Pub Date : 2025-01-17DOI: 10.1136/gutjnl-2024-332619
Karol M Córdoba, Daniel Jericó, Lei Jiang, María Collantes, Manuel Alegre, Leyre García-Ruiz, Oscar Manzanilla, Ana Sampedro, Jose M Herranz, Iñigo Insausti, Antonio Martinez de la Cuesta, Francesco Urigo, Patricia Alcaide, María Morán, Miguel A Martín, José Luis Lanciego, Thibaud Lefebvre, Laurent Gouya, Gemma Quincoces, Carmen Unzu, Sandra Hervas-Stubbs, Juan M Falcón-Pérez, Estíbaliz Alegre, Azucena Aldaz, María A Fernández-Seara, Iván Peñuelas, Pedro Berraondo, Paolo G V Martini, Matias A Avila, Antonio Fontanellas
Objective: Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.
Design: We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic PBGD gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.
Results: Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than the current standards of care for AIP.
Conclusion: This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment.
{"title":"Systemic messenger RNA replacement therapy is effective in a novel clinically relevant model of acute intermittent porphyria developed in non-human primates.","authors":"Karol M Córdoba, Daniel Jericó, Lei Jiang, María Collantes, Manuel Alegre, Leyre García-Ruiz, Oscar Manzanilla, Ana Sampedro, Jose M Herranz, Iñigo Insausti, Antonio Martinez de la Cuesta, Francesco Urigo, Patricia Alcaide, María Morán, Miguel A Martín, José Luis Lanciego, Thibaud Lefebvre, Laurent Gouya, Gemma Quincoces, Carmen Unzu, Sandra Hervas-Stubbs, Juan M Falcón-Pérez, Estíbaliz Alegre, Azucena Aldaz, María A Fernández-Seara, Iván Peñuelas, Pedro Berraondo, Paolo G V Martini, Matias A Avila, Antonio Fontanellas","doi":"10.1136/gutjnl-2024-332619","DOIUrl":"10.1136/gutjnl-2024-332619","url":null,"abstract":"<p><strong>Objective: </strong>Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors.</p><p><strong>Design: </strong>We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic <i>PBGD</i> gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue.</p><p><strong>Results: </strong>Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than the current standards of care for AIP.</p><p><strong>Conclusion: </strong>This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"270-283"},"PeriodicalIF":23.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11874285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Objective: In utero exposure to maternal inflammation may impact immune system development and subsequent risk of disease. We investigated whether a maternal diagnosis of IBD before childbirth is linked to a higher risk of IBD in offspring compared with a diagnosis after childbirth. Further, we analysed paternal IBD status for comparison.
Design: Using Danish health registers, we identified all individuals born in Denmark between 1997 and 2022 and their legal parents, as well as their IBD status. Cox proportional hazards regression analyses adjusted for calendar period and mode of delivery were used to estimate offspring IBD risk by maternal and paternal IBD status before and after childbirth.
Results: Of 1 290 358 children, 10 041 (0.8%) had mothers with IBD diagnosis before childbirth and 9985 (0.8%) had mothers with IBD diagnosis after childbirth. Over 18 370 420 person-years, 3537 individuals were diagnosed with IBD. Offspring of mothers with IBD before childbirth had an adjusted HR of IBD of 6.27 (95% CI 5.21, 7.54) compared with those without maternal IBD, while offspring of mothers with IBD after childbirth had an adjusted HR of 3.88 (95% CI 3.27, 4.60). Corresponding adjusted HRs were 5.26 (95% CI 4.22, 6.56) among offspring with paternal IBD before childbirth and 3.73 (95% CI 3.10, 4.50) for paternal IBD after childbirth.
Conclusion: Offspring had a greater risk of IBD when either parent was diagnosed before childbirth rather than later, emphasising genetic predisposition and environmental risk factors rather than maternal inflammation in utero as risk factors for IBD.
