Plasma Hepatocyte Growth Factor Research Articles

Hepatocyte growth factor as indicator for subclinical atherosclerosis.

Background: Hepatocyte growth factor (HGF) is a pleiotropic cytokine mainly produced by mesenchymal cells. After endothelial damage by oxidized low-density lipoprotein (LDL), HGF is produced and released into the circulation in response. Due to this mechanism HGF has been proposed as possible clinical biomarker for clinical as well as subclinical atherosclerosis. Patients and methods: The conducted study is an observational, single centre, cohort study, including 171 patients with at least one cardiovascular risk factor or already established cardiovascular disease (CVD). Each patient underwent 3D plaque volumetry of the carotid and femoral arteries as well as physical examination and record of the medical history. Additionally, plasma HGF and further laboratory parameters like high sensitivity C-reactive protein and LDL-cholesterol were determined. Results: 169 patients were available for statistical analysis. In bivariate correlation, HGF showed a highly significant correlation with total plaque volume (TPV, r=0.48; p<0.001). In receiver operating characteristic (ROC) analysis for high TPV, HGF showed an area under the curve (AUC) of 0.68 (CI 95%: 0.59-0.77, p<0.001) with a sensitivity of 78% and a specificity of 52% to predict high TPV at a cut-off of 959 ng/ml. In the ROC-analysis for the presence of CVD, HGF demonstrated an AUC of 0.65 (95% CI 0.55-0.73; p=0.01) with a sensitivity of 77% and a specificity of 52%. Conclusions: Higher plasma levels of HGF are associated with higher atherosclerotic plaque volume as measured by 3D-ultrasound.

Plasma hepatocyte growth factor as a noninvasive biomarker in small cell lung cancer

BackgroundHepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine, which is overexpressed and/or activated in multiple malignancies and is reported to be associated with tumor development and inferior survival. At present, the role of HGF in small cell lung cancer (SCLC) has not been fully explored yet.Materials and methodsThe expression of HGF and its value in predicting survival in SCLC were explored from GEO database and in pan-cancer analysis. Furthermore, we detected the expression of HGF using tumor tissue and paired plasma samples from a validation cohort of 71 SCLC patients at our institute. Correlation between tumor and plasma HGF expression and the prognostic values were analyzed.ResultsGEO database analysis revealed that tumor tissue had lower HGF expression than paired normal tissue in SCLC. At our institute, immunohistochemical staining showed negative expression of HGF in tumor tissue of SCLC at our institute (47/47, 100%). The average baseline plasma HGF was 1.28 (range,0.42–4.35) ng/ml. However, plasma HGF was higher in SCLC patients with patients with N3, M1, liver metastasis (LM) and bone metastasis (BM) disease compared with those N0 − 2 (1.25 vs. 1.75 ng/mL, P = 0.000), M0 (1.26 vs. 1.63 ng/mL, P = 0.003), non-LM (1.32 vs. 2.06 ng/mL, P = 0.009), and non-BM (1.35 vs. 1.77 ng/mL, P = 0.047), respectively. Multivariate analysis revealed plasma HGF was an independent predictor for LM and prognostic factor of OS.ConclusionOur results revealed that plasma HGF rather than tumor HGF exhibited a potential role in predicting metastasis and survival in SCLC. Plasma HGF might be used as a non-invasive detecting and monitoring tool for SCLC.

Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors.

