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Gastroenterology
Journal Prestige (SJR): 7.958
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ISSN (Print) 0016-5085
Published by Elsevier Homepage  [3183 journals]
  • Liver Fibrosis and Metabolic Alterations in Adults With
           alpha-1-antitrypsin Deficiency Caused by the Pi*ZZ Mutation
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Karim Hamesch, Mattias Mandorfer, Vítor M. Pereira, Linda S. Moeller, Monica Pons, Grace E. Dolman, Matthias C. Reichert, Carolin V. Schneider, Vivien Woditsch, Jessica Voss, Cecilia Lindhauer, Malin Fromme, Igor Spivak, Nurdan Guldiken, Biaohuan Zhou, Anita Arslanow, Benedikt Schaefer, Heinz Zoller, Elmar Aigner, Thomas ReibergerBackground & AimsAlpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD.MethodsWe collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant.ResultsSerum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%–36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion.ConclusionsIn studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.Graphical abstractGraphical abstract for this article
       
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    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Amit G. Singal
       
  • Historical Data Are Not Relevant to the Diagnostic Performance of
           Ultrasound in Surveillance for Hepatocellular Carcinoma
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Korosh Khalili
       
  • Future Possibility of Mizagliflozin on Functional Constipation and/or
           Irritable Bowel Syndrome With Constipation
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Shin Fukudo, Kohei Kaku
       
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    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Mahdi Sheikh, Paul Brennan, Reza Malekzadeh
       
  • Tobacco Smoking and Alcohol Drinking: Two Clinically Significant Risk
           Factors for Esophageal Squamous Cell Carcinoma
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Farid Najafi
       
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    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Yingchang Lu, Wei Zheng
       
  • Population Difference and Disease Status Affect the Association Between
           Genetic Variants and Gene Expression
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Guiyou Liu, Yang Hu, Qinghua Jiang
       
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    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): M. Scott Harris, Colin W. Howden
       
  • Improving Clinical Trial Efficiency in Gastroenterology
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Christopher Ma, Leonardo Guizzetti, Vipul Jairath
       
  • Accurate and Dynamic Monitoring of Pancreatic Endocrine Function Is
           Required in Discharged Patients With Necrotizing Pancreatitis
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Lin Gao, Lu Ke, Wei-qin Li
       
  • Colonoscopy Surveillance Intervals for Small Nonadvanced Adenomas: Does
           Size Matter'
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): John W. Birk, Joseph C. Anderson
       
  • Prevention of Biliary Cancer With Statins: Still a Long Way to Go
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Massimo Colombo, Federica Turati, Carlo La Vecchia
       
  • Noninvasive Detection of High-Risk Adenomas Using Stool-Derived Eukaryotic
           RNA Sequences as Biomarkers
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Erica K. Barnell, Yiming Kang, Elizabeth M. Wurtzler, Malachi Griffith, Aadel A. Chaudhuri, Obi L. Griffith, Andrew R. Barnell, Katie M. Campbell, Kimberly R. Kruse, Dave Messina, Ira Kodner, Mark Manary, Phil Needleman
       
  • Gluten Does Not Induce Gastrointestinal Symptoms in Healthy Volunteers: A
           Double-Blind Randomized Placebo Trial
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Iain David Croall, Imran Aziz, Nick Trott, Paola Tosi, Nigel Hoggard, David S. Sanders
       
  • AGA Clinical Practice Guidelines on the Laboratory Evaluation of
           Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in
           Adults (IBS-D): Patient Summary
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): American Gastroenterological Association
       
  • Irritable Bowel Syndrome in Adults (IBS-D): Clinical Decision Support Tool
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): American Gastroenterological Association
       
  • AGA Clinical Practice Guidelines on the Laboratory Evaluation of
           Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in
           Adults (IBS-D)
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Walter Smalley, Corinna Falck-Ytter, Alonso Carrasco-Labra, Sachin Wani, Lyubov Lytvyn, Yngve Falck-Ytter
       
  • Axon Guidance Molecules Promote Perineural Invasion and Metastasis of
           Orthotopic Pancreatic Tumors in Mice
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Noelle R. Jurcak, Agnieszka A. Rucki, Stephen Muth, Elizabeth Thompson, Rajni Sharma, Ding Ding, Qingfeng Zhu, James R. Eshleman, Robert A. Anders, Elizabeth M. Jaffee, Kenji Fujiwara, Lei ZhengBackground & AimsLittle is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice.MethodsWe performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves.ResultsDRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI.ConclusionsDRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.
       
  • Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic
           Cancer Cells With Activated KRAS in Response to Hypoxia
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Paul C. McDonald, Shawn C. Chafe, Wells S. Brown, Saeed Saberi, Mridula Swayampakula, Geetha Venkateswaran, Oksana Nemirovsky, Jordan A. Gillespie, Joanna M. Karasinska, Steve E. Kalloger, Claudiu T. Supuran, David F. Schaeffer, Ali Bashashati, Sohrab P. Shah, James T. Topham, Donald T. Yapp, Jinyang Li, Daniel J. Renouf, Ben Z. Stanger, Shoukat DedharBackground & AimsMost pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer.MethodsWe knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database.ResultsUnder hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors.ConclusionsIn response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer.Graphical abstractGraphical abstract for this article
       
  • Hepatocellular Carcinomas With Mutational Activation of Beta-Catenin
           Require Choline and Can Be Detected by Positron Emission Tomography
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Angélique Gougelet, Chiara Sartor, Nadia Senni, Julien Calderaro, Laetitia Fartoux, Marie Lequoy, Dominique Wendum, Jean-Noël Talbot, Aurélie Prignon, Julia Chalaye, Sandrine Imbeaud, Jessica Zucman-Rossi, Thierry Tordjmann, Cécile Godard, Pascale Bossard, Olivier Rosmorduc, Giuliana Amaddeo, Sabine ColnotBackground & AimsIn one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate β-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically.MethodsWe studied mice with activation of β-catenin in liver (Apcko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with 18F-fluorodeoxyglucose, followed by 18F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet.ResultsLivers and tumors from Apcko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated β-catenin were positive in 18F-fluorocholine PET, but not 18F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apcko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apcko-liv mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors.ConclusionsIn mice and humans, HCCs with mutations that activate β-catenin are characterized by increased uptake of a fluorocholine tracer, but not 18F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress β-catenin.
       
  • Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic
           Stellate Cells and Liver Fibrogenesis in Mice
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Jiong Yan, Hung-Chun Tung, Sihan Li, Yongdong Niu, Wojciech G. Garbacz, Peipei Lu, Yuhan Bi, Yanping Li, Jinhan He, Meishu Xu, Songrong Ren, Satdarshan P. Monga, Robert F. Schwabe, Da Yang, Wen XieBackground & AimsThe role of aryl hydrocarbon receptor (AhR) in liver fibrosis is controversial because loss and gain of AhR activity both lead to liver fibrosis. The goal of this study was to investigate how the expression of AhR by different liver cell types, hepatic stellate cells (HSCs) in particular, affects liver fibrosis in mice.MethodsWe studied the effects of AhR on primary mouse and human HSCs, measuring their activation and stimulation of fibrogenesis using RNA-sequencing analysis. C57BL/6J mice were given the AhR agonists 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); were given carbon tetrachloride (CCl4); or underwent bile duct ligation. We also performed studies in mice with disruption of Ahr specifically in HSCs, hepatocytes, or Kupffer cells. Liver tissues were collected from mice and analyzed by histology, immunohistochemistry, and immunoblotting.ResultsAhR was expressed at high levels in quiescent HSCs, but the expression decreased with HSC activation. Activation of HSCs from AhR-knockout mice was accelerated compared with HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor β–induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis after administration of CCl4 or bile duct ligation. C57BL/6J mice given ITE did not develop CCl4-induced liver fibrosis, whereas mice without HSC AhR given ITE did develop CCl4-induced liver fibrosis. In studies of mouse and human HSCs, we found that AhR prevents transforming growth factor β–induced fibrogenesis by disrupting the interaction of Smad3 with β-catenin, which prevents the expression of genes that mediate fibrogenesis.ConclusionsIn studies of human and mouse HSCs, we found that AhR prevents HSC activation and expression of genes required for liver fibrogenesis. Development of nontoxic AhR agonists or strategies to activate AhR signaling in HSCs might be developed to prevent or treat liver fibrosis.Graphical abstractGraphical abstract for this article
       
  • Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver
           Fibrosis, Inflammation, and Steatosis in Mouse Models of Nonalcoholic
           Steatohepatitis
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Anissa A. Widjaja, Brijesh K. Singh, Eleonora Adami, Sivakumar Viswanathan, Jinrui Dong, Giuseppe A. D’Agostino, Benjamin Ng, Wei Wen Lim, Jessie Tan, Bhairav S. Paleja, Madhulika Tripathi, Sze Yun Lim, Shamini Guna Shekeran, Sonia P. Chothani, Anne Rabes, Martina Sombetzki, Eveline Bruinstroop, Lio Pei Min, Rohit A. Sinha, Salvatore AlbaniBackground & AimsWe studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis (NASH) using hepatic stellate cells (HSCs), hepatocytes, and mouse models of NASH.MethodsWe stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and enzyme-linked immunosorbent assays. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha1 gene (Il11ra1–/–) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with methionine- and choline-deficient diet for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA sequencing, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays.ResultsHSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis, hepatocyte cell death and inflammation. Following the HFMCD or WDF, livers from Il11ra1–/– mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA antibodies to wild-type mice on the HFMCD or WDF, or to db/db mice on the methionine and choline-deficient diet, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1–/– mice fed WDF, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1.ConclusionsNeutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies also improve the cardiometabolic profile of mice and might be developed for the treatment of NASH.Graphical abstractGraphical abstract for this article
       
  • Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy
           Against Hepatocellular Carcinoma and Markers of Response
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Stefano Caruso, Anna-Line Calatayud, Jill Pilet, Tiziana La Bella, Samia Rekik, Sandrine Imbeaud, Eric Letouzé, Léa Meunier, Quentin Bayard, Nataliya Rohr-Udilova, Camille Péneau, Bettina Grasl-Kraupp, Leanne de Koning, Bérengère Ouine, Paulette Bioulac-Sage, Gabrielle Couchy, Julien Calderaro, Jean-Charles Nault, Jessica Zucman-Rossi, Sandra RebouissouBackground and aimsHepatocellular carcinomas (HCCs) are heterogeneous aggressive tumors with low rates of response to treatment at advanced stages. We screened a large panel of liver cancer cell lines (LCCLs) to identify agents that might be effective against HCC and markers of therapeutic response.MethodsWe performed whole-exome RNA and microRNA sequencing and quantification of 126 proteins in 34 LCCLs. We screened 31 anticancer agents for their ability to decrease cell viability. We compared genetic, RNA, and protein profiles of LCCLs with those of primary HCC samples and searched for markers of response.ResultsThe protein, RNA and mutational signatures of the LCCLs were similar to those of the proliferation class of HCC, which is the most aggressive tumor type. Cell lines with alterations in genes encoding members of the Ras-MAPK signaling pathway and that required fibroblast growth factor (FGF)19 signaling via FGF receptor 4 for survival were more sensitive to trametinib than to FGF receptor 4 inhibitors. Amplification of FGF19 resulted in increased activity of FGF19 only in tumor cells that kept a gene expression pattern of hepatocyte differentiation. We identified single agents and combinations of agents that reduced viability of cells with features of the progenitor subclass of HCC. LCCLs with inactivating mutations in TSC1 and TSC2 were sensitive to the mammalian target of rapamycin inhibitor rapamycin, and cells with inactivating mutations in TP53 were sensitive to the Aurora kinase A inhibitor alisertib. Amplification of MET was associated with hypersensitivity to cabozantinib and the combination of sorafenib and inhibitors of MAP kinase 1 and MAP kinase2 had a synergistic antiproliferative effect.ConclusionLCCLs can be screened for drugs and agents that might be effective for treatment of HCC. We identified genetic alterations and gene expression patterns associated with response to these agents. This information might be used to select patients for clinical trials.Graphical abstractGraphical abstract for this article
       
  • Intestinal PPARĪ± Protects Against Colon Carcinogenesis via Regulation of
           Methyltransferases DNMT1 and PRMT6
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Yuhong Luo, Cen Xie, Chad N. Brocker, Jie Fan, Xuan Wu, Lijin Feng, Qiong Wang, Jie Zhao, Dasheng Lu, Mayank Tandon, Maggie Cam, Kristopher W. Krausz, Weiwei Liu, Frank J. GonzalezBackground & AimsMany genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis.MethodsColon cancer was induced in mice with intestine-specific disruption of Ppara (PparaΔIE), Pparafl/fl (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry.ResultsLevels of Ppara messenger RNA were reduced in colon tumors from mice. PparaΔIE mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from PparaΔIE mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from PparaΔIE mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues.ConclusionsLoss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.Graphical abstractGraphical abstract for this article
       
