Search results for "TYROSINE KINASE"
showing 10 items of 362 documents
MERTK rs4374383 polymorphism affects the severity of fibrosis in non-alcoholic fatty liver disease
2015
Background & Aim Homozygosity for a common non-coding rs4374383 G>A polymorphism in MERTK (myeloid-epithelial-reproductive tyrosine kinase) has been associated with the protection against fibrosis progression in chronic hepatitis C. The main study objective was to assess whether MERTK AA genotype influences liver fibrosis, and secondarily MERTK expression in patients with non-alcoholic fatty liver disease (NAFLD). We also investigated whether MERTK is expressed in human hepatic stellate cells (HSC) and in murine models of fibrogenesis. Methods We considered 533 consecutive patients who underwent liver biopsy for suspected non-alcoholic steatohepatitis (NASH) without severe obesity from two …
Mer Tyrosine Kinase (MERTK) modulates liver fibrosis progression and hepatocellular carcinoma development.
2022
BackgroundMerTK is a tyrosine kinase receptor that belongs to the TAM (Tyro3/Axl/Mer) receptor family. It is involved in different processes including cellular proliferation/survival, cellular adhesion/migration, and release of the inflammatory/anti-inflammatory cytokines. Although it is reported that MERTK polymorphisms affect the severity of viral and metabolic liver diseases, being able to influence fibrosis progression and hepatocellular carcinoma development, the mechanisms remain unknown. Methods: using a microarray approach, we evaluated the liver expression of genes involved in fibrogenesis and hepatocarcinogenesis in patient with chronic hepatitis C (CHC), stratified for MERTK geno…
Optimizing systemic therapy for advanced hepatocellular carcinoma: the key role of liver function
2022
The number of effective systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC) is rapidly increasing, and the advent of immunotherapy has changed the treatment paradigm for these patients, leading to significantly improved survival outcomes. However, many patients with HCC will continue to receive tyrosine kinase inhibitors, partly because of contraindications to immune checkpoint inhibitors. Currently, the best sequential first- and second-line systemic treatment remains elusive. Maintenance of optimal liver function is crucial, it is likely to impinge on temporary or permanent treatment discontinuation, and should also be considered when defining the treatment seq…
Clinical, immunological, and molecular analysis in a large cohort of patients with X-linked agammaglobulinemia: an Italian multicenter study
2002
A questionnaire-based retrospective clinical and immunological survey was conducted in 73 males with a definite diagnosis of X-linked agammaglobulinemia based on BTK sequence analysis. Forty-four were sporadic and 29 familial cases. At December 2000, the patients' ages ranged from 2 to 33 years; mean age at diagnosis and mean duration of follow-up were 3.5 and 10 years respectively. After the mid-1980s all but 2 were on intravenous immunoglobulin (IVIG) substitution therapy, with residual IgG >500 mg/dl in 94% of the patients at the time of enrollment. Respiratory infections were the most frequent manifestation both prior to diagnosis and over follow-up. Chronic lung disease (CLD) was prese…
Driver mutations and differential sensitivity to targeted therapies: a new approach to the treatment of lung adenocarcinoma
2010
The adenocarcinoma of the lung has recently shown peculiar molecular characteristics, which relate with both carcinogenesis and response to targeted drugs. Several molecular alterations have been defined as "driver mutations". These are responsible for both the initiation and maintenance of the malignancy. The epidermal growth factor receptor (EGFR) pathway is the main regulator of cell function and cancer development. It has a widely defined role in the occurrence of driver mutations. Up till now EGFR gene mutations, KRAS gene mutations and EML4-ALK fusion genes are the most widely recognized alterations involved in both the biology and the clinical management of lung adenocarcinoma. In th…
The role of cMET in non-small cell lung cancer resistant to EGFR-Inhibitors: Did we really find the target?
2014
Abstract: The advent of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represented the most important innovation in NSCLC treatment over the last years. However, despite a great initial activity, secondary mutations in the same target, or different alterations in other molecular pathways, inevitably occur, leading to the emergence of acquired resistance, in median within the first year of treatment. In this scenario, the mesenchymal-epidermal transition (cMET) tyrosine kinase receptor and its natural ligand, the hepatocyte growth factor (HGF), seem to play an important role. Indeed either the overexpression or the amplification of cMET, as well as the overexpr…
Requirement of caveolae microdomains in extracellular signal-regulated kinase and focal adhesion kinase activation induced by endothelin-1 in primary…
1999
Endothelin-1 (ET-1) mitogenic activity in astrocytes is mediated by the activation of the extracellular signal-regulated kinase (ERK) pathway together with the Rho-dependent activation of the focal adhesion kinase (FAK) pathway. To clarify the mechanisms responsible for the coordinate activation of both pathways in the ET-1 signal propagation, the involvement of caveolae microdomains, suggested to play a role in signal transduction, was evaluated. In this study, it is reported that caveolae of primary astrocytes are enriched in endothelin receptor (ETB-R). Furthermore, signaling molecules such as the adaptor proteins Shc and Grb2, and the small G protein Rho, also reside within these microd…
Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and G(alpha)q.
2001
Endothelins are potent mitogens that stimulate extracellular signal-regulated kinases (ERK/MAP kinases) through their cognate G-protein-coupled receptors, ET(A) and ET(B). To address the role of post-translational ET receptor modifications such as acylation on ERK activation and to identify relevant downstream effectors coupling the ET receptor to the ERK signaling cascades we have constructed a panel of palmitoylation-deficient ET receptor mutants with differential G(alpha) protein binding capacity. Endothelin-1 stimulation of wild-type ET(A) or ET(B) induced a fivefold to sixfold increase in ERK in COS-7 and CHO cells whereas full-length nonpalmitoylated ET(A) and ET(B) mutants failed to …
Bis(1H-indol-2-yl)methanones are effective inhibitors of FLT3-ITD tyrosine kinase and partially overcome resistance to PKC412A in vitro.
2009
Inhibition of the mutated fms-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase is a promising therapeutic strategy in acute myeloid leukaemia (AML). However, development of resistance to FLT3 tyrosine kinase inhibitors (TKI), such as PKC412A, has been described recently. This observation may have an increasing impact on the duration of response and relapse rates in upcoming clinical trials employing FLT3-TKI. Herein we investigated two representatives of a novel class of FLT3-TKI: Bis(1H-indol-2-yl)methanones. Both compounds effectively induced apoptosis in FLT3-internal tandem duplicate (ITD)-transfected murine myeloid cells and in primary FLT3-ITD positive blasts. Combination of bot…
Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein k…
1999
Collagenase-3 (matrix metalloproteinase-13, MMP-13) is a recently identified human MMP with an exceptionally wide substrate specificity and restricted tissue-specific expression. Here we show that MMP-13 expression is induced in normal human skin fibroblasts cultured within three-dimensional collagen gel resulting in production and proteolytic activation of MMP-13. Induction of MMP-13 mRNAs by collagen gel was potently inhibited by blocking antibodies against alpha1 and alpha2 integrin subunits and augmented by activating antibody against beta1 integrin subunit, indicating that both alpha1 beta1 and alpha2 beta1 integrins mediate the MMP-13-inducing cellular signal generated by three-dimens…