ABSTRACT
BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel. RESULTS: 173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2. CONCLUSION: These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.
Subject(s)
Biomarkers/blood , Breast Neoplasms/blood , Breast Neoplasms/drug therapy , Cardiotoxicity/blood , Cardiovascular Abnormalities/blood , Aged , Breast Neoplasms/complications , Breast Neoplasms/pathology , Cardiotoxicity/pathology , Cardiovascular Abnormalities/chemically induced , Cardiovascular Abnormalities/pathology , Drug-Related Side Effects and Adverse Reactions , Female , Humans , Lapatinib/administration & dosage , Lapatinib/adverse effects , Middle Aged , Natriuretic Peptide, Brain/blood , Neoplasm Staging , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Receptor, ErbB-2/genetics , Trastuzumab/administration & dosage , Trastuzumab/adverse effects , Troponin T/bloodABSTRACT
The receptor for epidermal growth factor (EGF) plays an important role in epidermal keratinocytes and is known to move out of lipid raft after cholesterol depletion, leading to ligand-independent activation. Accumulation of evidence indicates the ability of EGF receptor (EGFR) to undergo internalization without participation of the ligand under the control of p38 MAPK during stress conditions. Since cholesterol depletion using methyl-beta-cyclodextrin is known to induce ligand-independent activation of EGFR in keratinocytes, we investigated by confocal microscopy and ligand-binding tests the processing and localization of EGFR following lipid raft disruption. Here, we report the dimerization and the slow internalization of the receptor accompanied by the delayed phosphorylation of tyrosine 1068 and its degradation by the proteasome. We also demonstrate the involvement of p38 MAPK during the process of internalization, which can be considered as a protective response to stress. Moreover, cholesterol-depleted keratinocytes recover their ability to proliferate during the recovery period that follows lipid raft disruption.
Subject(s)
Endocytosis , ErbB Receptors/metabolism , Keratinocytes/cytology , Keratinocytes/enzymology , Membrane Microdomains/enzymology , p38 Mitogen-Activated Protein Kinases/metabolism , Cell Line, Tumor , Cholesterol/deficiency , Dimerization , Endocytosis/drug effects , Enzyme Activation/drug effects , Epidermal Growth Factor/pharmacology , Humans , Hydrogen Peroxide/pharmacology , Keratinocytes/drug effects , Membrane Microdomains/drug effects , Oxidative Stress/drug effects , Phosphorylation/drug effects , Phosphotyrosine/metabolism , Proteasome Endopeptidase Complex/metabolism , Protein Processing, Post-Translational/drug effects , Signal Transduction/drug effects , beta-Cyclodextrins/pharmacologyABSTRACT
A multiplex DNA microarray chip aimed at the identification of allelic polymorphisms was developed for simultaneous detection of swine disease resistance genes underlying malignant hyperthermia (RYR), postweaning diarrhea, edema disease (FUT1), neonatal diarrhea (MUC4), and influenza (MX1). The on-chip detection was performed with fragmented polymerase chain reaction (PCR)-amplified products. Particular emphasis was placed on the reduction of the number of PCR reactions required. The targets were biotin labeled during the PCR reaction, and the arrays were detected using a colorimetric methodology. Target recognition was provided by specific capture probes designed for each susceptible or resistant allelic variant. Sequencing was chosen as the gold standard to assess chip accuracy. All genotypes retrieved from the microarray (476) fit with sequencing data despite the fact that each pig was heterozygote for at least 1 target gene.