Plasma Gas6 Concentration Research Articles

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.

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.

Growth arrest-specific protein 6 (Gas6) as a noninvasive biomarker for early detection of diabetic nephropathy

ABSTRACTBackground: To investigate the diagnostic level of cystatin C and growth arrest-specific gene 6 (Gas6) levels in elderly type 2 diabetic patients with different degrees of diabetic nephropathy (DN). Methods: Four hundred and eighty-two old people, including 130 healthy controls, 130 normoalbuminuric diabetic patients, 122 with microalbuminuria, and 100 with macroalbuminuria, were recruited. Plasma Gas6 and serum cystatin C levels were measured. Results: Plasma Gas6 concentration was significantly lower in diabetic patients with microalbuminuria or macroalbuminuria, as compared with diabetic subjects with normoalbuminuria; while cystatin C was significantly higher. Gas6 was inversely correlated with BMI, WHR, and HbA1c, while cystatin C was inversely correlated with urea nitrogen and creatinine. Multivariate logistic regression analysis showed that, after adjusted for established diabetes risk factors, higher plasma Gas6 was significantly associated with a decreased risk of DN, while higher serum cystatin C was significantly associated with an increased risk. Receiver operating characteristic curve analysis showed that Gas6 was better than cystatin C as a biomarker for early diagnosis and detection of DN, with a cutoff value of 9.435 ng/mL (86.1% sensitivity and 84.6% specificity). Conclusion: Compared to cystatin C, Gas6 may be potentially a better noninvasive diagnostic biomarker for early detection of DN.

Growth Arrest-Specific 6 Protein in Patients with Sjögren Syndrome: Determination of the Plasma Level and Expression in the Labial Salivary Gland.

AimsGrowth arrest-specific protein 6 (Gas6) is a vitamin K-dependent protein expressed by endothelial cells and leukocytes that are involved in cell survival, migration, and proliferation in response to inflammatory processes. The aim of this study was to assess the implications of Gas6 in Sjögren syndrome (SS) and its expression in the labial salivary gland.Methods and ResultsA total of 254 adults, including 159 with primary Sjögren syndrome (pSS), 34 with secondary Sjögren syndrome (sSS), and 61 normal controls, were recruited. Plasma Gas6 concentrations were determined, and Gas6 expressions in labial salivary gland (LSG) tissues from controls and pSS and sSS patients were also evaluated. Plasma Gas6 concentrations were significantly lower among patients with pSS than normal controls (13.5 ± 8.6 vs. 19.9 ± 13.4 ng/ml, p < 0.001). There were, however, no significant differences in plasma Gas6 levels between pSS and sSS patients (13.5 ± 8.6 vs. 16.9 ± 11.2 ng/ml, p = 0.068). In multivariate logistic regression analysis, after adjustment for white blood cell count, hemoglobin level, platelet count, lymphocyte count, and C3 and C4 levels, lower plasma Gas6 concentrations were significantly associated with an increased risk of SS. Moreover, by using a semi-quantitative scale to evaluate Gas6 expression in LSG tissues, Gas6 expression was found to be markedly lower in LSG tissues from pSS patients than in tissues from normal controls.ConclusionsDecreased plasma Gas6 concentration and LSG expression were associated with pSS. As such, Gas6 may represent a novel independent risk factor for pSS, with a potential role in salivary gland inflammation and dysfunction.

Gender differences in plasma growth arrest-specific protein 6 levels in adult subjects

BackgroundGrowth-arrest-specific 6 (Gas6) is recognized as a secreted vitamin K-dependent protein, as it interacts with receptor tyrosine kinases of the TAM (Tyro-3, Axl, Mer) family. The plasma Gas6 are important to the inflammatory process, and are involved in diverse human diseases. Few studies have shown plasma Gas6 concentration varies with genders. We determined whether plasma Gas6 concentrations are associated with sex hormones in both genders. MethodsA total of 589 adult subjects, including 361 male and 228 female were recruited. Plasma Gas6 concentration, biochemical, testosterone, estradiol (E2), and sex hormone-binding globulin were assayed. The indices of free androgen (FAI) and free E2 (FEI) were calculated. ResultsSignificantly higher Gas6 concentrations were observed in adult male rather than female (P<0.05). In univariate regression analysis, plasma Gas6 concentrations were positively associated with FAI in male (β=0.167, P=0.002) and both E2 and FEI in female (β=0.384, P<0.001 andβ=0.292, P<0.001, respectively). Otherwise, Gas6 concentrations were inversely associated with ages in both genders (β=−0.234, P<0.001 in male and β=−0.226, P=0.001 in female, respectively). In multivariate regression analysis, only age in male and E2 in female were independent variables to determine the plasma Gas6 concentrations (β=−0.231, P=0.002 and β=0.458, P=0.001). ConclusionsPlasma Gas6 is associated with sex hormones in female and ages in male, indicating a potential role of sex hormones and ages involving the Gas6/TAM system.

