眞嶋 浩聡

Background and aims: At Saitama Medical Center, for remission induction in active ulcerative colitis (UC) patients with endoscopic evidence of severe disease, we tend to preferentially use tacrolimus (TAC) over anti-tumor necrosis factor (TNF)-a agents. We conducted this study to evaluate the validity of our therapeutic strategies. Patients and methods: This retrospective study was conducted in 52 steroid-refractory active UC patients with a Clinical Activity Index (CAI) score of ≥7 who were receiving remission induction therapy with TAC or anti-TNF-α agents. The patients were divided into a TAC treatment group (TAC group, n = 29) and an anti-TNF-α agent treatment group (anti-TNF group, n = 23). The CAI, Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and incidence of events (relapse, hospitalization and surgery) were retrospectively analyzed. Results: At treatment initiation, the CAI score was 12.6 in the TAC group and 11.5 in the anti-TNF group (P = 0.09), while the corresponding values of the UCEIS were 6.5 and 5.1, respectively (P = 0.0035). The clinical remission rate at 12 weeks was 55% (65% when only the subgroup that received rapid induction therapy was included in the analysis) in the TAC group and 57% in the anti-TNF group, with no significant difference. The cumulative event-free rates at 1, 6 and 12 months were 65.5%, 39.4%, and 39.4%, respectively, in the TAC group and 95.7%, 77.2% and 71.7%, respectively, in the anti-TNF group (P = 0.0037). Conclusion: Rapid induction therapy with TAC tended to be selected for active UC patients with endoscopic evidence of severe disease, and the present study supported the validity of this therapeutic approach. However, transition to the remission-maintenance phase was more favorable in the anti-TNF group.

Although endoscopic submucosal dissection (ESD) is becoming the mainstay of the treatment strategies, rather than surgical treatment, for colorectal tumors extending to the dentate line, ESD is technically more difficult. This study was aimed at assessing the usefulness of ESD for the treatment of colorectal tumors extending to the dentate line. This study included 531 patients with colorectal tumors who underwent colorectal ESD between 2008 and 2015. They were divided into three groups: rectal tumors extending to the dentate line (anorectal group), those not extending to the dentate line (proximal rectal group), and colonic tumors (colonic group), and a retrospective comparative analysis was carried out. Of the total patients, 18 (3.4%) had lesions extending to the dentate line area. The procedure times were 103.4 +/- 84.0, 80.4 +/- 64.3, and 71.8 +/- 52.3 min, respectively (P = 0.0318). All the patients in the anorectal group were operated by operators who had performed at least 20 colorectal ESDs (P < 0.0001). No significant difference among the three groups was found in the en bloc resection rate, complete resection rate, or curative resection rate. Although no significant difference in the incidence of perforation was observed among the three groups, intraoperative bleeding was observed in 61% of the patients in the anorectal group (P < 0.0001). ESD is an effective treatment strategy for colorectal tumors extending to the dentate line. However, it seems that anorectal ESD, which is technically more difficult than colorectal ESD, should be performed by operators with ample experience in performing ESD.

Although aberrations of intracellular vesicle transport systems towards lysosomes including autophagy and endocytosis are involved in the onset and progression of acute pancreatitis, the molecular mechanisms underlying such aberrations remain unclear. The pathways of autophagy and endocytosis are closely related, and Rab7 plays crucial roles in both. In this study, we analyzed the function of Rab7 in acute pancreatitis using pancreas-specific Rab7 knockout (Rab7(Delta pan)) mice. In Rab7(Delta pan) pancreatic acinar cells, the maturation steps of both endosomes and autophagosomes were deteriorated, and the lysosomal functions were affected. In experimental models of acute pancreatitis, the histopathological severity, serum amylase concentration and intra-pancreatic trypsin activity were significantly higher in Rab7(Delta pan) mice than in wild-type mice. Furthermore, the autophagy process was blocked in Rab7(Delta pan) pancreas compared with wild-type mice. In addition, larger autophagic vacuoles that colocalize with early endosome antigen 1 (EEA1) but not with lysosomal-associated membrane protein (LAMP)-1 were much more frequently formed in Rab7(Delta pan) pancreatic acinar cells. Accordingly, Rab7 deficiency exacerbates the severity of acute pancreatitis by impairing the autophagic and endocytic pathways toward lysosomes.

