Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: An impaired intestinal barrier with the activation of corticotropin-releasing factor (CRF), Toll-like receptor 4 (TLR4), and proinflammatory cytokine signaling, resulting in visceral hypersensitivity, is a crucial aspect of irritable bowel syndrome (IBS). The gut exhibits abundant expression of neurotensin; however, its role in the pathophysiology of IBS remains uncertain. This study aimed to clarify the effects of PD149163, a specific agonist for neurotensin receptor 1 (NTR1), on visceral sensation and gut barrier in rat IBS models. METHODS: The visceral pain threshold in response to colonic balloon distention was electrophysiologically determined by monitoring abdominal muscle contractions, while colonic permeability was measured by quantifying absorbed Evans blue in colonic tissue in vivo in adult male Sprague-Dawley rats. We employed the rat IBS models, i.e., lipopolysaccharide (LPS)- and CRF-induced visceral hypersensitivity and colonic hyperpermeability, and explored the effects of PD149163. KEY RESULTS: Intraperitoneal PD149163 (160, 240, 320 μg kg-1) prevented LPS (1 mg kg-1, subcutaneously)-induced visceral hypersensitivity and colonic hyperpermeability dose-dependently. It also prevented the gastrointestinal changes induced by CRF (50 μg kg-1, intraperitoneally). Peripheral atropine, bicuculline (a GABAA receptor antagonist), sulpiride (a dopamine D2 receptor antagonist), astressin2-B (a CRF receptor subtype 2 [CRF2] antagonist), and intracisternal SB-334867 (an orexin 1 receptor antagonist) reversed these effects of PD149163 in the LPS model. CONCLUSIONS AND INFERENCES: PD149163 demonstrated an improvement in visceral hypersensitivity and colonic hyperpermeability in rat IBS models through the dopamine D2, GABAA, orexin, CRF2, and cholinergic pathways. Activation of NTR1 may modulate these gastrointestinal changes, helping to alleviate IBS symptoms.

DOI： 10.1111/nmo.14925

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Intestinal barrier dysfunction, leaky gut, is implicated in various diseases, including irritable bowel syndrome (IBS) and neurodegenerative conditions like Alzheimer's disease. Our recent investigation revealed that basal forebrain cholinergic neurons (BFCNs), critical for cognitive function, receive signals from butyrate and orexin, playing a role in regulating intestinal barrier function through adenosine A2B signaling and the vagus. This study explores the involvement and function of brain histamine, linked to BFCNs, in the regulation of intestinal barrier function. Colonic permeability, assessed by quantifying absorbed Evans blue in rat colonic tissue, showed that histamine did not affect increased colonic permeability induced by LPS when administered subcutaneously. However, intracisternal histamine administration improved colonic hyperpermeability. Elevating endogenous histamine levels in the brain with SKF91488, a histamine N-methyltransferase inhibitor, also improved colonic hyperpermeability. This effect was abolished by intracisternal chlorpheniramine, an histamine H1 receptor antagonist, not ranitidine, an H2 receptor antagonist. The SKF91488-induced improvement in colonic hyperpermeability was blocked by vagotomy, intracisternal pirenzepine (suppressing BFCNs activity), or alloxazine (an adenosine A2B receptor antagonist). Additionally, intracisternal chlorpheniramine injection eliminated butyrate-induced improvement in colonic hyperpermeability. These findings suggest that brain histamine, acting via the histamine H1 receptor, regulates intestinal barrier function involving BFCNs, adenosine A2B signaling, and the vagus. Brain histamine appears to centrally regulate intestinal barrier function influenced by butyrate, differentiating its actions from peripheral histamine in conditions like IBS, where mast cell-derived histamine induces leaky gut. Brain histamine emerges as a potential pharmacological target for diseases associated with leaky gut, such as dementia and IBS.

DOI： 10.1016/j.bcp.2024.116201

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background and study aims Gastric adenocarcinoma of the fundic gland type (GA-FG) is characterized by an elevated lesion with vessel dilation exhibiting branching architecture (DVBA). However, this feature is also found in fundic gland polyps (FGPs), posing a challenge in their differentiation. In this study, we aimed to investigate the clinicopathological features of gastric elevated lesions with DVBA and assess the efficacy of the white ring sign (WRS) as a novel marker for distinguishing between FGPs and GA-FGs. Methods We analyzed 159 gastric elevated lesions without DVBA and 51 gastric elevated lesions with DVBA, further dividing the latter into 39 in the WRS-positive group and 12 in the WRS-negative group. The clinicopathological features, diagnostic accuracy, and inter-rater reliability were analyzed. Results Univariate and multivariate analyses for gastric elevated lesions with DVBA identified the histological type consistent with FGPs and GA-FGs, along with the presence of round pits in the background gastric mucosa, as independent predictors. FGPs were present in 92.3% (36/39) of the WRS-positive group and GA-FGs were observed in 50.0% (6/12) of the WRS-negative group. WRS positivity and negativity exhibited high diagnostic accuracy, with 100% sensitivity, 80.0% specificity, and 94.1% accuracy for FGPs, and 100% sensitivity, 86.7% specificity, and 88.2% accuracy for GA-FGs. Kappa values for WRS between experts and nonexperts were 0.891 and 0.841, respectively, indicating excellent agreement. Conclusions WRS positivity and negativity demonstrate high diagnostic accuracy and inter-rater reliability for FGPs and GA-FGs, respectively, suggesting that WRS is a useful novel marker for distinguishing between FGPs and GA-FGs.

DOI： 10.1055/a-2301-6248

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: A remission induction therapy of granulocyte and monocyte adsorptive apheresis (GMA) was given to patients with Crohn's disease (CD). However, establishing an appropriate treatment strategy for GMA in patients with CD remains unclear. METHODS: This study evaluated the clinical efficacy and subsequent clinical progression after GMA in patients with CD who underwent GMA in seven independent institutions in Japan from 2010 to 2023. RESULTS: Sixteen patients were enrolled. The overall remission and response rates were 25.0% and 68.8%, respectively. All patients responding to GMA received biologics that were continuously used and 36.4% of patients remained on the same biologics 52 weeks after GMA. Notably, all patients who continued the same biologics had previously experienced a loss of response to biologics. CONCLUSION: GMA may exhibit effectiveness even in cases with refractory CD. Moreover, it represents a potential novel therapeutic option for refractory CD with loss of response to biologics.

DOI： 10.1111/1744-9987.14103

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Visceral hypersensitivity resulting from compromised gut barrier with activated immune system is a key feature of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and Toll-like receptor 4 (TLR4) activate proinflammatory cytokine signaling to induce these changes, which is one of the mechanisms of IBS. As activation of the NLRP3 inflammasome by lipopolysaccharide (LPS) or TLR4 leads to release interleukin (IL)-1β, the NLRP3 inflammasome may be involved in the pathophysiology of IBS. Tranilast, an anti-allergic drug has been demonstrated to inhibit the NLRP3 inflammasome, and we evaluated the impact of tranilast on visceral hypersensitivity and colonic hyperpermeability induced by LPS or CRF (IBS rat model). Visceral pain threshold caused by colonic balloon distention was measured by monitoring abdominal muscle contractions electrophysiologically. Colonic permeability was determined by quantifying the absorbed Evans blue within the colonic tissue. Colonic protein levels of NLRP3 and IL-1β were assessed by immunoblot or ELISA. Intragastric administration of tranilast (20-200 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Simultaneously, tranilast also abolished these alterations induced by CRF (50 µg/kg). LPS increased colonic protein levels of NLRP3 and IL-1β, and tranilast inhibited these changes. β-hydroxy butyrate, an NLRP3 inhibitor, also abolished visceral hypersensitivity and colonic hyperpermeability caused by LPS. In contrast, IL-1β induced similar GI alterations to LPS, which were not modified by tranilast. In conclusion, tranilast improved visceral pain and colonic barrier by suppression of the NLRP3 inflammasome in IBS rat models. Tranilast may be useful for IBS treating.

DOI： 10.1016/j.intimp.2024.112099

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

A male patient in his 70s with recurrent hepatocellular carcinoma (HCC) after surgery received atezolizumab plus bevacizumab (Atezo+Bev) therapy. Initial computed tomography (CT) revealed tumor growth along with an increase in tumor markers, and contrast-enhanced ultrasonography (CEUS) showed multiple round avascular areas within the nodules with an appearance similar to a slice of Swiss cheese. Continuation of immunotherapy with consideration of the potential for pseudoprogression produced a dramatic response. Although it is difficult to distinguish between true progression and pseudoprogression, the Swiss cheese-like appearance on CEUS may be important for the early diagnosis of pseudoprogression.

DOI： 10.2169/internalmedicine.2349-23

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Visualization of the pancreatobiliary junction is one of the challenges faced by endoscopic ultrasonography (EUS). The water-filling technique, which allows for the observation of the ampulla at a suitable distance by injecting water into the lumen of the duodenum, was used for this purpose. However, a new gel immersion technique has recently been introduced for visualizing the gastrointestinal tract. This study investigated the effectiveness of visualizing the pancreatobiliary junction in EUS by comparing both water filling and the new gel immersion technique in identical cases. METHODS: The study ran from June to December 2021. Ten images from each technique were retrospectively compared by three independent researchers. The primary result of the study was the number of images depicting the "Pancreatic and Biliary Ducts Penetrating the Duodenal Muscularis Propria" (defined as Excellent observation) in each technique. The secondary outcome was defined as gel immersion technique's safety and impact on duodenal lumen distension. RESULTS: Ten patients used the gel immersion technique. All patients underwent the water-filling technique first, followed by gel injection after the water was completely aspirated. The average number of pictures rated as "Excellent observation," which is the primary outcome, was significantly higher with the gel immersion technique than with water filling, and no adverse events were observed. The subanalysis revealed that both convex and radial echoendoscopes are equally effective at depicting the ampulla with the gel immersion technique. CONCLUSIONS: The ability to depict the pancreatobiliary junction using the gel immersion technique is superior to that of the water-filling method, which may allow for a more detailed assessment of the ampullary region with both radial and convex echoendoscopes. This can be a useful EUS technique for diagnosing pancreaticobiliary maljunction or periampullary tumors.

DOI： 10.1007/s00464-024-10762-6

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Esophageal cancer, which is common among the elderly, has the poorest prognosis among gastrointestinal cancers. Previously, we demonstrated that ferrichrome, produced by the probiotic Lactobacillus casei, exhibited anti-tumor effects in various gastrointestinal cancers, including colorectal and gastric cancers, with minimal effects on non-cancerous intestinal cells. However, it remains unclear whether ferrichrome exerts anti-tumor effects in esophageal cancer. A sulforhodamine B assay revealed that ferrichrome suppressed esophageal adenocarcinoma (OE33, OE19) and squamous cell carcinoma (KYSE70) cells. Ki-67 staining indicated that ferrichrome inhibited the proliferation of esophageal cancer cells. Cell cycle analysis showed that ferrichrome inhibited the DNA synthesis. TUNEL staining revealed that ferrichrome-induced DNA fragmentation. We also confirmed the cleavage of caspase-9 and PARP in ferrichrome-treated cells. Reverse transcription polymerase chain reaction demonstrated an increase in the mRNA of DNA damage-inducible transcript 3 (DDIT-3), a key regulator of programmed cell death, in ferrichrome-treated OE33 cells. In an in vivo OE33 xenograft model, intraperitoneal administration of 5-mg/kg ferrichrome for 14 days resulted in an almost complete inhibition of tumor growth. However, 14 days of intraperitoneal administration of 20-mg/kg 5-fluorouracil (5-FU), but not 20-mg/kg ferrichrome, induced weight loss and myelosuppression in both young and aged mice. Our findings indicate that ferrichrome induces DNA damage-inducible transcript-3, thereby producing anti-tumor effects, including cell cycle arrest and apoptosis, with minimal adverse effects in esophageal cancer cells. This illustrates the high potential of ferrichrome as an anti-tumor drug against esophageal carcinoma.

DOI： 10.1016/j.heliyon.2024.e28070

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

A young patient diagnosed with advanced colon cancer and liver metastasis was found to have familial adenomatous polyposis (FAP) through comprehensive genomic analysis. Whole-genome array comparative genomic hybridization (aCGH) revealed germline deletions at chromosome 5q22.1-22.2 encompassing the entire APC gene. The patient and her son exhibited mild intellectual disability without developmental delay. This case highlights the need for further exploration of the characteristics associated with whole APC deletions. aCGH is a valuable tool for studying FAP and provides a detailed analysis of large deletions.

DOI： 10.1038/s41439-024-00270-3

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

Objectives

The role of long noncoding RNAs (lncRNAs) in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Extracellular vesicle (EV)–encapsulated RNAs could be effective targets for liquid biopsy. We aimed to identify previously unknown EV-encapsulated lncRNAs in PDAC and establish highly accurate methods for isolating EVs.

Materials and Methods

Extracellular vesicles were isolated using existing and newly developed methods, namely, PEViA-UC and PEViA-IP, from serum samples of 20 patients with PDAC, 22 patients with intraductal papillary mucinous neoplasms, and 21 healthy individuals. Extracellular vesicle lncRNA expression was analyzed using digital PCR.

Results

Gene expression analysis using cDNA microarray revealed a highly expressed lncRNA, HEVEPA, in serum EVs from patients with PDAC. We established PEViA-UC and PEViA-IP using PEViA reagent, ultracentrifugation, and immunoprecipitation. Although detection of EV-encapsulated HEVEPA using existing methods is challenging, PEViA-UC and PEViA-IP detected EV HEVEPA, which was highly expressed in patients with PDAC compared with non-PDAC patients. The detection sensitivity for discriminating PDAC from non-PDAC using the combination of HEVEPA and HULC, which are highly expressed lncRNAs in PDAC, and carbohydrate antigen 19-9 (CA19-9), was higher than that of HEVEPA, HULC, or CA19-9 alone.

Conclusions

Extracellular vesicle lncRNAs isolated using PEViA-IP and CA19-9 together could be effective targets in liquid biopsy for PDAC diagnosis.

DOI： 10.1097/mpa.0000000000002315

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

This study investigated the trends in idiopathic peptic ulcers, examined the characteristics of refractory idiopathic peptic ulcer, and identified the optimal treatment. The characteristics of 309 patients with idiopathic peptic ulcer were examined. We allocated idiopathic peptic ulcers that did not heal after 8 weeks' treatment (6 weeks for duodenal ulcers) to the refractory group and those that healed within this period to the healed group. The typical risk factors for idiopathic peptic ulcer (atherosclerosis-related underlying disease or liver cirrhosis complications) were absent in 46.6% of patients. Absence of gastric mucosal atrophy (refractory group: 51.4%, healed group: 28.4%; p = 0.016), and gastric fundic gland polyps (refractory group: 17.6%, healed group: 5.9%; p = 0.045) were significantly more common in the refractory group compared to the healed group. A history of H. pylori eradication (refractory group: 85.3%, healed group: 66.0%; p = 0.016), previous H. pylori infection (i.e., gastric mucosal atrophy or history of H. pylori eradication) (refractory group: 48.5%, healed group: 80.0%; p = 0.001), and potassium-competitive acid blocker treatment (refractory group: 28.6%, healed group, 64.1%; p = 0.001) were significantly more frequent in the healed group compared to the refractory group. Thus, acid hypersecretion may be a major factor underlying the refractoriness of idiopathic peptic ulcer.

DOI： 10.3164/jcbn.23-82

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Carbazochrome sodium sulfonate (CSS) is a hemostatic agent that reduces capillary permeability and enhances capillary resistance. However, its specific effects on colorectal endoscopic submucosal dissection (ESD) outcomes remain uncertain. This study aimed to assess the risk factors for post-ESD bleeding and the effect of CSS on colorectal ESD outcomes. METHODS: First, we retrospectively analyzed the risk factors for post-ESD bleeding using data from 1,315 lesions in 1,223 patients who underwent ESD for superficial colorectal neoplasms at eight institutions. Second, patients were divided into CSS and non-CSS groups using propensity score matching, and their outcomes from colorectal ESD were analyzed. RESULTS: The risk factors for post-colorectal ESD bleeding were identified as age of ≥70 years, tumor located in the rectum, tumor size of ≥40 mm, and post-ESD defect unclosure in both univariate and multivariate analyses. The CSS and non-CSS groups each consisted of 423 lesions after propensity score matching. The post-colorectal ESD bleeding rate was 3.5% (15/423) and 3.3% (14/423) in the CSS and non-CSS groups, respectively, indicating no significant differences. Among patients with the high-risk factors for post-ESD bleeding, the administration of CSS also did not demonstrate a significant reduction in the post-ESD bleeding rate compared to the non-CSS group. CONCLUSION: CSS administration is ineffective in preventing post-colorectal ESD bleeding in both the general population and individuals at a high risk for such bleeding. Our results indicate the necessity to reconsider the application of CSS for preventing post-colorectal ESD bleeding.

DOI： 10.1159/000539367

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic abdominal symptoms, but its pathogenesis is not fully understood. SUMMARY: We have recently shown in rats that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve the intestinal barrier dysfunction, which is a major pathophysiology of IBS. We have additionally shown that the neuropeptides injected intracisternally induced a visceral antinociceptive action against colonic distension. Since it has been known that intestinal barrier dysfunction causes visceral hypersensitivity, the other main pathophysiology of IBS, the neuropeptides act centrally to reduce leaky gut, followed by improvement of visceral sensation, leading to therapeutic action on IBS. It has been recently reported that there is a bidirectional relationship between neuroinflammation in the brain and the pathophysiology of IBS. For example, activation of microglia in the brain causes visceral hypersensitivity. Accumulating evidence has suggested that orexin, ghrelin, or oxytocin could improve neuroinflammation in the CNS. All these results suggest that neuropeptides such as orexin, ghrelin, and oxytocin act in the brain to improve intestinal barrier function and visceral sensation and also induce a protective action against neuroinflammation in the brain. KEY MESSAGES: We therefore speculated that orexin, ghrelin, or oxytocin in the brain possess dual actions, improvement of visceral sensation/leaky gut in the gut, and reduction of neuroinflammation in the brain, thereby inducing a therapeutic effect on IBS in a convergent manner.

DOI： 10.1159/000533275

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

We herein report a rare case of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome that occurred in an 18-year-old man. He visited our hospital with recurrent episodes of a fever, pharyngitis and adenitis without suggestive findings of infection. These episodes resolved within 5 days and recurred quite regularly, with an interval of about 30 days. As the febrile episodes significantly impaired his quality of life, he was treated with colchicine (0.5 mg) as prophylaxis. This completely prevented the episodes during six months of follow-up. Colchicine may therefore be effective in cases of adult-onset PFAPA syndrome.

DOI： 10.2169/internalmedicine.1364-22

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIMS: Multiple myeloma (MM), a neoplasm of plasma cells (PCs), is a highly heterogeneous disease with multifocal dissemination throughout the body. Minimal residual disease (MRD) detected using PCs in bone marrow (BM) is important for MM management; however, frequent invasive examinations impose a significant burden on patients. METHODS: Analysis using plasma cell-free DNA (cfDNA) might represent an alternative tool for disease monitoring. In this study, we observed the disease status in a patient with MM by examining the KRAS mutation allele frequency (MAF) in plasma cfDNA using digital PCR. RESULTS: During treatment, the MAF was correlated with serum immunoglobulin A and free light chain-kappa levels. After the second autologous peripheral blood stem cell transplantation, the KRAS MAF became immediately positive after confirming MRD negativity using PCs from BM. Shortly thereafter, the patient experienced clinical relapse primarily involving bone lesions. CONCLUSION: Mutant KRAS monitoring in cfDNA using serial blood collection might reflect the disease status more accurately than invasive BM examinations, especially in patients with MM whose primary lesions have extra-BM locations. It could also help predict treatment responses and outcomes.

DOI： 10.1016/j.cca.2023.117590

PubMed

researchmap

Language：English  

DOI： 10.1007/s00535-023-02044-0

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Postoperative ileus (POI) is a major complication of abdominal surgery (AS). Impaired gut barrier mediated via Toll-like receptor 4 (TLR4) and interleukin-1 (IL-1) receptor is involved in the development of POI. Phlorizin is a nonselective inhibitor of sodium-linked glucose transporters (SGLTs) and is known to improve lipopolysaccharide (LPS)-induced impaired gut barrier. This study aimed to clarify our hypothesis that AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, and phlorizin improves the ileus. METHODS: AS consisted of a celiotomy and manipulation of the cecum for 1 min. Gastric emptying (GE) in 20 min with liquid meal was determined 3 h after the surgery in rats. The effect of subcutaneous (s.c.) injection of LPS (1 mg kg-1 ) was also determined 3 h postinjection. KEY RESULTS: AS delayed GE, which was blocked by TAK-242, an inhibitor of TLR4 signaling and anakinra, an IL-1 receptor antagonist. LPS delayed GE, which was also mediated via TLR4 and IL-1 receptor. Phlorizin (80 mg kg-1 , s.c.) significantly improved delayed GE induced by both AS and LPS. However, intragastrical (i.g.) administration of phlorizin did not alter it. As gut mainly expresses SGLT1, SGLT2 may not be inhibited by i.g. phlorizin. The effect of phlorizin was blocked by ghrelin receptor antagonist in the LPS model. CONCLUSIONS & INFERENCES: AS-induced gastric ileus is mediated via TLR4 and IL-1 signaling, which is simulated by LPS. Phlorizin improves the gastric ileus via activation of ghrelin signaling, possibly by inhibition of SGLT2. Phlorizin may be useful for the treatment of POI.

