Host factors influence Barrett\u27s carcinogenesis: findings from a mouse gastroduodenal reflux model.

Background:Rat gastroduodenal reflux models have been used for analyzing Barrett\u27s carcinogenesis. Mice seem to be more useful than rats for studies targeting genes.Methods:We induced gastroduodenal contents reflux by esophagojejunostomy using C57BL/6J mice. Mice were divided into a standard diet and high-fat diet groups and kept for 60 weeks. Bile was sampled from the gallbladder to analyze bile acid fractions, and the esophagus was removed for a histological investigation. Human esophagogastric junction adenocarcinoma cells (OE19) were exposed to taurocholic acid (TCA), after which cell proliferative activity was measured. Rat esophageal cancer cell lines, ESCC-DR and ESCC-DRtca with higher malignant potential induced by continuous TCA exposure, were used to perform comprehensive genetic analysis (CGH).Results:Barrett\u27s epithelium onset occurred in all mice, and no differences in histological changes were noted between the standard diet and high-fat diet groups. However, no development of adenocarcinoma was noted. Most of the mouse bile acid was taurine conjugates. In the experiment using OE-19 cells, TCA promotes cell proliferation in a dose-dependent manner. Array CGH analysis revealed a large number of chromosomal abnormalities in the ESCC-DR, in addition to genetic abnormalities such as in the UGT2B gene, the substrate of which is bile acid. TCA administration resulted in more chromosomal abnormalities being detected.Conclusions:We showed the effects of TCA in cancer progression in vitro. However, Barrett\u27s adenocarcinoma onset rates differ between mice and rats despite undergoing similar reflux stimulation including taurine-conjugated bile acids being detected in mouse bile juice. These results suggest that host factors seem to influence Barrett\u27s carcinogenesis.滋賀医科大学令和元年

Development of Pancreatic Acinar Cell Metaplasia During Gastric Repair in a Rat Duodenal Contents Reflux Model.

Background: We previously reported the development of pancreatic acinar cell metaplasia (PACM) in the glandular stomach of a duodenal contents reflux model (reflux model).Aims: We aimed to investigate the characteristics and histogenesis of PACM using a reflux model.Methods: A reflux model was created using 8-week-old male Wistar rats, which were killed up to 30 weeks postoperatively. Histological examination was performed to analyze the glandular stomach-jejunal anastomosis. Furthermore, electron microscopic images of PACM samples were compared with pancreatic and gastric glands removed from rats that had not undergone surgery. Immunostaining for α-amylase, HIK1083, TFF2, and Ki-67 was performed, and double fluorescent staining was carried out using antibodies against α-amylase and HIK1083, or α-amylase and TFF2.Results: In all reflux model rats, PACM was observed proximal to the glandular stomach-jejunal anastomosis, surrounded by pseudopyloric metaplasia. The number of chief cells was decreased in the deep part of the gland, where PACM occurred. Electron microscopy showed that PACM cells had greater numbers of rough endoplasmic reticulum tubules than chief cells, and exhibited pancreatic acinar cell morphology. Upon immunochemical staining, the regenerative foveolar epithelium and part of the pseudopyloric glands stained strongly positive for TFF2, whereas PACM cells were only weakly positive. Double fluorescent staining identified early lesions of PACM in the neck, which were double positive for α-amylase and TFF2, but negative for HIK1083.Conclusions:PACM could be induced by duodenal contents reflux. PACM originates from stem cells located in the neck of oxyntic glands during gastric mucosal regeneration

