Randomized controlled trial comparing the costs of gastric cancer screening systems between serological risk-based upper gastrointestinal endoscopy and the existing barium photofluorography: gastric cancer screening labeled by serum examination in place of aged gastric cancer organized screening systems (GALAPAGOS study).

BACKGROUND: Although the risk of gastric cancer can be stratified according to Helicobacter pylori (H. pylori) IgG antibody titer and pepsinogen levels (ABC classification), a population-based gastric cancer screening system combining serological tests and endoscopy has not been introduced. This study aimed to compare the total testing cost per participant between the ABC classification method and the existing protocol. METHODS: Using the minimization method with sex and age as allocation factors, 1206 participants were randomly assigned to the following two methods for a 5-year intervention: barium photofluorography as primary examination followed by detailed examination with upper gastrointestinal endoscopy (Ba-Endo) and risk-based upper gastrointestinal endoscopy by ABC classification (ABC-Endo). The primary endpoint was the total testing cost per participant over a 5-year period. The secondary endpoint was the expense required to detect one gastric cancer. RESULTS: The total testing cost per participant was 39,711 yen in Ba-Endo (604 participants) and 45,227 yen in ABC-Endo (602 participants), with the latter being significantly higher (p < 0.001). During the intervention period, gastric cancer was found in 11 and eight participants in Ba-Endo and ABC-Endo, respectively. The expenses required to detect one gastric cancer were 2,240,931 yen in Ba-Endo and 3,486,662 yen in ABC-Endo. CONCLUSIONS: The testing cost per participant turned out to be higher in the ABC-Endo group than in the Ba-Endo group. This superiority trial, based on the hypothesis that the cost of testing is lower for ABC-Endo than for Ba-Endo, was rejected.

Rab7 localized on zymogen granules is involved in maturation but not in autophagy or regulated exocytosis in pancreatic acinar cells.

Rab7 is known to function in the autophagy and endocytosis pathways in eukaryocytes and is related to various diseases. We recently reported that Rab7 plays a protective role against acute pancreatitis. However, its physiological function in exocytic cells remains unclear. Therefore, we investigated the role of Rab7 in pancreas-specific Rab7 knockout mice (Rab7Δpan). Immunofluorescence microscopy revealed that Rab7 colocalized with amylase in pancreatic acinar cells of wild-type mice, but not in Rab7Δpan mice. Western blotting confirmed Rab7 localization in the zymogen granule (ZG) membranes of wild-type mice. Cholecystokinin (CCK)-stimulated amylase secretion examined using isolated pancreatic acini was similar in Rab7Δpan and wild-type mice. In contrast, electron microscopy revealed that the diameters of ZGs were shorter and the number of ZGs was larger in the pancreatic acinar cells of Rab7Δpan mice than in those of wild-type mice. However, the number of ZGs decreased in both Rab7Δpan and wild-type mice after 24 h of starvation. In addition, the amount of amylase in the pancreas was decreased in both Rab7Δpan and wild-type mice. These data indicate that Rab7 localized on ZGs plays a crucial role in the maturation of ZGs but not in their autophagy or regulated exocytosis in pancreatic acinar cells.

A Comparative Study of Endoscopic Ultrasonography and Histopathology Images for the Diagnosis of Early Chronic Pancreatitis.

OBJECTIVE: The concept of early chronic pancreatitis (ECP) and its diagnostic criteria were first proposed by Japan, using endoscopic ultrasonography (EUS) findings for diagnosis. However, these findings have not been supported by pathological findings. We aimed to examine the association between the EUS and pathological findings of the same area of the pancreas. METHODS: In 12 patients who underwent pancreaticoduodenectomy for distal bile duct cancer without accompanying pancreatitis, a comparative analysis between preoperative EUS and pathological findings was performed. The part of the pancreas adjoining the portal vein was evaluated. RESULTS: In 7 cases, abnormal EUS findings included in the diagnostic criteria for ECP were seen; the correlation of the accuracy of lobularity seen on EUS compared with the pathological findings of the pancreatic parenchyma (inflammatory cell infiltration, atrophy of acinar cells, and fibrosis) was high (83.3%-91.7%). Pancreatic duct findings revealed that the accuracy of the hyperechoic margin of the pancreatic duct on EUS compared with pathological findings (wall thickness of pancreatic duct) was high (83.3%). CONCLUSIONS: Endoscopic ultrasonography findings for ECP, according to Japan's 2019 revised criteria, lobularity, and the hyperechoic margin of the pancreatic duct may highly correspond to the pathological findings of chronic inflammation.

