Oxidative-Stress-Mediated ER Stress Is Involved in Regulating Manoalide-Induced Antiproliferation in Oral Cancer Cells.

Manoalide provides preferential antiproliferation of oral cancer but is non-cytotoxic to normal cells by modulating reactive oxygen species (ROS) and apoptosis. Although ROS interplays with endoplasmic reticulum (ER) stress and apoptosis, the influence of ER stress on manoalide-triggered apoptosis has not been reported. The role of ER stress in manoalide-induced preferential antiproliferation and apoptosis was assessed in this study. Manoalide induces a higher ER expansion and aggresome accumulation of oral cancer than normal cells. Generally, manoalide differentially influences higher mRNA and protein expressions of ER-stress-associated genes (PERK, IRE1α, ATF6, and BIP) in oral cancer cells than in normal cells. Subsequently, the contribution of ER stress on manoalide-treated oral cancer cells was further examined. ER stress inducer, thapsigargin, enhances the manoalide-induced antiproliferation, caspase 3/7 activation, and autophagy of oral cancer cells rather than normal cells. Moreover, N-acetylcysteine, an ROS inhibitor, reverses the responses of ER stress, aggresome formation, and the antiproliferation of oral cancer cells. Consequently, the preferential ER stress of manoalide-treated oral cancer cells is crucial for its antiproliferative effect.

Pomegranate extract inhibits migration and invasion of oral cancer cells by downregulating matrix metalloproteinase-2/9 and epithelial-mesenchymal transition.

Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 µg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC-3 and Ca9-22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)-2 and MMP-9 activities and expressions as well as epithelial-mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal-regulated kinases 1/2 (ERK1/2), but not c-Jun N-terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx-suppressed transwell migration and MMP-2/-9 activities in HSC-3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells.

The influence of dental experience on a dental implant navigation system.

BACKGROUND: This study evaluated the operating performance of an implant navigation system used by dental students and dentists of prosthodontic background with varying levels of experience. A surgical navigation system and optical tracking system were used, and dentists' accuracies were evaluated in terms of differences between the positions of actually drilled holes and those of the holes planned using software before surgeries. METHODS: The study participants were 5 dental students or dentists who had studied in the same university and hospital but had different experience levels regarding implants. All participants were trained in operating the AqNavi system in the beginning of the study. Subsequently, using 5 pairs of dental models, each participant drilled 5 implant holes at 6 partially edentulous positions (11, 17, 26, 31, 36, and 47). In total, each participant conducted 30 drilling tests. RESULTS: In total, 150 tests among 5 dentists at 6 tooth positions (11, 17, 26, 31, 36, and 47) were conducted. Although a comparison of the tests revealed significant differences in the longitudinal error (P < .0001) and angular error (P = .0011), no significant difference was observed in the total error among the dentists. CONCLUSIONS: A relatively long operating time was associated with relatively little implant experience. Through the dental navigation system, dental students can be introduced to dental implant surgery earlier than what was possible in the past. The results demonstrated that the operational accuracy of the dental implant navigation system is not restricted by participants' implant experience levels. The implant navigation system assists the dentist in the ability to accurately insert the dental implant into the correct position without being affected by his/her own experience of implant surgery.

Fracture resistance of monolithic zirconia crowns with different occlusal thicknesses in implant prostheses.

