Vous êtes ici : Accueil > Espace Médecin > La revue de Presse > GUT

Mise ŕ jour le : 28-05-2017




Les derniers abstracts de la revue Gut current issue :


    Date de mise en ligne : Vendredi 12 mai 2017
    Duell, E. J.
    Telomere length and pancreatic cancer risk: breaking down the evidence

    Telomeres, located at the ends of chromosomes and composed of a protein complex and tandem repeats of TTAGGG nucleotides, function to protect chromosomes from end-to-end fusions, breakage and degradation in dividing cells. Due to the inherent nature of DNA replication (‘the end replication problem’) and oxidative stress—telomeres gradually shorten with age. This has been demonstrated cross-sectionally in most tissues examined including the pancreas, and especially in cells with extensive proliferation (eg, leucocytes).1 2 Cells with critically short telomeres enter growth arrest, or senescence, and may remain viable for extended periods. Premalignant cells can avoid senescence and continue to proliferate by upregulating telomerase or elongating telomeres by alternative mechanisms.1

    Shortened telomeres are thought to contribute to chromosomal instability and age-related diseases in humans, including cancer. Up to 90% of human tumours reactivate telomerase, which is epigenetically silenced in most adult somatic cells.1...


    Date de mise en ligne : Vendredi 12 mai 2017
    Hawinkels, L. J., Hardwick, J. C.
    Putting the Wnt up colon cancer

    If there is one cancer signalling pathway that Gut readers should be comfortable with, it is the Wnt pathway. Central to this pathway is the adenomatous polyposis coli (APC) gene responsible for familial adenomatous polyposis. Identification of the APC gene in 1991 heralded the start of an ongoing period of exponential growth in our understanding of the molecular basis of cancer, particularly of the large bowel. Clinicians can perhaps be forgiven for finding the ever-expanding list of genes and interacting pathways with their inaccessible names and acronyms daunting. For many, the paper in this issue by Elvira Bakker and coworkers at the Netherlands Cancer Institute revealing the detailed role of RSPO3 in colorectal carcinogenesis may only serve to widen the expanding clinician–researcher divide. However, those brave enough to dive deeper into this paper will be rewarded with an insight into the current state of the art of molecular research...


    Date de mise en ligne : Vendredi 12 mai 2017
    Peng, J., Gassama-Diagne, A.
    Apicobasal polarity and Ras/Raf/MEK/ERK signalling in cancer

    Many glandular epithelia such as the GI tract are composed of a sheet of cells polarised along their apicobasal axes with the apical membrane facing the lumen of the tube and the basolateral membrane binding to neighbouring cells and the basal extracellular matrix (ECM). Generation of these two membrane domains with distinct cellular macromolecular contents (including proteins and lipids) provides the basic building blocks that support tissue architecture and their various functions.1

    The apicobasal polarisation of epithelial cells is a complex and multistage programme controlled by a network of proteins and lipids. It is initiated by cues from the ECM and cell–cell contacts that trigger changes to the cytoskeleton and hence the polarised organisation of endosomal trafficking that sort and deliver proteins and lipids to the apical and basolateral membrane domains. These events lead to the establishment of cell–cell junctional complexes comprising tight and adherens junctions


    Date de mise en ligne : Vendredi 12 mai 2017
    Brooks, A. J., Smith, P. J., Cohen, R., Collins, P., Douds, A., Forbes, V., Gaya, D. R., Johnston, B. T., McKiernan, P. J., Murray, C. D., Sebastian, S., Smith, M., Whitley, L., Williams, L., Russell, R. K., McCartney, S. A., Lindsay, J. O.
    UK guideline on transition of adolescent and young persons with chronic digestive diseases from paediatric to adult care

    The risks of poor transition include delayed and inappropriate transfer that can result in disengagement with healthcare. Structured transition care can improve control of chronic digestive diseases and long-term health-related outcomes. These are the first nationally developed guidelines on the transition of adolescent and young persons (AYP) with chronic digestive diseases from paediatric to adult care. They were commissioned by the Clinical Services and Standards Committee of the British Society of Gastroenterology under the auspices of the Adolescent and Young Persons (A&YP) Section. Electronic searches for English-language articles were performed with keywords relating to digestive system diseases and transition to adult care in the Medline (via Ovid), PsycInfo (via Ovid), Web of Science and CINAHL databases for studies published from 1980 to September 2014. The quality of evidence and grading of recommendations was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. The limited number of studies in gastroenterology and hepatology required the addition of relevant studies from other chronic diseases to be included.

    These guidelines deal specifically with the transition of AYP living with a diagnosis of chronic digestive disease and/or liver disease from paediatric to adult healthcare under the following headings;

    1. Patient populations involved in AYP transition

    2. Risks of failing transition or poor transition

    3. Models of AYP transition

    4. Patient and carer/parent perspective in AYP transition

    5. Surgical perspective


    Date de mise en ligne : Vendredi 12 mai 2017
    Gifford, G. B., Demitrack, E. S., Keeley, T. M., Tam, A., La Cunza, N., Dedhia, P. H., Spence, J. R., Simeone, D. M., Saotome, I., Louvi, A., Siebel, C. W., Samuelson, L. C.
    Notch1 and Notch2 receptors regulate mouse and human gastric antral epithelial cell homoeostasis
    Objective

    We tested the ability of Notch pathway receptors Notch1 and Notch2 to regulate stem and epithelial cell homoeostasis in mouse and human gastric antral tissue.

