Fine structural human phantom in dentistry and instance tooth segmentation

In this study, we present the development of a fine structural human phantom designed specifically for applications in dentistry. This research focused on assessing the viability of applying medical computer vision techniques to the task of segmenting individual teeth within a phantom. Using a virtual cone-beam computed tomography (CBCT) system, we generated over 170,000 training datasets. These datasets were produced by varying the elemental densities and tooth sizes within the human phantom, as well as varying the X-ray spectrum, noise intensity, and projection cutoff intensity in the virtual CBCT system. The deep-learning (DL) based tooth segmentation model was trained using the generated datasets. The results demonstrate an agreement with manual contouring when applied to clinical CBCT data. Specifically, the Dice similarity coefficient exceeded 0.87, indicating the robust performance of the developed segmentation model even when virtual imaging was used. The present results show the practical utility of virtual imaging techniques in dentistry and highlight the potential of medical computer vision for enhancing precision and efficiency in dental imaging processes.


A dual composite resin injection molding technique with 3D-printed flexible indices for biomimetic replacement of a missing mandibular lateral incisor.

The bilayered direct composite RBFPD using 3D printed flexible indices prepared with a full digital workflow has several advantages over other dental prosthetic solutions, including noninvasiveness, cost-effectiveness, biomimetic esthetics, repairability, and shortened treatment times. Although the initial results are promising, further longitudinal studies with larger patient cohorts are required to confirm the long-term efficacy of this approach.


Digitally Guided Direct Composite Injection Technique with a Bi-layer Clear Mini-Index for the Management of Extensive Occlusal Caries in a Pediatric Patient: A Case Report.

The injection technique with a bi-layer clear mini-index accurately translated the digital wax-ups into large, final restorations. Precise morphology and shortened chair time enhanced patient satisfaction, but at the expense of multiple visits.


術後に顎関節に疼痛を訴えた顎偏位を伴う骨格性上顎前突症例

術後に顎関節に疼痛を訴えた顎偏位を伴う骨格性上顎前突症例

The Journal of Chu-Shikoku Orthodontic Society

中·四国矯正歯科学会雑誌


上顎左側第二小臼歯先天欠如を伴う片側性唇顎口蓋裂患者に対して下顎左側第二小臼歯を移植した一症例．

中·四国矯正歯科学会雑誌


Restoration of a Microdont Using the Resin Composite Injection Technique With a Fully Digital Workflow: A Flexible 3D-printed Index With a Holding Clip.

Direct composite restorations are accepted as a treatment option for microdontia, which is a relatively prevalent condition that poses esthetic concerns. While free-hand composite placement is technique-sensitive and time-consuming, the resin composite injection technique is more straightforward and predictable. A fully digital workflow has been recently introduced, but the 3D-printed resin index is rigid and challenged by undercuts, as opposed to the silicone index. This case report presents a flexible 3D-printed resin index, which can accurately transfer the digitally simulated functional and esthetic form to the final restoration. In addition, a rigid holding clip was designed to stabilize the flexible index.


A patient with unilateral posterior crossbite treated with modified unilateral surgically-assisted rapid maxillary expansion.


Nonsurgical orthodontic treatment for a patient with Sotos syndrome.

Sotos syndrome is a genetic disorder characterized by overgrowth in childhood, specific facial manifestations, advanced bone age, and mental retardation. The purpose of this article is to describe the nonsurgical orthodontic treatment of a 10-year-old boy with a skeletal mandibular protrusion, unilateral posterior crossbite, and Sotos syndrome. After maxillary lateral expansion, the skeletal Class III relationship with an anterior crossbite improved because of mandibular clockwise rotation, whereas the facemask had a marginal effect. After growth at 16 years, he had a skeletal Class I relationship, and thus, conventional orthodontic treatment with preadjusted edgewise appliances was initiated. After 41 months of multibracket treatment, acceptable occlusion with a functional Class I relationship was obtained. One year postretention, few changes in occlusion and facial features were observed. Our results demonstrate that considering the maxillofacial vertical growth during the peripubertal period associated with Sotos syndrome, more attention should be paid to the early orthopedic treatment with the facemask and/or chincap.

American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO)


Possibility and Future of Intraoral Scanner Application to Change the Method of Taking Impressions


ピエール・ロバン症候群乳児における維持と調整機構を付与したPre-epiglottic baton plateの製作

Journal of Japanese Academy of Oral and Maxillofacial Rehabilitation Technology

日本口腔顎顔面技工学会会誌


Accuracy of three-dimensional printed models derived from cone-beam computed tomography

