Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

Background: Vidian neurectomy was an option for treating allergic rhinitis in the past but outcomes varied. A modified transsphenoidal approach is proposed to simplify endoscopic vidian neurectomy. The postoperative evaluation of rhinorrhea, sneezing, and recurrence was investigated. Methods: A total of 317 patients with refractory allergic rhinitis underwent 414 transsphenoidal vidian neurectomies from September 2006 to December 2010. A rigid nasal endoscope was used through a transsphenoidal approach to reach the vidian canal inside the sphenoid sinus (type I) or through its anterior opening into the pterygopalatine fossa (type II) and to cut or cauterize the vidian nerve. The surgical outcomes were analyzed for patients with at least 6 months of follow-up. Results: Our approach was successful in 90.3% of the 414 vidian neurectomies. Vidian neurectomy was successful via the type I approach in 27 sides and type II approach in 347 sides. The short-term surgical outcomes of 163 patients who underwent a total of 236 vidian neurectomies with at least 6 months of follow-up were analyzed. Immediate, complete cessation of sneezing and rhinorrhea occurred uniformly. Three recurrences were detected during the 1–2 years of follow-up. The symptom of dry eye was reported for 172 surgical sides, but only 6 had persistent symptoms for > 6 months. Conclusion: The transsphenoidal approach in a vidian neurectomy is a simple method that removes the need for sphenopalatine artery ligation and causes less surgical morbidity. However, the possibility of recurrence of this condition in the long term needs further investigation.

Background: The transient receptor potential channel melastatin 8 (TRPM8) has been proposed to be a cold receptor. However, its distribution and physiologic role in the nose is not yet fully explored. Objective: We investigated the expression of TRPM8 in human nasal mucosa and its function when using the TRPM8 agonist. Methods: Immunohistochemistry was used to study TRPM8 receptors in the nasal mucosa from patients with and those without allergic rhinitis (AR). By using isometric contraction studies, we also tested the effectiveness of the TRPM8 agonist menthol on nasal mucosa. Changes in nasal mucosal contractility in response to the application of the adrenergic agent methoxamine were also measured. We explored the effect of menthol on electrical field stimulation (EFS) induced nasal mucosal contractions. Results: TRPM8 immunoreactivity was present principally in the nasal cilia, epithelium, and subepithelium around the glands. Except for nerve fibers, no obvious TRPM8-immunoreactive cells were detected in connective tissues. The immunoreactivity revealed no significant difference between patients with AR and those without AR. Adding menthol had a negligible effect on the basal tension of the nasal mucosa, but higher doses of menthol had a significant spasmolytic effect on nasal mucosa precontracted with methoxamine. Menthol inhibited the spike contraction induced by EFS, even at low doses. Conclusions: The finding of the TRPM8 immunoreactivity underlines the important physiologic role of the nose in temperature regulation, both in patients with allergy and those without allergy. Isometric contraction studies demonstrate the role of TRPM8 in regulating nasal patency and airway resistance. The antiadrenergic effect of menthol showed an effect apparently opposite that of clinical observations, that we usually feel decongested after menthol inhalation. The underlying mechanisms deserve further investigation, and the TRPM8 antagonists deserve consideration for treatment of rhinitis in a therapeutic trial.

Background: Research has demonstrated that some tumor cells can transform into drug-tolerant persisters (DTPs), which serve as a reservoir for the recurrence of the disease. The persister state in cancer cells arises due to temporary molecular reprogramming, and exploring the genetic composition and microenvironment during the development of head and neck squamous cell carcinoma (HNSCC) can enhance our comprehension of the types of cell death that HNSCC, thus identifying potential targets for innovative therapies. This project investigated lipid-metabolism-driven ferroptosis and its role in drug resistance and DTP generation in HNSCC. Methods: High levels of FSP1 were discovered in the tissues of patients who experienced relapse after cisplatin treatment. RNA sequencing indicated that a series of genes related to lipid metabolism were also highly expressed in tissues from these patients. Consistent results were obtained in primary DTP cells isolated from patients who experienced relapse. The Cancer Genome Atlas database confirmed this finding. This revealed that the activation of drug resistance in cancer cells is influenced by FSP1, intracellular iron homeostasis, and lipid metabolism. The regulatory roles of ferroptosis suppressor protein 1 (FSP1) in HNSCC metabolic regulation were investigated. Results: We generated human oral squamous cell carcinoma DTP cells (HNSCC cell line) to cisplatin and observed higher expression of FSP1 and lipid-metabolism-related targets in vitro. The shFSP1 blockade attenuated HNSCC-DTP cell stemness and downregulated tumor invasion and the metastatic rate. We found that cisplatin induced FSP1/ACSL4 axis expression in HNSC-DTPC cells. Finally, we evaluated the HNSCC CSC-inhibitory functions of iFSP1 (a metabolic drug and ferroptosis inducer) used for neo-adjuvant chemotherapy; this was achieved by inducing ferroptosis in a patient-derived xenograft mouse model. Conclusions: The present findings elucidate the link between iron homeostasis, ferroptosis, and cancer metabolism in HNSCC-DTP generation and acquisition of chemoresistance. The findings may serve as a suitable model for cancer treatment testing and prediction of precision treatment outcomes. In conclusion, this study provides clinically oriented platforms for evaluating metabolism-modulating drugs (FSP1 inhibitors) and new drug candidates of drug resistance and ferroptotic biomarkers.