Chengcheng Hu

Pancreatic cancer is characterized by a desmoplastic reaction that creates a dense fibroinflammatory microenvironment, promoting hypoxia and limiting cancer drug delivery due to decreased blood perfusion. Here, we describe a novel tumor-stroma interaction that may help explain the prevalence of desmoplasia in this cancer. Specifically, we found that activation of hypoxia-inducible factor-1α (HIF-1α) by tumor hypoxia strongly activates secretion of the sonic hedgehog (SHH) ligand by cancer cells, which in turn causes stromal fibroblasts to increase fibrous tissue deposition. In support of this finding, elevated levels of HIF-1α and SHH in pancreatic tumors were determined to be markers of decreased patient survival. Repeated cycles of hypoxia and desmoplasia amplified each other in a feed forward loop that made tumors more aggressive and resistant to therapy. This loop could be blocked by HIF-1α inhibition, which was sufficient to block SHH production and hedgehog signaling. Taken together, our findings suggest that increased HIF-1α produced by hypoxic tumors triggers the desmoplasic reaction in pancreatic cancer, which is then amplified by a feed forward loop involving cycles of decreased blood flow and increased hypoxia. Our findings strengthen the rationale for testing HIF inhibitors and may therefore represent a novel therapeutic option for pancreatic cancer.

Noise exposures and hearing loss in the mining industry continue to be a major problem, despite advances in noise control technologies. This study evaluated the effectiveness of engineering, administrative, and personal noise controls using both traditional and in-ear dosimetry by job task, work shift, and five types of earplug. The noise exposures of 22 miners performing deep shaft-sinking tasks were evaluated during 56 rotating shifts in an underground mine. Miners were earplug-insertion trained, earplug fit-tested, and monitored utilizing traditional and in-ear dosimetry. The mean TWA8 noise exposure via traditional dosimetry was 90.1 ± 8.2 dBA, while the mean in-ear TWA8 was 79.6 ± 13.8 dBA. The latter was significantly lower (p 0.05) than the Mine Safety and Health Administration (MSHA) personal exposure limit (PEL) of 90 dBA. Dosimetry mean TWA8 noise exposures for bench blowing (103.5 ± 0.9 dBA), jumbo drill operation (103.0 ± 0.8 dBA), and mucking tasks (99.6 ± 4.7 dBA) were significantly higher (p 0.05) than other tasks. For bench blowing, cable pulling, grinding, and jumbo drill operation tasks, the mean in-ear TWA8 was greater than 85 dBA. Those working swing shift had a significantly higher (p 0.001) mean TWA8 noise exposure (95.4 ± 7.3 dBA) than those working day shift. For percent difference between traditional vs. in-ear dosimetry, there was no significant difference among types of earplug used. Reflective of occupational hearing loss rate trends across the mining industry, this study found that, despite existing engineering and administrative controls, noise exposure levels exceeded regulatory limits, while the addition of personal hearing protection limited excessive exposures.

Out-of-hospital hypotension has been associated with increased mortality in traumatic brain injury. The association of traumatic brain injury mortality with the depth or duration of out-of-hospital hypotension is unknown. We evaluated the relationship between the depth and duration of out-of-hospital hypotension and mortality in major traumatic brain injury.

The hormonal metabolite of vitamin D, 1,25-dihydroxyvitamin D(1,25D), binds to the vitamin D receptor (VDR) and promotes heterodimerization of VDR with a retinoid-X-receptor (RXR) to genomically regulate diverse cellular processes. Herein, it is revealed for the first time that VDR is post-translationally acetylated, and that VDR immunoprecipitated from human embryonic kidney (HEK293) cells displays a dramatic decrease in acetylated receptor in the presence of 1,25D-ligand, sirtuin-1 (SIRT1) deacetylase, or the resveratrol activator of SIRT1. To elucidate the functional significance of VDR deacetylation, vitamin-d-responsive-element (VDRE)-based transcriptional assays were performed to determine if deacetylase overexpression affects VDR/VDRE-driven transcription. In HEK293 kidney and TE85 bone cells, co-transfection of low amounts (1-5ng) of a SIRT1-expression vector elicits a reproducible and statistically significant enhancement (1.3- to 2.6-fold) in transcription mediated by VDREs from the CYP3A4 and cyp24a1 genes, where the magnitude of response to 1,25D-ligand is 6- to 30-fold. Inhibition of SIRT1 via EX-527, or utilization of a SIRT1 loss-of-function mutant (H363Y), resulted in abrogation of SIRT1-mediated VDR potentiation. Studies with a novel, non-acetylatable VDR mutant (K413R) showed that the mutant VDR possesses enhanced responsiveness to 1,25D, in conjunction with reduced, but still significant, sensitivity to exogenous SIRT1, indicating that acetylation of lysine 413 is relevant, but that other acetylated residues in VDR contribute to modulation of its activity. We conclude that the acetylation of VDR comprises a negative feedback loop that attenuates 1,25D-VDR signaling. This regulatory loop is reversed by SIRT1-catalyzed deacetylation of VDR to amplify VDR signaling and 1,25D actions.