Search results for "Kinase inhibitor"
showing 10 items of 414 documents
TP53 and p16INK4A, but not H-KI-Ras, are involved in tumorigenesis and progression of pleomorphic adenomas.
2006
The putative role of TP53 and p16INK4A tumor suppressor genes and Ras oncogenes in the development and progression of salivary gland neoplasias was studied in 28 cases of pleomorphic adenomas (PA), 4 cases of cystic adenocarcinomas, and 1 case of carcinoma ex-PA. Genetic and epigenetic alterations in the above genes were analyzed by Polymerase Chain Reaction/Single Strand Conformational Polymorphism (PCR/SSCP) and sequencing and by Methylation Specific-PCR (MS-PCR). Mutations in TP53 were found in 14% (4/28) of PAs and in 60% (3/5) of carcinomas. Mutations in H-Ras and K-Ras were identified in4%(1/28) and7% (2/28) of PAs, respectively. Only 20% (1/5) of carcinomas screened displayed mutatio…
Posttranslationally modified proteins as mediators of sustained intestinal inflammation.
2006
Oxidative and carbonyl stress leads to generation of N(epsilon)-carboxymethyllysine-modified proteins (CML-mps), which are known to bind the receptor for advanced glycation end products (RAGE) and induce nuclear factor (NF)-kappaB-dependent proinflammatory gene expression. To determine the impact of CML-mps in vivo, RAGE-dependent sustained NF-kappaB activation was studied in resection gut specimens from patients with inflammatory bowel disease. Inflamed gut biopsy tissue demonstrated a significant up-regulation of RAGE and increased NF-kappaB activation. Protein extracts from the inflamed zones, but not from noninflamed resection borders, caused perpetuated NF-kappaB activation in cultured…
Expression of cell-cycle regulatory proteins cyclin D1, cyclin E, and their inhibitor p21 WAF1/CIP1 in gastric cancer.
1999
The expression and prognostic role of cyclin D1, cyclin E, and p21 (WAF1/CIP1) were immunohistochemically investigated in 413 curatively resected gastric carcinomas. p21 was expressed in 65.4 per cent (n=270), cyclin D1 in 23.7 per cent (n=98), and cyclin E in 13.6 per cent ( n=56) of the tumours. The expression of p21, cyclin D1, and cyclin E was positively associated with the papillary or tubular type of the WHO classification, as well as with the intestinal type according to the Lauren classification. No significant correlation could be found between the expression of p21, cyclin D1 and cyclin E and the parameters pT category, lymph node involvement, and blood vessel and lymphatic vessel…
MDM2 and CDKN1A gene polymorphisms and risk of Kaposi's sarcoma in African and Caucasian patients
2010
A single-nucleotide polymorphism in the MDM2 promoter (SNP309; rs2279744) causes elevated transcription of this major negative regulator of p53 in several cancer types. We investigated MDM2 SNP309 and CDKN1A (p21/Waf1/Cip1) codon 31 (rs1801270) polymorphisms in 86 cases of cutaneous Kaposi's sarcoma (KS) from African and Caucasian patients, and 210 healthy controls. A significant increase of the MDM2 SNP309 T/G genotype was observed among classic KS cases (odds ratio 2.38, 95% confidence interval 1.0-5.5). Frequencies of CDKN1A codon 31 genotypes were not significantly different between cases and controls. The results suggest that the MDM2 SNP309 G allele may act as a susceptibility gene fo…
Molecular analysis of the 9p21 locus and p53 genes in Ewing family tumors.