  • RNA-Binding Protein HuR Regulates Paneth Cell Function by Altering
           Membrane Localization of TLR2 via Post-transcriptional Control of CNPY3
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Lan Xiao, Xiao-Xue Li, Hee Kyoung Chung, Sudhakar Kalakonda, Jia-Zhong Cai, Shan Cao, Ning Chen, Yulan Liu, Jaladanki N. Rao, Hong-Ying Wang, Myriam Gorospe, Jian-Ying WangBackground & AimsPaneth cells secrete antimicrobial proteins including lysozyme via secretory autophagy as part of the mucosal protective response. The ELAV like RNA-binding protein 1 (ELAVL1, also called HuR) regulates stability and translation of messenger RNAs (mRNAs) and many aspects of mucosal physiology. We studied the posttranscriptional mechanisms by which HuR regulates Paneth cell function.MethodsIntestinal mucosal tissues were collected from mice with intestinal epithelium (IE)-specific disruption of HuR (IE-HuR–/–), HuRfl/fl-Cre– mice (controls), and patients with inflammatory bowel diseases and analyzed by histology and immunohistochemistry. Paneth cell functions were determined by lysozyme-immunostaining assays. We isolated primary enterocytes from IE-HuR–/– and control mice and derived intestinal organoids. HuR and the chaperone CNPY3 were overexpressed from transgenes in intestinal epithelial cells (IECs) or knocked down with small interfering RNAs. We performed RNA pulldown assays to investigate interactions between HuR and its target mRNAs.ResultsIntestinal tissues from IE-HuR–/– mice had reduced numbers of Paneth cells, and Paneth cells had fewer lysozyme granules per cell, compared with tissues from control mice, but there were no effects on Goblet cells or enterocytes. Intestinal mucosa from patients with inflammatory bowel diseases had reduced levels of HuR and fewer Paneth cells. IE-HuR–/– mice did not have the apical distribution of TLR2 in the intestinal mucosa as observed in control mice. IECs from IE-HuR–/– mice expressed lower levels of CNPY3. Intestinal organoids from IE-HuR–/– mice were smaller and contained fewer buds compared with those generated from controls, and had fewer lysozyme-positive cells. In IECs, knockdown of HuR decreased levels of the autophagy proteins LC3-I and LC3-II, compared with control cells, and prevented rapamycin-induced autophagy. We found HuR to interact directly with the Cnpy3 mRNA coding region and increase levels of CNPY3 by increasing the stability and translation of Cnpy3 mRNA. CNPY3 bound TLR2, and cells with knockdown of CNPY3 or HuR lost membrane localization of TLR2, but increased cytoplasmic levels of TLR2.ConclusionsIn studies of mice, IECs, and human tissues, we found HuR to increase expression of CNPY3 at the posttranscriptional level. CNPY3 is required for membrane localization of TLR2 and Paneth cell function.Graphical abstractGraphical abstract for this article
       
  • The Transplantation of Fecal Microbiota for Cirrhotic Patients
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Gin-Ho Lo
       
  • Amino Acid Substitutions in Genotype 3a Hepatitis C Virus Polymerase
           Protein Affect Responses to Sofosbuvir
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Peter A.C. Wing, Meleri Jones, Michelle Cheung, Sampath DaSilva, Connor Bamford, Wing-Yiu Jason Lee, Elihu Aranday-Cortes, Ana Da Silva Filipe, John McLauchlan, David Smith, William Irving, Morven Cunningham, Azim Ansari, Eleanor Barnes, Graham R. FosterBackground & AimsSofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England’s National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure.MethodsWe collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon.ResultsWe identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system.ConclusionsA common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.
       
  • Safety of Proton Pump Inhibitors Based on a Large, Multi-Year, Randomized
           Trial of Patients Receiving Rivaroxaban or Aspirin
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Paul Moayyedi, John W. Eikelboom, Jackie Bosch, Stuart J. Connolly, Leanne Dyal, Olga Shestakovska, Darryl Leong, Sonia S. Anand, Stefan Störk, Kelley R.H. Branch, Deepak L. Bhatt, Peter B. Verhamme, Martin O’Donnell, Aldo P. Maggioni, Eva M. Lonn, Leopoldo S. Piegas, Georg Ertl, Matyas Keltai, Nancy Cook Bruns, Eva MuehlhoferBackground & AimsProton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.MethodsWe performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.ResultsThere was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01–1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.ConclusionsIn a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.
       
  • Right-Sided Location Not Associated With Missed Colorectal Adenomas in an
           Individual-Level Reanalysis of Tandem Colonoscopy Studies
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Katharina Zimmermann-Fraedrich, Susanne Sehner, Douglas K. Rex, Tonya Kaltenbach, Roy Soetikno, Michael Wallace, Wai K. Leung, Chuanguo Guo, Ian M. Gralnek, Eelco C. Brand, Stefan Groth, Guido Schachschal, Hiroaki Ikematsu, Peter D. Siersema, Thomas RöschBackground & AimsInterval cancers occur more frequently in the right colon. One reason could be that right-sided adenomas are frequently missed in colonoscopy examinations. We reanalyzed data from tandem colonoscopies to assess adenoma miss rates in relation to location and other factors.MethodsWe pooled data from 8 randomized tandem trials comprising 2218 patients who had diagnostic or screening colonoscopies (adenomas detected in 49.8% of patients). We performed a mixed-effects logistic regression with patients as cluster effects with different independent parameters. Factors analyzed included location (left vs right, splenic flexure as cutoff), adenoma size, form, and histologic features. Analyses were controlled for potential confounding factors such as patient sex and age, colonoscopy indication, and bowel cleanliness.ResultsRight-side location was not an independent risk factor for missed adenomas (odds ratio [OR] compared with the left side, 0.94; 95% CI, 0.75–1.17). However, compared with adenomas ≤5 mm, the OR for missing adenomas of 6–9 mm was 0.62 (95% CI, 0.44–0.87), and the OR for missing adenomas of ≥10 mm was 0.51 (95% CI, 0.33–0.77). Compared with pedunculated adenomas, sessile (OR, 1.82; 95% CI, 1.16–2.85) and flat adenomas (OR, 2.47; 95% CI, 1.49–4.10) were more likely to be missed. Histologic features were not significant risk factors for missed adenomas (OR for adenomas with high-grade intraepithelial neoplasia, 0.68; 95% CI, 0.34–1.37 and OR for sessile serrated adenomas, 0.87; 95% CI, 0.47–1.64 compared with low-grade adenomas). Men had a higher number of adenomas per colonoscopy (1.27; 95% CI, 1.21–1.33) than women (0.86; 95% CI, 0.80–0.93). Men were less likely to have missed adenomas than women (OR for missed adenomas in men, 0.73; 95% CI, 0.57–0.94).ConclusionsIn an analysis of data from 8 randomized trials, we found that right-side location of an adenoma does not increase its odds for being missed during colonoscopy but that adenoma size and histologic features do increase risk. Further studies are needed to determine why adenomas are more frequently missed during colonoscopies in women than men.Graphical abstractGraphical abstract for this article
       
  • Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella
           Review of Meta-analyses
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Daniele Piovani, Silvio Danese, Laurent Peyrin-Biroulet, Georgios K. Nikolopoulos, Theodore Lytras, Stefanos BonovasBackground & AimsMultiple environmental factors have been associated with the development of inflammatory bowel diseases (IBDs). We performed an umbrella review of meta-analyses to summarize available epidemiologic evidence and assess its credibility.MethodsWe systematically identified and appraised meta-analyses of observational studies examining environmental factors and risk of IBD (Crohn’s disease [CD] or ulcerative colitis [UC]). For each meta-analysis, we considered the random effects estimate, its 95% confidence interval, the estimates of heterogeneity, and small-study effects, and we graded the evidence according to prespecified criteria. Methodologic quality was assessed with AMSTAR (ie, A Measurement Tool to Assess Systematic Reviews) 2.ResultsWe examined 183 estimates in 53 meta-analyses of 71 environmental factors related to lifestyles and hygiene, surgeries, drug exposures, diet, microorganisms, and vaccinations. We identified 9 factors that increase risk of IBD: smoking (CD), urban living (CD and IBD), appendectomy (CD), tonsillectomy (CD), antibiotic exposure (IBD), oral contraceptive use (IBD), consumption of soft drinks (UC), vitamin D deficiency (IBD), and non–Helicobacter pylori–like enterohepatic Helicobacter species (IBD). We identified 7 factors that reduce risk of IBD: physical activity (CD), breastfeeding (IBD), bed sharing (CD), tea consumption (UC), high levels of folate (IBD), high levels of vitamin D (CD), and H pylori infection (CD, UC, and IBD). Epidemiologic evidence for all of these associations was of high to moderate strength; we identified another 11 factors associated with increased risk and 16 factors associated with reduced risk with weak credibility. Methodologic quality varied considerably among meta-analyses. Several associations were based on findings from retrospective studies, so it is not possible to determine if these are effects of IBD or the results of recall bias.ConclusionsIn an umbrella review of meta-analyses, we found varying levels of evidence for associations of different environmental factors with risk of IBD. High-quality prospective studies with analyses of samples from patients with recent diagnoses of IBD are needed to determine whether these factors cause or are results of IBD and their pathogenic mechanisms.
       
  • Fecal Microbial Transplantation for Diseases Beyond Recurrent Clostridium
           Difficile Infection
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Geert R. D’Haens, Christian JobinAs microbiome research has moved from associative to mechanistic studies, the activities of specific microbes and their products have been investigated in the development of inflammatory bowel diseases, cancer, metabolic syndrome, and neuropsychiatric disorders. Findings from microbiome research have already been applied to the clinic, such as in fecal microbiota transplantation for treatment of recurrent Clostridium difficile infection. We review the evidence for associations between alterations in the intestinal microbiome and gastrointestinal diseases and findings from clinical trials of fecal microbiota transplantation. We discuss opportunities for treatment of other diseases with fecal microbiota transplantation, based on findings from small clinical and preclinical studies.
       
  • What Is the Peri-Pancreas Cystic Lesion'
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Yong Gao, Baobao Cai, Yi Miao
       
  • An Unusual Cause of Acute Pancreatitis in a Young Woman
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Tzu-Wei Yang, Cheng-Ming Peng, Ming-Chang Tsai
       
  • A Rare Cause of Multiple Hepatic Masses
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Sung Bum Kim, Jae Woon Kim, Joon Hyuk Choi
       
  • An Incidentally Identified Liver Mass
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Xu-Feng Zhang, Xue-Min Liu, Yi Lv
       
  • Unusual Case of Abdominal Fullness in a Middle-Aged Woman
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Yasuhiko Hamada, Kyosuke Tanaka, Misaki Nakamura
       
  • Young Patient with Cystic Fibrosis With Right Lower Quadrant Abdominal
           Pain
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Carolina González-Olivares, Miguel García, Beatriz Peñas
       
  • Circumferential Ulcerations in the Ascending Colon
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Michiel Bronswijk, Paul Christiaens, August Van Olmen
       
  • A Case of Episodic Abdominal Pain and Fevers
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Adam C. Bledsoe, Glenn L. Alexander
       
  • A Rare Complication of a Rare Disease
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Luke J. Nayak, Arjun R. Sondhi, Maria Westerhoff
       
  • An Unusual Cause of Colonic Ulceration
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Heleen S. De Lil, Marten A. Lantinga, Ham A.M. Sinnige
       
  • An Unusual Cause of Esophageal Varices
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Rohit Agrawal, Muhammad Majeed, Seema Gandhi
       
  • Gastroparesis Mimicry: Thinking Beyond the Pylorus
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Benjamin Nunley, Hampton Collins, Frederick Weber
       
  • Will Science Sway Beliefs About Gluten'
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Emma P. Halmos, Peter R. Gibson
       
  • Safety and Complications of Long-Term Proton Pump Inhibitor Therapy:
           Getting Closer to the Truth
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Douglas A. Corley
       
  • Are Phosphodiesterase-5 Inhibitors a New Frontier for Prevention of
           Colorectal Cancer'
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Manol Jovani, Andrew T. Chan
       
  • How to Foster Academic Promotion and Career Advancement of Women in
           Gastroenterology
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Ellen M. Zimmermann
       
  • Opportunities for Innovation and Improved Care Using Telehealth for
           Nutritional Interventions
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Holly Knotowicz, Angela Haas, Stephanie Coe, Glenn T. Furuta, Pooja Mehta
       
  • Toward More Accurate Nomenclature for Fatty Liver Diseases
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Mohammed Eslam, Arun J. Sanyal, Jacob George
       
  • Covering the Cover
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Andrew T. Chan, Christopher S. Williams
       
  • Information for Authors and Readers
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s):
       
  • Elsewhere in The AGA Journals
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s):
       
  • Cover 1
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s):
       
  • Reply
    • Abstract: Publication date: September 2019Source: Gastroenterology, Volume 157, Issue 3Author(s): Jasmohan S. Bajaj, Patrick M. Gillevet
       
