Search

BackgroundOral squamous cell carcinoma (OSCC) progression is accompanied by bone invasion. Therefore, maintaining oral function is necessary to regulate tumor progression. Also, interleukin-12 (IL-12), a well-known anti-tumor cytokine, can suppress osteoclast differentiation in vitro. Accordingly, this study evaluated the therapeutic effects of locally administered IL-12 in an immunocompetent mouse model with mandibular bone invasion mimicking clinical features.MethodsWe investigated anti-bone resorption effects using SCCVII subcutaneous and bone invasion models both in immunocompetent and athymic mice. Furthermore, we measured bone resorption using micro-computed tomography.ResultsIntratumoral injection of recombinant murine IL-12 (r-mIL-12) significantly prolonged immunocompetent mouse survival and suppressed tumor growth and bone resorption. Real-time PCR analysis revealed that interferon-gamma (IFN-γ) and Fas ligand (FasL) were upregulated after r-mIL-12 administration, compared to control levels. However, when the athymic mouse bone invasion model was evaluated, r-mIL-12-mediated suppression of tumor growth and bone resorption were equivalent to those observed in the control group, highlighting the key role of T cells in the bone invasion.Conclusionsr-mIL-12 may represent a potent therapeutic agent for OSCC accompanied by bone invasion.SUMMARYIntratumoral injection of recombinant murine IL-12 showed anti-tumor and anti-bone resorption effects in an immunocompetent mouse bone invasion model through a T cell-dependent mechanism.

Objective: Using labial vestibular flap was performed to close the primary alveolar and hard palate cleft at the second stage of early 2-stage closure surgery for unilateral cleft lip and palate for minimizing the damage to the maxillary periosteum. We analyzed maxillary development to clarify the influence of cleft palate surgery. Design: Retrospective longitudinal study in 5 years after primary palatal closure. Setting: Institutional study Patients: Study subjects included 214 patients with nonsyndromic complete unilateral cleft lip and palate who were consecutively treated in our clinic. Main Outcome: We used a 3D dental model scanner to assess maxillary development in patients aged 3 months to 5 years after using either the conventional pushback method (PB) (51 cases) or 2-stage closure (Local palatal flap closure: LF [67 cases] and Labial vestibular flap closure: VF [96 cases]). Results: Comparing the measurement results, the major axis of maxilla, width, intercanine distance, and intermolar distance was significantly larger in the LF group compared to the PB group. After the age of 3, the cleft side of VF group had grown significantly to compare with LF group in width. It was also confirmed that the inserted labial mucosal flap itself grew. Enlargement of the labial mucosal flap was observed at all sites except the canine. Conclusion: Good maxillary growth occurred in the following order: VF groups > LF group > PB group. Poor growth was correlated with the extent of periosteal damage during surgery and the degree of postoperative bone surface exposure.

Endodontic procedures can result in various complications. Separation of the endodontic instrument is a common complication of incorrect use or overuse of the instrument. However, a separated endodontic instrument may hinder cleaning and shaping during endodontic treatment procedures, which can potentially impact prognosis. Therefore, it is necessary to manage this complication by removal of the separated instruments from inside the root canal. Although several devices are used, nonsurgical removal for retreatment remains difficult. We report the case of a failed attempt to manage a separated endodontic instrument nonsurgically by a private dentist, which resulted in extrusion of the instrument beyond the root apex and its migration into the mandible. We describe a novel surgical approach involving intentional tooth replantation combined with alveolar osteotomy. There have been few reports on the management of separated endodontic instruments that were pushed out beyond the root apex. Our novel surgical approach suggests a technique for the potential removal of a separated endodontic instrument extruded beyond the root apex.

