[Posted 23/Nov/2022]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Identified and characterised a subpopulation of unconventional Crohn-associated invariant T (CAIT) cells. Multiple evidence suggests these cells to be part of the NKT type II population. The potential implications of this population for CD or a subset thereof remain to be elucidated, and the immunophenotype and antigen reactivity of CAIT cells need further investigations in future studies.

BACKGROUND: One of the current hypotheses to explain the proinflammatory immune response in IBD is a dysregulated T cell reaction to yet unknown intestinal antigens. As such, it may be possible to identify disease-associated T cell clonotypes by analysing the peripheral and intestinal T-cell receptor (TCR) repertoire of patients with IBD and controls.

DETAILS: Bulk TCR repertoire profiling of both the TCR alpha and beta chains was performed using high-throughput sequencing in peripheral blood samples of a total of 244 patients with IBD and healthy controls as well as from matched blood and intestinal tissue of 59 patients with IBD and disease controls. It was further characterised specific T cell clonotypes via single-cell RNAseq. Identified a group of clonotypes, characterised by semi-invariant TCR alpha chains, to be significantly enriched in the blood of patients with Crohn's disease (CD) and particularly expanded in the CD8+ T cell population. Single-cell RNAseq data showed an innate-like phenotype of these cells, with a comparable gene expression to unconventional T cells such as mucosal associated invariant T and natural killer T (NKT) cells, but with distinct TCRs.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Rosati, E., Rios Martini G., Pogorelyy, M. V., et al. (2022). A Novel Unconventional T Cell Population Enriched In Crohn's Disease. Gut. 2022; 71(11): 2194-2204. Published: November, 2022. DOI: XXXXXXXX.

Fluoropyrimidine Chemotherapy: Mortality and Cardiovascular Risk in Gastrointestinal Cancer

[Posted 4/Jul/2025]

AUDIENCE: Oncologists, Cardiologists, Cardio-Oncologists, and Researchers involved in the treatment of gastrointestinal cancers.

KEY FINDINGS:

• Fluoropyrimidine-based chemotherapy significantly reduced the absolute risk of all-cause mortality at 1 year (RD: -7.7%; 95% CI: -8.7% to -6.7%).
• There was a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%), primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%).
• No increased risk of acute coronary syndromes was observed, even in patients with pre-existing coronary artery disease.
• The substantial survival benefit of fluoropyrimidines in GI cancer patients outweighs the small risk of cardiac arrhythmia and arrest.

BACKGROUND: Fluoropyrimidine chemotherapy is a primary first-line treatment for many gastrointestinal cancers. However, concerns regarding its cardiotoxicity often lead to the use of alternative treatments in patients with pre-existing cardiovascular disease. This study aimed to quantitatively assess the risks of all-cause mortality and acute cardiovascular events associated with fluoropyrimidine treatment to inform clinical decision-making.

DETAILS: This observational cohort study utilized a target trial emulation framework with linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. The study included 103,110 adult patients (mean age 69.7 years, 59% male) diagnosed with tumors eligible for first-line fluoropyrimidine-based chemotherapy. Researchers compared all-cause mortality and a composite of hospitalization for acute cardiovascular events (including acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) between patients receiving fluoropyrimidine-based chemotherapy and those undergoing alternative management. The findings indicate that the improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer is a significant benefit that should encourage oncologists to avoid undue clinical conservatism, particularly when treating patients with co-existing cardiovascular disease.

Copyright © Authors. All rights reserved.

Source: Abiodun, A. T., Ju, C., Welch, C. A., et al. Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer. J Am Coll Cardiol CardioOnc.. 2025; 7(4): 345-356. Published: June, 2025. DOI: 10.1016/j.jaccao.2025.01.019.

[Posted 27/May/2025]

AUDIENCE: Gastroenterology, Ob/Gyn, Internal Medicine

KEY FINDINGS: Pregnancy MDC exposures may increase risk of liver injury and steatosis, particularly in children. Adequate FA supplementation and maternal cobalt levels may attenuate these associations.

BACKGROUND: Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on steatotic liver disease limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver outcomes, and effect modification by folic acid (FA) supplementation in mother-child pairs.

DETAILS: Authors studied ~200 mother-child pairs from the Mexican PROGRESS cohort, with 43 MDCs measured during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide metabolites), and serum liver enzymes (ALT, AST) at ~9 years post-parturition. Outcomes included elevated liver enzymes in children and established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian-weighted quantile sum regression assessed MDC-mixture associations with liver outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation. In children, many MDC-mixtures were associated with liver injury. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95% CI 1.67%, 19.4%) and AST by 5.27% (95% CI 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations (p-interactions <0.05). In mothers, only the LMWP-mixture was associated with odds for steatosis (odds ratio = 1.53, 95% CI 1.01-2.28 for HSI >36, and odds ratio 1.62, 95% CI 1.05-2.49 for AST:ALT <1). In mothers and children, most associations were attenuated (null) at FA supplementation >=600 µg/day (p-interactions <0.05).

Copyright © Elsevier Inc. All rights reserved.

