Endothelial Cell-specific Molecule-1 Research Articles

Histone lactylation facilitates hepatocellular carcinoma progression by upregulating endothelial cell-specific molecule 1 expression.

Hepatocellular carcinoma (HCC) is a common malignant tumor. Histone lactylation, a novel epigenetic modification, plays a crucial role in various cancers. However, the functional role and underlying mechanism of histone lactylation in HCC progression have not yet been investigated. Histone lactylation levels in HCC tissues and cells were assessed using a densitometric kit and western blot analysis. The role of histone lactylation in cell malignant phenotypes was determined through functional assays in vitro, and a xenograft tumor model was established to verify the function of histone lactylation in vivo. ChIP assay was performed to explore the interaction between histone lactylation and endothelial cell-specific molecule 1 (ESM1). Additionally, gain-and-loss-of-function assays were conducted to investigate the regulatory role of ESM1 in HCC pathogenesis. Histone lactylation levels were increased in HCC tissues and cells, and H3K9 lactylation (H3K9la) and H3K56 lactylation (H3K56la) were identified as the histone modification sites. We observed that H3K9la and H3K56la caused abnormal histone lactylation and were associated with poor prognosis. Functionally, histone lactylation was found to promote HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro. However, histone lactylation inhibition with 2-deoxy-d-glucose (2-DG) reduced the malignant phenotypes of HCC cells. In vivo, 2-DG treatment reduced tumor growth and metastasis in the HCC mouse model. Mechanistically, it was revealed that histone lactylation activated ESM1 transcription in HCC cells. ESM1 was expressed at a high level in HCC and exerted a carcinogenic role. Histone lactylation facilitates cell malignant phenotypes, tumor growth, and metastasis by upregulating ESM1 expression in HCC, which reveals the downstream molecular mechanism of histone lactylation and might provide a novel therapeutic target for HCC therapy.

Endothelial cell specific molecule 1 promotes epithelial-mesenchymal transition of cervical cancer via the E-box binding homeobox 1.

To investigate the mechanism of endothelial cell specific molecule 1 (ESM1) promoting cervical cancer cell proliferation and EMT characteristics through zinc finger E-box binding homeobox 1 (ZEB1)/EMT pathway. The correlation between ESM1 expression and prognosis of cervical cancer patients was analyzed by bioinformatics. SiHa, HeLa cell lines and corresponding control cell lines with stable ESM1 expression were obtained. Cell proliferation ability was detected by CCK-8 assay. The invasion and migration ability of Hela and SiHa cells were detected by Transwell assay and scratch closure assay. Expressions of EMT-related markers E-cadherin and Vimentin were detected by real-time PCR. The ability of silenced ESM1 to tumor formation in vivo was detected by tumor formation in nude mice. The effects of aloe-emodin on inhibit ESM1 expression and its inhibitory effect on cervical cancer cells in vitro and in vivo were analyzed by the same method. ESM1 was highly expressed in cervical cancer, and the high expression of ESM1 was associated with poor prognosis of cervical cancer patients. CCK-8 results showed that the proliferation, invasion and migration of Hela and SiHa cells were significantly reduced after siRNA interfered with ESM1 expression. Overexpression of ESM1 promoted the proliferation and migration of cervical cancer cells. Mechanism studies have shown that the oncogenic effect of ESM1 is realized through the ZEB1/PI3K/AKT pathway. High throughput drug screening found that aloe-emodin can target ESM1. Inhibitory effect of aloe emodin on ESM1/ZEB1/EMT signaling pathway and cervical cancer cells. The silencing of ESM1 expression may inhibit the proliferation, invasion, metastasis and epithelial-mesenchymal transformation of cervical cancer cells by inhibiting ZEB1/PI3K/AKT. Aloe-emodin is a potential treatment for cervical cancer, which can play an anti-tumor role by inhibiting ESM1/ZEB1.