    Design

    Mice were treated with the pan-Notch inhibitor dibenzazepine (DBZ) or inhibitory antibodies targeting Notch1 and/or Notch2. Epithelial proliferation, apoptosis and cellular differentiation were measured by histological and molecular approaches. Organoids were established from mouse and human antral glands; growth and differentiation were measured after treatment with Notch inhibitors.

    Results

    Notch1 and Notch2 are the predominant Notch receptors expressed in mouse and human antral tissue and organoid cultures. Combined inhibition of Notch1 and Notch2 in adult mice led to decreased epithelial cell proliferation, including reduced proliferation of LGR5 stem cells, and increased apoptosis, similar to the response to global Notch inhibition with DBZ. Less pronounced effects were observed after inhibition of individual receptors. Notch pathway inhibition with DBZ or combined inhibition of Notch1 and Notch2 led to increased differentiation of all gastric antral lineages, with remodelling of cells to express secretory products normally associated with other regions of the GI tract, including intestine. Analysis of mouse and human organoids showed that Notch signalling through Notch1 and Notch2 is intrinsic to the epithelium and required for organoid growth.

    Conclusions

    Notch signalling is required to maintain gastric antral stem cells. Notch1 and Notch2 are the primary Notch receptors regulating epithelial cell homoeostasis in mouse and human stomach.


    Date de mise en ligne : Vendredi 12 mai 2017
    Sundaresan, S., Kang, A. J., Hayes, M. M., Choi, E.-Y. K., Merchant, J. L.
    Deletion of Men1 and somatostatin induces hypergastrinemia and gastric carcinoids
    Background

    Gastric carcinoids are slow growing neuroendocrine tumours arising from enterochromaffin-like (ECL) cells in the corpus of stomach. Although most of these tumours arise in the setting of gastric atrophy and hypergastrinemia, it is not understood what genetic background predisposes development of these ECL derived tumours. Moreover, diffuse microcarcinoids in the mucosa can lead to a field effect and limit successful endoscopic removal.

    Objective

    To define the genetic background that creates a permissive environment for gastric carcinoids using transgenic mouse lines.

    Design

    The multiple endocrine neoplasia 1 gene locus (Men1) was deleted using Cre recombinase expressed from the Villin promoter (Villin-Cre) and was placed on a somatostatin null genetic background. These transgenic mice received omeprazole-laced chow for 6 months. The direct effect of gastrin and the gastrin receptor antagonist YM022 on expression and phosphorylation of the cyclin inhibitor p27Kip1 was tested on the human human gastric adenocarcinoma cell line stably expressing CCKBR (AGSE) and mouse small intestinal neuroendocrine carcinoma (STC)-1 cell lines.

    Results

    The combination of conditional Men1 deletion in the absence of somatostatin led to the development of gastric carcinoids within 2 years. Suppression of acid secretion by omeprazole accelerated the timeline of carcinoid development to 6 months in the absence of significant parietal cell atrophy. Carcinoids were associated with hypergastrinemia, and correlated with increased Cckbr expression and nuclear export of p27Kip1 both in vivo and in gastrin-treated cell lines. Loss of p27Kip1 was also observed in human gastric carcinoids arising in the setting of atrophic gastritis.

    Conclusions

    Gastric carcinoids require threshold levels of hypergastrinemia, which modulates p27Kip1 cellular location and stability.


    Date de mise en ligne : Vendredi 12 mai 2017
    Ward, S. T., Hancox, A., Mohammed, M. A., Ismail, T., Griffiths, E. A., Valori, R., Dunckley, P.
    The learning curve to achieve satisfactory completion rates in upper GI endoscopy: an analysis of a national training database
    Objective

    The aim of this study was to determine the number of OGDs (oesophago-gastro-duodenoscopies) trainees need to perform to acquire competency in terms of successful unassisted completion to the second part of the duodenum 95% of the time.

    Design

    OGD data were retrieved from the trainee e-portfolio developed by the Joint Advisory Group on GI Endoscopy (JAG) in the UK. All trainees were included unless they were known to have a baseline experience of >20 procedures or had submitted data for <20 procedures. The primary outcome measure was OGD completion, defined as passage of the endoscope to the second part of the duodenum without physical assistance. The number of OGDs required to achieve a 95% completion rate was calculated by the moving average method and learning curve cumulative summation (LC-Cusum) analysis. To determine which factors were independently associated with OGD completion, a mixed effects logistic regression model was constructed with OGD completion as the outcome variable.

