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A new individualized, cost-effective, modified semi-computer-assisted surgery (MSCAS) concept for free fibular flap mandibular reconstruction is reported and compared with the computer-assisted surgery (CAS) concept. Patients were divided into two groups and retrospectively reviewed. In the MSCAS and CAS groups, intraoperative guides were created using computer-aided design with manual fabrication and computer-aided design and manufacturing, respectively. Differences in specific linear and angular parameters on pre- and postoperative computed tomography scans were calculated for morphometric comparison, and clinical parameters and efficiency were analysed. RESULTS: Eighteen patients (CAS, 7; MSCAS, 11), were included. The morphometric comparison showed no significant differences between the groups. The mean deviation of the mandibular ramus length, body length, width 1 and width 2 was 0.82 ± 0.29 mm, 1.84 ± 0.43 mm, 1.89 ± 0.61 mm and 1.45 ± 0.61 mm in the CAS group versus 1.56 ± 0.54 mm, 1.72 ± 0.33 mm, 2.24 ± 0.55 mm and 2.36 ± 0.50 mm in the MSCAS group (p = 0.7804, p = 0.9997, p = 0.9814 and p = 0.6334). The mean deviation of the sagittal, axial and coronal mandibular angles was 1.56 ± 0.48°, 1.93 ± 0.50° and 2.15 ± 0.72° in the CAS group versus 2.19 ± 0.35°, 1.86 ± 0.35° and 1.94 ± 0.55° in the MSCAS group (p = 0.7594, p = 0.9996 and p = 0.9871). There were no significant differences in clinical parameters, efficiency or postoperative complications between the groups. CONCLUSION: The accuracy and operative efficiency of the MSCAS concept are comparable to those of the more expensive CAS concept. Therefore, in times of increasing clinical costs, this concept might be an adequate and inexpensive alternative to preoperative CAS.

Growing evidence indicates that the non-coding 3'-untranslated region (3'UTR) of genes acts as competing endogenous RNAs (ceRNAs) to exert their roles in a number of diseases, including cancer. In the present study, MMP1 messenger RNA was identified to be significantly up-regulated in oral squamous cell carcinoma (OSCC) tissues, and both MMP1 and its 3'UTR promoted tumor growth and cell motility. Further mechanism investigations indicated that MMP1 3'UTR was able to antagonize miR-188-5p; in addition, overexpression of MMP1 3'UTR up-regulated the expression level of SOX4 and CDK4, target genes of miR-188-5p, which have also been identified as oncogenic driver genes in OSCC. Therefore, a ceRNA regulatory network among MMP1, SOX4, and CDK4 mediated via competing for binding to miR-188-5p was proved. Taken together, the present study demonstrates for the first time that MMP1 mRNA participates in the development of OSCC via ceRNA regulatory mechanism and genes involved in the ceRNA network may provide a novel avenue for target therapy.

Background Tooth regeneration depends on the longevity of the dental epithelial lamina. However, the exact mechanism of dental lamina regression has not yet been clarified. To explore the role of the sonic hedgehog (Shh) signaling pathway in regression process of the rudimentary successional dental lamina (RSDL) in mice, we orally administered a single dose of a Shh signaling pathway inhibitor to pregnant mice between embryonic day 13.0 (E13.0) and E17.0. Results We observed that the Shh signaling pathway inhibitor effectively inhibited the expression of Shh signaling pathway components and revitalized RSDL during E15.0-17.0 by promoting cell proliferation. In addition, mRNA-seq, RT-qPCR, and immunohistochemical analyses indicated that diphyodontic dentition formation might be related to FGF signal upregulation and the Sostdc1-Wnt negative feedback loop. Conclusion Overall, our results indicated that the Shh signaling pathway may play an initial role in preventing further development of mouse RSDL in a time-dependent manner. This article is protected by copyright. All rights reserved.

The Hedgehog (Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development. Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 mg•kg−1 or 150 mg•kg−1 body weight at preselected time points between embryonic days (E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg•kg−1. Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death., Bone Development: Critical period for Hedgehog pathway in bone development During embryonic development, the Hedgehog signalling pathway regulates the migration, proliferation and differentiation of cranial neural crest cells in the early frontal bone. The Hedgehog signalling pathway transmits information to embryonic cells for their proper cell differentiation, and increased or reduced function of that signalling results in various craniofacial malformations. A team headed by Weihui Chen at Fujian Medical University in China investigated the patterns of abnormalities caused by inhibition of Hedgehog signalling in pregnant mice at preselected embryonic time points. The team was able to identify the critical period for sensitivity to GDC-0449, a potent Hedgehog signalling inhibitor. The authors believe that their mouse model can be effective in further investigating the mechanisms of craniofacial malformations and will have a profound impact on identifying candidate human disease genes and associated environmental factors.

This review introduces Robert Putnam’s article “Diplomacy and Domestic Politics: The Logic of Two Level Games” and analyzes its merits and limitations. Putnam’s article is an approach to analyzing international foreign policy beyond the state-centric assumption and placing focus on domestic factions, which are pillar causes determining the ‘ratification’ of international agreements. Diplomacy, in Putnam’s view, is not only the affairs for professional diplomats, but also a public agenda for various social groups, thus the “win-set” in negotiation of a state actor should be determined by their respective domestic situations. The review concedes that Putnam’s idea is comprehensive and provides new foundations for IR research after the system-based approach, but his comprehensiveness is also a defect for his theory compared with his latecomers.