To determine the accuracy of three-dimensional (3D) printed models fabricated from cone-beam computed tomography (CBCT) scans of human mandibular dry skulls in comparison with models derived from intraoral scanner (IOS) data. Six human mandibular dry skulls were scanned by IOS and CBCT. Digital models (DMs) constructed from the IOS and CBCT data were fabricated physically using a 3D printer. The width and thickness of individual teeth and intercanine and molar widths were measured using a digital caliper. The accuracy of the DMs was compared between IOS and CBCT. Paired t-tests were used for intergroup comparisons. All intraclass correlation coefficient values for the three measurements (mesial-distal, buccal-lingual, width) exceeded 0.9. For the mandibular teeth, there were significant discrepancies in model accuracy between the IOS (average discrepancies of 0.18 ± 0.08 mm and 0.16 ± 0.12 mm for width and thickness, respectively) and CBCT (0.28 ± 0.07 mm for width, 0.37 ± 0.2 mm for thickness; P < .01). Intercanine (P = .38) and molar widths (P = .41) showed no significant difference between groups. There was a statistically significant difference in the accuracy of DMs obtained from CBCT and IOS; however, this did not seem to result in any important clinical difference. CBCT could be routinely used as an orthodontic diagnostic tool and for appliance construction.


犬歯の埋伏による重度歯根吸収を呈した上顎切歯に対して下顎小臼歯の自家移植を行った歯性上顎前突の一治験例

中·四国矯正歯科学会雑誌


Site-specific characteristics of bone and progenitor cells in control and ovariectomized rats

One-third of postmenopausal women experience at least one osteoporotic bone fracture in their lifetime that occurs spontaneously or from low-impact events. However, osteoporosis-associated jaw bone fractures are extremely rare. It was also observed that jaw bone marrow stem cells (BMSCs) have a higher capacity to form mineralized tissues than limb BMSCs. At present, the underlying causes and mechanisms of variations between jaw bone and limb bone during postmenopause are largely unknown. Thus, the objective of the current study was to examine the site-specific effects of estrogen deficiency using comprehensive analysis of bone quantity and quality, and its association with characterization of cellular components of bone. Nine rats (female, 6 months old) for each bilateral sham and ovariectomy (OVX) surgery were obtained and maintained for 2 months after surgery. A hemi-mandible and a femur from each rat were characterized for parameters of volume, mineral density, cortical and trabecular morphology, and static and dynamic mechanical analysis. Another set of 5 rats (female, 9 months old) was obtained for assays of BMSCs. Following cytometry to identify BMSCs, bioassays for proliferation, and osteogenic, adipogenic, chondrogenic differentiation, and cell mitochondrial stress tests were performed. In addition, mRNA expression of BMSCs was analyzed. OVX decreased bone quantity and quality (mineral content, morphology, and energy dissipation) of femur while those of mandible were not influenced. Cellular assays demonstrated that mandible BMSCs showed greater differentiation than femur BMSCs. Gene ontology pathway analysis indicated that the mandibular BMSCs showed most significant differential expression of genes in the regulatory pathways of osteoblast differentiation, SMAD signaling, cartilage development, and glucose transmembrane transporter activity. These findings suggested that active mandibular BMSCs maintain bone formation and mineralization by balancing the rapid bone resorption caused by estrogen deficiency. These characteristics likely help reduce the risk of osteoporotic fracture in postmenopausal jawbone.


Thread shape, cortical bone thickness, and magnitude and distribution of stress caused by the loading of orthodontic miniscrews: finite element analysis.

Cortical bone thickness is assumed to be a major factor regulating miniscrew stability. We investigated stress distribution in two miniscrews with different thread shapes (type A and B) and in cortical bone of three different thicknesses using three-dimensional (3D) finite element (FE) models. More specifically, 3D FE models of two different miniscrews were created and placed obliquely or vertically into a cylindrical bone model representing different cortical bone thicknesses. When force was applied to the miniscrew, the stress distribution on the screw surface and in the peri-implant bone was assessed using FE methodology. Miniscrew safety was evaluated using a modified Soderberg safety factor. Screw head displacement increased with a decrease in cortical bone thickness, irrespective of screw type. The smallest minimum principal stresses on the screw surfaces remained constant in type A miniscrews on changes in cortical bone thickness. Minimum principal stresses also appeared on the cortical bone surface. Lower absolute values of minimum principal stresses were seen in type A miniscrews when placed vertically and with upward traction in obliquely placed type B miniscrews. Both miniscrews had acceptable safety factor values. Taken together, orthodontists should select and use the suitable miniscrew for each patient in consideration of bone properties.


Quantitative evaluation of training method in placing miniscrews in orthodontic graduate program

The purpose of this study was to assess the effectiveness of training residents in an orthodontic program in the placement of miniscrews by using cone beam computed tomography (CBCT) images. A total of 90 miniscrews were placed in 15 pig mandibles over a 3-year period by 15 first-year orthodontic residents. Miniscrews were divided into three groups (Control group: no radiographs; 2D group: placement with 2D radiographs; CBCT group: placement with CBCT). Proximity of the miniscrew to the neighboring root was measured. The miniscrew success rate was examined in the graduate clinic from 2015 to 2021. The percentage of root contact for each group was: 36.7% (11/30), 20.0% (6/30), 0% (0/30), for the Control, 2D, and CBCT groups, respectively. The CBCT group was significantly different from the Control and 2D groups (p < 0.05). For root proximity, the miniscrews were significantly closer to the roots in the Control (p < 0.001) and 2D (p < 0.001) groups compared with the CBCT group. No significant difference was observed between the Control and 2D groups (p = 0.80). There was no significant difference among the years in the miniscrew success rate. Training the residents in an orthodontic graduate program using CBCT may be helpful to avoid root damage and to decrease the miniscrew failure rate.


