Abstract. Oral verrucous carcinoma (OVC) is a verrucous variant of oral squamous cell carcinoma (OSCC), which accounts for 2-12% of all oral carcinomas with a 5-year survival rate of only approximately 50%. Enormous effort has been dedicated to this cancer, and the past decades have witnessed significant advances in relevant diagnostic and therapeutic approaches. Currently, there exist three challenges from primary sub-fields of research and clinical practice of the cancer, namely multifactorial etiology, complex molecular mechanism, and deficient treatment. This study reviews the existing literature on the cancer, encompassing its etiology, clinical manifestations and pathology, molecular mechanism, diagnosis and differential diagnosis, and treatment. For improved treatment of OVC, multifactorial etiology analysis, incorporation of effective biomarkers for mechanism illustration, and integration of multidisciplinary modalities are expounded, in an attempt to resolve the challenges and to provide a useful guide for future research in the field.

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Several studies have shown coronary artery bypass surgery (CABG) to be beneficial in patients with type 2 diabetes mellitus (T2DM) and multivessel coronary artery diseases. Patients with insulin-treated T2DM (ITDM) are usually patients with poor glycemic control and are expected to suffer more complications compared with patients with non-insulin-treated T2DM (NITDM). However, the adverse clinical outcomes in patients with ITDM and NITDM after CABG are still not very clear. Hence, to solve this issue, we aim to compare the short-and long-term adverse clinical outcomes in a larger number of patients with ITDM and NITDM after CABG, respectively.Randomized controlled trials and observational studies comparing the adverse clinical outcomes such as mortality, major adverse events (MAEs), stroke, myocardial infarction, and repeated revascularization in patients with ITDM and NITDM after CABG have been searched from Medline, EMBASE, Cochrane, and PubMed databases. A short-term follow-up (≤30 days) and a long-term follow-up (≥1 year) were considered. Odds ratio (OR) with 95% confidence interval (CI) was used to express the pooled effect on discontinuous variables and the pooled analyses were performed with RevMan 5.3.Eleven studies involving a total of 64,152 patients with T2DM (23,781 patients with ITDM and 40,371 patients with NITDM) have been included in this meta-analysis. During the short-term follow-up period, patients with ITDM had a significantly higher mortality (OR: 1.47; 95% CI: 1.33–1.61, P < 0.00001) and MAEs (OR: 1.66; 95% CI: 1.48–1.87, P < 0.00001). During the long-term follow-up period, patients with ITDM still had a significantly higher rate of mortality, MAEs, and stroke (OR: 1.23, 95% CI: 1.02–1.49, P = 0.03; OR: 1.50, 95% CI: 1.07–2.12, P = 0.02; OR: 1.39, 95% CI: 1.22–1.59, P < 0.00001, respectively) after CABG. However, our results showed similar repeated revascularization rate between the ITDM and NITDM groups after CABG (OR: 1.31, 95% CI: 0.81–2.12, P = 0.27).According to this study, patients with ITDM had a significantly higher rate of mortality and MAEs compared with patients with NITDM after CABG. Stroke was also significantly higher in patients with ITDM during a long-term follow-up period. However, since the result for the long-term mortality had a higher heterogeneity as compared with the other subgroups, and because a similar revascularization rate was observed between the ITDM and NITDM groups after CABG maybe because of a limited number of patients analyzed, further studies still need to be conducted to completely solve this issue.

Dental tissue-derived mesenchymal stem cells (MSCs) are a reliable cell source for dental tissue regeneration. However, the molecular mechanisms underlying the directed differentiation of MSCs remain unclear; thus, their use is limited. The histone demethylase, lysine (K)-specific demethylase 4B (KDM4B), plays critical roles in the osteogenic commitment of MSCs by up-regulating distal-less homeobox 2 (DLX2) expression. The DLX2 gene is highly expressed in dental tissue-derived MSCs but the roles of DLX2 in osteogenesis are unclear. Here, we investigate DLX2 function in stem cells from apical papilla (SCAPs). We found that, in vitro, DLX2 expression was up-regulated in SCAPs by adding BMP4 and by inducing osteogenesis. The knock-down of DLX2 in SCAPs decreased alkaline phosphatase (ALP) activity and mineralization. DLX2 depletion affected the mRNA expression of ALP, bone sialoprotein (BSP) and osteocalcin (OCN) and inhibited SCAP osteogenic differentiation in vitro. Over-expression of DLX2 enhanced ALP activity, mineralization and the expression of ALP, BSP and OCN in vitro. In addition, transplant experiments in nude mice confirmed that SCAP osteogenesis was triggered when DLX2 was activated. Furthermore, DLX2 expression led to the expression of the key transcription factor, osterix (OSX) but not to the expression of runt-related transcription factor 2 (RUNX2). Taken together, these results indicate that DLX2 is stimulated by BMP signaling and enhances SCAP osteogenic differentiation by up-regulating OSX. Thus, the activation of DLX2 signaling might improve tissue regeneration mediated by MSCs of dental origin. These results provide insight into the mechanism underlying the directed differentiation of MSCs of dental origin.