    Results

    Data were analysed for 1255 trainees over 288 centres, representing 243 555 OGDs. By moving average method, trainees attained a 95% completion rate at 187 procedures. By LC-Cusum analysis, after 200 procedures, >90% trainees had attained a 95% completion rate. Total number of OGDs performed, trainee age and experience in lower GI endoscopy were factors independently associated with OGD completion.

    Conclusions

    There are limited published data on the OGD learning curve. This is the largest study to date analysing the learning curve for competency acquisition. The JAG competency requirement for 200 procedures appears appropriate.


    Date de mise en ligne : Vendredi 12 mai 2017
    Lim, M. Y., You, H. J., Yoon, H. S., Kwon, B., Lee, J. Y., Lee, S., Song, Y.-M., Lee, K., Sung, J., Ko, G.
    The effect of heritability and host genetics on the gut microbiota and metabolic syndrome
    Objective

    Metabolic syndrome (MetS) arises from complex interactions between host genetic and environmental factors. Although it is now widely accepted that the gut microbiota plays a crucial role in host metabolism, current knowledge on the effect of host genetics on specific gut microbes related to MetS status remains limited. Here, we investigated the links among host genetic factors, gut microbiota and MetS in humans.

    Design

    We characterised the gut microbial community composition of 655 monozygotic (n=306) and dizygotic (n=74) twins and their families (n=275), of which approximately 18% (121 individuals) had MetS. We evaluated the association of MetS status with the gut microbiota and estimated the heritability of each taxon. For the MetS-related and heritable taxa, we further investigated their associations with the apolipoprotein A-V gene (APOA5) single nucleotide polymorphism (SNP) rs651821, which is known to be associated with triglyceride levels and MetS.

    Results

    Individuals with MetS had a lower gut microbiota diversity than healthy individuals. The abundances of several taxa were associated with MetS status; Sutterella, Methanobrevibacter and Lactobacillus were enriched in the MetS group, whereas Akkermansia, Odoribacter and Bifidobacterium were enriched in the healthy group. Among the taxa associated with MetS status, the phylum Actinobacteria, to which Bifidobacterium belongs, had the highest heritability (45.7%). Even after adjustment for MetS status, reduced abundances of Actinobacteria and Bifidobacterium were significantly linked to the minor allele at the APOA5 SNP rs651821.

    Conclusions

    Our results suggest that an altered microbiota composition mediated by a specific host genotype can contribute to the development of MetS.


    Date de mise en ligne : Vendredi 12 mai 2017
    Sokol, H., Leducq, V., Aschard, H., Pham, H.-P., Jegou, S., Landman, C., Cohen, D., Liguori, G., Bourrier, A., Nion-Larmurier, I., Cosnes, J., Seksik, P., Langella, P., Skurnik, D., Richard, M. L., Beaugerie, L.
    Fungal microbiota dysbiosis in IBD
    Objective

    The bacterial intestinal microbiota plays major roles in human physiology and IBDs. Although some data suggest a role of the fungal microbiota in IBD pathogenesis, the available data are scarce. The aim of our study was to characterise the faecal fungal microbiota in patients with IBD.

    Design

    Bacterial and fungal composition of the faecal microbiota of 235 patients with IBD and 38 healthy subjects (HS) was determined using 16S and ITS2 sequencing, respectively. The obtained sequences were analysed using the Qiime pipeline to assess composition and diversity. Bacterial and fungal taxa associated with clinical parameters were identified using multivariate association with linear models. Correlation between bacterial and fungal microbiota was investigated using Spearman's test and distance correlation.

    Results

    We observed that fungal microbiota is skewed in IBD, with an increased Basidiomycota/Ascomycota ratio, a decreased proportion of Saccharomyces cerevisiae and an increased proportion of Candida albicans compared with HS. We also identified disease-specific alterations in diversity, indicating that a Crohn's disease-specific gut environment may favour fungi at the expense of bacteria. The concomitant analysis of bacterial and fungal microbiota showed a dense and homogenous correlation network in HS but a dramatically unbalanced network in IBD, suggesting the existence of disease-specific inter-kingdom alterations.

    Conclusions

    Besides bacterial dysbiosis, our study identifies a distinct fungal microbiota dysbiosis in IBD characterised by alterations in biodiversity and composition. Moreover, we unravel here disease-specific inter-kingdom network alterations in IBD, suggesting that, beyond bacteria, fungi might also play a role in IBD pathogenesis.


    Date de mise en ligne : Vendredi 12 mai 2017
    Panes, J., Sandborn, W. J., Schreiber, S., Sands, B. E., Vermeire, S., D'Haens, G., Panaccione, R., Higgins, P. D. R., Colombel, J.-F., Feagan, B. G., Chan, G., Moscariello, M., Wang, W., Niezychowski, W., Marren, A., Healey, P., Maller, E.
    Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials
    Objective

    Tofacitinib is an oral, small-molecule Janus kinase inhibitor that is being investigated for IBD. We evaluated the efficacy and safety of tofacitinib for induction and maintenance treatment in patients with moderate-to-severe Crohn's disease (CD).

