Unraveling the crosstalk: circRNAs and the wnt signaling pathway in cancers of the digestive system.

Circular RNA (circRNA) is a unique type of noncoding RNA molecule characterized by its closed-loop structure. Functionally versatile, circRNAs play pivotal roles in gene expression regulation, protein activity modulation, and participation in cell signaling processes. In the context of cancers of the digestive system, the Wnt signaling pathway holds particular significance. Anomalous activation of the Wnt pathway serves as a primary catalyst for the development of colorectal cancer. Extensive research underscores the notable participation of circRNAs associated with the Wnt pathway in the progression of digestive system tumors. These circRNAs exhibit pronounced dysregulation across esophageal cancer, gastric cancer, liver cancer, colorectal cancer, pancreatic cancer, and cholangiocarcinoma. Furthermore, the altered expression of circRNAs linked to the Wnt pathway correlates with prognostic factors in digestive system tumors. Additionally, circRNAs related to the Wnt pathway showcase potential as diagnostic, therapeutic, and prognostic markers within the realm of digestive system tumors. This comprehensive review outlines the interplay between circRNAs and the Wnt signaling pathway in cancers of the digestive system. It seeks to provide a comprehensive perspective on their association while delving into ongoing research that explores the clinical applications of circRNAs associated with the Wnt pathway.

The Role of Inflammatory Biomarkers in Mediating the Effect of Inflammatory Bowel Disease on nonmalignant Digestive System Diseases: A Multivariable Mendelian Randomized Study.

Background: While observation studies have shown a positive correlation between inflammatory bowel disease (IBD) and the risk of nonmalignant digestive system diseases, a definitive causal relationship has not yet been clearly established. Methods: Mendelian randomization (MR) was employed to investigate the potential causal association between genetic susceptibility to IBD and nonmalignant gastrointestinal diseases. Genetic variants were extracted as instrumental variables (IVs) from a genome-wide association study (GWAS) meta-analysis, which included 12,194 cases of Crohn's disease (CD) and 28,072 control cases of European ancestry. The GWAS for ulcerative colitis (UC) included 12,366 UC and 33,609 control cases of European ancestry. All IVs reached genome-wide significance (GWAS p value <5 × 10-8). Summary-level data for acute pancreatitis (AP), irritable bowel syndrome (IBS), gastroesophageal reflux disease, cholelithiasis, and CeD (celiac disease) were obtained from the GWAS meta-analysis and the FinnGen dataset. Summary-level data on relevant inflammatory factors were provided by the International Genetic Consortium. Univariate MR analysis was conducted using inverse variance weighting as the primary method for estimating causal effects. Multivariate MR analyses were also performed to detect possible mediators. Results: Genetic susceptibility to UC was associated with an increased risk of AP (OR = 1.08; 95% CI = 1.03-1.13; p=0.002) and IBS odds ratio (OR] = 1.07; 95% confidence interval (CI] = 1.03-1.11; (p < 0.001). In terms of potential mediators, interleukin 6 (IL-6) had a driving effect on the association between UC and AP. There was no apparent evidence of increased risk with CD. Meanwhile, genetic susceptibility to CD increases the risk of CeD (OR = 1.14; 95% CI = 1.03-1.25; p=0.01). Conclusions: The evidence suggests that UC is associated with an elevated risk of AP and IBS, and IL-6 may be responsible in AP. CD is associated with an increased risk of developing CeD. Implementing a proactive monitoring program for assessing the risk of gastrointestinal diseases in UC patients, particularly those with elevated IL-6 levels, may be of interest. In addition, the presence of AP and IBS may indicate the presence of UC. Preventing CeD is an essential consideration in the therapeutic management of patients with CD.

The association between tea consumption and non-malignant digestive system diseases: A Mendelian randomized study.

