Digestion最新文献

Background: Colon cancer (CC) is a malignant tumor commonly found in the intestines with high incidence and mortality rates. Oxaliplatin (OXA) is a platinum-based chemotherapy drug widely used to treat CC. However, frequent drug resistance in patients results in suboptimal treatment outcomes. Though kinesin family member 4A (KIF4A) has been reported to be upregulated in various cancers and linked with poor prognosis in patients, its regulatory mechanism in cellular metabolism remains unclear.

Methods: The Human CC/OXA-resistant cell line (HCT116-R) was constructed. CCK-8 assay was employed to calculate the half-maximal inhibitory concentration (IC50) of CC cells. The level of cell stemness was assessed by cell sphere formation assay. The enrichment of KIF4A in signaling pathways of CC was analyzed through gene set enrichment analysis (GSEA). The bioinformatics analysis was applied to reveal the differential expression of KIF4A in CC and its correlation with genes related to stemness or glycolysis. The assessment of lactate in the supernatant was finished by utilizing the lactate detection kit. The oxidative phosphorylation and glycolysis levels in cells were measured by a Seahorse analyzer. The mRNA expression level of KIF4A was detected by quantitative real-time PCR. Furthermore, the western blot (WB) was employed to determine the protein expression of glycolysis-related enzymes in cells. A mouse OXA-resistant CC xenograft tumor model was established, with changes in tumor volume and final weight recorded. TUNEL was utilized to detect the apoptosis level in tissues and immunohistochemistry (IHC) to examine the distribution of KIF4A and ki-67 in tissues. The levels of stemness-related proteins in tissues were detected through WB.

Results: KIF4A was upregulated in CC, exhibiting a positive association with OXA resistance. High expression of KIF4A promoted cancer cell survival and cancer stemness. In GSEA prediction, KIF4A in CC may be linked with the glycolysis pathway. Correspondingly, the expression of KIF4A in CC was positively correlated with the expression of glycolysis-related proteins. Tests for lactate content and glycolysis/oxidative phosphorylation levels revealed that knocking down KIF4A repressed glycolytic function in the drug-resistant strain but reinforced mitochondrial oxidative phosphorylation. Furthermore, KIF4A overexpression effectively boosted the OXA resistance and stemness of cells, which was reversed by glycolysis inhibitor. The mouse model validated the above results.

Conclusion: KIF4A is significantly upregulated in CC to reinforce the glycolysis of cancer cells, thus facilitating cell stemness and resistance to OXA-based therapy.

Introduction, The activity of the mitogen insulin-like growth factor (IGF) is controlled by IGF-binding protein (IGFBP). Colorectal cancers (CRCs) are heterogeneous, with left- and right-sided CRC showing different clinical and molecular characteristics. This case-control study, nested in the Japan Collaborative Cohort study, assessed associations between serum levels of IGF-related molecules and incidences of CRC by location. Methods, A baseline survey obtained serum samples from 39,242 participants. Subjects diagnosed with CRC during follow-up were regarded as cases. Conditional logistic regression modeling was used to calculate odds ratios (ORs) for cancer incidence associated with IGF-related molecules. Results, This analysis included 176 cases and 524 controls. No IGF-related molecules appeared associated with risks of overall or left-sided CRC. Both total IGFBP3 and free IGFBP3 (estimated as IGFBP3-(IGF1+IGF2)) were associated with incidence of right-sided CRC (P-for-trends=0.027 and 0.003, respectively), with the third tertile of total and free IGFBP3 showing the highest risk (OR=6.25 and 7.96, respectively). Free IGF, estimated as (IGF1+IGF2)/IGFBP3, was inversely associated with incidence of right-sided CRC (P-for-trends=0.014), with the third tertile showing the lowest risk (OR=0.18). Among subjects followed for over 3 years, association of IGF-related molecules with overall CRC was similar. Free IGFBP3 was associated with incidence of right-sided CRC (P-for-trends=0.004). Free IGF was inversely associated with incidence of right-sided CRC (P-for-trends=0.002). However, free IGFs were associated with risk of left-sided CRC (P-for-trends=0.041), with the third tertile showing the highest risk (OR=3.10). Conclusions, Serum IGF-related molecules are associated with risk of CRC. These associations might differ by tumor location.