    Design

    We conducted two randomised, double-blind, placebo-controlled, multicentre phase IIb studies. Adult patients with moderate-to-severe CD were randomised to receive induction treatment with placebo, tofacitinib 5 or 10 mg twice daily for 8 weeks. Those achieving clinical response-100 or remission were re-randomised to maintenance treatment with placebo, tofacitinib 5 or 10 mg twice daily for 26 weeks. Primary endpoints were clinical remission at the end of the induction study, and clinical response-100 or remission at the end of the maintenance study.

    Results

    180/280 patients randomised in the induction study were enrolled in the maintenance study. At week 8 of induction, the proportion of patients with clinical remission was 43.5% and 43.0% with 5 and 10 mg twice daily, respectively, compared with 36.7% in the placebo group (p=0.325 and 0.392 for 5 and 10 mg twice daily vs placebo). At week 26 of maintenance, the proportion of patients with clinical response-100 or remission was 55.8% with tofacitinib 10 mg twice daily compared with 39.5% with tofacitinib 5 mg twice daily and 38.1% with placebo (p=0.130 for 10 mg twice daily vs placebo). Compared with placebo, the change in C-reactive protein from baseline was statistically significant (p<0.0001) with 10 mg twice daily after both induction and maintenance treatments.

    Conclusions

    Primary efficacy endpoints were not significantly different from placebo, although there was evidence of a minor treatment effect. No new safety signals were observed for tofacitinib.

    Trial registration numbers

    NCT01393626 and NCT01393899.


    Date de mise en ligne : Vendredi 12 mai 2017
    Schwerd, T., Pandey, S., Yang, H.-T., Bagola, K., Jameson, E., Jung, J., Lachmann, R. H., Shah, N., Patel, S. Y., Booth, C., Runz, H., Düker, G., Bettels, R., Rohrbach, M., Kugathasan, S., Chapel, H., Keshav, S., Elkadri, A., Platt, N., Muise, A. M., Koletzko, S., Xavier, R. J., Marquardt, T., Powrie, F., Wraith, J. E., Gyrd-Hansen, M., Platt, F. M., Uhlig, H. H.
    Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn's disease
    Objective

    Patients with Niemann–Pick disease type C1 (NPC1), a lysosomal lipid storage disorder that causes neurodegeneration and liver damage, can present with IBD, but neither the significance nor the functional mechanism of this association is clear. We studied bacterial handling and antibacterial autophagy in patients with NPC1.

    Design

    We characterised intestinal inflammation in 14 patients with NPC1 who developed IBD. We investigated bacterial handling and cytokine production of NPC1 monocytes or macrophages in vitro and compared NPC1-associated functional defects to those caused by IBD-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) variants or mutations in X-linked inhibitor of apoptosis (XIAP).

    Results

    Patients with the lysosomal lipid storage disorder NPC1 have increased susceptibility to early-onset fistulising colitis with granuloma formation, reminiscent of Crohn's disease (CD). Mutations in NPC1 cause impaired autophagy due to defective autophagosome function that abolishes NOD2-mediated bacterial handling in vitro similar to variants in NOD2 or XIAP deficiency. In contrast to genetic NOD2 and XIAP variants, NPC1 mutations do not impair NOD2-receptor-interacting kinase 2 (RIPK2)-XIAP-dependent cytokine production. Pharmacological activation of autophagy can rescue bacterial clearance in macrophages in vitro by increasing the autophagic flux and bypassing defects in NPC1.

    Conclusions

    NPC1 confers increased risk of early-onset severe CD. Our data support the concept that genetic defects at different checkpoints of selective autophagy cause a shared outcome of CD-like immunopathology linking monogenic and polygenic forms of IBD. Muramyl dipeptide-driven cytokine responses and antibacterial autophagy induction are parallel and independent signalling cascades downstream of the NOD2-RIPK2-XIAP complex.


    Date de mise en ligne : Vendredi 12 mai 2017
    Lin, P.-Y., Tang, J.-H., Chang, C.-C.
    A rare cause of GI bleeding in a 56-year-old man

    A 56-year-old man, with a known history of diabetes for 1 year, presented with a 5-day history of melena that was associated with one episode of haematemesis. One month prior, he had completed a course of oral amoxicillin for a dental infection that occurred after a tooth extraction. The only other significant past medical problem was hypertension for 10 years. Physical examination only showed pallor and abdominal examination was normal. Laboratory investigations revealed haemoglobin level of 8.4 g/dL and HbA1C of 7.8%. His upper GI endoscopy showed a diffuse irregular friable exudative ulcerative lesion involving the gastric fundus (figure 1). Endoscopic ultrasonography (EUS) demonstrated disrupted gastric wall layers with wall thickening of 5.1 mm and regional lymph nodes (figure 2). Abdominal CT also showed gastric wall thickening and cluster of regional lymph nodes (figure 3). Upper GI series showed a focal irregular mucosal pattern with relatively flattened gastric...


