Plasma Gas6 Research Articles

Neoadjuvant cabozantinib restores CD8+ T cells in patients with locally advanced non-metastatic clear cell renal cell carcinoma: a phase 2 trial.

Cabozantinib is an oral multikinase inhibitor approved for treatment in metastatic renal cell carcinoma (RCC). We hypothesized that neoadjuvant cabozantinib could downstage localized tumors, facilitating partial nephrectomy, and facilitating surgery in patients with locally advanced tumors that would require significant adjacent organ resection. We, therefore, conducted a phase 2, single-arm trial of cabozantinib treatment for 12 weeks in 17 patients with locally advanced biopsy-proven non-metastatic clear cell RCC before surgical resection. Six patients (35%) experienced a partial response, and 11 patients (65%) had stable disease. We identified that plasma cell-free DNA (cfDNA), VEGF, c-MET, Gas6, and AXL were significantly increased while VEGFR2 decreased during cabozantinib treatments. There was a trend towards CD8+ T cells becoming activated in the blood, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Cabozantinib treatment depleted myeloid populations acutely. Importantly, immune niches made up of the stem-like CD8+ T cells and antigen presenting cells were increased in every patient. These data suggest that cabozantinib treatment was clinically active and safe in the neoadjuvant setting in patients with locally advanced non-metastatic clear cell RCC and activated the anti-tumor CD8+ T cell response. The trial is registered at ClinicalTrials.gov under registration no. NCT04022343.

Elevated Plasma Levels of Growth Arrest Specific 6 (Gas6) Protein in Severe Obesity: Implications for Adipose Tissue and Inflammation.

BACKGROUND Preliminary data suggest an adipogenic role for growth arrest-specific 6 (Gas6), a pleiotropic molecule involved in inflammation, proliferation, and hemostasis through its Tyro3, Axl, and MerTK (TAM) receptors. This study compares Gas6 expression in plasma and visceral and subcutaneous adipose tissue in 42 adults with obesity (body mass index ≥40 kg/m²) and 32 normal-weight controls to elucidate its role in obesity and related metabolic alterations. MATERIAL AND METHODS Using a case-control design, we measured Gas6 levels in plasma via a validated sandwich enzyme-linked immunosorbent assay and in adipose tissues through quantitative polymerase chain reactio with specific probes. Medians and correlations were analyzed using Mann-Whitney and Spearman tests. A general linear model assessed the impact of covariates on the Gas6-anthropometric relationship, with statistical significance determined by P values. RESULTS Plasma Gas6 levels were significantly higher in the obese group than in controls (P=0.0006). While Gas6 mRNA expression did not significantly differ in subcutaneous adipose tissue between groups, it was notably higher in visceral than subcutaneous adipose tissue in controls (P<0.05). A significant correlation was found between plasma Gas6 levels and body mass index (P=0.001). CONCLUSIONS Gas6 plasma levels are elevated in morbid obesity, particularly in visceral adipose tissue, and are linked to altered glucose tolerance in female patients. These findings highlight the role of Gas6 in obesity-related metabolic complications and suggest avenues for further research and potential therapies.

Role of growth arrest-specific protein 6 in diagnosis and prognosis of sepsis in infants and children

