EMT Dynamics in Lymph Node Metastasis of Oral Squamous Cell Carcinoma.

BACKGROUND: Epithelial-mesenchymal transition (EMT) enables tumor cell invasion and metastasis. Many studies have demonstrated the critical role of EMT in lymph node metastasis in oral squamous cell carcinoma (OSCC). During EMT, epithelial cancer cells lose intercellular adhesion and apical-basal polarity and acquire mesenchymal properties such as motility and invasiveness. A significant feature of EMT is cadherin switching, involving the downregulation of E-cadherin and upregulation of N-cadherin. The TGF-ß/SMAD pathway can also induce EMT. We aimed to evaluate EMT markers as predictors of lymph node metastasis in OSCC. METHODS: We performed genetic profiling of 159 primary OSCCs from TCGA and analyzed the expression of EMT markers, including cadherin switch genes (CDH1, CDH2), and TGF-ß/SMAD pathway genes. Samples were divided into advanced (stage III-IV) and early (stage I-II) stage groups. Differential expression analysis was performed, as well as an independent validation study containing fresh OSCC samples. RESULTS: TGF-ß/SMAD pathway genes such as SMAD6 were upregulated in advanced stage tumors. N-cadherin and SNAIL2 were overexpressed in node-positive tumors. Keratins were downregulated in these groups. CONCLUSION: Our findings demonstrate that EMT marker expression correlates with lymph node metastasis in OSCC. Developing therapies targeting regulators such as N-cadherin may prevent metastasis and improve outcomes.

TMJ arthroscopic level 1 vs arthrocentesis in the management of internal derangement of the temporomandibular joint.

OBJECTIVES: The technique of lysis and lavage has shown excellent success rates in treating internal derangement of the temporomandibular joint (TMJ). This procedure has been shown to reduce pain and improve joint mobility, sometimes even in patients suffering from advanced stages of degenerative joint disease (Wilkes IV to V). There are two different approaches to lavage and arthrolysis: arthrocentesis and TMJ arthroscopy. The objective was to assess both approaches' efficacy in managing internal derangement of TMJ. METHOD AND MATERIALS: In total, 92 patients with clinical and radiographic documentation of internal derangement of the TMJ unresponsive to nonsurgical therapy were randomized to one of two surgical groups: arthroscopic lysis and lavage level 1 (64 patients) and arthrocentesis (28 patients). Radiologic changes in the joint, pain (visual analog scale), interincisal distance, lateral and protrusive movements, and clicks and sounds of the joints were recorded. Data were compared presurgically (T0) and in postoperative periods of 1 week (T1), and 1 (T2), 3 (T3), and 6 (T4) months. RESULTS: Both surgical modalities achieved a similar outcome. A gradual improvement was demonstrated during the follow-up periods with no reliance on radiologic changes to the joint or the TMJ diagnosis. More than that, significant differences were encountered in all parameters but protrusion between T0 and T4. Pain decreased from 7.16 ± 2.48 to 1.75 ± 1.98 for the arthroscopic group and from 7.53 ± 2.69 to 1.00 ± 1.86 for the arthrocentesis group (P = .000). CONCLUSION: Both the approaches of arthrocentesis and arthroscopic level 1 reduced pain and improved mouth opening and lateral and protrusive movements over time.

Clinical and Prognostic Significance of the Eighth Edition Oral Cancer Staging System.

Objectives: The most notable changes in the eighth edition of the AJCC Cancer Staging System include incorporating the depth of invasion (DOI) into T staging and extranodal extension (ENE) into N staging. In this study, we retrospectively assessed the prognostic and clinical implications of the eighth TNM staging system. Materials and Methods: Patients with Oral Squamous Cell Carcinoma (OSCC) who were treated surgically between 2010 and 2017 were retrospectively reviewed. Tumors were first staged according to the seventh edition and restaged using the eighth edition. The prognostic value of the resultant upstaging was evaluated. Results: Integrating the DOI into the T classification resulted in the upstaging of 65 patients, whereas incorporating ENE into the N staging resulted in the upstaging of 18 patients (p < 0.001). Upstaging due to DOI integration had no significant effect on OS or DSS (p > 0.05). Conclusion: Our results demonstrate the importance of incorporating ENE into nodal staging and considering adjuvant therapy when ENE is present.

