2,506 results on '"HGF"'
Search Results
2. Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment.
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Yao, Shuxi, Liu, Xinyue, Feng, Yanqi, Li, Yiming, Xiao, Xiangtian, Han, Yuelin, and Xia, Shu
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ANAPLASTIC lymphoma kinase , *EPIDERMAL growth factor receptors , *HEPATOCYTE growth factor , *NON-small-cell lung carcinoma , *TUMOR microenvironment - Abstract
Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal–epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy. [ABSTRACT FROM AUTHOR]
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- 2024
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3. IFN-β Overexpressing Adipose-Derived Mesenchymal Stem Cells Mitigate Alcohol-Induced Liver Damage and Gut Permeability.
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Hwang, Soonjae, Eom, Young Woo, Kang, Seong Hee, Baik, Soon Koo, and Kim, Moon Young
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HEPATOCYTE growth factor , *MESENCHYMAL stem cells , *INTESTINAL barrier function , *CELL permeability , *CELL death , *ENDOTOXINS - Abstract
Alcoholic liver disease (ALD) is a form of hepatic inflammation. ALD is mediated by gut leakiness. This study evaluates the anti-inflammatory effects of ASCs overexpressing interferon-beta (ASC-IFN-β) on binge alcohol-induced liver injury and intestinal permeability. In vitro, ASCs were transfected with a non-viral vector carrying the human IFN-β gene, which promoted hepatocyte growth factor (HGF) secretion in the cells. To assess the potential effects of ASC-IFN-β, C57BL/6 mice were treated with three oral doses of binge alcohol and were administered intraperitoneal injections of ASC-IFN-β. Mice treated with binge alcohol and administered ASC-IFN-β showed reduced liver injury and inflammation compared to those administered a control ASC. Analysis of intestinal tissue from ethanol-treated mice administered ASC-IFN-β also indicated decreased inflammation. Additionally, fecal albumin, blood endotoxin, and bacterial colony levels were reduced, indicating less gut leakiness in the binge alcohol-exposed mice. Treatment with HGF, but not IFN-β or TRAIL, mitigated the ethanol-induced down-regulation of cell death and permeability in Caco-2 cells. These results demonstrate that ASCs transfected with a non-viral vector to induce IFN-β overexpression have protective effects against binge alcohol-mediated liver injury and gut leakiness via HGF. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Growth Factors and Their Application in the Therapy of Hereditary Neurodegenerative Diseases.
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Issa, Shaza, Fayoud, Haidar, Shaimardanova, Alisa, Sufianov, Albert, Sufianova, Galina, Solovyeva, Valeriya, and Rizvanov, Albert
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HUNTINGTON disease ,ALZHEIMER'S disease ,PARKINSON'S disease ,GROWTH factors ,GENETIC disorders - Abstract
Hereditary neurodegenerative diseases (hNDDs) such as Alzheimer's, Parkinson's, Huntington's disease, and others are primarily characterized by their progressive nature, severely compromising both the cognitive and motor abilities of patients. The underlying genetic component in hNDDs contributes to disease risk, creating a complex genetic landscape. Considering the fact that growth factors play crucial roles in regulating cellular processes, such as proliferation, differentiation, and survival, they could have therapeutic potential for hNDDs, provided appropriate dosing and safe delivery approaches are ensured. This article presents a detailed overview of growth factors, and explores their therapeutic potential in treating hNDDs, emphasizing their roles in neuronal survival, growth, and synaptic plasticity. However, challenges such as proper dosing, delivery methods, and patient variability can hinder their clinical application. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Differential Immune Checkpoint Protein Expression in HNSCC: The Role of HGF/MET Signaling.
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Boschert, Verena, Boenke, Johannes, Böhm, Ann-Kathrin, Teusch, Jonas, Steinacker, Valentin, Straub, Anton, and Hartmann, Stefan
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IMMUNE checkpoint proteins , *LIGANDS (Biochemistry) , *CELL lines , *SQUAMOUS cell carcinoma , *EPITHELIAL-mesenchymal transition , *PROTEIN expression - Abstract
Although inhibitors targeting the PD1/PD-L1 immune checkpoint are showing comparably good outcomes, a significant percentage of head and neck squamous cell carcinoma (HNSCC) patients do not respond to treatment. Apart from using different treatment strategies, another possibility would be to target other immune checkpoints operating in these non-responding tumors. To obtain an overview of which checkpoint ligands are expressed on HNSCC tumor cells and if these ligands are affected by HGF/MET signaling, we used mRNA sequencing and antibody-based techniques for identifying checkpoint ligands in six HNSCC tumor cell lines. Furthermore, we compared our results to mRNA sequencing data. From the checkpoint ligands we investigated, VISTA was expressed the highest at the RNA level and was also the most ubiquitously expressed. PD-L2 and B7-H3 were expressed comparably lower and were not present in all cell lines to the same extent. B7-H4, however, was only detectable in the Detroit 562 cell line. Concerning the effect of HGF on the ligand levels, PD-L2 expression was enhanced with HGF stimulation, whereas other checkpoint ligand levels decreased with stimulation. B7-H4 levels in the Detroit 562 cell line drastically decreased with HGF stimulation. This is of interest because both the checkpoint ligand and the growth factor are reported to be connected to epithelial–mesenchymal transition in the literature. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Comparing machine learning screening approaches using clinical data and cytokine profiles for COVID-19 in resource-limited and resource-abundant settings.
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Rashidi, Hooman H., Ikram, Aamer, Dang, Luke T., Bashir, Adnan, Zohra, Tanzeel, Ali, Amna, Tanvir, Hamza, Mudassar, Mohammad, Ravindran, Resmi, Akhtar, Nasim, Sikandar, Rana I., Umer, Mohammed, Akhter, Naeem, Butt, Rafi, Fennell, Brandon D., and Khan, Imran H.
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RESOURCE-limited settings , *MEDICAL screening , *MACHINE learning , *COVID-19 , *CYTOKINES - Abstract
Accurate screening of COVID-19 infection status for symptomatic patients is a critical public health task. Although molecular and antigen tests now exist for COVID-19, in resource-limited settings, screening tests are often not available. Furthermore, during the early stages of the pandemic tests were not available in any capacity. We utilized an automated machine learning (ML) approach to train and evaluate thousands of models on a clinical dataset consisting of commonly available clinical and laboratory data, along with cytokine profiles for patients (n = 150). These models were then further tested for generalizability on an out-of-sample secondary dataset (n = 120). We were able to develop a ML model for rapid and reliable screening of patients as COVID-19 positive or negative using three approaches: commonly available clinical and laboratory data, a cytokine profile, and a combination of the common data and cytokine profile. Of the tens of thousands of models automatically tested for the three approaches, all three approaches demonstrated > 92% sensitivity and > 88 specificity while our highest performing model achieved 95.6% sensitivity and 98.1% specificity. These models represent a potential effective deployable solution for COVID-19 status classification for symptomatic patients in resource-limited settings and provide proof-of-concept for rapid development of screening tools for novel emerging infectious diseases. [ABSTRACT FROM AUTHOR]
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- 2024
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7. A HGF Mutation in the Familial Case of Primary Lymphedema: A Report.
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Koksharova, Galina, Kokh, Natalia, Gridina, Maria, Khapaev, Rustam, Nimaev, Vadim, and Fishman, Veniamin
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HEPATOCYTE growth factor , *LYMPHEDEMA , *EXTRACELLULAR fluid , *GENETIC mutation , *FAMILIAL spastic paraplegia - Abstract
Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern. [ABSTRACT FROM AUTHOR]
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- 2024
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8. The MET Oncogene: Thirty Years of Insights into Molecular Mechanisms Driving Malignancy.
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Crepaldi, Tiziana, Gallo, Simona, and Comoglio, Paolo Maria
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HEPATOCYTE growth factor , *GENE rearrangement , *CANCER cell proliferation , *CANCER remission , *PROTEIN-tyrosine kinases , *ONCOGENES , *GENE amplification - Abstract
The discovery and subsequent research on the MET oncogene's role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing "flare effect" phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET's involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Effect of novel ora-aid intraoral dressing on salivary healing markers in smokers with tooth extraction: A randomized controlled clinical study.
