Journal of Gastroenterology最新文献

Background: Pancreatic fibrosis is the main pathological feature of chronic pancreatitis. There is a lack of medications that effectively alleviate or reverse pancreatic fibrosis and thus cure chronic pancreatitis.

Methods: We screened drugs that could alleviate pancreatic fibrosis from 80 traditional Chinese medicine monomers and verified their efficacy and mechanisms.

Results: We preliminarily identified corynoline as an antifibrotic candidate by drug screening among 80 compounds. In vitro, corynoline dose-dependently reduces collagen I synthesis in pancreatic stellate cells induced by TGF-β1 and inhibits its activation. Furthermore, we found that corynoline could alleviate the morphological disruption, such as acinar cell atrophy, collagen deposition etc., as well as reduced pancreatic weight in mice with chronic pancreatitis. We further validated the antifibrotic effect of corynoline in mRNA and protein levels. We also found that corynoline could inhibit NF-κB signaling pathway in vitro and in vivo. Next, we identified PSMA2 as the binding protein of corynoline by Lip-SMap and validated it using DARTS. Moreover, the siRNA of PSMA2 disrupts the anti-fibrotic effect of corynoline.

Conclusion: In conclusion, corynoline is a promising agent for the treatment of pancreatic fibrosis and chronic pancreatitis.

Background and aims: Inositol 1,4,5-trisphosphate receptor type 1 (IP₃R1) has been proposed to play a physiological role in regulating gastrointestinal (GI) motility, but the underlying cell-dependent mechanism remains unclear. Here, we utilized cell-specific IP₃R1 deletion strategies to address this question in mice.

Methods: Conditional IP₃R1 knockout mice using Wnt1-Cre, Islet1-Cre mice, and smMHC-Cre^EGFP were generated. Cell lineage tracing was performed to determine where gene deletion occurred in the GI tract. Whole-gut transit assay and isometric tension recording were used to assess GI function in vivo and in vitro.

Results: In the mouse GI tract, Islet1-Cre targeted smooth muscle cells (SMCs) and interstitial cells of Cajal (ICCs), but not enteric neurons. IP₃R1 deletion by Islet1-Cre (isR1KO) caused a phenotype of intestinal pseudo-obstruction (IPO), evidenced by prolonged whole-gut transit time, enlarged GI tract, abdominal distention, and early lethality. IP₃R1 deletion by Islet1-Cre not only reduced the frequency of spontaneous contractions but also decreased the contractile responses to the muscarinic agonist carbachol (CCh) and electrical field stimulation (EFS) in colonic circular muscles. By contrast, smMHC-Cre^EGFP only targeted SMCs in the mouse GI tract. Although IP₃R1 deletion by smMHC-Cre^EGFP (smR1KO) also reduced the contractile responses to CCh and EFS in colonic circular muscles, the frequency of spontaneous contractions was less affected, and neither global GI abnormalities nor early lethality was found in smR1KO mice.

Conclusions: IP₃R1 deletion in both ICCs and SMCs but not in SMCs alone causes an IPO phenotype, suggesting that IP₃R1 in ICCs plays an essential role in regulating GI motility in vivo.

Background: Subharmonic-aided pressure estimation (SHAPE) is a technique for determining changes in ambient pressure. We aimed to analyze a novel SHAPE integrated into ultrasound diagnostic equipment to predict patients with liver cirrhosis at high risk of esophagogastric varices (EV).

Methods: This prospective study included 111 patients with liver cirrhosis diagnosed between 2020 and 2023. We obtained liver stiffness measurements (LSM) and spleen stiffness measurements (SSM) using shear wave elastography and hepatic vein-portal vein (HV-PV) gradient using the SHAPE method. The EV risk was determined either as null, low, or high by esophagoscopy and Child-Pugh stage.

Results: HV-PV gradient increased concordantly with the increase in EV risk (- 7.0 dB in null-risk, - 4.4 dB in low-risk, and - 2.0 dB in high-risk) with statistically significant difference among any two groups. The most appropriate cut-off value of the HV-PV gradient was - 3.5 dB, and sensitivity, specificity, and positive and negative predictive values were 80.0%, 89.0%, 80.0%, and 88.0%, respectively. The areas under the curve values for predicting the high-risk EV were 0.920, 0.843, and 0.824 for the HV-PV gradient, LSM, and SSM, respectively.

Conclusions: The novel SHAPE system demonstrated high accuracy in identifying patients with liver cirrhosis at a high risk of EV.

Background: Prophylactic chemoradiation therapy (CRT) using 40-41.4 Gy post-endoscopic submucosal dissection (ESD) for clinical T1N0M0 esophageal cancer reportedly yields favorable outcomes. However, it cannot completely prevent locoregional lymph node (LN) metastases. We retrospectively analyzed outcomes and adverse events associated with our dose-escalated treatment regimen (definitive-dose radiotherapy [RT] of 50-61.2 Gy, with/without chemotherapy) for these patients, and predictors of progression-free survival (PFS) and overall survival (OS).

