Platinum-based chemotherapy induces demyelination of Schwann cells in oral squamous cell carcinoma treatment.

BACKGROUND: Cisplatin, carboplatin, and oxaliplatin are the only three platinum-based antineoplastic drugs that have been accepted worldwide for treating various cancers. Up to 83.6% of patients treated with platinum-based antineoplastic drugs will develop chemotherapy-induced peripheral neuropathy (CIPN), manifesting as sensory paresthesias, dysesthesias, and hypoesthesias that can cause significant adverse impact to daily activities. AIM: To investigate how these three platinum-based drugs affect mitochondrial function and myelination state of Schwann cells and the signalling pathway involved. METHOD: 2 µM Cisplatin, 20 µM carboplatin, and 1 µM oxaliplatin were used to inhibit the growth of CAL-27 by 20% respectively. These drugs were then used to induce chemotherapy-induced peripheral neuropathy in Rat Schwann Cells (RSC96). The changes in cell metabolism and myelin formation in RSC96 were investigated. RESULT: Cisplatin and carboplatin, but not oxaliplatin increased intracellular and mitochondrial reactive oxygen species in RSC96. Only Cisplatin and carboplatin decreased mitochondrial membrane potential (ΔΨm) and ATP production in RSC96. Both Cisplatin and carboplatin led to demyelination of RSC96, characterized by increased expression of p75NTR and decreased expression of myelin protein zero (MPZ). CONCLUSION: Cisplatin and carboplatin, but not oxaliplatin, caused mitochondrial dysfunction and induced demyelination in RSC96 while showing similar toxicity to head and neck cancer cells. Oxaliplatin may be a potential chemotherapy drug to prevent CIPN in patients with head and neck cancer.

Multifunctional Nanofibrous Scaffolds Capable of Localized Delivery of Theranostic Nanoparticles for Postoperative Cancer Management.

Postoperative recovery of cancer patients can be affected by complications, such as tissue dysfunction or disability caused by tissue resection, and also cancer recurrence resulting from residual cancer cells. Despite impressive progress made for tissue engineering scaffolds that assist tissue regeneration for postoperative cancer patients, the majority of existing tissue engineering scaffolds still lack functions for monitoring and killing residual cancer cells, if there are any, upon their detection. In this study, multifunctional scaffolds that comprise biodegradable nanofibers and core-shell structured microspheres encapsulated with theranostic nanoparticles (NPs) are developed. The multifunctional scaffolds possess an extracellular matrix-like nanofibrous architecture and soft tissue-like mechanical properties, making them excellent tissue engineering patch candidates for assisting in the repair and regeneration of tissues at the cancerous sites after surgery. Furthermore, they are capable of localized delivery of theranostic NPs upon quick degradation of core-shell structured microspheres that contain theranostic NPs. Leveraging on folic acid-mediated ligand-receptor binding, surface-enhanced Raman scattering activity, and near-infrared-responsive photothermal effect of the theranostic gold NPs (AuNPs) delivered locally, the multifunctional scaffolds display excellent active targeting, diagnosis, and photothermal therapy functions for cancer cells, showing great promise for adaptive postoperative cancer management.

Rate of Malignant Transformation Differs Based on Diagnostic Criteria for Oral Lichenoid Conditions: A Systematic Review and Meta-Analysis of 24,277 Patients.