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Al Jothery, A. H., Al-essa, H. E., and Agele, A. Al
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Background and objectives. Socket healing following tooth extraction is considered a big challenge among dentists. However, there is no previous research testing the effects of novel commercial ora-aid dressing on the levels of salivary markers of wounds healing, osteoprotegerin (OPG) and hepatocyte growth factor (HGF) with relation to the smoking status among patients undergone tooth extraction. Material and methods. The current study represents the first randomized, controlled, and clinical research conducted in Iraq from February to May 2022. Forty male outpatients (aged from 20-60 years) who visited the Surgery Clinic of the College of Dentistry, University of Babylon, Iraq, had tooth extraction. The patients were randomly allocated into four groups: smoker patients with ora-aid applied following extraction (N=11), non-smoker patients with ora-aid applied following extraction (N=9), smoker patients without ora-aid applied (gauze only; N=11), and non-smoker patients without ora-aid applied (gauze only; N=9). Levels of preoperative and postoperative (2 weeks after extraction) salivary HGF and OPG were measured. Results. The results indicated that the levels of postoperative HGF were significantly higher in patients with ora-aid dressing compared to those without. Levels of postoperative OPG were significantly lower compared to their preoperative levels in non-smokers without ora-aid dressing. Smoking had significantly negative impacts on the levels of preoperative HGF. Conclusions. The study concludes that commercial ora-aid attachable dressing can be safely applied on the fresh socket after tooth extraction and it can accelerate the healing of intraoral wounds by significantly elevating healing of salivary markers (HGF|) and maintaining the levels of other healing marker (OPG). [ABSTRACT FROM AUTHOR]
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- 2024
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10. Translation of circHGF RNA encodes an HGF protein variant promoting glioblastoma growth through stimulation of c-MET
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Saunders, Jacquelyn T, Kumar, Sunil, Benavides-Serrato, Angelica, Holmes, Brent, Benavides, Kennedy E, Bashir, Muhammad T, Nishimura, Robert N, and Gera, Joseph
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Biomedical and Clinical Sciences ,Neurosciences ,Oncology and Carcinogenesis ,Genetics ,Rare Diseases ,Cancer ,Biotechnology ,Brain Disorders ,Brain Cancer ,Animals ,Humans ,Mice ,Brain Neoplasms ,Cell Line ,Tumor ,Cell Proliferation ,Glioblastoma ,Hepatocyte Growth Factor ,RNA ,Signal Transduction ,Proto-Oncogene Proteins c-met ,Circular RNA ,HGF ,Translation ,c-MET ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
IntroductionHGF/c-MET signaling is a significant driver of glioblastoma (GBM) growth and disease progression. Unfortunately, c-MET targeted therapies have been found to be largely ineffective suggesting additional redundant mechanisms of c-MET activation.MethodsUtilizing RNA-sequencing (RNA-seq) and ribosome profiling analyses of circular RNAs, circ-HGF (hsa_circ_0080914) was identified as markedly upregulated in primary GBM and found to potentially encode an HGF protein variant (C-HGF) 119 amino acids in length. This candidate HGF variant was characterized and evaluated for its ability to mediate c-MET activation and regulate PDX GBM cell growth, motility and invasive potential in vitro and tumor burden in intracranial xenografts in mice.ResultsAn internal ribosome entry site (IRES) was identified within the circ-HGF RNA which mediated translation of the cross-junctional ORF encoding C-HGF and was observed to be highly expressed in GBM relative to normal brain tissue. C-HGF was also found to be secreted from GBM cells and concentrated cell culture supernatants or recombinant C-HGF activated known signaling cascades downstream of c-MET. C-HGF was shown to interact directly with the c-MET receptor resulting in its autophosphorylation and activation in PDX GBM lines. Knockdown of C-HGF resulted in suppression of c-MET signaling and marked inhibition of cell growth, motility and invasiveness, whereas overexpression of C-HGF displayed the opposite effects. Additionally, modulation of C-HGF expression regulated tumor growth in intracranial xenografted PDX GBM models.ConclusionsThese results reveal an alternative mechanism of c-MET activation via a circular RNA encoded HGF protein variant which is relevant in GBM biology. Targeting C-HGF may offer a promising approach for GBM clinical management.
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- 2023
11. T-cell acute lymphoblastic leukemia progression is supported by inflammatory molecules including hepatocyte growth factor
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Charly Le Maout, Lucine Fahy, Laurent Renou, Caroline Devanand, Charlotte Duwat, Vilma Barroca, Morgane Le Gall, Paola Ballerini, Arnaud Petit, Julien Calvo, Benjamin Uzan, Françoise Pflumio, and Vanessa Petit
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T-ALL ,Inflammation ,Myeloid cells ,Molecule secretion ,HGF ,Therapeutics. Pharmacology ,RM1-950 - Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. We show in two mouse T-ALL cell models that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils using anti-Ly6G treatment or resident monocytes by clodronate liposomes treatment does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA, an agonist of adenosine receptors, diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. Altogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF/cMET pathway as important to target for limiting T-ALL progression.
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- 2024
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12. Hepatocyte growth factor (HGF) gene: molecular characterisation of complete coding sequence and expression profile in Tarim red deer (Cervus hanglu yarkandensis) antlers.
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Chuan Lin, Miao Wang, Xue Rui, Hong Chen, Hao Lv, Fei Huang, Qinghua Gao, and Chunmei Han
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HEPATOCYTE growth factor , *RED deer , *GENE expression , *ESCHERICHIA coli , *RECOMBINANT proteins , *ANTLERS - Abstract
Context. The cDNA sequence of hepatocyte growth factor (HGF) gene in Tarim red deer has not been reported yet. Aims. This study aims to obtain the full-length cDNA sequence of HGF and analyse its expression in different parts of developing antler tissues. The result provides foundational data for understanding the potential role of HGF in regulating antler growth and development. Methods. Rapid amplification of cDNA ends was used to obtain the full-length cDNA sequence of Tarim red deer HGF. The pET28a (+) vector was constructed for prokaryotic expression of the recombinant protein in E. coli BL21 (DE3). The expression of HGF in different antler tissues was detected using real-time quantitative polymerase chain reaction and immunohistochemistry. Key results. The full-length cDNA of Tarim red deer HGF was found to consist of a 156 bp 5'untranslated region (UTR), a 112 bp 3'UTR, and a 2193 bp open reading frame encoding a protein of 730 amino acids. The recombinant HGF protein expressed in prokaryotic cells formed inclusion bodies. HGF and its receptor c-Met were expressed in all four different antler tissues, with the highest expression level in velvet skin, followed by bone, cartilage, and the lowest in the mesenchyme. Conclusions. The study successfully obtained the full-length cDNA sequence of Tarim red deer HGF and identified the expression profile of HGF and c-Met in different antler tissues. HGF is a candidate gene that may play a role in regulating the growth and development of deer antler. Implications. These findings provide fundamental data for further investigations into the role of HGF in antler development. Understanding the function of HGF in antler development could have implications for elucidating the mechanism of antler regeneration. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Cytokine IL-5 and HGF: combined prediction of non-/low immune response to hepatitis B vaccination at birth in infants born to HBsAg-positive mothers.
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Guanyong Ou, Ling Qing, Li Zhang, Yang Yang, Guoguo Ye, Ling Peng, Yanjie Li, Liuqing Yang, and Yingxia Liu
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HEPATOCYTE growth factor ,HEPATITIS B vaccines ,IMMUNE response ,HEPATITIS associated antigen ,INFANTS ,BREASTFEEDING - Abstract
Background: The immune response to hepatitis B vaccine may be influenced by numerous factors, and patients with non/low response re-exposed to hepatitis B virus remain susceptible. Thus, a better understanding of the underlying mechanisms of non/low immune response in infants born to Hepatitis B surface antigen (HBsAg)-positive mothers is essential. Methods: 100 infants born to HBsAg-positive mothers from 2015 to 2020 were enrolled in the study, further divided into the non/low response group (n=13) and the moderate strong response group (n=87) based on the quantification of hepatitis B surface antibody at 12 months of age. The differential expression of 48 immunerelated cytokines in the two groups was compared and analyzed in detail. The key cytokines were further identified and clinically predictive models were developed. Results: We found that 13 cytokines were lowly expressed and one cytokine was highly expressed in the non/low response group, compared with the moderate strong response group at birth. In addition, 9 cytokines were lowly expressed and one cytokine was highly expressed in the non/low response group at 12 months of age. Furthermore, we found that IL-5 and HGF were promising predictors for predicting the immunization response to hepatitis B vaccine in infants, and the combination of the two cytokines showed the best predictive efficiency, with an area under the curve (AUC) value of 0.844. Conclusion: The present study provides a theoretical basis on cytokines for developing and implementing effective immunotherapies against non/low immune response in infants born to HBsAg-positive mothers. [ABSTRACT FROM AUTHOR]
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- 2024
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14. 仑伐替尼联合 TACE 对不可切除肝细胞癌患者肿瘤标志物、 凋亡分子和血清 ST6GAL1、ANG-2、HGF 的影响.
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冯旭晶, 苏 州, 税 莲, 舒泓铭, 夏 蓉, and 罗文娟
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To investigate the effects of lenvatinib combined with transcatheter arterial chemoembolization (TACE) on tumor markers apoptotic molecules serum sialic acid transferase 1 (ST6Gal1) angiopoietin-2 (ANG-2) and hepatocyte growth factor(HGF) in patients with unresectable hepatocellular carcinoma. 114 patients with unresectable hepatocellular carcinoma who were admitted to Sichuan Mianyang 404 Hospital from March 2020 to December 2022 were divided into control group (n=57 TACE treatment) and study group (n=57 lenvatinib combine with TACE treatment) by random number table method. The efficacy tumor markers [alpha-fetoprotein (AFP) carbohydrate antigen 199 (CA199) carcinoembryonic antigen (CEA)] serum apoptotic molecules [B-celllymphoma-2-associated X protein (Bax) B-cell lymphoma-2 gene (Bcl-2) survivin (Survivin) cysteine aspartic protease-4 (Caspase-4)]and serum ST6Gal1 ANG-2 HGF levels were compared between two groups and the incidence of adverse reactions during treatment was observed. Compared with control group the total clinical effective rate in study group was higher (P<0. 05). Compared with control group the levels of AFP CA199 and CEA in study group were lower after treatment (P<0. 05). Compared with control group the levels of Bcl-2 and Survivin in study group were lower after treatment and the levels of Bax and Caspase-4 were higher (P<0. 05). Com-pared with control group the levels of ST6Gal1 ANG-2 and HGF in study group were lower after treatment (P<0. 05). There was no difference in the total incidence of adverse reactions between two groups (P>0. 05). Lenvatinib combined with TACE for patients with unresectable hepatocellular carcinoma which can improve the clinical treatment effect regulate the levels of tumor markers, apoptotic molecules and serum ST6Gal1 ANG-2 and HGF with good safety [ABSTRACT FROM AUTHOR]
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- 2024
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15. An Overview of Growth Factors as the Potential Link between Psoriasis and Metabolic Syndrome.
