Treatment of liver cirrhosis using hepatocyte-derived liver progenitor-like cells: a prospective, open-label, single-arm, safety trial

Serum Apoptosis Markers in Acute Liver Failure: A Pilot Study

Background: RA is a chronic inflammatory disease of the synovial joints leading to progressive joint destruction, functional impairment and, in severe cases, the need for joint replacement. There is a need to identify which of these patients are more likely to need a joint replacement in order to plan both clinically and economically for patient care. Previous research has identified several biomarkers that may be associated with inflammation and disease activity in RA. Hepatocyte growth factor (HGF) is a pleiotropic cytokine that regulates cell growth, cell motility and tissue regeneration. Expression of HGF has been reported in the synovium of patients with RA and may be associated with disease activity. The objective of our study was to investigate the association between levels of HGF and total joint replacement of the hip and knee in patients with RA. Methods: Data were collected from 412 RA patients with established disease who were followed prospectively. The mean (S.D.) age of the cohort was 61 (10.8) years with a disease duration of 11(4.8) years and 279 (67.7%) of the cohort were female. Clinical indices of disease severity were recorded including whether each patient had undergone hip or knee replacement. Of the 412 patients enrolled, 209 have reached 5 year follow-up (50.7%). Serum levels of HGF at recruitment were quantified using a fluorescent bead-based assay system (Luminex) and at the 5-year follow-up using enzyme-linked immunosorbent assays (ELISA). Associations between joint replacement and HGF levels were analysed using the Mann–Whitney U test for non-parametric data. Results: High levels of HGF were associated with joint replacement of the hip or knee at baseline and at 5-year follow-up. At baseline, significantly higher levels of serum HGF were found in patients who had previously had a hip or knee replacement (n1⁄463) compared with patients who had not received a joint replacement: median (IQR) HGF level (1502 (665) vs 1388 (554) pg/ml, P1⁄40.048). This association was significantly greater for knee replacement alone: median (IQR) HGF level (1610 (683) vs 1382 (548) pg/ml, P1⁄40.016). At 5-year follow-up, serum HGF levels were significantly higher in patients who had received a new hip or knee replacement since baseline (n1⁄433) compared with those who had not had these joints replaced: median (IQR) HGF level (1296 (1894) vs 1115 (862) pg/ml, P1⁄40.040). Conclusion: Joint replacement of the hip or knee in patients with RA is associated with high circulating levels of HGF and may reflect a role for HGF in joint damage. Disclosure statement: The authors have declared no conflicts of interest.

Objective To investigate the dynamic levels of hepatocyte growth factor (HGF), vascular endothelial growth factor(VEGF) in bronchopulmonary dysplasia (BPD), so that to reveal the relationship between two growth factors and BPD. Methods Sixty preterm newborns ( 0.05). Bronchoalveolar lavage fluid(BALF) samples were collected from 60 ventilated preterm infants on 1st, 3rd, 7th, 14th day after birth. The levels of HGF, VEGF and secreted immunoglobulin (sIg) A were quantified by enzyme linked immunosorbent assay (ELISA), at the same time, clinical information were collected. The study protocol was approved by the Ethical Review Board of Investigation in Human Being of Jinhua Central Hospital and The 2nd Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University. Informed consent was obtained from the parents of each participating child. Results ①Ventilator therapy duration in BPD group was significantly longer than that in BPD-free group (Z=3.283, P=0.001). ②BPD group has lower levels of VEGF and HGF than those in BPD-free group at four different time-points (P<0.05), while the levels of VEGF became higher and higher, and the levels of HGF became lower and lower. The levels of HGF and VEGF on the 3rd day after birth showed negative connection with BPD(OR=0.806, 95%CI: 0.764~0.851, P<0.01; OR=0.288, 95%CI: 0.189~0.439, P<0.01). Conclusions Low levels of HGF and VEGF contribute to the development of BPD. The levels of VEGF and HGF on the 3rd day after birth are connected with the development of BPD. Key words: Bronchopulmonary dysplasia; Hepatocyte growth factor; Vascular endothelial growth factor; Infant, premature

