The prognosis and treatment of newly diagnosed bone metastasis of head and neck squamous cell cancer: an analysis of racial disparity / El pronóstico y el tratamiento de las metástasis óseas recién diagnosticadas de cáncer de células escamosas de cabeza y cuello: un análisis de la disparidad racial

Objective: There is a lack of research investigating racial disparity in newly diagnosed head and neck squamous cell carcinoma with isolated bone metastases (HNSCC-BM). This study aims to investigate the clinical characteristics and prognostic factors in HNSCC-BM patients from different racial backgrounds to aid clinical decision making and management. Methods: We retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database for 345 cases of HNSCC-BM that were diagnosed between 2010 and 2017. Survival was compared using univariate and multivariate Cox proportional hazards models, Kaplan–Meier analysis, and log-rank tests. We also used propensity score matching to adjust for confounders. Results: In white patients, those who were over 40 years of age had a significantly shorter survival (HR, 4.49; 95% CI 1.03–19.56; P < 0.05). Female black patients were found to survive longer compared to male patients (HR, 0.34; 95% CI 0.15–0.76; P < 0.01). Single (never married) Asians had shorter survival than married Asians (HR, 4.68; 95% CI 1.34–16.41; P < 0.05). In all three racial groups, patients who received radiotherapy in addition to chemotherapy did not survive longer than those receiving chemotherapy (P > 0.05). In Asian patients, those who underwent surgery at the primary site combined with chemoradiotherapy had significantly better survival outcomes than those who received chemoradiotherapy (HR: 0.10, 95% CI 0.01–0.88; P = 0.01). Conclusion: Prognostic factors differ between HNSCC-BM patients from different racial backgrounds.(AU)

Identification and characterization of TOR in Macrobrachium rosenbergii and its role in muscle protein and lipid production.

The recent scarcity of fishmeal and other resources means that studies on the intrinsic mechanisms of nutrients in the growth and development of aquatic animals at the molecular level have received widespread attention. The target of rapamycin (TOR) pathway has been reported to receive signals from nutrients and environmental stresses, and regulates cellular anabolism and catabolism to achieve precise regulation of cell growth and physiological activities. In this study, we cloned and characterized the full-length cDNA sequence of the TOR gene of Macrobrachium rosenbergii (MrTOR). MrTOR was expressed in all tissues, with higher expression in heart and muscle tissues. In situ hybridization also indicated that MrTOR was expressed in muscle, mainly around the nucleus. RNA interference decreased the expression levels of MrTOR and downstream protein synthesis-related genes (S6K, eIF4E, and eIF4B) (P < 0.05) and the expression and enzyme activity of the lipid synthesis-related enzyme, fatty acid synthase (FAS), and increased enzyme activity of the lipolysis-related enzyme, lipase (LPS). In addition, amino acid injection significantly increased the transcript levels of MrTOR and downstream related genes (S6K, eIF4E, eIF4B, and FAS), as well as triglyceride and total cholesterol tissue levels and FAS activity. Starvation significantly increased transcript levels and enzyme activities of adenylate-activated protein kinase and LPS and decreased transcript levels and enzyme activities of FAS, as well as transcript levels of MrTOR and its downstream genes (P < 0.05), whereas amino acid injection alleviated the starvation-induced decreases in transcript levels of these genes. These results suggested that arginine and leucine activated the TOR signaling pathway, promoted protein and lipid syntheses, and alleviated the pathway changes induced by starvation.

The prognosis and treatment of newly diagnosed bone metastasis of head and neck squamous cell cancer: an analysis of racial disparity.

OBJECTIVE: There is a lack of research investigating racial disparity in newly diagnosed head and neck squamous cell carcinoma with isolated bone metastases (HNSCC-BM). This study aims to investigate the clinical characteristics and prognostic factors in HNSCC-BM patients from different racial backgrounds to aid clinical decision making and management. METHODS: We retrieved data from the Surveillance, Epidemiology, and End Results (SEER) database for 345 cases of HNSCC-BM that were diagnosed between 2010 and 2017. Survival was compared using univariate and multivariate Cox proportional hazards models, Kaplan-Meier analysis, and log-rank tests. We also used propensity score matching to adjust for confounders. RESULTS: In white patients, those who were over 40 years of age had a significantly shorter survival (HR, 4.49; 95% CI 1.03-19.56; P < 0.05). Female black patients were found to survive longer compared to male patients (HR, 0.34; 95% CI 0.15-0.76; P < 0.01). Single (never married) Asians had shorter survival than married Asians (HR, 4.68; 95% CI 1.34-16.41; P < 0.05). In all three racial groups, patients who received radiotherapy in addition to chemotherapy did not survive longer than those receiving chemotherapy (P > 0.05). In Asian patients, those who underwent surgery at the primary site combined with chemoradiotherapy had significantly better survival outcomes than those who received chemoradiotherapy (HR: 0.10, 95% CI 0.01-0.88; P = 0.01). CONCLUSION: Prognostic factors differ between HNSCC-BM patients from different racial backgrounds.