B cell lymphoma 6 promotes hepatocellular carcinoma progression by inhibiting tumor infiltrating CD4+T cell cytotoxicity through ESM1

Immunotherapy exhibited potential effects for advanced hepatocellular carcinoma, unfortunately, the clinical benefits are often countered by cancer adaptive immune suppressive response. Uncovering the mechanism how cancer cells evade immune surveillance would help to develop new immunotherapy approaches and combination therapy. In this article, by analyzing the transcriptional factors which modulate the differentially expressed genes between T cell infiltration high group and low group, we identified oncoprotein B cell lymphoma 6 (BCL6) suppresses the infiltration and activation of tumor infiltrating T lymphocytes, thus correlated with poorer clinical outcome. By using antibody deletion experiment, we further demonstrated that CD4+T cells but not CD8+T cells are the main lymphocyte population suppressed by Bcl6 to promote HCC development. Mechanistically, BCL6 decreases cancer cell expression of pro-inflammatory cytokines and T lymphocyte chemokines such as IL6, IL1F6, and CCL5. Moreover, BCL6 upregulates Endothelial cell-specific molecule 1 (ESM1) to inhibit T lymphocyte recruitment and activation possibly through ICAM-1/LFA-1 signaling pathway. Our findings uncovered an unappreciated paracrine mechanism how cancer cell-derived BCL6 assists cancer cell immune evasion, and highlighted the role of CD4+T cells in HCC immune surveillance.

Esm-1 mediates transcriptional polarization associated with diabetic kidney disease.

Esm-1, endothelial cell-specific molecule-1, is a susceptibility gene for diabetic kidney disease (DKD) and is a secreted proteoglycan, with notable expression in kidney, which attenuates inflammation and albuminuria. However, little is known about Esm1 expression in mature tissues in the presence or absence of diabetes. We utilized publicly available single-cell RNA sequencing data to characterize Esm1 expression in 27,786 renal endothelial cells (RECs) obtained from three mouse and four human databases. We validated our findings using bulk transcriptome data from 20 healthy subjects and 41 patients with DKD and using RNAscope. In both mice and humans, Esm1 is expressed in a subset of all REC types and represents a minority of glomerular RECs. In patients, Esm1(+) cells exhibit conserved enrichment for blood vessel development genes. With diabetes, these cells are fewer in number and shift expression toward chemotaxis pathways. Esm1 correlates with a majority of genes within these pathways, delineating a glomerular transcriptional polarization reflected by the magnitude of Esm1 deficiency. Diabetes correlates with lower Esm1 expression and with changes in the functional characterization of Esm1(+) cells. Thus, Esm1 appears to be a marker for glomerular transcriptional polarization in DKD.NEW & NOTEWORTHY Esm-1 is primarily expressed in glomerular endothelium in humans. Cells expressing Esm1 exhibit a high degree of conservation in the enrichment of genes related to blood vessel development. In the context of diabetes, these cells are reduced in number and show a significant transcriptional shift toward the chemotaxis pathway. In diabetes, there is a transcriptional polarization in the glomerulus that is reflected by the degree of Esm1 deficiency.

Abstract 3591: Upregulation of CXCL8 is an early step in the oncogenic transition of human thyroid cells by BRAFV600E

Abstract Introduction: BRAFV600E is one of the most common oncogenic mutations in human thyroid cancers, especially in papillary thyroid carcinoma (PTC). However, the early molecular changes caused by this mutation have not been studied previously in human thyrocytes in vitro. Methods: Primary cultures of cells derived from noncancerous thyroid tissue of patients (at least n=3) were infected with BRAFV600E adenovirus to mimic the mutated condition. Changes induced by the infection were measured at early times (<24h). Transcriptome analysis was performed on infected thyrocytes (n=6) to determine the highest differentially expressed genes between the control and infected groups, which were then verified at the gene and protein levels. RNAi downregulation experiments were performed to determine the cross-regulatory function of the genes. Results: The induction of BRAFV600E mutation, confirmed at the protein level, increased proliferation of the cells, and morphological changes were observed at approximately 24h post-infection. The decreased expression of thyroid-specific genes, viz. TSHR, TG, and TPO were observed after >72h post-introduction of BRAFV600E mutation. Transcriptome and protein expression analysis of BRAFV600E-positive thyrocytes showed the overexpression of chemokines CXCL8 and CXCL12, and upregulation of endothelial cell-specific molecule 1 (ESM1). These molecules are known to be associated with increased neoangiogenesis and proliferation. Functional studies showed that siRNA knockdown of CXCL8 decreased the expressions of CXCL12 and ESM1, whereas knockdown of either CXCL12 or ESM1 did not decrease the expression of CXCL8. Conclusion: Increased proliferation, de-differentiation, upregulation of chemokines, and endothelial-specific factor are effects associated with BRAFV600E-driven thyroid carcinogenesis. CXCL8 appears to play an important early regulatory role in this process. Citation Format: Rhitajit Sarkar, Priyanka Bolel, Joanna Klubo-Gwiezdzinska, Marvin C. Gershengorn. Upregulation of CXCL8 is an early step in the oncogenic transition of human thyroid cells by BRAFV600E [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3591.