    Date de mise en ligne : Vendredi 12 mai 2017
    Sperber, A. D., Dumitrascu, D., Fukudo, S., Gerson, C., Ghoshal, U. C., Gwee, K. A., Hungin, A. P. S., Kang, J.-Y., Minhu, C., Schmulson, M., Bolotin, A., Friger, M., Freud, T., Whitehead, W.
    The global prevalence of IBS in adults remains elusive due to the heterogeneity of studies: a Rome Foundation working team literature review
    Objectives

    The global prevalence of IBS is difficult to ascertain, particularly in light of the heterogeneity of published epidemiological studies. The aim was to conduct a literature review, by experts from around the world, of community-based studies on IBS prevalence.

    Design

    Searches were conducted using predetermined search terms and eligibility criteria, including papers in all languages. Pooled prevalence rates were calculated by combining separate population survey prevalence estimates to generate an overall combined meta-prevalence estimate. The heterogeneity of studies was assessed.

    Results

    1451 papers were returned and 83, including 288 103 participants in 41 countries, met inclusion criteria. The mean prevalence among individual countries ranged from 1.1% in France and Iran to 35.5% in Mexico. There was significant variance in pooled regional prevalence rates ranging from 17.5% (95% CI 16.9% to 18.2%) in Latin America, 9.6% (9.5% to 9.8%) in Asia, 7.1% (8.0% to 8.3%) in North America/Europe/Australia/New Zealand, to 5.8% (5.6% to 6.0%) in the Middle East and Africa. There was a significant degree of heterogeneity with the percentage of residual variation due to heterogeneity at 99.9%.

    Conclusions

    The main finding is the extent of methodological variance in the studies reviewed and the degree of heterogeneity among them. Based on this, we concluded that publication of a single pooled global prevalence rate, which is easily calculated, would not be appropriate or contributory. Furthermore, we believe that future studies should focus on regional and cross-cultural differences that are more likely to shed light on pathophysiology.


    Date de mise en ligne : Vendredi 12 mai 2017
    Castro, J., Harrington, A. M., Garcia-Caraballo, S., Maddern, J., Grundy, L., Zhang, J., Page, G., Miller, P. E., Craik, D. J., Adams, D. J., Brierley, S. M.
    {alpha}-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors
    Objective

    α-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability to inhibiting human dorsal root ganglion (DRG) neuroexcitability and reducing chronic visceral pain (CVP) is unknown.

    Design

    We determined the inhibitory actions of Vc1.1 on human DRG neurons and on mouse colonic sensory afferents in healthy and chronic visceral hypersensitivity (CVH) states. In mice, visceral nociception was assessed by neuronal activation within the spinal cord in response to noxious colorectal distension (CRD). Quantitative-reverse-transcription-PCR, single-cell-reverse-transcription-PCR and immunohistochemistry determined -aminobutyric acid receptor B (GABABR) and voltage-gated calcium channel (CaV2.2, CaV2.3) expression in human and mouse DRG neurons.

    Results

    Vc1.1 reduced the excitability of human DRG neurons, whereas a synthetic Vc1.1 analogue that is inactive at GABABR did not. Human DRG neurons expressed GABABR and its downstream effector channels CaV2.2 and CaV2.3. Mouse colonic DRG neurons exhibited high GABABR, CaV2.2 and CaV2.3 expression, with upregulation of the CaV2.2 exon-37a variant during CVH. Vc1.1 inhibited mouse colonic afferents ex vivo and nociceptive signalling of noxious CRD into the spinal cord in vivo, with greatest efficacy observed during CVH. A selective GABABR antagonist prevented Vc1.1-induced inhibition, whereas blocking both CaV2.2 and CaV2.3 caused inhibition comparable with Vc1.1 alone.

    Conclusions

    Vc1.1-mediated activation of GABABR is a novel mechanism for reducing the excitability of human DRG neurons. Vc1.1-induced activation of GABABR on the peripheral endings of colonic afferents reduces nociceptive signalling. The enhanced antinociceptive actions of Vc1.1 during CVH suggest it is a novel candidate for the treatment for CVP.


    Date de mise en ligne : Vendredi 12 mai 2017
    Hilkens, J., Timmer, N. C., Boer, M., Ikink, G. J., Schewe, M., Sacchetti, A., Koppens, M. A. J., Song, J.-Y., Bakker, E. R. M.
    RSPO3 expands intestinal stem cell and niche compartments and drives tumorigenesis
    Objective

    The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models. The current study determines the extent into which solely a gain in RSPO3 actually functions as a driver of intestinal cancer in a direct, causal fashion, and addresses the in vivo activities of RSPO3 in parallel.

    Design

    We generated a conditional Rspo3 transgenic mouse model in which the Rspo3 transgene is expressed upon Cre activity. Cre is provided by cross-breeding with Lgr5-GFP-CreERT2 mice.