In order to evaluate the accuracy and reproducibility of determination of hepatocyte growth factor (HGF) levels in faeces, the stability of HGF in samples processed in different ways was investigated. An ELISA method was used for determination of HGF concentrations. Faeces samples from healthy controls and patients with infectious diarrhoea were studied. It was found that faeces HGF concentration remained stable irrespective of whether samples were freeze‐thawed several times, kept for 6, 12 or 24 h at room temperature or refrigerated for 6, 12, 24 or 36 h; the levels of HGF did not change significantly when samples were freeze‐dried. Adding protease inhibitor to the faeces samples did not affect the HGF levels. There were no significant differences between HGF levels using phosphate buffered saline (PBS) (pH 7.4) or NaCL as buffer, but it was observed that levels of HGF were significantly lower in the samples that were diluted in distilled water. Although both HGF and albumin through various mechanisms may increase in faeces during infectious diarrhoea, there was no significant correlation between faeces HGF levels and albumin levels, which might indicate local production of HGF in the bowel in response to infection. It is concluded that determination of faeces HGF levels is feasible with a high degree of stability. Increased HGF levels in faeces might represent a local production of HGF during bowel injury and might be of use as a diagnostic and monitoring assay.

We retrospectively investigated whether the level of serum hepatocyte growth factor could predict the prognosis and extent of transitional-cell carcinoma of the urinary bladder. Serum samples were collected from 113 patients with bladder cancer and from 200 healthy controls. Of the 113 patients, 59 had superficial bladder cancer and 54 had muscle-invasive cancer. Thirteen bladder cancer tissues (eight superficial and five muscle-invasive) were also collected. The levels of hepatocyte growth factor in the serum and tissues of these individuals were measured by enzyme-linked immunoadsorbent assay using hepatocyte growth factor antibodies. The levels of hepatocyte growth factor in the serum and tissues of patients with muscle-invasive cancer were significantly higher than those of patients with superficial bladder cancer (P <.0001 and P =.0054, respectively). The degree of elevation above the normal level of serum hepatocyte growth factor of the former (61.1%) was significantly higher than that of the latter (8.4%; P <.0001). The elevation was highest in patients with visceral metastasis (93.3%). Among patients with superficial bladder cancer, the overall survival rate of those with low levels of serum hepatocyte growth factor was significantly greater than that of those with high levels (P =.005). Among patients with minimally invasive bladder cancer, the disease-free and overall survival rates of those with high levels of serum hepatocyte growth factor were significantly lower than the same rates of those with low levels (P <.001 and P =.0028, respectively). Our study suggests that the level of hepatocyte growth factor in serum could be a predictor of patient survival and extent of bladder cancer.

6614 Background: Angiogenesis may have a role in the pathophysiology of hematological malignancies and also be a therapeutic target. Increased levels of angiogenic factors have been correlated with poor prognosis in several solid tumors. Accordingly, we evaluated the serum level of variable angiogenic factors and analyzed their prognostic significance in newly diagnosed patients with hematological malignancies. Methods: The ELISA were performed to quantify basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), tumor necrosis factor-α (TNF-α), angiogenin, and matrix metalloproteinase-9 (MMP-9) in stored samples obtained before treatment from patients with AML (30 patients), ALL (10 patients), CML (14 patients) and MDS (9 patients). Results: VEGF, HGF, angiogenin, and MMP-9 levels were significantly higher in patients with CML than in healthy individuals (p<0.0001 for VEGF, HGF and MMP-9, p=0.024 for angiogenin). HGF levels were also higher in patients with AML than healthy individuals (p<0.001). Higher HGF levels correlated significantly with white blood cell count (p=0.014), monocyte counts (p=0.009), and serum levels of LDH (P=0.009) in AML patients. Among 24 AML patients who received remission induction chemotherapy, 17 patients (70.8%) obtained a complete remission (CR). In univariate analysis, HGF levels (p=0.015) and age (p=0.034) were significant parameters predictive for an achievement of CR. In multivariate analysis using logistic regression model, HGF levels was the only parameter strongly predictive for CR (p=0.047). Leukemia free survival (LFS) for AML patients with lower HGF concentrations was superior to that for those with higher HGF concentrations (1-year LFS rates = 75.0% versus 37.5%, P=0.065). Conclusions: The current study demonstrated elevated serum VEGF, angiogenin, and MMP-9 in patients with CML and elevated serum HGF in patients with CML and AML. The HGF concentrations were significantly correlated with an achievement of CR and high HGF levels were associated with worse survival in patients with AML. No significant financial relationships to disclose.