Objective: Unusual setting of medical care Background: Tacrolimus is reportedly effective for the treatment of refractory ulcerative colitis (UC). At our hospital, there has been an increase in the number of patients, including elderly patients, with refractory UC treated with tacrolimus. Here, we review the data from 5 patients with elderly-onset UC treated with tacrolimus as remission induction therapy. Case Report: The subjects were 5 patients ≥65 years of age with refractory UC who had received oral tacrolimus as remission induction therapy between 2009 and 2014 (3 men and 2 women median age at onset, 75 years). At the start of the tacrolimus treatment, the median duration of disease was 3 months, and the type of UC was total colitis in 4 cases, and left-sided colitis in 1 case. The drugs used concomitantly at the start of tacrolimus treatment were mesalazine (5 cases) and an immunomodulator drug (1 case). Standard induction therapy (0.05 mg/kg/day) was used in 2 patients and rapid induction therapy (0.1 mg/kg/day) was used in the remaining 3 patients. One week after the start of treatment, the blood trough concentrations of tacrolimus were over the target level of 15 mg/mL in 4 patients. The clinical activity index values on day 0 and day 14 were 10.6±2.1 and 7.6±3.4, respectively. The ulcerative colitis endoscopic index of severity in the remaining 3 patients, after excluding the 2 patients who required colectomy within 14 days after the start of tacrolimus therapy, was 7.3±1.0 before the start of the tacrolimus treatment, improving to 4.5±0.5 on day 14. Subsequently, 1 of these 3 patients was also judged to need surgery due to symptom exacerbation, while complete remission was maintained in the other 2 patients. Conclusions: In elderly-onset refractory UC patients, tacrolimus appears to be effective as remission induction therapy. However, since tacrolimus concentrations in the blood can rise easily in elderly patients, frequent monitoring of the drug concentrations and dosage adjustments are necessary.

Objective: Unusual setting of medical care Background: Serrated polyposis syndrome (SPS) is characterized by numerous hyperplastic polyps and sessile serrated ad-enoma/polyp (SSA/P) in the large intestine. SSA/P is known to transform into malignant lesions through the serrated pathway instead of the adenoma-carcinoma sequence. Early diagnosis with lower gastrointestinal endoscopy and early treatment are now considered to be essential. Case Report: We had an experience with a case of SPS to which endoscopic treatment was applied in multiple sessions. Endoscopic treatment was performed for 16 lesions in total, and the pathological findings were SSA/P for 15 and adenoma for the other lesion. We intend to continue performing endoscopic surveillance for any newly developing lesions. Conclusions: SPS has a potential for malignant transformation, and issues, such as long-term prognosis and optimal therapeutic strategies, await resolution. However, multiple endoscopic treatments are useful for cases with lesions that are controllable employing this modality.

Objective: We attempted to develop a scoring system for facilitating decision making regarding the performance of emergency endoscopy in patients with colonic diverticular hemorrhage. Methods : This study involved analysis of the data of 178 patients who presented with hematochezia and were diagnosed as having colonic diverticular hemorrhage by colonoscopy. The patients were divided into 2 groups depending on whether the bleeding source was identified or not at the initial endoscopy (source-identified and source-not-identified groups), and on the basis of the results obtained, we established a scoring system for predicting successful identification of the bleeding source. Res ults : The percentages of patients on oral anticoagulant therapy or with a Charlson comorbidity index of ≥6, serum C-reactive protein level of ≥1 mg/dL, or extravasation of contrast medium visualized on contrast-enhanced computed tomographic (CT) images were all significantly higher in the identified than in the nonidentified group. Multivariate analysis identified extravasation of contrast medium on contrastenhanced CT images (odds ratio [OR]: 10.6 95% confidence interval [CI]: 2.7-42.2) and use of anticoagulants (OR: 4.5 95% CI: 1.5-13.5) as independent predictors of successful identification of the bleeding source at the initial endoscopy in patients with colonic diverticular hemorrhage. On the basis of these results, we established a scoring system, which showed a sensitivity of 80% and specificity of 81% for successful identification of the bleeding source at the initial endoscopy. Conclusions: Herein, we propose a scoring system as a useful tool for determining whether emergency endoscopy is indicated in individual patients with suspected colonic diverticular hemorrhage.

Although biologics are important inflammatory bowel disease therapies, loss of response (LOR) remains problematic. We evaluated LOR to biologics in our Crohn disease (CD) patients receiving biologics. Of 137 biologic-treated CD patients, 68 continuously receiving the same biologic type for at least 1 year were divided into 2 groups: infliximab (IFX) (n= 39) and adalimumab (ADA) (n= 29). Clinical courses were compared at biologic introduction and at 1 year. Both groups were retrospectively analyzed for LOR at and beyond 1 year after biologic introduction (study endpoint). Patients were then divided into LOR and non-LOR groups to identify factors predicting LOR. At 1 year after biologic introduction, decreases in CD activity index were 94 +/- 105 in the IFX and 102 +/- 89 in the ADA group, not significantly different. Blood test data did not differ between these groups. LOR occurred in 14 IFX and 5 ADA group patients. Event-free rates at 5 years after biologic introduction were 62% in the IFX and 61% in the ADA group. Patients achieving clinical remission 1 year after biologic introduction accounted for 69% of the IFX and 90% of the ADA group, while respective rates of secondary LOR at 5 years were 32% and 26%. C-reactive protein (CRP) at biologic introduction (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.04-2.06; P=. 02) and age at CD onset (OR, 1.1; 95% CI, 1.01-1.20; P=. 03) predicted LOR. As to IFX and ADA efficacies after 1 year of administration, there were no significant differences in event-free rates for the 5 years after biologic introduction or the secondary LOR rate. CRP at biologic introduction and age at CD onset predicted LOR.

