Journal of Gastroenterology最新文献

Background: Intracellular calcium (Ca²⁺) signaling regulates key cancer processes. Research findings suggest that the SEC61 complex, involved in protein translocation, contributes to calcium leakage from the endoplasmic reticulum. However, the mechanism by which SEC61 Translocon Subunit Gamma (SEC61G), a component of this complex, influences colorectal cancer (CRC) progression remains unclear.

Methods: Bioinformatics analysis was performed using The Cancer Genome Atlas data sets to identify candidate genes on chromosome 7p, examine their association with DNA copy number amplification. In addition, SEC61G expression in CRC cells and tissues was validated using reverse-transcription quantitative polymerase chain reaction and immunohistochemistry. Moreover, in vitro and in vivo experiments were performed to investigate the effects of SEC61G overexpression and knockdown on CRC cell proliferation. Furthermore, publicly available single-cell RNA sequencing (scRNA-seq) and spatial transcriptome sequencing (ST-seq) data were used to validate the role of SEC61G in CRC.

Results: SEC61G was significantly upregulated in CRC tissues and was correlated with poor prognosis in patients with CRC. SEC61G overexpression enhanced cell proliferation and activated the EGFR pathway, promoting cell cycle progression from the G1 to S phase. In addition, SEC61G overexpression increased cytosolic Ca²⁺ levels, which activated EGFR signaling via calmodulin. Moreover, analyses of scRNA-seq and ST-seq data confirmed that SEC61G expression was higher in tumor epithelial cells and that it was co-expressed with EGFR pathway-related genes.

Conclusions: SEC61G promotes CRC progression by regulating cytosolic Ca²⁺ concentration, EGFR activation, and cell cycle progression, highlighting its potential as a prognostic biomarker and therapeutic target in CRC.

Background: Direct-acting-antivirals (DAAs) achieve high sustained-virologic response (SVR) rates, even in patients with hepatitis C virus (HCV)-related decompensated liver cirrhosis (LC). However, predictors of post-treatment liver function improvement and survival remain unclear. This study evaluated pretreatment angiopoietin-2 (Ang2) levels as a predictor of prognosis and liver functional reserve after DAA treatment.

Methods: This multicenter retrospective study included 123 patients with HCV-related decompensated LC treated with sofosbuvir/velpatasvir. Serum Ang2 levels were quantified, and liver function was assessed using the Child-Pugh grading at baseline and 12 weeks after the end of treatment (SVR12). Factors associated with prognosis and post-SVR liver functional reserve (Child-Pugh grade C) were investigated.

Results: Multivariate Cox regression analysis revealed that, in addition to age and creatinine levels at SVR12, baseline Ang2 levels (hazard ratio [HR] = 1.151 per 1000 pg/mL, P = 0.033) and Child-Pugh grade C at SVR12 (HR = 11.765, P < 0.001), but not baseline Child-Pugh grade C, were significantly associated with the overall survival. Multivariate analysis revealed that baseline Ang2 levels and baseline Child-Pugh grade C were significantly and independently associated with Child-Pugh grade C at SVR12. The combination of elevated baseline Ang2 levels (≥ 8684 pg/mL; 1 point) and baseline Child-Pugh grade C (1 point) effectively stratified patients with a high likelihood of having Child-Pugh Grade C at SVR12. The incidence rates were as follows: 0 points, 2.1% (2/96); 1 point, 37.5% (9/24); and 2 points, 100% (2/2) (P < 0.001).

Conclusions: Pretreatment Ang2 levels predict survival and liver functional reserve after SVR in HCV-related decompensated LC.

Background: Complete oncological local control is essential for a potential cure in patients with pancreatic ductal adenocarcinoma (PDAC), but predicting local recurrence following curative surgery remains clinically challenging. In this study, we performed comprehensive biomarker discovery to identify an Axon guidance-related miRNA panel (AGMP) for risk-stratification of perivascular plexus recurrence (PPR) following curative surgery in patients with PDAC.

Methods: To identify axon guidance-related microRNAs, we performed the pathway-miRNA interaction analysis using the miRPathDB2.0. Subsequently, the predictive performance of the miRNAs was trained and validated in three independent clinical surgically resected sample cohorts and one pretreatment blood sample cohort with different disease statuses [upfront surgery cohort: n = 162 (training: n = 103, internal validation: n = 59), neoadjuvant chemoradiotherapy (NACRT) cohort: n = 217, arterial invasion cohort: n = 62, pretreatment blood sample cohort: n = 53].