Background: In gastric endoscopic submucosal dissection (ESD), both vonoprazan alone and intravenous proton pump inhibitor (PPI) followed by vonoprazan have lower delayed bleeding risk than PPI alone. This study aimed to clarify an optimal acid-suppressive method in gastric ESD.

Methods: This population-based cohort study included patients who underwent gastric ESD on only vonoprazan (vonoprazan alone group) or intravenous PPI followed by vonoprazan (intravenous PPI group) using the Diagnosis Procedure Combination database in Japan between 2014 and 2021. The primary outcome was delayed bleeding. To balance the two comparison groups, propensity score matching (PSM), based on 18 variables, was performed; subsequently, to compare the bleeding outcome, logistic regression analysis was performed.

Results: Of 63,952 patients, 24,710 pairs were compared following PSM. The delayed bleeding risk in the vonoprazan alone group was similar to that in the intravenous PPI group (odds ratio [OR], 1.00; 95% confidence interval, 0.93-1.08; delayed bleeding rate, 5.9% vs. 5.9%). The results were consistent in some sensitivity and subgroup analyses; however, the result was modified by the status of antithrombotic agents (p for interaction = 0.029). In additional analyses, in patients with antithrombotic agent, the vonoprazan alone group had a higher delayed bleeding risk than the intravenous PPI group (OR, 1.15).

Conclusion: Both vonoprazan alone and intravenous PPI followed by vonoprazan might be acceptable in gastric ESD when antithrombotic agents were not administered, whereas intravenous PPI followed by vonoprazan might be favorable in patients with antithrombotic agents.

Background and aim: Proton pump inhibitors (PPIs) can lead to false-negative results in Helicobacter pylori stool antigen (HpSA) testing. A new bioluminescent enzyme immunoassay (BLEIA)-based HpSA test was introduced. This study aimed to evaluate the sensitivity of this test in patients on PPIs and compare its sensitivity with that of the enzyme immunoassay (EIA).

Methods: We included patients without a history of H. pylori eradication who were diagnosed as H. pylori-positive via culture, microscopy, rapid urease tests, urea breath tests, serum H. pylori antibody tests, or HpSA tests. The sensitivity of HpSA detection was compared among patients based on their PPI intake using both BLEIA and conventional EIA.

Results: Enrolment occurred from December 2020 to July 2022 across 10 facilities, with 109 patients enrolled in both the PPI and non-PPI groups. The sensitivity of BLEIA was 65.9% in the PPI group and 87.1% in the non-PPI group, showing a difference of -22.0% (95% CI: -11.0% to -32.9%) (P=0.0003). For EIA, the sensitivity was 54.1% in the PPI group and 72.4% in the non-PPI group, with a difference of -18.3% (95% CI: -5.5% to -30.4%) (P=0.0076). Significant differences in sensitivity were observed for both BLEIA and EIA between the PPI and non-PPI groups (p=0.005 and p<0.0001, respectively), with BLEIA demonstrating higher sensitivity.

Conclusions: This study indicated that the sensitivity of HpSA detection using BLEIA decreased under PPI administration. Additionally, BLEIA may have higher sensitivity than EIA.

Introduction: Recent studies indicate that the gut microbiota controls the host's immune system. Probiotics use different signaling pathways to regulate intestinal permeability, barrier integrity, and energy balance.

Methods: This research examined how Akkermansia muciniphila and its extracellular vesicles (EVs) impact inflammation and genes related to the endocannabinoid system in the STC-1 cell line through RT-PCR and ELISA assays.

Results: The study's results indicated that EVs had a significant impact on GLP-1 expression compared to the multiplicity of infections (MOI) ratio. Notably, there was a substantial increase in the expression of PYY and GLP-1 genes across all treatments (p < 0.05). Conversely, the expression of CB-1, CB-2, and FAAH genes notably decreased in the STC-1 cell line when treated with MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL (p < 0.05). Both MOI 50 of A. muciniphila and an EV concentration of 100 μg/mL significantly enhanced the expression of the TLR-2 gene. In contrast, EVs at a concentration of 100 μg/mL substantially reduced TLR-4 gene expression. A. muciniphila-derived EVs notably decreased the levels of inflammatory cytokines (TNF-α and IL-6), while increasing IL-10 expression at MOI 100 and an EV concentration of 100 μg/mL. These findings suggest that A. muciniphila and its EVs could regulate the expression of specific genes, serving as targets for maintaining host energy balance.

