Hiromasa Kawana

xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma

The targeting of antioxidant systems that allow stem-like cancer cells to avoid the adverse consequences of oxidative stress might be expected to improve the efficacy of cancer treatment. Here, we show that head and neck squamous cell carcinoma (HNSCC) cells that express variant isoforms of CD44 (CD44v) rely on the activity of the cystine transporter subunit xCT for control of their redox status. xCT inhibition selectively induces apoptosis in CD44v-expressing tumor cells without affecting CD44v-negative differentiated cells in the same tumor. In contrast to CD44v-expressing undifferentiated cells, CD44v-negative differentiated cells manifest EGF receptor (EGFR) activation and rely on EGFR activity for their survival. Combined treatment with inhibitors of xCT-dependent cystine transport and of EGFR resulted in a synergistic reduction of EGFR-expressing HNSCC tumor growth. Thus, xCT-targeted therapy may deplete CD44v-expressing undifferentiated HNSCC cells and concurrently sensitize the remaining differentiating cells to available treatments including EGFR-targeted therapy.

Cell fusion in osteoclasts plays a critical role in controlling bone mass and osteoblastic activity

The balance between osteoclast and osteoblast activity is central for maintaining the integrity of bone homeostasis. Here we show that mice lacking dendritic cell specific transmembrane protein (DC-STAMP), an essential molecule for osteoclast cell-cell fusion, exhibited impaired bone resorption and upregulation of bone formation by osteoblasts, which do not express DC-STAMP, which led to increased bone mass. On the contrary, DC-STAMP over-expressing transgenic (DC-STAMP-Tg) mice under the control of an actin promoter showed significantly accelerated cell-cell fusion of osteoclasts and bone resorption, with decreased osteoblastic activity and bone mass. Bone resorption and formation are known to be regulated in a coupled manner, whereas DC-STAMP regulates bone homeostasis in an un-coupled manner. Thus our results indicate that inhibition of a single molecule provides both decreased osteoclast activity and increased bone formation by osteoblasts, thereby increasing bone mass in an un-coupled and a tissue specific manner.

Purified Human Dental Pulp Stem Cells Promote Osteogenic Regeneration

Human dental pulp stem/progenitor cells (hDPSCs) are attractive candidates for regenerative therapy because they can be easily expanded to generate colony-forming unit–fibroblasts (CFU-Fs) on plastic and the large cell numbers required for transplantation. However, isolation based on adherence to plastic inevitably changes the surface marker expression and biological properties of the cells. Consequently, little is currently known about the original phenotypes of tissue precursor cells that give rise to plastic-adherent CFU-Fs. To better understand the in vivo functions and translational therapeutic potential of hDPSCs and other stem cells, selective cell markers must be identified in the progenitor cells. Here, we identified a dental pulp tissue–specific cell population based on the expression profiles of 2 cell-surface markers LNGFR (CD271) and THY-1 (CD90). Prospectively isolated, dental pulp–derived LNGFRLow+THY-1High+ cells represent a highly enriched population of clonogenic cells—notably, the isolated cells exhibited long-term proliferation and multilineage differentiation potential in vitro. The cells also expressed known mesenchymal cell markers and promoted new bone formation to heal critical-size calvarial defects in vivo. These findings suggest that LNGFRLow+THY-1High+ dental pulp–derived cells provide an excellent source of material for bone regenerative strategies.

Telerobotic-assisted bone-drilling system using bilateral control with feed operation scaling and cutting force scaling

Drilling is used in the medical field, especially in oral surgery and orthopaedics. In recent years, oral surgery involving dental implants has become more common. However, the risky drilling process causes serious accidents. To prevent these accidents, supporting systems such as robotic drilling systems are required.

TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFα is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wild-type mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFα-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFα treatment, suggesting that TNFα maintains AX cells in an undifferentiated state. TNFα inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFα inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1α/IL-1β doubly deficient mice. We found that both TNFα and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFα/IL-1 and ERK may represent therapeutic targets for osteosarcoma.

A comparison of stresses in implantation for grafted and plate-and-screw mandible reconstruction.

OBJECTIVE During oral rehabilitation by dental implantation for mandibles reconstructed with plate and screws, intensified stresses can develop at the implant-bone interfaces and fixation screw-bone interfaces that might cause complications at these interfaces. The present study aims to evaluate the stresses occurring at these sites using the finite element method. STUDY DESIGN Ten computer-aided design models simulating 10 mandibles were produced and were termed normal models. Simulation surgery was performed on these normal models, where parts of the models were removed and replaced by fibula or reconstruction plates plus screws. Depending on the replaced part (body [B] or body and symphysis [BS]) and the reconstruction materials (fibula [Fib] or reconstruction plate [Plate]), the modified models were termed B-Fib, B-Plate, BS-Fib, and BS-Plate models, respectively. For each model, an implant was embedded in the first molar region. Stresses occurring at the implant-bone interfaces and fixation screw-bone interfaces on mastication were calculated using the finite element method and compared among the model groups. RESULTS The stresses at the implant-bone interfaces showed no statistically significant differences among the 5 model groups. With the B-Plate and BS-Plate models, stresses at the fixation screw-bone interfaces were nearly twice as intense as those at the implant-bone interfaces. CONCLUSION If it is allowed that complication risks correlate with stresses, fixation screws are more subject to failure than implants in performing implantation for mandibles reconstructed with a plate and fixation screws. Therefore, the fixation screws deserve special attention in performing oral rehabilitation for such patients.

