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The current dental curriculum in China was developed from the system in the Soviet Union in the 1950s. This curriculum is outdated and must be reformed to keep pace with the developments of modern dental education. The new dental educational system should be customized to China’s needs: care for a large population with poor overall oral health, operating within a government-owned, centralized health care delivery system. Chinese research universities have a mission to produce competent dentists who will also be educators and researchers. To efficiently train academic dentists who can also meet the clinical needs of today’s Chinese population, a new dental curriculum was developed at the Institute and Hospital of Dentistry, Nanjing University Medical School. This curriculum has four main features: 1) a two-year general higher education plus five-year dental education (“2+5”) model; 2) improved integration of didactic and practical learning; 3) improved integration of dental education with research training; and 4) improved overall sequencing of the entire curriculum. This article describes the details of this new dental curriculum.

Solid tumors often contain hypoxic and necrotic areas that can be targeted by attenuated Salmonella typhimurium VNP20009 (VNP). We sought to develop a hypoxia- inducible promoter system based on the tumor-specific delivered strain VNP to confine expression of therapeutic gene specifically or selectively within the tumor microenvironment. A hypoxia-inducible promoter - adhE promoter was screened from the hypoxia-regulated endogenous proteins of Salmonella through two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization-time-of-flight/time-of-flight MS-based proteomics approaches. The efficiency and specificity of the selected adhE promoter were validated first in both bacteria and animal tumor models. The adhE promoter could specifically drive GFP gene expression under hypoxia, but not under normoxia. Furthermore, luciferase reporter expression controlled by the system was also confined to the tumors. Finally, we investigated the anticancer efficacy of VNP delivering human endostatin controlled by our adhE promoter system in both murine melanoma and Lewis lung carcinoma models. Our results demonstrated that by the dual effects of tumoricidal and anti-angiogenic activities, the recombinant Salmonella strain could generate enhanced antitumor effects compared with those of unarmed VNP treatment or untreated control. The recombinant VNP could retard tumor growth significantly and extend survival of tumor-bearing mice by inducing more apoptosis and more severe necrosis as well as inhibiting blood vessel density within tumors. Therefore, VNP carrying the endostatin gene under our tumor-targeted expression system holds promise for the treatment of solid tumors.

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Tumor-targeting bacteria have been developed as powerful anticancer agents. Salmonella typhimurium VNP20009, a representative tumor-targeting strain, has been systemically administered as a single-agent therapy at doses of 1 x 10(6) to 3 x 10(6) colony-forming unit (cfu)/mouse, or in combination with other antitumor agents at doses of 1 x 10(4) to 2 x 10(5) cfu/mouse. Recently, we reported that oral delivery of VNP20009 at the dose of 1 x 10(9) cfu/mouse induced significant anticancer effects comparable to that induced by systemic administration of this strain at 1 x 10(4) cfu/mouse. To further address the efficacy and safety of oral administration of bacteria, here we performed a systemically comparative analysis of anticancer efficacy and toxicity of VNP20009 administered: (i) orally at a dose of 1 x 10(9) cfu/mouse (VNP9-oral); (ii) intraperitoneally at a dose of 1 x 10(4) cfu/mouse (VNP4-i.p.); or (iii) intraperitoneally at a dose of 1 x 10(6) cfu/mouse in tumor-free and tumor-bearing murine models. The results showed that VNP9-oral, similar to VNP4-i.p., induced significant tumor growth inhibition whereas VNP6-i.p. induced better anticancer effect in the B16F10 melanoma model. Among three treatments, VNP9-oral induced the mildest and reversible toxicity whereas VNP6-i.p. resulted in the most serious and irreversible toxicities when compared to other two treatments. Moreover, the combination of VNP9-oral with a low dose of chemotherapeutics produced comparable antitumor effects but displayed significantly reduced toxicity when compared to VNP6-i.p. The findings demonstrated that oral administration, as a novel avenue in the application of bacteria, is highly safe and effective. Moreover, the present preclinical study should facilitate the optimization of bacterial therapies with improved anticancer efficacy and reduced adverse effects in future clinical trials.