OBJECTIVES: This systematic review and meta-analysis aims to evaluate the evidence on the malignant potential of oral lichenoid conditions (OLCs) including oral lichen planus (OLP), oral lichenoid lesions (OLL), and lichenoid mucositis dysplasia (LMD). In addition, it aims to compare the rate of malignant transformation (MT) in OLP patients diagnosed according to different diagnostic criteria, and to investigate the possible risk factors for OLP MT into OSCC. MATERIALS AND METHODS: A standardized search strategy was applied across four databases (PubMed, Embase, Web of Science, and Scopus). Screening, identification and reporting followed the PRISMA framework. Data on MT were calculated as a pooled proportion (PP), subgroup analyses and possible risk factors for MT were pooled as odds ratios (ORs). RESULTS: Among 54 studies with 24,277 patients, the PP for OLCs MT was 1.07% (95% CI [0.82, 1.32]). The estimated MT rate for OLP, OLL and LMD was 0.94%, 1.95% and 6.31%, respectively. The PP OLP MT rate using the 2003 modified WHO criteria group was lower than that using the non-2003 criteria (0.86%; 95% CI [0.51, 1.22] versus 1.01%; 95% CI [0.67, 1.35]). A higher odds ratio of MT was observed for red OLP lesions (OR = 3.52; 95% CI [2.20, 5.64]), smokers (OR = 1.79; 95% CI [1.02, 3.03]), alcohol consumers (OR = 3.27, 95% CI [1.11, 9.64]) and those infected with HCV (OR = 2.55, 95% CI [1.58, 4.13]), compared to those without these risk factors. CONCLUSIONS: OLP and OLL carry a low risk of developing OSCC. MT rates differed based on diagnostic criteria. A higher odds ratio of MT was observed among red OLP lesions, smokers, alcohol consumers, and HCV-positive patients. These findings have implications for practice and policies.

Explainable ensemble learning model improves identification of candidates for oral cancer screening.

OBJECTIVES: Artificial intelligence could enhance the use of disparate risk factors (crude method) for better stratification of patients to be screened for oral cancer. This study aims to construct a meta-classifier that considers diverse risk factors to identify patients at risk of oral cancer and other suspicious oral diseases for targeted screening. MATERIALS AND METHODS: A retrospective dataset from a community oral cancer screening program was used to construct and train the novel voting meta-classifier. Comprehensive risk factor information from this dataset was used as input features for eleven supervised learning algorithms which served as base learners and provided predicted probabilities that are weighted and aggregated by the meta-classifier. Training dataset was augmented using SMOTE-ENN. Additionally, Shapley additive explanations (SHAP) values were generated to implement the explainability of the model and display the important risk factors. RESULTS: Our meta-classifier had an internal validation recall, specificity, and AUROC of 0.83, 0.86, and 0.85 for identifying the risk of oral cancer and 0.92, 0.60, and 0.76 for identifying suspicious oral mucosal disease respectively. Upon external validation, the meta-classifier had a significantly higher AUROC than the crude/current method used for identifying the risk of oral cancer (0.78 vs 0.46; p = 0.001) Also, the meta-classifier had better recall than the crude method for predicting the risk of suspicious oral mucosal diseases (0.78 vs 0.47). CONCLUSION: Overall, these findings showcase that our approach optimizes the use of risk factors in identifying patients for oral screening which suggests potential clinical application.

Machine Learning-Based Genome-Wide Salivary DNA Methylation Analysis for Identification of Noninvasive Biomarkers in Oral Cancer Diagnosis.

This study aims to examine the feasibility of ML-assisted salivary-liquid-biopsy platforms using genome-wide methylation analysis at the base-pair and regional resolution for delineating oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). A nested cohort of patients with OSCC and OPMDs was randomly selected from among patients with oral mucosal diseases. Saliva samples were collected, and DNA extracted from cell pellets was processed for reduced-representation bisulfite sequencing. Reads with a minimum of 10× coverage were used to identify differentially methylated CpG sites (DMCs) and 100 bp regions (DMRs). The performance of eight ML models and three feature-selection methods (ANOVA, MRMR, and LASSO) were then compared to determine the optimal biomarker models based on DMCs and DMRs. A total of 1745 DMCs and 105 DMRs were identified for detecting OSCC. The proportion of hypomethylated and hypermethylated DMCs was similar (51% vs. 49%), while most DMRs were hypermethylated (62.9%). Furthermore, more DMRs than DMCs were annotated to promoter regions (36% vs. 16%) and more DMCs than DMRs were annotated to intergenic regions (50% vs. 36%). Of all the ML models compared, the linear SVM model based on 11 optimal DMRs selected by LASSO had a perfect AUC, recall, specificity, and calibration (1.00) for OSCC detection. Overall, genome-wide DNA methylation techniques can be applied directly to saliva samples for biomarker discovery and ML-based platforms may be useful in stratifying OSCC during disease screening and monitoring.