STATEMENT OF PROBLEM: The use of monolithic zirconia crowns in implant prostheses is increasing, especially when the interdental space is insufficient. However, fractures have been reported in clinical practice. PURPOSE: The purpose of this study was to determine the minimal thickness of a complete zirconia crown used for an implant prosthesis in the posterior dental region. MATERIAL AND METHODS: Fifty complete zirconia crowns were produced using a computer-aided design/computer-aided manufacturing technique. In each group, 5 crowns of varying thicknesses (0.4, 0.5, 0.6, 0.7, and 0.8 mm) were subjected to cycles of vertical and 10-degree oblique compressive loading at 5 Hz and 300 N in a servohydraulic testing machine. Five finite element models comprising 5 different occlusal thicknesses (0.4, 0.5, 0.6, 0.7, and 0.8 mm) were simulated at 2 loading angles (0 and 10 degrees) and 3 loading forces (300, 500, and 800 N). Data were statistically analyzed, and fracture patterns were observed with a scanning electron microscope. RESULTS: Cyclic loading tests revealed that the fracture resistance of the specimens was positively associated with prosthesis thickness (P<.01). Low von Mises stress values were obtained for prostheses with a minimal thickness of 0.7 mm under varying loading directions and forces. CONCLUSIONS: Zirconia prostheses with a minimal thickness of 0.7 mm had a high fracture resistance and the lowest stress values. Therefore, dentists and laboratory technicians should carefully choose the optimum thickness of zirconia prostheses.

Accuracy comparison of scan segmental sequential ranges with two intraoral scanners for maxilla and mandible.

Background/purpose: The accuracy of a full-arch scan by using an intraoral scanner should be validated under clinical conditions. This study aimed to compare the accuracy of full-arch digital impressions in the maxilla and mandible using two intra oral scanners with three different scan segmental sequential ranges. Materials and methods: A dental model with 28 teeth in their normal positions served as the reference. Sixty full-arch scans were performed using Trios 3 and Trios 4, employing scanning strategy O (manufacturer's original method), OH (segmental sequential ranges one half), and TQ (segmental sequential ranges third quarter). Trueness was evaluated by comparing digital impressions with a reference dataset using specialized software. One-way ANOVA and Tukey tests assessed differences between the groups. Results: For Trios 3 on the maxilla, no significant difference was found among the groups of trueness; in the mandible, strategy O exhibited a significant difference (P = 0.008) with the highest deviation. For Trios 4 on the maxilla, strategy TQ demonstrated the lowest deviation with a significant difference (P = 0.006); in the mandible, no significant difference was found among the groups of trueness. Conclusion: Strategy TQ exhibited the best trueness for Trios 3 and Trios 4, suggesting it may be preferred for higher accuracy. Clinicians should consider these findings when selecting scanning strategies and intraoral scanners for specific cases.

Trueness of intraoral scanning for different tooth-size arch-length deficiencies.

Background/purpose: As science and technology continue to advance, the utilization of intraoral scanners (IOSs) has become increasingly popular in the orthodontic workflow. The aim of this study was to discuss whether the degree of crowded arches affects scan accuracy. Materials and methods: Three different crowding levels of dental models (model MI: mild, model MO: moderate, and model SE: severe) were scanned using both an IOS and desktop scanner. Stereolithographic files were obtained and superimposed via CAD software to calculate differences between each measuring point of a model and the farthest corresponding point. The deviations from three models were compared with statistical analysis. Results: The trueness of different crowding arches showed that the deviation value of model SE was the maximum, followed by model MI, and model MO in the maxillary arch. In the mandibular arch, the order of the deviation from greatest to least was firstly model SE, then model MO, and model MI. Significant differences were observed among the maxillary models (P < 0.001), but there was no significant difference between models in the mandible (P = 0.669). Conclusion: The trueness of the three crowded arches is in the clinically acceptable range. The degree of crowding increases, the trueness of scanning at each position decreases. In the maxillary arch, more severe crowding corresponds to higher deviations. In the mandible, the degree of crowding is not explicitly related to the maximum deviation; therefore, the clinician should notice the deviation when using IOSs for crowding cases.

Convolutional-neural-network-based radiographs evaluation assisting in early diagnosis of the periodontal bone loss via periapical radiograph.

