Gastroenterology Report最新文献

Background: Gastric cancer (GC) is the fifth-leading cause of cancer-related mortality, with a 5-year survival rate less than 20%. It develops from preneoplastic lesions to adenocarcinoma, but these early genetic alterations remain poorly understood. Therefore, we aimed to identify early genetic drivers underlying the development of preneoplastic lesions and the initiation of gastric carcinogenesis.

Methods: We characterized preneoplastic and early gastric adenocarcinoma using 48 samples from 16 Guatemalan patients, a country with a high incidence of GC. We sequenced a panel of 127 genes to identify early genetic drivers and possible actionable targets.

Results: We identified extensive genetic heterogeneity, including single nucleotide and copy number variations. After comparing our data with other studies, we identified TP53 and APC as the most mutated genes in preneoplastic lesions and early GC. Our mean tumor mutational burden was higher in diffuse (0.017 mutations/Mb) and intestinal adenocarcinomas (0.015) than in chronic gastritis (0.005), and analysis of the mutational signatures revealed several processes acting at different stages of the disease. Signatures S15 (DNA mismatch repair deficiency) and S03 (homologous recombination deficiency) were more frequent in early adenocarcinoma than in chronic gastritis, intestinal metaplasia, necrosis, tubular adenoma, and atrophy. Notably, 10 of 16 patients (62.5%) had at least one actionable mutation in their preneoplastic lesions or gastric adenocarcinomas.

Conclusions: We show that at the preneoplastic and earliest stages, GC is genetically heterogeneous and presents key cancer-driving mutations that may participate in neoplastic transformation and progression, with 62.5% of lesions having the potential for treatment. This study expands the limited research on early GC and highlights key opportunities for precision medicine in populations with high GC incidence.

Alcohol-related liver disease (ALD) is a prevalent global health issue, contributing to significant mortality and encompassing a spectrum of liver damage from steatosis to decompensated cirrhosis and hepatocellular carcinoma. This review summarizes the current state of ALD, emphasizing both early and advanced stages, including alcohol-related hepatitis (AH). The epidemiology, diagnostic tools, natural history, and key progression factors of ALD are discussed, highlighting the role of diagnostic tools and pathways in early and advanced stages of ALD. The review also addresses the importance and particularities of the treatment of alcohol use disorder in patients with ALD, covering both psychological and pharmaceutical interventions. Finally, treatments for ALD-related fibrosis and AH are discussed, presenting both the currently available and future treatment options. The conclusions of this review underscore the need for comprehensive strategies to improve diagnosis, prognostic stratification, and treatment strategies at all stages of ALD.

Background: Transglutaminase 2 (TG2)-mediated enzymatic modification of gliadin peptides plays a major role in the pathogenesis of celiac disease (CD). Different inhibitory mechanisms have been reported to reduce TG2 activity but comparative data on the cellular level are lacking. Furthermore, recent evidence suggested that endogenous redox proteins such as endoplasmic reticulum resident protein 57 (ERp57, inhibits TG2) and thioredoxin-1 (TRX, activates TG2) may regulate TG2 activity. In this study, we aimed to compare the effects and applicability of different inhibitors on the activity of recombinant and cellular TG2. Furthermore, we investigated the role of ERp57 and TRX in the context of CD by using siRNA-mediated knockdown in Caco-2 cells.

Methods: The effect of TG2 inhibitors on recombinant and extracellular TG2 activity was investigated by using photometric and fluorometric quantitation of the cross-linking of biotinylated gliadin peptide P56-88 or 5-(biotinamido)-pentylamine. After siRNA knockdown, the protein levels of ERp57, TRX, and TG2 as well as TG2 activity were investigated by using Western blotting and fluorometry in Caco-2 cells.