Wound healing in the oral and maxillofacial region is a complicated and interactive process. Severe mucosal or skeletal muscle injury by trauma or surgery induces worse healing conditions, including delayed wound closure and repair with excessive scar tissue. These complications lead to persistent functional impairment, such as digestive behavior or suppression of maxillofacial growth in infancy. Osteopontin (OPN), expressed in a variety of cells, is multifunctional and comprises a number of functional domains. Seven amino acids sequence, SVVYGLR (SV peptide), exposed by thrombin cleavage of OPN, has angiogenic activity and promotes fibroblast differentiation into myofibroblasts and increased expression of collagen type III. Additionally, synthetic SV peptide shows faster dermal and oral mucosal wound closure by facilitating cell motility and migratory activities in dermal- or mucosal-derived keratinocytes and fibroblasts. Moreover, cell motility and differentiation in myogenic cell populations are accelerated by SV peptide, which contributes to the facilitation of matured myofibers and scarless healing and favorable functional regeneration after skeletal muscle injury. SV peptide has high affinity with TGF-β, with potential involvement of the TGF-β/Smad signaling pathway. Clinical application of single-dose SV peptide could be a powerful alternative treatment option for excessive oral and maxillofacial wound care to prevent disadvantageous events.

Sclerosing odontogenic carcinoma is a rare, locally destructive neoplasm that is difficult to diagnose. In a 65-year-old man with pain and swelling in the mandible, radiographs of the mandibular anterior region revealed cortical destruction and infiltration of the soft tissue by a mass lesion. Biopsy did not yield a definitive diagnosis. In accordance with a differential diagnosis of epithelial malignant tumor of the mandible, resection of the mass, bilateral superior neck dissection, and reconstruction with abdominal muscle grafts were performed. Histopathological study revealed asymmetric nuclei and cells with endoplasmic reticulum in which islands and cords of epithelial cells with low-grade cytological features were surrounded by a dense sclerotic stroma. Immunostaining yielded positive results for cytokeratin (CK) 5/6, CK19, and p63 and negative results for CK20. Because of the rarity of the disease process, clinicians, radiologists, and pathologists collaborated closely to establish a diagnosis of sclerosing odontogenic carcinoma.

Objective To examine skeletal morphology and dental arch relationships at 8 years of age following early 2-stage palatoplasty, which consists of soft palate plasty at 1 year of age and hard palate closure at 1.5 years of age, and to compare the results with those of conventional pushback palatoplasty. Design Retrospective. Setting Single institutional study. Patients Eighty-six patients with nonsyndromic complete unilateral cleft lip and palate (UCLP) were selected. Intervention The subjects were divided into 2 groups according to the palatoplasty protocols, as follows: 45 patients, who underwent early 2-stage palatoplasty (ETS group), and 41 patients, who underwent 1-stage pushback palatoplasty (PB group). Main Outcome Measures Skeletal morphology was assessed using lateral cephalometric analysis, and dental arch relationships were examined using the GOSLON yardstick. Results Cephalometric analysis revealed that the anterior-posterior length of the maxilla, measured by PTM-A and PTM-ANS, both projected to the nasal floor (NF) plane, was longer in the ETS group than in the PB group (PTM-A/NF, p = .04; PTM-ANS/NF, p = .03, unpaired t-test), although no significant difference was observed in SNA ( p = .09, unpaired t-test). Upper posterior facial height was shorter in the ETS group than in the PB group ( p = .02, unpaired t). Assessments with the GOSLON yardstick showed that the ETS group presented better dental arch relationships than the PB group ( p = 0.04, Mann–Whitney's U-test). Conclusions The present results suggested that the ETS protocol reduced the negative effects of palatal surgery on facial development and dental arch relationships in patients with complete UCLP at 8 years of age.

In the present study, we investigated the possible involvement of the TGF-β/Smad signaling pathway in the osteopontin-derived SVVYGLR (SV) peptide-mediated migratory activities of myogenic cells and evaluated the facilitative effects of the SV peptide on the differentiation of myogenic cells in vitro. The SV peptide-induced migration in both human-derived satellite cells and myoblasts was substantially suppressed by the TGF-β1 receptor inhibitor SB431542 or SB505124. Besides, the expression level of the Smad3 phosphorylation was further enhanced by the addition of the SV peptide in comparison with control groups. Furthermore, an increase in the expression of myogenin-positive nuclei and a higher number of nascent myotubes with myosin heavy chain expression was confirmed in cultured myoblasts supplemented with the SV peptide. These results suggest that the involvement of the TGF-β/Smad signaling pathway in the SV peptide-mediated migration and the facilitative effect of the SV peptide on the differentiation of myogenic cells into myotubes.