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Matwiejuk, Mateusz, Myśliwiec, Hanna, Chabowski, Adrian, and Flisiak, Iwona
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GROWTH factors , *METABOLIC syndrome , *PSORIASIS , *PSORIATIC arthritis , *ITCHING , *CARDIOVASCULAR diseases - Abstract
Psoriasis is a chronic, complex, and immunologically mediated systemic disease that not only affects the skin, but also the joints and nails. It may coexist with various other disorders, such as depression, psoriatic arthritis, cardiovascular diseases, diabetes mellitus, and metabolic syndrome. In particular, the potential link between psoriasis and metabolic syndrome is an issue worthy of attention. The dysregulation of growth factors could potentially contribute to the disturbances of keratinocyte proliferation, inflammation, and itch severity. However, the pathophysiology of psoriasis and its comorbidities, such as metabolic syndrome, remains incompletely elucidated. Growth factors and their abnormal metabolism may be a potential link connecting these conditions. Overall, the objective of this review is to analyze the role of growth factor disturbances in both psoriasis and metabolic syndrome. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer.
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Jones, Vivian Truong, Graves-Deal, Ramona, Cao, Zheng, Bogatcheva, Galina, Ramirez, Marisol A., Harmych, Sarah J., Higginbotham, James N., Sharma, Vineeta, Damalanka, Vishnu C., Wahoski, Claudia C., Joshi, Neeraj, Irudayam, Maria Johnson, Roland, Joseph T., Ayers, Gregory D., Liu, Qi, Coffey, Robert J., Janetka, James W., and Singh, Bhuminder
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Although amplifications and mutations in receptor tyrosine kinases (RTKs) act as bona fide oncogenes, in most cancers, RTKs maintain moderate expression and remain wild-type. Consequently, cognate ligands control many facets of tumorigenesis, including resistance to anti-RTK therapies. Herein, we show that the ligands for the RTKs MET and RON, HGF and HGFL, respectively, are synthesized as inactive precursors that are activated by cellular proteases. Our newly generated HGF/HGFL protease inhibitors could overcome both de novo and acquired cetuximab resistance in colorectal cancer (CRC). Conversely, HGF overexpression was necessary and sufficient to induce cetuximab resistance and loss of polarity. Moreover, HGF-induced cetuximab resistance could be overcome by the downstream MET inhibitor, crizotinib, and upstream protease inhibitors. Additionally, HAI-1, an endogenous inhibitor of HGF proteases, (i) was downregulated in CRC, (ii) exhibited increased genomic methylation that correlated with poor prognosis, (iii) HAI-1 expression correlated with cetuximab response in a panel of cancer cell lines, and (iv) exogenous addition of recombinant HAI-1 overcame cetuximab resistance in CC-HGF cells. Thus, we describe a targetable, autocrine HAI-1/Protease/HGF/MET axis in cetuximab resistance in CRC. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Betaglycan sustains HGF/Met signaling in lung cancer and endothelial cells promoting cell migration and tumor growth
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Rodolfo Daniel Cervantes-Villagrana, Valentín Mendoza, Cynthia S. Hinck, Rosa Luz de la Fuente-León, Andrew P. Hinck, Guadalupe Reyes-Cruz, José Vázquez-Prado, and Fernando López-Casillas
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TGFBR3 ,Betaglycan ,HGF ,Glycosaminoglycans ,RhoGEF ,P-Rex1 ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Persistent HGF/Met signaling drives tumor growth and dissemination. Proteoglycans within the tumor microenvironment might control HGF availability and signaling by affecting its accessibility to Met (HGF receptor), likely defining whether acute or sustained HGF/Met signaling cues take place. Given that betaglycan (BG, also known as type III TGFβ receptor or TGFBR3), a multi-faceted proteoglycan TGFβ co-receptor, can be found within the tumor microenvironment, we addressed its hypothetical role in oncogenic HGF signaling. We found that HGF/Met promotes lung cancer and endothelial cells migration via PI3K and mTOR. This effect was enhanced by recombinant soluble betaglycan (solBG) via a mechanism attributable to its glycosaminoglycan chains, as a mutant without them did not modulate HGF effects. Moreover, soluble betaglycan extended the effect of HGF-induced phosphorylation of Met, Akt, and Erk, and membrane recruitment of the RhoGEF P-Rex1. Data-mining analysis of lung cancer patient datasets revealed a significant correlation between high MET receptor, HGF, and PREX1 expression and reduced patient survival. Soluble betaglycan showed biochemical interaction with HGF and, together, they increased tumor growth in immunocompetent mice. In conclusion, the oncogenic properties of the HGF/Met pathway are enhanced and sustained by GAG-containing soluble betaglycan.
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- 2024
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18. An HGF‐dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis
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Yuting Li, Hanhao Zheng, Yuming Luo, Yan Lin, Mingjie An, Yao Kong, Yue Zhao, Yina Yin, Le Ai, Jian Huang, and Changhao Chen
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bladder cancer ,Cancer‐associated fibroblasts ,extracellular vesicles ,HGF ,lymphangiogenesis ,lymph node metastasis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Cancer‐associated fibroblasts (CAFs) play a vital role in facilitating tumor progression through extensive reciprocal interplay with cancer cells. Tumor‐derived extracellular vesicles (EVs) are the critical mediators involved in the crosstalk between cancer cells and stromal cells, contributing to the metastasis of cancers. Yet, the biological mechanisms of tumor‐derived EVs in triggering CAFs phenotype to stimulate the lymph node (LN) metastasis of bladder cancer (BCa) are largely unknown. Here, we aimed to explore the effects and molecular mechanisms of tumor‐derived EV‐mediated CAFs phenotype in regulating BCa LN metastasis. Methods The high‐throughput sequencing was utilized to identify the crucial long non‐coding RNA (lncRNA) associated with CAF enrichment in BCa. The functional role of the transition of fibroblasts to CAFs induced by LINC00665‐mediated EVs was investigated through the in vitro and in vivo assays. Chromatin isolation by RNA purification assays, fluorescence resonance energy transfer assays, cytokine profiling and patient‐derived xenograft (PDX) model were performed to explore the underlying mechanism of LINC00665 in the LN metastasis of BCa. Results We found that CAFs are widely enriched in the tumor microenvironment of BCa, which correlated with BCa lymphangiogenesis and LN metastasis. We then identified a CAF‐associated long non‐coding RNA, LINC00665, which acted as a crucial mediator of CAF infiltration in BCa. Clinically, LINC00665 was associated with LN metastasis and poor prognosis in patients with BCa. Mechanistically, LINC00665 transcriptionally upregulated RAB27B expression and induced H3K4me3 modification on the promoter of RAB27B through the recruitment of hnRNPL. Moreover, RAB27B‐induced EVs secretion endowed fibroblasts with the CAF phenotype, which reciprocally induced LINC00665 overexpression to form a RAB27B‐HGF‐c‐Myc positive feedback loop, enhancing the lymphangiogenesis and LN metastasis of BCa. Importantly, we demonstrated that blocking EV‐transmitted LINC00665 or HGF broke this loop and impaired BCa lymphangiogenesis in a PDX model. Conclusion Our study uncovers a precise mechanism that LINC00665 sustains BCa LN metastasis by inducing a RAB27B‐HGF‐c‐Myc positive feedback loop between BCa cells and fibroblasts, suggesting that LINC00665 could be a promising therapeutic target for patients with LN metastatic BCa.
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- 2023
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19. Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment
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Shuxi Yao, Xinyue Liu, Yanqi Feng, Yiming Li, Xiangtian Xiao, Yuelin Han, and Shu Xia
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HGF ,c-MET ,tumor microenvironment ,immunotherapy ,NSCLC ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal–epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy.
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- 2024
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20. IFN-β Overexpressing Adipose-Derived Mesenchymal Stem Cells Mitigate Alcohol-Induced Liver Damage and Gut Permeability
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Soonjae Hwang, Young Woo Eom, Seong Hee Kang, Soon Koo Baik, and Moon Young Kim
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mesenchymal stem cell ,binge alcohol ,gut leakiness ,IFN-β ,HGF ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Alcoholic liver disease (ALD) is a form of hepatic inflammation. ALD is mediated by gut leakiness. This study evaluates the anti-inflammatory effects of ASCs overexpressing interferon-beta (ASC-IFN-β) on binge alcohol-induced liver injury and intestinal permeability. In vitro, ASCs were transfected with a non-viral vector carrying the human IFN-β gene, which promoted hepatocyte growth factor (HGF) secretion in the cells. To assess the potential effects of ASC-IFN-β, C57BL/6 mice were treated with three oral doses of binge alcohol and were administered intraperitoneal injections of ASC-IFN-β. Mice treated with binge alcohol and administered ASC-IFN-β showed reduced liver injury and inflammation compared to those administered a control ASC. Analysis of intestinal tissue from ethanol-treated mice administered ASC-IFN-β also indicated decreased inflammation. Additionally, fecal albumin, blood endotoxin, and bacterial colony levels were reduced, indicating less gut leakiness in the binge alcohol-exposed mice. Treatment with HGF, but not IFN-β or TRAIL, mitigated the ethanol-induced down-regulation of cell death and permeability in Caco-2 cells. These results demonstrate that ASCs transfected with a non-viral vector to induce IFN-β overexpression have protective effects against binge alcohol-mediated liver injury and gut leakiness via HGF.