Lymphocyte infiltrates have been observed in the microenvironment of oral cancer; however, little is known about whether the immune response of the lymphocyte infiltrate affects tumor biology. For a deeper understanding of the role of the infiltratinglymphocytes in oral squamous cell carcinoma (OSCC), we characterized the lymphocyte infiltrate repertoires and defined their features. Immunohistochemistry revealed considerable T and B cell infiltrates and lymphoid follicles with germinal center-like structures within the tumor microenvironment. Flow cytometry demonstrated that populations of antigen-experienced CD41 and CD81 cells were present, as well as an enrichment of regulatory T cells; and T cells expressing programmed death-1 (PD-1) and T cell Ig and mucin protein-3 (Tim-3), indicative of exhaustion, within the tumor microenvironment. Characterization of tumorinfiltrating B cells revealed clear evidence of antigen exposure, in that the cardinal features of an antigen-driven B cell response were present, including somatic mutation, clonal expansion, intraclonal variation and isotype switching. Collectively, our results point to an adaptive immune response occurring within the OSCC microenvironment, which may be sustained by the expression of specific antigens in the tumor.Oral cancer is the sixth most common cancer in the world, most of which is oral squamous cell carcinoma (OSCC), accounting for 3% of all malignancies and increasing by 275,000 new cases per year.1,2 Oral cancer is life-threatening because of its invasion of critical structures responsible for speaking, swallowing, and respiration. 3 The treatment of oral cancer has advanced considerably from surgery to a comprehensive sequential treatment that include surgery in combination with chemoradiotherapy; however, the 5-year survival rate has not significantly improved in recent decades, primarily because of its extreme malignancy, including local metastasis, and high recurrence potential. 3,4 Thus, more substantial efforts have stimulated in developing more effective treatments in order to improve the survival rate. Due to the progress in the field of tumor immunology, immunotherapy emerges as a promising option. 5,6The immune response between host and tumor is extremely complex. The function of immune system is to eliminate alien cells; however within the tumor microenvironment, tumor cells escape the immune surveillance and

There is a great demand for dental implants with the ability to accelerate periimplant bone regeneration. Modification of surface micro- and nanotopographies has been revealed to affect bone cell metabolism. In this study, we utilized dielectric barrier discharge (DBD) technology to modify commercially pure titanium (Ti-tr) surfaces and then investigated the cytocompability of DBD-modified Ti surface when compared with machined (Ti-m) and polished (Ti-p) Ti surfaces. These three kinds of Ti plates exhibited different surface energies and topographies at the micro- and nanoscale levels. The DBD-treated pure Ti surface significantly enhances cell adhesion, spread, and proliferation of MC3T3-E1 preosteoblast cells compared with the Ti-p and Ti-m surfaces, suggesting that Ti-tr has better cytocompatibility compared with the other two surfaces. Preosteoblast cells on Ti-m surface exhibited higher alkaline phosphatase activity than cells on Ti-tr and Ti-p surfaces 14 days after seeding. No significant difference in alkaline phosphatase activity was observed between cells grown on Ti-tr and Ti-p surfaces. Our study demonstrated that DBD modification significantly enhanced cell adhesion, spread, and proliferation of preosteoblasts with no negative effects on cell differentiation. Microtopography and nanotopography of the surfaces of different materials and chemical/energetic properties have a synergistic effect on cell attachment, proliferation, and differentiation.

Background: Non-coding RNAs play a critical role in the occurrence and development of oral cancer. The present study is aimed to identify long non-coding RNA (lncRNA) that might be novel effective targets for the treatments of oral cancer and the underlying mechanism. Methods: The microarray profiling and RNA-sequencing analysis were performed to identify lncRNAs related to oral cancer development, and lncRNA DNM3OS was selected. DNM3OS knockdown was generated in cancer cell lines, and the specific effects of DNM3OS knockdown on cell phenotype were examined. DNM3OS targeted miRNA and miRNA targeted downstream mRNA were selected, the predicted bindings were verified, and the specific effects of miRNA on oral cancer cells were examined. Finally, the dynamic effects of DNM3OS and miRNA on target mRNA expression and oral cancer cell phenotype were examined. Results: DNM3OS was upregulated in oral cancer tissues and cells. DNM3OS knockdown in CAL27 and SCC-9 cells inhibited cell viability and migration. DNM3OS targeted miR-204-5p to inhibit miR-204-5p expression. miR-204-5p overexpression suppressed oral cancer cell aggressiveness. miR-204-5p targeted HIP1 to inhibit HIP1 expression. HIP1 knockdown inhibited oral cancer cell viability and migration. The effects of DNM3OS knockdown were significantly reversed by miR-204-5p inhibition. Within oral carcinoma tissue samples, expression of DNM3OS and HIP1 was increased whereas the miR-204-5p expression was downregulated; miR-204-5p had a negative correlation with DNM3OS and HIP1, respectively, while DNM3OS and HIP1 were positively correlated with each other. Conclusion: Long non-coding RNA DNM3OS, miR-204-5p, and HIP1 form an axis that modulates oral cancer cell viability and migration.

Background The establishment of adaptive immune responses to neoplasms involves not only the tumour tissue, but also the peripheral blood. We aimed to conduct a preliminary exploration to understand the immune response of T lymphocytes of peripheral blood mononuclear cells (PBMC‐Ts) in oral squamous cell carcinoma (OSCC). Methods A total of 103 blood samples from OSCC patients and 18 blood samples from healthy donors (HD) were analysed by flow cytometry. Results Compared to those in HD, a series of unique features of PBMC‐Ts were observed in OSCC patients including a significant increase in CD4+ T cells, a shift from naïve to memory/effector phenotype, an increased frequency of exhausted phenotypes (programmed death‐1 [PD‐1], T cell Ig and mucin protein‐3 [Tim‐3] and Tregs), an abundance of Th17s and Tc17s and an imbalance in Th17/Tc17 and Th17/Treg ratios. Furthermore, in OSCC patients, we also found that CD4+ T cells were significantly increased in patients with larger tumours than smaller tumours, memory/effector phenotype and exhausted phenotypes were significantly associated with advanced clinical stage and lymph node metastasis, and the Th17/Treg ratio was associated with early clinical stage and no lymph node metastasis. Conclusion PBMC‐Ts may be involved in the development and progression of OSCC, which suggested to be a manifestation of an immune response between host and tumour neoantigens.