Results: The active-site-directed inhibitors ERW1041, KCC009, and cysteamine as well as the allosteric inhibitor LDN27219 revealed the most prominent reduction in recombinant and cellular (35%-50%) TG2 activity. In contrast, PX12, S-Nitroso-N-acetyl-DL-penicillamine, zinc chloride, and ascorbic acid either did not affect TG2 activity or had only moderate effects at high doses close to cytotoxic concentrations. SiRNA knockdown of TG2 resulted in a prominent reduction (63%) in TG2 activity, whereas knockdown of ERp57 did not; knockdown of TRX only slightly (27%) reduced TG2 activity.

Conclusion: Active-site-directed inhibitors, LDN27219 and knockdown of TG2 expression significantly reduced extracellular TG2 activity and represent potential alternative treatment targets in the context of CD.

Background: Here, we aimed to identify the impact of the histamine (HA)-histamine receptor H2 (HRH2) signaling pathway on stimulating the secretion of hepatocyte growth factor (HGF) by cancer-associated fibroblasts (CAFs), as well as elucidating the mechanisms through which HGF promotes the progression of cholangiocarcinoma. In addition, our study has identified novel targets and investigated the potential use of Cimetidine and Capmatinib in cholangiocarcinoma.

Methods: Single-cell RNA sequencing revealed a noteworthy correlation between the expression of HRH2 and HGF in CAFs. HA was able to promote the transcription of HGF through the upregulation of the transcription factor hypoxia inducible factor 1 subunit alpha (HIF-1α), which was revealed by using in vitro/vivo experiments. That HGF promotes the progression of cholangiocarcinoma was identified by using orthotopic models and in vitro experiments.

Results: HRH2 and HGF were primarily expressed in CAFs within the tumor microenvironment of cholangiocarcinoma. HA sourced from mast cells could bind to the HRH2 receptor on CAFs, consequently upregulating HIF-1α and subsequently enhancing the transcription and secretion levels of HGF. HGF upregulates the phosphorylation of FOS-like 1 (FOSL1) within cholangiocarcinoma cells, promoting the expression of matrix metallopeptidase 10 (MMP10), and consequently enhancing the invasive and migratory abilities of cholangiocarcinoma cells.

Conclusions: The HA-HRH2 signaling pathway mediates the proliferation and secretion of HGF in CAFs. HIF-1α and FOSL1 played crucial roles in driving the proliferation, invasion, and migration of cholangiocarcinoma cells within the tumor microenvironment, orchestrated by CAFs. Furthermore, this study has provided theoretical support for the application of the HA receptor HRH2 inhibitor, Cimetidine, and the HGF receptor cellular mesenchymal-epithelial transition factor (c-MET) inhibitor, Capmatinib, in biliary tract tumors.

Background: Artificial intelligence-driven large language models demonstrate immense potential in the medical field. It remains unclear whether ChatGPT has the ability to provide appropriate recommendations for patients with inflammatory bowel disease (IBD) that are comparable to those of gastroenterologists. This study quantitatively assessed the performance of ChatGPT's generated IBD-related recommendations from the distinct perspectives of gastroenterologists and patients.

Methods: Healthcare questions regarding IBD were solicited from IBD patients and specialized physicians. Those questions were then presented to GPT-4 Omni and three independent senior gastroenterologists for responses. These responses were subsequently evaluated by a blinded panel of five board-certified gastroenterologists using a five-point Likert scale, assessing accuracy, completeness, and readability. Furthermore, 10 IBD patients as blinded assessors performed assessments of both ChatGPT's and gastroenterologists' responses.

Results: Thirty high-frequency questions were selected, encompassing basic knowledge, treatment, and management domains. ChatGPT demonstrated high reproducibility in responding to these questions. Regarding accuracy and readability, ChatGPT's performance was comparable to that of gastroenterologists. For completeness of responses, ChatGPT outperformed gastroenterologists (4.42 ± 0.67 vs 4.19 ± 0.65; P = 0.012). Overall, IBD patients were satisfied with both ChatGPT's and gastroenterologists' responses but, for treatment-related questions, patients rated gastroenterologists higher than ChatGPT (4.54 ± 0.32 vs 4.21 ± 0.38; P = 0.040).