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- 2024
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21. Differential Immune Checkpoint Protein Expression in HNSCC: The Role of HGF/MET Signaling
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Verena Boschert, Johannes Boenke, Ann-Kathrin Böhm, Jonas Teusch, Valentin Steinacker, Anton Straub, and Stefan Hartmann
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HNSCC ,MET ,HGF ,PD-L2 ,PD-L1 ,VISTA ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Although inhibitors targeting the PD1/PD-L1 immune checkpoint are showing comparably good outcomes, a significant percentage of head and neck squamous cell carcinoma (HNSCC) patients do not respond to treatment. Apart from using different treatment strategies, another possibility would be to target other immune checkpoints operating in these non-responding tumors. To obtain an overview of which checkpoint ligands are expressed on HNSCC tumor cells and if these ligands are affected by HGF/MET signaling, we used mRNA sequencing and antibody-based techniques for identifying checkpoint ligands in six HNSCC tumor cell lines. Furthermore, we compared our results to mRNA sequencing data. From the checkpoint ligands we investigated, VISTA was expressed the highest at the RNA level and was also the most ubiquitously expressed. PD-L2 and B7-H3 were expressed comparably lower and were not present in all cell lines to the same extent. B7-H4, however, was only detectable in the Detroit 562 cell line. Concerning the effect of HGF on the ligand levels, PD-L2 expression was enhanced with HGF stimulation, whereas other checkpoint ligand levels decreased with stimulation. B7-H4 levels in the Detroit 562 cell line drastically decreased with HGF stimulation. This is of interest because both the checkpoint ligand and the growth factor are reported to be connected to epithelial–mesenchymal transition in the literature.
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- 2024
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22. New and Old Key Players in Liver Cancer.
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Cuesta, Ángel M., Palao, Nerea, Bragado, Paloma, Gutierrez-Uzquiza, Alvaro, Herrera, Blanca, Sánchez, Aránzazu, and Porras, Almudena
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- *
LIVER cancer , *PROGENITOR cells , *HEPATOCELLULAR carcinoma , *TUMOR microenvironment , *LIVER cells , *LIVER tumors - Abstract
Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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23. c-Met + Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models.
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Benkhoucha, Mahdia, Tran, Ngoc Lan, Senoner, Isis, Breville, Gautier, Fritah, Hajer, Migliorini, Denis, Dutoit, Valérie, and Lalive, Patrice H.
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CYTOTOXIC T cells ,IMMUNE checkpoint proteins ,HUMAN cloning ,CYTOTOXINS ,IPILIMUMAB ,HEPATOCYTE growth factor ,MICROPHTHALMIA-associated transcription factor ,MELANOMA - Abstract
CD8
+ cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, we identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met+ CTLs), that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met+ CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met+ CTLs in a three-dimensional (3D) setting, we studied their function within B16 melanoma spheroids and examined the impact of cell–cell contact on the modulation of inhibitory checkpoint molecules' expression, such as KLRG1, PD-1, and CTLA-4. Additionally, we evaluated the cytolytic capacity of human CTL clones expressing c-Met (c-Met+ ) and compared it to c-Met− CTL clones. Our results indicated that, similar to their murine counterparts, c-Met+ human CTL clones exhibited increased cytolytic activity compared to c-Met− CTL clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, our findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promise for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer. [ABSTRACT FROM AUTHOR]- Published
- 2023
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24. The role of ginger's extract and N-acetylcysteine against docetaxel-induced oxidative stress and genetic disorder.
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Motafeghi, Farzaneh, Mortazavi, Parham, Salman Mahiny, Amir Hossein, Abtahi, Mohammad Mehdi, and Shokrzadeh, Mohammad
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- *
DOCETAXEL , *OXIDATIVE stress , *GINGER , *GENETIC disorders , *ACETYLCYSTEINE , *REACTIVE oxygen species - Abstract
Oxidative stress plays a prominent role in expanding toxicity and various diseases. This study investigated the potential protective effects of ginger (Zingiber officinale) rhizome extract and NAC on docetaxel induced genotoxicity and oxidative stress. The antioxidant power of NAC and ginger extract on the genetic toxicity induced by docetaxel was assessed by micronucleus test. The ROS test with DCFH reagent was used to assess the reactive oxygen species. The thiobarbituric acid method was used to evaluate the amount of MDA produced by docetaxel. The amounts of phenol and flavonoids in the ginger extracts were also evaluated. The amount of phenol in the ginger extract was 0.886 mg of gallic acid per gram of dry extract. The amount of flavonoids were 0.242 mg/mL of quercetin per gram of dry extract. As shown by the micronucleus results, concentrations of 100 and 500 μM NAC and all concentrations of the ginger extract significantly reduced the number of micronuclei produced by docetaxel. On the other hand, the results of oxidative stress tests (ROS and LPO) showed that docetaxel in HGF cells increased the production of ROS and LPO, and the concentrations of ginger extract and NAC decreased oxidative stress in HGF cells in a dose-dependent manner. The results indicate that using these two antioxidants helps inhibit genetic toxicity and oxidative stress caused by docetaxel. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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25. Role of hepatocyte growth factor (HGF)/c?Met signaling pathway in early follicular development in mice.
- Author
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Li Mingxing, Li Zhuoxian, Li Kangmei, Chen Xiurong, Zhou Yanping, Huang Yulin, Bai Lin, Wu Zhansh- Uai, Xia Meng, and He Guozhen
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- *
HEPATOCYTE growth factor , *MET receptor , *CELLULAR signal transduction , *PI3K/AKT pathway , *GENE expression - Abstract
Objective: To investigate the role of hepatocyte growth factor and its receptor c-Met (HGF/ c-Met) signaling pathway in early follicular development in mice via detecting the expression of HGF/c-Met in early mouse ovarian tissue and then analyze the biological process of HGF/c-Met signaling pathway and its possible involvement in intracellular signaling pathways by using bioinformatics for the purpose of further studying the molecular mechanism of the signaling pathway in the early follicle development. Methods. Thirty-five female Kunming mice and 15 male ones were fed in 15 cages with the female-to-male ratio of 2,1. The ovaries of mice at 3, 7, 14 and 21 days after birth were collected. Immunohistochemical staining and Western blotting were applied to detect the expression levels of HGF and c-Met protein in the ovarian tissues. Quantitative Real-time PCR,q-PCR, was used to detect the expression levels of HGF and C-Met mRNA in the early ovarian tissues of mice. Results, HGF and c-Met proteins were expressed in the ovarian tissues of the mice at 3, 7, 14 and 21 days, presenting an increasing trend with the increase of age by day,P < 0.05,. The mRNA levels of HGF and c-Met also showed the same trend,P < 0.05,. Bioinformatics analysis revealed that the HGF/c-Met signaling pathway involved in a variety of biological processes and signaling pathways such as PI3K/AKT. Conclusions,HGF/c-Met signaling pathway is involved in early follicular development in mice. It may regulate primal follicular initiation and follicular develop, ment through intracellular signaling pathway PI3K/AKT. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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26. Complementary Gene Therapy after Revascularization with the Saphenous Vein in Diabetic Foot Syndrome.
- Author
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Kupczyńska, Diana, Lubieniecki, Paweł, Antkiewicz, Maciej, Barć, Jan, Frączkowska-Sioma, Katarzyna, Dawiskiba, Tomasz, Dorobisz, Tadeusz, Małodobra-Mazur, Małgorzata, Baczyńska, Dagmara, Pańczak, Konrad, Witkiewicz, Wojciech, Janczak, Dariusz, Skóra, Jan Paweł, and Barć, Piotr
- Subjects
- *
DIABETIC foot , *GENE therapy , *COMPLEMENTATION (Genetics) , *SAPHENOUS vein , *FOOT , *DUPLEX ultrasonography - Abstract
Diabetic foot syndrome (DFS) is one of the most serious macroangiopathic complications of diabetes. The primary treatment option is revascularization, but complementary therapies are still being sought. The study group consisted of 18 patients diagnosed with ischemic ulcerative and necrotic lesions in DFS. Patients underwent revascularization procedures and, due to unsatisfactory healing of the lesions, were randomly allocated to two groups: a group in which bicistronic VEGF165/HGF plasmid was administered and a control group in which saline placebo was administered. Before gene therapy administration and after 7, 30, 90, and 180 days, color duplex ultrasonography (CDU) was performed, the ankle-brachial index (ABI) and transcutaneous oxygen pressure (TcPO2) were measured, and DFS changes were described and documented photographically. In the gene therapy group, four out of eight patients (50%) healed their DFS lesions before 12 weeks. During this time, the ABI increased by an average of 0.25 and TcPO2 by 30.4 mmHg. In the control group, healing of the lesions by week 12 occurred in six out of nine patients (66.67%), and the ABI increased by an average of 0.14 and TcPO2 by 27.1 mmHg. One major amputation occurred in each group. Gene therapy may be an attractive option for complementary treatment in DFS. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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27. A HGF Mutation in the Familial Case of Primary Lymphedema: A Report
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Galina Koksharova, Natalia Kokh, Maria Gridina, Rustam Khapaev, Vadim Nimaev, and Veniamin Fishman
- Subjects
primary lymphedema ,Meige disease ,whole-exome sequencing ,HGF ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.