Background Sepsis is a main cause of mortality in the pediatrics and neonates. Early goal-directed therapy is the cornerstone in sepsis management that is focuses on keeping organ perfusion and function normally. Diagnosis of pediatric sepsis in the emergency department is considered a significant challenge for clinicians for many reasons. These include a lack of fast and accurate diagnostic tools, an absence of simple and specific diagnostic criteria, and unclear symptoms during the early phase of illness. The best predictive tool in the future will likely be a combination of multiple biomarkers and physiomarkers. Growth arrest-specific protein 6 (Gas6) is an anti-apoptotic vitamin-K-dependent protein. It is secreted by endothelial cells and is important for the activation of endothelium during inflammation. Several studies hypothesize the use of Gas6 as a biomarker in the pathophysiology of sepsis, an early predictor of mortality, and were able to identify some life-threatening sepsis complications. Aim Evaluation of the diagnostic and prognostic values of plasma Gas6 in patients with sepsis, septic shock, and multiple organ dysfunction syndrome in infants and children. Patients and methods Case-control study was carried out from April 2019 to April 2020. 90 children were included and divided into two equal groups (cases and controls). The patients aged from 1 month to 18 years were diagnosed with sepsis, septic shock, or multiple organ dysfunction syndrome in the pediatric intensive care unit of Mansoura University Children’s Hospital. The level of plasma Gas6 was measured in both cases and controls and evaluated as regards its relation to diagnosis and outcome of the cases. Results The two groups were age and sex matched. The outcome of the cases group was: 16 cases are discharged, and 29 died. A significant elevation of plasma Gas6 level in the cases more than the controls (sensitivity= 84.4% and specificity= 66.7%). However, no statistically significant difference as regard the relation between plasma Gas6 level and the outcome of the cases (sensitivity= 55.2% and specificity= 62.7%). Conclusion Gas6 show statistically significant elevation in cases of sepsis, septic shock and multiorgan failure. Gas6 plasma level has high accuracy in prediction of sepsis and can be considered as a good negative marker of sepsis but not a reliable prognostic marker in septic patients.

Assessment of growth arrest-specific 6 protein as a biomarker of glomerular damage in sickle cell anaemia

Objective: To assess growth arrest-specific 6 (Gas6) protein as a biomarker of glomerular damage (glomerulopathy; nephropathy) in patients with sickle cell anaemia (SCA). Methods: seventy SCA patients on routine clinic visit and seventy apparently healthy controls were recruited into the study and their blood and urine samples were collected while plasma Gas6 as well as urinary albumin and creatinine measured. Their socio-demographic and other anthropometric indices were documented. The study participants and controls were screened for urinary tract infection (UTI) using the urine dipstick combi-10 on their urine. The plasma Gas6 of all patients were compared with the albumin creatinine ratio (ACR) along with the ages. Albumin and creatinine levels were also compared with ages. Results: Gas6 had an inverse though insignificant relationship with ACR and age in the patients; albumin, creatinine and albumin creatinine ratio varied directly with age in these patients. Conclusion: Gas 6 was not found a useful marker of glomerulopathy in sickle cell anaemia.

GAS6/sAXL ratio correlates with National Institutes of Health Stroke Scale (NIHSS) and infarction size in patients with acute ischemic stroke

Background &amp; Objective: Ischemic stroke is the leading cause of death and long-term disability worldwide. In patients with ischemic stroke, both cell loss and inflammation are observed. GAS6/sAXL signaling is effective in both inflammation and clearance of dead/dying cells. This study investigated the GAS6/sAXL pathway and its role in patients with acute stroke. Specifically, we evaluated whether GAS6/sAXL was associated with stroke severity and infarct volume. Methods: This study involved 53 patients with acute ischemic stroke (AIS) and 49 healthy controls. GAS6 and sAXL proteins were collected in the first 24 hours in the acute stroke. NIHSS scores, GCS, and demographic data of the patients at the time of admission to the hospital were recorded. The infarct area was calculated using cranial magnetic resonance imaging. Results: Mean age of the patients was 64±12 years, 60% were female. HDL was lower in AIS group (40.5±13.01 mg/dl) than in the control group (55.4±14.9 mg/ dl) (p&lt;0.05). The GAS6 levels of patients with ischemic stroke (30.58 [1.58-162.33] ng/dL) were significantly lower than the control group (83.33 [10.71-181.96] ng/dL) (p &lt; 0.001). There was a significant difference in the GAS6/sAXL ratio between the AIS (8.60 [0.55-48] ng/mL) and control groups (14.78 [1.82-53.71] ng/mL) (p &lt; 0.001). The serum GAS6 level and MR infarct area was positively correlated (r = 0.381 p = 0.005). The GAS6/sAXL ratio was positively correlated with the NIHSS and infarct area (p = 0.004). The GAS6/sAXL ratio and GCS showed a negative correlation (p = 0.001). Conclusion: Plasma GAS6 levels were positively correlated with infarct size, and the GAS6/sAXL ratio was positively correlated with the NIHSS score and infarct area in patients with AIS. Plasma GAS levels and GAS6/sAXL ratio can be used as an indicator of severity of AIS.

