Plunging Ranula Presenting as a Giant Anterior Cervical Cystic Mass: A Case Report and Literature Review.

Plunging ranula, a subtype of ranula, commonly presents as a submandibular or submental cystic mass without oral counterpart, and its clinical management remains challenging. Herein, the authors report an extremely rare case of 30-year-old female patient with plunging ranula involving the root of the left anterior neck.

Tailoring biomaterials and applications targeting tumor-associated macrophages in cancers.

Tumor-associated macrophages (TAMs) play a critical role in supporting tumor growth and metastasis, taming host immunosurveillance, and augmenting therapeutic resistance. As the current treatment paradigms for cancers are generally insufficient to exterminate cancer cells, anti-cancer therapeutic strategies targeting TAMs have been developed. Since TAMs are highly heterogeneous and the pro-tumoral functions are mediated by phenotypes with canonical surface markers, TAM-associated materials exert anti-tumor functions by either inhibiting polarization to the pro-tumoral phenotype or decreasing the abundance of TAMs. Furthermore, TAMs in association with the immunosuppressive tumor microenvironment (TME) and tumor immunity have been extensively exploited in mounting evidence, and could act as carriers or accessory cells of anti-tumor biomaterials. Recently, a variety of TAM-based materials with the capacity to target and eliminate cancer cells have been increasingly developed for basic research and clinical practice. As various TAM-based biomaterials, including antibodies, nanoparticles, RNAs, etc., have been shown to have potential anti-tumor effects reversing the TME, in this review, we systematically summarize the current studies to fully interpret the specific properties and various effects of TAM-related biomaterials, highlighting the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-cancer therapy.

TGF-ßRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-ß signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-ßRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-ßRII in CAFs glucose metabolism and suggests that targeting TGF-ßRII in CAFs might represent a therapeutic approach for oral cancer.

Glycolysis reprogramming in cancer-associated fibroblasts promotes the growth of oral cancer through the lncRNA H19/miR-675-5p/PFKFB3 signaling pathway.

As an important component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) secrete energy metabolites to supply energy for tumor progression. Abnormal regulation of long noncoding RNAs (lncRNAs) is thought to contribute to glucose metabolism, but the role of lncRNAs in glycolysis in oral CAFs has not been systematically examined. In the present study, by using RNA sequencing and bioinformatics analysis, we analyzed the lncRNA/mRNA profiles of normal fibroblasts (NFs) derived from normal tissues and CAFs derived from patients with oral squamous cell carcinoma (OSCC). LncRNA H19 was identified as a key lncRNA in oral CAFs and was synchronously upregulated in both oral cancer cell lines and CAFs. Using small interfering RNA (siRNA) strategies, we determined that lncRNA H19 knockdown affected proliferation, migration, and glycolysis in oral CAFs. We found that knockdown of lncRNA H19 by siRNA suppressed the MAPK signaling pathway, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and miR-675-5p. Furthermore, the lncRNA H19/miR-675-5p/PFKFB3 axis was involved in promoting the glycolysis pathway in oral CAFs, as demonstrated by a luciferase reporter system assay and treatment with a miRNA-specific inhibitor. Our study presents a new way to understand glucose metabolism in oral CAFs, theoretically providing a novel biomarker for OSCC molecular diagnosis and a new target for antitumor therapy.

A personalized computational model predicts cancer risk level of oral potentially malignant disorders and its web application for promotion of non-invasive screening.

BACKGROUND: Despite their high accuracy to recognize oral potentially malignant disorders (OPMDs) with cancer risk, non-invasive oral assays are poor in discerning whether the risk is high or low. However, it is critical to identify the risk levels, since high-risk patients need active intervention, while low-risk ones simply need to be follow-up. This study aimed at developing a personalized computational model to predict cancer risk level of OPMDs and explore its potential web application in OPMDs screening. METHODS: Each enrolled patient was subjected to the following procedure: personal information collection, non-invasive oral examination, oral tissue biopsy and histopathological analysis, treatment, and follow-up. Patients were randomly divided into a training set (N = 159) and a test set (N = 107). Random forest was used to establish classification models. A baseline model (model-B) and a personalized model (model-P) were created. The former used the non-invasive scores only, while the latter was incremented with appropriate personal features. RESULTS: We compared the respective performance of cancer risk level prediction by model-B, model-P, and clinical experts. Our data suggested that all three have a similar level of specificity around 90%. In contrast, the sensitivity of model-P is beyond 80% and superior to the other two. The improvement of sensitivity by model-P reduced the misclassification of high-risk patients as low-risk ones. We deployed model-P in web.opmd-risk.com, which can be freely and conveniently accessed. CONCLUSION: We have proposed a novel machine-learning model for precise and cost-effective OPMDs screening, which integrates clinical examinations, machine learning, and information technology.