Surgical resection of the cancerous tissue represents one of the few curative treatment options for neoplastic liver disease. Such partial hepatectomy (PHx) induces hepatocyte hyperplasia, which restores liver function. PHx is associated with bacterial translocation, leading to an immediate immune response involving neutrophils and macrophages, which are indispensable for the priming phase of liver regeneration. Additionally, PHx induces longer-lasting intrahepatic apoptosis. Herein, we investigated the effect of apoptotic extracellular vesicles (aEVs) on neutrophil function and their role in this later phase of liver regeneration. A total of 124 patients undergoing PHx were included in this study. Blood levels of the apoptosis marker caspase-cleaved cytokeratin-18 (M30) and circulating aEVs were analyzed preoperatively and on the first and fifth postoperative days. Additionally, the invitro effects of aEVs on the secretome, phenotype and functions of neutrophils were investigated. Circulating aEVs increased at the first postoperative day and were associated with higher concentrations of M30, which was only observed in patients with complete liver recovery. Efferocytosis of aEVs by neutrophils induced an activated phenotype (CD11bhighCD16highCD66bhighCD62Llow); however, classical inflammatory responses such as NETosis, respiratory burst, degranulation, or secretion of pro-inflammatory cytokines were not observed. Instead, efferocytosing neutrophils released various growth factors including fibroblast growth factor-2 and hepatocyte growth factor (HGF). Accordingly, we observed an increase of HGF-positive neutrophils after PHx and a correlation of plasma HGF with M30 levels. These data suggest that the clearance of PHx-induced aEVs leads to a population of non-inflammatory but regenerative neutrophils, which may support human liver regeneration. In this study, we show that the surgical removal of a diseased part of the liver triggers a specific type of programmed cell death in the residual liver tissue. This results in the release of vesicles from dying cells into the blood, where they are cleared by circulating immune cells. These respond by secreting hepatocyte growth factors that could potentially support the regeneration of the liver remnant.

Plasma human growth cytokines in children with vasovagal syncope.

PurposeThe study was designed to investigate the profile of plasma human growth cytokines in pediatric vasovagal syncope (VVS).Materials and methodsIn the discovery set of the study, plasma human growth cytokines were measured using a Quantiboby Human Growth Factor Array in 24 VVS children and 12 healthy controls. Scatter and principal component analysis (PCA) diagrams were used to describe the samples, an unsupervised hierarchical clustering analysis was used to categorize the samples. Subsequently, the cytokines obtained from the screening assays were verified with a suspension cytokine array in the validation set of the study including 53 VVS children and 24 controls. Finally, the factors associated with pediatric VVS and the predictive value for the diagnosis of VVS were determined.ResultsIn the discovery study, the differential protein screening revealed that the plasma hepatocyte growth factor (HGF), transforming growth factor b1 (TGF-b1), insulin-like growth factor binding protein (IGFBP)-4, and IGFBP-1 in children suffering from VVS were higher than those of the controls (all adjust P- value < 0.05). However, the plasma IGFBP-6, epidermal growth factor (EGF), and IGFBP-3 in pediatric VVS were lower than those of the controls (all adjust P- value < 0.01). Meanwhile, the changes of 7 differential proteins were analyzed by volcano plot. Unsupervised hierarchical cluster analysis demonstrated that patients in the VVS group could be successfully distinguished from controls based on the plasma level of seven differential proteins. Further validation experiments showed that VVS patients had significantly higher plasma concentrations of HGF, IGFBP-1, and IGFBP-6, but lower plasma concentrations of EGF and IGFBP-3 than controls. The logistics regression model showed that increased plasma concentration of HGF and IGFBP-1 and decreased plasma concentration of EGF were correlated with the development of pediatric VVS. ROC curve analysis showed that the abovementioned 3 proteins were useful for assisting the diagnosis of VVS.ConclusionPlasma human growth cytokine profiling changed in pediatric VVS. Elevated plasma concentrations of HGF and IGFBP-1, and decreased EGF were associated factors in the development of pediatric VVS. The abovementioned three proteins are helpful for the diagnosis of pediatric VVS.