Background/Purpose: The preciseness of detecting periodontal bone loss is examiners dependent, and this leads to low reliability. The need for automated assistance systems on dental radiographic images has been increased. To the best of our knowledge, no studies have quantitatively and automatically staged periodontitis using dental periapical radiographs. The purpose of this study was to evaluate periodontal bone loss and periodontitis stage on dental periapical radiographs using deep convolutional neural networks (CNNs). Materials and methods: 336 periapical radiographic images (teeth: 390) between January 2017 and December 2019 were collected and de-identified. All periapical radiographic image datasets were divided into training dataset (n = 82, teeth: 123) and test dataset (n = 336, teeth: 390). For creating an optimal deep CNN algorithm model, the training datasets were directly used for the segmentation and individual tooth detection. To evaluate the diagnostic power, we calculated the degree of alveolar bone loss deviation between our proposed method and ground truth, the Pearson correlation coefficients (PCC), and the diagnostic accuracy of the proposed method in the test datasets. Results: The periodontal bone loss degree deviation between our proposed method and the ground truth drawn by the three periodontists was 6.5 %. In addition, the overall PCC value of our proposed system and the periodontists' diagnoses was 0.828 (P < 0.01). The total diagnostic accuracy of our proposed method was 72.8 %. The diagnostic accuracy was highest for stage III (97.0 %). Conclusion: This tool helps with diagnosis and prevents omission, and this may be especially helpful for inexperienced younger doctors and doctors in underdeveloped countries. It could also dramatically reduce the workload of clinicians and timely access to periodontist care for people requiring advanced periodontal treatment.

Modern therapy for severe alveolar ridge atrophy.

This clinical report illustrates a modern method for oral rehabilitation of severe edentulous atrophic ridge. Shallow vestibule and small denture-bearing area of the maxilla provide insufficient retention, and only the symphyseal region of the mandible has obvious alveolar ridge. The surgery of deepening vestibule of the maxilla ridge was done by using tentative miniscrew combined with old denture and soft liner. The osseointegrated dental implants were installed over symphyseal region of the mandible to act as retentive devices for prostheses. In addition, functional reline with rebase material to build buccal-tongue contact over the retromolar area after denture delivery obtained high satisfaction from the patient. Many clinical conditions cannot be managed solely with implants or preprosthetic surgery alone, whereas a combination of the 2 can achieve successful outcome.

Stress analysis and risk of failure during clenching in ceramic assembly models: 3-dimensional finite element analysis.

Background/purpose: Clenching is a dental parafunctional disorder that jeopardizes the life of teeth and/or dental prostheses. Computer-aided design and computer-aided manufacturing (CAD/CAM)-fabricated or 3-dimensional-printed dental prostheses are aesthetic, strong, and of good quality, but noticeable damage can still be observed after clenching. Stress analysis of synthetic ceramic assemblies with various parameters was conducted to provide data that may be used to improve the fabrication of CAD/CAM-fabricated dental prostheses. Materials and methods: Abaqus software was used to run the simulations. A total of 96 axisymmetric finite element ceramic assembly models were simulated under 800 N vertical loading and different contact radii (0.25, 0.5, 0.75, 1.0 mm), materials (IPS e.max CAD and Vita Enamic), layer thicknesses and combinations. Results: Four-layered ceramic assembly models produced promising results with the following parameters: contact radius of at least 0.5 mm, total thickness of at least 0.5 mm, and use of IPS e.max CAD as the first layer and Vita Enamic as the second layer without cement. Conclusion: The ideal four-layered assembly model design uses 0.25-mm-thick IPS e.max CAD as its outer layer to simulate enamel binding and 0.25-mm-thick Vita Enamic as its inner layer to imitate the natural tooth. This design may be used as reference for prosthodontic treatment.

Investigation on the effect of recasting palladium-silver alloy by argon arc vacuum pressure casting process.

