Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2.

Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.

The role of blood metabolites in oral cancer: insights from a Mendelian randomization approach.

Aim: This research aimed to explore the causal impact of blood metabolites on oral cancer using a two-sample Mendelian randomization (MR) analysis. The study endeavored to identify potential biomarkers for oral cancer's clinical management. Materials and methods: Based on the large individual-level datasets from UK Biobank as well as GWAS summary datasets, we first constructed genetic risk scores (GRSs) of 486 human blood metabolites and evaluated the effect on oral cancer. Various statistical methods, including inverse variance weighted (IVW), MR-Egger, and weighted median, among others, were employed to analyze the potential causal relationship between blood metabolites and oral cancer. The sensitivity analyses were conducted using Cochran's Q tests, funnel plots, leave-one-out analyses, and MR-Egger intercept tests. Results: 29 metabolites met the stringent selection criteria. Out of these, 14 metabolites demonstrated a positive association with oral cancer risk, while 15 metabolites indicated a protective effect against oral cancer. The IVW-derived estimates were significant, and the results were consistent across different statistical methodologies. Both the Cochran Q test and the MR-Egger intercept test indicated no heterogeneity and pleiotropy. Conclusion: This MR study offers evidence of the role specific blood metabolites play in oral cancer, pinpointing several with potential risk or protective effects. These findings could be helpful for new diagnostic tools and treatments for oral cancer. While the results are promising, additional research is necessary to fully validate and refine these conclusions. This study serves as a foundational step towards more comprehensive understandings in the future.

Macrophages-bone marrow mesenchymal stem cells crosstalk in bone healing.

Bone healing is associated with many orthopedic conditions, including fractures and osteonecrosis, arthritis, metabolic bone disease, tumors and periprosthetic particle-associated osteolysis. How to effectively promote bone healing has become a keen topic for researchers. The role of macrophages and bone marrow mesenchymal stem cells (BMSCs) in bone healing has gradually come to light with the development of the concept of osteoimmunity. Their interaction regulates the balance between inflammation and regeneration, and when the inflammatory response is over-excited, attenuated, or disturbed, it results in the failure of bone healing. Therefore, an in-depth understanding of the function of macrophages and bone marrow mesenchymal stem cells in bone regeneration and the relationship between the two could provide new directions to promote bone healing. This paper reviews the role of macrophages and bone marrow mesenchymal stem cells in bone healing and the mechanism and significance of their interaction. Several new therapeutic ideas for regulating the inflammatory response in bone healing by targeting macrophages and bone marrow mesenchymal stem cells crosstalk are also discussed.

The role of tumor-associated macrophages in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a common head and neck cancer with a high recurrence rate and a low 5-year survival rate. Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment, which play an important role in the progression of many tumors. This article reviews the origin, and the role of TAMs in the invasion, metastasis, angiogenesis and immunosuppression of OSCC. Therapeutic strategies targeting TAMs are also discussed in hopes of providing new ideas for the treatment of OSCC.

Lipopolysaccharide-activated macrophages regulate the osteogenic differentiation of bone marrow mesenchymal stem cells through exosomes.

Background: Periodontal tissue regeneration is the ultimate goal of periodontitis treatment. Exosomes are nanoscale vesicles secreted by cells that participate in and regulate the physiological activities between cells. However, the relationship between inflammatory macrophage-derived exosomes and osteoblast differentiation in periodontitis has not been thoroughly reported. Here, we attempt to explore the role of inflammatory macrophage-derived exosomes in crosstalk with osteoblasts. Methods: Porphyromonas gingivalis lipopolysaccharide was used to stimulate macrophages and inflate their inflammatory cellular state. Exosomes were extracted from inflammatory macrophages using supercentrifugation, and their characteristics were detected by transmission electron microscopy, particle size analysis, and Western blotting. Exosome uptake bybone marrow mesenchymal stem cells (BMSCs) was observed by fluorescence microscopy. The effects of exosomes on the BMSC inflammatory response and on osteogenic differentiation were detected by quantitative polymerase chain reaction and Western blot analysis. Alkaline phosphatase activity was tested for verification. Results: We successfully extracted and identified inflammatory macrophage-derived exosomes and observed that BMSCs successfully took up exosomes. Inflammatory macrophage-derived exosomes upregulated the expression levels of the inflammatory factors interleukin-6 and tumour necrosis factor-alpha in BMSCs and mediated inflammatory stimulation. Additionally, they inhibited the transcription levels of the osteogenic genes alkaline phosphatase, type I collagen, and Runt-related transcription factor 2 as well as the alkaline phosphatase activity, while the use of the exosome inhibitor GW4869 attenuated this effect. Conclusion: Our study shows that macrophages in periodontitis can mediate inflammatory stimulation and inhibit the osteogenic differentiation of bone marrow mesenchymal stem cells through the exosome pathway. Interference with exosome secretion is likely to be a promising method for bone tissue regeneration in inflammatory states.

