IPNet: An Interpretable Network with Progressive Loss for Whole-stage Colorectal Disease Diagnosis.

Colorectal cancer plays a dominant role in cancer-related deaths, primarily due to the absence of obvious early-stage symptoms. Whole-stage colorectal disease diagnosis is crucial for assessing lesion evolution and determining treatment plans. However, locality difference and disease progression lead to intra-class disparities and inter-class similarities for colorectal lesion representation. In addition, interpretable algorithms explaining the lesion progression are still lacking, making the prediction process a "black box". In this paper, we propose IPNet, a dual-branch interpretable network with progressive loss for whole-stage colorectal disease diagnosis. The dual-branch architecture captures unbiased features representing diverse localities to suppress intra-class variation. The progressive loss function considers inter-class relationship, using prior knowledge of disease evolution to guide classification. Furthermore, a novel Grain-CAM is designed to interpret IPNet by visualizing pixel-wise attention maps from shallow to deep layers, providing regions semantically related to IPNet's progressive classification. We conducted whole-stage diagnosis on two image modalities, i.e., colorectal lesion classification on 129,893 endoscopic optical images and rectal tumor T-staging on 11,072 endoscopic ultrasound images. IPNet is shown to surpass other state-of-the-art algorithms, accordingly achieving an accuracy of 93.15% and 89.62%. Especially, it establishes effective decision boundaries for challenges like polyp vs. adenoma and T2 vs. T3. The results demonstrate an explainable attempt for colorectal lesion classification at a whole-stage level, and rectal tumor T-staging by endoscopic ultrasound is also unprecedentedly explored. IPNet is expected to be further applied, assisting physicians in whole-stage disease diagnosis and enhancing diagnostic interpretability.

Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization.

Although deubiquitinases (DUBs) have been well described in liver tumorigenesis, their potential roles and mechanisms have not been fully understood. In this study, we identified ubiquitin-specific protease 1 (USP1) as an oncogene with essential roles during hepatocellular carcinoma (HCC) progression. USP1, with elevated expression levels and clinical significance, was identified as a hub DUB for HCC in multiple bioinformatics datasets. Functionally, USP1 overexpression significantly enhanced the malignant behaviors in HCC cell lines and spheroids in vitro, as well as the zebrafish model and the xenograft model in vivo. In contrast, genetic ablation or pharmacological inhibition of USP1 dramatically impaired the phenotypes of HCC cells. Specifically, ectopic USP1 enhanced aggressive properties and metabolic reprogramming of HCC cells by modulating mitochondrial dynamics. Mechanistically, USP1 induced mitochondrial fission by enhancing phosphorylation of Drp1 at Ser616 via deubiquitination and stabilization of cyclin-dependent kinase 5 (CDK5), which could be degraded by the E3 ligase NEDD4L. The USP1/CDK5 modulatory axis was activated in HCC tissues, which was correlated with poor prognosis of HCC patients. Furthermore, Prasugrel was identified as a candidate USP1 inhibitor for targeting the phenotypes of HCC by an extensive computational study combined with experimental validations. Taken together, USP1 induced malignant phenotypes and metabolic reprogramming by modulating mitochondrial dynamics in a CDK5-mediated Drp1 phosphorylation manner, thereby deteriorating HCC progression.

The safety and efficacy of endoscopic submucosal fenestration in the treatment of completely embedded upper gastrointestinal foreign body.

BACKGROUND: Upper gastrointestinal foreign body ingestion is a common digestive tract emergency, of which completely embedded ones were challenging for most endoscopists. We aim to evaluate the efficacy and safety of endoscopic submucosal fenestration in the treatment of completely embedded upper gastrointestinal foreign bodies. METHODS: From December 2018 to December 2021, 19 patients with completely embedded upper gastrointestinal foreign bodies who underwent endoscopic submucosal fenestration in Zhongshan Hospital, Fudan University were included. The safety, efficacy, and outcome were retrospectively reviewed. RESULTS: Among the 19 patients, 15 foreign bodies were embedded in the esophagus, 3 located in the gastric wall, and 1 located in the duodenal bulb. The foreign bodies were successfully managed in 12 cases, and 7 failed after attempts of repeated exploration. Two cases confirmed completely traversing into the mediastinum were successfully removed after transfer to surgery. One case had retrieval of a foreign body in a half-year examination. Till now, 3 failed patients had great relief of symptoms and only one patient claimed occasional thoracodynia. Of note, there were neither serious adverse events, nor long-term complications during the follow-up. CONCLUSION: In disposing of foreign bodies completely embedded in the upper gastrointestinal tract, ESF is a safe and effective alternative to surgery.

Long-term outcomes of endoscopic resection for well-differentiated nonampullary duodenal neuroendocrine tumors.