Associations between inflammatory and angiogenic proteomic biomarkers, and cardiovascular events and mortality in relation to kidney function

ABSTRACT Background The links between chronic kidney disease (CKD) and the high burden of cardiovascular disease remain unclear. We aimed to explore the association between selected inflammatory and angiogenic biomarkers, kidney function and long-term outcome in patients with an acute coronary syndrome (ACS) and to test the hypothesis that CKD status modifies this association. Methods A total of 1293 ACS patients hospitalized between 2008 and 2015 were followed until 31 December 2017. Plasma was collected on days 1–3 after admission. A total of 13 biomarkers were a priori identified and analysed with two proteomic methods, proximity extension assay or multiple reaction monitoring mass spectrometry. Boxplots and multiple linear regression models were used to study associations between biomarkers and kidney function and adjusted standardized Cox regression with an interaction term for CKD was used to assess whether CKD modified the association between biomarkers and major adverse cardiovascular events and death (MACE+). Results The concentrations of nine biomarkers—endothelial cell-specific molecule-1 (ESM-1), fibroblast growth factor 23 (FGF-23), fractalkine (CX3CL1), interleukin-1 receptor antagonist (IL-1RA), interleukin-18 (IL-18), monocyte chemotactic protein-1 (MCP-1), placenta growth factor (PlGF), transmembrane immunoglobulin 1 (TIM-1) and vascular endothelial growth factor A (VEGFA)—were inversely associated with kidney function. ESM-1, FGF-23 and TIM-1 showed associations with MACE+. Only FGF23 remained independently associated after adjustment for the other biomarkers (hazard ratio per standard deviation increase 1.34; 95% Bonferroni corrected confidence interval 1.19–1.50). None of the biomarkers showed an interaction with CKD. Conclusions The concentrations of 9 of the 13 prespecified inflammatory and angiogenic proteomic biomarkers increased when kidney function declined. Only FGF-23 demonstrated an independent association with MACE+, and this association was not modified by CKD status. These findings further support FGF-23 as an independent prognostic marker in ACS patients with and without CKD.

Roles of endothelial cell specific molecule‑1 in tumor angiogenesis (Review).

Angiogenesis plays a crucial role in tumor growth and metastasis, and is heavily influenced by the tumor microenvironment (TME). Endothelial cell dysfunction is a key factor in tumor angiogenesis and is characterized by the aberrant expression of pro-angiogenic factors. Endothelial cell specific molecule-1 (ESM1), also known as endocan, is a marker of endothelial cell dysfunction. Although ESM1 is primarily expressed in normal endothelial cells, dysregulated ESM1 expression has been observed in human tumors and animal tumor models, and implicated in tumor growth, metastasis and angiogenesis. The precise role of ESM1 in tumor angiogenesis and its potential regulatory mechanisms are not yet conclusively defined. However, the aim of the present review was to explore the involvement of ESM1 in the process of tumor angiogenesis in the TME and the characteristics of neovascularization. In addition, the present review discusses the interaction between ESM1 and angiogenic factors, as well as the mechanisms through which ESM1 contributes to tumor angiogenesis. Furthermore, the reciprocal regulation between ESM1 and the TME is explored. Finally, the potential of targeting ESM1 as a therapeutic strategy for tumor angiogenesis is presented.

Intermittent hypoxia increased the expression of ESM1 and ICAM-1 in vascular endothelial cells via the downregulation of microRNA-181a1.

Sleep apnea syndrome (SAS) exposes cells throughout the body to intermittent hypoxia (IH). Intermittent hypoxia is a risk factor not only for hypertension and insulin resistance but also for vascular dysfunction. We have reported correlations between IH, insulin resistance and hypertension. However, the details of why IH leads to vascular dysfunction remain unclear. In this study, we investigated inflammation-related transcripts in vascular endothelial cells (human HUEhT-1 and mouse UV2) exposed to IH by real-time RT-PCR and found that intercellular adhesion molecule-1 (ICAM-1) and endothelial cell-specific molecule-1 (ESM1) mRNAs were significantly increased. ELISA confirmed that, in the UV2 cell medium, ICAM-1 and ESM1 were significantly increased by IH. However, the promoter activities of ICAM-1 and ESM1 were not upregulated. On the other hand, IH treatment significantly decreased microRNA (miR)-181a1 in IH-treated cells. The introduction of miR-181a1 mimic but not miR-181a1 mimic NC abolished the IH-induced upregulation of Ican-1 and ESM1. These results indicated that ICAM-1 and ESM1 were upregulated by IH via the IH-induced downregulation of miR-181a1 in vascular endothelial cells and suggested that SAS patients developed atherosclerosis via the IH-induced upregulation of ICAM-1 and ESM1.

