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Gastroenterology
Journal Prestige (SJR): 7.958
Citation Impact (citeScore): 7
Number of Followers: 220  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0016-5085
Published by Elsevier Homepage  [3183 journals]
  • Mutated CEACAMs Disrupt Transforming Growth Factor beta Signaling and
           Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis
    • Abstract: Publication date: Available online 1 October 2019Source: GastroenterologyAuthor(s): Shoujun Gu, Sobia Zaidi, Md. Imtaiyaz Hassan, Taj Mohammad, Tathiane M. Malta, Houtan Noushmehr, Bryan Nguyen, Keith A. Crandall, Jigisha Srivastav, Vincent Obias, Paul Lin, Bao-Ngoc Nguyen, Michael Yao, Ren Yao, Charles Hadley King, Raja Mazumder, Bibhuti Mishra, Shuyun Rao, Lopa MishraABSTRACTBACKGROUND AND AIMSWe studied interactions among proteins of the carcinoembryonic antigen related cell adhesion molecule (CEACAM) family, which interact with microbes, and transforming growth factor beta (TGFB) signaling pathway, which is often altered in colorectal cancer cells. We investigated mechanisms by which CEACAM proteins inhibit TGFB signaling and alter the intestinal microbiome to promote colorectal carcinogenesis.METHODSWe collected data on DNA sequences, mRNA expression levels, and patient survival times from 456 colorectal adenocarcinoma cases, and a separate set of 594 samples of colorectal adenocarcinomas, in the Cancer Genome Atlas. We performed shotgun metagenomic sequencing analyses of feces from wild-type mice and mice with defects in TGFB signaling (Sptbn1+/– and Smad4+/–/Sptbn1+/–) to identify changes in microbiota composition before development of colon tumors. Proteins were knocked down in SW480 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and in proliferation and colony formation assays.RESULTSIn colorectal adenocarcinomas, high expression levels of genes encoding CEACAM proteins, especially CEACAM5, were associated with reduced survival times of patients. There was an inverse correlation between expression of CEACAM genes and expression of TGFB pathway genes (TGFBR1, TGFBR2, and SMAD3). In colorectal adenocarcinomas, we also found an inverse correlation between expression of genes in the TGFB signaling pathway and genes that regulate stem cell features of cells. We found mutations encoding L640I and A643T in the B3 domain of human CEACAM5 in colorectal adenocarcinomas; structural studies indicated that these mutations would alter the interaction between CEACAM5 and TGFBR1. Overexpression of these mutants in SW480 and HCT116 colorectal cancer cell lines increased their anchorage-independent proliferation and inhibited TGFB signaling to a greater extent than overexpression of wild-type CEACAM5, indicating that they are gain of function mutations. Compared with feces from wild-type mice, feces from mice with defects in TGFB signaling had increased abundance of bacterial species that have been associated with the development of colon tumors, including Clostridium septicum, and decreased amounts of beneficial bacteria such as Bacteroides vulgatus and Parabacteroides distasonis.CONCLUSIONWe found expression of CEACAMs and genes that regulate stem cell features of cells to be increased in colorectal adenocarcinomas and inversely correlated with expression of TGFB pathway genes. We found colorectal adenocarcinomas to express mutant forms of CEACAM5 that inhibit TGFB signaling and increase proliferation and colony formation. We propose that CEACAM proteins disrupt TGFB signaling, which alters the composition of the intestinal microbiome to promote colorectal carcinogenesis.
       
  • Mouse Models of Human Gastric Cancer Subtypes with Stomach-Specific
           CreERT2-Mediated Pathway Alterations
    • Abstract: Publication date: Available online 1 October 2019Source: GastroenterologyAuthor(s): Therese Seidlitz, Yi-Ting Chen, Heike Uhlemann, Sebastian Schölch, Susan Kochall, Sebastian R. Merker, Anna Klimova, Alexander Hennig, Christine Schweitzer, Kristin Pape, Gustavo B. Baretton, Thilo Welsch, Daniela E. Aust, Jürgen Weitz, Bon-Kyoung Koo, Daniel E. StangeAbstractBackground & AimsPatterns of genetic alterations characterize different molecular subtypes of human gastric cancer. We aimed to establish mouse models of these subtypes.MethodsWe searched database to identify Anxa10 with exclusive expression in the stomach epithelium. We generated mice with tamoxifen-inducible Cre recombinase (CreERT2) in the Anxa10 gene locus. We created 3 mouse models with alterations in pathways that characterize the chromosomal instability (CIN) and the genomically stable (GS) subtypes of human gastric cancer: Anxa10-CreERT2;KrasG12D/+;Tp53R172H/+;Smad4fl/f (CIN mice), Anxa10-CreERT2; Cdh1fl/fl; KrasG12D/+, Smad4fl/fl (GS-TGBF mice), and Anxa10-CreERT2; Cdh1fl/fl; KrasG12D/+; Apcfl/fl (GS-Wnt mice). We analyzed tumors that developed in these mice by histology for cell types and metastatic potential. We derived organoids from the tumors and tested their response to chemotherapeutic agents and the EGFR signaling pathway inhibitor trametinib.ResultsThe gastric tumors from the CIN mice had an invasive phenotype and formed liver and lung metastases. The tumor cells had a glandular morphology, similar to human intestinal type gastric cancer. The gastric tumors from the GS-TGFB mice were poorly differentiated with diffuse morphology and signet ring cells, resembling human diffuse-type gastric cancer. Cells from these tumors were invasive and mice developed peritoneal carcinomatosis as well as lung metastases. GS-Wnt mice developed adenomatous tooth-like gastric cancer. Organoids derived from tumors of GS-TGBF and GS-Wnt mice were more resistant to docetaxel, whereas organoids from the CIN tumors were more resistant to trametinib.ConclusionsUsing a stomach-specific CreERT2 system, we created mice that develop tumors with morphologic similarities to subtypes of human gastric cancer. These tumors have different patterns of local growth, metastasis, and response to therapeutic agents. They can be used to study different subtypes of human gastric cancer.
       