The role of calcium-binding protein S100g (CalbindinD-9K) and annexin A10 in acute pancreatitis.

BACKGROUND: We reported that the pancreas of the interferon-regulatory factor (IRF) 2 knock-out (KO) mouse represents an early phase of acute pancreatitis, including defective regulatory exocytosis, intracellular activation of trypsin, and disturbance of autophagy. The significantly upregulated and downregulated genes in the IRF2 KO pancreas have been reported. The catalogue of gene transcripts included two types of calcium-binding proteins (S100 calcium binding protein G [S100g] and Annexin A10 [Anxa10]), which were highly upregulated in the IRF2 KO pancreas. As the intracellular calcium signal plays a pivotal role in regulatory exocytosis and its disturbance is related to pancreatitis, we then evaluated the role of S100g and Anxa10 in acute pancreatitis. METHOD: We induced cerulein-pancreatitis in wild-type mice and examined the changes in the expression of these genes by qPCR and immunohistochemistry. We constructed S100g-overexpressing or Anxa10-overexpressing AR42J cells (AR42J-S100g, AR42J-Anxa10). We examined the changes in amylase secretion, intracellular calcium ([Ca2+]i), and cell viability in these cells, when incubated with cholecystokinin (CCK). RESULTS: The expression of S100g and Anxa10 was increased in cerulean-induced pancreatitis. The acini were patchily stained for S100g and the cytosol of acini was evenly but weakly stained for Anxa10. Stimulation with 100pM CCK-8, decreased amylase secretion and inhibited the [Ca2+]i increase in AR42J-S100g cells. These effects were weak in AR42J-Anxa10 cells. Cell viability was not changed by incubation with cerulein. CONCLUSION: In cerulean pancreatitis, the expression of S100g and Anxa10 was induced in the acini. S100g may work as a Ca2+ buffer in acute pancreatitis.

Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet.

Nonalcoholic steatohepatitis (NASH) is a common cause of liver cirrhosis and hepatocellular carcinoma (HCC). However, effective therapeutic strategies for preventing and treating NASH-mediated liver cirrhosis and HCC are lacking. Cholesterol is closely associated with vascular endothelial growth factor (VEGF), a key factor that promotes HCC. Recent reports have demonstrated that statins could prevent HCC development. In contrast, we have little information on ezetimibe, an inhibitor of cholesterol absorption, in regards to the prevention of NASH-related liver cirrhosis and HCC. In the present study, a steatohepatitis-related HCC model, hepatocyte-specific phosphatase and tensin homolog (Pten)-deficient (PtenΔhep ) mice were fed a high-fat (HF) diet with/without ezetimibe. In the standard-diet group, ezetimibe did not reduce the development of liver tumors in PtenΔhep mice, in which the increase of serum cholesterol levels was mild. Feeding of a HF diet increased serum cholesterol levels markedly and subsequently increased serum levels of VEGF, a crucial component of angiogenesis. The HF diet increased the number of VEGF-positive cells and vascular endothelial cells in the tumors of PtenΔhep mice. Kupffer cells, macrophages in the liver, increased VEGF expression in response to fat overload. Ezetimibe treatment lowered cholesterol levels and these angiogenetic processes. As a result, ezetimibe also suppressed inflammation, liver fibrosis and tumor growth in PtenΔhep mice on the HF diet. Tumor cells were highly proliferative with HF-diet feeding, which was inhibited by ezetimibe. In conclusion, ezetimibe suppressed development of liver tumors by inhibiting angiogenesis in PtenΔhep mice with hypercholesterolemia.

The role of Gαq/Gα11 signaling in intestinal epithelial cells.