    Results

    Upon in vivo Rspo3 expression, mice rapidly developed extensive hyperplastic, adenomatous and adenocarcinomatous lesions throughout the intestine. RSPO3 induced the expansion of Lgr5+ stem cells, Paneth cells, non-Paneth cell label-retaining cells and Lgr4+ cells, thus promoting both intestinal stem cell and niche compartments. Wnt/β-catenin signalling was modestly increased upon Rspo3 expression and mutant Kras synergised with Rspo3 in hyperplastic growth.

    Conclusions

    We provide in vivo evidence that RSPO3 stimulates the crypt stem cell and niche compartments and drives rapid intestinal tumorigenesis. This establishes RSPO3 as a potent driver of intestinal cancer and proposes RSPO3 as a candidate target for therapy in patients with colorectal cancer harbouring RSPO3 fusions.


    Date de mise en ligne : Vendredi 12 mai 2017
    Borovski, T., Vellinga, T. T., Laoukili, J., Santo, E. E., Fatrai, S., van Schelven, S., Verheem, A., Marvin, D. L., Ubink, I., Borel Rinkes, I. H. M., Kranenburg, O.
    Inhibition of RAF1 kinase activity restores apicobasal polarity and impairs tumour growth in human colorectal cancer
    Background and aim

    Colorectal cancer (CRC) remains one of the leading causes of cancer-related death. Novel therapeutics are urgently needed, especially for tumours with activating mutations in KRAS (~40%). Here we investigated the role of RAF1 in CRC, as a potential, novel target.

    Methods

    Colonosphere cultures were established from human tumour specimens obtained from patients who underwent colon or liver resection for primary or metastatic adenocarcinoma. The role of RAF1 was tested by generating knockdowns (KDs) using three independent shRNA constructs or by using RAF1-kinase inhibitor GW5074. Clone-initiating and tumour-initiating capacities were assessed by single-cell cloning and injecting CRC cells into immune-deficient mice. Expression of tight junction (TJ) proteins, localisation of polarity proteins and activation of MEK-ERK pathway was analysed by western blot, immunohistochemistry and immunofluorescence.

    Results

    KD or pharmacological inhibition of RAF1 significantly decreased clone-forming and tumour-forming capacity of all CRC cultures tested, including KRAS-mutants. This was not due to cytotoxicity but, at least in part, to differentiation of tumour cells into goblet-like cells. Inhibition of RAF1-kinase activity restored apicobasal polarity and the formation of TJs in vitro and in vivo, without reducing MEK-ERK phosphorylation. MEK-inhibition failed to restore polarity and TJs. Moreover, RAF1-impaired tumours were characterised by normalised tissue architecture.

    Conclusions

    RAF1 plays a critical role in maintaining the transformed phenotype of CRC cells, including those with mutated KRAS. The effects of RAF1 are kinase-dependent, but MEK-independent. Despite the lack of activating mutations in RAF1, its kinase domain is an attractive therapeutic target for CRC.


    Date de mise en ligne : Vendredi 12 mai 2017
    Bao, Y., Prescott, J., Yuan, C., Zhang, M., Kraft, P., Babic, A., Morales-Oyarvide, V., Qian, Z. R., Buring, J. E., Cochrane, B. B., Gaziano, J. M., Giovannucci, E. L., Manson, J. E., Ng, K., Ogino, S., Rohan, T. E., Sesso, H. D., Stampfer, M. J., Fuchs, C. S., De Vivo, I., Amundadottir, L. T., Wolpin, B. M.
    Leucocyte telomere length, genetic variants at the TERT gene region and risk of pancreatic cancer
    Objective

    Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer.

    Design

    We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively.

    Results

    Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; ptrend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r2<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023).

    Conclusions

    Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.


    Date de mise en ligne : Vendredi 12 mai 2017
    Arriazu, E., Ge, X., Leung, T.-M., Magdaleno, F., Lopategi, A., Lu, Y., Kitamura, N., Urtasun, R., Theise, N., Antoine, D. J., Nieto, N.
    Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury
    Objective

    Liver fibrosis is associated with significant collagen-I deposition largely produced by activated hepatic stellate cells (HSCs); yet, the link between hepatocyte damage and the HSC profibrogenic response remains unclear. Here we show significant induction of osteopontin (OPN) and high-mobility group box-1 (HMGB1) in liver fibrosis. Since OPN was identified as upstream of HMGB1, we hypothesised that OPN could participate in the pathogenesis of liver fibrosis by increasing HMGB1 to upregulate collagen-I expression.