Purpose. To investigate clinical factors related to the aqueous humor levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with proliferative diabetic retinopathy (PDR). Methods. Undiluted aqueous humor was obtained during ocular surgery from 46 eyes of 46 patients and the levels of growth factors were measured using enzyme-linked immunosorbent assays. VEGF and HGF levels were compared with the number of photocoagulation. VEGF and HGF levels in patient groups stratified according to the existence of vitreous hemorrhage, retinal detachment, and fibrovascular membrane were analyzed. And clinical parameters associated with the growth factors were determined by multiple regression analysis. Results. The levels of VEGF decreased significantly as the extent of photocoagulation increased and showed significant positive correlation with the existence of vitreous hemorrhage. There was no significant correlation between VEGF levels and the existence of fibrovascular membrane and traction retinal detachment. The levels of HGF also decreased significantly as the extent of photocoagulation increased, but increased significantly when fibrovascular membrane existed. There were no significant correlations between HGF levels and the existence of vitreous hemorrhage and traction retinal detachment. Concerning systemic conditions, each growth factor has no significant correlation with duration and type of diabetes mellitus, the treatment regimen, the control of hemoglobin A1C, and the existences of hypertension or renal dysfunction. Conclusion. The therapeutic effect of panretinal photocoagulation on PDR might be partly exerted by reduction of the levels of VEGF and HGF in ocular fluid. Since the clinical parameters associated with VEGF were different from those associated with HGF, these growth factors might influence the progression of retinopathy in different ways.

To examine the effects of Sho-saiko-to extract on liver regeneration, Sho-saiko-to extract (0.75%, 1.5% or 3%) was administered to 70% partial hepatectomized rats with dimethylnitrosamine-induced liver-injury. S phase cell number, liver retinoid levels, hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-beta) levels in each intraorgan were measured as indicators of liver regeneration. Three to seven days after hepatectomy, HGF and TGF-beta levels of the liver and spleen of the Sho-saiko-to extract groups were significantly different from the levels of the ordinary food group (P < 0.05-0.1). HGF levels in the Sho-saiko-to extract groups were approximately 1.3-1.8 times higher in the liver and approximately 1.8-2.1 times higher in the spleen compared with the levels found in the ordinary food group. TGF-beta levels in the Sho-saiko-to extract groups were approximately 0.38-0.47 times the level in the liver and 0.58-0.77 times the level in the spleen of the ordinary food group. There was no difference in HGF and TGF-beta levels of the kidney and lung between the Sho-saiko-to extract group and the ordinary food group. There was a significant and positive correlation between HGF level and S phase cell number in the liver (r = 0.826, P < 0.01). There was a significant and negative correlation between TGF-beta level and the retinoid level in the liver (r = -0.696, P < 0.01). In addition, the levels of the active constituents of Sho-saiko-to extract (glycyrrhetic acid, baicalin and baicalein) showed high values in the liver and spleen of partial hepatectomized rats, and increased from the third day after partial hepatectomy. These results show that Sho-saiko-to extract induces liver regeneration by increasing the production of HGF and suppressing the production of TGF-beta in the liver and spleen of partial hepatectomized rats. It was considered that the increase in the Sho-saiko-to extract active constituent levels in the liver and spleen greatly influences this action.