Background/purpose: Palladium-silver (Pd-Ag) alloys are important as an alternative to gold-based alloys. The purpose of this study was to investigate the effect of an argon-arc vacuum pressure casting process on the recasting of the Pd-Ag alloy. Materials and methods: The recasting Pd-Ag alloys were compared with conventional horizontal centrifugal (HC) casting to an argon (Ar)-arc vacuum pressure (Ar-arc/VP) casting. The first-generation castings were made from a Pd-Ag alloy purchased from a supplier. Next-generation castings were made from 50 wt% Pd-Ag alloy before casting and 50 wt% from previous castings. This sequence was repeated over three generations to form the 2nd, 3rd and 4th recasting ingots. The ingots were then measured for marginal accuracy, interfacial oxidation, hardness and phase identification. Results: The recasting success rate of recastibility reached 100%. Compared with the HC group, the Ar-arc/VP group had better edge precision, smaller oxide layer thickness and lower hardness. The comparison of X-ray diffraction intensity showed that the relative intensities of Pd and Ag in the first, second and third generations recasting of the Ar-arc/VP group were significantly higher than those of the HC group. Phase analysis showed that the trace elements of indium and tin contents in the Pd-Ag recasting ingots of the Ar-arc/VP group were higher than those of the HC group. Conclusion: The results showed that the casting process used for recasting affected the quality of the Pd-Ag alloy. Therefore, Ar-arc/VP casting process could improve the effect of Pd-Ag recasting and maintain the alloy properties in comparison with HC casting.

Accuracy of intraoral scanning methods for maxillary Kennedy class I arch.

Background/purpose: The optimal strategy for scanning removable partial dentures remains unknown. This study investigated scanning strategies for patients with a maxillary Kennedy Class I arch as well as the measurement deviations of three scanning strategies. Materials and methods: A standard maxilla model was positioned with a holder in a dental chair to simulate a natural patient position and posture. Standard Tessellation Language files for reference models were formatted with a desktop scanner, and model operation files were obtained with a TRIOS 3 Pod intraoral scanner and superimposed using Exocad computer-aided design software. The three scanning strategies evaluated in this study (Strategy M, T-R, and R-T) were used for nine scans each, and the resulting data were recorded. The deviation of the three strategies was statistically analyzed through one-way ANOVA and Tukey post hoc testing. Results: The trueness of Strategy M, T-R, and R-T was 52.6 ± 31.0, 54.9 ± 27.6, and 50.1 ± 22.3 µm, respectively. No statistically significant differences in trueness were detected among the three groups (P > 0.05). However, Strategy T-R had the evenest distribution of all measuring points. The deviations of the measurements obtained by three scanning strategies were mostly between 30 and 70 µm. The precision of the three strategies was similar as well. Conclusion: Trueness did not differ significantly among the three strategies. However, Strategy T-R is recommended for use with a TRIOS 3 Pod scanner because of its reduction of the seesaw effect and high stabilization of the RPD framework.

Questionnaire survey on the satisfaction of SimEx dental education system.

Background/purpose: The SimEx is dental training system that applies new technology in a computerized dental simulator. The purpose of this study was to understand the usability satisfaction of the SimEx dental education and evaluation system by dental students and dentists at Tohoku University. Materials and methods: In this study, the Tohoku University IRB execution number was 2020-3-33. The number of subjects accepted was 59 at Tohoku University and divided into 4 groups based on years of clinical experience (Group A: 0 years; Group B: 1-2 years; Group C: 2-5 years; Group D: at least 5 years), and a total of 58 usability questionnaires were collected. Subjects completed the SimEx Usability Satisfaction Questionnaire after operating the SimEx (EPED Inc., Kaohsiung, Taiwan) course, which contained 16 questions. Results: Among the 58 questionnaires collected by Tohoku University, there were 19 undergraduate students (4th∼6th grade), 12 post-graduate students, 14 residents, and 13 dentists. Significant differences between Group A and Group B, and between Group A and Group D were found (P < 0.05). The same results were obtained for the "experience satisfaction index". In the items where significant differences were found, longer clinical experience tended to result in lower scores. Conclusion: From these results, we can conclude that the SimEx education and evaluation system facilitates students' self-learning, and this system is very useful for continued study and clinical skill training for dentists, especially for students and junior dentists with high usability satisfaction.

Immediate implant placement with and without provisionalization: A comparison of a one-year longitudinal study.

