1,25-Dihydroxyvitamin D3 Suppresses Prognostic Survival Biomarkers Associated with Cell Cycle and Actin Organization in a Non-Malignant African American Prostate Cell Line.

Vitamin D3 is a steroid hormone that confers anti-tumorigenic properties in prostate cells. Serum vitamin D3 deficiency has been associated with advanced prostate cancer (PCa), particularly affecting African American (AA) men. Therefore, elucidating the pleiotropic effects of vitamin D on signaling pathways, essential to maintaining non-malignancy, may provide additional drug targets to mitigate disparate outcomes for men with PCa, especially AA men. We conducted RNA sequencing on an AA non-malignant prostate cell line, RC-77N/E, comparing untreated cells to those treated with 10 nM of vitamin D3 metabolite, 1α,25(OH)2D3, at 24 h. Differential gene expression analysis revealed 1601 significant genes affected by 1α,25(OH)2D3 treatment. Pathway enrichment analysis predicted 1α,25(OH)2D3- mediated repression of prostate cancer, cell proliferation, actin cytoskeletal, and actin-related signaling pathways (p < 0.05). Prioritizing genes with vitamin D response elements and associating expression levels with overall survival (OS) in The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA PRAD) cohort, we identified ANLN (Anillin) and ECT2 (Epithelial Cell Transforming 2) as potential prognostic PCa biomarkers. Both genes were strongly correlated and significantly downregulated by 1α,25(OH)2D3 treatment, where low expression was statistically associated with better overall survival outcomes in the TCGA PRAD public cohort. Increased ANLN and ECT2 mRNA gene expression was significantly associated with PCa, and Gleason scores using both the TCGA cohort (p < 0.05) and an AA non-malignant/tumor-matched cohort. Our findings suggest 1α,25(OH)2D3 regulation of these biomarkers may be significant for PCa prevention. In addition, 1α,25(OH)2D3 could be used as an adjuvant treatment targeting actin cytoskeleton signaling and actin cytoskeleton-related signaling pathways, particularly among AA men.

Toll-like receptors in the mechanism of tributyltin-induced production of pro-inflammatory cytokines, IL-1ß and IL-6.

Tributyltin (TBT) is an environmental contaminant due to its use in a variety of applications as a biocide, including in marine anti-fouling paints. It has been detected in a number of human tissues including blood. Previous studies have shown that exposure to TBT increases the cellular production (secretion plus intracellular levels) of the pro-inflammatory cytokines IL-1ß and IL-6 by peripheral blood mononuclear cells (PMBCs) and this increase requires MAPK activation. Toll-like receptors (TLR) activate immune cells to produce pro-inflammatory cytokines in response to pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) leading to activation of MAPKs as well as other intracellular components that regulate cytokine production. The current study shows that selective inhibition of TLRs 4,1/2, and 8 diminishes the ability of TBT to stimulate IL-1ß and IL-6 production. However, selective inhibition of TLR3 enhanced the TBT-induced production of IL-1ß. This indicates that TBT may be either directly or indirectly interacting with certain TLR receptors as part of its mechanism of stimulating pro-inflammatory cytokine production. These results provide an important advance in understanding TBT stimulation of IL-1ß and IL-6, which has the potential to cause chronic inflammation and its attendant pathologies.

Speaking Tongues Are Actively Braced.

Purpose: Bracing of the tongue against opposing vocal-tract surfaces such as the teeth or palate has long been discussed in the context of biomechanical, somatosensory, and aeroacoustic aspects of tongue movement. However, previous studies have tended to describe bracing only in terms of contact (rather than mechanical support), and only in limited phonetic contexts, supporting a widespread view of bracing as an occasional state, peculiar to specific sounds or sound combinations. Method: The present study tests the pervasiveness and effortfulness of tongue bracing in continuous English speech passages using electropalatography and 3-D biomechanical simulations. Results: The tongue remains in continuous contact with the upper molars during speech, with only rare exceptions. Use of the term bracing (rather than merely contact) is supported here by biomechanical simulations showing that lateral bracing is an active posture requiring dedicated muscle activation; further, loss of lateral contact for onset /l/ allophones is found to be consistently accompanied by contact of the tongue blade against the anterior palate. In the rare instances where direct evidence for contact is lacking (only in a minority of low vowel and postvocalic /l/ tokens), additional biomechanical simulations show that lateral contact is maintained against pharyngeal structures dorsal to the teeth. Conclusion: Taken together, these results indicate that tongue bracing is both pervasive and active in running speech and essential in understanding tongue movement control.