Conclusions: In summary, this study illustrates that A. muciniphila-derived EVs exhibit anti-inflammatory properties and have the potential to modulate gene expression in cases of obesity and gastrointestinal tract inflammation.

Introduction: Autoimmune gastritis (AIG), a type of chronic atrophic gastritis, is characterized by positive anti-parietal cell antibodies and mucosal atrophy predominantly in the corpus. In Japan, AIG has garnered increasing attention owing to the recent decline in Helicobacter pylori (HP) infection rates, leading to the proposal of diagnostic criteria. These criteria encompass serological test results, endoscopic findings, and histological findings, emphasizing the need for collaboration between endoscopists and pathologists to make an accurate diagnosis. In the present study, we aimed to clarify the annual number of patients with AIG diagnosed over the past 11 years and analyze their endoscopic and histological characteristics.

Methods: We retrospectively reviewed patients with AIG newly diagnosed at our institution between 2013 and 2023. Patients were categorized into the "prior endoscopically diagnosed group" (ED group) and the "prior pathologically diagnosed group" (PD group). The annual trend in AIG diagnosis was analyzed, and clinicopathological characteristics were compared between the groups.

Results: In total, 118 patients were diagnosed with AIG during the study period. The number of diagnoses increased after 2018, when a focused effort to identify AIG began, peaking in 2021 with 32 cases. All patients diagnosed before 2018 belonged to the ED group, but subsequent years saw increases in both groups of patients. The PD group had significantly more cases of coexisting gastric carcinoma (86.3% vs. 26.9%, p < 0.001) or HP-associated gastritis (72.4% vs. 32.8%, p = 0.002) than the ED group, whereas the ED group frequently exhibited typical endoscopic findings, such as atrophic gastritis predominantly in the corpus and adherent mucus.

Conclusion: Accurate diagnosis of AIG requires familiarity with the diagnostic criteria by endoscopists and pathologists. In cases complicated by gastric carcinoma or HP-associated gastritis, endoscopic findings alone may not suffice for diagnosis, underscoring the critical role of pathologists in interpreting histological findings.

Introduction: Assessing the malignancy of focal liver lesions (FLLs) is an important yet challenging aspect of routine patient care. Contrast-enhanced ultrasound (CEUS) has proved to be a highly reliable tool but is very dependent on the examiner's expertise. The emergence of artificial intelligence has opened doors to algorithms that could potentially aid in the diagnostic process. In this study, we evaluate the performance of a weakly supervised deep learning model in classifying FLLs as malignant or benign.

Methods: Our retrospective feasibility study was based on a cohort of patients from a tertiary care hospital in Germany undergoing routine CEUS examination to evaluate malignancy of FLL. We trained a weakly supervised attention-based multiple instance learning algorithm during 5-fold cross-validation to distinguish malignant from benign liver tumors, without using any manual annotations, only case labels. We aggregated the on-average best performing cross-validation cycle and tested this combined model on a held-out test set. We evaluated its performance using standard performance metrics and developed explainability methods to gain insight into the model's decisions.

Results: We enrolled 370 patients, comprising a total of 955,938 images extracted from CEUS videos or manually captured during the examination. Our combined model was able to identify malignant lesions with a mean area under the receiver operating curve of 0.844 in the cross-validation experiment and 0.94 (95% CI: 0.89-0.99) in the held-out test set. The accuracy, sensitivity, specificity, and F1-Score of the combined model in finding malignant lesions in the held-out test, yielded 80.0%, 81.8%, 84.6%, and 0.81, respectively. Our exploratory analysis using visual explainability methods revealed that the model appears to prioritize information that is also highly relevant to expert clinicians in this task.

Conclusion: Weakly supervised deep learning can classify malignancy in CEUS examinations of FLLs and thus might one day be able to assist doctors' decision-making in clinical routine.

Introduction: In recent years, the effect of "intestinal-hepatic axis" in tumorigenesis of hepatocellular carcinoma (HCC) has been paid more and more attention, and the imbalance of gut microbiota is closely related to the pathogenesis of HCC. The Xiayuxue decoction (XYXD) has inhibitory effect on hepatic fibrosis, but the effect of XYXD on HCC is not clear.

