Mitochondrial outer membrane protein MTUS1/ATIP1 exerts antitumor effects through ROS-induced mitochondrial pyroptosis in head and neck squamous cell carcinoma.

We showed that microtubule-associated tumor suppressor gene (MTUS1/ATIP) downregulation correlated with poor survival in head and neck squamous cell carcinoma (HNSCC) patients and that MTUS1/ATIP1 was the most abundant isoform in HNSCC tissue. However, the location and function of MTUS1/ATIP1 have remain unclear. In this study, we confirmed that MTUS1/ATIP1 inhibited proliferation, growth and metastasis in HNSCC in cell- and patient-derived xenograft models in vitro and in vivo. MTUS1/ATIP1 localized in the outer mitochondrial membrane, influence the morphology, movement and metabolism of mitochondria and stimulated oxidative stress in HNSCC cells by directly interacting with MFN2. MTUS1/ATIP1 activated ROS, recruiting Bax to mitochondria, facilitating cytochrome c release to the cytosol to activate caspase-3, and inducing GSDME-dependent pyroptotic death in HNSCC cells. Our findings showed that MTUS1/ATIP1 localized in the outer mitochondrial membrane in HNSCC cells and mediated anticancer effects through ROS-induced pyroptosis, which may provide a novel therapeutic strategy for HNSCC treatment.

Application of delayed extubation for the free-flap reconstruction of oral and maxillofacial defects in patient with oral diseases.

Tracheostomy and delayed extubation (DE) are two methods for managing patients' airways postoperatively after oral and maxillofacial free flap transplantation. We aimed to determine the safety of both the tracheostomy and DE by conducting a retrospective study in patients undergoing oral and maxillofacial free-flap transfer from September, 2017 to September, 2022. The primary outcome was incidence of postoperative complication. Secondary outcome was measured as factors leading to perioperative performance of airway management. Ninety-five of 148 patients received delayed extubation perioperatively. In comparison to the tracheostomy group, the DE group had fewer overall postoperative complications (p = 0.028). During the postoperative period, fewer patients from the DE group required a return to the operating room, in comparison to those from the tracheostomy group (p = 0.045). The duration of surgery (p = 0.006), time in ICU (p = 0.015), duration of artificial nutrition (p < 0.001), duration of hospitalization (p < 0.001) in the DE group were all significantly shorter when compared with the tracheostomy group. In conclusion, when used in appropriate cases of oral and maxillofacial free flap transplantation patients, delayed extubation can be a safe and effective alternative to tracheostomy.

Ischemia-reperfusion injury of free tissue flaps, airway management, and prognosis in oral cancer patients / 口腔疾病防治

@#Free tissue flap transplantation is the preferred option for repairing and reconstructing postoperative defects in oral and maxillofacial-head malignant tumors. However, challenges remain for oral and maxillofacial-head and neck oncology surgeons in terms of ischemia-reperfusion (I/R) injury, airway management, quality of life and prognosis. I/R injury is an inevitable complication of free-flap transplantation surgery. In addition to shortening the vascular anastomosis time as much as possible during the surgical process, many studies have attempted to further prevent and treat free-flap I/R injury using physical intervention therapy, antioxidant and reactive oxygen species (ROS) scavenger therapy, hyperbaric oxygen therapy, etc. However, there is a lack of large-scale clinical randomized controlled trial evidence to further support these methods. Postoperative tracheal management of patients receiving free tissue flap transplantation is very important. In recent years, delayed extubation has been proposed as an alternative to traditional tracheostomy. This method can facilitate wound care for patients, reduce infections, speed up patient recovery, and reduce the incidence of vascular crises. In the future, such management is expected to improve the practicality and safety of delayed extubation by formulating more appropriate patient selection criteria and intensive care plans. Preoperative selection of suitable free tissue flaps according to the defect for repair and reconstruction is beneficial for improving the quality of life and survival rate of patients. At the same time, for patients who require postoperative radiotherapy, reducing the complications of postoperative radiotherapy and improving the quality of life of patients can be achieved through intraoperative nerve anastomosis, preradiation oral hygiene maintenance, early speech training, and other methods.