DOI： 10.1111/nmo.14659

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: There have been several reports that some probiotics improve non-alcoholic fatty liver disease (NAFLD); however, many studies have involved cocktail therapies. We evaluated whether heat-killed Lactobacillus brevis SBL88 (L. brevis SBL88) monotherapy improves the clinical features of NAFLD. METHODS: The NAFLD model was induced in mice fed a high-fat diet (HFD) (HFD mice) or HFD + 1% heat-killed L. brevis SBL88 (SBL mice) for 16 weeks. Histopathological liver findings were analyzed. To evaluate the gut microbiota, a modified terminal restriction fragment length polymorphism analysis of the feces was performed. RNA sequencing in the liver was performed with Ion Proton™. To investigate the direct effects of heat-killed L. brevis SBL88, an in vitro study was performed. RESULTS: Histopathological findings revealed that fat droplets in the liver were significantly reduced in SBL mice; however, terminal restriction fragment length polymorphism did not show alterations in the gut microbiota between HFD mice and SBL mice. RNA sequencing and pathway analysis revealed that the regulation of lipid and insulin metabolism was affected. The mRNA expression of insulin receptor substrate 2 (IRS-2) was significantly higher in SBL mice, whereas the expression of IRS-1 was not significantly different. Phospho-IRS-2 expression was also significantly increased in SBL mice. In addition, an in vitro study revealed significant alterations in IRS-2 and forkhead box protein O1 expression levels. CONCLUSION: SBL mice exhibited partially improved selective hepatic insulin resistance. Our data suggest that heat-killed L. brevis SBL88 could attenuate the clinical features of NAFLD that are not mediated by alterations in the gut microbiota.

DOI： 10.1111/jgh.16337

PubMed

researchmap

Language：Japanese   Publisher：(一財)日本消化器病学会  

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Visceral hypersensitivity and leaky gut, which are mediated via corticotropin-releasing factor (CRF) and Toll-like receptor 4 are key pathophysiology of irritable bowel syndrome (IBS). Metformin was reported to improve these gastrointestinal (GI) changes. In this study, we attempted to determine the effects of imeglimin, which was synthesized from metformin on GI function in IBS rat models. Imeglimin blocked lipopolysaccharide- or CRF-induced visceral hypersensitivity and colonic hyperpermeability. These effects were prevented by compound C or naloxone. These results suggest that imeglimin may be effective for the treatment of IBS by improved visceral sensation and colonic barrier via AMPK and opioid receptor.

DOI： 10.1016/j.jphs.2023.07.002

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Accumulating evidence suggest that ghrelin plays a role as an antiseptic peptide. The present study aimed to clarify whether the brain may be implicated ghrelin's antiseptic action. We examined the effect of brain ghrelin on survival in a novel endotoxemic model achieved by treating rats with lipopolysaccharide (LPS) and colchicine. The observation of survival stopped three days after chemicals' injection or at death. Intracisternal ghrelin dose-dependently reduced lethality in the endotoxemic model; meanwhile, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin injection affected the mortality rate. The brain ghrelin-induced lethality reduction was significantly blocked by surgical vagotomy. Moreover, intracisternal injection of a ghrelin receptor antagonist blocked the improved survival achieved by intracisternal ghrelin injection or intravenous 2-deoxy-d-glucose administration. Intracisternal injection of an adenosine A2B receptor agonist reduced the lethality and the ghrelin-induced improvement of survival was blocked by adenosine A2B receptor antagonist. I addition, intracisternal ghrelin significantly blocked the colonic hyperpermeability produced by LPS and colchicine. These results suggest that ghrelin acts centrally to reduce endotoxemic lethality. Accordingly, activation of the vagal pathway and adenosine A2B receptors in the brain may be implicated in the ghrelin-induced increased survival. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the decreased septic lethality caused by brain ghrelin.

DOI： 10.1007/s13105-023-00962-4

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn has been used as a remission induction therapy for patients with active ulcerative colitis (UC). Herein, we investigated the influence of concomitant medications in the remission induction of GMA in patients with active UC. METHODS: This multicenter retrospective cohort study included patients with UC underwent GMA in five independent institutions in Japan from January 2011 to July 2021. Factors including concomitant medications associated with clinical remission (CR) were analyzed statistically. RESULT: A total of 133 patients were included. Seventy-four patients achieved a CR after GMA. The multivariable analysis revealed that concomitant medication with 5-aminosalicylic acid, Mayo endoscopic subscore (MES), and concomitant medication with immunosuppressors (IMs) remained as predictors of CR after GMA. In the subgroup analysis in patients with MES of 2, concomitant medication with IMs was demonstrated as a significant negative factor of CR after GMA (P = .042, OR 0.354). Seventy-four patients who achieved CR after GMA were followed up for 52 weeks. In the multivariable analysis, the maintenance therapy with IMs was demonstrated as a significant positive factor of sustained CR up to 52 weeks (P = .038, OR 2.214). Furthermore, the rate of sustained CR in patients with biologics and IMs was significantly higher than that in patients with biologics only (P = .002). CONCLUSION: GMA was more effective for patients with active UC that relapsed under treatment without IMs. Furthermore, the addition of IMs should be considered in patients on maintenance therapy with biologics after GMA.

DOI： 10.1002/jca.22040

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Latent tuberculosis (TB) infection screening before inducing anti-tumor necrosis factor (anti-TNF) alpha agents is important to prevent TB reactivation. However, latent TB infection reactivation may still occur, and the ideal therapeutic strategy for patients with inflammatory bowel disease (IBD) who develop active TB infection has not been established. Vedolizumab (VDZ) has a good safety profile, with low incidence rates of serious infections. However, its safety in patients with latent TB infection reactivation associated with anti-TNF-alpha agents remains unknown. PATIENT CONCERNS: A 21-year-old Vietnamese male patient presented to our hospital with hemorrhagic stool. He had no personal or family history of IBD or TB. DIAGNOSES: Colonoscopy revealed multiple longitudinal ulcers and a cobblestone appearance in the terminal ileum, as well as multiple small erosions and aphtha throughout the colon. Computed tomography revealed a right lung nodular lesion. Serological interferon-gamma release assay and several culture tests were all negative. Thus, he was diagnosed with ileocolonic Crohn's disease (CD) without TB. INTERVENTIONS: The intravenous anti-TNF-alpha agent administration with an immunomodulator was initiated. OUTCOMES: Computed tomography revealed nodular lesion expansion at the right lung, and serological interferon-gamma release assay was positive. He was diagnosed with latent TB infection reactivation. Anti-TNF-alpha agent with an immunomodulator was immediately discontinued, and anti-TB therapy was initiated. His endoscopic findings were still active, and VDZ was selected for maintenance therapy because VDZ has a favorable safety profile with low incidence rates of serious infections. Consequently, mucosal healing was achieved without active TB relapse. LESSONS: This case report presented a patient in whom VDZ was continued as maintenance therapy without inducing TB relapse in a patient with CD who developed latent TB infection reactivation associated with anti-TNF-alpha agents and summarized the safety profile of VDZ for patients with IBD with active or latent TB infection. VDZ may be a safe option for induction and maintenance therapy in patients with CD, even in cases with latent TB infection reactivation.

DOI： 10.1097/MD.0000000000034331

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本膵臓学会  

researchmap

Language：Japanese   Publisher：(一財)日本消化器病学会  

炎症性腸疾患(IBD)患者の基幹病院と地域中核病院における医療連携の確立は,本邦において重要な課題となっている.本研究は,北海道内の多施設による後ろ向きコホート研究とアンケート調査から,その診療実態と医療連携構築の課題を明らかにすることを目的とした.その結果,IBD患者の基幹病院へ集中と診療格差が明らかとなり,地域中核病院での病院機能,メディカルスタッフのIBD診療理解度の低さが逆紹介の課題と考えられた.課題の解決には,重症度に応じた診療の棲み分け,教育活動やチーム医療の充実化が重要と考える.基幹病院と地域中核病院でIBD医療連携が進むことで,IBD診療の均てん化を実現できると考える.(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01118&link_issn=&doc_id=20230721350007&doc_link_id=1390015333244307072&url=https%3A%2F%2Fcir.nii.ac.jp%2Fcrid%2F1390015333244307072&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_2.gif

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9-39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.

DOI： 10.1016/j.brainres.2023.148371

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

In this study, we attempted to clarify a role of prostaglandin (PG) I2 and its specific receptor, IP in the pathogenesis of irritable bowel syndrome (IBS) using a maternal separation (MS)-induced IBS model. Administration of beraprost (BPS), a specific IP agonist, improved visceral hypersensitivity and depressive state with decreased serum CRF level in the IBS rats. To clarify the mechanism of the effect of BPS, we performed serum metabolome analysis and 1-methylnicotinamide (1-MNA) was identified as a possible candidate for a clue metabolite of pathogenesis of IBS. The serum 1-MNA levels revealed inverse correlation to the level of visceral sensitivity, and positive correlation to a depression marker, immobilizing time. Administration of 1-MNA induced visceral hypersensitivity and depression with increased levels of serum CRF. Since fecal 1-MNA is known for a marker of dysbiosis, we examined the composition of fecal microbiota by T-RFLP analysis. The proportion of clostridium cluster XI, XIVa and XVIII was significantly changed in MS-induced IBS rats treated with BPS. Fecal microbiota transplant of BPS-treated rats improved visceral hypersensitivity and depression in IBS rats. These results suggest for the first time that PGI2-IP signaling plays an important role in IBS phenotypes such as visceral hypersensitivity and depressive state. BPS modified microbiota, thereby inhibition of 1-MNA-CRF pathway, followed by improvement of MS-induced IBS phenotype. These results suggest that the PGI2-IP signaling could be considered to be a therapeutic option for IBS.

DOI： 10.1016/j.bbagen.2023.130344

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND : Transnasal endoscopy presents a technical difficulty when inserting the flexible endoscope. It is unclear whether a particular breathing method is useful for transnasal endoscopy. Therefore, we conducted a prospective randomized controlled trial to compare endoscopic operability and patient tolerance between patients assigned to nasal breathing or oral breathing groups. METHODS : 198 eligible patients were randomly assigned to undergo transnasal endoscopy with nasal breathing or with oral breathing. Endoscopists and patients answered questionnaires on the endoscopic operability and patient tolerance using a 100-mm visual analog scale ranging from 0 (non-existent) to 100 (most difficult/unbearable). The visibility of the upper-middle pharynx was recorded. RESULTS : Patient characteristics did not differ significantly between the groups. Nasal breathing showed a higher rate of good visibility of the upper-middle pharynx than oral breathing (91.9 % vs. 27.6 %; P < 0.001). Nasal breathing showed lower mean [SD] scores than oral breathing in terms of overall technical difficulty (21.0 [11.4] vs. 35.4 [15.0]; P < 0.001). Regarding patient tolerance, nasal breathing showed lower scores than oral breathing for overall discomfort (22.1 [18.8] vs. 30.5 [20.9]; P = 0.004) and other symptoms, including nasal and throat pain, choking, suffocating, gagging, belching, and bloating (all P < 0.05). The pharyngeal bleeding rate was lower in the nasal breathing group than in the oral breathing group (0 % vs. 9.2 %; P = 0.002). CONCLUSIONS : Nasal breathing is superior to oral breathing for those performing and undergoing transnasal endoscopy. Nasal breathing led to good visibility of the upper-middle pharynx, improved endoscopic operability, and better patient tolerance, and was safer owing to decreased pharyngeal bleeding.

DOI： 10.1055/a-1900-6004

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Baishideng Publishing Group Inc.  

BACKGROUND: Mucinous adenocarcinoma of the colorectum is a rare histological subtype characterized by an abundant mucinous component. Mucinous tumors are frequently diagnosed at an advanced stage, which indicates an aggressive subtype. However, few case reports have been published, and little information is available concerning genetic alterations in mucinous adenocarcinoma. CASE SUMMARY: A 76-year-old man underwent en bloc endoscopic submucosal dissection (ESD) for the management of a type 0-Is+IIa lesion. Histological examination revealed an intramucosal mucinous adenocarcinoma with signet-ring cell carcinoma and well-to-moderately differentiated tubular adenocarcinoma. Three years after the ESD, local recurrence was detected by an endoscopic examination, revealing a new 0-Is+IIa lesion with a phenotype similar to the previously resected lesion. Re-ESD was chosen for the management of the recurrent tumor, and the histological examination showed positive tumor infiltration at the vertical margin. Additional surgical resection was performed for the curative treatment. Genetic analysis showed pathogenic alterations in RNF43 and TP53 in the adenoma and an additional SMAD4 alteration in the carcinoma. CONCLUSION: This mucinous mucosal adenocarcinoma case was suggested to have an aggressive phenotype and a careful and close follow-up are required.

DOI： 10.4251/wjgo.v15.i1.186

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

A 24-year-old woman was admitted to our hospital due to abdominal pain and a high fever. She was diagnosed with ileocolonic Crohn's disease (CD), complicated with a gastro-colic fistula and splenomegaly. After initial treatment with an infliximab-biosimilar, all blood cell line counts markedly decreased. Three-dimensional reconstructed computed tomography revealed splenic vein narrowing. Thus, her pancytopenia was deemed to have likely been caused by hypersplenism. Surgery was performed, and clinical remission was maintained without pancytopenia. This is the first report of a CD patient with pancytopenia caused by hypersplenism that was triggered by gastro-colic fistula-associated splenic vein obstruction.

DOI： 10.2169/internalmedicine.9590-22

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Spontaneous necrosis of hepatocellular carcinoma (HCC) is rare and difficult to diagnose preoperatively if it occurs before the definitive diagnosis of HCC; this is because spontaneous necrosis of HCC exhibits various patterns in imaging studies. We compared imaging and pathological findings, and examined the possibility of diagnosing spontaneous necrosis of HCC using contrast-enhanced ultrasonography (CEUS). We experienced 2 cases of spontaneous necrosis of HCC. In case 1, spontaneous necrosis occurred after HCC diagnosis, while in case 2 it occurred before the first admission. The tumor in case 2 contained internal nodules and outer fibrous tissue. CEUS revealed a vascular spot in the hypovascular area during the vascular phase and a complete defect during the Kupffer phase. These findings accorded with the pathological findings and may be important for diagnosing spontaneous necrosis of HCC.

DOI： 10.1016/j.radcr.2022.10.019

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本消化管学会  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 53-year-old man was presented with fever, eyelid edema, and thrombocytopenia. Based on examination outcomes, he was diagnosed with immune thrombocytopenia. He was prescribed prednisolone (PSL) at 0.5 mg/kg/day; subsequently, his platelet count improved and fever improved. PSL dose was tapered and stopped without relapse. However, 1 month later, the patient presented to our hospital with fever, generalized edema, thrombocytopenia, and acute renal failure. Computed tomography revealed multiple lymphadenopathies, hepatomegaly, pleural effusion, and ascites. Bone marrow biopsy indicated reticulin fibrosis, and lymph node biopsy revealed mixed-type Castleman disease. Based on these findings, he was diagnosed with grade 5 TAFRO syndrome (very severe). Steroid pulse therapy and tocilizumab were ineffective in improving his condition. Therefore, rituximab was administered instead of tocilizumab, and his condition eventually improved. The optimal treatment for TAFRO syndrome is yet to be established. If tocilizumab is ineffective as the second-line treatment, then rituximab might be effective.

DOI： 10.11406/rinketsu.64.265

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

A 63-year-old man with hepatitis C was treated with atezolizumab plus bevacizumab for unresectable diffuse hepatocellular carcinoma (HCC). After four cycles of atezolizumab plus bevacizumab, the diffuse HCC markedly shrank; however, he complained of general fatigue, loss of appetite, and slight loss of muscle strength in the lower legs. He was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD), hypothyroidism, and myopathy, suggesting multisystem immune-related adverse events (irAEs). After administration of hydrocortisone, the clinical symptoms rapidly disappeared. Patients with multisystem irAEs can have favorable outcomes; thus, to continue immune-checkpoint inhibitors therapy, a correct diagnosis and management of multisystem irAEs are important.

DOI： 10.2169/internalmedicine.9393-22

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Intestinal barrier dysfunction, a leaky gut, contributes to the pathophysiology of various diseases such as dementia and irritable bowel syndrome (IBS). We recently clarified that orexin, ghrelin, or adenosine A2B signaling in the brain improved leaky gut through the vagus nerve. The present study was performed to clarify whether basal forebrain cholinergic neurons (BFCNs) are implicated in the central regulation of intestinal barrier function. We activated BFCNs using benzyl quinolone carboxylic acid (BQCA), a positive muscarinic M1 allosteric modulator, and evaluated colonic permeability by quantifying the absorbed Evans blue in rat colonic tissue. Intracisternal (not intraperitoneal) injection of BQCA blocked the increased colonic permeability in response to lipopolysaccharide. Vagotomy blocked BQCA-induced improvement of colonic hyperpermeability. Intracisternally administered pirenzepine, a muscarinic M1 selective antagonist, prevented intestinal barrier function improvement by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Adenosine A2B receptor antagonist but not dopamine or opioid receptor antagonist prevented BQCA-induced blockade of colonic hyperpermeability. Additionally, intracisternal injection of pirenzepine blocked orexin- or butyrate-induced intestinal barrier function improvement. These results suggest that BFCNs improve leaky gut through adenosine A2B signaling and the vagal pathway. Furthermore, BFCNs mediate orexin- or butyrate-induced intestinal barrier function improvement. Since BFCNs play a role in cognitive function and a leaky gut is associated with dementia, the present finding may lead us to speculate that BFCNs are involved in the development of dementia by regulating intestinal barrier function.

DOI： 10.1016/j.bcp.2022.115331

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Brain oxytocin plays a role in gastrointestinal functions. Among them, oxytocin acts centrally to modulate gastrointestinal motility and visceral sensation. Intestinal barrier function, one of important gut functions, is also regulated by the central nervous system. Little is, however, known about a role of central oxytocin in the regulation of intestinal barrier function. The present study was performed to clarify whether brain oxytocin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of oxytocin dose-dependently abolished increased colonic permeability in response to lipopolysaccharide while intraperitoneal injection of oxytocin at the same dose failed to block it. Either atropine or surgical vagotomy blocked the central oxytocin-induced improvement of colonic hyperpermeability. Cannabinoid 1 receptor antagonist but not adenosine or opioid receptor antagonist prevented the central oxytocin-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of oxytocin receptor antagonist blocked the ghrelin- or orexin-induced improvement of intestinal barrier function. These results suggest that oxytocin acts centrally in the brain to reduce colonic hyperpermeability. The vagal cholinergic pathway or cannabinoid 1 receptor signaling plays a vital role in the process. The oxytocin-induced improvement of colonic hyperpermeability mediates the central ghrelin- or orexin-induced improvement of intestinal barrier function. We would therefore suggest that activation of central oxytocin signaling may be useful for leaky gut-related diseases such as irritable bowel syndrome and autism.

DOI： 10.1016/j.physbeh.2022.113914

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Various heterogeneous nuclear ribonucleoproteins (hnRNPs) have been reported to be associated with cancer cell growth. However, it remains unclear whether hnRNP G-T, which is specifically expressed in the testis, is expressed in tumor cells, and whether hnRNP G-T expressed in colorectal cancer (CRC) cells is associated with tumor progression. We herein report that hnRNP G-T promoted cancer cell growth and stabilized mRNA of ZDHHC11 in CRC. The cell growth was inhibited by transfection of siRNA of hnRNP G-T in cancer cells, but not in non-cancerous epithelial cells. The tumor promotive effect of hnRNP G-T was confirmed in an HCT116 transplanted mouse model. RT-PCR and western blotting indicated the augmentation of hnRNP G-T in CRC in comparison to non-cancerous cells. The downregulation of hnRNP G-T inhibited cancer cell growth and promoted apoptosis in CRC. A transcriptome analysis combined with immunoprecipitation revealed that hnRNP G-T stabilized 174 mRNAs, including ZDHHC11 mRNA. The cell growth was also suppressed by the transfection of siRNA of ZDHHC11 and the mRNA and the protein expression were decreased by the transfection of siRNA of hnRNP G-T. These results suggested that hnRNP G-T promotes the cell growth of CRC by regulating the mRNA of ZDHHC11. Therefore, hnRNP G-T will be highlighted as an effective therapeutic target with less adverse effects in CRC therapy.

DOI： 10.1002/cam4.4738

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Carbazochrome sodium sulfonate (CSS) is conventionally administered to prevent post-endoscopic submucosal dissection (ESD) bleeding in many institutions, but research on its preventive efficacy is lacking. Therefore, we investigated the risk of post-ESD bleeding and the preventive efficacy of CSS administration. METHODS: We retrospectively reviewed 304 lesions in 259 patients with gastric neoplasms who underwent ESD at Asahikawa Medical University Hospital from 2014 to 2021. In the CSS group, CSS 100 mg/day was intravenously infused with maintenance fluid replacement on postoperative days 0-2. The risk factors of post-ESD bleeding, including CSS administration, were investigated. RESULTS: The overall rate of post-ESD bleeding was 4.6% (14/304). The univariate analysis showed that atrial fibrillation (Af), warfarin intake, heparin replacement, and tumor location in the lower third were significant risk factors for increasing the likelihood of postoperative bleeding. In the multivariate analysis, Af (odds ratio [OR] 3.83, 95% CI 1.02-14.30; p &lt; 0.05), heparin replacement (OR 4.60, 95% CI 1.02-20.70; p &lt; 0.05), and tumor location in the lower third of the stomach (OR 6.67, 95% CI 1.43-31.00; p &lt; 0.05) were independent factors for post-ESD bleeding. Post-ESD bleeding was observed in 5.2% (9/174) of the CSS group and 3.8% (5/130) of the non-CSS group, with no significant difference between the two groups (p = 0.783). Additionally, CSS was not shown to have preventive effects in groups with higher-risk factors, such as Af diagnosis, warfarin use, heparin replacement, and tumor location in the lower third of the stomach. CONCLUSION: CSS administration was not effective for the prevention of the post-ESD bleeding in the overall patient population as well as in higher-risk patients. This suggests that the administration of CSS for post-ESD bleeding prevention may need to be reconsidered.

