Spatiotemporal analysis of the UPR transition induced by methylmercury in the mouse brain

Methylmercury (MeHg), an environmental toxicant, induces neuronal cell death and injures a specific area of the brain. MeHg-mediated neurotoxicity is believed to be caused by oxidative stress and endoplasmic reticulum (ER) stress but the mechanism by which those stresses lead to neuronal loss is unclear. Here, by utilizing the ER stress-activated indicator (ERAI) system, we investigated the signaling alterations in the unfolded protein response (UPR) prior to neuronal apoptosis in the mouse brain. In ERAI transgenic mice exposed to MeHg (25 mg/kg, S.C.), the ERAI signal, which indicates activation of the cytoprotective pathway of the UPR, was detected in the brain. Interestingly, detailed ex vivo analysis showed that the ERAI signal was localized predominantly in neurons. Time course analysis of MeHg exposure (30 ppm in drinking water) showed that whereas the ERAI signal was gradually attenuated at the late phase after increasing at the early phase, activation of the apoptotic pathway of the UPR was enhanced in proportion to the exposure time. These results suggest that MeHg induces not only ER stress but also neuronal cell death via a UPR shift. UPR modulation could be a therapeutic target for treating neuropathy caused by electrophiles similar to MeHg

Utility of Combined Use of Transabdominal Ultrasonography and Fecal Immunochemical Test Examinations in Ulcerative Colitis

This study examined the utility of the combined use of transabdominal ultrasonography (TUS) and fecal immunochemical testing (FIT) to detect mucosal inflammation, vis-a-vis the Mayo endoscopic subscore (MES), in ulcerative colitis (UC). Sixty-three UC patients who underwent TUS and FIT were retrospectively enrolled. For TUS, the colon was divided into five segments, and the bowel wall thickness was measured and evaluated. The accuracy of FIT (> 100 ng/ml) in detecting mucosal inflammation (MES>0) was 0.93, whereas that of TUS (BWT>2 mm) in each segment was 0.84-0.97. The combined use of TUS and FIT may be helpful in noninvasive treatment strategies

Detection of the Onset of Ischemia and Carcinogenesis by Hypoxia-Inducible Transcription Factor-Based In Vivo Bioluminescence Imaging

An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential

チュウゴク タイイク ト ホンガク ショウガイ スポーツ トノ チガイ : ホンガク リュウガクセイ アンケート ヨリ

本研究は体育の授業方法研究の基礎とするために、中国人留学生を対象として本学体育授業「生涯スポーツ」に関するアンケート調査を行った。結果は次の通りであった。①本学生涯スポーツで行っているバスケットボールとバレーボール、バトミントン、卓球について「と ても 楽しかった・だいたい楽しかった」にほぼ全員が回答した。②感想は「健康に役立つ」と「楽しみに役立つ」、「友人関係に役立つ」に全員が回答した。③中国体育との違いの肯定的感想は「健康的」、「自主的」が多かった。しかし、「覚えやすいとは思 わない」に1/3、「難しい」に1/2 の留学生が回答した。　以上のことから、本学生涯スポーツの目的である「生涯楽しく行うスポーツへの理解」に沿った感想を得ることが出来た。一方、「分かりにくい」が推察され、今後の課題を見出すことが出来た

Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study

Introduction: In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. Methods: The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. Results: We included 1,325 patients with HCC and treated with lenvatinib in our analysis. Median OS was 16.1 months. Overall response rate was 38.5%. Multivariate analysis for OS highlighted that HBsAg positive, NLR >3, and AST >38 were independently associated with poor prognosis in all models. Conversely, NAFLD/NASH-related etiology was independently associated with good prognosis. Median progression-free survival was 6.3 months. Multivariate analysis for progression-free survival revealed that NAFLD/NASH, BCLC, NLR, and AST were independent prognostic factors for progression-free survival. A proportion of 75.2% of patients suffered from at least one adverse effect during the study period. Multivariate analysis exhibited the appearance of decreased appetite grade ≥2 versus grade 0-1 as an independent prognostic factor for worse progression-free survival. 924 patients of 1,325 progressed during lenvatinib (69.7%), and 827 of them had a follow-up over 2 months from the beginning of second-line treatment. From first-line therapy, the longest median OS was obtained with the sequence lenvatinib and immunotherapy (47.0 months), followed by TACE (24.7 months), ramucirumab (21.2 months), sorafenib (15.7 months), regorafenib (12.7 months), and best supportive care (10.8 months). Conclusions: Our study confirms in a large and global population of patients with advanced HCC, not candidates for locoregional treatment the OS reported in the registration study and a high response rate with lenvatinib