Effects of TGF-β1 on the migration of oral cancer-associated fibroblasts in two and three dimensional co-culture models / 口腔疾病防治

Objective@#To observe the effect of transforming growth factor-β1 (TGF-β1) on the migration of oral carcinoma associated fibroblasts (CAFs) with two-dimensional culture model and three-dimensional model.@*Methods @# Under two-dimensional culture conditions, CAFs stimulated by TGF-β1 with the addition of 10 ng/mL medium were used as the experimental group, and untreated CAFs were used as the control group. The migration of CAFs with the stimulation of TGF-β1 was measured by cell scratch assay and transwell assay. CAFs positive for green fluorescent protein (GFP) were cultured by retrovirus transfection. Human tongue squamous cell carcinoma cells SCC25, GFP(+) CAFs and CAFs with three-dimensional cell co-culture models were established. The three-dimensional model cultured under the stimulation of TGF-β1 with 10 ng/mL medium was used as the experimental group, and the three-dimensional model without TGF-β1 was used as the control group. The migration of CAFs with the stimulation of TGF-β1 was also measured by the three-dimensional models.@*Results@# It was verified that 10 ng/mL TGF-β1 promoted the migration of CAFs in the two-dimensional culture model. The three-dimensional co-culture models of SCC25, GFP(+) CAFs and CAFs were successfully established. The migration of SCC25 and CAFs was detected in the three-dimensional model. However, 10 ng/mL TGF-β1 had little effect on their migration.@*Conclusion@#The effect of TGF-β1 in vitro on the migration of oral CAFs was associated with different culture models in two and three dimensions.

FEN1 expression in oral carcinoma-associated fibroblasts and its relationship with PCNA / 口腔疾病防治

Objective@#To research the expression levels of FEN1 and PCNA in carcinoma-associated fibroblasts (CAFs) and analyze their correlation. @*Methods@#Fresh specimens of oral squamous cell carcinoma tissues and normal oral mucosal tissues excised during oral and maxillofacial plastic surgery were collected. Primary oral CAFs and normal fibroblasts (NFs) were obtained by tissue culture, identified by immunocytochemistry and divided into the CAF and NF groups. Western blot and quantitative real-time PCR were used to detect the protein and mRNA expression levels of both FEN1 and PCNA in the oral CAFs and NFs. The correlation between FEN1 and PCNA expression in oral CAFs was analyzed. @*Results@#Oral CAFs and oral NFs were successfully cultured and identified from 12 samples. Both the protein and mRNA expression levels of FEN1 and PCNA were higher in the oral CAFs than NFs, but there were no significant differences (P > 0.05). In the oral CAFs, the linear correlation coefficient between FEN1 and PCNA was 0.677 (P = 0.016) at the mRNA level, indicating a strong positive correlation; however, at the protein level, no correlation was found (P > 0.05). @*Conclusion@# In primary cultured oral CAFs and NFs, there were no significant differences in the FEN1 and PCNA protein and mRNA expression levels. However, in the CAFs, the mRNA levels of FEN1 and PCNA had a strong positive correlation. The relationship and the regulatory mechanism of the two genes require further study.

Reduced CX3CL1 Secretion Contributes to the Susceptibility of Oral Leukoplakia-Associated Fibroblasts to Candida albicans.

Candida leukoplakia (OLK) is a kind of oral leukoplakia combined with chronic candidal infection, which plays an important role in the malignant transformation of OLK. However, little is known about the etiology, including susceptibility of leukoplakia to candidal adhesion, invasion and infection. Some antimicrobial peptides secreted by oral epithelial cells or fibroblasts potentially have antifungal activities against Candida albicans (C. albicans). In this study, we established three co-culture models to simulate different C. albicans-fibroblasts interactions during progression of candida leukoplakia. The susceptibility of oral leukoplakia-associated fibroblasts (LKAFs) to C. albicans and its underlying mechanism were determined. Samples of 14 LKAFs and 10 normal fibroblasts (NFs) were collected. The co-culture models showed that LKAFs had promoted the adhesion, invasion, and survival of C. albicans compared with NFs. CX3CL1, a chemokine with antifungal activity, was less abundant in LKAFs than NFs. Overexpression of CX3CL1 via transfection in LKAFs could partly restore the resistance to C. albicans. We also showed that inhibition of ERK could suppress CX3CL1 secretion. While phosphor-ERK was inhibited in LKAFs compared with NFs. Besides, the mRNA expression of a shedding enzyme for CX3CL1, disintegrin and metalloproteinase domain (ADAM) 17 was decreased in LKAFs than NFs. In conclusion, LKAFs produced and secreted less CX3CL1 by inhibiting the ERK signaling pathway, thereby contributing to impaired cell resistance to C. albicans.

