Dual-/multi-organelle-targeted AIE probes associated with oxidative stress for biomedical applications.

In situ monitoring of biological processes between different organelles upon oxidative stress is one of the most important research hotspots. Fluorescence imaging is especially suitable for biomedical applications due to its distinct advantages of high spatiotemporal resolution, high sensitivity, non-invasiveness, and in situ monitoring capabilities. However, most fluorescent probes can only achieve light-up imaging of single organelles, thus the combined use of two or more probes is usually required for monitoring biological processes between organelles, which can suffer from tedious staining and washing procedures, increased cytotoxicity and poor photostability. Exogenetic oxidants can affect broad-spectrum subcellular organelles, which are not conducive to in situ monitoring of biological processes between specific organelles. To tackle these challenges, a series of dual-/multi-organelle-targeted aggregation-induced emission (AIE) probes associated with oxidative stress have been designed and developed in the past few years. Herein, the recent progress of these AIE probes is summarized in biomedical applications, such as apoptosis monitoring, interplay between organelles, microenvironmental changes of organelles, organelle morphology tracking, precise cancer therapy, and so forth. Moreover, the further outlook for dual-/multi-organelle-targeted AIE probes is discussed, aiming to promote innovative research in biomedical applications.

ALOX5 acts as a key role in regulating the immune microenvironment in intrahepatic cholangiocarcinoma, recruiting tumor-associated macrophages through PI3K pathway.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is poorly treated due to the presence of an inhibitory immune microenvironment. Tumor-associated macrophages (TAM) are an important component of TME. ALOX5 is an important lipid metabolism enzyme in cancer progression, but the mechanism by which it regulates TAM to promote ICC progression is unknown. The aim of this study was to investigate the potential mechanism of TAM regulation by ALOX5 and the translational effect of targeting ALOX5. METHODS: In this study, we investigated the association between the spatial localization of epithelial cells and TAMs by combining scRNA-seq analysis with multiplex immunofluorescence analysis. Through bulk sequencing analysis and spatial analysis, lipid metabolism genes closely related to TAM infiltration were screened. In vitro co-culture model was constructed to verify that ALOX5 and its downstream metabolite LTB4 promote M2 macrophage migration. Bulk sequencing after co-culture combined with single-cell analysis was performed to identify key pathways for up-regulation of M2 macrophage migration. Finally, the effect of CSF1R inhibitor (PLX3397) combined with ALOX5 inhibitor (Zileuton) in vivo was investigated by by xenograft tumor formation experiment in nude mice. RESULTS: ALOX5 in ICC cells was a key lipid metabolism gene affecting the infiltration of M2 macrophages in TME. Mechanically, LTB4, a metabolite downstream of ALOX5, recruited M2 macrophages to migrate around tumor cells by binding to BLT1/BLT2 and activating the PI3K pathway, which ultimately lead to the promotion of ICC progression. Targeting CSF1R in combination with ALOX5 inhibitor effectively reduced tumor volume and M2 macrophage infiltration abundance. CONCLUSION: In ICC, LTB4, a metabolite secreted by ALOX5 of epithelial cells, binded to BLT1/BLT2 on TAM surface to activate PI3K pathway and promote TAM migration, thus promoting ICC progression. Targeting CSF1R in combination with ALOX5 inhibitor for ICC is a promising combination therapy modality.

Disruption of cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis alleviates liver fibrosis.

B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-ß signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-ß or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.

C-C motif chemokine receptor 2 inhibition reduces liver fibrosis by restoring the immune cell landscape.

The accumulation of extracellular matrix (ECM) proteins in the liver leads to liver fibrosis and end-stage liver cirrhosis. C-C motif chemokine receptor 2 (CCR2) is an attractive target for treating liver fibrosis. However, limited investigations have been conducted to explore the mechanism by which CCR2 inhibition reduces ECM accumulation and liver fibrosis, which is the focus of this study. Liver injury and liver fibrosis were induced by carbon tetrachloride (CCl4) in wild-type mice and Ccr2 knockout (Ccr2-/-) mice. CCR2 was upregulated in murine and human fibrotic livers. Pharmacological CCR2 inhibition with cenicriviroc (CVC) reduced ECM accumulation and liver fibrosis in prevention and treatment administration. In single-cell RNA sequencing (scRNA-seq), CVC was demonstrated to alleviate liver fibrosis by restoring the macrophage and neutrophil landscape. CVC administration and CCR2 deletion can also inhibit the hepatic accumulation of inflammatory FSCN1+ macrophages and HERC6+ neutrophils. Pathway analysis indicated that the STAT1, NFκB, and ERK signaling pathways might be involved in the antifibrotic effects of CVC. Consistently, Ccr2 knockout decreased phosphorylated STAT1, NFκB, and ERK in the liver. In vitro, CVC could transcriptionally suppress crucial profibrotic genes (Xaf1, Slfn4, Slfn8, Ifi213, and Il1ß) in macrophages by inactivating the STAT1/NFκB/ERK signaling pathways. In conclusion, this study depicts a novel mechanism by which CVC alleviates ECM accumulation in liver fibrosis by restoring the immune cell landscape. CVC can inhibit profibrotic gene transcription via inactivating the CCR2-STAT1/NFκB/ERK signaling pathways.

STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome.

The activation of stimulator of interferon genes (STING) and NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnections between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown. STING and NLRP3 inflammasome signaling pathways are activated in fibrotic livers but are suppressed by Sting knockout. Sting knockout ameliorated hepatic pyroptosis, inflammation, and fibrosis. In vitro, STING induces pyroptosis in primary murine hepatocytes by activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) are identified to regulate NLRP3 expression in STING-overexpressing AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhances interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promotes STING-induced Nlrp3 transcription in hepatocytes. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gasdermin D (Gsdmd) knockout attenuate hepatic pyroptosis, inflammation, and fibrosis. RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes show that oxidative stress and metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. The STING-NLRP3-GSDMD axis inhibition suppresses hepatic ROS generation. In conclusion, this study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

Proangiogenic role of circRNA-007371 in liver fibrosis.

Circular RNAs (circRNAs) are crucially involved in cancers as competing endogenous RNA (ceRNA) or microRNA (miRNA) sponges. However, the function and mechanism of circRNAs in liver fibrosis remain unknown and are the focus of this study. Murine fibrotic models were induced by thioacetamide (TAA) or carbon tetrachloride (CCl4 ). Increased angiogenesis is accompanied by liver fibrosis in TAA- and CCl4 -induced murine fibrotic livers. circRNA microarray and argonaute 2 (AGO2)-RNA immunoprecipitation (RIP) sequencing (AGO2-RIP sequencing) were performed in murine livers to screen for functional circRNAs. Compared to control livers, 86 differentially expressed circRNAs were obtained in TAA-induced murine fibrotic livers using circRNA microarray. In addition, 551 circRNAs were explored by AGO2-RIP sequencing of murine fibrotic livers. The circRNA-007371 was then selected and verified for back-spliced junction, resistance to RNase R, and loop formation. In vitro, murine hemangioendothelioma endothelial (EOMA) cells were transfected with circRNA-007371 overexpressing plasmid or empty plasmid. circRNA-007371 overexpression promoted tube formation, migration, and cell proliferation of EOMA cells. RNA sequencing and miRNA sequencing were then performed to explore the mechanism of the proangiogenic effects of circRNA-007371. circRNA-007371 promotes liver fibrosis via miRNA sponges or ceRNA mechanisms. Stag1, the parent gene of circRNA-007371, may play a significant role in proangiogenic progression. In conclusion, circRNA-007371 enhances angiogenesis via a miRNA sponge mechanism in liver fibrosis. The antiangiogenic effect of circRNA-007371 inhibition may provide a new strategy for treating patients with liver cirrhosis.

Establishment and experimental validation of a novel cuproptosis-related gene signature for prognostic implication in cholangiocarcinoma.

Background: Cholangiocarcinoma (CCA) is a highly malignant, heterogeneous bile duct malignancy with poor treatment options. A novel type of cell death termed cuproptosis was recently demonstrated to closely correlate with tumor progression. To gain more insight into the role of cuproptosis in CCA, we investigated the prognostic implications of cuproptosis related genes (CRGs) and their relationship to the development of CCA. Methods: Gene expression data for CCA were obtained from the European Bioinformatics Institute (EMBL-EBI) database. Least absolute shrinkage and selection operator (LASSO) penalized Cox regression was used to construct a prognostic risk model based on CRGs. RNA-seq, qRT-PCR and immunohistochemistry staining were used to verify the expression of CRGs in human CCA tissues or cell lines. Further in vitro experiments were performed to demonstrate the role of cuproptosis in CCA. Results: We established a 4-gene signature (ATP7A, FDX1, DBT and LIAS) that exhibited good stability and was an independent prognostic factor for CCA. Seventy-five CCA samples were divided into high- and low-risk groups based on the risk score. Enrichment analysis revealed increased extracellular activity in the high-risk group and increased lipid metabolic activity in the low-risk group. Moreover, the 4 signature genes were verified in clinical samples and cell lines by RNA-seq, qRT-PCR and immunohistochemistry. Further experiments confirmed that cuproptosis can significantly inhibit the viability of CCA cells. Knockdown of the key gene LIAS ameliorated the toxicity of cuproptosis to CCA cells. Conclusion: We established a 4-gene prognostic signature based on cuproptosis and explored the role of cuproptosis in CCA. The results provide an effective indicator for predicting the prognosis of cuproptosis in CCA.