Impact of metformin, statin, aspirin and insulin on the prognosis of uHCC patients receiving first line Lenvatinib or Atezolizumab plus Bevacizumab

: Recently, in Hepatocellular carcinoma (HCC) setting, the use of metformin has been associated to a trend toward worse response rate, overall survival and progression free survival in patients who received immunotherapy. The study population included individuals from both Eastern and Western regions with a confirmed diagnosis of HCC and receiving first line treatment with Atezolizumab plus bevacizumab or Lenvatinib. Univariate and multivariate analyses were performed by Cox proportional. For the analysis, patients were stratified based on their use of concomitant medication or not. At the time of database lock, 319 deaths were observed: 209 in the Lenvatinib cohort, 110 in the Atezolizumab plus bevacizumab cohort. In the Atezolizumab plus Bevacizumab arm, 50 (16.5%) patients were on chronic metformin use. At the univariate analysis for OS, patients who used metformin showed significantly shorter OS compared to patients who did not use metformin (HR 1.9, 95% CI 1.1-3.2). Multivariate analysis confirmed that patients in metformin group had significantly shorter OS compared to patients in no-metformin group (HR 1.9; 95% CI 1.1-3.1). At the univariate analysis for PFS, patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.6, 95% CI 1.0-2.6). Multivariate analysis confirmed that patients in metformin group had significantly shorter PFS compared to patients in no-metformin group (HR 1.7; 95% CI 1.1-2.7; p = 0.0147). No differences were reported in terms of ORR and DCR between patients in metformin group and those in no-metformin group. In the Lenvatinib cohort, 65 (15%) patients were recorded to chronically use metformin. No statistically significant differences in terms of both OS and PFS were found between patients in metformin group and patients in no-metformin group. This analysis unveils a negative prognostic role associated with metformin use specifically within the Atezolizumab plus Bevacizumab group

Conduction-band electronic states of YbInCu4 studied by photoemission and soft x-ray absorption spectroscopies

We have studied conduction-band (CB) electronic states of a typical valence-transition compound YbInCu4 by means of temperature-dependent hard x-ray photoemission spectroscopy (HX-PES) of the Cu 2p3/2 and In 3d5/2 core states taken at hν=5.95 keV, soft x-ray absorption spectroscopy (XAS) of the Cu 2p3/2 core absorption region around hν∼935 eV, and soft x-ray photoemission spectroscopy (SX-PES) of the valence band at the Cu 2p3/2 absorption edge of hν=933.0 eV. With decreasing temperature below the valence transition at TV=42 K, we have found that (1) the Cu 2p3/2 and In 3d5/2 peaks in the HX-PES spectra exhibit the energy shift toward the lower binding-energy side by ∼40 and ∼30 meV, respectively, (2) an energy position of the Cu 2p3/2 main absorption peak in the XAS spectrum is shifted toward higher photon-energy side by ∼100 meV, with an appearance of a shoulder structure below the Cu 2p3/2 main absorption peak, and (3) an intensity of the Cu L3VV Auger spectrum is abruptly enhanced. These experimental results suggest that the Fermi level of the CB-derived density of states is shifted toward the lower binding-energy side. We have described the valence transition in YbInCu4 in terms of the charge transfer from the CB to Yb 4f states

Convergence of Notch and β-catenin signaling induces arterial fate in vascular progenitors

The Notch intracellular domain and β-catenin team up with RBP-J to regulate gene transcription and promote the development of arterial endothelial cells