Results: The pathway-miRNA interaction analysis identified 13 miRNAs related to axon guidance pathway. Subsequently, we trained a 13-miRNA risk-prediction model, AGMP, which robustly distinguished PPR after surgery in the training cohort (AUC = 0.95). The AGMP was successfully validated in three independent cohorts (AUC: validation = 0.94, NACRT = 0.94, Arterial invasion = 0.90). Furthermore, we additionally validated the performance of AGMP in a pretreatment blood cohort, which again confirmed the robustness of risk-stratification for PPR (AUC = 0.86).

Conclusions: We developed a novel biomarker, AGMP that demonstrated remarkable predictive performance for PPR following curative surgery in patients with PDAC; highlighting the clinical importance of the nerve-cancer cross-talk and the hopefulness as a guidepost for designing future clinical and basic research to establish individualized treatment strategies.

Background: Inflammatory bowel disease (IBD) can occur at any age. In pediatric patients, the disease may present with a broader range of symptoms and more severe course than in adults, due to ongoing growth and development. Therefore, pediatric IBD often exhibits an atypical clinical course and laboratory findings. It is essential to recognize differences in disease presentation, differential diagnoses, and evaluation strategies specific to children. The revised Porto criteria, proposed by the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) in 2014, are widely used globally, including in Japan, for the diagnosis of pediatric IBD.

Purpose: Despite the widespread use of these criteria, no formal diagnostic guidelines for pediatric IBD have been developed in Japan. We aimed to support future guideline development by summarizing important diagnostic considerations and clinical practices for pediatric IBD in Japan.

Methods: This review was developed based on relevant international diagnostic guidelines and the expert opinions of Japanese pediatric gastroenterologists. It outlines key clinical and laboratory evaluations, as well as current treatment and follow-up approaches.

Results: We summarized recommended diagnostic tests and clinical points that require special attention in children with suspected IBD. The article reflects both global standards and domestic clinical experience.

Conclusion: Although this article does not provide formal diagnostic criteria or assess evidence levels, it offers accurate and practical information to guide physicians and patients in the diagnosis and management of pediatric IBD in Japan.

Long-term survival following a diagnosis of hepatocellular carcinoma (HCC) is greatly diminished when transplantation and surgical resection are ruled out. Fortunately, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced unresectable HCC (uHCC), prolonging median survival by over a year. T lymphocytes normally eliminate neoplastic cells, but some tumors suppress this response by binding to immune checkpoint receptors. Blocking this interaction via ICIs restores immune-mediated targeting of cancer cells. While ICI-based combination immunotherapy is currently recommended as the first-line systemic therapy for uHCC, the objective radiological response rate remains limited to 20-30%, as not all tumors exploit this mechanism. Consequently, strategies are being explored to modulate the immune microenvironment into a "hot" environment more responsive to ICIs by combining local therapies such as transarterial chemoembolization, ablation, and radiation therapy. Therapeutic options have also expanded beyond ICIs, emphasizing the importance of selecting the most appropriate treatment. Therefore, the development of biomarkers capable of predicting the efficacy of immunotherapy is a priority. Direct evaluation of immune cell infiltration through biopsy is currently the most effective method but involves issues such as invasiveness and susceptibility to sampling bias. In this review, we aim to highlight promising non-invasive biomarkers and scoring systems that have the potential to improve treatment outcomes, including blood-based biomarkers such as lymphocyte ratios, cytokines, C-reactive protein, and alpha-fetoprotein; imaging biomarkers such as MRI, ultrasound, and contrast-enhanced CT; and other clinical indicators such as sarcopenia, grip strength, and diversity of the gut microbiome.

Background: While the development in multimodal therapies has helped improve treatment outcomes for patients with locally advanced gastric adenocarcinoma (LAGC), there still exist disparities in opinion with an optimal treatment plan. This consensus hopes to provide clinicians with structured guidelines to aid in the decision-making for treatment options for LAGC.