Plasma GAS6 predicts mortality risk in acute heart failure patients: insights from the DRAGON-HF trial

BackgroundGrowth arrest-specific 6 (GAS6) is a vitamin K-dependent protein related to inflammation, fibrosis, as well as platelet function. Genetic ablation of GAS6 in mice protects against cardiac hypertrophy and dysfunction. Nonetheless, the association between plasma GAS6 levels and acute heart failure (AHF) patients is still unknown.MethodsWe measured plasma GAS6 concentrations in 1039 patients with AHF who were enrolled in the DRAGON-HF trial (NCT03727828). Mean follow-up of the study was 889 days. The primary endpoint is all-cause death.ResultsIn total, there were 195 primary endpoints of all-cause death and 135 secondary endpoints of cardiovascular death during the mean follow-up duration of 889 days. The higher levels of GAS6 were associated with higher rates of all-cause and cardiovascular death (P < 0.05). Baseline plasma GAS6 levels were still strongly correlated with clinical outcomes in different models after adjustment for clinical factors and N-terminal pro-brain natriuretic peptide (NT-proBNP, P < 0.05). GAS6 could further distinguish the risks of clinical outcomes based on NT-proBNP measurement.ConclusionElevated plasma GAS6 levels were associated with an increased risk of all-cause and cardiovascular death in patients with AHF.Trial registration NCT03727828 (DRAGON-HF trial) clinicaltrials.gov

Baseline Plasma Gas6 Protein Elevation Predicts Adverse Outcomes in Hospitalized COVID-19 Patients.

Reliable biomarkers allowing early patients' stratification for the risk of adverse outcomes in COVID-19 are lacking. Gas6, together with its tyrosine kinase receptors named TAM, is involved in the regulation of immune homeostasis, fibrosis, and thrombosis. Our aim was to evaluate whether Gas6, sAxl, and sMerTK could represent early predictors of disease evolution either towards a negative (death or need of ICU admission) or a positive (discharge and/or clinical resolution within the first 14 days of hospitalization) outcome. To this purpose, between January and May 2021 (corresponding to third pandemic wave in Italy), 139 consecutive SARS-CoV-2 positive patients were enrolled in a prospective observational study. Plasma levels of these molecules were measured by ELISA at the time of hospitalization and after 7 and 14 days. We observed that higher plasma Gas6 concentrations at hospital admission were associated with a worsening in clinical conditions while lower sMerTK concentrations at baseline and after 7 days of hospitalization were associated with a more favorable outcome. At multivariate analysis, after correction for demographic and COVID-19 severity variables (NEWS2 and PiO2/FiO2), only Gas6 measured at baseline predicted an adverse prognosis with an odds ratio of 1.03 (C.I. 1.01-10.5). At ROC curve analysis, baseline Gas6 levels higher than 58.0 ng/ml predicted a severe disease evolution with 53.3% sensitivity and 77.6% specificity (area under the curve 0.653, p = 0.01, likelihood ratio of 2.38, IQR: 1.46-3.87). Taken together, these results support the hypothesis that a dysregulation in the Gas6/TAM axis could play a relevant role in modulating the course of COVID-19 and suggest that plasma Gas6 may represent a promising prognostic laboratory parameter for this condition.

Growth arrest-specific 6 protein in HIV-infected patients: Determination of plasma level and different antiretroviral regimens.