Intestinal homeostasis and the coordinated actions of digestion, absorption and excretion are tightly regulated by a number of gastrointestinal hormones. Most of them exert their actions through G-protein-coupled receptors. Recently, we showed that the absence of Gαq/Gα11 signaling impaired the maturation of Paneth cells, induced their differentiation toward goblet cells, and affected the regeneration of the colonic mucosa in an experimental model of colitis. Although an immunohistochemical study showed that Gαq/Gα11 were highly expressed in enterocytes, it seemed that enterocytes were not affected in Int-Gq/G11 double knock-out intestine. Thus, we used an intestinal epithelial cell line to examine the role of signaling through Gαq/Gα11 in enterocytes and manipulated the expression level of Gαq and/or Gα11. The proliferation was inhibited in IEC-6 cells that overexpressed Gαq/Gα11 and enhanced in IEC-6 cells in which Gαq/Gα11 was downregulated. The expression of T-cell factor 1 was increased according to the overexpression of Gαq/Gα11. The expression of Notch1 intracellular cytoplasmic domain was decreased by the overexpression of Gαq/Gα11 and increased by the downregulation of Gαq/Gα11. The relative mRNA expression of Muc2, a goblet cell marker, was elevated in a Gαq/Gα11 knock-down experiment. Our findings suggest that Gαq/Gα11-mediated signaling inhibits proliferation and may support a physiological function, such as absorption or secretion, in terminally differentiated enterocytes.

Disruption of Small GTPase Rab7 Exacerbates the Severity of Acute Pancreatitis in Experimental Mouse Models.

Although aberrations of intracellular vesicle transport systems towards lysosomes including autophagy and endocytosis are involved in the onset and progression of acute pancreatitis, the molecular mechanisms underlying such aberrations remain unclear. The pathways of autophagy and endocytosis are closely related, and Rab7 plays crucial roles in both. In this study, we analyzed the function of Rab7 in acute pancreatitis using pancreas-specific Rab7 knockout (Rab7Δpan) mice. In Rab7Δpan pancreatic acinar cells, the maturation steps of both endosomes and autophagosomes were deteriorated, and the lysosomal functions were affected. In experimental models of acute pancreatitis, the histopathological severity, serum amylase concentration and intra-pancreatic trypsin activity were significantly higher in Rab7Δpan mice than in wild-type mice. Furthermore, the autophagy process was blocked in Rab7Δpan pancreas compared with wild-type mice. In addition, larger autophagic vacuoles that colocalize with early endosome antigen 1 (EEA1) but not with lysosomal-associated membrane protein (LAMP)-1 were much more frequently formed in Rab7Δpan pancreatic acinar cells. Accordingly, Rab7 deficiency exacerbates the severity of acute pancreatitis by impairing the autophagic and endocytic pathways toward lysosomes.

Altered Gut Microbiota Composition and Immune Response in Experimental Steatohepatitis Mouse Models.

BACKGROUND: Although several types of diet have been used in experimental steatohepatitis models, comparison of gut microbiota and immunological alterations in the gut among diets has not yet been performed. AIM: We attempted to clarify the difference in the gut environment between mice administrated several experimental diets. METHODS: Male wild-type mice were fed a high-fat (HF) diet, a choline-deficient amino acid-defined (CDAA) diet, and a methionine-choline-deficient (MCD) diet for 8 weeks. We compared the severity of steatohepatitis, the composition of gut microbiota, and the intestinal expression of interleukin (IL)-17, an immune modulator. RESULTS: Steatohepatitis was most severe in the mice fed the CDAA diet, followed by the MCD diet, and the HF diet. Analysis of gut microbiota showed that the composition of the Firmicutes phylum differed markedly at order level between the mice fed the CDAA and HF diet. The CDAA diet increased the abundance of Clostridiales, while the HF diet increased that of lactate-producing bacteria. In addition, the CDAA diet decreased the abundance of lactate-producing bacteria and antiinflammatory bacterium Parabacteroides goldsteinii in the phylum Bacteroidetes. In CDAA-fed mice, IL-17 levels were increased in ileum as well as portal vein. In addition, the CDAA diet also elevated hepatic expression of chemokines, downstream targets of IL-17. CONCLUSIONS: The composition of gut microbiota and IL-17 expression varied considerably between mice administrated different experimental diets to induce steatohepatitis.

Toll-like Receptor 4 on Macrophage Promotes the Development of Steatohepatitis-related Hepatocellular Carcinoma in Mice.