Human oral mucosa-derived neural crest-like stem cells differentiate into functional osteoprogenitors that contribute to regeneration of critical size calvaria defects.

BACKGROUND AND OBJECTIVE: Regeneration of large bony defects is an unmet medical need. The therapeutic effect of fully developed bony constructs engineered in vitro from mineralized scaffold and adult stem cells is hampered by deficient long-term graft integration. The purpose of the present study was to investigate the regenerative capacity of a bony primordial construct consisting of human oral mucosa stem cells (hOMSC)-derived osteoprogenitors and absorbable Gelfoam® sponges. METHODS: Gingiva and alveolar mucosa-derived hOMSC were differentiated into osteoprogenitors (Runx2 and osterix positive) and loaded into Gelfoam® sponges to generate primordial hOMSC constructs. These were implanted into critical size calvaria defects in the rat. Defects treated with human dermal fibroblasts (HDF) constructs; Gelfoam® sponges and untreated defects served as controls. RESULTS: After 120-day post-implantation defects treated with hOMSC constructs, HDF constructs and gelatin and untreated defects exhibited 86%, 30%, 21%, and 9% of new bone formation, respectively. Immunofluorescence analysis for human nuclear antigen (HNA), bone sialoprotein (BSP), and osteocalcin (OCN) revealed viable hOMSC-derived osteoblasts and osteocytes that formed most of the cell population of the newly formed bone at 30 and 120 days post surgery. Few HNA-positive HDF that were negative for BSP and OCN were identified together with inflammatory cells in the soft tissue adjacent to new bone formation only at 30 days post implantation. CONCLUSION: Collectively, the results demonstrate that primordial in vitro engineered constructs consisting of hOMSC-derived osteoprogenitors and absorbable gelatin almost completely regenerate critical size defects in an immunocompetent xenogeneic animal by differentiating into functional osteoblasts that retain the immunomodulatory ability of naïve hOMSC.

Human Oral Mucosal Stem Cells Reduce Anastomotic Leak in an Animal Model of Colonic Surgery.

BACKGROUND: Anastomotic leak is regarded as one of the most feared complications of bowel surgery; avoiding leaks is a major priority. Attempts to reduce or eliminate leaks have included alternate anastomotic techniques. Human oral mucosa stem cells (hOMSC) are self-renewing and expandable cells derived from buccal mucosa. Studies have shown that hOMSC can accelerate tissue regeneration and wound healing. The objective of this study was to evaluate whether hOMSC can decrease anastomotic leak rates in a murine model of colon surgery. METHODS: Two experiments were performed. In the first study, mice underwent colonic anastomosis using five interrupted sutures. hOMSC (n = 7) or normal saline (NS; n = 17) was injected into the colon wall at the site of the anastomosis. To evaluate whether hOMSC can impact anastomotic healing, the model was stressed by repeating the first experiment, reducing the number of sutures used for the construction of the anastomosis from five to four. Either hOMSC (n = 8) or NS (n = 20) was injected at the anastomosis. All mice that survived were sacrificed on postoperative day 7. Anastomotic leak rate, mortality, daily weight, and daily wellness scores were compared. RESULTS: In the five-suture anastomosis, there were no differences in anastomotic leak rate, mortality, or daily weight. Mice that received hOMSC had significantly higher wellness scores on postoperative day 2 (p < 0.05). In the four-suture anastomosis, there was a significant decrease in leak rate (70% [NS] vs. 25% [hOMSC], p = 0.029) and higher wellness scores in mice that received hOMSC (p < 0.05). CONCLUSION: Our study suggests that injecting hOMSC at the colonic anastomosis can potentially reduce anastomotic leak and improve postoperative wellness in a murine model of colon surgery.

Pediatric maxillofacial trauma: Epidemiologic study between the years 2012 and 2015 in an Israeli medical center.