  • Efficacy and Safety of Early vs Elective Colonoscopy for Acute Lower
           Gastrointestinal Bleeding
    • Abstract: Publication date: Available online 26 September 2019Source: GastroenterologyAuthor(s): Ryota Niikura, Naoyoshi Nagata, Atsuo Yamada, Tetsuro Honda, Kenkei Hasatani, Naoki Ishii, Yasutoshi Shiratori, Hisashi Doyama, Tsutomu Nishida, Tetsuya Sumiyoshi, Tomoki Fujita, Shu Kiyotoki, Tomoyuki Yada, Katsumi Yamamoto, Tomohiro Shinozaki, Munenori Takata, Tatsuya Mikami, Katsuhiro Mabe, Kazuo Hara, Mitsuhiro FujishiroAbstractBackground & AimsWe performed a large, multicenter randomized controlled trial to determine the efficacy and safety of early colonoscopy on outcomes of patients with acute lower-gastrointestinal bleeding (ALGIB).MethodsWe performed an open-label study, at 15 hospitals in Japan, of 170 patients with ALGIB randomly assigned (1:1) to groups that underwent early colonoscopy (within 24 hrs of initial visit to the hospital) or elective colonoscopy (24–96 hrs after hospital admission). The primary outcome was identification of stigmata of recent hemorrhage (SRH). Secondary outcomes were rebleeding within 30 days, endoscopic treatment success, need for transfusion, length of stay, thrombotic events within 30 days, death within 30 days, and adverse events.ResultsSRH were identified in 17/79 patients (21.5%) in the early colonoscopy group vs 17/80 patients (21.3%) in the elective colonoscopy group (difference=0.3, 95% CI, –12.5 to 13.0; P=.967). Rebleeding within 30 days of hospital admission occurred in 15.3% of patients in the early colonoscopy group and 6.7% of patients in the delayed colonoscopy group (difference=8.6, 95% CI, -1.4 to 18.7); there were no significant differences between groups in successful endoscopic treatment rate, transfusion rate, length of stay, thrombotic events, or death within 30 days. The adverse event of hemorrhagic shock occurred during bowel preparation in no patient in the early group vs 2 patients (2.5%) in the delayed colonoscopy group.ConclusionsIn a randomized controlled study, we found that colonoscopy within 24 hrs after hospital admission did not increase SRH or reduce rebleeding compared with colonoscopy at 24–96 hrs in patients with ALGIB. ClinicalTrials.gov no: UMIN000021129 and NCT03098173
       
  • Crohn’s disease with progressive renal impairment
    • Abstract: Publication date: Available online 26 September 2019Source: GastroenterologyAuthor(s): Jakob Benedict Seidelin, Lene Buhl Riis, Rizwan Ahmed Butt
       
  • Colorectal Cancer Incidence and Mortality After Removal of Adenomas During
           Screening Colonoscopies
    • Abstract: Publication date: Available online 26 September 2019Source: GastroenterologyAuthor(s): Paulina Wieszczy, Michal F. Kaminski, Robert Franczyk, Magnus Loberg, Jarek Kobiela, Maria Rupinska, Bartlomiej Kocot, Maciej Rupinski, Oyvind Holme, Urszula Wojciechowska, Joanna Didkowska, David Ransohoff, Michael Bretthauer, Mette Kalager, Jaroslaw RegulaAbstract:Background & AimsRecommendation of surveillance colonoscopy should be based on risk of colorectal cancer and death after adenoma removal. We aimed to develop risk classification system based on colorectal cancer incidence and mortality following adenoma removal.MethodsWe performed a multicenter population-based cohort study of 236,089 individuals (median patient age, 56 years; 37.8% male) undergoing screening colonoscopies with adequate bowel cleansing and cecum intubation at 132 centers in the Polish National Colorectal Cancer Screening Program, from 2000 through 2011. Subjects were followed for a median 7.1 years and information was collected on colorectal cancer development and death. We used recursive partitioning and multivariable Cox models to identify associations between colorectal cancer risk and patient and adenoma characteristics (diameter, growth pattern, grade of dysplasia and number of adenomas). We developed a risk classification system based on standardized incidence ratios, using data from the Polish population for comparison. The primary endpoints were colorectal cancer incidence and colorectal cancer death.ResultsWe identified 130 colorectal cancers in individuals who had adenomas removed at screening (46.5 per 100,000 person-years) vs 309 in individuals without adenomas (22.2 per 100,000 person-years). Compared with individuals without adenomas, adenomas ≥20 mm in diameter and high-grade dysplasia were associated with increased risk of colorectal cancer (adjusted hazard ratios, 9.25; 95% CI, 6.39–13.39 and 3.58; 95% CI, 1.96–6.54, respectively). Compared with the general population, colorectal cancer risk was higher or comparable only for individuals with adenomas ≥20 mm in diameter (standardized incidence ratio [SIR], 2.07; 95% CI, 1.40–2.93) or with high-grade dysplasia (SIR, 0.79; 95% CI, 0.39–1.41), whereas for individuals with other adenoma characteristics the risk was lower (SIR, 0.35; 95% CI, 0.28–0.44). We developed a high-risk classification based on adenoma size ≥20 mm or high-grade dysplasia (instead of the current high-risk classification cutoff of ≥3 adenomas or any adenoma with villous growth pattern, high-grade dysplasia, or ≥10 mm in diameter). Our classification system would reduce the number of individuals classified as high-risk and requiring intensive surveillance from 15,242 (36.5%) to 3980 (9.5%), without increasing risk of colorectal cancer in patients with adenomas (risk difference per 100,000 person-years, 5.6; 95% CI, –10.7 to 22.0).ConclusionsUsing data from the Polish National Colorectal Cancer Screening Program, we developed a risk classification system that would reduce the number of individuals classified as high risk and require intensive surveillance more than 3-fold, without increasing risk of colorectal cancer in patients with adenomas. This system could optimize the use of surveillance colonoscopy.
       