Fecal fungal microbiota alterations associated with clinical phenotypes in Crohn's disease in southwest China.

Although previous studies reported that gut fungal microbiota was associated with Crohn's disease (CD), only a few studies have focused on the correlation between gut fungi and clinical phenotypes of CD. Here, we aimed to analyze the association between intestinal fungi and the occurrence of CD, disease activity, biological behaviors, and perianal lesions. Stool samples from subjects meeting the inclusion and exclusion criteria were collected for running internal transcribed spacer 2 (ITS2) high-throughput sequencing. Then, correlation analysis was conducted between intestinal fungi and different clinical groups. There were 45 patients with CD and 17 healthy controls (HCs) enrolled. Results showed that two phyla, Rozellomycota and Mortierellomycota, were not present in patients with CD compared to HCs. At the same time, there was a higher abundance of fungal genera and species belonging to the phylum Ascomycota in patients with CD. SparCC network analysis showed fewer interactions among the fungal communities in patients with CD compared to HCs. Exophiala dermatitidis was positively associated with the clinical active stage and platelet count. The genus Candida was with significantly higher abundance in the non-B1 CD group based on the Montreal classification. Clonostachys, Humicola, and Lophiostoma were significantly enriched in patients with CD with perianal lesions. Our results demonstrated that the composition of the intestinal fungal microbiota in patients with CD and HCs was markedly different, some of which might play a pathogenic role in the occurrence of CD and perianal lesions. Exophiala dermatitidis and genus Candida might be associated with active disease stage and type non-B1 CD (CD with intestinal stenosis or penetrating lesions, or both), respectively.

Role of Immune Cells in Biliary Repair.

The biliary system is comprised of cholangiocytes and plays an important role in maintaining liver function. Under normal conditions, cholangiocytes remain in the stationary phase and maintain a very low turnover rate. However, the robust biliary repair is initiated in disease conditions, and different repair mechanisms can be activated depending on the pathological changes. During biliary disease, immune cells including monocytes, lymphocytes, neutrophils, and mast cells are recruited to the liver. The cellular interactions between cholangiocytes and these recruited immune cells as well as hepatic resident immune cells, including Kupffer cells, determine disease outcomes. However, the role of immune cells in the initiation, regulation, and suspension of biliary repair remains elusive. The cellular processes of cholangiocyte proliferation, progenitor cell differentiation, and hepatocyte-cholangiocyte transdifferentiation during biliary diseases are reviewed to manifest the underlying mechanism of biliary repair. Furthermore, the potential role of immune cells in crucial biliary repair mechanisms is highlighted. The mechanisms of biliary repair in immune-mediated cholangiopathies, inherited cholangiopathies, obstructive cholangiopathies, and cholangiocarcinoma are also summarized. Additionally, novel techniques that could clarify the underlying mechanisms of biliary repair are displayed. Collectively, this review aims to deepen the understanding of the mechanisms of biliary repair and contributes potential novel therapeutic methods for treating biliary diseases.

Inhibition of Transketolase Improves the Prognosis of Colorectal Cancer.