Simultaneous Assessment of Hepatocyte Growth Factor and Vascular Endothelial Growth Factor in Epithelial Lining Fluid From Patients With COPD

Hepatocyte growth factor (HGF) is a well-known multifunctional growth factor, and evidence has accumulated indicating that the HGF/MET (HGF receptor) signaling axis is involved in the progression of cancer. Macrophage-stimulating protein (MSP) is also known as a growth factor which activates not only macrophages but also cancer cells and osteoclasts through the activation of the specific Receptor d'origine nantais (RON). Pro-HGF and pro-MSP lack biological activity and, therefore, require proteolytic activation for conversion to an active two-chain form by HGF activator (HGFA). Although, there are several studies on HGF/MET signaling with castration-resistant prostate cancer (CRPC) and bone metastasis, reports on plasma protein are rare. In addition, the MSP/RON signaling axis in PC is not well understood. Here, we analyzed associations between PC progression and plasma HGF and MSP levels. We tested plasma samples from 58 patients with PC: 36 with castration-resistant (CR) PC and 22 with pretreatment for PC as control. We used enzyme-linked immunosorbent assay (ELISA) kit to determine plasma levels of HGF, MSP and HGFA, and examined correlations with clinicopathological characteristics such as Gleason grade and bone metastasis. PCR was used to evaluate HGF and MSP-related molecules in PC cell lines. Plasma levels of HGF, MSP and HGFA in the CRPC group were higher than in the control group (HGF: P < 0.001; MSP: P = 0.008; HGFA: P < 0.001). HGF and MSP levels were significantly correlated (P = 0.003). In the CRPC group, plasma HGF and MSP levels and Gleason score were not correlated; however, high plasma MSP level correlated with bone metastasis. (P = 0.016). In cell lines, PC3 expressed significantly more HGF, MET and RON than did LNCaP (P < 0.001), and both cell lines expressed MSP. Plasma concentrations of HGF, MSP and HGFA are significantly elevated in patients with CRPC. Also, as plasma MSP levels are significantly associated with bone metastasis in CRPC patients, MSP may be a candidate for serum marker of bone metastasis. Our results show the importance of the HGF/MET and MSP/RON signaling systems in CRPC.

Background. Transforming growth factor-beta (TGF-β) and hepatocyte growth factor (HGF) are inflammatory cytokines which function as key regulators of immunological homeostasis and inflammatory responses. They have been linked to inflammatory bowel diseases (IBD). In this study, we aim to assess the levels of TGF-β and HGF and other inflammatory markers in patients with IBD and correlate them with the disease activity. Study Design. A cross-sectional study involving 100 patients with ulcerative colitis (UC) and 100 patients with Crohn's disease (CD) and 50 control subjects. TGF-β and HGF levels were measured and correlated with disease activity. Results and Conclusion. Serum levels of TGF-β and HGF were significantly higher in IBD patients compared with the control group. In the UC group, the levels of HGF and TGF-β were significantly higher than in the CD group. Levels of TGF-β and HGF correlate with the activity of IBD.

It has been thought that hepatocyte growth factor (HGF) levels increase during acute phases of infectious diseases. The aim of this study was to determine whether HGF, C-reactive protein (CRP), and proinflammatory cytokines have any diagnostic and prognostic value, and to assess HGF as a biomarker in patients with febrile neutropenia. Materials and methods: This study included 20 patients with febrile neutropenia as the study group and 20 healthy individuals as the control group. Serial measurements of serum HGF, CRP, and proinflammatory cytokine levels were performed by enzyme-linked immunosorbent assay (ELISA) at the baseline, after 48 h of treatment, and at posttreatment. Results: It was found that HGF levels at the baseline were significantly higher than those in the healthy controls (P = 0.001). It was also seen that HGF levels 48 h after treatment and at posttreatment were significantly lower than those at the baseline (P = 0.012). High-risk group patients had higher mean serum HGF levels compared with the low-risk group. It was detected that IL-6 and TNF-a levels at the baseline were significantly decreased after treatment (P = 0.02 and P = 0.005). Conclusion: Our findings suggested that serial measurement of serum HGF levels may be an important marker to identify risk levels of febrile neutropenia and to predict its prognosis.