2種の大腸内視鏡前処置薬polyethilene glycol(PEG)高張液(新P)と等張クエン酸マグネシウム液(M)の大腸内視鏡挿入時間を比較し、腸管洗浄度および患者受容性について比較検討した。対象は、新P法使用23例(男女比0.48、平均年齢54.7歳)、M法使用22例(男女比0.38、平均年齢57.6歳)である。その結果、新P法はM法と比較して大腸内視鏡平均挿入時間が長い傾向で、洗浄度、受容度ともに劣ることが示唆された。また、M法の方が医療費が安く経済性が高いことが分かった。

Background: Gastric foveolar hyperplastic polyps (GFHPs) are common findings in clinical practice. GFHPs commonly arise in a background of chronic atrophic gastritis, including autoimmune gastritis (type A gastritis), and have a potential risk of malignant transformation. Case presentation: In 2005, a 55-year-old Japanese woman underwent upper endoscopy at another hospital and was found to have a pedunculated polyp (10 mm in diameter) on the greater curvature of the lower gastric body. On biopsy, the polyp was diagnosed as a GFHP. Nine years later, the polyp had grown to 20 mm in diameter, and the biopsy specimen taken at this time showed tubular adenocarcinoma. On admission to our hospital, the serum Helicobacter Pylori (H. pylori) immunoglobulin G antibody and stool H. pylori antigen were both negative. Anti-gastric parietal cell antibody was positive, as was the anti-intrinsic factor antibody, and the fasting serum gastrin level was markedly increased. In 2014, en bloc resection of the pedunculated polyp was performed by endoscopic submucosal dissection. The final histological diagnosis was adenocarcinoma of the stomach with submucosal and lymphatic invasion. Subsequently, additional radical distal gastrectomy was performed. At the latest follow-up (12 months postoperatively), no recurrence was noted. Conclusions: We here reported a rare case of malignant transformation of GFHP arising in a context of type A gastritis. To our knowledge, there are no previous reports on malignant transformation of GFHP with submucosal and lymphatic invasion arising in a background of type A gastritis in the English literature. Further, there is currently no effective treatment other than endoscopic or surgical treatment for such cases. Given the potential risk of malignant transformation due to hypergastrinemia, we consider that endoscopic treatment should be considered as a first-line therapy when a malignant growth is suspected.

症例は58歳男性で、1週間ほど前に空腹時心窩部痛、嘔気、嘔吐が出現し、近医で胃炎と診断された。H2ブロッカーと胃粘膜保護薬を処方されたが、深夜に症状が増悪し、救急搬送された。血液検査所見で好中球優位の白血球高増加、直接型優位のビリルビン値上昇、肝胆道系酵素上昇を認めた。腹部CT所見では両側の肝内胆管、総胆管が拡張しており、十二指腸乳頭部近傍の下部胆管内に10mm大の高吸収域を認めた。胆石性胆管炎の診断で緊急内視鏡的逆行性胆管膵管造影を施行し、生検で十二指腸乳頭部腺腫と診断した。内視鏡的乳頭切除術(EP)を施行したところ、切除病理組織所見は高度異型を伴う管状絨毛腺腫で断端陰性であった。EP施行後第12病日に残存する総胆管結石に対して内視鏡的切石術を行い、胆管開口部をEPBDバルーンで拡張し採石バルーンで排石した。その後の経過は良好で、半年後の内視鏡MR胆管膵管撮影で乳頭部腺腫や胆管結石の再発を認めていない。

急性膵炎はトリプシンの異所性活性化が中心的な役割を果たすと考えられてきたが、NF-κBの活性化、オートファジー不全、酸化ストレス、小胞体ストレス、細胞内カルシウムの異常などの多くの異常が同時に進行することが明らかとなってきた。これらにも進行の序列はあるはずだが、未だ明らかにされておらず、急性膵炎の発症のメカニズムの詳細は不明のままである。膵酵素の調節性外分泌は細胞内カルシウムによって制御されている。アセチルコリンやコレシストキニンの分泌刺激が基底膜側の受容体から入ると頂端側にカルシウムスパイクが生じて開口放出が起こる。過剰な分泌刺激などを加えて膵炎を発症させると細胞内全体に異常なカルシウム濃度の上昇がみられて遷延する。その異常な上昇をカルシウム結合蛋白やキレート剤、カルシウムチャンネルの阻害剤などを用いて制御すると膵炎発症が抑制されることが明らかになってきた。本項ではカルシウムシグナルに焦点をあてて膵炎との関係を概説する。(著者抄録)

Diversion colitis is a benign inflammatory process that occurs in any part of the large bowel excluded from the fecal stream by a diverting colostomy. While most of the patients with diversion colitis usually are asymptomatic, a minority has abdominal pain and rectal discharge of blood or mucus. A 65-year-old Japanese man was diagnosed as having diversion colitis with ulcerative colitis at 4 months after subtotal colectomy. Corticosteroid and mesalazine enemas were started nonsynchronously. A proctoscopy after 2 months showed no response. Prednisolone injections were started at 1.0 mg/kg daily, but the mucosal inflammation still failed to improve. A combined mesalazine 1 g plus prednisolone sodium phosphate 20 mg enema was started once daily. The rectal bleeding and endoscopic findings improved. Finally proctectomy and ileal pouch-anal anastomosis were successfully performed. A combined mesalazine plus corticosteroid enema may be effective in patients with diversion colitis associated with ulcerative colitis.