Endothelial cell-specific molecule 1 is regulated separately in follicular and serum compartments of PCOS patients: a pilot study.

The aim of our study is to detect endothelial cell-specific molecule 1 (ESM-1) levels in the serum and follicular fluids (FF) of patients undergoing IVF/ICSI for PCOS. The presence of ESM-1 traffic between the serum and follicular compartment was analyzed. A total of 50 patients, including 25 infertile patients diagnosed with PCOS according to the Revised Rotterdam criteria, and 25 patients in infertility follow-up for reasons other than PCOS, were included in the pilot study. Patients in the control group were required to have no clinical and laboratory findings of PCOS. Non-PCOS controls were selected from patients diagnosed with a male factor or unexplained infertility, and a homogeneous group was formed. Patients in PCOS and control groups were matched in terms of age and BMI. IVF/ICSI was started with antagonist protocol in both groups. Follicular fluids obtained on the day of egg collection were centrifuged, put into RNAlater, frozen, and stored until the day of analysis. Endothelial cell-specific Molecule 1 levels were measured in follicular fluid and serum samples of PCOS patients by enzyme-linked immunosorbent assay (ELISA) using the Human ESM-1 kit. Serum ESM-1 levels of the PCOS group were significantly lower than FF-ESM1 levels (668.6±189.2 vs. 979.0±233.9 ng/L, p<0.02). FF-ESM1 levels of the control group were significantly higher than serum ESM1 levels (639.3±206.4 ng/L vs. 503.2±102.4 ng/L, p<0.01). Serum ESM1 levels of the PCOS group were significantly higher than the control group (668.6±189.2 ng/L vs. 503.2±102.4 ng/L, p<0.01). Similarly, FF-ESM1 levels of the PCOS group were significantly higher than the control group (979.0±233.9 ng/L vs. 639.3±206.4 ng/L, p<0.01). There was no significant correlation between serum and FF-ESM1 levels. A positive and significant correlation was found between FF-ESM1 and serum LH levels in PCOS (r=0.655, p<0.02). Similarly, a positive and significant correlation was found between FF-ESM1 and serum testosterone levels in PCOS (r=0.470, p<0.03). Moreover, a positive and significant correlation was detected between FF-ESM-1, AFC, MII, and total oocyte counts in PCOS. Serum and FF-ESM-1 are regulated independently of each other in PCOS patients. ESM-1 may play a role in ovulatory dysfunction due to PCOS.

EpCAM, Ki67, and ESM1 Predict Hepatocellular Carcinoma Recurrence After Liver Transplantation.

Liver transplantation (LT) is a good therapeutic decision, cures hepatocellular carcinoma (HCC) and promotes survival of cases with unrespectable HCC based on the Milan criteria. HCC still recur after LT. Identifying high risk tissue markers that predict recurrence becomes important for LT decision-making. Little is known regarding use of tissue expression of epithelial cell adhesion molecule (EpCAM) to predict HCC recurrence. This study investigates the role of EpCAM, Ki67, and endothelial-cell-specific molecule-1 (ESM1) as immunohistochemical markers to predict HCC recurrence after LT. It included 52 explanted HCC tissues from Egyptian patients who had undergone LT for HCC according to Milan criteria. Immunohistochemical staining was done on paraffin-embedded formalin-fixed tissue sections. HCC recurrence occurred in 13.5% cases. Positive EpCAM expression in HCC, was significantly associated with HCC recurrence, ( P =0.011), achieving 71.43% sensitivity, 84.44% specificity and 78.8% accuracy in predicting recurrence. High Ki67 percentage was significantly associated with HCC recurrence, ( P =0.005), achieving 57.14% sensitivity, 86.67% specificity and 82.69% accuracy in predicting HCC recurrence. ESM1 showed significant association with HCC recurrence ( P =0.041), with 71.43% sensitivity, 71.11% specificity and 71.15% accuracy in predicting HCC recurrence. EpCAM score and Ki67 percentage showed positive correlation. In conclusion, it is suggested that large tumor size (≥3cm), advanced pathologic staging and Ki67 could be stratified as high risk predictors of HCC recurrence after LT. Although higher classes of Child-Turcotte-Pugh classification, high serum alpha-fetoprotein, microvascular invasion, positive EpCAM and ESM1 are stratified as lower risk predictors of HCC recurrence after LT.

