Journal Cover Gut
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   ISSN (Print) 0017-5749 - ISSN (Online) 1468-3288
   Published by BMJ Publishing Group Homepage  [56 journals]
  • CDK20 inhibition and immune checkpoint blockade: bringing cancer biology
    • Authors: Greten, T. F; Korangy, F.
      Pages: 783 - 784
      Abstract: On 22 September 2017 the Food and Drug Administration granted accelerated approval to nivolumab for the treatment of hepatocellular carcinoma (HCC) in patients who have been previously treated with sorafenib. Approval was based on a 154-patient subgroup of a multicentre, open-label trial conducted in patients with HCC and Child-Pugh A cirrhosis who progressed on or were intolerant to sorafenib.1 With an overall response rate of close to 15%, which lasted in more than 90% of the patients 6 months or longer, immune checkpoint blockade has become a treatment option for patients with HCC after many years of failures in drug development. However, these data also call for future combination studies, which will increase the number of patients responding to immunotherapy. But what is the best combination partner for an immune checkpoint inhibitor in HCC' While immune checkpoint inhibitors successfully lead to activation of T cells in patients with...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-315091
      Issue No: Vol. 67, No. 5 (2018)
  • MAIT cells: a novel therapeutic target for alcoholic liver disease'
    • Authors: Gao, B; Ma, J, Xiang, X.
      Pages: 784 - 786
      Abstract: Bacterial infection is one of the most frequent and severe complications of advanced alcoholic liver disease (ALD), including alcoholic cirrhosis and severe alcoholic hepatitis (SAH). Patients who suffered from SAH are susceptible to bacterial infection with one study reporting 50% of them developed bacterial infection.1 Additionally, standard corticosteroid treatment further increased the risk of bacterial infection in patients with SAH.1 Thus, infection is highly relevant for the outcome of SAH and represents an important therapeutic target. However, except antibiotic treatment, there are currently no other specific therapies that effectively control bacterial infection in SAH due to incomplete understanding of the pathogenesis of bacterial infection in these patients. The mechanisms underlying the increased risk of bacterial infection in ALD are complex and multifactorial. The high incidence of bacterial infection may be partly explained by gut bacterial overgrowth, dysbiosis and translocation of gut bacteria and their products in...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-315284
      Issue No: Vol. 67, No. 5 (2018)
  • HBV infection and HCC: the 'dangerous liaisons
    • Authors: Bertoletti, A; Kennedy, P. T. F, Durantel, D.
      Pages: 787 - 788
      Abstract: Long-term relationships are somehow unpredictable. Periods of harmony are often followed by times of conflict with outcomes which are difficult to predict. This precept can apply to the relationship between HBV and human species. HBV acquired at birth or in early childhood establishes lifelong persistent infection in the majority of subjects, which is evolving, and characterised by fluctuations of virological and clinical parameters. The overall impact of these fluctuations in the development of liver fibrosis and hepatocellularcarcinoma has often puzzled clinicians and researchers studying this complex and somewhat fascinating interaction between HBV and our species. An interesting new piece of information, related to this interaction, has now been added, thanks to the work of the group of GA Kim and YS Lim, published in Gut.1 Let’s try to first summarise the main points of this puzzle. The early phase of the HBV-host relationship is characterised by normal...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-315528
      Issue No: Vol. 67, No. 5 (2018)
  • European evidence-based guidelines on pancreatic cystic neoplasms
    • Authors: The European Study Group on Cystic Tumours of the Pancreas; Del Chiaro, Besselink, Scholten, Bruno, Cahen, Gress, van Hooft, Lerch, Mayerle, Hackert, Satoi, Zerbi, Cunningham, Angelis, Giovannini, De-Madaria, Hegyi, Rosendahl, Friess, Manfredi, Levy, Real, Sauvanet, Abu Hilal, Marchegiani, Esposito, Ghaneh, Engelbrecht, Fockens, van Huijgevoort, Wolfgang, Bassi, Gubergrits, Verbeke, Klöppel, Scarpa, Zamboni, Lennon, Sund, Kartalis, Grenacher, Falconi, Arnelo, Kopchak, Oppong, Mckay, Hauge, Conlon, Adham, Ceyhan, Salvia, Dervenis, Allen, Paye, Bartsch, Löhr, Mutignani, Laukkarinen, Schulick, Valente, Seufferlein, Capurso, Siriwardena, Neoptolemos, Pukitis, Segersvärd, Aghdassi, Andrianello, Bossuyt, Bülow, Cardenas-Jaen, Cortegoso, Fontana, Haeberle, Heckler, Litvin, Mann, Michalski, Michl, Nappo, Perri, Persson, Scheufele, Sclafani, Schmidt, Venezia, Volker, Vullierm, Wüsten
      Pages: 789 - 804
      Abstract: Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring 5 mm, and MPD diameter>10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.
