Suppression of Met/HGF Receptor Activation by the Met Juxtamembrane Function and Cell-Cell Contact

Division of Tumor Dynamics and Regulatio

Sensitization to secretoglobin and lipocalins in a group of young children with risk of developing respiratory allergy

Background: Multiple sensitizations in early age have been reported to be a risk for development of asthma. This study evaluates the emergence and evolution of IgE to aeroallergens among a cohort of children with physician-diagnosed atopic dermatitis and/or showing food allergy symptoms and to examine the relation to asthma development. Methods: Three-hundred and four children (median age 13.4 months at entry) with food allergy symptoms and/or atopic dermatitis without asthma at inclusion were analysed for IgE antibodies against food-, indoor- and outdoor-allergens and pet allergen components and correlated to the individuals’ outcome on asthma inception. Results: At 2 years of follow-up, physician-diagnosed asthma was 19.7% (n = 49) and asthma diagnosed any time was 24% (n = 67). History of persistent cough and asthma of father, combination of milk- and wheat-allergy symptoms and dual sensitization to house dust mite and Japanese cedar were independent risk factors for asthma. Sensitization to dog was the most prevalent inhalant allergen at entry. Asthma children had a higher proportion of sensitization to dog, cat and horse allergens at entry compared with non-asthma children. Being sensitized to both food, house dust mite and pet allergens was strongly associated with asthma (p = 0.0006). Component resolved diagnosis for dog and cat allergens showed that IgE antibodies to Can f 1 and Fel d 1 was common even at very young age. Conclusions: Early sensitization to inhalant allergens increases the risk of developing asthma as well as having milk and wheat allergy symptoms. Sensitization to dog, was common at an early age despite dog ownership. Sensitization to secretoglobin and lipocalins and less to serum albumins explained the pet sensitization

Development of Materials for “Goal” Games Focused on “Movement without a Ball (Tactical Movement)”: Practical Study Conducted in the Classes of Middle and High Grades of an Elementary School and a Middle School

本研究は「ゴール型」ゲームの「ボールを持たない動き（戦術的な動き）」を中心的な学習課題として設定した教材の開発を目的としている。その教材として，ハンドボールを選択し，小学校中学年から中学校までの発達段階に応じた「つけたい力」を明確にして実践を行い，検討を行った。本研究により，「ボールを持たないときの動き」を子どもたちが思考し，実際にその動きを獲得するためには，ゴール前の空間をいかに攻めるかが課題となった。つまり，その空間にボール非保持者がどのように走りこむのか，走りこむための空間をどのようにうみ出すのかが，どの学年でも共通の課題となり学習を進めることになった。これは，ハンドボールという教材が，ゴールエリアラインよりゴール側は攻撃も守備もはいることができない空間があったからだと考える。したがって，本教材は，「ボールを持たないときの動き」を学習していく「ゴール型」ゲームの教材として有効であったと考察した。The purpose of this study was to develop materials focused on the learning task of “movement without a ball (tactical movement)” in “goal” games. The students practiced handball in a class with the clear purpose of acquiring the “targeted skills” appropriate to their developmental stages. We examined how to practice to achieve this goal. The students considered the “movement without a ball,” finding it difficult to run into the space facing the goal, and deliberated how to create that space. This was a common challenge across grades that facilitated their learning. This active learning was thought to be caused by the fact that there was a space in front of the goal in the handball court wherein neither the offence nor the defense could run. Therefore, we concluded that handball was effective as material that focuses on “movement without a ball.

p53 mutation in colon cancer.

金沢大学ナノ生命科学研究所The accumulation of genetic alterations in driver genes is responsible for the development and malignant progression of colorectal cancer. Comprehensive genome analyses have revealed the driver genes, including APC, KRAS, TGFBR2, and TP53, whose mutations are frequently found in human colorectal cancers. Among them, the p53 mutation is found in ~60% of colorectal cancers, and a majority of mutations are missense-type at ‘hot spots’, suggesting an oncogenic role of mutant p53 by ‘gain-of-function’ mechanisms. Mouse model studies have shown that one of these missense-type mutations, p53 R270H (corresponding to human R273H), causes submucosal invasion of intestinal tumors, while the loss of wild-type p53 has a limited effect on the invasion process. Furthermore, the same mutant p53 promotes metastasis when combined with Kras activation and TGF-β suppression. Importantly, either missense-type p53 mutation or loss of wild-type p53 induces NF-κB activation by a variety of mechanisms, such as increasing promoter accessibility by chromatin remodeling, which may contribute to progression to epithelial–mesenchymal transition. These results indicate that missense-type p53 mutations together with loss of wild-type p53 accelerate the late stage of colorectal cancer progression through the activation of both oncogenic and inflammatory pathways. Accordingly, the suppression of the mutant p53 function via the inhibition of nuclear accumulation is expected to be an effective strategy against malignant progression of colorectal cancer

顎舌骨筋運動ニューロンと一次求心線維のシナプス接合について

Horseradish peroxidase conjugated with wheat germ agglutinin (HRP-WGA) was injected into the muscle branch of the mylohyoid nerve in rats. HRP-labeled neuronal cell bodies were observed ipsilaterally in the caudal portion of the trigeminal mesencephalic nucleus and the ventromedial division of the trigeminal motor nucleus (Vmo.vm). Electron microscope observations were carried out on sections through Vmo.vm containing HRP-labeled cell bodies. Synaptic contacts were found between HRP-labeled axon terminals and HRP-labeled nerve cells. The results suggested that mylohyoid muscle spindle afferents are synaptic contacts on the mylohyoid motoneurons

Combined mutation of Apc, Kras and Tgfbr2 effectively drives metastasis of intestinal cancer.