The role of Toll-like receptor (TLR) signaling has attracted much attention in the development of hepatic inflammation and hepatocellular carcinoma (HCC). We herein sought to determine the role of TLRs and responsible cells in steatohepatitis-related HCC. We used hepatocyte-specific Pten-deficient (Pten(Δ) (hep)) mice, which exhibit steatohepatitis followed by liver tumor formation, including HCC. We then generated Pten(Δ) (hep)/Tlr4(-/-) and Pten(Δ) (hep)/Tlr2(-/-) double-mutant mice and investigated the role of macrophages using reconstitution of bone marrow (BM)-derived cells, chemical depletion of macrophages, and isolated macrophages. Tlr4 but not Tlr2 deficiency in the Pten(Δ) (hep) mice suppressed tumor growth as well as hepatic inflammation. Gut sterilization by an antibiotic mixture reduced the portal LPS levels as well as tumor growth in the Pten(Δ) (hep) mice. Tumor growth was also decreased by reconstitution of BM-derived cells to Tlr4(-/-) BM cells. In addition, chemical depletion of macrophages significantly reduced tumor size and numbers. Macrophages expressing Ly6C were increased in number, which was associated with inflammation and tumor progression in the Pten(Δ) (hep) mice. Hepatic macrophages isolated from the Pten(Δ) (hep) mice abundantly expressed the Ly6C gene and produced much more IL-6 and TNFα in response to LPS. These proinflammatory cytokines induced the proliferation of HCC cells as well as oval cells, putative cancer progenitor cells. Indeed, putative cancer progenitor cells emerged before the development of macroscopic liver tumors and then increased in number under sustained inflammation. TLR4 on macrophages contributes to the development of steatohepatitis-related HCC in mice.

Requirement of Gαq/Gα11 Signaling in the Preservation of Mouse Intestinal Epithelial Homeostasis.

BACKGROUND & AIMS: Proliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein-coupled receptors. We herein investigated the role of Gαq/11-mediated signaling in intestinal homeostasis. METHODS: Intestinal tissues from control (Gnaqflox/floxGna11+/+ ), Int-Gq knock-out (KO) (VilCre+/-Gnaqflox/floxGna11+/+ ), G11 KO (Gnaqflox/floxGna11-/- ), and Int-Gq/G11 double knock-out (DKO) (VilCre+/-Gnaqflox/floxGna11-/- ) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry. The effect of Gαq/11-mediated signaling was studied in the cell lineage, proliferation, and apoptosis. Dextran sodium sulfate (DSS) colitis was induced to study the role of Gαq/11 in colon. RESULTS: Paneth cells were enlarged, increased in number, and mislocalized in Int-Gq/G11 DKO small intestine. Paneth cells also reacted with PAS and Muc2 antibody, indicating an intermediate character of Paneth and goblet cells. The nuclear ß-catenin, T-cell factor 1, and Sox9 expression were reduced severely in the crypt base of Int-Gq/G11 DKO intestine. Proliferation was activated in the crypt base and apoptosis was enhanced along the crypt. Int-Gq/G11 DKO mice were susceptible to DSS colitis. Proliferation was inhibited in the crypt of unaffected and regenerative areas. Cystic crypts, periodic acid-Schiff-positive cells, and Muc2-positive cells were unusually observed in the ulcerative region. CONCLUSIONS: The Gαq/11-mediated pathway plays a pivotal role in the preservation of intestinal homeostasis, especially in Paneth cell maturation and positioning. Wnt/ß-catenin signaling was reduced significantly in the crypt base in Gαq/G11-deficient mice, resulting in the defective maturation of Paneth cells, induction of differentiation toward goblet cells, and susceptibility to DSS colitis.

True Primary Enterolith Treated by Balloon-assisted Enteroscopy.

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

Parkinsonism Improved With Levodopa After Endoscopic Third Ventriculostomy in Shunted Hydrocephalus Due to Aqueductal Stenosis.