Mechanical stability of orthodontic miniscrew depends on a thread shape.

The miniscrew with a novel thread shape showed a higher initial stability compared to those with a regular thread shape. Thus, in order to obtain a sufficient initial stability, it is important to select the type of screw thread that is appropriate for the thickness of the cortical bone.

The MIT, RT, TR and K of type C miniscrew were significantly greater than those of type A and B miniscrews when the miniscrews were placed in the thinner artificial bone. Furthermore, the TR value of type C miniscrew was more than 1, indicating the MRT value was larger than the MIT value in the novel miniscrew. The values of K∗ and tan


Evaluation of clinical parameters for the stability of 2 types of miniscrews

The purpose of this research was to compare insertion techniques and effects on mechanical and clinical parameters between 2 types of miniscrews. Forty-four consecutive patients whose orthodontic treatment involved the use of miniscrews (miniscrew A [MA] and miniscrew B [MB]) for anchorage were included in this study. Miniscrews were placed with predrilling or self-drilling; peak maximum insertion torque (MIT) and Periotest values were measured. Cone-beam computed tomography was performed after the insertion of miniscrews and root proximity determination; cortical bone thickness was also analyzed. Periotest values were measured after the application of orthodontic force. Self-drilling produced higher Periotest values (P <0.01) for MA and higher MIT (P <0.01) for MB with closer root proximity (P <0.05). MB had higher MIT and Periotest values with drilling compared with MA (P <0.05); MB also showed closer root proximity (P <0.05). Successful miniscrews had lower MIT (P <0.05) for MB and lower Periotest values (P <0.01) for both MA and MB, with significantly more distant root proximity (P <0.01). Self-drilling produced higher Periotest values at the time of placement (P <0.01) and after 4 weeks (P <0.05) in MA. Drilling produced higher Periotest values for MB at the time of placement (P <0.05). MIT had positive correlations with Periotest values for MB with self-drilling (P <0.01) and with root proximity for MA with drilling (P <0.01). Periotest values had negative correlations with root proximity for MA and the MB group with drilling (P <0.01). For miniscrews with larger diameters, higher MIT may result in more mobility (higher Periotest values). Drilling can avoid root contact and enhance primary stability, thus producing lower Periotest values.

American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO)


Long-term Management of a Patient with Apert Syndrome.

The two-stage operation combining early distraction osteogenesis and postgrowth orthognathic surgery proves to be an effective therapy for correcting midfacial hypoplasia and skeletal mandibular protrusion caused by Apert syndrome.

The Journal of Contemporary Dental Practice


Influence of insertion depth on stress distribution in orthodontic miniscrew and the surrounding bone by finite element analysis.

We aimed to elucidate stress distribution in miniscrews and the surrounding bone when miniscrews inserted at different depths were implanted vertically or obliquely. The distributions of the equivalent stress on the screw surface and the minimum principal stress in the surrounding bone were calculated using finite element models. When the miniscrews were inserted vertically and obliquely, screw head displacement, greatest equivalent stress on the miniscrew surface, and absolute value of minimum principal stresses in the surrounding bone decreased with increasing insertion depth. Stresses in the obliquely inserted miniscrew with upward traction were smaller than in other insertion conditions, irrespective of insertion depth. With the application of orthodontic force, stress distribution around the miniscrew and surrounding bone is closely related to the insertion depth and insertion angle, which mutually affect each other. In particular, the obliquely inserted miniscrew with upward traction might be the most secure against screw failure and fracture.


歯科矯正用アンカースクリューの導入に伴う治療方針の変化(第一報) 抜歯・非抜歯および抜歯部位の判定に関する検討

【目的】近年，歯科矯正用アンカースクリュー(以降アンカーと明記する)の普及により，臼歯の固定や移動が容易に行えるようになり，抜歯，非抜歯，抜歯部位の選択についても変化が起きている．今回，アンカーの導入前後での治療方針の変化について，とくに臼歯抜歯の適応に関する調査を行ったので報告する．【方法】徳島大学病院矯正歯科を受診した初診時年齢12歳以上の患者を対象とし，2002年以前にマルチブラケット治療の診断を受けた100名(Pre群)と2008年以降に診断を受けた100名(Post群)を無作為に抽出した．先天性疾患および歯牙欠損症例，顎変形症は除外した．診断内容における臼歯抜歯(第三大臼歯は除く)の有無，抜歯部位等に関する比較検討を行った．【結果および考察】Pre群とPost群の間で抜歯症例数および抜歯部位に違いは認められなかった．一方，skeletal Class IIの症例はPre群では上顎片顎小臼歯抜歯によるカムフラージュ治療が多かったのに対し，Post群ではその割合は減少していた．また，skeletal Class IIIの症例ではアンカーを用いた非抜歯治療の割合が増加していた．High mandibular plane angle caseにおいてはアンカーの使用により，上顎第一大臼歯の挺出防止ならびに圧下が可能となり上下顎第一小臼歯を抜去する割合が増えた．【結論】アンカー導入で，臼歯の移動や挺出の防止および圧下が可能となり抜歯部位の選択基準に変化が生じたと考えられた．(著者抄録)