The present study was designed to evaluate the effects of the osteopontin-derived multifunctional short peptide, SVVYGLR (SV) peptide on the biological properties of skeletal muscle-specific myogenic cells. We employed human-derived satellite cells (HSkMSC) and skeletal muscle myoblasts (HSMM) and performed a series of biochemical experiments. The synthetic SV peptide showed no influence on the proliferation and adhesion properties of HSkMSC and HSMM, while it showed a significant increase in cell motility, including migration activities upon treatment with the SV peptide. In a rat model with volumetric loss of masticatory muscle, immunohistochemical staining of regenerating muscle tissue immediately after injury demonstrated an increase of the number of both MyoD- and myogenin-positive cells in SV peptide-treated group. These results suggest that SV peptide plays a potent role in facilitating skeletal muscle regeneration by promoting the migration, and differentiation of myogenic precursor and progenitor cells.

The development of the posterior lingual glands, namely Weber’s and von Ebner’s glands, of rats was examined with respect to lectin histochemistry. Weber’s glands were fully developed by postnatal (PN) day 21. Mucous cells of the Weber’s glands were shown to bind dolichos biflorus agglutinin (DBA) in adult rats, and soybean agglutinin (SBA), wheat germ agglutinin (WGA), and peanut agglutinin (PNA) in the early developmental stage. The lectin-binding pattern in Weber’s glands of developing rats became identical to that of adult rats on PN day 21. von Ebner’s glands were fully developed around PN day 21. Matured taste buds were found on the circumvallate papillae on PN day 1. Serous cells of von Ebner’s glands were shown to bind SBA, WGA, and PNA in adult rats, and DBA in the developmental stage. The lectin-binding pattern in von Ebner’s glands of developing rats became almost identical to that of adult rats on PN day 21. The present findings indicate that the maturation of posterior lingual glands is closely associated with changes in food habit, and that the Weber’s gland functions as a serous gland in the early postnatal stage, while the von Ebner’s gland is not yet mature.

To determine dental and palatal morphology in children with cleft lip and/or palate (CL/P) and identify morphological prognostic factors for orthognathic surgery (OGS). Retrospective cohort study. Orthodontic department of a university dental hospital. This study included 80 patients with bilateral and unilateral CL/P who had lateral cephalograms at the ages of 7 (T1), 15 (T2) years, and a dental plaster model at T1. Plaster models at T1 were scanned with a three-dimensional (3D) scanner. Morphological features were extracted from 3D models with geometric morphometrics software as principal components (PCs). The combinations of the PCs and other predictive factors (ie, the No. of clefts in the lip and alveolus, the palatal repair method, sex, cephalometric variables at T1, and the No. of missing teeth) were examined by logistic regression to determine the predictability for OGS. The need for OGS and skeletal and dental discrepancies at T2 were examined as outcomes. Shrinkage of the palate, including vertical shallowing and transverse narrowing of the posterior maxilla and cleft-side asymmetry of the anterior maxilla at T1, as well as the No. of clefts in the lip and alveolus, the palatal repair method, male sex, several cephalometric variables for the sagittal and vertical dimensions, and the No. of missing teeth, were found to be predictive factors for OGS. Morphological prognostic factors for OGS in children with CL/P were determined.

BACKGROUND Salivary duct carcinoma (SDC) is a rare, extremely aggressive malignancy that arises in the submandibular gland. It can metastasize locally early and therefore is an important differential diagnosis of metastatic disease in cervical lymph nodes or specific lymphadenitis such as tuberculous cervical lymphadenitis. CASE SUMMARY We report a case of SDC in the submandibular gland that presented diagnostic difficulty. The lesion was coincidentally discovered through examination of the radiolucent area of the maxilla. Imaging failed to confirm the possibility of specific inflammation, leading us to execute an open biopsy to verify the diagnosis. The surgical specimen showed that the submandibular gland was primarily replaced with a calcified body. Following histological analysis and confirmation, we performed surgical resection, radiotherapy, and various chemotherapies. CONCLUSION Radiographic imaging characteristics of lymph node metastases of salivary gland cancer, especially of SDC, may resemble other cervical lymphadenitis; calcification at the submandibular gland is the landmark of SDC occurring at the subman-dibular gland.

