ラットの三叉神経脊髄路核尾側核および網様亜核の侵害受容細胞に対する扁桃体条件刺激の抑制効果

We have shown that conditioning stimulation of the amygdaloid nucleus has an inhibitory effect on the nociceptive responses of the somatosensory cortex. The purpose of this study is to investigate whether amygdaloid conditioning stimulation exerts influence on the nociceptive neurons in the medullary dorsal horn in the rat. The animals were anesthetized with N_2O-O_2 (2 : 1) and 0.5%-halothane, and immobilized with pancuronium bromide. The peripheral test stimulus (a single rectangular pulse of 2.0 msec in duration) was applied to the receptive field of nociceptive neurons, and the ipsilateral amygdaloid conditioning stimulation were trains of 33 pulses (0.5 msec in duration, 300 μA) delivered at 330Hz. Fifty-five WDR neurons were distributed in the superficial layers of the caudal nucleus and diffusely throughout the reticular subnucleus, whereas most of NS neurons (13/17) were distributed in the dorsal part of reticular subnucleus. The conditioning stimulation in the central nucleus, basomedial nucleus and basolateral nucleus, markedly inhibited the activities in 24 of 43 nociceptive neurons. The inhibitory effect was 45.3±16.1% (n=24) at maximum. The conditioning stimulation had almost no effect on the discharges of non-nociceptive neurons. In contrast, the conditioning stimulation in the lateral amygdaloid nucleus had no effect on the nociceptive and non-nociceptive neurons. The present results suggest that amygdaloid nucleus inhibits the ascending nociceptive information at the second order neurons. This amygdaloid antinociceptive effect may provide one of the neurophysiological bases for the stress-induced analgesia (SIA) observed in the presence of stress and fear

Novel extracellular role of REIC/Dkk-3 protein in PD-L1 regulation in cancer cells

The adenovirus-REIC/Dkk-3 expression vector (Ad-REIC) has been the focus of numerous clinical studies due to its potential for the quenching of cancers. The cancer-suppressing mechanisms of the REIC/DKK-3 gene depend on multiple pathways that exert both direct and indirect effects on cancers. The direct effect is triggered by REIC/Dkk-3-mediated ER stress that causes cancer-selective apoptosis, and the indirect effect can be classified in two ways: (i) induction, by Ad-REIC-mis-infected cancer-associated fibroblasts, of the production of IL-7, an important activator of T cells and NK cells, and (ii) promotion, by the secretory REIC/Dkk-3 protein, of dendritic cell polarization from monocytes. These unique features allow Ad-REIC to exert effective and selective cancer-preventative effects in the manner of an anticancer vaccine. However, the question of how the REIC/Dkk-3 protein leverages anticancer immunity has remained to be answered. We herein report a novel function of the extracellular REIC/Dkk-3—namely, regulation of an immune checkpoint via modulation of PD-L1 on the cancer-cell surface. First, we identified novel interactions of REIC/Dkk-3 with the membrane proteins C5aR, CXCR2, CXCR6, and CMTM6. These proteins all functioned to stabilize PD-L1 on the cell surface. Due to the dominant expression of CMTM6 among the proteins in cancer cells, we next focused on CMTM6 and observed that REIC/Dkk-3 competed with CMTM6 for PD-L1, thereby liberating PD-L1 from its complexation with CMTM6. The released PD-L1 immediately underwent endocytosis-mediated degradation. These results will enhance our understanding of not only the physiological nature of the extracellular REIC/Dkk-3 protein but also the Ad-REIC-mediated anticancer effects

Histidine-Rich Glycoprotein Suppresses the S100A8/A9-Mediated Organotropic Metastasis of Melanoma Cells

The dissection of the complex multistep process of metastasis exposes vulnerabilities that could be exploited to prevent metastasis. To search for possible factors that favor metastatic outgrowth, we have been focusing on secretory S100A8/A9. A heterodimer complex of the S100A8 and S100A9 proteins, S100A8/A9 functions as a strong chemoattractant, growth factor, and immune suppressor, both promoting the cancer milieu at the cancer-onset site and cultivating remote, premetastatic cancer sites. We previously reported that melanoma cells show lung-tropic metastasis owing to the abundant expression of S100A8/A9 in the lung. In the present study, we addressed the question of why melanoma cells are not metastasized into the brain at significant levels in mice despite the marked induction of S100A8/A9 in the brain. We discovered the presence of plasma histidine-rich glycoprotein (HRG), a brain-metastasis suppression factor against S100A8/A9. Using S100A8/A9 as an affinity ligand, we searched for and purified the binding plasma proteins of S100A8/A9 and identified HRG as the major protein on mass spectrometric analysis. HRG prevents the binding of S100A8/A9 to the B16-BL6 melanoma cell surface via the formation of the S100A8/A9 complex. HRG also inhibited the S100A8/A9-induced migration and invasion of A375 melanoma cells. When we knocked down HRG in mice bearing skin melanoma, metastasis to both the brain and lungs was significantly enhanced. The clinical examination of plasma S100A8/A9 and HRG levels showed that lung cancer patients with brain metastasis had higher S100A8/A9 and lower HRG levels than nonmetastatic patients. These results suggest that the plasma protein HRG strongly protects the brain and lungs from the threat of melanoma metastasis

Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness

Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes

DNAX-activating protein 10 (DAP10) membrane adaptor associates with receptor for advanced glycation end products (RAGE) and modulates the RAGE-triggered signaling pathway in human keratinocytes.

