Explore the vast range of titles available.

Proton pump inhibitors (PPIs) alter the composition of the intestinal microbiome, exacerbating indomethacin (IND)-induced small intestinal damage. Vonoprazan fumarate inhibits gastric acid secretion using a different mechanism from PPIs. We investigated the effects of both drugs on the intestinal microbiome and IND-induced small intestinal damage. We sought to clarify whether PPI-induced dysbiosis and worsening of the damage were due to a specific drug class effect of PPIs. Rabeprazole administration increased operational taxonomic unit numbers in the small intestines of C57BL/6 J mice, whereas the difference was not significant in the vonoprazan-treated group but exhibited a trend. Permutational multivariate analysis of variance of the unweighted UniFrac distances showed significant differences between vehicle- and vonoprazan- or rabeprazole-treated groups. L. johnsonii was the predominant microbial species, and the population ratio decreased after vonoprazan and rabeprazole administration. The vonoprazan- and rabeprazole-treated groups showed increased IND-induced damage. This high sensitivity to IND-induced damage was evaluated by transplantation with contents from the small intestine of mice treated with either vonoprazan or rabeprazole. Supplementation of L. johnsonii orally in mice treated with rabeprazole and vonoprazan prevented the increase in IND-induced small intestinal damage. In conclusion, both rabeprazole and vonoprazan aggravated NSAID-induced small intestinal injury by reducing the population of L. johnsonii in the small intestine via suppressing gastric acid secretion.

We determined the bone mineral density (BMD) and the expression of serum bone formation marker (procollagen type I N-terminal propeptide: PINP) and bone resorption marker (C-terminal telopeptide of collagen: CTX) by ELISA to evaluate ovariectomy-induced osteoporosis in ovariectomized (OVX) mice. The intestinal microbiota of the mice was assessed using 16S rRNA gene sequencing. OVX mice exhibited a lower BMD of 87% with higher serum levels of CTX and PINP compared to sham-operated (sham) mice. The cecum microbiome of OVX mice showed lower bacterial diversity than that of sham mice. TNFα mRNA levels in the colon were 1.6 times higher, and zonula occludens-1 mRNA and protein expression were lower in OVX mice than in sham mice, suggesting that ovariectomy induced inflammation and increased intestinal permeability. Next, we used antibiotic treatment followed by fecal microbiota transplantation (FMT) to remodel the gut microbiota in the OVX mice. A decrease in PINP was observed in antibiotic-treated mice, while there was no change in BMD or CTX between mice with and without antibiotic treatment. Oral transplantation of the luminal cecal content of OVX or sham mice to antibiotic-treated mice did not affect the BMD or PINP and CTX expression. Additionally, transplantation of the luminal contents of OVX or sham mice to antibiotic-treated OVX mice had similar effects on BMD, PINP, and CTX. In conclusion, although ovariectomy induces dysbiosis in the colon, the changes in the gut microbiota may only have a minor role in ovariectomy-induced osteoporosis.

A 74‐year‐old man with decreased appetite, weight, and heartburn was referred to our hospital. His medications included olmesartan. Esophagogastroduodenoscopy (EGD) revealed antral‐dominant erosive gastritis and nodular mucosa. A gastric biopsy revealed inflammatory cell infiltration. The serum anti‐ Helicobacter pylori immunoglobulin G antibody test result was negative. Famotidine was ineffective in relieving his symptoms, and esomeprazole failed to prevent overt gastric bleeding, which required endoscopic hemostasis. The working diagnosis was drug‐induced gastritis, particularly olmesartan‐induced gastritis. His appetite loss started to improve within a week of olmesartan withdrawal. The erosions healed on EGD 2 months later. Over the next 10 months, he remained in his usual state until olmesartan was inadvertently administered. Subsequent EGD revealed a mild gastritis relapse. We diagnosed olmesartan‐induced gastritis and discontinued olmesartan treatment. Mucosal healing was confirmed by EGD 1 year later. Olmesartan is known to cause angiotensin II receptor blocker‐induced enteropathy. Although angiotensin II receptor blocker‐induced enteropathy affects the stomach, angiotensin II receptor blocker‐induced gastritis without lower gastrointestinal symptoms is rare. The characteristic endoscopic appearance may provide a clue to the correct diagnosis.

To understand the effect of prolonged intravenous acetaminophen infusion on blood pressure. We retrospectively studied a cohort of intensive care patients receiving initial intravenous acetaminophen. We used propensity score matching to adjust for differences between patients who were classified into two groups: control (acetaminophen infusion for 15 minutes) and prolonged administration (acetaminophen infusion for > 15 minutes). After acetaminophen administration, diastolic blood pressure was unchanged in the control group, and was significantly lower at 30 and 60 minutes in the prolonged administration group. Prolonged duration of acetaminophen infusion did not prevent acetaminophen-induced blood pressure reduction.

