinum-based chemotherapy. SDC1 concentrations were evaluated by ELISA in 52 baseline and 90 follow-up serum samples and tissue expressions were analyzed by immunohistochemistry in an independent cohort of 69 formalin-fixed paraffin-embedded tumor samples. Pre-treatment SDC1 serum levels were significantly higher in lymph node metastatic (p = 0.009) and female patients (p = 0.026). SDC1 tissue expression did not correlate with clinicopathological parameters. High pre-treatment SDC1 serum level and the presence of distant metastasis were independent risk factors for overall survival (Hazard ratio (HR): 1.439, 95% Confidence interval (CI): 1.003–2.065, p = 0.048; HR: 2.269, 95%CI: 1.053–4.887, p = 0.036). Our results demonstrate an independent association between high baseline serum SDC1 concentration and poor survival in platinum-treated patients. Analyzing baseline serum SDC1 levels may help to predict platinum-containing chemotherapy and could help to optimize therapeutic decision-making.

Evaluation of the Diagnostic and Prognostic Value of Syndecan-1 in Acute Leukemia Patients.

Syndecan-1 (also known as SDC-1 or CD138) is a transmembrane proteoglycan that is expressed in many hematological and solid tumors and affects the prognosis of those cancers. We conducted this study to investigate the prognostic role of syndecan-1 in acute leukemia. Forty cases of de novo acute leukemia patients, 24 with acute myeloid leukemia (AML) and 16 with acute lymphoblastic leukemia (ALL), presented at the Oncology Center of Mansoura University, Mansoura, Egypt, with a follow-up period of 26 months. Syndecan-1 was determined in serum and leukocytes by enzyme-linked immunosorbent assay (ELISA). The results from acute leukemia patients were compared with those of 15 healthy subjects. We observed that soluble syndecan-1 was higher in AML (median, 160.60 ng/ml) compared with ALL (median, 76.10 ng/ml) and healthy controls (median, 30.95 ng/ml). There was a significant correlation between syndecan-1 either in leukocytes or soluble form and response to treatment in patients with AML (p = 0.02 and p = 0.04, respectively), but these correlations were not statistically significant for ALL cases. Finally, there was a significant correlation between the soluble syndecan-1 level and overall survival in AML cases (p = 0.04), but the correlation was not significant for ALL cases. In conclusion, syndecan-1 is a useful biomarker for AML but not for ALL.

Endothelial Injury and Glycocalyx Degradation in Critically Ill Coronavirus Disease 2019 Patients: Implications for Microvascular Platelet Aggregation.

Coronavirus disease 2019 is caused by the novel severe acute respiratory syndrome coronavirus 2 virus. Patients admitted to the ICU suffer from microvascular thrombosis, which may contribute to mortality. Our aim was to profile plasma thrombotic factors and endothelial injury markers in critically ill coronavirus disease 2019 ICU patients to help understand their thrombotic mechanisms. Daily blood coagulation and thrombotic factor profiling with immunoassays and in vitro experiments on human pulmonary microvascular endothelial cells. Tertiary care ICU and academic laboratory. All patients admitted to the ICU suspected of being infected with severe acute respiratory syndrome coronavirus 2, using standardized hospital screening methodologies, had daily blood samples collected until testing was confirmed coronavirus disease 2019 negative on either ICU day 3 or ICU day 7 if the patient was coronavirus disease 2019 positive. None. Age- and sex-matched healthy control subjects and ICU patients that were either coronavirus disease 2019 positive or coronavirus disease 2019 negative were enrolled. Cohorts were well balanced with the exception that coronavirus disease 2019 positive patients were more likely than coronavirus disease 2019 negative patients to suffer bilateral pneumonia. Mortality rate for coronavirus disease 2019 positive ICU patients was 40%. Compared with healthy control subjects, coronavirus disease 2019 positive patients had higher plasma von Willebrand factor (p < 0.001) and glycocalyx-degradation products (chondroitin sulfate and syndecan-1; p < 0.01). When compared with coronavirus disease 2019 negative patients, coronavirus disease 2019 positive patients had persistently higher soluble P-selectin, hyaluronic acid, and syndecan-1 (p < 0.05), particularly on ICU day 3 and thereafter. Thrombosis profiling on ICU days 1-3 predicted coronavirus disease 2019 status with 85% accuracy and patient mortality with 86% accuracy. Surface hyaluronic acid removal from human pulmonary microvascular endothelial cells with hyaluronidase treatment resulted in depressed nitric oxide, an instigating mechanism for platelet adhesion to the microvascular endothelium. Thrombosis profiling identified endothelial activation and glycocalyx degradation in coronavirus disease 2019 positive patients. Our data suggest that medications to protect and/or restore the endothelial glycocalyx, as well as platelet inhibitors, should be considered for further study.