  • "Double Lumen" Esophagus - A Striking Endoscopic Finding
    • Abstract: Publication date: Available online 26 September 2019Source: GastroenterologyAuthor(s): Anish Vinit Patel, Ishita Dalal
       
  • An unusual web stricture in the cervical esophagus
    • Abstract: Publication date: Available online 26 September 2019Source: GastroenterologyAuthor(s): Yuhei Umeda, Kyosuke Tanaka, Reiko Yamada
       
  • Ability of Noninvasive Scoring Systems to Identify Individuals in the
           Population at Risk for Severe Liver Disease
    • Abstract: Publication date: Available online 26 September 2019Source: GastroenterologyAuthor(s): Hannes Hagström, Mats Talbäck, Anna Andreasson, Göran Walldius, Niklas HammarAbstractBackground & AimsNon-invasive scoring systems are used to identify persons with advanced liver fibrosis. We investigated the ability of scoring systems to identify individuals in the general population at risk for future liver-related events.MethodsWe collected data from the Swedish Apolipoprotein Mortality Risk cohort on persons 35–79 years old who had blood samples collected from 1985 through 1996. We collected APRI (n=127,302), BARD (n=75,303), FIB-4 (n=126,941), Forns (n=122,419), and the nonalcoholic fatty liver disease (NAFLD) fibrosis scores (NFS, n=13,160). We ascertained incident cases of cirrhosis or complications by linking Swedish health data registers. Cox regression was used to estimate hazard ratios (HRs) for severe liver disease at 5, 10, and a maximum follow-up time of 27 years. The predictive ability of the scores was evaluated using area under the receiver operating characteristic (AUROC) curve and C-statistics analyses. Our specific aims were to investigate the predictive capabilities of scoring systems for fatal and non-fatal liver disease, determine which scoring system has the highest level of accuracy, and investigate the predictive abilities of the scoring systems in persons with a higher probability of NAFLD at baseline.ResultsA similar proportion of individuals evaluated by each scoring system developed cirrhosis or complications thereof (1.0%–1.4%). The incidence of any outcome was increased in intermediate- and high-risk groups compared with low-risk groups, with HRs at 10 years in the high-risk group ranging from 1.67 for the BARD score to 45.9 for the APRI score. The predictive abilities of all scoring systems decreased with time and were higher in men. All scoring systems were more accurate in persons with risk factors for NAFLD at baseline, with AUROCs reaching 0.83.ConclusionsHigher scores from non-invasive scoring systems to evaluate fibrosis are associated with an increased risk of cirrhosis in a general population, but their predictive ability is modest. Performance was better when patients were followed for shorter time periods and in persons with a higher risk of NAFLD, with AUROC values reaching 0.83. New scoring systems are needed to evaluate risk of fibrosis in the general population and in primary care.
       
  • Chemoprevention of Colorectal Cancer
    • Abstract: Publication date: Available online 26 September 2019Source: GastroenterologyAuthor(s): Bryson W. Katona, Jennifer M. WeissAbstractAlthough colorectal cancer (CRC) screening has reduced the incidence and mortality from CRC, chemoprevention strategies have potential to further reduce CRC incidence and mortality. Chemoprevention agents might be used for average-risk as well as high-risk groups, and to prevent colorectal cancer recurrence after therapy. CRC chemoprevention agents that have been studied include aspirin, non-aspirin non-steroidal anti-inflammatory drugs, statins, agents that target metabolic pathways, and vitamins and minerals. We review the prospect of chemoprevention of CRC, results from preclinical and human studies, challenges, and future directions.
       
  • An Uncommon Cause of Cholecystitis
    • Abstract: Publication date: Available online 25 September 2019Source: GastroenterologyAuthor(s): Laureline Moser, Ismail Labgaa, Luca Di Mare
       
  • Multiple polypoid lesions in the sigmoid colon
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Joon Woo Park, Dong Hoon Baek, So Jeong Lee
       
  • An unusual cause of left lower quadrant abdominal pain
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Chia-Che Chen, Chien-Jui Cheng, Li-Jen Kuo
       
  • An unusual cause of acute massive lower gastrointestinal bleeding
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Meng Xue, Wei-hong Weng, Liang-jing Wang
       
  • Unusual case of repeated hospitalisation of a young man
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Abdelkader Taibi, Anne Guyot, Jeremie Jacques
       
  • A dramatic gastric distension
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Roberto Grassia, Marino Daniel Gusolfino, Clara Benedetta Conti
       
  • Acute epigastric pain after gastric endoscopic submucosal dissection
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Neal Shahidi, Scott Schoeman, Michael J. Bourke
       
  • Preparation of Gluten-Free Foods Alongside Gluten-Containing Food May Not
           Always Be as Risky for Celiac Patients as Diet Guides Suggest
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Vanessa M. Weisbrod, Jocelyn A. Silvester, Catherine Raber, Joyana McMahon, Shayna S. Coburn, Benny Kerzner
       
  • Intermittent severe epigastoric pain and abdominal bruit varying with
           respiration
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Hiroki Matsuura, Atsushi Okita, Yu Suganami
       
  • The Key to a Boy’s Heart is Through His Intestine
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Amir Jazayeri, Dieudonne Nonga, Meenakshi Rao
       
  • The cause of melena in a female with Von Hippel-Lindau disease
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Peace Eneh, Priya Vijayvargiya, Conor Loftus
       
  • A stony cause of GI bleeding
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): V. Zimmer, K. Emrich
       
  • Unilateral Scrotal Swelling after Acute Pancreatitis of Pancreas
           Transplant Graft
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Scott Ketcham, Kevin D. Platt, Matthew J. DiMagno
       
  • New onset diffuse parenchymal lung disease in a 52-year old female with
           ulcerative colitis
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Eva De Backer, Hannelore Bode, Filip Baert
       
  • Dyspnea in Hepatocellular Carcinoma
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Al Tripathi, Raj Paspulati, Stanley Martin Cohen
       
  • Septic shock after travel to rural Africa
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Bill Quach, Samuel Han, Augustin Attwell
       