475-P: Intermittent Hypoxia Increased the Expression of Intercellular Adhesion Molecule-1 and Endothelial Cell–Specific Molecule-1 in Vascular Endothelial Cells via the Downregulation of MicroRNA-181a1

Sleep apnea syndrome (SAS), which is characterized by recurrent episodes of oxygen desaturation and reoxygenation (intermittent hypoxia [IH]), is a risk factor for vascular dysfunction, as well as hypertension, and insulin resistance/Type 2 diabetes. We have reported correlations between IH and insulin resistance/Type 2 diabetes, and hypertension. However, the question of why vascular dysfunction is induced by IH has remained unanswered. Here, we investigated the effects of IH on the expression of endothelial inflammatory transcripts such as intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-8, C-C motif chemokine ligand 5 (CCL5), endothelial nitric oxide synthase (NOS3), vascular cell adhesion molecule-1 (VCAM-1), endothelial cell specific molecule 1 (ESM1), and endothelin-1 (EDN-1) using an in vitro IH system. Human and mouse vascular endothelial cells (HUEhT-1 and UV2) were exposed to IH or normoxia for 24 hours. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of ICAM-1 and ESM1 in both HUEhT-1 (P=0.0436 and P=0.0145, respectively) and UV2 cells (P&amp;lt;0.0001 and P=0.0422, respectively). ELISA showed that ICAM-1 and ESM1 were significantly increased (P=0.0105 and P&amp;lt;0.0001, respectively) in the UV2 cell medium by IH. Reporter assays revealed that the promoter activities of ICAM-1 and ESM1 were not increased by IH. The microRNA (miR)-181a1 level of IH-treated cells was significantly decreased relative to that of normoxia-treated cells (P=0.0374). The IH-induced upregulation of ICAM-1 and ESM1 was abolished by the introduction of miR-181a1 mimic, indicating that IH stress increased levels of ICAM-1 and ESM1 via the inhibition of miR-181a1-mediated mRNA degradation, leading SAS patients to develop atherosclerosis. Disclosure S.Takasawa: None. M.Makino: None. A.Yamauchi: None. S.Sakuramoto-tsuchida: None. Y.Takeda: None. T.Uchiyama: None. R.Shobatake: None.

Prognostic role of the endothelial cell-specific molecule-1 histopathologic expression in renal cell cancer.

To measure the level of endothelial cell-specific molecule-1 (ESM-1) expression among the Renal Cell Cancer (RCC) variants using by immunohistochemical method and determine the relationship between ESM-1 expression and RCC prognosis. ESM-1 immunoreactivity scores (IR) were measured in appropriate renal tumoral tissue blocks of 153 consecutive RCC patients in this retrospective analysis of prospectively collected data. Mean ESM-1 IR scores were calculated in patients who were pathologically diagnosed with clear cell RCC (ccRCC), papillary RCC (pRCC), and chromophobe RCC (chRCC). Progression-free survival and overall survival were evaluated using the log-rank test according to ESM-1 IR scores. Survival rates were calculated using Kaplan-Meier survival analysis. In the ccRCC group, the mean ESM-1 IR scores of those with local invasion were significantly higher than those without local invasion (P = 0.014). The mean ESM-1 IR score of patients with metastatic ccRCC was significantly higher than those with non-metastatic ccRCC (P < 0.001). Considering all patients regardless of RCC subtype pathologies, the mean ESM-1 IR score in clinical stage 1 tumor was 3.82 ± 1.98, 4.87 ± 1.74 in clinical stage 2, 5.88 ± 2 in clinical stage 3, and 6.60 ± 2.23 in clinical stage 4. The mean ESM-1 IR score of patients with metastatic ccRCC was significantly higher than those with non-metastatic ccRCC (P < 0.001). The mean follow-up period for all patients in this study was 71 months (range 1-120 months). It has been shown that the higher the ESM-1 IR score, the lower the 10-year overall survival and disease-free survival rates (P = 0.026, P = 0.005). Immunohistochemical expression of ESM-1 may be a promising prognostic biomarker in RCC. Currently, some prognostic scoring systems are available for patients with localized and metastasized RCC. Incorporating ESM-1 expression in RCC into these existing prognostic scoring systems could improve these models and enhance the quality of individual oncologic management in RCC patients.