Conclusions: ChatGPT has the potential to provide stable, accurate, comprehensive, and comprehensible healthcare-related information for IBD patients. Further validation of the reliability and practicality of large language models in real-world clinical settings is crucial.

Background: Incision and drainage (I&D) for perianal abscesses is associated with high rates of fistula formation. Our study aimed to evaluate the effectiveness of a novel technique, trans-intersphincteric double seton (TRISDS), designed to preserve anal sphincter integrity and improve clinical outcomes compared to I&D.

Methods: This prospective, randomized, non-blinded controlled study included adult patients with perianal abscesses located below the levator ani muscle with an internal opening. Patients were randomly assigned to either the TRISDS group (n = 55) or the I&D group (n = 51). The TRISDS technique involved two incisions: intersphincteric and drainage incisions with the placement of two loose setons. One seton was positioned to preserve the internal anal sphincter and facilitate drainage through the intersphincteric space, while the other seton aimed to protect the external anal sphincter to ensure comprehensive drainage. The I&D group underwent conventional I&D without damaging the anal sphincter complex. The primary outcome was the cure rate of perianal abscesses, which was defined as complete epithelialization of wounds without fistula or exudate and no recurrence within 12 months after surgery.

Results: The TRISDS group achieved a significantly higher cure rate of 78.2% (43/55) compared to 41.2% (21/51) in the I&D group (P < 0.05). There were no significant differences in anal function at 2 months postoperatively between the groups (median Wexner score, IQR: 1.0 [0.0-1.0] vs 1.0 [0.0-1.0], P > 0.05).

Conclusions: The study highlighted the effectiveness of TRISDS in improving cure rate without compromising anal function. The TRISDS technique represents a promising strategy for the treatment of perianal abscesses. Further multicenter studies are recommended to validate these findings and expand the application of TRISDS in diverse patient populations.

Colorectal cancer is one of the most prevalent malignant tumors worldwide, and it has one of the highest rates of mortality and morbidity. Its emergence and progression are intricately linked to various genetic and epigenetic factors influencing colonic epithelial cells. Long non-coding RNAs function as crucial regulators of the epigenetic landscape, playing significant roles in the development, progression, invasion, metastasis, and drug resistance of various tumors, particularly colorectal cancer. Epigenetic modifications, such as DNA methylation, RNA methylation, and histone modification, facilitate heritable gene expression regulation without changing the underlying DNA sequence. Recent studies have increasingly highlighted the intricate interactions between lncRNAs and these epigenetic modifications in colorectal cancer, illuminating their participation in critical processes, including cell proliferation, apoptosis, invasion, and metastasis. This review concentrates on the relationship between long non-coding RNAs and several significant epigenetic modifications that drive colorectal cancer development, offering fresh insights for future research that aims at devising more effective treatment strategies.

Background: The management of high complex anal fistulas has posed a significant challenge for surgeons. In this study, we presented a novel surgical procedure for managing high complex anal fistulas that combines core-out fistulectomy with suture repair of the external anal sphincter defect and endorectal advancement flap.

Methods: A cohort of patients with high complex anal fistulas undergoing core-out fistulectomy combined with suture repair of the external anal sphincter defect and endorectal advancement flap between December 2020 and December 2021 was reviewed retrospectively.

Results: The median age of the patients was 43 (range: 25-53) years. All patients had high transsphincteric fistulas. Two of the five cases involved recurrent anal fistulas. During the median follow-up period of 23 (range: 23-34) months, no recurrence events were observed in the cohort. Furthermore, it was noted that no patients developed anal incontinence after the operation.

Conclusion: Core-out fistulectomy combined with suture repair of the external anal sphincter defect and endorectal advancement flap is an effective procedure for the treatment of high complex anal fistulas.