      Keywords: Open access, Editor's choice, Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2018-316027
      Issue No: Vol. 67, No. 5 (2018)
  • A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse
    • Authors: Petersen, C. P; Meyer, A. R, De Salvo, C, Choi, E, Schlegel, C, Petersen, A, Engevik, A. C, Prasad, N, Levy, S. E, Peebles, R. S, Pizarro, T. T, Goldenring, J. R.
      Pages: 805 - 817
      Abstract: ObjectiveAlternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown.DesignTo determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice.ResultsProfiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss.ConclusionsMetaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-312779
      Issue No: Vol. 67, No. 5 (2018)
  • Clinical relevance of detecting anti-infliximab antibodies with a
           drug-tolerant assay: post hoc analysis of the TAXIT trial
    • Authors: Van Stappen, T; Vande Casteele, N, Van Assche, G, Ferrante, M, Vermeire, S, Gils, A.
      Pages: 818 - 826
      Abstract: ObjectiveTo evaluate the clinical relevance of antidrug antibodies (ADAs) measured using a drug-tolerant assay in a post hoc analysis of the Trough Concentration (TC) Adapted Infliximab Treatment (TAXIT) randomised controlled trial.DesignADA in serum samples (n=221) of 76 patients enrolled in TAXIT, who presented with an infliximab TC
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-313071
      Issue No: Vol. 67, No. 5 (2018)
  • Age-dependent shift in macrophage polarisation causes
           inflammation-mediated degeneration of enteric nervous system
    • Authors: Becker, L; Nguyen, L, Gill, J, Kulkarni, S, Pasricha, P. J, Habtezion, A.
      Pages: 827 - 836
      Abstract: ObjectiveThe enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS.DesignLongitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old mice were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR.ResultsAgeing causes a shift in macrophage polarisation from anti-inflammatory ‘M2’ to proinflammatory ‘M1’ that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS.ConclusionsA shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-312940
      Issue No: Vol. 67, No. 5 (2018)
  • Randomised controlled trial of transanal endoscopic microsurgery versus
           endoscopic mucosal resection for large rectal adenomas (TREND Study)
    • Authors: Barendse, R. M; Musters, G. D, de Graaf, E. J. R, van den Broek, F. J. C, Consten, E. C. J, Doornebosch, P. G, Hardwick, J. C, de Hingh, I. H. J. T, Hoff, C, Jansen, J. M, van Milligen de Wit, A. W. M, van der Schelling, G. P, Schoon, E. J, Schwartz, M. P, Weusten, B. L. A. M, Dijkgraaf, M. G, Fockens, P, Bemelman, W. A, Dekker, E, on behalf of the TREND Study group
      Pages: 837 - 846
      Abstract: ObjectiveNon-randomised studies suggest that endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM), but EMR might be more cost-effective and safer. This trial compares the clinical outcome and cost-effectiveness of TEM and EMR for large rectal adenomas.DesignPatients with rectal adenomas ≥3 cm, without malignant features, were randomised (1:1) to EMR or TEM, allowing endoscopic removal of residual adenoma at 3 months. Unexpected malignancies were excluded postrandomisation. Primary outcomes were recurrence within 24 months (aiming to demonstrate non-inferiority of EMR, upper limit 10%) and the number of recurrence-free days alive and out of hospital.ResultsTwo hundred and four patients were treated in 18 university and community hospitals. Twenty-seven (13%) had unexpected cancer and were excluded from further analysis. Overall recurrence rates were 15% after EMR and 11% after TEM; statistical non-inferiority was not reached. The numbers of recurrence-free days alive and out of hospital were similar (EMR 609±209, TEM 652±188, p=0.16). Complications occurred in 18% (EMR) versus 26% (TEM) (p=0.23), with major complications occurring in 1% (EMR) versus 8% (TEM) (p=0.064). Quality-adjusted life years were equal in both groups. EMR was approximately 3000 cheaper and therefore more cost-effective.ConclusionUnder the statistical assumptions of this study, non-inferiority of EMR could not be demonstrated. However, EMR may have potential as the primary method of choice due to a tendency of lower complication rates and a better cost-effectiveness ratio. The high rate of unexpected cancers should be dealt with in further studies.
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-313101
      Issue No: Vol. 67, No. 5 (2018)
  • Gut symbiotic microbes imprint intestinal immune cells with the innate
           receptor SLAMF4 which contributes to gut immune protection against enteric
    • Authors: Cabinian, A; Sinsimer, D, Tang, M, Jang, Y, Choi, B, Laouar, Y, Laouar, A.