DOI： 10.1007/s00464-022-09171-4

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：English   Publisher：(一社)日本癌治療学会  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Growing evidence indicates that visceral hypersensitivity and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). In animal models, these changes are known to be mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4 (TLR4)-proinflammatory cytokine signaling. Apelin, an endogenous ligand of APJ, was reported to modulate CRF-induced enhanced colonic motility. In this context, we hypothesized that apelin also modulates visceral sensation and gut barrier, and tested this hypothesis. We measured visceral pain threshold in response to colonic balloon distention by abdominal muscle contractions assessed by electromyogram in rats. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal (ip) administration of [Ala13]-apelin-13, an APJ antagonist, blocked lipopolysaccharide (LPS)- or CRF-induced visceral hypersensitivity and colonic hyperpermeability (IBS model) in a dose-response manner. These inhibitory effects were blocked by compound C, an AMPK inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor or naloxone in the LPS model. On the other hand, ip [Pyr1]-apelin-13, an APJ agonist, caused visceral hypersensitivity and colonic hyperpermeability, and these effects were reversed by astressin, a CRF receptor antagonist, TAK-242, a TLR4 antagonist or anakinra, an interleukin-1 receptor antagonist. APJ system modulated CRF-TLR4-proinflammatory cytokine signaling to cause visceral hypersensitivity and colonic hyperpermeability. APJ antagonist blocked these GI changes in IBS models, which were mediated via AMPK, NO and opioid signaling. Apelin may contribute to the IBS pathophysiology, and the inhibition of apelinergic signaling may be a promising therapeutic option for IBS.

DOI： 10.1016/j.npep.2022.102248

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background and study aims  Recent advances in cancer treatment have involved the clinical application of immune checkpoint inhibitors (ICIs) for various type of cancers. The adverse events associated with ICIs are generally referred to as immune-related adverse events (irAEs). Gastrointestinal irAEs are a major disorder, but gastritis is not frequently observed. The aims of this study were to elucidate the clinical, endoscopic, and histological characteristics of irAE gastritis. Patients and methods  Information on patients treated with ICIs were collected from a single institute over 3 years. IrAE gastritis was identified based on the clinical course and endoscopic and histopathological findings. Of the 359 patients treated with ICIs, four cases of irAE gastritis were identified in clinical records from the endoscopy unit. The endoscopic and histopathological findings were analyzed, and further immunohistochemical studies with immune subtype markers and programmed cell death ligand-1 (PD-L1) antibody were conducted. Results  Among four patients with irAE gastritis, the remarkable endoscopic characteristics were network-pattern erosion, erythematous and edematous mucosa with thick purulent discharge, and fragile mucosa. Corresponding histological features were fibrinopurulent exudate, severe inflammatory cell infiltration, and epithalaxia, respectively. The PD-L1 expression rate was ≥ 1 % in the gastric tissue of all patients with gastritis. These patients were treated with prednisolone (PSL) and their symptoms improved within a few days to 2 weeks. Conclusions  IrAE gastritis were characterized by specific endoscopic findings. The appropriate endoscopic diagnosis may lead to effective treatment with PSL.

DOI： 10.1055/a-1839-4303

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Irritable bowel syndrome is a functional gastrointestinal disease. Visceral hypersensitivity is the most important pathophysiology in irritable bowel syndrome. Currently, diagnosis of irritable bowel syndrome is based on symptoms and exclusion of other organic diseases. Although the diagnosis of irritable bowel syndrome can be made based on the Rome IV criteria, one may speculate that complete exclusion of other organic diseases is not so easy, especially in cases uncontrolled with standard therapies. CASE PRESENTATION: We present herein a case of familial Mediterranean fever in a young Japanese patient who had been suffering from an irritable bowel syndrome-like clinical course. A 25-year-old Japanese male had been diagnosed as having diarrhea-predominant irritable bowel syndrome 5 years earlier. Unfortunately, standard therapies failed to improve irritable bowel syndrome symptoms. After careful medical history-taking, we understood that he had also experienced periodic fever since 10 years ago. Although no mutation was identified in the Mediterranean fever gene, not only periodic fever but abdominal symptoms improved completely after colchicine administration. He was therefore diagnosed as having familial Mediterranean fever and that the abdominal symptoms may be related to the disease. CONCLUSIONS: Familial Mediterranean fever should be considered as a cause of irritable bowel syndrome-like symptoms.

DOI： 10.1186/s13256-022-03446-z

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.gie.2022.02.009

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Irritable bowel syndrome (IBS) displays chronic abdominal pain with altered defecation. Most of the patients develop visceral hypersensitivity possibly resulting from impaired gut barrier and altered gut microbiota. We previously demonstrated that colonic hyperpermeability with visceral hypersensitivity in animal IBS models, which is mediated via corticotropin-releasing factor (CRF)-Toll-like receptor 4 (TLR4)-proinflammatory cytokine signaling. CRF impairs gut barrier via TLR4. Leaky gut induces bacterial translocation resulting in dysbiosis, and increases lipopolysaccharide (LPS). Activation of TLR4 by LPS increases the production of proinflammatory cytokines, which activate visceral sensory neurons to induce visceral hypersensitivity. LPS also activates CRF receptors to further increase gut permeability. Metabolic syndrome (MS) is a cluster of cardiovascular risk factors, including insulin resistance, obesity, dyslipidemia, and hypertension, and recently several researchers suggested the possibility that impaired gut barrier and dysbiosis with low-grade systemic inflammation are involved in MS. Moreover, TLR4-proinflammatory cytokine contributes to the development of insulin resistance and obesity. Thus, the existence of pathophysiological commonality between IBS and MS is expected. This review discusses the potential mechanisms of IBS and MS with reference to gut barrier and microbiota, and explores the possibility of existence of a pathophysiological link between these diseases with a focus on CRF, TLR4, and proinflammatory cytokine signaling. We also review epidemiological data supporting this possibility, and discuss the potential of therapeutic application of the drugs used for MS to IBS treatment. This notion may pave the way for exploring novel therapeutic approaches for these disorders.

DOI： 10.5056/jnm21002

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Posttransplant lymphoproliferative disease (PTLD) is a critical complication of hematopoietic stem cell transplantation (HSCT). PTLD is classified into early and late-onset PTLDs. In post-HSCT patients, late-onset PTLD is rare, particularly PTLD after HSCT for Epstein-Barr virus (EBV)-related lymphoproliferative disease. Here, we report the case of a patient diagnosed with late-onset EBV-related hemophagocytic lymphohistiocytosis (HLH), that of PTLD, after HSCT for chronic active EBV infection (CAEBV), that of EBV related lymphoproliferative disease, probably because of EBV reactivation. PATIENT CONCERNS AND DIAGNOSIS: A 22-year-old woman with abdominal fullness visited our hospital. Blood examination showed pancytopenia with atypical lymphocytes, liver dysfunction, and elevated lactate dehydrogenase level. In contrast, bone marrow aspiration showed slight hemophagocytosis with increased natural-killer cells (NK cells). As serum antibodies against EBV were atypical, we calculated the EBV-DNA level in peripheral blood and this level was significantly high. EBV was infected with NK cells, and EBV's monoclonality in NK cells was confirmed. Thus, the patient was diagnosed with CAEBV. INTERVENTIONS AND OUTCOMES: The patient received chemotherapy and cord blood cell transplantation (CBT); CAEBV was well controlled. Approximately 6years from CBT for CAEBV, she visited our hospital because of fever. Blood examination revealed pancytopenia with atypical lymphocytes, liver dysfunction, and elevated lactate dehydrogenase level. In contrast, bone marrow aspiration showed hemophagocytosis with increased B and T cell counts without increased NK cell count. Additionally, serum antibody titers against EBV were atypical, and the EBV-DNA level in the peripheral blood was high. EBV was infected with only B cells, and EBV's monoclonality was confirmed. A more detailed analysis indicated that EBV-specific cytotoxic T lymphocytes were inactive. Therefore, she was diagnosed with late-onset EBV-related HLH. She received extensive treatment, but EBV-related HLH did not improve. Finally, she died about 3 weeks after diagnosis. CONCLUSION: PTLD, including HLH, is a life-threatening complication after transplantation, including HSCT. To our knowledge, this is the first case of late-onset EBV-related HLH after CBT for CAEBV. Late-onset PTLD has an indolent clinical course, but our patient's disease course was extremely aggressive. Therefore, late-onset EBV-related PTLD may be life-threatening.

DOI： 10.1097/MD.0000000000029055

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：(一財)日本消化器病学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Mutations in GNAS drive pancreatic tumorigenesis and frequently occur in intraductal papillary mucinous neoplasm (IPMN); however, their value as a therapeutic target is yet to be determined. This study aimed at evaluating the involvement of mutant GNAS in tumor aggressiveness in established pancreatic cancer. METHODS: CRISPR/Cas9-mediated GNAS R201H silencing was performed using human primary IPMN-associated pancreatic cancer cells. The role of oncogenic GNAS in tumor maintenance was evaluated by conducting cell culture and xenograft experiments, and western blotting and transcriptome analyses were performed to uncover GNAS-driven signatures. RESULTS: Xenografts of GNAS wild-type cells were characterized by a higher Ki-67 labeling index relative to GNAS-mutant cells. Phenotypic alterations in the GNAS wild-type tumors resulted in a significant reduction in mucin production accompanied by solid with massive stromal components. Transcriptional profiling suggested an apparent conflict of mutant GNAS with KRAS signaling. A significantly higher Notch intercellular domain (NICD) was observed in the nuclear fraction of GNAS wild-type cells. Meanwhile, inhibition of protein kinase A (PKA) induced NICD in GNAS-mutant IPMN cells, suggesting that NOTCH signaling is negatively regulated by the GNAS-PKA pathway. GNAS wild-type cells were characterized by a significant invasive property relative to GNAS-mutant cells, which was mediated through the NOTCH regulatory pathway. CONCLUSIONS: Oncogenic GNAS induces mucin production, not only via MUC2 but also via MUC5AC/B, which may enlarge cystic lesions in the pancreas. The mutation may also limit tumor aggressiveness by attenuating NOTCH signaling; therefore, such tumor-suppressing effects must be considered when therapeutically inhibiting the GNAS pathway.

DOI： 10.1007/s00535-021-01846-4

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Chemotherapy for advanced gastric cancer is recommended in the guidelines; however, later-line treatment remains controversial. Since immune checkpoint inhibitors have been used for the treatment of various malignancies, trials have been performed for gastric cancer. A phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens. PATIENTS AND METHODS: A regional cohort study was undertaken to determine the real-world data of nivolumab treatment for patients with advanced or recurrent gastric cancer. The patients were enrolled for 2 years from October 2017 to October 2019 and were prospectively followed for 1 year to examine the overall survival (OS). The patient characteristics were analyzed in a multivariate analysis and a nomogram to predict the probability of survival was generated. RESULTS: In total, 70 patients who received nivolumab as ≥third-line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The median OS was 7.5 (95% CI, 4.8-10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68-0.91). The responders were aged and were frequently diagnosed with intestinal type gastric cancer, including patients with a HER2-positive status (27.3%) or microsatellite instability-high (27.3%) status. CONCLUSIONS: The regional cohort study of nivolumab monotherapy for gastric cancer patients revealed prognostic factors and a nomogram was developed that could predict the probability of survival.

DOI： 10.1002/cam4.4461

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Objective Epipericardial fat necrosis (EFN) has been considered to be a rare cause of acute chest pain, and especially important for emergency physicians. Chest computed tomography (CT) is often used for the diagnosis of EFN after excluding life-threatening states, such as acute coronary syndrome and pulmonary embolism. While the proportion of EFN patients who underwent chest CT in emergency departments is being clarified, little is still known about other departments in Japan. To investigate the proportion of EFN patients who underwent chest CT for acute chest pain in various departments. Methods Chest CT performed from January 2015 to July 2020 in Asahikawa Medical University Hospital in Japan was retrospectively analyzed in this study. All images were reviewed by two radiologists. Results There were 373 outpatients identified by a search using the word 'chest pain' who underwent chest CT. Eight patients satisfying the imaging criteria were diagnosed with EFN. The proportions of patients diagnosed with EFN were 10.7%, 4.8%, 2.8%, 0.9% and 0% in the departments of general medicine, cardiovascular surgery, emergency medicine, cardiovascular internal medicine and respiratory medicine, respectively. Only 12.5% of the patients were correctly diagnosed with EFN, and the other patients were treated for musculoskeletal symptoms, acute pericarditis or hypochondriasis. Conclusion EFN is not rare and is often overlooked in various departments. All physicians as well as emergency physicians should consider the possibility of EFN as the cause of pleuritic chest pain.

DOI： 10.2169/internalmedicine.8161-21

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The impact of the body composition on the pathophysiology and clinical course of Crohn's disease (CD) has not been fully elucidated. AIMS: To reveal the correlations among body composition and long-term outcomes in CD after anti-TNF therapy. METHODS: Ninety-one patients who received anti-TNF therapy as their first biologic treatment were enrolled. The skeletal muscle index (SMI), visceral and subcutaneous fat area (VFA, SFA), and the ratio of the VFA to SFA (mesenteric fat index; MFI) at the 3rd lumbar level were measured using computed tomography (CT) imaging before the induction. The correlation among the body composition and outcomes were retrospectively analyzed. RESULTS: The 5-year cumulative secondary failure- and resection-free rates in patients with a low SMI (39.1% and 64.8%) were significantly lower than those with a high SMI (67.5% and 92.7%; p = 0.0071 and 0.0022, respectively). The 5-year cumulative secondary failure-free rate in the patients with low VF (45.0%) was significantly lower than that in those with high VF (77.6%; p = 0.016), and the 5-year cumulative resection-free rate in patients with a high MFI (68.9%) was significantly lower than that in those with a low MFI (83.0%; p = 0.031). Additionally, patients with low age and BMI had significantly lower cumulative secondary failure- and resection-free rates than those with high age and BMI (low age: 37.4% and 71.2%; high age: 70.7% and 88.9%; p = 0.0083 and 0.027, respectively) (low BMI: 27.2% and 64.8%; high BMI: 68.3% and 87.9%; p = 0.014 and 0.030, respectively), respectively. In the multivariate analyses, a low SMI was the only independent risk factor for secondary failure (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.04-4.44), while low age (HR 4.06, 95% CI 1.07-15.4), a low SMI (HR 4.19, 95% CI 1.01-17.3) and high MFI were risk factors for bowel resection (HR 4.31, 95% CI 1.36-13.7). CONCLUSION: The skeletal muscle mass and ratio of visceral to subcutaneous fat were suggested to reflect the long-term clinical outcome and may be helpful as prognostic markers after anti-TNF therapy in CD.

DOI： 10.3389/fnut.2022.765209

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1093/jjco/hyab125

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

The therapeutic goal in inflammatory bowel disease (IBD) patients has shifted from controlling the clinical activity alone to managing other associated problems. The concept of mucosal healing (MH) and deep remission (DR) are advocated and regarded as new therapeutic goals in IBD. However, the definition of MH still remains controversial. It is unclear whether or not the histological structures or functional factors should be included in the definition of DR in addition to clinical remission and MH. The classifications of white-light imaging (e.g. Mayo endoscopic subscore, UCEIS, CD Endoscopic Index of Severity, simple Endoscopic Score-CD) have been proposed and are now widely used to assess the severity as well as the MH of inflammation in IBD. In ulcerative colitis, magnifying chromoendoscopy has been shown to be useful to assess the MH of inflammation while other types of image-enhanced endoscopy, such as narrow-band imaging, have not. Endocytoscopy and confocal laser endomicroscopy (CLE) are also applied to assess the activity in IBD. These endoscopic procedures can estimate MH with more precision through observing the details of superficial structures, such as crypt openings. In addition, CLE can partially assess the mucosal function by detecting fluorescence leakage. Molecular imaging can possibly detect the molecules associated with inflammation, intestinal regeneration and differentiation, and various functions including the intestinal barrier and mucus secretion. These novel procedures may improve the diagnosis strategy of DR through the assessment of DR-associated factors such as the histological structures and functional factors in the near future.

DOI： 10.1111/den.13863

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Neuroendocrine carcinoma (NEC) of the esophagogastric junction (EGJ) is a rare disease with no established treatments. Herein, we describe a case of recurrent squamous cell carcinoma (SCC) after achieving complete response to chemotherapy against NEC of the EGJ. A 67-year-old man was referred to our hospital because of epigastric discomfort. Computed tomography imaging and esophagogastroduodenoscopy revealed ulcerated tumors at the EGJ. Endoscopic biopsy revealed small tumor cells with a high nuclear/cytoplasmic ratio, suggesting small-cell NEC. Immunohistochemistry (IHC) analysis showed tumor cells with an MIB-1 index of 80%. The patient achieved complete response after 10 cycles of chemotherapy. Follow-up endoscopic examination revealed small red-colored mucosal lesions in the center of the cicatrized primary lesion. Re-biopsy detected cancer cells harboring large eosinophilic cytoplasm with keratinization and no evidence of NEC components. IHC of the cells were cytokeratin 5/6-positive and p53-negative. The tumor persisted without evidence of metastases after chemoradiotherapy, and total gastrectomy with lymph node dissection was performed. Pathological assessment of the resected specimens revealed SCC, without evidence of NEC. The patient survived without a recurrence for &amp;gt;3 years after the initial presentation. Somatic mutation profiles of the primary NEC and recurrent SCC were analyzed by targeted amplicon sequencing covering common cancer-related mutations. Both tumors possessed <italic>TP53</italic> Q192X mutation, whereas <italic>SMAD4</italic> S517T was found only in SCC, suggesting that both tumor components originated from a founder clone with a stop-gain mutation in <italic>TP53</italic>. The somatic mutation profile of the tumors indicated that that loss of heterozygosity (LOH) at the <italic>TP53</italic> gene might have occurred during the differentiation of the founder clone into NEC, while a <italic>SMAD4</italic> mutation might have contributed to SCC development, indicating branching and subclonal evolution from common founder clone to both NEC and SCC. The mutation assessments provided valuable information to better understand the clonal evolution of metachronous cancers.

DOI： 10.3389/fgene.2021.608324

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The abscopal effect refers to the phenomenon in which local radiotherapy is associated with the regression of metastatic cancer that is distantly located from the irradiated site. Here, we present a case of a patient with advanced gastric cancer and brain metastases who was successfully treated with brain radiotherapy and anti-programmed death-1 (PD-1) therapy-induced abscopal effect. Although anti-PD-1 therapy alone could not prevent disease progression, the metastatic lesions in the brain and also in the abdominal lymph node showed a drastic response after brain radiotherapy and anti-PD-1 therapy. To our knowledge, this is the first reported case of successful treatment of advanced gastric cancer with multiple brain and abdominal lymph node metastases, possibly through anti-PD-1 therapy combined with brain radiotherapy-induced abscopal effect. We suggest that the combination of brain radiotherapy and anti-PD-1 therapy may be considered as a therapeutic option for advanced gastric cancer, especially when there is brain metastasis.

DOI： 10.5230/jgc.2021.21.e24

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.dld.2020.08.002

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Endoscopic submucosal dissection (ESD) is currently a common procedure although it requires a long procedural time. We conducted a prospective study to determine the efficacy and safety of lidocaine injection for shortening the procedural time and relieving bowel peristalsis during ESD. METHODS: A multicenter randomized controlled study was conducted in three hospitals. Ninety-one patients who underwent colorectal ESD were enrolled. Patients were randomly divided into two groups using the envelope method: the lidocaine group and saline group. The primary endpoint was the procedural time, and the secondary endpoints were the procedural time in each part of the colon and the grade of bowel peristalsis and the incidence and amounts of antispasmodic drugs use and adverse events. RESULTS: The patients' demographics were not markedly different between the two groups. The mean procedural time in the lidocaine group was not markedly different from that in the saline group. In contrast, at the proximal site, the procedural time in the lidocaine group (57 min) was significantly shorter in the saline group (80 min). The grade of bowel peristalsis in the lidocaine group (0.67) was significantly lower than in the saline group (1.17). Antispasmodic drug use was significantly rarer in the lidocaine group than in the saline group. The incidence of adverse events was not markedly different between the two groups. CONCLUSIONS: Local lidocaine injection is a feasible option for preventing bowel peristalsis, particularly in the proximal colon, leading to a reduced procedural time for ESD and decreased antispasmodic drug use. University Hospital Medical Information Network Center (UMIN number: 000022843).