Clinical Prediction Nomograms to Assess Overall Survival and Disease-Specific Survival of Patients with Salivary Gland Adenoid Cystic Carcinoma.

Aim: Salivary gland adenoid cystic carcinoma (SACC) is the second highest incidence of malignant salivary gland tumor. The purpose of this study was to establish nomograms combined with SACC patients based on the Surveillance, Epidemiology, and End Results (SEER) database. Methods: Patients with SACC were included in the SEER∗Stat Database from 2004 to 2016. The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was applied to filter potential prognostic clinical variables. Multivariate analysis from the Cox proportional hazards model was performed to determine the independent prognostic factors on overall survival (OS) and disease-specific survival (DSS), applied to develop nomograms. The Schönfeld residual test verified the proportional hazard assumption. The discrimination and consistency of nomograms was assessed and validated according to concordance index (C-index), receiver operating characteristic (ROC) curves, and calibration curves using an internal 1,000 times bootstrap resampling. The nomogram's net clinical benefit was assessed through decision curve analysis (DCA). Results: A total of 658 patients with SACC were included. Age, T stage, N stage, M stage, histologic grade, and surgery were independent prognostic factors for OS and DSS. Based on these independent prognostic factors, nomograms were developed to predict 3-, 5-, and 10-year OS and DSS. In the validation of 1,000 times bootstrap resampling, the C-index and ROC curves had good discriminatory ability. The calibration curves indicated excellent consistency between the predicted and actual survival results in the nomograms. The DCA curves demonstrated that the nomograms had good clinical benefit and were superior to the TNM stage and other variables. Conclusions: Two nomograms developed in this study precisely predicted the 3-, 5-, and 10-year OS and DSS rates of patients with SACC in accordance with independent prognostic factors, and their clinical value is better than TNM staging, providing a prognostic reference for other SACC patients.

The systemic inflammation response index predicts the survival of patients with clinical T1-2N0 oral squamous cell carcinoma.

OBJECTIVE: The systemic inflammation response index (SIRI) is an independent prognostic factor for many malignant tumors. However, the value of this factor in patients with clinical T1-2N0 (cT1-2N0) oral squamous cell carcinoma (OSCC) is still unclear. METHODS: We calculated SIRI of 235 cT1-2N0 OSCC patients from 2013 to 2017. Multivariate cox regression analysis was applied to verify the prognostic significance of SIRI. Kaplan-Meier curves were plotted to analyze the overall survival (OS) and disease-specific survival (DSS) for cT1-2N0 OSCC patients. RESULTS: According to the optimal cutoff point of SIRI, we divided cT1-2N0 OSCC patients into high SIRI group (SIRI ≥ 1.3) and low SIRI group (SIRI < 1.3). SIRI was an independent prognostic indicator for OS (HR = 2.87; 95% CI = 1.35-6.10; p = .006) and DSS (HR = 2.17; 95% CI = 1.10-4.27; p = .025). High SIRI had a significantly poorer OS (p = .001) and DSS (p = .007) in survival analysis than the low SIRI. Moreover, the prognostic value of SIRI was significantly stronger than neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR). CONCLUSIONS: Preoperative SIRI can be regarded as a meaningful indicator for poor survival of cT1-2N0 OSCC patients, and it is a promising tool to formulate the best individualized treatment for high-risk patients.

N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma.