膵臓の3大疾患とも言うべき急性膵炎、慢性膵炎、ならびに膵臓癌は依然難治性疾患であり、未だこれら疾患の画期的な予防法および治療法は開発されていない。一方、これら疾患の病態を解明し新たな治療法を開発すべく多くの研究者が膵疾患基礎研究に日夜尽力してきた結果、急性膵炎発症機転や慢性膵炎の発症・進展に関して新たな知見が次々と得られている。急性膵炎におけるオートファジー機構の関与や慢性膵炎の発症・進展における膵星細胞の役割がその代表的なものである。本稿ではこれら膵疾患の病態に関する知見を概説する。(著者抄録)

I型インターフェロンは抗ウイルス作用にとどまらず、免疫調整作用や抗腫瘍効果などの多彩な生物学的活性を有している。インターフェロン制御因子(IRF)はインターフェロン誘導遺伝子の転写を制御する因子として発見されたが、免疫関連遺伝子の転写調節の他に、細胞増殖・アポトーシスの制御、癌化などに関与する。膵臓においてIRF2は調節性外分泌にかかわっており、IRF2ノックアウトマウスの膵臓は急性膵炎の発症初期像を呈する。また、膵癌においてIRF1は癌抑制遺伝子、IRF2は癌遺伝子としての機能を有していることが明らかとなった。生物学的悪性度が高く、浸潤傾向が強い膵癌に対しては、多方面からの治療が不可欠である。インターフェロンシグナルの膵癌の発癌、進展に及ぼす影響やIRFの分子メカニズムの解明を進めることによって、膵癌の新たな治療法に結びつく可能性がある。(著者抄録)

膵臓は消化・吸収のための消化酵素を高率に産生するがゆえに、小胞体ストレスや酸化ストレスに曝されやすい。急性膵炎の発症にはトリプシンの異所性活性化やNF-κBの活性化、細胞内ストレス、オートファジーなどが関与している。オートファジーは老廃物の分解やリサイクルを通して細胞の恒常性の維持に寄与するが、膵炎発症時にも細胞内環境を維持するために動員されると考えられる。しかし、機能不全に陥って膵炎の発症に関与し、p62/SQSTM1(p62)の蓄積や転写因子Nrf2の活性化が細胞内で生じる。p62はオートファジーの基質であるだけでなく、シグナル伝達、細胞増殖、アポトーシス、炎症などをつなぐハブとしての機能を有している。オートファジーと膵炎発症の関係が注目されており、p62やKeap1-Nrf2を介するシグナルが重要な役割を果たしている可能性がある。(著者抄録)

Primary enterolith is a rare condition that can induce ileus and intestinal perforation. We report the first case of a true primary enterolith treated by balloon-assisted enteroscopy. The patient presented with a small intestinal ileus. After its improvement following the insertion of an ileus tube, radiography with amidotrizoate sodium meglumine detected a round, movable defect in the ileum measuring 42 mm diameter. The patient was diagnosed with a primary enterolith based on her past history. The enterolith was fractured and removed using balloon-assisted enteroscopy. This case suggests that balloon-assisted enteroscopy may be an effective non-invasive treatment option for enteroliths.

Objective: Pancreatic cancer is one of the most malignant diseases worldwide. Interferon regulatory factor (IRF) 1 and IRF2 function as a tumor suppressor and oncoprotein, respectively, in several types of cancers. We investigated whether IRF1 and IRF2 are involved in the progression of pancreatic cancer. Methods: We examined the expressions of IRF1 and IRF2 in pancreatic cancer specimens and analyzed the association with clinicopathologic features. We evaluated the biological effects of IRF1 and IRF2 using a pancreatic cancer cell line. Results: The expression levels of IRF1 and IRF2 were decreased and increased, respectively, in the pancreatic cancer cells compared with those observed in the paired normal areas. A higher expression of IRF1 was associated with better features of tumor differentiation, infiltration depth, tumor size, and survival, whereas that of IRF2 was associated with a worse feature of tumor infiltration depth. Interferon regulatory factor 2-overexpressing PANC-1 cells exhibited an increase in cell growth, less apoptotic features, and chemoresistance to gemcitabine treatment. In contrast, IRF1-overexpressing cells exhibited the opposite characteristics. Conclusions: Interferon regulatory factors 1 and 2 may regulate the progression of pancreatic cancer by functioning as an antioncoprotein and oncoprotein, respectively. These molecules may serve as potential targets of therapy.