DISASTER RESPONSE OF FACILITIES FOR THE ELDERLY IN MIHARA CITY, WHICH WERE INUNDATED BY THE FLOOD OF THE NUMATA RIVER

平成30年7月豪雨では広島県の沼田川流域で堤防からの溢水や決壊が生じ，三原市内の複数の高齢者施設で浸水被害が発生した．そこで，被災した3施設を対象に被害状況，水害発生時の避難行動，被災後の業務再開状況等について聞き取り調査を実施した．また，聞き取り調査から得られた浸水過程や避難行動を確認し，詳細分析を行うため，各施設周辺の浸水痕跡調査及び沼田川流域を対象とした河川氾濫数値解析も実施した．浸水エリア内の微高地に立地する施設では臨時の避難場所の役割を果たしたが，避難者との連携が課題となった．深刻な床上浸水被害を受けた施設では緊急時の職員参集体制，近隣の支援者の確保など，水害を想定した具体的な避難計画の作成が急務であることが明らかとなった．また，災害休業時における雇用対策も事業継続上重要な課題であることがわかった．Several elderly facilities in Mihara city, Hiroshima Prefecture were damaged by flooding in the Nuta River basin in the the heavy rain event of July 2018. Interview surveys were conducted with staff members of the disaster-affected facilities on the damage situation, evacuation behavior and business continuity after the disaster. In order to confirm the results of the interview surveys, we conducted inundation trace surveys and numerical simulation of river inundation around these facilities. From this result, the followings were found. It was difficult to cooperate with the evacuees at the facilities that served as temporary evacuation sites. There is an urgent need to build an emergency assembly system for staff, secure collaborators at the time of evacuation, and formulate an evacuation security plan for flood damage. Maintaining employment during suspension of business due to the disaster is important for business continuity

Metastatic colorectal cancer responsive to regorafenib for 2 years: a case report

Abstract Background Regorafenib is an oral multikinase inhibitor that has been demonstrated as clinically effective in patients with metastatic colorectal cancer in phase III studies. Although disease control was achieved in 40% of the pretreated patients with metastatic colorectal cancer in the pivotal studies, radiological response has rarely been reported. Severe adverse events associated with regorafenib are known to occur during the first and second courses of treatment. We present a case of a 62-year-old Japanese patient whose metastatic colorectal cancer has been responding to treatment with regorafenib for 2 years. Case presentation A 54-year-old Japanese man visited our institute exhibiting general malaise, and he was diagnosed with ascending colon cancer in April 2006. He underwent right hemicolectomy, and the final staging was T3N0M0, stage II. After 19 months, pulmonary metastasis and anastomotic recurrences were detected, and a series of operations were performed to resect both metastatic lesions. After that, liver metastasis, a duodenal metastasis with right renal invasion, right adrenal metastasis, and para-aortic lymph node metastases were observed during follow-up, and chemotherapy and resection were performed. The patient had metastatic para-aortic lymph nodes after the fifth tumor resection and underwent multiple lines of chemotherapy in April 2014. Regorafenib monotherapy was started at 80 mg/day. Then, regorafenib was increased to 120 mg/day in the second cycle. Regorafenib monotherapy led to 60% tumor shrinkage within the initial 2 months, and the tumor further decreased in size over 4 months until it became unrecognizable on imaging studies. The clinical effects of regorafenib monotherapy have shown a partial response according to Response Evaluation Criteria in Solid Tumors criteria. No severe adverse events were observed, except for mild fatigue and hand-foot syndrome. The patient has received 24 courses of regorafenib over 2 years without exhibiting tumor progression. Conclusions To the best of our knowledge, this is the longest treatment with regorafenib without tumor progression ever reported. A reduced dosage of regorafenib at induction may ameliorate the cutaneous and hepatic toxicity associated with its use

Characterization of Heme Orientational Disorder in a Myoglobin Reconstituted with a Trifluoromethyl-Group-Substituted Heme Cofactor

The orientation of a CF₃-substituted heme in sperm whale myoglobin and L29F, H64L, L29F/H64Q, and H64Q variant proteins has been investigated using ¹⁹F NMR spectroscopy to elucidate structural factors responsible for the thermodynamic stability of the heme orientational disorder, i.e., the presence of two heme orientations differing by a 180° rotation about the 5–15 <i>meso</i> axis, with respect to the protein moiety. Crystal structure of the met-aquo form of the wild-type myoglobin reconstituted with 13,17-bis­(2-carboxylatoethyl)-3,8-diethyl-2,12,18-trimethyl-7-trifluoromethylporphyrinatoiron­(III), determined at resolution of 1.25 Å, revealed the presence of the heme orientational disorder. Alterations of the salt bridge between the heme 13-propionate and Arg45­(CD3) side chains due to the mutations resulted in equilibrium constants of the heme orientational disorder ranging between 0.42 and 1.4. Thus, the heme orientational disorder is affected by the salt bridge associated with the heme 13-propionate side chain, confirming the importance of the salt bridge in the heme binding to the protein