Submandibular gland transfer for the prevention of postradiation xerostomia in patients with head and neck cancer: a systematic review and meta-analysis.

BACKGROUND: Submandibular gland transfer has been widely used to prevent postradiation xerostomia in head-and-neck cancers. However, there are still some controversies. METHODS: Six databases were searched, data extraction was performed and the risk of bias was assessed by 2 reviewers independently. The meta-analysis was performed using Review Manager, version 5.2. RESULTS: A total of 7 trials (12 articles) and 369 participants were included. CONCLUSIONS: The present clinical evidence suggests that submandibular gland transfer might be highly effective to prevent postradiation xerostomia in head-and-neck cancers without serious adverse events. However, more randomized controlled trials are still needed to confirm this conclusion.

Interventions for the treatment of Frey's syndrome.

BACKGROUND: Frey's syndrome is a rare disorder, the symptoms of which include sweating, flushing and warming over the preauricular and temporal areas following a gustatory stimulus. It often occurs in patients who have undergone parotidectomy, submandibular gland surgery, radical neck dissection, infection and traumatic injury in the parotid region, and is caused by the aberrant regrowth of facial autonomic nerve fibres. Currently there are several options used to treat patients with Frey's syndrome; for example, the topical application of anticholinergics and antiperspirants, and the intradermal injection of botulinum toxin. It is uncertain which treatment is most effective and safe. OBJECTIVES: To assess the efficacy and safety of different interventions for the treatment of Frey's syndrome. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and unpublished trials. The date of the search was 28 April 2014. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials (RCTs) in participants diagnosed with Frey's syndrome using a clinical standard such as Minor's starch-iodine test. We planned to include trials in which participants received any intervention versus no treatment (observation) or an alternative intervention, with or without a second active treatment. Our primary outcome measures were success rate (as assessed clinically by Minor's starch-iodine test, the iodine-sublimated paper histogram method, blotting paper technique or another method) and adverse events. Our secondary outcome measure was success rate as assessed by patients (disappearance or improvement of symptoms). DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified no RCTs or quasi-RCTs that fulfilled the inclusion criteria. Our searches retrieved eight potentially relevant studies, but after assessment of the full-text reports we excluded all of them due to the absence of randomisation or because the patients did not have Frey's syndrome. We excluded one randomised controlled trial that compared two different doses of botulinum toxin in patients with Frey's syndrome because the comparator was not an alternative treatment. AUTHORS' CONCLUSIONS: We are unable to establish the efficacy and safety of the different methods used for the treatment of Frey's syndrome.RCTs are urgently needed to assess the effectiveness of interventions for the treatment of Frey's syndrome. Future RCTs should include patients with Frey's syndrome of different ranges of severity and report these patients separately. Studies should investigate all possibly effective treatments (such as anticholinergics, antiperspirants and botulinum toxin) compared to control groups using different treatments or placebo. Subjective assessment of Frey's syndrome should be considered as one of the outcome measures.

[Closed suction drainage to prevent postoperative complications after parotidectomy: a systematic review].

PURPOSE: To evaluate the efficacy and safety of closed suction drainage for prevention of postoperative complications after parotidectomy. METHODS: Pubmed, Cochrane Controlled Trials Register, Embase, Open Sigle, CBM, VIP and Wanfang database were searched electronically from the date of their establishment to May 10,2013. Hand-searching covering 19 relevant Chinese journals were also performed, and the literature of randomized controlled trials comparing closed suction drainage and open drainage for prevention of postoperative complications after parotidectomy were included. Risk of bias assessment, which was suggested by Cochrane handbook for systematic reviewers of intervention review, and data extraction of included studies were delivered by two reviewers in duplicate; and meta analysis was performed with Revman 5.2 software. RESULTS: Ten randomized controlled trials were included. All studies had unclear risk of bias. When compared with open drainage, closed suction drainage showed a significant advantage on reducing postoperative complications (salivary fistula/effusion, edema) after parotidectomy; it also improved clinical comprehensive effect and patients' quality of life (P<0.05). CONCLUSIONS: To a certain extent, closed suction drainage has better efficacy and safety than controls in preventing postoperative complications after parotidectomy. However, as the quality of some included studies is limited, more randomized controlled trials are needed to reinforce the conclusion.