  • Getting to the Root of the Problem
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Jennifer Wang, Oliver S. Eng, Dejan Micic
       
  • Genomic and Epigenomic Features of Primary and Recurrent Hepatocellular
           Carcinomas
    • Abstract: Publication date: Available online 24 September 2019Source: GastroenterologyAuthor(s): Xiaofan Ding, Mian He, Anthony W.H. Chan, Qi Xiu Song, Siu Ching Sze, Hui Chen, Matthew K.H. Man, Kwan Man, Stephen L. Chan, Paul B.S. Lai, Xin Wang, Nathalie WongAbstract:Background & AimsIntratumor heterogeneity and divergent clonal lineages within and among primary and recurrent hepatocellular carcinomas (HCCs) produce challenges to patient management. We investigated genetic and epigenetic variations within liver tumors, among hepatic lesions, and between primary and relapsing tumors.MethodsTumor and matched non-tumor liver specimens were collected from 113 patients who underwent partial hepatectomy for primary or recurrent HCC at 2 hospitals in Hong Kong. We performed whole-genome, whole-exome, or targeted capture sequencing analyses of 356 HCC specimens collected from multiple tumor regions and matched initial and recurrent tumors. We performed parallel DNA methylation profiling analyses of 95 specimens. Genomes and epigenomes of non-tumor tissues that contained areas of cirrhosis or fibrosis were analyzed. We developed liver cancer cell lines that endogenously expressed a mutant form of TP53 (R249S) or overexpressed mutant forms of STAT3 (D170Y, K348E, and Y640F) or JAK1 (S703I and L910P) and tested the abilities of pharmacologic agents to reduce activity. Cells were analyzed by immunoblotting and chromatin immunoprecipitation with quantitative PCR.ResultsWe determined the monoclonal origins of individual tumors using a single sample collection approach that captured more than 90% of mutations that are detected in all regions of tumors. Phylogenetic and phylo-epigenetic analyses revealed interactions and codependence between the genomic and epigenomic features of HCCs. Methylation analysis revealed a field effect in cirrhotic liver tissues that predisposes them to tumor development. Comparisons of genetic features revealed that 52% of recurrent HCCs derive from the clonal lineage of the initial tumor. The clonal origin if recurrent HCCs allowed construction of a temporal map of genetic alterations that associated with tumor recurrence. Activation of JAK signaling to STAT was a characteristic of HCC progression via mutations that associate with response to drug sensitivity. The combination of a mutation that increases the function of TP53 and the 17p chromosome deletion might provide liver cancer cells with a replicative advantage. Chromatin immunoprecipitation analysis of TP53 with the R249S substitution revealed its interaction with genes that encode chromatin regulators (MLL1 and MLL2). We validated MLL1 and MLL2 as direct targets of TP53R249S and affirmed their association in the cancer genome atlas dataset. The MLL-complex antagonists MI-2-2 (inhibitor of protein interaction) and OICR-9492 (inhibitor of activity) specifically inhibited proliferation of HCC cells that express TP53R249S at nanomolar concentrations.ConclusionsWe performed a systematic evaluation of intra- and inter-tumor genetic heterogeneity in HCC samples and identified genetic and epigenetic changes that associate with tumor progression and recurrence. We identified chromatin regulators that are upregulated by mutant TP53 in HCC cells and inhibitors that reduce proliferation of these cells. DNA methylation patterns in cirrhotic or fibrotic liver tissues might be used to identify those at risk of HCC development.
       
  • Reply
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Jana C. Mossanen, Frank Tacke
       
  • Genome-Wide Association Studies of Drug-Induced Liver Injury Make Progress
           Beyond the HLA Region
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Galen E.B. Wright, Britt I. Drögemöller, Colin J.D. Ross, Bruce C. Carleton
       
  • Evolving Trends in Machine Liver Perfusion: Comments on Clinical End
           Points and Selection Criteria
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Zoltan Czigany, Frank Tacke, Georg Lurje
       
  • Reply
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Sudarshan Paramsothy, Nadeem O. Kaakoush
       
  • Roseburia Species: Prime Candidates for Microbial Therapeutics in
           Inflammatory Bowel Disease
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Richard Kellermayer
       
  • Reply
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Vinay Sundaram, Rajiv Jalan
       
  • Factors Associated With Survival of Patients With Severe Acute-On-Chronic
           Liver Failure Before and After Liver Transplantation: Unanswered Questions
           
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Narendra S. Choudhary, Neeraj Saraf, Sanjiv Saigal, Arvinder S. Soin
       
  • Reply
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Konstantinos Gerasimidis, Vaios Svolos, Ben Nichols, Rodanthi Papadopoulou, Christopher Quince, Umer Z. Ijaz, Simon Milling, Daniel R. Gaya, Richard K. Russell, Richard Hansen
       
  • Treatment of Active Crohn’s Disease With an Ordinary Food-Based Diet
           That Replicates Exclusive Enteral Nutrition
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): James J. Ashton, R. Mark Beattie
       
  • Single Dose Aspirin before Fecal Immunochemical Testing Does Not Increase
           Sensitivity for Advanced Colorectal Neoplasia
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Brian Sullivan, Jatin Roper
       
  • Towards Precision Medicine in Nonalcoholic Fatty Liver Disease with PNPLA3
           as a Therapeutic Target
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Massimo Colombo, Serena Pelusi
       
  • MET Signaling Overcomes Epidermal Growth Factor Receptor Inhibition in
           Normal and Colorectal Cancer Stem Cells Causing Drug Resistance
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Sander P.J. Joosten, Tomohiro Mizutani, Marcel Spaargaren, Hans Clevers, Steven T. Pals
       
  • CME Exam 4: Microbiome Signatures Associated with Steatohepatitis and
           Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver
           Disease
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s):
       
  • CME Exam 3: Epithelial Indoleamine 2,3-Dioxygenase 1 Modulates Aryl
           Hydrocarbon Receptor and Notch Signaling to Increase Differentiation of
           Secretory Cells and Alter Mucus-Associated Microbiota
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s):
       