The treatment failures of oral squamous cell carcinoma (OSCC) are mostly local and regional recurrences. The aim was to estimate the prognosis of patients with recurrent OSCC through the prognostic staging system. We reviewed 81 patients with recurrent OSCC from April 1, 1999, to April 1, 2005. The independent prognostic factors for the patients with recurrent OSCC were identified by the univariate and multivariate Cox regression analyses. Then, to develop a prognostic staging system, and according to this staging system, the patients with recurrent OSCC were divided to 4 stages. By the Kaplan-Meier and log-rank statistical analyses, we found that the survival rate of patients with recurrent OSCC was significantly different at the different developmental stages. The primary TNM cancer stage before initial treatment, the extent of recurrence, and the recurrent tumor size are the independent prognostic factors for the patients with recurrent OSCC. Through this clinical study, the earlier-stage cases (stages I and II) for the patients with recurrent OSCC had a significantly better survival outcome compared with the advanced-stage cases (stages III and IV), and at the early recurrent stage, the salvage surgery represented a reliable and feasible treatment method.

Compartment syndrome is a rare donor-site morbidity of the free fibula osteocutaneous flap in mandibular reconstruction. A case is reported where the major complication of compartment syndrome occurred in a 34-year-old man when the donor site defect was closed primarily after taking a skin paddle with a width of 3 cm. Then an anterolateral thigh flap was designed to cover the donor left leg defect.

This paper presents a new method of designing restoration model of maxillectomy defect through Computer aided technology. Firstly, 3D maxillectomy triangle mesh model is constructed from Helical CT data. Secondly, the triangle mesh model is transformed into initial computer-aided design (CAD) model of maxillectomy through reverse engineering software. Thirdly, the 3D virtual restoration model of maxillary defect is obtained after designing and adjusting the initial CAD model through CAD software according to the patient's practical condition. Therefore, the 3D virtual restoration can be fitted very well with the broken part of maxilla. The exported design data can be manufactured using rapid prototyping technology and foundry technology. Finally, the result proved that this method is effective and feasible.

Aim: To explore the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in traumatic brain injury (TBI)-induced intestinal inflammatory response and gut barrier dysfunction in the mice. Methods: Wild-type Nrf2 (+/+) and Nrf2 (−/−)-deficient mice were subjected to a moderately severe weight-drop impact-acceleration head injury. We measured nuclear factor kappa B (NF-κB) by electrophoretic mobility shift assay (EMSA); tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) by enzyme-linked immunosorbent assay (ELISA); intercellular adhesion molecule-1 (ICAM-1) by immunohistochemistry; intestinal permeability by lactulose/mannitol (L/M) test; plasma endotoxin by chromogenic limulus amebocyte lysate test. Results: Intestinal levels of NF-κB, pro-inflammatory cytokines and ICAM-1 in Nrf2 (−/−)-deficient mice were significantly higher compared with Nrf2 (+/+) mice at 24 h after TBI. Furthermore, higher intestinal permeability and plasma level of endotoxin were observed in the Nrf2 (−/−) mice compared with Nrf2 (+/+) mice. Conclusion: Nrf2 plays an important protective role in limiting intestinal inflammatory response and gut barrier dysfunction after TBI.

FADD (Fas-associated death domain) has been widely expressed in various tissues and its expression has been recently demonstrated to correlate with tumour progression and prognosis. Currently, measurement of FADD expression mainly depends on Western-blot or immunohistochemical approaches. To develop a conventional sandwich ELISA avenue for the detection of FADD protein to supplement Western blotting or immunohistochemistry, a series of mAbs (monoclonal antibodies) specific for FADD protein, designated 3A3, 3F9, 3G4, 4B9, 4G1, 7A8, 7B8 and 7F4, were produced by fusing mouse s/p20 myeloma cells with the spleen cells of a mouse immunized with the Escherichia coli-expressed recombinant His(6)-FADD protein. On the basis of the characterization of these mAbs, purified 3F9 was selected as the capture antibody and the biotin-conjugated 3A3 was selected as the detection antibody in sandwich ELISA. The limit of detection for the ELISA was 0.3 ng of purified His(6)-FADD (FADD tagged with hexahistidine), and it could detect both recombinant and native human FADD protein. Furthermore, the positive reaction of the ELISA could be blocked by rabbit anti-FADD sera. All of these results indicated that the ELISA developed in the present paper could be a promising tool for detection of FADD protein.