2001
The EWS-ETS rearrangements, and their respective fusion gene products, are specifically associated with histopathologically Ewing family tumors (EFT). These translocations are implicated in generating malignant transformation of EFT, but the presence of additional genetic alterations must be considered in the pathogenesis of such tumors. We analyzed 26 samples (biopsies and/or nude mice xenotransplants) collected from 19 patients with an EFT to determine whether molecular and cytogenetic alterations of the G(1)/S checkpoint genes are implicated in the pathogenesis of EFT. We found inactivating p53 mutations in three (16%) cases, which correlated with a loss of p21(WAF1/Cip1) expression and …
Immunohistochemical expression of p21 in normal tissues of salivary gland, pleomorphic adenoma and carcinoma ex pleomorphic adenoma (undifferentiated…
2009
Objective: Our study aimed to characterize alteration in the immunohistochemical expression of p21 in normal tissue of the salivary gland surrounding pleomorphic adenoma, the tumor cells of pleomorphic adenomas, and carcinoma arising in pleomorphic adenoma. Study design: A selected series of 29 cases of pleomorphic adenomas, and 27 cases of carcinoma ex-pleomorphic adenoma (undifferentiated and adenocarcinoma types) were examined. Results: The results showed that p21 expression was negative in the most components of normal tissue of the salivary gland surrounding pleomorphic adenoma, 24 cases out of 29 of the non tumour duct cells (82.8%), and 28 (96.6%) cases out of 29 of the acinar cells …
Frequent Alteration of the Yin Yang 1/Raf-1 Kinase Inhibitory Protein Ratio in Hepatocellular Carcinoma
2011
The transcription factor Yin Yang 1 (YY1) can favor several aspects of tumorigenesis. In turn, Raf-1 Kinase Inhibitor Protein (RKIP) inhibits the oncogenic activities of MAPK and NF-κB pathways and promotes drug-induced apoptosis. Mutual influences between YY1 and RKIP may exist, and there are already separate evidences that relevant increases in YY1 and reductions in RKIP occur in hepatocellular carcinoma (HCC). However, the levels of the two factors have never been concomitantly examined in HCC. We evaluated by RT-PCR the mRNA levels of YY1, YY1AP, RKIP, and survivin in 35 clinical HCCs (91% HCV-related), in their adjacent cirrhotic tissues and in 6 healthy livers. Immunohistochemical ana…
Safety and Efficacy of Sorafenib in Patients With Advanced Hepatocellular Carcinoma in Consideration of Concomitant Stage of Liver Cirrhosis
2009
GOALS AND BACKGROUND: The multikinase inhibitor sorafenib provides survival benefit for patients with advanced hepatocellular carcinoma (HCC) and liver cirrhosis (LCI) Child-Pugh A. We report our experiences with sorafenib in advanced HCC, particularly in patients with LCI Child-Pugh B/C, where only limited data are available in regard to safety and efficacy of sorafenib. METHODS: Thirty-four patients with advanced HCC were treated with sorafenib regardless of liver function and prior anticancer therapy. Adverse events (AEs) were graded using Common Toxicity Criteria version 3.0, tumor response was assessed according to Response Evaluation Criteria in Solid Tumors. RESULTS: Fifteen patients…
Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractor…
2018
AbstractPurpose:Here, we report results of the first phase I study of erdafitinib, a potent, oral pan-FGFR inhibitor.Patients and Methods:Patients age ≥18 years with advanced solid tumors for which standard antineoplastic therapy was no longer effective were enrolled (NCT01703481). Parts 2 to 4 employed molecular screening for activating FGFR genomic alterations. In patients with such alterations, two selected doses/schedules identified during part 1 dose-escalation [9 mg once daily and 10 mg intermittently (7 days on/7 days off), as previously published (Tabernero JCO 2015;33:3401-8)] were tested.Results:The study included 187 patients. The most common treatment-related adverse events were…
A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid …
2016
Abstract Activation of AKT signaling by PTEN loss or PIK3CA mutations occurs frequently in human cancers, but targeting AKT has been difficult due to the mechanism-based toxicities of inhibitors that target the inactive conformation of AKT. Ipatasertib (GDC-0068) is a novel selective ATP-competitive small-molecule inhibitor of AKT that preferentially targets active phosphorylated AKT (pAKT) and is potent in cell lines with evidence of AKT activation. In this phase I study, ipatasertib was well tolerated; most adverse events were gastrointestinal and grade 1–2 in severity. The exposures of ipatasertib ≥200 mg daily in patients correlated with preclinical TGI90, and pharmacodynamic studies co…