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Gastroenterology
Journal Prestige (SJR): 7.958
Citation Impact (citeScore): 7
Number of Followers: 202  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0016-5085
Published by Elsevier Homepage  [3185 journals]
  • A Case of Unremitting Diarrhea
    • Abstract: Publication date: Available online 14 June 2019Source: GastroenterologyAuthor(s): Arjun R. Sondhi, Luke J. Nayak, Michael D. Rice
       
  • A Baby Girl with Failure to Thrive: Ultrasound as an Important Clue for
           Diagnosis
    • Abstract: Publication date: Available online 14 June 2019Source: GastroenterologyAuthor(s): Ya Ma, Qian Jiang, Zhengrong Wang
       
  • New Ascites and Omental Thickening in Ulcerative Colitis
    • Abstract: Publication date: Available online 14 June 2019Source: GastroenterologyAuthor(s): Joy C.Y. Chen, Houssam Halawi, Conor G. Loftus
       
  • Telehealth for Nutritional Interventions - Opportunities for Innovation
           and Improved Care
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Holly Knotowicz, Angela Haas, Stephanie Coe, Glenn T. Furuta, Pooja Mehta
       
  • Reply to GASTRO-D-19-00677
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Jeri W. Nieves, Maria Claudia Perez, David C. Metz, Karen E. Hansen
       
  • The "red queen" is up and running: virus-host interactions revealed
           through the prism of multiomics
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Meital Gal-Tanamy
       
  • AGA Editorial Fellowship: Three Lasting Lessons
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Rishi D. Naik
       
  • Reply to GASTRO-D-18-02437, GASTRO-D-18-02671, and GASTRO-D-18-02689
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Francis K.L. Chan, Moe H. Kyaw
       
  • Patients Value Symptoms and Quality of Life in Treating Eosinophilic
           Esophagitis: Not a Hard Truth to Swallow
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Joy W. Chang, Evan S. Dellon
       
  • Response to letters to the Editor (LTE 18-02713, LTE 19-00379)
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Ji Young Bang, Shyam Varadarajulu
       
  • Neonatal exposures and risk of IBD – when does the clock starts
           ticking'
    • Abstract: Publication date: Available online 13 June 2019Source: GastroenterologyAuthor(s): Joana Torres, Inga Peter
       
  • Hepatocellular Carcinomas With Mutational Activation of Beta Catenin
           Require Choline and can be Detected by Positron Emission Tomography
    • Abstract: Publication date: Available online 10 June 2019Source: GastroenterologyAuthor(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 Colnot Background & AimsIn one third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate beta 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 beta 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 (MCD) 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, mRNA quantification, and RNA-seq analyses. Fifty-two patients with HCC underwent PET imaging with 18F-fluorodeoxyglucose (FDG) followed by 18F-fluorocholine (FHC) tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative PCR, 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 beta catenin were positive in FCH-PET but not FDG-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 MCD 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 beta catenin are characterized by increased uptake of a fluorocholine tracer (FCH), but not FDG, 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 beta catenin.
       
  • Correction
    • Abstract: Publication date: Available online 10 June 2019Source: GastroenterologyAuthor(s):
       
  • Vedolizumab Induces Endoscopic and Histologic Remission in Patients With
           Crohn’s Disease
    • Abstract: Publication date: Available online 5 June 2019Source: GastroenterologyAuthor(s): Mark Löwenberg, Severine Vermeire, Nahid Mostafavi, Frank Hoentjen, Denis Franchimont, Peter Bossuyt, Pieter Hindryckx, Theo Rispens, Annick de Vries, C. Janneke van der Woude, Sophie Berends, Carmen A. Ambarus, Ron Mathot, Esme Clasquin, Filip Baert, Geert D’Haens Background & AimsWe evaluated the ability of vedolizumab to induce endoscopic and histologic remission in patients with Crohn's disease (CD).MethodsWe performed a prospective study of 110 patients with active CD, based on CD activity index (CDAI) scores> 220 and mucosal ulcerations, who received open-label vedolizumab (300 mg) infusions at weeks 0, 2, and 6, and every 8 weeks thereafter through week 52 at tertiary centers in Europe. Patients received an additional infusion at week 10 if their CDAI score had not decreased by 70 points. Patients underwent ileocolonoscopy with collection of biopsies at baseline and weeks 26 and 52; a local and central reader determined simple endoscopic index for CD (SES-CD) scores. Histologic features were assessed by a blinded pathologist at week 26. Serum concentrations of vedolizumab were measured at serial time points. The primary outcome was endoscopic and histologic remission in patients with active CD treated with vedolizumab for 52 weeksResultsAt weeks 26 and 52, 36 patients (29%) and 34 patients (31%), respectively, were in corticosteroid-free clinical remission (CDAI score
       
  • Intraductal Papillary Mucinous Neoplasms Arise from Multiple Independent
           Clones, Each With Distinct Mutations
    • Abstract: Publication date: Available online 5 June 2019Source: GastroenterologyAuthor(s): Catherine G. Fischer, Violeta Beleva Guthrie, Alicia M. Braxton, Lily Zheng, Pei Wang, Qianqian Song, James F. Griffin, Peter E. Chianchiano, Waki Hosoda, Noushin Niknafs, Simeon Springer, Marco Dal Molin, David Masica, Robert B. Scharpf, Elizabeth D. Thompson, Jin He, Christopher L. Wolfgang, Ralph H. Hruban, Nicholas J. Roberts, Anne Marie Lennon Background & AimsIntraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis.MethodsWe microdissected neoplastic tissues from 6–24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations.ResultsWe found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P
       