INTRODUCTION: Levodopa-responsive parkinsonism has been reported following ventriculoperitoneal (VP) shunt in patients with obstructive hydrocephalus due to aqueductal stenosis. It has been thought to arise from injury to the global rostral midbrain including the nigrostriatal pathway by a transtentorial pressure gradient. We present a similar patient, but his parkinsonism resisted levodopa administration during the initial therapy. CASE REPORT: A 51-year-old man suffered from hydrocephalus due to secondary aqueductal stenosis presumably attributed to massive bleeding during surgery for a fourth ventricle hemangioblastoma. After resolution of the hydrocephalus with VP shunt, he developed severe parkinsonism, Parinaud syndrome, and hyperreflexia, suggesting global rostral midbrain dysfunction, but high-dosage levodopa therapy was not effective. An inverted transtentorial pressure gradient suggested by his unilateral slit-like ventricle was assumed to be the cause of the levodopa resistance. Also based on an assumption that the absorption of cerebrospinal fluid was impaired due to the intraoperative bleeding, a lumbar peritoneal shunt was added to the preexisting VP shunt, but it failed to control the ventricular size. Instead, endoscopic third ventriculostomy stabilized it, characteristically inducing levodopa responsiveness in our patient. An increase of the levodopa dosage led to clinical improvement, which needed a maintenance dosage because of dependency. CONCLUSION: The details of this patient suggest that a transtentorial pressure gradient may have impaired more distal basal ganglia connections over a global rostral midbrain including the nigrostriatal pathway, and that aggressive levodopa therapy after endoscopic third ventriculostomy can be effective for refractory parkinsonism.

Successful treatment with infliximab for refractory para-ileostomal ulceration in a patient with BehÒ«et's disease.

BehÒ«et's disease (BD) is a chronic disorder involving multiple organ systems including the small and large intestines. A 46-year-old female diagnosed with intestinal BD presented with ileocecal perforation and diffuse peritonitis and subsequently underwent ileocolic resection with ileostomy. After surgery, she suffered from refractory para-ileostomal ulceration associated with BD. Most importantly, however, treatment with infliximab was significantly effective in healing the ulceration. This is the first report of para-ileostomal ulceration associated with BD successfully treated with infliximab, suggesting the possible use of infliximab as a therapeutic option for para-stomal ulcers related to BD.

Efficacy of combined balloon-occluded retrograde transvenous obliteration and simultaneous endoscopic injection sclerotherapy.

OBJECTIVE: We evaluated the efficacy and safety of balloon-occluded retrograde transvenous obliteration (B-RTO) performed using absolute ethanol with iodized oil (ET+LPD) and simultaneous endoscopic injection sclerotherapy (EIS) with cyanoacrylate (CA) for gastric varices (GVs). METHODS: A total of 16 patients with endoscopically proven high-risk GVs treated using combined B-RTO with ET+LPD and EIS with CA between January 2007 and July 2012 were enrolled. RESULTS: Twelve cases included GVs involving both the cardia and fundus, two cases included fundal varices and two cases included cardiac varices. In terms of the form of GVs, 10 cases involved F2 lesions and six cases involved F3 lesions. The flow vein was the left gastric vein in 13 cases and the posterior gastric vein in three cases. The drainage route was a splenorenal shunt in all cases. The average dose of ET+LPD was 12.0 mL, while that of CA was 2.45 mL. All complications were transient, and no major complications occurred after the procedures. None of the patients experienced bleeding or recurrence of gastric varices after the combined B-RTO and EIS procedures during an average follow-up period of 38.3 months. CONCLUSION: Combined B-RTO with ET+LPD and simultaneous EIS with CA is considered to be an effective and safe procedure for treating GVs.

Clinical course of gastrointestinal stromal tumor diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

BACKGROUND AND AIM: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract. However, little is known about the clinical presentation of GIST, especially small lesions. The purpose of the present study was to clarify the efficacy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of GIST and to determine its clinical course. METHODS: Pathological and clinical records of GIST extracted from our institutional database between 1996 and 2012 were reviewed. All GIST cases were diagnosed pathologically by surgical specimen or EUS-FNA. To examine the efficacy of EUS-FNA for the diagnosis of GIST, the pathological findings of EUS-FNA were compared with the surgical findings from resected cases. Next, to clarify the clinical presentation of GIST, imaging findings and changes in tumor size over time were evaluated in follow up. RESULTS: Of 84 cases of GIST, 67 were resected surgically after EUS-FNA; tumor size was <20 mm in 19 patients, and ≥20 mm in 48 patients. For the diagnosis of small GIST<20 mm, sensitivity and positive predictive value of EUS-FNA were 81.3% and 100%, respectively. A total of 27 patients with GIST was follow up for more than 1 year. Tumor size increased significantly during follow up. However, generalized linear analysis showed that there was no significant relationship between tumor size and follow up period. CONCLUSIONS: The present results showed that even small GIST can be correctly identified by EUS-FNA. Moreover, size of small GIST increased significantly during follow up.

Randomized controlled trial comparing gastric cancer screening by gastrointestinal X-ray with serology for Helicobacter pylori and pepsinogens followed by gastrointestinal endoscopy.