Growth arrest-specific 6 (Gas6) protein is involved in cell proliferation, differentiation, adhesion, migration in response to inflammatory processes. Human immunodeficiency virus (HIV) infection induces a chronic inflammatory condition and combination of antiretroviral therapy improves immune function and decreases the inflammatory state. The aim of this study was to assess the implications of Gas6 in chronic inflammation status of HIV-infected patients undergoing different third regimens of antiretroviral therapy. The Gas6 may be a marker of chronic inflammation of HIV-infected patients. A total of 356 adult males, including 258 HIV-infected patients and 98 healthy controls, were recruited. The demographic and clinical characteristics of the patients were collected. Laboratory assessment included hemogram, CD4 count, plasma HIV RNA load (PVL), hepatitis B and C viruses, and serum biochemistry. Plasma Gas6 concentrations were determined. The values of Gas6 were lower in HIV patients compared to healthy subjects (14.3±6.4 vs 21.5±15.2, p=0.01). HIV patients that received antiviral regimen with abacavir had similar Gas6 level than those who received antiviral regimens with tenofovir (14.3±6.5 vs 13.8±5.9, p=0.99). HIV patients that received antiviral regimen with protease inhibitors (PIs) had lower Gas6 level (13.1±3.5 vs 14.2±6.6 vs 14.6±6.5, p=0.03) than those who received antiviral regimens with non-nucleoside reverse transcriptase inhibitors (nNRTIs) and integrase inhibitors (INSTIs), respectively. Decreased plasma Gas6 concentrations were observed in HIV patients. Gas6 levels are associated with different third regimen of highly active antiretroviral therapy. Gas6 may represent a unique marker for assessing the chronic inflammation state difference among cART regimens in HIV patients.

Gas6 expression and Tyrosine kinase Axl Sky receptors: Their relation with tumor stage and grade in patients with bladder cancer.

It has been shown that the dysregulation of tyrosine kinase Axl receptor and its ligand growth arrest-specific gene (Gas6) are associated with poor prognosis in various types of tumors but there is not enough study about their importance in bladder cancer (BC). We evaluated the relation of Gas6 gene expression and tyrosine- kinase Axl and Sky (Tyro 3) receptors with tumor stage and grade in patients with BC. The study group consists of 55 patients whose transurethral resection of bladder (TUR-B) has been performed due to BC and the control group consists of 12 patients with normal bladder mucosa. In tissues mRNAs of Gas6, Axl, and Sky receptors were examined by quantitative (Real-Time) PCR (qPCR). Protein expression was measured by immunohistochemistry. Plasma Gas6 protein levels were compared with control group by ELISA method. Patients with BC were grouped as Ta low (n=17), Ta high (n=5), T1 low (n=9), T1 high (n=8) and T2 (n=16) according to their TUR-B pathologies. The qPCR analysis showed that the expression of Gas6 gene and Axl receptor is higher in the tumor-positive group and the immune-histochemical showed that the bladder samples of the tumor-positive group stained significantly positive. When the patients are grouped according to the TUR-B pathologies, a statistical significant difference was observed among groups in the qPCR analysis ratios of Gas6 gene and Axl receptor by (p < 0.05) but no significance was found for Sky receptor (p > 0.05). When Gas6 protein levels in plasma samples were compared by ELISA method, a statistical significance was determined among groups (p = 0.001). Our findings indicate that mRNAs of Gas6 and Axl receptor are closely related to tumor stage and grade in patients with BC. Further studies are needed for understanding the role of Gas6 and its receptors on the neoplastic transformation in terms of novel biomarkers and potential therapeutic targets.

Growth arrest-specific 6 as a predictor of gastroesophageal varices in patients with liver cirrhosis

Background and aim Early detection of patients with gastroesophageal varices at high risk of bleeding is crucial. Nevertheless, sparing endoscopy to low-risk patients would be of value. Therefore, noninvasive methods have been proposed. Our study aimed to verify whether plasma GAS6 concentrations are related to the presence and/or degree of esophageal varices in patients with LC. Patients and methods This cross-sectional study included 100 patients with LC who underwent upper gastrointestinal endoscopy. Results Mean level of GAS6 was 77.70±21.31 among enrolled patients. Patients with varices had significantly higher level of GAS6 in comparison with those without varices (82.93±18.12 vs. 45.57±4.18 ng/ml; P&lt;0.001). Level of serum GAS6 was also increased with advancement in the variceal grade. Conclusion Plasma level of GAS6 was higher among patients having varices in comparison with those without, and its level was increased with advancement in the grade of varices. GAS6 is reported to have a good predictive value for hepatic fibrosis in patients with chronic liver disease.