Source: India-Aldana, S., Midya, V., Betanzos-Robledo, L., et al. Impact of Metabolism-Disrupting Chemicals and Folic Acid Supplementation on Liver Injury and Steatosis in Mother-Child Pairs. Journal of Hepatology. 2025; 82(6): 956-966. Published: June, 2025. DOI: 10.1016/j.jhep.2024.11.050 .

A Meta-analysis of Diagnostic Test Accuracy

[Posted 12/May/2025]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Study establishes evidence of the superior diagnostic accuracy of conventional SATs over rapid SATs for detecting H. pylori infection in adults. Also, authors provide valuable insights into the impact of using monoclonal or polyclonal antibodies and different assessment techniques on diagnostic accuracy measures.

BACKGROUND: The stool antigen test (SAT) is a convenient noninvasive option for the diagnosis of Helicobacter pylori (H. pylori) infection. However, despite having been previously evaluated, there is currently a lack of evidence regarding the comparative accuracy of conventional and rapid SATs utilizing monoclonal or polyclonal antibodies in adults. Here, authors perform a thorough statistical synthesis to determine and compare the diagnostic accuracy of conventional and rapid SATs for the diagnosis of H. pylori infection in adults.

DETAILS: Authors conducted independent searches through July 25, 2023, for studies evaluating the accuracy of SAT against a reference standard. Authors assessed methodological quality using Quality Assessment of Diagnostic Accuracy Studies-2 and calculated overall accuracy measures using the bivariate random-effect model. Authors also conducted subgroup analyses based on model and assessment technique, and Spearman correlation analysis to investigate a possible threshold effect. Authors generated summary receiver operating characteristic curves to assess heterogeneity and evaluated publication bias. Conventional SAT demonstrated superior sensitivity (92.19% vs 85.79%), specificity (92.93% vs 91.18%), likelihood ratios (LR+ 9.68 vs 8.16; LR- 0.10 vs 0.15), and area under the curve (0.958 vs 0.940) compared with rapid SAT. Notably, the diagnostic odds ratio for conventional SAT (114.70) significantly outperformed rapid SAT (diagnostic odds ratio: 57.72). Correlation analysis revealed no threshold effect and summary receiver operating characteristic curves showed consistent accuracy for both tests.

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Silva Luz, M., Tianeze de Castro, C., Bueno Lemos, F. F., et al. (20245). Stool Antigen Test for Helicobacter Pylori Infection in Adults: A Meta-analysis of Diagnostic Test Accuracy. Journal of Clinical Gastroenterology. 2025; 59(5): 393-404. Published: May/June 2025, 2025. DOI: 10.1097/MCG.0000000000002102.

[Posted 14/Mar/2025]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: IQGAP3 knockdown suppressed the RAS-TGFβ signalling crosstalk, leading to a significant reduction of the tumour microenvironment. In particular, IQGAP3 maintains functional heterogeneity of cancer cells to enhance malignant growth. IQGAP3 is thus a highly relevant therapy target in GC.

BACKGROUND: The elevation of IQGAP3 expression in diverse cancers indicates a key role for IQGAP3 in carcinogenesis. Although IQGAP3 was established as a proliferating stomach stem cell factor and a regulator of the RAS-ERK pathway, how it drives cancer growth remains unclear.

DETAILS: Goal of the study is to define the function of IQGAP3 in gastric cancer (GC) development and progression. Authors studied the phenotypic changes caused by IQGAP3 knockdown in three molecularly diverse GC cell lines by RNA-sequencing. In vivo tumorigenesis and lung metastasis assays corroborated IQGAP3 as a mediator of oncogenic signalling. Spatial analysis was performed to evaluate the intratumoral transcriptional and functional differences between control tumours and IQGAP3 knockdown tumours. Transcriptomic profiling showed that IQGAP3 inhibition attenuates signal transduction networks, such as KRAS signalling, via phosphorylation blockade. IQGAP3 knockdown was associated with significant inhibition of MEK/ERK signalling-associated growth factors, including TGFβ1, concomitant with gene signatures predictive of impaired tumour microenvironment formation and reduced metastatic potential. Xenografts involving IQGAP3 knockdown cells showed attenuated tumorigenesis and lung metastasis in immunodeficient mice. Accordingly, immunofluorescence staining revealed significant reductions of TGFβ/SMAD signalling and αSMA-positive stromal cells; digital spatial analysis indicated that IQGAP3 is indispensable for the formation of two phenotypically diverse cell subpopulations, which played crucial but distinct roles in promoting oncogenic functions.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Shimura, M., Matsuo, J., Pang, S.,et al. (2024). IQGAP3 Signalling Mediates Intratumoral Functional Heterogeneity to Enhance Malignant Growth. Gut. 2025; 74(3): 364-386. Published: March, 2025. DOI: 10.1136/gutjnl-2023-330390.

[Posted 6/Nov/2024]

AUDIENCE: Gastroenterology, Infectious Disease, Internal Medicine

KEY FINDINGS: The results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection.

BACKGROUND: New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression.

DETAILS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined. The HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line.

Copyright © Elsevier Inc. All rights reserved.

Source: McCoullough, L. C., Fareh, M., Hu, W., et al. (2024). CRISPR-Cas13b-mediated Suppression of HBV Replication and Protein Expression. Journal of Hepatology. 2024; 81(5): 794-805. Published: November, 2024. DOI: 10.1016/j.jhep.2024.05.025.