DOI： 10.1007/s00464-020-08017-1

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Granulocyte and monocyte adsorptive apheresis (GMA) is widely used as a remission induction therapy for active ulcerative colitis (UC) patients. However, there are no available biomarkers for predicting the clinical outcome of GMA. We investigated the utility of Fecal calprotectin (FC) as a biomarker for predicting the clinical outcome during GMA therapy in active UC patients. METHODS: In this multicenter prospective observation study, all patients received 10 sessions of GMA, twice a week, for 5 consecutive weeks. FC was measured at entry, one week, two weeks, and at the end of GMA. Colonoscopy was performed at entry and after GMA. The clinical activity was assessed based on the partial Mayo score when FC was measured. Clinical remission (CR) was defined as a partial Mayo score of ≤ 2 and endoscopic remission (ER) was defined as Mayo endoscopic subscore of either 0 or 1. We analyzed the relationships between the clinical outcome (CR and ER) and the change in FC concentration. RESULT: Twenty-six patients were included in this study. The overall CR and ER rates were 50.0% and 19.2%, respectively. After GMA, the median FC concentration in patients with ER was significantly lower than that in patients without ER (469 mg/kg vs. 3107 mg/kg, p = 0.03). When the cut-off value of FC concentration was set at 1150 mg/kg for assessing ER after GMA, the sensitivity and specificity were 0.8 and 0.81, respectively. The FC concentration had significantly decreased by one week. An ROC analysis demonstrated that the reduction rate of FC (ΔFC) at 1 week was the most accurate predictor of CR at the end of GMA (AUC = 0.852, P = 0.002). When the cut-off value of ΔFC was set at ≤ 40% at 1 week for predicting CR at the end of GMA, the sensitivity and specificity were 76.9% and 84.6%, respectively. CONCLUSION: We evaluated the utility of FC as a biomarker for assessing ER after GMA and predicting CR in the early phase during GMA in patients with active UC. Our findings will benefit patients with active UC by allowing them to avoid unnecessary invasive procedures and will help establish new strategies for GMA.

DOI： 10.1186/s12876-021-01889-0

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/OBJECTIVES: Decrease in skeletal muscle mass and function is associated with a poor prognosis following surgical resection of pancreatic ductal adenocarcinomas (PDAs). This study evaluated whether skeletal muscle mass decrease affects PDA outcomes. METHODS: Data of 112 patients with advanced and unresectable PDA who underwent chemotherapy in a single institution were retrospectively analyzed. Information on age, sex, hematological investigations, including systemic inflammation-based markers and nutritional assessment biomarkers, and imaging parameters of skeletal muscle mass and visceral adipose tissue were retrieved from the patients' medical records. The efficiency of the Cox, Weibull, and standardized exponential models were compared using hazard ratios and the Akaike Information Criterion (AIC). RESULTS: Results from the Weibull, Cox, and standardized exponential model analyses indicated that low skeletal muscle mass, Eastern Cooperative Oncology Group performance status (PS), and the requirement of biliary drainage were associated with the highest risk of death, followed by carcinoembryonic antigen (CEA) levels and the presence of ascites. The AIC value from the four significant parameters was lowest for the Weibull-exponential distribution (222.3) than that of the Cox (653.7) and standardized exponential models (265.7). We developed a model for estimating the 1-year survival probability using the Weibull-exponential distribution. CONCLUSIONS: Low-skeletal muscle index, PS, requirement of biliary drainage, CEA levels, and presence of ascites are independent factors for predicting poor patient survival after chemotherapy. Improved survival modeling using a parametric approach may accurately predict the outcome of patients with advanced-stage PDA.

DOI： 10.1016/j.pan.2021.03.002

PubMed

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Short chain fatty acids readily crosses the gut-blood and blood-brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.

DOI： 10.1016/j.jphs.2021.04.005

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Gastric cancer is a heterogenous disease with different phenotypes, genotypes, and clinical outcomes, including sensitivity to treatments and prognoses. Recent medical advances have enabled the classification of this heterogenous disease into several groups and the consequent analysis of their clinicopathological characteristics. Gastric cancer associated with Epstein-Barr virus (EBV) and microsatellite-unstable tumors are considered to be the two major subtypes as they are clearly defined by well-established methodologies, such as in situ hybridization and polymerase chain reaction-based analyses, respectively. However, discrepancies in the histological diagnosis of gastric neoplasms remain problematic, and international harmonization should be performed to improve our understanding of gastric carcinogenesis. We re-evaluated Japanese cases of early gastric cancer according to the current World Health Organization (WHO) criteria and classified them into genomic subtypes based on microsatellite instability (MSI) and EBV positivity to determine the initial genetic events in gastric carcinogenesis. A total of 113 Japanese early gastric cancers (including low- and high-grade dysplasias) treated with endoscopic resection over 5 years were archived in our hospital. A histological re-evaluation according to the WHO criteria revealed 54 adenocarcinomas, which were divided into 6 EBV-positive (11.1%), 7 MSI-high (MSI-H, 13.0%), and 41 microsatellite stable cases (75.9%). MSI-H adenocarcinoma was confirmed by an immunohistochemistry assay of mismatch repair proteins. Programmed death-ligand 1 immunostaining with two antibodies (E1L3N and SP263) was positive in tumor cells of one MSI-H adenocarcinoma case (1/7, 14.3%). The proportion of stained cells was higher with clone SP263 than with E1L3N. Histologically, EBV-positive carcinomas were poorly differentiated (83.8%), and MSI-H cancers were frequent in well to moderately differentiated adenocarcinoma (85.7%), indicating that the EBV-positive subtype presented with high-grade morphology even when an early lesion. Our study indicates that the WHO criteria are useful for subdividing Japanese early gastric cancers, and this subdivision may be useful for comparative analysis of precursor lesions and early carcinoma.

DOI： 10.1002/cjp2.209

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Leaky gut that is a condition reflecting intestinal barrier dysfunction has been attracting attention for its relations with many diseases such as irritable bowel syndrome or Alzheimer dementia. We have recently demonstrated that ghrelin acts in the brain to improve leaky gut via the vagus nerve. In the present study, we tried to clarify the precise central mechanisms by which ghrelin improves intestinal barrier function through the vagus nerve. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), blocked the intracisternal ghrelin-induced improvement of intestinal hyperpermeability while dopamine, cannabinoid or opioid receptor antagonist failed to prevent it. Since DPCPX can block adenosine A1 and adenosine A2B receptors, we examined which subtype is involved in the mechanism. Intracisternal injection of adenosine A2B agonist but not adenosine A1 agonist improved colonic hyperpermeability, while peripheral injection of adenosine A2B agonist failed to improve it. Intracisternal adenosine A2B agonist-induced improvement of colonic hyperpermeability was blocked by vagotomy. Adenosine A2B specific antagonist, alloxazine blocked the ghrelin- or central vagal stimulation by 2-deoxy-d-glucose-induced improvement of intestinal hyperpermeability. These results suggest that activation of adenosine A2B receptors in the central nervous system is capable of improving intestinal barrier function through the vagal pathway, and the adenosine A2B receptors may mediate the ghrelin-induced improvement of leaky gut in a vagal dependent fashion. These findings may help us understand the pathophysiology in not only gastrointestinal diseases but also non-gastrointestinal diseases associated with the altered intestinal permeability.

DOI： 10.1016/j.expneurol.2021.113708

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Visceral hypersensitivity and impaired gut barrier are crucial contributors to the pathophysiology of irritable bowel syndrome (IBS), and those are mediated via corticotropin-releasing factor (CRF)-Toll like receptor 4-pro-inflammatory cytokine signaling. Phlorizin is an inhibitor of sodium-linked glucose transporters (SGLTs), and known to have anti-cytokine properties. Thus, we hypothesized that phlorizin may improve these gastrointestinal changes in IBS, and tested this hypothesis in rat IBS models, i.e., lipopolysaccharide (LPS) or CRF-induced visceral hypersensitivity and colonic hyperpermeability. The visceral pain threshold in response to colonic balloon distention was estimated by abdominal muscle contractions by electromyogram, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue. Subcutaneous (s.c.) injection of phlorizin inhibited visceral hypersensitivity and colonic hyperpermeability induced by LPS in a dose-dependent manner. Phlorizin also blocked CRF-induced these gastrointestinal changes. Phlorizin is known to inhibit both SGLT1 and SGLT2, but intragastric administration of phlorizin may only inhibit SGLT1 because gut mainly expresses SGLT1. We found that intragastric phlorizin did not display any effects, but ipragliflozin, an orally active and selective SGLT2 inhibitor improved the gastrointestinal changes in the LPS model. Compound C, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor and naloxone, an opioid receptor antagonist reversed the effects of phlorizin. In conclusions, phlorizin improved visceral hypersensitivity and colonic hyperpermeability in IBS models. These effects may result from inhibition of SGLT2, and were mediated via AMPK, NO and opioid pathways. Phlorizin may be effective for the treatment of IBS.

DOI： 10.1016/j.biopha.2021.111649

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Recent studies have revealed that tumor cells decrease their immunogenicity by epigenetically repressing the expression of highly immunogenic antigens to survive in immunocompetent hosts. We hypothesized that these epigenetically hidden "stealth" antigens should be favorable targets for cancer immunotherapy due to their high immunogenicity. To identify these stealth antigens, we treated human lung cell line A549 with DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5Aza) and its prodrug guadecitabine for 3 d in vitro and screened it using cDNA microarray analysis. We found that the gene encoding sperm equatorial segment protein 1 (SPESP1) was re-expressed in cell lines including solid tumors and leukemias treated with 5Aza, although SPESP1 was not detected in untreated tumor cell lines. Using normal human tissue cDNA panels, we demonstrated that SPESP1 was not detected in normal human tissue except for testis and placenta. Moreover, we found using immunohistochemistry SPESP1 re-expression in xenografts in BALB/c-nu/nu mice that received 5Aza treatment. To assess the antigenicity of SPESP1, we stimulated human CD4+ T-cells with a SPESP1-derived peptide designed using a computer algorithm. After repetitive stimulation, SPESP1-specific helper T-cells were obtained; these cells produced interferon-γ against HLA-matched tumor cell lines treated with 5Aza. We also detected SPESP1 expression in freshly collected tumor cells derived from patients with acute myeloid leukemia or lung cancer. In conclusion, SPESP1 can be classified as a stealth antigen, a molecule encoded by a gene that is epigenetically silenced in tumor cells but serves as a highly immunogenic antigen suitable for cancer immunotherapy.

DOI： 10.1111/cas.14973

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Visceral hypersensitivity and impaired gut barrier are crucial pathophysiology of irritable bowel syndrome (IBS), and injection of lipopolysaccharide or corticotropin-releasing factor, and repeated water avoidance stress simulate these gastrointestinal changes in rat (IBS models). We previously demonstrated that losartan, an angiotensin II type 1 (AT1) receptor antagonist prevented these changes, and we attempted to determine the effects of EMA401, an AT2 receptor antagonist in the current study. EMA401 blocked visceral hypersensitivity and colonic hyperpermeability in these models, and naloxone reversed the effects by EMA401. These results suggest that EMA401 may improve gut function via opioid signaling in IBS.

DOI： 10.1016/j.jphs.2021.04.001

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Previous investigations have indicated that RNA-binding proteins (RBPs) are key molecules for the development of organs, differentiation, cell growth and apoptosis in cancer cells as well as normal cells. A bioinformatics analysis based on the mRNA expression and a somatic mutational database revealed the association between aberrant expression/mutations of RBPs and cancer progression. However, this method failed to detect functional alterations in RBPs without changes in the expression, thus leading to false negatives. To identify major tumor-associated RBPs, we constructed an siRNA library based on the database of RBPs and assessed the influence on the growth of colorectal, pancreatic and esophageal cancer cells. A comprehensive analysis of siRNA functional screening findings using 1198 siRNAs targeting 416 RBPs identified 41 RBPs in which 50% inhibition of cell growth was observed in cancer cells. Among these RBPs, 12 showed no change in the mRNA expression and no growth suppression in non-cancerous cells when downregulated by specific siRNAs. We herein report for the first time cancer-promotive RBPs identified by a novel functional assessment using an siRNA library of RBPs combined with expressional and mutational analyses.

DOI： 10.3390/cancers13133165

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

TRIAL DESIGN: Elimination of small colorectal polyps with cold snare polypectomy (CSP) is reported to be as safe as hot snare polypectomy (HSP). The effectiveness of CSP has not been clearly defined, and the incidence of long-term recurrence has not been determined. We conducted a randomized control study and one-year follow-up study to assess their safety and efficacy. METHODS: Patients with small colorectal polyps were randomized to receive CSP or HSP. Polypectomy was performed to determine the pathological curability, and patients completed a questionnaire about the tolerability of the procedure. Follow-up colonoscopy was performed to determine the local recurrence of adenoma. The major outcome was the non-inferiority of CSP to HSP in the rate of delayed bleeding and minor outcomes, including the incidence of immediate bleeding and perforation, procedural time, and the resection rate. RESULTS: A total of 119 participants were recruited in this randomized study and underwent polypectomy. Among the 458 polyps, 332 eligible polyps were analyzed. The rate of adverse events was 0.6% (1/175) for CSP and 0% (0/157) for HSP, which showed the non-inferiority of CSP. While the complete resection rate of CSP was very high (100%), the R0 rate was not satisfactory (horizontal margin, 65.5%; vertical margin, 89.1%). Two local recurrences (2.5%) were observed in the follow-up of 80 adenomas treated with CSP. No recurrence was found in 79 lesions in the HSP group, which was not significant (P = .06). CONCLUSIONS: Colorectal polyps were safely resected using CSP, similar to HSP. Most would agree to say that CSP is considered safer than HSP. The main question is then related to efficacy. Our results of the present study demonstrate that recurrence after CSP should be carefully managed for curative treatment.

DOI： 10.1097/MD.0000000000026296

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against factor VIII (FVIII). Hematological malignancies, especially lymphoid malignancies, are known to be underlying causes of AHA; however, thus far, there is no report of AHA associated with Epstein-Barr-virus-associated T/natural killer-cell lymphoproliferative disease (EBV-T/NK-LPD). Here, we present a case of AHA that developed during treatment for EBV-T/NK-LPD. HISTORY: A 69-year-old man visited our hospital because of general fatigue. Blood examination showed pancytopenia, and computed tomography revealed whole-body lymphadenopathy, but there were no findings indicating hematological malignancy from bone marrow aspiration and cervical lymph node biopsy. The level of EBV DNA in peripheral blood was extremely high, and he was diagnosed with EBV-T/NK-LPD. EBV-T/NK-LPD improved with prednisolone (PSL) administration. Seventeen months after starting treatment, the patient complained of back and right leg pain. At that time, he had been treated with low-dose PSL, and EBV-T/NK-LPD was well controlled. Imaging revealed hematoma of the right iliopsoas muscle. Prolonged activated partial thromboplastin time (APTT) was the only abnormal finding in a screening coagulation test. FVIII coagulant activity was below detection limit, and FVIII inhibitor level was increased. From these results, he was diagnosed with AHA.A higher dose of PSL was administered, and, after 1 month of treatment, FVIII activity gradually increased, and FVIII inhibitor level became undetectable. APTT also normalized, and complete remission was achieved and maintained for 13 months with low-dose PSL. During treatment, EBV-T/NK-LPD was well controlled. CONCLUSION: It is speculated that proliferating lymphocytes interfere with normal immune functions and that abnormal autoantibodies are produced from those lymphocytes in patients with LPD. Therefore, we speculate that EBV-infected and proliferating monoclonal NK cells might have modulated the immune system and produced autoantibodies against FVIII, thus causing AHA in this patient with EBV-T/NK-LPD.

DOI： 10.1097/MD.0000000000025518

PubMed

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Visceral hypersensitivity is a major pathophysiology in irritable bowel syndrome (IBS). Although brain-gut interaction is considered to be involved in the regulation of visceral sensation, little had been known how brain controls visceral sensation. To improve therapeutic strategy in IBS, we should develop a novel approach to control visceral hypersensitivity. Here, we summarized recent data on central control of visceral sensation by neuropeptides in rats. Orexin, ghrelin or oxytocin in the brain is capable of inducing visceral antinociception. Dopamine, cannabinoid, adenosine, serotonin or opioid in the central nervous system (CNS) plays a role in the visceral hyposensitivity. Central ghrelin, levodopa or morphine could induce visceral antinociception via the orexinergic signaling. Orexin induces visceral antinociception through dopamine, cannabinoid, adenosine or oxytocin. Orexin nerve fibers are identified widely throughout the CNS and orexins are implicated in a number of functions. With regard to gastrointestinal functions, in addition to its visceral antinociception, orexin acts centrally to stimulate gastrointestinal motility and improve intestinal barrier function. Brain orexin is also involved in regulation of sleep/awake cycle and anti-depressive action. From these evidence, we would like to make a hypothesis that decreased orexin signaling in the brain may play a role in the pathophysiology in a part of patients with IBS who are frequently accompanied with sleep disturbance, depressive state and disturbed gut functions such as gut motility disturbance, leaky gut and visceral hypersensitivity.

DOI： 10.1016/j.npep.2021.102129

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.gie.2020.10.008

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.

DOI： 10.1007/s00535-020-01746-z

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Gastric adenocarcinoma of the fundic gland mucosa type (GA-FGM) was proposed as a new variant of gastric adenocarcinoma of the fundic gland type (GA-FG). However, at present, the influence of Helicobacter pylori and the speed of progression and degree of malignancy in GA-FGM remain unclear. Herein, we report the first case of intramucosal GA-FGM that was endoscopically observed before and after H. pylori eradication over 15 years. The lesion showed the same tumor size with no submucosal invasion and a low MIB-1 labeling index 15 years after its detection using endoscopy. The endoscopic morphology changed from 0-IIa before H. pylori eradication to 0-IIa+IIc and then 0-I after H. pylori eradication. These findings suggest that the unaltered tumor size reflects low-grade malignancy and slow growth, and that the endoscopic morphology is influenced by H. pylori eradication.

DOI： 10.5230/jgc.2021.21.e11

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：(一社)日本大腸肛門病学会  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We previously showed that Lactobacillus brevis-derived polyphosphate (poly P) exerts a curative effect on intestinal inflammation. However, whether or not poly P improves the inflammation and injury of distant organs remains unclear. AIMS: We aimed to investigate the change in the intestinal microbiome and to evaluate the protective effect of poly P on injuries in a cerulein-induced acute pancreatitis (AP) mouse. METHODS: Poly P was orally administered to BALB/C mice every day for 24 days, and then mice were intraperitoneally injected with cerulein. Before cerulein injection, stool samples were collected and analyzed by 16S rRNA gene sequencing. Mice were sacrificed at 24 h after the last cerulein injection; subsequently, the serum, pancreas, and colon were collected. RESULTS: The microbial profile differed markedly between poly P and control group. Notably, the levels of beneficial bacteria, including Alistipes and Candidatus_Saccharimonas, were significantly increased, while those of the virulent bacteria Desulfovibrio were decreased in the poly P group. The elevations of the serum amylase and lipase levels by cerulein treatment were suppressed by the pre-administration of poly P for 24 days, but not for 7 days. The numbers of cells MPO-positive by immunohistology were decreased and the levels of MCP-1 significantly reduced in the AP + Poly P group. An immunofluorescence analysis showed that the ZO-1 and occludin in the colon was strongly augmented in the epithelial cell membrane layer in the AP + Poly P group. CONCLUSIONS: Poly P attenuates AP through both modification of the intestinal microbiome and enhancement of the intestinal barrier integrity.

DOI： 10.1007/s10620-020-06747-9

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Fecal impaction is defined as a large mass of compacted feces in the colon and has the potential to induce a serious medical condition in elderly individuals. Fecal impaction is generally preventable, and early recognition of the typical radiological findings is important for making an early diagnosis. The factors that lead to fecal impaction are usually similar to those causing constipation. Few cases with fecal impaction associated with a diverticulum have been reported. CASE SUMMARY: We present the case of a 62-year-old woman who suffered from abdominal pain and vomiting, had a medical history of repeated acute abdomen and was diagnosed with fecal impaction in the descending colon based on X-ray and computed tomography (CT) imaging. After examination by gastrografin-enhanced colonography following colonoscopy and CT colonography, the fecalith was suspected to have been produced at the site of a large diverticulum in the transverse colon. The fecalith was surgically resected, and a histological diagnosis of pseudodiverticulum was made. There was no recurrence during 33 mo of follow-up. CONCLUSION: This case highlights the importance of accurate identification and treatment of a fecal impaction. This case indicated that the endoscopic evacuation and subsequent colonography were effective for identifying a diverticulum that might have caused fecal impaction. A fecal impaction was associated with the diverticulum. Consequently, the planned diverticulectomy was performed. Appropriate emergency medical treatment and maintenance treatments should be selected in such cases to prevent recurrence.

DOI： 10.12998/wjcc.v9.i2.416

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Colorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. METHODS: SRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo. RESULTS: Ferrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway. CONCLUSIONS: Ferrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.