The Journal of Chu-Shikoku Orthodontic Society

中·四国矯正歯科学会雑誌


Hemifacial Microsomia Caused by First and Second Brachial Arch Syndrome Treated with Orthodontic Approach: A Case Report.

This report proposes an efficacy of conventional orthodontic treatment for growing patients with hemifacial microsomia involved in the FSBAS.


徳島大学病院矯正歯科における保険診療に関する実態調査-先天性疾患における裂奇形の併発について

矯正歯科治療に健康保険が導入されて約40年が経過し，唇顎口蓋裂と顎変形症の他に2018年現在53項目が保険治療の対象になっている．今回，我々は当科における矯正歯科治療の保険適用患者の実態を調査し，特に唇顎口蓋裂と他の先天性疾患との関連性について臨床統計学的検討を行ったので報告する．徳島大学病院病院情報システム・データウェアハウスを用い，2008年1月から2018年12月までの11年間に当院矯正歯科を受診した患者から保険治療を受けている患者を抽出し，顎変形症単独症例を除く先天性疾患患者について，電子カルテ全文検索システムを用いて臨床統計学的検討を行った．研究対象期間に当科にて保険治療を受けた矯正患者は345人で，そのうち，本研究対象患者は，顎変形症単独症例を除く207人であった．患者の内訳は，裂奇形を主徴候とする症例が全体の5割を占め最も多く，次いで，6歯以上の先天性部分性無歯症，ゴールデンハー症候群(鰓弓異常症を含む)，ダウン症候群の順であった．また，症候性疾患の中で裂奇形の併発は，ピエール・ロバン症候群，ダウン症候群，ゴールデンハー症候群の順に多く，その裂型は，口蓋裂(軟口蓋裂を含む)，唇顎口蓋裂，唇裂の順に多かった．以上のことから，当病院は裂奇形を併発した先天性疾患への専門的な対応が不可欠であり，希少疾患にも柔軟に対応できるよう複数の診療科，職種による診療科の枠組みを超えたチーム医療体制の構築が必要であることが示唆された．

中·四国矯正歯科学会雑誌


Regional variations of jaw bone characteristics in an ovariectomized rat model.

Journal of the Mechanical Behavior of Biomedical Materials


Mechanical and clinical evaluation of the effect of microscrew on root proximity and cortical bone thickness.

Primary stability is required for successful use of microscrew. This study investigated correlations among biomechanical, morphological, and clinical values in relationship to root contact and different placement locations. Thirty-three microscrews were placed between the molars (n = 18) or in the body of the mandible (n = 15) in three pigs. Insertion torque, Periotest, resonance frequency analysis (RFA), and static and dynamic stiffness were measured. Cone beam computed tomography was performed before and after the insertion of microscrews. Interproximal microscrews were divided into root contacted microscrews (n = 9) and non-root contact microscrews (n = 9). Factorial analysis of variance was conducted, with significance set at P < 0.05. A significant difference was observed between bodily and root contacted microscrews in Periotest, RFA, static and dynamic stiffness, Tan , and bone density (RFA, P = 0.045; all others, P < 0.001). A significant difference was observed between bodily and non-root contact microscrews in Periotest, RFA, and bone density (RFA, P = 0.025; all others, P < 0.001). A significant difference was observed in static (P = 0.01) and dynamic (P = 0.038) stiffness between microscrews with and without contact. Dynamic stiffness (P = 0.02) and Tan (P = 0.03) showed significant correlations with Periotest results only in bodily microscrews. Since a pig bone was used, some differences in the quality and quantity of the bone might be observed between humans. Stiffness values distinguished between microscrews with and without contact. Periotest and RFA results indicated that bodily microscrews were more stable than interproximal microscrews. Periotest and RFA may be useful with large, microscrews and/or in thick cortical bone, but further investigation is required to determine the stability of interproximal microscrews.


Dentoalveolar Defects in the Mouse Model of X-linked Hypophosphatemia.

