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Mashup Score: 2ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation - 9 hour(s) ago
Objective Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression. Design RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1 -KO and Fxr -KO mice, patient liver tissue and computer simulations. Results Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1 -KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction a
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 3Recent advances in clinical practice: mastering the challenge—managing IBS symptoms in IBD - 9 hour(s) ago
Many patients with IBD report persisting symptoms, despite resolution of the inflammatory process. Although by definition, a diagnosis of IBS cannot be made, the prevalence of ‘IBS in IBD’ surpasses the rate of IBS in the global population by fivefold. Because IBS-like symptoms are associated with a decreased quality of life and increased healthcare utilisation in IBD, diagnosis and treatment are necessary. In this review, we summarise the current knowledge on IBS-like symptoms in IBD. A pathophysiological common ground is present, which includes genetic susceptibility, environmental triggers, gut microbial dysbiosis, increased intestinal permeability, visceral hypersensitivity and involvement of brain–gut interaction. When symptoms persist after resolution of inflammation, other GI diseases should be excluded based on the chief complaint, considering any possible psychological co-morbidity early in the diagnostic work-up. Subsequent treatment should be initiated that is evidence-based
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
Read the #GUTOnline #RecentAdvancesInClinicalPractice paper entitled "Recent advances in clinical practice: mastering the challenge—managing IBS symptoms in IBD" via https://t.co/05b9mm1yo7 @JudithWellens @JoaoPGSabino @SeverineVermei1 #IBS #IBD #GUTBrainAxis https://t.co/fD7LI604ru
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Mashup Score: 1Liquid biopsy to identify Barrett’s oesophagus, dysplasia and oesophageal adenocarcinoma: the EMERALD multicentre study - 9 hour(s) ago
Background There is no clinically relevant serological marker for the early detection of oesophageal adenocarcinoma (EAC) and its precursor lesion, Barrett’s oesophagus (BE). Objective To develop and test a blood-based assay for EAC and BE. Design Oesophageal MicroRNAs of BaRRett, Adenocarcinoma and Dysplasia ( EMERALD ) was a large, international, multicentre biomarker cohort study involving 792 patient samples from 4 countries ([NCT06381583][1]) to develop and validate a circulating miRNA signature for the early detection of EAC and high-risk BE. Tissue-based miRNA sequencing and microarray datasets (n=134) were used to identify candidate miRNAs of diagnostic potential, followed by validation using 42 pairs of matched cancer and normal tissues. The usefulness of the candidate miRNAs was initially assessed using 108 sera (44 EAC, 34 EAC precursors and 30 non-disease controls). We finally trained a machine learning model (XGBoost+AdaBoost) on RT-qPCR results from circulating miRNAs fro
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
Read the #GUTOnline paper by Miyoshi + @AlexMannucci et al on "Liquid biopsy to identify Barrett’s oesophagus, dysplasia and oesophageal adenocarcinoma: the EMERALD multicentre study" via https://t.co/bB5G9rIJTm @gaofeng21cn #BarrettsOesophagus https://t.co/PFsYQZrDaC
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Mashup Score: 1Targeting squalene epoxidase restores anti-PD-1 efficacy in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma - 9 hour(s) ago
Objective Squalene epoxidase (SQLE) promotes metabolic dysfunction-associated steatohepatitis-associated hepatocellular carcinoma (MASH-HCC), but its role in modulating the tumour immune microenvironment in MASH-HCC remains unclear. Design We established hepatocyte-specific Sqle transgenic (tg) and knockout mice, which were subjected to a choline-deficient high-fat diet plus diethylnitrosamine to induce MASH-HCC. SQLE function was also determined in orthotopic and humanised mice. Immune landscape alterations of MASH-HCC mediated by SQLE were profiled by single-cell RNA sequencing and flow cytometry. Results Hepatocyte-specific Sqle tg mice exhibited a marked increase in MASH-HCC burden compared with wild-type littermates, together with decreased tumour-infiltrating functional IFN-γ+ and Granzyme B+ CD8+ T cells while enriching Arg-1+ myeloid-derived suppressor cells (MDSCs). Conversely, hepatocyte-specific Sqle knockout suppressed tumour growth with increased cytotoxic CD8+ T cells and
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
#GUTImage from the paper by Wen et al entitled "Targeting squalene epoxidase restores anti-PD-1 efficacy in metabolic dysfunction-associated steatohepatitis-induced hepatocellular carcinoma" via https://t.co/BcyFloRLAJ #HCC https://t.co/PDWSM7MS5O
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Mashup Score: 2
We read with interest the findings by Zhou et al that identified the microbiota-induced S100A11-RAGE axis as a basis for immune evasion in proximal colorectal cancer (CRC), the targeting potential of this pathway in enhancing the efficacy of anti-PD-1 therapy.1 Currently, despite showing a response more favourably in hypermutated tumours, the effectiveness of immunotherapy in microsatellite stable CRC patients remains controversial, largely due to the imprecision in defining the subset of patients who benefit.2 The authors addressed CRC in different anatomical locations, focusing on different anatomical subsites, where microsatellite instability (MSI) represents one of the key molecular distinctions. However, the underlying causes of the differential MSI patterns between anatomical sites and the development of precise, effective therapies targeting MSI remain unclear.3 The present study did not investigate whether distinct microbial communities might …
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
#GUTLetter by Qu et al entitled "Potential microbial effects on microsatellite instability possibly drive divergence in colorectal cancer immunotherapy responses among different anatomical subsites" via https://t.co/RXjLHaB4CR #GUTOnline https://t.co/qhNs3kZ5Xj
