Clinical significance of RNA methylation in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary liver malignancy with high mortality rates and poor prognosis. Recent advances in high-throughput sequencing and bioinformatic technologies have greatly enhanced the understanding of the genetic and epigenetic changes in liver cancer. Among these changes, RNA methylation, the most prevalent internal RNA modification, has emerged as a significant contributor of the development and progression of HCC. Growing evidence has reported significantly abnormal levels of RNA methylation and dysregulation of RNA-methylation-related enzymes in HCC tissues and cell lines. These alterations in RNA methylation play a crucial role in the regulation of various genes and signaling pathways involved in HCC, thereby promoting tumor progression. Understanding the pathogenesis of RNA methylation in HCC would help in developing prognostic biomarkers and targeted therapies for HCC. Targeting RNA-methylation-related molecules has shown promising potential in the management of HCC, in terms of developing novel prognostic biomarkers and therapies for HCC. Exploring the clinical application of targeted RNA methylation may provide new insights and approaches for the management of HCC. Further research in this field is warranted to fully understand the functional roles and underlying mechanisms of RNA methylation in HCC. In this review, we described the multifaceted functional roles and potential mechanisms of RNA methylation in HCC. Moreover, the prospects of clinical application of targeted RNA methylation for HCC management are discussed, which may provide the basis for subsequent in-depth research on RNA methylation in HCC.

Clinical features of hepatic manifestations among adult patients with hemophagocytic lymphohistiocytosis: a retrospective study.

INTRODUCTION Liver dysfunction is common in patients with hemophagocytic lymphohistiocytosis (HLH). However, whether the severity of liver injury is associated with the prognosis of patients with HLH remains to be determined. This study aims to assess the association of the severity of liver involvement with short-term prognosis among adult patients with HLH. METHODS A retrospective study was performed from January 2012 to December 2020, including 150 patients with newly diagnosed HLH and liver injury. RESULTS The majority of our cohort suffered from mild to moderate hepatic damage, presenting with Child-Turcotte-Pugh (CTP) class A (55, 36.7%) or B (74, 49.3%). The prevalence of acute liver failure (ALF) was 9.3% in our cohort. The overall 30-day mortality rate was 49.3% among the study population. HLH patients with ALF showed an extremely adverse prognosis, with a mortality rate as high as 92.9%. In a multivariate analysis, age ≥ 60 years (p = 0.016), BUN ≥ 7 µmol/L (p < 0.001) and malignancy-associated HLH (p < 0.001) at the diagnosis of HLH were identified as being strongly correlated with 30-day prognosis. An excellent predictive power was found. Among the predictive scores used to assess early death of HLH patients with liver injury, the prognostic efficiency of chronic liver failure-sequential organ failure assessment (CLIF-SOFA) (AUROC: 0.936 ± 0.0211) and SOFA score (0.901 ± 0.026) were significantly better than those of the APACHE II (p < 0.001), Model for end-stage liver disease score (p < 0.001) and CTP scores (p < 0.001). The CLIF-SOFA score was slightly better than the SOFA score (p = 0.068). CONCLUSION Patients with old age, elevated BUN and malignancy had inferior survival. CLIF-SOFA and SOFA enables a more accurate prediction of early death in HLH patients with liver injury than other liver-specific and general prognostic models.

Effects of N6-methyladenosine modification on metabolic reprogramming in digestive tract tumors.

N6-methyladenosine (m6A), the most abundant RNA modification within cells, participates in various biological and pathological processes, including self-renewal, invasion and proliferation, drug resistance, and stem cell characteristics. The m6A methylation plays a crucial role in tumors by regulating multiple RNA processes such as transcription, processing, and translation. Three protein types are primarily involved in m6A methylation: methyltransferases (such as METTL3, METTL14, ZC3H13, and KIAA1429), demethylases (such as FTO, ALKBH5), and RNA-binding proteins (such as the family of YTHDF, YTHDC1, YTHDC2, and IGF2BPs). Various metabolic pathways are reprogrammed in digestive tumors to meet the heightened growth demands and sustain cellular functionality. Recent studies have highlighted the extensive impact of m6A on the regulation of digestive tract tumor metabolism, further modulating tumor initiation and progression. Our review aims to provide a comprehensive understanding of the expression patterns, functional roles, and regulatory mechanisms of m6A in digestive tract tumor metabolism-related molecules and pathways. The characterization of expression profiles of m6A regulatory factors and in-depth studies on m6A methylation in digestive system tumors may provide new directions for clinical prediction and innovative therapeutic interventions.

Identification and analysis of necroptosis-associated signatures for prognostic and immune microenvironment evaluation in hepatocellular carcinoma.