  • CME Exam 2: An Unexpected Consequence of a Clinical Trial
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s):
       
  • CME Exam 1: Feasibility of Using Hydrogel Spacers for
           Borderline-Resectable and Locally Advanced Pancreatic Tumors
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s):
       
  • Gene Expression Signatures Associated With Survival Times of Pediatric
           Patients With Biliary Atresia Identify Potential Therapeutic Agents
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Zhenhua Luo, Pranavkumar Shivakumar, Reena Mourya, Sridevi Gutta, Jorge A. BezerraBackground & AimsLittle is known about the factors that affect outcomes of patients with biliary atresia and there are no medical therapies that increase biliary drainage.MethodsLiver biopsies and clinical data were obtained from infants with cholestasis and from children without liver disease (controls); messenger RNA (mRNA) was isolated, randomly assigned to discovery (n = 121) and validation sets (n = 50), and analyzed by RNA sequencing. Using the Superpc R package followed by Cox regression analysis, we sought to identify gene expression profiles that correlated with survival without liver transplantation at 24 months of age. We also searched for combinations of gene expression patterns, clinical factors, and laboratory results obtained at diagnosis and at 1 and 3 months after surgery that associated with transplant-free survival for 24 months of age. We induced biliary atresia in BALB/c mice by intraperitoneal administration of Rhesus rotavirus type A. Mice were given injections of the antioxidants N-acetyl-cysteine (NAC) or manganese (III) tetrakis-(4-benzoic acid)porphyrin. Blood and liver tissues were collected and analyzed by histology and immunohistochemistry.ResultsWe identified a gene expression pattern of 14 mRNAs associated with shorter vs longer survival times in the discovery and validation sets (P < .001). This gene expression signature, combined with level of bilirubin 3 months after hepatoportoenterostomy, identified children who survived for 24 months with an area under the curve value of 0.948 in the discovery set and 0.813 in the validation set (P < .001). Computer models correlated a cirrhosis-associated transcriptome with decreased times of transplant-free survival; this transcriptome included activation of genes that regulate the extracellular matrix and numbers of activated stellate cells and portal fibroblasts. Many mRNAs expressed at high levels in liver tissues from patients with 2-year transplant-free survival had enriched scores for glutathione metabolism. Among mice with biliary atresia given injections of antioxidants, only NAC reduced histologic features of liver damage and serum levels of aminotransferase, gamma-glutamyl transferase, and bilirubin. NAC also reduced bile duct obstruction and liver fibrosis and increased survival times.ConclusionsIn studies of liver tissues from infants with cholestasis, we identified a 14-gene expression pattern that associated with transplant-free survival for 2 years. mRNAs encoding proteins that regulate fibrosis genes were increased in liver tissues from infants who did not survive for 2 years, whereas mRNAs that encoded proteins that regulate glutathione metabolism were increased in infants who survived for 2 years. NAC reduced liver injury and fibrosis in mice with biliary atresia, and increased survival times. Agents such as NAC that promote glutathione metabolism might be developed for treatment of biliary atresia.Graphical abstractGraphical abstract for this article
       
  • Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent
           Clones, Each With Distinct Mutations
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(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 LennonBackground & AimsIntraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute 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 < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis.ConclusionsIn an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.Graphical abstractGraphical abstract for this article
       
  • Microbiome Signatures Associated With Steatohepatitis and Moderate to
           Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Jeffrey B. Schwimmer, Jethro S. Johnson, Jorge E. Angeles, Cynthia Behling, Patricia H. Belt, Ingrid Borecki, Craig Bross, Janis Durelle, Nidhi P. Goyal, Gavin Hamilton, Mary L. Holtz, Joel E. Lavine, Makedonka Mitreva, Kimberly P. Newton, Amy Pan, Pippa M. Simpson, Claude B. Sirlin, Erica Sodergren, Rahul Tyagi, Katherine P. YatesBackground & AimsThe intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD.MethodsWe performed a prospective, observational, cross-sectional study of 87 children (age range, 8–17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis.ResultsFecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-d-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87).ConclusionsIn an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.
       
  • Epithelial Indoleamine 2,3-Dioxygenase 1 Modulates Aryl Hydrocarbon
           Receptor and Notch Signaling to Increase Differentiation of Secretory
           Cells and Alter Mucus-Associated Microbiota
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): David M. Alvarado, Baosheng Chen, Micah Iticovici, Ameet I. Thaker, Nattalie Dai, Kelli L. VanDussen, Nurmohammad Shaikh, Chai K. Lim, Gilles J. Guillemin, Phillip I. Tarr, Matthew A. CiorbaBackground & AimsInflammation, injury, and infection up-regulate expression of the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the intestinal epithelium. We studied the effects of cell-specific IDO1 expression in the epithelium at baseline and during intestinal inflammation in mice.MethodsWe generated transgenic mice that overexpress fluorescence-tagged IDO1 in the intestinal epithelium under control of the villin promoter (IDO1-TG). We generated intestinal epithelial spheroids from mice with full-length Ido1 (controls), disruption of Ido1 (knockout mice), and IDO1-TG and analyzed them for stem cell and differentiation markers by real-time polymerase chain reaction, immunoblotting, and immunofluorescence. Some mice were gavaged with enteropathogenic Escherichia coli (E2348/69) to induce infectious ileitis, and ileum contents were quantified by polymerase chain reaction. Separate sets of mice were given dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid to induce colitis; intestinal tissues were analyzed by histology. We utilized published data sets GSE75214 and GDS2642 of RNA expression data from ilea of healthy individuals undergoing screening colonoscopies (controls) and patients with Crohn’s disease.ResultsHistologic analysis of small intestine tissues from IDO1-TG mice revealed increases in secretory cells. Enteroids derived from IDO1-TG intestine had increased markers of stem, goblet, Paneth, enteroendocrine, and tuft cells, compared with control enteroids, with a concomitant decrease in markers of absorptive cells. IDO1 interacted non-enzymatically with the aryl hydrocarbon receptor to inhibit activation of NOTCH1. Intestinal mucus layers from IDO1-TG mice were 2-fold thicker than mucus layers from control mice, with increased proportions of Akkermansia muciniphila and Mucispirillum schaedleri. Compared to controls, IDO1-TG mice demonstrated an 85% reduction in ileal bacteria (P = .03) when challenged with enteropathogenic E coli, and were protected from immune infiltration, crypt dropout, and ulcers following administration of dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid. In ilea of Crohn’s disease patients, increased expression of IDO1 correlated with increased levels of MUC2, LYZ1, and aryl hydrocarbon receptor, but reduced levels of SLC2A5.ConclusionsIn mice, expression of IDO1 in the intestinal epithelial promotes secretory cell differentiation and mucus production; levels of IDO1 are positively correlated with secretory cell markers in ilea of healthy individuals and Crohn’s disease patients. We propose that IDO1 contributes to intestinal homeostasis.Graphical abstractGraphical abstract for this article
       