      Pages: 847 - 859
      Abstract: BackgroundInteractions between host immune cells and gut microbiota are crucial for the integrity and function of the intestine. How these interactions regulate immune cell responses in the intestine remains a major gap in the field.AimWe have identified the signalling lymphocyte activation molecule family member 4 (SLAMF4) as an immunomodulator of the intestinal immunity. The aim is to determine how SLAMF4 is acquired in the gut and what its contribution to intestinal immunity is.MethodsExpression of SLAMF4 was assessed in mice and humans. The mechanism of induction was studied using GFPtg bone marrow chimaera mice, lymphotoxin α and TNLG8A-deficient mice, as well as gnotobiotic mice. Role in immune protection was revealed using oral infection with Listeria monocytogenes and Cytobacter rodentium.ResultsSLAMF4 is a selective marker of intestinal immune cells of mice and humans. SLAMF4 induction occurs directly in the intestinal mucosa without the involvement of the gut-associated lymphoid tissue. Gut bacterial products, particularly those of gut anaerobes, and gut-resident antigen-presenting cell (APC)TNLG8A are key contributors of SLAMF4 induction in the intestine. Importantly, lack of SLAMF4 expression leads the increased susceptibility of mice to infection by oral pathogens culminating in their premature death.ConclusionsSLAMF4 is a marker of intestinal immune cells which contributes to the protection against enteric pathogens and whose expression is dependent on the presence of the gut microbiota. This discovery provides a possible mechanism for answering the long-standing question of how the intertwining of the host and gut microbial biology regulates immune cell responses in the gut.
      Keywords: Open access
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-313214
      Issue No: Vol. 67, No. 5 (2018)
  • Toxin-positive Clostridium difficile latently infect mouse colonies and
           protect against highly pathogenic C. difficile
    • Authors: Etienne-Mesmin, L; Chassaing, B, Adekunle, O, Mattei, L. M, Bushman, F. D, Gewirtz, A. T.
      Pages: 860 - 871
      Abstract: ObjectiveClostridium difficile is a toxin-producing bacterium and a leading cause of antibiotic-associated disease. The ability of C. difficile to form spores and infect antibiotic-treated persons at low multiplicity of infection (MOI) underlies its large disease burden. However, C. difficile-induced disease might also result from long-harboured C. difficile that blooms in individuals administered antibiotics.DesignMice purchased from multiple vendors and repeatedly testing negative for this pathogen by quantitative PCR bloomed C. difficile following antibiotic treatment. This endogenous C. difficile strain, herein termed LEM1, which formed spores and produced toxin, was compared with highly pathogenic C. difficile strain VPI10463.ResultsWhole-genome sequencing revealed that LEM1 and VPI10463 shared 95% of their genes, including all known virulence genes. In contrast to VPI10463, LEM1 did not induce overt disease when administered to antibiotic-treated or germ-free mice, even at high doses. Rather, blooms of LEM1 correlated with survival following VPI10463 inoculation, and exogenous administration of LEM1 before or shortly following VPI10463 inoculation prevented C. difficile-induced death. Accordingly, despite similar growth properties in vitro, LEM1 strongly outcompeted VPI10463 in mice even at 100-fold lower inocula.ConclusionsThese results highlight the difficulty of determining whether individual cases of C. difficile infection resulted from a bloom of endogenous C. difficile or a new exposure to this pathogen. In addition to impacting the design of studies using mouse models of C. difficile-induced disease, this study identified, isolated and characterised an endogenous murine spore-forming C. difficile strain able to decrease colonisation, associated disease and death induced by a pathogenic C. difficile strain.
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-313510
      Issue No: Vol. 67, No. 5 (2018)
  • Multivariate modelling of faecal bacterial profiles of patients with IBS
           predicts responsiveness to a diet low in FODMAPs
    • Authors: Bennet, S. M. P; Böhn, L, Störsrud, S, Liljebo, T, Collin, L, Lindfors, P, Törnblom, H, Öhman, L, Simren, M.