Methods: Between 2006 and 2018, 44 consecutive patients (42 men and 2 women; median age, 70 years) who underwent definitive-dose RT post-ESD and had a pathological depth of the muscularis mucosa with lymphovascular invasion (LVI) or the upper-middle submucosal third at our institution were included. We excluded patients who could not obtain a margin-free resection by ESD. If feasible, systemic chemotherapy with 5-fluorouracil plus high- or low-dose cisplatin or nedaplatin was administered concurrently.

Results: Five-year PFS, OS, and disease-specific survival rates were 78.8%, 88.4%, and 97.7%, respectively. Six metachronous esophagus (14%), two locoregional LN within the irradiated area with a prophylactic dose of 41.4 Gy (5%), and two locoregional LN plus liver (5%) recurrences occurred. No LN recurrence occurred within the definitive dose of ≥ 50 Gy in the irradiated area. Metachronous esophageal recurrence involved areas receiving ≥ 50 Gy. Univariate and multivariate analyses revealed that age was an independent prognostic factor for both PFS and OS.

Conclusions: Definitive-dose RT/CRT post-ESD could provide favorable locoregional LN control and PFS/OS regardless of patient characteristics, including pathological findings and chemotherapy regimen/course, except for age. These results need to be interpreted carefully given several limitations, therefore, definitive-dose RT/CRT should be conducted with caution in clinical practice until high-quality prospective clinical trials evaluating the effectiveness and safety.

Background: Fecal immunochemical tests are commonly performed for colorectal cancer screening. Instant fecal occult blood measurement in toilet bowel movements would improve convenience. Hyperspectral imaging (HSI) enables the nondestructive evaluation of materials that are difficult to assess visually. This study aimed to determine whether HSI could be used to identify fecal occult blood on stool surfaces.

Methods: The study included 100 patients who underwent colonoscopy, divided into groups A and B (50 patients, each) for creating a discriminant algorithm and validating the accuracy of the algorithm, respectively. In group A, 100 areas were randomly selected from the stool surface, and the fecal occult blood quantitative values were measured and photographed using a hyperspectral camera (cutoff: > 400 ng/mL). A discriminant algorithm image was created to extract spectral feature differences obtained from HSI via machine learning. In group B, 250 random areas were evaluated and compared to fecal occult blood quantitative values, measuring sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV).

Results: Groups A and B comprised 28 and 26 patients with cancer, respectively. Cancer detection sensitivity at the 400 ng/mL cutoff was 67.9% and 42.3% in groups A and B, respectively. The discriminant algorithm image exhibited high accuracy in group A (sensitivity; 77.1%, specificity; 96.9%, accuracy; 90.0%, PPV; 93.1%, NPV; 88.7%). In group B, the sensitivity, specificity, accuracy, PPV, and NPV were 83.3, 92.9, 90.8, 76.3, and 95.3%, respectively.

Conclusion: HSI can effectively discriminate high quantitative fecal occult blood, highlighting its potential for improved colorectal cancer screening.

Background: The effects of age at HBsAg seroclearance on clinical outcomes and survival in chronic hepatitis B (CHB) have not been adequately assessed. We evaluated the impact of age at HBsAg seroclearance on long-term outcomes, along with how coexisting factors modified risks and life expectancy in CHB patients.

Methods: We used multi-state modeling approach to examine transitions through the CHB continuum in a longitudinal cohort study of male civil servants recruited in 1989-1992. Hepatic outcomes and deaths were identified by clinical evaluation and linkage with national health databases. Four sets of risk factors (CHB-related, metabolic, lifestyle, and genetic factors) were assessed.

Results: Of 2551 HBsAg carriers, with follow-up until 2021 or death, 695 achieved HBsAg seroclearance, 490 developed cirrhosis (88 decompensated), 252 developed hepatocellular carcinoma (HCC), and 652 died. The cumulative rates for HCC were 1.1% and 1.5% at 10 years after HBsAg seroclearance, respectively, for patients achieving seroclearance at age 50 and 60; correspondingly, the rates for cirrhosis were 2.3% and 3.0%. Developing HBsAg seroclearance was associated with a reduced risk of cirrhosis (HR = 0.37, 95% CI 0.15-0.92) but not HCC. Patients experiencing HBsAg seroclearance lived longer years free of major liver diseases than HBsAg-persistent patients, and achieving seroclearance at age 50 (vs 60) led to a greater increase in the disease-free life expectancy. However, obesity and smoking were associated with adverse hepatic outcomes and loss of the disease-free life expectancy following HBsAg seroclearance.

Conclusions: Our findings highlight the benefit of earlier HBsAg seroclearance for gains in disease-free life expectancy and the impact of obesity and smoking on loss of the life years free of major liver diseases following HBsAg seroclearance.