Background The hedgehog signaling pathway is critical for developmental patterning of the limb, craniofacial and axial skeleton. Disruption of this pathway in mice leads to a series of structural malformations, but the exact role and critical period of the Hh pathway in the early development of the cranial base have been rarely described. Results Embryos exposed to vismodegib from E7.5, E9.5, and E10.5 had a higher percentage of cranial base fenestra. The peak incidence of hypoplasia in sphenoid winglets and severe craniosynostosis in cranial base synchondroses was observed when vismodegib was administered between E9.5 and E10.5. Cranial base craniosynostosis results from accelerating terminal differentiation of chondrocytes and premature osteogenesis. Conclusions We define the critical periods for the induction of cranial base deformity by vismodegib administration at a meticulous temporal resolution. Our findings suggest that the Hh pathway may play a vital role in the early development of the cranial base. This research also establishes a novel and easy-to-establish mouse model of synostosis in the cranial base using a commercially available pathway-selective inhibitor.

Background Gain-of- and loss-of-function studies have demonstrated that changes in bone morphogenetic protein (BMP) signaling during embryo development cause craniofacial malformations, including cleft palate. It remains uncertain whether BMP signaling could be targeted pharmacologically to affect craniofacial morphogenesis. Methods Pregnant C57Bl/6J mice were treated with the BMP type I receptor inhibitor LDN-193189 at the dose of 3, 6, or 9 mg/kg twice a day by intraperitoneal injection from embryonic day 10.5 (E10.5) to E15.5. At E16.5, embryos were investigated by facial measurement analysis and histology to determine the optimal concentration for malformation. Subsequent embryonic phenotypes were analyzed in detail by histology, whole-mount skeletal staining, micro-computed tomography, and palatal organic culture. We further used immunohistochemistry to analyze protein expression of the BMP-mediated canonical and noncanonical signaling components. Results The optimal concentration of LDN-193189 was determined to be 6 mg/kg. In utero, LDN-193189 exposures induced partial clefting of the anterior palate or complete cleft palate, which was attributed to a reduced cell proliferation rate in the secondary palate, and delayed palatal elevation caused by micrognathia. Analysis of signal transduction in palatal shelves at E12.5 and E13.5 identified a significant reduction of BMP/Smad signaling (p-Smad1/5/8) and unchanged BMP noncanonical signaling (p-p38, p-Erk1/2) after treatment with LDN-193189. Conclusion The results of this study indicate that LDN-193189 can be used to manipulate BMP signaling by selectively targeting the BMP/Smad signaling pathway to affect palatal morphogenesis and produce phenotypes mimicking those caused by genetic mutations. This work established a novel mouse model for teratogen-induced cleft palate. Birth Defects Research (Part A) 106:612–623, 2016. © 2016 Wiley Periodicals, Inc.

Purpose This study aimed to investigate the feasibility of adopting the ThormalGEN surgical patch (a porcine decellularized pericardial patch) in the superficial parotidectomy to prevent postoperative Frey's syndrome in patients with benign parotid tumor. Materials and methods A total of 59 patients with benign parotid tumor undergoing superficial parotidectomy between April 2016 and January 2017 were enrolled, and divided into the ThormalGEN group (n = 37) and the control group (n = 22) based on their willingness to have the ThormalGEN surgical patch used in the superficial parotidectomy. At 6 months postoperation, the incidences of postoperative complications and Frey's syndrome were assessed by subjective assessment (patient self-assessment) and objective assessment (starch-iodine test), respectively. The risk factor of Frey's syndrome was analyzed by the multivariate logistic regression model. Results The starch-iodine test, for objective assessment, showed that the ThormalGEN group had a significantly lower incidence of Frey's syndrome than the control group (8.11% vs. 40.91%, p = 006). However, in the patient self-assessment, there was no significant difference in the incidence of Frey's syndrome between groups (8.11% [3/37] vs. 13.64% [3/22], p = 0.4968). The incidences of postoperative complications were not significantly different between group (all p > 0.05). Two patients (5.41%) in the ThormalGEN group had salivary fistula. Multivariate logistic regression analysis showed that the ThormalGEN group had a significantly lower risk of Frey's syndrome than the control group (odds ratio = 0.11, 95% confidence interval = 0.02–0.51, p Conclusion These results suggest that the ThormalGEN surgical patch can effectively reduce the incidence of Frey's syndrome following superficial parotidectomy in patients with benign parotid tumor, and that this patch has a good safety and biocompatibility profile.

The function of hedgehog signaling has previously been shown to be crucial for craniofacial development. In this study, we treated C57/BL6J mice with the hedgehog pathway inhibitor vismodegib by oral gavage to establish a stable vismodegib-induced cleft palate model. At E10.5 and E12.5, mice in the experimental group were treated with 100 mg/kg of vismodegib, whereas mice in the control group were treated with solvent. The treated pregnant mice were sacrificed on E13.5, E14.5, E15.5, and E16.5. Palatal shelf growth was evaluated via histological and immunohistochemical analyses as well as palatal organ culture. Immunohistochemical staining was performed to examine the expression of osteogenic proteins in the palatal tissue. A high proportion of the mice administered 2 doses of 100 mg/kg of vismodegib displayed a cleft palate. Histologic examination revealed severely retarded palatal shelf growth and thickened epithelium in the experimental group. Vismodegib exposure induced complete cleft palate, which was attributed to a reduced cell proliferation rate in the palatal mesenchyme along the anterior-posterior axis. Moreover, this model also showed delayed ossification in the region of palatine bone with downregulation of Indian hedgehog (Ihh) protein. Our results suggest that vismodegib can be used to inhibit hedgehog signaling to affect palatal morphogenesis. Under treatment with this exogenous inhibitor, the cell proliferation rate of the palatal shelves and the osteogenic potential of the hard palate were decreased, which likely contributed to the complete cleft palate.