  • Crohn’s Disease Exclusion Diet Plus Partial Enteral Nutrition Induces
           Sustained Remission in a Randomized Controlled Trial
    • Abstract: Publication date: Available online 4 June 2019Source: GastroenterologyAuthor(s): A. Levine, E. Wine, A. Assa, R. Sigall Boneh, R. Shaoul, M. Kori, S. Cohen, S. Peleg, H. Shamali, A. On, P. Millman, L. Abramas, T. Ziv-Baran, S. Grant, G. Abitbol, K.A. Dunn, J.P. Bielawski, J. Van Limbergen Background & AimsExclusive enteral nutrition (EEN) is recommended for children with mild-to-moderate Crohn’s disease (CD) but implementation is challenging. We compared EEN to the CD exclusion-diet (CDED), a whole-food diet coupled with partial enteral nutrition (PEN), designed to reduce exposure to dietary components that have adverse effects on the microbiome and intestinal barrier.MethodsWe performed a 12-week prospective trial of children with mild to moderate CD. The children were randomly assigned to a group that received CDED plus 50% of calories from formula (Modulen, Nestlé) for 6 weeks (stage 1) followed by CDED with 25% PEN from weeks 7–12 (stage-2) (n=40, group 1) or a group that received EEN for 6 weeks followed by a free diet with 25% PEN from weeks 7–12 (n=38, group 2). Patients were evaluated at baseline and weeks 3, 6, and 12 and laboratory tests were performed. 16S rRNA gene (V4V5) sequencing was performed on stool samples. The primary endpoint was dietary tolerance. Secondary endpoints were intention to treat (ITT) remission at week 6 ( pediatric CD activity index score below 10) and corticosteroid-free ITT sustained remission at week 12.ResultsFour patients withdrew from the study because of intolerance by 48 hours, 74 patients (mean age 14.2±2.7 years) were included for remission analysis. The combination of CDED and PEN was tolerated in 39 children (97.5%), whereas EEN was tolerated by 28 children (73.6%) (P=.002; odds ratio for tolerance of CDED and PEN, 13.92; 95% CI, 1.68–115.14). At week 6, 30/40 children (75%) given CDED plus PEN were in corticosteroid-free remission vs 20/34 children (59%) given EEN (P=.38). At week 12, 28/37 children (75.6%) given CDED plus PEN were in corticosteroid-free remission compared with 14/31 children (45.1%) given EEN and then PEN (P=.01; odds ratio for remission in children given CDED and PEN, 3.77; CI, 1.34–10.59). In children given CDED plus PEN, corticosteroid-free remission was associated with sustained reductions in inflammation (based on serum level of C-reactive protein and fecal level of calprotectin) and fecal Proteobacteria.ConclusionCDED plus PEN was better tolerated than EEN in children with mild to moderate CD. Both diets were effective in inducing remission by week 6. The combination CDED plus PEN induced sustained remission in a significantly higher proportion of patients than EEN, and produced changes in the fecal microbiome associated with remission. These data support use of CDED plus PEN to induce remission in children with CD. Clinicaltrials.gov no: NCT01728870
       
  • Aryl Hydrocarbon Receptor Signaling Prevents Activation of Hepatic
           Stellate Cells and Liver Fibrogenesis in Mice
    • Abstract: Publication date: Available online 3 June 2019Source: GastroenterologyAuthor(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 Xie Background & AimsThe role of aryl hydrocarbon receptor (AHR) in liver fibrosis is controversial, because loss and gain of AHR activity each lead to liver fibrosis. The goal of this study is 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-seq analysis. C57BL/6J mice were given the AHR agonists TCDD or ITE, or 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 to HSCs from wild-type mice. In contrast, TCDD or ITE inhibited spontaneous and transforming growth factor beta (TGFB)-induced activation of HSCs. Mice with disruption of Ahr in HSCs, but not hepatocytes or Kupffer cells, developed more severe fibrosis following 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 TGFB-induced fibrogenesis by disrupting the interaction of SMAD3 with beta-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 non-toxic AHR agonists or strategies to activate AHR signaling in HSCs might be developed to prevent or treat liver fibrosis.
       
  • Incidence and Etiology of Drug-Induced Liver Injury in Mainland China
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Tao Shen, Yingxia Liu, Jia Shang, Qing Xie, Jun Li, Ming Yan, Jianming Xu, Junqi Niu, Jiajun Liu, Paul B. Watkins, Guruprasad P. Aithal, Raúl J. Andrade, Xiaoguang Dou, Lvfeng Yao, Fangfang Lv, Qi Wang, Yongguo Li, Xinmin Zhou, Yuexin Zhang, Peilan ZongBackground & AimsWe performed a nationwide, retrospective study to determine the incidence and causes of drug-induced liver injury (DILI) in mainland China.MethodsWe collected data on a total of 25,927 confirmed DILI cases, hospitalized from 2012 through 2014 at 308 medical centers in mainland China. We collected demographic, medical history, treatment, laboratory, disease severity, and mortality data from all patients. Investigators at each site were asked to complete causality assessments for each case whose diagnosis at discharge was DILI (n = 29,478) according to the Roussel Uclaf Causality Assessment Method.ResultsMost cases of DILI presented with hepatocellular injury (51.39%; 95% confidence interval [CI] 50.76–52.03), followed by mixed injury (28.30%; 95% CI 27.73–28.87) and cholestatic injury (20.31%; 95% CI 19.80–20.82). The leading single classes of implicated drugs were traditional Chinese medicines or herbal and dietary supplements (26.81%) and antituberculosis medications (21.99%). Chronic DILI occurred in 13.00% of the cases and, although 44.40% of the hepatocellular DILI cases fulfilled Hy’s Law criteria, only 280 cases (1.08%) progressed to hepatic failure, 2 cases underwent liver transplantation (0.01%), and 102 patients died (0.39%). Among deaths, DILI was judged to have a primary role in 72 (70.59%), a contributory role in 21 (20.59%), and no role in 9 (8.82%). Assuming the proportion of DILI in the entire hospitalized population of China was represented by that observed in the 66 centers where DILI capture was complete, we estimated the annual incidence in the general population to be 23.80 per 100,000 persons (95% CI 20.86–26.74). Only hospitalized patients were included in this analysis, so the true incidence is likely to be higher.ConclusionsIn a retrospective study to determine the incidence and causes of DILI in mainland China, the annual incidence in the general population was estimated to be 23.80 per 100,000 persons; higher than that reported from Western countries. Traditional Chinese medicines, herbal and dietary supplements, and antituberculosis drugs were the leading causes of DILI in mainland China.Graphical abstractGraphical abstract for this article
       
  • Axon Guidance Molecules Promote Perineural Invasion and Metastasis of
           Orthotopic Pancreatic Tumors in Mice
    • Abstract: Publication date: Available online 1 June 2019Source: GastroenterologyAuthor(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 Zheng Background & 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.
       
