Serum Hepatocyte Growth Factor Research Articles

Overexpression of Hepatocyte growth factor and its soluble receptor (s-cMet) in the serum of patients with different grades of meningioma

ObjectivesMeningiomas are the most common primary intracranial tumor. Hepatocyte growth factor (HGF) and its receptor, cMet, were shown to be involved in meningioma. This study was aimed to determine the concentration of HGF and soluble cMet (s-cMet) in the serum of patients with different grades of meningioma. MethodsNinety serum samples from different grades of meningioma patients (42 cases of grade I, 28 grade II, 20 grade III) and 51 controls were included in this study. The serum total protein concentration (TPC) was measured by a Bio-Rad protein assay and serum concentration of HGF and s-cMet by enzyme linked immunosorbent assay (ELISA). ResultsNo significant change in the serum TPC of patients was seen as compared to controls. We also showed that serum HGF and s-cMet concentration in meningioma patients was higher than in controls. The results showed that starting from grades I to III meningioma, a significant increase in HGF and s-cMet serum concentration was observed (HGF; 380 ± 57.69, 430.27 ± 48.72, 596.36 ± 104.49 pg/ml, respectively, as compared to controls which was 327.72 ± 49.68 pg/ml and for s-cMet was 274.45 ± 45.05, 314.81 ± 38.71, 433.54 ± 51.81 ng/ml, respectively, as compared to controls which was 213.72 ± 29.13 ng/ml). The results showed that a high concentration of HGF and s-cMet is associated with advanced grades of meningioma. ConclusionIt is concluded that HGF and s-cMet serum levels increased in meningioma patients and their concentration was significantly higher in more advanced grades of the disease. It is also suggested that HGF/s-cMet might be involved in the progression of meningioma.

Encephalopathies Associated With Severe COVID-19 Present Neurovascular Unit Alterations Without Evidence for Strong Neuroinflammation.

ObjectiveCoronavirus disease (COVID-19) has been associated with a large variety of neurologic disorders. However, the mechanisms underlying these neurologic complications remain elusive. In this study, we aimed at determining whether neurologic symptoms were caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) direct infection or by either systemic or local proinflammatory mediators.MethodsIn this cross-sectional study, we checked for SARS-CoV-2 RNA by quantitative reverse transcription PCR, SARS-CoV-2–specific antibodies, and 49 cytokines/chemokines/growth factors (by Luminex) in the CSF +/− sera of a cohort of 22 COVID-19 patients with neurologic presentation and 55 neurologic control patients (inflammatory neurologic disorder [IND], noninflammatory neurologic disorder, and MS).ResultsWe detected anti–SARS-CoV-2 immunoglobulin G in patients with severe COVID-19 with signs of intrathecal synthesis for some of them. Of the 4 categories of tested patients, the CSF of IND exhibited the highest level of cytokines, chemokines, and growth factors. By contrast, patients with COVID-19 did not present overall upregulation of inflammatory mediators in the CSF. However, patients with severe COVID-19 (intensive care unit patients) exhibited higher concentrations of CCL2, CXCL8, and vascular endothelium growth factor A (VEGF-A) in the CSF than patients with a milder form of COVID-19. In addition, we could show that intrathecal CXCL8 synthesis was linked to an elevated albumin ratio and correlated with the increase of peripheral inflammation (serum hepatocyte growth factor [HGF] and CXCL10).ConclusionsOur results do not indicate active replication of SARS-CoV-2 in the CSF or signs of massive inflammation in the CSF compartment but highlight a specific impairment of the neurovascular unit linked to intrathecal production of CXCL8.

Serum hepatocyte growth factor as a predictor of disease severity and future exacerbations in patients with non-cystic fibrosis bronchiectasis

BackgroundSerum biomarkers associated with the severity of non-cystic fibrosis (CF) bronchiectasis are insufficient. This study determined the association of serum hepatocyte growth factor (HGF), osteopontin, and pentraxin-3 levels with disease severity and exacerbation in patients with non-CF bronchiectasis. MethodsSerum levels of HGF, osteopontin, and pentraxin-3 were measured in patients with clinically stable non-CF bronchiectasis (n = 61). The correlation between the biomarkers and bronchiectasis severity index (BSI) and FACED score was assessed using univariate and multivariate linear regression analyses. Predictive variables associated with exacerbation were analyzed using a Cox proportional hazards model and the time to first exacerbation in high and low HGF groups during the observation period was compared using Kaplan-Meier survival curves. ResultsThe BSI showed significant correlation with HGF (r = 0.423; p = 0.001) and pentraxin-3 (r = 0.316; p = 0.013). The FACED score was significantly correlated with HGF (r = 0.406; p = 0.001). Univariate and multivariate linear regression analysis revealed that serum level of HGF was independently associated with both scoring systems. The high HGF group showed a significantly shorter time to first exacerbation (Log-rank test, p = 0.014). Multivariate Cox proportional hazards regression analysis revealed that high serum HGF level and colonization with non-pseudomonas organisms were independent predictors of future exacerbations (HR 2.364; p = 0.024 and HR 2.438; p = 0.020, respectively). ConclusionSerum level of HGF is a potential biomarker that is closely associated with disease severity and future risk of exacerbations in patients with non-CF bronchiectasis.