Endothelial Dysfunction is Associated With Increased Incidence, Worsened Severity, and Prolonged Duration of Acute Kidney Injury After Severe Trauma.

Nearly half of severely injured patients suffer acute kidney injury (AKI), but little is known about its pathogenesis or optimal management. We hypothesized that endothelial dysfunction, evidenced by elevated systemic soluble thrombomodulin (sTM) and syndecan-1, would be associated with higher incidence, worsened severity, and prolonged duration of AKI after severe trauma. A single-center cohort study of severely injured patients surviving ≥24 h from 2012 to 2016 was performed. Arrival plasma sTM and syndecan-1 were measured by ELISA. Outcomes included 7-day AKI incidence, stage, and prolonged AKI ≥2 days. The Kidney Disease Improving Global Outcomes guidelines were used for AKI diagnosis and staging. Univariate and multivariable analyses were performed. Of 477 patients, 78% were male. Patients had a median age of 38 (interquartile ranges [IQR] 27-54) and injury severity score of 17 (IQR 10-26). AKI developed in 51% of patients. Those with AKI were older and displayed worse arrival physiology. Patients with AKI had higher plasma levels of syndecan-1 (median 34.9 ng/mL vs. 20.1 ng/mL) and sTM (6.5 ng/mL vs. 4.8 ng/mL). After adjustment, sTM and syndecan-1 were both associated with higher AKI incidence, worse AKI severity, and prolonged AKI duration. The strength and precision of the association of sTM and these outcomes were greater than those for syndecan-1. A sensitivity analysis excluding patients with AKI on arrival demonstrated the same relationship. Elevated sTM and syndecan-1, indicating endothelial dysfunction, were associated with higher incidence, worsened severity, and prolonged duration of AKI after severe trauma. Treatments that stabilize the endothelium hold promise for AKI treatment in severely injured patients.

Prolonged Cardiopulmonary Bypass is Associated With Endothelial Glycocalyx Degradation

BackgroundThe endothelial glycocalyx (EG) is involved in critical regulatory mechanisms that maintain endothelial vascular integrity. We hypothesized that prolonged cardiopulmonary bypass (CPB) may be associated with EG degradation. We performed an analysis of soluble syndecan-1 levels in relation to duration of CPB, as well as factors associated with cell stress and damage, such as mitochondrial DNA (mtDNA) and inflammation. MethodsBlood samples from subjects undergoing cardiac surgery with CPB (n = 54) were obtained before and during surgery, 4-8 h and 24 h after completion of CPB, and on postoperative day 4. Flow cytometry was used to determine subpopulations of white blood cells. Plasma levels of mtDNA were determined using quantitative polymerase chain reaction and plasma content of shed syndecan-1 was measured. To determine whether syndecan-1 was signaling white blood cells, the effect of recombinant syndecan-1 on mobilization of neutrophils from bone marrow was tested in mice. ResultsCPB is associated with increased mtDNA during surgery, increased syndecan-1 blood levels at 4-8 h, and increased white blood cell count at 4-8 h and 24 h. Correlation analysis revealed significant positive associations between time on CPB and syndecan-1 (rs = 0.488, P < 0.001) and level of syndecan-1 and neutrophil count (rs = 0.351, P = 0.038) at 4-8 h. Intravenous administration of recombinant syndecan-1 in mice resulted in a 2.5-fold increase in the number of circulating neutrophils, concurrent with decreased bone marrow neutrophil number. ConclusionsLonger duration of CPB is associated with increased plasma levels of soluble syndecan-1, a signal for EG degradation, which can induce neutrophil egress from the bone marrow. Development of therapy targeting EG shedding may be beneficial in patients with prolonged CPB.

Reactive hyperemia correlates with the presence of sepsis and glycocalyx degradation in the intensive care unit: a prospective cohort study.

ObjectiveTo investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness.MethodsA prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection.ResultsFifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m.ConclusionReactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.

