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 Show more
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 Show less
Bardet-Biedl syndrome is a heterogeneous disorder causing a spectrum of symptoms, including visual impairment, kidney disease, and hearing impairment. Evidence suggests that BBS gene mutations cause d Show more
Bardet-Biedl syndrome is a heterogeneous disorder causing a spectrum of symptoms, including visual impairment, kidney disease, and hearing impairment. Evidence suggests that BBS gene mutations cause defective ciliogenesis and/or cilium dysfunction. Cochlear development is affected by BBS gene deletion, and adult Bbs6(-/-) and Bbs4(-/-) mice are hearing impaired. This study addresses BBS protein expression in the rodent cochlea, to gain a better understanding of its function in vivo. As predicted by in vitro studies, Bbs6 immunofluorescence was localized to the basal bodies of supporting cells and sensory hair cells prior to the onset of hearing. In adult tissue, Bbs6 expression persisted in afferent neurons, including within the dendrites that innervate hair cells, implicating Bbs6 in a sensory neuronal function. Bbs2, which interacts with Bbs6, was also localized to hair cell basal bodies and stereociliary bundles. Additionally, Bbs2 was expressed in supporting cells at their intercellular boundaries, in a spatiotemporal pattern mirroring the development of the microtubule network. Bbs4 localized to cilia and developing cytoplasmic microtubule arrays. Pcm-1, a microtubular protein that interacts with Bbs4 in vitro, showed a comparable expression. Depolymerization of microtubules in slice preparations of the living cochlea resulted in Bbs4 and Pcm-1 mislocalization. Pcm-1 was also mislocalized in Bbs4(-/-) mice. This suggests that Bbs4/Pcm-1 interactions may be important in microtubule-dependent cytoplasmic trafficking in vivo. In summary, our findings indicate that BBS proteins adopt a range of cellular distributions in vivo, not restricted to the centrosome or cilium, and so broaden the possible underlying pathomechanisms of the disease. Show less