Hepatocyte Growth Factor and Primary Systemic Amyloidosis.

A 75-year-old-man experienced liver dysfunction and was diagnosed with decompensated liver cirrhosis. His serum hepatocyte growth factor (HGF) was very high (16.24 ng/ml). Because the etiology was unclear, we considered the possibility of amyloidosis. Biopsy of the mucosa of the stomach, duodenum and rectum demonstrated amyloid deposition. From the findings of Congo red staining and immunohistochemical analyses, we made a diagnosis of systemic amyloid light-chain amyloidosis. Unfortunately, the patient died one month after the diagnosis. We considered that serum HGF was useful for the diagnosis and prediction of prognosis of primary systemic amyloidosis.

Abstract P008: Ideal Cardiovascular Health And Hepatocyte Growth Factor In The Multi-ethnic Study Of Atherosclerosis

Background: Hepatocyte growth factor (HGF) is a cytokine released in response to vascular injury and a novel biomarker of cardiovascular disease (CVD) risk. However, the relationship between ideal cardiovascular health (CVH) and HGF is unknown. We examined whether ideal CVH is associated with lower HGF levels in a multi-ethnic cohort of adults free from clinical CVD at baseline. Methods: We analyzed data from the MESA study of 6,490 men and women aged 45-84 years. The independent variable was the CVH score derived from 7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose). Each metric was scored 0 points (poor), 1 point (intermediate) and 2 points (ideal). The total CVH score ranged from 0-14. An inadequate score was 0-8, average, 9-10 and optimal, 11-14. The number of ideal metrics was also counted. The dependent variable was logarithmically transformed HGF. We examined the association between the CVH score and HGF using linear regression models adjusted for age, sex, race/ethnicity, education, income, health insurance and study site. Results: The mean (SD) age of participants was 62 (10) years. Fifty-three percent were women. Participants with optimal CVH scores had the lowest HGF concentration [Median (IQR): 807 (678-962) pg/mL] compared to those with average [870 (740-1,036)] and inadequate scores [969 (821-1,159)]. A one-unit increment in the CVH score was significantly associated with a 3% lower HGF concentration (Table). Average and optimal CVH scores were also significantly associated with 8% and 12% lower HGF concentrations, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF concentrations. Interactions by age, sex and race/ethnicity were not significant. Conclusion: In this ethnically diverse cohort, optimal CVH was significantly associated with lower HGF levels. Interventions aimed at promoting ideal CVH may reduce vascular injury as indicated by lower serum HGF levels.

POS1064 SERUM BIOMARKERS BEFORE AND AFTER A SIX MONTHS STRUCTURED WEIGHT LOSS INTERVENTION IN PATIENTS WITH PSORIATIC ARTHRITIS AND OBESITY COMPARED WITH CONTROLS