BACKGROUND: Tea consumption might be closely related to non-malignant digestive diseases. Nevertheless, this correlation remains inadequately comprehended. Therefore, our objective was to elucidate the essence of these connections. METHODS: This study employed a Mendelian randomization approach to investigate the impact of tea consumption on specific digestive disorders. Genetic data associated with tea consumption were obtained from the UK Biobank (UKB), encompassing 447,485 participants. We chose a gene-wide association study with no sample overlap and UKB as our data source for all outcomes. The primary analytical method utilized was inverse variance weighting, and multiple analytical models were employed to enhance the analysis's reliability and ensure robust results. RESULT: Our investigation revealed that tea consumption was linked to an elevated susceptibility to gastroesophageal reflux disease (GERD). However, there was a lack of substantial evidence suggesting an association between tea intake and Crohn's disease (CD), ulcerative colitis (UC), or non-alcoholic fatty liver disease (NAFLD). CONCLUSIONS: Our study suggests that the excessive consumption of tea may heighten the likelihood of GERD. These results hold potential significance in guiding dietary pattern modifications for individuals with GERD. Furthermore, there may be value in implementing GERD monitoring and preventive measures in populations with elevated tea consumption.

Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer.

Liver cancer (LC) poses a significant global health challenge due to its high incidence and poor prognosis. Current systemic treatment options, such as surgery, chemotherapy, radiofrequency ablation, and immunotherapy, have shown limited effectiveness for advanced LC patients. Moreover, owing to the heterogeneous nature of LC, it is crucial to uncover more in-depth pathogenic mechanisms and develop effective treatments to address the limitations of the existing therapeutic modalities. Increasing evidence has revealed the crucial role of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway in the pathogenesis of LC. The specific mechanisms driving the JAK-STAT pathway activation in LC, participate in a variety of malignant biological processes, including cell differentiation, evasion, anti-apoptosis, immune escape, and treatment resistance. Both preclinical and clinical investigations on the JAK-STAT pathway inhibitors have exhibited potential in LC treatment, thereby opening up avenues for the development of more targeted therapeutic strategies for LC. In this study, we provide an overview of the JAK-STAT pathway, delving into the composition, activation, and dynamic interplay within the pathway. Additionally, we focus on the molecular mechanisms driving the aberrant activation of the JAK-STAT pathway in LC. Furthermore, we summarize the latest advancements in targeting the JAK-STAT pathway for LC treatment. The insights presented in this review aim to underscore the necessity of research into the JAK-STAT signaling pathway as a promising avenue for LC therapy.

The interaction between intratumoral bacteria and metabolic distortion in hepatocellular carcinoma.

BACKGROUND: Intratumoral bacteria might play essential roles in tumorigenesis in different cancer types. However, its features and potential roles in hepatocellular carcinoma (HCC) are largely unknown. METHODS: In this study, we assessed bacterial RNA by 16S rRNA fluorescence in situ hybridization and detected bacterial lipopolysaccharide (LPS) via immunohistochemistry. Hepa1-6 cells were used to establish orthotopic HCC models in mice. 2bRAD sequencing for microbiome was performed to determine the intratumoral bacterial characteristics, and liquid chromatography-mass spectrometry was conducted to explore the metabolic profile. The potential association between different intratumoral microbiota and metabolites were evaluated. RESULTS: We detected bacterial 16S rRNA and LPS in HCC tissues from the patients with HCC. In HCC mouse model, we found that the intratumor bacteria in HCC tissues were significantly different to adjacent nontumor tissues. Furthermore, we observed different metabolites in HCC tissues and adjacent nontumor tissues, such as N-acetyl-D-glucosamine and a-lactose. Our results showed that several bacteria were significantly associated with metabolites, such as Pseudomonas koreensis, which was positively correlated with N-acetyl-D-glucosamine and negatively correlated with citrulline. CONCLUSIONS: This study confirmed the close association between different bacteria and metabolites, which might provide novel opportunities for developing new biomarkers and therapeutic targets for HCC.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation.