Abstract 5138: Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancer

Abstract Background: Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the therapeutic implications of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancer (CRC). Methods: Clinical outcomes were analyzed according to the plasma HGF levels in patients with metastatic CRC (mCRC) receiving palliative first-line cetuximab or bevacizumab + FOLFIRI chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition in the HGF-high population. Results: From March 2015 to September 2019, a total of 80 patients were enrolled. The median age was 63 (range, 24-85) years. Of these, 45 patients (56.2%) were treated with bevacizumab + FOLFIRI and 35 patients (43.8%) were treated with cetuximab + FOLFIRI. Among patients with evaluable disease (43 patients (95.6%) in the bevacizumab group and 34 patients (97.1%) in the cetuximab group), the objective response rate was 60.0% and 37.8%, respectively (p=0.162). The median serum HGF level was 374.75 (range, 9.43-30,644.44) pg/mL, and the optimal cut-off value of HGF levels was 12.70 pg/mL by the maximal chi-square method. During a median follow-up of 29.3 (range, 1.2-71.3) months, both progression-free survival (PFS) and overall survival (OS) were significantly shorter in the high HGF group compared with the low HGF group: median 11.8 (95% confidence interval [CI], 10.5-13.1) months vs. 24.7 (95% CI, 23.4-25.9) months for PFS (p=0.009), and median 21.1 (95% CI, 17.9-24.3) months vs. not reached for OS (p=0.018). The difference in PFS and OS was statistically significant in the cetuximab group (p=0.003 for PFS and p=0.035 for OS), but not in the bevacizumab group. In five RAS/RAF wild-type CRC cell lines (Caco-2, COLO 320DM, KM12C, SNU-C1, and SNU-C4), the addition of HGF activated ERK1/2 and AKT via MET phosphorylation. In the cytotoxicity assays, Caco-2 and SNU-C4 were relatively sensitive to cetuximab compared with the others and, in the presence of HGF, cetuximab sensitivity was significantly decreased in the two cells. Moreover, capmatinib, a MET inhibitor, abrogated the effect of HGF on common downstream signaling pathways of EGFR and MET and thus the cetuximab resistance was significantly overcome in vitro. Conclusions: Among patients with mCRC receiving cetuximab + FOLFIRI, those with high plasma HGF levels had significantly worse PFS and OS. HGF induced cetuximab resistance by AKT and ERK activation while capmatinib, a MET inhibitor, significantly increased the anti-tumor effects of cetuximab in the presence of HGF in vitro. Our data may provide evidence of future clinical trials of dual EGFR and MET targeting strategies in patients with HGF-high, RAS/RAF wild-type mCRC. Citation Format: Sang-A Kim, Hyejoo Park, Kui-Jin Kim, Ji-Won Kim, Ji Hea Sung, Milang Nam, Ju Hyun Lee, Eun Hee Jung, Koung Jin Suh, Ji Yun Lee, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Soo-Mee Bang, Jong Seok Lee, Keun-Wook Lee. Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5138.

Prognostic tools at hospital arrival in acute myocardial infarction: copeptin and hepatocyte growth factor

BackgroundPrompt evaluation and treatment of acute coronary syndrome has demonstrated to reduce mortality. Although several biomarkers have been studied for risk stratification and prognostic purposes, none is recommended to guide treatment based on its prognostic value. Copeptin and hepatocyte growth factor have been associated with poor outcome in patients with acute myocardial infarction. The aim of this study is to evaluate the early prognostic value of measurements of copeptin and hepatocyte growth factor for hospital mortality risk and 1-year-follow-up mortality, in patients with acute myocardial infarction. In our retrospective observational study, we measured hepatocyte growth factor and copeptin in blood samples collected at hospital arrival in patients with acute myocardial infarction; and follow-up them until 1-year.Results84 patients with were included in the study, mainly male (65%) with a median age of 70.3 ± 13.56 years. Hospital mortality was 11.9%. Plasma levels of copeptin at hospital arrival were statistically significant higher in patients who died during hospital admission (145.60 pmol/L [52.21–588.50] vs. 24.79 pmol/L [10.90–84.82], p 0.01). However, we found no statistically significant association between plasma levels of hepatocyte growth factor and hospital mortality (381.05 pg/ml [189.95–736.65] vs. 355.24 pg/ml [175.55–521.76], p 0.73). 1-year follow-up mortality was 21.4%. Plasma levels of copeptin at hospital arrival were higher in those patients who died in the following year (112.28 pmol/L [25.10–418.27] vs. 23.82 pmol/L [10.96–77.30], p 0.02). In the case of HGF, we also find no association between hepatocyte growth factor plasma levels and 1 -year follow-up mortality (350.00 pg/ml [175.05–555.08] vs. 345.53 pg/ml [183.68–561.15], p 0.68).ConclusionsIn patients with acute myocardial infarction measurement of copeptin at hospital arrival could be a useful tool to assess the prognosis of these patients, since their elevation is associated with a higher hospital mortality and higher 1-year follow-up mortality. We have not found this association in the case of hepatocyte growth factor measurement.

Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancers.

Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7months, respectively, for PFS (p = 0.009), and median 21.1months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.

Hepatocyte growth factor and soluble cMet levels in plasma are prognostic biomarkers of mortality in patients with severe acute kidney injury.

BackgroundHepatocyte growth factor (HGF)/cMet pathway is necessary for repair and regeneration following acute kidney injury (AKI). We evaluated the clinical potential of plasma HGF and soluble cMet as prognostic biomarkers for severe AKI requiring continuous renal replacement therapy (CRRT).MethodsOne hundred thirty-six patients with severe AKI who participated in the VENUS (volume management under body composition monitoring in critically ill patients on CRRT) trial between 2017 and 2019 were enrolled in this study. We investigated associations between plasma HGF and cMet concentrations and all-cause mortality.ResultsPlasma HGF and soluble cMet levels were positively correlated. Patients were divided into three groups based on their HGF and soluble cMet concentrations. The day D 0, D2, and D7 highest concentration HGF groups had significantly higher in-hospital mortality after adjusting for sex, body mass index, Acute Physiology and Chronic Health Evaluation II, and age-adjusted Charlson comorbidity index score, especially on D7 (hazard ratio, 4.26; 95% confidence interval, 1.71–10.62; p = 0.002). D7 soluble cMet level was also associated with mortality. Receiver operating characteristic curve analysis indicated that D7 HGF and soluble cMet levels were best at predicting mortality. Addition of plasma HGF and soluble cMet to conventional prognostic indices significantly improved the predictive value for mortality on D7. However, plasma HGF and soluble cMet were not associated with fluid status.ConclusionPlasma HGF and soluble cMet levels were significant predictors of the outcomes of severe AKI patients undergoing CRRT. There was no correlation between plasma HGF and soluble cMet levels and fluid balance.

The Incremental Prognostic Value of Hepatocyte Growth Factor in First-Ever Acute Ischemic Stroke: An Early Link Between Growth Factor and Interleukins.

Hepatocyte growth factor (HGF) is a potential prognostic factor for acute ischemic stroke (AIS). In this study, we sought to validate its earlier predictive accuracy within 24 h for first-ever AIS. Moreover, as HGF interacts with interleukins, their associations may lead to novel immunomodulatory therapeutic strategies. Patients with first-ever AIS (n = 202) within 24 h were recruited. Plasma HGF and related interleukin concentrations were measured by multiplex immunoassays. The primary and secondary outcomes were major disability (modified Rankin scale score ≥3) at 3 months after AIS and death, respectively. Elastic net regression was applied to screen variables associated with stroke outcome; binary multivariable logistic analysis was then used to explore the relationship between HGF level and stroke outcome. After multivariate adjustment, upregulated HGF levels were associated with an increased risk of the primary outcome (odds ratio, 7.606; 95% confidence interval, 3.090–18.726; p < 0.001). Adding HGF to conventional risk factors significantly improved the predictive power for unfavorable outcomes (continuous net reclassification improvement 37.13%, p < 0.001; integrated discrimination improvement 8.71%, p < 0.001). The area under the receiver operating characteristic curve value of the traditional model was 0.8896 and reached 0.9210 when HGF was introduced into the model. An elevated HGF level may also be a risk factor for mortality within 3 months poststroke. The HGF level was also positively correlated with IL-10 and IL-16 levels, and HGF before interaction with all interleukins was markedly negatively correlated with the lymphocyte/neutrophil ratio. HGF within 24 h may have prognostic potential for AIS. Our findings reinforce the link between HGF and interleukins.

