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| Open AccessA ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy
Radiation colitis is a major side effect for pelvic radiotherapy patients, but there are limited available treatments. Here, the authors use a halloysite clay based material for the alleviation of radiation colitis in mice by inhibiting ferroptosis.
- Yue Feng
- , Xiang Luo
- & Mingxian Liu
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Article
| Open AccessRORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation
IL-17 secreting Th17 cells have established roles in numerous immune-pathologies but paradoxically are required homeostatically in the maintenance of the intestinal barrier. Here the authors establish Raftlin-1 in the recruitment of phospholipids that are linked to the emergence of pathogenic Th17 cells in animal models of bowel inflammation.
- Amir Kumar Singh
- , Ritesh Kumar
- & K. Venuprasad
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Article
| Open AccessGut microbiota-derived tryptamine and phenethylamine impair insulin sensitivity in metabolic syndrome and irritable bowel syndrome
Here, the authors show a causal role for gut bacteria-derived metabolites tryptamine and phenethylamine in contributing to insulin resistance and the development of metabolic syndrome in patients with irritable bowel syndrome and type 2 diabetes.
- Lixiang Zhai
- , Haitao Xiao
- & Zhao-Xiang Bian
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Article
| Open AccessNeoadjuvant sintilimab in combination with concurrent chemoradiotherapy for locally advanced gastric or gastroesophageal junction adenocarcinoma: a single-arm phase 2 trial
Neoadjuvant chemotherapy followed by gastrectomy is considered standard of care for locally advanced gastric and gastroesophageal junction (G/GEJ) cancers. Here the authors report the results of a phase 2 trial of neoadjuvant sintilimab (anti-PD1) plus chemoradiotherapy in patients with locally advanced G/GEJ tumors.
- Jia Wei
- , Xiaofeng Lu
- & Baorui Liu
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Article
| Open AccessA single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia
Achalasia is a rare motility disorder of the esophagus resulting from abnormal immune responses, but the immunologic mechanism is unclear. Here the authors use scRNA-seq of PBMC and esophageal lower sphincter tissue and find C1QC+ macrophages and tissue-resident memory T cells with expanded compositions and altered transcriptional profiles in achalasia.
- Zu-Qiang Liu
- , Hao Dai
- & Quan-Lin Li
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Article
| Open AccessSchwann cells regulate tumor cells and cancer-associated fibroblasts in the pancreatic ductal adenocarcinoma microenvironment
The effects of Schwann cells on the neuro-stroma niche in pancreatic ductal adenocarcinoma (PDAC) remain to be explored. Here, single-cell RNA-sequencing and spatial transcriptome analysis of PDAC tissues reveal that Schwann cells induce malignant subtypes of tumour cells and cancer associated fibroblasts.
- Meilin Xue
- , Youwei Zhu
- & Hao Chen
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Article
| Open AccessMacrophage and neutrophil heterogeneity at single-cell spatial resolution in human inflammatory bowel disease
Chronic intestinal inflammatory diseases including ulcerative colitis and Crohn’s disease display extensive heterogeneity in the immunopathology, disease manifestation and response to treatment. Here the authors apply single cell transcriptomic and spatial molecular imaging, and characterise macrophage and neutrophils in samples from patients with inflammatory bowel diseases.
- Alba Garrido-Trigo
- , Ana M. Corraliza
- & Azucena Salas
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Article
| Open AccessNFIC regulates ribosomal biology and ER stress in pancreatic acinar cells and restrains PDAC initiation
Pancreatic acinar differentiation can be tumour suppressive for pancreatic ductal adenocarcinoma (PDAC). Here the authors identify nuclear factor I family of transcription factors NFIC as a regulator of pancreatic acinar cell function that restrains mutant KRas-driven pancreas cancer initiation in mice.
- Isidoro Cobo
- , Sumit Paliwal
- & Francisco X. Real
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Article
| Open AccessSelective oxidative protection leads to tissue topological changes orchestrated by macrophage during ulcerative colitis
Ulcerative colitis is associated with increased infiltration and cellularity, yet the precise tissue topology remains poorly understood. Here the authors employ imaging mass cytometry and single-cell RNA sequencing to characterise intestinal lesions in patients with ulcerative colitis, and show the architecture at the individual cell level which includes a decrease in the resident macrophage population.