Atypical lipomatous tumor (ALT), one of the histologic subtypes of liposarcoma, is locally aggressive with intermediate malignant potential and is categorized as a synonymous entity with well-differentiated liposarcoma (ALT/WDLPS). Although ALT/WDLPS is the most common subtype of liposarcoma in the oral and maxillofacial region, its occurrence is extremely rare, and asymptomatic clinical behavior often delays definitive diagnosis and treatment. We present an extremely rare case of ALT/WDLPS in the buccal mucosa of an elderly Japanese woman. A provisional diagnosis of benign tumor was made from clinical symptoms that involved findings on magnetic resonance imaging. Microscopic examination revealed mature adipocytes with substantial variation in cell size, fewer multivacuolated lipoblasts, and positive stain with MDM-2 and P16, which resulted in a definitive diagnosis of ALT/WDLPS. Conservative surgical resection resulted in locoregional recurrence; however, no evidence of dedifferentiation was detected, and repeat conservative resection finally allowed the patient to avoid esthetic and functional disorder and to obtain an uneventful clinical prognosis over the long-term follow-up period. We also review previous reports of cases of ALT/WDLPS arising from the cheek/buccal mucosa.

Objective Treatment of mandibular lesions sometimes leads to the formation of large defects in the bone. Mandible reconstruction using grafted tissue, bone, and/or medical implants is required following the resection of such lesions. However, such grafts may not completely restore the continuity of the mandible. Facial transplantations using allografts are common, but mandibular allotransplantation has not been performed in humans, due to the unstable immune reaction of the complex tissue. In this study, mandibular transplantations performed under the effect of the immunosuppressive agent, FK506, were evaluated in dogs. Methods Mandibular allotransplantations were performed in 21 pairs of sex-blind beagle dogs. The left side of the mandible in the donor dog was transplanted to the left side of the mandible in the recipient dog. The FK506 doses were 0 mg for 3 dog pairs, 0.08 mg/kg/day for 3, 0.12 mg/kg/day for 5, 0.16 mg/kg/day for 5, and 0.32 mg/kg/day for 5 pairs. Twelve weeks after transplantation, the dogs were euthanized. Computed tomography (CT) and histological examinations of the transplanted sides were performed. Results Successful graft acceptance was dependent on immunosuppressive agent doses, and dogs administered more than 0.16 mg/kg/day FK506 showed 100 % survival. However, dogs administered 0.32 mg/kg/day FK506 showed significant weight loss 12 weeks after the surgery. CT findings showed thick mandibular cortical bone in the transplanted sites. Conclusions These results indicate that 0.16 mg/kg/day FK506 was the ideal dose for allotransplantations. Bone hyperplasia was observed in the transplanted sides, but it is not a disadvantage for allotransplantations.

Canalicular adenomas are uncommon benign salivary gland tumors that typically arise from minor salivary glands. They are usually solitary tumors; only a few cases of multiple tumors have been reported. We describe an unusual case of canalicular adenomas that appeared simultaneously in the buccal mucosa and upper lip of an elderly Japanese woman. Microscopic examination revealed that the tumors were composed of columnar cells in a canal-like structure and accompanied by cystic cavities. Immunohistochemical evaluation further revealed that the tumor cells were positive for CK7, CK14, and S100, whereas staining yielded negative results for β-catenin, calponin, Ki-67 protein, p63, and α-smooth muscle actin (α-SMA). We also review previous reports of cases of multiple canalicular adenomas and discuss their clinical features.

