Epidemiological studies have demonstrated that cooking oil fumes (COF) are an environmental risk factor for the development of lung adenocarcinoma among nonsmoking females in Taiwan. Aside from polycyclic aromatic hydrocarbons, aldehydes, especially trans, trans-2,4-decadienal (tt-DDE) are found to be abundant in COF. Although there is indication that tt-DDE induces DNA damage, the precise role of tt-DDE in the induction of DNA damage in lung cells is still not clear. When we assessed DNA breaks with the Comet assay, we found that the DNA breaks induced by 1 muM tt-DDE in human bronchial epithelial cells (BEAS-2B) could be significantly reduced by antioxidants, suggesting that oxidative stress was involved. Indeed, when tt-DDE-treated cells were coincubated with endonuclease III/formamidopyrimidine-DNA glycosylase or with nuclear extract (NE), an enhancement of DNA breaks was observed at 1 hr after tt-DDE exposure. Furthermore, when NE was incubated with an antibody against 8-oxoguanine DNA glycosylase (anti-OGG1), a reduction in tt-DDE/NE-induced DNA breaks could be demonstrated. Since OGG1 is a specific repair enzyme for 8-oxo-deoxyguanosine (8-oxo-dG), these findings indicated that 8-oxo-dG was involved. On the other hand, when NE was incubated with antibodies against nucleotide excision repair enzymes, there was a significant reduction in tt-DDE/NE-induced DNA breaks at 4 hr after tt-DDE treatment. These observations indicate that, in addition to early oxidative DNA damage, nonoxidative DNA damage such as bulky adduct formation, was also induced by tt-DDE. Our study further affirms that tt-DDE is genotoxic to human lung cells and can increase carcinogenic risk.

Background. Chronic neck pain is a common musculoskeletal disorder caused by overuse of neck and upper back muscles or poor posture, and it is commonly combined with a limited range of motion in the neck and shoulders. Most cases will recover within a few days; however, the symptoms often recur easily. Fu’s subcutaneous needling (FSN) is a new therapeutic approach used to treat patients with chronic neck pain. However, there is no solid evidence to support the effectiveness of FSN on chronic neck pain and disability. Methods. Participants (n = 60) with chronic neck pain for more than 2 months with pain intensity scored by visual analog scale (VAS) more than five were enrolled in this trial. Participants were equally randomized into the FSN or transcutaneous electrical nerve stimulation (TENS) group who received interventions once a day on day 1, day 2, and day 4. They were assessed by outcome measurements during pre- and post-treatment and followed up for 15 days. Results. The VAS was immediately reduced in the FSN and TENS groups and sustained for 15 days of follow-up (all P < 0.001 ). The immediate effects were also observed as the pressure pain threshold increased in the FSN group on day 2 ( P = 0.006 ) and day 4 ( P = 0.023 ) after treatment, and tissue hardness decreased by FSN on day 1 and day 2 after treatment (both P < 0.001 ). FSN and TENS treatment improved neck disability and mobility; moreover, FSN promoted participants to receive better sleep quality, as determined by PSQI assessment ( P = 0.030 ). TENS had no benefit on sleep quality. Conclusion. FSN was able to relieve pain and relax muscle tightness. Notably, FSN significantly improved neck disability and mobility and enhanced sleep quality. These findings demonstrated that FSN could be an effective alternative treatment option for patients with chronic neck pain. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03605576, registered on July 30, 2018.

The members of the interleukin-17 (IL-17) cytokine family and their receptors were identified decades ago. Unlike IL-17 receptor A (IL-17RA), which heterodimerizes with IL-17RB, IL-17RC, and IL-17RD and mediates proinflammatory gene expression, IL-17RB plays a distinct role in promoting tumor growth and metastasis upon stimulation with IL-17B. However, the molecular basis by which IL-17RB promotes oncogenesis is unknown. Here, we report that IL-17RB forms a homodimer and recruits mixed-lineage kinase 4 (MLK4), a dual kinase, to phosphorylate it at tyrosine-447 upon treatment with IL-17B in vitro. Higher amounts of phosphorylated IL-17RB in tumor specimens obtained from patients with pancreatic cancer correlated with worse prognosis. Phosphorylated IL-17RB recruits the ubiquitin ligase tripartite motif containing 56 to add lysine-63–linked ubiquitin chains to lysine-470 of IL-17RB, which further assembles NF-κB activator 1 (ACT1) and other factors to propagate downstream oncogenic signaling. Consequentially, IL-17RB mutants with substitution at either tyrosine-447 or lysine-470 lose their oncogenic activity. Treatment with a peptide consisting of amino acids 403 to 416 of IL-17RB blocks MLK4 binding, tyrosine-477 phosphorylation, and lysine-470 ubiquitination in vivo, thereby inhibiting tumorigenesis and metastasis and prolonging the life span of mice bearing pancreatic tumors. These results establish a clear pathway of how proximal signaling of IL-17RB occurs and provides insight into how this pathway provides a therapeutic target for pancreatic cancer.