{"title":"Impact of prenatal and postnatal maternal IBD status on offspring's risk of IBD: a population-based cohort study.","authors":"Linéa Bonfils, Gry Poulsen, Manasi Agrawal, Mette Julsgaard, Joana Torres, Tine Jess, Kristine Højgaard Allin","doi":"10.1136/gutjnl-2024-332885","DOIUrl":"10.1136/gutjnl-2024-332885","url":null,"abstract":"<p><strong>Objective: </strong>In utero exposure to maternal inflammation may impact immune system development and subsequent risk of disease. We investigated whether a maternal diagnosis of IBD before childbirth is linked to a higher risk of IBD in offspring compared with a diagnosis after childbirth. Further, we analysed paternal IBD status for comparison.</p><p><strong>Design: </strong>Using Danish health registers, we identified all individuals born in Denmark between 1997 and 2022 and their legal parents, as well as their IBD status. Cox proportional hazards regression analyses adjusted for calendar period and mode of delivery were used to estimate offspring IBD risk by maternal and paternal IBD status before and after childbirth.</p><p><strong>Results: </strong>Of 1 290 358 children, 10 041 (0.8%) had mothers with IBD diagnosis before childbirth and 9985 (0.8%) had mothers with IBD diagnosis after childbirth. Over 18 370 420 person-years, 3537 individuals were diagnosed with IBD. Offspring of mothers with IBD before childbirth had an adjusted HR of IBD of 6.27 (95% CI 5.21, 7.54) compared with those without maternal IBD, while offspring of mothers with IBD after childbirth had an adjusted HR of 3.88 (95% CI 3.27, 4.60). Corresponding adjusted HRs were 5.26 (95% CI 4.22, 6.56) among offspring with paternal IBD before childbirth and 3.73 (95% CI 3.10, 4.50) for paternal IBD after childbirth.</p><p><strong>Conclusion: </strong>Offspring had a greater risk of IBD when either parent was diagnosed before childbirth rather than later, emphasising genetic predisposition and environmental risk factors rather than maternal inflammation in utero as risk factors for IBD.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"206-213"},"PeriodicalIF":23.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-17DOI: 10.1136/gutjnl-2024-332429
Yang Yang, Tianduo Pei, Chaobao Liu, Mingtao Cao, Xiaolin Hu, Jie Yuan, Fengqian Chen, Bao Guo, Yuemei Hong, Jibin Liu, Bin Li, Xiaoguang Li, Hui Wang
Objective: The metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains unclear.
Design: Human samples and multiple murine models were employed to evaluate the correlation between GPR109A and liver cancer progression. GPR109A knockout mice, immune cells depletion and primary cell coculture models were used to determine the regulation of GPR109A on tumour microenvironment and identify the underlying mechanism responsible for the formation of intratumour GPR109A+myeloid cells.
Results: We demonstrate that glutamine shortage in liver cancer tumour microenvironment drives an immunosuppressive GPR109A+myeloid cells infiltration, leading to the evasion of immune surveillance. Blockade of GPR109A decreases G-MDSCs and M2-like TAMs abundance to trigger the antitumour responses of CD8+ T cells and further improves the immunotherapy efficacy against liver cancer. Mechanistically, tumour cells and tumour-infiltrated myeloid cells compete for glutamine uptake via the transporter SLC1A5 to control antitumour immunity, which disrupts the endoplasmic reticulum (ER) homoeostasis and induces unfolded protein response of myeloid cells to promote GPR109A expression through IRE1α/XBP1 pathway. The restriction of glutamine uptake in liver cancer cells, as well as the blockade of IRE1α/XBP1 signalling or glutamine supplementation, can eliminate the immunosuppressive effects of GPR109A+ myeloid cells and slow down tumour progression.
Conclusion: Our findings identify the immunometabolic crosstalk between liver cancer cells and myeloid cells facilitates tumour progression via a glutamine metabolism/ER stress/GPR109A axis, suggesting that GPR109A can be exploited as an immunometabolic checkpoint and putative target for cancer treatment.
{"title":"Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A<sup>+</sup> myeloid cells to promote liver cancer progression.","authors":"Yang Yang, Tianduo Pei, Chaobao Liu, Mingtao Cao, Xiaolin Hu, Jie Yuan, Fengqian Chen, Bao Guo, Yuemei Hong, Jibin Liu, Bin Li, Xiaoguang Li, Hui Wang","doi":"10.1136/gutjnl-2024-332429","DOIUrl":"10.1136/gutjnl-2024-332429","url":null,"abstract":"<p><strong>Objective: </strong>The metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains unclear.</p><p><strong>Design: </strong>Human samples and multiple murine models were employed to evaluate the correlation between GPR109A and liver cancer progression. GPR109A knockout mice, immune cells depletion and primary cell coculture models were used to determine the regulation of GPR109A on tumour microenvironment and identify the underlying mechanism responsible for the formation of intratumour GPR109A<sup>+</sup>myeloid cells.