Combined Vorinostat and Chloroquine Inhibit Sodium Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo

Purpose Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo.Experimental DesignInformed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells. Systemic drug responses were monitored via 99mTc pertechnetate gamma counting and gene expression in BALB/c mice.ResultsWe identify an acidic dipeptide within the NIS C-terminus which mediates binding to the 2 subunit of the Adaptor Protein 2 (AP2) heterotetramer. We discovered that the FDA-approved drug chloroquine modulates NIS accumulation at the PM in a functional manner that is AP2 dependent. In vivo, chloroquine treatment of BALB/c mice significantly enhanced thyroidal uptake of 99mTc pertechnetate in combination with the histone deacetylase (HDAC) inhibitor vorinostat/ SAHA, accompanied by increased thyroidal NIS mRNA. Bioinformatic analyses validated the clinical relevance of AP2 genes with disease-free survival in RAI-treated DTC, enabling construction of an AP2 gene-related risk score classifier for predicting recurrence.ConclusionsNIS internalisation is specifically druggable in vivo. Our data therefore provide new translatable potential for improving RAI therapy using FDA-approved drugs in patients with aggressive thyroid cancer.<br/

Co-Existance of Isaba1/Bla(Oxa-51/23) Is Increasing in Carbapenem Rersistant Acinetobacter Baumannii Isolates in Turkey

WOS: 000411949500017Introduction: Carbapenem resistant Acinetobacter baumannii (A. baumannii) strains are challenging topics for hospitals. We determined the antibiotic susceptibilities and genetic resistance mechanisms of 135 A. baumannii isolates from Giresun State Hospital, Turkey between January 2013 and September 2014. Material and methods: Antimicrobial susceptibility tests were performed according to the Clinical and Laboratory Standarts Institute guidelines. beta-lactamase coding genes were investigated by simplex/multiplex PCR. Results: High rates of multi drug resistance (51.11%) and extensively drug-resistance (48.14%) were remarkable. Colistin was seemed to be the only active compound against all clinical strains. Isolates were found 100% positive for bla(OXA-51) and 95.55% positive for bla(OXA-23). Of all the isolates, 97.05% were found to be blaTEM (n=131) positive concomitant with whether bla(OXA-51) or bla(OXA23) or both them. All strains were negative for the rest of the beta-lactamase coding genes. ISAb1 element was positive in the 98.51% (n=133) of the isolates and 100% of them were located upstream of bla(OXA-51/23). Conclusion: To our knowledge this study revealed the highest co-existence of bla(OXA-51/23) and also demonstrated the increase of co-existence of both bla(OXA-51/23) and ISAba1/bla(OXA-51/23) over time in Turkey. The increasing combination of these genes and element may lead more resistance against to carbapenems among A. baumannii isolates