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  • AN INSOLUBLE MYSTERY: FIBER AND DIVERTICULITIS
    Gastroenterology (IF 19.233) Pub Date : 2020-01-15
    Kara Wegermann; Jatin Roper

    Approximately 60% of adults over the age of 60 have diverticulosis, of whom 5% will experience complications such as diverticulitis or diverticular bleeding. There are an estimated 300,000 hospital admissions per year in the United States for diverticulitis (Clin Gastroenterol Hepatol 2013;11:1609-13). Despite this burden of disease, risk stratification and prevention strategies for diverticulitis are lacking. Based on the observation that diverticulitis prevalence is significantly higher in developed countries where diets are typically low in fiber, it has been hypothesized that high fiber intake is protective. However, the relationship between specific fiber sources and diverticulitis risk has been difficult to elucidate, as studies have used patient-reported diet data and have quantified fiber intake indirectly. Therefore, the paper by Ma et al. addresses a knowledge gap by evaluating whether subtypes of fiber, and/or particular foods, are associated with the risk for diverticulitis.

    更新日期:2020-01-15
  • AGA Technical Review on the Management of Moderate to Severe Ulcerative Colitis
    Gastroenterology (IF 19.233) Pub Date : 2020-01-13
    Siddharth Singh; Jessica R. Allegretti; Shazia Mehmood Siddique; Jonathan P. Terdiman

    A subset of patients with ulcerative colitis (UC) present with, or progress to, moderate to severe disease activity. These patients are at high-risk for colectomy, hospitalization, corticosteroid-dependence, and serious infections. The risk of life-threatening complications and emergency colectomy is particularly high among those patients hospitalized with acute severe ulcerative colitis (ASUC). Optimal management of outpatients or inpatients with moderate-severe UC often requires the use of immunomodulator and/or biologic therapies including thiopurines, methotrexate, cyclosporine, tacrolimus, tumor necrosis factor (TNF)-α antagonists, vedolizumab, tofacitnib or ustekinumab, either as monotherapy, or in combination (with immunomodulators), to mitigate these risks. Decisions about optimal drug therapy in moderate-severe UC are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Therefore, the American Gastroenterological Association prioritized development of clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the GRADE framework. Focused questions in adult outpatients with moderate-severe UC included: (1) overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to TNF-α antagonists, (2) comparative efficacy and safety of biologic monotherapy vs. combination therapy with immunomodulators, (3) comparative efficacy of top-down (upfront use of biologics and/or immunomodulator therapy) vs. step-up therapy (acceleration to biologic and/or immunomodulator therapy only after failure of 5-aminosalicylates), and (4) role of continuing vs. stopping 5-aminosalicylates in patients being treated with immunomodulator and/or biologic therapy for moderate-severe UC. Focused questions in adults hospitalized with ASUC included: (5) overall and comparative efficacy of pharmacological interventions for inpatients refractory to corticosteroids, in reducing risk of colectomy, (6) optimal dosing regimens for intravenous corticosteroids and infliximab in these patients and (7) role of adjunctive antibiotics in the absence of confirmed infections.

    更新日期:2020-01-14
  • Mechanisms, Evaluation, and Management of Chronic Constipation
    Gastroenterology (IF 19.233) Pub Date : 2020-01-13
    Adil E. Bharucha; Brian E. Lacy

    With a worldwide prevalence of 15%, chronic constipation is one of the most frequent gastrointestinal diagnoses made in ambulatory medicine clinics and is a common source cause for referrals to gastroenterologists and colorectal surgeons in the United States. Symptoms vary among patients; straining, incomplete evacuation, and a sense of anorectal blockage are just as important as decreased stool frequency. Chronic constipation is either a primary disorder (such as normal transit, slow transit, or defecatory disorders) or a secondary one (due to medications or in rare cases anatomic alterations). Colonic sensorimotor disturbances and pelvic floor dysfunction (such as defecatory disorders) are the most widely recognized pathogenic mechanisms. Guided by efficacy and cost, management of constipation should begin with dietary fiber supplementation and stimulant and/or osmotic laxatives, as appropriate, followed, if necessary, by intestinal secretagogues and/or prokinetic agents. Peripherally acting μ-opiate antagonists are another option for opioid-induced constipation. Anorectal tests to evaluate for defecatory disorders should be performed in patients who do not respond to over-the-counter agents. Colonic transit, followed if necessary with assessment of colonic motility with manometry and/or a barostat, can identify colonic dysmotility. Defecatory disorders often respond to biofeedback therapy. For specific patients, slow-transit constipation may necessitate a colectomy. No studies have compared inexpensive laxatives with newer drugs with different mechanisms. We review the mechanisms, evaluation, and management of chronic constipation. We discuss the importance of meticulous analyses of patients’ histories and physical examination, advantages and disadvantages of diagnostic testing, guidance for individualized treatment, and management of medically refractory patients.

    更新日期:2020-01-13
  • LKB1 Represses ATOH1 via PDK4 and Energy Metabolism and Regulates Intestinal Stem Cell Fate
    Gastroenterology (IF 19.233) Pub Date : 2020-01-11
    Yajing Gao; Yan Yan; Sushil Tripathi; Nalle Pentinmikko; Ana Amaral; Pekka Päivinen; Eva Domènech-Moreno; Simon Andersson; Iris P.L. Wong; Hans Clevers; Pekka Katajisto; Tomi P. Mäkelä

    Background & Aims In addition to Notch and Wnt signaling pathways, energy metabolism also regulates intestinal stem cell (ISC) function. Tumor suppressor and kinase STK11 (also called LKB1) regulates stem cells and cell metabolism. We investigated whether loss of LKB1 alters ISC homeostasis in mice. Methods We deleted LKB1 from ISCs in mice using Lgr5-regulated CRE–ERT2 (Lkb1Lgr5-KO mice) and the traced lineages using a CRE-dependent TdTomato reporter. Intestinal tissues were collected and analyzed by immunohistochemical and immunofluorescence analyses. We purified ISCs and intestinal progenitors using flow cytometry and performed RNA sequencing analysis. We measured organoid-forming capacity and ISC percentages using intestinal tissues from Lkb1Lgr5-KO mice. We analyzed human Ls174t cells with knockdown of LKB1 or other proteins by immunoblotting, real-time quantitative PCR, and the Seahorse live-cell metabolic assay. Results Some intestinal crypts from Lkb1Lgr5-KO mice lost ISCs, compared with crypts from control mice. However, most crypts from Lkb1Lgr5-KO mice contained functional ISCs that expressed increased levels of Atoh1 mRNA, acquired a gene expression signature associated with secretory cells, and generated more cells in the secretory lineage, compared with control mice. Knockdown of LKB1 in Ls174t cells induced expression of Atoh1 mRNA and a phenotype of increased mucin production; knockdown of ATOH1 prevented induction of this phenotype. The increased expression of Atoh1 mRNA following LKB1 loss from ISCs or Ls174t cells did not involve Notch or Wnt signaling. Knockdown of pyruvate dehydrogenase kinase 4 (PDK4) or inhibition with dichloroacetate reduced the upregulation of Atoh1 mRNA following LKB1 knockdown in Ls174t cells. Cells with LKB1 knockdown had a reduced rate of oxygen consumption, which was partially restored by PDK4 inhibition with dichloroacetate. ISCs with knockout of LKB1 increased expression of PDK4 and had an altered metabolic profile. Conclusions LKB1 represses transcription of ATOH1, via PDK4, in ISCs, restricting their differentiation into secretory lineages. These findings provide a connection between metabolism and fate determination of ISCs.

    更新日期:2020-01-13
  • Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-onset Chronic Pancreatitis
    Gastroenterology (IF 19.233) Pub Date : 2020-01-10
    Atsushi Masamune; Hiroshi Kotani; Franziska Lena Sörgel; Jian-Min Chen; Shin Hamada; Reiko Sakaguchi; Emmanuelle Masson; Eriko Nakano; Yoichi Kakuta; Tetsuya Niihori; Ryo Funayama; Matsuyuki Shirota; Tatsuya Hirano; Tetsuya Kawamoto; Atsuki Hosokoshi; Kiyoshi Kume; Lara Unger; Maren Ewers; Tooru Shimosegawa

    Background and Aims Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. Methods We performed whole-exome sequencing DNA from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (controls). In replication studies, we sequenced DNA from patients with early-onset CP (20 y or younger), not associated with alcohol consumption, from France (n=470) or Germany (n=410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. Results We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13/300 cases (4.3%) and 1/1070 controls (0.1%) from Japan (OR, 48.4; 95% CI, 6.3–371.7; P=2.4 × 10-8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 controls (P=6.2 × 10-8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese cases vs controls (OR, 10.9; 95% CI, 4.5–25.9; P=7.4 × 10-9 for p.I223T; and P=.01 for p.D324N), whereas the p.L299Q was overrepresented in European cases vs controls (OR, 3.0; 95% CI, 1.9–4.8; P = 1.2 × 10-5). TRPV6mut/mut given cerulein developed more severe pancreatitis than control mice, demonstrated by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. Conclusions We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.

    更新日期:2020-01-11
  • Safety of Janus Kinase Inhibitors in Patients with Inflammatory Bowel Diseases or Other Immune-mediated Diseases: a Systematic Review and Meta-Analysis
    Gastroenterology (IF 19.233) Pub Date : 2020-01-09
    Pablo Olivera; Juan Lasa; Stefanos Bonovas; Silvio Danese; Laurent Peyrin-Biroulet

    Background & Aims Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. Methods We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990 through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. Results We identified 973 studies; of these 82 were included in the final analysis, comprising 66159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of and serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared to patients given placebo or active comparator (relative risk 0.72; 95% CI, 0.40–1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% CI, 1.04–2.37). Conclusions In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

    更新日期:2020-01-09
  • Risk Factors for Early-Onset Colorectal Cancer
    Gastroenterology (IF 19.233) Pub Date : 2020-01-09
    Eric E. Low; Joshua Demb; Lin Liu; Ashley Earles; Ranier Bustamante; Christina D. Williams; Dawn Provenzale; Tonya Kaltenbach; Andrew J. Gawron; Maria Elena Martinez; Samir Gupta

    Background & Aims Colorectal cancer (CRC) incidence and mortality are increasing among persons in the United States younger than 50 years old, but risk factors associated with early-onset CRC (EOCRC) have not been widely studied. Methods We conducted a case–control study of United States veterans 18–49 years old who underwent colonoscopy examinations from 1999 through 2014. EOCRC cases were identified from a national cancer registry; veterans who were free of CRC at their baseline colonoscopy through 3 years of follow up were identified as controls. We collected data on age, sex, race/ethnicity, body weight, body mass index (BMI), diabetes, smoking status, and aspirin use. Multivariate-adjusted EOCRC odds were estimated for each factor, with corresponding 95% CI values. Results Our final analysis included 651 EOCRC cases and 67,416 controls. Median age was 45.3 years, and 82.3% were male. Higher proportions of cases were older, male, current smokers, non-aspirin users, and had lower BMIs, compared with controls (P<.05). In adjusted analyses, increasing age and male sex were significantly associated with increased risk of EOCRC, whereas aspirin use and being overweight or obese (relative to normal BMI) were significantly associated with decreased odds of EOCRC. In post-hoc analyses, weight loss of 5 kg or more within the 5-year period preceding colonoscopy was associated with higher odds of EOCRC (odds ratio, 2.23; 95% CI, 1.76–2.83). Conclusions In a case–control study of veterans, we found increasing age and male sex to be significantly associated with increased risk of EOCRC, and aspirin use to be significantly associated with decreased risk; these factors also affect risk for CRC onset after age 50. Weight loss may be an early clinical sign of EOCRC. More intense efforts are required to identify the factors that cause EOCRC and signs that can be used to identify individuals at highest risk.