Background Heterotopic gastrointestinal cysts have gastrointestinal epithelium in the cyst wall and rarely occur in the oral cavity. Most are found in the neonatal period. However, heterotopic gastrointestinal cysts that are diagnosed as a congenital tongue cyst by routine ultrasonography are extremely rare. Case summary A 12-day-old female presented with swelling of the anterior tongue. The obstetrician had detected significant tongue swelling on fetal ultrasonography in the 35th gestational week. The female was born by cesarean delivery at gestational week 39. She soon became dyspneic, and the cyst was aspirated. After the aspiration, her breathing recovered and she started breastfeeding. The cyst was excised under general anesthesia on the 67th day. Histopathologic examination showed that that cyst wall consisted of a lining of columnar gastrointestinal-type epithelium and pseudostratified ciliated epithelium. The patient restarted breastfeeding 3 h after surgery. The postoperative course was uneventful. Conclusion Airway distress and feeding difficulty were successfully avoided by cyst aspiration, and surgical resection was performed with no perioperative complications.

The frontal craniofacial skeleton derived from neural crest cells is vital for facial structure and masticatory functions. The exact role of Indian hedgehog (Ihh) in facial and masticatory development has not been fully explored. In this study, we generated craniofacial neural crest cells-specific Ihh deletion mice (Wnt1-Cre;Ihhfl/fl ;Tomatofl/+ ) and found the gradual dwarfism without perinatal lethality. Morphological and histological analyses revealed unambiguous craniofacial phenotypes in mutants, where we observed skeletal malocclusion accompanied by markedly hypoplastic nasomaxillary complex and reversed incisor occlusion. Both the replacement of nasal concha cartilage by turbinate bones and the endochondral ossification of nasal septum ethmoid bone were substantially delayed. We also observed hypoplastic mandibles in mutants where the mandibular ramus was unexpectedly the most affected. Both the condylar process and mandibular angle cartilages were distorted. However, dental examination showed no significant changes in teeth and dentition. Finally, a comprehensive RNA sequence analysis utilizing condylar cartilage identified Ihh-associated gene network including several cell cycle genes and 16 genes related to the extracellular matrix, sulfate transporters, transcription factors, receptors, a ciliogenesis factor, and an adhesion molecule. Our data provide direct in vivo evidence that Ihh plays crucial roles in midface and masticatory system formation, likely by activating key genes.

Neuropeptide Y (NPY) is one of a number of neuropeptides with powerful orexigenic effects. Intracerebroventricular administration of NPY induces increases in food intake and alters feeding rate. Besides it role in feeding behavior, NPY also has significant effects on neuronal systems related to other spontaneous behaviors such as rearing and grooming. In the present study, we examined the direct effects of NPY on mesencephalic V neurons (Mes V), which are important sensory neurons involved in oral motor reflexes and rhythmical jaw movements, as well as masticatory proprioception. Coronal brain slices were prepared from neonatal Sprague-Dawley rats (P3-17) and whole-cell patch clamp recordings were obtained from Mes V neurons. Bath application of NPY depolarized the membrane potential and induced inward current in most neurons. Application of NPY shortened the duration of the afterhyperpolarization following an action potential, and increased the mean spike frequency during repetitive discharge. In those neurons which exhibited rhythmical burst discharge in response to maintained current injection, the bursting frequency was also increased. These effects were mediated predominately by both Y1 and Y5 receptors.

Orexins (Oxs) are multifunctional neuropeptides, secreted from the lateral hypothalamus, that stimulate feeding behavior and energy expenditure. In this study, the direct effects of Oxs on the membrane properties of trigeminal motoneurons (TMNs) were examined, which critically participate in the genesis of rhythmical oral motor activities underlying suckling and mastication. Sprague-Dawley rats (3-6 day-old) were used to obtain whole-cell patch-clamp recordings from TMNs. Bath application of Ox-A depolarized the membrane potential and induced inward current, wherein Na+ and Ca2+ were charge carriers. Transient receptor potential channel activation potentially contributed to current and voltage responses by way of Ox-A. Ox-A increased the peak amplitude and duration at half-amplitude of the medium-duration after hyperpolarization following the action potential. The interspike frequency of steady-state firings during repetitive discharge was increased, along with a shift in the frequency-current relationship occurring toward the left. Extracellular and intracellular Ca2+ were involved in regulating modulatory effects, but a requisite level of intracellular Ca2+ was not essential for Ox-induced upregulation of the interspike frequency. Ox-A also enhanced conditional bursting induced by N-methyl-d-aspartate and 5-HT, suggesting it participates in modulating TMNs' discharge patterns during various oral motor activities.