膵臓は外分泌機能を担う膵腺房および導管、内分泌機能を担うランゲルハンス氏島、ならびに膵星細胞などによって構成される臓器である。とくにランゲルハンス氏島(ラ氏島)の各種内分泌細胞にて産生・分泌される膵ホルモンは膵腺房細胞の生理的機能を制御していると考えられている。さらに最近では、生理的条件下ならびに各種病態において膵臓においてTGF-betaスーパーファミリーに属するサイトカインであるactivin Aが発現し、膵の発生、分化、ならびに線維化などにおいて大きな役割を果たしていることが明らかになってきている。本稿では、膵内分泌相関として知られる膵ホルモンの膵外分泌機構への作用とその分子機序、ならびにactivin Aのさまざまな膵生理機能ならびに膵疾患病態に対する作用を中心に紹介する。(著者抄録)

We report a case of a 64-year-old woman with Stage IV breast cancer who responded well to chemotherapy containing bevacizumab. She noticed a left breast tumor with acute progression and was diagnosed as having Stage IV, estrogen receptor (ER) (-), progesterone receptor (PgR) (-), human epidermal growth factor receptor 2 (HER2) (-) breast cancer (T4cN3cM1 [lymph nodes]). She received 5 courses of adriamycin (60 mg/m2) plus cyclophosphamide (600mg/m2) (AC therapy) and 4 courses of weekly paclitaxel (PTX 90 mg/m2) plus bevacizumab (AVA 10 mg/m2) as systemic therapy. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a complete response (CR). After local resection of the breast tumor and radiation to the breast and regional lymph nodes, capecitabine therapy was initiated. Currently, at 5 months after surgery, no new lesion has been detected.

We describe the case of a 74-year-old female with a mesenteric lymph node abscess caused by a Yersinia enterocolitica infection. She had been administered an immunosuppressive drug and was admitted to the hospital due to a high fever, right lower abdominal pain and advanced leukocytosis. We initially diagnosed her with lymphadenitis based on the symptoms and the imaging studies. However, conservative treatment with antibiotics did not yield any improvement, and abscess formation was suspected. Surgical treatment was performed, and the culture from the drainage fluid grew Y. enterocolitica. The histological findings suggested that an ulcerative lesion of the terminal ileum was the entry port of Y. enterocolitica. The pathogen infected the mesenteric lymph nodes and spread along the ileocecal lymphatic vessels, resulting in the formation of an abscess. We also provide a review of the previously published literature on lymph node abscesses due to Y. enterocolitica infections. © Springer 2014.

異時性に内分泌細胞癌小細胞型と扁平上皮癌の多発を認めた稀な食道癌の1例を経験したので報告する．症例は62歳，男性．嚥下時つかえ感を主訴に施行した内視鏡検査で胸部食道に2型腫瘍を認め，生検で内分泌細胞癌小細胞型と診断された．CTでは気管膜様部浸潤，リンパ節転移などを認め，cStage IVa（T4N3M0）と診断され，肺小細胞癌に準じてCDDP，CPT-11による化学療法と放射線療法を併用した．化学療法計11コース終了後，CT，内視鏡検査では腫瘍，リンパ節腫脹が消失し，完全奏効であったが，腹部食道に表面隆起型扁平上皮癌を認め，内視鏡的粘膜下層剥離術を施行した（moderately to poorly differentiated squamous cell carcinoma，pT1a（MM），ly0，v0，pHM0，pVM0）．内分泌細胞癌の診断から現在まで，3.5年間無再発生存中である．

Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosa] healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5 RXFP4 signaling might play a role in an autocrine/ paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors. (C) 2013 Elsevier Inc. All rights reserved.

We herein describe the case of a 51-year-old man with a duodenocolic fistula (DCF) caused by a stomal ulcer. The patient complained of watery diarrhea, dysgeusia and malnutrition. His medical history included distal gastrectomy with Billroth I reconstruction for duodenal ulcer perforation. A combination study using endoscopy and contrast imaging confirmed the presence of DCF. Laparotomic fistulectomy was performed, which resulted in the patient's recovery from diarrhea and malnutrition. The histological findings suggested that the fistula had originated from a stomal ulcer. In patients with chronic watery diarrhea of obscure origin following gastrectomy, DCF is a possible cause of the diarrhea.

胃がん検診は、X線検査のみがいくつかの症例対照研究によって死亡率減少効果を示したことにより対策型検診として推奨されている。一方で近年、血清検査を用いた効率的な胃がん検診法が提唱されている。しかし、内視鏡検診も含めて有効性の評価がなされていないのが現状である。そこで、新しい胃がん検診システムの評価をおこなうことを目的として、「X線検査・精査内視鏡検査群」(バリウム検診群)と「抗H.pylori抗体+ペプシノゲン測定・内視鏡検査群」(血清胃癌リスク検診群)の無作為化比較対照試験をスタートさせた。(著者抄録)