Background:Obesity is highly overrepresented in psoriatic arthritis (PsA) and associated with increased disease activity. We have previously shown in 41 patients with PsA (Caspar criteria) and obesity (here body mass index BMI ≥33 kg/m2) that weight loss treatment including Very Low Energy Liquid Diet (VLED) resulted in a median weight loss of 18.6% and concomitantly a significant improvement in CRP and disease activity in joints, entheses and skin at six months (M6) follow up.Objectives:To analyze serum biomarkers associated with inflammation, cartilage and bone metabolism before and after weight loss treatment in PsA patients compared with controls, without PsA or psoriasis, matched for age, sex and weight.Methods:The weight loss treatment included VLED (640 kcal/day) during 12 or 16 weeks (depending on baseline (BL) BMI <40 or ≥40 kg/m2), followed by a structured reintroduction of an energy restricted diet. cs/bDMARDs were held unchanged from 3 months before BL until M6. The patients were assessed with 66/68 joints counts.Serum levels of vascular endothelial growth factor (VEGF), S100A8, S100A9, matrix metalloproteinases (MMP-3, 8 and 13), hepatocyte growth factor (HGF), B-cell activating factor (BAFF), Dickkopf (DKK)-1, sclerostin (SOST), soluble receptor activator of nuclear factor-kB ligand (RANKL), osteprotegerin (OPG) and aggrecan were measured at BL and M6 in PsA patients and controls with Magnetic Luminex Assays (R&D-systems) following the manufacturer’s instructions using a Bio-Plex 200 system (BioRad). Serum cartilage oligomeric matrix protein (COMP) (R&D-systems), carboxyterminal telopeptide of type-1 collagen (CTX-1) (Immunodiagnostics systems: IDS) and osteocalcin (IDS) were measured with enzyme-linked immunosorbent assay (ELISA).Results:Totally 41 PsA patients [age median 54 (IQR 48-62) yrs; 63 % women] and 39 controls [age 55 (46-60) yrs, 72 % women] were included. At M6 the weight-loss since BL was 18.7 (14.6-26.5) kg in the PsA patients and 22.6 (14.7-28.4) kg in the controls (p=0.546). Significant reductions in DAS28CRP [2.9 (2.1–3.7) vs. 2.4 (1.7–3.0)] and DAPSA [15.3(6.6-29.1) vs. 11.0 (2.8–17.6)] (p<0.001) were seen in the PsA patients.At BL serum levels of the biomarkers were not significantly different in patients vs. controls.After weight-loss significant reductions were seen in serum VEGF, S100A8, MMP-8, HGF, BAFF, COMP and DKK-1, whereas serum SOST and CTX-1 were significantly increased in both patients and controls (Table 1). The other biomarkers were not significantly changed.Conclusion:Weight loss in patients with PsA and controls was associated with lowered serum levels of several biomarkers related to inflammation and cartilage degradation, along with increased levels of biomarkers for bone turnover.Table 1.PsA (N=41)BL median (IQR)PsA (N=41)M6 median (IQR)PsAp-valueCtrl (N=39)BL median (IQR)Ctrl (N=39)M6 median (IQR)Ctrlp-valueBMI (kg/m2)35.2 (34.1-38.1)29.8 (26.6-31.5)<0.00137.7 (36.7–41.5)30.4 (27.9–33.2)<0.001CRP (mg/L)4 (2–8.5)2 (1–6.5)0.0414 (2–6)2 (1–4)<0.001VEGF (pg/mL)79.6 (55.9–113.5)69.6 (53.1–105.3)0.01082.3 (48.0–125.9)65.0 (42.2-85.5)<0.001S100A8 (pg/mL)75.5 (48.0–99.5)63.3 (42.8–93.6)0.02171.8 (40.5–101.0)63.3 (40.3-85.7)0.006MMP-8 (pg/mL)9975.4(6811.8–14154.8)9202.6(5767.1–12049.6)0.0177494.7(4805.2-12616.9)7218.3(3466.0-9785.3)0.112HGF (pg/mL)327.9 (250.3–413.6)271.3 (206.9–331.0)<0.001307.9 (239.1–348.3)239.8 (200.3-276.0)<0.001BAFF (pg/mL)794.4 (716.4–868.2)674.6 (613.2–790.5)<0.001760.8 (664.1–827.3)678.1 (603.7–719.8)<0.001COMP (pg/mL)266.1 (209.8–366.0)217.0 (156.0–272.0)0.008293.6 (185.2–340.5)221.6 (163.5-300.0)0.018Dkk-1 (pg/mL)3608.4(3055.0–4401.3)3382.6(2802.5–4218.2)0.0023635.8(3212.8-4380.6)3480.4(2948.9–4087.3)0.007SOST (pg/mL)52.9 (32.5–65.4)60.3 (37.2–85.6)0.01450.0 (30.8–79.3)61.3(35.7–81.4)0.019CTX-1 (ng/mL)0.27 (0.20–0.39)0.51 (0.35–0.64)<0.0010.23 (0.16–0.34)0.50(0.30–0.61)<0.001Disclosure of Interests:None declared.

Prognostic relevance of longitudinal HGF levels in serum of patients with ovarian cancer.