  • Imbalance of Genes Encoding Natural Killer Immunoglobulin-Like Receptors
           and Human Leukocyte Antigen in Patients With Biliary Cancer
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Martin Cornillet, Hannes Jansson, Marie Schaffer, Laura Hertwig, Lena Berglin, Christine L. Zimmer, Helene Johansson, Ewa Ellis, Bengt Isaksson, Faviel F. Gonzalez-Galarza, Derek Middleton, Karl-Johan Malmberg, Ernesto Sparrelid, Niklas K. BjörkströmBackground & AimsBile duct tumors are rare and have poor prognoses. Natural killer (NK) cells are frequent in human liver and infiltrate these tumors but do not control their progression. Responses of NK cells are regulated by NK immunoglobulin-like receptors (KIRs), which interact with HLA class I ligands. We aimed to characterize the features of the KIR gene loci and their ligands in patients with bile duct cancer (BDC).MethodsWe performed combined multidimensional characterization of genes that encode KIRs and their ligands in blood samples from patients with BDC from Sweden, followed for up to 8 years after diagnosis (n = 148), in 2 geographically matched cohorts of healthy individuals from Northern Europe (n = 204 and n = 900), and in healthy individuals from 6 geographically unrelated populations (n = 2917). We used real-time polymerase chain reaction, RNA sequencing, immunohistochemistry, and flow cytometry to evaluate NK-cell presence, as well as KIR and KIR-ligand expression in bile duct tumors and control tissues.ResultsPatients with bile duct tumors had multiple alterations at the KIR gene loci. KIR loci are grouped into genotypes that encode more inhibitory (group A) and more activating (group B) receptors, which can be subdivided into centromeric and telomeric fragments. Patients with BDC had a lower prevalence of KIR2DL3, which was linked to disequilibrium in centromeric A/B and B/B genotypes, compared with control individuals. The associations between KIRs and KIR ligands differed between patients with BDC and control individuals; patients had an altered balance between activating and inhibitory KIRs. KIR-positive NK cells infiltrated biliary tumors that expressed matched KIR ligands.ConclusionsIn a multidimensional analysis of DNA from blood samples of patients with BDC in Europe, we found patients to have multiple alterations at the KIR and HLA gene loci compared with control individuals. These alterations might affect NK-cell tumor surveillance. NK cells from bile duct tumors expressed KIRs and were found in tumors that expressed cognate ligands. This should be considered in development of immune-based therapies for BDC.Graphical abstractGraphical abstract for this article
       
  • Approaches to Integrating Biomarkers Into Clinical Trials and Care
           Pathways as Targets for the Treatment of Inflammatory Bowel Diseases
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Parambir S. Dulai, Laurent Peyrin-Biroulet, Silvio Danese, Bruce E. Sands, Axel Dignass, Dan Turner, Gerassimos Mantzaris, Juergen Schölmerich, Jean-Yves Mary, Walter Reinisch, William J. SandbornBackground & AimsThere is no consensus on the best way to integrate biomarkers into inflammatory bowel disease (IBD) research and clinical practice. The International Organization for the Study of Inflammatory Bowel Disease aimed to outline biomarker definitions, categories, and operating properties required for their use in registration trials and clinical practice. Using fecal calprotectin as an example, we provide a framework for biomarker development and validation in patients with IBD.MethodsWe reviewed international society guidelines, regulatory agency guidance documents, and standardized reporting guidelines for biomarkers, in combination with publications on fecal calprotectin levels in patients with IBD. We assessed the validity of fecal calprotectin to serve as a surrogate biomarker of IBD activity and outlined a framework for further validation and development of biomarkers.ResultsNo endpoints have been fully validated as surrogates of risk of disease complications; mucosal healing is the most valid endpoint used to determine risk of disease complications. Fecal level of calprotectin has not been validated as a biomarker for IBD activity because of lack of technical and clinical reliability, assessment of performance when used as a replacement for endoscopy, and assessment of responsiveness to changes in disease states. The level of fecal calprotectin can be used only as a prognostic factor for disease recurrence in patients in remission after medical or surgical treatment.ConclusionsWe reviewed guidelines, regulatory documents, and publications to identify properties required for the development of biomarkers of IBD activity and areas in need of clarification from regulatory agencies and societies. We propose a path forward for research of biomarkers for IBD.
       
  • Effects of Ustekinumab on Histologic Disease Activity in Patients With
           Crohn’s Disease
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Katherine Li, Joshua R. Friedman, Daphne Chan, Paul Pollack, Feifei Yang, Douglas Jacobstein, Carrie Brodmerkel, Christopher Gasink, Brian G. Feagan, William J. Sandborn, Paul Rutgeerts, Gert De HertoghBackground & AimsAlthough ustekinumab is an effective therapy for moderate to severe Crohn’s disease (CD), its effects on the microscopic manifestations of CD are unknown.MethodsWe evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs).ResultsAt week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline.ConclusionsIn an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355.
       