Inhibition of autophagy enhances the anticancer effect of Schisandrin B on head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide and has a poor prognosis. Autophagy regulation has been proposed as a possible treatment option for HNSCC. Schisandrin B (Sch B) exerts anticancer effects by regulating apoptosis and autophagy, but the anticancer effect of Sch B in HNSCC remains unclear. This study aimed to investigate the effects of Sch B on human Cal27 HNSCC cells and to further reveal its potential regulatory mechanisms. The anticancer effect of Sch B was evaluated in vitro by flow cytometry, clonogenic assays, and Western blot analysis. The regulatory mechanism of Sch B-induced apoptosis and autophagy was further explored by polymerase chain reaction, luciferase assay, and reactive oxygen species (ROS) detection. The results showed that Sch B significantly induced apoptosis and autophagy in Cal27 cells and that inhibition of autophagy enhanced the apoptotic effect of Sch B on Cal27 cells. Additionally, Sch B-activated autophagy in Cal27 cells was dependent on the nuclear factor-kappa B (NF-κB) pathway, and ROS acted as a regulator of the NF-B pathway. N-acetylcysteine, a scavenger of ROS, inhibited Sch B-dependent autophagy via the NF-κB pathway. Based on the results, Sch B is a potential therapeutic agent for HNSCC and activates the NF-κB pathway by increasing ROS production, which subsequently promotes autophagy in HNSCC cells. Therefore, the strategy of enhancing the anticancer effect of Sch B by inhibiting autophagy deserves further attention.

Cell membrane-coated nanomaterials for cancer therapy.

With the development of nanotechnology, nanoparticles have emerged as a delivery carrier for tumor drug therapy, which can improve the therapeutic effect by increasing the stability and solubility and prolonging the half-life of drugs. However, nanoparticles are foreign substances for humans, are easily cleared by the immune system, are less targeted to tumors, and may even be toxic to the body. As a natural biological material, cell membranes have unique biological properties, such as good biocompatibility, strong targeting ability, the ability to evade immune surveillance, and high drug-carrying capacity. In this article, we review cell membrane-coated nanoparticles (CMNPs) and their applications to tumor therapy. First, we briefly describe CMNP characteristics and applications. Second, we present the characteristics and advantages of different cell membranes as well as nanoparticles, provide a brief description of the process of CMNPs, discuss the current status of their application to tumor therapy, summarize their shortcomings for use in cancer therapy, and propose future research directions. This review summarizes the research progress on CMNPs in cancer therapy in recent years and assesses remaining problems, providing scholars with new ideas for future research on CMNPs in tumor therapy.

Integration of transcriptomics and metabolomics reveals a novel gene signature guided by FN1 associated with immune response in oral squamous cell carcinoma tumorigenesis.

PURPOSE: Oral squamous cell carcinomas (OSCCs) are primary head and neck malignant tumours with a high incidence and mortality. However, the molecular mechanisms involved in OSCC tumorigenesis are not fully understood. METHODS: OSCC and paired para-carcinoma samples were collected and used to perform multi-omics study. Transcriptomic analysis was used to reveal significant alterations in inflammatory and immune processes in OSCC. Ingenuity Pathway Analysis (IPA) combined with the LASSO Cox algorithm was used to identify and optimize a crucial gene signature. Metabolomics analysis was performed to identify the important metabolites which linked to the crucial gene signature. The public data TCGA-HNSCC cohort was used to perform the multiple bioinformatic analysis. RESULTS: These findings identified a FN1-mediated crucial network that was composed of immune-relevant genes (FN1, ACP5, CCL5, COL1A1, THBS1, BCAT1, PLAU, IGF2BP3, TNF, CSF2, CXCL1 and CXCL5) associated with immune infiltration and influences the tumour microenvironment, which may contribute to OSCC tumorigenesis and progression. Moreover, we integrated the relevant genes with altered metabolites identified by metabolic profiling and identified 7 crucial metabolites (Glu-Glu-Lys, Ser-Ala, Ser-Ala, N-(octadecanoyl) sphing-4-enine-1-phosphocholine, N-methylnicotinamide, pyrrhoxanthinol and xanthine) as potential downstream targets of the FN1-associated gene signature in OSCC. Importantly, FN1 expression is positively correlated with immune infiltration levels in HNSCC, which was confirmed at the single-cell level. CONCLUSIONS: Overall, these results revealed the differential genetic and metabolic patterns associated with OSCC tumorigenesis and identified an essential molecular network that plays an oncogenic role in OSCC by affecting amino acid and purine metabolism. These genes and metabolites might, therefore, serve as predictive biomarkers of survival outcomes and potential targets for therapeutic intervention in OSCC.