    更新日期:2020-01-09
  • Microscopic Colitis and Risk of Inflammatory Bowel Disease in a Nationwide Cohort Study
    Gastroenterology (IF 19.233) Pub Date : 2020-01-08
    Hamed Khalili; Kristin E. Burke; Bjorn Roelstraete; Michael C. Sachs; Ola Olén; Jonas F. Ludvigsson

    Background and Aims Microscopic colitis shares pathogenetic mechanisms with inflammatory bowel disease (IBD). We studied the association between microscopic colitis and risk of incident IBD using data from a nationwide cohort study. Methods We conducted a prospective cohort study of all adults who received a diagnosis of microscopic colitis from 1990 through 2017 in Sweden and risk of incident IBD. Cases of microscopic colitis (n= 13,957) were identified through SNOMED codes from the ESPRESSO study, which included gastrointestinal pathology reports from all of Sweden’s 28 centers. Individuals with microscopic colitis were matched to 5 general population controls (n= 66,820) and to unaffected siblings (n=13,943). Cox regression was used to estimate adjusted hazard ratio (aHRs) and 95% CIs. Results Through December of 2017, we identified 323 incident cases of ulcerative colitis (UC) and 108 incident cases of Crohn’s disease (CD) in microscopic colitis patients compared to 94 UC and 42 CD cases in population comparators. Mean times from diagnosis of microscopic colitis to diagnosis of CD was 3.3±3.2 years and to diagnosis of UC was 3.2±3.5 years. In multivariable models, microscopic colitis was associated with an aHR of 12.6 (95%CI 8.8-18.1) for CD, 17.3 (95%CI 13.7-21.8) for UC, and 16.8 (95%CI 13.9-20.3) for IBD. The 10-year absolute excess risk of CD and UC were 0.9 (95% 0.7-1.1) and 2.6 (95% CI 2.2-2.9) percentage points, respectively. In sensitivity analyses, comparing microscopic colitis patients to their unaffected siblings, the aHRs of CD and UC were 5.4 (95%CI 3.2-9.2) and 9.4 (95%CI 6.4-13.8), respectively. Conclusions In a population-based study in Sweden, we found a significant increase in risk of incident IBD among patients with microscopic colitis. Future studies should focus on potential mechanisms underlying these observed associations.

    更新日期:2020-01-09
  • Causes of Post-colonoscopy Colorectal Cancers Based on World Endoscopy Organization System of Analysis
    Gastroenterology (IF 19.233) Pub Date : 2020-01-08
    Rebecca Anderson; Nicholas E. Burr; Roland Valori

    Background & Aims Post-colonoscopy colorectal cancer (PCCRC) is CRC diagnosed after a colonoscopy in which no cancer was found. A consensus article from the World Endoscopy Organization (WEO) proposed an approach for investigating and categorizing PCCRCs detected within 4 years of a colonoscopy. We aimed to identify cases of PCCRC and the factors that cause them, test the WEO system of categorization, quantify the proportion of avoidable PCCRCs, and propose a target rate for PCCRCs detected within 3 years of a colonoscopy that did not detect CRC. Methods We performed a retrospective analysis of 107 PCCRCs identified at a single medical center in England from Jan 1, 2010 through December 31, 2017 using coding and endoscopy data. For each case, we reviewed clinical, pathology, radiology, and endoscopy findings. Using the WEO recommendations, we performed a root cause analysis of each case, categorizing lesions as: possible missed lesion, prior examination adequate; possible missed lesion, prior examination inadequate; detected lesion, not resected; or likely incomplete resection of previously identified lesion. We determined whether PCCRCs could be attributed to the colonoscopist for technical or decision-making reasons, and whether the PCCRC was avoidable or unavoidable, based on the WEO categorization and size of tumor. The endoscopy reporting system provided performance data for individual endoscopists. Results Of the PCCRCs identified, 43% were in high-risk patients (those with inflammatory bowel disease, previous CRC, previous multiple large polyps or hereditary cancer syndromes) and 66% were located distal to the hepatic flexure. There was no correlation between post-colonoscopy colorectal tumor size and time to diagnosis after index colonoscopy. Bowel preparation was poor in 19% of index colonoscopies, and only 36% of complete colonoscopies had adequate photo documentation of completion. Development of 73% of PCCRCs was determined to be affected by technical endoscopic factors, 17% of PCCRCs by administrative factors (follow-up procedures delayed/not booked by administrative staff), and 27% of PCCRCs by decision-making factors. Twenty-seven percent of PCCRCs were categorized as possible missed lesion, prior examination adequate; 58% as possible missed lesion, prior examination inadequate; 8% as detected lesion, not resected; and 7% as incomplete resection of previously observed lesion; 89% were deemed to be avoidable. Conclusions In a retrospective analysis of PCCRCs, using the WEO system of categorization, we found 43% to occur in high-risk patients; this might be reduced with more vigilant surveillance. Measures are needed to reduce technical, decision-making and administrative factors. We found that 89% of PCCRCs may be avoidable. If half of avoidable PCCRCs could be prevented, the target rate of 2% for the PCCRC-3y benchmark would be achievable.

    更新日期:2020-01-09
  • Associations of Pathogenic Variants in MLH1, MSH2, and MSH6 With Risk of Colorectal Adenomas and Tumors and With Somatic Mutations in Patients With Lynch Syndrome
    Gastroenterology (IF 19.233) Pub Date : 2020-01-08
    Christoph Engel; Aysel Ahadova; Toni Seppälä; Stefan Aretz; Marloes Bigirwamungu-Bargeman; Hendrik Bläker; Karolin Bucksch; Reinhard Büttner; Wouter de Vos tot Nederveen Cappel; Volker Endris; Elke Holinski-Feder; Stefanie Holzapfel; Robert Hüneburg; Maarten A.J.M. Jacobs; Jan J. Koornstra; Alexandra M. Langers; Anna Lepistö; Monika Morak; Hans F. Vasen

    Background & Aims Lynch syndrome is caused by variants in DNA mismatch repair (MMR) genes and associated with an increased risk of colorectal cancer (CRC). In patients with Lynch syndrome, CRCs can develop via different pathways. We studied associations between Lynch syndrome-associated variants in MMR genes and risks of adenoma and CRC and somatic mutations in APC and CTNNB1 in tumors in an international cohort of patients. Methods We combined clinical and molecular data from 3 studies. We obtained clinical data from 2747 patients with Lynch syndrome associated with variants in MLH1, MSH2, or MSH6 from Germany, the Netherlands, and Finland who received at least 2 surveillance colonoscopies and were followed for a median time of 7.8 years for development of adenomas or CRC. We performed DNA sequence analyses of 48 colorectal tumors (from 16 patients with mutations in MLH1, 29 patients with mutations in MSH2, and 3 with mutations in MSH6) for somatic mutations in APC and CTNNB1. Results Risk of advanced adenoma in 10 y was 17.8% in patients with pathogenic variants in MSH2 vs 7.7% in MLH1 (P<.001). Higher proportions of patients with pathogenic variants in MLH1 or MSH2 developed CRC in 10 y (11.3% and 11.4%) than patients with pathogenic variants in MSH6 (4.7%) (P=.001 and P=.003 for MLH1 and MSH2 vs MSH6, respectively). Somatic mutations in APC were found in 75% of tumors from patients with pathogenic variants in MSH2 vs 11% in MLH1 (P=.015). Somatic mutations in CTNNB1 were found in 50% of tumors from patients with pathogenic variants in MLH1 vs 7% in MSH2 (P=.002). None of the 3 tumors with pathogenic variants in MSH6 had a mutation in CTNNB1, but all had mutations in APC. Conclusions In an analysis of clinical and DNA sequence data from patients with Lynch syndrome from 3 countries, we associated pathogenic variants in MMR genes with risk of adenoma and CRC, and somatic mutations in APC and CTNNB1 in colorectal tumors. If these findings are confirmed, surveillance guidelines might be adjusted based on MMR gene variants.

    更新日期:2020-01-09
  • Expression of FFAR2 by Dendritic Cells Prevents Their Expression of IL27 and is Required For Maintenance of Mucosal Barrier and Immune Response Against Colorectal Tumors in Mice
    Gastroenterology (IF 19.233) Pub Date : 2020-01-07
    Sydney Lavoie; Eunyoung Chun; Sena Bae; Caitlin A. Brennan; Carey Ann Gallini Comeau; Jessica K. Lang; Monia Michaud; Hamid R. Hoveyda; Graeme L. Fraser; Miles H. Fuller; Brian T. Layden; Jonathan N. Glickman; Wendy S. Garrett

    Background & Aims Intestinal microbes and their metabolites affect development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that affects the composition of the intestinal microbiome, contributes to the pathogenesis of CRC. Methods We performed studies with ApcMin/+ mice, ApcMin/+Ffar2-/- mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2fl/flCD11c-Cre mice), ApcMin/+Ffar2fl/flCD11c-Cre mice, and Ffar2fl/fl mice (controls); some mice were given dextran sodium sulfate to induce colitis, with or without a FFAR2 agonist or an antibody against interleukin 27 (IL27). Colon and tumor tissues were analyzed by histology, quantitative PCR, and 16S rRNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured following gavage with fluorescently labeled dextran. We collected data on colorectal tumors from the Cancer Genome Atlas. Results ApcMin/+Ffar2-/- mice developed significantly more spontaneous colon tumors than ApcMin/+ mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from ApcMin/+Ffar2-/- mice had a higher number of bacteria than tumors from ApcMin/+ mice, as well as higher frequencies of CD39+CD8+ T cells and exhausted or dying T cells. DCs from ApcMin/+Ffar2-/- mice had an altered state of activation, increased death, and higher production of IL27. Administration of an antibody against IL27 reduced the numbers of colon tumors in ApcMin/+ mice with colitis. Frequencies of CD39+CD8+ T cells and IL27+ DCs were increased in colon lamina propria from Ffar2fl/flCD11c-Cre mice with colitis compared with control mice or mice without colitis. ApcMin/+Ffar2fl/flCD11c-Cre mice developed even more tumors than ApcMin/+Ffar2fl/fl mice, and their tumors had even higher numbers of IL27+ DCs. ApcMin/+ mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27+ DCs, than mice not given the agonist. DCs incubated with FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production. Conclusions Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8+ T cells, and over-activating DCs, leading to their death. Antibodies against IL27 and agonists of FFAR2 reduce tumorigenesis in mice and might be developed for treatment of CRC.

    更新日期:2020-01-07
  • Autophagy of Intestinal Epithelial Cells Inhibits Colorectal Carcinogenesis Induced by Colibactin-producing Escherichia coli in ApcMin/+ Mice
    Gastroenterology (IF 19.233) Pub Date : 2020-01-07
    Cécily Lucas; Laurène Salesse; My Hanh Thi Hoang; Mathilde Bonnet; Pierre Sauvanet; Anaïs Larabi; Catherine Godfraind; Johan Gagnière; Denis Pezet; Philip Rosenstiel; Nicolas Barnich; Richard Bonnet; Guillaume Dalmasso; Hang Thi Thu Nguyen

    Background and aims Colibactin-producing Escherichia coli (CoPEC) colonize the colon mucosa of higher proportions of patients with vs without colorectal cancer (CRC) and promote colorectal carcinogenesis in susceptible mouse models of CRC. Autophagy degrades cytoplasmic contents, including intracellular pathogens, via lysosomes and regulates intestinal homeostasis. We investigated whether inhibiting autophagy affects colorectal carcinogenesis in susceptible mice infected with CoPEC. Methods Human intestinal epithelial cells (IECs, HCT-116) were infected with a strain of CoPEC (11G5 strain) isolated from a patient or a mutant strain that does not produce colibactin (11G5ΔclbQ). Levels of ATG5, ATG16L1, and SQSTM1 (also called p62) were knocked down in HCT-116 cells using small interfering RNAs. ApcMin/+ mice with and without IEC-specific disruption of Atg16l1 (ApcMin/+/Atg16l1ΔIEC) were infected with 11G5 or 11G5ΔclbQ. Colonic tissues were collected from mice and analyzed for tumor size and number and by histology, immunoblot, and quantitative reverse transcription PCR analyses for markers of autophagy, DNA damage, cell proliferation and inflammation. We analyzed levels of mRNAs encoding proteins involved in autophagy in colonic mucosal tissues from patients with sporadic CRC colonized with vs without CoPEC by quantitative reverse transcription PCR. Results Patient colonic mucosa with CoPEC colonization had higher levels of mRNAs encoding proteins involved in autophagy than colonic mucosa without these bacteria. Infection of cultured IECs with 11G5 induced autophagy and DNA damage repair, whereas infection with 11G5ΔclbQ did not. Knockdown of ATG5 in HCT-116 cells increased numbers of intracellular 11G5, secretion of interleukin 6 (IL6) and IL8, and markers of DNA double-strand breaks, but reduced markers of DNA repair, indicating that autophagy is required for bacteria-induced DNA damage repair. Knockdown of ATG5 in HCT-116 cells increased 11G5-induced senescence, promoting proliferation of uninfected cells. ApcMin/+/Atg16l1ΔIEC mice developed fewer and smaller colon tumors than ApcMin/+ mice. However, following infection with 11G5, ApcMin/+/Atg16l1ΔIEC mice developed more and larger tumors, with a significant increase in mean histologic score, than infected ApcMin/+ mice. Increased levels of Il6, Tnf, and Cxcl1 mRNAs, and decreased level of Il10 mRNA, and increased markers of DNA double-strand breaks and proliferation were observed in colonic mucosa of 11G5-infected ApcMin/+/Atg16l1ΔIEC mice vs 11G5-infected ApcMin/+ mice. Conclusion Infection of IECs and susceptible mice with CoPEC promotes autophagy, which is required to prevent colorectal tumorigenesis. Loss of ATG16L1 from IECs increases markers of inflammation, DNA damage, and cell proliferation and increases colorectal tumorigenesis in ApcMin/+ mice. These findings indicate the importance of autophagy in response to CoPEC infection and strategies to induce autophagy might be developed for patients with CRC and CoPEC colonization.