Mutations in cause X-linked hypophosphatemia (XLH), a form of hypophosphatemic rickets. ( mutant) mice recapitulate the XLH phenotype. Dental disorders are prevalent in individuals with XLH; however, underlying dentoalveolar defects remain incompletely understood. We analyzed mouse dentoalveolar defects at 42 and 90 d postnatal to comparatively define effects of XLH on dental formation and function. mRNA was expressed by odontoblasts (dentin), osteocytes (bone), and cementocytes (cellular cementum) in wild-type (WT) mice. Enamel density was unaffected, though enamel volume was significantly reduced in mice. Dentin defects in molars were indicated histologically by wide predentin, thin dentin, and extensive interglobular dentin, confirming micro-computed tomography (micro-CT) findings of reduced dentin volume and density. Acellular cementum was thin and showed periodontal ligament detachment. Mechanical testing indicated dramatically altered periodontal mechanical properties in versus WT mice. mandibles demonstrated expanded alveolar bone with accumulation of osteoid, and micro-CT confirmed decreased bone volume fraction and alveolar bone density. Cellular cementum area was significantly increased in versus WT molars owing to accumulation of hypomineralized cementoid. Histology, scanning electron microscopy, and nanoindentation revealed hypomineralized "halos" surrounding cementocyte and osteocyte lacunae. Three-dimensional micro-CT analyses confirmed larger cementocyte/osteocyte lacunae and significantly reduced perilacunar mineral density. While long bone and alveolar bone osteocytes in mice overexpressed fibroblast growth factor 23 (), its expression in molars was much lower, with cementocyte expression particularly low. Expression and distribution of other selected markers were disturbed in versus WT long bone, alveolar bone, and cementum, including osteocyte/cementocyte marker dentin matrix protein 1 (). This study reports for the first time a quantitative analysis of the mouse dentoalveolar phenotype, including all mineralized tissues. Novel insights into cellular cementum provide evidence for a role for cementocytes in perilacunar mineralization and cementum biology.


徳島大学病院矯正歯科における口唇裂・口蓋裂患者の永久歯の歯数異常に関する調査

徳島大学病院矯正歯科における口唇裂・口蓋裂患者の永久歯の歯数異常に関する調査

中·四国矯正歯科学会雑誌


Effectiveness of presurgical nasoalveolar molding therapy on unilateral cleft lip nasal deformity.

To evaluate the effectiveness of pre-surgical nasoalveolar molding (PNAM) in patients with unilateral cleft lip nasal deformities. Methods: This was a retrospective study involving 29 patients with unilateral cleft lip and palate defects, of whom 13 were treated with palatal devices with nasal stents (PNAM group) and 16 were treated with palatal devices without nasal stents or surgical tapes (control group). Submental oblique photographs and orthodontic models were longitudinally obtained at the initial visit (T1) and immediately before (T2) and after cheiloplasty (T3). Asymmetry of the external nose, degree of columellar shifting, nasal tip/ala nose ratio, nasal base angle, interalveolar gap, and the sagittal difference in the alveolar gap were measured. The study was conducted in the Orthodontic Clinic at Tokushima University Hospital, Tokushima, Japan between 1997 and 2012. Results: At T1, there were no significant intergroup differences in the first 4 asymmetry parameters. At T2, the PNAM group showed a significant improvement in all values compared to the control group. At T3, the PNAM group showed significant improvement in nasal asymmetry and columellar shifting. Model analysis showed significantly greater changes in the inter-alveolar gap and the sagittal difference of the alveolar cleft gap from T1 to T2 in the PNAM group. Conclusion: The use of PNAM is indispensable for pre-surgical orthodontic treatment at the early postnatal age.


A Survey of Orthodontic Treatment in Team Care for Patients With Syndromic Craniosynostosis in Japan.

To understand the actual condition of orthodontic treatment in team care for patients with syndromic craniosynostosis (SCS) in Japan. A nationwide collaborative survey. Twenty-four orthodontic clinics in Japan. A total of 246 patients with SCS. Treatment history was examined based on orthodontic records using common survey sheets. Most patients first visited the orthodontic clinic in the deciduous or mixed dentition phase. Midface advancement was performed without visiting the orthodontic clinic in about a quarter of the patients, and more than a half of the patients underwent "surgery-first" midface advancement. First-phase orthodontic treatment was carried out in about a half of the patients, and maxillary expansion and protraction were performed. Tooth extraction was required in about two-thirds of patients, and the extraction of maxillary teeth was required in most patients. Tooth abnormalities were found in 37.8% of patients, and abnormalities of maxillary molars were frequently (58.3%) found in patients who had undergone midface surgery below the age of 6 years. Many patients underwent "surgery-first" midface advancement, and visiting the orthodontic clinic at least before advancement was considered desirable. First-phase orthodontic treatment should be performed considering the burden of care. Midface advancement below the age of 6 years had a high risk of injury to the maxillary molars. This survey is considered useful for improving orthodontic treatment in team care of patients with SCS.


TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists induce tumor-specific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-B ligand-induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor -activated kinase-1 (TAK1), and thus activated NF-B signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-B activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL's anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8-dependent apoptosis toward NF-B activation, and that TAK1 inhibition subverts TRAIL-mediated NF-B activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL.


