DNA Damage Response Gene Signature as Potential Treatment Markers for Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, the identification of biomarkers capable of monitoring the clinical progression of OSCC and its responsiveness to therapy is strongly required. To meet this need, here we have employed Whole Genome Sequencing and RNA-seq data from a cohort of 316 patients retrieved from the TCGA Pan-Cancer Atlas to analyze the genomic and transcriptomic status of the DNA damage response (DDR) genes in OSCC. Then, we correlated the transcriptomic data with the clinical parameters of each patient. Finally, we relied on transcriptomic and drug sensitivity data from the CTRP v2 portal, performing Pearson's correlation analysis to identify putative vulnerabilities of OSCC cell lines correlated with DDR gene expression. Our results indicate that several DDR genes show a high frequency of genomic and transcriptomic alterations and that the expression of some of them correlates with OSCC grading and infection by the human papilloma virus. In addition, we have identified a signature of eight DDR genes (namely CCNB1, CCNB2, CDK2, CDK4, CHECK1, E2F1, FANCD2, and PRKDC) that could be predictive for OSCC response to the novel antitumor compounds sorafenib and tipifarnib-P1. Altogether, our data demonstrate that alterations in DDR genes could have an impact on the biology of OSCC. Moreover, here we propose a DDR gene signature whose expression could be predictive of OSCC responsiveness to therapy.

The Multiple Roles of CD147 in the Development and Progression of Oral Squamous Cell Carcinoma: An Overview.

Cluster of differentiation (CD)147, also termed extracellular matrix metalloprotease inducer or basigin, is a glycoprotein ubiquitously expressed throughout the human body, the oral cavity included. CD147 actively participates in physiological tissue development or growth and has important roles in reactive processes such as inflammation, immunity, and tissue repair. It is worth noting that deregulated expression and/or activity of CD147 is observed in chronic inflammatory or degenerative diseases, as well as in neoplasms. Among the latter, oral squamous cell carcinoma (OSCC) is characterized by an upregulation of CD147 in both the neoplastic and normal cells constituting the tumor mass. Most interestingly, the expression and/or activity of CD147 gradually increase as healthy oral mucosa becomes inflamed; hyperplastic/dysplastic lesions are then set on, and, eventually, OSCC develops. Based on these findings, here we summarize published studies which evaluate whether CD147 could be employed as a marker to monitor OSCC development and progression. Moreover, we describe CD147-promoted cellular and molecular events which are relevant to oral carcinogenesis, with the aim to provide useful information for assessing whether CD147 may be the target of novel therapeutic approaches directed against OSCC.

Decellularized Hydrogels in Bone Tissue Engineering: A Topical Review.

Nowadays, autograft and allograft techniques represent the main solution to improve bone repair. Unfortunately, autograft technique is expensive, invasive and subject to infections and hematoma, frequently affecting both donor sites and surgical sites. A recent advance in tissue engineering is the fabrication of cell-laden hydrogels with custom-made geometry, depending on the clinical case. The use of ECM (Extra-Cellular Matrix)-derived Hydrogels from bone tissue is the new opportunity to obtain good results in bone regeneration. Several micro-engineering techniques and approaches are available to fabricate different cell gradients and zonal structures in hydrogels design, in combination with the advancement in biomaterials selection. In this review, we analyse the stereolithografy, the Bio-patterning, the 3D bioprinting and 3D assembly, the Laser-Induced Forward Transfer Bioprinting (LIFT), the Micro-extrusion bioprinting, the promising Electrospinning technology, the Microfluidics and the Micromolding. Several mechanical properties are taken into account for bone regeneration scaffolds. However, each typology of scaffold presents some advantages and some concerns. The research on biomaterials is the most promising for bone tissue engineering: the new biomimetic materials will allow us to obtain optimal results in the next clinical application of basic research.

Mechanical influence of tissue culture plates and extracellular matrix on mesenchymal stem cell behavior: A topical review.