  • Antigen-specific Mucosal Immunity Regulates Development of Intestinal
           Bacteria-mediated Diseases
    • Abstract: Publication date: Available online 21 August 2019Source: GastroenterologyAuthor(s): Kosuke Fujimoto, Yunosuke Kawaguchi, Masaki Shimohigoshi, Yoshiyuki Gotoh, Yoshiko Nakano, Yuki Usui, Tetsuya Hayashi, Yasumasa Kimura, Miho Uematsu, Takuya Yamamoto, Yukihiro Akeda, Joon Haeng Rhee, Yoshikazu Yuki, Ken J. Ishii, Sheila E. Crowe, Peter B. Ernst, Hiroshi Kiyono, Satoshi UematsuAbstractBackground & AimsDysregulation of the microbiome has been associated with development of complex diseases such as obesity and diabetes. However, no method has been developed to control disease-associated commensal microbes. We investigated whether immunization with microbial antigens, using CpG oligodeoxynucleotides (CpG-ODN) and/or curdlan as adjuvants, induces systemic antigen-specific immunoglobulin (Ig)A and IgG production and affects development of diseases in mice.MethodsC57BL/6 mice were given intramuscular injections of antigens (ovalbumin, cholera toxin (CT) B-subunit, or PspA) combined with CpG-ODN and/or curdlan. Blood and fecal samples were collected weekly and antigen-specific IgG and IgA titers were measured. Lymph nodes and spleens were collected and analyzed by ELISA for antigen-specific splenic T-helper (Th)1 cells, Th17 cells, and memory B cells. Six weeks after primary immunization, mice were given a oral, nasal, or vaginal boost of ovalbumin; intestinal lamina propria, bronchial lavage, and vaginal swab samples were collected and antibodies and cytokines were measured. Some mice were also given oral CT or intranasal Streptococcus pneumoniae and the severity of diarrhea or pneumonia was analyzed. Gnotobiotic mice were gavaged with fecal material from obese individuals, which had a high abundance of Clostridium ramosum (a commensal microbe associated with obesity and diabetes), and were placed on a high-fat diet 2 weeks after immunization with C. ramosum. Intestinal tissues were collected and analyzed by quantitative real-time PCR.ResultsSerum and fecal samples from mice given injections of antigens in combination with CpG-ODN and curdlan for 3 weeks contained antigen-specific IgA and IgG, and splenocytes produced IFNG and IL17A. Lamina propria, bronchial, and vaginal samples contained antigen-specific IgA following the ovalbumin boost. This immunization regimen prevented development of diarrhea following injection of CT, and inhibited lung colonization by S. pneumoniae. In gnotobiotic mice colonized with C. ramosum and placed on a high-fat diet, the mice that had been immunized with C. ramosum became less obese than the non-immunized mice.ConclusionsInjection of mice with microbial antigens and adjuvant induces antigen-specific mucosal and systemic immune responses. Immunization with S pneumoniae antigen prevented lung infection by this bacteria, and immunization with C ramosum reduced obesity in mice colonized with this microbe and placed on a high-fat diet. This immunization approach might be used to protect against microbe-associated disorders of intestine.
       
  • Competition for Clinical Trials in Inflammatory Bowel Diseases
    • Abstract: Publication date: Available online 21 August 2019Source: GastroenterologyAuthor(s): M. Scott Harris, Jolanta Wichary, Matt Zadnik, Walter Reinisch
       
  • Neonatal life events and the risk of inflammatory bowel disease
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): João Sabino, Joana Torres, Jean-Fréderic Colombel, Inga Peter
       
  • Activation of Hedgehog Signaling Promotes Development of Mouse and Human
           Enteric Neural Crest Cells, Based on single-cell Transcriptome Analyses
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Sin-Ting Lau, Zhixin Li, Frank Pui-Ling Lai, Kathy Nga-Chu Lui, Peng Li, Jorge O. Munera, Guangjin Pan, Maxime M. Mahe, Chi-Chung Hui, James M. Wells, Elly Sau-Wai NganAbstractBackground & AimsIt has been a challenge to develop fully functioning cells from human pluripotent stem cells (hPSCs). We investigated how activation of hedgehog signaling regulates derivation of enteric neural crest (NC) cells from hPSCs.MethodsWe analyzed transcriptomes of mouse and hPSC-derived enteric NCs using single-cell RNA sequencing (scRNA-seq) to identify changes in expression associated with lineage differentiation. Intestine tissues were collected from Tg(GBS-GFP), Sufuf/f; Wnt1-cre, Ptch1+/- and Gli3Δ699/Δ699 mice and analyzed by flow cytometry and immunofluorescence for levels of mRNAs encoding factors in the hedgehog signaling pathway during differentiation of enteric NCs. Human NC cells (HNK-1+ p75NTR+) were derived from IMR90 and UE02302 hPSC lines. hPSC were incubated with hedgehog agonists (SAG) and antagonists (cyclopamine) and analyzed for differentiation. hPSC-based innervated colonic organoids were derived from these hPSC lines and analyzed by immunofluorescence and neuromuscular coupling assay for expression of neuronal subtype markers and for assessing the functional maturity of the hPSC-derived neurons, respectively.ResultsscRNA-seq analysis revealed that neural fate acquisition by human and mouse enteric NCs requires reduced expression of NC- and cell cycle- specific genes and upregulation of neuronal- or glial-lineage specific genes. Activation of the hedgehog pathway was associated with progression of mouse enteric NCs to the more mature state along the neuronal and glial lineage differentiation trajectories. Activation of the hedgehog pathway promoted development of cultured hPSC into NCs of greater neurogenic potential by activating expression of genes in the neurogenic lineage. The hedgehog agonist increased differentiation of hPSCs into cells of the neuronal lineage by upregulating expression of GLI2 target genes, including INSM1, NHLH1, and various bHLH family members. The hedgehog agonist increased expression of late neuronal markers and neuronal activities in hPSC-derived neurons.ConclusionsIn enteric NCs from humans and mice, activation of hedgehog signaling promotes differentiation into neurons by promoting cell-state transition, expression of genes in the neurogenic lineage, and functional maturity of enteric neurons.
       
