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| Open AccessFaecal microbiota transplantation for the treatment of diarrhoea induced by tyrosine-kinase inhibitors in patients with metastatic renal cell carcinoma
Tyrosine kinase inhibitors (TKIs) have improved the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC), however TKI-related diarrhoea is a common and serious adverse effect. Here the authors show in a randomized clinical trial that faecal microbiota transplantation from healthy donors can improve TKI-induced diarrhoea in patients with mRCC.
- Gianluca Ianiro
- , Ernesto Rossi
- & Giovanni Cammarota
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Article
| Open AccessLumenal Galectin-9-Lamp2 interaction regulates lysosome and autophagy to prevent pathogenesis in the intestine and pancreas
Galectins are carbohydrate binding proteins previously implicated in sensing and repairing damaged lysosomes. Here, the authors show that galectin-9 has specific lysosomal roles in autophagy and contributes to cell degeneration and apoptosis in colitis and pancreatitis in mice.
- Janaki N. Sudhakar
- , Hsueh-Han Lu
- & Jr-Wen Shui
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Article
| Open AccessStructure and dynamics of the active Gs-coupled human secretin receptor
The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Here, authors present a cryo-EM structure and biochemical studies of secretin binding to the SecR:Gs complex which show that interactions between peptide and receptor were dynamic.
- Maoqing Dong
- , Giuseppe Deganutti
- & Laurence J. Miller
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Article
| Open AccessGut microbial co-abundance networks show specificity in inflammatory bowel disease and obesity
Gut microbiome alterations have been linked to inflammatory bowel disease (IBD) and obesity. Here, the authors characterize the metagenomes of four large human cohorts and perform co-abundance network analysis showing that dysbiosis in disease is marked by the altered co-abundance relationships, suggesting that pathway coabundance networks are more heterogeneous than species network.
- Lianmin Chen
- , Valerie Collij
- & Jingyuan Fu
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Matters Arising
| Open AccessReply to “Acid inhibitors and allergy: comorbidity, causation and confusion”
- Erika Jensen-Jarolim
- , Michael Kundi
- & Galateja Jordakieva
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Matters Arising
| Open AccessAcid inhibitors and allergy: comorbidity, causation and confusion
- Kewin Tien Ho Siah
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Article
| Open AccessSilencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation
Non-alcoholic fatty liver (NAFLD) disease causes degeneration of the liver, affects about 25% of people globally, and has no approved treatment. Here, the authors show that the therapeutic siRNA-driven silencing of MCJ in the liver is an effective and safe treatment for NAFLD in multiple mouse models.
- Lucía Barbier-Torres
- , Karen A. Fortner
- & Mercedes Rincón
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Article
| Open AccessTransplantation of discarded livers following viability testing with normothermic machine perfusion
The shortage of viable donated livers limits patient access to liver transplantation. Here the authors report the use of normothermic machine perfusion to help identify viable organs from livers discarded based on current clinical criteria, which are then transplanted to recipients in a single-arm clinical trial.
- Hynek Mergental
- , Richard W. Laing
- & Darius F. Mirza
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Article
| Open AccessDiagnostic evaluation of a deep learning model for optical diagnosis of colorectal cancer
Colonoscopy is the most commonly used tool to screen for colorectal cancer (CRC). Here, the authors develop a deep learning model to perform optical diagnosis of CRC by training on a large data set of white-light colonoscopy images and achieve endoscopist-level performance on three independent datasets.
- Dejun Zhou
- , Fei Tian
- & Xiangchun Li
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Article
| Open AccessHuman norovirus targets enteroendocrine epithelial cells in the small intestine
Human norovirus pathogenesis is incompletely understood due to a lack of appropriate animal disease models. Here, Green et al. show norovirus replication in chromogranin A-positive enteroendocrine cells and other epithelial cells in tissue from a pediatric intestinal transplant recipient with severe gastroenteritis.
- Kim Y. Green
- , Stuart S. Kaufman
- & Stanislav V. Sosnovtsev
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Article
| Open AccessThe ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion
The common ABCG2 variant Q141K contributes to hyperuricemia and gout risk. Here, using a human interventional study and a new orthologous mouse model, the authors report a tissue specific pathobiology of the Q141K variant, and support a significant role for ABCG2 in urate excretion in both the kidney and intestine.
