RESUMEN
We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.
Asunto(s)
Reordenamiento Génico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Fusión de Oncogenes , Receptor trkA/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Antígenos de Diferenciación de Linfocitos B/genética , Línea Celular Tumoral , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidoresRESUMEN
Characterization of traditional cheeses is important for the protection of diversity of tradition and contributing baseline data for further research and quality control. Sepet cheese is a traditional cheese and specific to the Aegean region of Turkey. In this study, 52 Sepet cheese samples were analyzed to characterize the physicochemical, textural, volatile compounds, and sensory profiles. The changes in the physicochemical and volatile compositions were investigated during production and ripening periods. The average dry matter (DM; 55.16%), fat-in-DM (45.80%), protein (29.18%), salt-in-DM (12.88%), water activity (0.83), pH (5.50), titratable acidity (1.69%), ripening and lipolysis indices (11.06 and 6.36), firmness (212.20N), springiness (0.62), cohesiveness (0.57), adhesiveness (0.48 Nmm), and chewiness (66.87N) values of Sepet cheese samples were determined. Hexanoic, octanoic, decanoic, and butyric acids, which were responsible for the cheesy, waxy, goaty odors, were the most abundant volatile compounds in these cheeses. Most of the volatile compounds increased significantly during production and ripening. Significant changes in most of the physicochemical characteristics were observed up to the third month of ripening. As a result of the descriptive sensory analysis, Sepet cheeses were described with descriptors such as free fatty acid, animal like, sulfurous, creamy, cooked, and whey, and aromatics with high salty basic taste.
Asunto(s)
Queso/normas , Adhesividad , Queso/análisis , Ácidos Grasos Volátiles/análisis , Manipulación de Alimentos , Dureza , Proteínas de la Leche/análisis , Gusto , TurquíaRESUMEN
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, gefitinib and erlotinib are effective therapies against mutant non-small cell lung cancers (NSCLCs). Treatment is limited by the development of resistance in part explained by the gain of a secondary EGFR mutation, T790M, at the gatekeeper residue. Irreversible EGFR inhibitors, including PF00299804, are effective in vitro and in vivo against EGFR mutant tumors that contain EGFR T790M and are currently under clinical development. In this study, we generate models of resistance to PF00299804, using cell lines with EGFR T790M and show that the PF00299804-resistant models develop focal amplification of EGFR that preferentially involves the T790M-containing allele. These PF00299804-resistant cell lines remain dependent on EGFR for growth as downregulation of EGFR by shRNA compromises their viability. We show that resistance to PF00299804 arises, at least in part, through selection of a pre-existing EGFR T790M-amplified clone both in vitro and using a xenograft model in vivo. Our findings show that EGFR T790M is a common resistance mechanism to both reversible, and when amplified, the irreversible EGFR kinase inhibitors further emphasizing the need to develop more potent therapies against EGFR T790M. These findings can be used to guide studies of patient tumor specimens from ongoing clinical trials of irreversible EGFR kinase inhibitors.