The diagnosis of squamous cell carcinoma (SCC) of the tongue metastasising to the lingual lymph nodes is rare. Until now lingual lymph nodes have not been mentioned in any system of lymph node classification. We report a case of SCC of the tongue with metastases to the lymph nodes in the superficial floor of the mouth, and to levels I and II lymph nodes. We provide evidence of the existence of lingual lymph nodes, and validate the practice of removing the lymph node-bearing-tissue of the floor of the mouth during neck dissection in cancers of the oral cavity.

Human S-phase kinase-associated protein (skp) 2, the specific ubiquitin ligase subunit that targets the negative regulator p27 Kip1 of the cell cycle and brings about its degradation, is overexpressed in various cancers, including human oral squamous cell carcinomas; its expression levels are inversely related to those of p27 Kip1 in these cells. Recently, a technique known as RNA interference (RNAi) has successfully been applied to mammalian cells. In order to evaluate the applications of the RNAi strategy for cancer gene therapy, the authors treated Tca8113 cells expressing high levels of Skp2 with a small interfering RNA (siRNA) expression plasmid vector targeting skp2 in vitro and in vivo. They demonstrated that the Skp2 protein levels decreased, while the p27 Kip1 protein levels increased in Tca8113 cells transfected with skp2siRNA. Further, skp2siRNA inhibited growth in the Tca8113 cells in vitro and suppressed tumor proliferation in vivo. These results suggest that siRNA-mediated silencing of the skp2 gene may represent a useful strategy for gene therapy of tumors expressing high levels of Skp2.

Hang Su,1,* Qiong Luo,2,* Hao Xie,3 Xiaofeng Huang,1 Yanhong Ni,1 Yongbin Mou,1 Qingang Hu1,4 1Center Laboratory of Stomatology, Stomatological Hospital Affiliated Medical School, 2State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 3Institute of Life Sciences, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, People’s Republic of China; 4Leeds Dental Institute, Faculty of Medicine and Health, University of Leeds, Leeds, UK *These authors contributed equally tothis work Purpose: Vaccines play important roles in antitumor biotherapy. Autophagy in tumor cells plays a critical role in depredating proteins, including tumor-specific antigens and tumor-associated antigens. We aimed to induce and collect tumor-derived autophagosomes (DRibbles) from tumor cells as a novel antitumor vaccine by inhibiting the functions of proteasomes and lysosomes.Materials and methods: DRibbles were prepared and their morphological and autophagic properties characterized. Dendritic cells (DCs) generated from the bone marrow monocytes of mice were cocultured with DRibbles, then surface molecules of DCs and B cells, as well as apoptosis of DCs, were determined by flow cytometry. Meanwhile, functional properties of the DRibble-DCs were examined by mixed lymphocyte reactions and animal experiments.Results: The diameter of autophagic nanoparticles with spherical and double-membrane structure was between 200 nm and 500 nm. DRibbles resulted in the upregulation of costimulatory molecules CD40 and CD86 as well as major histocompatibility complex (MHC)-I molecules on DCs, but not MHC-II. The expressions of CD40, CD80, and CD86 and that of MHC-II molecules on B cells were also upregulated. Moreover, suppression of tumor growth and lifetime prolongation was observed in DRibble-DC-vaccinated tumor-bearing mice.Conclusion: Our results demonstrate that naïve T cells can be activated effectively by DC cross-presenting antigens on upregulated MHC-I, suggesting that DRibbles be deployed as an effective antitumor vaccine for head and neck cancer immunotherapy in clinical trials. Keywords: autophagy, nanoparticles, dendritic cells, antitumor immunity, head and neck cancer