Methods: The consensus statement was initiated by establishing a taskforce in collaboration with the Asia Pacific Gastroesophageal Cancer Congress (APGCC) and a multidisciplinary expert panel was selected. Clinical questions on LAGC where perceived variance in practice or opinion may exist were formulated. Studies involving patients with Stage 2 or 3 gastric or Siewert 3 junctional cancers with treatment arms of perioperative chemotherapy, neoadjuvant chemotherapy, adjuvant chemotherapy, immunotherapy and surgery were included. A total of two rounds of voting were performed. Consensus was determined to be reached when a single answer or a combination of either "strongly agree/agree" or "strongly disagree/disagree" responses exceeded 75%.

Results: A total of thirteen clinical questions were developed. They were identified through five main categories: Distal LAGC, Proximal LAGC, Deficient mismatch repair tumors, Chemotherapy and Immunotherapy, and Elderly/Unfit patients. After two rounds of voting by our multidisciplinary expert panel, eleven out of a total thirteen clinical questions had reached consensus. No consensus was reached for two clinical questions.

Conclusion: The APGCC consensus statement aims to guide clinicians in the treatment options for LAGC and Siewert 3 junctional cancer and has clarified some of the roles of perioperative chemotherapy and immunotherapy.

Background: A method for predicting ulcerative colitis (UC) onset has not been established. Serum autoantibodies have been suggested as potential predictive biomarkers for UC onset. We aimed to validate the risks associated with serological and environmental factors and construct a model for predicting UC development.

Methods: Using the population-based cohort studies (n > 83,000), we identified 42 individuals who were diagnosed with UC later in life and compared them with matched healthy controls. We analyzed serum anti-integrin αvβ6 antibody (anti-αvβ6) and anti-endothelial protein C receptor antibody (anti-EPCR) titers, and lifestyle and dietary habits to explore UC onset predictors. The predictive performance of the models was evaluated based on these predictors.

Results: The sensitivity and specificity of anti-EPCR for predicting UC onset were 51.4% and 97.8%, respectively, comparable to those of anti-αvβ6 (52.5% and 97.6%, respectively). The proportion of individuals with insomnia was significantly higher in the preclinical UC group (adjusted odds ratio = 2.14, 95% confidence interval [CI] 1.11-4.04, p = 0.019). The predictive performance of anti-EPCR alone was high with an area under the curve (AUC) of 0.89 (95%CI 0.83-0.96), and that of anti-EPCR combined with anti-αvβ6 was even better with an AUC of 0.92 (95%CI 0.87-0.97); the lifestyle model had lower predictive accuracy (AUC = 0.65, 95%CI 0.55-0.74).

Conclusions: Anti-EPCR and anti-αvβ6 each strongly predict UC onset. The combined anti-EPCR and anti-αvβ6 model had stronger predictive performance than the single models.

Background: Pancreatic cancer (PC) has a strong ability to invade and metastasize, which has brought insurmountable obstacles to the treatment of PC. Exploring the molecular mechanism of PC metastasis is still the focus of PC research. The purpose of this study was to explore the molecular mechanism of long noncoding RNA HNF1A-AS1 in promoting PC metastasis, hoping to provide help for the diagnosis and treatment of PC.

Methods: CRISPR/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA)-pooled lncRNA libraries were used to screen for the critical lncRNAs regulating PC metastasis. Investigation into HNF1A-AS1's impact on PC cell migration and invasion were conducted through both loss-of-function and gain-of-function approaches. A range of techniques, including fluorescence in situ hybridization (FISH), mRNA sequencing, bioinformatics analysis, dual-luciferase reporter assays, RNA pull-down assays, ChIP-PCR, and rescue assay to explore the regulatory mechanism of HNF1A-AS1 in PC metastasis.

Results: SNAI2 activates HNF1A-AS1 transcription. HNF1A-AS1 recruits U2SURP (RRM-dependent domain-dependent) through the 1001-1500 nt region (BR3) to form a functional complex (SNAI2-lncRNA HNF1A-AS1-U2SURP) within the nucleus of PC cells, specifically promoting alternative splicing of CD44 pre-mRNA, transforming it from standard isoform CD44s-CD44v (3-10) isoform, thereby promoting PC invasion and metastasis.

Conclusions: This study revealed for the first time that SNAI2 activates the transcription of HNF1A-AS1, and HNF1A-AS1 promote U2SURP to regulate the alternative splicing of CD44 pre-mRNA, causing it to produce a large number of CD44v (3-10) isoforms, thereby promoting the invasion and metastasis of PC.