The pleiotropic protein hepatocyte growth factor (HGF) is the only known ligand of the tyrosine kinase mesenchymal–epithelial transition (cMET) receptor. The HGF/cMET pathway mediates invasion and migration of ovarian cancer cells, and upregulation of HGF/cMET pathway components has been associated with poor prognosis. This study investigated the clinical relevance of circulating HGF in serum of patients with ovarian cancer. Serum HGF (sHGF) was determined by enzyme‐linked immunosorbent assay in a total of 471 serum samples from 82 healthy controls and 113 patients with ovarian cancer (88.5% with ≥ FIGO III). Patient samples were collected at primary diagnosis and at four follow‐up time points throughout treatment and at disease recurrence. Patients with ovarian cancer showed elevated median sHGF levels at primary diagnosis, and sHGF levels transiently increased after surgery and normalized in the course of chemotherapy, even dropping below initial baseline. Higher levels of sHGF were an independent predictor for shorter overall survival (OS) (a) at primary diagnosis (HR = 0.41, 95% CI: 0.22–0.78, P = 0.006), (b) at longitudinal follow‐up time points (after surgery and before/during/after chemotherapy), (c) along the patients’ individual dynamics (HR = 0.21, 95% CI: 0.07–0.63, P = 0.005), and (d) among a subgroup analysis of patients with BRCA1/2 wild‐type ovarian cancer. This is the first study proposing sHGF as an independent prognostic biomarker for ovarian cancer at primary diagnosis and in the course of platinum‐based chemotherapy, irrespective of the postoperative residual disease after surgical debulking. sHGF could be implemented into clinical diagnostics as a CA125 auxiliary tumor marker for individualized prognosis stratification and sHGF‐guided therapy monitoring.

Elevated serum level of hepatocyte growth factor predicts development of new syndesmophytes in men with ankylosing spondylitis.

ObjectivesTo study baseline serum hepatocyte growth factor (s-HGF) as a predictor of spinal radiographic progression overall and by sex and to analyse factors correlated to changes in s-HGF in patients with AS.MethodsAt baseline and the 5-year follow-up, s-HGF was analysed with ELISA. Spinal radiographs were graded according to modified Stoke Ankylosing Spondylitis Spinal Score. Radiographic progression was defined as ≥2 modified Stoke Ankylosing Spondylitis Spinal Score units/5 years or development of ≥1 syndesmophyte. Logistic regression analyses were used.ResultsOf 204 baseline participants, 163 (80%) completed all examinations at the 5-year follow-up (54% men). Baseline s-HGF was significantly higher in men who developed ≥1 syndesmophyte compared with non-progressors, median (interquartile range) baseline s-HGF 1551 (1449–1898) vs 1436 (1200–1569) pg/ml, P = 0.003. The calculated optimal cut-off point for baseline s-HGF ≥1520 pg/ml showed a sensitivity of 70%, a specificity of 69% and univariate odds radio (95% CI) of 5.25 (1.69, 14.10) as predictor of development of ≥1 new syndesmophyte in men. Baseline s-HGF ≥1520 pg/ml remained significantly associated with development of ≥1 new syndesmophyte in men in an analysis adjusted for the baseline variables age, smoking, presence of syndesmophytes and CRP, odds radio 3.97 (1.36, 11.60). In women, no association with HGF and radiographic progression was found. Changes in s-HGF were positively correlated with changes in ESR and CRP.ConclusionIn this prospective cohort study elevated s-HGF was shown to be associated with development of new syndesmophytes in men with AS.

Association of Hepatocyte Growth Factor Genetic Variation (S3735520) and Its Concentration in Autism Spectrum Disorders: A Case-control Study

Background: Hepatocyte Growth Factor (HGF) was shown to play a key role in synaptogenesis, survival, maturation, and reconstruction of neuron cells and was shown to be implicated in Autism Spectrum Disorder (ASD). Objectives: Assessing the relationship between HGF (rs3735520) gene polymorphism and its circulating levels in ASD. Materials & Methods: A total of 140 ASD patients and 120 children healthy controls referred to Shahid Rajaei Hospital, Mazandaran, Iran from September 2017 to January 2019 were enrolled in the study. Genomic DNA was extracted from blood samples, HGF polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism and HGF serum concentration was measured by enzyme-linked immunosorbent assay. Statistical analysis was done by ANOVA and the Chi-square test, using χ² in MedCalc statistical software ver. 12.1.4. Results: Genotype frequencies of CC, CT, and TT in the ASD group were 25.71%, 52.86%, and 21.43%, and in controls were 26.67%, 68.33%, and 5%, respectively (P=0003) and C and T alleles frequencies in patients were 53% and 47% and in controls were 61% and 39%, respectively (P=0.046). Moreover, the Mean±SD serum HGF levels in the controls and ASD patients were 363.33±118.44 and 219.95±73.61 pg/mL, respectively (P=0.009). Furthermore, ASD patients carrying TT genotype had lower serum HGF levels than CT and TT carriers (CC, CT, and TT Mean±SD serum levels were 271.88±30.47, 217.77±33.59 and 156.33±22.72 pg/mL, respectively). Conclusion: There was a significant relationship between HGF gene polymorphism and its serum levels with ASD in an Iranian population. We also suggest that TT genotype may be associated with a decrease in HGF circulation levels in ASD.