Unplanned Reoperations in Oral and Maxillofacial Surgery.

PURPOSE: The purpose of this study was to determine the incidence of and reasons for unplanned reoperations in oral and maxillofacial surgery. MATERIALS AND METHODS: During a 4-year period, a total of 169 patients undergoing reoperations were encountered. The clinical characteristics and causes were reviewed. RESULTS: There were 11,151 patients who underwent surgery, and the incidence of unplanned reoperations was 1.52%. The male-to-female ratio was 2.45:1. The average age in this cohort was 51.5 years. Among the common causes of an unplanned return to the operating room, the most common were reoperations performed for postoperative bleeding, diagnostic issues, and vascular crisis (32.54%, 28.40%, and 29.59%, respectively). CONCLUSIONS: The unplanned reoperation rate was 1.52%. The main causes were postoperative bleeding, diagnostic issues, and vascular crisis. Patients with malignant tumors or microvascular flaps were more likely to undergo unplanned reoperations. Improving perioperative management and diagnostic capability might reduce the incidence of unplanned reoperations.

Salivary duct carcinoma: A clinopathological report of 11 cases.

The aim of the present study was to summarize the clinicopathological and immunohistochemical characteristics of salivary duct carcinoma (SDC) and to evaluate the currently available treatment modalities. Between 2001 and 2011, 11 patients with SDC were diagnosed and treated at the Affiliated Hospital of Stomatology of Nanjing University (Nanjing, Jiangsu, China). The present study retrospectively reviewed the clinicopathological and immunohistochemical data of these 11 patients and the results indicated that the parotid gland was the most commonly affected site, followed by the submandibular gland and the palate. Furthermore, the mean age of onset was 58.8 years and all cases were treated with surgery, with 72.7% receiving post-operative radiation therapy. The range for the follow-up period was 10-89 months and of the 11 patients investigated, only two succumbed to the disease. In addition, the two-year overall survival rate was 75% according to Kaplan-Meier analysis and the mean overall survival time was 72.8 months. In conclusion, the present study determined that the site of the malignancy is the best predictor of survival in patients with the rare salivary malignancy SDC, while age, gender, T stage, N stage, American Joint Committee on Cancer stage, nerve paralysis, post-operative radiation, neck dissection, and protein expression levels of Ki-67, androgen receptor and human epidermal growth factor-2/neu are less influential factors.

Gelsolin regulates proliferation, apoptosis, migration and invasion in human oral carcinoma cells.

Gelsolin (GSN) is one of the most abundant actin-binding proteins, and is involved in several pathological processes, including Alzheimer's disease, cardiac injury and cancer. The aim of the present study was to assess the effect of GSN on the growth and motility of oral squamous cell carcinoma Tca8113 cells. The overexpression vector pcDNA3.1-GSN was transfected into Tca8113 cells and the stable GSN overexpression cell line was identified based on G418 antibiotic selection. The effect of GSN overexpression on the proliferation, apoptosis, migration and invasion of Tca8113 cells was examined using a cell counting kit-8 assay, flow cytometry and Transwell assays. The results revealed that GSN overexpression significantly promoted the cell proliferation and apoptosis of Tca8113 cells. In addition, Transwell assays demonstrated that the migration and invasion abilities of Tca8113 cells were enhanced by GSN overexpression. Therefore, the upregulation of GSN promotes cell growth and motility, indicating that it may perform a vital function in the progression of human oral cancers.

Lipopolysaccharide enhances OSCC migration by promoting epithelial-mesenchymal transition.