  • Enigmatic Abdominal Pain
    • Abstract: Publication date: Available online 31 May 2019Source: GastroenterologyAuthor(s): Danmei Zhang, Charles Maltz
       
  • Abnormal Polypoid Finding During Colonoscopy
    • Abstract: Publication date: Available online 31 May 2019Source: GastroenterologyAuthor(s): Frederick B. Peng, Hyun-seok Kim, Suneal K. Agarwal
       
  • Incidental jejunal polyps
    • Abstract: Publication date: Available online 31 May 2019Source: GastroenterologyAuthor(s): Eun Young Park, Dong Hoon Baek, Geun Am Song
       
  • “Doctor, I just can’t seem to swallow!”
    • Abstract: Publication date: Available online 31 May 2019Source: GastroenterologyAuthor(s): Anusha Shirwaikar Thomas, Jae Y. Ro, Gulchin A. Ergun
       
  • On The Hot Seat: A Rare Cause of Rectal Pain
    • Abstract: Publication date: Available online 31 May 2019Source: GastroenterologyAuthor(s): Benjamin Nunley, Christopher Truss
       
  • Are Non-alcoholic Fatty Liver Disease and Alcoholic Fatty Liver Disease
           More Than Just Semantics'
    • Abstract: Publication date: Available online 31 May 2019Source: GastroenterologyAuthor(s): Mohammed Eslam, Arun J. Sanyal, Jacob George
       
  • Noninvasive Detection of High-risk Adenomas Using Stool-derived Eukaryotic
           RNA Sequences as Biomarkers
    • Abstract: Publication date: Available online 30 May 2019Source: GastroenterologyAuthor(s): Erica Barnell, Yiming Kang, Elizabeth Wurtzler, Malachi Griffith, Aadel A. Chaudhuri, Obi L. Griffith, Geneoscopy Scientists, Andrew Barnell, Katie Campbell, Kimberly R. Kruse
       
  • Hepatitis, Pancreatitis and Rash in a Patient with Chronic Lymphocytic
           Leukemia
    • Abstract: Publication date: Available online 30 May 2019Source: GastroenterologyAuthor(s): Inuk Zandvakili, James W. Lloyd, Karthik V. Giridhar
       
  • Itchy hyperkeratotic acral plaque in a patient with chronic calcific
           pancreatitis
    • Abstract: Publication date: Available online 30 May 2019Source: GastroenterologyAuthor(s): T.P. Afra, Muhammed Razmi T, Saleem Suhail
       
  • Intestinal PPARα Protects Against Colon Carcinogenesis via Regulation of
           Methyltransferases DNMT1 and PRMT6
    • Abstract: Publication date: Available online 30 May 2019Source: GastroenterologyAuthor(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. Gonzalez Background & 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 PCR, 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 mRNA 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 (RB1), 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 RB1 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 mRNA and protein than non-tumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.
       
  • A Rare Complication of a Rare Disease
    • Abstract: Publication date: Available online 30 May 2019Source: GastroenterologyAuthor(s): Luke J. Nayak, Arjun R. Sondhi, Maria Westerhoff
       
  • A Rare Complication Of Peptic Ulcer Disease
    • Abstract: Publication date: Available online 30 May 2019Source: GastroenterologyAuthor(s): Savan Kabaria, Kalpesh G. Patel, Sushil Ahlawat
       
  • Gastrointestinal Ulcers in a Patient with a Solitary Enlarged Lymph Node
    • Abstract: Publication date: Available online 30 May 2019Source: GastroenterologyAuthor(s): Kai-Ruo Wang, Zhen Li, Yan-Qing Li
       
  • An unusual cause of colonic ulceration
    • Abstract: Publication date: Available online 29 May 2019Source: GastroenterologyAuthor(s): H.S. De Lil, M.A. Lantinga, H.A.M. Sinnige
       
  • Safety of Proton Pump Inhibitors Based on a Large, Multi-year, Randomized
           Trial of Patients Receiving Rivaroxaban or Aspirin
    • Abstract: Publication date: Available online 29 May 2019Source: GastroenterologyAuthor(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 Muehlhofer Background & 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 3x2 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% CI, 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 identifier: NCT01776424 (https://clinicaltrials.gov/ct2/show/NCT01776424)
       
  • CME Exam 1: A Complication of Crohn’s Disease'
    • Abstract: Publication date: Available online 29 May 2019Source: GastroenterologyAuthor(s):
       
  • Constipation with a palpable abdominal mass in a young woman
    • Abstract: Publication date: Available online 29 May 2019Source: GastroenterologyAuthor(s): Yan-Jiun Huang, Hwa-Lin Kao, Wen-Ke Wang
       
  • www.thieme.com,+ISBN:+9783131258533.+Web+address+for+ordering:&rft.title=Gastroenterology&rft.issn=0016-5085&rft.date=&rft.volume=">Gastroenterological Endoscopy, 3rd edition, Michael B. Wallace, Paul
           Fockens, Joseph Jao-Yiu Sung (Eds.). Thieme, Stuttgart, Germany (2018),
           438, www.thieme.com, ISBN: 9783131258533. Web address for ordering:
    • Abstract: Publication date: Available online 29 May 2019Source: GastroenterologyAuthor(s): Jonathan M. Buscaglia
       