- Published
- 2024
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28. Immunohistochemical expression of the hepatocyte growth factor in chromophobe renal cell carcinoma
- Author
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Maximilian Erlmeier, Marie Mikuteit, Stefanie Zschäbitz, Michael Autenrieth, Wilko Weichert, Arndt Hartmann, Sandra Steffens, and Franziska Erlmeier
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Renal Cell Carcinoma ,HGF ,Chromophobe histology ,Survival ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background The prognostic value of Hepatocyte growth factor (HGF) in non-clear cell renal cell carcinoma (RCC) is still unclear. The aim of this study is to evaluate the prognostic impact of HGF expression in a large cohort of chromophobe RCC (chRCC). Methods Patients who underwent renal surgery due to chRCC were recruited. Clinical data was retrospectively evaluated. Tumor specimen were analyzed for HGF expression by immunohistochemistry. Results 81 chRCC patients were eligible for analysis, thereof 37 (45.7%) patients were positive for HGF. No significant associations were found for HGF expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis revealed no differences in 5-year overall survival (OS) for patients with HGF− compared to HGF+ tumors (95.0% versus 90.9%; p = 0.410). Conclusions In chRCC HGF expression is not associated with parameters of aggressiveness or survival.
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- 2023
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29. Hepatic regenerative response to long-term consumption of cinnamon-rich diet in aged rats
- Author
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Mahmoud Zardast, Samaneh Nakhaee, Mohammad Attarzadeh Firouzabadi, Mohammad Dastjerdi, Masumeh Askari, Zahra Ghiravani, and Khadijeh Farrokhfall
- Subjects
cinnamomum zeylanicum ,liver resection ,oxidative stress ,ageing ,hgf ,tnf-α ,nitric oxide ,regeneration ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Objective: The present study aimed to investigate the impact of cinnamon on liver regeneration in a rat model of partial hepatectomy (PH).Materials and Methods: Thirty-two old male Sprague-Dawley rats (12 weeks old) were randomly divided into two equal groups (n=16). One group was fed with a standard diet (control) while the other group was fed with the same diet containing 1% cinnamon for 41 weeks. Then, all animals were subjected to the PH procedure and their livers were studied on postoperative days 2, 10 and 28. The liver contents of hepatic growth factor (HGF), insulin, malondialdehyde (MDA), nitric oxide metabolites (NOx), superoxide dismutase (SOD) and tumor necrosis factor-alpha (TNF-α) were evaluated. Also, the serum levels of liver function markers (alanine aminotransferase (ALT) and aspartate aminotransferase (AST), MDA, NOx and SOD activity were measured.Results: The regenerated liver weight was significantly higher in cinnamon-treated animals than the controls on both day 10 and 28 post hepatectomy. The hepatic MDA levels in the cinnamon-treated animals were significantly lower than the control rats. Cinnamon led to a significant increase of SOD on day 2 after hepatectomy in serum and liver content. The basal level of HGF in the liver of cinnamon-consuming rats was significantly higher than in the control rats. Hepatic insulin level was significantly increased relative to baseline and control on day 2 in the cinnamon-consuming rats. Hepatic TNF-α levels dramatically decreased on postoperative days (POD) 2 relative to baseline in the control and cinnamon-treated rats.Conclusion: Long-term cinnamon consumption enhanced liver regeneration outcomes in old rats.
- Published
- 2023
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30. Development of a contacting transwell co-culture system for the in vitro propagation of primary central nervous system lymphoma
- Author
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Mayuko Nishi, Kensuke Tateishi, Jeremiah Stanleyraj Sundararaj, Yoko Ino, Yusuke Nakai, Yasuyoshi Hatayama, Yutaro Yamaoka, Yusaku Mihana, Kei Miyakawa, Hirokazu Kimura, Yayoi Kimura, Tetsuya Yamamoto, and Akihide Ryo
- Subjects
PCNSL ,lymphoma ,vitrigel ,pericytes ,HGF ,Pin1 ,Biology (General) ,QH301-705.5 - Abstract
Primary central nervous system lymphoma (PCNSL) is a malignant neoplasm of the central nervous system that is refractory to treatment and has extremely poor prognosis. One factor hindering the development of therapeutic options for PCNSL is its molecular heterogeneity and the extreme difficulty in establishing in vitro cell lines that permit intensive research on this disease. In the present study, we developed a method to propagate PCNSL cells in vitro using a contacting transwell cell culture system involving brain vascular pericytes. The co-culture system was found to recapitulate the tumor microenvironment that is influenced by the biological activity of adjacent pericytes, and to sustain the survival and proliferation of PCNSL cells in vitro. We further delineated the underlying molecular mechanisms and found that the HGF–c-Met axis may be involved in the long-term in vitro culture of PCNSL cells. Moreover, the peptidylprolyl isomerase Pin1 was found to play a key role in PCNSL cell survival and it sustained proliferation through interactions with key transcription factors related to B-cell lymphomagenesis. These results suggest that our in vitro co-culture system is well suited to analyzing the biological and molecular characteristics of PCNSL, and may contribute to the discovery of new therapeutic interventions.
- Published
- 2023
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31. HGF-Based CAR-T Cells Target Hepatocellular Carcinoma Cells That Express High Levels of c-Met.
- Author
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Ma, Haiyan, Wei, Wenwen, Liang, Dandan, Xu, Xing, Yang, Dong, Wang, Qiong, Wang, Yun, Wei, Quan, Sun, Bin, and Zhao, Xudong
- Subjects
- *
ENZYME-linked immunosorbent assay , *HEMATOLOGIC malignancies , *T cells , *HAIRPIN (Genetics) , *CELL lines , *POLYPEPTIDES - Abstract
CAR-T is emerging as an effective treatment strategy for hematologic malignancies, however its effectiveness for treating solid tumors, such as Hepatocellular Carcinoma (HCC) is limited. Here, we screened a variety of CAR-T cells that target c-Met to investigate their potential to induce HCC cell death in vitro. Human T cells were transduced to express CARs by lentiviral vector transfection. c-Met expression in human HCC cell lines and CARs expression were monitored by flow cytometry. Tumor cell killing was evaluated by Luciferase Assay System Kit. The concentrations of cytokine were tested by Enzyme-linked immunosorbent assays. Knock down and overexpression studies targeting c-Met were conducted to assess the targeting specificity of CARs. We found that CAR T cells expressing a minimal amino-terminal polypeptide sequence comprising the first kringle (kringle 1) domain (denoted as NK1 CAR-T cells), efficiently killed HCC cell lines that expressed high levels of the HGF receptor c-Met. Furthermore, we report that while NK1 CAR-T cells were efficient at targeting SMMC7221 cells for destruction, and its potency was significantly attenuated in parallel experiments with cells stably expressing short hairpin RNAs (shRNAs) that suppressed c-Met expression. Correspondingly, overexpression of c-Met in the embryonic kidney cell line HEK293T led to their enhanced killing by NK1 CAR-T cells. Our studies demonstrate that a minimal amino-terminal polypeptide sequence comprising the kirngle1 domain of HGF is highly relevant to the design of effective CAR-T cell therapies that kill HCC cells expressing high levels of c-Met. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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32. In vitro differentiated human CD4+ T cells produce hepatocyte growth factor.
- Author
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Ford, Shayne Lavondua, Buus, Terkild Brink, Nastasi, Claudia, Geisler, Carsten, Bonefeld, Charlotte Menné, Ødum, Niels, and Woetmann, Anders
- Subjects
HEPATOCYTE growth factor ,T cells ,REGULATORY T cells ,IMMUNOLOGIC memory ,CELL differentiation - Abstract
Differentiation of naive CD4
+ T cells into effector T cells is a dynamic process in which the cells are polarized into T helper (Th) subsets. The subsets largely consist of four fundamental categories: Th1, Th2, Th17, and regulatory T cells. We show that human memory CD4+ T cells can produce hepatocyte growth factor (HGF), a pleiotropic cytokine which can affect several tissue types through signaling by its receptor, c-Met. In vitro differentiation of T cells into Th-like subsets revealed that HGF producing T cells increase under Th1 conditions. Enrichment of HGF producing cells was possible by targeting cells with surface CD30 expression, a marker discovered through single-cell RNA-sequencing. Furthermore, pharmacological inhibition of PI3K or mTOR was found to inhibit HGF mRNA and protein, while an Akt inhibitor was found to increase these levels. The findings suggest that HGF producing T cells could play a role in disease where Th1 are present. [ABSTRACT FROM AUTHOR]- Published
- 2023
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33. Hepatocyte growth factor combined with adenosine deaminase as biomarker for diagnosis of tuberculous pleural effusion.
