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Mashup Score: 15Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy - 28 day(s) ago
Objective Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. Design We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival 23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 3Immunosuppressive CD29+ Treg accumulation in the liver in mice on checkpoint inhibitor therapy - 1 month(s) ago
Objective Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown. Design Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy. Results We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29+ ( Itgb1 , integrin β1) Tregs, that were highly proliferative
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 15Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy - 1 month(s) ago
Objective Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. Design We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival 23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 3Immunosuppressive CD29+ Treg accumulation in the liver in mice on checkpoint inhibitor therapy - 1 month(s) ago
Objective Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown. Design Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy. Results We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29+ ( Itgb1 , integrin β1) Tregs, that were highly proliferative
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 15Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy - 1 month(s) ago
Objective Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. Design We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival 23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 3Immunosuppressive CD29+ Treg accumulation in the liver in mice on checkpoint inhibitor therapy - 2 month(s) ago
Objective Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown. Design Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy. Results We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29+ ( Itgb1 , integrin β1) Tregs, that were highly proliferative
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 15Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy - 2 month(s) ago
Objective Cytotoxic agents are the cornerstone of treatment for patients with advanced intrahepatic cholangiocarcinoma (iCCA), despite heterogeneous benefit. We hypothesised that the pretreatment molecular profiles of diagnostic biopsies can predict patient benefit from chemotherapy and define molecular bases of innate chemoresistance. Design We identified a cohort of advanced iCCA patients with comparable baseline characteristics who diverged as extreme outliers on chemotherapy (survival 23 m in long survivors, LS). Diagnostic biopsies were characterised by digital pathology, then subjected to whole-transcriptome profiling of bulk and geospatially macrodissected tissue regions. Spatial transcriptomics of tumour-infiltrating myeloid cells was performed using targeted digital spatial profiling (GeoMx). Transcriptome signatures were evaluated in multiple cohorts of resected cancers. Signatures were also characterised using in vitro cell lines, in
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 3Immunosuppressive CD29+ Treg accumulation in the liver in mice on checkpoint inhibitor therapy - 2 month(s) ago
Objective Liver metastases are often resistant to immune checkpoint inhibitor therapy (ICI) and portend a worse prognosis compared with metastases to other locations. Regulatory T cells (Tregs) are one of several immunosuppressive cells implicated in ICI resistance of liver tumours, but the role played by Tregs residing within the liver surrounding a tumour is unknown. Design Flow cytometry and single-cell RNA sequencing were used to characterise hepatic Tregs before and after ICI therapy. Results We found that the murine liver houses a Treg population that, unlike those found in other organs, is both highly proliferative and apoptotic at baseline. On administration of αPD-1, αPD-L1 or αCTLA4, the liver Treg population doubled regardless of the presence of an intrahepatic tumour. Remarkably, this change was not due to the preferential expansion of the subpopulation of Tregs that express PD-1. Instead, a subpopulation of CD29+ ( Itgb1 , integrin β1) Tregs, that were highly proliferative
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 13Inhibition of YTHDF1 by salvianolic acid overcomes gluten-induced intestinal inflammation - 5 month(s) ago
Coeliac disease (CD) is a chronic inflammatory and autoimmune disorder, primarily affecting the small intestine, developed in genetically susceptible individuals upon gluten ingestion. The only effective treatment so far is a lifelong, strict gluten-free diet. However, difficulties to follow dietary compliance can lead to complications, highlighting the unmet need for adjuvant therapies. Recently in Gut, we described a novel m6A-XPO1-NFκB pathway that is activated in patients with CD. Specifically, YTHDF1 m6A reader was found to selectively bind the 5’ UTR of XPO1 mRNA and induce its translation, increasing XPO1-mediated inflammation in intestinal cells both in vitro and in vivo .1 These findings opened the door to new therapeutic approaches directed to m6A machinery proteins, already in use for the treatment of other disorders.2 Interestingly, novel studies have described salvianolic acid (SAC) as a selective inhibitor of YTHDF1, which can rescue Fragile X syndrome linked defects in n
Source: gut.bmj.comCategories: General Medicine News, GastroenterologyTweet
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Mashup Score: 5
Objective Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option. Design A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC. Results Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in
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#GUTImage from the paper by Cao et al entitled "Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling" via https://t.co/t7hvMLG1wX @DrJashDatta https://t.co/W4c32nViK6
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#GUTImage from the paper by O'Rourke et al "Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy" via https://t.co/dGTwdekWgr @antoniopea @analleo @nigeljamieson @jaboeje https://t.co/HrweJXAkWu