    Design and results

    Patients with long-term hepatitis C virus (HCV) progressing in disease stage displayed enhanced hepatic OPN and HMGB1 immunostaining, which correlated with fibrosis stage, whereas it remained similar in non-progressors. Hepatocyte cytoplasmic OPN and HMGB1 expression was significant while loss of nuclear HMGB1 occurred in patients with HCV-induced fibrosis compared with healthy explants. Well-established liver fibrosis along with marked induction of HMGB1 occurred in CCl4-injected OpnHep transgenic yet it was less in wild type and almost absent in Opn–/– mice. Hmgb1 ablation in hepatocytes (Hmgb1Hep) protected mice from CCl4-induced liver fibrosis. Coculture with hepatocytes that secrete OPN plus HMGB1 and challenge with recombinant OPN (rOPN) or HMGB1 (rHMGB1) enhanced collagen-I expression in HSCs, which was blunted by neutralising antibodies (Abs) and by Opn or Hmgb1 ablation. rOPN induced acetylation of HMGB1 in HSCs due to increased NADPH oxidase activity and the associated decrease in histone deacetylases 1/2 leading to upregulation of collagen-I. Last, rHMGB1 signalled via receptor for advanced glycation end-products and activated the PI3K–pAkt1/2/3 pathway to upregulate collagen-I.

    Conclusions

    During liver fibrosis, the increase in OPN induces HMGB1, which acts as a downstream alarmin driving collagen-I synthesis in HSCs.


    Date de mise en ligne : Vendredi 12 mai 2017
    Adams, L. A., Anstee, Q. M., Tilg, H., Targher, G.
    Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases

    Key physiological functions of the liver, including glucose and lipid metabolism, become disturbed in the setting of non-alcoholic fatty liver disease (NAFLD) and may be associated with a systemic inflammatory ‘milieu’ initiated in part by liver-secreted cytokines and molecules. Consequently, the pathophysiological effects of NAFLD extend beyond the liver with a large body of clinical evidence demonstrating NAFLD to be independently associated with both prevalent and incident cardiovascular disease (CVD), chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). The magnitude of risk of developing these extrahepatic diseases parallels the underlying severity of NAFLD, such that patients with non-alcoholic steatohepatitis (NASH) appear to be at greater risk of incident CVD, CKD and T2DM than those with simple steatosis. Other modifiers of risk may include genetic variants (eg, patatin-like phospholipase domain-containing 3 and trans-membrane 6 superfamily member 2 polymorphisms), visceral adipose tissue accumulation, dietary intake and the gut microbiome. Emerging data also suggest that NAFLD may be a risk factor for colonic neoplasia and reduced bone mineral density, especially among men. Importantly, improvement/resolution of NAFLD is associated with a reduced incidence of T2DM and improved kidney function, adding weight to causality and suggesting liver focused treatments may reduce risk of extrahepatic complications. Awareness of these associations is important for the clinicians such that CVD risk factor management, screening for T2DM and CKD are part of the routine management of patients with NAFLD.


    Date de mise en ligne : Vendredi 12 mai 2017
    Kullak-Ublick, G. A., Andrade, R. J., Merz, M., End, P., Benesic, A., Gerbes, A. L., Aithal, G. P.
    Drug-induced liver injury: recent advances in diagnosis and risk assessment

    Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption–distribution–metabolism–elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public–private partnerships.


    Date de mise en ligne : Vendredi 12 mai 2017
    McLean, M. H.
    GI highlights from the literature
    Basic scienceRedefining liver zonation

     Bahar Halpern K, Shenhav R, Matcovitch–Natan O, et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver Nature 2017;542:352–6.

    Hepatocytes in distinct anatomical locations within the liver lobule are thought to have specialised functions, a paradigm termed liver zonation. In this study, the authors use singlemolecule fluorescence in situ hybridisation and single-cell RNA sequencing (scRNA-seq) to define exhaustively the zonation profiles of all liver genes in mice. Using a panel of six zonally distributed genes (Glul, Cyp2e1, Ass1, Asl, Alb, Cyp2f2), they defined a ‘spatial barcode’, whereby the relative expression of these zonal genes could infer the location of a given cell within one of nine lobule layers between the central vein and portal node. They proceeded to perform scRNA-seq on freshly isolated hepatocytes and used expression levels of the spatial barcode genes to assign each sequenced hepatocyte to...


    Date de mise en ligne : Vendredi 12 mai 2017
    Zhong, L., Shanahan, E. R., Raj, A., Koloski, N. A., Fletcher, L., Morrison, M., Walker, M. M., Talley, N. J., Holtmann, G.
    Dyspepsia and the microbiome: time to focus on the small intestine

    We note with interest two recent publications in Gut regarding alterations to the gut microbiome in individuals on proton pump inhibitor (PPI) therapy.1 2 With PPI use, both studies observed an increase in oral bacteria in the stool. These changes overlap with those described in patients with cirrhosis of the liver.3 However, very little is known about the impact of this dysbiosis over the length of the GI tract, and how it may link to gut function.

    While the data from both Jackson et al1 and Imhann et al2 are demonstrative of a shift towards oral-associated bacteria, it is important to note that many of these bacteria have also been identified in the stomach and small intestine. Recently, we have shown that although the microbiota found in the healthy duodenum are taxonomically similar to the oral microbiota, their presence...


    Date de mise en ligne : Vendredi 12 mai 2017
    Schiavon, L. L., Narciso-Schiavon, J. L., Ferraz, M. L. G., Silva, A. E. B., Carvalho-Filho, R. J.
    The {gamma}-glutamyl transpeptidase to platelet ratio (GPR) in HBV patients: just adding up?