      Pages: 872 - 881
      Abstract: ObjectiveThe effects of dietary interventions on gut bacteria are ambiguous. Following a previous intervention study, we aimed to determine how differing diets impact gut bacteria and if bacterial profiles predict intervention response.DesignSixty-seven patients with IBS were randomised to traditional IBS (n=34) or low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) (n=33) diets for 4 weeks. Food intake was recorded for 4 days during screening and intervention. Faecal samples and IBS Symptom Severity Score (IBS-SSS) reports were collected before (baseline) and after intervention. A faecal microbiota dysbiosis test (GA-map Dysbiosis Test) evaluated bacterial composition. Per protocol analysis was performed on 61 patients from whom microbiome data were available.ResultsResponders (reduced IBS-SSS by ≥50) to low FODMAP, but not traditional, dietary intervention were discriminated from non-responders before and after intervention based on faecal bacterial profiles. Bacterial abundance tended to be higher in non-responders to a low FODMAP diet compared with responders before and after intervention. A low FODMAP intervention was associated with an increase in Dysbiosis Index (DI) scores in 42% of patients; while decreased DI scores were recorded in 33% of patients following a traditional IBS diet. Non-responders to a low FODMAP diet, but not a traditional IBS diet had higher DI scores than responders at baseline. Finally, while a traditional IBS diet was not associated with significant reduction of investigated bacteria, a low FODMAP diet was associated with reduced Bifidobacterium and Actinobacteria in patients, correlating with lactose consumption.ConclusionsA low FODMAP, but not a traditional IBS diet may have significant impact on faecal bacteria. Responsiveness to a low FODMAP diet intervention may be predicted by faecal bacterial profiles.Trial registration numberNCT02107625.
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-313128
      Issue No: Vol. 67, No. 5 (2018)
  • Leveraging sequence-based faecal microbial community survey data to
           identify a composite biomarker for colorectal cancer
    • Authors: Shah, M. S; DeSantis, T. Z, Weinmaier, T, McMurdie, P. J, Cope, J. L, Altrichter, A, Yamal, J.-M, Hollister, E. B.
      Pages: 882 - 891
      Abstract: ObjectiveColorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the USA. The faecal microbiome may provide non-invasive biomarkers of CRC and indicate transition in the adenoma–carcinoma sequence. Re-analysing raw sequence and metadata from several studies uniformly, we sought to identify a composite and generalisable microbial marker for CRC.DesignRaw 16S rRNA gene sequence data sets from nine studies were processed with two pipelines, (1) QIIME closed reference (QIIME-CR) or (2) a strain-specific method herein termed SS-UP (Strain Select, UPARSE bioinformatics pipeline). A total of 509 samples (79 colorectal adenoma, 195 CRC and 235 controls) were analysed. Differential abundance, meta-analysis random effects regression and machine learning analyses were carried out to determine the consistency and diagnostic capabilities of potential microbial biomarkers.ResultsDefinitive taxa, including Parvimonas micra ATCC 33270, Streptococcus anginosus and yet-to-be-cultured members of Proteobacteria, were frequently and significantly increased in stools from patients with CRC compared with controls across studies and had high discriminatory capacity in diagnostic classification. Microbiome-based CRC versus control classification produced an area under receiver operator characteristic (AUROC) curve of 76.6% in QIIME-CR and 80.3% in SS-UP. Combining clinical and microbiome markers gave a diagnostic AUROC of 83.3% for QIIME-CR and 91.3% for SS-UP.ConclusionsDespite technological differences across studies and methods, key microbial markers emerged as important in classifying CRC cases and such could be used in a universal diagnostic for the disease. The choice of bioinformatics pipeline influenced accuracy of classification. Strain-resolved microbial markers might prove crucial in providing a microbial diagnostic for CRC.
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-313189
      Issue No: Vol. 67, No. 5 (2018)
  • Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates
           alcoholic liver disease
    • Authors: Grander, C; Adolph, T. E, Wieser, V, Lowe, P, Wrzosek, L, Gyongyosi, B, Ward, D. V, Grabherr, F, Gerner, R. R, Pfister, A, Enrich, B, Ciocan, D, Macheiner, S, Mayr, L, Drach, M, Moser, P, Moschen, A. R, Perlemuter, G, Szabo, G, Cassard, A. M, Tilg, H.
      Pages: 891 - 901
      Abstract: ObjectiveAlcoholic liver disease (ALD) is a global health problem with limited therapeutic options. Intestinal barrier integrity and the microbiota modulate susceptibility to ALD. Akkermansia muciniphila, a Gram-negative intestinal commensal, promotes barrier function partly by enhancing mucus production. The aim of this study was to investigate microbial alterations in ALD and to define the impact of A. muciniphila administration on the course of ALD.DesignThe intestinal microbiota was analysed in an unbiased approach by 16S ribosomal DNA (rDNA) sequencing in a Lieber-DeCarli ALD mouse model, and faecal A. muciniphila abundance was determined in a cohort of patients with alcoholic steatohepatitis (ASH). The impact of A. muciniphila on the development of experimental acute and chronic ALD was determined in a preventive and therapeutic setting, and intestinal barrier integrity was analysed.ResultsPatients with ASH exhibited a decreased abundance of faecal A. muciniphila when compared with healthy controls that indirectly correlated with hepatic disease severity. Ethanol feeding of wild-type mice resulted in a prominent decline in A. muciniphila abundance. Ethanol-induced intestinal A. muciniphila depletion could be restored by oral A. muciniphila supplementation. Furthermore, A. muciniphila administration when performed in a preventive setting decreased hepatic injury, steatosis and neutrophil infiltration. A. muciniphila also protected against ethanol-induced gut leakiness, enhanced mucus thickness and tight-junction expression. In already established ALD, A. muciniphila used therapeutically ameliorated hepatic injury and neutrophil infiltration.ConclusionEthanol exposure diminishes intestinal A. muciniphila abundance in both mice and humans and can be recovered in experimental ALD by oral supplementation. A. muciniphila promotes intestinal barrier integrity and ameliorates experimental ALD. Our data suggest that patients with ALD might benefit from A. muciniphila supplementation.