PDGFBB promotes PDGFRα-positive cell migration into artificial bone in vivo

Bone defects caused by traumatic bone loss or tumor dissection are now treated with auto- or allo-bone graft, and also occasionally by artificial bone transplantation, particularly in the case of large bone defects. However, artificial bones often exhibit poor affinity to host bones followed by bony union failure. Thus therapies combining artificial bones with growth factors have been sought. Here we report that platelet derived growth factor bb (PDGFBB) promotes a significant increase in migration of PDGF receptor α (PDGFRα)-positive mesenchymal stem cells/pre-osteoblastic cells into artificial bone in vivo. Growth factors such as transforming growth factor beta (TGFβ) and hepatocyte growth factor (HGF) reportedly inhibit osteoblast differentiation; however, PDGFBB did not exhibit such inhibitory effects and in fact stimulated osteoblast differentiation in vitro, suggesting that combining artificial bones with PDGFBB treatment could promote host cell migration into artificial bones without inhibiting osteoblastogenesis.

Complicated surgical resection of malignant tumors in the upper cervical spine after failed ion-beam radiation therapy.

Study Design. Case report. Objective. To report 3 cases of malignant tumors in the upper cervical spine that were treated surgically by a combination of posterior tumor resection and stabilization and anterior tumor resection through a mandible-splitting approach after failed ion-beam radiation therapy. Summary of Background Data. Few clinical reports have described in detail the postoperative complications associated with transoral surgical resection of tumors in the upper cervical spine after unsuccessful ion-beam radiation therapy. Methods. Three patients with malignant tumors in the upper cervical spine who had undergone ion-beam radiotherapy and experienced tumor recurrence were treated by a combination of posterior and anterior surgery through a mandible-splitting approach. One patient (patient 1, a 32-year-old man) had a hemangioendothelioma at the C2 and C3 level, whereas the other 2 patients (patient 2, a 66-year-old woman and patient 3, a 65-year-old man) had a chordoma at the C2 and C3 level. Results. The intralesional but macroscopic total resection of the tumors was achieved in all 3 patients. However, serious complications developed after surgery, including deep wound infection, cerebrospinal fluid leakage, and meningitis in patient 1, prolonged swallowing difficulty, subsidence of the strut graft, and recurrence in patient 2, and deep wound infection and discitis causing progressive paralysis in patient 3. All patients underwent salvage surgery, including debridement of the wound in patient 1, posterior reinforcement using instrumentation and posterior tumor resection for the recurrent tumor in patient 2, and anterior debridement of the wound with a pedicle flap using the pectoral major muscle in patient 3 to address these problems. Patients 1 and 3 had no signs of recurrence at the time of a follow-up examination. Conclusion. Severe complications, mainly associated with the disturbance in healing of the retropharyngeal wall, were observed in all 3 patients. A preventive method, such as primary repair of the retropharyngeal wall using muscular/musculocutaneous flaps, should be considered for patients undergoing resection through a transoral approach after ion-beam irradiation.

Perspectives of teleconsultation in craniomaxillofacial surgery.

The application of computer technology in craniomaxillofacial surgery has opened new perspectives in preoperative planning and accurate intraoperative realization of treatment concepts. To simulate the postoperative outcome, the treatment plan is based on 3-dimensional (3D) visualization of computed tomography (CT) or cone-beam CT data. To transfer the implant simulation to the patient, passive navigation with the help of surgical guides or active navigation with real feedback during surgery is used. 1-3 Both concepts show similar accuracy in vitro 4 because the simulation of dental implant position is based on CT or cone-beam CT data. In vivo accuracy can be compromised by patient head movement during scan acquisition 5 and limitations of CT accuracy. 6,7 The transmission of digital imaging data and the corresponding treatment plan via telecommunication have opened new horizons for telemedicine in diagnosis and care delivery. In the case of image-guided surgery, the preoperative 3D simulation combined with the realtime display of the virtual instrument 3D position relative to the patient’s anatomy that guides the surgeon during surgery can be transmitted via high-speed transmission networks. There are 2 ways to convey the knowledge and the physical skill of a surgeon over long distances: telesurgery or teleconsultation. Telesurgery is performed

Applications of Mesenchymal Stem Cells and Neural Crest Cells in Craniofacial Skeletal Research

Craniofacial skeletal tissues are composed of tooth and bone, together with nerves and blood vessels. This composite material is mainly derived from neural crest cells (NCCs). The neural crest is transient embryonic tissue present during neural tube formation whose cells have high potential for migration and differentiation. Thus, NCCs are promising candidates for craniofacial tissue regeneration; however, the clinical application of NCCs is hindered by their limited accessibility. In contrast, mesenchymal stem cells (MSCs) are easily accessible in adults, have similar potential for self-renewal, and can differentiate into skeletal tissues, including bones and cartilage. Therefore, MSCs may represent good sources of stem cells for clinical use. MSCs are classically identified under adherent culture conditions, leading to contamination with other cell lineages. Previous studies have identified mouse- and human-specific MSC subsets using cell surface markers. Additionally, some studies have shown that a subset of MSCs is closely related to neural crest derivatives and endothelial cells. These MSCs may be promising candidates for regeneration of craniofacial tissues from the perspective of developmental fate. Here, we review the fundamental biology of MSCs in craniofacial research.