ITRAQ-based comparative proteomics analysis reveals specific urinary biomarkers for various kidney diseases.

Background: Proteome studies for multiple renal diseases is bare. Methodology & results: Using isobaric tags for relative and absolute quantitation labeling, many differentially expressed proteins (DEPs) were identified in acute kidney injury (AKI), AKI+chronic kidney disease (CKD), diabetic CKD and nondiabetic CKD with or without IgA nephropathy (IgAN). Comparative analysis indicated that 34, 35, 17, 91 and 14 unique DEPs were found in AKI, AKI + CKD, CKD, diabetic CKD and nondiabetic CKD. Compared with nondiabetic CKD with IgAN, 47 unique DEPs were found in that without IgAN. Serum amyloid A1 (SAA1) and hepatocyte growth factor activator were unregulated in AKI and nondiabetic CKD without IgAN, respectively. Regenerating islet-derived protein 3-α (Reg3A) upregulation is associated with AKI and AKI + CKD patients. Conclusion: This research contributes to urinary biomarker discovery from multiple renal diseases.

A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway.

Background: Increasing evidence has demonstrated that postoperative infectious complications (PICs) after digestive surgery are significantly associated with negative long-term outcomes; however, precise mechanisms of how PICs affect the poor long-term survival remain unclear. Here, we focused on the hepatocyte growth factor (HGF)/c-Met signaling pathway as one of those mechanisms. Methods: In the clinical setting, serum HGF levels were measured in the patients with sepsis and those with PICs after undergoing esophagectomy. Using a liver metastasis mouse model with cecal ligation and puncture (CLP), expressions of HGF and the roles of the HGF/c-Met pathway in the progression of tumor cells were examined. Results: Serum HGF levels were very high in the patients with intra-abdominal infection on postoperative days (PODs) 1, 3, and 5; similarly, compared to the patients without PICs, those with PICs had significantly higher serum HGF levels on 1, 3, and 5 days after esophagectomy. The patients with PICs showed poorer overall survival than those without PICs, and the patients with high serum HGF levels on POD 3 showed poorer prognosis than those with low HGF levels. Similarly, at 24 and 72 h after operation, serum levels of HGF in CLP mice were significantly higher than those in sham-operated mice. Intraperitoneal injection of mouse recombinant HGF significantly promoted liver metastases in sham-operated mice on 14 days after surgery. Knocking down c-Met expression on NL17 tumor cells by RNAi technology significantly inhibited the promotion of CLP-induced liver metastases. Conclusions: Infections after surgery increased serum HGF levels in the clinical as well as experimental settings. Induction of high serum HGF levels by CLP promoted liver metastases in a murine liver metastasis model, suggesting the involvement of the HGF/c-Met signaling pathway in tumor promotion mechanisms. Thus, targeting the HGF/c-Met signaling pathway may be a promising approach for malignant tumors, particularly in the patients with PICs.

Serum Hepatocyte Growth Factor Level as the Biomarker for Postoperative Intimal Hyperplasia

Postoperative intimal hyperplasia is still the major cause of the vein graft occlusion. It may be useful to find the biomarker for the progression of postoperative intimal hyperplasia. The endothelial injury is considered as the first step for postoperative intimal hyperplasia. Hepatocyte growth factor (HGF) is not only the organ specific growth actor, but also the vascular endothelial growth factor. Edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan) is not only the first free radical scavenger commercially available, but also alleviates the endothelial injury in vivo. In this study, we evaluated whether serum HGF levels can be the biomarker for postoperative intimal hyperplasia in the rat model. Moreover, we estimated whether edaravone can suppress postoperative intimal hyperplasia. In the 17 male rats (mean weight 498 ± 53 g), we interposed the right epigastric vein graft into the common femoral artery with 10-0 interrupted sutures, as previously described. The rats were divided into two groups: the Edaravone group, which received preoperative administration of edaravone (3.0 mg/kg) into peritoneal cavity; and the control group, which received the same dose of saline. Vein grafts from each group were stained with hematoxylin and eosin and Elastica Verhoeff’s van Gieson’s. Three unoperated right epigastric veins were also examined a Shame. The initial areas of vein graft were measured using computerized planimetry (NIH Image Ver. 1.61). Serum HGF levels were also measured and compared (unpaired t-test). This study was approved by the Hyogo College of Medicine Animal Research Committee (No. 235). The average of intimal area in Group Control were gradually increased (30 ± 16 × 10-3 mm2 at 2 weeks and 434 ±111 × 10-3 mm2 at 4 weeks), which were significantly suppressed in the Edaravone group (53 ± 54 × 10-3 mm2 at 4 weeks; P < .01). Serum HGF levels were also gradually increased (4.94 ± 0.50 ng/mL at 2 weeks and 7.20 ±1.40 ng/mL at 4 weeks), comparing with that of Shame (3.96 ± 0.22 ng/mL; P < .05) (Figure). Serum HGF levels in the Edaravone group at 4 weeks seemed to be suppressed, but not be significantly when compared with the Control group (5.46 ± 0.55 ng/mL; P = .20) (Fig). Serum HGF levels might be the biomarker for postoperative intimal hyperplasia in the rat model, which can be suppressed with edaravone.