歯科矯正用アンカースクリューを用いて上下歯列遠心移動を行った三年保定症例

歯科矯正用アンカースクリューを用いて上下歯列遠心移動を行った三年保定症例

The Journal of Chu-Shikoku Orthodontic Society

中·四国矯正歯科学会雑誌


A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.

Myeloma (MM) cells and osteoclasts are mutually interacted to enhance MM growth while creating acidic bone lesions. Here, we explored acid sensing of MM cells and its role in MM cell response to acidic conditions. Acidic conditions activated the PI3K-Akt signaling in MM cells while upregulating the pH sensor transient receptor potential cation channel subfamily V member 1 (TRPV1) in a manner inhibitable by PI3K inhibition. The acid-activated PI3K-Akt signaling facilitated the nuclear localization of the transcription factor Sp1 to trigger the expression of its target genes, including TRPV1 and HDAC1. Consistently, histone deacetylation was enhanced in MM cells in acidic conditions, while repressing a wide variety of genes, including DR4. Indeed, acidic conditions deacetylated histone H3K9 in a DR4 gene promoter and curtailed DR4 expression in MM cells. However, inhibition of HDAC as well as either Sp1 or PI3K was able to restore DR4 expression in MM cells suppressed in acidic conditions. These results collectively demonstrate that acid activates the TRPV1-PI3K-Akt-Sp1 signaling in MM cells while inducing HDAC-mediated gene repression, and suggest that a positive feedback loop between acid sensing and the PI3K-Akt signaling is formed in MM cells, leading to MM cell response to acidic bone lesions.


The Effectiveness of Human Parathyroid Hormone and Low-Intensity Pulsed Ultrasound on the Fracture Healing in Osteoporotic Bones.

Osteoporotic fracture has become a major public health problem, and until today, the treatments available are not satisfactory. While there is growing evidence to support the individual treatment of parathyroid hormone (PTH) administration and low-intensity pulsed ultrasound (LIPUS) exposure as respectively systemic and local therapies during osteoporotic fracture healing, their effects have not yet been investigated when introduced concurrently. This study aimed to evaluate the effects of combined treatment with PTH (1-34) and LIPUS on fracture healing in ovariectomized (OVX) rats. Thirty-two, 12-week-old female Sprague-Dawley rats were OVX to induce osteoporosis. After 12 weeks, the rats underwent surgery to create bilateral mid-diaphyseal fractures of proximal tibiae. All animals were randomly divided into 4 groups (n = 8 for each): control group as placebo, PTH group, LIPUS group, and combined group. PTH group had PTH administration at a dose of 30 μg/kg/day for 3 days/week for 6 weeks. LIPUS group received ultrasound 5 days/week for 20 min/day for 6 weeks and combined group had both PTH administration and LIPUS exposure for 6 weeks. Fracture healing was observed weekly by anteroposterior radiography and micro-CT. Five weeks after the fracture, the tibia were harvested to permit histological assessments and at week 6, for mechanical property of the fracture callus. Micro-CT showed that the PTH and combined groups exhibited significantly higher BMD and trabecular bone integrity than control group at weeks 4-6. Radiography, fracture healing score and mean callus area indicated that the combined group revealed better healing processes than the individual groups. Mechanically, bending moment to failure was significantly higher in LIPUS, PTH and combined groups than in control group. These data suggest that the combined treatment of PTH and LIPUS have been shown to accelerate fracture bone healing and enhance bone properties rather than single agent therapy, and may be considered as a treatment remedy for fracture healing in postmenopausal osteoporosis.


顎関節内障を有する骨格性下顎前突症に対する矯正歯科治療の一治験例

顎関節内障を有する骨格性下顎前突症に対する矯正歯科治療の一治験例

中·四国矯正歯科学会雑誌


Induction of endoplasmic reticulum stress by bortezomib sensitizes myeloma cells to DR5-mediated cell death

TNF-related apoptosis-including ligand/Apo2 (TRAIL)-mediated immunotherapy is an attractive anti-tumor modality with high tumor specificity. In order to improve its therapeutic efficacy, we further need to implement a novel maneuver for sensitization of malignant cells to TRAIL. Bortezomib (BTZ), a novel anti-myeloma (MM) agent, potently induces endoplasmic reticulum (ER) stress to cause apoptosis. Here, we explored the roles of BTZ in the cytotoxicity of anti-TRAIL receptor agonistic antibodies against MM cells with special reference to ER stress. BTZ enhanced the expression of death receptor 5 (DR5) but not DR4 in MM cells at surface protein as well as mRNA levels. However, the DR5 expression was not affected by BTZ without ER stress induction in MM cells with a point mutation in a BTZ-binding proteasome β5 subunit. Tunicamycin, an ER stress inducer, was able to enhance the DR5 expression even in the BTZ-resistant MM cells, suggesting the role of ER stress in up-regulation of DR5 expression. Interestingly, BTZ facilitated extrinsic caspase-mediated apoptosis by anti-DR5 agonistic antibody in MM cells along with reducing c-FLICE-like interleukin protein, a caspase 8 inhibitor. These results suggest that BTZ enhances DR5 expression and its downstream apoptotic signaling through ER stress to sensitize MM cells to TRAIL-mediated immunotherapy.


Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma.

Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-, transforming growth factor- (TGF-) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF- signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.Leukemia advance online publication, 30 May 2014; doi:10.1038/leu.2014.147.


Novel PAX9 Mutations Cause Non-syndromic Tooth Agenesis.

PAX9 is a transcription factor expressed in the tooth mesenchyme during tooth morphogenesis. In Pax9-null mice, tooth development is arrested at the bud stage. In humans, heterozygous mutations in PAX9 have been associated with non-syndromic tooth agenesis, predominantly in the molars. Here, we report 2 novel mutations in the paired domain of PAX9, a three-nucleotide deletion (73-75 delATC) and a missense mutation (C146T), in two unrelated Japanese patients with non-syndromic tooth agenesis. The individual with the 73-75del ATC mutation was missing all maxillary molars and mandibular second and third molars. The individual with the C146T mutation was missing the mandibular central incisors, maxillary second premolars, and first molars, along with all second and third molars. Both mutations affected amino acids that are highly conserved among different species and are critical for DNA binding. When both mutants were transfected to COS7 cells, nuclear localization of PAX9 proteins was not affected. However, reduced expression of the mutant proteins and almost no transcriptional activity of the target BMP4 gene were observed, suggesting haploinsufficiency of PAX9 as the cause of non-syndromic tooth agenesis.


Hypodontiaを伴う二卵性双生児の下顎後退症例

Hypodontiaを伴う二卵性双生児の下顎後退症例

中·四国矯正歯科学会雑誌


Activating transcription factor 4, an ER stress mediator, is required for, but exce ssive ER stress suppresses osteoblastogenesis by bortezomib.

Endoplasmic reticulum (ER) stress is induced in matrix-producing osteoblasts and plays an essential role in osteoblastogenesis. Although the bone anabolic activity of proteasome inhibitors has been demonstrated, the roles of ER stress induced by proteasome inhibition in osteoblastogenesis remain largely unknown. Here we show that bortezomib translationally increases protein levels of activating transcription factor 4 (ATF4), a downstream mediator of ER stress, in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells. The suppression of ATF4 expression by siRNA abrogated osteocalcin expression and mineralized nodule formation by MC3T3-E1 cells induced by bortezomib, indicating a critical role for ATF4 in bortezomib-mediated osteoblastogenesis. However, bortezomib at 20 nM or higher abolished the mineralized nodule formation along with reductions in the expression of osteoblastogenesis mediators β-catenin and Osterix. Furthermore, at 50 nM, bortezomib induced the expression of C/EBP homologous protein (CHOP), suggesting activation of the ATF4-CHOP pro-apoptotic pathway. These results suggest that a low dose of bortezomib induces osteogenic activity, but that, in contrast, excessive ER stress caused by bortezomib at higher doses hampers osteoblastogenesis. Therefore, dosing schedules for proteasome inhibitors warrant further study to maximize anabolic actions without compromising anti-MM activity in patients with multiple myeloma (MM).


Segmental distraction osteogenesis with modified LeFort II osteotomy for a patient with craniosynostosis

In this article, we report successful orthodontic treatment combined with segmental distraction osteogenesis after a modified LeFort II osteotomy in a patient with craniosynostosis. An 8-year-old boy diagnosed with craniosynostosis had a dished-in face, an anterior crossbite, and a skeletal Class III jaw relationship because of midfacial hypoplasia. At the age of 13 years 6 months, the maxillary second and mandibular first premolars were extracted, and leveling and alignment of both arches was started with preadjusted edgewise appliances. At age 14 years 11 months, the patient had a modified LeFort II osteotomy, and the maxillary segment was advanced 7 mm and fixed to the zygomatic bone. At the same time, segmental distraction osteogenesis was started with a rigid external distraction system, and the nasal segment was advanced for 20 days at a rate of 1.0 mm per day. The total active treatment period was 40 months. As a result of the modified segmental distraction osteogenesis, significant improvement of his severe midfacial hypoplasia was achieved without excessive advancement of the maxillary dentition. Both the facial profile and the occlusion were stable after 1 year of retention. However, the nasal segment relapsed 1.4 mm during the 1.5 years after the segmental distraction osteogenesis. Evaluation of the stability and retention suggests that some overcorrection in midfacial advancement is recommended.

American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO)


Severity of alveolar cleft before palatoplasty affects vertical maxillofacial growth in 6-year-old patients with complete unilateral cleft lip and palate.