</p><p><strong>Results: </strong>We demonstrate that glutamine shortage in liver cancer tumour microenvironment drives an immunosuppressive GPR109A<sup>+</sup>myeloid cells infiltration, leading to the evasion of immune surveillance. Blockade of GPR109A decreases G-MDSCs and M2-like TAMs abundance to trigger the antitumour responses of CD8<sup>+</sup> T cells and further improves the immunotherapy efficacy against liver cancer. Mechanistically, tumour cells and tumour-infiltrated myeloid cells compete for glutamine uptake via the transporter SLC1A5 to control antitumour immunity, which disrupts the endoplasmic reticulum (ER) homoeostasis and induces unfolded protein response of myeloid cells to promote GPR109A expression through IRE1α/XBP1 pathway. The restriction of glutamine uptake in liver cancer cells, as well as the blockade of IRE1α/XBP1 signalling or glutamine supplementation, can eliminate the immunosuppressive effects of GPR109A<sup>+</sup> myeloid cells and slow down tumour progression.</p><p><strong>Conclusion: </strong>Our findings identify the immunometabolic crosstalk between liver cancer cells and myeloid cells facilitates tumour progression via a glutamine metabolism/ER stress/GPR109A axis, suggesting that GPR109A can be exploited as an immunometabolic checkpoint and putative target for cancer treatment.</p>","PeriodicalId":12825,"journal":{"name":"Gut","volume":" ","pages":"255-269"},"PeriodicalIF":23.0,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1136/gutjnl-2024-333446
Maarten te Groen, Anouk M Wijnands, Nathan den Broeder, Dirk J de Jong, Willemijn A van Dop, Marjolijn Duijvestein, Herma H Fidder, Fiona van Schaik, Meike M C Hirdes, Andrea E van der Meulen-de Jong, P W Jeroen Maljaars, Philip W Voorneveld, K H Nanne de Boer, Charlotte P Peters, Bas Oldenburg, Frank Hoentjen
Background It remains unclear if the increased colorectal neoplasia detection rate in inflammatory bowel disease (IBD) by high-definition (HD) dye-based chromoendoscopy compared with HD white-light endoscopy is due to enhanced contrast or increased inspection times. Longer withdrawal times may yield similar neoplasia detection rates as found by HD chromoendoscopy. Objective To compare colorectal neoplasia detection rates for HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy, using single-pass HD white-light endoscopy as an additional control group. Design In a multicentre, randomised controlled trial, IBD patients aged ≥18 years without active disease and scheduled for endoscopic surveillance were included. Patients were 2:2:1 randomised to HD white-light endoscopy with segmental re-inspection of each colonic segment (double pass), HD chromoendoscopy or single-pass HD white-light endoscopy. The primary outcome was colorectal neoplasia detection rate. Assuming equal colorectal neoplasia rates (non-inferiority margin of 10%) between segmental re-inspection and chromoendoscopy and superiority of segmental re-inspection vs single-pass HD white-light endoscopy, a sample size of 566 patients was required. Results In total, 563 patients were analysed per-protocol. Colorectal neoplasia detection rates were 10.3% (n=24/234) for HD white-light endoscopy with segmental re-inspection and 13.1% (n=28/214) for HD chromoendoscopy. This confirmed non-inferiority to HD chromoendoscopy (Δ−2.8%, lower limit 95% CI −7.8, p<0.01). In addition, the number of detected colorectal neoplasia per 10 min of withdrawal time was similar between HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy (0.062 vs 0.058, p=0.83). Single-pass HD white-light endoscopy yielded a lower colorectal neoplasia rate (6.1%; n=7/115) than segmental re-inspection but this was not statistically significant (Δ4.1%, 95% CI −2.2:9.6%, p=0.19). Conclusions HD white-light endoscopy with segmental re-inspection was non-inferior to HD chromoendoscopy for colorectal neoplasia detection in IBD patients. It can therefore be assumed that the benefit of HD chromoendoscopy may be explained by the longer withdrawal time and not necessarily the enhanced contrast. However, re-inspection per se did not lead to a significantly higher colorectal neoplasia rate than single-pass HD white-light endoscopy alone. Data are available upon reasonable request. The data that support the findings of this study are available on request from the corresponding author [F.H].
{"title":"Surveillance in inflammatory bowel disease: white light endoscopy with segmental re-inspection versus dye-based chromoendoscopy – a multi-arm randomised controlled trial (HELIOS)","authors":"Maarten te Groen, Anouk M Wijnands, Nathan den Broeder, Dirk J de Jong, Willemijn A van Dop, Marjolijn Duijvestein, Herma H Fidder, Fiona van Schaik, Meike M C Hirdes, Andrea E van der Meulen-de Jong, P W Jeroen Maljaars, Philip W Voorneveld, K H Nanne de Boer, Charlotte P Peters, Bas Oldenburg, Frank Hoentjen","doi":"10.1136/gutjnl-2024-333446","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333446","url":null,"abstract":"Background It remains unclear if the increased colorectal neoplasia detection rate in inflammatory bowel disease (IBD) by high-definition (HD) dye-based chromoendoscopy compared with HD white-light endoscopy is due to enhanced contrast or increased inspection times. Longer withdrawal times may yield similar neoplasia detection rates as found by HD chromoendoscopy. Objective To compare colorectal neoplasia detection rates for HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy, using single-pass HD white-light endoscopy as an additional control group. Design In a multicentre, randomised controlled