N6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes and plays an important role in tumorigenesis. However, the underlying mechanism remains largely unclear. Here, we established a cell model of rapamycin-induced autophagy to screen m6A-modifying enzymes. We found that m6A demethylase fat mass and obesity-associated protein (FTO) plays a key role in regulating autophagy and tumorigenesis by targeting the gene encoding eukaryotic translation initiation factor gamma 1 (eIF4G1) in oral squamous cell carcinoma (OSCC). Knocked down of FTO expression in OSCC cell lines, resulting in downregulation of eIF4G1 along with enhanced autophagic flux and inhibition of tumorigenesis. Rapamycin inhibited FTO activity, and directly targeted eIF4G1 transcripts and mediated their expression in an m6A-dependent manner. Dual-luciferase reporter and mutagenesis assays confirmed that YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) targets eIF4G1. Conclusively, after FTO silencing, YTHDF2 captured eIF4G1 transcripts containing m6A, resulting in mRNA degradation and decreased expression of eIF4G1 protein, thereby promoting autophagy and reducing tumor occurrence. Therefore, rapamycin may regulate m6A levels, determining the autophagic flux of OSCC, thereby affecting the biological characteristics of cancer cells. This insight expands our understanding of the crosstalk between autophagy and RNA methylation in tumorigenesis, which is essential for therapeutic strategy development for OSCC.

Impact of lymphovascular invasion in oral squamous cell carcinoma: A meta-analysis.

OBJECTIVE: Lymphovascular invasion (LVI) has been reported as a predictor of prognosis in multiple cancers. The aim of this meta-analysis was to investigate the potential value of LVI as a prognostic predictor of oral squamous cell carcinoma (OSCC). STUDY DESIGN: To identify relevant studies, PubMed, Embase, Web of Science, and Cochrane Library database were searched from inception to October 2020. All studies exploring the association of LVI with overall survival (OS), disease-specific survival (DSS), or disease-free survival (DFS) and lymph node metastasis (LNM) were identified. RESULT: Pooled odds ratios for LNM and hazard ratios for survival were calculated using fixed effects or random effects models. Thirty-six studies involving 17,109 patients with OSCC were included and further analyzed. The results showed that positive LVI was significantly associated with LNM and worse survival in patients with OSCC. Moreover, positive LVI was correlated with LNM in patients with early stage OSCC. CONCLUSIONS: These findings indicate that LVI may serve as a prognostic predictor for the metastasis and prognosis of OSCC and could be considered a routine pathologic examination in clinical work.

Development and Validation of Autophagy-Related Gene Signature and Nomogram for Predicting Survival in Oral Squamous Cell Carcinoma.

BACKGROUND: Autophagy, a highly conserved self-digesting process, has been deeply involved in the development and progression of oral squamous cell carcinoma (OSCC). However, the prognostic value of autophagy-related genes (ARGs) for OSCC still remains unclear. Our study set out to develop a multigene expression signature based on ARGs for individualized prognosis assessment in OSCC patients. METHODS: Based on The Cancer Genome Atlas (TCGA) database, we identified prognosis-related ARGs through univariate COX regression analysis. Then we performed the least absolute shrinkage and selection operator (LASSO) regression analysis to identify an optimal autophagy-related multigene signature with the subsequent validation in testing set, GSE41613 and GSE42743 datasets. RESULTS: We identified 36 prognosis-related ARGs for OSCC. Subsequently, the multigene signature based on 13 prognostic ARGs was constructed and successfully divided OSCC patients into low and high-risk groups with significantly different overall survival in TCGA training set (p < 0.0001). The autophagy signature remained as an independent prognostic factor for OSCC in univariate and multivariate Cox regression analyses. The area under the curve (AUC) values of the receiver operating characteristic (ROC) curves for 1, 3, and 5-year survival were 0.758, 0.810, 0.798, respectively. Then the gene signature was validated in TCGA testing set, GSE41613 and GSE42743 datasets. Moreover, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and single-sample gene set enrichment analysis (ssGSEA) revealed the underlying biological characteristics and signaling pathways associated with this signature in OSCC. Finally, we constructed a nomogram by combining the gene signature with multiple clinical parameters (age, gender, TNM-stage, tobacco, and alcohol history). The concordance index (C-index) and calibration plots demonstrated favorable predictive performance of our nomogram. CONCLUSION: In summary, we identified and verified a 13-ARGs prognostic signature and nomogram, which provide individualized prognosis evaluation and show insight for potential therapeutic targets for OSCC.