The management and survival outcomes of nasopharyngeal cancer in the Nordic countries

Peer reviewe

The EIF4EBP3 translational repressor is a marker of CDC73 tumor suppressor haploinsufficiency in a parathyroid cancer syndrome

Germline mutation of the tumor suppressor gene CDC73 confers susceptibility to the hyperparathyroidism-jaw tumor syndrome associated with a high risk of parathyroid malignancy. Inactivating CDC73 mutations have also been implicated in sporadic parathyroid cancer, but are rare in sporadic benign parathyroid tumors. The molecular pathways that distinguish malignant from benign parathyroid transformation remain elusive. We previously showed that a hypomorphic allele of hyrax (hyx), the Drosophila homolog of CDC73, rescues the loss-of-ventral-eye phenotype of lobe, encoding the fly homolog of Akt1s1/ PRAS40. We report now an interaction between hyx and Tor, a central regulator of cell growth and autophagy, and show that eukaryotic translation initiation factor 4E-binding protein (EIF4EBP), a translational repressor and effector of mammalian target of rapamycin (mTOR), is a conserved target of hyx/CDC73. Flies heterozygous for Tor and hyx, but not Mnn1, the homolog of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor associated with benign parathyroid tumors, are starvation resistant with reduced basal levels of Thor/4E-BP. Human peripheral blood cell levels of EIF4EBP3 were reduced in patients with CDC73, but not MEN1, heterozygosity. Chromatin immunoprecipitation demonstrated occupancy of EIF4EBP3 by endogenous parafibromin. These results show that EIF4EBP3 is a peripheral marker of CDC73 function distinct from MEN1-regulated pathways, and suggest a model whereby starvation resistance and/or translational de-repression contributes to parathyroid malignant transformation

Role of Kv1 Potassium Channels in Regulating Dopamine Release and Presynaptic D2 Receptor Function

Dopamine (DA) release in the CNS is critical for motor control and motivated behaviors. Dysfunction of its regulation is thought to be implicated in drug abuse and in diseases such as schizophrenia and Parkinson's. Although various potassium channels located in the somatodendritic compartment of DA neurons such as G-protein-gated inward rectifying potassium channels (GIRK) have been shown to regulate cell firing and DA release, little is presently known about the role of potassium channels localized in the axon terminals of these neurons. Here we used fast-scan cyclic voltammetry to study electrically-evoked DA release in rat dorsal striatal brain slices. We find that although G-protein-gated inward rectifying (GIRK) and ATP-gated (KATP) potassium channels play only a minor role, voltage-gated potassium channels of the Kv1 family play a major role in regulating DA release. The use of Kv subtype-selective blockers confirmed a role for Kv1.2, 1.3 and 1.6, but not Kv1.1, 3.1, 3.2, 3.4 and 4.2. Interestingly, Kv1 blockers also reduced the ability of quinpirole, a D2 receptor agonist, to inhibit evoked DA overflow, thus suggesting that Kv1 channels also regulate presynaptic D2 receptor function. Our work identifies Kv1 potassium channels as key regulators of DA release in the striatum

Measurements of metastatic renal cell tumours as determined by diffusion weighted imaging or computed tomography are in close agreement, a pilot study

Background: Diffusion weighted magnetic resonance imaging (DWI) provides both functional and anatomical information regarding tumours but can also be used for tumour detection. Today, tumour treatment response in clinical trials is mainly assessed on Computed Tomography (CT) using established criteria. Despite availability of dedicated software, CT still requires significant manual work for selection and measurement in treatment response evaluation of solid tumours. Purpose: To compare the maximum diameter of tumour lesions on CT with the corresponding measurements on diffusion weighted images. Materials and methods: In this prospective cohort, metastatic lesions were identified on CT and on DWI in five patients with metastatic renal cell carcinoma before and after three months of treatment with pazopanib. Two radiologists independently measured the same lesions on axial CT images and separately also on axial DWI images. The measurements were compared between CT and DWI with respect to the number of target lesions measured, size of the lesions, size reduction due to treatment and the inter-observer variability. Wilcoxon signed rank test, linear regression and Bland-Altman plots were used for statistical analyses. Results: In this pilot study, there was no significant inter-observer variability in terms of numbers of lesion selected between CT and DWI. A significant reduction of lesion size was observed both for CT and DWI when post-treatment scans were compared to pre-treatment scans. There was no significant difference in measurement of lesion size on both pre- and post treatment scans between CT and DWI (p = 0.099 and p = 0.388 respectively). Conclusion: Measurement of the size of metastatic lesions on the basis of axial DWI images are in close agreement with measurement based on conventional axial CT images, the most often employed approach in clinical trials today. The results in this pilot study can be used to estimate sufficient sample size in a larger trial with adequate power, were the results can be confirmed in a wider range of cancers other than renal cell carcinoma. Keywords: DWI, CT, RECIST1.1, Biomarker, Clinical trial