To assess any correlation of plasma hepatocyte growth factor (HGF) levels with relevant endothelial cell injury parameters and determine the prognostic value in septic patients. A prospective, observational study was conducted in patients with sepsis admitted to the Department of Critical Care Medicine at the Zhongda Hospital from November 2017 to March 2018. Plasma HGF levels were measured by enzyme-linked immunosorbent assay in the first 24 h after admission (day 1) and on day 3. The primary endpoint was defined as all-cause 28-day mortality. Furthermore, we analyzed the correlation of HGF with relevant endothelial cell injury markers. Eighty-six patients admitted with sepsis were included. HGF levels of nonsurvivors were elevated compared to those of survivors on day 1 (1940.62 ± 74.66 pg/mL vs. 1635.61 ± 47.49 pg/mL; P = 0.002) and day 3 (1824.82 ± 137.52 pg/mL vs. 1309.77 ± 83.49 pg/mL; P = 0.001) and showed a strong correlation with von Willebrand factor (r = 0.45, P < 0.0001), lactate (r = 0.35, P = 0.0011), pulmonary vascular permeability index (r = 0.38, P = 0.0241), first 24 h fluid administration (r = 0.38, P < 0.0001), and sequential organ failure assessment score (r = 0.40, P = 0.0001). Plasma HGF levels were able to prognostically discriminate between survivors and nonsurvivors on day 1 (AUC: 0.72, 95%CI: 0.60-0.84) and day 3 (AUC: 0.77, 95%CI: 0.63-0.91). HGF levels are associated with sepsis and correlated with established markers of endothelial cell injury. Elevated HGF levels in sepsis patients are an efficient indicator of poor prognosis. The study was registered in Clinical Trial (Registration Number: NCT02883231).

Background: Obesity is one of the modifiable risk factors for the development and progression of pancreatic cancer. However, the mechanisms of obesity-related pancreatic cancer has not been well defined. In our previous analysis of the genome-wide association data, we identified a significant interaction of obesity with cytokine signaling pathway. Methods: In the current study, we selected several genes from this pathway that code for secreted or membrane proteins and measured the protein levels in plasma samples of 100 pancreatic patients and 100 healthy controls drawn from a case-control study conducted at MD Anderson. Cases and controls were frequency matched by age, sex, race and body mass index (BMI). Plasma levels of HGF (hepatocyte growth factor), MIP-1β (microphage infiltration factor 1-beta), FasL (Fas ligand) and PLA2 (phospholipase A2) were measured using the Luminex and ELISA methods. The protein levels were analyzed in relation to cancer risk and patient survival using analysis of variance, non-parametric test, Kaplan Meier plot, log-rank test, and Cox proportional hazard regression models. Results: A significantly higher level of HGF and MIP-1β and lower level of FasL was observed in cancer patients than in controls, with the mean values of 365.7 vs. 146.2 pg/ml, P&amp;lt; 0.001; 216.5 vs.122.3 pg/ml, P = 0.002, 23.1 versus 29.4 pg/ml, P&amp;lt;0.001, respectively. Individuals with a high HGF or low FasL level had, respectively, 4.6-fold (95% confidence interval [CI] = 2.4-9.1, P&amp;lt;0.001) and 2.9-fold (95% CI = 1.55-5.38, P = 0.001) increased risk of pancreatic cancer with adjustment for other known risk factors. Furthermore, a significant association of HGF level with BMI was observed in cases (R2 = 0.269, P = 0.005). The HGF level (mean ± SE pg/ml) was significantly higher in obese (682±204) than that in overweight (268±40) or normal weight patients (313±71), P = 0.01 and 0.005, respectively. Patients with higher levels of HGF had a significantly reduced overall survival than those with lower levels (9.3 vs. 13.3 months, P = 0.006). Cox proportional hazard regression analysis demonstrated that a higher level of HGF was an independent prognostic factor (Hazard Ratio = 2.61, 95% CI = 1.22-5.64, P = 0.01) after adjusting for BMI, disease stage and other clinical factors. Conclusion: A higher plasma level of HGF was related to obesity and overall survival in pancreatic adenocarcinoma, which may serve as a potential diagnostic and prognostic marker for pancreatic cancer. Citation Format: Dong Yan, Ping Chang, Donghui Li. Plasma HGF level is associated with obesity, increased risk and reduced survival of pancreatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-358.

Hepatocyte growth factor (HGF) in patients with hepatitis B and meningitis.