  • Vedolizumab Induces Endoscopic and Histologic Remission in Patients With
           Crohn’s Disease
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(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’HaensBackground & 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 weeks.ResultsAt weeks 26 and 52, 36 patients (29%) and 34 patients (31%), respectively, were in corticosteroid-free clinical remission (CDAI score
       
  • More Evidence Needed on the Combination of Diclofenac and Sublingual
           Nitrates in Preventing Pancreatitis After Endoscopic Retrograde
           Cholangiopancreatography
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Zhi-Feng Zhang
       
  • Terminology, Molecular Features, Epidemiology, and Management of Serrated
           Colorectal Neoplasia
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Seth D. Crockett, Iris D. NagtegaalIn addition to the adenoma to carcinoma sequence, colorectal carcinogenesis can occur via the serrated pathway. Studies have focused on clarification of categories and molecular features of serrated polyps, as well as endoscopic detection and risk assessment. Guidelines from the World Health Organization propose assigning serrated polyps to categories of hyperplastic polyps, traditional serrated adenomas, and sessile serrated lesions (SSLs). Traditional serrated adenomas and SSLs are precursors to colorectal cancer. The serrated pathway is characterized by mutations in RAS and RAF, disruptions to the Wnt signaling pathway, and widespread methylation of CpG islands. Epidemiology studies of serrated polyps have been hampered by inconsistencies in terminology and reporting, but the prevalence of serrated class polyps is 20%–40% in average-risk individuals; most serrated polyps detected are hyperplastic. SSLs, the most common premalignant serrated subtype, and are found in up to 15% of average-risk patients by high-detecting endoscopists. Variations in rate of endoscopic detection of serrated polyps indicate the need for careful examination, with adequate bowel preparation and sufficient withdrawal times. Risk factors for SSLs include white race, family history of colorectal cancer, smoking, and alcohol intake. Patients with serrated polyps, particularly SSLs and traditional serrated adenomas, have an increased risk of synchronous and metachronous advanced neoplasia. Surveillance guidelines vary among countries, but SSLs and proximal hyperplastic polyps require special attention in assignment of surveillance interval—especially in light of concerns regarding incomplete detection and resection.
       
  • Massive Bleeding and Perforation With Endoscopic Multiple Deep Ulcers in a
           Patient With Ulcerative Colitis After Colectomy
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Lingna Ye, Zhinong Jiang, Qian Cao
       
  • An Unexpected Consequence of a Clinical Trial
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Daniel Bushyhead, Russell K. Dorer, Michael Gluck
       
  • Constipation With a Palpable Abdominal Mass in a Young Woman
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Yan-Jiun Huang, Hwa-Lin Kao, Wen-Ke Wang
       
  • Gastrointestinal Ulcers in a Patient With a Solitary Enlarged Lymph Node
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Kai-Ruo Wang, Zhen Li, Yan-Qing Li
       
  • Hepatitis, Pancreatitis and Rash in a Patient With Chronic Lymphocytic
           Leukemia
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Inuk Zandvakili, James W. Lloyd, Karthik V. Giridhar
       
  • Fist-Sized Radiographic Consolidation in a Man With Difficulty Swallowing
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Yi-Ming Chan, Wen-Hsin Huang
       
  • A Rare Cause of Paradoxical Nausea and Abdominal Pain
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Andree H. Koop, Raouf E. Nakhleh, Ming-Hsi Wang
       
  • Hemoperitoneum: From What, Where, and Why'
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Alex Zhornitskiy, Camellia Dalai, James H. Tabibian
       
  • On The Hot Seat: A Rare Cause of Rectal Pain
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Benjamin Nunley, Christopher Truss
       
  • Abnormal Polypoid Finding During Colonoscopy
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Frederick B. Peng, Hyun-seok Kim, Suneal K. Agarwal
       
  • “Doctor, I Just Can’t Seem to Swallow!”
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Anusha Shirwaikar Thomas, Jae Y. Ro, Gulchin A. Ergun
       
  • A Rare Complication of Peptic Ulcer Disease
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Savan Kabaria, Kalpesh G. Patel, Sushil Ahlawat
       
  • Feasibility of Using Hydrogel Spacers for Borderline-Resectable and
           Locally Advanced Pancreatic Tumors
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Tossapol Kerdsirichairat, Amol K. Narang, Elizabeth Thompson, Seong-Hun Kim, Avani Rao, Kai Ding, Eun Ji Shin
       
  • Intraductal Papillary Mucinous Neoplasms: Attack of the Clones
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Harrys K.C. Jacob, Sulagna Banerjee
       
  • Taking a Closer Look at the Biogeography of the Human Gastrointestinal
           Microbiome
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Melinda Engevik, James Versalovic
       
  • Ver(s)ifying the Efficacy of Vedolizumab Therapy on Mucosal Healing in
           Patients With Crohn’s Disease
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Lorant Gonczi, Talat Bessissow, Peter Lakatos
       
  • Is It Prime Time for Proactive Therapeutic Drug Monitoring of Anti-Tumor
           Necrosis Factor Therapy in Inflammatory Bowel Disease'
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Konstantinos Papamichael, Adam S. Cheifetz
       
  • How to Advance Research, Education, and Training in the Study of Rare
           Diseases
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Stephen C. Groft, Rashmi Gopal-Srivastava, Evan S. Dellon, Sandeep K. Gupta
       
  • Hepatitis C Virus Infection in Patients With Cancer: Impact on Clinical
           Trial Enrollment, Selection of Therapy, and Prognosis
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Harrys A. Torres, Pooja Pundhir, Vincent Mallet
       
  • Information for Authors and Readers
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s):
       
  • Elsewhere in The AGA Journals
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s):
       
  • Cover 1
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s):
       
  • Role of CXCR6-Deficient Natural Killer T Cells and CD4 T Cells in
           Hepatocarcinogenesis
    • Abstract: Publication date: October 2019Source: Gastroenterology, Volume 157, Issue 4Author(s): Huan Tao, Xuyong Chen
       