Plasma growth arrest-specific protein 6 levels in premenopausal and postmenopausal women: the role of endogenous estrogen

Growth arrest-specific 6 (Gas6) is a vitamin K-dependent protein that interacts with receptor tyrosine kinases of the Tyro-3, AXL, Mer (TAM) family. The Gas6/TAM system contributes to the regulation of cell survival and proliferation, cell adhesion and migration, and inflammatory cytokines release. Plasma Gas6 plays an important role in the inflammatory process, and is involved in diverse human diseases. Few studies have investigated gender-specific variations in plasma Gas6 concentration. Hence, the aim of this study was to determine whether plasma Gas6 levels are associated with sex hormones in premenopausal and postmenopausal women. A total of 103 premenopausal and 135 postmenopausal women were recruited. Plasma Gas6 concentration, estradiol (E2), and sex hormone-binding globulin were assayed. The free estrogen index (FEI) was calculated. The results showed significantly lower Gas6 levels in the postmenopausal compared to the premenopausal women (P < 0.005). Plasma Gas6 levels were positively correlated with E2 levels in the pre- and postmenopausal women (r = 0.359, P < 0.001 and r = 0.261, P = 0.002, respectively). Gas6 levels were also correlated with FEI in the pre- and postmenopausal women (r = 0.234, P = 0.017 and r = 0.188, P = 0.029, respectively). After adjusting for confounders, the correlations still remained significant. In multiple stepwise regression analysis, only E2 in premenopausal and both age and E2 in postmenopausal women were independently correlated with the plasma Gas6 levels (all P < 0.001). These results suggest that plasma Gas6 is associated with sex hormones in both pre- and postmenopausal women, indicating a potential role of sex hormones in the Gas6/TAM system.

The levels of plasma growth arrest-specific protein 6 is associated with insulin sensitivity and inflammation in women

AimsVitamin K-dependent growth arrest-specific protein 6 (Gas6) and its receptors of the TAM (TYRO-3/Axl/Mer) family are ubiquitously expressed in immune, cardiovascular, and reproductive systems. They play pivotal roles of regulating tissue homeostasis via anti-inflammatory effects. Recent studies show that the Gas6/TAM system is involved in glucose tolerance-related metabolic disorders. Our aim was to investigate the link between Gas6 protein, insulin sensitivity and inflammatory cytokines in men and women. MethodsA total of 278 adults (126 men and 152 women) were recruited in this study. Plasma Gas6 concentration and various biochemical, proinflammatory and endothelial markers were measured. Insulin sensitivity was estimated by homeostasis model assessment. ResultsWaist, fasting and 2h post-load glucose, and glycated hemoglobin (HbA1C) were significantly lower in women than in men. Age, high-density lipoprotein cholesterol, and highly-sensitive C-reactive protein levels were significantly higher in women than in men. Plasma Gas6 levels were negatively correlated with waist (r=−0.187, P=0.022), HOMA-IR (r=−0.171, P=0.035), interleukin 6 (r=−0.362, P<0.001), and E-selectin (r=−0.216, P=0.008), while they were positively correlated with insulin sensitivity (QUICKI) (r=0.168, P=0.039) in women, but not in men. Stepwise multiple regression analysis showed that TNF-α was independently correlated with plasma Gas6 levels in both the sexes (P<0.001). ConclusionPlasma Gas6 is associated with obesity, insulin sensitivity, inflammation, and endothelial dysfunction in women and may be a general marker of inflammatory conditions in women.

Gas6 and TAM Receptors in Mouse Platelets

Abstract 5199 Objective:Growth Arrest Specific-6 (Gas6) is a new vitamin K-dependent protein and is a ligand for TAM receptors, three receptors (Tyro, Axl and Mer) belonging to the receptor tyrosine kinase subfamily. The number of publications concerning the physiological importance of the new vitamin-K dependent proteins, which are not members of the coagulation cascade, is growing. Gas6 has a structural homology to natural anticoagulant of protein S, but has no anticoagulant activity. Some research groups have reported contradictory results concerning the presence of Gas6 and its receptors in mouse platelets. The purpose of this study is to investigate the presence of Gas6 and its receptors in mouse platelets as mRNA and protein levels. Material and Methods:25 specific pathogen-free, 8–10 week old, 25–30 g in weight, race of Balb-C male/female mice were anesthetized under light ether anesthesia and blood samples were taken from their hearts. Total RNAs were isolated from platelets, then mRNAs encoding Gas6 and TAM receptors were detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Protein concentrations of Gas6 and TAM receptors in platelets were measured by ELISA. We were unable to measure the Mer protein level because of the absence of any commercial ELISA kit for mouse Mer. Results:RT-PCR results indicated the presence of mRNAs encoding to Gas6 and Mer in mouse platelets. However, although RT-PCR reactions were performed at various temperatures and cycles, we could not detect the presence of mRNAs encoding Axl and Tyro. Receptor levels of Axl and Tyro were below the detection limits of the ELISA method. Plasma Gas6 concentration was found to be 26 ng/ml. Conclusion:We found the presence of mRNAs encoding Gas6 and only receptor Mer in mouse platelets but not Axl and Tyro. Protein Gas6, Axl and Tyro levels were below the detection limits of the ELISA methods. The presence of mRNA is not evidence of protein expression in platelets because they have no DNA. Further studies are required to clarify the presence of Gas6 and TAM receptors in platelets using Real Time PCR, and more sensitive immunological methods, and then, as studies of their effects on mechanisms. Original results from these further studies will provide reliable information as to whether Gas6 and its TAM receptors may be a pharmacological target in thrombosis, hemostasis, restenosis and atherosclerosis. Disclosures:No relevant conflicts of interest to declare.