- Kazi Mirajul Hoque
- , Eryn E. Dixon
- & Owen M. Woodward
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Article
| Open AccessA genome-wide gain-of-function screen identifies CDKN2C as a HBV host factor
Here the authors perform a gain-of-function screen and identify CDKN2C as a host factor for HBV replication, inducing cell cycle arrest and expression of HBV transcription enhancers. CDKN2C expression correlates with disease progression suggesting a potential role in HBV-induced liver disease.
- Carla Eller
- , Laura Heydmann
- & Thomas F. Baumert
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Article
| Open AccessProimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy
Immune checkpoint inhibitors have limited efficacy in tumors with lower mutational burden and non-permissive microenvironment. Here, the authors show that combining MEK inhibition with an agonist anti-CD40 immunostimulatory antibody improves antitumor treatment by inducing immunogenic changes in the tumor microenvironment.
- Daniel Baumann
- , Tanja Hägele
- & Rienk Offringa
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Article
| Open AccessDysregulation of bile acids increases the risk for preterm birth in pregnant women
Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications with limited treatment options. Here the authors show that dysregulation of bile acids increases risk for PTB in pregnant women while restoring bile acid homeostasis delays or prevents PTB in the mouse models.
- Sangmin You
- , Ai-Min Cui
- & Ruitang Deng
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Article
| Open AccessCytokines regulate the antigen-presenting characteristics of human circulating and tissue-resident intestinal ILCs
Murine ILCs can modulate T cell responses in MHCII-dependent manner. Here the authors show that human ILCs process and present antigens and induce T-cell responses upon exposure to IL-1-family cytokines; along with the article by Lehmann et al, this work elucidates how cytokines set context specificity of ILC-T cell crosstalk by regulating ILC antigen presentation.
- Anna Rao
- , Otto Strauss
- & Jenny Mjösberg
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Article
| Open AccessThe platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure
The molecular mechanisms that drive irreversible acute liver failure remain poorly characterized. Here, the authors show that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage during acute liver injury by blocking restorative neutrophil driven inflammation.
- Abhishek Chauhan
- , Lozan Sheriff
- & Patricia F. Lalor
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Article
| Open AccessHepatic saturated fatty acid fraction is associated with de novo lipogenesis and hepatic insulin resistance
Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use 1H-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.
- Kay H. M. Roumans
- , Lucas Lindeboom
- & Vera B. Schrauwen-Hinderling
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Article
| Open AccessDietary lipids fuel GPX4-restricted enteritis resembling Crohn’s disease
Dietary lipids are linked to the development of inflammatory bowel diseases through unclear mechanisms. Here, the authors report that dietary polyunsaturated fatty acids trigger intestinal inflammation resembling aspects of Crohn’s disease, which is restricted by glutathione peroxidase 4 in the intestinal epithelium.
- Lisa Mayr
- , Felix Grabherr
- & Timon E. Adolph
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Article
| Open AccessGrasp55−/− mice display impaired fat absorption and resistance to high-fat diet-induced obesity
The physiological roles of the Golgi reassembly-stacking protein 55 (GRASP55/GORASP55) remain largely elusive. Here, the authors show that the Golgi-resident protein GRASP55 plays a crucial role in lipid homeostasis by regulating intestinal lipid uptake.
- Jiyoon Kim
- , Hyeyon Kim
- & Min Goo Lee
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Article
| Open AccessPrimary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation
Mechanisms regulating the formation of pre-metastatic niches remain poorly understood. Here, the authors show that ITGBL1-containing extracellular vesicles derived from primary colorectal cancer cells activate the production of inflammatory cytokines by resident fibroblasts in distant organs, promoting metastatic cancer growth.
- Qing Ji
- , Lihong Zhou
- & Qi Li
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Article
| Open AccessPlasmid-mediated metronidazole resistance in Clostridioides difficile
Cases of C. difficile (CD) resistant to metronidazole have been reported but the mechanism remains enigmatic. Here the authors identify a plasmid, which correlates with metronidazole resistance status in a large international collection of CD isolates, and demonstrate that the plasmid can confer metronidazole resistance.