Endocan as an Early Predictor of Endothelial Dysfunction and Atherosclerosis in Egyptian Patients with Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Inflammation leads to endothelial cells activation. Activated endothelial cells with increased leukocytes adhesion molecules expression, which can induce endothelial dysfunction (ED) and atherosclerosis.&#x0D; Aim: to measure the serum level of Human endothelial cell-specific molecule-1 (endocan) in patients with rheumatoid arthritis and to evaluate its relation to endothelial dysfunction and atherosclerosis.&#x0D; Materials and methods: the study included 30 consecutive RA patients, and 30 healthy control subjects. RA disease activity was measured by the DAS-28 score. Serum endocan was measured by enzyme-linked immunosorbent assay (ELISA). The collected data were statistically analyzed using SPSS program version 16.&#x0D; Results: There was a significant elevation in Endocan level in RA patients (1.81 ± 0.66 ng/ml) compared to control group (1.41 ± 0.59ng/ml) (P= 0.012). Serum endocan levels showed significant positive correlation with disease activity score-28(DAS-28), ESR, CRP, LDL and carotid intima media thickness (cIMT) (P = 0.015, 0.004, &lt;0.001, 0.008, 0.005 respectively). Linear regression analysis revealed that the serum endocan level, age and disease activity were independent predictors for cIMT, and atherosclerosis development in RA patients. &#x0D; Conclusion: Endocan is a useful marker to predict endothelial dysfunction and atherosclerosis in patients with rheumatoid arthritis.

Association of clinical characteristics and biomarkers with recurrent atrial fibrillation after hybrid ablation

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Atrial fibrillation ablation research at our institution was supported by an unrestricted grant from AtriCure. Background Hybrid ablation is an alternative treatment for both persisting and therapy-resistant, symptomatic atrial fibrillation (AF), combining the strengths of endocardial catheter and epicardial surgical ablation. Although results exhibit lower rates of recurrence and higher reduction of AF burden, there is a considerable risk of procedure-related complications. Therefore, the identification of patient groups who benefit most of this procedure can help in pre-procedural selection and tailoring of optimal therapy post-ablation. Purpose This study aimed to identify clinical factors and blood biomarkers associated with recurrence of AF within 1 year post-ablation. Methods A total of 96 consecutive patients undergoing hybrid ablation between January 2015 and December 2018 in a tertiary care center were enrolled. Blood samples were collected pre-ablation. Seven biomarkers [Bone Morphogenetic Protein 10 (BMP10), angiopoietin-2 (ANG2), Dickkopf WNT Signaling Pathway Inhibitor 3 (DKK3), Endothelial Cell Specific Molecule 1 (ESM1), Fibroblast Growth Factor 23 (FGF23), Insulin Like Growth Factor Binding Protein 7 (IGFBP7) and total N-terminal pro b-type natriuretic peptide (NT-proBNP)] were assayed at Roche Diagnostics based on their possible association with recurrence of AF. Clinical follow-up visits combined with 12-lead ECG and 24-hour Holter monitoring were scheduled at 3, 6 and 12 months post-procedure. Cox proportional hazards regression models were used to study the association with recurrence of AF. Results Out of the 96 patients (mean age 58±8 years; 18% women), 17 (17.7%) developed recurrence of AF within 1 year post-ablation. Median time to diagnosis was 191 days (range: 92-344). Comparisons between patients with and without recurrence of AF are depicted in Table 1. Multivariable Cox proportional hazard regression, adjusted for sex, showed that older age (HR 1.104, 95% CI 1.003-1.215, p=0.043), type of AF (HR 0.322, 95% CI 0.117-0.886, p=0.028), a history of peripheral vascular disease (HR 13.84, 95% CI 3.13-61.14, p&amp;lt;0.001) and recurrence in the blanking period (HR 14.25, 95% CI 3.99-50.85, p&amp;lt;0.001) were associated with recurrence of AF within 1 year post-ablation, but no blood biomarkers (Figure 1). Conclusion In AF patients undergoing extensive ablation, older age, type of AF, a history of peripheral vascular disease and recurrence in the blanking period were determinants of AF recurrence within 1 year post-ablation.