DOI： 10.1186/s12935-020-01723-9

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本消化管学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Myeloid sarcoma (MS), which involves extramedullary lesions, is classified as a unique subtype of acute myeloid leukemia (AML). At present, no standard treatments for MS have been established. The patient was an 89-year-old man with myelodysplastic syndrome-excess blast-2 (MDS-EB-2) with a 2-year history of intermittent treatment with azacitidine (AZA) during a 4-year history of MDS. He developed painful cutaneous tumors 8 months after the second discontinuation of AZA. They were refractory for antibiotics and topical tacrolimus hydrate. A tumor biopsy was performed, and the histological findings of the tumor lesion showed a proliferation of tumor cells that were positive for myeloperoxidase and CD68 and negative for CD4 and CD123. The patient was diagnosed with MDS-associated MS. MDS-EB-2 quickly progressed to AML with the appearance of peripheral blood blasts and 25% bone marrow blasts. Monotherapy with reduced-dose AZA (37.5 mg/m2 for 7 days, every 4-6 weeks) was restarted, and the MS quickly disappeared. The patient's MS was successfully treated with 16 cycles of AZA treatment over a 22-month period. There have been 10 reported cases in which MS was successfully treated with AZA. Among the 10 cases, the patient in the present case was the oldest. Treatment with reduced-dose AZA should be considered as a therapeutic option for MS in elderly patients with MDS, especially patients who are ineligible for intensive chemotherapy.

DOI： 10.1155/2021/6640597

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

A 60-year-old man had received octreotide for a metastatic neuroendocrine tumor (NET) in the rectum. Computed tomography and ultrasonography revealed a cardiac tumor, diffuse thickness of the ventricular wall and pericardial effusion, which was diagnosed as cardiac metastasis. The metastatic lesions continued to grow despite the alteration of chemotherapy, and the patient complained of repeated syncope and was admitted to our hospital at 11 months after the diagnosis of cardiac metastasis. An electrocardiogram during syncope showed sustained ventricular tachycardia, which was considered to be caused by the cardiac metastasis. We herein report a case of NET with cardiac metastasis which caused lethal arrhythmia along with a review of the pertinent literature.

DOI： 10.2169/internalmedicine.5208-20

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

An attempt to use combination therapy with anti-tumor necrosis factor α (TNFα) antibodies and tacrolimus (TAC) has been tried to induce remission in ulcerative colitis (UC). However, the optimal dose of TAC in combination therapy with anti-TNFα antibodies (TAC + anti-TNFα therapy) remains unclear. We examined the efficacy of various doses of TAC + anti-TNFα therapy in a mouse colitis model. Dextran sulfate sodium induced colitis model mice were divided into an anti-TNFα antibody monotherapy group and the groups that received various doses of TAC + anti-TNFα therapy. The nuclear factor expression of activated T-cells, cytoplasmic 1 (NFATc1) in the nuclei and the mRNA expression of inflammatory cytokines were assessed by immunohistochemistry and RT-PCR, respectively. The serum anti-TNFα antibody concentration was measured with an enzyme-linked immunosorbent assay. The colon length and histological severity were significantly improved in the groups that received any dose of TAC + anti-TNFα therapy. The nuclear expression of NFATc1 was inversely proportional to the administered doses of TAC. The expression levels of inflammatory cytokines tended to decrease in proportion to the dose of TAC. The serum concentration of anti-TNFα antibodies in the high-dose TAC + anti-TNFα therapy was significantly higher than those in the other groups. Low-dose TAC exerted its immunosuppressive effect on T-cells, and additionally, high-dose TAC maintained the serum anti-TNFα antibody concentration. When administered in combination with anti-TNFα antibodies, the dose of TAC should be adjusted according to the disease severity.

DOI： 10.1248/bpb.b20-00916

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), is an intractable intestinal inflammation associated with the disruption of the intestinal mucosa. We previously demonstrated that Lactobacillus brevis-derived long-chain polyphosphate (poly P) improved the intestinal barrier function by the upregulation of cell adhesion and relieved intestinal inflammation, thereby exerting a curing effect on colitis in vitro, in vivo, and in an investigator-initiated clinical study of UC. However, how poly P improves mucosal defects induced by intestinal inflammation has not been elucidated. In this study, we detected the accumulation of platelets in inflamed tissues induced by poly P in a dextran sulfate sodium- (DSS-) induced colitis mouse model. A light transmission aggregometry analysis and scanning electron microscopy showed that poly P promoted the platelet aggregation. An SRB assay and ki-67 staining showed that the supernatant of poly P-treated platelet-rich plasma (PRP) increased intestinal epithelial cell growth. A wound healing assay showed that the supernatant of poly P-treated PRP, but not poly P itself, accelerated wound healing. A Western blotting analysis indicated that mitogen-activated protein kinase activation was induced by the supernatant of poly P-treated human PRP in the epithelial cells and its wound healing effect was significantly decreased by the inhibition of ERK signaling. These data suggested that platelet-derived mediators induced by poly P improved intestinal inflammation through the promotion of epithelial cell growth by the activation of the ERK signaling pathway. The mechanism is a novel host-microbe interaction through mammalian platelet-derived mediators induced by bacterial molecules.

DOI： 10.1155/2021/5582943

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Non-coding RNAs (ncRNAs), or RNA molecules that do not code for proteins, are generally categorized as either small or long ncRNA (lncRNA) and are involved in the pathogenesis of several diseases including many cancers. Identification of a large number of ncRNAs could help to elucidate previously unknown mechanisms in phenotype regulation. Some ncRNAs are encapsulated by extracellular vesicles (EVs) and transferred to recipient cells to regulate cellular processes, including epigenetic and post-transcriptional regulations. Recent studies have uncovered novel molecular mechanisms and functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC), one of the most intractable cancers that is highly invasive and metastatic. As the epithelial-mesenchymal transition (EMT) triggers tumor cell invasion and migration, clarification of the roles of lncRNA in EMT and tumor cell stemness would be critical for improving diagnostic and therapeutic approaches in metastatic cancers. This review provides an overview of relevant studies on lncRNA and its involvement with EMT in PDAC. Emerging knowledge offers evidence for the dysregulated expression of lncRNAs and essential insights into the potential contribution of both lncRNAs and EVs in the pathogenesis of PDAC. Future directions and new clinical applications for PDAC are also discussed.

DOI： 10.3389/fmolb.2021.717890

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Orexins are neuropeptides implicated in several physiological functions. Accumulating findings suggest a relationship between orexin and sepsis. A recent study demonstrated that orexin acts centrally to improve conditions in sepsis. The present study aims to clarify the precise mechanisms by which central orexin could induce a protective action against septic conditions. We established a new septic model by treating rats with lipopolysaccharide (LPS) and colchicine and used this to examine the effect of brain orexin on survival. Observation of survival was stopped three days after the chemicals injection or at death. We established a lethal model (rats died within 24 h) by injecting subcutaneously a combination of 1 mg/kg LPS and 1 mg/kg colchicine. A Toll-like receptor 4 (TLR4) inhibitor completely blocked lethality, suggesting a vital role of LPS-TLR4 signaling in the process. Intracisternal orexin-A dose-dependently reduced lethality in the sepsis model while neither intracisternal orexin-B nor intraperitoneal orexin-A changed the mortality rate. Vagal stimulation with carbachol or 2-deoxy-D-glucose improved survival and atropine potently blocked the protection by carbachol or 2-deoxy-D-glucose. The orexin-A-induced reduction of lethality was significantly blocked by atropine or surgical vagotomy. Intracisternal injection of an OX1 receptor antagonist blocked the improvement of survival by intracisternal injection of orexin-A, carbachol, or 2-deoxy-D-glucose. These results suggest that orexin acts centrally to reduce the lethality in our septic model treated (LPS and colchicine). Activation of the vagal cholinergic pathway may mediate the action of orexin, and the OX1 receptor in the brain might play a role in the process. Since the efferent vagus nerve mediates anti-inflammatory mechanisms, we speculate that the vagal cholinergic anti-inflammatory pathway is implicated in the mechanisms of septic lethality reduction by brain orexin.

DOI： 10.1016/j.bcp.2020.114262

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cell-free DNA (cfDNA) shed from tumors into the circulation offers a tool for cancer detection. Here, we evaluated the feasibility of cfDNA measurement and utility of digital PCR (dPCR)-based assays, which reduce subsampling error, for diagnosing pancreatic ductal adenocarcinoma (PDA) and surveillance of intraductal papillary mucinous neoplasm (IPMN). METHODS: We collected plasma from seven institutions for cfDNA measurements. Hot-spot mutations in KRAS and GNAS in the cfDNA from patients with PDA (n = 96), undergoing surveillance for IPMN (n = 112), and normal controls (n = 76) were evaluated using pre-amplification dPCR. RESULTS: Upon Qubit measurement and copy number assessment of hemoglobin-subunit (HBB) and mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 1 (MT-ND1) in plasma cfDNA, HBB offered the best resolution between patients with PDA relative to healthy subjects [area under the curve (AUC) 0.862], whereas MT-ND1 revealed significant differences between IPMN and controls (AUC 0.851). DPCR utilizing pre-amplification cfDNA afforded accurate tumor-derived mutant KRAS detection in plasma in resectable PDA (AUC 0.861-0.876) and improved post-resection recurrence prediction [hazard ratio (HR) 3.179, 95% confidence interval (CI) 1.025-9.859] over that for the marker CA19-9 (HR 1.464; 95% CI 0.674-3.181). Capturing KRAS and GNAS could also provide genetic evidence in patients with IPMN-associated PDA and undergoing pancreatic surveillance. CONCLUSIONS: Plasma cfDNA quantification by distinct measurements is useful to predict tumor burden. Through appropriate methods, dPCR-mediated mutation detection in patients with localized PDA and IPMN likely to progress to invasive carcinoma is feasible and complements conventional biomarkers.

DOI： 10.1007/s00535-020-01724-5

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

An impaired gut barrier, possibly leading to visceral hypersensitivity has been recently recognized to be one of the pivotal pathophysiology of irritable bowel syndrome (IBS). We previously showed that lipopolysaccharide (LPS), corticotropin-releasing factor (CRF), and repeated water avoidance stress (WAS) induce visceral hypersensitivity and colonic hyperpermeability via pro-inflammatory cytokine signaling (rat IBS models). Although the precise mechanisms of action are unclear, imipramine, a tricyclic antidepressant, improves IBS symptoms, and also has anticytokine properties. In this study, we hypothesized that imipramine improves the gut barrier to ameliorate IBS symptoms. To test this hypothesis, we determined its effects on visceral hypersensitivity and colonic hyperpermeability in rat IBS models. The visceral pain threshold in response to colonic balloon distention was electrophysiologically estimated by abdominal muscle contractions, and colonic permeability was measured by quantifying the absorbed Evans blue in colonic tissue in vivo. Subcutaneous imipramine injection (7, 20, 50 mg/kg) dose-dependently inhibited LPS-induced (1 mg/kg, subcutaneously) visceral hypersensitivity and colonic hyperpermeability. Imipramine also blocked these gastrointestinal (GI) changes induced by CRF (50 μg/kg, intraperitoneally) or repeated WAS (1 h daily for 3 days). Yohimbine (an α2-adrenoceptors antagonist), sulpiride (a dopamine D2 receptor antagonist), and naloxone hydrochloride (an opioid receptor antagonist) reversed these effects of imipramine in the LPS model. Therefore, imipramine may block GI changes in IBS via α2-adrenoceptors, dopamine D2, and opioid signaling. The improvement in the gut barrier resulting in inhibition of visceral pain is considered a valid mechanism of imipramine to ameliorate IBS symptoms.

DOI： 10.1016/j.ejphar.2020.173565

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Introduction: Familial adenomatous polyposis (FAP) is typically characterized by more than hundred adenomatous polyps in the colorectum, caused by germline APC mutation. A small proportion of the polyps progress to colorectal adenocarcinoma via adenoma-carcinoma sequence. Serrated lesions and polyps, characterized by a serrated architecture of the epithelium, are noted for two types of genetic pathways in colorectal carcinogenesis. BRAF and KRAS mutations are observed in the serrated pathway. Case Report: We report a young FAP patient with rectal serrated adenomas that were removed by colonoscopic procedures. The histological features with villiform projections and slit-like serration indicated traditional serrated adenoma. A genetic examination with next-generation sequencing showed a somatic BRAF mutation in the serrated adenoma and APC mutations in the tubular adenomas. His germline mutation was found at APC p.Q1928fs*. Conclusion: Serrated adenomas with dual genetic alterations in a FAP patient may be associated with colorectal carcinogenesis and should be considered a target lesion for treatment. The present study demonstrated the malignant potential of serrated adenoma in a FAP patient.

DOI： 10.1007/s00384-020-03657-0

Scopus

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本小腸学会  

researchmap

Language：Japanese   Publisher：(一財)日本消化器病学会  

researchmap

Language：English   Publisher：(一社)日本癌学会  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Gastric mixed adenoneuroendocrine carcinoma (gMANEC) is a rare malignant tumor. Most gMANECs are diagnosed at an advanced stage and have a worse prognosis than gastric adenocarcinoma. In order to improve the prognosis, it is necessary to diagnose gMANEC at an early stage. However, the endoscopic features of early gMANECs are unclear. We, herein, report a case of early gMANEC that showed characteristic magnifying endoscopic findings. PATIENT CONCERNS: A 78-year-old man was referred to our institution for endoscopic resection of a gastric lesion. He had a medical history of distal gastrectomy due to early gastric cancer with negative surgical margins 9 years previously. DIAGNOSIS: Esophagogastroduodenoscopy showed a reddish depressed lesion on the suture line of the gastric remnant, which was classified as type 0-IIc according to the Paris classification. ME-NBI at the oral side of the lesion revealed the absence of the microsurface pattern (MSP) and scattered microvessels with dilation and caliber variation, while ME-NBI at the anal side showed an irregularly tubular MSP. An endoscopic forceps biopsy showed a well- to moderately differentiated adenocarcinoma. INTERVENTIONS: We performed endoscopic submucosal dissection, and en bloc resection of the tumor was successfully achieved. OUTCOMES: The histological findings showed two distinct components: neuroendocrine carcinoma (NEC) and well-differentiated adenocarcinoma, which comprised ∼60% and 40% of the tumor, respectively. The NEC component corresponded to the site with the absence of an MSP and scattered microvessels on ME-NBI, while the well-differentiated adenocarcinoma component corresponded to the site with an irregularly tubular MSP. The pathological diagnosis was mixed adenoneuroendocrine carcinoma, infiltrating into the deep submucosal layer. LESSONS: We propose that the absence of an MSP plus an irregular MSP is characteristics of gMANEC, which was useful for the diagnosis of gMANEC before treatment.

DOI： 10.1097/MD.0000000000022306

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC. Background: Familial adenomatous polyposis (FAP) is characterized by colorectal polyposis and adenocarcinoma that is frequently accompanied by extracolonic neoplasm. The risk of gastric carcinoma is increasing in Western FAP patients as well as Asian patients. Methods: We report the case of an FAP patient with fundic gland polyposis who developed gastric adenocarcinoma and metachronous pyloric gland adenomas. These tumors were endoscopically resected, and immunohistochemistry with gastric mucin (i.e., MUC6, MUC5AC) showed that the tumors belonged to the gastric subtype. Somatic mutation profiles were determined by target amplicon sequencing using a next-generation sequencer. Results: Germline APC variant c.5782delC was found by direct sequencing and somatic KRAS mutations in these tumors were identified by next-generation sequencing. Different KRAS mutation alleles (KRAS p.Gly12Ala, p.Gly12Arg, and p.Gly12Asp) indicated these dysplastic lesions developed from a distinct origin in fundic gland polyposis. Sequential mutations of the APC and KRAS were judged—based on a database search—to be characteristic of the adenoma-carcinoma sequence in colorectal carcinogenesis. Conclusion: The colonic adenoma-carcinoma sequence among gastric adenocarcinoma and dysplastic lesions was indicated in FAP-associated gastric carcinogenesis.

DOI： 10.1002/mgg3.1348

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Spandidos Publications  

Pancreatic cancer is associated with a poor prognosis due to challenges in early detection, severe progression of the primary tumor, metastatic lesions, and resistance to antitumor agents. However, previous studies have indicated a relationship between the microbiome and pancreatic cancer outcomes. Our previous study demonstrated that ferrichrome derived from Lactobacillus casei, a probiotic bacteria, exhibited tumor‑suppressive effects in colorectal and gastric cancer, and that the suppressive effects were stronger than conventional antitumor agents, such as 5‑fluorouracil (5‑FU) and cisplatin, suggesting that certain probiotics exert antitumorigenic effects. However, whether or not probiotic‑derived molecules, including ferrichrome, exert a tumor‑suppressive effect in other gastrointestinal tumors, such as pancreatic cancer, remains unclear. In the present study, it was demonstrated that probiotic‑derived ferrichrome inhibited the growth of pancreatic cancer cells, and its tumor‑suppressive effects were further revealed in 5‑FU‑resistant pancreatic cancer cells in vitro and in vivo in a mouse xenograft model. Ferrichrome inhibited the progression of cancer cells via dysregulation of the cell cycle by activating p53. DNA fragmentation and cleavage of poly (ADP‑ribose) polymerase were induced by ferrichrome treatment, suggesting that ferrichrome induced apoptosis in pancreatic cancer cells. A transcriptome analysis revealed that the expression p53‑associated mRNAs was significantly altered by ferrichrome treatment. Thus, the tumor‑suppressive effects of probiotics may mediated by probiotic‑derived molecules, such as ferrichrome, which may have applications as an antitumor drug, even in refractory and 5‑FU‑resistant pancreatic cancer.

DOI： 10.3892/ijo.2020.5096

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Brain ghrelin plays a role in gastrointestinal functions. Among them, ghrelin acts centrally to stimulate gastrointestinal motility and induce visceral antinociception. Intestinal barrier function, one of important gastrointestinal functions, is also controlled by the central nervous system. Little is, however, known about a role of central ghrelin in regulation of intestinal permeability. The present study was performed to clarify whether brain ghrelin is also involved in regulation of intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of ghrelin dose-dependently abolished increased colonic permeability in response to LPS while intraperitoneal injection of ghrelin at the same dose or intracisternal injection of des-acyl-ghrelin failed to block it. Carbachol potently attenuated LPS-induced intestinal hyperpermeability, and atropine or bilateral subdiaphragmatic vagotomy prevented the improvement of intestinal hyperpermeability by central ghrelin. Intracisternal (D-Lys3)-GHRP-6, a selective ghrelin receptor antagonist, significantly blocked improvement of intestinal barrier function by intravenously administered 2-deoxy-d-glucose, central vagal stimulant. Intracisternal injection of orexin 1 receptor antagonist, SB-334867 blocked intracisternal ghrelin-induced improvement of colonic hyperpermeability. These results suggest that exogenously administered or endogenously released ghrelin acts centrally to improve a disturbed intestinal barrier function through orexinergic signaling and the vagal cholinergic pathway. Central ghrelin may be involved in the pathophysiology and be a novel therapeutic option in not only gastrointestinal diseases such as irritable bowel syndrome but also non-gastrointestinal diseases associated with the altered intestinal permeability.

DOI： 10.1016/j.neuropharm.2020.108116

PubMed

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We have recently demonstrated that levodopa acts centrally to induce antinociceptive action against colonic distension through dopamine D2 receptors in rats. Since serotonin (5-HT) and cannabinoid are involved in the regulation of visceral sensation, we hypothesized that they may contribute to levodopa-induced visceral antinociception. We evaluated visceral sensation by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered levodopa increased the threshold of colonic distension-induced AWR; moreover, an intracisternal injection of methiothepin, an unspecific 5-HT receptor antagonist, blocked the levodopa-induced visceral antinociception. Subsequently, we examined the roles of three 5-HT receptor subtypes: 5-HT1A, 5-HT1B, and 5-HT2A, in levodopa-induced visceral antinociception. Ketanserin is a 5-HT2A receptor antagonist that was intracisternally injected and blocked the levodopa-induced antinociception, but neither WAY100635 (5-HT1A receptor antagonist) nor isomoltane (5-HT1B receptor antagonist) did so. Antagonists AM251 (cannabinoid 1 receptor antagonist) or AM630 (cannabinoid 2 receptor antagonist) did not change the levodopa-induced visceral antinociception, suggesting that cannabinoid signaling may not be implicated in levodopa-induced visceral antinociception. We also examined the relation between dopamine D2 and 5-HT2A receptor signaling in the control of visceral sensation. Ketanserin, but not WAY100635, potently blocked the visceral antinociception by quinpirole, which is a dopamine D2 agonist. These results suggest that 5-HT2A receptors in the central nervous system may play specific roles in levodopa-dopamine D2 receptor-induced antinociceptive action against colonic distension.

DOI： 10.1007/s00210-020-01842-0

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

It is challenging to secure a cytopathologic diagnosis using minute amounts of tumor fluids and tissue fragments. Hence, we developed a rapid, accurate, low-cost method for detecting tumor cell-derived DNA from limited amounts of specimens and samples with a low tumor cellularity, to detect KRAS mutations in pancreatic ductal carcinomas (PDA) using digital PCR (dPCR). The core invention is based on the suspension of tumor samples in pure water, which causes an osmotic burst; the crude suspension could be directly subjected to emulsion PCR in the platform. We examined the feasibility of this process using needle aspirates from surgically resected pancreatic tumor specimens (n = 12). We successfully amplified and detected mutant KRAS in 11 of 12 tumor samples harboring the mutation; the positive mutation frequency was as low as 0.8%. We used residual specimens from fine-needle aspiration/biopsy and needle flush processes (n = 10) for method validation. In 9 of 10 oncogenic KRAS pancreatic tumor samples, the "water-burst" method resulted in a positive mutation call. We describe a dPCR-based, super-sensitive screening protocol for determining KRAS mutation availability using tiny needle aspirates from PDAs processed using simple steps. This method might enable pathologists to secure a more accurate, minimally invasive diagnosis using minute tissue fragments.