  • Six of One Steroid, Half a Dozen of the Other
    • Abstract: Publication date: Available online 28 May 2019Source: GastroenterologyAuthor(s): Robert T. Kavitt, David A. Katzka
       
  • Reply
    • Abstract: Publication date: Available online 28 May 2019Source: GastroenterologyAuthor(s): Yee Hui Yeo, Mindie H. Nguyen
       
  • Reply
    • Abstract: Publication date: Available online 28 May 2019Source: GastroenterologyAuthor(s): Suzanne P. MacFarland, Bryson W. Katona, Kara N. Maxwell
       
  • When Occam's Razor meets Hickam's Dictum
    • Abstract: Publication date: Available online 28 May 2019Source: GastroenterologyAuthor(s): Rochelle E. Wong, Baldeep S. Pabla, Anthony M. Gamboa
       
  • Reply
    • Abstract: Publication date: Available online 28 May 2019Source: GastroenterologyAuthor(s): Werna T. Uniken Venema, Michiel D. Voskuil, Eleonora A. Festen
       
  • How to Incorporate Bariatric Training Into Your Fellowship Program
    • Abstract: Publication date: Available online 28 May 2019Source: GastroenterologyAuthor(s): Pichamol Jirapinyo, Christopher C. Thompson
       
  • Abdominal Semicircular Calcified Lesion in a Febrile Woman
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Yu-Chuan Hsu, Wen-Hsin Huang
       
  • Reply
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Aldo J. Montano-Loza, Maryam Ebadi, Andrew L. Mason
       
  • Recurrence of Primary Biliary Cholangitis After Liver Transplantation: Is
           Tacrolimus Really Worse Than Other Drugs'
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Michel Rayar, Edouard Bardou-Jacquet
       
  • Goodbye for Good: Stepping Away From Recurrence
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Amika Moro, Keita Okubo, Kazunari Sasaki
       
  • RE: Effects of Long-Term Norfloxacin Therapy in Patients With Advanced
           Cirrhosis
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Andrea Lombardi, Mario U. Mondelli, Raffaele Bruno
       
  • Effectiveness of Infliximab Biosimilar in Crohn’s Disease: A Dime, A
           Dozen
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Gionata Fiorino, Laurent Peyrin-Biroulet, Silvio Danese
       
  • Noninvasively Predicting Hemodynamic Response to Carvedilol in Cirrhotic
           Patients With Varices: You Have Some Ex-Spleening to Do
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Hannah P. Kim, Andrew M. Moon, Evan S. Dellon
       
  • Depression, Antidepressants, and Inflammatory Bowel Disease: Implications
           for Future Models of Care
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): David J. Gracie, Alexander C. Ford
       
  • Vedolizumab Does Not Impair Sperm DNA Integrity in Men With Inflammatory
           Bowel Disease
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Anne Grosen, Mona Bungum, Christian Lodberg Hvas, Mette Julsgaard, Eugenia Cordelli, Jens Kelsen
       
  • Gene Expression Signature in Surgical Tissues and Endoscopic Biopsies
           Identifies High-Risk T1 Colorectal Cancers
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Raju Kandimalla, Tsuyoshi Ozawa, Feng Gao, Xin Wang, Ajay Goel, Hiroaki Nozawa, Keisuke Hata, Hiroshi Nagata, Satoshi Okada, Toshiaki Watanabe, Daisuke Izumi, Hideo Baba, James Fleshman, Maria Pellise, Francesc Balaguer, Luis Bujanda, Miriam Cuatrecasas
       
  • Long-term Safety and Efficacy of Local Microinjection Combining Autologous
           Microfat and Adipose-Derived Stromal Vascular Fraction for the Treatment
           of Refractory Perianal Fistula in Crohn’s Disease
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Mélanie Serrero, Fanny Grimaud, Cécile Philandrianos, Carine Visée, Florence Sabatier, Jean-Charles Grimaud
       
  • Presentation of the Julius M. Friedenwald Medal to John I. Allen
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Loren Laine, Robert A. Ganz
       
  • CME Exam 3: Real-time Targeted Genome Profile Analysis of Pancreatic
           Ductal Adenocarcinomas Identifies Genetic Alterations that Might be
           Targeted With Existing Drugs or Used as Biomarkers
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s):
       
  • CME Exam 2: Events Within the First Year of Life, But Not the Neonatal
           Period, Affect Risk for Later Development of Inflammatory Bowel Diseases
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s):
       
  • CME Exam 1: Zenker’s Diverticulum Per-Oral Endoscopic Myotomy
           Techniques: Changing Paradigms
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s):
       
  • HCV-Induced Epigenetic Changes Associated With Liver Cancer Risk Persist
           After Sustained Virologic Response
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Nourdine Hamdane, Frank Jühling, Emilie Crouchet, Houssein El Saghire, Christine Thumann, Marine A. Oudot, Simonetta Bandiera, Antonio Saviano, Clara Ponsolles, Armando Andres Roca Suarez, Shen Li, Naoto Fujiwara, Atsushi Ono, Irwin Davidson, Nabeel Bardeesy, Christian Schmidl, Christoph Bock, Catherine Schuster, Joachim Lupberger, François HabersetzerBackground & AimsChronic hepatitis C virus (HCV) infection is an important risk factor for hepatocellular carcinoma (HCC). Despite effective antiviral therapies, the risk for HCC is decreased but not eliminated after a sustained virologic response (SVR) to direct-acting antiviral (DAA) agents, and the risk is higher in patients with advanced fibrosis. We investigated HCV-induced epigenetic alterations that might affect risk for HCC after DAA treatment in patients and mice with humanized livers.MethodsWe performed genome-wide ChIPmentation-based ChIP-Seq and RNA-seq analyses of liver tissues from 6 patients without HCV infection (controls), 18 patients with chronic HCV infection, 8 patients with chronic HCV infection cured by DAA treatment, 13 patients with chronic HCV infection cured by interferon therapy, 4 patients with chronic hepatitis B virus infection, and 7 patients with nonalcoholic steatohepatitis in Europe and Japan. HCV-induced epigenetic modifications were mapped by comparative analyses with modifications associated with other liver disease etiologies. uPA/SCID mice were engrafted with human hepatocytes to create mice with humanized livers and given injections of HCV-infected serum samples from patients; mice were given DAAs to eradicate the virus. Pathways associated with HCC risk were identified by integrative pathway analyses and validated in analyses of paired HCC tissues from 8 patients with an SVR to DAA treatment of HCV infection.ResultsWe found chronic HCV infection to induce specific genome-wide changes in H3K27ac, which correlated with changes in expression of mRNAs and proteins. These changes persisted after an SVR to DAAs or interferon-based therapies. Integrative pathway analyses of liver tissues from patients and mice with humanized livers demonstrated that HCV-induced epigenetic alterations were associated with liver cancer risk. Computational analyses associated increased expression of SPHK1 with HCC risk. We validated these findings in an independent cohort of patients with HCV-related cirrhosis (n = 216), a subset of which (n = 21) achieved viral clearance.ConclusionsIn an analysis of liver tissues from patients with and without an SVR to DAA therapy, we identified epigenetic and gene expression alterations associated with risk for HCC. These alterations might be targeted to prevent liver cancer in patients treated for HCV infection.Graphical abstractGraphical abstract for this article
       