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Mashup Score: 9Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma - 2 day(s) ago
Objective Fat mass and obesity-associated protein (FTO), an eraser of N 6-methyadenosine (m6A), plays oncogenic roles in various cancers. However, its role in hepatocellular carcinoma (HCC) is unclear. Furthermore, small extracellular vesicles (sEVs, or exosomes) are critical mediators of tumourigenesis and metastasis, but the relationship between FTO-mediated m6A modification and sEVs in HCC is unknown. Design The functions and mechanisms of FTO and glycoprotein non-metastatic melanoma protein B (GPNMB) in HCC progression were investigated in vitro and in vivo. Neutralising antibody of syndecan-4 (SDC4) was used to assess the significance of sEV-GPNMB. FTO inhibitor CS2 was used to examine the effects on anti-PD-1 and sorafenib treatment. Results FTO expression was upregulated in patient HCC tumours. Functionally, FTO promoted HCC cell proliferation, migration and invasion in vitro, and tumour growth and metastasis in vivo. FTO knockdown enhanced the activation and recruitment of tumo
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
#GUTAbstract by Chen et al on the paper entitled "Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma" via https://t.co/9dP3SOotia @HKUniversity #HCC https://t.co/SLdjUKtVf9
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Mashup Score: 33Age-related patterns of microbial dysbiosis in multiplex inflammatory bowel disease families - 2 day(s) ago
Objective IBD is characterised by dysbiosis, but it remains unclear to what extent dysbiosis develops in unaffected at-risk individuals. To address this, we investigated age-related patterns of faecal and serum markers of dysbiosis in high-risk multiplex IBD families (two or more affected first-degree relatives). Design Faecal and serum samples were collected from multiplex IBD and control families (95 IBD, 292 unaffected, 51 controls). Findings were validated in independent cohorts of 616 and 1173 subjects including patients with IBD, infants born to mothers with IBD and controls. 16S rRNA gene sequencing and global untargeted metabolomics profiling of faeces and serum were performed. Results Microbial and metabolomic parameters of dysbiosis progressively decreased from infancy until age 8. This microbial maturation process was slower in infants born to mothers with IBD. After age 15, dysbiosis steadily increased in unaffected relatives throughout adulthood. Dysbiosis was accompanied
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
#GUTImage from the paper by Jacobs et al entitled "Age-related patterns of microbial dysbiosis in multiplex inflammatory bowel disease families" via https://t.co/8UdzLRBZa4 #IBD https://t.co/birklhWNSR
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Mashup Score: 10
Objective The objective of this study is to improve the efficacy of CLDN18.2/CD3 bispecific T-cell engagers (BiTEs) as a promising immunotherapy against pancreatic ductal adenocarcinoma (PDAC). Design Humanised hCD34+/hCD3e+, Trp53R172HKrasG12DPdx1-Cre (KPC), pancreas-specific Cldn18.2 knockout (KO), fibroblast-specific Fcgr1 KO and patient-derived xenograft/organoid mouse models were constructed. Flow cytometry, Masson staining, Cell Titer Glo assay, virtual drug screening, molecular docking and chromatin immunoprecipitation were conducted. Results CLDN18.2 BiTEs effectively inhibited early tumour growth, but late-stage efficacy was significantly diminished. Mechanically, the Fc fragment of BiTEs interacted with CD64+ cancer-associated fibroblasts (CAFs) via activation of the SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A-α-SMA/collagen-I pathway, which enhanced desmoplasia and limited late-stage infiltration of T cells. Molecular docking analysis found that vilanterol suppressed BiTEs-induced phosph
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
#GUTImage from the paper by Zhou et al on "CD64+ fibroblast-targeted vilanterol and a STING agonist augment CLDN18.2 BiTEs efficacy against pancreatic cancer by reducing desmoplasia and enriching stem-like CD8+ T cells" via https://t.co/K40rETi1hy #PancreaticCancer https://t.co/DP4WpeHhUL
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Mashup Score: 2MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer - 3 day(s) ago
Objective Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC. Design To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice. Results Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
#GUTImage by Tang et al on the paper "MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer" via https://t.co/bLDfR7H2cr #PancreaticCancer https://t.co/jccQUEbLOE
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Mashup Score: 3
Objective In patients with Crohn’s disease (CD) on combination therapy (infliximab and immunosuppressant) and stopping infliximab (cohort from the study of infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors (STORI)), the risk of short-term (≤6 months) and mid/long-term relapse (>6 months) was associated with distinct blood protein profiles. Our aim was to test the external validity of this finding in the SPARE cohort (A proSpective Randomized Controlled Trial comParing infliximAb-antimetabolites Combination Therapy to Anti-metabolites monotheRapy and Infliximab monothErapy in Crohn’s Disease Patients in Sustained Steroid-free Remission on Combination Therapy). Design In SPARE, patients with CD in sustained steroid-free clinical remission and on combination therapy were randomly allocated to three arms: continuing combination therapy, stopping infliximab or stopping immunosuppressant. In the baseline serum of the STORI a
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet-
#GUTImage from the paper by Pierre et al on "External validation of serum biomarkers predicting short-term and mid/long-term relapse in patients with Crohn’s disease stopping infliximab" via https://t.co/xuX3LBPZOf @ibd_kliniek #Infliximab #CrohnsDisease https://t.co/4HQqunBrSc
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#GUTImage from the paper by Link et al entitled "ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation" via https://t.co/ktdQzpjcY9 @SaiWang_0404 @sdooley1b @prof_ebert @LiebeRoman #LiverTwitter https://t.co/FEPRuimc54