    更新日期:2020-01-07
  • Prevalence of Rome IV Functional Bowel Disorders Among Adults in the United States, Canada, and the United Kingdom
    Gastroenterology (IF 19.233) Pub Date : 2020-01-07
    Olafur S. Palsson; William Whitehead; Hans Törnblom; Ami D. Sperber; Magnus Simren
    更新日期:2020-01-07
  • Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses
    Gastroenterology (IF 19.233) Pub Date : 2019-12-27
    Neil Murphy; Robert Carreras-Torres; Mingyang Song; Andrew T. Chan; Richard M. Martin; Nikos Papadimitriou; Niki Dimou; Konstantinos K. Tsilidis; Barbara Banbury; Kathryn E. Bradbury; Jelena Besevic; Sabina Rinaldi; Elio Riboli; Amanda J. Cross; Ruth C. Travis; Claudia Agnoli; Demetrius Albanes; Sonja I. Berndt; Marc J. Gunter

    Background Aims Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. Methods Serum levels of IGF1 and other proteins were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) Results After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 level associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% CI, 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio, 1.08; 95% CI, 1.03–1.12; P=3.3 x 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI, 1.06–1.18; P =4.2 x 10–5). Colorectal cancer risk was associated with only 1 variant in IGFBP3 (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. Conclusions In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

    更新日期:2019-12-27
  • Cumulative Burden of Colorectal Cancer-Associated Genetic Variants is More Strongly Associated With Early-onset vs Late-onset Cancer
    Gastroenterology (IF 19.233) Pub Date : 2019-12-19
    Alexi N. Archambault; Yu-Ru Su; Jihyoun Jeon; Minta Thomas; Yi Lin; David V. Conti; Aung Ko Win; Lori C. Sakoda; Iris Lansdorp-Vogelaar; Elisabeth FP. Peterse; Ann G. Zauber; David Duggan; Andreana N. Holowatyj; Jeroen R. Huyghe; Hermann Brenner; Michelle Cotterchio; Stéphane Bézieau; Stephanie L. Schmit; Richard B. Hayes

    Background & Aims Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. Methods We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single-nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. Results Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction=.01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI, 3.28–4.24) vs 2.9-fold for late-onset CRC (95% CI, 2.80–3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction=5.61x10–5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI, 3.61–5.01) vs 2.9-fold for late-onset CRC (95% CI, 2.70–3.00). Sensitivity analyses were consistent with these findings. Conclusions In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer—particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventative measures.

    更新日期:2019-12-19
  • Prevalence of Gastroesophageal Reflux Disease and Proton Pump Inhibitor-Refractory Symptoms
    Gastroenterology (IF 19.233) Pub Date : 2019-12-19
    Sean D. Delshad; Christopher V. Almario; William D. Chey; Brennan M.R. Spiegel

    Background & Aims There are few data on the prevalence of gastroesophageal reflux disease (GERD) in the United States. We performed a population-based study to determine the prevalence of GERD symptoms and persistent GERD symptoms despite use of proton pump inhibitors (PPIs). Methods We conducted the National Gastrointestinal Survey in 2015 using MyGiHealth, an app that guides participants through National Institutes of Health gastrointestinal PROMIS surveys. Primary outcomes were prevalence of GERD symptoms in the past and persistence of GERD symptoms (heartburn or regurgitation 2 or more days in past week) among participants taking PPIs. Population weights were applied to the data and multivariable regression was used to adjust for confounding. Results Among 71,812 participants, 32,878 (44.1%) reported having had GERD symptoms in the past and 23,039 (30.9%) reported having GERD symptoms in the last week. We also found that 35.1% of those who had experienced GERD symptoms were currently on therapy (55.2% on PPIs, 24.3% on histamine-2 receptor blockers, and 24.4% on antacids). Among 3,229 participants taking daily PPIs, 54.1% had persistent GERD symptoms. Younger individuals, women, Latinos, and participants with irritable bowel syndrome or Crohn’s disease were more likely to have continued symptoms, even when taking PPIs. Conclusions Using a population-based survey, we found GERD symptoms to be common: 2 of 5 participants have had GERD symptoms in the past and 1 of 3 had symptoms in the last week. We also found that half of PPI users have persistent symptoms. Given the significant effect of GERD on quality of life, further research and development of new therapies are needed for patients with PPI-refractory GERD symptoms.

    更新日期:2019-12-19
  • Oncogenic Mutations in Armadillo Repeats 5 and 6 of β-catenin Reduce Binding to APC, Increasing Signaling and Transcription of Target Genes
    Gastroenterology (IF 19.233) Pub Date : 2019-12-17
    Pengyu Liu; Binyong Liang; Menggang Liu; Joyce H.G. Lebbink; Shan Li; Manning Qian; Marla Lavrijsen; Maikel P. Peppelenbosch; Xin Chen; Ron Smits
    更新日期:2019-12-18
  • Interleukin 22 Signaling Regulates Acinar Cell Plasticity to Promote Pancreatic Tumor Development in Mice
    Gastroenterology (IF 19.233) Pub Date : 2019-12-14
    Mirna Perusina Lanfranca; Yaqing Zhang; Alexander Girgis; Samantha Kasselman; Jenny Lazarus; Illona Kryczek; Lawrence Delrosario; Andrew Rhim; Lada Koneva; Maureen Sartor; Lei Sun; Christopher Halbrook; Hari Nathan; Jiaqi Shi; Howard C. Crawford; Marina Pasca di Magliano; Weiping Zou; Timothy L. Frankel
    更新日期:2019-12-17
  • Incidence of Venous Thromboembolism in Patients with Newly Diagnosed Pancreatic Cancer and Factors Associated With Outcomes
    Gastroenterology (IF 19.233) Pub Date : 2019-12-14
    Corinne Frere; Barbara Bournet; Sophie Gourgou; Julien Fraisse; Cindy Canivet; Jean M. Connors; Louis Buscail; Dominique Farge
    更新日期:2019-12-17
  • Differences in Fecal Microbiomes and Metabolomes of People With vs Without Irritable Bowel Syndrome and Bile Acid Malabsorption
    Gastroenterology (IF 19.233) Pub Date : 2019-12-14
    Ian B. Jeffery; Anubhav Das; Eileen O’Herlihy; Simone Coughlan; Katryna Cisek; Michael Moore; Fintan Bradley; Tom Carty; Meenakshi Pradhan; Chinmay Dwibedi; Fergus Shanahan; Paul W. O’Toole
    更新日期:2019-12-17
  • Lactotrehalose, an Analog of Trehalose, Increases Energy Metabolism Without Promoting Clostridioides difficile Infection in Mice
    Gastroenterology (IF 19.233) Pub Date : 2019-12-12
    Yiming Zhang; Nurmohammad Shaikh; Jeremie L. Ferey; Umesh D. Wankhade; Sree V. Chintapalli; Cassandra B. Higgins; Jan R. Crowley; Monique R. Heitmeier; Alicyn I. Stothard; Belgacem Mihi; Misty R. Good; Takanobu Higashiyama; Benjamin M. Swarts; Paul W. Hruz; Kartik Shankar; Phillip I. Tarr; Brian J. DeBosch

    Background Aims Trehalose is a disaccharide that might be used in treatment of cardiometabolic diseases. However, trehalose consumption promotes expansion of Clostridioides difficile ribotypes that metabolize trehalose via trehalose-6-phosphate hydrolase (treA). Furthermore, brush border and renal trehalases can reduce the efficacy of trehalose by cleaving it into monosaccharides. We investigated whether a trehalase-resistant analogue of trehalose (lactotrehalose) has the same metabolic effects of trehalose without expanding C difficile. Methods We performed studies with HEK293 and Caco2 cells, primary hepatocytes from mice, and human intestinal organoids. Glucose transporters were overexpressed in HEK293 cells and glucose transport was quantified. Primary hepatocytes were cultured with or without trehalose or lactotrehalose and gene expression patterns were analyzed. C57B6/J mice were given oral antibiotics and trehalose or lactotrehalose in drinking water, or only water (control), followed by gavage with the virulent C difficile ribotype 027 (CD027); fecal samples were analyzed for ToxA or ToxB by ELISA. Other mice were given trehalose or lactotrehalose in drinking water for 2 days before placement on a chow or 60% fructose diet for 10 days. Liver tissues were collected and analyzed by histologic, serum biochemical, and RNAseq, autophagic flux, and thermogenesis analyses. We quantified portal trehalose and lactotrehalose bioavailability by gas chromatography mass spectrometry. Fecal microbiomes were analyzed by 16S rRNA sequencing and principal component analyses. Results Lactotrehalose and trehalose each blocked glucose transport in HEK293 cells, and induced a gene expression pattern associated with fasting in primary hepatocytes. Compared with mice on the chow diet, mice on the high-fructose diet had increased circulating cholesterol, higher ratios of liver weight:body weight, hepatic lipid accumulation (steatosis), and liver gene expression patterns of carbohydrate-responsive de novo lipogenesis. Mice given lactotrehalose while on the high-fructose diet did not develop any of these features and had increased whole-body caloric expenditure compared with mice given trehalose or water and fed a high-fructose diet. Livers from mice given lactotrehalose had increased transcription of genes that regulate mitochondrial energy metabolism compared with liver from mice given trehalose or controls. Lactotrehalose was bioavailable in venous and portal circulation and fecal samples. Lactotrehalose reduced fecal markers of microbial branched chain amino acid biosynthesis and increased expression of microbial genes that regulate insulin signaling. In mice given antibiotics followed by CD027, neither lactotrehalose nor trehalose increased levels of the bacteria or its toxin in stool—in fact, trehalose reduced the abundance of CD027 in stool. Lactotrehalose and trehalose reduced markers of inflammation in rectal tissue following CD027 infection. Conclusions Lactotrehalose is a trehalase-resistant analogue that increases metabolic parameters, compared with trehalose, without increasing the abundance or virulence of C difficile strain CD027. Trehalase-resistant trehalose analogues might be developed as next-generation fasting-mimetics for treatment of diabetes and nonalcoholic fatty liver disease.

    更新日期:2019-12-13
  • Approaches and Challenges to Management of Pediatric and Adult Patients With Eosinophilic Esophagitis
    Gastroenterology (IF 19.233) Pub Date : 2019-12-10
    Ikuo Hirano, Glenn T. Furuta

    Treatment of eosinophilic esophagitis (EoE) has progressed from elemental formula for children and esophageal dilation for adults to selective exclusion of food triggers and swallowed topical corticosteroids. Management guidelines are available from the American Gastroenterological Association and the Joint Task Force on Allergy Immunology Practice Parameters. We cannot, however, evaluate the efficacy of treatments without a definition of response. We propose a treat to target approach, based on symptoms and findings from endoscopy and histology. This approach addresses dissociations between outcomes such as symptom persistence despite normalization of histologic features and symptom resolution after esophageal dilation despite histologic features of active disease. EoE can now be treated with biologic agents that target specific immune pathways, and findings from prospective trials have indicated that less-restrictive, empiric, elimination diets can be effective and reduce the need for repeated endoscopic assessment of disease activity during food reintroduction. We also discuss EoE subtypes, factors associated with disease, and advances in management.