Association of matrix metalloproteinase-9 and nitric oxide with hypertension in obstructive sleep apnea.

Background: Patients with obstructive sleep apnea (OSA) are more likely to suffer from hypertension. At the same time, the serum levels of matrix metalloproteinase-9 (MMP-9) and nitric oxide (NO) in patients with OSA are also changed in OSA patients. We investigated the correlation between serum levels of MMP-9, NO in patients with OSA and their association with hypertension in those patients, and the effects of continuous positive airway pressure therapy (CPAP) on these serum biomarkers and blood pressure. Methods: Serum MMP-9 and NO levels and blood pressure of 57 patients with newly diagnosed OSA and 30 controls were measured; among them, 30 patients with moderate to severe OSA underwent 3-month CPAP treatment. Results: In comparison to the control group, the MMP-9 serum levels were higher (232.8 ± 103.2 ng/ml versus 161.6 ± 56.5 ng/ml, p < .001*), there was no statistical significance difference among serum NO (26.7 ± 9.1 IU/ml versus 31.0 ± 11.7 IU/ml, p = .06), and MMP-9 was negatively correlated to NO, especially in patients with hypertension (r = -.644, p = .02*). MMP-9, NO, and blood pressure were significantly recovered in the patients with OSA after CPAP treatment for 3 months (p < .05*). Conclusion: The MMP-9 level and the NO level were altered in OSA patients. The relationship between the two especially in patients with hypertension suggests the potential mechanism of OSA-induced hypertension.

Long non-coding RNA KRT16P2/miR-1294/EGFR axis regulates laryngeal squamous cell carcinoma cell aggressiveness.

Laryngeal squamous cell carcinoma (LSCC) is one of the most commonly seen head and neck malignancies. Identifying potent markers and/or targets for early diagnosis and individualized therapies for LSCC remains a considerable challenge. The present study analyzed online data and identified lncRNA KRT16P2 as a significantly upregulated long non-coding RNA (lncRNA) in LSCC. KRT16P2 knockdown in LSCC cells inhibited cancer cell proliferation, invasion, and migration. Similar to KRT16P2, EGFR expression was also significantly upregulated in LSCC. KRT16P2 and EGFR were positively correlated in LSCC tissue samples. EGFR knockdown also dramatically inhibited LSCC cell proliferation and aggressiveness (invasion and migration). Through online data and online tools, miR-1294 was predicted to target KRT16P2 and EGFR 3'UTR simultaneously. KRT16P2 inhibited miR-1294 expression, and miR-1294 inhibited EGFR expression through direct binding. miR-1294 overexpression repressed LSCC cell proliferation and aggressiveness. The effects of KRT16P2 silence on the expression of EGFR, LSCC cell proliferation, invasion, and migration, the protein levels of ki-67, PCNA, and cleaved-Caspase 3, as well as the phosphorylation of AKT, were all significantly reversed by miR-1294 inhibition. In conclusion, we demonstrated a lncRNA KRT16P2/miR-1294/EGFR axis that regulates LSCC cell proliferation, invasion, and migration. The clinical application of this axis needs further in vivo and clinical investigation.

Clinical significance of neuropilin-2 expression in laryngeal squamous cell carcinoma.

