Dielectric properties of human glioma and surrounding tissue from five patients were measured. Experiments were performed at frequencies of 5-500 MHz at 24 +/- 0.5 degrees C using a Network Analyser and a coaxial line capacitive sensor. The permittivity and conductivity of tumours were 30% higher than that of the surrounding tissues due to their higher water content. The characteristic of less differentiation in tumours clearly was reflected in the dielectric properties, namely a smaller parameter for the relaxation time distribution of the tumour's dielectric relaxation. With the dielectric data, the power absorption ratios of tumour to surrounding tissue were calculated for four representative electromagnetic (EM) irradiation cases. The calculation shows that power absorption ratios are strongly dependent on the incident direction of the EM wave and optimum frequency. To improve therapeutic efficiency, it is appropriate to have the electric field vector (E) parallel to the interface of tumour/surrounding tissue at optimum frequencies around 100 MHz, and the case of E perpendicular to the interface must be avoided in applications of EM hyperthermia for brain tumours.
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are effective targeted therapy drugs for advanced non-small cell lung cancer (NSCLC) patients carrying sensitized EGFR mutations. The rapid development of EGFR-TKIs resistance represents a major clinical challenge for managing NSCLC. The chromosome 4q12 is the first genome-wide association study (GWAS)-reported locus associated with progression-free survival (PFS) of NSCLC patients treated with EGFR-TKIs. However, the biological significance of the noncoding transcripts at 4q12 in NSCLC remains elusive. In the present study, we identified two 4q12 long noncoding RNAs (lncRNAs) LCETRL3 and LCETRL4 which could significantly dimmish EGFR-TKIs efficiency. In line with their oncogenic role, evidently higher LCETRL3 and LCETRL4 levels were observed in NSCLC tissues as compared with normal specimens. Importantly, lncRNA LCETRL3 can interact with oncoprotein TDP43 and inhibit ubiquitination and degradation of TDP43. Similarly, lncRNA LCETRL4 can bind and stabilize oncoprotein EIF2S1 through reducing ubiquitin-proteasome degradation of EIF2S1. In particular, elevated levels of LCETRL3 or LCETRL4 in NSCLC cells resulted in stabilization of TDP43 or EIF2S1, increased levels of NOTCH1 or phosphorylated PDK1, activated AKT signaling and, thus, EGFR-TKIs resistance. Taken together, our data revealed a novel model that integrates two lncRNAs transcribed from the 4q12 locus into the regulation of EGFR-TKIs resistance in NSCLC. These findings shed new light on the importance of functionally annotating lncRNAs in the GWAS loci and provided insights to declare novel druggable targets, i.e., lncRNAs, which may unlock the therapeutic potential of EGFR-TKIs resistant NSCLC in the clinic.
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