Intraflagellar transport protein 88 interacts with polycystin 2 to regulate mechanosensitive hedgehog signaling in mandibular condylar chondrocytes.

OBJECTIVE: This study aimed to explore whether intraflagellar transport protein 88 (IFT88) was associated with polycystin 2 during mechanotransduction of mandibular condylar chondrocytes. METHODS: Rat mandibular condylar chondrocytes isolated from the condylar bone-cartilage junction were subjected to cyclic tensile strain (0.1 Hz, 10% elongation). Overexpression of IFT88 was achieved by lentiviral vector-mediated transfection. Knockdown of IFT88 and polycystin 2 was achieved by small interfering RNA (siRNA). The prevalence and length of cilia were reflected by immunofluorescence staining. The activities of hedgehog signaling were evaluated by western blot analysis. The interaction between polycystin 2 and IFT88 was evaluated by conducting a co-immunoprecipitation (co-IP) assay. RESULTS: Overexpression of IFT88 increased the length of cilia. Protein levels of polycystin 2, Indian hedgehog (Ihh), Patched 1 (Ptch1), Smoothened (Smo), and Glioma-associated oncogene homolog 1 (Gli1) were elevated in IFT88-overexpressing mandibular condylar chondrocytes under cyclic tensile strain. Knockdown of the protein level of IFT88 reduced the prevalence and length of cilia, and protein levels of polycystin 2, Ihh, Ptch1, Smo, and Gli1. A co-IP assay showed that IFT88 formed a complex with polycystin 2 under cyclic tensile strain. Knockdown of polycystin 2 decreased the protein levels of IFT88, Ihh, Ptch1, Smo, and Gli1 in mandibular condylar chondrocytes following cyclic tensile strain. CONCLUSION: These findings highlight the vital role of an interaction between IFT88 and polycystin 2 in mechanosensitive hedgehog signaling in mandibular condylar chondrocytes following cyclic tensile strain, which suggest that therapies regulating polycystin 2 may be considered for the disorders of temporomandibular joints.

Performance of a simplified scoring system for risk stratification in oral cancer and oral potentially malignant disorders screening.

BACKGROUND: Impact and efficiency of oral cancer and oral potentially malignant disorders screening are most realized in "at-risk" individuals. However, tools that can provide essential knowledge on individuals' risks are not applied in risk-based screening. This study aims to optimize a simplified risk scoring system for risk stratification in organized oral cancer and oral potentially malignant disorders screening. METHODS: Participants were invited to attend a community-based oral cancer and oral potentially malignant disorders screening program in Hong Kong. Visual oral examination was performed for all attendees and information on sociodemographic characteristics as well as habitual, lifestyle, familial, and comorbidity risk factors were obtained. Individuals' status of those found to have suspicious lesions following biopsy and histopathology were classified as positive/negative and this outcome was used in a multiple logistic regression analysis with variables collected during screening. Odds ratio weightings were then used to develop a simplified risk scoring system which was validated in an external cohort. RESULTS: Of 979 participants, 4.5% had positive status following confirmatory diagnosis. A 12-variable simplified risk scoring system with weightings was generated with an AUC, sensitivity, and specificity of 0.82, 0.71, and 0.78 for delineating high-risk cases. Further optimization on the validation cohort of 491 participants yielded a sensitivity and specificity of 0.75 and 0.87 respectively. CONCLUSIONS: The simplified risk scoring system was able to stratify oral cancer and oral potentially malignant disorders risk with satisfactory sensitivity and specificity and can be applied in risk-based disease screening.

Deep Learning Predicts the Malignant-Transformation-Free Survival of Oral Potentially Malignant Disorders.