  • GNAI1 and GNAI3 Reduce Colitis-Associated Tumorigenesis in Mice by
           Blocking IL6 Signaling and Down-regulating Expression of GNAI2
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Zhi-Wei Li, Beicheng Sun, Ting Gong, Sheng Guo, Jianhua Zhang, Junlong Wang, Atsushi Sugawara, Meisheng Jiang, Junjun Yan, Alexandra Gurary, Xin Zheng, Bifeng Gao, Shu-Yuan Xiao, Wenlian Chen, Chi Ma, Christine Farrar, Chenjun Zhu, Owen T.M. Chan, Can Xin, Andrew WinnickiBackground & AimsInterleukin 6 (IL6) and tumor necrosis factor contribute to the development of colitis-associated cancer (CAC). We investigated these signaling pathways and the involvement of G protein subunit alpha i1 (GNAI1), GNAI2, and GNAI3 in the development of CAC in mice and humans.MethodsB6;129 wild-type (control) or mice with disruption of Gnai1, Gnai2, and/or Gnai3 or conditional disruption of Gnai2 in CD11c+ or epithelial cells were given dextran sulfate sodium (DSS) to induce colitis followed by azoxymethane (AOM) to induce carcinogenesis; some mice were given an antibody against IL6. Feces were collected from mice, and the compositions of microbiomes were analyzed by polymerase chain reactions. Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) isolated from spleen and colon tissues were analyzed by flow cytometry. We performed immunoprecipitation and immunoblot analyses of colon tumor tissues, MDSCs, and mouse embryonic fibroblasts to study the expression levels of GNAI1, GNAI2, and GNAI3 and the interactions of GNAI1 and GNAI3 with proteins in the IL6 signaling pathway. We analyzed the expression of Gnai2 messenger RNA by CD11c+ cells in the colonic lamina propria by PrimeFlow, expression of IL6 in DCs by flow cytometry, and secretion of cytokines in sera and colon tissues by enzyme-linked immunosorbent assay. We obtained colon tumor and matched nontumor tissues from 83 patients with colorectal cancer having surgery in China and 35 patients with CAC in the United States. Mouse and human colon tissues were analyzed by histology, immunoblot, immunohistochemistry, and/or RNA-sequencing analyses.ResultsGNAI1 and GNAI3 (GNAI1;3) double-knockout (DKO) mice developed more severe colitis after administration of DSS and significantly more colonic tumors than control mice after administration of AOM plus DSS. Development of increased tumors in DKO mice was not associated with changes in fecal microbiomes but was associated with activation of nuclear factor (NF) κB and signal transducer and activator of transcription (STAT) 3; increased levels of GNAI2, nitric oxide synthase 2, and IL6; increased numbers of CD4+ DCs and MDSCs; and decreased numbers of CD8+ DCs. IL6 was mainly produced by CD4+/CD11b+, but not CD8+, DCs in DKO mice. Injection of DKO mice with a blocking antibody against IL6 reduced the expansion of MDSCs and the number of tumors that developed after CAC induction. Incubation of MDSCs or mouse embryonic fibroblasts with IL6 induced activation of either NF-κB by a JAK2-TRAF6-TAK1-CHUK/IKKB signaling pathway or STAT3 by JAK2. This activation resulted in expression of GNAI2, IL6 signal transducer (IL6ST, also called GP130) and nitric oxide synthase 2, and expansion of MDSCs; the expression levels of these proteins and expansion of MDSCs were further increased by the absence of GNAI1;3 in cells and mice. Conditional disruption of Gnai2 in CD11c+ cells of DKO mice prevented activation of NF-κB and STAT3 and changes in numbers of DCs and MDSCs. Colon tumor tissues from patients with CAC had reduced levels of GNAI1 and GNAI3 and increased levels of GNAI2 compared with normal tissues. Further analysis of a public human colorectal tumor DNA microarray database (GSE39582) showed that low Gani1 and Gnai3 messenger RNA expression and high Gnai2 messenger RNA expression were significantly associated with decreased relapse-free survival.ConclusionsGNAI1;3 suppresses DSS-plus-AOM–induced colon tumor development in mice, whereas expression of GNAI2 in CD11c+ cells and IL6 in CD4+/CD11b+ DCs appears to promote these effects. Strategies to induce GNAI1;3, or block GNAI2 and IL6, might be developed for the prevention or therapy of CAC in patients.Graphical abstractGraphical abstract for this article
       
  • MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in
           Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis
           in Mice
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Yuhua Tian, Jiuzhi Xu, Yuan Li, Ran Zhao, Sujuan Du, Cong Lv, Wei Wu, Ruiqi Liu, Xiaole Sheng, Yongli Song, Xueyun Bi, Guilin Li, Mengzhen Li, Xi Wu, Pengbo Lou, Huiwen You, Wei Cui, Jinyue Sun, Jianwei Shuai, Fazheng RenBackground & AimsLevels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis.MethodsWe obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn’s disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People’s Hospital. MIR31- knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin was used to generate peptosome nanoparticles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome–MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry.ResultsLevels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and nuclear factor-κB activated transcription of MIR31 in colorectal cancer cells and organoids in response to tumor necrosis factor and interleukin (IL)6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared with control mice. MIR31 bound to 3ʹ untranslated regions of Il17ra and Il7r messenger RNAs (RNAs) (which encode receptors for the inflammatory cytokines IL17 and IL7) and Il6st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome–MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation.ConclusionsMIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome–MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis. Transcript Profiling: GSE123556Graphical abstractGraphical abstract for this article
       
  • Lactobacilli Degrade Wheat Amylase Trypsin Inhibitors to Reduce Intestinal
           Dysfunction Induced by Immunogenic Wheat Proteins
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Alberto Caminero, Justin L. McCarville, Victor F. Zevallos, Marc Pigrau, Xuechen B. Yu, Jennifer Jury, Heather J. Galipeau, Alexandra V. Clarizio, Javier Casqueiro, Joseph A. Murray, Stephen M. Collins, Armin Alaedini, Premysl Bercik, Detlef Schuppan, Elena F. VerduBackground & AimsWheat-related disorders, a spectrum of conditions induced by the ingestion of gluten-containing cereals, have been increasing in prevalence. Patients with celiac disease have gluten-specific immune responses, but the contribution of non-gluten proteins to symptoms in patients with celiac disease or other wheat-related disorders is controversial.MethodsC57BL/6 (control), Myd88–/–, Ticam1–/–, and Il15–/– mice were placed on diets that lacked wheat or gluten, with or without wheat amylase trypsin inhibitors (ATIs), for 1 week. Small intestine tissues were collected and intestinal intraepithelial lymphocytes (IELs) were measured; we also investigated gut permeability and intestinal transit. Control mice fed ATIs for 1 week were gavaged daily with Lactobacillus strains that had high or low ATI-degrading capacity. Nonobese diabetic/DQ8 mice were sensitized to gluten and fed an ATI diet, a gluten-containing diet or a diet with ATIs and gluten for 2 weeks. Mice were also treated with Lactobacillus strains that had high or low ATI-degrading capacity. Intestinal tissues were collected and IELs, gene expression, gut permeability and intestinal microbiota profiles were measured.ResultsIn intestinal tissues from control mice, ATIs induced an innate immune response by activation of Toll-like receptor 4 signaling to MD2 and CD14, and caused barrier dysfunction in the absence of mucosal damage. Administration of ATIs to gluten-sensitized mice expressing HLA-DQ8 increased intestinal inflammation in response to gluten in the diet. We found ATIs to be degraded by Lactobacillus, which reduced the inflammatory effects of ATIs.ConclusionsATIs mediate wheat-induced intestinal dysfunction in wild-type mice and exacerbate inflammation to gluten in susceptible mice. Microbiome-modulating strategies, such as administration of bacteria with ATI-degrading capacity, may be effective in patients with wheat-sensitive disorders.Graphical abstractGraphical abstract for this article
       
  • Blood-Derived DNA Methylation Signatures of Crohn's Disease and Severity
           of Intestinal Inflammation
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Hari K. Somineni, Suresh Venkateswaran, Varun Kilaru, Urko M. Marigorta, Angela Mo, David T. Okou, Richard Kellermayer, Kajari Mondal, Dawayland Cobb, Thomas D. Walters, Anne Griffiths, Joshua D. Noe, Wallace V. Crandall, Joel R. Rosh, David R. Mack, Melvin B. Heyman, Susan S. Baker, Michael C. Stephens, Robert N. Baldassano, James F. MarkowitzBackground & AimsCrohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression.MethodsWe obtained blood samples from 164 pediatric patients (1–17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1–3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease.ResultsWe identified 1189 5′-cytosine–phosphate–guanosine-3′ (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease.ConclusionsMethylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease–associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.Graphical abstractGraphical abstract for this article
       
  • Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal
           Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted With
           Existing Drugs or Used as Biomarkers
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Aatur D. Singhi, Ben George, Joel R. Greenbowe, Jon Chung, James Suh, Anirban Maitra, Samuel J. Klempner, Andrew Hendifar, Javle M. Milind, Talia Golan, Randall E. Brand, Amer H. Zureikat, Somak Roy, Alexa B. Schrock, Vincent A. Miller, Jeffrey S. Ross, Siraj M. Ali, Nathan BaharyBackground & AimsIt has been a challenge to select treatment for patients with pancreatic ductal adenocarcinomas (PDACs) based on genome alterations. We performed targeted genomic profile analyses of a large number of PDACs to assess the full spectrum of actionable genomic alterations.MethodsWe performed targeted genomic profile analyses of 3594 PDAC samples from an international cohort, including capture-based targeted genomic profiling of as many as 315 cancer-associated genes and intron regions of 28 genes that are rearranged in cancer cells. Tumor mutation burden (TMB) and microsatellite instability (MSI) status were also assessed. TMB was calculated across a 1.14-megabase region; TMB-high was defined as ≥20 mutations/megabase. MSI-high status was assigned based on analysis of 114 intron homopolymer loci.ResultsKRAS, TP53, CDKN2A, and SMAD4 were the most frequently altered genes in PDAC. We found KRAS mutations in 88% of samples. Among PDACs without mutations in KRAS, we found alterations in genes whose products are in the mitogen-activated protein kinase signaling pathway and are candidate drug targets (actionable targets, n = 132; 4%), as well as gene fusions (n = 51), gene amplifications (n = 35), genes with missense mutations (n = 30), and genes that contain deletions (n = 16). Many of these encode proteins in receptor tyrosine kinase, RAS, or mitogen-activated protein kinase signaling pathways. Aside from TP53, alterations in genes encoding DNA damage repair proteins (BRCA and FANC) were detected in 14% of PDACs. Among PDACs evaluated for MSI (n = 2563) and TMB (n = 1021), MSI-high and/or TMB-high phenotypes were detected in 0.5% of samples. Alterations in FGF23, CCND2, PIK3CA, and FGF6 were more commonly detected in intraductal papillary mucinous neoplasm-associated PDACs.ConclusionsIn targeted genomic profile analyses of 3594 PDACs, we found 17% to contain genomic alterations that might make the tumor cells susceptible to currently used anticancer agents. We identified mutations in genes that could contribute to progression of intraductal papillary mucinous neoplasms into malignancies. These alterations might be used as biomarkers for early detection.
       