- Ilse M. Boekhoud
- , Bastian V. H. Hornung
- & Wiep Klaas Smits
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Article
| Open AccessImpact of commonly used drugs on the composition and metabolic function of the gut microbiota
Here, via a metagenomics analysis of population-based and disease cohorts, Vich Vila et al. study the impact of 41 commonly used medications on the taxonomic structures, metabolic potential and resistome of the gut microbiome, underscoring the importance of correcting for multiple drug use in microbiome studies.
- Arnau Vich Vila
- , Valerie Collij
- & Rinse K. Weersma
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Article
| Open AccessIntratumoral heterogeneity and clonal evolution in liver cancer
Immune-mediated selection pressures impact the clonal evolution of tumours. Here, in hepatocellular carcinoma the authors map spatio-temporal interactions between tumor and immune cells, highlighting the regulatory substrate of intra-tumoural heterogeneity that correlates with regional adaptive immune responses.
- Bojan Losic
- , Amanda J. Craig
- & Augusto Villanueva
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Article
| Open AccessSUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis
FXR agonists have been investigated for the treatment of non-alcoholic steatohepatitis and liver fibrosis but the clinical efficacy is not optimal. Here the authors show that enhanced FXR SUMOylation in activated hepatic stellate cells reduces FXR signaling and that this can be rescued by SUMOylation inhibitors.
- Jiyu Zhou
- , Shuang Cui
- & Haiping Hao
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Article
| Open AccessGeneration of mesenchyme free intestinal organoids from human induced pluripotent stem cells
Human induced pluripotent stem cell-derived intestinal organoids (HIOs) are powerful tools to study development and diseases of the gastrointestinal tract. Here, the authors develop a directed differentiation protocol to generate mesenchyme-free HIOs that can be patterned towards proximal small intestine or colonic epithelium, and demonstrated their utility in modeling CFTR function.
- Aditya Mithal
- , Amalia Capilla
- & Gustavo Mostoslavsky
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Article
| Open AccessGut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway
Intestinal aging is associated with declines in structure and absorption of nutrients. Here, the authors show that aging related intestinal decline is mediated by activation of the mTORC1-p38MAPK-p53 pathway in intestinal stem cells and can be ameliorated by abrogating mTORC1 or p38MAPK activity.
- Dan He
- , Hongguang Wu
- & Baojie Li
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Article
| Open AccessFlagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases
Gut microbiota alterations, including enrichment of flagellated bacteria, are associated with metabolic syndrome and chronic inflammatory diseases. Here, Tran et al. show, in mice, that elicitation of mucosal anti-flagellin antibodies protects against experimental colitis and ameliorates diet-induced obesity.
- Hao Q. Tran
- , Ruth E. Ley
- & Benoit Chassaing
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Article
| Open AccessLeptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn’s disease
The adipokine leptin modulates intestinal inflammation in mice. Here the authors describe a patient with inflammatory bowel disease and lipodystrophy, providing evidence that leptin aggravates intestinal inflammation with proinflammatory effects on leukocytes that are reversible by TNFα blockade.
- Jörn F. Ziegler
- , Chotima Böttcher
- & Carl Weidinger
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Article
| Open AccessEngineered E. coli Nissle 1917 for the delivery of matrix-tethered therapeutic domains to the gut
Anti-inflammatory treatments for gastrointestinal diseases can often have detrimental side effects. Here the authors engineer E. coli Nissle 1917 to create a fibrous matrix that has a protective effect in DSS-induced colitis mice.
- Pichet Praveschotinunt
- , Anna M. Duraj-Thatte
- & Neel S. Joshi
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Article
| Open AccessDeletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity
Histone deacetylase 3 (HDAC3) is a regulator of lipid homeostasis in several tissues, however, its role in intestinal lipid metabolism was not yet known. Here the authors study intestine specific HDAC3 knock out mice and report that these animals have increased fatty acid oxidation and undergo remodeling of the intestinal epithelial cell lipidome.