Colorectal cancer (CRC) remains a heavy health burden worldwide. Transketolase (TKT) is a crucial enzyme in the non-oxidative phase of the Pentose Phosphate Pathway (PPP), and is up-regulated in multiple cancer types. However, the role of TKT in the prognosis of CRC remains unclear. We aimed to explore whether TKT expression is altered in CRC, how TKT is associated with the prognosis of CRC, and whether the regulation of TKT might have an impact on CRC. Differentially expressed genes (DEGs) were identified using bioinformatics analysis. TKT expression was examined in the human colon adenocarcinoma tissue microarray and xenografts. Cell viability, proliferation, migration, and apoptosis assays in vitro were applied to evaluate the protumoral effects of TKT on CRC. TKT was found to be a risk factor for the poor prognosis of CRC by bioinformatics analysis among the DEGs. TKT was significantly up-regulated in colon adenocarcinoma tissues compared with normal colon tissues in patients. Moreover, similar results were found in HCT116 and RKO human colon adenocarcinoma xenografts in nude mice. TKT expression was positively associated with advanced TNM stage, positive lymph nodes, and poor 5 or 10-year overall survival of CRC patients. In vitro, inhibition of TKT reduced cell viability, proliferation, and migration, and induced cell apoptosis. In addition, inhibition of TKT decreased the protein levels of NICD and Hes1. In conclusion, high TKT expression was associated with the poor prognosis of CRC patients. The protumoral effects of downregulating TKT may be realized by suppressing the Notch signaling pathway. TKT may be a new prognostic biomarker and therapeutic target for CRC.

Application of Bone Marrow Mesenchymal Stem Cells Effectively Eliminates Endotoxemia to Protect Rat from Acute Liver Failure Induced by Thioacetamide.

BACKGROUND: Endotoxemia is related to worse clinical outcomes in acute liver failure (ALF), but its management remains unsatisfactory. In this study, we aimed to assess whether the application of bone marrow mesenchymal stem cells (BMSCs) could eliminate endotoxemia and protect rats against ALF induced by thioacetamide (TAA). METHODS: BMSCs were isolated from rats and identified by the specific morphology, differentiation potential, and surface markers. The optimal dose of TAA for this study was explored and TAA-induced ALF rats were randomized to three groups: the normal control group (Saline), ALF group (TAA + Saline), and BMSCs-treated group (TAA + BMSCs). The intestinal migration and differentiation of BMSCs was tracked in vivo, and intestinal permeability, endotoxin and inflammatory cytokines, histology, and mortality were analyzed. Moreover, we added the inhibitor of the PI3K/AKT/mTOR signaling pathway into the co-culture system of BMSCs with enterocytes and then performed CK and Villin expression experiments to assess the role of PI3K/AKT/mTOR signal pathway in the intestinal differentiation of BMSCs. RESULTS: BMSCs migrated to the intestinal injury sites and differentiated into enterocytes, intestinal permeability was decreased compared with the ALF group. The higher expression of endotoxin and inflammatory cytokines were reversed after BMSCs transplantation in rats with ALF. Mortality and intestinal lesion were significantly decreased. Blocking the PI3K/AKT/mTOR signal pathway inhibited BMSCs' intestinal differentiation in vitro. CONCLUSION: BMSCs can eliminate endotoxemia and reduce mortality in rats with ALF, and the PI3K/AKT/mTOR signal pathway is involved in intestinal differentiation. BMSCs transplantation could be a potential candidate for the treatment of endotoxemia in ALF.

Chinese Consensus Report on Family-Based Helicobacter pylori Infection Control and Management (2021 Edition).

OBJECTIVE: Helicobacter pylori infection is mostly a family-based infectious disease. To facilitate its prevention and management, a national consensus meeting was held to review current evidence and propose strategies for population-wide and family-based H. pylori infection control and management to reduce the related disease burden. METHODS: Fifty-seven experts from 41 major universities and institutions in 20 provinces/regions of mainland China were invited to review evidence and modify statements using Delphi process and grading of recommendations assessment, development and evaluation system. The consensus level was defined as ≥80% for agreement on the proposed statements. RESULTS: Experts discussed and modified the original 23 statements on family-based H. pylori infection transmission, control and management, and reached consensus on 16 statements. The final report consists of three parts: (1) H. pylori infection and transmission among family members, (2) prevention and management of H. pylori infection in children and elderly people within households, and (3) strategies for prevention and management of H. pylori infection for family members. In addition to the 'test-and-treat' and 'screen-and-treat' strategies, this consensus also introduced a novel third 'family-based H. pylori infection control and management' strategy to prevent its intrafamilial transmission and development of related diseases. CONCLUSION: H. pylori is transmissible from person to person, and among family members. A family-based H. pylori prevention and eradication strategy would be a suitable approach to prevent its intra-familial transmission and related diseases. The notion and practice would be beneficial not only for Chinese residents but also valuable as a reference for other highly infected areas.

Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease.