Tissue engineering applications need a continuous development of new biomaterials able to generate an ideal cell-extracellular matrix interaction. The stem cell fate is regulated by several factors, such as growth factors or transcription factors. The most recent literature has reported several publications able to demonstrate that environmental factors also contribute to the regulation of stem cell behavior, leading to the opinion that the environment plays the major role in the cell differentiation.The interaction between mesenchymal stem cells (MSCs) and extracellular environment has been widely described, and it has a crucial role in regulating the cell phenotype. In our laboratory (Tecnologica Research Institute, Crotone, Italy), we have recently studied how several physical factors influence the distribution and the morphology of MSCs isolated from dental pulp, and how they are able to regulate stem cell differentiation. Mechanical and geometrical factors are only a small part of the environmental factors able to influence stem cell behavior, however, this influence should be properly known: in fact, this assumption must be clearly considered during those studies involving MSCs; furthermore, these interactions should be considered as an important bias that involves an high number of studies on the MSCs, since in worldwide laboratories the scientists mostly use tissue culture plates for their experiments.

Influence of endodontic treatment on systemic oxidative stress.

INTRODUCTION: An increased production of oxidizing species related to reactive oral diseases, such as chronic apical periodontitis, could have systemic implications such as an increase in cardiovascular morbidity. Based on this consideration, we conducted a prospective study to assess whether subjects affected by chronic periodontitis presented with higher values of oxidative stress than reference values before endodontic treatment, and whether endodontic treatment can reduce the oxidative imbalance and bring it back to normal in these subjects. MATERIALS AND METHODS: The authors recruited 2 groups of patients from private studies and dental clinics: these patients were recruited randomly. The oxidative balance in both patients with chronic apical periodontitis (CAP) and healthy control patients was determined by measuring the oxidant status, using an identification of the reactive oxygen metabolites (d-ROMs) test, while the antioxidant status in these patients was determined using a biological antioxidant potential (BAP) test. Both these tests were carried on plasma samples taken from enrolled patients. Values were measured both before the endodontic treatment of the patients with chronic apical periodontitis, and 30 and 90 days after treatment, and compared to those obtained from healthy control patients. RESULTS: It was found that, on recruitment, the patients with chronic apical periodontitis exhibited significantly higher levels of oxidative stress than control patients, as determined by the d-ROMs and BAP tests. Furthermore, the d-ROMs test values were shown to decrease and the BAP test values to increase over time in patients with chronic apical periodontitis following endodontic therapy. As the levels of oxidative stress in these patients tended to reduce and return to normal by 90 days following treatment. CONCLUSIONS: This study has demonstrated a positive association between chronic apical periodontitis and oxidative stress. Subjects affected by chronic apical periodontitis are exposed to a condition of oxidative stress, which is extremely dangerous to general health. Moreover, one can infer from these findings that through proper endodontic therapy, a good oxidative balance can be restored, thereby avoiding the risk of contracting the abovementioned diseases.

Comparison between Early Loaded Single Implants with Internal Conical Connection or Implants with Transmucosal Neck Design: A Non-Randomized Controlled Trial with 1-Year Clinical, Aesthetics, and Radiographic Evaluation.

To evaluate the implant and prosthetic of two implants with different surfaces and neck design. Enrolled patients received bone level, 12° conical connection implants (Nobel Parallel, Nobel Biocare; NOBEL group) with anodized surface (TiUnite) and roughness of 1.35 µm, or transmucosal implant system (Prama, Sweden and Martina; PRAMA group) with convergent collar, ZIrTi surface, and roughness 1.4-1.7 µm. Both implants were made of pure grade IV titanium, with similar diameter and length, chosen according to the dentistry department availability and patient's request. After early prosthesis delivery, patients were filled for at least one year. Outcome measures were: implant and prosthetic survival and success rates, physiological marginal bone remodeling, periodontal parameters and pink esthetic score (PES). Results: Fifteen patients were allocated and treated in each group. At the one-year follow-up, three patients dropped out, one in the NOBEL group and two in the PRAMA group. During the entire time of investigation, all implants survived and the prostheses were successful. No statistically significant differences were found in term of marginal bone loss, periodontal parameters, and aesthetics (p > 0.05). Conclusion: With the limitations of the present study, both implant systems showed successful clinical results. Finally, many other clinical and surgical variables may influenced marginal bone levels, implant survival, and periodontal parameters. More homogenous clinical trials with larger samples are needed to confirm these preliminary conclusions.

Histomorphometry of Bone after Intentionally Exposed Non-Resorbable d-PTFE Membrane or Guided Bone Regeneration for the Treatment of Post-Extractive Alveolar Bone Defects with Implant-Supported Restorations: A Pilot Randomized Controlled Trial.