Machine-intelligence platforms for the prediction of the probability of malignant transformation of oral potentially malignant disorders are required as adjunctive decision-making platforms in contemporary clinical practice. This study utilized time-to-event learning models to predict malignant transformation in oral leukoplakia and oral lichenoid lesions. A total of 1098 patients with oral white lesions from two institutions were included in this study. In all, 26 features available from electronic health records were used to train four learning algorithms-Cox-Time, DeepHit, DeepSurv, random survival forest (RSF)-and one standard statistical method-Cox proportional hazards model. Discriminatory performance, calibration of survival estimates, and model stability were assessed using a concordance index (c-index), integrated Brier score (IBS), and standard deviation of the averaged c-index and IBS following training cross-validation. This study found that DeepSurv (c-index: 0.95, IBS: 0.04) and RSF (c-index: 0.91, IBS: 0.03) were the two outperforming models based on discrimination and calibration following internal validation. However, DeepSurv was more stable than RSF upon cross-validation. External validation confirmed the utility of DeepSurv for discrimination (c-index-0.82 vs. 0.73) and RSF for individual survival estimates (0.18 vs. 0.03). We deployed the DeepSurv model to encourage incipient application in clinical practice. Overall, time-to-event models are successful in predicting the malignant transformation of oral leukoplakia and oral lichenoid lesions.

Rapamycin enhances the anti-angiogenesis and anti-proliferation ability of YM155 in oral squamous cell carcinoma.

YM155, a small molecule inhibitor of survivin, has been studied in many tumors. It has been shown that YM155 inhibited oral squamous cell carcinoma through promoting apoptosis and autophagy and inhibiting proliferation. It was found that YM155 also inhibited the oral squamous cell carcinoma-mediated angiogenesis through the inactivation of the mammalian target of rapamycin pathway. Rapamycin, a mammalian target of rapamycin inhibitor, played an important role in the proliferation and angiogenesis of oral squamous cell carcinoma cell lines. In our study, cell proliferation assay, transwell assay, tube formation assay, and western blot assay were used to investigate the synergistic effect of rapamycin on YM155 in oral squamous cell carcinoma. Either in vitro or in vivo, rapamycin and YM155 exerted a synergistic effect on the inhibition of survivin and vascular endothelial growth factor through mammalian target of rapamycin pathway. Overall, our results revealed that low-dose rapamycin strongly promoted the sensitivity of oral squamous cell carcinoma cell lines to YM155.

Evidence of phenotypic stability after transduction of fluorescent proteins in two human tongue cancer cell lines.

OBJECTIVES: This study investigated the phenotypic stability and biological properties of two human tongue cancer cell lines after transduction of fluorescent proteins. DESIGN: The human tongue cancer cell lines UM1 and UM2 were cultured with GFP and RFP lentiviral particles stock for 72h. Cells with successful transduction of fluorescent proteins were selected in a medium containing G418 antibiotics for two weeks. The proliferation rates of parental and transduced cell lines were evaluated by their population doubling time (PDT). Transduction efficiency was assessed by fluorescence microscope and flow cytometry. The transduced cells in passage 1, 2, 10, 20 and 30 were collected to check the stability of fluorescent protein expression. Phenotypic stability of the transduced cells was detected by means of cell morphology, cell surface markers and cell function evaluating essay. RESULTS: The proliferation rates of the transduced cell lines showed no significant difference compared to their parental cells. Successful transduction with high efficiency (99% up) was demonstrated. High fluorescence expression on both transduced cells was detected until the thirtieth generation. UM1 and UM1-GFP displayed mesenchymal cell characteristics, while UM2 and UM2-RFP cell lines showed properties characteristic of epithelial. CONCLUSIONS: Two human tongue cancer cell lines of epithelial and mesenchymal phenotype respectively, have been successfully labelled with green and red fluorescent proteins. The fluorescence maintained a high expression rate over thirty generations without influencing the original morphological phenotype and cadherin expression.

Arresting rampant dental caries with silver diamine fluoride in a young teenager suffering from chronic oral graft versus host disease post-bone marrow transplantation: a case report.