DOI： 10.1038/s41598-020-69221-6

PubMed

researchmap

Language：Japanese   Publisher：(一財)日本消化器病学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

The oncogenic properties of heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) have been reported, although the tumor-promoting mechanism remains unclear. We herein report the mechanism underlying colorectal cancer cell progression mediated by hnRNP H1. The growth of colorectal cancer cells was suppressed by hnRNP H1 downregulation. A terminal deoxynucleotidyl transferase dUTP nick-end labeling assay revealed the anti-apoptotic effect of hnRNP H1 in colorectal cancer cells. An RNA immunoprecipitation assay revealed that hnRNP H1 bound to sphingosine-1-phosphate lyase 1 (SGPL1). Reverse transcription-polymerase chain reaction revealed the high expression of hnRNP H1 mRNA in colorectal cancer cells and Spearman's rank correlation coefficient showed a strong positive correlation between hnRNP H1 mRNA and SGPL1 mRNA. An siRNA of hnRNP H1 decreased SGPL1 mRNA expression in colorectal cancer cells, but not in non-tumorous cells. These findings suggested that hnRNP H1 increased SGPL1 mRNA expression specifically in cancer cells through direct binding. Targeted knockdown of hnRNP H1 or SGPL1 with siRNAs upregulated p53 phosphorylation and p53-associated molecules, resulting in cell growth inhibition, while hnRNP H1 upregulated the mRNA of SGPL1 and inhibited p53 activation, thereby promoting tumor cell growth. This is a novel mechanism underlying colorectal cancer cell progression mediated by hnRNP H1-SGPL1 mRNA stabilization.

DOI： 10.3390/ijms21124514

PubMed

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We have recently demonstrated that N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, acts centrally to induce a visceral antinociception. Since serotonin (5-HT), cannabinoid (CB), dopamine or opioid signaling in the central nervous system is involved in the regulation of visceral sensation, we made a hypothesis that the signaling may play a role in the CPA-induced visceral antinociception. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneously administered CPA significantly increased the threshold of colonic distension-induced AWR. Intracisternal injection of either 5-HT1A or 5-HT2A receptor antagonist blocked the CPA-induced visceral antinociception while 5-HT1B antagonist did not block the CPA-induced visceral antinociception. Subcutaneous injection of dopamine D1 receptor antagonist, CB1 receptor antagonist or naloxone significantly blocked the CPA-induced visceral antinociception while neither subcutaneous injection of dopamine D2 receptor antagonist nor CB2 receptor antagonist blocked the CPA-induced anti-pain action. These results suggest that 5-HT1A, 5-HT2A, dopamine D1, CB1 receptors and the opioid system in the CNS may specifically mediate the CPA-induced visceral antinociception. These findings may help in understanding the physiological relevance of central adenosine with special reference to the pathophysiology of altered visceral sensation especially in irritable bowel syndrome.

DOI： 10.1016/j.physbeh.2020.112881

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

Introduction: Surgical management is not a standard treatment option for metastatic recurrence of pancreatic adenocarcinoma. However, the surgical management of a solitary metastasis is useful in selected cases. Patient concerns: A 42-year-old woman was referred to our hospital on account of epigastric pain associated with a mass in the pancreatic body. The patient had a family history of branch duct-type intraductal papillary mucinous neoplasm of the pancreas. Diagnosis: The patient was diagnosed with pancreatic ductal adenocarcinoma (PDA) complicated with pancreatitis due to pancreatic duct involvement. Interventions: The patient underwent distal pancreatectomy, and pathological examination revealed a tubular adenocarcinoma. Solitary liver and lung metastatic tumors were found 6 and 43 months after the initial presentation, respectively, and sequential metastasectomies were performed. Outcomes: The patient survived until 8 years after her initial presentation. The genetic profiles of the resected specimens, primary PDA, and recurrent tumors in the liver and lung possessed identical KRAS mutations at codon 12, whereas there were no mutations in the main tumor suppressor genes, such as TP53, CDKN2A, and SMAD4. Multiplex polymerase chain reaction-based microsatellite instability assay demonstrated microsatellite stability. Conclusion: In our case, the patient with pancreatic adenocarcinoma survived for over 8 years following the resection of the primary tumor and resections of metachronous metastatic tumors. The outcome of PDA may be associated with the genetic profile that regulates its biological behavior. Operative management of solitary metastatic tumors may be a therapeutic options for selected patients with pancreatic cancer.

DOI： 10.1097/MD.0000000000020564

Web of Science

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Because of their survival benefits, immune checkpoint inhibitors (ICIs) are widely administered to patients with various advanced-stage malignancies. During ICI treatment, drug-induced liver injury (DILI) occasionally occurs. In particular, hepatic immune-related adverse events (irAEs) are rare but serious and fatal. In patients with hepatic irAEs, immediate steroid treatment is generally recommended; however, the risk factors for ICI-associated DILI remain unknown. In the present study, we identified a risk factor for ICI-associated DILI. METHODS: We retrospectively analyzed 135 patients treated with anti-programmed cell death-1 (PD-1) antibodies, such as nivolumab and pembrolizumab, at Asahikawa Medical University Hospital. We investigated grade ≥ 2 hepatotoxic AEs during anti-PD-1 therapy, and PD-1 inhibitor-associated DILI was then diagnosed according to the Digestive Disease Week Japan (DDW-J) 2004 scale. The risk factors for PD-1 inhibitor-associated DILI were identified by Cox hazard analysis. RESULTS: Thirty-six patients developed grade ≥ 2 hepatic AEs during anti-PD-1 therapy. Among them, eight patients were diagnosed with PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. Cox hazard analysis revealed that non-alcoholic fatty liver disease (NAFLD) was a risk factor for PD-1 inhibitor-associated DILI. In addition, we revealed that the outcomes of patients with the DDW-J 2004 score = 3 were improved without steroid treatment. CONCLUSIONS: NAFLD is a potential risk factor for PD-1 inhibitor-associated DILI based on the DDW-J 2004 scale. The DDW-J 2004 scale might be useful for determining whether steroid treatment is required in patients with PD-1 inhibitor-associated DILI.

DOI： 10.1111/jgh.14889

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and colonic hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is considered to be a rat irritable bowel syndrome (IBS) model. As losartan is known to inhibit proinflammatory cytokine release, we hypothesized that it improves these visceral changes. METHODS: The threshold of visceromotor response (VMR), that is, abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15 minutes spectrophotometrically. KEY RESULTS: Lipopolysaccharide (1 mg kg-1 ) subcutaneously (s.c.) reduced the threshold of VMR and increased colonic permeability. Losartan (5-25 mg kg-1  s.c.) for 3 days inhibited these changes in a dose-dependent manner. Moreover, repeated WAS (1 hour daily for 3 days) or intraperitoneal injection of CRF (50 µg kg-1 ) induced the similar visceral changes as LPS, which were also eliminated by losartan. These effects by losartan in LPS model were reversed by GW9662 (a peroxisome proliferator-activated receptor-γ [PPAR-γ] antagonist), NG -nitro-L-arginine methyl ester (a nitric oxide [NO] synthesis inhibitor), or naloxone (an opioid receptor antagonist). Moreover, it also inhibited by sulpiride (a dopamine D2 receptor antagonist) or domperidone (a peripheral dopamine D2 antagonist). CONCLUSION & INFERENCES: Losartan prevented visceral allodynia and colonic hyperpermeability in rat IBS models. These actions may be PPAR-γ-dependent and also mediated by the NO, opioid, and dopamine D2 pathways. Losartan may be useful for IBS treatment.

DOI： 10.1111/nmo.13819

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.dld.2020.04.003

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

RNA regulation mediating RNA-binding proteins (RBPs) have been shown to be related to the maintenance of homeostasis as well as cancer progression. However, the tumor-associated functions as well as the detailed mechanisms underlying the anti-tumor effects of most RBPs have yet to be explored. We herein report that the phosphorylated heterogeneous ribonucleoprotein (hnRNP) A0 promotes mitosis through the RAS-associated protein 3 GTPase-activating protein catalytic subunit 1 (RAB3GAP1)-Zeste white 10 interactor (ZWINT1) cascade. The downregulation assay of 20 representative hnRNPs, a major family of RNA-binding proteins, in colorectal cancer cells revealed that hnRNPA0 is a strong regulator of cancer cell growth. The tumor promotive function of hnRNPA0 was confirmed in gastrointestinal cancer cells, including pancreatic, esophageal, and gastric cancer cells, but not in non-cancerous cells. Flow cytometry and Western blotting analyses revealed that hnRNPA0 inhibited the apoptosis through the maintenance of G2/M phase promotion in colorectal cancer cells. A comprehensive analysis of mRNAs regulated by hnRNP A0 and immunostaining revealed that mitotic events were regulated by the hnRNPA0-RAB3GAP1 mRNA-mediated ZWINT-1 stabilization in colorectal cancer cells, but not in non-tumorous cells. The interaction of hnRNP A0 with mRNAs was dramatically changed by the deactivation of its phosphorylation site in cancer cells, but not in non-tumorous cells. Therefore, the tumor-specific biological functions characterized by the abnormal phosphorylation of RBPs are considered to be an attractive target for tumor treatment.

DOI： 10.1038/s41419-020-2439-7

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

A 59-year-old man who was receiving lenvatinib as a third-line tyrosine kinase inhibitor to treat hepatocellular carcinoma and multiple bone metastases complained of general fatigue four months after starting lenvatinib. A blood examination showed unexpectedly elevated serum C-reactive protein (CRP) levels. Computed tomography (CT) revealed rupture of the gallbladder wall, indicating gallbladder perforation. After conservative treatment, the patient received lenvatinib again under informed consent; however, one month later, CT revealed repeated rupture of the gallbladder wall. Gallbladder perforation had again been induced by lenvatinib. For this reason, lenvatinib is strongly considered a causative drug for gallbladder perforation.

DOI： 10.2169/internalmedicine.3806-19

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

The goal of ulcerative colitis (UC) treatment has recently been shown to be "mucosal healing," as no drug directly induces mucosal healing. Probiotics possess sufficient safety, but their efficacy in the treatment of UC remains controversial because of the influence of intestinal conditions. It is believed that the identification of bioactive molecules produced by probiotics and their application will help to solve this issue. We therefore identified a probiotic-derived long-chain polyphosphate as a molecule enhancing the intestinal barrier function. This study demonstrated that long-chain polyphosphate exhibited antiinflammatory effects in a human macrophage and interleukin-10 knockout transfusion mouse model. The first-in-human trial showed that 7 of the 10 enrolled patients acquired clinical remission, 4 of whom achieved endoscopic remission despite a history of treatment with anti-tumor necrosis factor (TNF)-α agents. No adverse reactions were observed. Long-chain polyphosphate might be useful for the treatment of refractory UC, even in patients with failure or intolerance to anti-TNF-α therapy.

DOI： 10.1002/cpt.1628

PubMed

researchmap

Language：Japanese   Publisher：(株)東京医学社  

炎症性腸疾患(IBD)にはCrohn病(CD)と潰瘍性大腸炎(UC)が存在し、いずれの疾患も下部消化管が病変の主座の慢性炎症性疾患である。しかし上部消化管にも特徴的所見を伴うことがあり、診断確定に寄与する症例が少なくない。そのためIBD上部消化管病変の特徴を把握し診療にあたる必要がある。CDでは、胃体部～穹窿部の竹の節状外観や縦走配列の幽門部びらん、十二指腸病変としてはnotch様外観や数珠状隆起などの所見が高い特異性を示し、確定診断の一助となる。またUCの上部消化管病変は、大腸病変に類似したびまん性の脆弱な細顆粒状の粘膜であり、出血を伴う場合はUCに準じた治療が必要となる。以上から、IBD診断においては下部に加え、上部消化管内視鏡検査を行うべきである。(著者抄録)

researchmap

Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J02312&link_issn=&doc_id=20200225170019&doc_link_id=%2Faq9syokd%2F2020%2F003202%2F020%2F0290-0296%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faq9syokd%2F2020%2F003202%2F020%2F0290-0296%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Orexins are neuropeptides that are implicated in a number of functions. With regard to the gastrointestinal functions, orexin acts centrally to regulate gastric secretion, gastrointestinal motility and visceral sensation. Little is however known about a role of central orexin in the control of intestinal barrier function. The present study was performed to clarify whether brain orexin plays a role in the control of intestinal permeability. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternally administered orexin-A but not orexin-B dose-dependently blocked the increased intestinal permeability by lipopolysaccharide (LPS) or corticotropin-releasing factor while intraperitoneally injected orexin-A failed to block it. Atropine or vagotomy abolished the action by central orexin-A. Intravenous injection of 2-deoxy-D-glucose (2-DG), a central vagal stimulant, significantly blocked the LPS-induced increase in intestinal permeability and atropine prevented the action of 2-DG. Intracisternal injection of SB-334687, a selective orexin 1 receptor antagonist, significantly blocked the action of 2-DG-induced improvement of intestinal hyperpermeability. These results suggest that exogenously administered or endogenously released orexin acts centrally to improve the intestinal hyperpermeability by LPS via the vagal cholinergic pathway. The findings also suggest for the first time that the brain could control intestinal permeability. The neuronal rapid protective advantage to the host by improving the intestinal barrier function by the neuropeptide may help us understand the brain-gut interaction in stress sensitive gastrointestinal disorders like irritable bowel syndrome associated with the altered intestinal permeability.

DOI： 10.1016/j.neulet.2019.134592

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Juvenile hemochromatosis (JH) is known as a progressive iron-storage disease, and causes severe organ impairments, including cardiomyopathy and liver cirrhosis. However, JH is a rare genetic disorder, and information for genetic mutations and phenotypes is limited. Here, we report a case of JH with heterozygous p.Y150C and p.V274M mutations in the HJV gene. A 39-year-old Japanese man was referred to Kurume University Hospital, Kurume, Japan, for fatigue and liver injury, which first appeared at the age of 25 years. There was no history of alcohol abuse and medication, and viral hepatitis, autoimmune liver diseases, and Wilson's disease were absent. However, transferrin saturation, serum ferritin, and fasting serum hepcidin levels were 98.4%, 6421 ng/mL, and 7.4 ng/mL, respectively. Furthermore, a marked reduction in signal intensity of the liver in T1/T2-weighted magnetic resonance images was seen and the R2* maps showed hepatic iron overload. Family history of hemochromatosis and severe organ impairment, such as cardiac dysfunction and diabetes mellitus, were negative. In addition, the HFE and HAMP genes did not show any mutation. However, we identified novel heterozygous p.Y150C and p.V274M mutations in the HJV gene in the patient. The p.Y150C and p.V274M mutations were seen in his mother and father, respectively. After phlebotomy, fatigue disappeared and serum transaminase levels were normalized. Furthermore, R2* maps showed a reduction of hepatic iron concentration. We first demonstrated heterozygous p.Y150C and p.V274M mutations in the HJV gene of patients with a mild JH phenotype. Thus, genetic testing should be considered even in patients with a mild phenotype of hemochromatosis.

DOI： 10.1111/hepr.13423

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Pancreatobiliary tumors frequently contain multiple malignant and precancerous lesions; however, the origin of the driver mutations and the mechanisms that underlie the generation of distinct clones within an organ field remain unclear. Herein, we describe a 76-year-old male suffering from moderately differentiated adenocarcinomas of the pancreas that primarily involved the distal bile duct and multiple "dispersing" invasive lesions in the pancreatic head. The patient underwent pylorus-preserving pancreaticoduodenectomy with superior mesenteric vein resection, and targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical analysis of RNF43 and ARID1A were performed on each tumor compartment, including the invasive and non-invasive areas. Multi-region sequencing revealed shared KRAS and TGFBR1 mutations in all invasive foci, including those involving the distal bile duct. Distinct KRAS variants were found to be present in other non-continuous and non-invasive lesions in the pancreas. Intraductal lesions with KRAS G12D and RNF43 V50R mutations were evident in the main pancreatic duct. This appeared to be a founder clone, given that the mutation profile was common to the invasive foci as well as the additional high-grade dysplasia harboring ARID1A mutations, thereby suggesting a clonal branch-off during tumor evolution. In addition, we also observed independent intraductal papillary mucinous neoplasms with KRAS G12V and GNAS R201H mutations. Our theory, learned from this patient, was that lesions skipped dissemination and wide-spread movement potentially through the pancreatic ductal system as a process of pancreatic cancer development.

DOI： 10.3389/fonc.2020.00728

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral allodynia and gut hyperpermeability via corticotropin-releasing factor (CRF) and proinflammatory cytokines, which is a rat irritable bowel syndrome (IBS) model. As butyrate is known to suppress the release of proinflammatory cytokine, we hypothesized that butyrate alleviates these colonic changes in IBS models. The visceral pain was assessed by electrophysiologically measuring the threshold of abdominal muscle contractions in response to colonic distention. Colonic permeability was determined by measuring the absorbance of Evans blue in colonic tissue. Colonic instillation of sodium butyrate (SB; 0.37-2.9 mg/kg) for 3 days inhibited LPS (1 mg/kg)-induced visceral allodynia and colonic hyperpermeability dose-dependently. Additionally, the visceral changes induced by repeated WAS (1 h for 3 days) or CRF (50 µg/kg) were also blocked by SB. These effects of SB in the LPS model were eliminated by compound C, an AMPK inhibitor, or GW9662, a PPAR-γ antagonist, NG-nitro-L-arginine methyl ester, a NO synthesis inhibitor, naloxone or sulpiride. SB attenuated visceral allodynia and colonic hyperpermeability in animal IBS models. These actions may be AMPK and PPAR-γ dependent and also mediated by the NO, opioid and central dopamine D2 pathways. Butyrate may be effective for the treatment of IBS.

DOI： 10.1038/s41598-019-56132-4

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background and study aims  Needle tract seeding during endoscopic ultrasound fine-needle biopsy (EUS-FNB) remains a concern. We investigated whether such seeding occurred in a patient with pancreatic ductal adenocarcinoma (PDA). Patient and methods  Surgically resected and EUS-FNB-derived specimens were genotyped to determine if a gastric wall tumor that emerged 3 years after curative resection of an early-stage PDA was clonally related to the original tumor. Results  The gastric tumor histologically resembled the primary PDA; the lesions also shared KRAS , SMAD4 , and RNF43 mutations. Genotyping of the preoperative EUS-FNB specimen, in which cancer was not detected, nevertheless revealed mutations that were identical to those in the resected primary and recurrent tumors. While the primary PDA had a low frequency of mutant SMAD4 , such mutations were highly prevalent in both the EUS-FNB and recurrent tumor specimens. Conclusions  The genetic lineages of sampled tissues from our patient revealed that needle tract seeding may have incidentally occurred when a subset of neoplastic cells within a heterogeneous tumor ( i. e. , an aggressive clone) was targeted during EUS-FNB.

DOI： 10.1055/a-1034-7700

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Metachronous development of intraductal papillary mucinous neoplasms in the remnant pancreas following resection is a significant clinical burden. Our aim was to characterize the clinicopathological and molecular features of the patients with metachronous tumor development to identify predictive factors and the possible route(s) of dissemination. Seventy-four patients who underwent resection of intraductal papillary mucinous neoplasms with no invasive compartment or associated carcinoma were retrospectively analyzed. In patients with metachronous tumor development, targeted sequencing of 18 genes associated with pancreatic tumorigenesis and immunohistochemical detection of four proteins (p53, SMAD4, p16, and β-catenin) were performed on both primary and metachronous tumors. The distributions of microscopic neoplastic lesions were examined at surgical margins and in apparently normal tissue apart from the primary tumor. During the median follow-up period of 52 months, 9 patients (12%) developed metachronous tumors in the remnant pancreas. Primary tumors located in the body/tail of the pancreas (odds ratio, 15; 95% confidence interval, 1.6-131) and of the pancreatobiliary type (odds ratio, 6.1; 95% confidence interval, 1.1-35.7) were identified as significant risk factors for subsequent metachronous tumor development. Eight of the nine patients shared molecular aberrations between their primary and metachronous tumors, suggesting migrations from the primary tumor to the pancreatic duct as the cause of metachronous tumor development. Our data suggest that these post-resection metachronous tumors develop by skip dissemination of the primary tumor, potentially via the pancreatic duct. The development of strategies to better predict and prevent this form of tumor progression is necessary.

DOI： 10.1038/s41379-019-0405-7

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1177/0004563219861413

PubMed

researchmap

Language：Japanese   Publisher：日本小腸学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Epstein-Barr virus (EBV)-associated carcinoma is a gastric cancer subtype with a morphology characterized by gastric carcinoma with lymphoid stroma (GCLS). Clinicopathological studies have indicated a better prognosis for GCLS than for common gastric carcinomas. Some previous cases of early gastric cancer associated with EBV had been diagnosed by endoscopic resection. CASE SUMMARY: We present two GCLS cases subjected to endoscopic submucosal dissection (ESD) for a definitive diagnosis. A protruded gastric lesion was identified by routine endoscopic examination, but forceps biopsy showed no atypical cells before ESD. The resected specimen showed a poorly differentiated adenocarcinoma with lymphoid cells involving the mucosa and submucosa. The final diagnosis was submucosa-invasive poorly differentiated gastric adenocarcinoma. Accordingly, additional gastrectomy was recommended to obtain a complete cure. One patient underwent additional distal gastrectomy with lymph node dissection, but the other was refused because of cardiovascular complications. Both patients remained in remission for more than half a year. EBV positivity was determined by EBV-encoded RNA in situ hybridization. We also conducted a literature review of cases of early gastric cancer associated with EBV that had been diagnosed by ESD. CONCLUSION: Submucosa-invasive GCLS could be dissected using ESD, and EBV positivity should be subsequently assessed to determine whether or not any additional curative surgery is required. Further prospective investigations on the prevalence of lymph node metastasis in EBV-associated carcinoma should be performed to expand the indications for endoscopic resection.