  • Events Within the First Year of Life, but Not the Neonatal Period, Affect
           Risk for Later Development of Inflammatory Bowel Diseases
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Charles N. Bernstein, Charles Burchill, Laura E. Targownik, Harminder Singh, Leslie L. RoosBackground & AimsWe performed a population-based study to determine whether there was an increased risk of inflammatory bowel diseases (IBD) in persons with critical events at birth and within 1 year of age.MethodsWe collected data from the University of Manitoba IBD Epidemiology Database, which contains records on all Manitobans diagnosed with IBD from 1984 through 2010 and matched controls. From 1970 individuals’ records can be linked with those of their mothers, so we were able to identify siblings. All health care visits or hospitalizations during the neonatal and postnatal periods were available from 1970 through 2010. We collected data on infections, gastrointestinal illnesses, failure to thrive, and hospital readmission in the first year of life and sociodemographic factors at birth. From 1979, data were available on gestational age, Apgar score, neonatal admission to the intensive care unit, and birth weight. We compared incident rate of infections, gastrointestinal illnesses, and failure to thrive between IBD cases and matched controls as well as between IBD cases and siblings.ResultsData on 825 IBD cases and 5999 matched controls were available from 1979. Maternal diagnosis of IBD was the greatest risk factor for IBD in offspring (odds ratio [OR], 4.53; 95% confidence interval [CI], 3.08–6.67). When we assessed neonatal events, only being in the highest vs lowest socioeconomic quintile increased risk for later development of IBD (OR, 1.35; 95% CI, 1.01–1.79). For events within the first year of life, being in the highest socioeconomic quintile at birth and infections (OR, 1.39; 95% CI, 1.09–1.79) increased risk for developing IBD at any age. Infection in the first year of life was associated with diagnosis of IBD before age 10 years (OR, 3.06; 95% CI, 1.07–8.78) and before age 20 years (OR, 1.63; 95% CI, 1.18–2.24). Risk for IBD was not affected by gastrointestinal infections, gastrointestinal disease, or abdominal pain in the first year of life.ConclusionsIn a population-based study, we found infection within the first year of life to be associated with a diagnosis of IBD. This might be due to use of antibiotics or a physiologic defect at a critical age for gut microbiome development.Graphical abstractGraphical abstract for this article
       
  • Genetic Factors and the Intestinal Microbiome Guide Development of
           Microbe-Based Therapies for Inflammatory Bowel Diseases
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Louis J. Cohen, Judy H. Cho, Dirk Gevers, Hiutung ChuThe intestinal microbiota is a dynamic community of bacteria, fungi, and viruses that mediates mucosal homeostasis and physiology. Imbalances in the microbiome and aberrant immune responses to gut bacteria can disrupt homeostasis and are associated with inflammatory bowel diseases (IBDs) in humans and colitis in mice. We review genetic variants associated with IBD and their effects on the intestinal microbiome, the immune response, and disease pathogenesis. The intestinal microbiome, which includes microbial antigens, adjuvants, and metabolic products, affects the development and function of the intestinal mucosa, influencing inflammatory responses in the gut. Therefore, strategies to manipulate the microbiome might be used in treatment of IBD. We review microbe-based therapies for IBD and the potential to engineer patients’ intestinal microbiota. We discuss how studies of patients with IBD and mouse models have advanced our understanding of the interactions between genetic factors and the gut microbiome, and challenges to the development of microbe-based therapies for IBD.
       
  • Gastric Parietal Cell Physiology and Helicobacter
           pylori
    –Induced Disease
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Xuebiao Yao, Adam J. SmolkaAcidification of the gastric lumen poses a barrier to transit of potentially pathogenic bacteria and enables activation of pepsin to complement nutrient proteolysis initiated by salivary proteases. Histamine-induced activation of the PKA signaling pathway in gastric corpus parietal cells causes insertion of proton pumps into their apical plasma membranes. Parietal cell secretion and homeostasis are regulated by signaling pathways that control cytoskeletal changes required for apical membrane remodeling and organelle and proton pump activities. Helicobacter pylori colonization of human gastric mucosa affects gastric epithelial cell plasticity and homeostasis, promoting epithelial progression to neoplasia. By intervening in proton pump expression, H pylori regulates the abundance and diversity of microbiota that populate the intestinal lumen. We review stimulation–secretion coupling and renewal mechanisms in parietal cells and the mechanisms by which H pylori toxins and effectors alter cell secretory pathways (constitutive and regulated) and organelles to establish and maintain their inter- and intracellular niches. Studies of bacterial toxins and their effector proteins have provided insights into parietal cell physiology and the mechanisms by which pathogens gain control of cell activities, increasing our understanding of gastrointestinal physiology, microbial infectious disease, and immunology.
       