- Author
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Sheng-Cai Zheng, Zhong-Yin Huang, Kan Zhai, Huan-Zhong Shi, and Ming-Ming Shao
- Subjects
HEPATOCYTE growth factor ,ADENOSINE deaminase ,PLEURAL effusions ,ENZYME-linked immunosorbent assay ,RECEIVER operating characteristic curves - Abstract
Background: The simple, rapid, and accurate diagnosis of tuberculous pleural effusion (TPE) remains difficult. This study aimed to determine the accuracy of hepatocyte growth factor (HGF) in the diagnosis of TPE. Methods: We quantified the expression of HGF, adenosine deaminase (ADA), and interferon gamma (IFN-γ) in pleural effusion (PE) in 97 TPE subjects and 116 non-TPE subjects using an enzyme-linked immunosorbent assay (ELISA) or a fully automatic biochemical analyzer. The diagnostic performance of these three biomarkers was evaluated using a receiver operating characteristic (ROC) curve of subjects by age and gender. Results: We discovered that the TPE group had much higher levels of HGF than the non-TPE group, regardless of age or gender, and that there was no statistically significant difference between the two groups' levels of HGF expression in peripheral plasma. In female TPE patients aged ≤65 years, the AUCs of TPE and non-TPE diagnosed by HGF, ADA or IFN-γ were 0.988, 0.964, and 0.827, respectively. HGF plus ADA had the highest diagnostic efficacy in female TPE patients aged ≤65 years. With HGF plus ADA having a cut-off value of 0.219 for distinguishing TPE from non-TPE, the area under the curve (AUC), sensitivity (SEN), specificity (SPE), positive predictive value (PPV), and negative predictive value (NPV) were, respectively, 0.998 (95% confidence interval [CI], 0.993-1.000), 100 (95% CI, 89.997-100.000), 96.667 (95% CI, 82.783-99.916), 97.222 (95% CI, 83.594-99.586), and 100. Conclusion: This study confirmed that HGF plus ADA has high diagnostic efficacy in younger female TPE patients and has the potential to be an excellent biomarker. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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34. High CD142 Level Marks Tumor-Promoting Fibroblasts with Targeting Potential in Colorectal Cancer.
- Author
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Soós, András Áron, Kelemen, Andrea, Orosz, Adrián, Szvicsek, Zsuzsanna, Tölgyes, Tamás, Dede, Kristóf, Bursics, Attila, and Wiener, Zoltán
- Subjects
- *
COLORECTAL cancer , *HEPATOCYTE growth factor , *FIBROBLASTS , *MITOGEN-activated protein kinases , *CELL populations , *MITOGENS - Abstract
Colorectal cancer (CRC) has a high incidence and is one of the leading causes of cancer-related death. The accumulation of cancer-associated fibroblasts (CAF) induces an aggressive, stem-like phenotype in tumor cells, and it indicates a poor prognosis. However, cellular heterogeneity among CAFs and the targeting of both stromal and CRC cells are not yet well resolved. Here, we identified CD142high fibroblasts with a higher stimulating effect on CRC cell proliferation via secreting more hepatocyte growth factor (HGF) compared to CD142low CAFs. We also found that combinations of inhibitors that had either a promising effect in other cancer types or are more active in CRC compared to normal colonic epithelium acted synergistically in CRC cells. Importantly, heat shock protein 90 (HSP90) inhibitor selected against CD142high fibroblasts, and both CRC cells and CAFs were sensitive to a BCL-xL inhibitor. However, targeting mitogen-activated protein kinase kinase (MEK) was ineffective in fibroblasts, and an epigenetic inhibitor selected for a tumor cell population with markers of aggressive behavior. Thus, we suggest BCL-xL and HSP90 inhibitors to eliminate cancer cells and decrease the tumor-promoting CD142high CAF population. This may be the basis of a strategy to target both CRC cells and stromal fibroblasts, resulting in the inhibition of tumor relapse. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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- View/download PDF
35. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations
- Author
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Affo, Silvia, Nair, Ajay, Brundu, Francesco, Ravichandra, Aashreya, Bhattacharjee, Sonakshi, Matsuda, Michitaka, Chin, LiKang, Filliol, Aveline, Wen, Wen, Song, Xinhua, Decker, Aubrianna, Worley, Jeremy, Caviglia, Jorge Matias, Yu, Lexing, Yin, Deqi, Saito, Yoshinobu, Savage, Thomas, Wells, Rebecca G, Mack, Matthias, Zender, Lars, Arpaia, Nicholas, Remotti, Helen E, Rabadan, Raul, Sims, Peter, Leblond, Anne-Laure, Weber, Achim, Riener, Marc-Oliver, Stockwell, Brent R, Gaublomme, Jellert, Llovet, Josep M, Kalluri, Raghu, Michalopoulos, George K, Seki, Ekihiro, Sia, Daniela, Chen, Xin, Califano, Andrea, and Schwabe, Robert F
- Subjects
Genetics ,Liver Disease ,Cancer ,Digestive Diseases - (Gallbladder) ,Chronic Liver Disease and Cirrhosis ,Digestive Diseases ,Liver Cancer ,Rare Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Aged ,Animals ,Bile Duct Neoplasms ,Bile Ducts ,Intrahepatic ,Cancer-Associated Fibroblasts ,Cholangiocarcinoma ,Collagen Type I ,Female ,Hepatic Stellate Cells ,Hepatocyte Growth Factor ,Humans ,Hyaluronan Synthases ,Hyaluronic Acid ,Male ,Mice ,Transgenic ,Middle Aged ,Proto-Oncogene Proteins c-met ,Tumor Microenvironment ,CellPhoneDB ,HGF ,KRAS ,YAP ,cholangiocarcinoma ,immune ,mechanosensitive ,single cell ,stiffness ,tumor microenvironment ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.
- Published
- 2021
36. State of the structure address on MET receptor activation by HGF
- Author
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Linossi, Edmond M, Estevam, Gabriella O, Oshima, Masaya, Fraser, James S, Collisson, Eric A, and Jura, Natalia
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Emerging Infectious Diseases ,Animals ,Hepatocyte Growth Factor ,Humans ,Ligands ,Models ,Molecular ,Mutation ,Protein Binding ,Protein Domains ,Proto-Oncogene Proteins c-met ,Signal Transduction ,HGF ,MET ,RTK ,activation ,autoinhibition ,ligand binding ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology - Abstract
The MET receptor tyrosine kinase (RTK) and its cognate ligand hepatocyte growth factor (HGF) comprise a signaling axis essential for development, wound healing and tissue homeostasis. Aberrant HGF/MET signaling is a driver of many cancers and contributes to drug resistance to several approved therapeutics targeting other RTKs, making MET itself an important drug target. In RTKs, homeostatic receptor signaling is dependent on autoinhibition in the absence of ligand binding and orchestrated set of conformational changes induced by ligand-mediated receptor dimerization that result in activation of the intracellular kinase domains. A fundamental understanding of these mechanisms in the MET receptor remains incomplete, despite decades of research. This is due in part to the complex structure of the HGF ligand, which remains unknown in its full-length form, and a lack of high-resolution structures of the complete MET extracellular portion in an apo or ligand-bound state. A current view of HGF-dependent MET activation has evolved from biochemical and structural studies of HGF and MET fragments and here we review what these findings have thus far revealed.
- Published
- 2021
37. Immunological and tumor-intrinsic mechanisms mediate the synergistic growth suppression of experimental glioblastoma by radiotherapy and MET inhibition
- Author
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Manuela Silginer, Eleanna Papa, Emese Szabó, Flavio Vasella, Martin Pruschy, Christopher Stroh, Patrick Roth, Tobias Weiss, and Michael Weller
- Subjects
Glioma ,HGF ,Immunotherapy ,Irradiation ,Synergy ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract The hepatocyte growth factor (HGF)/MET signaling pathway has been proposed to be involved in the resistance to radiotherapy of glioblastoma via proinvasive and DNA damage response pathways. Here we assessed the role of the MET pathway in the response to radiotherapy in vitro and in vivo in syngeneic mouse glioma models. We find that the murine glioma cell lines GL-261, SMA-497, SMA-540 and SMA-560 express HGF and its receptor MET and respond to exogenous HGF with MET phosphorylation. Glioma cell viability or proliferation are unaffected by genetic or pharmacological MET inhibition using tepotinib or CRISPR/Cas9-engineered Met gene knockout and MET inhibition fails to sensitize glioma cells to irradiation in vitro. In contrast, the combination of tepotinib with radiotherapy prolongs survival of orthotopic SMA-560 or GL-261 glioma-bearing mice compared with radiotherapy or tepotinib treatment alone. Synergy is lost when such experiments are conducted in immunodeficient Rag1 −/− mice, and, importantly, also when Met gene expression is disrupted in the tumor cells. Combination therapy suppresses a set of pro-inflammatory mediators including matrix metalloproteases that are upregulated by radiotherapy alone and that have been linked to poor outcome in glioblastoma. Several of these mediators are positively regulated by transforming growth factor (TGF)-β, and pSMAD2 levels as a surrogate marker of TGF-β pathway activity are suppressed by combination treatment. We conclude that synergistic suppression of experimental syngeneic glioma growth by irradiation and MET inhibition requires MET expression in the tumor as well as an intact immune system. Clinical evaluation of this combined strategy in newly diagnosed glioblastoma is warranted.