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-313432
      Issue No: Vol. 67, No. 5 (2018)
  • Persistent cough: A question for the gastroenterologist'
    • Authors: Parsons, E; Warner, B. E, Braden, B.
      Pages: 902 - 902
      Abstract: Case An 80-year-old female retired teacher was admitted under the medical team with right-lower-lobe pneumonia. The patient, a non-smoker with minimal alcohol intake, had a medical history of non-Hodgkin’s lymphoma treated with radiotherapy and splenectomy 30 years before, Barrett’s oesophagus (C9M9 Prague Classification) with distal oesophageal ulcer diagnosed 8 months previously, hiatus hernia and dual-chamber pacemaker for sinus-arrest. Medications were omeprazole 80 mg and ranitidine 300 mg daily. During the preceding two years, the patient had consulted Respiratory and Gastroenterology teams for a persistent cough worsened by eating and drinking and two stone weight loss (admission BMI 16). High-resolution CT demonstrated subsegmental atelectasis and ground glass changes in the lower lobes consistent with chronic aspiration or infection. Her symptoms were attributed to recurrent aspiration due to persistent reflux and poor swallow. During the medical admission, a follow-up oesophagogastroduodenoscopy (OGD) for Barrett’s oesophagus was performed (figure 1) and biopsy samples...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-314247
      Issue No: Vol. 67, No. 5 (2018)
  • CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient,
           hyperdiploid colorectal cancer stem cells
    • Authors: Manic, G; Signore, M, Sistigu, A, Russo, G, Corradi, F, Siteni, S, Musella, M, Vitale, S, De Angelis, M. L, Pallocca, M, Amoreo, C. A, Sperati, F, Di Franco, S, Barresi, S, Policicchio, E, De Luca, G, De Nicola, F, Mottolese, M, Zeuner, A, Fanciulli, M, Stassi, G, Maugeri-Sacca, M, Baiocchi, M, Tartaglia, M, Vitale, I, De Maria, R.
      Pages: 903 - 917
      Abstract: ObjectiveCancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies.DesignTo discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents.ResultsThe drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (~36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368.ConclusionsLY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.
      Keywords: Open access
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-312623
      Issue No: Vol. 67, No. 5 (2018)
  • Mucosa-associated invariant T cells link intestinal immunity with
           antibacterial immune defects in alcoholic liver disease
    • Authors: Riva, A; Patel, V, Kurioka, A, Jeffery, H. C, Wright, G, Tarff, S, Shawcross, D, Ryan, J. M, Evans, A, Azarian, S, Bajaj, J. S, Fagan, A, Patel, V, Mehta, K, Lopez, C, Simonova, M, Katzarov, K, Hadzhiolova, T, Pavlova, S, Wendon, J. A, Oo, Y. H, Klenerman, P, Williams, R, Chokshi, S.
      Pages: 918 - 930
      Abstract: Background/aimsIntestinal permeability with systemic distribution of bacterial products are central in the immunopathogenesis of alcoholic liver disease (ALD), yet links with intestinal immunity remain elusive. Mucosa-associated invariant T cells (MAIT) are found in liver, blood and intestinal mucosa and are a key component of antibacterial host defences. Their role in ALD is unknown.Methods/designWe analysed frequency, phenotype, transcriptional regulation and function of blood MAIT cells in severe alcoholic hepatitis (SAH), alcohol-related cirrhosis (ARC) and healthy controls (HC). We also examined direct impact of ethanol, bacterial products from faecal extracts and antigenic hyperstimulation on MAIT cell functionality. Presence of MAIT cells in colon and liver was assessed by quantitative PCR and immunohistochemistry/gene expression respectively.ResultsIn ARC and SAH, blood MAIT cells were dramatically depleted, hyperactivated and displayed defective antibacterial cytokine/cytotoxic responses. These correlated with suppression of lineage-specific transcription factors and hyperexpression of homing receptors in the liver with intrahepatic preservation of MAIT cells in ALD. These alterations were stronger in SAH, where surrogate markers of bacterial infection and microbial translocation were higher than ARC. Ethanol exposure in vitro, in vivo alcohol withdrawal and treatment with Escherichia coli had no effect on MAIT cell frequencies, whereas exposure to faecal bacteria/antigens induced functional impairments comparable with blood MAIT cells from ALD and significant MAIT cell depletion, which was not observed in other T cell compartments.ConclusionsIn ALD, the antibacterial potency of MAIT cells is compromised as a consequence of contact with microbial products and microbiota, suggesting that the ‘leaky’ gut observed in ALD drives MAIT cell dysfunction and susceptibility to infection in these patients.