BACKGROUND AND AIMS: Nonampullary duodenal neuroendocrine tumors (NAD-NETs) are rare, with limited evidence regarding endoscopic treatment. This study investigated the efficacy and safety of endoscopic resection of well-differentiated NAD-NETs and evaluated long-term outcomes, including local recurrence and metastasis. METHODS: Seventy-eight patients with NAD-NETs who underwent endoscopic resection between January 2011 and August 2022 were included. Clinicopathologic characteristics and treatment outcomes were collected and analyzed. RESULTS: En-bloc resection was achieved for 74 tumors (94.9%) and R0 resection for 68 tumors (87.2%). Univariate analysis identified tumors in the second part of the duodenum, tumor size ≥10 mm, and muscularis propria invasion as risk factors for noncurative resection. Two patients with R1 resection (vertical margin involvement) and 2 patients with lymphovascular invasion underwent additional surgery. Four patients experienced adverse events (5.1%), including 2 cases of delayed bleeding and 2 cases of perforation, all successfully managed conservatively. During a median follow-up period of 62.6 months, recurrence and lymph node metastasis were only detected in 1 patient with R1 resection 3 months after the original procedure. CONCLUSIONS: Endoscopic resection is safe and effective and provides a favorable long-term outcome for patients with well-differentiated NAD-NETs without regional lymph node or distant metastasis.

Integrated analysis and validation of TRIM23/p53 signaling pathway in hepatic stellate cells ferroptosis and liver fibrosis.

BACKGROUND: Tripartite motif containing proteins 23(TRIM23) is identified as an E3 ubiquitin ligase involved in signal transduction, but its role in liver fibrosis remains unknown. AIMS: To investigate the effects and mechanisms of TRIM23 on hepatic stellate cells(HSCs) ferroptosis and liver fibrosis. METHODS: We utilized the Gene Expression Omibus database to identify differentially expressed genes and downstream pathways. TRIM23 expression was examined in fibrotic liver tissues. The effects of TRIM23 on HSCs ferroptosis were validated through assessing cell viability, lipid peroxidation, and ferroptotic markers using HSC-T6 cell lines and primary rat HSCs. Co-immunoprecipitation assays were conducted to analyze the interactions between TRIM23 and p53. A CCl4-induced liver fibrosis rat model was employed to confirm the in vivo effects. RESULTS: TRIM23 expression was positively correlated with the severity of liver fibrosis. Upregulated TRIM23 expression promoted HSCs viability and activation by attenuating ferroptosis. Furthermore, the upregulation of TRIM23 expression significantly enhanced p53 ubiquitination. In contrast, TRIM23 knockdown induced HSCs ferroptosis by regulating p53, leading to the suppression of cell viability and activation. Silencing TRIM23 led to the regression of liver fibrosis induced by CCl4 treatment in vivo. CONCLUSION: Our study uncovers a novel mechanism in which TRIM23 inhibits HSCs ferroptosis, promotes cell activation and contributes to liver fibrosis by regulating p53 ubiquitination.

A single-cell transcriptional landscape of immune cells shows disease-specific changes of T cell and macrophage populations in human achalasia.

Achalasia is a rare motility disorder of the esophagus caused by the gradual degeneration of myenteric neurons. Immune-mediated ganglionitis has been proposed to underlie the loss of myenteric neurons. Here, we measure the immune cell transcriptional profile of paired lower esophageal sphincter (LES) tissue and blood samples in achalasia and controls using single-cell RNA sequencing (scRNA-seq). In achalasia, we identify a pattern of expanded immune cells and a specific transcriptional phenotype, especially in LES tissue. We show C1QC+ macrophages and tissue-resident memory T cells (TRM), especially ZNF683+ CD8+ TRM and XCL1+ CD4+ TRM, are significantly expanded and localized surrounding the myenteric plexus in the LES tissue of achalasia. C1QC+ macrophages are transcriptionally similar to microglia of the central nervous system and have a neurodegenerative dysfunctional phenotype in achalasia. TRM also expresses transcripts of dysregulated immune responses in achalasia. Moreover, inflammation increases with disease progression since immune cells are more activated in type I compared with type II achalasia. Thus, we profile the immune cell transcriptional landscape and identify C1QC+ macrophages and TRM as disease-associated immune cell subsets in achalasia.

The role of type II esophageal microbiota in achalasia: Activation of macrophages and degeneration of myenteric neurons.