BACKGROUND: Rampant caries is an advanced and severe dental disease that affects multiple teeth. This case describes the management of rampant caries in a young teenager suffering from chronic oral graft versus host disease after allogeneic bone marrow transplantation. CASE PRESENTATION: A 14-year-old Chinese boy suffering from ß-thalassemia major was referred to the dental clinic for the management of rampant dental caries. An oral examination revealed pale conjunctiva, bruising of lips, and depapillation of tongue indicating an underlying condition of anemia. The poor oral condition due to topical and systemic immunosuppressants was seriously aggravated, and rampant caries developed rapidly, affecting all newly erupted, permanent teeth. The teeth were hypersensitive and halitosis was apparent. Strategies for oral health education and diet modification were given to the patient. Xylitol chewing gum was used to stimulate saliva flow to promote remineralization of teeth. Silver diamine fluoride was topically applied to arrest rampant caries and to relieve pain from hypersensitivity. Carious teeth with pulpal involvement were endodontically treated. Stainless steel crowns were provided on molars to restore chewing function, and polycarbonate crowns were placed on premolars, upper canines and incisors. CONCLUSION: This case report demonstrates success in treating a young teenager with severe rampant dental decay by contemporary caries control and preventive strategy.

Alveolar distraction osteogenesis for dental implant rehabilitation following fibular reconstruction: a case series.

OBJECTIVE: Alveolar distraction osteogenesis (ADO), a novel bone augmentation technique, is gaining acceptance in restoring the vertical bone discrepancy between the transplanted graft and the residual alveolar bone after mandibular reconstruction. This case series presents the outcomes of ADO in fibula-reconstructed mandibles rehabilitated with dental implants, with an emphasis on clinical indications, surgical protocol, clinical outcomes, histologic evidence, and complications. MATERIALS AND METHODS: Five patients underwent fibula distraction procedures after undergoing mandibular reconstruction with a vascularized fibula bone graft. The indication for the application of ADO was for the correction of the vertical discrepancy between the top of the reconstructed fibula and the adjacent alveolar crest to achieve adequate vertical bone height before implant placement. RESULTS: The mean vertical bone height achieved was 13.58 mm. Twenty-two dental implants were placed in 5 patients. All patients were rehabilitated with implant-supported prostheses. Bone biopsies showed the distracted area was filled with newly formed, bony trabeculae between the transported fibula and the basal segments. The most common complication was transient infection around the distractor rod. CONCLUSIONS: ADO can be performed on fibula-reconstructed mandibles to achieve the restoration of alveolar height, which then can be rehabilitated with dental implant-supported prostheses. The procedure has a minor risk of infection associated with the distractor rod, which does not compromise the bone regeneration from distraction. Patients with mandibles reconstructed with fibulas can attain dental implant rehabilitation with ADO, achieving good esthetic and occlusal outcomes.

LMO2 promotes angiogenesis probably by up-regulation of bFGF in endothelial cells: an implication of its pathophysiological role in infantile haemangioma.

AIMS: Infantile haemangiomas (IHs) are common benign vascular tumours distinctive for their perinatal presentation, rapid growth during the first year of life and subsequent slow involution. Recent research has indicated that endothelial cells of haemangiomas express LIM-only protein 2 (LMO2). The aim of this study was to investigate the role of LMO2 in the pathogenesis of IHs was investigated. METHODS AND RESULTS: Immunoreactivity of LMO2 was assessed in specimens of 19 IH. Stable transfection of LMO2 into human endothelial cell lines (EAhy926) was performed to evaluate the role of LMO2 in terms of the change in cell proliferation, cell cycle and cell migration as well as the expression level of angiogenic factors. Immunoreactivity for LMO2 was detected in all IH specimens, specifically in the nucleus of the endothelial cells. The intensity of LMO2 immunostaining decreased significantly from proliferative to involuting stages. Furthermore, the overexpression of LMO2 enhanced the proliferation and migration of the endothelial cells and promoted G0/G1-S-phase transition in vitro, together with an up-regulation of bFGF expression. CONCLUSIONS: LMO2 probably promotes angiogenesis by up-regulation of bFGF expression and thereby consequently influences progression of IH.

Comparison of two resorbable membrane systems in bone regeneration after removal of wisdom teeth: a randomized-controlled clinical pilot study.