    更新日期:2019-12-11
  • Combating gastric cancer in Alaska Native people: An expert and community symposium
    Gastroenterology (IF 19.233) Pub Date : 2019-12-10
    Leisha D. Nolen, Stephen M. Vindigni, Julie Parsonnet, Michael G. Bruce, Holly A. Martinson, Timothy K. Thomas, Frank Sacco, Sarah Nash, Matthew J. Olnes, Karen Miernyk, Dana Bruden, Maya Ramaswamy, Brian McMahon, Karen J. Goodman, Adam J. Bass, Chin Hur, Manami Inoue, Stephanie Melkonian

    Alaska Native (AN) people experience higher incidence of, and mortality from, gastric cancer compared to other U.S. populations1, 2. Compared to the general U.S. population, gastric cancer in AN people occurs at a younger age, is diagnosed at later stages, is more evenly distributed between the sexes, and is more frequently signet-ring or diffuse histology3. It is known that the prevalence of Helicobacter pylori (Hp) infection, a risk factor for gastric cancer, is high in AN people4; however, high antimicrobial resistance combined with high reinfection rates in Alaska make treatment at the population level complex5. In addition, health issues in AN people are uniquely challenging due to the extremely remote locations of many residents. A multiagency workgroup hosted a symposium in Anchorage that brought internationally-recognized experts and local leaders together to evaluate issues around gastric cancer in the AN population. The overall goal of this symposium was to identify the best strategies to combat gastric cancer in the AN population through prevention and early diagnosis.

    更新日期:2019-12-11
  • Effects of Belapectin, an Inhibitor of Galectin-3, in Patients with Nonalcoholic Steatohepatitis With Cirrhosis And Portal Hypertension
    Gastroenterology (IF 19.233) Pub Date : 2019-12-05
    Naga Chalasani, Manal F. Abdelmalek, Guadalupe Garcia-Tsao, Raj Vuppalanchi, Naim Alkhouri, Mary Rinella, Mazen Noureddin, Maxmillan Pyko, Mitchell Shiffman, Arun Sanyal, Adam Allgood, Harold Shlevin, Rex Horton, Eliezer Zomer, William Irish, Zachary Goodman, Stephen A. Harrison, Peter G. Traber

    Background & Aims Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contributes to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. Methods Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n=54), 8 mg/kg (n=54), or placebo (n=54) for 52 weeks. The primary endpoint was change in HVPG (-28) at the end of the 52 week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. Results We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (-0.28 mmHG vs 0.10 mmHG, P=1.0) or between the 8 mg/kg belapectin and placebo group (-0.25 mmHG vs 0.10 mmHG, P=1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n=81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P=.02) and reduced development of new varices (P=.03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. Conclusions In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis, compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices.

    更新日期:2019-12-05
  • Differences in Gut Microbiota in Patients With vs Without Inflammatory Bowel Diseases: a Systematic Review
    Gastroenterology (IF 19.233) Pub Date : 2019-12-05
    Rapat Pittayanon, Jennifer T. Lau, Grigorios I. Leontiadis, Frances Tse, Yuhong Yuan, Michael Surette, Paul Moayyedi

    Background & Aims Altering the intestinal microbiota has been proposed as a treatment for inflammatory bowel diseases (IBD), but there are no established associations between specific microbes and IBD. We performed a systematic review to identify frequent associations. Methods We searched the MEDLINE, EMBASE, Cochrane CDSR, and CENTRAL databases, through April 2, 2018 for studies that compared intestinal microbiota (from fecal or colonic or ileal tissue samples) among patients (adult or pediatric) with IBD vs healthy individuals (controls). The primary outcome was difference in specific taxa in fecal or intestinal tissue samples from patients with IBD vs controls. We used the Newcastle-Ottawa scale to assess the quality of studies included in the review. Results We identified 2631 citations; 48 studies from 45 articles were included in the analysis. Most studies evaluated adults with Crohn’s disease or ulcerative colitis. All 3 studies of Christensenellaceae and Coriobacteriaceae and 6 of 11 studies of Faecalibacterium prausnitzii reported a decreased amount of those organisms compared with controls, whereas 2 studies each of Actinomyces, Veillonella, and Escherichia coli revealed an increased amount in patients with Crohn’s disease. For patients with ulcerative colitis, Eubacterium rectale and Akkermansia were decreased in all 3 studies whereas E coli was increased in 4 of 9 studies. The microbiota diversity was either decreased or not different in patients with IBD vs controls. Fewer than 50% of the studies stated comparable sexes and ages of cases and controls. Conclusions In a systematic review, we found evidence for differences in abundances of some bacteria in patients with IBD vs controls, but we cannot make conclusions due to inconsistent results and methods among studies. Further large-scale studies, with better methods of assessing microbe populations, are needed

    更新日期:2019-12-05
  • Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B cell-Based Vaccine Development
    Gastroenterology (IF 19.233) Pub Date : 2019-12-04
    Fang Chen, Kenna Nagy, Deborah Chavez, Shelby Willis, Ryan McBride, Erick Giang, Andrew Honda, Jens Bukh, Phillip Ordoukhanian, Jiang Zhu, Sharon Frey, Robert Lanford, Mansun Law

    Background & Aims We investigated antibody responses to hepatitis C virus (HCV) antigens E1 and E2 and the relevance of animal models for vaccine development. We compared antibody responses to vaccination with recombinant E1E2 complex in heathy volunteers, non-human primates (NHPs), and mice Methods We analyzed 519 serum samples from participants in a phase 1 vaccine trial (NCT00500747) and compared them with serum or plasma samples from C57BL/6J mice (n=28) and rhesus macaques (n=4) immunized with the same HCV E1E2 antigen. Blood samples were collected at different timepoints and analyzed for antibody binding, neutralizing activity, and epitope specificity. Monoclonal antibodies from the immunized NHPs were isolated from single plasmablasts and memory B cells, and their immunogenetic properties were characterized. Results Antibody responses of the volunteers, NHPs, and mice, to the non-neutralizing epitopes on the E1 N-terminus and E2 hypervariable region 1 did not differ significantly. Antibodies from volunteers and NHPs that neutralized heterologous strains of HCV primarily interacted with epitopes in the antigen region 3. However, the neutralizing antibodies were not produced in sufficient levels for broad neutralization of diverse HCV isolates. Broadly neutralizing antibodies similar to the human VH1-69 class antibody specific for antigen region 3 were produced in the immunized NHPs. Conclusions In an analysis of vaccinated volunteers, NHPs, and mice, we found that recombinant E1E2 vaccine antigen induces high-antibody titers that are insufficient to neutralize diverse HCV isolates. Antibodies from volunteers and NHPs bind to the same neutralizing epitopes for virus neutralization. NHPs can therefore be used as a preclinical model to develop HCV vaccines. These findings also provide useful baseline values for development of vaccines designed to induce production of neutralizing antibodies.

    更新日期:2019-12-04
  • Diphenylbutylpiperidine Antipsychotic Drugs Inhibit Prolactin Receptor Signaling to Reduce Growth of Pancreatic Ductal Adenocarcinoma in Mice
    Gastroenterology (IF 19.233) Pub Date : 2019-11-29
    Prasad Dandawate, Gaurav Kaushik, Chandrayee Ghosh, David Standing, Afreen Asif Ali Sayed, Sonali Choudhury, Dharmalingam Subramaniam, Ann Manzardo, Tuhina Banerjee, Santimukul Santra, Prabhu Ramamoorthy, Merlin Butler, Subhash B. Padhye, Joaquina Baranda, Anup Kasi, Weijing Sun, Ossama Tawfik, Domenico Coppola, Shrikant Anant

    Background & Aims Prolactin (PRL) signaling is upregulated in hormone-responsive cancers. The PRL receptor (PRLR) is class I cytokine receptor that signals via the JAK–STAT and MAPK pathways to regulate cell proliferation, migration, stem-cell features, and apoptosis. Patients with pancreatic ductal adenocarcinoma (PDAC) have high plasma levels of PRL. We investigated whether PRLR signaling contributes to growth of pancreatic tumors in mice. Methods We used immunohistochemical analyses to compare levels of PRL and PRLR in multi-tumor tissue microarrays. We used structure-based virtual screening and fragment-based drug discovery to identify compounds likely to bind PRLR and interfere with its signaling. Human pancreatic cell lines (AsPC-1, BxPC-3, Panc-1, and MiaPaCa-2), with or without knockdown of PRLR (CRISPR or small-hairpin RNA), were incubated with PRL or penfluridol and analyzed in proliferation, spheroid formation. C57BL/6 mice were given injections of UNKC-6141 cells, with or without knockdown of PRLR, into pancreas, and tumor development was monitored for 4 weeks, with some mice receiving penfluridol treatment for 21 days. Human pancreatic tumor tissues were implanted into interscapular fat pads of NSG mice and mice were given injections of penfluridol daily for 28 days. Nude mice were given injections of Panc-1 cells, xenograft tumors were grown for 2 weeks, and mice were then given intraperitoneal penfluridol for 21 days. Tumors were collected from mice and analyzed by histology, immunohistochemistry, and immunoblots. Results Levels of PRLR were increased in PDAC compared with non-tumor pancreatic tissues. Incubation of pancreatic cell lines with PRL activated signaling via JAK2–STAT3 and ERK, as well as formation of pancospheres and cell migration; these activities were not observed in cells with PRLR knock down. Pancreatic cancer cells with PRLR knockdown formed significantly smaller tumors in mice. We identified several diphenylbutylpiperidine-class antipsychotic drugs as agents that decreased PRL-induced JAK2 signaling; incubation of pancreatic cancer cells with these compounds reduced their proliferation and formation of spheres. Injections of 1 of these compounds, penfluridol, slowed growth of xenograft tumors in the different mouse models, reducing proliferation and inducing autophagy of the tumor cells. Conclusions Levels of PRLR are increased in PDAC, and exposure to PRL increases proliferation and migration of pancreatic cancer cells. Antipsychotic drugs such as penfluridol block JAK2 signaling in pancreatic cancer cells to reduce their proliferation, induce autophagy, and slow growth of xenograft tumors in mice. These drugs might be tested in patients with PDAC.

    更新日期:2019-11-29
  • Deep-Learning System Detects Neoplasia in Patients With Barrett’s Esophagus With Higher Accuracy Than Endoscopists in a Multi-Step Training and Validation Study with Benchmarking
    Gastroenterology (IF 19.233) Pub Date : 2019-11-22
    A.J. de Groof, M.R. Struyvenberg, J. van der Putten, F. van der Sommen, K.N. Fockens, W.L. Curvers, S. Zinger, R.E. Pouw, E. Coron, F. Baldaque-Silva, O. Pech, B. Weusten, A. Meining, H. Neuhaus, R. Bisschops, J. Dent, E.J. Schoon, P.H. de With, J.J. Bergman

    Background & Aims We aimed to develop and validate a deep-learning computer-aided detection (CAD) system, suitable for use in real time in clinical practice, to improve endoscopic detection of early neoplasia in patients with Barrett’s esophagus (BE). Methods We developed a hybrid ResNet-UNet model CAD system using 5 independent endoscopy datasets. We performed pre-training using 494,364 labelled endoscopic images collected from all intestinal segments. Then, we used 1704 unique esophageal high-resolution images of rigorously confirmed early-stage neoplasia from patients with BE, and non-dysplastic BE, derived from 669 patients. System performance was assessed using datasets 4 and 5. Dataset 5 was also scored by 53 general endoscopists with a wide range of experience from 4 countries to benchmark CAD system performance. Coupled with histopathology findings, scoring of images that contained early-stage neoplasia in datasets 2–5 were delineated in detail for neoplasm position and extent by multiple experts whose evaluations served as the ground truth for segmentation. Results The CAD system classified images as containing neoplasms or non-dysplastic BE with 89% accuracy, 90% sensitivity, and 88% specificity (dataset 4, 80 patients and images). In dataset 5 (80 patients and images) values for the CAD system vs those of the general endoscopists were 88% vs 73% accuracy, 93% vs 72% sensitivity, and 83% vs 74% specificity. The CAD system achieved higher accuracy than any of the individual 53 non-expert endoscopists, with comparable delineation performance. CAD delineations of the area of neoplasm overlapped with those from the BE experts in all detected neoplasia in datasets 4 and 5. The CAD system identified the optimal site for biopsy of detected neoplasia in 97% and 92% of cases (dataset 4 and 5 respectively). Conclusions We developed, validated, and benchmarked a deep-learning computer-aided system for primary detection of neoplasia in patients with BE. The system detected neoplasia with high accuracy and near-perfect delineation performance.