BACKGROUND: Based on the results of several case-control and cohort studies gastrointestinal X-ray (GI X-ray) has been recommended for use in the nationwide screening program for gastric cancer.. Although this was the only effective screening program when almost all of the Japanese population were Helicobacter pylori (H. pylori) positive, there has been concern whether an alternative effective screening system should be established for the future H. pylori-negative generation. We therefore conducted the first randomized controlled trial (RCT) comparing GI X-ray and gastrointestinal endoscopy (GIE) scheduled according to results of serological testing (ST); this was done to determine the potential for an alternative screening method. METHODS: Subjects who fulfilled the inclusion criteria were residents between the ages of 30 and 74 and who were able to receive gastric cancer screening in the Yurihonjo area. Participants were assigned to the GI X-ray group or the GIE-ST group by computer randomization. Subjects in each group were further subdivided into 4 categories according to their different risks for gastric cancer. The feasibility of stratified randomization was serologically assessed and detection rates of gastric cancer at entry by the different screening methods were also compared. RESULTS: Of the 2,962 subjects invited, 1,206 individuals (41 percent) were included in the first stage of this stratified RCT, and 604 and 602 individuals were assigned to the GI X-ray group and the GIE-ST group, respectively. There were no statistically significant differences in sex, age, height, body weight, smoking, alcohol intake and family history of cancer between the 2 groups. During ST the GI X-ray group showed a distribution that was not statistically different from that of the GIE-ST group. Although 3 cases of gastric cancer were detected in the GIE-ST group, there was no statistically significant difference between the 2 groups. One complication found was barium aspiration during the examination in the X-ray group. CONCLUSION: We confirmed that baseline demographic features of the 2 groups were well balanced. We are now organizing the first RCT to compare the existing screening method and the alternative method (Clinical trial registration number: UMIN000005962).

Successful treatment of hepatocellular carcinoma with lung metastasis using hepatic and bronchial artery infusion chemotherapy.

We herein report a case of hepatocellular carcinoma (HCC) with lung metastasis that was successfully treated with transcatheter arterial infusion chemotherapy via the hepatic and bronchial arteries. A 64-year-old man diagnosed with HCC in 2003 was treated with locoregional therapy followed by sorafenib for recurrent HCC. Tumor thrombosis and lung metastasis were noted in April 2012. We administered IA-call(®), a fine-powder formulation of cisplatin, via the hepatic and bronchial arteries. This therapy resulted in the disappearance of the lung metastases and a partial response to tumor thrombosis. The patient remained alive for 23 months after developing lung metastasis.

Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease.

Emerging data have shown a close association between compositional changes in gut microbiota and the development of nonalcoholic fatty liver disease (NAFLD). The change in gut microbiota may alter nutritional absorption and storage. In addition, gut microbiota are a source of Toll-like receptor (TLR) ligands, and their compositional change can also increase the amount of TLR ligands delivered to the liver. TLR ligands can stimulate liver cells to produce proinflammatory cytokines. Therefore, the gut-liver axis has attracted much interest, particularly regarding the pathogenesis of NAFLD. The abundance of the major gut microbiota, including Firmicutes and Bacteroidetes, has been considered a potential underlying mechanism of obesity and NAFLD, but the role of these microbiota in NAFLD remains unknown. Several reports have demonstrated that certain gut microbiota are associated with the development of obesity and NAFLD. For instance, a decrease in Akkermansia muciniphila causes a thinner intestinal mucus layer and promotes gut permeability, which allows the leakage of bacterial components. Interventions to increase Akkermansia muciniphila improve the metabolic parameters in obesity and NAFLD. In children, the levels of Escherichia were significantly increased in nonalcoholic steatohepatitis (NASH) compared with those in obese control. Escherichia can produce ethanol, which promotes gut permeability. Thus, normalization of gut microbiota using probiotics or prebiotics is a promising treatment option for NAFLD. In addition, TLR signaling in the liver is activated, and its downstream molecules, such as proinflammatory cytokines, are increased in NAFLD. To data, TLR2, TLR4, TLR5, and TLR9 have been shown to be associated with the pathogenesis of NAFLD. Therefore, gut microbiota and TLRs are targets for NAFLD treatment.

The roles of interferon regulatory factors 1 and 2 in the progression of human pancreatic cancer.

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