SO023HEPATOCYTE GROWTH FACTOR (HGF) PRECLUDE HIGH-FAT DIET-INDUCED OBESITY AND IMPROVED INSULIN RESISTANCE IN MICE

Abstract Background and Aims Obesity and its associated chronic inflammation in adipose tissue initiate insulin resistance, which is related to several pathologies including hypertension and atherosclerosis. Previous reports demonstrated that circulating hepatocyte growth factor (HGF) level was associated with obesity and type 2 diabetes. However, its precise role in obesity and related-pathology is unclear. Method In this experiment, cardiac-specific over-expression of human HGF in mice (HGF-Tg mice) which showed 4-5 times higher serum HGF levels than wild-type mice were used. We chose cardiac specific HGF overexpression, as other strain of HGF transgenic mice such as liver and kidney specific HGF overexpression mice develop cancer and cystic diseases, which are rare in the heart. In the present study, using HGF-Tg mice and anti-HGF neutralizing antibody (HGF-Ab), we explored the role of HGF in obese and insulin resistance induced by high fat diet (HFD) for 14 weeks (200 or 400ug/week). Results With normal chow diet (ND), there were no significant changes in body weight between WT and HGF-Tg mice. While body weight in wild-type mice fed with HFD for 14 weeks was significantly increased accompanied with insulin resistance, HGF-Tg mice prevented body weight gain and insulin resistance. Insulin resistance in obesity arises from the combination of altered functions of insulin target cells (e.g., liver, skeletal muscle, and adipose tissue) and the accumulation of macrophages that secrete pro-inflammatory mediators in adipose tissue. The accumulation of macrophages and elevated levels of inflammatory mediators in adipose tissue were significantly inhibited in HGF-Tg mice as compared to wild-type mice. In the gWAT, the mRNA levels of the mature macrophage marker F4/80, the chemoattractants, MCP-1 and CXCL2, and the inflammatory cytokines, such as TNF-α and iNOS, were significantly increased in WT mice fed with HFD. However, these levels were markedly reduced in HGF-Tg mice fed with HFD. Additionally, activation of Akt by insulin administration was significantly reduced in the gWAT SM, and liver by HFD; however, this activation was restored in HGF-Tg mice. Moreover, insulin-induced Akt signaling was decreased in HGF-Ab groups as compared to saline group under HFD condition. Importantly, HFD significantly increased the level of HGF mRNA by approximately 2 fold in gWAT, SM, and liver without changing cMet expression. All together, these data indicate that the HGF as one of the systemic gWAT, SM, and liver-derived growth factor plays a role in compensatory mechanism against insulin-resistance through the at least anti-inflammatory effect in adipose tissue. The HFD-induced obesity in wild-type mice treated with HGF-neutralizing antibody showed an exacerbated response to the glucose tolerance test. Conclusion HGF suppresses inflammation in adipose tissue induced by a high-fat diet, and as a result improves systemic insulin resistance. These gain-of-function and loss-of-function studies demonstrated that the elevated HGF level induced by HFD have protective role against obesity and insulin resistance.

Melatonin inhibits macrophage infiltration and promotes plaque stabilization by upregulating anti-inflammatory HGF/c-Met system in the atherosclerotic rabbit: USPIO-enhanced MRI assessment

Macrophage plays critical roles in the pathogenesis of atherosclerosis (AS), and is an attractive target for detecting and treating vulnerable plaque. Our previous study showed that melatonin (MLT) ameliorated AS by suppressing the pro-inflammatory Toll-like receptor 4/nuclear factor kappa B system in high-fat-fed rabbit. However, it is unknown whether the anti-atherosclerotic properties of MLT are associated with the upregulation of anti-inflammatory hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (c-Met) system. In present study, we examined whether MLT could inhibit macrophage infiltration and promote plaque stabilization by upregulating HGF/c-Met system with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) assessment in AS rabbit. Rabbits in this study were randomly divided into three groups and treated with a standard diet, high-fat diet, and high-fat diet plus 10 mg/kg/day MLT for 12 weeks, respectively. MLT treatment significantly reversed spotty signal void in 3D-TOF MRI, standard signal intensity reduction in T2WI MRI and aortic luminal area reduction in 2D-TOF MRI of the atherosclerotic abdominal aorta 72 h after USPIO injection. It also decreased serum interleukin-6 (IL-6), intima/media thickness ratio of the abdominal aorta, CD68 and iron-positive areas in the aortic intima, and increased serum IL-10, HGF and c-Met protein expression and the accumulation of vascular smooth muscle cell and collagen fiber in the aortic intima of AS rabbit. Our data demonstrated that MLT significantly decreased plaque macrophage infiltration and promoted plaque stability in AS rabbit assessed by USPIO-enhanced MRI. Remarkably, it was very first revealed that upregulation of anti-inflammatory HGF/c-Met system might contribute to the atheroprotective mechanisms of MLT.