OBJECTIVES: To compare the performance and safety of Inion GTR(TM) Biodegradable Membrane System and Geistlich resorbable bilayer Bio-Gide((R)) membrane in human bone regeneration. MATERIAL AND METHODS: In a multicenter, split blind, comparative, randomized, prospective, pilot study 15 patients have been randomized at surgery whether to be treated either with Inion GTR(TM) Biodegradable Membrane System on one and Geistlich resorbable bilayer Bio-Gide((R)) membrane on the other side or vice versa after surgical removal of both fully impacted wisdom teeth. During the follow-up visits at week 1, 2 and 6 and at months 3 and 6 the general state, the wound, eventual adverse events and the medication of the patients were assessed. Computed Tomography (CT) scans were performed immediately and 3 months after the surgery, before biopsy collection. Semi-quantitative histological evaluation and histomorphometric analyses were performed according to the ISO 10993-6 standard. New bone formation and membrane integration were evaluated by CT scan measurements. Tissue healing was evaluated clinically and by photographs between the time on teeth extraction and during follow ups. RESULTS: Five patients were smokers, none drank alcohol. Mild adverse events like wound infection, haematoma or late swelling of the gums occurred in three patients. The trephine bur harvest of bone biopsies under local anaesthesia was uneventful. Whereas specimens from the sites treated with the Inion membrane yielded 17.0% (SD 24%), the Bio-Gide membrane sites yielded 13.5% (SD 15%) of bone tissue density. In sites treated with the Inion membrane, 9.5% of old bone density and 7.5% of newly formed bone could be found, whereas the Bio-Gide((R)) membrane sites showed 3.8% of old bone density and 9.8% of newly formed bone. There were no statistically significant differences between the two groups with respect to the two variables. The osteoid rim was more extended with the Bio-Gide((R)) (6.6 mm) than with the Inion membrane (5.1 mm) but the difference between the two treatments did not reach statistical significance. Highly significant reductions in the area of the defect with both membranes were detected with significant increases in CT density at the immediate inferio-buccal adjacent bone and in the surgical defect area with both membranes. However, there was neither significant change in CT density in the immediate inferior-lingual adjacent bone of the two membranes, nor significant difference between the membranes on any of the four measurements (area of defect: P=0.1354; CT density immediate inferio-buccal adjacent bone: P=0.7615; CT density surgical defect area: P=0.1876; CT density immediate inferio-lingual adjacent bone: P=0.4212). CONCLUSION: The overall clinical outcome was satisfying and the majority of the patients showed an uneventful healing phase. Both membranes presented similar capacities regarding their barrier function and were associated with analogous bone regeneration. No statistically valid evidence about the superiority of one particular membrane was obtained. For the patient the only difference is that one product is animal derived and the other synthetic.

Surgical induction of temporomandibular joint ankylosis: an animal model.

PURPOSE: The aim of this study was to develop an animal model of temporomandibular joint (TMJ) bony ankylosis for future evaluation of surgical reconstructive methods. MATERIALS AND METHODS: An animal model was selected on the basis of 2 sequential experiments. Four goats and 4 minipigs were used in the first experiment, in which 1 goat and 1 minipig served as control animals. Condylectomy with disc preservation was performed on 1 side of 3 animals in each group. On the contralateral TMJ, condylectomy with discectomy was performed, and the arthroplasty gap was filled with the autogenous bone chips. In the second experiment, TMJ ankylosis was induced bilaterally in 3 additional animals of the species that achieved better ankylosis results in the first experiment. All animals were killed postoperatively at 3 months, and the TMJ complexes were examined by plain radiography, computed tomography, and histological evaluation. RESULTS: In the first experiment, only fibrous ankylosis was observed in the bone-grafted side of 2 goats and 3 minipigs, whereas fibro-osseous ankylosis was achieved in the remaining goat. The extent of ankylosis was found to be more severe in the goats than the minipigs. Hence, goats were selected for bilateral surgery in the second experiment, which achieved consistent bony ankylosis of the TMJ in all animals. CONCLUSIONS: Goats provide a better TMJ bony ankylosis model than minipigs. Consistent bony ankylosis can be induced by bilateral condylectomy, disectomy, and bone grafting of the arthroplasty gap.