- Juan Du
- , Junlei Zhang
- & Jianpeng Sheng
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Article
| Open AccessTemperature-triggered in situ forming lipid mesophase gel for local treatment of ulcerative colitis
Treatment of the chronic disease ulcerative colitis is impeded by systemic side effects of orally administered drugs. Here the authors develop a gel that uses the rectal temperature as a mechanism to trigger solidification for localized delivery of colitis therapeutics.
- Marianna Carone
- , Marianne R. Spalinger
- & Simone Aleandri
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Article
| Open AccessA probiotic bi-functional peptidoglycan hydrolase sheds NOD2 ligands to regulate gut homeostasis in female mice
Lactobacillus-based probiotics have been reported to be beneficial for colitis through incompletely understood mechanisms. Here the authors identify an uncharacterized secreted enzyme named LPH from multiple probiotic Lactobacillus strains, which protects female mice from chemically induced colitis and colorectal cancer via NOD2 signalling.
- Jie Gao
- , Lei Wang
- & Xiaolong He
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Article
| Open AccessColitis ameliorates cholestatic liver disease via suppression of bile acid synthesis
The association between primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) has been known for decades, but mechanisms of gut-liver crosstalk are incompletely understood. Here, the authors show a colitis-triggered protective circuit suppressing cholestatic liver disease which encourages multi-organ treatment strategies for PSC.
- Wenfang Gui
- , Mikal Jacob Hole
- & Kai Markus Schneider
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Article
| Open AccessBacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis
Patients with primary sclerosing cholangitis (PSC) harboring Klebsiella pneumoniae (Kp) exhibit poor clinical outcomes. Here, the authors show that administration of a phage cocktail targeting PSC-derived Kp reduces bacterial burden in Kp-colonized mice and alleviates liver injury.
- Masataka Ichikawa
- , Nobuhiro Nakamoto
- & Takanori Kanai
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Article
| Open AccessGiardia hinders growth by disrupting nutrient metabolism independent of inflammatory enteropathy
Giardia lamblia intestinal infection is independently associated with faltering linear growth in children in low-middle income countries, yet the mechanistic pathway has not been clearly identified. Authors utilise the MAL-ED cohort, and a gnotobiotic murine model, to explain Giardia-induced effects on childhood growth.
- Natasa Giallourou
- , Jason Arnold
- & Luther A. Bartelt
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Article
| Open AccessMicrobiota-assisted iron uptake promotes immune tolerance in the intestine
Iron deficiencies are a common non intestinal symptom seen in patients with irritable bowel disease. Here the authors show an associative link between microbiota assisted uptake of nutrients including iron and the promotion of immune tolerance in the intestine.
- Lizhen Zhu
- , Geng Li
- & Xing Chang
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Article
| Open AccessLigand dependent interaction between PC-TP and PPARδ mitigates diet-induced hepatic steatosis in male mice
Deletion of PC-TP has many beneficial effects, mostly ascribed to its role in regulating THEM2. Here, the authors show a novel interaction between PC-TP and PPARδ that explains aspects of the beneficial metabolic phenotype associated with PC-TP deletion.
- Samuel A. Druzak
- , Matteo Tardelli
- & Eric A. Ortlund
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Article
| Open AccessPancreatic cancer is associated with medication changes prior to clinical diagnosis
Pancreatic cancer patients have previously been noted to have a change in medication history prior to diagnosis. Here, the authors utilise two large population cohorts to show associations between recent medication changes and risk of a subsequent pancreatic cancer diagnosis.
- Yin Zhang
- , Qiao-Li Wang
- & Brian M. Wolpin
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Article
| Open AccessIdentifying high-impact variants and genes in exomes of Ashkenazi Jewish inflammatory bowel disease patients
Inflammatory bowel disease (IBD) is highly prevalent among the Ashkenazi Jewish population. Here, the authors identify novel IBD-associated variants and genes, validated by transcriptomic and phenome-wide associations.
- Yiming Wu
- , Kyle Gettler
- & Yuval Itan
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Article
| Open AccessAltered human gut virome in patients undergoing antibiotics therapy for Helicobacter pylori
Here, Wang et al. use metagenomic sequencing to explore the impact of antibiotic treatment for Helicobacter pylori on the gut virome community in infected patients, showing that recurrent treatment leads to a lower virus community diversity and altered virus-bacteria interactions, compared with treatment naive patients.