trial, IBD patients aged ≥18 years without active disease and scheduled for endoscopic surveillance were included. Patients were 2:2:1 randomised to HD white-light endoscopy with segmental re-inspection of each colonic segment (double pass), HD chromoendoscopy or single-pass HD white-light endoscopy. The primary outcome was colorectal neoplasia detection rate. Assuming equal colorectal neoplasia rates (non-inferiority margin of 10%) between segmental re-inspection and chromoendoscopy and superiority of segmental re-inspection vs single-pass HD white-light endoscopy, a sample size of 566 patients was required. Results In total, 563 patients were analysed per-protocol. Colorectal neoplasia detection rates were 10.3% (n=24/234) for HD white-light endoscopy with segmental re-inspection and 13.1% (n=28/214) for HD chromoendoscopy. This confirmed non-inferiority to HD chromoendoscopy (Δ−2.8%, lower limit 95% CI −7.8, p<0.01). In addition, the number of detected colorectal neoplasia per 10 min of withdrawal time was similar between HD white-light endoscopy with segmental re-inspection and HD chromoendoscopy (0.062 vs 0.058, p=0.83). Single-pass HD white-light endoscopy yielded a lower colorectal neoplasia rate (6.1%; n=7/115) than segmental re-inspection but this was not statistically significant (Δ4.1%, 95% CI −2.2:9.6%, p=0.19). Conclusions HD white-light endoscopy with segmental re-inspection was non-inferior to HD chromoendoscopy for colorectal neoplasia detection in IBD patients. It can therefore be assumed that the benefit of HD chromoendoscopy may be explained by the longer withdrawal time and not necessarily the enhanced contrast. However, re-inspection per se did not lead to a significantly higher colorectal neoplasia rate than single-pass HD white-light endoscopy alone. Data are available upon reasonable request. The data that support the findings of this study are available on request from the corresponding author [F.H].","PeriodicalId":12825,"journal":{"name":"Gut","volume":"13 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1136/gutjnl-2024-334358
Catherine Reenaers, Edouard Louis
Inflammatory bowel diseases (IBDs) encompass chronic conditions predominantly affecting young individuals and necessitate long-term, advanced treatments to manage disease burden and mitigate progressive tissue damage.1 Within this context, the matter of treatment discontinuation in patients who have achieved sustained remission, including those undergoing combination therapy, holds significant importance for both clinicians and patients. The primary considerations for potential treatment de-escalation or cessation include safety concerns, the financial implications of prolonged therapy and patients’ willingness or preference. In Gut, Gisbert et al 2 address this important question and report the results of the EXIT trial, a randomised placebo-controlled trial on 140 patients in clinical remission under anti-tumour necrosis factor (TNF) antibody and immunomodulators who were randomly assigned to either withdraw or maintain the anti-TNF antibody. Four prospective clinical trials have investigated the question of anti-TNF de-escalation in IBD3–6 but two specifically address treatment de-escalation in patients achieving clinical remission while on combination therapy with infliximab (IFX) and an immunomodulator.3 4 The STORI (infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors) trial was the first prospective, single-arm study evaluating clinical relapse after IFX withdrawal in patients in corticosteroid-free remission for at least 6 months on combination therapy with an immunomodulator.3 After a median follow-up of 24 months, 45% experienced relapse. Key findings included …
{"title":"Challenge of treatment de-escalation in inflammatory bowel diseases","authors":"Catherine Reenaers, Edouard Louis","doi":"10.1136/gutjnl-2024-334358","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334358","url":null,"abstract":"Inflammatory bowel diseases (IBDs) encompass chronic conditions predominantly affecting young individuals and necessitate long-term, advanced treatments to manage disease burden and mitigate progressive tissue damage.1 Within this context, the matter of treatment discontinuation in patients who have achieved sustained remission, including those undergoing combination therapy, holds significant importance for both clinicians and patients. The primary considerations for potential treatment de-escalation or cessation include safety concerns, the financial implications of prolonged therapy and patients’ willingness or preference. In Gut, Gisbert et al 2 address this important question and report the results of the EXIT trial, a randomised placebo-controlled trial on 140 patients in clinical remission under anti-tumour necrosis factor (TNF) antibody and immunomodulators who were randomly assigned to either withdraw or maintain the anti-TNF antibody. Four prospective clinical trials have investigated the question of anti-TNF de-escalation in IBD3–6 but two specifically address treatment de-escalation in patients achieving clinical remission while on combination therapy with infliximab (IFX) and an immunomodulator.3 4 The STORI (infliximab diSconTinuation in CrOhn’s disease patients in stable Remission on combined therapy with