  • Reply to “Incidence and Etiology of Drug-Induced Liver Injury in
           Mainland China”
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Weihong Cong, Qiqi Xin, Yueqiu Gao
       
  • RE: Incidence and Etiology of Drug-Induced Liver Injury in Mainland China
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Harshad Devarbhavi, Einar s Bjornsson
       
  • Can retrospective studies confirm the causation of drug induced liver
           injury'
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Ming Yang, Zhiguo Li, Dou Dou
       
  • Friend or Foe in IBD Pathogenesis: Not All Infections are Equal
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Shailja C. Shah
       
  • Events Early in Life, But Not The Neonatal Period, Affect Risk For Later
           Development of Inflammatory Bowel Disease
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Richard L. Mones
       
  • Eradication of Helicobacter pylori in Children Restores the Structure of
           the Gastric Bacterial Community to That of Non-infected Children
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Carolina A. Serrano, Reinaldo Pierre, William J. Van Der Pol, Casey D. Morrow, Phillip D. Smith, Paul R. Harris
       
  • The Histone Demethylase KDM3A, Increased in Human Pancreatic Tumors,
           Regulates Expression of DCLK1 in and Promotes Tumorigenesis in Mice
    • Abstract: Publication date: Available online 20 August 2019Source: GastroenterologyAuthor(s): Prasad Dandawate, Chandrayee Ghosh, Kanagaraj Palaniyandi, Santanu Paul, Sonia Rawal, Rohan Pradhan, Afreen Asif Ali Sayed, Sonali Choudhury, David Standing, Dharmalingam Subramaniam, Subhash Padhye, Sumedha Gunewardena, Sufi M. Thomas, Moura O’ Neil, Ossama Tawfik, Danny R. Welch, Roy A. Jensen, Sally Maliski, Scott Weir, Tomoo IwakumaAbstractBackground & AimsThe histone lysine demethylase 3A (KDM3A) demethylates demethylates H3K9me1 and H3K9Me2 to increase gene transcription and is upregulated in tumors, including pancreatic tumors. We investigated its activities in pancreatic cancer cell lines and its regulation of the gene encoding doublecortin calmodulin-like kinase 1 (DCLK1), a marker of cancer stem cells.MethodsWe knocked down KDM3A in MiaPaCa-2 and S2-007 pancreatic cancer cell lines and overexpressed KDM3A in HPNE cells (a human pancreatic cell line); we evaluated cell migration, invasion, and spheroid formation under hypoxic and normoxic conditions. Nude mice were given orthotopic injections of S2-007 cells, with or without (control) knockdown of KDM3A, and HPNE cells, with or without (control) overexpression of KDM3A; tumor growth was assessed. We analyzed pancreatic tumor tissues from mice and pancreatic cancer cell lines by immunohistochemistry and immunoblotting. We performed RNA-seq analysis of MiaPaCa-2 and S2-007 cells with knockdown of KDM3A and evaluated localization of DCLK1 and KDM3A by immunofluorescence. We analyzed the cancer genome atlas for levels of KDM3A and DCLK1 mRNA in human pancreatic ductal adenocarcinoma (PDAC) tissues and association with patient survival time.ResultsLevels of KDM3A were increased in human pancreatic tumor tissues and cell lines, compared with adjacent non-tumor pancreatic tissues such as islet and acinar cells. Knockdown of KDM3A in S2-007 cells significantly reduced colony formation, invasion, migration, and spheroid formation, compared with control cells, and slowed growth of orthotopic tumors in mice. We identified KDM3A-binding sites in the DCLK1 promoter; S2-007 cells with knockdown of KDM3A had reduced levels of DCLK1. HPNE cells that overexpressed KDM3A formed foci and spheres in culture and formed tumors and metastases in mice, whereas control HPNE cells did not. Hypoxia induced sphere formation and increased levels of KDM3A in S2-007 cells and in HPNE cells that overexpressed DCLK1, but not control HPNE cells. Levels of KDM3A and DCLK1 mRNA were higher in human PDAC than non-tumor pancreatic tissues and correlated with shorter survival times of patients.ConclusionsWe found human PDAC samples and pancreatic cancer cell lines to overexpress KDM3A. KDM3A increases expression of DCLK1, and levels of both proteins are increased in human PDAC samples. Knockdown of KDM3A in in pancreatic cancer cell lines reduced their invasive and sphere-forming activities in culture and formation of orthotopic tumors in mice. Hypoxia increased expression of KDM3A in pancreatic cancer cells. Strategies to disrupt this pathway might be developed for treatment of pancreatic cancer.
       
  • Strain-photoacoustic imaging as a potential tool for characterizing
           intestinal fibrosis
    • Abstract: Publication date: Available online 13 August 2019Source: GastroenterologyAuthor(s): Yunhao Zhu, Laura A. Johnson, Jonathan M. Rubin, Henry Appelman, Linyu Ni, Jie Yuan, Xueding Wang, Peter D.R. Higgins, Guan Xu
       
  • Transgenic Expression of PRSS1R122H Sensitizes Mice to Pancreatitis
    • Abstract: Publication date: Available online 13 August 2019Source: GastroenterologyAuthor(s): Haojie Huang, Agnieszka Katarzyna Swidnicka-Siergiejko, Jaroslaw Daniluk, Sebastian Gaiser, Yao Yao, Lisi Peng, Yang Zhang, Yan Liu, Minyu Dong, Xianbao Zhan, Huamin Wang, Yan Bi, Zhaoshen Li, Baoan Ji, Craig D. LogsdonAbstractBackground & AimsMutations in the trypsinogen gene (PRSS1) cause human hereditary pancreatitis. However, it is not clear how mutant forms of PRSS1 contribute to disease development. We studied the effects of expressing mutant forms of human PRSS1 in mice.MethodsWe expressed forms of PRSS1 with and without the mutation encoding R122H (PRSS1R122H) specifically in pancreatic acinar cells under control of a full-length pancreatic elastase gene promoter. Mice that did not express these transgenes were used as controls. Mice were given injections of caerulein to induce acute pancreatitis or injections of lipopolysaccharide (LPS) to induce chronic pancreatitis. Other groups of mice were fed ethanol or placed on a high-fat diet to induce pancreatitis. Pancreata were collected and analyzed by histology, immunoblots, real-time PCR, and immunohistochemistry. Trypsin enzymatic activity and chymotrypsin enzymatic activity were measured in pancreatic homogenates. Blood was collected and serum amylase activity was measured.ResultsPancreata from mice expressing transgenes encoding PRSS1 or PRSS1R122H had focal areas of inflammation; these lesions were more prominent in mice that express PRSS1R122H. Pancreata from mice that express PRSS1 or PRSS1R122H had increased levels of HSP70 and NRF2 and reduced levels of chymotrypsin C (CTRC), compared with control mice. Increased expression of PRSS1 or PRSS1R122H increased focal damage in pancreatic tissues and increased the severity of acute pancreatitis after caerulein injection. Administration of LPS exacerbated inflammation in mice that express PRSS1R122H compared to mice that express PRSS1 or control mice. Mice that express PRSS1R122H developed more severe pancreatitis after ethanol feeding or a high-fat diet than mice that express PRSS1 or control mice. Pancreata from mice that express PRSS1R122H had more DNA damage, apoptosis, and collagen deposition and increased trypsin activity and infiltration by inflammatory cells than mice that express PRSS1 or control mice.ConclusionsExpression of a transgene encoding PRSS1R122H in mice promoted inflammation and increase the severity of pancreatitis, compared with mice that express PRSS1 or control mice. These mice might be used as a model for human hereditary pancreatitis and can be studied to determine mechanisms of induction of pancreatitis by LPS, ethanol, or a high-fat diet.
       