BACKGROUND: This study was performed to examine whether lipopolysaccharide can influence cell migration and epithelial-mesenchymal transition of oral squamous cell carcinoma. METHODS: Three oral squamous cell carcinoma cell lines (HSC3, CAL27, and SCC4) were obtained for the study. TLR4 expression in three cell lines was analyzed by Q-PCR and Western blot. After cells treated with LPS, cell migration was analyzed by wound-healing and chemotaxis cell migration assay. Changes of E-cadherin and vimentin expression were tested by Western blot and immunofluorescence staining. To examine NF-κB activation, NF-κB nuclear translocation was investigated. RESULTS: TLR4 was expressed in all three cell lines and was highest in HSC3 while lowest in SCC4. TLR4 ligand lipopolysaccharide accelerated wound healing and enhanced cell migration. Also, it stimulated epithelial-mesenchymal transition demonstrated by decreased E-cadherin and increased vimentin expression. Lipopolysaccharide also provoked NF-κB nuclear translocation. Either TLR4 or NF-κB blocking reverted these effects. CONCLUSIONS: Lipopolysaccharide can induce TLR4-mediated epithelial-mesenchymal transition and cell migration in oral squamous cell carcinoma. These responses could further affect tumor progressing by inducing tumor cell metastasis.

Upregulation of a potential prognostic biomarker, miR-155, enhances cell proliferation in patients with oral squamous cell carcinoma.

OBJECTIVE: We sought to investigate the role and diagnostic value of microRNA 155 (miR-155) in OSCC patients. STUDY DESIGN: Using real-time quantitative polymerase chain reaction analysis, miR-155 expression levels were assessed in OSCC cell lines and a cancerous HB cell line. The correlation between miR-155 expression level and clinical parameters was analyzed in 46 patients with OSCC. In addition, the effects of miR-155 on OSCC cell proliferation were evaluated by modulating its expression using an miR-155 mimic and antisense miR-155. RESULTS: Significant upregulation of miR-155 was found in OSCC cell lines and in tissues of patients with OSCC. The receiver operator characteristic analysis indicated fair-to-good predictability. Overexpression of miR-155 correlated with the histologic grade (P = .033), and the upregulation of miR-155 enhanced OSCC cell proliferation. CONCLUSIONS: In OSSC, upregulation of miR-155 correlated with the histologic grade and can be used as a potential prognostic biomarker.

Cervical metastases from squamous cell carcinoma of hard palate and maxillary alveolus: a retrospective study of 10 years.

BACKGROUND: The purpose of this study was to investigate the incidence of cervical metastasis in squamous cell carcinoma (SCC) of hard palate and maxillary alveolus and to define its impact factors. METHODS: We conducted a retrospective study of patients surgically treated for SCC of hard palate and maxillary alveolus from 2002 to 2011. In situ hybridization was performed to detect high-risk human papillomavirus (HPV) infection. RESULTS: The incidences of cervical metastasis and occult metastasis were 17.2% (11/64) and 9.8% (5/51), respectively. The pT classification and vascular invasion were correlated with cervical metastasis. Occult metastatic risk was significantly higher among patients with pT4. Presence of positive nodes impaired prognosis significantly. CONCLUSION: SCC of hard palate and maxillary alveolus has nonnegligible incidences of both overall and occult metastasis, which were highly associated with pT classification. We recommend routine, synchronous elective neck dissection for T4 lesions, whereas observation is an alternative for T1 to T3 lesions.

Salivary gland neoplasms in children.

PURPOSE: Salivary gland neoplasms in pediatric population are extremely rare. The aim of the present study was to determine the clinicopathologic characteristics of salivary gland neoplasms in patients younger than 19 years at our institution. METHODS: During a 38-year period, a total of 119 pediatric patients met the diagnosis of epithelial salivary gland neoplasms. Clinicopathologic parameters were reviewed. RESULTS: There were 87 (73.1%) benign and 32 (26.9%) malignant neoplasms. The mean age of pediatric patients was 15.1 years. The male-to-female ratio was 1:1.25. One hundred thirteen cases occurred among patients not younger than 10 years. The highest frequency of epithelial salivary gland neoplasms was pleomorphic adenoma (70.6%). Mucoepidermoid carcinoma (16 cases) was the most common malignant tumor in the salivary gland, occupying 50.0% of the malignancies and 13.4% of all salivary gland neoplasms. CONCLUSIONS: Salivary gland neoplasms in Chinese pediatric patients are rare. There is a female predominance. Most of the tumors occur among patients not younger than 10 years. The most common benign tumor is pleomorphic adenomas, and the most common malignant tumor is mucoepidermoid carcinomas.

Salivary adenocarcinoma, not otherwise specified: a clinicopathological study of 28 cases.