Syndecan-1 Is Critical in ARF6-Dependent Macropinocytosis Driven By KRAS Mutation in the Pathophysiology of Multiple Myeloma

Syndecan-1 (SDC1), also known as CD138, is a member of integral membrane heparin sulfate proteoglycans constantly expressed in plasma cells (PCs) and a primary diagnostic marker for human multiple myeloma (MM). We here further define new functions of SDC1 in the MM pathobiology. Firstly, flow cytometry and qRT-PCR analysis showed that SDC1 is expressed at relatively higher levels in AMO-1, U266, OPM2, H929, MM1S, and MM1R MM cells when compared with JJN3, RPMI 8226, and ANBL6 MM cells. SDC1 levels are comparable in paired MM cell lines sensitive or resistant to current anti-MM therapies including lenalidomide, pomalidomide, and bortezomib. Significantly increased SDC1 mRNA levels in advanced MM stages (p&lt;0.05) were further correlated with elevated soluble SDC1 protein levels in patient serum by ELISA. As expected, higher soluble SDC1 was also detected in culture media (CM) from MM cell lines with higher mRNA levels. Next, the effects of SDC1 were studied by SDC1 knockout (KO) in OPM2, JJN3 and H929 cells via CRISPR/Ca9 gene modification, followed by RNA-Seq analysis. Neglectable shed SDC1 in CM of all SDC1 KO MM cells confirm null SDC1 expression. Expression of anti-apoptosis gene BCL2L1, cell cycle genes (CCND1, CCND2), and transcription factor RELA gene were decreased in SDC1 KO vs control MM cells. Permanent SDC1 KO cells were eventually derived, indicating additional SDC1 function besides its role in MM cell growth and survival. KEGG pathway analysis associated with genes downregulated following SDC1 KO showed biological processes (BPs) enrichment in ECM-receptor interaction (hsa04512; p&lt; 0.001), cell adhesion molecules (hsa04514; p&lt;0.001), focal adhesion (hsa04510; p&lt;0.001), cytokine-cytokine receptor interaction (hsa04060; p=0.005), chemokine signaling pathway ( hsa04062; p=0.006), gap junction (hsa04540; p=0.002), axon guidance (hsa04360; p=0.016), JAK-STAT signaling pathway (hsa04630; p=0.026), lysosome (hsa04142; p=0.047).Specifically, IL-21R, related to JAK-STAT signaling pathway and cytokine-cytokine receptor interaction, was significantly decreased in SDC1 KO MM cells, as validated by qRT-PCR and human receptor array analysis. IL-21R contains the common cytokine-receptor gamma-chain shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15, indicating potential cross-talks between MM cells and surrounding immune cells via SDC1. Since its natural ligand IL-21 is mainly secreted by non-myeloma bone marrow (BM) accessory cells, SDC1 could also modulate interactions between myeloid lineages and MM cells via IL-21/IL-21R circuit in the BM microenvironment. Of note, other key MM antigens, i.e., CD38, BCMA, SLAMF7 were affected at mRNA levels in SDC1 KO vs control MM cells. Moreover, human receptor array data showed decreased expression in Flt-3L, DR6, Endoglin, GITR, HVEM, IL-2RG, IL-17RA, IL-21R, PECAM-1, PDGFRB, RAGE, Trappin-2 and µPAR in SDC1 KO MM cells. BPs through GO analysis in these downregulated receptors were cell activation (GO:0001775), cell surface receptor signaling pathway (GO:0007166), and immune system process (GO:0002370). KEGG analysis showed that those receptors molecular were enriched in cytokine-cytokine receptor interaction pathway (KEGG:04060).Consistent with RNA seq data, µPAR, an important factor of ARF6-dependent trafficking, was also found significantly downregulated in SDC1 KO MM cells. Since ARF6 activation regulates macropinocytosis, an essential metabolic pathway fueling Ras-driven cancer cells, these data suggest that SDC1 may involve in ARF6-dependent macropinocytosis in MM cells. ARF6 is induced by KRAS mutation, we thus checked macropinocytic index in KRAS-mutated MM cell lines. Increased macropinocytosis occur in KRAS-mutated MM cells (KMS28-BM, MM1S, MM1R) compared with KRAS WT OPM2 and KMS12-BM. Importantly, macropinocytosis was inhibited following SDC1 depletion in KRAS-mutated MM cells, indicating that SDC1 critically mediates KRAS-driven macropinocytosis in MM cells. These data highlight the requirements for SDC1 to mediate nutrient-scavenging macropinocytosis in MM cells, most prominently harboring KRAS-mutation. Taken together, our results identify new functions of SDC1 which are crucial to enhance myeloma cell fitness and adaptation to various conditions in the BM milieu, thereby further supporting SDC1 targeted immunotherapy in MM. Disclosures Munshi: Celgene: Consultancy; Amgen: Consultancy; Adaptive: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Oncopep: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Adaptive: Consultancy. Anderson:Celgene: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau.