- Published
- 2023
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38. MET kinase inhibitor reverses resistance to entrectinib induced by hepatocyte growth factor in tumors with NTRK1 or ROS1 rearrangements
- Author
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Yohei Takumi, Sachiko Arai, Chiaki Suzuki, Koji Fukuda, Akihiro Nishiyama, Shinji Takeuchi, Hiroki Sato, Kunio Matsumoto, Kenji Sugio, and Seiji Yano
- Subjects
entrectinib ,HGF ,MET ,NTRK ,ROS1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Entrectinib is an effective drug for treating solid tumors with NTRK gene rearrangement and non‐small cell lung cancer (NSCLC) with ROS1 gene rearrangement. However, its efficacy is limited by tolerance and acquired resistance, the mechanisms of which are not fully understood. The growth factors produced by the tumor microenvironment, including hepatocyte growth factor (HGF) produced by tumor‐associated fibroblasts, critically affect the sensitivity to targeted drugs. Methods We investigated whether growth factors that can be produced by the microenvironment affect sensitivity of NTRK1‐rearranged colon cancer KM12SM cells and ROS1‐rearranged NSCLC HCC78 cells to entrectinib both in vitro and in vivo. Results Among the growth factors assessed, HGF most potently induced entrectinib resistance in KM12SM and HCC78 cells by activating its receptor MET. HGF‐induced entrectinib resistance was reversed by the active‐HGF‐specific macrocyclic peptide HiP‐8 and the MET kinase inhibitor capmatinib in vitro. In addition, HGF‐producing fibroblasts promoted entrectinib resistance in vitro (culture model) and in vivo (subcutaneous tumor model). The use of capmatinib circumvented entrectinib resistance in a subcutaneous tumor model inoculated with KM12SM and HGF‐producing fibroblasts. Conclusion Our findings suggest that growth factors in the tumor microenvironment, such as HGF, may induce resistance to entrectinib in tumors with NTRK1 or ROS1 rearrangements. Our results further suggest that optimally co‐administering inhibitors of resistance‐inducing growth factors may maximize the therapeutic efficacy of entrectinib.
- Published
- 2023
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39. The MET Oncogene: Thirty Years of Insights into Molecular Mechanisms Driving Malignancy
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Tiziana Crepaldi, Simona Gallo, and Paolo Maria Comoglio
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MET ,HGF ,genetic alterations ,protein overexpression ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
The discovery and subsequent research on the MET oncogene’s role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing “flare effect” phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET’s involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy.
- Published
- 2024
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40. Development of a lyophilized preparation enriched with hepatocyte growth factor
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Inozemcev P.O., Grigoriev G.E., and Lepekhova S.A.
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lyophilization ,liver cells ,hepatocyte growth factor ,hgf ,liver failure ,Microbiology ,QR1-502 ,Physiology ,QP1-981 ,Zoology ,QL1-991 - Abstract
The study was performed using neonatal livers from Wistar rats. To obtain cells, it is proposed to use a mixed disaggregation method. A significant increase in the amount of the regulatory peptide on the 5th day was revealed to 46.8 (38.4–50.0) ng/ml, and therefore for lyophilization it is better to use a 5-day cell culture containing the maximum amount of HGF. Optimally selected technological conditions made it possible to preserve biologically active substances secreted by liver cells and obtain a stable form of lyophilized liver cells enriched with hepatocyte growth factor.
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- 2024
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41. In vitro differentiated human CD4+ T cells produce hepatocyte growth factor
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Shayne Lavondua Ford, Terkild Brink Buus, Claudia Nastasi, Carsten Geisler, Charlotte Menné Bonefeld, Niels Ødum, and Anders Woetmann
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T cell ,HGF ,c-Met ,hepatocyte growth factor ,cytokine ,growth factor ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Differentiation of naive CD4+ T cells into effector T cells is a dynamic process in which the cells are polarized into T helper (Th) subsets. The subsets largely consist of four fundamental categories: Th1, Th2, Th17, and regulatory T cells. We show that human memory CD4+ T cells can produce hepatocyte growth factor (HGF), a pleiotropic cytokine which can affect several tissue types through signaling by its receptor, c-Met. In vitro differentiation of T cells into Th-like subsets revealed that HGF producing T cells increase under Th1 conditions. Enrichment of HGF producing cells was possible by targeting cells with surface CD30 expression, a marker discovered through single-cell RNA-sequencing. Furthermore, pharmacological inhibition of PI3K or mTOR was found to inhibit HGF mRNA and protein, while an Akt inhibitor was found to increase these levels. The findings suggest that HGF producing T cells could play a role in disease where Th1 are present.
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- 2023
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42. Comparison of C-reactive protein with distinct hyperinflammatory biomarkers in association with COVID-19 severity, mortality and SARS-CoV-2 variants.
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Paranga, Tudorita Gabriela, Pavel-Tanasa, Mariana, Constantinescu, Daniela, Plesca, Claudia Elena, Petrovici, Cristina, Miftode, Ionela-Larisa, Moscalu, Mihaela, Cianga, Petru, and Miftode, Egidia Gabriela
- Subjects
SARS-CoV-2 ,C-reactive protein ,SARS-CoV-2 Delta variant ,COVID-19 pandemic ,COVID-19 ,THYROID crisis - Abstract
C-reactive protein (CRP) has been one of the most investigated inflammatorybiomarkers during the ongoing COVID-19 pandemics caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The severe outcome among patients with SARS-CoV-2 infection is closely related to the cytokine storm and the hyperinflammation responsible for the acute respiratory distress syndrome and multiple organ failure. It still remains a challenge to determine which of the hyperinflammatory biomarkers and cytokines are the best predictors for disease severity and mortality in COVID-19 patients. Therefore, we evaluated and compared the outcome prediction efficiencies between CRP, the recently reported inflammatory modulators (suPAR, sTREM-1, HGF), and the classical biomarkers (MCP-1, IL-1b, IL-6, NLR, PLR, ESR, ferritin, fibrinogen, and LDH) in patients confirmed with SARS-CoV-2 infection at hospital admission. Notably, patients with severe disease had higher serum levels of CRP, suPAR, sTREM-1, HGF and classical biomarkers compared to the mild and moderate cases. Our data also identified CRP, among all investigated analytes, to best discriminate between severe and non-severe forms of disease, while LDH, sTREM-1 and HGF proved to be excellent mortality predictors in COVID-19 patients. Importantly, suPAR emerged as a key molecule in characterizing the Delta variant infections. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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43. Genetic Ablation of the MET Oncogene Defines a Crucial Role of the HGF/MET Axis in Cell-Autonomous Functions Driving Tumor Dissemination.
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Modica, Chiara, Cortese, Marco, Bersani, Francesca, Lombardi, Andrea Maria, Napoli, Francesca, Righi, Luisella, Taulli, Riccardo, Basilico, Cristina, and Vigna, Elisa
- Subjects
- *
CYTOKINES , *DISEASE progression , *IN vitro studies , *FLOW cytometry , *IN vivo studies , *ONCOGENES , *ANIMAL experimentation , *WESTERN immunoblotting , *IMMUNOHISTOCHEMISTRY , *GENE expression , *CELLULAR signal transduction , *ENZYME-linked immunosorbent assay , *CELL proliferation , *RESEARCH funding , *CELL lines , *LIGANDS (Biochemistry) , *MICE - Abstract
Simple Summary: The MET receptor and its ligand Hepatocyte Growth Factor (HGF) sustain cell proliferation, survival, motility, and invasion. Several pieces of evidence suggest that these biological activities support the metastatic potential of transformed cells. Cancer cell dissemination is sustained by cell-autonomous (executed by cancer cells) and non-cell-autonomous (executed by cells composing the tumor microenvironment) functions. To define the role of the HGF/MET axis in this complex process, we genetically knocked out the MET gene in cancer cells that were not dependent on MET signaling for their growth. In this way, we exclusively evaluated the relevance of the HGF/MET axis in prompting cell-autonomous activities (MET signaling in tumor microenvironment cells is maintained intact) independently of their intrinsic ability to proliferate (that is sustained by different oncogenic drivers). Our results proved that HGF/MET axis plays a crucial role in directing cell-autonomous functions regulating cancer cell dissemination, supporting a possible use of MET inhibitors in metastatic cancers. Cancer cell dissemination is sustained by cell-autonomous and non-cell-autonomous functions. To disentangle the role of HGF (Hepatocyte Growth Factor) and MET ligand/receptor axis in this complex process, we genetically knocked out the MET gene in cancer cells in which MET is not the oncogenic driver. In this way, we evaluated the contribution of the HGF/MET axis to cancer cell dissemination independently of its direct activities in cells of the tumor microenvironment. The lack of MET expression in MET−/− cells has been proved by molecular characterization. From a functional point of view, HGF stimulation of MET−/− cancer cells was ineffective in eliciting intracellular signaling and in sustaining biological functions predictive of malignancy in vitro (i.e., anchorage-independent growth, invasion, and survival in the absence of matrix adhesion). Cancer cell dissemination was assessed in vivo, evaluating: (i) the ability of MET−/− lung carcinoma cells to colonize the lungs following intravenous injection and (ii) the spontaneous dissemination to distant organs of MET−/− pancreatic carcinoma cells upon orthotopic injection. In both experimental models, MET ablation affects the time of onset, the number, and the size of metastatic lesions. These results define a crucial contribution of the HGF/MET axis to cell-autonomous functions driving the metastatic process. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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44. Immunohistochemical expression of the hepatocyte growth factor in chromophobe renal cell carcinoma.