To evaluate the effect of locoregional immunotherapy of interleukin 2 (IL-2) in combination with chemotherapy upon intratumoral lymphocytes in oral squamous cell carcinomas.Thirty-four patients with stage T3 or T4 oral squamous cell carcinoma were randomly divided into two groups, and treated with two therapies. 23 cases of them received immunochemotherapy and 11 cases received PVP chemotherapy. Changes of T lymphocyte subsets and B cells at tumor site in the two groups were compared before and after therapy.The relative numbers of CD4+, CD8+, CD20+ before and after treatment in immunochemotherapy were respectively 36.96, 35.65, 28.65 and 56.61, 38.52, 38.70. The numbers of CD4+, CD20+ increased significantly after immunochemotherapy. However, in chemotherapy group, there was no significant difference in numbers of CD4+, CD8+ and CD20+ cells between pre and post treatment.Immunochemotherapy for oral squamous cell carcinomas may play an important role in increasing local immunity.

The internal jugular vein (IJV) has been described as the optimal recipient vessel in oral and maxillofacial microsurgical rehabilitation and reconstruction. However, few studies have been reported on IJV thrombosis, which could compromise flap survival. In the current study, a case of flap vascular crisis following IJV thrombosis is presented, and salvage operation as a management strategy is discussed. Although rare, surgeons specializing in oral and maxillofacial microsurgical reconstruction should be aware of the possibility of the occurrence of this condition, considering early surgical intervention is critical.

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase critically involved in cancer metastasis. We found an elevation of FAK expression in highly metastatic melanoma B16F10 cells compared with its less metastatic partner B16F1 cells. Down-regulation of the FAK expression by either small interfering RNA or dominant negative FAK (FAK Related Non-Kinase, FRNK) inhibited the B16F10 cell migration in vitro and invasiveness in vivo. The mechanism by which FAK activity is up-regulated in highly metastatic cells remains unclear. In this study, we reported for the first time that one of the Est family proteins, PEA3, is able to transactivate FAK expression through binding to the promoter region of FAK. We identified a PEA3-binding site between nucleotides −170 and +43 in the FAK promoter that was critical for the responsiveness to PEA3. A stronger affinity of PEA3 to this region contributed to the elevation of FAK expression in B16F10 cells. Both in vitro and in vivo knockdown of PEA3 gene successfully mimicked the cell migration and invasiveness as that induced by FAK down-regulation. The activation of the well-known upstream of PEA3, such as epidermal growth factor, JNK, and ERK can also induce FAK expression. Furthermore, in the metastatic human clinic tumor specimens from the patients with human primary oral squamous cell carcinoma, we observed a strong positive correlation among PEA3, FAK, and carcinoma metastasis. Taking together, we hypothesized that PEA3 might play an essential role in the activation of the FAK gene during tumor metastasis.

Yongbin Mou1, Yayi Hou2, Baoan Chen3, Zichun Hua4, Yu Zhang5, Hao Xie2, Guohua Xia3, Zhiyong Wang1, Xiaofeng Huang1, Wei Han1, Yanhong Ni1, Qingang Hu1,6 1Central Laboratory of Stomatology, Stomatological Hospital Affiliated Medical School, Nanjing University, Nanjing, People's Republic of China; 2Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, Nanjing, People's Republic of China; 3Department of Hematology, Zhongda Hospital, Medical School, Southeast University, Nanjing, People's Republic of China; 4Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, People's Republic of China; 5State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, Nanjing, People's Republic of China; 6Leeds Dental Institute, Faculty of Medicine and Health, University of Leeds, Leeds, UK Background: Successful treatment of cancer with dendritic cell tumor vaccine is highly dependent on how effectively the vaccine migrates into lymph nodes and activates T cells. In this study, a simple method was developed to trace migration of dendritic cells to lymph nodes. Methods: Superparamagnetic iron oxide (SPIO) of γ-Fe2O3 nanoparticles were prepared to label dendritic cells generated from bone marrow of enhanced green fluorescent protein (EGFP) transgenic mice, to explore the fluorescence intensity of EGFP influenced by the SPIO, and to make images of labeled dendritic cells with the help of magnetic resonance imaging in vitro. The SPIO-EGFP-labeled dendritic cells were injected into the footpads of five mice. After 48 hours, magnetic resonance imaging, optical imaging, confocal imaging, and Prussian blue staining were used to confirm migration of the SPIO-EGFP-labeled dendritic cells into draining lymph nodes. Results: The synthetic SPIO nanoparticles had a spherical shape and desirable superparamagnetism, and confocal imaging and Prussian blue staining showed perfect labeling efficiency as well. Furthermore, the dendritic cells dual-labeled by SPIO and EGFP could migrate into lymph nodes after footpad injection, and could be detected by both magnetic resonance imaging and optical imaging simultaneously, which was further confirmed by immunohistochemistry and Prussian blue staining. The percentage of dendritic cells migrated to the draining lymph nodes was about 4%. Conclusion: Synthetic SPIO nanoparticles are strong contrast agents with good biocompatibility, and EGFP transgenic dendritic cells can be labeled efficiently by SPIO, which are suitable for further study of the migratory behavior and biodistribution of dendritic cells in vivo. Keywords: magnetic resonance imaging, optical imaging, dendritic cell, superparamagnetic iron oxide, cell tracking