  • AGA Clinical Practice Update on Interaction Between Oral Direct-Acting
           Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma:
           Expert Review
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Amit G. Singal, Joseph K. Lim, Fasiha KanwalDescriptionThe purpose of this clinical practice update is to evaluate the evidence describing the interaction between direct-acting antiviral (DAA) therapy for hepatitis and hepatocellular carcinoma (HCC) with regard to HCC incidence, HCC recurrence, and DAA efficacy, and to summarize best practice advice regarding HCC surveillance and timing of DAA therapy.MethodsThe recommendations outlined in this expert review are based on available published evidence, including observational studies and systematic reviews, and incorporates expert opinion where applicable.Best practice advice 1DAA treatment is associated with a reduction in the risk of incident HCC. The relative risk reduction is similar in patients with and without cirrhosis.Best practice advice 2Patients with advanced liver fibrosis (F3) or cirrhosis should receive surveillance imaging before initiating DAA treatment.Best practice advice 3Patients with advanced liver fibrosis (F3) or cirrhosis at the time of DAA treatment represent the highest-risk group for HCC after DAA-induced sustained virologic response. These patients should stay in HCC surveillance.Best practice advice 4HCC surveillance should be performed using ultrasound with or without α–fetoprotein every 6 months. Current data do not support shorter surveillance intervals or the use of alternative surveillance modalities.Best practice advice 5Future studies may show a reduction in HCC risk over time after DAA-induced sustained virologic response. However, in the interim, HCC surveillance should continue indefinitely if patients are otherwise eligible for potentially curative therapy.Best practice advice 6The presence of active HCC is associated with a small but statistically significant decrease in sustained virologic response with DAA therapy.Best practice advice 7Patients with HCC who are eligible for potentially curative therapy with liver resection or ablation should defer DAA therapy until after HCC treatment is completed.Best practice advice 8Timing of DAA therapy for patients with HCC who are listed for liver transplantation should be determined with consideration of median wait times, availability of hepatitis C virus–positive organs, and degree of liver dysfunction.Best practice advice 9There are insufficient data evaluating benefits and cost-effectiveness of DAA therapy in patients with active intermediate or advanced HCC. Decisions regarding DAA treatment in these patients should be considered in light of HCC tumor burden, degree of liver dysfunction, life expectancy, and patient preferences.Best practice advice 10There are no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy.Best practice advice 11DAA therapy should not be withheld from patients with complete response to HCC therapy; however, DAA therapy can be deferred 4–6 months to confirm response to HCC therapy.Best practice advice 12Patients with complete response to HCC therapy who are treated with DAAs have a continued risk of HCC recurrence and require HCC surveillance, which should be conducted indefinitely with dynamic contrast-enhanced computed tomography or magnetic resonance imaging every 3–6 months. Current data do not support more frequent surveillance in these patients. This Clinical Practice Update was produced by the AGA Institute.
       
  • A Hypervascular Pancreatic Tumor
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Amrit K. Kamboj, Patrick Hoversten, Conor G. Loftus
       
  • A Fatal Cause of Small Bowel Obstruction
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Agha Wajdan Baqir, Mouyed Alawad, Kristina Loukeris
       
  • Small Bowel Necrosis After Colonoscopy
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Daniel Bushyhead, Flavio G. Rocha, Richard A. Kozarek
       
  • A Rare Cause of Neonatal Cholestasis Without Liver Dysfunction
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Kathryn Mullany, Susan Arbuckle, Susan Mei-Ling Siew
       
  • Colon Cancer Risk and VacA Toxin of Helicobacter pylori
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Antonio Ponzetto, Natale Figura
       
  • A Set Up for Small Intestinal Bacterial Overgrowth
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Patrick Hoversten, Amrit K. Kamboj, Shounak Majumder
       
  • Unusual Fever and Diarrhea in an Infant
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Linqian Zhang, Xiaobing Li, Mizu Jiang
       
  • Hidden in Plain Sight
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Amrit K. Kamboj, Vandana Nehra, Cadman L. Leggett
       
  • A Rare Cause of Fever and Abdominal Pain
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Gina Treichler, Antonia Töpfer, Bernhard Morell
       
  • You Just Got Burned! What Is Wrong With This Gastric Pouch'
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Diogo Turiani Hourneaux de Moura, Kelly E. Hathorn, Christopher C. Thompson
       
  • A Rare Tumor Disseminated to the Gastrointestinal Tract After Treatment
           for HIV-Associated Lymphoproliferative Disease
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Hiroki Kitamoto, Daisuke Yamashita, Tetsuro Inokuma
       
  • Zenker’s Diverticulum Per-Oral Endoscopic Myotomy Techniques:
           Changing Paradigms
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Olaya I. Brewer Gutierrez, Yervant Ichkhanian, Marco Spadaccini, Kia Vosoughi, Alessandro Repici, Mouen A. Khashab
       
  • Indelibly Stamped by Hepatitis C Virus Infection: Persistent Epigenetic
           Signatures Increasing Liver Cancer Risk
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Volker Lohmann, Ralf Bartenschlager
       
  • The Present State and Future Direction of Regenerative Medicine for
           Perianal Crohn’s Disease
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Amy L. Lightner
       
  • Techniques and Technologies for Increasing Adenoma Detection at
           Colonoscopy: Seeing More With Blue
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): David G. Hewett
       
  • Confirming Complexity: Assessing Environmental and Genetic Risk Factors
           for Inflammatory Bowel Disease
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Sonia Friedman, Bente Mertz Nørgård
       
  • How to Incorporate Esophageal Manometry Teaching in Your Fellowship
           Program
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Cary Kraft, Priya Kathpalia, Jeffrey M. Baumgardner, John E. Pandolfino, Justin L. Sewell
       
  • Covering the Cover
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Andrew T. Chan, Christopher S. Williams
       
  • Information for Authors and Readers
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s):
       
  • Elsewhere in The AGA Journals
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s):
       
  • Cover 1
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s):
       
  • Reply
    • Abstract: Publication date: June 2019Source: Gastroenterology, Volume 156, Issue 8Author(s): Julia Butt, Matthew G. Varga, Meira Epplein
       
  • Correction
    • Abstract: Publication date: Available online 3 May 2019Source: GastroenterologyAuthor(s):
       
 
 
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