Dynamics of soluble syndecan-1 in maternal serum during and after pregnancies complicated by preeclampsia: a nested case control study.

Background We investigated the dynamics and the predictive value of soluble syndecan-1 (Sdc-1), a biomarker of endothelial dysfunction, in uneventful pregnancies and pregnancies complicated by preeclampsia (PE). Methods Serum levels of Sdc-1 were measured at sequential time points during and after uneventful pregnancies (control, n = 95) and pregnancies developing PE (PE_long, n = 12). Levels were further measured in women with symptomatic PE (PE_state, n = 46) at a single time point. Results Sdc-1 levels increased consistently throughout pregnancy. In the PE_long group Sdc-1 levels were lower at all visits throughout pregnancy, and reached significance in weeks 18-22 (p = 0.019), 23-27 (p = 0.009), 28-32 (p = 0.006) and 33-36 (p = 0.008). After delivery, Sdc-1 levels dropped sharply in all pregnancies but were significantly elevated in the PE_long group. The predictive power of Sdc-1 was evaluated analyzing receiver operating characteristic (ROC) curves. A significant power was reached at weeks 14-17 (area under the curve [AUC] 0.65, p = 0.025), 23-27 (AUC 0.73, p = 0.004) and 33-36 (AUC 0.75, p = 0.013). Conclusions In summary, Sdc-1 levels were lower in women developing PE compared to uneventful pregnancies and Sdc-1 might be useful to predict PE. After delivery, Sdc-1 levels remained higher in women with PE. Additional studies investigating the link between glycocalyx degradation, Sdc-1 levels and placental and endothelial dysfunction in pregnancies affected by PE are warranted.

Relationship of mottling score, skin microcirculatory perfusion indices and biomarkers of endothelial dysfunction in patients with septic shock: an observational study

BackgroundIn patients with septic shock, the skin is often chosen for the evaluation of peripheral perfusion and oxygenation. Changes in skin microcirculatory vessel oxygen saturation and relative hemoglobin concentration can be described using a mottling score or captured with hyperspectral imaging. However, the effectiveness of the mottling score in assessing microcirculation remains to be shown. We hypothesize that the mottling score in patients with septic shock is related to skin microcirculatory perfusion indices quantified by hyperspectral imaging, biomarkers that reflect endothelium activation and damage, and clinical outcome.MethodsHyperspectral imaging of the knee area was performed in 95 intensive care patients with septic shock enrolled in a single-center observational study to obtain relative oxy/deoxyhemoglobin concentration values and construct anatomical maps of skin microcirculatory saturation. The blood was sampled to obtain concentrations of thrombomodulin, plasminogen activator inhibitor-1 (PAI-1), soluble intercellular adhesion molecule-1 (ICAM-1), soluble vascular cell adhesion molecule-1 (VCAM-1), angiopoietin-2, and syndecan-1. The spectrophotometrically obtained skin microvascular perfusion indices were compared to the mottling score and biomarker concentration. The association between mottling score, skin microcirculatory perfusion indices, and 28-day mortality was also analyzed.ResultsMicrocirculatory oxygen saturation was significantly lower and total hemoglobin concentration was significantly higher in patients with a mottling score of 2 compared to those with a score of 0 (p = 0.02), with no difference between other scores. We found an association between microcirculatory oxygen saturation and PAI-1 levels (rho = − 0.3; p = 0.007). Increased mottling score and decreased microcirculatory oxygen saturation were predictive of 28-day mortality (mottling score 2 vs 0: OR 15.31, 95% CI 4.12–68.11; microcirculatory oxygen saturation: OR 0.90, 95% CI 0.85–0.95). Endothelial biomarkers did not increase the predictive value of skin microcirculatory perfusion indices.ConclusionsHigher mottling scores are associated with lower microcirculatory oxygen saturation but with significant overlap between scores. Microcirculatory oxygen saturation is a quantitative measure of peripheral oxygenation and is more specific than the mottling score in predicting 28-day mortality.

The association of endothelial injury and systemic inflammation with perioperative myocardial infarction.