A systems biology approach identifies effective tumor-stroma common targets for oral squamous cell carcinoma.

The complex interactions between cancer cells and their surrounding stromal microenvironment play important roles in tumor initiation and progression and represent viable targets for therapeutic intervention. Here, we propose a concept of common target perturbation (CTP). CTP acts simultaneously on the same target in both the tumor and its stroma that generates a bilateral disruption for potentially improved cancer therapy. To employ this concept, we designed a systems biology strategy by combining experiment and computation to identify potential common target. Through progressive cycles of identification, TGF-ß receptor III (TßRIII) is found as an epithelial-mesenchymal common target in oral squamous cell carcinoma. Simultaneous perturbation of TßRIII in the oral cancerous epithelial cells and their adjacent carcinoma-associated fibroblasts effectively inhibits tumor growth in vivo, and shows superiority to the unilateral perturbation of TßRIII in either cell type alone. This study indicates the strong potential to identify therapeutic targets by considering cancer cells and their adjacent stroma simultaneously. The CTP concept combined with our common target discovery strategy provides a framework for future targeted cancer combinatorial therapies.

[The anesthetic effects of Gow-Gates technique of inferior alveolar nerve block in impacted mandibular third molar extraction].

OBJECTIVE: To evaluate the anesthetic effects and safety of Gow-Gates technique of inferior alveolar nerve block in impacted mandibular third molar extraction. METHODS: A split-mouth study was designed. The bilateral impacted mandibular third molar of 32 participants were divided into Gow-Gates technique of inferior alveolar nerve block (Gow-Gates group) and conventional technique of inferior alveolar nerve block (conventional group) randomly with third molar extracted. The anesthetic effects and adverse events were recorded. RESULTS: All the participants completed the research. The anesthetic success rate was 96.9% in Gow-Gates group and 90.6% in conventional group with no statistical difference ( P= 0.317); but when comparing the anesthesia grade, Gow-Gates group had a 96.9% of grade A and B, and conventional group had a rate of 78.1% (P = 0.034). And the Gow-Gates group had a much lower withdrawn bleeding than conventional group (P = 0.025). Two groups had no hematoma. CONCLUSION: Gow-Gates technique had a reliable anesthesia effects and safety in impacted mandibular third molar extraction and could be chosen as a candidate for the conventional inferior alveolar nerve block.

Management of multicentric myopericytoma in the maxillofacial region: a case report.

Myopericytoma (MPC) is a rare kind of benign neoplasm, showing derivation from perivascular myoid cells. About 115 cases have been reported in the English literature; however, most of the literature focuses on the description and classification of pathology. The case presented here is that of a 42-year-old woman with a surgical management experience of multicentric MPC in the maxillofacial region. Although small MPC can be completely and easily excised, large MPC, especially in certain anatomic sites, necessitates careful preoperative preparation.

[Alcohol withdrawal syndrome associated with oral cancer operation: a case report].

Alcohol withdrawal syndrome (AWS) is a rare complication associated with oral cancer operation. This article reported a case of AWS after resection of squamous cell cancer of the right floor of mouth combined with radical neck dissection and trapezius myocutaneous flap reconstruction. The discussion included diagnosis, treatment and prevention of AWS.

Downregulation of TGF-beta receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts.

BACKGROUND: The purpose of this study was to assess the expression levels for TßRI, TßRII, and TßRIII in epithelial layers of oral premalignant lesions (oral leukoplakia, OLK) and oral squamous cell carcinoma (OSCC), as well as in oral carcinoma-associated fibroblasts (CAFs), with the final goal of exploring the roles of various types of TßRs in carcinogenesis of oral mucosa. METHODS: Normal oral tissues, OLK, and OSCC were obtained from 138 previously untreated patients. Seven primary human oral CAF lines and six primary normal fibroblast (NF) lines were established successfully via cell culture. The three receptors were detected using immunohistochemical (IHC), quantitative RT-PCR, and Western blot approaches. RESULTS: IHC signals for TßRII and TßRIII in the epithelial layer decreased in tissue samples with increasing disease aggressiveness (P < 0.05); no expression differences were observed for TßRI, in OLK and OSCC (P > 0.05); and TßRII and TßRIII were significantly downregulated in CAFs compared with NFs, at the mRNA and protein levels (P < 0.05). Exogenous expression of TGF-ß1 led to a remarkable decrease in the expression of TßRII and TßRIII in CAFs (P < 0.05). CONCLUSION: This study provides the first evidence that the loss of TßRII and TßRIII expression in oral epithelium and stroma is a common event in OSCC. The restoration of the expression of TßRII and TßRIII in oral cancerous tissues may represent a novel strategy for the treatment of oral carcinoma.