    更新日期:2019-11-22
  • HNF4 Regulates Fatty Acid Oxidation and is Required for Renewal of Intestinal Stem Cells in Mice
    Gastroenterology (IF 19.233) Pub Date : 2019-11-22
    Lei Chen, Roshan P. Vasoya, Natalie H. Toke, Aditya Parthasarathy, Shirley Luo, Eric Chiles, Juan Flores, Nan Gao, Edward M. Bonder, Xiaoyang Su, Michael P. Verzi
    更新日期:2019-11-22
  • CATCHING UP TO THE COLON: TIME FOR AN ADENOMA DETECTION RATE EQUIVALENT IN BARRETT’S ESOPHAGUS?
    Gastroenterology (IF 19.233) Pub Date : 2019-11-22
    Blake Jones, Sachin Wani

    Barrett’s esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), a cancer associated with a dismal 5-year survival rate (Am J Gastroenterol 2017;112(7):1032-1048). Despite all the advances in this field, we have had minimal impact on the incidence, morbidity and mortality related to this lethal cancer. This has provided the impetus for major gastroenterology societies to propose quality indicators to guide diagnostic, surveillance and treatment strategies including endoscopic eradication therapies and ultimately improve outcomes associated with EAC (Gastroenterology 2015;149(6):1599-1606, Am J Gastroenterol 2017;112(7)1032-1048). Adenoma detection rate (ADR) is a well-established quality indicator in colon cancer screening; a measure that not only has face validity but also associated with risk of interval colorectal cancer. Whether a similar quality indicator can be utilized in patients with BE undergoing their index screening endoscopy is the focus of this summary.

    更新日期:2019-11-22
  • Use of Family History and Genetic Testing to Determine Risk of Colorectal Cancer
    Gastroenterology (IF 19.233) Pub Date : 2019-11-21
    Fay Kastrinos, N. Jewel Samadder, Randall W. Burt

    Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease, due to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5%–10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes—this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes, based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality.

    更新日期:2019-11-21
  • High-content Screen Identifies MicroRNAs Required for Liver Repopulation After Injury in Mice
    Gastroenterology (IF 19.233) Pub Date : 2019-11-20
    Adam M. Zahm, Amber W. Wang, Yue J. Wang, Jonathan Schug, Kirk J. Wangensteen, Klaus H. Kaestner

    Background & Aims Liver regeneration is impaired in mice with hepatocyte-specific deficiencies in microRNA (miRNA) processing, but it is not clear which miRNAs regulate this process. We developed a high-throughput screen to identify miRNAs that regulate hepatocyte repopulation following toxic liver injury using Fah–/– mice. Methods We constructed plasmid pools encoding more than 30,000 tough decoy iRNA inhibitors (hair-pin nucleic acids designed to specifically inhibit interactions between miRNAs s and their targets) to target hepatocyte miRNAs in a pairwise manner. The plasmid libraries were delivered to hepatocytes in Fah-/- mice at time of liver injury via hydrodynamic tail vein injection. Integrated transgene-containing transposons were quantified following liver repopulation via high-throughput sequencing. Changes in polysome-bound transcripts following miRNA inhibition were determined using translating ribosome affinity purification followed by high-throughput sequencing. Results Analyses of tough decoy abundance in hepatocyte genomic DNA and input plasmid pools identified several thousand miRNA inhibitors that were significantly lost or gained following repopulation. We classified a subset of miRNA binding sites as those that have strong effects on liver repopulation, implicating the targeted hepatocyte miRNAs as regulators of this process. We then generated a high-content map of pairwise interactions between 171 miRNA-binding sites and identified synergistic and redundant effects. Conclusions We developed a screen to identify miRNAs required for liver regeneration after injury in live mice.

    更新日期:2019-11-21
  • Optimizing the Quality of Colorectal Cancer Screening Worldwide
    Gastroenterology (IF 19.233) Pub Date : 2019-11-20
    M.F. Kaminski, D.J. Robertson, C. Senore, D.K. Rex

    Screening, followed by colonoscopic polypectomy (or surgery for malignant lesions), prevents incident colorectal cancer and mortality. However, there are variations in effective application of nearly every aspect of the screening process. Screening is a multistep process, and failure in any of single step could result in unnecessary morbidity and mortality. Awareness of variations in operator- and system-dependent performance has led to detailed, comprehensive recommendations in the United States and Europe on how colonoscopy screening should be performed and measured. Likewise, guidance has been provided on quality assurance for non-primary colonoscopy-based screening programs, including strategies to maximize adherence. Quality improvement is now a validated science, and there is clear evidence that higher quality prevents incident cancer and cancer death. Quality must be addressed at the levels of the system, provider, and individuals, to maximize the benefits of screening for any population. We review the important aspects of measuring and improving the quality of colorectal cancer screening.

    更新日期:2019-11-21
  • 更新日期:2019-11-19
  • Clip Closure After Resection of Large Colorectal Lesions With Substantial Risk of Bleeding
    Gastroenterology (IF 19.233) Pub Date : 2019-07-27
    Eduardo Albéniz, Marco Antonio Álvarez, Jorge C. Espinós, Oscar Nogales, Carlos Guarner, Pedro Alonso, Manuel Rodríguez-Téllez, Alberto Herreros de Tejada, José Santiago, Marco Bustamante-Balén, Joaquín Rodríguez Sánchez, Felipe Ramos-Zabala, Eduardo Valdivielso, Felipe Martínez-Alcalá, María Fraile, Alfonso Elosua, María Fernanda Guerra Veloz, Berta Ibáñez Beroiz, Mónica Enguita-Germán
    更新日期:2019-11-18
  • Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn’s Disease
    Gastroenterology (IF 19.233) Pub Date : 2019-07-20
    Pieter Hindryckx, Vipul Jairath, Guangyong Zou, Brian G. Feagan, William J. Sandborn, Jaap Stoker, Reena Khanna, Larry Stitt, Tanja van Viegen, Lisa M. Shackelton, Stuart A. Taylor, Cynthia Santillan, Banafsche Mearadji, Geert D’Haens, Marie-Paule Richard, Julian Panes, Jordi Rimola

    Background & Aims There is no validated magnetic resonance imaging (MRI) index for assessment of perianal fistulas in patients with Crohn’s disease (CD). We developed and internally validated a new instrument. Methods We used paired baseline and week-24 MRI scans from 160 participants in a randomized placebo-controlled trial of stem cell therapy for patients with perianal fistulizing CD. Four radiologists scored disease activity using index items identified during previous studies and exploratory items. Reliability was assessed using intraclass correlation coefficients. We developed an index using backward elimination linear regression analysis, in which potential independent variables were items having intraclass correlation coefficients of at least 0.4 and the dependent variable was perianal fistulizing disease activity, measured on a 100-mm visual analogue scale. The final model was internally validated using the .632 bootstrap method to correct model optimism and quantify calibration accuracy. We evaluated responsiveness of the index by assessing longitudinal validity and estimating standardized effect sizes. Results We developed the magnetic resonance novel index for fistula imaging in CD (MAGNIFI-CD) using 6 items. The optimism-corrected R2 of the model was 0.71, which was comparable to R2 for the original sample (0.74). The calibration slope for the model was 0.98. Compared with the original and modified versions of the Van Assche Index, the MAGNIFI-CD had improved operating characteristics. Estimates of intraclass correlation coefficients for MAGNIFI-CD, the modified Van Assche Index, and Van Assche Index were 0.85 (95% confidence interval [CI], 0.77–0.90), 0.81 (95% CI, 0.74–0.86), and 0.81 (95% CI, 0.71–0.86) for intra-rater reliability, and 0.74 (95% CI, 0.63–0.80), 0.67 (95% CI, 0.55–0.75) and 0.68 (95% CI, 0.56–0.77) for inter-rater reliability. Corresponding standardized effect size estimates were 1.02 (95% CI, 0.65–1.39), 0.84 (95% CI, 0.48–1.21), and 0.68 (95% CI, 0.33–1.03). Conclusions We developed an index called the MAGNIFI-CD, which is based on 6 items. It assesses MRI data and determines perianal fistulizing CD activity with improved operating characteristics compared to previous indices. This index may be used as an outcome measure in clinical trials comparing treatment effects in patients with perianal fistulizing CD. Although the performance of the MAGNIFI-CD indicates its stability and reasonable external validity, external validation is needed.

    更新日期:2019-11-18
  • Development and Validation of a Model Consisting of Comorbidity Burden to Calculate Risk of Death Within 6 Months for Patients With Suspected Drug-Induced Liver Injury
    Gastroenterology (IF 19.233) Pub Date : 2019-07-11
    Marwan Ghabril, Jiezhun Gu, Lindsay Yoder, Laura Corbito, Amit Ringel, Christian D. Beyer, Raj Vuppalanchi, Huiman Barnhart, Paul H. Hayashi, Naga Chalasani

    Background & Aims Patients with drug-induced liver injury (DILI) frequently have comorbid conditions, but the effects of non-liver comorbidities on outcomes are not well understood. We investigated the association between comorbidity burden and outcomes of patients with DILI, and developed and validated a model to calculate risk of death within 6 months. Methods A multiple logistic regression model identified variables independently associated with death within 6 months of presenting with suspected DILI (6-month mortality) for 306 patients enrolled in the Drug-Induced Liver Injury Network prospective study at Indiana University (discovery cohort). The model was validated using data from 247 patients with suspected DILI enrolled in the same study at the University of North Carolina (validation cohort). Medical comorbidity burden was calculated using the Charlson Comorbidity Index—patients with scores higher than 2 were considered to have significant comorbidities. Results Six-month mortality was 8.5% in the discovery cohort and 4.5% in the validation cohort. In the discovery cohort, significant comorbidities (odds ratio, 5.4; 95% confidence interval [CI], 2.1–13.8), Model for End-Stage Liver Disease score (odds ratio, 1.11; 95% CI, 1.04–1.17), and serum level of albumin at presentation (odds ratio, 0.39; 95% CI, 0.2–0.76) were independently associated with 6-month mortality. A model based on these 3 variables identified patients who died within 6 months, with c-statistic values of 0.89 (95% CI, 0.86–0.94) in the discovery cohort and 0.91 (95% CI, 0.83–0.99) in the validation cohort. We developed a web-based calculator for use in the clinic to determine risk of death within 6 months for patients with suspected DILI. Conclusions We developed and validated a model based on comorbidity burden, Model for End-Stage Liver Disease score, and serum level of albumin that predicts 6-month mortality in patients with suspected DILI.