The Pattern of Plasma Gas-6 elevation among Type II Diabetes Mellitus Patients in Relation to Microalbuminuria using Urinary Albumin Creatinine Ratio

Due to the global increase in diabetes, diabetic nephropathy is becoming a significant issue. Diagnosis and treatment in the early stages of nephropathy may avert this considerable complication, and new biomarkers other than microalbuminuria are required to detect diabetic nephropathy earlier in type 2 diabetes mellitus. Moreover, the pathogenesis of complications associated with diabetes as indicated in recent experimental studies showed that growth arrest-specific-6 protein (Gas-6) might have a role. We therefore, embarked on this study to determine the pattern of plasma Gas-6 elevation among type 2 diabetes mellitus patients and to describe any relationship with microalbuminuria using urinary albumin creatinine ratio. This research was a descriptive; a hospital-based cross-sectional study conducted at the Endocrinology Clinic, University College Hospital, Ibadan, Oyo State, Nigeria. We recruited 71 type-2 diabetic participants, and 71 apparently-healthy participants who served as the control. The study showed that the concentrations of Gas-6 protein and UACR in the diabetic participants were all significantly higher than in the healthy control participants (p ˂ 0.001). There was also a positive correlation between Gas-6 protein and UACR value which was statistically significant (rho = 0.41, p = ˂0.001). The sensitivity and specificity of Gas-6 was 75.0% and 19.1% respectively, with a PPV and NPV of 0.68 and 0.25 respectively. In conclusion, Plasma Gas-6protein correlated with microalbuminuria. However, Gas-6 protein alone may be of limited diagnostic value in diabetic nephropathy.

Increased plasma levels of Gas6 and its soluble tyrosine kinase receptors Mer and Axl are associated with immunological activity and severity of lupus nephritis.

Growth arrest-specific 6 (Gas6) and its receptors have been shown to play a crucial role in the homeostasis of the innate immune system by regulating apoptosis and inflammation. We aimed to verify whether an impairment of this system is associated with systemic lupus erythematosus (SLE) disease activity and with lupus nephritis (LN). Plasma Gas6 and the soluble cleaved form of the receptors MerTK (sMer) and Axl (sAxl) concentrations were measured in n=59 SLE patients (n=44 with nephritis, 75%) and analysed in relationship to clinical and laboratory data. Patients with LN were characterised by higher Gas6 (19.0 ng/mL [16.8-24.5] vs. 16.5 ng/mL [13.89-18.91]; p=0.03) and sAxl plasma levels than those without LN (31.36 ng/mL [25.1-41.4] vs. 20.2 ng/mL [15.6-30.7]; p=0.03); conversely sMer plasma concentrations were similar between groups. All the three biomarkers studied were directly correlated to creatinine and daily proteinuria, being inversely related to creatinine clearance. 39 patients had a proteinuria level of <0.5 mg/day, 14 between 0.5 and 3.5 mg/day and 5 had ≥3.5 g/day; Gas6, sAxl and sMer plasma concentrations significantly increased for increasing degree of proteinuria (test for trend p=0.0002; p=0.02; p=0.009, respectively).These correlations were confirmed in multiple linear regression analysis models accounting for gender, age, disease duration and concomitant treatment. Plasma Gas6, sAxl and sMer concentrations are associated with the severity of LN in patients affected by SLE. The excess cleavage of TAM receptors might contribute to LN pathogenesis.

Possible Association of Elevated Plasma Levels of Growth Arrest-Specific Protein 6 and the Soluble Form of Tyrosine Kinase Receptor Axl with Low Hepatitis C Viral Load in Patients with Type 2 Diabetes Mellitus.