Chronic liver disease (CLD) represents a global health problem, accounting for the heavy burden of disability and increased health care utilization. Epigenome alterations play an important role in the occurrence and progression of CLD. Histone modifications, which include acetylation, methylation, and phosphorylation, represent an essential part of epigenetic modifications that affect the transcriptional activity of genes. Different from genetic mutations, histone modifications are plastic and reversible. They can be modulated pharmacologically without changing the DNA sequence. Thus, there might be chances to establish interventional solutions by targeting histone modifications to reverse CLD. Here we summarized the roles of histone modifications in the context of alcoholic liver disease (ALD), metabolic associated fatty liver disease (MAFLD), viral hepatitis, autoimmune liver disease, drug-induced liver injury (DILI), and liver fibrosis or cirrhosis. The potential targets of histone modifications for translation into therapeutics were also investigated. In prospect, high efficacy and low toxicity drugs that are selectively targeting histone modifications are required to completely reverse CLD and prevent the development of liver cirrhosis and malignancy.

Quantification of chromogranin A using a surface plasmon resonance-based biosensor.

The chromogranin A (CgA) level in the blood is an important biomarker for neuroendocrine tumors and other diseases. Traditional methods for detecting CgA are expensive and time-consuming with low reproducibility. In this study, surface plasmon resonance (SPR), a simple and label-free technique, was validated for quantifying CgA. CgA antibody (CgA-Ab) was immobilized on the CM5 sensor chip (CgA-Ab-CM5) at optimal conditions (pH 5.0, 10 µg mL-1). Next, different concentrations of CgA were measured by CgA-Ab-CM5. The binding and regeneration conditions were optimized and used in each measurement. A binding time of 240 s, and flow rate of 30 µL min-1 were chosen as the optimal binding conditions. A pH of 1.75 was the optimal regeneration condition. Compared to the detection range of 23.4-187 ng mL-1 for enzyme-linked immunosorbent assay (ELISA), a linear range of 0.2-187 ng mL-1 was detected based on the response unit (RU), showing high sensitivity and reliability of SPR. Finally, the reproducibility of the CgA-Ab-CM5 chip was accessed by consecutive binding-regeneration cycles for 300 times. In conclusion, the SPR-based CgA-Ab-CM5 chip is a sensitive and reproducible method for quantifying CgA levels in a real-time manner.

Circular RNA as An Epigenetic Regulator in Chronic Liver Diseases.

Circular RNA (circRNA) is a type of non-coding RNA characterized by a covalently closed continuous loop. CircRNA is generated by pre-mRNA through back-splicing and is probably cleared up by extracellular vesicles. CircRNAs play a pivotal role in the epigenetic regulation of gene expression at transcriptional and post-transcriptional levels. Recently, circRNAs have been demonstrated to be involved in the regulation of liver homeostasis and diseases. However, the epigenetic role and underlying mechanisms of circRNAs in chronic liver diseases remain unclear. This review discussed the role of circRNAs in non-neoplastic chronic liver diseases, including alcoholic liver disease (ALD), metabolic-associated fatty liver disease (MAFLD), viral hepatitis, liver injury and regeneration, liver cirrhosis, and autoimmune liver disease. The review also highlighted that further efforts are urgently needed to develop circRNAs as novel diagnostics and therapeutics for chronic liver diseases.

Management and outcomes of surgical patients with intestinal Behçet's disease and Crohn's disease in southwest China.

BACKGROUND: Gastrointestinal involvement in Behçet's disease (GIBD) and Crohn's disease (CD) are inflammatory diseases sharing a considerable number of similarities. However, different from CD, the operative and postoperative management of GIBD remains largely empirical because of the lack of comprehensive treatment guidelines. AIM: To compare surgical patients with GIBD and those with CD in a medical center and identify notable clinical features and effective postoperative treatment for surgical patients with GIBD. METHODS: We searched patients diagnosed with CD and GIBD who underwent operations for gastrointestinal complications from 2009 to 2015 at West China Hospital of Sichuan University. A total of 10 surgical patients with GIBD and 106 surgical patients with CD were recruited. Information including demographic data, medication, and operative and postoperative parameters were collected and analyzed. As the incidence of surgical GIBD is low, their detailed medical records were reviewed and compared to previous studies. Moreover, the prognoses of CD and GIBD were evaluated respectively between groups treated with biological and non-biological agents. RESULTS: Indication for first surgery was often acute intestinal perforation for GIBD patients (7/10 vs 0/106, P < 0.001), whereas intestinal fistulae (0/10 vs 44/106, P = 0.013) and ileus (0/10 vs 40/106, P = 0.015) were the indications for surgical CD patients. Approximately 40% of patients with GIBD and 23.6% of patients with CD developed postoperative complications, 50% of patients with GIBD and 38.7% of patients with CD had recurrence postoperatively, and 40% (4/10) of patients with GIBD and 26.4% (28/106) of patients with CD underwent reoperations. The average period of postoperative recurrence was 7.87 mo in patients with Behçet's disease (BD) and 10.43 mo in patients with CD, whereas the mean duration from first surgery to reoperation was 5.75 mo in BD patients and 18.04 mo in CD patients. Surgical patients with GIBD more often used corticosteroids (6/10 vs 7/106, P < 0.001) and thalidomide (7/10 vs 9/106, P < 0.001) postoperatively, whereas surgical patients with CD often used infliximab (27/106), azathioprine, or 6-mercaptopurine (74/106) for maintenance therapy. CONCLUSION: Patients suffering GIBD require surgery mostly under emergency situations, which may be more susceptible to recurrence and reoperation and need more aggressive postoperative treatment than patients with CD.