Circulating Hepatocyte Growth Factor Reflects Activation of Vascular Repair in Response to Stress

Background: Acute cardiovascular events arise when the arterial wall fails to repair the damage caused by cardiovascular risk factors. Hepatocyte growth factor (HGF) stimulates growth of vascular cells but has been associated with increased risk of cardiovascular disease (CVD) in epidemiological studies. Here we tested the hypothesis that this association reflects activation of a protective vascular repair response. Methods: Small interfering RNA (siRNA) and recombinant human HGF were used to assess the role of HGF in regulation of human umbilical cord endothelial and coronary artery smooth muscle cell proliferation, migration and viability. Proximity extension assay was used to determine HGF and other biomarkers in 4742 subjects participating in the Malmo Diet and Cancer study and in extracts of 200 human carotid plaques. Findings: HGF promoted migration, proliferation and survival of human endothelial and smooth muscle cells. Human atherosclerotic plaques with a high content of HGF had a more stable phenotype. Cultured vascular cells expressed HGF in response to stress. Plasma HGF correlated with circulating levels of cellular stress biomarkers such as soluble TRAIL receptor-2 and caspase-8. Decreased ability to respond with elevated HGF levels to cellular stress, as assessed by the ratios of HGF to soluble TRAIL receptor-2 and caspase-8, associated with increased risk of cardiovascular events during a follow-up period of 19.4±5.0 years. Interpretations: These findings provide support for a protective role of HGF in CVD and show that subjects with a low ability to express HGF in response to stress have an increased risk of cardiovascular events. Funding Information: The work was supported by the Swedish Society for Medical Research, Emil and Wera Cornell foundation, Hjelt foundation, the Swedish Research Council, the Swedish Foundation for International Cooperation in Research and Higher Education, Crafoord foundation, the Swedish Medical Society, Diabetes foundation, Swedish Heart and Lung Foundation, Diabetes Research and Wellness foundation, Albert Pahlssons foundation, SUS foundations and funds, Lund University Infrastructure grant ”Malmo population-based cohorts” (STYR 2019/2046) and Lund University Diabetes Center (Swedish Research Council - Strategic Research Area Exodiab Dnr 2009-1039 and the Swedish Foundation for Strategic Research Dnr IRC15-006). Declaration of Interests: None. Ethics Approval Statement: All studies were approved by the respective Regional Ethical Review Boards and conducted in accordance with the Helsinki Declaration. All subjects gave written consent.

Prognostic Significance of Plasma Hepatocyte Growth Factor in Sepsis.

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).

The use of elevated circulating hepatocyte growth factor (HGF) level as a potential prognostic biomarker in locally advanced pancreatic cancer.

429 Background: The hepatocyte growth factor (HGF)/c-MET pathway has pleiotropic functions in tumor progression including invasion and cancer cell survival. The potential use of circulating plasma HGF as a prognostic biomarker is not known. Methods: This was an analysis of plasma HGF in patients enrolled in a single arm phase II study (NCT01821729) of patients with previously untreated locally advanced pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX and losartan followed by chemoradiotherapy before resection was attempted (Murphy JE et al., 2019). Eligible patients from the trial included those who had undergone baseline research labs including HGF. Circulating HGF was measured in the plasma on day 1 of treatment using ELISA, and the median value was used to define high vs low levels for the purpose of analysis. The association of elevated HGF with overall survival (OS) was analyzed by univariable and multivariable Cox regression, adjusting for tumor size (≤ versus &gt; 40 mm) and serum CA19-9 (≤ versus &gt; 37 U/mL). Results: There were 46 eligible patients with a median follow up of 31 months. The median age was 63 (range 42-78) and 52% were female (24/46). Median tumor size was 41.4 mm (range 18–68 mm). There were 41/46 patients (89.1%) with elevated baseline CA19-9. Median baseline HGF was 1,250.55 pg/mL (range 650.9–6,459.1). Median OS was 38.4 months for patients with baseline HGF at or below the median, and 19.3 months for those with elevated HGF. On univariate analysis, elevated HGF was associated with poorer OS (HR 2.28, 95% CI 1.06–4.87, p = 0.03). On multivariate analysis, after controlling for tumor size and baseline CA19-9, elevated plasma HGF remained significantly associated with poorer OS (HR 2.58, 95% CI 1.16–5.70, p = 0.02). Conclusions: In conclusion, elevated baseline circulating plasma HGF is an independent biomarker of poorer OS in patients with locally advanced PDAC treated with neoadjuvant therapy. Further randomized studies are needed to define the negative predictive biomarker value for high plasma HGF and identify the optimal HGF range as well as determine applicability to other stages of disease. These results support the continued investigation of plasma HGF in ongoing clinical trials with PDAC patients.