BackgroundThe pathogenesis of eosinophilic esophagitis involves immunoglobulin G4 (IgG4) deposition. However, the relationship between IgG4 and eosinophilic gastroenteritis (EGE) is unclear.AimsTo investigate gastrointestinal deposition of IgG4 in EGE.MethodsBiopsies of the esophagus, stomach, and small intestine were evaluated in patients with and without EGE. Immunohistochemical staining for IgG4 was performed, and the proportions of the stained areas were compared. Sera from patients with EGE were assayed for food-specific IgG4, including egg white, wheat, rice, soy, and cow milk.ResultsSeventeen patients were included in this study (EGE group, n = 10; control group, n = 7). Compared with the control group, the proportion of IgG4-stained area in the EGE group was approximately threefold higher (40.2% [32.3–49.5]) vs. 12.1% [4.0–21.9], p = 0.014) in the esophagus, fivefold higher in the stomach (17.3% [11.1–26.2] vs. 3.7% [1.5–5.2], p = 0.014), and sixfold higher in the small intestine (28.0% [15.0–33.2] vs. 4.5% [2.6–9.8], p = 0.019). There was no significant association between the proportion of IgG4-stained area and the number of infiltrating eosinophils. Serum egg white-specific IgG4 levels were correlated with the proportion of IgG4-stained areas in the small intestine (R = 0.7, p = 0.035).ConclusionsIgG4 accumulated within the gastrointestinal mucosa in EGE. The positive correlation between serum egg white-specific IgG4 levels and the proportion of IgG4-stained areas in the small intestine suggests a role for IgG4 in the disease pathophysiology.

Background and Aim: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1β (IL-1β) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis. Methods: Small intestinal mucositis was induced in wild-type, NLRP3 –/– , and caspase-1 –/– mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1β or IL-18, or neutralizing antibody against IL-1β. Results: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1β and protein expression of cleaved caspase-1 and mature IL-1β. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3 –/– mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1β and neutralized by IL-1β antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1β were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells. Conclusions: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1β maturation.

Interactive networks of transcription factors (TFs) have critical roles in epigenetic and gene regulation for cancer progression. It is required to clarify underlying mechanisms for transcriptional activation through concerted efforts of TFs. Here, we show the essential role of disease phase-specific TF collaboration changes in advanced prostate cancer (PC). Investigation of the transcriptome in castration-resistant PC (CRPC) revealed OCT4 as a key TF in the disease pathology. OCT4 confers epigenetic changes by promoting complex formation with FOXA1 and androgen receptor (AR), the central signals for the progression to CRPC. Meanwhile, OCT4 facilitates a distinctive complex formation with nuclear respiratory factor 1 (NRF1) to gain chemo-resistance in the absence of AR. Mechanistically, we reveal that OCT4 increases large droplet formations with AR/FOXA1 as well as NRF1 in vitro. Disruption of TF collaborations using a nucleoside analogue, ribavirin, inhibited treatment-resistant PC tumor growth. Thus, our findings highlight the formation of TF collaborations as a potent therapeutic target in advanced cancer. Transcription factors (TFs) often form distinct networks to regulate transcriptional program during cancer progression. Here the authors show that OCT4 is a common transcriptional factor in two types of advanced PC and as such, OCT4 accelerates a TF complex formation with the FOXA1/AR in castration-resistant PC and NRF1 in neuroendocrine PC.

An 80‐year‐old man, who developed multiple lymph node and skin metastasis of malignant melanoma, received nivolumab monotherapy. Two weeks after the first dose, he experienced anorexia and fatigue, and suffered from progressive, severe dyspnea and muscle weakness. We diagnosed him with myocarditis, myositis, and myasthenic crisis induced by nivolumab. We commenced steroid therapy, immune absorption therapy, plasma exchange therapy, and i.v. immunoglobulin therapy, and succeeded in saving his life. Because his serum level of anti‐acetylcholine receptor antibodies in a sample collected before nivolumab treatment were positive and were elevated significantly after nivolumab, we suspected that nivolumab triggered a severe autoimmune response, which progressed subclinical myasthenia gravis to myasthenic crisis. We carried out T cell receptor repertoire analysis using next‐generation sequencing technologies and identified infiltration of clonally expanded T cell populations in the skeletal muscle after nivolumab treatment, implying a very strong T cell immune response against muscular cells. To avoid severe immune‐related adverse events, the exclusion of patients with subclinical autoimmune disease is very important for treatment with immune checkpoint inhibitors. Myasthenic crisis and polymyositis were induced by one dose of nivolumab. We performed T cell receptor repertoire analysis using the next‐generation sequencing technologies and identified infiltration of clonally expanded T cell populations in the skeletal muscle tissue after the nivolumab treatment, implying the very strong T cell immune response against muscular cells