  • Reply to GASTRO-D-18-02688
    • Abstract: Publication date: Available online 10 August 2019Source: GastroenterologyAuthor(s): Konstantinos Gerasimidis, Vaios Svolos, Ben Nichols, Rodanthi Papadopoulou, Christopher Quince, Umer Z. Ijaz, Simon Milling, Daniel R. Gaya, Richard K. Russell, Richard Hansen
       
  • An Unusual Gastrointestinal Cause of Hypokalemia
    • Abstract: Publication date: Available online 9 August 2019Source: GastroenterologyAuthor(s): Puneet Chhabra, Vibhu V. Mittal, Rooma Ambastha
       
  • An Unfortunate Consequence of Duodenogastric Reflux
    • Abstract: Publication date: Available online 9 August 2019Source: GastroenterologyAuthor(s): Michiel Bronswijk, Claire Bourgain, Lieven Pouillon
       
  • Targeting Gut Microbiome Interactions in Service-related Gastrointestinal
           and Liver Diseases of Veterans: Meeting Summary
    • Abstract: Publication date: Available online 9 August 2019Source: GastroenterologyAuthor(s): Jasmohan S. Bajaj, Arun Sharma, Pradeep K. Dudeja
       
  • A Slow and Distended Stomach
    • Abstract: Publication date: Available online 9 August 2019Source: GastroenterologyAuthor(s): Amrit K. Kamboj, Adam C. Bledsoe, Amindra S. Arora
       
  • Acute Diarrheal Illness: A Practical Teaching Case
    • Abstract: Publication date: Available online 9 August 2019Source: GastroenterologyAuthor(s): Claire L. Jansson-Knodell, Andrea Shin, Nicholas Rogers
       
  • Efficacy of Glecaprevir and Pibrentasvir in Patients with Genotype 1
           Hepatitis C Virus Infection with Treatment Failure after NS5A Inhibitor
           Plus Sofosbuvir Therapy
    • Abstract: Publication date: Available online 8 August 2019Source: GastroenterologyAuthor(s): Anna S. Lok, Mark S. Sulkowski, Jens J. Kort, Ira Willner, K. Rajender Reddy, Mitchell L. Shiffman, Mohamed A. Hassan, Brian L. Pearlman, Federico Hinestrosa, Ira M. Jacobson, Giuseppe Morelli, Joy A. Peter, Monika Vainorius, Larry C. Michael, Michael W. Fried, Gary P. Wang, Wenjing Lu, Lois Larsen, David R. NelsonAbstractBackground/AimsTreatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor.MethodsWe performed a phase 3b, open label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n=78, group A) or 16 weeks (n=49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n=21, group C) or G/P for 16 weeks (n=29, group D). The primary endpoint was a sustained virologic response 12 weeks after treatment (SVR12). Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions (RASs) in NS3 and NS5A.ResultsOf the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with an SVR12 in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 patients with HCV genotype 1a infection (7.3%), 6 in group A (7.9%), 3 in group B (6.1%), 3 in group C (14.3%), and 1 in group D (3.4%). Most patients had baseline RASs in NS5A. Treatment-emergent RASs in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy.ConclusionsIn a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced an SVR12 in more than 90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov no: NCT03092375
       
  • Infliximab–Tumor Necrosis Factor Complexes Elicit Formation of
           Anti-drug Antibodies
    • Abstract: Publication date: Available online 8 August 2019Source: GastroenterologyAuthor(s): Haggai Bar-Yoseph, Sigal Pressman, Alexandra Blatt, Shiran Gerassy Vainberg, Naama Maimon, Elina Starosvetsky, Bella Ungar, Shomron Ben-Horin, Shai S. Shen-Orr, Yehuda ChowersAbstractBackground & AimsSome patients develop anti-drug antibodies (ADAs), which reduce the efficacy of infliximab, a monoclonal antibody against tumor necrosis factor (TNF), in treatment of immune-mediated diseases, including inflammatory bowel diseases. ADAs arise inconsistently, and it is not clear what factors determine their formation. We investigated features of the immune system, the infliximab antibody, and its complex with TNF that might contribute to ADA generation.MethodsC57BL/6 mice were given injections of infliximab and recombinant human TNF or infliximab F(ab’)2 fragments. Blood samples were collected every 2–3 days for 2 weeks, and weekly thereafter for up to 6 weeks; infliximab–TNF complexes and ADAs were measured by ELISA. Intestinal biopsies and blood samples were obtained from patients undergoing endoscopy who had received infliximab therapy for inflammatory bowel diseases; infliximab–TNF complexes were measured using an ELISA. Infliximab-specific plasma cells were detected in patient tissue samples using mass cytometry. We studied activation of innate immune cells in peripheral blood-mononuclear cells (PBMC, from healthy donors) incubated with infliximab or infliximab–TNF complexes; toll like receptors (TLR) were blocked with antibodies, endocytosis was blocked with the inhibitor PitStop2, and cytokine expression was measured by real-time PCR and ELISAs. Uptake of infliximab and infliximab–TNF complexes by THP-1 cells was measured with confocal microscopy.ResultsMice given increasing doses of infliximab dose produced increasing levels of antibodies against the drug (ADAs). Blood samples from mice given injections of human TNF and infliximab contained infliximab–TNF complexes; complex formation associated with ADA formation with an area under the curve of 0.944 (95% CI, 0.851–1.000; P=.003). Intestinal tissues from patients, but not blood samples, contained infliximab–TNF complexes and infliximab-specific plasma cells. Incubation of PBMC with infliximab–TNF complexes resulted in a 4.74-fold increase in level of interleukin 1beta (IL1B) mRNA (P for comparison=.005), increased IL1B protein secretion, and a 2.69-fold increase in expression of TNF mRNA (P for comparison 0.013) compared with control PBMC. Infliximab only reduced IL1B and TNF expression. Antibodies against TLR2 or TLR4 did not block the increases in IL1B or TNF expression, but endocytosis was required. THP-1 cells endocytosed higher levels of infliximab-TNF complexes than infliximab alone.ConclusionsIn mice, we found ADA formation to increase with dose of infliximab given and concentration of infliximab–TNF complexes detected in blood. Based on studies of human intestinal tissues and blood samples, we propose that infliximab–TNF complexes formed in the intestine are endocytosed by and activate innate immune cells, which increase expression of IL1B and TNF and production of antibodies against the drug complex. It is therefore important to optimize the infliximab dose to a level that is effective but does not activate an innate immune response against the drug–TNF complex.
       
