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en: Acute accumulation of PIM2 and NRF2 and recovery of β5 subunit activity mitigate multiple myeloma cell susceptibility to proteasome inhibitors.

en: Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM.1S cells, but not PI-resistant KMS-11 cells. Inhibition of β5 subunit activity decreased at 24 h in KMS-11 cells, even with the irreversible PI carfilzomib, but not under suppression of protein synthesis with cycloheximide. Furthermore, the proteasome-degradable pro-survival factors PIM2 and NRF2 acutely accumulated in MM cells subjected to pulsatile PI treatments. Accumulated NRF2 was trans-localized into the nucleus to induce the expression of its target gene, HMOX1, in MM cells. PIM and Akt inhibition restored the anti-MM effects of PIs, even against PI-resistant KMS-11 cells. Collectively, these results suggest that increased synthesis of β5 proteasome subunit and acute accumulation of PIM2 and NRF2 reduce the anti-MM effects of PIs.

en: International journal of hematology

ja: International journal of hematology


en: 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

ja: 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

en: The Journal of Chu-Shikoku Orthodontic Society

ja: 中·四国矯正歯科学会雑誌


en: 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．

ja: 中·四国矯正歯科学会雑誌


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

en: 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.

en: Operative Dentistry

ja: Operative Dentistry


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

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


en: Mechanisms of preferential bone formation in myeloma bone lesions by proteasome inhibitors.

en: Proteasome inhibitors (PIs) can preferentially restore bone in bone-defective lesions of patients with multiple myeloma (MM) who respond favorably to these drugs. Most prior in vitro studies on PIs used continuous exposure to low PI concentrations, although pharmacokinetic analysis in patients has shown that serum concentrations of PIs change in a pulsatile manner. In the present study, we explored the effects of pulsatile treatment with PIs on bone metabolism to simulate in vivo PI pharmacokinetics. Pulsatile treatment with bortezomib, carfilzomib, or ixazomib induced MM cell death but only marginally affected the viability of osteoclasts (OCs) with F-actin ring formation. Pulsatile PI treatment suppressed osteoclastogenesis in OC precursors and bone resorption by mature OCs. OCs robustly enhanced osteoblastogenesis in cocultures with OCs and MC3T3-E1 pre-osteoblastic cells, indicating OC-mediated coupling to osteoblastogenesis. Importantly, pulsatile PI treatment did not impair robust OC-mediated osteoblastogenesis. These results suggest that PIs might sufficiently reduce MM cell-derived osteoblastogenesis inhibitors to permit OC-driven bone formation coupling while suppressing OC differentiation and activity in good responders to PIs. OC-mediated coupling to osteoblastogenesis appears to be a predominant mechanism for preferential occurrence of bone regeneration at sites of osteoclastic bone destruction in good responders.

en: International Journal of Hematology

ja: International Journal of Hematology


en: Novel antimyeloma therapeutic option with inhibition of the HDAC1-IRF4 axis and PIM kinase

en: Multiple myeloma (MM) preferentially expands and acquires drug resistance in the bone marrow (BM). We herein examined the role of histone deacetylase 1 (HDAC1) in the constitutive activation of the master transcription factor IRF4 and the prosurvival mediator PIM2 kinase in MM cells. The knockdown or inhibition of HDAC1 by the class I HDAC inhibitor MS-275 reduced the basal expression of IRF4 and PIM2 in MM cells. Mechanistically, the inhibition of HDAC1 decreased IRF4 transcription through histone hyperacetylation and inhibiting the recruitment of RNA polymerase II at the IRF4 locus, thereby reducing IRF4-targeting genes, including PIM2. In addition to the transcriptional regulation of PIM2 by the HDAC1-IRF4 axis, PIM2 was markedly upregulated by external stimuli from BM stromal cells and interleukin-6 (IL-6). Upregulated PIM2 contributed to the attenuation of the cytotoxic effects of MS-275. Class I HDAC and PIM kinase inhibitors cooperatively suppressed MM cell growth in the presence of IL-6 and in vivo. Therefore, the present results demonstrate the potential of the simultaneous targeting of the intrinsic HDAC1-IRF4 axis plus externally activated PIM2 as an efficient therapeutic option for MM fostered in the BM.

en: Blood Advances

ja: Blood Advances


en: Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.

en: MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.

en: Journal of Bone and Mineral Metabolism

ja: Journal of Bone and Mineral Metabolism


en: Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81.

en: assessment of cancer pain and

ja: influx, suggesting that the sensory neuron excitation was inhibited. These results suggested that lactate released from BC cells via MCT4 induced BC‑BP through the activation of GPR81 of sensory neurons. In conclusion, the activation of GPR81 of sensory neurons by lactate released via MCT4 from BC was demonstrated to contribute to the induction of BC‑BP, and disruption of the interactions among lactate, MCT4 and GPR81 may be a novel approach to control BC‑BP.

en: International Journal of Oncology

ja: International Journal of Oncology


en: Cancer-nerve interplay in cancer progression and cancer-induced bone pain.

en: It is suggested that SNs may be a newly-recognized important component of the bone microenvironment that contribute to not only in the pathophysiology of CIBP but also cancer progression in bone and dissemination from bone. Suppression of the activity of bone-innervating SNs, thus, may provide unique opportunities in the treatment of cancer progression and dissemination, as well as CIBP.


en: The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2.

en: Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess reactive oxygen species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a xanthine oxidase inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another xanthine oxidase inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.

en: Antioxidants

ja: Antioxidants


en: Nonsurgical orthodontic treatment for a patient with Sotos syndrome.

en: 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.