PURPOSE: The purpose of the study is to evaluate the expression of NRP-2 and explore its role in Laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: NRP-2 expression in 70 primary LSCC tissue specimens were analyzed by immunohistochemistry and correlated with clinicopathological parameters and patients´ survival rate. Additionally, 9 paired LSCC tissues were evaluated for NRP-2 expression by Western blotting. RESULTS: The Western blotting indicated that NRP-2 expression levels in LSCC were significantly higher than those in the paraneoplastic tissues (P < 0.05). Immunohistochemistry staining revealed that NRP-2 was detected in all primary tumor samples, moreover, high expression of NRP-2 was significantly correlated with TNM stage (P < 0.05), clinical stage (P < 0.05), histological classification (P < 0.05), lymph node metastasis (P < 0.05) and recurrence (P = 0.001). Survival curves determined by the Kaplan-Meier method showed that high expression of NRP-2 can reduce overall survival (both group P < 0.05). Then we combined the NRP-2 expression and lymph node status, and Kaplan-Meier survival showed patients with high expression of NRP-2 or lymph node metastasis (+) had both shorter disease-free and overall survival than others (both P < 0.05). Multivariate Cox proportional hazards model analysis confirmed that histological grade (P = 0.045), lymph node metastasis (P = 0.020) and high expression of NRP-2 (P = 0.033) were statistically significant, independent predictor of prognosis. CONCLUSIONS: NRP-2 may contribute to LSCC progression and represents as a novel prognostic indicator as well as a potential therapeutic target for LSCC.

OGFOD1 negatively regulated by miR-1224-5p promotes proliferation in human papillomavirus-infected laryngeal papillomas.

Laryngeal papillomas (LP) is a difficult disease to manage due to its frequent recurrence, airway compromise, and risk of cancer. Recently, growing evidence indicates the aberrant expression of OGFPD1, a stress granule protein, links closely to the development of tumorigenesis; however, little is known about its role in LP progression. Here, we investigated the tumor promoting action of OGFOD1 in LP. The transcriptional and translational levels of OGFOD1 were significantly up-regulated in LP tissues and cells. Moreover, OGFOD1 promoted viability and proliferation, and inhibited LP cells apoptosis. We further revealed that OGFOD1 was directly targeted by miR-1224-5p, which was significantly down-regulated in LP. Overexpression of the miR-1224-5p suppressed OGFOD1-induced cell proliferation and viability, and promoted apoptosis of LP. In accordance, knockdown of miR-1224-5p inversed the inhibitory effects. In confederation of the central involvement of OGFOD1 in LP progression, targeting the miR-1224-5p/OGFOD1 pathway might provide a novel strategy for LP treatment.

lncRNA-NKILA/NF-κB feedback loop modulates laryngeal cancer cell proliferation, invasion, and radioresistance.

Laryngeal cancer is one of the most common head and neck malignant tumors and is commonly resistant to X-ray-based radiotherapy. NF-κB interacting lncRNA (NKILA) has been reported to serve as a tumor suppressor in several cancers through combining with NF-κB: IκB complex thereby inhibiting NF-κB activation. Herein, we demonstrated a low NKILA expression in laryngeal cancer and its correlation with shorter overall survival in patients with laryngeal cancer. NKILA serves as a tumor suppressor in laryngeal cancer by suppressing laryngeal cancer cell viability and migration, whereas promoting cell apoptosis; NKILA knockdown reverses the cytotoxicity of X-ray radiation on laryngeal cancer cells through combining with NF-κB: IκB complex to inhibit IκB phosphorylation, inhibit p65 nuclear translocation, and finally inhibit NF-κB activation. NF-κB binds to the promoter region of NKILA to activate its transcriptional activity, upregulated NKILA then inhibits IκB phosphorylation and NF-κB activation, thus forming a negative feedback loop to sensitize laryngeal cancer cell to X-ray radiation. In conclusion, NKILA can serve as a promising agent of enhancing the cytotoxicity of X-ray radiation on laryngeal cancer and addressing the radioresistance of laryngeal cancer.

Reconstruction of human oncological tracheal defects with xenogenic acellular dermal matrix.

OBJECTIVE: This study aimed to explore the effectiveness of xenogenic acellular dermal matrix (xeno-ADM) in tracheal reconstruction. METHOD: Two patients were treated with this surgical method to reconstruct the trachea in 2013. The patients were diagnosed with tracheal adenoid cystic carcinoma by histopathological biopsy. The tumor was resected with half of the tracheal circumference and repaired by xeno-ADM. The patients were followed up for 31 and 33 months, respectively. RESULT: No infection or tracheal fistula was observed. The grafts were clear. Both patients were successfully decannulated without dyspnea and could breathe and speak without prosthesis. The cervical mobility was not impaired. CONCLUSION: Xeno-ADM was successfully used to reconstruct a stable and well-functioning trachea. This surgical method is simple, safe, and effective with fewer complications.