First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients.

Background:YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody.Materials and Methods:YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg).Results:In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema (n = 7, 18.9%) followed by pruritis and nausea (n = 5, 13.5%, each), fatigue, anemia, and decreased appetite (n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders.Conclusion:YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned.Conclusion:ClinicalTrials.gov Identifier: NCT02499224

Abstract CT078: Cyfi: Results from a Phase Ib expansion cohort of anti-hepatocyte growth factor and cytarabine in relapsed and refractory AML

Abstract Objective: Patients with AML who are refractory to induction therapy or relapse within 1 year have poor outcomes. Elevated serum hepatocyte growth factor (HGF) level is an adverse prognostic factor. Pre-clinical models have shown that myeloid blasts produce HGF in an autocrine fashion and pharmacologic blockade of the HGF/c-Met axis sensitizes blasts to cell death. We initiated a Phase Ib study with dose expansion cohort study to assess the safety and tolerability of the anti-HGF antibody ficlatuzumab with cytarabine in AML patients who are refractory to 7+3 or have relapsed within 1 year of induction. Methodology: The 3 x 3 design was used for the Phase I with an expansion cohort of an additional 13 patients accrued and treated at the MTD. Ficlatuzumab was administered in escalated dosing of 10, 15, or 20 mg/Kg for 4 doses every 2 weeks starting on day 1. 20 mg/Kg dose was used for the expansion cohort. Cytarabine was administered at a fIxed dose of 2 g/m2 on days 2-7. PBMCs were collected at defined time points. Differential expression from multiplexed single cell RNA sequencing (scRNAseq) was used to assess biomarkers predictive of response. Results: Of the total 18 patients accrued thus far, 16 are evaluable. 5 had progressive disease, and 11 responded, all complete responses. Most frequent grade 3/4 TEAEs were febrile neutropenia, LFT abnormalities, and electrolyte disturbance. There was 1 death from sepsis and multi-organ failure on day 23, following ANC recovery, from the disease, and 1 patient who withdrew from the study due to grade 4 gastrointestinal bleed, likely ficlatuzumab related, both prior to response assessment. scRNA sequencing identified a TNF alpha and IFN gamma inflammatory signature that correlates with response to ficlatuzumab at count recovery. Conclusion: Cytarabine and ficlatuzumab is a safe combination with promising efficacy in high risk relapsed and refractory AML. This combination is warranted in further Phase II studies. scRNAseq may be used to identify biomarkers of response. Citation Format: Victoria E. Wang, Charalambos Andreadis. Cyfi: Results from a Phase Ib expansion cohort of anti-hepatocyte growth factor and cytarabine in relapsed and refractory AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT078.

Endothelial injury is closely related to osteopontin and TNF receptor-mediated inflammation in end-stage renal disease

BackgroundEndothelial dysfunction, inflammation and active mineralization are key processes involved in cardiovascular burden in end stage renal disease (ESRD). Serum (soluble) thrombomodulin (sTM) is an established marker of endothelial injury. Patients80 patients in ESRD were recruited consecutively. Baseline distribution of sex, age, main comorbidities and Framingham score was similar. A biochemical panel including sTM, intact PTH (iPTH), interleukin-6 (IL-6), pentraxin 3 (PTX3), fibroblast growth factor 23 (FGF-23), osteopontin (OPN), osteoprotegerin (OPG), osteocalcin (OC), osteonectin (ON), soluble tumor necrosis factor receptor type 2 (TNFR2), transforming growth factor-β (TGF-β), hepatocyte growth factor (HGF), vascular endothelial growth factor receptor type 2 (sVEGFR2) and stromal cell-derived factor 1α (SDF1α) was investigated in each patient. Samples obtained while establishing haemodialysis (HD) access were stained for radial artery calcifications (RACs) with Alizarin red and examined histologically. ResultsAfter adjustment for HD status, sTM showed a significant positive correlation with serum creatinine, TNFR2, OPN, HGF, SDF1α, sVEGFR2, Pi, iPTH, FGF-23, OPG, OC and ON. In forward stepwise multiple regression, serum creatinine, TNFR2, and OPN were identified as significant, independent predictors of sTM. Grades 1–3 of RACs correlated with sTM (R = 0.50, p = 0.017), while grade 3 RACs were significantly associated with higher sTM (p = 0.02) than less advanced lesions. ConclusionAmong novel renal and cardiovascular biomarkers, OPN and TNFR2 are closely related to sTM. This may link endothelial damage, vascular remodeling and inflammation. Progression of RAC parallels a presumed compensatory rise in sTM, reflecting endothelial injury. sTM has an intricate role in endothelial function and potential clinical and prognostic applications.