Aim: The aim of the present study was to investigate quantitative histological examination of bone reconstructed with non-resorbable high-density polytetrafluoroethylene membrane (d-PTFE), left intentionally exposed in post extraction sockets grafted with anorganic bone material, and removed after four weeks, versus extraction and guided bone regeneration (GBR), performed two months later. Materials and Methods: This study was designed as a multicenter randomized controlled trial of parallel-group design. Patients were selected and consecutively treated in three centers in Italy. Patients randomly received intentionally exposed non-resorbable d-PTFE membrane (group A), or guided bone regeneration (group B), to treat post-extractive alveolar bone defects with implant-supported restorations. Outcomes were: the implant failure, any mechanical and biological complications, patient satisfaction, and qualitative and histomorphometric evaluation of the collected bone samples. Results: Eighteen patients were consecutively enrolled in the trial. Of these, six out of 18 patients were male. All the included patients were treated according to the allocated interventions, and no drop out occurred. No implant failure and no complications were experienced, and all the patients were fully satisfied with the function and aesthetic of their implant-supported restoration, without difference between groups. Morphological analysis revealed no sign of tissue reaction, such as fibrosis or necrosis. Regenerated bone was well mineralized in both groups, but it seemed more mature in group B than in group A. Three samples showed a minimal number of lymphocytes. Several blood vessels of small size occupied the medullary spaces, where the tissue resulted in more maturity, indicating the activity of the tissue in progress. The histomorphometric evaluation showed no statistically significant differences in the tissue volume fractions between the two groups of patients. Conclusions: With the limitation of the present study, buccal plate reconstruction with an intentionally exposed non-resorbable membrane is an effective and easy procedure for regenerating a resorbed buccal bone plate, reducing the need for guided bone regeneration.

New Generation of Fixture-Abutment Connection Combining Soft Tissue Design and Vertical Screw-Retained Restoration: 1-Year Clinical, Aesthetics and Radiographic Preliminary Evaluation.

Implant design factors and the abutment connection are correlated with crestal bone stability. The aim of the present study was to evaluate a new type of screw-retained prostheses delivered on tissue-level implants with conical external vertical seal and internal hexagon connection. Implants 4.25 mm in diameter and 10 mm in length (Prama, Sweden and Martina) were placed in partially edentulous patients needing at least one implant in the healed site, having sufficient bone volume. The implant neck was positioned above the bone crest. A healing abutment was placed according to a one-stage approach. Outcome measures were implant and prosthesis survival rate, any complications, marginal bone loss (MBL), periodontal parameters, and pink esthetic score (PES). Overall, 13 patients (4 women and 9 men; mean age 50 ± 22 years) with the same number of implants were treated and followed for one year after loading. At the 12-month follow up, no implant and no prosthesis failed, and no complications were experienced. The mean MBL experienced at the one year follow-up was 0.65 ± 0.48 mm. One year after loading, 2 out of 13 implants present bleeding on probing (15.4%), 4 out of 13 patients presented with plaque at the one year of follow-up (30.8%) and the PES was 10.5 ± 2.3 mm. Within the limitations of the present study, the analyzed implants seem to be a viable treatment option for the rehabilitation of a single tooth gap.

Effectiveness of Ball Attachment Systems in Implant Retained- and Supported-Overdentures: A Three- to Five-Year Retrospective Examination.

PURPOSE: To evaluate implant and prosthetic survival rates, complications, patient satisfaction, and biological outcomes of patients rehabilitated with a ball attachment system for implant retained- and supported-overdentures (IOV), which was in function for 3 to 5 years. METHODS: This retrospective study evaluated data collected from patients treated between April 2001 and May 2018 with IOV on splinted and non-splinted implants and a ball attachment system. Patients were followed for 36 to 206 months (mean follow-up was 128.1 ± 51.9 months). Data were collected at the 3- and 5-year follow-up examination. Outcome measures were implant and prosthetic survival rates, technical complications, marginal bone loss (MBL), oral health impact profile (OHIP), and periodontal parameters (bleeding on probing and plaque index). RESULTS: A total of 46 patients (16 males and 30 females) with 124 implants were included in this study. Twenty-five implant-retained overdentures were delivered on 53 unsplinted implants, while the other 21 patients received an implant-supported overdentures and the implants were splinted. At the five-year follow-up examination, one implant and one prosthesis failed in the unsplinted group, resulting in a cumulative survival rate of 97.8% at the patient level. Two minor technical complications were experienced. CONCLUSIONS: Implant overdenture retained or supported by ball attachment systems showed high implant and prosthetic survival and success rates. A low number of complications, high patient satisfaction, and successful biological parameters were experienced in the mid-term follow-up. Data need to be confirmed by further randomized trials.