  • Kurt J. Isselbacher, M.D., 1925-2019
    • Abstract: Publication date: Available online 8 August 2019Source: GastroenterologyAuthor(s): Lawrence S. Friedman, Daniel K. Podolsky
       
  • How to Advance Research, Education and Training in the Study of Rare
           Diseases
    • Abstract: Publication date: Available online 8 August 2019Source: GastroenterologyAuthor(s): Stephen C. Groft, Rashmi Gopal-Srivastava, Evan S. Dellon, Sandeep Gupta
       
  • Inflammation-induced Occludin Downregulation Limits Epithelial Apoptosis
           by Suppressing Caspase 3 Expression
    • Abstract: Publication date: Available online 8 August 2019Source: GastroenterologyAuthor(s): Wei-Ting Kuo, Le Shen, Li Zuo, Nitesh Shashikanth, Ma. Lora Drizella M. Ong, Licheng Wu, Juanmin Zha, Karen L. Edelblum, Yitang Wang, Yingmin Wang, Steven P. Nilsen, Jerrold R. TurnerAbstractBackground & AimsEpithelial tight junctions are compromised in patients with gastrointestinal disease. Occludin is a protein component of tight junctions; its removal from tight junctions or reduced expression results in barrier loss. Knockout (KO) of occludin in mice, however, does not appear to affect intestinal in tight junction structure or function. We investigated whether mucosal injury or repair are compromised in occludin-KO mice.MethodsWe performed studies with occludin-KO mice, mice with intestinal epithelial cell-specific KO of occludin, and B6 (control) mice, as well as mice that overexpress occludin from a transgene in the intestinal epithelium. Colitis was induced by administration of dextran sulfate sodium or 2,4,6-trinitrobenzene sulphonic acid. Intestinal tissues were collected from mice, patients with Crohn’s disease or ulcerative colitis, or subject without these diseases (controls) and analyzed by histology, immunohistochemistry, quantitative real-time PCR, and immunoblots. Occludin was knocked down in Caco-2BBe cells.ResultsMice with intestinal epithelial cell-specific KO of occludin developed less-severe colitis than control mice. This protection was due to reduced activation of intrinsic and extrinsic apoptotic pathways. Promoter analysis revealed that occludin increased transcription of the caspase 3 gene (CASP3). Mucosal biopsies from patients with Crohn’s disease or ulcerative colitis had lower levels of occludin than controls; reduced occludin correlated with lower levels of CASP3. Incubation of Caco-2BBe monolayers with tumor necrosis factor caused occludin downregulation, which reduced CASP3 expression and prevented induction of apoptosis via the intrinsic pathway (stimulated by 5-fluorouracil) or extrinsic pathway (stimulated by tumor necrosis factor).ConclusionsIn intestinal epithelial cells, the tight junction protein occludin increases expression of CASP3. Occludin loss reduces expression of CASP3 and susceptibility of these cells to apoptosis. Reduced levels of occludin and CASP3 in intestinal epithelial cells of patients with inflammatory bowel diseases might promote restoration of mucosal homeostasis in response to inflammatory conditions.
       
  • Single Dose Aspirin Prior To Fecal Immunochemical Testing Does Not
           Increase Sensitivity for Advanced Colorectal Neoplasia
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Brian Sullivan, Jatin Roper
       
  • Reply to: Factors Associated with Survival of Patients With Severe
           Acute-On-Chronic Liver Failure Before and After Liver Transplantation:
           unanswered questions LTE 19-00600 DC
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Vinay Sundaram, Rajiv Jalan
       
  • Reply to 19-00977
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Jana C. Mossanen, Frank Tacke
       
  • Combination of Diclofenac and Sublingual Nitrates in Preventing
           Pancreatitis After Endoscopic Retrograde Cholangiopancreatography: More
           evidences still needed
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Zhi-Feng Zhang
       
  • Intraductal papillary mucinous neoplasms (IPMNs): Attack of the clones
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Harrys K.C. Jacob, Sulagna Banerjee
       
  • The role of CXCR6 deficient Natural Killer T- and CD4 + T cells in
           hepatocarcinogenesis
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Huan Tao, Xuyong Chen
       
  • RE: Effects of Oral Anticoagulants and Aspirin on Performance of Fecal
           Immunochemical Tests in Colorectal Cancer Screening
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Ryota Niikura, Tomohiro Shinozaki, Kazuhiko Koike
       
  • Is it prime time for proactive therapeutic drug monitoring of anti-TNF
           therapy in IBD'
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Konstantinos Papamichael, Adam S. Cheifetz
       
  • Taking a Closer Look at the Biogeography of the Human Gastrointestinal
           Microbiome
    • Abstract: Publication date: Available online 7 August 2019Source: GastroenterologyAuthor(s): Melinda Engevik, James Versalovic
       
  • CME Exam 3: Right-Sided Location Not Associated With Missed Colorectal
           Adenomas in an Individual-Level Reanalysis of Tandem Colonoscopy Studies
    • Abstract: Publication date: Available online 1 August 2019Source: GastroenterologyAuthor(s):
       
  • Correction
    • Abstract: Publication date: Available online 1 August 2019Source: GastroenterologyAuthor(s):
       
  • CME Exam 2: Environmental Risk Factors for Inflammatory Bowel Diseases: An
           Umbrella Review of Meta-analyses
    • Abstract: Publication date: Available online 1 August 2019Source: GastroenterologyAuthor(s):
       
  • CME Exam 1: An Unusual Cause of Acute Pancreatitis in a Young Woman
    • Abstract: Publication date: Available online 1 August 2019Source: GastroenterologyAuthor(s):
       
  • AGA Guideline on the Laboratory Evaluation of Functional Diarrhea and
           Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D)
    • Abstract: Publication date: Available online 1 August 2019Source: GastroenterologyAuthor(s): Walter Smalley, Corinna Falck-Ytter, Alonso Carrasco-Labra, Sachin Wani, Lyubov Lytvyn, Yngve Falck-Ytter
       
 
 
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