    We read with interest the article by Lemoine et al evaluating routine tests as non-invasive markers of fibrosis in patients with chronic hepatitis B (CHB).1 The -glutamyl transpeptidase to platelet ratio (GPR) has been proposed as a new fibrosis test, allegedly more accurate than classical biomarkers like the Aspartate Aminotransferase to Platelet Ratio Index (APRI) and FIB-4 in African cohorts. Therefore, we performed a validation analysis of GPR in 147 patients with untreated CHB from two Brazilian reference centres. The mean age was 40.6±13.7 years and 68% were male. Hepatitis B e antigen (HBeAg) was positive in 53% of cases and median HBV-DNA level was 107 700 IU/mL. Median aspartate aminotransferase and alanine aminotransferase (ALT) levels (and IQR) were 42 (30–76) IU/L and 58 (42–106) IU/L, respectively. The distribution of fibrosis stages was as follows: METAVIR F0–22%, F1–27%, F2–22%, F3–16% and F4–13%.

    Table 1 exhibits the diagnostic performances of...


    Date de mise en ligne : Vendredi 12 mai 2017
    Buchanan, D. D., Clendenning, M., Zhuoer, L., Stewart, J. R., Joseland, S., Woodall, S., Arnold, J., Semotiuk, K., Aronson, M., Holter, S., Gallinger, S., Jenkins, M. A., Sweet, K., Macrae, F. A., Winship, I. M., Parry, S., Rosty, C., on behalf of the Genetics of Colonic Polyposis Study
    Lack of evidence for germline RNF43 mutations in patients with serrated polyposis syndrome from a large multinational study

    Serrated polyposis syndrome (SPS) is characterised by the occurrence of multiple serrated polyps in the large bowel. Defined clinically by the 2010 revised WHO, SPS is associated with an increased risk of colorectal cancer (CRC) for affected individuals and their first-degree relatives. Yan et al1 recently reported their findings from whole-exome sequencing (WES) of six individuals with SPS from four families, identifying a single family carrying a germline likely pathogenic variant in RNF43 (c.953-1 G>A, c.953_954delAG, p.E318fs). In this family, six carriers were identified, five of whom met the WHO criteria for SPS. This adds to two previous reports of germline mutations within RNF43 in individuals with SPS or who developed multiple serrated polyps.2 3 The current study by Yan et al1 also importantly showed loss of second wildtype allele in 16 serrated polyps, five adenomatous polyps, and in the...


    Date de mise en ligne : Vendredi 12 mai 2017
    Yu, J., Yu, X.-l., Han, Z.-y., Cheng, Z.-g., Liu, F.-y., Zhai, H.-y., Mu, M.-j., Liu, Y.-m., Liang, P.
    Percutaneous cooled-probe microwave versus radiofrequency ablation in early-stage hepatocellular carcinoma: a phase III randomised controlled trial

    We read with interest the article by Bruix et al1 on currently available treatment options for hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) is now the first-line technique for HCC ablation. RFA produces tumour necrosis in situ through temperature modification. Compared with RFA, microwave ablation (MWA) is one relatively recent advancement of thermoablative technology, which shows multiple theoretical advantages over RFA.2–4 We wish to report the results of a phase III randomised controlled trial (RCT) by comparing ultrasound-guided percutaneous cooled-probe MWA and RFA in ≤5 cm HCC (NCT 02539212).

    From October 2008 to June 2015, 203 (265 nodules) subjects were randomised to MWA and 200 (251 nodules) were randomised to RFA. The indications were as follows: tumour size ≤5 cm in diameter, tumour number ≤3, Child–Pugh class A or B classification, no evidence of extrahepatic metastasis, vein or bile duct tumour embolus, lesions...


    Date de mise en ligne : Vendredi 12 mai 2017
    Molina-Infante, J., Hirano, I., Spechler, S. J., on behalf of the PPI-REE Task Force of the European Society of Eosinophilic Oesophagitis (EUREOS)
    Clarifying misunderstandings and misinterpretations about proton pump inhibitor-responsive oesophageal eosinophilia

    We appreciate the interest of Muir et al1 in our Position Paper on proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE).2 Their letter highlights the ongoing controversies related to PPI-REE, particularly regarding practical diagnostic concerns in paediatric patients. We would like to address several issues raised by the authors:

  • When the clinical presentation is consistent with gastro-oesophageal reflux disease (GORD), an empiric trial of PPI therapy is always appropriate. Teenagers and adults with dysphagia, however, should undergo an endoscopic procedure, because dysphagia is a red-flag symptom. In adult patients with dysphagia and suspected eosinophilic oesophagitis (EoE), a baseline endoscopy off PPI therapy has diagnostic value. This approach has not led to unnecessary endoscopies or diagnostic confusion, as suggested by Muir et al.1 Instead, it has elucidated the existence and improved our understanding of PPI-REE in adult patients.2 The different and more non-specific clinical...