    更新日期:2019-11-18
  • Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection Is Associated With Increased Survival in Patients With a History of Hepatocellular Carcinoma
    Gastroenterology (IF 19.233) Pub Date : 2019-07-30
    Amit G. Singal, Nicole E. Rich, Neil Mehta, Andrea D. Branch, Anjana Pillai, Maarouf Hoteit, Michael Volk, Mobolaji Odewole, Steven Scaglione, Jennifer Guy, Adnan Said, Jordan J. Feld, Binu V. John, Catherine Frenette, Parvez Mantry, Amol S. Rangnekar, Omobonike Oloruntoba, Michael Leise, Caitlin C. Murphy
    更新日期:2019-11-18
  • Increased Risk for Hepatocellular Carcinoma Persists Up to 10 Years After HCV Eradication in Patients With Baseline Cirrhosis or High FIB-4 Scores
    Gastroenterology (IF 19.233) Pub Date : 2019-07-26
    George N. Ioannou, Lauren A. Beste, Pamela K. Green, Amit G. Singal, Elliot B. Tapper, Akbar K. Waljee, Richard K. Sterling, Jordan J. Feld, David E. Kaplan, Tamar H. Taddei, Kristin Berry
    更新日期:2019-11-18
  • Metabolic Functions of Gut Microbes Associate With Efficacy of Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases
    Gastroenterology (IF 19.233) Pub Date : 2019-07-18
    Konrad Aden, Ateequr Rehman, Silvio Waschina, Wei-Hung Pan, Alesia Walker, Marianna Lucio, Alejandro Mena Nunez, Richa Bharti, Johannes Zimmerman, Johannes Bethge, Berenice Schulte, Dominik Schulte, Andre Franke, Susanna Nikolaus, Johann Oltmann Schroeder, Doris Vandeputte, Jeroen Raes, Silke Szymczak, Philip Rosenstiel
    更新日期:2019-11-18
  • Inhibiting PGGT1B Disrupts Function of RHOA, Resulting in T-cell Expression of Integrin α4β7 and Development of Colitis in Mice
    Gastroenterology (IF 19.233) Pub Date : 2019-07-11
    Rocío López-Posadas, Petra Fastancz, Luz del Carmen Martínez-Sánchez, Julia Panteleev-Ivlev, Veronika Thonn, Tatyana Kisseleva, Lukas S. Becker, Anja Schulz-Kuhnt, Sebastian Zundler, Stefan Wirtz, Raja Atreya, Birgitta Carlé, Oliver Friedrich, Sebastian Schürmann, Maximilian J. Waldner, Clemens Neufert, Cord H. Brakebusch, Martin O. Bergö, Imke Atreya
    更新日期:2019-11-18
  • Interferon Lambda Promotes Paneth Cell Death Via STAT1 Signaling in Mice and Is Increased in Inflamed Ileal Tissues of Patients With Crohn’s Disease
    Gastroenterology (IF 19.233) Pub Date : 2019-07-25
    Claudia Günther, Barbara Ruder, Iris Stolzer, Heidrun Dorner, Gui-Wei He, Mircea Teodor Chiriac, Konrad Aden, Anne Strigli, Miriam Bittel, Sebastian Zeissig, Philip Rosenstiel, Raja Atreya, Markus F. Neurath, Stefan Wirtz, Christoph Becker
    更新日期:2019-11-18
  • ECM1 Prevents Activation of Transforming Growth Factor β, Hepatic Stellate Cells, and Fibrogenesis in Mice
    Gastroenterology (IF 19.233) Pub Date : 2019-07-27
    Weiguo Fan, Tianhui Liu, Wen Chen, Seddik Hammad, Thomas Longerich, Ingrid Hausser, Yadong Fu, Nan Li, Yajing He, Cui Liu, Yaguang Zhang, Qiaoshi Lian, Xinhao Zhao, Chenghua Yan, Li Li, Chunyan Yi, Zhiyang Ling, Liyan Ma, Bing Sun
    更新日期:2019-11-18
  • Small-Molecule Inhibitors of Cyclophilins Block Opening of the Mitochondrial Permeability Transition Pore and Protect Mice From Hepatic Ischemia/Reperfusion Injury
    Gastroenterology (IF 19.233) Pub Date : 2019-07-20
    Mathieu Panel, Isaac Ruiz, Rozenn Brillet, Fouad Lafdil, Fatima Teixeira-Clerc, Cong Trung Nguyen, Julien Calderaro, Muriel Gelin, Fred Allemand, Jean-François Guichou, Bijan Ghaleh, Abdelhakim Ahmed-Belkacem, Didier Morin, Jean-Michel Pawlotsky
    更新日期:2019-11-18
  • Fibrogenic Activity of MECP2 Is Regulated by Phosphorylation in Hepatic Stellate Cells
    Gastroenterology (IF 19.233) Pub Date : 2019-07-25
    Eva Moran-Salvador, Marina Garcia-Macia, Ashwin Sivaharan, Laura Sabater, Marco Y.W. Zaki, Fiona Oakley, Amber Knox, Agata Page, Saimir Luli, Jelena Mann, Derek A. Mann

    Background & Aims Methyl-CpG binding protein 2, MECP2, which binds to methylated regions of DNA to regulate transcription, is expressed by hepatic stellate cells (HSCs) and is required for development of liver fibrosis in mice. We investigated the effects of MECP2 deletion from HSCs on their transcriptome and of phosphorylation of MECP2 on HSC phenotype and liver fibrosis. Methods We isolated HSCs from Mecp2–/y mice and wild-type (control) mice. HSCs were activated in culture and used in array analyses of messenger RNAs and long noncoding RNAs. Kyoto Encyclopedia of Genes and Genomes pathway analyses identified pathways regulated by MECP2. We studied mice that expressed a mutated form of Mecp2 that encodes the S80A substitution, MECP2S80, causing loss of MECP2 phosphorylation at serine 80. Liver fibrosis was induced in these mice by administration of carbon tetrachloride, and liver tissues and HSCs were collected and analyzed. Results MECP2 deletion altered expression of 284 messenger RNAs and 244 long noncoding RNAs, including those that regulate DNA replication; are members of the minichromosome maintenance protein complex family; or encode CDC7, HAS2, DNA2 (a DNA helicase), or RPA2 (a protein that binds single-stranded DNA). We found that MECP2 regulates the DNA repair Fanconi anemia pathway in HSCs. Phosphorylation of MECP2S80 and its putative kinase, HIPK2, were induced during transdifferentiation of HSCs. HSCs from MECP2S80 mice had reduced proliferation, and livers from these mice had reduced fibrosis after carbon tetrachloride administration. Conclusions In studies of mice with disruption of Mecp2 or that expressed a form of MECP2 that is not phosphorylated at S80, we found phosphorylation of MECP2 to be required for HSC proliferation and induction of fibrosis. In HSCs, MECP2 regulates expression of genes required for DNA replication and repair. Strategies to inhibit MECP2 phosphorylation at S80 might be developed for treatment of liver fibrosis.

    更新日期:2019-11-18
  • An Immune Gene Expression Signature Associated With Development of Human Hepatocellular Carcinoma Identifies Mice That Respond to Chemopreventive Agents
    Gastroenterology (IF 19.233) Pub Date : 2019-07-22
    Agrin Moeini, Sara Torrecilla, Victoria Tovar, Carla Montironi, Carmen Andreu-Oller, Judit Peix, Mónica Higuera, Dominik Pfister, Pierluigi Ramadori, Roser Pinyol, Manel Solé, Mathias Heikenwälder, Scott L. Friedman, Daniela Sia, Josep M. Llovet

    Background & Aims Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. Methods We analyzed gene expression profiles of nontumor liver tissues from 392 patients with early-stage HCC (training set, N = 167 and validation set, N = 225) and liver tissue from patients with cirrhosis without HCC (N = 216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up, 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of diethylnitrosamine (DEN) followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then orally given the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, orally given aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. Results We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of nontumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor β signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% confidence interval, 1.21–4.80). Mice with chemically induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel down-regulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. Conclusions We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that is associated with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and development of fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis.

    更新日期:2019-11-18
  • Oncogenic KRAS Reduces Expression of FGF21 in Acinar Cells to Promote Pancreatic Tumorigenesis in Mice on a High-Fat Diet
    Gastroenterology (IF 19.233) Pub Date : 2019-07-25
    Yongde Luo, Yaying Yang, Muyun Liu, Dan Wang, Feng Wang, Yawei Bi, Juntao Ji, Suyun Li, Yan Liu, Rong Chen, Haojie Huang, Xiaojie Wang, Agnieszka K. Swidnicka-Siergiejko, Tobias Janowitz, Semir Beyaz, Guoqiang Wang, Sulan Xu, Agnieszka B. Bialkowska, Weiqin Lu
    更新日期:2019-11-18
  • Drug Screen Identifies Leflunomide for Treatment of Inflammatory Bowel Diseases Caused by TTC7A Deficiency
    Gastroenterology (IF 19.233) Pub Date : 2019-11-16
    Sasha Jardine, Sierra Anderson, Stephen Babcock, Gabriella Leung, Jie Pan, Neel Dhingani, Neil Warner, Conghui Guo, Iram Siddiqui, Daniel Kotlarz, James J. Dowling, Roman Melnyk, Scott B. Snapper, Christoph Klein, Jay R. Thiagarajah, Aleixo M. Muise

    Background & Aims Mutations in the tetratricopeptide repeat domain 7A gene (TTC7A) cause intestinal epithelial and immune defects. Patients can become immune deficient and develop apoptotic enterocolitis, multiple intestinal atresia, and recurrent intestinal stenosis. The intestinal disease in patients with TTC7A deficiency is severe, untreatable, and recurs despite resection or allogeneic hematopoietic stem cell transplant. We screened drugs for those that prevent apoptosis of in cells with TTC7A deficiency and tested their effects in an animal model of the disease. Methods We developed a high-throughput screen to identify compounds approved by the Food and Drug Administration that reduce activity of caspases 3 and 7 in TTC7A-knockout HAP1 (human haploid) cells and reduce the susceptibility to apoptosis. We validated the effects of identified agents in HeLa cells that stably express TTC7A with point mutations found in patients. Signaling pathways in cells were analyzed by immunoblots. We tested the effects of identified agents in zebrafish with disruption of ttc7a, which develop intestinal defects, and colonoids derived from biopsies of patients with and without mutations in TTC7A. We performed real-time imaging of intestinal peristalsis in zebrafish and histologic analyses of intestinal tissues from patients and zebrafish. Colonoids were analyzed by immunofluorescence and for ion transport. Results TTC7A-knockout HAP1 cells have abnormal morphology and undergo apoptosis, due to increased levels of active caspases 3 and 7. We identified drugs that increased cell viability; leflunomide (used to treat patients with inflammatory conditions) reduced caspase 3 and 7 activity in cells by 96%. TTC7A-knockout cells contained cleaved caspase 3 and had reduced levels of phosphorylated AKT and XIAP; incubation of these cells with leflunomide increased levels of phosphorylated AKT and XIAP and reduced levels of cleaved caspase 3. Administration of leflunomide to ttc7a–/– zebrafish increased gut motility, reduced intestinal tract narrowing, increased intestinal cell survival, increased sizes of intestinal luminal spaces, and restored villi and goblet cell morphology. Exposure of patient-derived colonoids to leflunomide increased cell survival, polarity, and transport function. Conclusions In a drug screen, we identified leflunomide as an agent that reduces apoptosis and levels of caspase 3 and activates AKT signaling and in TTC7A-knockout cells. In zebrafish with disruption of ttc7a, leflunomide restores gut motility, reduces intestinal tract narrowing, and increases intestinal cell survival. This drug might be repurposed for treatment of TTC7A deficiency.

    更新日期:2019-11-18
  • Prostaglandin E2 Induces MIR675-5p to Promote Colorectal Tumor Metastasis via Modulation of p53 Expression
    Gastroenterology (IF 19.233) Pub Date : 2019-11-14
    Bo Cen, Jessica D. Lang, Yuchen Du, Jie Wei, Ying Xiong, Norma Bradley, Dingzhi Wang, Raymond N. DuBois

    Background & Aims Prostaglandin E2 (PGE2) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) might mediate the effects of PGE2 on colorectal cancer (CRC) development. Methods We incubated LS174T colorectal cancer cells with PGE2 or without (control) and used miRNA-seq technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative PCR, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NSG mice were given injections of LS174T cells and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes. Results We identified miRNA 675-5p (MIR675-5p) as the miRNA most highly upregulated by incubation of colorectal cancer cells with PGE2. PGE2 increased expression of MIR675-5p by activating expression of Myc, via activation of AKT, NF-κB, and β-catenin. PGE2 increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE2 formed more liver and lung metastases in mice than control LS174T cells. We identified a 3’UTR in the TP53 mRNA that bound MIR675-5p; binding resulted in loss of the p53 protein. Expression of MIR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC. Conclusions We found incubation of CRC cells with PGE2 to increase their invasive activity and ability to form liver and lung metastases in mice. PGE2 downregulates expression of p53 by increasing expression of MIR675-5p, which binds to and prevents translation of TP53 mRNA. These findings provide insight into the mechanisms by which PGE2 promotes tumor development and progression. Strategies to target the PGE2 might be developed for treatment of CRC.

    更新日期:2019-11-14
  • Clinical Practice Update: Endoscopic treatment of Barrett’s esophagus with dysplasia and/or early cancer
    Gastroenterology (IF 19.233) Pub Date : 2019-11-12
    Prateek Sharma, Nicholas J. Shaheen, David Katzka, J.J.G.H.M. Bergman

    Description The purpose of this best practice advice article is to describe, in patients with Barrett’s esophagus (BE) with dysplasia/early cancer, the role of Barrett’s endoscopic therapy (BET) and appropriate follow-up of these patients. Methods The best practice advice provided in this document is based on evidence and relevant publications reviewed by the committee.