金沢大学新学術創成研究機構ナノ生命科学研究所Embargo Period 12 month

The inflammatory microenvironment that promotes gastrointestinal cancer development and invasion.

金沢大学新学術創成研究機構ナノ生命科学研究所Accumulating evidence has indicated that the inflammatory response is important for tumor promotion. However, the mechanisms underlying the induction of the inflammatory response in cancer tissues and how it promotes tumorigenesis remain poorly understood. We constructed several mouse models that develop inflammation-associated gastric and intestinal tumors and examined the in vivo mechanisms of tumorigenesis. Of note, the activation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway and Toll-like receptor (TLR)/MyD88 signaling cooperatively induced the generation of an inflammatory microenvironment, which is required for early-stage tumorigenesis. The inflammatory response in the stroma induces TNF-α signaling in tumor cells, and the NOX1/ROS signaling pathway is activated downstream. In addition, the inflammatory pathway induces the expression of TLR2 in tumor epithelial cells. Both the NOX1/ROS and TLR2 pathways in tumor cells contribute to the acquisition and maintenance of stemness, which is an important tumor-promoting mechanism stimulated by inflammation. We also found that inflammation promotes malignant processes, like submucosal invasion, of TGF-β signaling-suppressed tumor cells through the activation of MMP2 protease. Moreover, we showed that mutant p53 induces innate immune and inflammatory signaling in the tumor stroma by a gain-of-function mechanism of mutant p53, which may explain the “cancer-induced inflammation” mechanism. These results indicate that the regulation of the inflammatory microenvironment via the inhibition of the COX-2/PGE2 and TLR/MyD88 pathways in combination will be an effective preventive or therapeutic strategy against gastrointestinal cancer development and malignant progression, especially those carrying p53 gain-of-function mutations. © 2018 Elsevier Ltd.Embargo Period 12 month

Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer

Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined ApcΔ716 TGFβr2ΔIEC compound mutant mice that carry mutations in Apc and TGFβr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple TGFβr2ΔIEC mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these TGFβr2ΔIEC mice developed invasive colon cancer associated with chronic inflammation.Wealso found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causingMMP2activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFβ signaling-repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in TGFβr2ΔIEC mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated TGFβr2ΔIEC mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFβ signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans

長崎県健康・栄養調査における食生活の自己評価と食習慣、身体状況、栄養摂取状況の関連

本研究は、長崎県健康・栄養調査の食生活習慣状況調査における食生活の自己評価と食習慣、身体状況、栄養摂取状況との関連を明らかにすることを目的とした。対象者は、平成28年度長崎県健康・栄養調査の対象者のうち590名を解析対象とし、食生活の自己評価により2群に分け、食習慣やBMI、栄養摂取状況を比較した。その結果、食生活の自己評価が高い者の特徴としては、年代が高いこと、食生活に関する意識が高いことが示唆されたが、対象者の自己評価と栄養摂取のコントロールには関連があまりみられなかった。その点から、自ら食をコントロールし、自己評価につなげられるように望ましい食生活について量などの具体的な知識の普及に関する健康教育を行い、食意識のレベルアップを図る必要がある

Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis.

金沢大学ナノ生命科学研究所Signal transducer and activator of transcription 3 (Stat3) has been shown to play a role in intestinal regeneration and colitis-associated colon carcinogenesis. However, the role of Stat3 in the Wnt-driven sporadic intestinal tumorigenesis remains poorly understood. We examined the roles of Stat3 in intestinal regeneration and tumorigenesis by organoid culture experiments using Stat3∆IEC mouse-derived intestinal epithelial cells in which Stat3 was disrupted. The regeneration of intestinal mucosa and organoid formation were significantly suppressed by Stat3 disruption, which was compensated by Wnt activation. Furthermore, once organoids were recovered, Stat3 was no longer required for organoid growth. These results indicate that Stat3 and Wnt signaling cooperatively protect epithelial cells at the early phase of intestinal regeneration. In contrast, intestinal tumorigenesis was not suppressed by Stat3 disruption in adenomatous polyposis coli ( Apc) Δ716 and Apc∆716 Tgfbr2∆IEC mice, thus indicating that Stat3 is not required for Wnt activation-driven intestinal tumorigenesis. Mechanistically, Itga5 and Itga6 were down-regulated by Stat3 disruption, and focal adhesion kinase (FAK) activation was also suppressed. Notably, FAK inhibitor suppressed the organoid formation of wild-type epithelial cells. These results indicate that Stat3 is indispensable for the survival of epithelial cells through the activation of integrin signaling and the downstream FAK pathway; however, it is not required for the Wnt signaling-activated normal or tumor epithelial cells.-Oshima, H., Kok, S.-Y., Nakayama, M., Murakami, K., Voon, D. C.-C., Kimura, T., Oshima, M. Stat3 is indispensable for damage-induced crypt regeneration but not for Wnt-driven intestinal tumorigenesis