BACKGROUND/AIM: Trauma is the leading cause of morbidity and mortality in the pediatric population worldwide, and Israel is no different in this aspect. Of these injuries, craniofacial trauma is a significant cause of morbidity in the pediatric population. The high occurrence of pediatric trauma is possibly related to a lower perception for the hazards that surround them, combined with the restless and adventurous nature that is typical of children. The aim was to perform a retrospective, epidemiological study on facial trauma in children examined in the emergency room in order to analyze the different patterns in pediatric maxillofacial trauma, to emphasize this data and educate those involved in preventing and treating children's injuries. MATERIALS AND METHODS: The database of pediatric maxillofacial trauma patients younger than 18 years registered at the Department of Oral and Maxillofacial Surgery at the Baruch Padeh Medical Center, Poriya during a period of 4 years (2012-2015) was reviewed and examined. The data collected were analyzed for each year separately and then comparisons and cross sections were made. RESULTS: This study examined 3034 files of pediatric maxillofacial and head trauma patients aged under 18. The comparison of frequency of the injuries between seasons reveals more injuries occur in the summer and 69.3% of the injuries occurred in boys. Average age was 6.5 years, with the most prevalent group being 0-5 years. The most common type of injury was blunt head trauma followed by facial lacerations and dental injuries. Most (84.5%) of the injuries occurred outside the education system. The number of injuries at the Arab villages was higher than in the Jewish villages. CONCLUSION: There is a marked difference in the injured children population with an increase incidence in the Arab child population and children under the age of 6.

Dopaminergic-like neurons derived from oral mucosa stem cells by developmental cues improve symptoms in the hemi-parkinsonian rat model.

Achieving safe and readily accessible sources for cell replacement therapy in Parkinson's disease (PD) is still a challenging unresolved issue. Recently, a primitive neural crest stem cell population (hOMSC) was isolated from the adult human oral mucosa and characterized in vitro and in vivo. In this study we assessed hOMSC ability to differentiate into dopamine-secreting cells with a neuronal-dopaminergic phenotype in vitro in response to dopaminergic developmental cues and tested their therapeutic potential in the hemi-Parkinsonian rat model. We found that hOMSC express constitutively a repertoire of neuronal and dopaminergic markers and pivotal transcription factors. Soluble developmental factors induced a reproducible neuronal-like morphology in the majority of hOMSC, downregulated stem cells markers, upregulated the expression of the neuronal and dopaminergic markers that resulted in dopamine release capabilities. Transplantation of these dopaminergic-induced hOMSC into the striatum of hemi-Parkinsonian rats improved their behavioral deficits as determined by amphetamine-induced rotational behavior, motor asymmetry and motor coordination tests. Human TH expressing cells and increased levels of dopamine in the transplanted hemispheres were observed 10 weeks after transplantation. These results demonstrate for the first time that soluble factors involved in the development of DA neurons, induced a DA phenotype in hOMSC in vitro that significantly improved the motor function of hemiparkinsonian rats. Based on their neural-related origin, their niche accessibility by minimal-invasive procedures and their propensity for DA differentiation, hOMSC emerge as an attractive tool for autologous cell replacement therapy in PD.

Astrocyte-like cells derived from human oral mucosa stem cells provide neuroprotection in vitro and in vivo.

Human oral mucosa stem cells (hOMSC) are a recently described neural crest-derived stem cell population. Therapeutic quantities of potent hOMSC can be generated from small biopsies obtained by minimally invasive procedures. Our objective was to evaluate the potential of hOMSC to differentiate into astrocyte-like cells and provide peripheral neuroprotection. We induced hOMSC differentiation into cells showing an astrocyte-like morphology that expressed characteristic astrocyte markers as glial fibrillary acidic protein, S100ß, and the excitatory amino acid transporter 1 and secreted neurotrophic factors (NTF) such as brain-derived neurotrophic factor, vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1. Conditioned medium of the induced cells rescued motor neurons from hypoxia or oxidative stress in vitro, suggesting a neuroprotective effect mediated by soluble factors. Given the neuronal support (NS) ability of the cells, the differentiated cells were termed hOMSC-NS. Rats subjected to sciatic nerve injury and transplanted with hOMSC-NS showed improved motor function after transplantation. At the graft site we found the transplanted cells, increased levels of NTF, and a significant preservation of functional neuromuscular junctions, as evidenced by colocalization of α-bungarotoxin and synaptophysin. Our findings show for the first time that hOMSC-NS generated from oral mucosa exhibit neuroprotective effects in vitro and in vivo and point to their future therapeutic use in neural disorders.