Background/purpose: Immediate implant placement (IIP) with and without immediate provisionalization (Ipro) may yield satisfactory results in appropriate indications and treatment, especially in the esthetic zone. The aim of this study was to compare implant stability, marginal bone loss (MBL), survival rates, and patient satisfaction between IIP with Ipro and IIP without Ipro. Materials and methods: Seventy patients, each with a failed maxillary anterior tooth, were randomly assigned to IIP with Ipro (Group A: n = 35) or IIP without Ipro (Group B: n = 35). Implant stability quotient (ISQ) and standardized periapical radiographs were performed at surgery and at 3, 6, 9, and 12 months postoperatively to investigate implant stability and MBL, respectively. Survival was assessed 1 year after surgery. Patient satisfaction was evaluated with a visual analogue scale (VAS). Results: Primary ISQ and MBL were not significantly different between groups A and B immediately after surgery (P ＞ 0.05). Implant survival was 100% in both groups, and only one mechanical complication was observed. Patient satisfaction was good at definitive crown delivery and postoperatively 1-year in both groups. However, the immediate postoperative VAS score in Group A was significantly higher than that in Group B (P < 0.05). Conclusion: Group A revealed significantly higher secondary ISQ than Group B at postoperatively 3, 6, 9, and 12 months. There were no significant differences between groups A and B in terms of MBL and survival. Notably, patient satisfaction in Group A was significantly higher than in Group B immediately after surgery.

Implant stability and marginal bone level changes: A 2-year prospective pilot study.

Background/purpose: Implant stability is crucial for successful osseointegration. Marginal bone level is considered an important indicator of long-term implant success and stability. The purposes of this study were to investigate 1) the effect of age, gender, bone density, implant length, and implant diameter on insertion torque (IT), primary implant stability quotient (ISQ), and secondary ISQ, 2) the impact of age, gender, bone density, implant length, implant diameter, IT, and ISQ on marginal bone loss (MBL). Materials and methods: Ninety patients who needed implant therapy were enrolled and overall 156 implants were installed to support single crowns. IT and ISQ were recorded for all implants during surgery and ISQ measurements were performed at follow-up visits. Age, gender, bone density, implant length and diameter were also registered. Radiographic evaluation of MBL was performed postoperative immediate (baseline), 3, 6, 9, 12, 18, and 24 months using digital periapical radiographs. Results: Age had little effect on IT and primary ISQ (P > 0.05). Generally, males had higher IT and primary ISQ, but no significant differences between genders were detected. Bone density showed significant effects on IT and primary ISQ. Correlation analysis revealed high positive correlations between IT/bone density and primary ISQ/implant diameter. Significant impacts of bone density and IT on MBL were found. Conclusion: Implant diameter had a more profound impact than length on IT/primary ISQ. Bone density played a considerable role in IT/primary ISQ determination. Bone density and IT had more impacts than primary ISQ on MBL.

Total solution of a smart shade matching.

Background/purpose: The simulated color of restorations plays an important role in improving patient satisfaction. The aim of this study was to test a new intelligent colorimetric solution using the Advanced Reflectionless Technology (ART) monitor and compare them using commercially available shade systems. Materials and methods: Six participants' right maxillary central incisors were tested with three devices, including the AUO Display Plus (Group A), a Canon single-lens reflex camera with eLAB's polar eyes filter (Group E), and the VITA Easyshade V (Group V). Each porcelain tooth was divided into three areas, and was assigned a CIELAB L∗a∗b∗ value by using the VITA Easyshade V. The original data were compared with the CIELAB L∗a∗b∗ obtained using the VITA Easyshade V. A prosthodontist compared the color of the porcelain veneers by eyes and gave the scores from 1 to 3. Results: For the ΔE, the three areas of Group A had the smallest differences between the color of the fabricated teeth and that of the original teeth. Colorimetric analysis indicated that Groups A and V did not differ much in the color of the three areas of the tooth. Groups E and A exhibited significant differences between the cervical third and middle third of the tooth, and Groups E and V exhibited significant differences between the middle third and incisal third of the tooth. Conclusion: Compared with traditional monitors, ART is closer to real images in terms of color, contrast, and detail grayscale. Technicians are able to produce realistic and pleasing colors.