Pancreatic acinar cells are used to study regulated exocytosis. We investigated the role of interferon regulatory factor-2 (IRF2) in exocytosis in pancreatic acinar cells.<br /> Pancreas tissues from Irf2⁺/⁺, Irf2⁺/⁻), and Irf2⁻/⁻ mice were examined by microscopy, immunohistochemical, and immunoblot analyses; amylase secretion was quantified. We also compared salivary glands and pancreatic islets of Irf2⁻/⁻ mice with those of Irf2⁺/⁻ mice. To examine the effects of increased signaling by type I interferons, we studied pancreatic acini from Irf2⁻/⁻Ifnar1⁻/⁻ mice. The effect of IRF2 on amylase secretion was studied using an acinar cell line and a retroviral system. We studied expression of IRF2 in wild-type mice with cerulein-induced pancreatitis and changes in pancreatic tissue of Irf2⁻/⁻ mice, compared with those of Irf2⁺/⁻ mice.<br /> Irf2⁻/⁻ pancreas was white and opaque; numerous and wide-spread zymogen granules were observed throughout the cytoplasm, along with lack of fusion between zymogen granules and the apical membrane, lack of secretagogue-stimulated amylase secretion, and low serum levels of amylase and elastase-1, indicating altered regulatio

BACKGROUND & AIMS: Pancreatic acinar cells are used to study regulated exocytosis. We investigated the role of interferon regulatory factor-2 (IRF2) in exocytosis in pancreatic acinar cells. METHODS: Pancreas tissues from Irf2(+/+), Irf2(+/-) and Irf2(-/-) mice were examined by microscopy, immunohistochemical, and immunoblot analyses; amylase secretion was quantified. We also compared salivary glands and pancreatic islets of Irf2(-/-) mice with those of Irf2(+/-) mice. To examine the effects of increased signaling by type I interferons, we studied pancreatic acini from Irf2(-/-) Ifnar1(-/-) mice. The effect of IRF2 on amylase secretion was studied using an acinar cell line and a retroviral system. We studied expression of IRF2 in wild-type mice with cerulein-induced pancreatitis and changes in pancreatic tissue of Irf2(-/-) mice, compared with those of Irf2(+/-) mice. RESULTS: Irf2(-/-) pancreas was white and opaque; numerous and wide-spread zymogen granules were observed throughout the cytoplasm, along with lack of fusion between zymogen granules and the apical membrane, lack of secretagogue-stimulated amylase secretion, and low serum levels of amylase and elastase- 1, indicating altered regulation of exocytosis. The expression pattern of soluble N-ethylmaleimide-sensitive factor attachment protein receptors changed significantly, specifically in pancreatic acini, and was not rescued by disruption of type I interferon signaling. Down-regulation of IRF2 decreased amylase secretion in an acinar cell line. In mice with pancreatitis, levels of IRF2 were reduced. Irf2(-/-) acini were partially resistant to induction of pancreatitis. CONCLUSIONS: IRF2 regulates exocytosis in pancreatic acinar cells; defects in this process might be involved in the early phases of acute pancreatitis.

In chronic pancreatitis, pancreatic stellate cells (PSCs) play a central role in tissue fibrogenesis. Transforming growth factor beta(1) (TGF-beta(1)) and the Th2 lymphokines such as interleukin (IL)-13 are major profibrogenic cytokines in many organs. Activated PSCs produce various inflammatory cytokines including TGF-beta(1). In this study, we investigated whether IL-13 affects pancreatic fibrogenesis by modulating the functions of PSCs. IL-13 promoted PSCs proliferation without activation through the suppression of autocrine TGF-beta(1). IL-13 enhanced Stat6 phosphorylation in PSCs but Stat6 was not involved in the suppression of TGF-beta(1). IL-13 inhibited the transcriptional activity of NF-kappa B, and the expression of mutant I-kappa B reproduced the suppression of autocrine TGF-beta(1) and promoted PSCs proliferation. Taken together, we demonstrated that IL-13 promotes PSCs proliferation through the suppression of the transcriptional activity of NF-kappa B, resulting in the decrease of autocrine TGF-beta(1). This finding provides an unequivocal evidence of IL-13 participation in pancreatic fibrosis, illustrating a new strategy for chronic pancreatitis. (C) 2010 Elsevier Inc. All rights reserved.

Although hepatic stellate cells, endothelial cells, glomerular podocytes and plateles were reported to be a source of ADAMTS13, it is not clarified which source is involved in the regulation of plasma ADAMTS13 activity. It was demonstrated previously that selective hepatic stellate cell damage in rats caused decreased plasma ADAMTS13 activity. To further elucidate the potential contribution of hepatic stellate cells to the regulation of plasma ADAMTS13 activity, this study examined plasma ADAMTS13 activity when hepatic stellate cells proliferate during the process of liver fibrosis by employing rat models of liver fibrosis due to cholestasis, bile duct ligation, and steatohepatitis, a choline-deficient L-amino acid-defined-diet. ADAMTS13 expression was increased with co-localisation with smooth muscle alpha-actin, a marker of hepatic stellate cells, in bile duct-ligated livers up to four weeks, in which a close correlation between ADAMTS13 and smooth muscle alpha-actin mRNA expressions was determined. Plasma ADAMTS13 activity, measured by a sandwich ELISA involving a specific substrate to ADAMTS I 3,was increased in bile duct-ligated rats with a significant correlation with ADAMTS13 mRNA expression levels in the liver. Furthermore, ADAMTS13 mRNA expression was increased with enhanced mRNA expression in smooth muscle alpha-actin in the livers of rats fed a choline-deficient L-amino acid-defined-diet for 16 weeks, in which increased plasma ADAMTS13 activity was determined. Thus, increased plasma ADAMTS13 activity in cholestasis and steatohepatitis in rats may be due, at least in part,to enhanced ADAMTS13 production in the liver, suggesting a significant role of hepatic stellate cells in the regulation of plasma ADAMTS13 activity.

