SGLT2阻害薬であるイプラグリフロジンは2型糖尿病自然発症モデルであるOLETFラットにおいて肝線維化進展を抑制する。

BACKGROUND: It is widely understood that insulin resistance (IR) critically correlates with the development of liver fibrosis in several types of chronic liver injuries. Several experiments have proved that anti-IR treatment can alleviate liver fibrosis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of antidiabetic agents that inhibit glucose reabsorption in the renal proximal tubules, improving IR. The aim of this study was to elucidate the effect of an SGLT2 inhibitor on the development of liver fibrosis using obese diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats and their littermate nondiabetic Long-Evans Tokushima Otsuka (LETO) rats. METHODS: Male OLETF and LETO rats were intraperitoneally injected with porcine serum twice a week for 12 weeks to augment liver fibrogenesis. Different concentrations of ipragliflozin (3 and 6 mg/kg) were orally administered during the experimental period. Serological and histological data were examined at the end of the experimental period. The direct effect of ipragliflozin on the proliferation of a human hepatic stellate cell (HSC) line, LX-2, was also evaluated in vitro. RESULTS: OLETF rats, but not LETO rats, received 12 weeks of porcine serum injection to induce severe fibrosis. Treatment with ipragliflozin markedly attenuated the development of liver fibrosis and expression of hepatic fibrosis markers, such as alpha smooth muscle actin, collagen 1A1, and transforming growth factor beta (TGF-β), and improved IR in a dose-dependent manner in OLETF rats. In contrast, the proliferation of LX-2 in vitro was not affected, suggesting that ipragliflozin had no significant direct effect on the proliferation of HSCs. CONCLUSION: In conclusion, our dataset suggests that an SGLT2 inhibitor could alleviate the development of liver fibrosis by improving IR in naturally diabetic rats. This may provide the basis for creating new therapeutic strategies for chronic liver injuries with IR.博士（医学）・甲第665号・平成29年3月15日© Japanese Society of Gastroenterology 2016The final publication is available at Springer via http://dx.doi.org/10.1007/s00535-016-1200-6

頭皮皮膚血管肉腫に対する根治的な寡分割高線量放射線治療の実行可能性と有効性の検討

Cutaneous angiosarcoma is a rare but highly aggressive vascular tumor resistant to all treatment modalities available. The aim of this study was to analyze the treatment outcomes of patients who received definitive hypofractionated high-dose radiotherapy (RT) for angiosarcoma of the scalp. Between April 2008 and December 2014, 11 patients with histologically proven cutaneous angiosarcoma of the scalp visited our Department of Radiation Oncology, because dermatologists suggested that there was no indication for surgery in those cases. One patient rejected all radical treatments and the other 10 patients were treated by RT with curative intent along with chemotherapy or immunotherapy. Eight patients were treated with 6 - 12 MeV electron beams and the other 2 patients were treated with 4 MV X-ray Intensity Modulated Radiation Therapy (IMRT) and electron beams. The total irradiated dose was 63 - 75 Gy (median: 72.5 Gy) in 26 - 30 fractions, and the fraction size was 2.5 Gy in principle. The median age of the patients treated with RT was 80 years old (range: 73 - 91) and the median follow-up time was 16.5 months (range: 5.6 - 86.3). Four patients are still alive. A complete response (CR) was achieved in 10 patients (100%) and only one patient suffered local relapse 20 months after RT. Medians of overall survival (OS), progression-free survival (PFS), and local relapse-free survival (LRFS) were 38.7, 13.4, and 19.8 months, respectively. Local control rates were 100 and 75% at 1 and 2 years, respectively. Skin ulceration was CTCAE grade 2 in 5 patients (50%) and grade 3 in 5 (50%), alopecia was grade 2 in all patients (100%), but no patient developed grade 4 or more severe adverse events after RT. Hypofractionated high-dose RT was feasible and achieved excellent local control of cutaneous angiosarcoma in the elderly patients.博士（医学）・甲第646号・平成28年3月15日Copyright: © 2015 Shimoda E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The definitive version is available at " http://clinmedjournals.org/articles/ijccr/international-journal-of-cancer-and-clinical-research-ijccr-2-032.php?jid=ijccr

フルクトースの経口投与はラット脂肪性肝炎モデルにおいて腸管透過性亢進作用を介して肝線維化および肝発癌を悪化させる

Recent reports have revealed the impact of a western diet containing large amounts of fructose on the pathogenesis of non-alcoholic steatohepatitis (NASH). Fructose exacerbates hepatic inflammation in NASH by inducing increasing intestinal permeability. However, it is not clear whether fructose contributes to the progression of liver fibrosis and hepatocarcinogenesis in NASH. The aim of this study was to investigate the effect of fructose intake on NASH in a rat model. A choline-deficient/L-amino acid diet was fed to F344 rats to induce NASH. Fructose was administrated to one group in the drinking water. The development of liver fibrosis and hepatocarcinogenesis were evaluated histologically. Oral fructose administration exacerbated liver fibrosis and increased the number of preneoplastic lesions positive for glutathione S-transferase placental form. Fructose-treated rats had significantly higher expression of hepatic genes related to toll-like receptor-signaling, suggesting that fructose consumption increased signaling in this pathway, leading to the progression of NASH. We confirmed that intestinal permeability was significantly higher in fructose-treated rats, as evidenced by a loss of intestinal tight junction proteins. Fructose exacerbated both liver fibrosis and hepatocarcinogenesis by increasing intestinal permeability. This observation strongly supports the role of endotoxin in the progression of NASH.博士（医学）・乙第1432号・令和元年9月27日Copyright © 2018 Impact Journals, LLCCopyright © Seki et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited