The aim of this study was to achieve an efficient therapy against RET/PTC3 junction oncogene using siRNA technology. We first established RET/PTC3 expressing cell line, named RP3, from murine NIH/3T3 fibroblasts. Then siRNAs were designed and studied for the RET/PTC3 silencing effects, apoptosis and cell cycle regulation pathways. The most efficient siRNA RET/PTC3 was conjugated to squalene and the efficiency of the resulting nanoassemblies was validated in vitro before testing in preclinical experiments. Our results strongly suggest that siRNA RET/PTC3-SQ NPs could be accredited as a potential new pharmacological approach for papillary thyroid carcinoma with RET/PTC3 junction oncogene. This also demonstrates that the siRNA RET/PTC3 is still active; after bio-conjugation with squalene, due to modification of the passenger sense strand only and the use of an ester hydrolysable bond between the squalene moiety and the siRNA part. The discrepancy between in vitro and in vivo nanoparticles uptake and silencing efficiency is probably due to differences between the enzymatic contents found in vivo biological fluids and in culture conditions, the possible rationalization was discussed previously. In conclusion, the significance of siRNA RET/PTC3-SQ NPs have been demonstrated in preclinical studies for thyroid cancer therapy and further pharmacological and clinical investigations can be proceeded to set-in the remedy of thyroid carcinoma. Furthermore, in future, we desire to extend our investigations to other cancer pathologies carrying junction oncogene, so that the “squalenoylation” could be used as a generic platform for the administration and the transport of therapeutic siRNA. Combined exposure to fluoride and arsenic may result in more complicated adverse health effects than exposure to fluoride or arsenic alone. Many health hazards caused by fluoride and arsenic alone have been reported, but less has been reported about their joint effects on health. Furthermore, some results have been contradictory. For example, different joint actions, including independent, synergistic, and antagonistic effects, have been observed in different experimental studies. Therefore, further research is needed to reveal the interaction between fluoride and arsenic with regard to their toxic effects. Fluoride and arsenic are able to cross the blood-brain barrier or placental barrier and accumulate in the brain in rats and mice exposed to high concentrations of fluoride and arsenic. Some epidemiological studies have demonstrated that chronic exposure to fluoride and arsenic in drinking water is associated with lower child intelligence and impairments in cognitive and neurobehavioral function. However, relatively little information is available in the literatures about the association between fluoride-arsenic co-exposure and cognitive and neurobehavioral function in humans.

In lymphoblastoid cells the motif for the transcription factor GABPA was the top ranked motif in all four samples, followed by those for the transcription factor BORIS, with the exception of stimulated GM10855 cells, where BORIS was replaced by IRF4. In stimulated lymphoblastoid cells also PU.1like motifs ranked high, whereas in unstimulated lymphoblastoid cells motifs for the transcription factor complex GFI1-STAF did the same. In contrast, both samples of LX2 cells had motifs for the transcription factors JUN, TEAD4 and RUNX as the top ranked. The stimulated LS180 cells also had JUN as the top ranking motif, but unlike for LX2 cells it had HNF4A and GFI1-STAF motifs as the next best ranked. In the small peak set for the unstimulated LS180 cells, motifs for the transcription factors STAT5, CHR and ZFX ranked the highest. Taken together, our de novo searches and DR3-type binding site screenings demonstrated as common findings for all six datasets that i) ligand-stimulated samples show a higher rate of DR3-type sequences than unstimulated samples of the same cellular model, ii) the more VDR peaks a stimulated dataset contains, the lower is the percentage of its DR3-type sequences, iii) by far not all VDR binding sites even at the stimulated state contain a DR3-type sequence and iv) the occurrence of non-DR3-type motifs differ considerably between the cell lines, especially in peaks that lack DR3-type motifs. The genome-wide location of VDR is an essential information for understanding the pleiotropic physiological action of 1,252D3. In this study, we generated VDR ChIP-seq data for LPS-differentiated THP-1 cells. These cells resemble M1-type macrophages and represent another tissue that is important for the interpretation of the immune-modulatory function of 1,252D3. This new VDR ChIP-seq dataset was compared with all the publically available VDR ChIP-seq datasets that we re-analyzed using identical settings and taking the benefit of the recent advances in the relevant bioinformatic tools. Thus, this study also represents the first meta-analysis of VDR ChIP-seq data from six different cell types and sets the basis for a compendium of all VDR binding sites genome-wide. The six ChIP-seq datasets differ largely in their total number of genome-wide VDR binding sites. While the two THP-1 datasets provide only 1,100-1,300 genome-wide VDR locations, the two lymphoblastoid cell lines suggest an up to 10-times higher number. This difference could arise from the number of sequence tags obtained in the ChIP-seq procedure, differences in signal-to-noise ratios or variations in the reference sample or simply from a much higher VDR expression in B lymphocytes than in monocytes/macrophages. However, the more likely explanation is that in B cells more VDR binding sites are accessible, i.e. the level of epigenomics. Nevertheless, it can be questioned, whether the regulation of a few hundred primary VDR target genes.