DOI： 10.4251/wjgo.v11.i10.925

PubMed

researchmap

Authorship：Last author   Language：English  

DOI： 10.1016/j.dld.2019.07.003

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Intraductal papillary neoplasm of the bile duct (IPNB) is a type of tumor that presents in the intra- or extrahepatic bile ducts. Cystic-type intrahepatic IPNB often mimics simple liver cysts, making the diagnosis difficult. Because the growth of IPNB is slow, careful follow-up and timely therapeutic intervention is recommended. There are few reports with a follow-up period longer than a decade; thus, we report the case of a patient with an IPNB that grew for over 13 years. CASE SUMMARY: A 65-year-old man was diagnosed, 13 years prior with a cystic hepatic tumor with abnormal imaging findings. The targeted tumor biopsy results showed no malignancy. Biannual follow-up examinations were performed because of the potential for malignancy. The cystic lesions showed gradual enlargement over 11 years and a 4 mm papillary proliferation appeared on the cyst wall, which is compatible with IPNB. The tumor was observed for another 2 years because of the patient's wishes. The imaging findings showed enlargement to 8 mm and a new 9 mm papillary proliferation of the cystic tumor. Contrast-enhanced ultrasonography showed hyperenhancement during the arterial phase in both cyst walls, indicating intraductal tumor progression in both tumors. Thus, liver segment 8 subsegmentectomy was performed. The pathological findings indicated that the tumors contained mucin, and high-grade atypia was observed in the papillary lesions, showing IPNB. CONCLUSION: The development of IPNB should be monitored in patients with cystic lesions and ultrasonography are useful tool for the evaluation.

DOI： 10.3748/wjg.v25.i36.5569

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Endoscopic ultrasound-guided sampling is indicated to achieve an accurate diagnosis of subepithelial lesions of the stomach when a standard biopsy fails. Gastric carcinoma with lymphoid stroma (GCLS) is located under the epithelial layer with dense lymphocytic infiltration, making a pathological diagnosis by a biopsy difficult. We herein report a case of the pathological diagnosis of GCLS using an endoscopic ultrasound-guided fine-needle biopsy. The patient underwent distal gastrectomy and was diagnosed with Epstein-Barr virus-negative cancer.

DOI： 10.1002/jcu.22696

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Several reports have demonstrated that skeletal muscle mass influences mortality in patients with hepatocellular carcinoma (HCC) receiving sorafenib treatment; however, there is still controversy with regard to whether skeletal muscle and adipose tissue are associated with the prognosis in HCC patients. We examined the relationship between body composition and prognosis in HCC patients. METHODS: We retrospectively analyzed 82 patients with unresectable HCC receiving sorafenib treatment. The skeletal muscle area and adipose tissue area were measured by computed tomography. Patients with low skeletal muscle index (male ≤36.2 cm2/m2, female ≤29.6 cm2/m2) and high visceral to subcutaneous adipose tissue area ratio (VSR) (male ≥ 1.33, female ≥ 0.93) were diagnosed as low skeletal muscle mass (LSMM) and high VSR, respectively. RESULTS: A total of 16 and 34 patients were classified as LSMM and high VSR, respectively. LSMM patients frequently experienced serious adverse events (SAEs) and thus had a shorter duration of sorafenib treatment than non-LSMM patients. High VSR was a significant factor for progression-free survival. LSMM patients less frequently received additional/subsequent therapies combined with sorafenib than non-LSMM patients. Multivariate Cox hazard analysis demonstrated that LSMM was a significant factor for the duration of sorafenib treatment. The treatment duration and receiving of additional/subsequent therapies were significantly associated with overall survival (OS) but not with LSMM or high VSR. CONCLUSION: LSMM was associated with the frequency of SAEs, treatment tolerability, and treatment duration. LSMM patients were less likely to receive additional/subsequent therapies than non-LSMM patients. Thus, LSMM could identify a subgroup of patients with poor OS.

DOI： 10.1002/jgh3.12167

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Steroid therapy is primarily used to prevent esophageal stricture after endoscopic submucosal dissection (ESD). However, esophageal stricture can still occur after preventive therapy, and the effect of preventive steroid therapy cannot be predicted before stricture formation. This study aimed to clarify the risk factors for esophageal stricture after preventive steroid therapy. METHODS: This was a retrospective study conducted at three institutions. From January 2011 to February 2018, 28 large-sized SENs in 26 patients who had a mucosal defect that involved more than three-quarters of the esophageal circumference were enrolled. We classified white coats on artificial ulcers after esophageal ESD into three groups (thin, moderately thick, thick) based on endoscopic images obtained on postoperative day 7. RESULTS: The white coat status on the artificial ulcer after ESD was a significant risk factor for post-ESD stricture (p < 0.05). The stricture rates in patients with thin, moderately thick and thick white coats were 10.0, 36.4 and 85.7%, respectively. When thin and moderately thick white coats were combined, the stricture rate was 23.8%. The rate of stricture in lesions with thick white coats was significantly higher than that in patients with thin white coats or thin to moderately thick white coats (p < 0.05). The multivariate analysis revealed that the white coat status was an independent factor related to esophageal stricture (odds ratio 13.70, 95% confidence interval 1.22-154.0; p = 0.034). CONCLUSIONS: The thickness of the white coat is a useful marker for predicting the risk of post-ESD stricture and the effectiveness of preventive steroid therapy.

DOI： 10.1007/s10388-019-00659-y

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

The patient was a 76-year-old man who was treated with nivolumab due to recurrent gastric cancer. A blood examination revealed grade 3 alkaline phosphatase (ALP) elevation. A histopathological examination revealed marked portal infiltration, including eosinophils and CD4+ and CD8+ T lymphocytes, suggesting nivolumab-related cholangitis accompanied by the features of both an immune-related adverse event (irAE) and drug-induced liver injury (DILI) with allergic reaction. The patient's ALP level immediately decreased after the administration of prednisolone. Although nivolumab-related cholangitis, a rare irAE, has been reported to be refractory to steroid therapy, patients with features of irAE and allergic DILI might immediately respond to prednisolone.

DOI： 10.2169/internalmedicine.2330-18

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Stress-induced altered visceral sensation and impaired gut barrier play an important role in the pathophysiology of irritable bowel syndrome (IBS). These responses were demonstrated to be peripheral corticotropin-releasing factor (CRF) dependent and also mediated via proinflammatory cytokine in animal IBS model. Dehydroepiandrosterone sulfate (DHEA-S) is known to have anti-inflammatory properties by suppressing proinflammatory cytokine release. We hypothesized that DHEA-S improves stress-induced visceral changes and is beneficial for IBS treatment. We explored the effects of DHEA-S on lipopolysaccharide (LPS)- or repeated water avoidance stress (WAS)-induced visceral allodynia and increased colonic permeability (rat IBS models). The threshold of visceromotor response, i.e. abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue. DHEA-S abolished visceral allodynia and colonic hyperpermeability induced by LPS in a dose-dependent manner. It also blocked repeated WAS- or peripheral injection of CRF-induced visceral changes. These effects by DHEA-S in LPS model were reversed by bicuculline, a γ-aminobutyric acid (GABA)A receptor antagonist, NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor, naloxone, an opioid receptor antagonist, or sulpiride, a dopamine D2 receptor antagonist. However, domperidone, a peripheral dopamine D2 receptor antagonist did not modify the effects. Peripheral injection of astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist also reversed these effects. In conclusion, DHEA-S blocked stress-induced visceral changes via GABAA, NO, opioid, central dopamine D2 and peripheral CRF2 signaling. DHEA-S may be useful for IBS treating.

DOI： 10.1016/j.ejphar.2019.03.037

PubMed

researchmap

Language：English   Publisher：MOSBY-ELSEVIER  

DOI： 10.1016/j.gie.2019.03.1110

Web of Science

researchmap

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

researchmap

Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞消化管は悪性リンパ腫の好発部位であり,肉眼型は多彩である.悪性リンパ腫の確定診断には,生検または外科的切除標本における病理組織学的診断が必要である.消化管の中でも,小腸は診断が最も困難な部位であり,CTやPET-CTなどのモダリティーでは小腸悪性リンパ腫の検出は困難な場合が多く,カプセル内視鏡やダブルバルーン内視鏡を用いた小腸精査を積極的に行うべきである.また腸管悪性リンパ腫と良性リンパ濾胞過形成の鑑別には積極的にNBI拡大観察を併用し,血管網減少や不整血管出現などの特徴的所見を拾い上げることが,リンパ腫の小病変の診断に有用である.

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Autofluorescence imaging (AFI) is useful for diagnosing colon neoplasms, but what affects the AFI intensity remains unclear. This study investigated the association between AFI and the histological characteristics, aberrant methylation status, and aberrant expression in colon neoplasms. METHODS: Fifty-three patients with colorectal neoplasms who underwent AFI were enrolled. The AFI intensity (F index) was compared with the pathological findings and gene alterations. The F index was calculated using an image analysis software program. The pathological findings were assessed by the tumor crypt density, cell densities, and N/C ratio. The aberrant methylation of p16, E-cadherin, Apc, Runx3, and hMLH1 genes was determined by a methylation-specific polymerase chain reaction. The aberrant expression of p53 and Ki-67 was evaluated by immunohistochemical staining. RESULTS: An increased N/C ratio, the aberrant expression of p53, Ki-67, and the altered methylation of p16 went together with a lower F index. The other pathological findings and the methylation status showed no association with the F index. CONCLUSIONS: AFI reflects the nuclear enlargement of tumor cells, the cell proliferation ability, and the altered status of cell proliferation-related genes, indicating that AFI is a useful and practical method for predicting the dysplastic grade of tumor cells and cell proliferation.

DOI： 10.3390/molecules24061106

PubMed

researchmap

Language：Japanese   Publisher：日本消化器病学会-北海道支部  

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND & AIMS: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. METHODS: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. RESULTS: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. CONCLUSIONS: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs-we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

DOI： 10.1053/j.gastro.2018.10.029

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本内科学会  

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Central oxytocin is implicated in a wide variety of physiological functions. With regard to gastrointestinal functions, oxytocin acts centrally to regulate gastrointestinal motility. Visceral sensation is also known as one of key gastrointestinal functions which are controlled by the central nervous system (CNS). Little is, however, known about a role of central oxytocin in visceral sensation. The present study was therefore performed to clarify whether oxytocin in the CNS may be involved in visceral sensation. Visceral sensation was evaluated by colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered oxytocin increased the threshold volume of colonic distension-induced AWR while intraperitoneal injection of oxytocin did not alter the threshold volume. Pretreatment with subcutaneous injection of naloxone hydrochloride, a peripheral and central opioid antagonist, blocked the oxytocin-induced visceral antinociception while neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, sulpiride, a dopamine D2 receptor antagonist, DPCPX, an adenosine A1 receptor antagonist, AM251, a cannabinoid 1 receptor antagonist nor AM630, a cannabinoid 2 receptor antagonist blocked the antinociception. Intracisternally administered oxytocin antagonist, L368,899 significantly blocked the intracisternal orexin-A-induced visceral antinociception. These results suggest that oxytocin specifically acts in the CNS to enhance antinociceptive response to colonic distension through the central opioid system. The oxytocin signaling may mediate the central orexin-induced visceral antinociception.

DOI： 10.1016/j.physbeh.2018.10.007

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Visceral hypersensitivity and impaired gut barrier with minor inflammation are considered to play an important role in the pathophysiology of irritable bowel syndrome (IBS). Since pioglitazone is known to have anti-inflammatory property, we hypothesized that pioglitazone is beneficial for treating IBS. In this study, the effect was tested in rat IBS models such as lipopolysaccharide or repeated water avoidance stress-induced visceral allodynia and increased colonic permeability. Pioglitazone blocked these visceral changes, and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist fully reversed the effect by pioglitazone. These results suggest that PPAR-γ activation by pioglitazone may be useful for IBS treatment.

DOI： 10.1016/j.jphs.2018.11.006

PubMed

researchmap

Authorship：Last author   Language：English  

DOI： 10.1111/den.13275

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.14309/ajg.0000000000000069

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Metformin has been shown to have anti-cytokine property. Lipopolysaccharide (LPS)-induced or repeated water avoidance stress (WAS)-induced visceral allodynia and increased gut permeability were pro-inflammatory cytokine-dependent responses, which were considered to be animal models of irritable bowel syndrome (IBS). We hypothesized that metformin improves symptoms in the patients with IBS by attenuating these visceral changes and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue for 15 min spectrophotometrically. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the threshold of visceromotor response, and metformin (5-50 mg/kg for 3 days) intraperitoneally attenuated this response in a dose-dependent manner. Repeated WAS (1 h daily for 3 days) induced visceral allodynia, which was also blocked by metformin. The antinociceptive effect of metformin on the LPS-induced allodynia was reversed by compound C, an adenosine monophosphate-activated protein kinase inhibitor or NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor but not modified by naloxone. Additionally, it was blocked by sulpiride, a dopamine D2 receptor antagonist, but domperidone, a peripheral dopamine D2 receptor antagonist, did not alter it. Metformin also blocked the LPS-induced or repeated WAS-induced increased colonic permeability. CONCLUSIONS: Metformin attenuated the visceral allodynia and increased gut permeability in animal IBS models. These actions may be evoked via activation of adenosine monophosphate-activated protein kinase, nitric oxide, and central dopamine D2 pathways. These results indicate the possibility that metformin can be useful for treating IBS.

DOI： 10.1111/jgh.14367

PubMed

researchmap

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

DOI： 10.11280/gee.61.1145

Scopus

researchmap

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11405/nisshoshi.116.552

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Background: Immuno-oncology is a novel target of cancer therapy. Nivolumab is a monoclonal anti-programed death-1 antibody recently used to treat patients with chemotherapy-resistant gastric and gastroesophageal cancer. Although the disease control rate is reported to be very high, few cases demonstrate a complete response. Case Presentation: A 25-year-old man diagnosed with gastroesophageal cancer was treated with chemotherapy followed by surgical resection. Pathological diagnosis was poorly differentiated adenocarcinoma with distant lymph node metastasis. Residual lymph node metastasis was treated with nivolumab monotherapy, resulting in complete disappearance. No recurrence has been observed for 2 years since discontinuation of nivolumab. This rare case was additionally subjected to pathological and genetic analysis, suggesting that a high tumor mutation burden (10.7 mutations/Mb) might be associated with sensitivity to nivolumab. Summary: We reported a case of advanced gastroesophageal junction cancer with distal lymph node metastasis that was successfully treated with chemotherapy, surgical resection, and nivolumab therapy. An aggressive search for biomarkers implying benefit effects of nivolumab should be performed.

DOI： 10.3389/fonc.2019.01375

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Venous thromboembolism (VTE) has been shown to be more frequent in inflammatory bowel disease (IBD) than in the general population in Western studies. However, the actual state of VTE in Asian IBD remains poorly understood. AIMS: To reveal the incidence of VTE in IBD patients in Japan. METHODS: Eighty-five patients admitted to 3 gastroenterology centers were registered from 2013 to 2018. The incidence of VTE in patients with IBD (n = 42) was prospectively compared to that among patients with other digestive diseases (n = 43). The presence of VTE was surveyed using contrast-enhanced computed tomography and/or ultrasonography at admission and at 1-2 weeks after admission. The patient characteristics and laboratory data of IBD patients with or without VTE were compared to determine the risk factors for VTE. RESULTS: The incidence of VTE with IBD was 16.7%, which was significantly more frequent than with other digestive diseases (2.3%; p = 0.0296). In IBD patients, VTE was detected in 6 of 22 patients with ulcerative colitis (27.2%) but in only 1 of 20 patients with Crohn's disease (5.0%). VTE was diagnosed at admission in 4 IBD patients and 2 weeks after admission in 3 IBD patients. The risk factors of VTE in IBD were the presence of an indwelling central venous catheter, a low level of total protein, a low activated partial thromboplastin time, and a high level of fibrinogen degradation products. CONCLUSION: VTE was frequently detected in Japanese IBD patients both at and after admission. Adequate screening and prophylaxis for VTE is deemed necessary in IBD.

DOI： 10.1159/000495289

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Background and study aims  Symptomatic capsule retention is a very rare adverse event following patency capsule, and the vast majority of cases are resolved without either surgical or endoscopic intervention. We herein describe a rare case of small bowel perforation after swallowing a patency capsule in a 37-year-old man suspected of having Crohn's disease.

DOI： 10.1055/a-0752-9903

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Background  Despite advances in the diagnosis of pancreatic ductal adenocarcinoma (PDA), histological evaluation of small and poorly defined masses in the pancreas is uncomfortable and unsafe. Methods  We herein report a case of early stage PDA, in which multiple KRAS mutations were detected in the pancreatic juice preoperatively. A small hypoechoic area adjacent to the portal vein was detected through endoscopic ultrasound in the pancreatic body. KRAS mutations were evaluated using plasma, and the pancreatic juice by digital PCR. Results  Pancreatic duct biopsy and pancreatic juice cytology were performed with no evidence of malignancy; however, KRAS mutations, KRAS G12V and G12D, were detected in the pancreatic juice. Histological assessment of the resected specimen demonstrated a solid tumor with desmoplastic reaction accompanied by carcinoma in situ in the main pancreatic duct where KRAS G12V mutation was identified. More detailed analysis demonstrated KRAS G12D mutation in the cluster of low grade pancreatic intraepithelial neoplasia, implying that the lesion developed independently. Conclusions  Our study indicates the potential of "endoscopic liquid biopsy" to capture the driver gene for PDA diagnosis.

DOI： 10.1055/a-0721-1747

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Visceral allodynia and increased colonic permeability are considered to be crucial pathophysiology of irritable bowel syndrome (IBS). Corticotropin-releasing factor (CRF) and immune-mediated mechanisms have been proposed to contribute to these changes in IBS, but the precise roles have not been determined. We explored these issues in rats in vivo. The threshold of visceromotor response, i.e., abdominal muscle contractions induced by colonic balloon distention was electrophysiologically measured. Colonic permeability was estimated by quantifying the absorbed Evans blue in colonic tissue. Intraperitoneal injection of CRF increased the permeability, which was blocked by astressin, a non-selective CRF receptor antagonist, but astressin2-B, a selective CRF receptor subtype 2 (CRF2) antagonist did not modify it. Urocortin 2, a selective CRF2 agonist inhibited the increased permeability by CRF. Eritoran, a toll-like receptor 4 (TLR4) antagonist or anakinra, an interleukin-1 receptor antagonist blocked the visceral allodynia and the increased gut permeability induced by CRF. Subcutaneous injection of lipopolysaccharide (immune stress) or repeated water avoidance stress (WAS, psychological stress), 1 h daily for 3 days induced visceral allodynia and increased gut permeability (animal IBS models), which were also blocked by astressin, eritoran or anakinra. In conclusion, stress-induced visceral allodynia and increased colonic permeability were mediated via peripheral CRF receptors. CRF induced these visceral changes via TLR4 and cytokine system, which were CRF1 dependent, and activation of CRF2 inhibited these CRF1-triggered responses. CRF may modulate immune system to alter visceral changes, which are considered to be pivotal pathophysiology of IBS.

DOI： 10.1530/JOE-18-0441

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本肝臓学会  

researchmap

Language：Japanese   Publisher：(一財)日本消化器病学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

researchmap

Language：Japanese   Publisher：日本小腸学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIMS: Venous thromboembolism (VTE) is a major extraintestinal manifestation in inflammatory bowel disease (IBD), regarded as an independent risk factor for VTE according to reports from Western countries. However, the incidence and risk factors of VTE in Asian IBD patients are not fully understood. We aimed to reveal the incidence and risk factors of VTE in Japanese IBD inpatients. METHODS: The incidence of VTE in inpatients with IBD (n=340), gastrointestinal cancers (n=557), and other gastrointestinal diseases (n=569) treated at our hospital from 2009 to 2013 was retrospectively investigated. The characteristics and laboratory data of IBD inpatients with and without VTE were compared in univariate and multivariate analyses. Clinical courses of VTE in IBD were surveyed. RESULTS: VTE was detected in 7.1% of IBD inpatients, significantly higher than in gastrointestinal cancer inpatients (2.5%) and inpatients with other gastrointestinal diseases (0.88%). The incidence of VTE in ulcerative colitis (UC) patients (16.7%) was much higher than that in those with Crohn's disease (3.6%). In the univariate analysis, the risk factors were an older age, central venous catheter, prednisolone, surgery, low serum albumin, high serum C-reactive protein and D-dimer. According to a multivariate analysis, >50 years of age and surgery were the only risk factors. The in-hospital mortality rate of IBD inpatients with VTE was 4.2%. CONCLUSIONS: The incidence of VTE with IBD, especially UC, was found to be high compared with other digestive disease, which was almost equivalent to that of Western countries. The efficacy of prophylaxis needs to be investigated in Asian IBD patients.