Pancreatic AR42J cells demonstrate the pluripotency in precursor cells of the gut endoderm and also provide an excellent model system to study the differentiation of the pancreas. Using the mRNA differential display technique, we identified junctional adhesion molecule-1 (JAM-1), a component of the tight junction, was highly up-regulated during the differentiation of AR42J cells, although junctions were not formed. The expression level of JAM-1 showed an up-regulation in the mRNA level after 3 hours and in the protein level after 24 hours in [activin A + betacellulin]-treated AR42J cells. The expressions of its signaling molecules, PAR-3 and atypical PKC lambda, also increased after the addition of activin A + betacellulin. When JAM-1 was over-expressed in [activin A + betacellulin]-treated AR42J cells, tagged-JAM-1 was observed in cytoplasm as vesicular structures and JAM-1 was colocalized with Rab3B and Rab13, members of the Rab family expressed at tight junctions. In streptozotocin-induced regenerating islets, the expression of JAM-1 was also up-regulated in the mRNA level and the protein level. JAM-1 might therefore play an important role in the differentiation of AR42J cells and the regeneration of pancreatic islets.

Indian hedgehog (Ihh) is a member of hedgehog peptides family that exerts diverse effects on multiple cellular functions. Since Ihh expression is elevated in the pancreas of chronic pancreatitis patients, Ihh has been assumed to participate in the chronic pancreatic injury, especially in pancreatic fibrosis. However, its function in pancreatic fibrosis is still unknown. We thus examined Ihh effects on rat activated pancreatic stellate cells (PSCs) that play a central role in pancreatic fibrosis. Activated PSCs express both patched-I and smoothened that are essential components of hedgehog receptor system. Ihh did not alter the PSC expression of collagen-I or alpha-smooth muscle actin, a parameter of PSC transformation, or did not change PSC proliferation. However, Ihh enhanced PSC migration in both chemotactic and chemokinetic manners. Furthermore, Inn increased the amount of membrane-type I matrix metalloproteinase (MTI-MMP) and altered its localization on the plasma membrane, which plays a stimulatory role in cellular migration. In addition, tissue inhibitor of metalloproteinase-2 (TIMP-2) attenuated lhh-stimulated PSC migration. Since most hedgehog intracellular signals are mediated by Gli-I transcription factor, we investigated its contribution to lhh-enhancement of PSC migration. Ihh induced Gli-I nuclear accumulation in PSCs, indicating that Ihh stimulates Gli-I-dependent signaling pathway in PSCs. Unexpectedly, however, adenovirus-mediated Gli-I overexpression blocked the Inn enhancement of both MTI-MMP localization on the plasma membrane and PSC migration. Furthermore, reduction of Gli-I expression with RNA interference augmented lhh-stimulated PSC migration. These data indicate that lhh promotes PSC migration by enhancing MTI-MMP localization on the plasma membrane but is negatively regulated by Gli-I.

Helicobacter pylori-produced cytotoxin VacA induces intracellular vacuolation. The VacA-induced vacuole is assumed to represent the pathological status of intracellular trafficking. The fusion mechanism of the endosomes requires the formation of a tight complex between the Q-SNAREs and the R-SNAREs. We recently reported that syntaxin 7, a family member of the Q-SNARE protein, is involved in VacA-induced vacuole formation. In order to further elucidate the molecular mechanism, we identified the participation of vesicle-associated membrane protein 7 (VAMP7) as a partner of syntaxin 7. Immunocytochemistry revealed endogenous VAMP7 to be localized to the vacuoles induced by VacA. A Northern blotting study demonstrated that VacA intoxication increased VAMP7 mRNA in a time-dependent manner. VAMP7 was coimmunoprecipitated with syntaxin 7, and the amounts of endogenous VAMP7 and syntaxin 7 bound to syntaxin 7 and VAMP7, respectively, increased in response to VacA. The down-regulation of VAMP7 using small interfering RNA inhibited VacA-induced vacuolation, and the transient transfection of dominant-negative mutant VAMP7, the N-terminal domain of VAMP7, also inhibited the vacuolation. We therefore conclude that R-SNARE VAMP7 plays an important role in VacA-induced vacuolation as a partner of Q-SNARE syntaxin 7.