Plasma Protein Growth Arrest–Specific 6 Levels Are Associated With Altered Glucose Tolerance, Inflammation, and Endothelial Dysfunction

OBJECTIVEPlasma protein growth arrest–specific 6 (Gas6) is important to the inflammatory process and is involved in the development of diabetic renal and vascular complications. We set out to determine whether plasma Gas6 levels are associated with altered glucose tolerance, insulin sensitivity, inflammation, and endothelial dysfunction.RESEARCH DESIGN AND METHODSA total of 278 adults, including 96 with normal glucose tolerance (NGT), 82 with impaired glucose tolerance (IGT), and 100 with type 2 diabetes were recruited. Plasma Gas6 concentration and biochemical, proinflammatory, and endothelial variables were determined. Insulin sensitivity was examined by homeostasis model assessment.RESULTSPlasma Gas6 concentration was significantly lower among patients with type 2 diabetes compared with subjects with NGT (P < 0.001). The plasma Gas6 value was inversely correlated with fasting glucose, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and vascular cell adhesion molecule (VCAM)-1. In multivariate logistic regression analysis, after adjustment for established diabetes risk factors, higher plasma Gas6 concentrations were significantly associated with a decreased risk of type 2 diabetes. Moreover, the association became slightly stronger after further adjustment for TNF-α, IL-6, high-sensitive C-reactive protein, E-selectin, intercellular adhesion molecule-1, and VCAM-1.CONCLUSIONSPlasma Gas6 is associated with altered glucose tolerance, inflammation, and endothelial dysfunction. It also may represent a novel independent risk factor of type 2 diabetes and a potential surrogate marker of inflammation and endothelial dysfunction.

Development and Validation of an ELISA Method for Detection of Growth Arrest Specific 6 (GAS6) Protein in Human Plasma

Gas6 protein is possibly involved in human diseases, but a validated plasma assay is lacking. So, we developed a sandwich enzyme‐linked immunosorbent assay (ELISA) method using commercially available reagents. An appropriate plasma‐based matrix was prepared to optimize the assay. The ELISA method showed inter‐ and intra‐assay coefficients of variation lower than 15%. Recoveries all fell within 15% of expected values. Plasma Gas6 concentration in 61 healthy donors was 20.3±3.8 ng/mL. Our assay meets FDA requirements for precision and accuracy for the validation of bioanalytical methods and it is suitable for research or diagnostic purposes.

Growth arrest-specific protein 6 plasma concentrations during septic shock

IntroductionThe product of growth arrest-specific gene 6 (Gas6) is a vitamin K dependent protein that is secreted by leucocytes and endothelial cells in response to injury and participates in cell survival, proliferation, migration and adhesion. Our purpose was to investigate plasma Gas6 concentration and its relation to organ dysfunction in patients with septic shock.MethodsForty-five patients with septic shock admitted to a medical adult intensive care unit were enrolled. Plasma Gas6 concentration was determined using enzyme-linked immunosorbent assay at days 1, 3, 7 and 14.ResultsThe median (interquartile range) Gas6 concentration was 51 (5 to 95) pg/ml at admission. A positive correlation (Spearman rank-order coefficient [rs] = 0.37, P = 0.01) was found between Gas6 level and Sepsis-related Organ Failure Assessment score. Patients requiring renal support had higher Gas6 concentration that those without need for haemofiltration (76.5 [52 to 164] pg/ml versus 10.5 [1.5 to 80.5] pg/ml; P = 0.04). Moreover, there was a positive correlation between Gas6 and aspartate transaminase (rs = 0.42, P = 0.006) and between Gas6 and prothrombin time (rs = 0.45, P = 0.02). Although there was a progressive decline in Gas6 concentration in survivors (analysis of variance, P = 0.01), nonsurvivors exhibited persistently elevated Gas6. However, the two populations diverged only after day 7 (P = 0.04).ConclusionPlasma concentrations of Gas6 correlate with disease severity, especially with renal and hepatic dysfunction, in septic shock.