Methods: We induced HCC mouse model by diethylnitrosamine and CCL4. HCC mice were treated with XYXD gavage. Hematoxylin-eosin staining was used to detect the pathological changes of liver tissue in mice. Immunohistochemistry was used to detect the level of Ki-67 in liver tumor and ZO-1 in colon tissue. The level of inflammatory factors in plasma, liver, and colon tissue of mice was detected by ELISA. The changes of macrophages and neutrophils in colorectal tissues of mice were counted by immunofluorescence. 16S sequencing was used to analyze the effect of XYXD treatment on gut microbiota of HCC mice.

Results: Our study found that XYXD could inhibit the progress of HCC. XYXD upregulated the expression levels of ZO-1, occludin, and claudin in colon tissue to repair intestinal mucosal barrier. XYXD could alleviate the infiltration of intestinal immune cells in HCC mice by inhibiting the data of macrophages and neutrophils in colon tissue and downregulating SIgA level. XYXD also regulated the composition of intestinal microorganisms and improved the diversity of gut microbiota, thus affecting the progress of HCC.

Conclusion: XYXD inhibits the progress of HCC by influencing gut microbiota to regulate intestinal and liver inflammation and intestinal immune response.

Introduction: The mucin-rich variant of traditional serrated adenoma (MR-TSA), pathologically defined by the presence of goblet cells comprising over 50% of the lesion compared to the absorptive epithelial eosinophilic cytoplasm, was recently introduced as one morphological variants of traditional serrated adenoma (TSA). This study aimed to characterize the endoscopic and clinicopathological characteristics of MR-TSAs.

Methods: Lesions pathologically diagnosed as TSAs at our hospital between 2011 and 2023 were reviewed. We analyzed the endoscopic and clinicopathological features of 49 MR-TSAs and 236 conventional TSAs (C-TSAs). Furthermore, immunohistochemical and genetic analyses were performed to ensure that there were no discrepancies with our previous study.

Results: MR-TSAs, like C-TSAs, were often located in the sigmoid colon and rectum, with no significant difference in lesion size. Macroscopically, MR-TSAs frequently appeared as type 0-Is with a weak reddish color and had a mucous cap, less often exhibiting a pinecone-like or coral-shaped appearance compared to C-TSAs (p < 0.001). Magnifying endoscopy showed expanded crypt openings in 80% of MR-TSAs (p < 0.001). Both groups had similar IIIH and IVH pit patterns. Immunohistochemical analysis revealed that MUC5AC was expressed more frequently in MR-TSAs than in C-TSAs. Additionally, genetic analysis showed that MR-TSAs more frequently harbored the BRAF mutation than C-TSAs (p < 0.001), whereas MR-TSAs less frequently harbored the KRAS mutation than C-TSAs (p = 0.047).

Conclusion: MR-TSAs, frequently harboring the BRAF but not KRAS mutation, exhibited several distinct endoscopic findings, including a sessile morphology, lack of pinecone-like or coral-like appearance, weak reddish color, and mucous cap.

Introduction: Immunomodulating effects of Helicobacter pylori (H. pylori) have been shown to inhibit antitumor immunity. Resistance to immune checkpoint inhibitor (ICI)-based therapies is common among patients with hepatocellular carcinoma (HCC). This study aimed to assess the effect of H. pylori on the outcomes of ICI in patients with HCC.

Methods: We conducted a multicenter study in patients with HCC across a broad range of treatments. Patients received either ICI-based combination regimens or sorafenib-based therapy. H. pylori serostatus and virulence factors were determined and correlated with overall survival (OS), progression-free survival (PFS), and safety across the treatment modalities.

Results: 180 patients with HCC were included; among these, 64 were treated with ICI-based regimen and 116 with sorafenib-based regimen. In patients treated with ICI, median OS was shorter in H. pylori-positive patients (10.9 months in H. pylori-positive vs. 18.3 months; p = 0.0384). H. pylori positivity was associated with a shorter PFS in ICI recipients (3.9 months vs. 6.8 months, p = 0.0499). In patients treated with sorafenib, median OS was not shorter among H. pylori-positive patients (13.4 months in H. pylori-positive vs. 10.6 months; p = 0.3353). Immune-related adverse events and rates of gastrointestinal bleeding were comparable between H. pylori-positive and -negative patients.

Conclusion: H. pylori seropositivity was linked to poorer outcomes in patients with HCC treated with ICI. This association was not observed among patients receiving sorafenib-based therapies.