BACKGROUND: Primary non-function (PNF) and early allograft failure (EAF) after liver transplantation (LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function (MEAF), PNF score by King's College (King-PNF) and Balance-and-Risk-Lactate (BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. METHODS: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic (ROC) and the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses. RESULTS: Of all 720 patients, 28 (3.9%) developed PNF and 67 (9.3%) developed EAF in 3 months. The overall early allograft dysfunction (EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0 (3.5-6.3), -2.1 (-2.6 to -1.2), and 5.0 (2.0-11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves (AUCs) of 0.871 and 0.891, superior to BAR-Lac (AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. CONCLUSIONS: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

Diagnosis and treatment of biliary mucinous cystic neoplasms: A single-center experience.

BACKGROUND: Biliary mucinous cystic neoplasms (BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center. METHODS: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Affiliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021. RESULTS: Among the 49 patients, 37 were female (75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients (44.9%) had no symptoms. Serum carbohydrate antigen (CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34 (70.8%) had low-grade intraepithelial neoplasms (LGINs), and 14 (29.2%) had high-grade intraepithelial neoplasms (HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin (CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival (OS) of BMCNs was not reached. The longest survival time was 137 months.The 5- and 10-year OS rates were 100% and 85.4%, respectively. The 5- and 10-year recurrence-free survival (RFS) rates were 93.9% and 80.2%, respectively. CONCLUSIONS: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable.

Single-center experience in the diagnosis and treatment of lymphoepithelioma-like hepatic carcinoma.

PURPOSE: Lymphoepithelioma-like hepatic carcinoma (LELC) is a rare malignant liver tumor and its preoperative diagnosis is challenging. The aim of this study was to optimize the diagnosis and treatment of LELC in a single large center. METHODS: We conducted this retrospective analysis of 16 patients diagnosed with LELC in the First Affiliated Hospital of Zhejiang University between 2010 and 2022. Thirty-two cases of cholangiocarcinoma (ICC) and 48 cases of hepatocellular carcinoma (HCC) served as controls. RESULTS: Most of the 16 patients with LELC included in this study had no specific symptoms. Histologically, 9 patients had lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC), 5 had lymphoepithelioma-like cholangiocarcinoma (LEL-ICC) and 2 had LEL-HCC-ICC. LEL-HCC was usually accompanied by hepatitis B virus infection, while LEL-ICC was often accompanied by Epstein Barr virus (EBV) infection. During the follow-up period, no complication and deaths were observed and only one patient experienced recurrence. These results were obviously better than those in patients with HCC and ICC. CONCLUSION: LELC is a rare malignant hepatic tumor. There are no specific symptoms or imaging modalities for accurate preoperative diagnosis of LELC. The diagnosis can be confirmed by pathology; however, the prognosis of LELC after resection is promising.

Effects of 3-HAA on HCC by Regulating the Heterogeneous Macrophages-A scRNA-Seq Analysis.

Kynurenine derivative 3-hydroxyanthranilic acid (3-HAA) is known to regulate the immune system and exhibit anti-inflammatory activity by inhibiting T-cell cytokine secretion and influencing macrophage activity. However, the definite role of 3-HAA in the immunomodulation of hepatocellular carcinoma (HCC) is largely unexplored. An orthotopic HCC model and treated with 3-HAA by intraperitoneal injection is developed. Furthermore, cytometry by time-of-flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) analyses are carried out to define the immune landscape of HCC. It is found that 3-HAA treatment can significantly suppress tumor growth in the HCC model and alter the level of various cytokines in plasma. CyTOF data shows that 3-HAA significantly increases the percentage of F4/80hi CX3CR1lo Ki67lo MHCIIhi macrophages and decreases the percentage of F4/80lo CD64+ PD-L1lo macrophages. scRNA-seq analyses demonstrate that 3-HAA treatment is proved to regulate the function of M1 macrophages, M2 macrophages, and proliferating macrophages. Notably, 3-HAA inhibits the proinflammatory factors TNF and IL-6 in multiple cell subsets, including resident macrophages, proliferating macrophages, and pDCs. This study reveals the landscape of immune cell subsets in HCC in response to 3-HAA, indicating that 3-HAA may be a promising therapeutic target for HCC.