Background Major surgery predisposes to endothelial glycocalyx injury. Endothelial glycocalyx injury associates with cardiac morbidity, including spontaneous myocardial infarction. However, the relation between endothelial glycocalyx injury and the development of perioperative myocardial infarction remains unknown. Methods Fifteen perioperative myocardial infarction patients and 60 propensity-matched controls were investigated in this prospective study. The diagnosis of perioperative myocardial infarction was based on repeated cardiac troponin T measurements, electrocardiographs and recordings of ischaemic signs and symptoms. We measured endothelial glycocalyx markers – soluble thrombomodulin, syndecan-1 and vascular adhesion protein 1 – and an inflammatory marker, namely interleukin-6, preoperatively and 6 h and 24 h postoperatively. We calculated the areas under the receiver operating characteristics curves (AUCs) to compare the performances of the different markers in predicting perioperative myocardial infarction. The highest value of each marker was used in the analysis. Results The interleukin-6 concentrations of perioperative myocardial infarction patients were significantly higher preoperatively and 6 and 24 h postoperatively ( P = 0.002, P = 0.002 and P = 0.001, respectively). The AUCs (95% confidence intervals) for the detection of perioperative myocardial infarction were 0.51 (0.34–0.69) for soluble thrombomodulin, 0.63 (0.47–0.79) for syndecan-1, 0.54 (0.37–0.70) for vascular adhesion protein 1 and 0.69 (0.54–0.85) for interleukin-6. Conclusions Systemic inflammation, reflected by interleukin-6, associates with cardiac troponin T release and perioperative myocardial infarction. Circulating interleukin-6 demonstrated some potential to predict perioperative myocardial infarction, whereas endothelial glycocalyx markers did not.

A novel biomarker score for the screening and management of patients with plasma cell proliferative disorders.

Monoclonal plasma cell proliferative disorders comprise a wide spectrum of diseases associated to clonal B-cell expansion. Serum protein electrophoretic profile (SPEP) and circulating free light chains (FLCs) levels are the mainstay of diseases management. Recently, soluble (s) Syndecan-1 (SDC1, CD138) produced by myeloma plasma cells has been suggested in the monitoring and follow-up of patients with myeloma. The aim of our study is to evaluate sCD138 in addition with FLCs and SPEP for the screening of patients with different evolutive disease pathways. Sera from 73 patients with monoclonal gammopathy of undetermined significance (MGUS), 120 smoldering and 42 multiple myeloma (SMM and MM, respectively), 70 HCV-related mixed cryoglobulinemia (MC), 35 B-cell non-Hodgkin's lymphoma (B-NHL) and sera from 50 healthy donors (HD), were tested for sCD138, FLCs (assessed by means of ELISA and turbidimetric assay, respectively) and electrophoresis pattern (performed on Capillarys system) for the generation of a novel biomarker score (BS). Our results were grouped according to the two main lines of disease progression (vs. MM or B-NHL): in one group we found BS mean values of 0.2, 3.4, 5.3, 7.1 for HD, MGUS, SMM and MM, respectively; in the other group of 0.2, 4.4, 6.7 for HD, MC and B-NHL. We showed that BS mean values follow the ingravescence disease status towards the two main lines of progression to cancerous conditions; it could represent an additional useful tool in the management of screening and/or follow-up.

253. Sublingual microvascular density and glycocalyx barrier dynamics, during and after normal and preeclamptic pregnancy