- Lingling Wang
- , Haobin Yao
- & Wai K. Leung
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Article
| Open AccessTranscriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation
Hirschsprung disease is caused by defects in enteric neural crest cell. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis the authors define various factors associated with Hirschsprung pathogenesis.
- Zhixin Li
- , Kathy Nga-Chu Lui
- & Elly Sau-Wai Ngan
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Article
| Open AccessMAIT cell inhibition promotes liver fibrosis regression via macrophage phenotype reprogramming
Liver cirrhosis is characterised by extensive fibrosis of the liver, and understanding the underpinning immunological processes is important in designing intervention. Here authors show that Mucosal-Associated Invariant T cells are instrumental to controlling the balance between profibrogenic and restorative macrophages and inhibiting their activation might reverse liver fibrosis.
- Morgane Mabire
- , Pushpa Hegde
- & Sophie Lotersztajn
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Article
| Open AccessComprehensive proteogenomic characterization of early duodenal cancer reveals the carcinogenesis tracks of different subtypes
Duodenal cancer (DC) has complex subtypes and undergoes complicated morphological changes throughout progression, so understanding the molecular basis is crucial. Here, the authors perform a proteogenomics analysis of 156 DCs, revealing molecular subtypes as well as the roles of smoking, AARS1 and PARP1.
- Lingling Li
- , Dongxian Jiang
- & Chen Ding
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Article
| Open AccessBlocking Dectin-1 prevents colorectal tumorigenesis by suppressing prostaglandin E2 production in myeloid-derived suppressor cells and enhancing IL-22 binding protein expression
The effect of β-glucans and their receptor Dectin-1 in tumor development remains controversial. Here the authors show that Dectin-1 signaling promotes the development of colorectal cancer (CRC) by inducing prostaglandin E2 production in myeloid-derived suppressor cells and by suppressing IL-22BP expression, suggesting dectin-1 blockade as a potential therapeutic target for CRC.
- Ce Tang
- , Haiyang Sun
- & Yoichiro Iwakura
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Article
| Open AccessLong-term gastrointestinal outcomes of COVID-19
SARS-CoV-2 infection can lead to varied post-acute symptoms in the lungs and other organs, including the gastrointestinal system. Here the authors estimate the risks and 1-year burdens of a set of pre-specified incident gastrointestinal outcomes following SARS-CoV-2 infection in an electronic health care record-based cohort study.
- Evan Xu
- , Yan Xie
- & Ziyad Al-Aly
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Article
| Open AccessTandem mass tag-based quantitative proteomic profiling identifies candidate serum biomarkers of drug-induced liver injury in humans
Diagnosis of rare, unpredictable, drug-induced liver injury (DILI) is a significant challenge for patients, clinicians, and drug development. Here, the authors discover, evaluate, and validate potential blood biomarkers to diagnose DILI and distinguish it from alternative causes of liver injury.
- Kodihalli C. Ravindra
- , Vishal S. Vaidya
- & Shashi K. Ramaiah
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Article
| Open AccessThe gut microbiome and early-life growth in a population with high prevalence of stunting
Here, using metagenomics, the authors show that the gut microbiome of rural Zimbabwean infants undergoes programmed maturation that is unresponsive to sanitation and nutrition interventions but is strongly associated with maternal HIV infection and can moderately predict linear growth.
- Ruairi C. Robertson
- , Thaddeus J. Edens
- & Amee R. Manges
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Article
| Open AccessSingle-cell sequencing of ascites fluid illustrates heterogeneity and therapy-induced evolution during gastric cancer peritoneal metastasis
Peritoneal metastasis is one of the most common forms of death for gastrointestinal cancers, however, its cell composition is incompletely understood. Here, the authors use single cell RNA-seq of peritoneal metastases from 35 patients and show diversity in immune cells, and plasticity in cancer cell phenotypes and autophagy related genes as biomarkers of prognosis.
- Xuan-Zhang Huang
- , Min-Jiao Pang
- & Zhen-Ning Wang
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Article
| Open AccessSplicing factor SRSF1 deficiency in the liver triggers NASH-like pathology and cell death
Nonalcoholic steatohepatitis (NASH) is an advanced form of fatty liver disease with complex pathogenic mechanisms. Here, the authors report that SRSF1 deficiency in mice livers provokes deleterious R-loop formation and genotoxicity, which impedes hepatocellular gene expression, metabolism, and lipid trafficking, resulting in NASH-like pathology.