Effect of Simultaneous Immediate Implant Placement and Guided Bone Reconstruction with Ultra-Fine Titanium Mesh Membranes on Radiographic and Clinical Parameters after 18 Months of Loading.

BACKGROUND: The aim of the present prospective case series study was to evaluate the implant and prosthetic survival rates, complications and marginal bone loss using ultra-fine titanium mesh membrane with simultaneous implant placement, to provide space maintenance mandatory for guided bone reconstruction of alveolar bone defects. MATERIALS AND METHODS: patients were recruited and treated at a private clinic in Rome, Italy, between March 2016 and October 2017. Self-tapping tapered implants were placed through a computer-guided template-assisted approach. Autogenous bone was placed alone over the exposed implant surface, then mixed with inorganic bovine bone material. Finally, the membrane was connected and shaped in order to securely enclose the graft area, and the healing cap was connected and screwed onto the height connector. Outcome measures were: implant and prosthetic failure, biological and mechanical complications, marginal and volumetric bone level changes, esthetic evaluation performed according to the pink aesthetic score (PES). RESULTS: in total, seven patients (five women, two men) with a mean age of 52.7 ± 20.3 years (range: 27-71) received 10 self-tapping tapered implants and simultaneous guided bone regeneration with ultra-fine titanium mesh membranes. No implants and no prostheses failed during the entire follow-up period. One slightly membrane exposure was observed one month after implant placement in one patient. The mean marginal bone loss (MBL) at implant loading was 0.13 ± 0.09 mm (95 % CI 0.08-0.19). At the 18-month follow-up examination, the mean MBL was 0.28 ± 0.33 mm (95 % CI 0.07-0.50) The difference was not statistically significant (0.15 ± 0.31; 95% CI 0.05-0.35; P = 0.1888). The mean horizontal alveolar ridge width was 3.72 ± 1.08 mm (95% CI 3.22-4.22 mm). At the II-stage surgery, the mean bone width was 8.79 ± 0.98 mm (95% CI 8.51-9.07 mm). The mean bone gain was 5.06 ± 1.13 mm (95% CI 4.68-5.44 mm; P = 0.000). The mean volume of the grafted bone calculated using the superimposition technique was 0.99 ± 0.38 CC (95% CI 0.75-1.23 CC). The mean PES at implant loading was 8.2 ± 0.8 mm (95 % CI 7.7-8.7). At the 18-month follow-up examination, the mean PES was 12.0 ± 0.7 mm (95 % CI 11.5-12.5) The difference was statistically significant (3.8 ± 0.4; 95 % CI 3.5-4.1; P = 0.0000); Conclusion: with the limitation of the present prospective study, the guided bone reconstruction using an ultra-fine titanium mesh membrane with simultaneous implant placement seems to provide good and stable results in implant/prosthesis success. Further research with a longer follow-up and a higher sample size are needed to confirm the results from this preliminary report.

Innovative approach for the in vitro research on biomedical scaffolds designed and customized with CAD-CAM technology.

INTRODUCTION: Studies on biomaterials involve assays aimed to assess the interactions between the biomaterial and the cells seeded on its surface. However, the morphology of biomaterials is heterogeneous and it could be tricky to standardize the results among different biomaterials and the classic plastic plates. In this light, we decided to create, by means of computer-aided design (CAD) technology, a standardized sample model, with equal shape and sizes, able to fit into a classic shape of a 96-wells tissue culture plate (TCP). METHODS: The design of this sample consists of a hole in the top in order to allow the injected cells to settle without them being able to slip from the sides of the sample to the bottom of the TCP wells. This CAD project is made using the software Pro-Engineer. The sample will totally fill the wells of the 96-well TCP. Dental pulp stem cells have been used to assess the ability of the different sample to support and promote the cell proliferation. RESULTS: Twelve titanium, 12 gold-palladium, and 12 zirconium oxide customized samples were designed by means of the software cam powermill, by importing the .stl file created in Pro-Engineer software. The proliferation rate of the tested scaffolds showed to be similar to the control in the group with the customized shape. CONCLUSION: We think that our method can be useful to test different types of scaffolds when a greater accuracy of the measurements is desirable in order to verify the cell behavior of these scaffolds. Our innovative method can improve the standardization process in the evaluation of cell behavior on different biomaterials to open the way to more reliable tests on biomatrices functionalized with drugs or growth factors applied to the future regenerative medicine.