- Author
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Erlmeier, Maximilian, Mikuteit, Marie, Zschäbitz, Stefanie, Autenrieth, Michael, Weichert, Wilko, Hartmann, Arndt, Steffens, Sandra, and Erlmeier, Franziska
- Subjects
HEPATOCYTE growth factor ,RENAL cell carcinoma ,PROGNOSIS ,OVERALL survival - Abstract
Background: The prognostic value of Hepatocyte growth factor (HGF) in non-clear cell renal cell carcinoma (RCC) is still unclear. The aim of this study is to evaluate the prognostic impact of HGF expression in a large cohort of chromophobe RCC (chRCC). Methods: Patients who underwent renal surgery due to chRCC were recruited. Clinical data was retrospectively evaluated. Tumor specimen were analyzed for HGF expression by immunohistochemistry. Results: 81 chRCC patients were eligible for analysis, thereof 37 (45.7%) patients were positive for HGF. No significant associations were found for HGF expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis revealed no differences in 5-year overall survival (OS) for patients with HGF
− compared to HGF+ tumors (95.0% versus 90.9%; p = 0.410). Conclusions: In chRCC HGF expression is not associated with parameters of aggressiveness or survival. [ABSTRACT FROM AUTHOR]- Published
- 2023
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- View/download PDF
45. Secreted Soluble Factors from Tumor-Activated Mesenchymal Stromal Cells Confer Platinum Chemoresistance to Ovarian Cancer Cells.
- Author
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Koren Carmi, Yifat, Khamaisi, Hazem, Adawi, Rina, Noyman, Eden, Gopas, Jacob, and Mahajna, Jamal
- Subjects
- *
STROMAL cells , *OVARIAN cancer , *DRUG resistance in cancer cells , *HEPATOCYTE growth factor , *PLATINUM - Abstract
Ovarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemotherapy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging for the treatment of patients. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and it can also be mediated by the tumor microenvironment (TME). In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5, respectively, and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells. Various OC cells exhibit variable sensitivity to CM activity. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (SuPAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Moreover, Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF's ability to promote platinum resistance and to restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM. Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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46. Hepatic regenerative response to long-term consumption of cinnamon-rich diet in aged rats.
- Author
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Zardast, Mahmoud, Nakhaee, Samaneh, Firouzabadi, Mohammad Attarzadeh, Dastjerdi, Mohammad, Askari, Masumeh, Ghiravani, Zahra, and Farrokhfall, Khadijeh
- Subjects
- *
ASPARTATE aminotransferase , *TUMOR necrosis factors , *LIVER regeneration , *ALANINE aminotransferase , *RATS , *SPRAGUE Dawley rats - Abstract
Objective: The present study aimed to investigate the impact of cinnamon on liver regeneration in a rat model of partial hepatectomy (PH). Materials and Methods: Thirty-two old male Sprague-Dawley rats (12 weeks old) were randomly divided into two equal groups (n=16). One group was fed with a standard diet (control) while the other group was fed with the same diet containing 1% cinnamon for 41 weeks. Then, all animals were subjected to the PH procedure and their livers were studied on postoperative days 2, 10 and 28. The liver contents of hepatic growth factor (HGF), insulin, malondialdehyde (MDA), nitric oxide metabolites (NOx), superoxide dismutase (SOD) and tumor necrosis factor-alpha (TNF-α) were evaluated. Also, the serum levels of liver function markers (alanine aminotransferase (ALT) and aspartate aminotransferase (AST), MDA, NOx and SOD activity were measured. Results: The regenerated liver weight was significantly higher in cinnamon-treated animals than the controls on both day 10 and 28 post hepatectomy. The hepatic MDA levels in the cinnamontreated animals were significantly lower than the control rats. Cinnamon led to a significant increase of SOD on day 2 after hepatectomy in serum and liver content. The basal level of HGF in the liver of cinnamon-consuming rats was significantly higher than in the control rats. Hepatic insulin level was significantly increased relative to baseline and control on day 2 in the cinnamon-consuming rats. Hepatic TNF-α levels dramatically decreased on postoperative days (POD) 2 relative to baseline in the control and cinnamon-treated rats. Conclusion: Long-term cinnamon consumption enhanced liver regeneration outcomes in old rats. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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47. Increase of phytomass and protein in hydroponic green forage through fertilization in Casanare, Colombia.
- Author
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Velásquez-Vargas, Wilmer L., Africano-Guevara, Diana M., Orjuela-Angulo, Mayerlin, Peña-Quemba, Diego C., and González-Cortés, Nicolas
- Subjects
CORN seeds ,CROP yields ,SOYBEAN ,RICE seeds ,IRRIGATION water ,RICE ,ORGANIC fertilizers ,HYDROPONICS - Abstract
Objective: To evaluate the effect of two types of fertilizers on the phytomass and protein content of hydroponic green forage (HGF) of corn (Zea mays L.), rice (Oryza sativa L.), and soybean (Glycine max L.). Design/Methodology/Approach: A 32x32 bifactorial design was implemented. The seeds were immersed in 1% chlorine for 15 min for their disinfection. A hydroponic system with nebulization irrigation was used; the plants were irrigated for 1 minute every 4 hours. Five cm³ of organic fertilizer (OF) and 5 cm³ inorganic fertilizer (IF) were applied per liter of irrigation water. Plant height (cm), fresh phytomass production (kg), actual phytomass yield (kg
-1 m2-1 ), and crude protein content (%) were measured. The data were analyzed by means of an ANOVA and a Tukey comparison test (p≥0.05), using the SPSS® Statistics 24 software (IBM). Results: A phytomass yield of 50.7 kg/m² of HGF and a protein content of 17% were obtained using 7.102 kg of corn seed; meanwhile, a yield of 30.53 kg/m³ and a protein content of 15% were obtained with rice seed. Finally, soybean obtained a yield of 19.17 kg/m² of HGF and a protein content of 38%. Study Limitations/Implications: The nitrogen content of the fertilizers can be considered as the main limitation factor in the production and quality of HGF. Findings/Conclusions: Inorganic fertilization has a significant effect on phytomass production and the protein production of HGF. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
48. Erk1/2 signaling mediates the HGF‐induced protection against ethanol and acetaldehyde‐induced toxicity in the pancreatic RINm5F cell line.
- Author
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Palestino‐Domínguez, Mayrel, Escobedo‐Calvario, Alejandro, Salas‐Silva, Soraya, Vergara‐Mendoza, Moises, Souza‐Arroyo, Veronica, Lazzarini, Roberto, Miranda‐Labra, Roxana, Bucio‐Ortiz, Leticia, Gutiérrez‐Ruiz, María Concepción, and Gomez‐Quiroz, Luis E.
- Subjects
LIPID peroxidation (Biology) ,HEPATOCYTE growth factor ,CELL lines ,ISLANDS of Langerhans ,ETHANOL ,REACTIVE oxygen species - Abstract
Alcohol‐induced pancreas damage remains as one of the main risk factors for pancreatitis development. This disorder is poorly understood, particularly the effect of acetaldehyde, the primary alcohol metabolite, in the endocrine pancreas. Hepatocyte growth factor (HGF) is a protective protein in many tissues, displaying antioxidant, antiapoptotic, and proliferative responses. In the present work, we were focused on characterizing the response induced by HGF and its protective mechanism in the RINm5F pancreatic cell line treated with ethanol and acetaldehyde. RINm5F cells were treated with ethanol or acetaldehyde for 12 h in the presence or not of HGF (50 ng/ml). Cells under HGF treatment decreased the content of reactive oxygen species and lipid peroxidation induced by both toxics, improving cell viability. This effect was correlated to an improvement in insulin expression impaired by ethanol and acetaldehyde. Using a specific inhibitor of Erk1/2 abrogated the effects elicited by the growth factor. In conclusion, the work provides mechanistic evidence of the HGF‐induced‐protective response to the alcohol‐induced damage in the main cellular component of the endocrine pancreas. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
49. Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer.
- Author
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Bauman, Julie E, Ohr, James, Gooding, William E, Ferris, Robert L, Duvvuri, Umamaheswar, Kim, Seungwon, Johnson, Jonas T, Soloff, Adam C, Wallweber, Gerald, Winslow, John, Gaither-Davis, Autumn, Grandis, Jennifer R, and Stabile, Laura P
- Subjects
EGFR ,HGF ,HNSCC ,cMet ,cetuximab ,ficlatuzumab ,Oncology and Carcinogenesis - Abstract
Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9-11.4) and 8.9 (90% CI = 2.7-15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6-40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.
- Published
- 2020
50. Pathogenesis of Endometriosis: Role of Macrophages in Endometriosis
- Author
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Khan, Khaleque N. and Oral, Engin, editor
- Published
- 2022
- Full Text
- View/download PDF
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