Targeted proteomics of right heart adaptation to pulmonary arterial hypertension.

No prior proteomic screening study has centred on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 (discovery cohort) and 76 (validation cohort) PAH patients. The association between proteomic markers and RHMP, defined by the Mayo right heart score (combining RV strain, New York Heart Association (NYHA) class and N-terminal pro-brain natriuretic peptide (NT-proBNP)) and Stanford score (RV end-systolic remodelling index, NYHA class and NT-proBNP), was assessed by partial least squares regression. Biomarker expression was measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatocyte growth factor (HGF), stem cell growth factor-β, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk of heart failure who warrant closer follow-up and intensified therapy.

Different Forms of Ursolic Acid and Their Effect on Liver Regeneration.

The aim of this study was to determine the effect of natural and encapsulated sources of ursolic acid on liver regeneration. Four ursolate sources were tested. Two forms of ursolic acid encapsulates were combined with cyclodextrins, i.e., gamma-CD (gCD) and beta-CD, and two natural sources were adjusted by homogenization (HAP) and micronization of apple peel using Jonagold apples. All ursolate forms were applied intragastrically in daily doses of 20 mg for 7 days. Laboratory rats were fed with standard laboratory diet. Further, gCD and MAP were also tested with a high-fat diet (6 weeks). Partial hepatectomy (PH) was performed 24 hours before the end of the experiment. The concentration of plasma hepatocyte growth factor (HGF) was determined with an immunoassay; simultaneously, the expression of HGF and CYP7A1 in the liver was quantified through qPCR. HGF expression and plasma levels were significantly increased 24 hours after PH in both the HAP (p=0.038) and HFgCD groups (p=0.036), respectively. The correlation between HGF expression and plasma values was significant (p=0.04). The positive effects on liver regeneration were found in both the gCD and HAP forms of ursolic acid, whose effects were confirmed through the upregulation of HGF.

Evaluation of Hepatocyte Growth Factor in Iraqi Patients with Acute Myeloid Leukemia: Its Correlation with Clinical Parameters and Response to Induction Therapy

BACKGROUND: Hepatocyte growth factor (HGF) is a proangiogenic factor that exerts different effects over stem cell survival growth, apoptosis, and adhesion. Its impact on leukemogenesis has been established by many studies.&#x0D; AIM: This study aimed to determine the effect of plasma HGF activity on acute myeloid leukemia (AML) patients at presentation and after remission.&#x0D; PATIENTS AND METHODS: This was a cross-sectional prospective study of 30 newly-diagnosed, adult, and AML patients. All patients received the 7+3 treatment protocol. Patients’ clinical data were taken at presentation, and patients were followed up for 6 months to evaluate the clinical status. Plasma HGF levels were estimated by ELISA based methods in the patients at two intervals first at diagnosis and the 2nd time after remission of disease. Plasma HGF levels were only measured once in twenty healthy control individuals.&#x0D; RESULTS: A statistically significant lowering in the median levels of HGF after remission induction therapy has been found when compared with those before treatment (p = 0.006) and in the group of patients who achieved complete remission in comparison with those before treatment (p = 0.005). Furthermore, a significant reduction was also demonstrated after treatment in patients presenting with extramedullary involvement (p = 0.003) and in the alive group (p = 0.001).&#x0D; CONCLUSION: Plasma HGF estimation can be a useful parameter in predicting treatment outcomes in patients with AML, and it can add potentially useful information to risk stratification parameters.