Background: Covert hepatic encephalopathy (CHE) significantly impacts the quality of life and prognosis in patients with liver cirrhosis. This study aims to analyze the prevalence and risk factors of CHE to identify high-risk patients who would benefit from therapeutic interventions.

Methods: This single-center, retrospective observational study included 126 patients without a history of overt hepatic encephalopathy (OHE). CHE was defined as a score above the age-based cutoff value in the Stroop test. Factors associated with the occurrence of CHE and the subsequent development of OHE were evaluated.

Results: CHE was detected in 47 patients (37.3%). A multiple logistic regression analysis identified serum zinc levels (per + 1 µg/dL, odds ratio 0.95, P = 0.0007) as the only risk factor associated with CHE, with a cutoff value of 60 µg/dL (AUC 0.71, P = 0.0001). Neither blood ammonia levels nor liver function were predictive of CHE. During a median observation period of 211 days, OHE developed in 18 patients (14.3%). The administration of more than 20 mg of furosemide was identified as a risk factor for developing OHE (hazard ratio 23.52, P = 0.0207).

Conclusion: Cirrhotic patients with serum zinc levels below 60 µg/dL exhibit a high risk of developing CHE, regardless of blood ammonia levels. These patients face a significant risk of developing OHE. Therefore, early zinc supplementation is recommended for the prevention of OHE, particularly for those prescribed 20 mg or more of furosemide.

Background: An artificial intelligence-based algorithm we developed, mrAI, satisfactorily segmented the rectal tumor, rectum, and mesorectum from MRI data of rectal cancer patients in an initial study. Herein, we aimed to validate mrAI using an independent dataset.

Methods: We utilized MRI images collected in another nationwide research project, "Open versus Laparoscopic Surgery for Advanced Low Rectal Cancer Patients". MRIs from 467 cases with upfront surgery were utilized; six radiologists centralized the MRI evaluations. The diagnostic accuracies of mrAI and the radiologists for tumor depth were compared using pathologic diagnosis as a reference.

Results: For all cases, centralized diagnosis demonstrated 84.2% sensitivity, 37.7% specificity, and 73.7% accuracy; mrAI exhibited 70.6% sensitivity, 61.3% specificity, and 68.5% accuracy. After limiting MRIs to those acquired by a Philips scanner, with an inter-slice spacing of ≤ 6 mm-both conditions similar to those used in the development of mrAI-the performance of mrAI improved to 76.8% sensitivity, 76.7% specificity, and 76.7% accuracy, while the centralized diagnosis showed 81.8% sensitivity, 36.7% specificity, and 71.3% accuracy. Regarding relapse-free survival, the prognosis for tumors staged ≥ T3 was significantly worse than for tumors staged ≤ T2 (P = 0.0484) in the pathologic diagnosis. While no significant difference was observed between ≥ T3 and ≤ T2 tumors in the centralized diagnosis (P = 0.1510), the prognosis for ≥ T3 was significantly worse in the mrAI diagnosis (P = 0.0318).

Conclusion: Proper imaging conditions for MRI can enhance the accuracy of mrAI, which has the potential to provide feedback to radiologists without overestimating tumor stage.

Background: Wilson's disease (WD) is a rare condition resulting from autosomal recessive mutations in ATP7B, a copper transporter, manifesting with hepatic, neurological, and psychiatric symptoms. Timely diagnosis and appropriate treatment yield a positive prognosis, while delayed identification and/or insufficient therapy lead to a poor outcome. Our aim was to establish a prognostic method for WD by characterising biomarkers based on circulating microRNAs.

Methods: We conducted investigations across three cohorts: discovery, validation (comprising unrelated patients), and follow-up (revisiting the discovery cohort 3 years later). All groups were compared to age- and gender-matched controls. Plasma microRNAs were analysed via RNA sequencing in the discovery cohort and subsequently validated using quantitative PCR in all three cohorts. To assess disease progression, we examined the microRNA profile in Atp7b^-/- mice, analysing serum samples from 6 to 44 weeks of age and liver samples at three time points: 20, 30, and 40 weeks of age.

Results: In patients, elevated levels of the signature microRNAs (miR-122-5p, miR-192-5p, and miR-885-5p) correlated with serum activities of aspartate transaminase, alanine aminotransferase and gamma-glutamyl transferase. In Atp7b^-/- mice, levels of miR-122-5p and miR-192-5p (miR-885-5p lacking a murine orthologue) increased from 12 weeks of age in serum, while exhibiting fluctuations in the liver, possibly attributable to hepatocyte regenerative capacity post-injury and the release of hepatic microRNAs into the bloodstream.

Conclusions: The upregulation of the signature miR-122-5p, miR-192-5p, and miR-885-5p in patients and their correlation with liver disease progression in WD mice support their potential as biomarkers of WD.