      Keywords: Open access, Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-314458
      Issue No: Vol. 67, No. 5 (2018)
  • Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor
           cell immunosuppression and enhances immune-checkpoint blockade efficacy
    • Authors: Zhou, J; Liu, M, Sun, H, Feng, Y, Xu, L, Chan, A. W. H, Tong, J. H, Wong, J, Chong, C. C. N, Lai, P. B. S, Wang, H. K.-S, Tsang, S.-W, Goodwin, T, Liu, R, Huang, L, Chen, Z, Sung, J. J, Chow, K. L, To, K. F, Cheng, A. S.-L.
      Pages: 931 - 944
      Abstract: ObjectiveMyeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).DesignImmunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK-inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.ResultsTumour-infiltrating CD11b+CD33+HLA-DR– MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR– MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-B (NF-B) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-B-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-B/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon +tumour necrosis factor-α+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.ConclusionOur results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-314032
      Issue No: Vol. 67, No. 5 (2018)
  • High risk of hepatocellular carcinoma and death in patients with
           immune-tolerant-phase chronic hepatitis B
    • Authors: Kim, G.-A; Lim, Y.-S, Han, S, Choi, J, Shim, J. H, Kim, K. M, Lee, H. C, Lee, Y. S.
      Pages: 945 - 952
      Abstract: ObjectiveHigh serum HBV DNA levels are associated with high risks of hepatocellular carcinoma (HCC) and cirrhosis in patients with chronic hepatitis B (CHB). Although the immune-tolerant (IT) phase is characterised by high circulating HBV DNA levels, it remains unknown whether antiviral treatment reduces risks of HCC and mortality.DesignThis historical cohort study included HBeAg-positive patients with CHB with high HBV DNA levels (≥20 000 IU/mL) and no evidence of cirrhosis at a tertiary referral hospital in Korea from 2000 to 2013. The clinical outcomes of 413 untreated IT-phase patients with normal alanine aminotransferase (ALT) levels (females,
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-314904
      Issue No: Vol. 67, No. 5 (2018)
  • miR-135a-5p-mediated downregulation of protein tyrosine phosphatase
           receptor delta is a candidate driver of HCV-associated
    • Authors: Van Renne, N; Roca Suarez, A. A, Duong, F. H. T, Gondeau, C, Calabrese, D, Fontaine, N, Ababsa, A, Bandiera, S, Croonenborghs, T, Pochet, N, De Blasi, V, Pessaux, P, Piardi, T, Sommacale, D, Ono, A, Chayama, K, Fujita, M, Nakagawa, H, Hoshida, Y, Zeisel, M. B, Heim, M. H, Baumert, T. F, Lupberger, J.
      Pages: 953 - 962
      Abstract: Background and aimsHCV infection is a leading risk factor of hepatocellular carcinoma (HCC). However, even after viral clearance, HCC risk remains elevated. HCV perturbs host cell signalling to maintain infection, and derailed signalling circuitry is a key driver of carcinogenesis. Since protein phosphatases are regulators of signalling events, we aimed to identify phosphatases that respond to HCV infection with relevance for hepatocarcinogenesis.MethodsWe assessed mRNA and microRNA (miRNA) expression profiles in primary human hepatocytes, liver biopsies and resections of patients with HCC, and analysed microarray and RNA-seq data from paired liver biopsies of patients with HCC. We revealed changes in transcriptional networks through gene set enrichment analysis and correlated phosphatase expression levels to patient survival and tumour recurrence.ResultsWe demonstrate that tumour suppressor protein tyrosine phosphatase receptor delta (PTPRD) is impaired by HCV infection in vivo and in HCC lesions of paired liver biopsies independent from tissue inflammation or fibrosis. In liver tissue adjacent to tumour, high PTPRD levels are associated with a dampened transcriptional activity of STAT3, an increase of patient survival from HCC and reduced tumour recurrence after surgical resection. We identified miR-135a-5p as a mechanistic regulator of hepatic PTPRD expression in patients with HCV.ConclusionsWe previously demonstrated that STAT3 is required for HCV infection. We conclude that HCV promotes a STAT3 transcriptional programme in the liver of patients by suppressing its regulator PTPRD via upregulation of miR-135a-5p. Our results show the existence of a perturbed PTPRD–STAT3 axis potentially driving malignant progression of HCV-associated liver disease.