Human bone marrow-derived mesenchymal stromal cells in combination with silymarin regulate hepatocyte growth factor expression and genotoxicity in carbon tetrachloride induced hepatotoxicity in Wistar rats.

To evaluate the antimutagenic potential of combination treatment of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) and silymarin and its effect on hepatocyte growth factor levels in CCl4 induced hepatotoxicity in Wistar rats. Hepatotoxicity was induced in adult female Wistar rats using carbon tetrachloride (CCl4 ). Thirty-six rats were randomly divided into six groups with six rats in each group: Group 1 (normal control group), Group 2 (received only CCl 4 ), Group 3 (CCl 4 +low dose BM-MSCs), Group 4 (CCl 4 +high dose BM-MSCs), Group 5 (CCl 4  + silymarin), Group 6 (CCl 4 +silymarin+high dose BM-MSCs). Thirty days after the treatment, blood samples were collected for hepatocyte growth factor estimation. The rats were then killed, bone marrow was extracted for chromosomal aberration assay. Liver tissue was processed for evaluating the DNA fragmentation assay, histopathology, and scanning electron microscopy study. Combination treatment of silymarin and high dose BM-MSCs significantly (P < 0.05) restored the plasma hepatocyte growth factor levels which were comparable with normal levels and exhibited significant antimutagenic and antiapoptotic activity by decreasing the frequency of structural chromosomal aberrations and suppressing the DNA fragmentation in liver tissue samples. The combination treatment produced significant hepatoprotective effect which was supported by histopathology and scanning electron microscopy study. Results indicate that the treatment of BM-MSCs in combination with silymarin had a better hepatoprotective and antimutagenic effect and represents a novel strategy for the treatment of hepatotoxicity.

Elevated plasma levels of hepatocyte growth factor in rats experimentally envenomated with Bothrops jararaca venom: Role of snake venom metalloproteases

The hepatocyte growth factor (HGF)/c-met pathway, which mainly consists of HGF activator (HGFA) and its substrate HGF, protects various types of cells via anti-apoptotic and anti-inflammatory signals. Thrombin is the main physiological activator of such plasmatic pathway, and increased plasma concentrations of HGF have been considered as a molecular marker for some pathological conditions, such as disseminated intravascular coagulation. Since thrombin generation is often linked to tissue injury, and these events are common during snake venom-induced consumption coagulopathies (VICC), our goals were to examine whether Bothrops jararaca venom (Bjv), which induces VICC in vivo: (i) activates the HGF/c-met pathway in vivo and (ii) cleaves zymogen forms of HGFA and HGF (proHGFA and proHGF, respectively) in vitro. Two experimental groups (n = 6, each) of male adult Wistar rats were subcutaneously injected with 500 μL of 0.9% NaCl solution (control) or sub-lethal doses (1.6 mg/kg) of Bjv. Three hours after envenomation, whole blood samples were collected from the carotid arteries to evaluate relevant coagulation parameters using rotational thromboelastometry and fibrinogen level (colorimetric assay). Additionally, the plasma concentration of HGF was assayed (ELISA). Thromboelastometric assays showed that blood clotting and fibrin polymerization were severely impaired 3 h after Bjv injection. Total plasma HGF concentrations were almost 6-fold higher in the Bjv-injected group (410.0 ± 91) compared with control values (68 ± 18 pg/mL, p < 0.05). Western blotting assay showed that Bjv processed proHGFA and proHGF, generating bands resembling those generated by thrombin and kallikrein, respectively. In contrast to the serine protease inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF), the metalloprotease inhibitor ethylenediaminetetraacetic acid disodium salt (Na2-EDTA) strongly reduced the ability of Bjv to process proHGFA and generated one active band similar to that of thrombin. Since Bjv contains prothrombin and factor X activators, increased intravascular thrombin formation might partly explain the increased HGF levels after bothropic envenomation. In conclusion, these findings suggest that snake venom metalloproteases may be determinant for elevation of plasma levels of HGF in rats experimentally envenomated with Bjv.