Embelin prevents LMP1-induced TRAIL resistance via inhibition of XIAP in nasopharyngeal carcinoma cells.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in the majority of tumor cells, whilst sparing normal cells. However, the potential use of TRAIL in the treatment of cancer is limited by the inevitable emergence of drug resistance. The present study reports the upregulation of latent membrane protein 1 (LMP1)-induced TRAIL resistance via the enhanced expression of X-linked inhibitor of apoptosis protein (XIAP) in nasopharyngeal carcinoma (NPC) cells. LMP1-positive NPC cells were indicated to be more sensitive to TRAIL compared with LMP1-negative NPC cells in three NPC cell lines. CNE-1 is a LMP1-negative NPC cell line that was transfected with pGL6-LMP1; following which, sensitivity to TRAIL decreased. LMP1-induced TRAIL resistance was associated with the decreased cleavage of caspase-8,-3 and -9, BH3 interacting domain death agonist (Bid) and mitochondrial depolarization, without any effects on the expression of the death receptors, B-cell lymphoma (Bcl)-2 and Bcl-extra long. Knockdown of XIAP with small interfering RNA increased caspase-3 and -9 and Bid cleavage, and prevented LMP1-induced TRAIL resistance. Furthermore, embelin, the inhibitor of XIAP, prevented LMP1-induced TRAIL resistance in the Epstein-Barr virus (EBV)-positive CNE-1-LMP1 and C666-1 NPC cell lines. However, embelin did not enhance TRAIL-induced apoptosis in NP-69, which was used as a benign nasopharyngeal epithelial cell line. These data show that LMP1 inhibits TRAIL-mediated apoptosis by upregulation of XIAP. Embelin may be used in an efficacious and safe manner to prevent LMP1-induced TRAIL resistance. The present study may have implications for the development and validation of novel strategies to prevent TRAIL resistance in EBV-positive NPC.

Pharyngoesophageal perforation 3 years after anterior cervical spine surgery: a rare case report and literature review.

Pharyngoesophageal perforation after anterior cervical spine surgery is rare and the delayed cases were more rarely reported but potentially life-threatening. We report a case of pharyngoesophageal perforation 3 years after anterior cervical spine surgery. The patient presented with dysphagia, fever, left cervical mass and developing dyspnea 3 years after cervical spine surgery for trauma. After careful examinations, he underwent an emergency tracheostomy, neck exploration, hardware removal, abscess drainage and infected tissue debridement. 14 days after surgery, CT of the neck with oral contrast demonstrated no contrast extravasation from the esophagus. Upon review of literature, only 14 cases of pharyngoesophageal perforation more than 1 year after anterior cervical spine surgery were found. We discussed possible etiology, diagnosis and management and concluded that in cases of dysphagia, dyspnea, cervical pain, swelling and edema of the cervical area even long time after anterior cervical spine surgery, potential pharyngoesophageal damage should be considered.

Xenogeneic acellular dermal matrix in combination with pectoralis major myocutaneous flap reconstructs hypopharynx and cervical esophagus.

The aim of this study was to explore xenogeneic acellular dermal matrix (ADM) in combination with pectoralis major myocutaneous flap in hypopharynx and cervical esophagus reconstruction. A total of five patients were treated with this surgical method to reconstruct hypopharynx and cervical esophagus in Second Xiangya Hospital between January 2012 and April 2013. Four of them had hypopharyngeal carcinoma with laryngeal and cervical esophageal invasion, while the fifth patient with hypopharyngeal cancer had developed scars and atresia after postoperative radiotherapy. The defect length after hypopharyngeal and cervical esophageal resection was 6-8 cm, and was repaired by a combination of ADM and pectoralis major myocutaneous flap by our team. Interestingly, the four patients had primary healing and regained their eating function about 2-3 weeks after surgery, the fifth individual suffered from pharyngeal fistula, but recovered after dressing change about 2 months. Postoperative esophageal barium meals revealed that the pharynx and esophagus were unobstructed in all five patients. Xenogeneic ADM in combination with pectoralis major myocutaneous flap for hypopharynx and cervical esophagus reconstruction is a simple, safe and effective method with fewer complications. Nevertheless, according to the defect length of the cervical esophagus, the patients need to strictly follow the medical advice.