Immunosuppressors) trial was the first prospective, single-arm study evaluating clinical relapse after IFX withdrawal in patients in corticosteroid-free remission for at least 6 months on combination therapy with an immunomodulator.3 After a median follow-up of 24 months, 45% experienced relapse. Key findings included …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"27 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear. Objective We aimed to illustrate the mechanisms of resistance to trametinib in PDAC and identify trametinib resistance-associated druggable targets, thus improving the treatment efficacy of trametinib-resistant PDAC. Design We established patient-derived xenograft (PDX) models and primary cell lines to conduct functional experiments. We also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing and Cleavage Under Targets and Tagmentation sequencing to explore the relevant molecular mechanism. Results We have identified a cancer cell subpopulation featured by hyperactivated viral mimicry response in trametinib-resistant PDXs. We have demonstrated that trametinib treatment of PDAC PDXs induces expression of transcription factor MAX dimerisation protein 1 (MXD1), which acts as a cofactor of histone methyltransferase mixed lineage leukaemia 1 to increased H3K4 trimethylation in transposable element (TE) loci, enhancing chromatin accessibility and thus the transcription of TEs. Mechanistically, enhanced transcription of TEs produces excessive double-stranded RNAs, leading to the activation of viral mimicry response and downstream oncogenic interferon-stimulated genes. Inhibiting MXD1 expression can recover the drug vulnerability of trametinib-resistant PDAC cells to trametinib. Conclusions Our study has discovered an important mechanism for trametinib resistance and identified MXD1 as a druggable target in treatment of trametinib-resistant PDAC. Data are available on reasonable request. The raw data of the ATAC-seq and CUT & Tag-seq have been deposited in the Gene Expression Omnibus under accession code GSE253341. The raw data of scRNA-seq and RNA-seq have been deposited in the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences under accession number CRA014564 and HRA009296, respectively. The transcriptomic data and clinical information of the TCGA PAAD cohort and GTEx pancreas cohort were downloaded from the UCSC Xena data portal (). The gene boundaries were defined using the GENCODE annotations and the repeat boundaries were defined using the GTF file obtained from the Hammell lab website (downloaded from [https://labshare.cshl.edu/shares/mhammelllab/www-data/TEtranscripts/TE_GTF/GRCh38_GENCODE_rmsk_TE.gtf.gz][1]). All custom codes used to generate the data in this study are available uponon reasonable request. [1]: https://labshare.cshl.edu/shares/mhammelllab/www-data/TEtranscripts/TE_GTF/GRCh38_GENCODE_rmsk_TE.gtf.gz
{"title":"Targeting MXD1 sensitises pancreatic cancer to trametinib","authors":"Shaoping Zhang, Shuang Deng, Ji Liu, Shuang Liu, Ziming Chen, Shaoqiu Liu, Chunling Xue, Lingxing Zeng, Hongzhe Zhao, Zilan Xu, Sihan Zhao, Yifan Zhou, Xinyi Peng, Xiaoyu Wu, Ruihong Bai, Shaojia Wu, Mei Li, Jian Zheng, Dongxin Lin, Jialiang Zhang, Xudong Huang","doi":"10.1136/gutjnl-2024-333408","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333408","url":null,"abstract":"Background The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying trametinib resistance in PDAC remain unclear. Objective We aimed to illustrate the mechanisms of resistance to trametinib in PDAC and identify trametinib resistance-associated druggable targets, thus improving the treatment efficacy of trametinib-resistant PDAC. Design We established patient-derived xenograft (PDX) models and primary cell lines to conduct functional experiments. We also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing and Cleavage Under Targets and Tagmentation sequencing to explore the relevant molecular mechanism. Results We have identified a cancer cell subpopulation featured by hyperactivated viral mimicry response in trametinib-resistant PDXs. We have demonstrated that trametinib treatment of PDAC PDXs induces expression of transcription factor MAX dimerisation protein 1 (MXD1), which acts as a cofactor of histone methyltransferase mixed lineage leukaemia 1 to increased H3K4 trimethylation in transposable element (TE) loci, enhancing chromatin accessibility and thus the transcription of TEs. Mechanistically, enhanced transcription of TEs produces excessive double-stranded RNAs, leading to the activation of viral mimicry response and downstream oncogenic interferon-stimulated genes. Inhibiting MXD1 expression can recover the drug vulnerability of trametinib-resistant PDAC cells to trametinib. Conclusions Our study has discovered an important mechanism for trametinib resistance and identified MXD1 as a druggable target in treatment of trametinib-resistant PDAC. Data are available on reasonable request. The raw data of the ATAC-seq and CUT & Tag-seq have been deposited in the Gene Expression Omnibus under accession code GSE253341. The raw data of scRNA-seq and RNA-seq have been deposited in the Genome Sequence Archive in BIG Data Center, Beijing Institute of Genomics, Chinese Academy of Sciences under accession number CRA014564 and