Introduction The apical surface of the vascular endothelium comprises a complex meshwork of membrane-bound proteoglycans and glycoproteins, the glycocalyx. The glycocalyx has important vasoregulatory roles; e.g., growth factor binding, signal transduction, coagulation and permeability. Glycocalyx damage has been implicated in several vascular diseases. Hypothesis Glycocalyx structural barrier integrity and microvascular perfusion are reduced in women with preeclampsia (PE). Methods We evaluated 17 women with PE and 27 with uncomplicated pregnancy (NL), just prior to delivery (LD) and at 24–48 h postpartum (PP). The sublingual microvasculature was interrogated using sidestream-darkfield imaging to compare glycocalyx integrity, microvascular density and percentage of perfused vascular segments. Glycocalyx integrity (for vessels 5–25 μm) was measured as depth of the RBC accessible region(AR), in which greater AR signifies diminished ability of glycocalyx to exclude RBCs. Plasma soluble syndecan-1, a shed glycocalyx component, was measured by ELISA. Results Microvascular density (segments/mm2) was greater in NL-LD (478 ± 28) compared to PE-LD (378 ± 35 p = 0.002), decreasing in both NL-PP (355 ± 28) and PE-PP (306 ± 35). Perfusion was not different between groups. AR in NL-LD (2.33 ± 0.05microns) was surprisingly greater than PE-LD (2.17 ± 0.06 p = 0.03), or NL-PP (2.19 ± 0.05 p = 0.05) but not different from PE-PP (2.26 ± 0.06). The change in AR between timepoints (LD-PP) indicates postpartum improvement in barrier function in NL (but not PE) group (−0.09 ± 0.4 vs 0.08 ± 0.3 p = 0.05). Maternal plasma syndecan-1 was higher in NL-LD (1126 ± 110.3 ng/mL) compared to PE-LD (715.5 ± 112.1 ng/mL; p = 0.008), and declined in both groups PP (NL-PP 210 ± 98, PE-PP 173 ± 120; NS). Conclusion Women with PE exhibited a reduction in functional microvascular density compared to NL. The increase in RBC accessibility(AR) in NL compared to PE was opposite to our hypothesis. This reduction in endothelial glycocalyx barrier function was accompanied by a higher level of circulating syndecan-1 prior to delivery in NL. The physiologic significance of these glycocalyx changes remain to be determined. Funding PO1-HD-30367, R21-HD-83659, AHA16SFRN27810001

Elevated soluble syndecan-1 levels in neuromyelitis optica are associated with disease severity

Syndecan-1 (SDC-1) is a transmembrane member that has a profound influence on the resolution of inflammation. Soluble syndecan-1 (sSDC-1) levels have been shown to increase in many inflammatory diseases. However, it remains unknown whether sSDC-1 concentration is elevated in neuromyelitis optica (NMO) and multiple sclerosis (MS) patients. The aims of this pilot study were to investigate the relationship between sSDC-1 and disease severity in NMO and MS and whether sSDC-1 has potential as an effective marker for disease severity. We measured sSDC-1 concentrations by using an enzyme-linked immunosorbent assay (ELISA). NMO patients had significantly higher CSF sSDC-1 levels than MS patients or controls. We also found a positive correlation between the increased CSF sSDC-1 levels and increased severity in NMO disease, but not in MS. In NMO, CSF sSDC-1 concentrations were positively correlated with CSF interleukin (IL)-6, IL-8 and IL-17. Overall, we showed levels of CSF sSDC-1 were higher in NMO patients and had a positive relationship with disease severity of NMO but not with MS. CSF sSDC-1 may be an effective marker of NMO disease severity.

An Overview of Celiac Disease in Childhood Type 1 Diabetes.

ContextCeliac disease (CD) is a common phenomenon in children with Type 1 diabetes (T1D). In the present review, we have discussed the pathogenesis, diagnostic biomarkers, risk factors, and prognosis of CD in the context of pediatric T1D.Evidence AcquisitionLiterature published in Web of Science, PubMed, Scopus, Google Scholar, and Cochrane Library were scrutinized up to the end of 2017. The keywords of celiac disease, Type 1 diabetes, children, and pediatric were used in different combinations.ResultsImmune cytotoxic reactions along with dampen immune regulatory functions contribute to CD in the context of pediatric T1D. Many children with simultaneous CD and T1D do not represent with the clinical signs of the enteropathy rendering a diagnostic challenge. The most common screening tests in these children are routine serological tests of CD, anti - endomysial, anti - transglutaminase, and anti - deamidated gliadin peptide antibodies. Typing for human leukocyte antigens of DQ - 2 and DQ - 8 may assist in the diagnosis of silent CD in children with T1D. The most significant shared non - HLA genetic loci of CD and T1D comprise CTLA - 4, TAGAP, IL - 18RAP, PTPN2, RGS1, SH2B3, CCR5. Interactions between these loci can be important in susceptibility to CD in T1D. Some new biomarkers have been suggested for diagnosis of CD including ischemia-modified albumin (IMA), soluble syndecan-1 (SSDC-1), regenerating gene Iα (REG-Iα), Neurotensin, and Zonulin, which can be useful for diagnosis and screening of CD in childhood T1D.ConclusionsOverall, active seropositive CD seems to be of clinical importance in T1D with significant impacts on the quality of life and predisposition to diabetes associated complications. It is important to detect CD in the context of T1D to prevent potential risks contributing to morbidities and mortalities associated with either CD or T1D.