- Waqar Arif
- , Bhoomika Mathur
- & Auinash Kalsotra
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Article
| Open AccessUnique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis
The aetiology of primary biliary cholangitis (PBC) remains unclear. Here, the authors find that the numbers of DUOX2 + ACE2 + small cholangiocytes in human and mouse livers are inversely associated with disease severity, and present data indicating that they may be the target of polymeric immunoglobulin receptor (pIgR) -mediated humoral responses, suggesting that preservation of these cells and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.
- Xi Li
- , Yan Li
- & Jin Chai
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Article
| Open AccessThe transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice
Aggravation of liver steatosis shifts the hepatocellular death mode from apoptosis to necroptosis in acute and chronic liver damage. Here the authors report that the transcription factor ATF3 regulates this shift through the induction of RIPK3, a regulator of necroptosis.
- Yuka Inaba
- , Emi Hashiuchi
- & Hiroshi Inoue
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Article
| Open AccessIn vivo detection of bile duct pre-cancer with endoscopic light scattering spectroscopy
Diagnosis of bile duct cancer often occur in advanced stages, leading to poor survival. Here, the authors combine light scattering and diffuse reflectance spectroscopies in a minimally invasive endoscopic technique for directly assessing the malignant potential of the bile duct lining, and demonstrate 97% detection accuracy.
- Douglas K. Pleskow
- , Mandeep S. Sawhney
- & Lev T. Perelman
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Article
| Open AccessChronic exposure to synthetic food colorant Allura Red AC promotes susceptibility to experimental colitis via intestinal serotonin in mice
Allura Red AC is a dye used in food products. Here the authors report that chronic, long-term exposure to Allura Red AC increases susceptibility to experimental colitis in mice dependent on the serotonin biosynthetic enzyme TPH1, while intermittent exposure more typical for the human setting did not increase susceptibility to experimental colitis.
- Yun Han Kwon
- , Suhrid Banskota
- & Waliul I. Khan
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Article
| Open AccessHepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice
Dysregulation of the post-translational modification neddylation has been implicated in liver diseases such as fibrosis and hepatocellular carcinoma. Here the authors report that hepatic neddylation deficiency via genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1) causes acute liver failure due to mitochondrial dysfunction and aberrant activation of NF-κB-inducing kinase in mice.
- Cheng Xu
- , Hongyi Zhou
- & Weiqin Chen
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Article
| Open AccessEnterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia
Enterotoxigenic Escherichia coli infections have been linked to non-diarrheal sequelae however, the reasons for this are unclear. Here, the authors present an additional role of heat-labile toxin in disrupting the structure and function of intestinal epithelial cells.
- Alaullah Sheikh
- , Brunda Tumala
- & James M. Fleckenstein
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Article
| Open AccessDisulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism
Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, the authors show that disulfiram (DSF) reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis and ameliorate NASH in mice, and validate DSF regulation of the gut-liver axis in healthy men in a self-controlled clinical trial.
- Yuanyuan Lei
- , Li Tang
- & Bo Tang
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Article
| Open AccessPhosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice
A truncating variant of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), a lipid droplet -associated protein, associates with lower risk of chronic liver disease. Here the authors identify a phosphorylation site in 17β-HSD13 which promotes lipolysis, and report that a knock-in mouse with a 17β-HSD13 mutant defective for phosphorylation is more susceptible to nonalcoholic steatohepatitis.
- Wen Su
- , Sijin Wu
- & Youfei Guan
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Article
| Open AccessDNA methyltransferase 3A controls intestinal epithelial barrier function and regeneration in the colon
DNA methyltransferase 3 A (DNMT3A) is involved in DNA methylation, and genetic variants in the DNMT3 locus have been associated with inflammatory bowel disease. Here the authors report that DNMT3A controls intestinal epithelial barrier function and restoration of the gut barrier function after intestinal epithelial perturbation.
- Antonella Fazio
- , Dora Bordoni
- & Philip Rosenstiel
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Article
| Open AccessInduction of the hepatic aryl hydrocarbon receptor by alcohol dysregulates autophagy and phospholipid metabolism via PPP2R2D
Alcohol consumption promotes neutral fat accumulation in the liver. Here, the authors report that alcohol induces aryl hydrocarbon receptor AhR in the liver, and hepatocyte-specific AhR deletion protects against alcohol induced accumulation potentially via transcriptional regulation of Protein phosphatase 2 regulatory subunit Bdelta and subsequent effects on autophagy.