Endocan is a key player in cardiovascular disease: A review

In recent years, the attention of scientists has been actively focused on studying the role of endocan as a biological marker of endothelial dysfunction in cardiovascular diseases. Until recent years, endocan has been studied in acute kidney injury, chronic kidney disease, and renal replacement therapy. Endocan, formerly known as endothelial cell-specific molecule-1, is a soluble dermatan sulfate proteoglycan expressed and secreted into the circulation from endothelial cells. Currently available studies demonstrate the diagnostic and prognostic value of endocan evaluation in cardiovascular pathology. It is expected that further scientific and clinical studies will demonstrate the possibilities of using endocan as an additional laboratory tool for diagnosing and assessing the prognosis in patients with a cardiac profile. Drug regulation of endocan concentration and expression may be a promising target for the treatment of cardiac and vascular pathology.

Serum E-selectin and endothelial cell-specific Molecule-1 levels among people living with HIV on long term ART in Uganda: a pilot cross-sectional study

BackgroundProlonged exposure to HIV and anti-retroviral therapy (ART) has been linked with endothelial cell activation which subsequently predisposes people living with HIV (PLWH) to cardiovascular diseases. Serum biomarkers of endothelial cell activation such as E-Selectin and endothelial cell-specific molecule-1 (ESM-1) could aid in early detection of PLWH at a risk of cardiovascular diseases. However, there is a paucity of data on these biomarkers like E-selectin and endothelial cell-specific molecule-1 (ESM-1) among PLWH on long term ART (≥ 10 years) in Uganda. The aim of this study is to determine the serum levels of these biomarkers in this population.MethodsThis was a cross-sectional study where we randomly sampled 73 stored serum samples of PLWH who were enrolled in the Infectious Diseases Institute (IDI) ART long term (ALT cohort). We measured serum levels of E-selectin and ESM-1 by ELISA. Data was summarized using median and interquartile range. Inferential statistics were performed to determine predictors of elevated levels of E-selectin.ResultsOf the 73 samples analyzed, 38 (52.1%) were from female participants. The mean age was 54 ± 9.0 years. Twenty participants (27.4%) had a history of smoking while 52 (71.2%) had a history of alcohol intake. Twenty-five (34.3%) of the participants were overweight whereas 4 (5.6%) were obese. Fifty-four (74%) had an undetectable viral load (≤ 0 copies/ml) and the mean duration of ART at the time of sampling (2014/2015) was 10.4 ± 0.4 years. While serum levels of ESM-1 were not detectable in any of our samples, the median E-selectin levels was 147.6 μm/L ranging from 8.44 μm/L and 1,979.36 μm/L. Sixty-seven participants (91.8%) had elevated levels of E-selectin (> 39 μm/L). CD4 count > 500 cells/µl compared to lower counts was a predictor of elevated levels of E-Selectin (adjusted Odd Ratio 12.5, 95% CI (1.03 — 149.95, p < 0.05).ConclusionsThe majority (91.8%) of PLWH on long term ART had elevated levels of E-selectin. Having high CD4 count (> 500 cells/µl) was predictive of elevated levels of E-Selectin. Future work should longitudinally assess the trend of levels of E-selectin and ESM-1 while assessing for cardiovascular diseases endpoint.

Elevated expression of endocan in the development of cervical squamous neoplasia of the uterus.

Accumulated evidence has shown that endocan, which was originally called endothelial cell-specific molecule-1, is an attractive prognostic factor in a variety of cancers. However, the relevance of endocan expression in human malignancies remains to be clarified. In the present study, the expression of endocan in cervical squamous neoplasia of the uterus, including low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), as well as in invasive squamous cell carcinoma was examined by immunohistochemistry. Endocan was not sufficiently expressed in the normal cervical epithelium. Endocan expression was present in LSIL cases but was limited to basal and parabasal areas of the cells. HSIL cases exhibited strong expression of endocan with widely distributed expression toward the epithelial surface. In contrast, further strong expression of endocan was not observed in patients with invasive carcinoma. This study is the first study showing increased expression of endocan in precancerous dysplastic lesions and malignancy of the cervix. The data suggest that a high expression level of endocan potentially contributes to the development of cervical squamous neoplasia of the uterus.

ESM1 promotes angiogenesis in colorectal cancer by activating PI3K/Akt/mTOR pathway, thus accelerating tumor progression.