Bile acids, which have been implicated in gastrointestinal-tract cell carcinogenesis, share properties with tumor promoters in that both affect signal transduction pathways responsible for cell proliferation and apoptosis. In the present study, we demonstrate that EGFR-ERK1/2 is activated following treatment of AGS human gastric carcinoma cells with bile acids. EGFR phosphoactivation is ligand-dependent, since treatment of cells with HB-EGF antisera or CM 197 (a selective inhibitor of HB-EGF) markedly inhibits deoxycholate (DC)-promoted activation. Membrane-type bile acid receptor (M-BAR)/TGR5 is a recently identified G-protein-coupled receptor (GPCR). In AGS cells, siRNAs that target M-BAR suppress DC-induced phosphorylation of EGFR. Furthermore, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2. These results suggest that in AGS cells, DC transactivates EGFR through M-BAR- and ADAM/HB-EGF-dependent mechanisms. (c) 2006 Elsevier Inc. All rights reserved.

Sonic Hedgehog (Shh), a member of hedgehog peptides family, is expressed in gastric gland epithelium. To elucidate Shh function to gastric mucosal cells, we examined the effect of Shh on the proliferation of a rat normal gastric mucosal cell line, RGM-1. RGM-1 cells express essential components of Shh receptor system, patched-1, and smoothened. Shh enhanced DNA synthesis in RGM-1 cells and elevated intracellular calcium concentration ([Ca2+](i)). In addition, Shh as well as calcium ionophore A32187 rapidly activated ERK. However, Shh failed to activate ERK under calcium-free culture condition. Pretreatment of cells with PD98059 attenuated the DNA synthesis promoted by Shh. Moreover, when cells were pretreated with cyclopamine, Shh could not elevate [Ca2+],, activate ERK or promote DNA synthesis. On the other hand, although Shh induced Gli-1 nuclear accumulation in RGM-1 cells, Shh activated ERK even in cells pretreated with actinomycin D. These results indicate that Shh promotes the proliferation of RGM-1 cells through an intracellular calcium- and ERK-dependent but transcription-independent pathway via Patched/Smoothened receptor system. (c) 2006 Elsevier Inc. All rights reserved.

Dieulafoy's ulcer is a rare cause of gastrointestinal bleeding. The lesion is usually located in the stomach, although it may occur anywhere in the gastrointestinal tract. A 44-year-old man was admitted to hospital due to cerebral infarction. On the 23rd day of hospitalization, he showed massive hematochezia. He underwent an urgent colonoscopy. There was a visible protuberant vessel without significant ulceration at the fundus of the rectum, consistent with a Dieulafoy's ulcer. It was treated by endoscopic hemoclipping. However, rebleeding occurred three times despite repeated hemoclipping. Finally, endoscopic hand ligation was successfully perk formed to achieve permanent hemostasis. Endoscopic hand ligation is an effective treatment for bleeding rectal Dieulafoy's ulcer.

Pancreatic stellate cells ( PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1 beta has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1 beta secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1 beta mRNA and secrete IL-1 beta peptide. Inhibition of TGF-beta(1) activity secreted from PSCs by TGF-beta(1)-neutralizing antibody attenuated IL-1 beta secretion from PSCs. Exogenous TGF-beta(1) increased IL-1 beta expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative ( dn) Smad2/3 expression reduced both basal and TGF-beta(1)-stimulated IL-1 beta expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1 beta expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1 beta activity secreted from PSCs by IL-1 beta-neutralizing antibody attenuated TGF-beta(1) secretion from PSCs. Exogenous IL-1 beta enhanced TGF-beta(1) expression and secretion by PSCs. IL-1 beta activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1 beta enhancement of TGF-beta(1) expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-beta(1) and IL-1 beta in activated PSCs through Smad3- and ERK-dependent pathways.

Activated pancreatic stellate cells (PSCs) play major roles in promoting pancreatic fibrosis. We previously reported that angiotensin II (Ang II) enhances activated PSC proliferation through EGF receptor transactivation. In the present study, we elucidated a novel intracellular mechanism by which Ang II stimulates cellular proliferation. TGF-beta(1) inhibits activated PSC proliferation via a Smad3 and Smad4-dependent pathway in an autocrine manner. We demonstrated that Ang II inhibited TGF-beta(1)-induced nuclear accumulation of Smad3 and Smad4. Furthermore, Ang II rapidly induced inhibitory Smad7 mRNA expression. Adenovirus-mediated Smad7 overexpression inhibited TGF-beta(1)-induced nuclear accumulation of Smad3 and Smad4, and potentiated activated PSC proliferation. PKC inhibitor Go6983 blocked the induction of Smad7 mRNA expression by Ang II. In addition, 12-O-tetradecanoyl-phorbol 13-acetate, a PKC activator, increased Smad7 mRNA expression. These results Suggest that Ang II enhances activated PSC proliferation by blocking autocrine TGF-beta(1)-mediated growth inhibition by inducing Smad7 expression via a PKC-dependent pathway. (c) 2005 Elsevier Inc. All rights reserved.