- Mercedes Dávalos-Salas
- , Magdalene K. Montgomery
- & John M. Mariadason
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Article
| Open AccessA morphogenetic EphB/EphrinB code controls hepatopancreatic duct formation
The hepatopancreatic ductal (HPD) system connects both liver and pancreas to the intestine but the molecular details of HPD development are unclear. Here, the authors describe how regionalised Eph/Ephrin signaling regulates HPD morphogenesis by promoting cellular rearrangements leading to an open tube.
- M. Ilcim Thestrup
- , Sara Caviglia
- & Elke A. Ober
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Article
| Open AccessIdentification of predictors of drug sensitivity using patient-derived models of esophageal squamous cell carcinoma
Predicting the drug response of patients with cancer is crucial for implementing targeted therapy. Here, Su et al. make patient-derived cell lines and perform targeted sequencing and RNA-seq to identify CDKN2A/2B loss as a predictor of response to CDK4/6 inhibitors in esophageal squamous cell carcinoma.
- Dan Su
- , Dadong Zhang
- & Weimin Mao
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Article
| Open AccessEpithelial CD47 is critical for mucosal repair in the murine intestine in vivo
The role of the transmembrane glycoprotein CD47 in healing injured intestinal mucosa is unclear. Here, the authors show that selective loss of CD47 in the murine intestinal epithelium results in defective mucosal repair after colonic wounding, with suggested impaired cell migration in vitro.
- Michelle Reed
- , Anny-Claude Luissint
- & Charles A. Parkos
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Article
| Open AccessTheabrownin from Pu-erh tea attenuates hypercholesterolemia via modulation of gut microbiota and bile acid metabolism
Pu-erh tea displays cholesterol-lowering properties. Here, Huang et al. show that this is mostly due to the action of a pigment in Pu-erh tea that induces changes in certain gut microbiota and bile acid levels, thus modulating the gut-liver metabolic axis.
- Fengjie Huang
- , Xiaojiao Zheng
- & Wei Jia
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Article
| Open AccessColonizing multidrug-resistant bacteria and the longitudinal evolution of the intestinal microbiome after liver transplantation
In a large prospective cohort of liver transplantation (LT) recipients, the authors identify associations between colonization by multidrug-resistant bacteria (MDRB) and microbiome dysbiosis pre- and post-LT, suggesting colonizing MDRB as an important target for microbiome-informed therapeutic approaches post-LT.
- Medini K. Annavajhala
- , Angela Gomez-Simmonds
- & Anne-Catrin Uhlemann
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Article
| Open AccessEmbryonic mesothelial-derived hepatic lineage of quiescent and heterogenous scar-orchestrating cells defined but suppressed by WT1
Activated hepatic stellate cells of putative mesodermal origin orchestrate scarring during injury. Here, the authors define a discrete morphologically plastic lineage of embryonic mesothelial-derived scar-orchestrating cells, through a distinct quiescent adult precursor, defined and paradoxically inhibited by WT1.
- Timothy James Kendall
- , Catherine Mary Duff
- & Nicholas Dixon Hastie
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Article
| Open AccessBRG1 attenuates colonic inflammation and tumorigenesis through autophagy-dependent oxidative stress sequestration
Dysfunctional autophagy induces inflammation that contributes to tumorigenesis. Here, the authors show that loss of BRG1 impairs autophagy and enhances reactive oxygen species production to disrupt intestinal barrier integrity, leading to spontaneous colitis and subsequent colorectal cancer development.
- Min Liu
- , Tongyu Sun
- & Wei-Qiang Gao
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Article
| Open AccessInterleukin 22 disrupts pancreatic function in newborn mice expressing IL-23
Necrotizing enterocolitis (NEC) is associated with severe neonatal morbidity. Here the authors show, mirroring the NEC phenotype, that IL-23 overexpression in neonates causes malabsorption and decreased expression of intestinal and pancreatic genes mediating food digestion and uptake through IL-22, which directly suppresses pancreatic cell differentiation.
- Lili Chen
- , Valentina Strohmeier
- & Glaucia C. Furtado
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Article
| Open AccessR-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon
Epithelial turnover in the colon requires stem cells in the crypt that express the R-spondin receptor Lgr5. Here, the authors show that regeneration after colon injury involving loss of Lgr5+ and Axin2+ cells requires stromal derived Rspo3-dependent reprogramming of Lgr4+ differentiated cells, including Krt20+ enterocytes.