OBJECTIVE: The gut microbiota plays a critical role in the appropriate development and maintenance of the enteric nervous system (ENS). Esophageal achalasia (EA) is a rare motility disorder characterized by the selective degeneration of inhibitory neurons in the esophageal myenteric plexus. This study aimed to evaluate the composition of the esophageal microbiota in achalasia and explore the potential microbial mechanisms involved in its pathogenesis. DESIGN: The lower esophageal mucosal microbiota was analyzed in patients with achalasia and control participants using 16 S rRNA sequencing. The association between the esophageal microbiota and achalasia was validated by inducing esophageal dysbiosis in C57BL/10 J and C57BL/10ScNJ (TLR4KO) mice via chronic exposure to ampicillin sodium in their drinking water. RESULTS: The esophageal microbiota in EA patients had lower diversity and a predominance of Gram-negative bacteria (Type II microbiota) compared to that in the healthy controls. Additionally, the relative abundance of Rhodobacter decreased significantly in patients with achalasia, which correlated with an enrichment of lipopolysaccharide (LPS) biosynthesis based on the COG database. Antibiotic-treated mice showed an esophageal microbiota characterized by increased abundance of Gram-negative bacteria (Type II microbiome), decreased abundance of Rhodobacter, and enriched LPS biosynthesis. Compared to the control and TLR4KO mice, the antibiotic-treated wild-type mice had higher LES resting pressure, increased LES contraction rate after carbachol stimulation, and decreased relaxation response to L-arginine. Moreover, the number of myenteric neurons decreased, while the number of lamina propria macrophages (LpMs) increased after antibiotic exposure. Furthermore, the TLR4-MYD88-NF-κB pathway was up-regulated, and the production of TNF-α, IL-1ß, and IL-6 increased in the antibiotic-treated mice. CONCLUSIONS: Patients with achalasia exhibit esophageal dysbiosis, which may induce aberrant esophageal motility.

Endoscopic resection and suturing methods for non-ampullary duodenal submucosal tumors: "mini-invasive" treatments that should never be underestimated.

OBJECTIVE: To evaluate the effectiveness and safety of endoscopic resection and various suturing methods to treat non-ampullary duodenal submucosal tumors (NAD-SMTs). DESIGN: We performed a retrospective observational study of patients with NAD-SMTs who underwent endoscopic resection at Zhongshan Hospital, Fudan University, China, between June 2017 and December 2020. Data on patient characteristics, treatments and follow-up results were collected. The association between clinicopathologic characteristics and different suturing methods or adverse events were analyzed. RESULTS: Of 128 patients analyzed, 26 underwent endoscopic mucosal resection (EMR), 64 underwent endoscopic submucosal excavation (ESE), and 38 underwent endoscopic full-thickness resection (EFTR). EMR and ESR are both appropriate for non-full-thickness lesions, whereas ESE is more appropriate for tumors located in the bulb or descending duodenum. Gastric tube drainage is more strongly recommended after ESE. Satisfactory suturing is also vital endoscopic resection of NAD-SMTs. Metallic clips are often used in EMR or ESE of non-full-thickness lesions. The pathological findings revealed that the full-thickness lesions were predominantly gastrointestinal stromal tumors (GIST), Brunner's tumor or lipoma, and the surgeons usually used purse-string sutures to close the wounds. The operation time was longer for purse-string suture closure than metallic clip closure. Eleven patients had complications. Risk factors for adverse events included large-diameter tumor (≥ 2 cm), location in the descending part of the duodenum, involvement of the fourth layer of the duodenal wall, EFTR, and GIST. CONCLUSIONS: Endoscopic resection of NAD-SMTs is effective but is associated with a high incidence of complications due to their anatomical peculiarities. Preoperative diagnosis is quite important. Careful selection of treatment and suturing methods are necessary to reduce the risk of adverse effects. Given the increased frequency of severe complications during or following duodenal endoscopic resection, this procedure should be performed by experienced endoscopists.

System Analysis Based on Lipid-Metabolism-Related Genes Identifies AGT as a Novel Therapy Target for Gastric Cancer with Neoadjuvant Chemotherapy.

Gastric cancer (GC) is one of the most common causes of cancer-related deaths worldwide, and chemotherapy is still a standard strategy for treating patients with advanced GC. Lipid metabolism has been reported to play an important role in the carcinogenesis and development of GC. However, the potential values of lipid-metabolism-related genes (LMRGs) concerning prognostic value and the prediction of chemotherapy responsiveness in GC remains unclear. A total of 714 stomach adenocarcinoma patients were enrolled from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. Using univariate Cox and LASSO regression analyses, we developed a risk signature based on LMRGs that can distinguish high-GC-risk patients from low-risk patients with significant differences in overall survival. We further validated this signature prognostic value using the GEO database. The R package "pRRophetic" was applied to calculate the sensitivity of each sample from high- and low-risk groups to chemotherapy drugs. The expression of two LMRGs, AGT and ENPP7, can predict the prognosis and response to chemotherapy in GC. Furthermore, AGT significantly promoted GC growth and migration, and the downregulation of AGT enhanced the chemotherapy response of GC both in vitro and in vivo. Mechanistically, AGT induced significant levels of epithelial-mesenchymal transition (EMT) through the PI3K/AKT pathway. The PI3K/AKT pathway agonist 740 Y-P can restore the EMT of GC cells impaired by AGT knockdown and treatment with 5-fluorouracil. Our findings suggest that AGT plays a key role in the development of GC, and targeting AGT may help to improve the chemotherapy response of GC patients.