HRA009296, respectively. The transcriptomic data and clinical information of the TCGA PAAD cohort and GTEx pancreas cohort were downloaded from the UCSC Xena data portal (<https://xenabrowser.net>). The gene boundaries were defined using the GENCODE annotations and the repeat boundaries were defined using the GTF file obtained from the Hammell lab website (downloaded from [https://labshare.cshl.edu/shares/mhammelllab/www-data/TEtranscripts/TE_GTF/GRCh38_GENCODE_rmsk_TE.gtf.gz][1]). All custom codes used to generate the data in this study are available uponon reasonable request. [1]: https://labshare.cshl.edu/shares/mhammelllab/www-data/TEtranscripts/TE_GTF/GRCh38_GENCODE_rmsk_TE.gtf.gz","PeriodicalId":12825,"journal":{"name":"Gut","volume":"28 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-09DOI: 10.1136/gutjnl-2024-333492
Shannon Nicole Russell, Constantinos Demetriou, Giampiero Valenzano, Alice Evans, Simei Go, Tess Stanly, Ahmet Hazini, Frances Willenbrock, Alex Nicolas Gordon-Weeks, Somnath Mukherjee, Matthias Tesson, Jennifer P Morton, Eric O'Neill, Keaton Ian Jones
Background The immune suppression mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unknown, but preclinical studies have implicated macrophage-mediated immune tolerance. Hence, pathways that regulate macrophage phenotype are of strategic interest, with reprogramming strategies focusing on inhibitors of phosphoinositide 3-kinase-gamma (PI3Kγ) due to restricted immune cell expression. Inhibition of PI3Kγ alone is ineffective in PDAC, despite increased infiltration of CD8+ T cells. Objective We hypothesised that the immune stimulatory effects of radiation, and its ability to boost tumour antigen availability could synergise with PI3Kγ inhibition to augment antitumour immunity. Design We used orthoptic and genetically engineered mouse models of pancreatic cancer (LSL-KrasG12D/+;Trp53R172H/+;Pdx1-Cre). Stereotactic radiotherapy was delivered using contrast CT imaging, and PI3Kγ inhibitors by oral administration. Changes in the tumour microenvironment were quantified by flow cytometry, multiplex immunohistochemistry and RNA sequencing. Tumour-educated macrophages were used to investigate efferocytosis, antigen presentation and CD8+ T cell activation. Single-cell RNA sequencing data and fresh tumour samples with autologous macrophages to validate our findings. Results Tumour-associated macrophages that employ efferocytosis to eradicate apoptotic cells can be redirected to present tumour antigens, stimulate CD8+ T cell responses and increase local tumour control. Specifically, we demonstrate how PI3Kγ signalling restricts inflammatory macrophages and that inhibition supports MERTK-dependent efferocytosis. We further find that the combination of PI3Kγ inhibition with targeted radiotherapy stimulates inflammatory macrophages to invoke a pathogen-induced like efferocytosis that switches from immune tolerant to antigen presenting. Conclusions Our data supports a new immunotherapeutic approach and a translational rationale to improve survival in PDAC. Data are available upon reasonable request. All data needed to evaluate the conclusions in the paper are present in the paper and/or online supplemental materials. Sequencing data will be deposited in a public database (NCBI-GEO for transcriptomic) upon publication.
{"title":"Induction of macrophage efferocytosis in pancreatic cancer via PI3Kγ inhibition and radiotherapy promotes tumour control","authors":"Shannon Nicole Russell, Constantinos Demetriou, Giampiero Valenzano, Alice Evans, Simei Go, Tess Stanly, Ahmet Hazini, Frances Willenbrock, Alex Nicolas Gordon-Weeks, Somnath Mukherjee, Matthias Tesson, Jennifer P Morton, Eric O'Neill, Keaton Ian Jones","doi":"10.1136/gutjnl-2024-333492","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333492","url":null,"abstract":"Background The immune suppression mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain unknown, but preclinical studies have implicated macrophage-mediated immune tolerance. Hence, pathways that regulate macrophage phenotype are of strategic interest, with reprogramming strategies focusing on inhibitors of phosphoinositide 3-kinase-gamma (PI3Kγ) due to restricted immune cell expression. Inhibition of PI3Kγ alone is ineffective in PDAC, despite increased infiltration of CD8+ T cells. Objective We hypothesised that the immune stimulatory effects of radiation, and its ability to boost tumour antigen availability could synergise with PI3Kγ inhibition to augment antitumour immunity. Design We used orthoptic and genetically engineered mouse models of pancreatic cancer (LSL-KrasG12D/+;Trp53R172H/+;Pdx1-Cre). Stereotactic radiotherapy was delivered using contrast CT imaging, and PI3Kγ inhibitors by oral administration. Changes in the tumour microenvironment were quantified by flow cytometry, multiplex immunohistochemistry and RNA sequencing. Tumour-educated macrophages were used to investigate efferocytosis, antigen presentation and CD8+ T cell activation. Single-cell RNA sequencing data and fresh tumour samples with autologous macrophages to validate our findings. Results Tumour-associated macrophages that employ efferocytosis to eradicate apoptotic cells can be redirected to present tumour antigens, stimulate CD8+ T cell responses and increase local tumour control. Specifically, we demonstrate how PI3Kγ signalling restricts inflammatory macrophages and that inhibition supports MERTK-dependent efferocytosis. We further find that the combination of PI3Kγ inhibition with targeted radiotherapy stimulates inflammatory macrophages to invoke a pathogen-induced like efferocytosis that switches from immune tolerant to antigen presenting. Conclusions Our data supports a new immunotherapeutic approach and a translational rationale to improve survival in PDAC. Data are available upon reasonable request. All data needed to evaluate the conclusions in the paper are present in the paper and/or online supplemental materials. Sequencing data will be deposited in a public database (NCBI-GEO for transcriptomic) upon publication.