Biomechanical analysis of alveolar bone stress around implants with different thread designs and pitches in the mandibular molar area.

Threaded implants have been shown to play an important role in increasing mechanical osseointegration. The aim of this study was to determine bone stress distribution when using different types of implant thread pitches and designs. Five 3D finite element models were constructed to simulate bone stresses induced in implant bodies with two types of thread form: triangular ("Tri" prefix) and trapezoidal ("Trap" prefix). The former had thread pitches of 0.8, 1.2, and 1.6 mm, while the latter had thread pitches of 1.2 and 1.6 mm. A biting load of 143 N was applied vertically and obliquely to the occlusal central fossa of the crown. The main effects of each level of the three factors investigated (loading type, pitch, and thread form) in terms of the stress value were computed for all models. Results indicated that the loading type was the main factor of influence on the peak compressive stress of the alveolar bone. Optimal thread pitch was 1.2 mm for a triangular-thread implant, and a trapezoidal-threaded implant with thread pitch of 1.6 mm had the lowest stress value among trapezoidal-threaded implants. This study concluded that each thread form has its unique optimal thread pitch with regard to lower concentration of bone stress. Clinically, this study suggests that in biomechanical consideration, thread pitch exceeding 0.8 mm is more appropriate for a screwed implant. For clinical cases that require greater bone-implant interface, trapezoidal-threaded implants with thread pitch of 1.6 mm provide greater primary stability and lower concentration of bone stress under different loading directions.

Contact fracture test of monolithic hybrid ceramics on different substrates for bruxism.

OBJECTIVES: To determine the minimum thickness required for a monolithic hybrid ceramic crown on different substrates (soft vs stiff) used in posterior dentition for bruxism. METHODS: 80 polymer-infiltrated ceramic networks Vita Enamic (PICN VE) disc specimens with four different occlusal thicknesses (0.8, 1.2, 1.6 and 2.0 mm), were produced using a computer-aided design/manufacturing system, and cemented on a stiff (zirconia) or soft (polyamide) substrate of 4-mm thickness. The ten specimens, in soft or stiff groups, were subjected to compressive loading by a MTS machine until fracture or maximum load (4500 N) was reached. The unbroken specimens were examined using optical coherence tomography. Eight axisymmetric finite element models and eight 3D models comprising the four different occlusal thicknesses and two substrates under different vertical loads and sliding movements were constructed. The maximum principal stress was selected to evaluate the stress distribution in this study. RESULTS: The fracture resistance of the specimens was significantly different between the two substrates (P < 0.001). Fracture resistance was positively associated with specimen thickness (r = 0.597 and 0.896 for the soft and stiff substrate respectively). Specimens on the soft substrate had lower fracture loads, whilst cone cracks were observed in unbroken samples on different soft/stiff substrate prior to final fracture. The finite element analysis confirmed that samples on the stiff substrate had lower maximum principal stress values than those on the soft substrate. For the maximum principal stress not to exceed the flexural strength of PICN VE, a stiff substrate and minimum thickness of 2.0 mm are required for the prostheses. SIGNIFICANCE: A minimum 2.0 mm thick, stiff substrate was needed for bruxism as shown by the effect of high/large chewing force on the posterior dentition of monolithic PICN VE crowns.

The influence of cone beam computed tomography on IRIS-100 implant navigation system.

Background/purpose: Cone beam computed tomography (CBCT) is frequently used in dental diagnosis and treatment. Comparative studies of the effects of CBCT on implant navigation, however, are still limited. The objective of this study was to evaluate whether the computed tomography images of the four commercial brands will affect the accuracy of the new version of IRIS implant navigation system. Materials and methods: In the first part, the accuracy of the IRIS implant navigation system was evaluated by a precision confirmation jig whose position is confirmed. In the second part, the IRIS implant navigation system was used in conjunction with 4 brands of CBCT scans analyzed by its effect on accuracy. Results: The results showed that the mean deviation of the new version of IRIS-100 system accuracy was less than 1 mm. Among the four groups, the overall average deviation caused by CBCT images showed that the 3D eXam group had the smallest error of approximately 0.94 ± 0.12 mm and the AZ 3000 CT group had the largest error of approximately 1.34 ± 0.10 mm. Conclusion: Based on the study, the accuracy of the IRIS implant navigation system will vary with the CBCT image resolution and the status of the CBCT machine.