    更新日期:2019-11-13
  • Isoforms of RNF128 Regulate the Stability of Mutant P53 in Barrett's Esophageal Cells
    Gastroenterology (IF 19.233) Pub Date : 2019-11-09
    Dipankar Ray, Paramita Ray, Daysha Ferrer-Torres, Zhuwen Wang, Derek Nancarrow, Hee-won Yoon, May San Martinho, Tonaye Hinton, Scott Owens, Dafydd Thomas, Hui Jiang, Theodore S. Lawrence, Jules Lin, Kiran Lagisetty, Andrew C. Chang, David G. Beer

    Background & Aims Barrett’s esophagus (BE) can progress to dysplasia and esophageal adenocarcinoma (EAC), accompanied by mutations in TP53 that increase the stability of its product, p53. We analyzed BE tissues for mRNAs that associate with BE progression and identified one that affects the stabilization of p53. Methods We obtained 54 BE samples collected from patients with high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC), from 1992 through 2015, and performed RNA sequence analyses, including isoform-specific analyses. We performed reverse transcription PCR analyses of 166 samples and immunohistochemical analyses of tissue microarrays that contained BE tissues from 100 patients with HGD or EAC and normal esophageal squamous mucosa (controls). Proteins were expressed from transfected plasmids or knocked down with small interfering RNAs in BE cells and analyzed by immunoblots and in immunoprecipitation and ubiquitin ligase assays. Athymic nude mice bearing EAC xenograft tumors (grown from OE-33 cells) were given intraperitoneal injections of simvastatin; tumor growth was monitored and tumors were collected and analyzed by immunoblotting for levels of RNF128, p53, and acetylated p53. Results Progression of BE to HGD or EAC associated with changes in expression of mRNAs that encoded mucins and promoted inflammation and activation of ATM and the DNA damage response. As tissues progressed from BE to HGD to EAC, they increased expression of mRNAs encoding isoform 1 of RNF128 (Iso1) and decreased expression of Iso2 of RNF128. RNF128 is an E3 ubiquitin ligase that targets p53 for degradation. Incubation of BE cells with interferon gamma (IFNG) caused them to increase expression of Iso1 and reduce expression of Iso2. Iso1 was heavily glycosylated with limited ubiquitin ligase activity for p53, resulting in p53 stabilization. Knockdown of Iso1 in BE and EAC cells led to degradation of the mutant form of p53 and reduced clonogenic survival. In contrast, Iso2 was a potent ligase that reduced levels of the mutant form of p53 in BE cells. In BE cells, Iso2 was hypoglycosylated and degraded, via ATM and GSK3B-mediated phosphorylation and activation of the BTRC-containing SCF ubiquitin ligase complex. Simvastatin, which degrades the mutant form of p53, also degraded RNF128 Iso1 protein in BE cells and slowed growth of EAC xenograft tumors in mice. Conclusions We found that isoform 2 of RNF128 is decreased in BE cells, resulting in increased levels of mutant p53, whereas isoform 1 of RNF128 is increased in BE cells, further promoting the stabilization of mutant p53.

    更新日期:2019-11-11
  • Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer
    Gastroenterology (IF 19.233) Pub Date : 2019-11-09
    Tej D. Azad, Aadel A. Chaudhuri, Penny Fang, Yawei Qiao, Mohammad S. Esfahani, Jacob J. Chabon, Emily G. Hamilton, Yi D. Yang, Alex Lovejoy, Aaron M. Newman, David M. Kurtz, Michael Jin, Joseph Schroers-Martin, Henning Stehr, Chih Long Liu, Angela Bik-Yu Hui, Viren Patel, Dipen Maru, Maximilian Diehn

    Background & Aims Biomarkers are needed to identify patients at risk of tumor progression following chemoradiotherapy for localized esophageal cancer. These could improve identification of patients at risk for cancer progression and selection of therapy. Methods We performed deep sequencing (CAPP-Seq) analyses of plasma cell-free DNA collected from 45 patients before and after chemoradiotherapy for esophageal cancer, as well as DNA from leukocytes, and fixed esophageal tumor biopsies collected during esophagogastroduodenoscopy. Patients were treated from May 2010 through October 2015; 23 patients subsequently underwent esophagectomy and 22 did not undergo surgery. We also sequenced DNA from blood samples from 40 healthy individuals (controls). We analyzed 802 regions of 607 genes for single-nucleotide variants previously associated with esophageal adenocarcinoma or squamous cell carcinoma. Patients underwent imaging analyses 6–8 weeks after chemoradiotherapy and were followed for 5 years. Our primary aim was to determine whether detection of circulating tumor DNA (ctDNA) following chemoradiotherapy is associated with risk of tumor progression (growth of local, regional, or distant tumors, detected by imaging or biopsy). Results The median proportion of tumor-derived DNA in total cell-free DNA before treatment was 0.07%, indicating that ultrasensitive assays are needed for quantification and analysis of ctDNA from localized esophageal tumors. Detection of ctDNA following chemoradiotherapy was associated with tumor progression (hazard ratio, 18.7; P<.0001), formation of distant metastases (hazard ratio, 32.1; P<.0001), and shorter disease-specific survival times (hazard ratio, 23.1; P<.0001). A higher proportion of patients with tumor progression had new mutations detected in plasma samples collected after chemoradiotherapy than patients without progression (P=.03). Detection of ctDNA after chemoradiotherapy preceded radiographic evidence of tumor progression by an average of 2.8 months. Among patients who received chemoradiotherapy without surgery, combined ctDNA and metabolic imaging analysis predicted progression in 100% of patients with tumor progression, compared with 71% for only ctDNA detection and 57% for only metabolic imaging analysis (P<.001 for comparison of either technique to combined analysis). Conclusions In an analysis of cell-free DNA in blood samples from patients who underwent chemoradiotherapy for esophageal cancer, detection of ctDNA was associated with tumor progression, metastasis, and disease-specific survival. Analysis of ctDNA might be used to identify patients at highest risk for tumor progression.

    更新日期:2019-11-11
  • ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3β1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells
    Gastroenterology (IF 19.233) Pub Date : 2019-11-09
    Mingyang Liu, Yuqing Zhang, Jingxuan Yang, Xiaobo Cui, Zhijun Zhou, Hanxiang Zhan, Kai Ding, Xiang Tian, Zhibo Yang, Kar-Ming A. Fung, Barish H. Edil, Russell G. Postier, Michael S. Bronze, Martin E. Fernandez-Zapico, Marc P. Stemmler, Thomas Brabletz, Yi-Ping Li, Courtney W. Houchen, Min Li

    Background & Aims Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice. Methods We obtained 93 pancreatic cancer specimens (tumor and adjacent non-tumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with small hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1 knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription PCR, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells and growth of xenograft tumors and metastases was measured. Results In pancreatic cancer specimens from patients, increased levels of ZIP4 associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-FU, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression of ITGA3 and ITGB1 was reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3β1 signaling, via JNK, inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine. Conclusions In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3β1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents.

    更新日期:2019-11-11
  • Lactose and Fructo-oligosaccharides Increase Visceral Sensitivity in Mice via Glycation Processes, Increasing Mast Cell Density in Colonic Mucosa
    Gastroenterology (IF 19.233) Pub Date : 2019-11-09
    J.B.J. Kamphuis, B. Guiard, M. Leveque, M. Olier, I. Jouanin, S. Yvon, V. Tondereau, P. Rivière, F. Guéraud, S. Chevolleau, M.-H. Noguer-Meireles, J.-F. Martin, L. Debrauwer, H. Eutamène, V. Theodorou

    Background and Aims Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and erratic bowel habits. A diet low in fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) can reduce symptoms of IBS, possibly by reducing microbial fermentation products. We investigated whether ingestion of FODMAPs can induce IBS-like visceral hypersensitivity mediated by fermentation products of intestinal microbes in mice. Methods C57Bl/6 mice were gavaged with lactose, with or without the anti-glycation agent pyridoxamine, or saline (controls) daily for 3 weeks. A separate group of mice were fed a diet containing fructo-oligosaccharides, with or without pyridoxamine in drinking water, or a normal chow diet (controls) for 6 weeks. Feces were collected and analyzed by 16S rRNA gene sequencing and bacterial community analyses. Abdominal sensitivity was measured by electromyography and mechanical von Frey filament assays. Colon tissues were collected from some mice and analyzed by histology and immunofluorescence, to quantify mast cells and expression of advanced glycosylation end-product specific receptor (AGER). Results Mice gavaged with lactose or fed fructo-oligosaccharides had increased abdominal sensitivity compared with controls, associated with increased numbers of mast cells in colon and expression of the receptor for AGER in proximal colon epithelium. These effects were prevented by administration of pyridoxamine. Lactose and/or pyridoxamine did not induce significant alterations in the composition of the fecal microbiota. Mass spectrometric analysis of carbonyl compounds in fecal samples identified signatures associated with mice given lactose or fructo-oligosaccharides vs controls. Conclusion We found that oral administration of lactose or fructo-oligosaccharides to mice increases abdominal sensitivity, associated with increased numbers of mast cells in colon and expression of AGER; these can be prevented with an anti-glycation agent. Lactose and/or pyridoxamine did not produce alterations in fecal microbiota of mice. Our findings indicate that preventing glycation reactions might reduce abdominal pain in patients with IBS with sensitivity to FODMAPs.

    更新日期:2019-11-11
  • Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients with Ulcerative Colitis
    Gastroenterology (IF 19.233) Pub Date : 2019-11-09
    William J. Sandborn, Laurent Peyrin-Biroulet, Jinkun Zhang, Michael Chiorean, Séverine Vermeire, Scott D. Lee, Tanja Kühbacher, Bruce Yacyshyn, Christopher H. Cabell, Snehal U. Naik, Preston Klassen, Julián Panés

    Background and Aims Etrasimod (APD334) is an oral, selective sphingosine 1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We assessed the efficacy and safety of etrasimod in patients with moderately to severely active ulcerative colitis (UC). Methods In a phase 2, proof of concept, double-blind, parallel-group study, adult outpatients with modified Mayo Clinic scores (MCSs; stool frequency, rectal bleeding, and endoscopy findings) of 4–9, endoscopic subscores of 2 or more, and rectal bleeding subscores of 1 or more were randomly assigned to groups given once-daily etrasimod 1 mg (n=52), etrasimod 2 mg (n=50), or placebo (n=54) for 12 weeks. The study was performed from October 15, 2015 through February 14, 2018 at 87 centers in 17 countries. The primary endpoint was an increase in the mean improvement in modified MCS from baseline to week 12. Secondary endpoints included the proportion of patients with endoscopic improvement (subscores of 1 or less) from baseline to week 12. Exploratory endpoints, including clinical remission, are reported in the manuscript, although the study was only statistically powered to draw conclusions on the primary endpoint. Results At week 12, the etrasimod 2 mg group met the primary and all secondary endpoints. Etrasimod 2 mg led to a significantly greater increase in mean improvement in modified MCS from baseline than placebo (difference from placebo, 0.99 points; 90% CI, 0.30–1.68; P=.009), and etrasimod 1 mg led to an increase in mean improvement from baseline in modified MCS of 0.43 points more than placebo (90% CI, reduction of 0.24 to increase of 1.11; nominal P=.15). Endoscopic improvement occurred in 41.8% of patients receiving etrasimod 2 mg vs 17.8% receiving placebo (P=.003). Most adverse events were mild to moderate. Three patients had a transient, asymptomatic, low-grade atrioventricular block that resolved spontaneously and did not recur with further dosing; 2 of the 3 patients had evidence of atrioventricular block prior to etrasimod exposure. Conclusions In patients with moderately to severely active UC, etrasimod 2 mg was more effective than placebo in producing clinical and endoscopic improvements. Further clinical development is warranted. Clinicaltrials.gov no: NCT02447302.