Measurement of Hepatocyte Growth Factor, Interleukin 6 and Tumor necrosis factor α in Acute Myocardial Infarction

Background: Early mortality rate due to acute myocardial infarction (AMI) is approximately 30%, and half of these deaths occur before reaching a hospital. The prevention and early detection play a key role in reducing mortality in AMI. Hepatocyte Growth Factor (HGF), Interleukin 6 (IL-6), and Tumor Necrosis Factor α (TNF-α) are most recent prognostic biomarkers for AMI. The present study was aimed to evaluate the level of these cytokines in AMI.&#x0D; Methods: In this case control study, 39 patients with AMI were compared with 30 healthy subjects. Age, sex and other possible confounding factors were matched. AMI diagnosis was confirmed by typical symptoms, electrocardiogram changes and serum concentration of troponin I and creatine kinase-MB. The levels of TNF-α, IL-6 an HGF at baseline and 3 and 7 days later were measured using ELISA method.&#x0D; Results: Levels of IL-6, TNF-α and HGF increased over time after AMI with ST-segment elevation in study group. The baseline IL-6 levels in AMI group were significantly higher than control group (P&lt;0.05).&#x0D; Conclusions: The results of this study suggest that baseline levels of IL-6 as well as serial changes of serum IL-6, TNF-α and HGF concentrations can be used as potential diagnostic biomarkers in AMI.

Hepatocyte growth factor levels in livers and serum at Kasai-portoenterostomy are not predictive of clinical outcome in infants with biliary atresia

Biliary atresia (BA) is characterized by progressive destruction of the biliary system leading to liver fibrosis and deterioration of liver function. Serum hepatocyte growth factor (HGF) has been shown to be increased in cirrhotic diseases including BA. The aim of this study was to investigate the prognostic value of HGF levels in sera and liver tissue for the further disease course. A total of 49 serum and liver samples from infants with BA were acquired during Kasai-portoenterostomy (KPE) and analyzed by multiplex immunoassay including HGF, as marker of liver regeneration, and Interleukin 6 (IL-6) as a marker of inflammation. Both mediators showed no correlation with the outcome defined as favorable (survival with native liver (SNL)) or, in contrast, rapid deterioration of liver function requiring transplantation. Our data suggest that the degree of liver regeneration indicated by high levels of HGF within the liver is a dismissible factor in the post-KPE disease course.

Effect of serum HGF and CK18 in patients with laryngeal cancer on postoperative prognosis

Objective: To investigate the correlation between the levels of serum cytokeratin 18 (CK18) and hepatocyte growth factor (HGF) and tumor stage and prognosis in patients with laryngeal carcinoma. Method: Patients with laryngeal cancer who were admitted to our hospital from January 2012 to December 2013 were enrolled. Blood samples were collected for CK18 and HGF detection, and postoperative prognosis data were collected at regular follow-up. Result: The serum CK18 and HGF concentration of patients with poorly differentiated tumor, high tumor grade and clinical stage were significantly higher than those with well differentiated tumor, low tumor grade and low clinical stage (P<0.05). The 5-year survival rate (69.9%) of patients with laryngeal cancer in the high CK18 group was significantly lower than that in the low CK18 group (92.3%) (P<0.05), and the 5-year survival rate (71.1%) of patients with laryngeal cancer in the high HGF group was significantly lower than that in the low HGF group (94.2%) (P<0.05). The results of univariate analysis showed that tumor type, differentiation, T grade, N grade and clinical stage affected the survival rate of patients with laryngeal cancer. Cox regression model analysis showed high CK18 and high HGF levels were risk factors for poor prognosis ［CK18 HR: 2.594 (1.558-4.318); P<0.001, HGF HR: 2.671 (1.605-4.446); P<0.001］. Conclusion:The results suggested that serum CK18 and HGF levels can be used as prognostic and disease monitoring biomarkers for laryngeal cancer.