- Yun Seok Kim
- , Bongsub Ko
- & Sang Geon Kim
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Article
| Open AccessTLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis
The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis.
- Kasparas Petkevicius
- , Henrik Palmgren
- & Xiao-Rong Peng
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Article
| Open AccessChronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue
Dietary sugar intake may contribute to the development non-alcoholic fatty liver disease. Here the authors investigated the effects of chronic dietary sucrose on the liver-adipose-microbiome axis in mice, and report that sex is a moderating factor that influences sucrose-driven lipid storage in the liver and adipose tissue lipolysis.
- Erin J. Stephenson
- , Amanda S. Stayton
- & Joan C. Han
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Article
| Open AccessHelicobacter pylori shows tropism to gastric differentiated pit cells dependent on urea chemotaxis
The carcinogenic bacterium Helicobacter pylori infects gastric cells. Here, the authors show that H. pylori preferentially infects differentiated cells in the pit region of gastric units, and this relies on bacterial chemotaxis towards host cell-released urea, which scales with host cell size.
- Carmen Aguilar
- , Mindaugas Pauzuolis
- & Sina Bartfeld
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Article
| Open AccessInterleukin-22 regulates neutrophil recruitment in ulcerative colitis and is associated with resistance to ustekinumab therapy
Mechanisms of non-response to ustekinumab, a biologic targeting IL-23, are currently unclear. Here, the authors show that the transcriptional program regulated by IL-22, an IL-23 responsive cytokine, is enriched in patients with ulcerative colitis unresponsive to ustekinumab and associated with higher colon neutrophil recruitment and activation of upstream IL-22 regulators.
- Polychronis Pavlidis
- , Anastasia Tsakmaki
- & Nick Powell
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Article
| Open AccessProteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies
The mechanisms of resistance to therapy in gastric cancer remain to be explored. Here, proteomic profiling of 206 tumour tissues from patients treated with chemotherapy and anti-HER2-based therapy results in the identification of four molecular subtypes and the development of prognostic models.
- Yan Li
- , Chen Xu
- & Chen Ding
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Article
| Open AccessBacteriophage-antibiotic combination therapy against extensively drug-resistant Pseudomonas aeruginosa infection to allow liver transplantation in a toddler
In this study, authors use combinatory bacteriophage-antibiotic therapy, as treatment for extensively drug-resistant Pseudomonas aeruginosa infection in a toddler post liver transplantation. They report on the clinical and microbiological improvement, and present their investigation on how bacterial phage resistance did not result in therapeutic failure.
- Brieuc Van Nieuwenhuyse
- , Dimitri Van der Linden
- & Jean-Paul Pirnay
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Article
| Open AccessInterferon regulatory factor 1 (IRF-1) promotes intestinal group 3 innate lymphoid responses during Citrobacter rodentium infection
Innate lymphoid cells (ILC) are involved with different immune responses. Here the authors show that Interferon regulatory factor 1 (IRF1) is important for intestinal ILC3 accumulation during Citrobacter rodentium infection and promotes release of the protective cytokine IL-22 and response to IL-23.
- Angelika Schmalzl
- , Tamara Leupold
- & Stefan Wirtz
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Article
| Open AccessIn vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis
Management of ulcerative colitis can require a combination of treatments targeting different pathways. Here the authors design a therapy for ulcerative colitis based on a multitargeted genetic circuit to simultaneously target TNF-α, B7-1 and integrin α4, and show the therapy is effective in male mice with induced or spontaneous genetic colitis.
- Xinyan Zhou
- , Mengchao Yu
- & Xi Chen
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Article
| Open AccessSirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity
Host defense against helminth infection is mediated by mucosal type 2 immunity. Using gain- and loss-of-function mouse models, and mouse intestinal organoids, Xiong et al. show that SIRT6 modulates tuft and goblet cell expansion in intestinal epithelium by activating STAT6 to maintain type 2 mucosal immunity in response to helminth infection.
- Xiwen Xiong
- , Chenyan Yang
- & Qingzhi Wang
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Article
| Open AccessPredicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open AccessGWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements
Investigation of variation in three cohorts has identified multiple genetic signals associated with the pregnancy-specific liver disorder, intrahepatic cholestasis of pregnancy, giving insight into the disease which can cause preterm birth and stillbirth.
- Peter H. Dixon
- , Adam P. Levine
- & Catherine Williamson
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