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"75 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142939909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-07DOI: 10.1136/gutjnl-2024-334456
Douglas K Rex, John J Guardiola, Daniel von Renteln, Yuichi Mori, Prateek Sharma, Cesare Hassan
Computer-aided detection (CADe) has increased adenoma detection in randomised trials. However, unlike other detection adjuncts, CADe is lesion specific, that is, it is trained on a specific set of lesions. If the training does not include sufficient examples of precancerous lesion subsets, CADe may not perform adequately for lesions in that subset. In a prospective assessment of a second-generation CADe programme in 165 colonoscopies, we identified 26 flat lesions ≥10 mm in 17 patients. The endoscopist identified 22 of 26 lesions before the CADe programme. In 13 lesions, the CADe either generated no detection signal or only a signal over part of the lesion after colonoscope position or luminal inflation adjustment. Thus, the second-generation CADe algorithm, like the first generation, frequently fails to effectively detect large flat colorectal lesions, which are likely very important lesions that a CADe programme should identify. The first CADe programme to be launched commercially in the USA was GI Genius (Medtronic, Minneapolis, Minnesota, USA). We showed that this CADe programme failed to generate a detection signal disproportionately for large flat lesions, particularly large serrated lesions,1 though CADe appears to overall improve detection of sessile serrated lesions.2 A new Medtronic CADe programme termed ‘ColonPRO’ offers new artificial intelligence (AI)-based features with potential value including automatic measurement of the Boston Bowel Preparation Score and various procedure-related times. In an initial assessment of this new programme, we recorded the frequency of an AI-based signal for large (≥10 mm) flat lesions. We conducted the evaluation as a quality assessment. Permission to report the findings was granted by the Indiana University Institutional Review Board on 15 October 2024. In a single centre, after exclusion of patients with familial polyposis and inflammatory bowel disease, ColonPRO was activated throughout 165 consecutive colonoscopies. In the 165 study patients, 18 lesions referred …
{"title":"Detection of large flat colorectal lesions by artificial intelligence: a persistent weakness and blind spot","authors":"Douglas K Rex, John J Guardiola, Daniel von Renteln, Yuichi Mori, Prateek Sharma, Cesare Hassan","doi":"10.1136/gutjnl-2024-334456","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-334456","url":null,"abstract":"Computer-aided detection (CADe) has increased adenoma detection in randomised trials. However, unlike other detection adjuncts, CADe is lesion specific, that is, it is trained on a specific set of lesions. If the training does not include sufficient examples of precancerous lesion subsets, CADe may not perform adequately for lesions in that subset. In a prospective assessment of a second-generation CADe programme in 165 colonoscopies, we identified 26 flat lesions ≥10 mm in 17 patients. The endoscopist identified 22 of 26 lesions before the CADe programme. In 13 lesions, the CADe either generated no detection signal or only a signal over part of the lesion after colonoscope position or luminal inflation adjustment. Thus, the second-generation CADe algorithm, like the first generation, frequently fails to effectively detect large flat colorectal lesions, which are likely very important lesions that a CADe programme should identify. The first CADe programme to be launched commercially in the USA was GI Genius (Medtronic, Minneapolis, Minnesota, USA). We showed that this CADe programme failed to generate a detection signal disproportionately for large flat lesions, particularly large serrated lesions,1 though CADe appears to overall improve detection of sessile serrated lesions.2 A new Medtronic CADe programme termed ‘ColonPRO’ offers new artificial intelligence (AI)-based features with potential value including automatic measurement of the Boston Bowel Preparation Score and various procedure-related times. In an initial assessment of this new programme, we recorded the frequency of an AI-based signal for large (≥10 mm) flat lesions. We conducted the evaluation as a quality assessment. Permission to report the findings was granted by the Indiana University Institutional Review Board on 15 October 2024. In a single centre, after exclusion of patients with familial polyposis and inflammatory bowel disease, ColonPRO was activated throughout 165 consecutive colonoscopies. In the 165 study patients, 18 lesions referred …","PeriodicalId":12825,"journal":{"name":"Gut","volume":"16 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-03DOI: 10.1136/gutjnl-2024-333522