This study aimed to explore the influence of endothelial cell-specific molecule 1 (ESM1) expression on colorectal cancer (CRC) cells and preliminarily analyze its possible mechanism, so as to lay a foundation for research about potential biological targets of CRC. First, CRC cells were transfected with ESM1-negative control (NC), ESM1-mimic and ESM1-inhibitor and randomly assigned to ESM1-NC group, ESM1-mimic group and ESM1-inhibitor group, respectively. Then the cells were harvested at 48 h after transfection for subsequent experiments. The results manifested that after up-regulation of ESM1, the distance of CRC SW480 and SW620 cell lines migrating to the scratch center rose notably, and the number of migrating cells, basement membrane-penetrating cells, colonies formed and angiogenesis was increased overtly, indicating that ESM1 overexpression can promote tumor angiogenesis in CRC and accelerate tumor progression. Combined with results of bioinformatics analysis, the molecular mechanism by which ESM1 promoted tumor angiogenesis in CRC and accelerated tumor progression was explored through suppressing the protein expression of phosphatidylinositol 3-kinase (PI3K). Western blotting revealed that after intervention with PI3K inhibitor, the protein expressions of phosphorylated PI3K (p-PI3K), phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) were decreased evidently, and the protein expressions of matrix metalloproteinase-2 (MMP-2), MMP-3, MMP-9, Cyclin D1, Cyclin A2, VEGF, COX-2 and HIF-1α subsequently declined. ESM1 may promote angiogenesis in CRC by activating the PI3K/Akt/mTOR pathway, thus accelerating tumor progression.

Combination of Maternal Serum ESM-1 and PLGF with Uterine Artery Doppler PI for Predicting Preeclampsia.

This study aimed to determine whether the combination of pregnancy-associated endothelial cell-specific molecule 1 (ESM-1), the placental growth factor (PLGF) in the first- and second-trimester maternal serum, and the uterine artery Doppler pulsatility index (PI) in the second trimester can predict preeclampsia (PE). The serum levels of ESM-1 and PLGF in 33 severe preeclampsia (SPE) patients, 18 mild preeclampsia patients (MPE), and 60 age-matched normal controls (CON) were measured. The Doppler ultrasonography was performed, and the artery pulsatility index (PI) was calculated for the same subjects. The 2nd PLGF level was significantly lower and the 2nd PI was higher than those in the MPE group. Combining the 2nd PLGF with the 2nd PI yielded an AUC of 0.819 (83.33% sensitivity and 70.00% specificity). In the SPE group, the 1st ESM-1 level and the 2nd PLGF level were significantly lower, and the 2nd ESM-1 level and the 2nd PI were significantly higher in the SPE group. The combination of the 1st ESM-1, the 2nd PLGF, and the 2nd PI yielded an AUC of 0.912 (72.73% sensitivity and 95.00% specificity). The 1st ESM-1 and the 2nd PLGF levels and the 2nd PI were associated with PE. The combination of serum biomarkers and the PI improved the screening efficiency of the PE prediction, especially for SPE.

Validation of ESM1 Related to Ovarian Cancer and the Biological Function and Prognostic Significance.

Background: Ovarian cancer (OC), a serious gynecological malignant disease, remains an enormous challenge in early diagnosis and medical treatment. Based on the GEO and TCGA databases in R language, endothelial cell-specific molecule 1 (ESM1) was confirmed separately with the bioinformatic analysis tool. ESM1 has been demonstrated to be upregulated in multiple cancer types, but the oncogenic mechanism by which ESM1 promotes OC is still largely unknown. Methods: In this study, we used WGCNA and random survival forest variable screening to filter out ESM1 in OC differentially expressed genes (DEGs). Next, we confirmed the mRNA and protein levels of ESM1 in OC samples via PCR and IHC. The correlation between the ESM1 level and clinical data of OC patients was further confirmed, including FIGO stage, lymph node metastasis, and recurrence. The role of ESM1 in OC development was explored by several functional experiments in vivo and in vitro. Then, the molecular mechanisms of ESM1 were further elucidated by bioinformatic end experimental analysis. Results: ESM1 was significantly upregulated in OC and was positively correlated with PFS but negatively correlated with OS. ESM1 knockdown inhibited cell proliferation, apoptosis escape, the cell cycle, angiogenesis, migration and invasion in multiple experiments. Moreover, GSVA found that ESM1 was associated with the Akt pathway, and our results supported this prediction. Conclusion: ESM1 was closely correlated with OC development and progression, and it could be considered a novel biomarker and therapeutic target for OC patients.