A novel variant in NBAS identified from an infant with fever-triggered recurrent acute liver failure disrupts the function of the gene.

Mutations in the neuroblastoma amplified sequence (NBAS) gene correlate with infantile acute liver failure (ALF). Herein, we identified a novel NBAS mutation in a female infant diagnosed with recurrent ALF. Whole-exome and Sanger sequencing revealed that the proband carried a compound heterozygous mutation (c.938_939delGC and c.1342 T > C in NBAS). NBAS c.938_939delGC was presumed to encode a truncated protein without normal function, whereas NBAS c.1342 T > C encoded NBAS harboring the conserved Cys448 residue mutated to Arg448 (p.C448R). The proportion of CD4 + T cells decreased in the patient's peripheral CD45 + cells, whereas that of CD8 + T cells increased. Moreover, upon transfecting the same amount of DNA expression vector (ectopic expression) encoding wild-type NBAS and p.C448R NBAS, the group transfected with the p.C448R NBAS-expressing vector expressed less NBAS mRNA and protein. Furthermore, ectopic expression of the same amount of p.C448R NBAS protein as the wild-type resulted in more intracellular reactive oxygen species and the induction of apoptosis and expression of marker proteins correlating with endoplasmic reticulum stress in more cultured cells. This study indicated that p.C448R NBAS has a function different from that of wild-type NBAS and that the p.C448R NBAS mutation potentially affects T-cell function and correlates with ALF.

Hypothermic Oxygenated Machine Perfusion Promotes Mitophagy Flux against Hypoxia-Ischemic Injury in Rat DCD Liver.

Hypothermic oxygenated machine perfusion (HOPE) can enhance organ preservation and protect mitochondria from hypoxia-ischemic injury; however, an understanding of the underlying HOPE mechanism that protects mitochondria is somewhat lacking. We hypothesized that mitophagy may play an important role in HOPE mitochondria protection. Experimental rat liver grafts were exposed to 30 min of in situ warm ischemia. Then, grafts were procured, followed by cold storage for 3 or 4 h to mimic the conventional preservation and transportation time in donation after circulatory death (DCD) in clinical contexts. Next, the grafts underwent hypothermic machine perfusion (HMP) or HOPE for 1 h through portal vein only perfusion. The HOPE-treated group showed a better preservation capacity compared with cold storage and HMP, preventing hepatocyte damage, nuclear injury, and cell death. HOPE can increase mitophagy marker expression, promote mitophagy flux via the PINK1/Parkin pathway to maintain mitochondrial function, and reduce oxygen free radical generation, while the inhibition of autophagy by 3-methyladenine and chloroquine could reverse the protective effect. HOPE-treated DCD liver also demonstrated more changes in the expression of genes responsible for bile metabolism, mitochondrial dynamics, cell survival, and oxidative stress. Overall, HOPE attenuates hypoxia-ischemic injury in DCD liver by promoting mitophagy flux to maintain mitochondrial function and protect hepatocytes. Mitophagy could pave the way for a protective approach against hypoxia-ischemic injury in DCD liver.

Exosome is involved in liver graft protection after remote ischemia reperfusion conditioning.

BACKGROUND: Remote ischemic perconditioning (RIPerC) has been demonstrated to protect grafts from hepatic ischemia-reperfusion injury (IRI). This study investigated the role of exosomes in RIPerC of liver grafts in rats. METHODS: Twenty-five rats (including 10 donors) were randomly divided into five groups (n = 5 each group): five rats were used as sham-operated controls (Sham), ten rats were for orthotopic liver transplantation (OLT, 5 donors and 5 recipients) and ten rats were for OLT + RIPerC (5 donors and 5 recipients). Liver architecture and function were evaluated. RESULTS: Compared to the OLT group, the OLT + RIPerC group exhibited significantly improved liver graft histopathology and liver function (P < 0.05). Furthermore, the number of exosomes and the level of P-Akt were increased in the OLT + RIPerC group. CONCLUSIONS: RIPerC effectively improves graft architecture and function, and this protective effect may be related to the increased number of exosomes. The upregulation of P-Akt may be involved in underlying mechanisms.