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


en: Osteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis.

en: did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes.

en: Nature Communications

ja: Nature Communications


en: 矯正歯科治療の経過予後からみた埋伏下顎大臼歯の歯科用CB-CT画像の特徴と牽引可否との関連性

en: The Journal of Chu-Shikoku Orthodontic Society

ja: 中·四国矯正歯科学会雑誌


en: Aberrant upregulation of the endogenous PP2A inhibitor CIP2A is vital for myeloma cell growth and survival

en: The serine/threonine kinase TAK1 is constitutively overexpressed and auto-phosphorylated in multiple myeloma (MM) cells. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase which dephosphorylates proteins phosphorylated by various serine/threonine kinases to regulate multiple cellular functions. We recently reported that the serine/threonine kinase TGF-β-activated kinase-1 (TAK1) is highly expressed and auto-phosphorylated to mediate critical growth and survival signaling in MM cells. We demonstrate here that regulation of PP2A activity inversely affects the phosphorylation levels of TAK1 in MM cells, and that MM cells aberrantly overexpress cancerous inhibitor of PP2A (CIP2A), an endogenous inhibitor for PP2A. CIP2A gene silencing as well as treatment with the CIP2A inhibitor TD52 potently induced MM cell death along with suppression of TAK1 expression in MM cells. These results suggest the critical role of PP2A inactivation via CIP2A upregulation in TAK1 phosphorylation and its protein expression and thereby MM cell growth and survival, posing the CIP2A-PP2A axis as an important therapeutic target.

en: International Journal of Myeloma

ja: International Journal of Myeloma


ja: 矯正歯科治療の経過予後からみた埋伏下顎大臼歯の歯科用CB-CT画像の特徴と牽引可否との関連性

en: 【目的】埋伏下顎大臼歯は，発生率は低いものの骨性癒着が認められた際は重大な不正咬合の原因となる．その治療予後の予測は未だ困難であり，重要な臨床課題の一つである．本研究では臨床的に牽引が不可能であった下顎大臼歯のエックス線画像を見直し，牽引可能であった例と比較することで，牽引の可否を鑑別するための特徴的な画像所見を検討した． 【方法】資料として徳島大学病院矯正歯科を受診した第三大臼歯を除く下顎大臼歯の埋伏を有する患者5 名の歯科用コーンビームCT (以下CB-CT) 画像とパノラマエックス線画像を用いた．Ducommun らの骨性癒着歯の評価項目である歯根膜腔消失・歯根吸収・組織置換に加え，置換性歯根吸収(歯根吸収により生じた歯根表面の凹凸部の骨硬化像)，歯根彎曲の有無を評価した． 【結果】パノラマエックス線画像では5 例全てで歯根膜腔の消失を認めたが，歯根吸収や組織置換像は観察されなかった．一方，CB-CT 画像では牽引が不可能であった3 例全てで歯根膜腔の消失と置換性歯根吸収像を認めた．牽引が可能であった2 例でも歯根膜腔の消失がみられ，うち1 例では歯根吸収像も認めたがその近傍に骨硬化像はなかった． 【考察】Ducommun らの評価項目のみでは，牽引可能であった1 例が偽陽性となったが，置換性歯根吸収の評価項目への追加により偽陽性はなくなった．このことから置換性歯根吸収の評価が埋伏下顎大臼歯の牽引の可否の鑑別に極めて重要であると考えられた． 【結論】埋伏下顎大臼歯の診断において，CB-CT 画像での当該歯の周囲組織の詳細な観察により，牽引が可能であるかを非常に高い精度で診断できる可能性が示唆された．

en: 中・四国矯正歯科学会雑誌

ja: 中・四国矯正歯科学会雑誌


en: Sensory nerves: A driver of the vicious cycle in bone metastasis?

en: Bone is one of the preferential target organs of cancer metastasis. Bone metastasis is associated with various complications, of which bone pain is most common and debilitating. The cancer-associated bone pain (CABP) is induced as a consequence of increased neurogenesis, reprogramming and axonogenesis of sensory nerves (SNs) in harmony with sensitization and excitation of SNs in response to the tumor microenvironment created in bone. Importantly, CABP is associated with increased mortality, of which precise cellular and molecular mechanism remains poorly understood. Bone is densely innervated by autonomic nerves (ANs) (sympathetic and parasympathetic nerves) and SNs. Recent studies have shown that the nerves innervating the tumor microenvironment establish intimate communications with tumors, producing various stimuli for tumors to progress and disseminate. In this review, our current understanding of the role of SNs innervating bone in the pathophysiology of CABP will be overviewed. Then the hypothesis that SNs facilitate cancer progression in bone will be discussed in conjunction with our recent findings that SNs play an important role not only in the induction of CABP but also the progression of bone metastasis using a preclinical model of CABP. It is suggested that SNs are a critical component of the bone microenvironment that drives the vicious cycle between bone and cancer to progress bone metastasis. Suppression of the activity of bone-innervating SNs may have potential therapeutic effects on the progression of bone metastasis and induction of CABP.

en: Journal of Bone Oncology

ja: Journal of Bone Oncology


en: Targeting myeloma-osteoclast interaction with V9V2 T cells.

en: 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.

en: International Journal of Hematology


en: Identification of key determinant for predicting feasible mandibular molars distalization

en: Journal of Dental Sciences

ja: Journal of Dental Sciences