Smad4 deficiency substitutes Cdkn2b but not Cdkn2a downregulation in pancreatic cancer following induction of genetic events in adult mice.

BACKGROUND: Minor progress in pancreatic cancer treatment and prognosis implies that more reliable animal models are urgently needed to decipher its molecular mechanisms and preclinical research. We recently reported a genetically engineered adult mouse model where Cdkn2b downregulation was required together with Cdkn2a downregulation to inactivate the Rb pathway. Besides, the role of Smad4, which is mutated more frequently than Cdkn2b in human pancreatic cancer, was determined critical on the development of the pancreas tumor by some reports. However, the impact of Smad4 deficiency in combination with PDAC-relevant mutations, such as Cdkn2a when induced in adult pancreas has not been completely elucidated in mice. METHODS: Lentiviral delivered oncogene/tumor suppressors in adult pancreas. The development of pancreatic cancer was monitored. Hematoxylin and eosin staining and immunofluorescence were performed for pathological identification of the pancreatic cancer. Real-time polymerase chain reaction, immunofluorescence and western blot were used to test gene expression. RESULTS: Loss of Smad4 could cooperate with alterations of KRAS, Trp53, and Cdkn2a to induce pancreatic cancer in adult mice. The role of Smad4 was mainly in downregulating the expression of Cdkn2b and further inducing phosphorylation of the Rb1 protein. CONCLUSIONS: These findings show an essential role of Smad4 deficiency in pancreatic ductal adenocarcinoma (PDAC) formation. This model better recapitulates the adult onset, clonal origin, and genetic alterations in human PDAC and can be simply generated on a large-scale.

Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats.

BACKGROUND: In liver cirrhosis, intestinal mucus barrier is rarely studied. AIMS: This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms. METHODS: Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments. RESULTS: The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed. CONCLUSIONS: In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1-Hes1-KLF4 signaling.

Detection of multiple lesions of gastrointestinal tract for endoscopy using artificial intelligence model: a pilot study.

BACKGROUND: This study was aimed to develop a computer-aided diagnosis (CAD) system with deep-learning technique and to validate its efficiency on detecting the four categories of lesions such as polyps, advanced cancer, erosion/ulcer and varices at endoscopy. METHODS: A deep convolutional neural network (CNN) that consists of more than 50 layers were trained with a big dataset containing 327,121 white light images (WLI) of endoscopy from 117,005 cases collected from 2012 to 2017. Two CAD models were developed using images with or without annotation of the training dataset. The efficiency of the CAD system detecting the four categories of lesions was validated by another dataset containing consecutive cases from 2018 to 2019. RESULTS: A total of 1734 cases with 33,959 images were included in the validation datasets which containing lesions of polyps 1265, advanced cancer 500, erosion/ulcer 486, and varices 248. The CAD system developed in this study may detect polyps, advanced cancer, erosion/ulcer and varices as abnormality with the sensitivity of 88.3% and specificity of 90.3%, respectively, in 0.05 s. The training datasets with annotation may enhance either sensitivity or specificity about 20%, p = 0.000. The sensitivities and specificities for polyps, advanced cancer, erosion/ulcer and varices reached about 90%, respectively. The detect efficiency for the four categories of lesions reached to 89.7%. CONCLUSION: The CAD model for detection of multiple lesions in gastrointestinal lumen would be potentially developed into a double check along with real-time assessment and interpretation of the findings encountered by the endoscopists and may be a benefit to reduce the events of missing lesions.