Non-iatrogenic implantation of cutaneous metastasis from hepatocellular carcinoma.

PURPOSE: Cutaneous metastases as an extrahepatic metastasis from hepatomas (HCC) is extremely rare and always carry a poor prognosis and less survival time. Previously, there has been a limited number of literature that reported skin metastasis in a large number of cases, which has rarely been discussed in the empirical treatment and therapy of cutaneous metastasis, especially for non-iatrogenic implantation. It is necessary to discuss this kind of metastasis. PATIENTS AND METHODS: We summarize cases from our medical center from 2013 to 2021, there are 12 patients diagnosed with non-iatrogenic implantation of cutaneous metastasis after HCC. We conducted the investigation of the clinical prognosis, pathological characteristics, and treatment of those patients. RESULTS: All patients were male, the age ranged from 21 to 71 years old, the average size of primary HCC was over 5 cm, there was four patient's cutaneous metastasis from the skin of head (including scalp and occipital region), followed by right abdominal (2 patients), right chest wall (2 patients), back (2 patients), umbilical (1 patient), gluteal region (1 patient). The cutaneous metastases presented as solitary or multiple nodules, papules, and erythema without ulcers with sizes between 0.5 cm and 5 cm. 7 patients died after being diagnosed with cutaneous metastasis within 2-19 months. CONCLUSIONS: The rate of non-iatrogenic implantation cutaneous metastasis is low, but the prognosis is poor, combining with histopathological analysis and history of diseases can be helpful in diagnosis. For large HCC (> 5 cm), systematic treatment is recommended to prevent the occurrence of cutaneous metastasis and improve the prognosis after hepatectomy.

Prediction of hepatocellular carcinoma prognosis and immunotherapeutic effects based on tryptophan metabolism-related genes.

BACKGROUND: L-tryptophan (Trp) metabolism involved in mediating tumour development and immune suppression. However, comprehensive analysis of the role of the Trp metabolism pathway is still a challenge. METHODS: We downloaded Trp metabolism-related genes' expression data from different public databases, including TCGA, Gene Expression Omnibus (GEO) and Hepatocellular Carcinoma Database (HCCDB). And we identified two metabolic phenotypes using the ConsensusClusterPlus package. Univariate regression analysis and lasso Cox regression analysis were used to establish a risk model. CIBERSORT and Tracking of Indels by DEcomposition (TIDE) analyses were adopted to assess the infiltration abundance of immune cells and tumour immune escape. RESULTS: We identified two metabolic phenotypes, and patients in Cluster 2 (C2) had a better prognosis than those in Cluster 1 (C1). The distribution of clinical features between the metabolic phenotypes showed that patients in C1 tended to have higher T stage, stage, grade, and death probability than those of patients in C2. Additionally, we screened 739 differentially expressed genes (DEGs) between the C1 and C2. We generated a ten-gene risk model based on the DEGs, and the area under the curve (AUC) values of the risk model for predicting overall survival. Patients in the low-risk subgroup tended to have a significantly longer overall survival than that of those in the high-risk group. Moreover, univariate analysis indicated that the risk model was significantly correlated with overall survival. Multivariate analysis showed that the risk model remained an independent risk factor in hepatocellular carcinoma (p < 0.0001). CONCLUSIONS: We identified two metabolic phenotypes based on genes of the Trp metabolism pathway, and we established a risk model that could be used for predicting prognosis and guiding immunotherapy in patients with hepatocellular carcinoma.