Development of Grb2 SH2 Domain Signaling Antagonists: A Potential New Class of Antiproliferative Agents

Aberrant signaling through protein-tyrosine kinase (PTK)-dependent pathways is associated with several proliferative diseases. Accordingly, PTK inhibitors are being developed as new approaches for the treatment of certain cancers. Growth factor receptor bound protein 2 (Grb2) is an important downstream mediator of PTK signaling that serves obligatory roles in many pathogenic processes. One of the primary functions of Grb2 is to bind to specific phosphotyrosyl (pTyr)-containing sequences through its Src homology 2 (SH2) domain. Agents that bind to the Grb2 SH2 domain and prevent its normal function could disrupt associated PTK signaling and serve as alternatives to kinase-directed inhibitors. Starting from the X-ray crystal structure of a lead peptide bound to the Grb2 SH2 domain, this review will summarize important contributions to these efforts. The presentation will be thematically arranged according to the region of peptide modified, proceeding from the N-terminus to the C-terminus, with a special section devoted to aspects of conformational constraint

Targeting c-Met in Cancer by MicroRNAs: Potential Therapeutic Applications in Hepatocellular Carcinoma

Cancer is one of the world's deadliest diseases, with very low survival rates and increased occurrence in the future. Successfully developed target-based therapies have significantly changed cancer treatment. However, primary and/or acquired resistance in the tumor is a major challenge in current therapies and novel combinational therapies are required. RNA interference-mediated gene inactivation, alone or in combination with other current therapies, provides novel promising therapeutics that can improve cure rate and overcome resistance mechanisms to conventional therapeutics. Hepatocyte Growth Factor/c-Met signaling is one of the most frequently dysregulated pathways in human cancers and abnormal c-Met activation is correlated with poor clinical outcomes and drug resistance in hepatocellular carcinoma (HCC). In recent years, a growing number of studies have identified several inhibitors and microRNAs (miRNAs), specifically targeting c-Met in various cancers, including HCC. In this review, we discuss current knowledge regarding miRNAs, focusing on their involvement in cancer and their potential as research tools and therapeutics. Then, we focus on the potential use of c-Met targeting miRNAs for suppressing aberrant c-Met signaling in HCC treatment. Drug Dev Res 76 : 357-367, 2015. (c) 2015 Wiley Periodicals, Inc

Management of close-range, high-energy shotgun and rifle wounds to the face.

Close-range, high-energy shotgun wounds of the face are life-threatening and devastating traumas of the face. Suicidal attempts are the main reason in the great majority of the patients in civilian life. There is no consensus on the timing of reconstruction for bone and soft tissue defects resulting from high-energy shotgun wounds. The conventional method is primary repair as soon as possible and serial debridements and definitive reconstruction in the delayed stage. An alternative to this approach is the immediate definitive surgical reconstruction of the patient during the first operation for acute management of trauma. We had 15 patients with close-range, high-energy shotgun wounds in 10 years. Six of 15 patients referred to our center for definitive reconstruction after the acute management of the patients were performed in another center and the rest were all admitted in the acute period. Either conventional approach with delayed reconstruction for 10 patients or immediate definitive surgical reconstruction for 5 patients was used. Immediate reconstruction eliminated disadvantages of the conventional method such as high infection and scarring rate and deformities resulting from contraction of tissues. The emotional conditions of the patients were evaluated and major depression signs were determined. Functional evaluation showed that there was great correlation between facial appearance after reconstruction and social activity level

Involvement of Intracellular Domain of EpCAM in Hepatocellular Carcinoma

103rd Annual Meeting of the United-States-and-Canadian-Academy-of-Pathology (USCAP) -- MAR 01-07, 2014 -- San Diego, CAWOS: 000331502202307US & Canadian Acad Pathol, Dako, Biocare Med, Leica Biosystems, LabCorp Specialty Testing Grp, Integrated Oncol, GenomOncology, Nephropath, Ventana, Diagnost BioSystem

Reciprocal activating crosstalk between c-Met and caveolin 1 promotes invasive phenotype in hepatocellular carcinoma

PubMed ID: 25148256c-Met, the receptor for Hepatocyte Growth Factor (HGF), overexpressed and deregulated in Hepatocellular Carcinoma (HCC). Caveolin 1 (CAV1), a plasma membrane protein that modulates signal transduction molecules, is also overexpressed in HCC. The aim of this study was to investigate biological and clinical significance of co-expression and activation of c-Met and CAV1 in HCC. We showed that c-Met and CAV1 were co-localized in HCC cells and HGF treatment increased this association. HGF-triggered c-Met activation caused a concurrent rise in both phosphorylation and expression of CAV1. Ectopic expression of CAV1 accelerated c-Met signaling, resulted in enhanced migration, invasion, and branching-morphogenesis. Silencing of CAV1 downregulated c-Met signaling, and decreased migratory/invasive capability of cells and attenuated branching morphogenesis. In addition, activation and co-localization of c-Met and CAV1 were elevated during hepatocarcinogenesis. In conclusion reciprocal activating crosstalk between c-Met and CAV1 promoted oncogenic signaling of c-Met contributed to the initiation and progression of HCC. © 2014 Korhan et al

TXNIP overexpression promotes aggressive phenotpe in HCC cell lines

WOS: 00038861450002