Ze-Rong Cai, Yong-Qiang Zheng, Yan Hu, Meng-Yao Ma, Yi-Jin Wu, Jia Liu, Lu-Ping Yang, Jia-Bo Zheng, Tian Tian, Pei-Shan Hu, Ze-Xian Liu, Lin Zhang, Rui-Hua Xu, Huai-Qiang Ju
Background and objective Gastric cancer (GC) remains a prevalent and preventable disease, yet accurate early diagnostic methods are lacking. Exosome non-coding RNAs (ncRNAs), a type of liquid biopsy, have emerged as promising diagnostic biomarkers for various tumours. This study aimed to identify a serum exosome ncRNA feature for enhancing GC diagnosis. Designs Serum exosomes from patients with GC (n=37) and healthy donors (n=20) were characterised using RNA sequencing, and potential biomarkers for GC were validated through quantitative reverse transcription PCR (qRT-PCR) in both serum exosomes and tissues. A combined diagnostic model was developed using LASSO-logistic regression based on a cohort of 518 GC patients and 460 healthy donors, and its diagnostic performance was evaluated via receiver operating characteristic curves. Results RNA sequencing identified 182 candidate biomarkers for GC, of which 31 were validated as potential biomarkers by qRT-PCR. The combined diagnostic score (cd-score), derived from the expression levels of four long ncRNAs (RP11.443C10.1, CTD-2339L15.3, LINC00567 and DiGeorge syndrome critical region gene (DGCR9)), was found to surpass commonly used biomarkers, such as carcinoembryonic antigen, carbohydrate antigen 19-9 (CA19-9) and CA72-4, in distinguishing GC patients from healthy donors across training, testing and external validation cohorts, with AUC values of 0.959, 0.942 and 0.949, respectively. Additionally, the cd-score could effectively identify GC patients with negative gastrointestinal tumour biomarkers and those in early-stage. Furthermore, molecular biological assays revealed that knockdown of DGCR9 inhibited GC tumour growth. Conclusions Our proposed serum exosome ncRNA feature provides a promising liquid biopsy approach for enhancing the early diagnosis of GC. Data are available in a public, open access repository. The raw sequence data generated in the screening phase have been deposited in the Genome Sequence Archive (GSA-Human: HRA008261) that are publicly accessible at .
{"title":"Construction of exosome non-coding RNA feature for non-invasive, early detection of gastric cancer patients by machine learning: a multi-cohort study","authors":"Ze-Rong Cai, Yong-Qiang Zheng, Yan Hu, Meng-Yao Ma, Yi-Jin Wu, Jia Liu, Lu-Ping Yang, Jia-Bo Zheng, Tian Tian, Pei-Shan Hu, Ze-Xian Liu, Lin Zhang, Rui-Hua Xu, Huai-Qiang Ju","doi":"10.1136/gutjnl-2024-333522","DOIUrl":"https://doi.org/10.1136/gutjnl-2024-333522","url":null,"abstract":"Background and objective Gastric cancer (GC) remains a prevalent and preventable disease, yet accurate early diagnostic methods are lacking. Exosome non-coding RNAs (ncRNAs), a type of liquid biopsy, have emerged as promising diagnostic biomarkers for various tumours. This study aimed to identify a serum exosome ncRNA feature for enhancing GC diagnosis. Designs Serum exosomes from patients with GC (n=37) and healthy donors (n=20) were characterised using RNA sequencing, and potential biomarkers for GC were validated through quantitative reverse transcription PCR (qRT-PCR) in both serum exosomes and tissues. A combined diagnostic model was developed using LASSO-logistic regression based on a cohort of 518 GC patients and 460 healthy donors, and its diagnostic performance was evaluated via receiver operating characteristic curves. Results RNA sequencing identified 182 candidate biomarkers for GC, of which 31 were validated as potential biomarkers by qRT-PCR. The combined diagnostic score (cd-score), derived from the expression levels of four long ncRNAs (RP11.443C10.1, CTD-2339L15.3, LINC00567 and DiGeorge syndrome critical region gene (DGCR9)), was found to surpass commonly used biomarkers, such as carcinoembryonic antigen, carbohydrate antigen 19-9 (CA19-9) and CA72-4, in distinguishing GC patients from healthy donors across training, testing and external validation cohorts, with AUC values of 0.959, 0.942 and 0.949, respectively. Additionally, the cd-score could effectively identify GC patients with negative gastrointestinal tumour biomarkers and those in early-stage. Furthermore, molecular biological assays revealed that knockdown of DGCR9 inhibited GC tumour growth. Conclusions Our proposed serum exosome ncRNA feature provides a promising liquid biopsy approach for enhancing the early diagnosis of GC. Data are available in a public, open access repository. The raw sequence data generated in the screening phase have been deposited in the Genome Sequence Archive (GSA-Human: HRA008261) that are publicly accessible at <https://ngdc.cncb.ac.cn/gsa-human>.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"72 1","pages":""},"PeriodicalIF":24.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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