OBJECTIVE: The objective of this study was to summarize the clinicopathologic features of salivary adenocarcinoma, not otherwise specified (ANOS) and to evaluate current treatments. STUDY DESIGN: Between 1992 and 2010, 28 patients with ANOS were diagnosed and treated. Clinical data of demographic features, resection margin, neck dissection status, recurrence, and mortality were reviewed. RESULTS: The parotid had the most frequent incidence of ANOS and the palate was second. The peak onset was between 40 and 60 years. The preferred management modality was surgical intervention in all cases. Neck dissection and postoperative radiotherapy were performed in 67.9% and 64.3%, respectively. The mean survival time was 97 months. The 5- and 10-year overall survival rates were 62.2% and 36.0%, respectively. CONCLUSIONS: The current data demonstrate that T, N, M, and Union for International Cancer Control staging, resection margin, and neck dissection status are the most powerful predictors of survival. Long-term follow-up is required to identify possible late recurrence.

[Comprehensive study on clinic presentation, radiology and pathology of recurrent ameloblastoma].

OBJECTIVE: To study the clinic presentation, radiology, pathology of recurrent ameloblastoma (RAB). METHODS: All RAB cases accepted treatment in School of Stomatology of Nanjing University during 1996.1-2008.3 were retrospected. The clinic presentation, the radiological classification and pathological classification were summarized and analyzed. RESULTS: There were 23 RAB patients during 1996.1-2008.3. 3 patients recurred twice, 20 patients recurred once, and 26 cases were found together. 19 patients were performed conservative surgery while 4 patients were performed radical surgery in the primary treatment; 4 patients were performed conservative surgery and 19 patients were performed radical surgery in the recurrence. The radiological classification included 12 cases multicystic, 6 cases unicystic, and 8 cases extraosseous. The pathological classification included 21 cases follicular ameloblastoma, and 5 cases plexiform ameloblastoma. The multicystic after conservative surgery (11 cases) and extraosseous ameloblastoma after radical treatment (8 cases) were more than others according the radiological classification and treatment. CONCLUSION: Conservative surgery has apparent higher recurrences rate than radical surgery. The follicular ameloblastoma has more aggressive biological behave and is more liable to recurred.

Massive osteolysis of the mandible.

We describe a case of massive osteolysis (MO) of the mandible and review related literature. Massive osteolysis in the craniofacial region is a rare condition characterized by progressive absorption of involved bones leading to craniofacial deformities. Currently, the cause and pathophysiology of MO are unclear, and its management or treatment continues to be based on clinical experiences. In our institution, we treat MO of the mandible with surgery; however, this kind of therapeutic management has been unsuccessful.

A salvage operation for flap compromise following internal jugular venous thrombosis.

The internal jugular vein (IJV) has been described as the optimal recipient vessel in oral and maxillofacial microsurgical rehabilitation and reconstruction. However, few studies have been reported on IJV thrombosis, which could compromise flap survival. In the current study, a case of flap vascular crisis following IJV thrombosis is presented, and salvage operation as a management strategy is discussed. Although rare, surgeons specializing in oral and maxillofacial microsurgical reconstruction should be aware of the possibility of the occurrence of this condition, considering early surgical intervention is critical.

WITHDRAWN: Salvage operations of free tissue transfer following internal jugular venous thrombosis in oral and maxillofacial microsurgical reconstruction.

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Ganglion cyst of the temporomandibular joint.

We describe a case of a ganglion cyst of the temporomandibular joint (TMJ) and review the literature of this rare entity. Because of the rarity of such cysts in the TMJ, an accurate diagnosis is not usually made preoperatively. Treatment is surgical but, if a diagnosis can be made, a period of conservative management is justified.

[Application of titanium mesh and free forearm flap for reconstruction of maxillary defect resulted from tumor resection].

OBJECTIVE: To investigate the application of titanium mesh and free forearm flap for reconstruction of maxillary defect resulted from tumor resection. METHODS: From 2004 to 2008, 19 cases with maxillary tumor underwent tumor resection. The defects were reconstructed immediately with titanium mesh for bony defects and free forearm flap for oral mucosa defects. RESULTS: 16 cases achieved satisfactory functional and cosmetic results. The speech assessment was good without oronasal reflux. The titanium mesh was exposed and infected in 3 cases. Then the meshes were taken out and the defects were covered with the forearm flap to close the oronasal fistula. The midface was slightly depressed with no functional morbidity. CONCLUSIONS: It is simple and practical to reconstruct maxillary defect with titanium mesh and free forearm flap. Both the functional and cosmetic results are satisfactory.