      Keywords: Open access
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-312270
      Issue No: Vol. 67, No. 5 (2018)
  • Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as
           a driver of liver inflammation
    • Authors: Ibrahim, S. H; Hirsova, P, Gores, G. J.
      Pages: 963 - 972
      Abstract: A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed non-alcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation.
      Keywords: GUT Recent advances in basic science, Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-315691
      Issue No: Vol. 67, No. 5 (2018)
  • Gastrointestinal ultrasound in inflammatory bowel disease: an underused
           resource with potential paradigm-changing application
    • Authors: Bryant, R. V; Friedman, A. B, Wright, E. K, Taylor, K. M, Begun, J, Maconi, G, Maaser, C, Novak, K. L, Kucharzik, T, Atkinson, N. S. S, Asthana, A, Gibson, P. R.
      Pages: 973 - 985
      Abstract: Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.
      Keywords: GUT Recent advances in clinical practice, Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-315655
      Issue No: Vol. 67, No. 5 (2018)
  • GI highlights from the literature
    • Authors: McLean M. H.
      Pages: 986 - 987
      Abstract: Basic scienceCross-talk between the gut microbiota and immune cells is vital for homeostasis Mao K, Baptista A, Tamoutounour S, et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature 2018;554:255–59. Gut homeostasis requires the gut microbiota to have a mutually beneficial relationship with the host. As the gut microbiota matures and becomes more complex, gut homeostasis is marked by a balanced commensalism and the absence of unwanted inflammation. The innate and adaptive immune responses shape the microbiota to maintain tissue homeostasis. However, defining the specific subsets of innate lymphoid cells (ILCs) and conventional T cells and the roles they play has not been determined. Mao and colleagues have shown that innate and adaptive lymphocytes operate sequentially through different mechanisms during normal development to establish steady-state commensalism. At early stages, these cells protect the gut by limiting the numbers of certain proinflammatory bacterial...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2018-316381
      Issue No: Vol. 67, No. 5 (2018)
  • Prognosis of immune-tolerant phase chronic hepatitis B
    • Authors: Chu, C.-M; Liaw, Y.-F.
      Pages: 988 - 988
      Abstract: We read with great surprise the article by Kim et al1  reporting high risks of hepatocellular carcinoma (HCC) and death in patients with untreated chronic hepatitis B who were classified by them as patients in ‘immune-tolerant’ (IT) phase. This conclusion contradicts to the general belief that there is little or no disease progression during the IT phase of chronic HBV infection, as best demonstrated in a 5-year histological follow-up study.2 Some issues of serious concern on this study, especially their IT phase patients, require clarification and further discussion to minimise misleading messages. IT phase of perinatally acquired chronic HBV infection is typically seen in Asian children or young adults with high HBV DNA, normal alanine aminotransferase (ALT), hepatitis B e-antigen (HBeAg) seropositivity and normal or minimal liver histological changes. After age of 20–25 years, IT phase may gradually convert to immune clearance or immune active (IA) phase, which is characterised...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-315603
      Issue No: Vol. 67, No. 5 (2018)
  • Response to: 'Prognosis of immune-tolerant phase chronic hepatitis B by
           Chu and Liaw
    • Authors: Kim, G.-A; Lim, Y.-S.
      Pages: 988 - 989
      Abstract: We appreciate the interest given to our article1 by Chu and Liaw.2 Determining disease phases of patients with chronic hepatitis B (CHB) is essential for assessing patient prognosis and need for treatment. Distinguishing between the immune-tolerant and immune-active phases among patients with hepatitis B e antigen (HBeAg)-positive CHB is best determined by identifying significant necroinflammation and/or fibrosis through liver biopsy. However, given the dynamic nature of CHB and the risks and costs of repeated liver biopsy, this recommendation may not always be realistic, especially in regions with high CHB prevalence. Current practice guidelines recommend considering HBeAg positivity and serum levels of HBV DNA and alanine aminotransferase (ALT) to determine the phases of CHB, and ALT levels are a crucial criterion for determining treatment initiation in patients with CHB. However, the HBV DNA cut-off levels for the immune-tolerant phase vary among guidelines. More importantly, as observed...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-315815
      Issue No: Vol. 67, No. 5 (2018)
  • Reassessment of gamma-glutamyl transpeptidase to platelet ratio (GPR): a
           large-sample, dynamic study based on liver biopsy in a Chinese population
           with chronic hepatitis B virus (HBV) infection
    • Authors: Zhang, W; Sun, M, Chen, G, An, Y, Lv, C, Wang, Y, Shang, Q.