The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many inflammatory, degenerative, and hyperproliferative diseases, including cancer. Previously, we revealed mechanisms of downstream signaling from ligand-activated RAGE, which recruits TIRAP/MyD88. Here, we showed that DNAX-activating protein 10 (DAP10), a transmembrane adaptor protein, also binds to RAGE. By artificial oligomerization of RAGE alone or RAGE-DAP10, we found that RAGE-DAP10 heterodimer formation resulted in a marked enhancement of Akt activation, whereas homomultimeric interaction of RAGE led to activation of caspase 8. Normal human epidermal keratinocytes exposed to S100A8/A9, a ligand for RAGE, at a nanomolar concentration mimicked the pro-survival response of RAGE-DAP10 interaction, although at a micromolar concentration, the cells mimicked the pro-apoptotic response of RAGE-RAGE. In transformed epithelial cell lines, A431 and HaCaT, in which endogenous DAP10 was overexpressed, and S100A8/A9, even at a micromolar concentration, led to cell growth and survival due to RAGE-DAP10 interaction. Functional blocking of DAP10 in the cell lines abrogated the Akt phosphorylation from S100A8/A9-activated RAGE, eventually leading to an increase in apoptosis. Finally, S100A8/A9, RAGE, and DAP10 were overexpressed in the psoriatic epidermis. Our findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes

Prevention of hypoglycemia by intermittent-scanning continuous glucose monitoring device combined with structured education in patients with type 1 diabetes mellitus : A randomized, crossover trial

Aims: We conducted a randomized, crossover trial to compare intermittent-scanning continuous glucose monitoring (isCGM) device with structured education (Intervention) to self-monitoring of blood glucose (SMBG) (Control) in the reduction of time below range. Methods: This crossover trial involved 104 adults with type 1 diabetes mellitus (T1DM) using multiple daily injections. Participants were randomly allocated to either sequence Intervention/Control or sequence Control/Intervention. During the Intervention period which lasted 84 days, participants used the first-generation FreeStyle Libre (Abbott Diabetes Care, Alameda, CA, USA) and received structured education on how to prevent hypoglycemia based on the trend arrow and by frequent sensor scanning (≥10 times a day). Confirmatory SMBG was conducted before dosing insulin. The Control period lasted 84 days. The primary endpoint was the decrease in the time below range (TBR; <70 mg/dL). Results: The time below range was significantly reduced in the Intervention arm compared to the Control arm (2.42 ± 1.68 h/day [10.1 %±7.0 %] vs 3.10 ± 2.28 h/day [12.9 %±9.5 %], P = 0.012). The ratio of high-risk participants with low blood glucose index >5 was significantly reduced (8.6 % vs 23.7 %, P < 0.001). Conclusions: The use of isCGM combined with structured education significantly reduced the time below range in patients with T1DM

下顎枝矢状分割術における生体内吸収性ポリ-L-乳酸骨接合ミニプレート固定の術後安定性について

左右非対称のない下顎前突症患者に対する下顎枝矢状分割術において,ポリ-L-乳酸製(PLLA)ミニプレート固定法による術後の顎態の安定性について検討を行った.両側下顎枝矢状分割術(SSRO)を施行し,下顎骨の後退量に左右差のない患者40名(男性17名,女性23名)を対象とした.これらの骨固定に際し,PLLAミニプレートを使用した患者22名(男性9名,女性13名)をPLLAプレート群とし,チタンミニプレートを使用した患者18名(男性8名,女性10名)をチタンプレート群とした.手術直前,手術後1か月,手術後1年に撮影した側面頭部X線規格写真の分析を行い,顎態の安定性について検討した.その結果,手術後1年ではPLLAプレート群およびチタンプレート群両群の男女ともに著しい後戻り様変化は認めなかった.このことから,SSROを用いた左右差のない下顎後退術に対するPLLAミニプレート固定は,術後顎態の安定性の観点からはチタンミニプレート固定と比較して何ら問題点はなく,プレートの除去手術が回避できる点で有益であると考えられる.アレルギーの有無や,顎骨の移動量等を総合的に判断し,PLLAミニプレートかチタンミニプレートを選択することができると考えられる.We studied the postsurgical stability of the mandible using biodegradable Poly-L-lactide bone mini plate fixation undergone sagittal split ramus osteotomy. The forty patients with mandibular prognathism without facial asymmetry (17 males and 23 females) operated from March 2003 to March 2009, were divided into two groups based on the types of osteosynthesis used. 22 patients (9 males and 13 females) using the PLLA mini-plate (PLLA plate group), and 18 patients (8 males and 10 females) using the titanium mini-plate (titanium plate group) were examined. Lateral cephalograms were taken immediately before the surgery, one month, and one year after surgery. Changes in position of the mandible were examined. As a result of this study, remarkable relapses were not recognized at one year after operation for males and females in both groups. It is thought the PLLA mini-plate fixation to the mandible without facial asymmetry setback doesn\u27t present as many problems from the viewpoint of postsurgical stability compared with the titanium mini-plate fixation, and it is profitable that we avoided the plate removal operation. We can select the PLLA or the titanium mini-plate from a comprehensive standpoint