Pretreatment plasma HGF as potential biomarker for susceptibility to radiation-induced liver dysfunction after radiotherapy

Radiotherapy shows excellent local control in liver cancers but carries the risk of radiation-induced liver dysfunction and liver failure. We conducted a study of plasma hepatocyte growth factor (HGF) in a clinical trial of proton radiotherapy in patients with unresectable liver cancers (NCT00976898), and in an observational study for liver cancer patients undergoing surgical treatments. Liver dysfunction within 3 months after radiotherapy—a Childs−Turcotte−Pugh (CTP) score increase of 1 point or more—occurred in 9/34 (26%) of patients. Patients with no increase in CTP score had lower pretreatment plasma HGF level (p = 0.015). Both the increase in CTP score (p = 0.034) and the pretreatment plasma HGF (p = 0.017) were associated with OS. Plasma HGF was significantly associated with presence of cirrhosis (p = 0.0027) and with Model for End-stage Liver Disease (MELD) score (p < 0.0001), but not with OS in surgical liver cancer patients. Pretreatment plasma HGF is a candidate biomarker for patient selection for radiotherapy.

Serial Assessment of Growth Factors Associated with Liver Regeneration in Patients Operated with Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy

Background: There is limited knowledge about the mechanisms behind the unparalleled growth of the future liver remnant (FLR) linked to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). In this study, liver regenerative markers were examined in patients subjected to ALPPS. Methods: Ten patients with colorectal liver metastases treated with neoadjuvant chemotherapy and ALPPS were included. Plasma was sampled at 6 time points and biopsies from both liver lobes were collected at both stages of ALPPS. The levels of interleukin (IL)-6, hepatocyte growth factor (HGF), tumor necrosis factor-α, epidermal growth factor, and vascular endothelial growth factor in plasma were measured at each time point. Expression of mRNA for markers of proliferation and apoptosis was studied in the biopsies from both liver lobes taken at both stages. Results: ALPPS resulted in a peak of IL-6 after stage 1 (p = 0.004), which decreased rapidly and did not increase again after stage 2. HGF also increased after stage 1 (p = 0.048), and the HGF levels correlated significantly with the degree of growth of the FLR before stage 2 (p = 0.02, r² = 0.47). There was a correlation between peak levels of IL-6 and HGF (p = 0.03, r² = 0.84). Conclusions: IL-6 and HGF seem to be early mediators of hypertrophy after stage 1 in the ALPPS procedure. The peak HGF plasma level correlates with the degree of FLR growth in patients subjected to ALPPS.

Heparin Induces the Mobilization of Heart-Derived Multipotent Mesoangioblasts During Cardiac Surgery With Cardiopulmonary Bypass or Cardiac Catheterization.

We previously identified circulating mesoangioblasts (cMABs), a subset of mesenchymal stem cells that express cardiac mesodermal markers, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). We also found that hepatocyte growth factor (HGF) is upregulated during cardiac surgery with CPB in humans, and induces MAB-like cell mobilization in rodents. These results strongly suggest that heparin induced MAB mobilization via HGF upregulation. Here, we tested this hypothesis in patients undergoing cardiac surgery or cardiac catheterization. We also examined whether human cMABs are derived from the heart.Methods and Results:Plasma HGF levels were determined by ELISA. Mononuclear cells isolated from blood samples were cultured on fibronectin-coated dishes, and outgrowing cMAB colonies were counted. We first confirmed that HGF upregulation and cMAB mobilization were observed before the start of CPB, excluding the possibility that CPB is the primary inducer of cMAB mobilization. We then examined patients undergoing cardiac catheterization and found that heparin significantly increased plasma HGF levels and the number of cMAB colonies in a dose-dependent manner. The results of simultaneous blood sampling from the aortic sinus, coronary sinus, and right atrium were consistent with the notion that human cMABs are derived from the heart. Human cMABs are mobilized by heparin injection during cardiac surgery or cardiac catheterization, presumably via HGF upregulation.