This study used cone beam computed tomography (CBCT) images to comparatively evaluate the three-dimensional microstructural features of reconstructed bone bridge based on the bone harvesting site and the presence/absence of artificial bone material, as well as the features of regenerated bone tissue after bone harvesting from mandibular symphysis in secondary alveolar bone grafting (SABG) for patients with cleft lip, with or without cleft palate. Thirty-one patients were divided into three groups in which SABG was performed by autologous bone harvesting from iliac crest (IC), mandibular symphysis (MS), or MS combined with β-TCP granules (MS+TCP). The microstructural trabecular bone parameters (TBPs) and bone structure indexes (SIs) were analyzed using datasets of CBCT images taken before and after SABG. TBPs showed differences between IC and MS groups (P < 0.05), resulting in greater values of bone volume density (P < 0.05) and inferior value of TBPf (P = 0.070) in IC group compared with MS group. Using MS+TCP or filling β-TCP granules into donor site significantly improved reconstructed or regenerated BV/TV and Tb.Th (P < 0.05) compared with group without β-TCP. Microstructural characteristics of reconstructed bone bridge were dependent on the donor site of bone harvesting; using an absorbable bone conductive material improved bone quality and increased bone volume density. Application of β-TCP granules as a partial alternative with autologous bone from mandibular symphysis could obtain comparable outcomes in the microstructure of bone bridge to SABG with autologous iliac crest.

The epithelial-to-mesenchymal transition (EMT) is a critical process by which cancer cells acquire malignant features. However, the molecular mechanism and functional implications of EMT and the mesenchymal-to-epithelial transition (MET) in tumor progression remain elusive. In this study, we established two aggressive cancer cell lines from the human oral cancer cell line SAS, mesenchymal-like SAS-m4 and epithelial-like SAS-δ. SAS-δ is a revertant cell obtained by inducing MET in SAS-m4. SAS-δ, but not SAS-m4, exhibited abnormal cell growth, including piled-up overgrowth and invasive tumor formation in the tongues of nude mice, suggesting that SAS-δ represented more advanced cancer cells than the parental SAS cells. EMT-related transcriptional factor SLUG is phosphorylated at T208 and partly stabilized by the Hippo pathway kinases, LATS1 and LATS2. Depletion of SLUG promoted the invasive activity of SAS-δ by increasing the protein levels of LATS1/2 and the proportion of the phosphorylated form among total SLUG protein. Our results suggest that the LATS1/2–SLUG axis regulates the transition of SAS cells to the advanced stage via repeated switching between EMT and MET. Therefore, an anti-SLUG-pT208 antibody would be valuable not alone as a malignant tumor marker antibody but also as a prognostic tool for patients with malignant disease.

Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelial-mesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGF-β isoforms, TGF-β1, TGF-β2 and TGF-β3, all of which engage in pro-tumorigenic activities by activating SMAD signaling pathways. All TGF-β isoforms activate signaling pathways by binding to their TGF-β type I (TβRI) and type II (TβRII) receptors. Thus, effective targeting of all TGF-β isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TβRI and/or TβRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TβRI and TβRII (TβRI-TβRII-Fc) effectively trapped all TGF-β isoforms. Conversely, TβRII-Fc chimeric receptor, that comprises TβRII only, was able to interact with TGF-β1 and TGF-β3 isoforms, but not with TGF-β2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TβRI-TβRII-Fc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGF-β isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TβRII-Fc chimeric receptor inhibited the EMT program induced by TGF-β1 and TGF-β3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TβRI-TβRII-Fc chimeric receptor indicating that Fc chimeric receptor could be applied to modify the tumor microenvironment (TME) of melanoma. Therefore, designing of Fc chimeric receptors targeting TGF-β signals that affect various components of the TME may result in the development of effective anti-melanoma agents.