    更新日期:2019-11-11
  • DEVELOPMENT AND VALIDATION OF A TEST TO MONITOR ENDOSCOPIC ACTIVITY IN PATIENTS WITH CROHN’S DISEASE BASED ON SERUM LEVELS OF PROTEINS
    Gastroenterology (IF 19.233) Pub Date : 2019-11-08
    Geert D’Haens, Orlaith Kelly, Robert Battat, Mark S. Silverberg, David Laharie, Edouard Louis, Edoardo Savarino, Giorgia Bodini, Andres Yarur, Brigid S. Boland, Waqqas Afif, Xiao-jun Li, Michael Hale, Jessica Ho, Venkateswarlu Kondragunta, Benjamin Huang, Crystal Kuy, Lauren Okada, Parambir S. Dulai

    Background & Aims Non-invasive tests to measure endoscopic activity in patients with Crohn’s disease (CD) have limitations. We aimed to develop a test to identify patients in remission, based on endoscopic analysis, and monitor CD activity based on serum levels of proteins. Methods We developed a test to measure 13 proteins in blood (ANG1, ANG2, CRP, SAA1, IL7, EMMPRIN, MMP1, MMP2, MMP3, MMP9, TGFA, CEACAM1, and VCAM1), called the endoscopic healing index [EHI] using samples from 278 patients with CD from multi-national training cohort. We validated the test using 2 independent cohorts of patients with CD: 116 biologic-naïve patients with early-stage CD (validation cohort 1) and 195 biologic-exposed patients with chronic CD (validation cohort 2). The ability of the test to identify patients with active disease vs patients in remission (defined as a simple endoscopic score for CD of ≤ 2 and ≤ 1 in each segment, or a total CD endoscopic index of severity score < 3) was assessed using area under receiver operating characteristic curve (AUROC) analysis. The diagnostic accuracy of the test was compared with that of measurement of serum CRP and fecal calprotectin (FC). Results The EHI scores range from 0 to 100 units; higher scores indicate more severe CD activity, based on endoscopy findings. The EHI identified patients in remission with an AUROC of 0.962 in validation cohort 1 (95% CI, 0.942–0.982) and an AUROC of 0.693 in validation cohort 2 (95% CI, 0.619–0.767), regardless of CD location or phenotype. A cut-off value of 20 points identified patients in remission with the highest level of sensitivity (97.1% in validation cohort 1 and 83.2% in validation cohort 2), with specificity values of 69.0% and 36.6%, respectively. A cut-off value of 50 points identified patients in remission with the highest level of specificity (100% in validation cohort 1 and 87.8% in validation cohort 2), with sensitivity values of 37.3% and 30.0%, respectively. The EHI identified patients in remission with a significantly higher AUROC value than the test for CRP (0.876, P<.001 in validation cohort 1 and 0.624, P=.109 in validation cohort 2). In analysis of patients with available FC measurements, the AUROC value for the EHI did not differ significantly from that of measurement of FC (AUROC, 0.950 for EHI vs AUROC, 0.923 for FC, P=.147 in validation cohort 1 and AUROC, 0.803 for EHI vs AUROC, 0.854 for FC, P=.298 in validation cohort 2). Conclusions We developed an index to identify patients with CD in endoscopic remission based on blood levels of 13 proteins, called the EHI. The EHI identified patients with resolution of endoscopic disease activity, with good overall accuracy, although with variation between the 2 cohorts assessed. The EHI AUROC values were comparable to measurement of FC and higher than measurement of serum CRP. The test might be used in practice for assessing endoscopic activity in patients with CD.

    更新日期:2019-11-08
  • Causes of Socioeconomic Disparities in Colorectal Cancer and Intervention Framework and Strategies
    Gastroenterology (IF 19.233) Pub Date : 2019-11-01
    John M. Carethers, Chyke A. Doubeni

    Colorectal cancer (CRC) disproportionately affects people from low socioeconomic backgrounds and some racial minorities. Disparities in CRC incidence and outcomes might result from differences in exposure to risk factors such as unhealthy diet and sedentary lifestyle; limited access to risk-reducing behaviors such as chemoprevention, screening, and follow up of abnormal test results; or lack of access to high-quality treatment resources. These factors operate at the individual, provider, health system, community, and policy levels to perpetuate CRC disparities. However, CRC disparities can be eliminated. Addressing the complex factors that contribute to development and progression of CRC with multicomponent, adaptive interventions, at multiple levels of the care continuum, can reduce gaps in mortality. These might be addressed with a combination of healthcare and community-based interventions and policy changes that promote healthy behaviors and ensure access to high-quality and effective measures for CRC prevention, diagnosis, and treatment. Improving resources and coordinating efforts in communities where people of low-socioeconomic status live and work would increase access to evidence-based interventions. Research is also needed to understand the role and potential mechanisms by which factors in diet, intestinal microbiome, and/or inflammation contribute to differences in colorectal carcinogenesis. Studies of large cohorts with diverse populations are needed to identify epidemiologic and molecular factors that contribute to CRC development in different populations.

    更新日期:2019-11-01
  • Uptake of Colorectal Cancer Screening by Physicians is Associated With Greater Uptake by Their Patients
    Gastroenterology (IF 19.233) Pub Date : 2019-11-01
    Owen Litwin, Jessica M. Sontrop, Eric McArthur, Jill Tinmouth, Linda Rabeneck, Christopher Vinden, Manish M. Sood, Nancy N. Baxter, Peter Tanuseputro, Blayne Welk, Amit X. Garg

    Background & Aims Physicians’ own screening practices might affect screening in their patients. We conducted a population-based study to evaluate whether family physicians who underwent colorectal cancer testing were more likely to have patients who underwent colorectal cancer testing. Methods We collected demographic and healthcare information on residents of Ontario, Canada from administrative databases; the sample was restricted to individuals at average risk of colorectal cancer who were 52–74 years old as of April 21, 2016. We obtained a list of all registered physicians in the province; physicians (n=11,434) were matched with non-physicians (n=45,736) on age, sex, and residential location. Uptake of colorectal tests was defined by a record of a fecal occult blood test in the past 2 years, flexible sigmoidoscopy in the past 5 years, or colonoscopy in the past 10 years. Patients were assigned to family physicians based on billing claim frequency, and then the association between colorectal testing in family physicians and their patients was examined using a modified Poisson regression model. Results Uptake of colorectal tests by physicians and non-physicians (median age 60; 71% men) was 67.9% (95% CI, 67.0%–68.7%) and 66.6% (95% CI, 66.2%–67.1%), respectively. Physicians were less likely than non-physicians to undergo fecal occult blood testing and were more likely to undergo colonoscopy; prevalence ratios were 0.44 (95% CI, 0.42–0.47) and 1.24 (95% CI, 1.22–1.26), respectively. Uptake of colorectal tests by family physicians was associated with greater uptake by their patients (adjusted prevalence ratio, 1.10; 95% CI, 1.08–1.12). Conclusions Approximately one third of physicians and non-physicians are overdue for colorectal cancer screening. Patients are more likely to be tested if their family physician has been tested. There is an opportunity for physicians to increase their participation in colorectal cancer screening, which could in turn motivate their patients to undergo screening.

    更新日期:2019-11-01
  • Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct
    Gastroenterology (IF 19.233) Pub Date : 2019-10-31
    Aatur D. Singhi, Laura D. Wood, Emma Parks, Michael S. Torbenson, Matthäus Felsenstein, Ralph H. Hruban, Marina N. Nikiforova, Abigail I. Wald, Cihan Kaya, Yuri E. Nikiforov, Laura Favazza, Jin He, Kevin McGrath, Kenneth E. Fasanella, Randall E. Brand, Anne Marie Lennon, Alessandro Furlan, Anil K. Dasyam, Adam Slivka

    Background & Aims Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes. Methods We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic cholangiocarcinomas from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n=5, collected before surgery) and bile duct brushings (n=2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls). Results All IOPNs evaluated were found to have recurring fusions of ATP1B1–PRKACB (n = 13), DNAJB1–PRKACA (n = 6), or ATP1B1–PRKACA (n = 4). These fusions were also found in corresponding invasive PDACs and intrahepatic cholangiocarcinomas, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions. Conclusions We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.

    更新日期:2019-11-01
  • Disruption of SIRT7 Increases the Efficacy of Checkpoint Inhibitor via MEF2D Regulation of PD-L1 in Hepatocellular Carcinoma Cells
    Gastroenterology (IF 19.233) Pub Date : 2019-10-31
    Junyu Xiang, Ni Zhang, Hui Sun, Li Su, Chengcheng Zhang, Huailong Xu, Juan Feng, Meiling Wang, Jun Chen, Limei Liu, Juanjuan Shan, Junjie Shen, Zhi Yang, Guiqin Wang, Haijun Zhou, Jesus Prieto, Matías A. Ávila, Chungang Liu, Cheng Qian

    Background & Aims Immune checkpoint inhibitors have some efficacy in treatment of hepatocellular carcinoma (HCC). Programmed cell death 1 ligand 1 (PD-L1), expressed on some cancer cells, binds to the receptor programmed cell death 1 (PDCD1, also called PD1) on T cells to prevent their proliferation and reduce the antigen-tumor immune response. Immune cells that infiltrate some types of HCCs secrete interferon gamma (IFNG). Some HCC cells express myocyte enhancer factor 2D (MEF2D), which has been associated with shorter survival times of patients. We studied whether HCC cell expression of MEF2D regulates expression of PD-L1 in response to IFNG. Methods We analyzed immune cells from 20 fresh HCC tissues by flow cytometry. We analyzed 225 fixed HCC tissues (from 2 cohorts) from patients in China by immunohistochemistry and obtained survival data. We created mice with liver-specific knockout of MEF2D (MEF2DLPC-KO mice). We knocked out or knocked down MEF2D, E1A binding protein p300 (p300), or sirtuin 7 (SIRT7) in SMMC-7721, Huh7, H22, and Hepa1-6 HCC cell lines, some incubated with IFNG. We analyzed liver tissues form mice and cell lines by RNA sequence, immunoblot, dual luciferase reporter, and chromatin precipitation assays. MEF2D protein acetylation and proteins that interact with MEF2D were identified by co-immunoprecipitation and pull-down assays. H22 cells, with MEF2D knockout or without (controls) were transplanted into BALB/c mice, some mice were given antibodies to deplete T cells. Mice bearing orthotopic tumors grown from HCC cells with or without knockout of SIRT7, were given injections of an antibody against PD1. Growth of tumors was measured and tumors were analyzed by immunohistochemistry and flow cytometry. Results In human HCC specimens, we found an inverse correlation between level of MEF2D and numbers of CD4+ and CD8+ T cells; level of MEF2D correlated with percentages of PD1-positive or TIM3-positive CD8+ T cells. Knockout of MEF2D from H22 cells reduced their growth as allograft tumors in immune-competent mice, but not in immune-deficient mice or mice with depletion of CD8+ T cells. When MEF2D-knockout cells were injected into immune-competent mice, they formed smaller tumors that had increased infiltration and activation of T cells, compared with control HCC cells. In human and mouse HCC cells, MEF2D knockdown or knockout reduced expression of PD-L1. MEF2D bound the promoter region of the CD274 gene (encodes PD-L1) and activated its transcription. Overexpression of p300 in HCC cells, or knockout of SIRT7, promoted acetylation of MEF2D and increased its binding, along with acetylated histones, to the promoter region of the CD274. Exposure of HCC cells to IFNG induced expression of p300 and its binding MEF2D, which reduced the interaction between MEF2D and SIRT7. MEF2D-induced expression of PD-L1 upon IFNG exposure was independent of interferon-regulatory factor 1 (IRF1) or IRF9. In HCC cells not exposed to IFNG, SIRT7 formed a complex with MEF2D that attenuated expression of PD-L1. Knockout of SIRT7 reduced proliferation of HCC cells and growth of tumors in immune-deficient mice. Compared with allograft tumors grown from control HCC cells, in immune-competent mice, tumors grown from SIRT7-knockout HCC cells expressed higher level of PD-L1 and had reduced infiltration and activation of T cells. In immune-competent mice given antibodies to PD1, allograft tumors grew more slowly from SIRT7-knockout HCC cells than from control HCC cells. Conclusions Expression MEF2D by HCC cells increases their expression of PD-L1, which prevents CD8+ T cell-mediated anti-tumor immunity. When HCC cells are exposed to IFNG, p300 acetylates MEF2D, causing it to bind the CD274 gene promoter and upregulate PD-L1 expression. In addition to promoting HCC cell proliferation, SIRT7 reduced acetylation of MEF2D and expression of PD-L1 in HCC cells not exposed to IFNG. Strategies to manipulate this pathway might increase the efficacy of immune therapies for HCC.

    更新日期:2019-11-01
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