Soluble Syndecan-1: A Novel Biomarker of Small Bowel Mucosal Damage in Children with Celiac Disease.

Syndecan-1 (SDC1) is essential for maintaining normal epithelial barrier. Shedding of SDC1 ectodomain, reflected by serum soluble syndecan-1 (SSDC1) levels, is regulated by inflammation. Increased intestinal permeability plays a central role in celiac disease (CD). The association between SSDC1 levels and mucosal damage in CD has not been evaluated. To evaluate serum SSDC1 levels in children with CD and to determine its relationship with histological grading classified by modified Marsh criteria. This is a cross-sectional, pilot study, in which serum SSDC1 was analyzed by ELISA in a cohort of 49 untreated children with CD and 15 children with nonspecific abdominal pain (AP). CD was diagnosed based on positive celiac serology and small intestinal biopsy. SSDC1 levels at the time of biopsy were correlated with Marsh grading. Controls were defined by AP, negative celiac serology, normal upper endoscopy, and small intestinal biopsies. SSDC1 levels were significantly higher in CD patients compared to AP controls (116.2±161 vs. 41.3±17.5ng/ml, respectively, p<0.01). SSDC1 levels were significantly higher in patients with Marsh 3c lesion compared to AP controls (170.6±201 vs. 41.3±17.5ng/ml, respectively, p<0.05). SSDC1 concentrations displayed a significant correlation with mucosal damage defined by Marsh (r=0.39, p<0.05). This is the first study demonstrating elevated levels of serum SSDC1 in children with CD. Our results suggest that SSDC1 is a potentially novel marker of intestinal mucosal damage in patients with CD. Its applicability as a surrogate biomarker in CD remains to be determined.

Shedding of Syndecan-1/CXCL1 Complexes by Matrix Metalloproteinase 7 Functions as an Epithelial Checkpoint of Neutrophil Activation.

Although neutrophils play critical roles in innate immunity, in excess these cells cause severe tissue damage. Thus, neutrophil activation must be tightly regulated to prevent indiscriminant damage. Previously, we reported that mice lacking matrix metalloproteinase (MMP) 7 are protected from lung injury owing to markedly impaired neutrophil movement from the interstitium into mucosal lumenal spaces. This phenotype resulted from a lack of MMP7 shedding of syndecan-1, a heparan sulfate proteoglycan that carries the neutrophil chemokine CXCL1 as cargo. Here, we assessed if shedding syndecan-1/CXCL1 complexes affects neutrophil activation. Whereas injured monolayers of wild-type alveolar type II cells potently stimulated neutrophil activation, as gauged by release of myeloperoxidase, cells from Mmp7(-/-) or syndecan-1-null (Sdc1(-/-)) mice or human cells with MMP7 knockdown did not. In vivo, we observed reduced myeloperoxidase release relative to neutrophil numbers in bleomycin-injured Mmp7(-/-) and Sdc1(-/-) mice. Furthermore, we determined that soluble syndecan-1 directly stimulated neutrophil activation in the absence of cellular damage. These data indicate that MMP7 shedding of syndecan-1/CXCL1 complexes functions as a checkpoint that restricts neutrophil activation at sites of epithelial injury.

Soluble syndecan-1 (SDC1) serum level as an independent pre-operative predictor of cancer-specific survival in prostate cancer.