Combined Treatment (Ultraviolet-C/Physapruin A) Enhances Antiproliferation and Oxidative-Stress-Associated Mechanism in Oral Cancer Cells.

Physapruin A (PHA), a Physalis peruviana-derived withanolide, exhibits antiproliferation activity against oral and breast cancer cells. However, its potential antitumor effects in combined treatments remain unclear. This investigation focused on evaluating the impact of the combined treatment of ultraviolet-C with PHA (UVC/PHA) on the proliferation of oral cancer cells. The UVC-caused antiproliferation was enhanced by combination with PHA in oral cancer (Ca9-22 and CAL 27) but not normal cells (SG), as evidenced by ATP detection, compared with UVC or PHA alone. UVC/PHA showed a greater extent of subG1 increase, G2/M arrest, annexin-V-assessed apoptosis, caspase 3/7 activation, and reactive oxygen species (ROS) in the UVC or PHA treatment of oral cancer compared to normal cells. Moreover, the mitochondrial functions, such as mitochondrial superoxide bursts and mitochondrial membrane potential destruction, of oral cancer cells were also enhanced by UVC/PHA compared to UVC or PHA alone. These oxidative stresses triggered γH2AX and 8-hydroxyl-2'-deoxyguanosine-assessed DNA damage to a greater extent under UVC/PHA treatment than under UVC or PHA treatment alone. The ROS inhibitor N-acetylcysteine reversed all these UVC/PHA-promoted changes. In conclusion, UVC/PHA is a promising strategy for decreasing the proliferation of oral cancer cells but shows no inhibitory effect on normal cells.

CD44 Mediates Oral Squamous Cell Carcinoma-Promoting Activity of MRE11 via AKT Signaling.

Oral cancer is one of the highest-incidence malignancies worldwide, with the occurrence of oral squamous cell carcinoma (OSCC) being the most frequently diagnosed form. A barrier for oral cancer management may arise from tumor cells that possess properties of cancer stemness, which has been recognized as a crucial factor in tumor recurrence and metastasis. As such, understanding the molecular mechanisms underlying these tumor cells may provide insights for improving cancer treatment. MRE11 is the core protein of the RAD50/MRE11/NBS1 complex with a primary role in DNA damage repair, and it has been diversely associated with tumor development including OSCC. In this study, we aimed to investigate the engagement of CD44, a cancer stemness marker functioning in the control of cell growth and motility, in OSCC malignancy under the influence of MRE11. We found that overexpression of MRE11 enhanced CD44 expression and tumorsphere formation in OSCC cells, whereas knockdown of MRE11 reduced these phenomena. In addition, the MRE11-promoted tumorsphere formation or cell migration ability was compromised in OSCC cells carrying siRNA that targets CD44, as was the MRE11-promoted AKT phosphorylation. These were further supported by analyzing clinical samples, where higher CD44 expression was associated with lymph node metastasis. Additionally, a positive correlation between the expression of MRE11 and CD44, or that of CD44 and phosphorylated AKT, was observed in OSCC tumor tissues. Finally, the expression of CD44 was found to be higher in the metastatic lung nodules from mice receiving tail vein-injection with MRE11-overexpressing OSCC cells compared with control mice, and a positive correlation between CD44 and phosphorylated AKT was also observed in these metastatic lung nodules. Altogether, our current study revealed a previously unidentified mechanism linking CD44 and AKT in MRE11-promoted OSCC malignancy, which may shed light to the development of novel therapeutic strategies in consideration of this new pathway in OSCC.