Carcinoma-associated fibroblasts promotes the proliferation of a lingual carcinoma cell line by secreting keratinocyte growth factor.

Carcinoma-associated fibroblasts (CAFs) have been confirmed to play an important role in the occurrence and development of many kinds of tumors. Regarding proliferation as one manifestation of malignance, the objective was to observe the effects of oral CAFs on the proliferation of oral squamous carcinoma cells (OSCC) and to explore the role of keratinocyte growth factor (KGF) in this process. The results showed that oral CAFs secreted a higher level of KGF than oral normal fibroblasts (NFs), and the conditioned medium of CAFs could increase the viability of carcinoma cells and promote more of them into G2 and S phase. However, after blocking with KGF antibody, the viability and cell cycle of Tca8113 cultured with CAFs conditioned medium changed to be similar with NFs control groups. It was concluded that CAFs could promote the proliferation of OSCC through secreting high levels of KGF. These findings support the use of carcinoma-associated fibroblasts as a novel target in anticancer therapy.

Derived vascular endothelial cells induced by mucoepidermoid carcinoma cells: 3-dimensional collagen matrix model.

Mucoepidermoid carcinoma undergoes uniquely vigorous angiogenic and neovascularization processes, possibly due to proliferation of vascular endothelial cells (ECs) induced by mucoepidermoid carcinoma cells (MCCs) in their three-dimensional (3D) microenvironment. To date, no studies have dealt with tumor cells and vascular ECs from the same origin of mucoepidermoid carcinoma using the in vitro 3D microenvironment model. In this context, the current research aims to observe neovascularization with mucoepidermoid carcinoma microvascular ECs (MCMECs) conditioned by the microenvironment in the 3D collagen matrix model. We observed the growth of MCMECs purified by immunomagnetic beads and induced by MCCs, and characteristics of tubule-like structures (TLSs) formed by induced MCMECs or non-induced MCMECs. The assessment parameters involved the growth curve, the length, the outer and inner diameters, and the wall thickness of the TLSs, and the cell cycle. Results showed that MCCs induced formation of the TLSs in the 3D collagen matrix model. A statistically significant difference was noted regarding the count of TLSs between the control group and the induction group on the 4th day of culture (t=5.00, P=0.001). The outer and inner diameters (t(1)=5.549, P(1)=0.000; t(2)=10.663, P(2)=0.000) and lengths (t=18.035, P=0.000) of the TLSs in the induction group were statistically significant larger than those in the control group. The TLSs were formed at the earlier time in the induction group compared with the control group. It is concluded that MCCs promote growth and migration of MCMECs, and formation of the TLSs. The 3D collagen matrix model with MCMECs induced by MCCs in the current research may be a favorable choice for research on pro-angiogenic factors in progression of mucoepidermoid carcinoma.

[Expression and significance of basic fibroblast growth factor and transforming growth factor-beta 1 in mucoepidermoid carcinoma with different malignant degree].

OBJECTIVE: To study the expression and significance of basic fibroblast growth factor(bFGF)and transforming growth factor-beta 1 (TGF-beta1) in mucoepidermoid carcinomas with different malignant degree. METHODS: Using immunohistochemistry (IHC) staining technique, bFGF and TGF-beta1 proteins in the mucoepidermoid carcinoma tissues with different malignant degree, including well-differentiated, moderately differentiated and poorly differentiated mucoepidermoid carcinoma, and normal salivary gland tissue were detected. RESULTS: The positive rate of bFGF and TGF-beta1 in normal salivary glands were apparently lower than those in malignant mucoepidermoid carcinomas (P<0.05). The positive rate of bFGF in moderately and poorly differentiated mucoepidermoid carcinoma was higher than that in the well-differentiated carcinoma (P <0.05). However, the positive expression of bFGF showed no relationship between the moderately and poorly differentiated mucoepidermoid carcinomas. The positive rate of TGF-beta1 in moderately and poorly differentiated mucoepidermoid carcinomas was lower than that in the well-differentiated carcinoma (P<0.05). The positive expression of TGF-beta1 showed no relationship between the moderately and poorly differentiated mucoepidermoid carcinomas. The expression of bFGF and TGF-beta1 showed negative correlation (r=- 0.471, P=0.0003). CONCLUSION: The expression of TGF-beta1 may inhibit the development of the mucoepidermoid carcinoma, contrariwise, the expression of bFGF may prompt the development of the mucoepidermoid carcinoma. The expression of bFGF and TGF-beta1 has a negative correlation.