PSA-screening detects many cases of clinically non-aggressive prostate cancer (PC) leading to significant overtreatment. Therefore, pre-operatively available prognostic biomarkers are needed to help therapy decisions. Syndecan-1 (SDC1) is a promising prognostic tissue marker in several cancers including PC but serum levels of shedded SDC1-ectodomain (sSDC1) have not been assessed in PC. A total of 150 patients with PC were included in this study (n = 99 serum samples, n = 103 paraffin-embedded samples (FFPE), n = 52 overlap). SDC1 protein expression and cellular localization was evaluated by immunohistochemistry (IHC), while sSDC1 serum concentrations were measured by ELISA. Serum sSDC1 levels were compared to those of MMP7, which is known to be a protease involved in SDC1 ectodomain-shedding. Clinico-pathological and follow-up data were collected and correlated with SDC1 tissue and serum levels. Disease (PC)-specific (DSS) and overall-survival (OS) were primary endpoints. Median follow-up was 167 months in the serum- and 146 months in the FFPE-group. SDC1-reactivity was higher in non-neoplastic prostate glands compared to PC. In addition, cytoplasmatic, but not membranous SDC1 expression was enhanced in PC patients with higher Gleason-score >6 PC (P = 0.016). Soluble SDC1-levels were higher in patients with Gleason-score >6 (P = 0.043) and metastatic disease (P = 0.022) as well as in patients with progressed disease treated with palliative transurethral resection (P = 0.002). In addition, sSDC1 levels were associated with higher MMP7 serum concentration (P = 0.005). In univariable analyses, only sSDC1-levels exhibited a trend to unfavorable DSS (P = 0.077). In a multivariable pre-operative model, high pre-operative sSDC1-level (>123 ng/ml) proved to be an independent marker of adverse OS (P = 0.048) and DSS (P = 0.020). The present study does not confirm the prognostic relevance of SDC1-IHC. The significant higher sSDC1 serum levels in advanced cases of PC, suggest that SDC1 shedding might be involved in PC progression. Additionally, high sSDC1-level proved to be an independent factor of adverse OS and DSS in a multivariable pre-operative model, making evaluation of sSDC1-levels a promising tool for pre-operative risk-stratification and/or therapy monitoring. Prostate 76:977-985, 2016. © 2016 Wiley Periodicals, Inc.

Syndecan-1 expression in cutaneous squamous cell carcinoma and its significance

Objective To measure serum and tissue levels of soluble syndecan-1 (SDC1) in patients with cutaneous squamous cell carcinoma (CSCC) , and to explore the relationship between the expression of SDC1 and clinicopathologic features of CSCC as well as between the serum and tissue levels of SDC1. Methods An immunohistochemical study was performed to measure SDC1 expression in the epidermis of lesional specimens from 93 patients with CSCC and normal skin specimens from 30 healthy human controls, and enzyme-linked immunosorbent assay (ELISA) to detect serum levels of soluble SDC1 in 81 patients with CSCC and 30 healthy human controls. Results The expression of SDC1 was significantly lower in CSCC tissues than in normal skin tissues (Z = 3.85, P 0.05) . CSCC patients with lymphatic metastasis showed significantly higher serum levels of SDC1 compared with those without (Z = 5.30, P < 0.01) . The serum levels of soluble SDC1 were significantly negatively correlated with its tissue levels in CSCC patients (rs =-0.625, P < 0.01) . Receiver operating characteristic (ROC) curve analysis showed that the best cutoff point of serum SDC1 levels was 65.5 μg/L for the diagnosis of lymphatic metastasis, with the sensitivity, specificity and area under the curve (AUC) being 73.7% , 87.1% and 0.904 (0.840-0.968) respectively. Conclusion The down-regulated tissue expression but up-regulated serum levels of SDC1 may be associated with the invasiveness of CSCC, and elevated serum SDC1 levels are somewhat valuable to the diagnosis of lymphatic metastasis. Key words: Carcinoma, squamous cell; Skin; Serum; Pathology; Syndecan-1

Reduced serum levels of syndecan‐1 in patients with tongue squamous cell carcinoma

To investigate soluble syndecan-1 (Sdc-1) in the sera of patients with tongue squamous cell carcinoma (SCC) and its correlation with the histopathological criteria of tumors. In a case-control study using a convenient method of sampling, 18 female and 25 male patients with confirmed diagnosis of tongue SCC, and 19 healthy females and 27 males were studied. Soluble Sdc-1 was measured in the sera of 43 patients with tongue SCC and was compared with that of healthy age-/sex-matched controls using a commercial enzyme-linked immunosorbent assay. Clinical and pathological data, along with the demographic characteristics of the patients, were recorded at the time of sampling. The levels of soluble Sdc-1 were decreased in the sera of patients compared to controls (91.17 ± 88.60 vs. 158.17 ± 103.47 ng/mL, P = .002). Although patients who smoke tended to have higher grades (P = .043), there was no significant difference in the level of syndecan-1 between smokers and non-smokers. A significant difference between syndecan-1 in the sera of patients with tumors of different stages was observed (Kruskal-Wallis test P=0.039); however, scarcity of patients in stages I and III decreased the power of the comparison. Sdc-1 levels in the sera of patients do not correlate with the tumor progression in the tongue SCC. This is in contrast with the reported inverse correlation between the expression level of membranous Sdc-1 and the histological grade and size of head and neck tumors. Therefore, Sdc-1 shedding may not be a major mechanism in the progressive loss of its expression regarding tongue tumor. NA Laryngoscope, 126:E191-E195, 2016.