Yongbin Mou1, Baoan Chen2, Yu Zhang3, Yayi Hou4, Hao Xie4, Guohua Xia2, Meng Tang5, Xiaofeng Huang1, Yanhong Ni1, Qingang Hu1,6 1Central Laboratory of Stomatology, Stomatological Hospital Affiliated Medical School, Nanjing University, 2Department of Hematology, Zhongda Hospital, Medical School, Southeast University, 3State Key Laboratory of Bioelectronics, Jiangsu Key Laboratory for Biomaterials and Devices, Southeast University, 4Immunology and Reproductive Biology Laboratory, Medical School, Nanjing University, 5Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China; 6Leeds Dental Institute, Faculty of Medicine and Health, University of Leeds, Leeds, UK Background: This study investigated the influence of synthetic superparamagnetic iron oxide (SPIO) on dendritic cells and provides a possible method for labeling these cells. Methods: SPIO nanoparticles were prepared, and their morphology and magnetic properties were characterized. The particles were endocytosed by dendritic cells generated from mouse bone marrow. Labeling efficiency and cellular uptake were analyzed by Prussian blue staining and quantitative spectrophotometric assay. Meanwhile, the surface molecules, cellular apoptosis, and functional properties of the SPIO-labeled dendritic cells were explored by flow cytometry and the mixed lymphocyte reaction assay. Results: The synthetic nanoparticles possessed a spherical shape and good superparamagnetic behavior. The mean concentration of iron in immature and mature dendritic cells was 31.8 ± 0.7 µg and 35.6 ± 1.0 µg per 1 × 106 cells, respectively. After 12 hours of incubation with SPIO at a concentration of 25 µg/mL, nearly all cells were shown to contain iron. Interestingly, cellular apoptosis and surface expression of CD80, CD86, major histocompatibility II, and chemokine receptor 7 in mature dendritic cells were not affected to any significant extent by SPIO labeling. T cell activation was maintained at a low ratio of dendritic cells to T cells. Conclusion: SPIO nanoparticles have good superparamagnetic behavior, highly biocompatible characteristics, and are suitable for use in further study of the migratory behavior and biodistribution of dendritic cells in vivo. Keywords: superparamagnetic iron oxide, dendritic cell, cell labeling

Here we report two unrelated Chinese families with congenital missing teeth inherited in an X-linked manner. We mapped the affected locus to chromosome Xp11-Xq21 in one family. In the defined region, both families were found to have novel missense mutations in the ectodysplasin-A (EDA) gene. The mutation of c.947A>G caused the D316G substitution of the EDA protein. The mutation of c.1013C>T found in the other family resulted in the Thr to Met mutation at position 338 of EDA. The EDA gene has been reported responsible for X-linked hypohidrotic ectodermal dysplasia (XLHED) in humans characterized by impaired development of hair, eccrine sweat glands, and teeth. In contrast, all the affected individuals in the two families that we studied here had normal hair and skin. Structural analysis suggests that these two novel mutants may account for the milder phenotype by affecting the stability of EDA trimers. Our results indicate that these novel missense mutations in EDA are associated with the isolated tooth agenesis and provide preliminary explanation for the abnormal clinical phenotype at a molecular structural level.