DOI： 10.5217/ir.2018.16.3.416

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: All Helicobacter pylori-infected patients are recommended for eradication with an appropriate regimen in each geographic area. The choice of the therapy is somewhat dependent on the antimicrobial susceptibility. The rate of clarithromycin resistance has been increasing and is associated with failure; thus, susceptibility testing is recommended before triple therapy with clarithromycin. However, antimicrobial susceptibility testing is not yet clinically available and an alternative newly developed acid inhibitor vonoprazan is used for triple therapy in Japan. The aim of this study was to determine whether vonoprazan-based triple therapy is plausible treatment in H. pylori eradication. METHODS: A retrospective observational study of H. pylori eradication was conducted in a single institute. The patients who requested antimicrobial susceptibility testing were treated with susceptibility-guided proton pump inhibitor-based triple therapy in International University of Health and Welfare Hospital from 2013 to 2016. Other patients were treated with empirical treatment with a proton pump inhibitor. From 2015 to 2016, vonoprazan-based triple treatment (vonoprazan, 20 mg; amoxicillin, 750 mg; and clarithromycin, 200 or 400 mg, b.i.d.) was conducted, and its effectiveness was compared with susceptibility-guided proton pump inhibitor-based triple therapy. We also investigated the improvement in eradication rate when antimicrobial susceptibility testing was performed, and compared the outcomes of vonoprazan-based and proton pump inhibitor-based empirical therapy. RESULTS: A total of 1355 patients who received first-line eradication treatment were enrolled in the present study. The eradication rates of the empirical proton pump inhibitor-based therapy and the vonoprazan-based therapy group in a per-protocol analysis were 86.3% (95% CI 83.8-88.8) and 97.4% (95% CI 95.7-99.1), respectively. In 212 patients who received antimicrobial susceptibility testing, the rate of clarithromycin resistant was 23.5% and the eradication rate in susceptibility-guided treatment was 95.7% (95% CI 92.9-98.4). The difference between susceptibility-guided and vonoprazan-based therapy was - 1.7% (95% CI - 4.9 to 1.5%), and the non-inferiority of vonoprazan-based triple therapy was confirmed. CONCLUSIONS: Vonoprazan-based triple therapy was effective as susceptibility-guided triple therapy for H. pylori eradication. An empirical triple therapy with vonoprazan is preferable even in area with high rates of clarithromycin-resistance. Trial registration The study was retrospectively registered in University Hospital Medical Information Network (UMIN000032351).

DOI： 10.1186/s12941-018-0281-x

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

A 67-year-old man with relapsed anaplastic large cell lymphoma received salvage chemotherapy, and pegfilgrastim was used to prevent febrile neutropenia. On day 18 of chemotherapy, he developed a pseudogout attack. Although the first symptoms improved, another pseudogout attack occurred when he received the second course of chemotherapy and pegfilgrastim. Filgrastim was then used for the third course of chemotherapy, and a pseudogout attack did not occur. The serum granulocyte-stimulating factor (G-CSF) level was extremely elevated only when pegfilgrastim was used, suggesting a relationship between pseudogout and G-CSF. Pseudogout should be recognized as an adverse effect of pegfilgrastim.

DOI： 10.2169/internalmedicine.9362-17

PubMed

researchmap

Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

We hypothesized that the cannabinoid (CB) system may mediate the brain orexin- or ghrelin-induced visceral antinociception. Intraperitoneal injection of either CB1/2 agonist, WIN 55212 or O-Arachidonoyl ethanolamine increased the threshold volume of colonic distension-induced abdominal withdrawal reflex in rats, suggesting CB could induce visceral antinociception. Pretreatment with either the CB1 or CB2 antagonist potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension while CB2 but not CB1 antagonist blocked the brain ghrelin-induced visceral antinociception. These results suggest that the cannabinoid signaling may be involved in the central orexin- or ghrelin-induced antinociceptive action in a different mechanistic manner.

DOI： 10.1016/j.jphs.2018.06.001

PubMed

researchmap

Language：Japanese   Publisher：(株)メディカルレビュー社  

researchmap

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Increasing evidence implicates brain ghrelin in a wide variety of physiological functions. Among its gastrointestinal functions, ghrelin is known to act centrally to regulate gastrointestinal motility. Visceral sensation is one of the key gastrointestinal functions controlled by the central nervous system. Little is, however, known about the role of central ghrelin in visceral sensation. The present study thus aimed to clarify whether brain ghrelin is involved in visceral sensation. Visceral sensation was evaluated by the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Intracisternally administered ghrelin increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner. By contrast, neither intraperitoneal injection of ghrelin nor intracisternal des-acyl-ghrelin altered the threshold volume. Pretreatment with subcutaneous injection of either naloxone hydrochloride or sulpiride, a dopamine D2 receptor antagonist, significantly blocked ghrelin-induced visceral antinociception; furthermore, neither subcutaneous injection of naloxone methiodide, a peripheral selective opioid antagonist, SCH23390, a dopamine D1 receptor antagonist, nor DPCPX, an adenosine A1 receptor antagonist, blocked antinociception. Although intracisternal SB334867, an orexin 1 receptor antagonist, alone failed to change the threshold volume, centrally injected SB334867 potently blocked ghrelin-induced antinociceptive action during colonic distension. These results provide the first evidence that ghrelin acts centrally in the brain to enhance antinociceptive response to colonic distension through the central opioid system, dopamine D2 signaling, and the orexinergic pathway.

DOI： 10.1016/j.brainres.2018.02.024

PubMed

researchmap

Authorship：Last author   Language：English   Publisher：W B SAUNDERS CO-ELSEVIER INC  

0

Web of Science

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Nonalcoholic steatohepatitis (NASH) is a hepatic manifestation of metabolic syndrome. Although the prostaglandin (PG)I2 receptor IP is expressed broadly in the liver, the role of PGI2-IP signaling in the development of NASH remains to be determined. Here, we investigated the role of the PGI2-IP system in the development of steatohepatitis using mice lacking the PGI2 receptor IP [IP-knockout (IP-KO) mice] and beraprost (BPS), a specific IP agonist. IP-KO and wild-type (WT) mice were fed a methionine- and choline-deficient diet (MCDD) for 2, 5, or 10 wk. BPS was administered orally to mice every day during the experimental periods. The effect of BPS on the expression of chemokine and inflammatory cytokines was examined also in cultured Kupffer cells. WT mice fed MCDD developed steatohepatitis at 10 wk. IP-KO mice developed steatohepatitis at 5 wk with augmented histologic derangements accompanied by increased hepatic monocyte chemoattractant protein-1 (MCP-1) and TNF-α concentrations. After 10 wk of MCDD, IP-KO mice had greater hepatic iron deposition with prominent oxidative stress, resulting in hepatocyte damage. In WT mice, BPS improved histologic and biochemical parameters of steatohepatitis, accompanied by reduced hepatic concentration of MCP-1 and TNF-α. Accordingly, BPS suppressed the LPS-stimulated Mcp-1 and Tnf-α mRNA expression in cultured Kupffer cells prepared from WT mice. PGI2-IP signaling plays a crucial role in the development and progression of steatohepatitis by modulating the inflammatory response, leading to augmented oxidative stress. We suggest that the PGI2-IP system is an attractive therapeutic target for treating patients with NASH.-Kumei, S., Yuhki, K.-I., Kojima, F., Kashiwagi, H., Imamichi, Y., Okumura, T., Narumiya, S., Ushikubi, F. Prostaglandin I2 suppresses the development of diet-induced nonalcoholic steatohepatitis in mice.

DOI： 10.1096/fj.201700590R

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12029-018-0078-3

PubMed

researchmap

Language：English   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

DOI： 10.14309/00000434-201802001-00107

Web of Science

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Statins have been reported to block inflammatory somatic pain and have an anti-cytokine property. Lipopolysaccharide (LPS) or repeated water avoidance stress (WAS) induces visceral hypersensitivity and increases gut permeability in rats, which are mediated through proinflammatory cytokine-dependent pathways. Since visceral hypersensitivity with increased gut permeability plays a crucial role in the pathophysiology of irritable bowel syndrome (IBS), these above animal models are considered to simulate IBS. We hypothesized that lovastatin improves symptoms in the patients with IBS by attenuating these visceral changes. The threshold of visceromotor response (VMR) induced by colonic balloon distention was measured for the assessment of visceral sensation in rats. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue in colonic tissue for 15min using a spectrophotometer. Subcutaneously (s.c.) injected LPS (1mg/kg) reduced the threshold of VMR after 3h. Pretreatment with lovastatin (20mg/kg s.c. daily for 3 days) abolished this response by LPS. Repeated WAS (1h daily for 3 days) induced visceral allodynia, which was also blocked by repeated injection of lovastatin before each stress session. The antinociceptive effect of lovastatin on the LPS-induced allodynia was reversed by mevalonolactone, NG-nitro-L-arginine methyl ester or naloxone. Lovastatin also blocked the LPS- or repeated WAS-induced increased gut permeability. These results indicate the possibility that lovastatin can be useful for treating IBS.

DOI： 10.1016/j.ejphar.2017.10.056

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Some single-nucleotide polymorphisms (SNPs) are associated with the development of non-alcoholic fatty liver disease (NAFLD). As one of the genetic factors, PNPLA3 rs738409 (I148M) is important to associate with pathogenesis of NAFLD. Because other SNPs remain unclear in Japan, we performed a high-throughput sequencing that targeted more than 1000 genes to identify a novel genetic variant in Japanese patients with NAFLD. METHODS: The present study in 36 NAFLD patients and 27 healthy volunteers was performed. A high-throughput sequencer was used to detect the gene variations. Candidate genes were validated by TaqMan SNP genotyping assay in 53 NAFLD patients and 41 healthy volunteers. To investigate the function of candidate gene, we performed biochemical analyses in cultured hepatocytes and liver tissues. RESULTS: EXO1 rs1047840, PTPRD rs35929428, IFNAR2 rs2229207, CPOX rs1131857, IL23R rs1884444, IL10RA rs2228055, and FAM3B rs111988437 were identified as candidate genetic variants, and PTPRD rs35929428 was only extracted as a SNP predicting to cause protein dysfunction. In validation analysis, PTPRD rs35929428 associated with the development of NAFLD (P = 0.015, odds ratio = 5.00, 95% confidence interval: 1.33-18.70). In addition, PTPRD rs35929428 was associated with Fib-4 index and with hepatic fat droplets. Biochemical analyses indicated that PTPRD rs35929428 promoted dephosphorylation of tyrosine 705 signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes. CONCLUSION: PTPRD rs35929428 was a novel SNP in patients with NAFLD. Through exacerbation of the dephosphorylation of signal transducer and activator of transcription 3 (Tyr 705) in hepatocytes, PTPRD rs35929428 might play a role in hepatic lipid accumulation and fibrosis, followed by the development of NAFLD.

DOI： 10.1111/jgh.13820

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: A glucagon-like peptide-1 analog, liraglutide, has been reported to block inflammatory somatic pain. We hypothesized that liraglutide attenuates lipopolysaccharide (LPS)-induced and repeated water avoidance stress (WAS)-induced visceral hypersensitivity and tested the hypothesis in rats. METHODS: The threshold of the visceromotor response induced by colonic balloon distention was measured to assess visceral sensation. Colonic permeability was determined in vivo by quantifying the absorbed Evans blue spectrophotometrically, which was instilled in the proximal colon for 15 min. The interleukin-6 level in colonic mucosa was also quantified using ELISA. RESULTS: Subcutaneously injected LPS (1 mg/kg) reduced the visceromotor response threshold after 3 h. Liraglutide (300 μg/kg subcutaneously) at 15 h and 30 min before injecting LPS eliminated LPS-induced allodynia. It also blocked the allodynia induced by repeated water avoidance stress for 1 h for three consecutive days. Neither vagotomy nor naloxone altered the antinociceptive effect of liraglutide, but NG -nitro-L-arginine methyl ester, a nitric oxide synthesis inhibitor, blocked it. LPS increased colonic permeability and the interleukin-6 level, and the analog significantly inhibited these responses. CONCLUSIONS: This study suggests that liraglutide blocked LPS-induced visceral allodynia, which may be a nitric oxide-dependent response, and was probably mediated by inhibiting pro-inflammatory cytokine production and attenuating the increased gut permeability. Because the LPS-cytokine system is considered to contribute to altered visceral sensation in irritable bowel syndrome, these results indicate the possibility that liraglutide can be useful for treating this disease.

DOI： 10.1111/jgh.13808

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1530/JOE-18-0441

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.14367

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jphs.2018.06.001

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s12941-018-0281-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1186/s13099-018-0251-z

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.13820

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ejphar.2017.10.056

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4103/eus.eus_90_17

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.brainres.2018.02.024

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2169/internalmedicine.9362-17

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Takayasu's arteritis (TA) is a large-vessel vasculitis pathologically characterized by granulomatous necrotizing vasculitis with giant cells. Although the cause of TA is still unclear, genetic factors as well as immunological abnormalities, particularly the overactivation of Th1 and Th-17, are considered to play important roles in the pathogenesis of this disease. Eosinophilic gastroenteritis (EGE) is a type of refractory inflammation in which numerous eosinophils infiltrate the inflammatory area. It is known that the overactivation of Th2 is associated with the pathogenesis of EGE, although the cause of EGE is still unclear. The immunological abnormalities in TA are therefore thought to be different from those in EGE. To date, no cases of complication of TA and EGE have been reported. CASE PRESENTATIONS: An 18 year-old female was diagnosed with EGE and treated with prednisolone. At 6 months after completion of the treatment, the patient experienced chest pain, and was diagnosed with TA. TH1 and TH17 immunity are thought to be involved with TA, while TH2 are considered to be involved with EGE. In this case, the expression of IL-17 mRNA in the colon mucosa greatly decreased after prednisolone treatment for EGE. CONCLUSIONS: This is the first report of TA complicated with EGE, and the overactivation of TH17 is considered to be associated with the pathogenesis of these two diseases.

DOI： 10.1186/s13099-018-0251-z

Scopus

PubMed

researchmap

Other Link： http://orcid.org/0000-0002-1068-7024

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. METHODS: The ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TC™. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. RESULTS: The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5-20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022). CONCLUSIONS: The level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).

DOI： 10.1186/s12885-018-4006-5

Scopus

PubMed

researchmap

Other Link： http://orcid.org/0000-0002-1068-7024

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4103/eus.eus_90_17

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Repeated water avoidance stress (WAS) induces visceral hypersensitivity. Additionally, it is also known to activate corticotropin-releasing factor (CRF), mast cells, and pro-inflammatory cytokines systems, but their precise roles on visceral sensation have not been determined definitely. The aim of the study was to explore this issue. METHODS: Abdominal muscle contractions induced by colonic balloon distention, that is, visceromotor response (VMR) was detected electrophysiologically in conscious rats. WAS or sham stress as control for 1 h daily was loaded, and the threshold of VMR was determined before and at 24 h after the stress. RESULTS: Repeated WAS for three consecutive days reduced the threshold of VMR, but sham stress did not induce any change. Astressin, a CRF receptor antagonist (50 μg/kg) intraperitoneally (ip) at 10 min before each WAS session, prevented the visceral allodynia, but the antagonist (200 μg/kg) ip at 30 min and 15 h before measurement of the threshold after completing 3-day stress session did not modify the response. Ketotifen, a mast cell stabilizer (3 mg/kg), anakinra, an interleukin (IL)-1 receptor antagonist (20 mg/kg) or IL-6 antibody (16.6 μg/kg) ip for two times before the measurement abolished the response. CONCLUSIONS: Repeated WAS for three consecutive days induced visceral allodynia, which was mediated through mast cells, IL-1, and IL-6 pathways. Inhibition of peripheral CRF signaling prevented but did not reverse this response, suggesting that peripheral CRF may be an essential trigger but may not contribute to the maintenance of repeated WAS-induced visceral allodynia.

DOI： 10.1111/jgh.13787

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Background Eradication therapies for Helicobacter pylori infection are advancing as new acid inhibitory reagents approved. The aim of this study was to assess the efficacy and safety of vonoprazan-based triple treatment.
Materials and Methods Triple therapy with vonoprazan and two antibiotics (amoxicillin and clarithromycin or metronidazole) received focus in this analysis. We performed a multicenter retrospective study of patients who received vonoprazan-based eradication therapy between February 2015 and February 2016 and conducted a review of the literature.
Results The eradication rate among the 799 patients in our multicenter study was 94.4% (95% confidence interval [CI] 92.6-96.2%) in the per-protocol analysis for first-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and clarithromycin 200 or 400 mg, twice a day for 7 days) and 97.1% (95% CI 93.0-101.1%) for second-line treatment (with vonoprazan 20 mg, amoxicillin 750 mg, and metronidazole 250 mg, twice a day for 7 days). The overall incidence of adverse events was 4.4% in an intention-to-treat analysis with no patients hospitalized. In a literature review, six reports, in which 1380 patients received vonoprazan-based first-line eradication therapy, were included and were all reported by Japanese researchers. The eradication success rates in per-protocol analysis were between 85 and 93%, which was roughly the same among the studies.
Conclusions Vonoprazan-based triple therapy was effective and safe for Helicobacter pylori eradication in real-world experience, confirmed by a multicenter study and a review of the pertinent literature.

DOI： 10.1007/s10620-017-4664-1

Web of Science

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Hypereosinophilic syndrome (HES) is a rare disorder characterized by hypereosinophilia and organ damage. Some cases of HES are caused by the FIP1L1/PDGFRA fusion gene and respond to imatinib. FIP1L1/PDGFRA-positive HES occasionally evolves into chronic eosinophilic leukemia or into another form of myeloproliferative neoplasm; however, the development of a malignant lymphoma is very rare. We present a rare case of angioimmunoblastic T-cell lymphoma (AITL) and HES with the FIP1L1/PDGFRA gene rearrangement. PATIENT CONCERNS: A man in his 30s presented to our hospital with fever, hypereosinophilia, widespread lymphadenopathy, and splenomegaly. Laboratory tests showed hypereosinophilia, increased soluble interleukin-2 receptor, and increased vitamin B12. Positron-emission tomography with F fluorodeoxyglucose (FDG) showed positive FDG uptake in multiple enlarged lymph nodes throughout the body and the red bone marrow. A bone-marrow biopsy showed hypereosinophilia without dysplasia and an increased number of blasts. The FIP1L1/PDGFRA fusion gene was positive upon fluorescence in situ hybridization (FISH) analysis of the peripheral blood. Furthermore, biopsy of a lymph node from the neck revealed restiform hyperplasia of capillary vessels, with small lymphoma cells arranged around the capillaries. Lymphoma cells were positive for CD3, CD4, and CD10, and negative for CD20. Lymphoma cells were also positive for the FIP1L1/PDGFRA fusion gene by FISH analysis. DIAGNOSES: From these findings, the patient was diagnosed with HES and AITL with FIP1L1/PDGFRA. INTERVENTIONS: After the diagnosis, corticosteroid was administered but was ineffective. Imatinib was then administered. OUTCOMES: Imatinib was very effective for treating HES and AITL, and complete remission was achieved in both. LESSONS: This report presents the first case in which the FIP1L1/PDGFRA fusion gene was positive both in peripheral blood and lymph nodes, implying the possibility that the tumor cells acquired the FIP1L1/PDGFRA fusion gene in the early stage of hematopoietic progenitor cell developments. Imatinib was very effective in treating both HES and lymphoma, suggesting that the FIP1L1/PDGFRA fusion gene plays a key role in the pathogenesis of both HES and lymphoma.

DOI： 10.1097/MD.0000000000008001

PubMed

researchmap

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

researchmap

Language：Japanese   Publisher：(一社)日本消化器内視鏡学会  

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Tegafur-uracil has been reported to have only minor adverse effects and is associated with liver injury in 1.79% of Japanese patients. The development of tegafur-uracil-induced hepatic fibrosis with portal hypertension is rare. Here, we report a case of a 74-year-old woman with rapidly developing tegafur-uracil-induced hepatic fibrosis. The patient had no history of liver disease and had been treated with tegafur-uracil for 8 mo after breast cancer surgery. The patient was admitted to our hospital for abdominal distension and leg edema associated with liver dysfunction. Computed tomography imaging revealed massive ascites and splenomegaly, and a non-invasive assessment of liver fibrosis indicated advanced fibrosis. The histopathological findings revealed periportal fibrosis and bridging fibrosis with septation. The massive ascites resolved after discontinuing tegafur-uracil. These findings suggest that advanced hepatic fibrosis can develop from a relatively short-term administration of tegafur-uracil and that non-invasive assessment is useful for predicting hepatic fibrosis.

DOI： 10.3748/wjg.v23.i31.5823

PubMed

researchmap

Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease characterized by recurrent fever with serosal inflammation. We experienced a 53-year-old male who had been suffering from periodic attacks with slight fever and myalgia which were mainly triggered by cold exposure in winter. Although his clinical course did not satisfy the criteria for familial Mediterranean fever, heterozygous E148Q/M694I mutation in the Mediterranean fever (MEFV) gene was detected. Further attacks were prevented by treatment with colchicine. Attention should therefore be paid to the possibility of atypical FMF symptoms, which should be accurately diagnosed by genetic analyses to prevent the development of amyloidosis.

DOI： 10.2169/internalmedicine.8274-16

PubMed

researchmap