This study aimed to investigate the plasma levels of Gas6 and soluble Axl (sAxl) in patients with chronic hepatitis C virus (HCV) infection with and without type 2 diabetes mellitus (T2DM). The study involved four groups; 50 patients with chronic HCV, 50 patients with T2DM, 50 patients with chronic HCV and T2DM, and 31 age- and sex-matched healthy controls. T2DM was diagnosed according to American Diabetes Association criteria, HCV antibodies were detected by enzyme-linked immunosorbent assays (ELISA) and confirmed by real-time-polymerase chain reaction. Plasma Gas6 and sAxl levels were assayed in all groups by ELISA. Significant low levels of GAS 6 in HCV/T2DM group versus HCV group were detected (7.92 ± 5.18 vs. 16.09 ± 7.36, respectively, p = 0.000), but higher than T2DM and control groups (p ≥ 0.05), although nonsignificant. HCV load was higher in the HCV group than the HCV/T2DM group (1,888,300 ± 5,595,070 vs. 1,417,900 ± 4,066,460 copies/mL, respectively, p = 0.632). Among HCV group, significant positive correlations were detected between Gas6 and sAxl levels with HCV viral load (r = 0.48, p = 0.000 and r = 0.43, p = 0.002, respectively), while among HCV/T2DM group, significant negative correlations were detected (r = -0.29, p = 0.04 and r = -0.34, p = 0.014, respectively). Significant negative correlations were detected between Gas6/sAxl levels and glycated hemoglobin (r = -0.36, p = 0.01 and r = -0.4, p = 0.003, respectively) in T2DM despite the positive correlations detected in HCV/T2DM (r = 0.27, p = 0.053 and r = 0.55, p = 0.000, respectively). In conclusion, Gas6/Axl system in combined HCV/T2DM diseases may affect the pathogenesis and can alter the biomarkers and complications of both diseases in a manner that differs from a solitary disease.

Tumor tissue and plasma levels of AXL and GAS6 before and after tyrosine kinase inhibitor treatment in EGFR‐mutated non–small cell lung cancer

BackgroundNon‐small cell lung cancer (NSCLC) positive for activating mutations of the epidermal growth factor receptor (EGFR) gene is initially sensitive to EGFR‐tyrosine kinase inhibitors (TKIs) but eventually develops resistance to these drugs. Upregulation of the receptor tyrosine kinase AXL in tumor tissue has been detected in about one‐fifth of NSCLC patients with acquired resistance to EGFR‐TKIs. However, the clinical relevance of the levels of AXL and its ligand GAS6 in plasma remains unknown.MethodsTumor tissue and plasma specimens were collected from 25 EGFR‐mutated NSCLC patients before EGFR‐TKI treatment or after treatment failure. The levels of AXL and of GAS6 mRNA in tumor tissue were evaluated by immunohistochemistry and chromogenic in situ hybridization, respectively. The plasma concentrations of AXL and GAS6 were measured with enzyme‐linked immunosorbent assays.ResultsAXL expression was detected in three of 12 (25%) and nine of 19 (47%) tumor specimens obtained before and after EGFR‐TKI treatment, respectively. All tumor specimens assayed were positive for GAS6 mRNA. The median values for the plasma AXL concentration before and after EGFR TKI treatment were 1 635 and 1 460 pg/mL, respectively, and those for the plasma GAS6 concentration were 4 615 and 6 390 pg./mL, respectively. There was no significant correlation between the plasma levels of AXL or GAS6 and the corresponding expression levels in tumor tissue.ConclusionPlasma concentrations of AXL and GAS6 do not reflect tumor expression levels, and their measurement is thus not a viable alternative to direct analysis of tumor tissue in EGFR‐mutated NSCLC.

A high Gas6 level in plasma predicts venous thromboembolism recurrence, major bleeding and mortality in the elderly: a prospective multicenter cohort study

Essentials Predictive ability of pro‐hemostatic Gas6 for recurrent venous thromboembolism (VTE) is unknown.We measured Gas6 levels in 864 patients with VTE over 3 years.High Gas6 (> 157%) at diagnosis is associated with VTE recurrence, major bleeding and mortality.Gas6 plasma levels measured 12 months after the index VTE are discriminatory for VTE recurrence. SummaryBackgroundGrowth arrest‐specific gene 6 (Gas6) is a prohemostatic protein with an unknown predictive ability for recurrent venous thromboembolism (VTE). In the elderly, VTE results in higher mortality but does not have a higher rate of recurrence than in younger patients. Consequently, anticoagulation management in the elderly is challenging.ObjectiveTo prospectively investigate the performance of Gas6 in predicting VTE recurrence, major bleeding and mortality in the elderly.MethodsConsecutive patients aged ≥ 65 years with acute VTE were followed for a period of 3 years. Primary outcomes were symptomatic VTE recurrence, major bleeding, and mortality. Plasma Gas6 was measured with ELISA.ResultsGas6 levels were measured in 864 patients at the time of the index VTE (T1) and, in 70% of them, also 12 months later (T2). The Gas6 level at T1 was discriminatory for VTE recurrence (C‐statistic, 0.56; 95% confidence interval [CI] 0.51–0.62), major bleeding (0.60, 95% CI 0.55–0.65) and mortality (0.69, 95% CI 0.65–0.73) up to 36 months. VTE recurrence up to 24 months after T2 was discriminated by the Gas6 level at T2 (0.62, 95% CI 0.54–0.71). High Gas6 levels (> 157%) and continuous Gas6 levels at T1 were associated with VTE recurrence up to 6 months and 12 months, respectively.ConclusionsIn elderly patients, a high Gas6 level is associated with higher risks of VTE recurrence, major bleeding, and death. These findings support further studies to assess the performance of Gas6 in adjusting the length of anticoagulation.

Plasma sMer, sAxl and GAS6 levels correlate with disease activity and severity in lupus nephritis.

The purpose of this study is to determine whether TAM receptors and ligands associated with the activity and severity of lupus nephritis. Clinical data were statistically analysed and studied in 122 SLE patients, diagnosed from 2013 to 2016 in First Hospital Affiliated to Harbin Medical University. Levels of TAM receptors and ligands in the plasma of 122 SLE patients were measured by ELISA. Renal biopsies were performed to confirm lupus nephritis (LN) by histopathology in 68 patients. The associations of TAM receptors and ligands with clinical and serological parameters were analysed in 68 LN patients. Amongst patients with SLE, those with LN had significantly higher plasma sMer, sAxl and GAS6 levels than those without renal involvement (P<0.01 for all comparisons). Additional comparisons on the renal function-associated clinical parameters confirmed an indicative role of the sMer, sAXL and GAS6 levels in the cohort of patients with more severe nephritis. Patients with higher sMer, sAXL and GAS6 levels of LN patients tended to suffer from proliferative glomerulonephritis. The sAXL and GAS6 levels had a strong positive correlation with activity index (AI) in LN patients. Furthermore, there was a significant drop of the sMer, sAXL and GAS6 concentrations from the time of the biopsy to month t6, but no further decrease from months t6 to t12. These results suggest that plasma sMer, sAxl and GAS6 can be an additional clinical marker related to the disease activity and severity in LN.

Plasma growth arrest-specific protein 6 expression in uremic patients with type 2 diabetes

Background: Diabetic kidney disease is a major cause of uremia worldwide; recently, controversial roles for growth arrest-specific protein 6 (GAS 6) have been revealed in the pathogenesis of diabetic nephropathy. A better understanding of the association between GAS6 and diabetic nephropathy may lead to the development of novel therapeutic approaches for the prevention and treatment of diabetic uremia. Objectives: The aim of this study was to investigate the levels of GAS6 and its role in uremic patients with Type 2 diabetes. Materials and Methods: A total of 109 adults were recruited, of whom 23 had Type 2 diabetes and uremia and 56 had newly diagnosed Type 2 diabetes without remarkable nephropathy; thirty individuals with normal glucose tolerance without significant clinical comorbidities served as controls. Plasma GAS6 concentration and common anthropometric and biochemical variables were analyzed. Results: Plasma GAS6 levels were significantly lower in patients with Type 2 diabetes than in controls regardless of nephropathy (P

Plasma Growth Arrest-Specific 6 Protein and Genetic Variations in the GAS6 Gene in Patients with Metabolic Syndrome.

Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein secreted by immune cells, endothelial cells, vascular smooth muscle cells, and adipocytes. Recent studies indicate that Gas6 and receptors of the TAM (Tyro3, Axl, and Mer) family may be involved in the pathogenesis of obesity, systemic inflammation, and insulin resistance. The aim of this study was to investigate the association between plasma Gas6 protein and the c.843 + 7G>A Gas6 polymorphism in metabolic syndrome (MetS). Two hundred five adults (88 men and 117 women) were recruited in this study. Plasma Gas6 concentration, general, and biochemical data were measured. All subjects were genotyped for the c.843 + 7G>A Gas6 polymorphism. Plasma Gas6 concentrations decreased in parallel with various MetS components in all groups (P = 0.017 for trend). Patients in the second and third tertiles of Gas6 level had higher high-density lipoprotein cholesterol (HDL-C) levels than those in the first tertile overall and in the female group. Plasma Gas6 levels were significantly positively correlated with HDL-C level and negatively with fasting glucose level in the female patients. The A allele and genotype AA in single nucleotide polymorphism c.843 + 7G>A were less frequent in the subjects with MetS compared to those without MetS. Our results demonstrated a positive correlation between Gas6 protein values and HDL-C and reinforce the association with fasting glucose. In addition, the presence of c.843 + 7G>A Gas6 polymorphisms, especially the AA genotype, had an association with MetS. The potential role of the Gas6/TAM system in MetS deserves further investigation.

Gas6 as a predictor of esophageal varices in patients affected by hepatitis C virus related-chronic liver disease.

Plasma Gas6 was tested as an alternative to Baveno VI criteria (liver stiffness<20kPa and platelet count>150×109/l) in an endoscopy-sparing strategy. A total of160 patients with chronic hepatitis C and advanced fibrosis/cirrhosis underwent, on the same occasion, liver elastography, upper endoscopy, a platelet count and serum Gas6 measurement. A total of74/160(46%) patients had esophageal varices, that were small (diameter<5mm) in 57/160(34%) and large in 17/160(11%) cases. A total of34/160(21%) patients satisfied Baveno VI criteria, according to which screening for esophageal varices could have been omitted; 1/34 had large varices (sensitivity 94%). A plasma Gas6 value<45ng/ml, detected in 34/160(21%) patients, was also 94% sensitive. Plasma Gas6 might represent a feasible alternative to Baveno VI criteria when transient elastography is unavailable/unsuccessful.

Elevated Plasma Growth Arrest-Specific 6 Protein Levels Are Associated with the Severity of Disease During Hantaan Virus Infection in Humans.

Hemorrhagic fever with renal syndrome (HFRS) is caused by Hantaan virus (HTNV) and Seoul virus infection in Asia. The clinical manifestation of HFRS is characterized by the rapid loss of renal function (acute kidney injury) and thrombocytopenia. The specific immune mechanisms that cause thrombocytopenia in HFRS are not well described. The growth arrest-specific 6 (Gas6) protein and TAM (Tyro3, Axl and Mer) receptors have been recently shown to play prominent roles in immune regulation, and high plasma levels of Gas6 may predict the severity of diseases. The association of TAM receptors with several autoimmune diseases has been investigated, although the relationship between TAM receptors and these diseases remains unclear in HFRS. Therefore, the aim of this study was to evaluate the clinical significance of Gas6 and TAM receptor expression in HFRS. The concentrations of Gas6 in the plasma from 144 patients and the expression of TAM receptors on monocytes from 117 patients were quantified. The relationship between Gas6 levels and disease course, severity, and clinical parameters was analyzed. We first found that the plasma Gas6 levels were significantly higher in HFRS patients, whereby they were positively correlated with white blood cell counts and negatively correlated with platelet counts. The expression of Tyro3 was increased on monocytes in HFRS patients compared with that in controls. Taken together, our data indicate that elevated plasma Gas6 levels is associated with the severity of disease during HTNV infection in humans, suggesting that Gas6 may play an important role by binding with Tyro3 on monocytes, which will be assessed in future studies.