In this study, we investigated the association between the severity of alveolar clefts in infants and the succeeding maxillofacial growth in patients affected by complete unilateral cleft lip and palate. The subjects were 35 nonsyndromic patients affected by unilateral cleft lip and palate (n = 27) or bilateral cleft lip and palate (n = 8). Plaster models and lateral cephalograms taken at 6 years of age were analyzed and compared with the Japanese norms. In the unilateral cleft lip and palate patients, the relationship between the width of the alveolar cleft before palatoplasty and the skeletal characteristics was also explored. Significant deficiencies of the posterior maxilla and steep palatal planes were noted in both the unilateral and bilateral cleft lip and palate patients. However, they were not clearly observed in the unilateral cleft lip and palate patients born with a small alveolar cleft and were correlated with the severity of alveolar cleft in infancy. Neither cleft type nor the severity of the alveolar cleft was implicated in the maxillary arch form in childhood, but the growth of the alveolar height on the cleft side was less in the unilateral cleft lip and palate patients born with a large alveolar cleft. The severity of the alveolar cleft before palatoplasty affects the succeeding vertical maxillofacial growth in patients affected by unilateral cleft lip and palate; this suggests the necessity of a different diagnosis and treatment in unilateral cleft lip and palate patients according to the severity of the alveolar cleft in infancy.


KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts.

The spicamycin analogue KRN5500 alters glycoprotein processing and induces damage in the endoplasmic reticulum (ER)-Golgi apparatus in cancer cells. In the present study, we explored the cytotoxic effects of KRN5500 on multiple myeloma (MM) cells and the bone marrow microenvironment with special reference to ER stress. Cell proliferation assay showed that KRN5500 induced G1 arrest and apoptosis in MM cells in a time- and dose-dependent manner. KRN5500 enhanced ER stress independently of caspase activation in MM cells. This cell death was observed even in the presence of bone marrow stroma cells or osteoclasts. Notably, KRN5500 induced cell death also in osteoclasts. In vivo effects of KRN5500 were evaluated using two xenograft models established in severe combined immunodeficient (SCID) mice by either subcutaneous injection of RPMI 8226 cells or intra-bone injection of INA-6 cells to subcutaneously implanted rabbit bones (SCID-rab model). KRN5500 significantly inhibited tumour growth in both animal models, and decreased the number of osteoclasts, which resulted in prevention of bone destruction in the SCID-rab model. These results suggest that KRN5500 exerts anti-MM effects through impairing both MM cells and osteoclasts. Therefore, this unique mechanism of KRN5500 might be a useful therapeutic option in patients with MM.


Long-term stability of LeFort III distraction osteogenesis with a rigid external distraction device in a patient with Crouzon syndrome.

A 6-year-old boy, diagnosed with Crouzon syndrome, had moderate exorbitism, a concave profile, an anterior crossbite of -4.0 mm, and a skeletal Class III jaw-base relationship caused by midfacial hypoplasia. At age 8 years 9 months, a LeFort III osteotomy was performed, and distraction osteogenesis was immediately started with the rigid external distractor system. The midface was advanced approximately 10.0 mm for 6 days, including overcorrection. After the distraction, a reverse headgear was used for 6 years to prevent relapse and to accelerate expected growth. At age 16 years 5 months, after extraction of the maxillary first premolars and mandibular third molars, 0.022-in preadjusted edgewise brackets were placed to treat the edge-to-edge incisor relationship and minor crowding. After 13 months of treatment, the facial profile was significantly improved, and an acceptable occlusion was achieved. During the 9-year observation period after the distraction, acceptable facial growth occurred, and no relapse of the maxillary advancement was observed. However, syndrome-specific growth and methodologically induced relapse should be considered when planning a LeFort III distraction in children for the treatment of Crouzon syndrome.


徳島大学病院矯正歯科における患者の動向調査

徳島大学病院矯正歯科における患者の動向調査

The Journal of Chu-Shikoku Orthodontic Society

中·四国矯正歯科学会雑誌


Targeting myeloma-osteoclast interaction with V9V2 T cells.

Multiple myeloma (MM) cells stimulate osteoclastogenesis, and osteoclasts (OCs) in turn enhance MM growth and drug resistance, resulting in a vicious cycle. V9V2 T cells exert potent anti-tumor effects, making T cell-based immunotherapies using these cells attractive candidates for currently incurable malignancies, such as MM. However, the impact of such treatments on the MM-OC interaction is largely unknown. We demonstrate here that V9V2 T cells expanded by zoledronic acid and IL-2 exerted potent cytotoxic effects on both MM cells and OCs, even in coculture settings, but showed no such effect on bone marrow stromal cells. V9V2 T cells marginally affected colony formation from normal hematopoietic progenitors, and furthermore migrated toward osteopontin and MIP-1, factors produced by the MM-OC interaction. These results suggest that V9V2 T cells expanded by zoledronic acid and IL-2 are able to migrate to MM bone lesions and preferentially target OCs as well as MM cells, thereby inhibiting both tumor expansion and bone destruction.


ミニスクリュー固定を用いて上顎歯列の遠心移動を行ったアングルⅡ級2類過蓋咬合症例

中·四国矯正歯科学会雑誌


Identification of key determinant for predicting feasible mandibular molars distalization