A Potential Prognostic Gene Signature Associated with p53-Dependent NTRK1 Activation and Increased Survival of Neuroblastoma Patients.

Neuroblastoma is the most common extracranial solid tumour in children, comprising close to 10% of childhood cancer-related deaths. We have demonstrated that activation of NTRK1 by TP53 repression of PTPN6 expression is significantly associated with favourable survival in neuroblastoma. The molecular mechanisms by which this activation elicits cell molecular changes need to be determined. This is critical to identify dependable biomarkers for the early detection and prognosis of tumours, and for the development of personalised treatment. In this investigation we have identified and validated a gene signature for the prognosis of neuroblastoma using genes differentially expressed upon activation of the NTRK1-PTPN6-TP53 module. A random survival forest model was used to construct a gene signature, which was then assessed across validation datasets using Kaplan-Meier analysis and ROC curves. The analysis demonstrated that high BASP1, CD9, DLG2, FNBP1, FRMD3, IL11RA, ISGF10, IQCE, KCNQ3, and TOX2, and low BSG/CD147, CCDC125, GABRB3, GNB2L1/RACK1 HAPLN4, HEBP2, and HSD17B12 expression was significantly associated with favourable patient event-free survival (EFS). The gene signature was associated with favourable tumour histology and NTRK1-PTPN6-TP53 module activation. Importantly, all genes were significantly associated with favourable EFS in an independent manner. Six of the signature genes, BSG/CD147, GNB2L1/RACK1, TXNDC5, FNPB1, B3GAT1, and IGSF10, play a role in cell differentiation. Our findings strongly suggest that the identified gene signature is a potential prognostic biomarker and therapeutic target for neuroblastoma patients and that it is associated with neuroblastoma cell differentiation through the activation of the NTRK1-PTPN6-TP53 module.

Characterising the chemical and physical properties of phase-change nanodroplets.

Phase-change nanodroplets have attracted increasing interest in recent years as ultrasound theranostic nanoparticles. They are smaller compared to microbubbles and they may distribute better in tissues (e.g. in tumours). They are composed of a stabilising shell and a perfluorocarbon core. Nanodroplets can vaporise into echogenic microbubbles forming cavitation nuclei when exposed to ultrasound. Their perfluorocarbon core phase-change is responsible for the acoustic droplet vaporisation. However, methods to quantify the perfluorocarbon core in nanodroplets are lacking. This is an important feature that can help explain nanodroplet phase change characteristics. In this study, we fabricated nanodroplets using lipids shell and perfluorocarbons. To assess the amount of perfluorocarbon in the core we used two methods, 19F NMR and FTIR. To assess the cavitation after vaporisation we used an ultrasound transducer (1.1 MHz) and a high-speed camera. The 19F NMR based method showed that the fluorine signal correlated accurately with the perfluorocarbon concentration. Using this correlation, we were able to quantify the perfluorocarbon core of nanodroplets. This method was used to assess the content of the perfluorocarbon of the nanodroplets in solutions over time. It was found that perfluoropentane nanodroplets lost their content faster and at higher ratio compared to perfluorohexane nanodroplets. The high-speed imaging indicates that the nanodroplets generate cavitation comparable to that from commercial contrast agent microbubbles. Nanodroplet characterisation should include perfluorocarbon concentration assessment as critical information for their development.