  • Cancer after colonoscopy: Are we sowing bad seeds'
    • Abstract: Publication date: Available online 20 September 2019Source: GastroenterologyAuthor(s): James E. East
       
  • Adipose derived therapeutic products for management of refractory
           Crohn’s fistula
    • Abstract: Publication date: Available online 19 September 2019Source: GastroenterologyAuthor(s): Fanny Grimaud, Mélanie Serrero, Jérémy Magalon
       
  • A summary of education scholarship presented at DDW 2019, and a vision for
           the future
    • Abstract: Publication date: Available online 19 September 2019Source: GastroenterologyAuthor(s): Christen K. Dilly, Matthew J. Whitson, Sheryl A. Pfeil, Arthur J. DeCross
       
  • Cost-effectiveness and National Effects of Initiating Colorectal Cancer
           Screening for Average-risk Persons at Age 45 Years Instead of 50 Years
    • Abstract: Publication date: Available online 19 September 2019Source: GastroenterologyAuthor(s): Dennis J. Ahnen, Swati G. Patel
       
  • Plasticity of Th17 cells contributes to Crohn’s disease
    • Abstract: Publication date: Available online 19 September 2019Source: GastroenterologyAuthor(s): Yuan Guo, Ai Ping Bai
       
  • Weight loss and granulomatous liver disease
    • Abstract: Publication date: Available online 16 September 2019Source: GastroenterologyAuthor(s): Hashroop Gurm, Daniel S. Jamorabo, Smruti R. Mohanty
       
  • Report from the AGA Center for GI Innovation and Technology’s Consensus
           Conference: Envisioning Next-Generation Paradigms in Colorectal Cancer
           Screening and Surveillance
    • Abstract: Publication date: Available online 13 September 2019Source: GastroenterologyAuthor(s): Neelendu Dey, Michael L. Kochman, Srinadh Komanduri, Joshua E. Melson, V. Raman Muthusamy
       
  • Factors to Consider in Development of Drugs for Pediatric Nonalcoholic
           Fatty Liver Disease
    • Abstract: Publication date: Available online 12 September 2019Source: GastroenterologyAuthor(s): Miriam B. Vos, Lara Dimick-Santos, Ruby Mehta, Stephanie O. Omokaro, Johannes Taminiau, Elmer Schabel, David E. Kleiner, Peter Szitanyi, Piotr Socha, Jeffrey B. Schwimmer, Stephanie Noviello, Debra G. Silberg, Richard Torstenson, Veronica Miller, Joel E. Lavine
       
  • Suppressive and Gut Reparative Functions of Human Type 1 T-regulatory
           Cells
    • Abstract: Publication date: Available online 10 September 2019Source: GastroenterologyAuthor(s): Laura Cook, Martin Stahl, Xiao Han, Aisha Nazli, Katherine N. MacDonald, May Q. Wong, Kevin Tsai, Sara Dizzell, Kevan Jacobson, Brian Bressler, Charu Kaushic, Bruce A. Vallance, Theodore S. Steiner, Megan K. LevingsBackground & AimsT-regulatory (Treg) cells suppress the immune response to maintain homeostasis. There are 2 main subsets of Treg cells: FOXP3-positive Treg cells, which do not produce high levels of effector cytokines, and type 1 Treg (Tr1) cells, which are FOXP3-negative and secrete interleukin 10 (IL10). IL10 is an anti-inflammatory cytokine, so Tr1 cells might be used in treatment of inflammatory bowel diseases. We aimed to develop methods to isolate and expand human Tr1 cells and define their functions.MethodsWe obtained blood samples and colon biopsies from patients with Crohn’s disease or ulcerative colitis or healthy individuals (controls). CD4+ T cells were isolated from blood samples, stimulated with anti-CD3 and anti-CD28 beads, and Tr1 cells were purified using an IL10 cytokine-capture assay and cell sorting. FOXP3-positive Treg cells were sorted as CD4+CD25highCD127low cells from unstimulated cells. Tr1 and FOXP3-positive Treg cells were expanded, and phenotypes and gene expression profiles were compared. T cells in peripheral blood mononuclear cells from healthy donors were stimulated with anti-CD3 and anti-CD28 beads and the suppressive abilities of Tr1 and FOXP3-positive Treg cells were measured. Human colon organoid cultures were established, cultured with supernatants from Tr1 or FOXP3-positive cells, and analyzed by immunofluorescence and flow cytometry. T84 cells (human colon adenocarcinoma epithelial cells) were incubated with supernatants from Tr1 or FOXP3-positive cells and trans-epithelial electrical resistance was measured to determine epithelial cell barrier function.ResultsPhenotypes of Tr1 cells isolated from controls vs patients with Crohn’s disease or ulcerative colitis did not differ significantly following expansion. Tr1 cells and FOXP3-positive Treg cells suppressed proliferation of effector T cells, but only Tr1 cells suppressed secretion of IL1beta (IL1B) and TNF from myeloid cells. Tr1 cells, but not FOXP3-positive Treg cells, isolated from healthy subjects and patients with Crohn’s disease or ulcerative colitis secreted IL22, which regulated repair of the epithelium and promoted barrier function of human intestinal epithelial cells. Tr1 cell culture supernatants promoted differentiation of mucin-producing goblet cells in intestinal organoid cultures.ConclusionsHuman Tr1 cells suppress proliferation of effector T cells (adaptive immune response) and production of IL1B and TNF by myeloid cells (inmate immune response). They also secrete IL22 to regulate repair of the epithelium and promote barrier function. They might be developed as a cell-based therapy for intestinal inflammatory disorders.Graphical abstractGraphical abstract for this article
       
  • Covering the Cover
    • Abstract: Publication date: Available online 28 August 2019Source: GastroenterologyAuthor(s): Andrew T. Chan, Christopher S. Williams
       
  • In Memoriam: Henry T. Lynch, MD. (Jan 4, 1928- June 2, 2019)
    • Abstract: Publication date: Available online 28 August 2019Source: GastroenterologyAuthor(s): C. Richard Boland
       
 
 
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