- Christine Harnack
- , Hilmar Berger
- & Michael Sigal
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Article
| Open AccessVAMP8-mediated MUC2 mucin exocytosis from colonic goblet cells maintains innate intestinal homeostasis
VAMP8 is a secretory pathway protein implicated in mucus secretion. Here the authors describe alterations in intestinal immune state and microbiota composition, as well as increased susceptibility to experimental colitis in mice deficient for VAMP8.
- Steve Cornick
- , Manish Kumar
- & Kris Chadee
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Article
| Open AccessRetrotransposon insertions can initiate colorectal cancer and are associated with poor survival
Retrotransposons are usually dormant in healthy tissue, but become activated during malignancy. Here, in colorectal cancer, Cajuso et al. show that retrotransposon activity associates with clinical features of the disease.
- Tatiana Cajuso
- , Päivi Sulo
- & Lauri A. Aaltonen
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Article
| Open AccessCD160 serves as a negative regulator of NKT cells in acute hepatic injury
BTLA is established as a negative regulator of natural killer T (NKT) cell function, and share its ligand HVEM with CD160. Here the authors show, by analyzing NKT activation in CD160-deficient mice or with BTLA blockade, that CD160 synergizes with BTLA to negatively regulate NKT cells during hepatic injury.
- Tae-Jin Kim
- , Gayoung Park
- & Kyung-Mi Lee
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Article
| Open AccessActive thrombin produced by the intestinal epithelium controls mucosal biofilms
The roles played by thrombin in the human intestinal mucosa are unclear. Here, the authors show that the commensal microbiota modulates epithelial production of active thrombin, which controls biofilm growth and contributes to protection of the mucosa from bacterial invasion.
- Jean-Paul Motta
- , Alexandre Denadai-Souza
- & Nathalie Vergnolle
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Article
| Open AccessGenomic signatures reveal DNA damage response deficiency in colorectal cancer brain metastases
The development of brain metastases is a lethal yet poorly understood event in the evolution of many cancers. Here, the authors perform whole-genome and whole-exome sequencing on matched normal, primary and metastatic tissue samples to explore the genomic features of brain metastases in colorectal cancer.
- Jing Sun
- , Cheng Wang
- & Yanhong Gu
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Article
| Open AccessDefective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis
Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.
- Josepmaria Argemi
- , Maria U. Latasa
- & Ramon Bataller
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Article
| Open AccessActivation of STAT3 signaling is mediated by TFF1 silencing in gastric neoplasia
Trefoil factor 1 (TFF1) is a protein secreted by the gastric mucosa that protects against gastric tumourigenesis. Here, the authors show that TFF1 inhibits the oncogenic inflammatory response and IL-6-mediated STAT3 activation by interfering with the binding of IL6 to its receptor IL6Rα.
- Mohammed Soutto
- , Zheng Chen
- & Wael El-Rifai
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Article
| Open AccessConserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification
Clinical and molecular heterogeneity of ulcerative colitis presents unresolved challenges to identify predictive biomarkers of response to therapies. Here, the authors combine mouse colitis time course with patient biopsy transcriptomes, achieving unsupervised clustering of UC patients correlating with therapeutic outcomes in independent data sets.
- Paulo Czarnewski
- , Sara M. Parigi
- & Eduardo J. Villablanca
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Article
| Open AccessMass cytometry reveals systemic and local immune signatures that distinguish inflammatory bowel diseases
Distinguishing clinical subtypes of IBD is critical for optimal treatments, outcome prediction, and better understanding of disease pathogenesis. Here the authors phenotype blood and intestinal immune cells by mass cytometry and identify signatures associated with distinct disease states.
- Samuel J. S. Rubin
- , Lawrence Bai
- & Aida Habtezion
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Article
| Open AccessTargeting EZH2 histone methyltransferase activity alleviates experimental intestinal inflammation
EZH2-mediated methylatation of histone 3 is essential for immune regulation. Here, the authors show that EZH2 inhibitors attenuate experimental colitis in mice by promoting the development of myeloid-derived suppressor cells, and delay the onset of colitis-associated cancer.
- Jie Zhou
- , Shuo Huang
- & Bo Zhu