Dental and maxillofacial alterations in patients affected from odontochondrodysplasia: a rare case report and review of literature.

INTRODUCTION: This paper has evaluated the dental and or facial disorders associated to Goldblatt syndrome, also known as odontochondrodysplasia. AIM: We report the analysis performed on a female young patient affected by this disease. We analyzed her dental and or facial features. MATERIALS AND METHODS: We adopted several diagnostic criteria: firstly, we performed radiographic investigations, followed by rhinomanometric measurements and by clinical analysis performed in order to determine the salivary flow in this typology of patients. The evidences obtained after a careful clinical, anamnestic, and radiographic analysis of our female patient allowed us to identify a number of odontostomatologic features, which are very likely to be related to this syndrome. Our patient showed some pathognomonic signs of odontochondrodysplasia already identified in the literature, that is, pectus carinatum, joint hyperextensibility, coxa valga and genu valgum, upper and lower limb asymmetry, and vertebral abnormalities. Moreover, we focused our attention on those odontostomatologic aspects that had never been analyzed by other reports in the literature: dentinogenesis imperfecta, ligamentous hyperlaxity of all joints and of temporomandibular joints in particular, poor lip competence, ogival palate, and oral respiration. Besides these, dental crowding and other important elements were identified through cephalometric measurements. DISCUSSION AND CONCLUSIONS: In the light of all these elements and of their comparison with the existing literature, it is possible to stereotype a few recurrent odontostomatologic and systemic-generalized features in patients with odontochondrodysplasia, which can be considered as closely associated with this syndrome.

Immediate loading of Brånemark system TiUnite and machined-surface implants in the posterior mandible, part II: a randomized open-ended 9-year follow-up clinical trial.

PURPOSE: To present clinical results with 9 years of follow-up of a protocol of immediately loaded implants with two different surfaces. MATERIALS AND METHODS: A total of 44 patients received 66 Brånemark System TiUnite and 55 Brånemark machined implants, all immediately loaded. Control examinations were performed on the day of surgery and at 1-, 3-, and 9-year follow-up visits. RESULTS: All implant sites had intact buccal and lingual bone walls. The prefabricated provisional restorations showed an excellent fit. Three TiUnite and 8 machined implants failed within 7 weeks of loading, resulting in a cumulative survival rate of 95.5% and 85.5% respectively after 9 years of load. The survival rate for implants in a partial prosthesis was 98.8% and 92.2% for single restorations in the TiUnite group, and 87.8% and 83.2%, respectively, for partial and single resorations in the control group. The marginal bone resorption in the first year was on average 0.9 mm in the TiUnite group and 1.0 mm in the machined group; at the third year it was 0.4 and 0.5 mm, respectively. On examination at 9 years, there was a general settlement of the bone, with a negligible further loss in height. CONCLUSIONS: The unchanged survival rate and the low bone loss after 9 years confirm the feasibility of an immediate loading protocol in the mandible, which included flapless surgery. TiUnite implants obtained a 10% higher success rate compared with machined fixtures .

Use of dermal-fat grafts in the post-oncological reconstructive surgery of atrophies in the zygomatic region: clinical evaluations in the patients undergone to previous radiation therapy.

INTRODUCTION: Grafting of autologous adipose tissue can be recommended in some cases of facial plastic surgery. Rhabdomyosarcoma is a type of cancer that can also affect the orbit. Enucleation of the eye can cause atrophy of the corresponding hemiface and decreased orbital growth. CASE REPORT: We report a case of a female patient with a medical history of surgical enucleation of the right eyeball, who had received rhabdomyosarcoma radiation therapy in her youth. The patient presented with a depression in the right zygomatic region. We took a dermal-fat flap from the abdominal region, which had been previously treated. RESULTS: The surgical outcome, 48 hours, and much clearly 31 days after the surgery, revealed that the right zygomatic region had returned to its proper anatomical shape, although there were still signs of postoperative edema. DISCUSSION: Very damaged tissues, like those exposed to radiation therapy, are generally not suitable for grafting of adipose tissue. CONCLUSIONS: In the described case, we achieved a technically and aesthetically satisfying result despite the patient's medical history involving several perplexities about the use of autologous dermal-fat tissues, because of prior radiation therapy exposure. The clinical case shows that even a region exposed to radiation therapy can be a valid receiving bed for dermal-fat grafting.