      Pages: 989 - 991
      Abstract: Recently, Lemoine and colleagues1 presented a novel marker of liver fibrosis, the gamma-glutamyl transpeptidase to platelet ratio (GPR), as a more accurate non-invasive marker than either the aspartate aminotransferase to platelet ratio index (APRI) or the fibrosis index based on four factors (FIB-4) for diagnosing liver fibrosis in patients with chronic hepatitis B virus (HBV) infection in West Africa, and a simple and inexpensive alternative to transient elastography and liver biopsy. Boyd and colleagues2 demonstrated good results for GPR in the diagnosis of liver fibrosis in patients with HBV/HIV co-infection in France. However, Stockdale and colleagues3 reported that in patients with HBV / human immunodeficiency virus (HIV) co-infection in West Africa, GPR showed poor correlation with transient elastography. Lemoine and colleagues4 subsequently responded that the diagnostic accuracy of GPR differed when using liver biopsy or transient elastography as the reference. These inconsistent...
      Keywords: Open access, Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-313896
      Issue No: Vol. 67, No. 5 (2018)
  • Non-invasive diagnosis of hepatocellular carcinoma revisited
    • Authors: Mueller, C; Waldburger, N, Stampfl, U, Kauczor, H.-U, Schirmacher, P, Sommer, C. M, Longerich, T.
      Pages: 991 - 993
      Abstract: We read with interest the recent work by Ho et al demonstrating mutational hyperactivation of mammalian target of rapamycin signalling in a subgroup of hepatocellular carcinoma (HCC).1 As Berasain and Lechel concluded that the prospect of a positive therapeutic response may outweigh the risk associated with the HCC biopsy procedure2 and histology is essential for confirming a diagnosis of intrahepatic cholangiocarcinoma (ICC),3 we revisited the performance of non-invasive HCC diagnosis as recommended by current guidelines (eg, American Association for the Study of Liver Diseases (AASLD)) in clinical practice.4 We retrospectively analysed all patients (n=182) in which a CT-guided liver biopsy was performed at a tertiary referral centre within a 9-year period due to the clinical differential diagnosis of HCC. After quality control, a total of 94 biopsies (figure 1A, see online ) could be evaluated. HCC development was associated with...
      Keywords: Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-314981
      Issue No: Vol. 67, No. 5 (2018)
  • Can the performance of a quantitative FIT-based colorectal cancer
           screening programme be enhanced by lowering the threshold and increasing
           the interval'
    • Authors: Digby, J; Fraser, C. G, Carey, F. A, Steele, R. J. C.
      Pages: 993 - 994
      Abstract: We read with interest the work by Haug et al published in Gut.1 Longitudinal data from 4523 participants in the first round of a faecal immunochemical test for haemoglobin (FIT)-based screening programme, of whom 3427 also participated in the second round, were studied. In both first and second rounds, a threshold of 10 µg Hb/g faeces was used. The cohort was followed up for 2 years. The cumulative positivity and the number of participants diagnosed with neoplasia over the two rounds of screening were determined and compared with a hypothetical strategy involving single round screening with use of lower faecal haemoglobin concentration (f-Hb) thresholds and omission of the second round. It was suggested that lowering the f-Hb threshold and extending the screening interval could possibly enhance population-based screening programmes. In our pilot evaluation of FIT-based screening in Scotland, a much higher f-Hb threshold (≥80 µg Hb/g faeces) was employed.
      Keywords: Gut, Screening (epidemiology)
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2017-314862
      Issue No: Vol. 67, No. 5 (2018)
  • Correction: Metabolic biomarker signature to differentiate pancreatic
           ductal adenocarcinoma from chronic pancreatitis
    • Pages: 994 - 994
      Abstract: Mayerle J, Kalthoff H, Reszka R, et al. Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. Gut 2017;67:128-37. doi: 10.1136/gutjnl-2016-312432 The colour keys in the figure 4 legend have been corrected to read: (A) Score of the pancreatic biomarker signature identified in the training set and applied on the test set. Non-pancreatic controls in grey (n=80), chronic pancreatitis in green (n=80) and pancreatic cancer in magenta (n=79). Box plots give median, upper quartile and lower quartile by the box and the upper adjacent and lower adjacent values by the whiskers. The upper adjacent value is the largest observation that is less than or equal to the upper inner fence, which is the third quartile plus 1.5-fold IQR. The lower adjacent value gives the corresponding value for downregulation. The diagnostic cut-off of the pancreatic biomarker score was set to ≥0.384. (B) Scatter plot for graphical representation of the biomarker...
      Keywords: Open access, Gut
      PubDate: 2018-04-06T01:30:44-07:00
      DOI: 10.1136/gutjnl-2016-312432corr1
      Issue No: Vol. 67, No. 5 (2018)
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Heriot-Watt University
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