Background: Hepatocellular carcinoma remains the third most common cause of cancer-related deaths worldwide. Although great achievements have been made in resection, chemical therapies and immunotherapies, the pathogenesis and mechanism of HCC initiation and progression still need further exploration. Necroptosis genes have been reported to play an important role in HCC malignant activities, thus it is of great importance to comprehensively explore necroptosis-associated genes in HCC. Methods: We chose the LIHC cohort from the TCGA, ICGC and GEO databases for this study. ConsensusClusterPlus was adopted to identify the necroptosis genes-based clusters, and LASSO cox regression was applied to construct the prognostic model based on necroptosis signatures. The GSEA and CIBERSORT algorithms were applied to evaluate the immune cell infiltration level. QPCR was also applied in this study to evaluate the expression level of genes in HCC. Results: We identified three clusters, C1, C2 and C3. Compared with C2 and C3, the C1 cluster had the shortest overall survival time and highest immune score. The C1 was samples were significantly enriched in cell cycle pathways, some tumor epithelial-mesenchymal transition related signaling pathways, among others. The DEGs between the 3 clusters showed that C1 was enriched in cell cycle, DNA replication, cellular senescence, and p53 signaling pathways. The LASSO cox regression identified KPNA2, SLC1A5 and RAMP3 as prognostic model hub genes. The high risk-score subgroup had an elevated expression level of immune checkpoint genes and a higher TIDE score, which suggested that the high risk-score subgroup had a lower efficiency of immunotherapies. We also validated that the necroptosis signatures-based risk-score model had powerful prognosis prediction ability. Conclusion: Based on necroptosis-related genes, we classified patients into 3 clusters, among which C1 had significantly shorter overall survival times. The proposed necroptosis signatures-based prognosis prediction model provides a novel approach in HCC survival prediction and clinical evaluation.

Mesenchymal stem cell-based cell-free strategies: safe and effective treatments for liver injury.

Various hepatoxic factors, such as viruses, drugs, lipid deposition, and autoimmune responses, induce acute or chronic liver injury, and 3.5% of all worldwide deaths result from liver cirrhosis, liver failure, or hepatocellular carcinoma. Liver transplantation is currently limited by few liver donors, expensive surgical costs, and severe immune rejection. Cell therapy, including hepatocyte transplantation and stem cell transplantation, has recently become an attractive option to reduce the overall need for liver transplantation and reduce the wait time for patients. Recent studies showed that mesenchymal stem cell (MSC) administration was a promising therapeutic approach for promoting liver regeneration and repairing liver injury by the migration of cells into liver sites, hepatogenic differentiation, immunoregulation, and paracrine mechanisms. MSCs secrete a large number of molecules into the extracellular space, and soluble proteins, free nucleic acids, lipids, and extracellular vesicles (EVs) effectively repair tissue injury in response to fluctuations in physiological states or pathological conditions. Cell-free-based therapies avoid the potential tumorigenicity, rejection of cells, emboli formation, undesired differentiation, and infection transmission of MSC transplantation. In this review, we focus on the potential mechanisms of MSC-based cell-free strategies for attenuating liver injury in various liver diseases. Secretome-mediated paracrine effects participate in the regulation of the hepatic immune microenvironment and promotion of hepatic epithelial repair. We look forward to completely reversing liver injury through an MSC-based cell-free strategy in regenerative medicine in the near future.

Variation in the gut microbial community is associated with the progression of liver regeneration.

AIM: To highlight a potential dynamic interaction between intestinal bacteria (IB) and metabolites that might contribute to liver regeneration (LR). METHODS: Male Sprague-Dawley rats were subjected to surgical removal of two-thirds of the liver and samples were collected over a 14-day period. Intestinal community and metabolic profiles were characterized to establish their potential interactions during liver regeneration. RESULTS: Partial hepatectomy caused fluctuating changes in the gut microbiome, which paralleled the biological processes of LR. Briefly, the enhanced cell proliferation occurring within 30-48 h was associated with a decreased ratio of Firmicutes to Bacteroidetes reflected by a reduction in Ruminococcaceae and Lachnospiraceae, and an increase in Bacteroidaceae, Rikenellaceae, and Porphyromonadaceae, which was indicative of a lean phenotype. The microbiota derived from rats at 12-24 h and 3-14 days were characterized by elevated F/B ratios, suggesting the differing energy extract behaviors of microbiota during the course of LR. Functional changes of the shifted microbiota revealed by PICRUSt software confirmed the pyrosequencing results. The microbiome derived from hour 12 rats showed overpresentation of metabolism-related modules. In contrast, the microbiome derived from day 2 rats was functionally unique in "replication and repair", "amino acid metabolism," and "nucleoid metabolism." Upon examining the dynamic pattern of metabolic response, the specific pathways, including glycerophospholipid metabolism, taurine, and hypotaurine metabolism, were identified to be attributable to the systemic alterations in LR-related metabolism. Moreover, our data indicated that several key functional bacteria were strongly related to perturbations of the above pathways. CONCLUSION: Gut flora could play a central role in manipulating metabolic responses in LR.

Altered Fecal Microbiota Correlates with Liver Biochemistry in Nonobese Patients with Non-alcoholic Fatty Liver Disease.

Increasing evidence suggests a role of intestinal dysbiosis in obesity and non-alcoholic fatty liver disease (NAFLD). But it remains unknown in nonobese NAFLD. This prospective, cross-sectional study sought to characterize differences in fecal microbiota between nonobese adult individuals with and without NAFLD and their potential association with metabolic markers of disease progression. A total of 126 nonobese subjects were enrolled: 43 NAFLD and 83 healthy controls (HC). The microbial community was profiled by denaturing gradient gel electrophoresis and examined by 454 pyrosequencing of the 16S ribosomal RNA V3 region. Lower diversity and a phylum-level change in the fecal microbiome were found in NAFLD. Compared with HC, patients had 20% more phylum Bacteroidetes (p = 0.005) and 24% less Firmicutes (p = 0.002). Within Firmicutes, four families and their 8 genera, which were short-chain fatty acids-producing and 7α-dehydroxylating bacteria, were significantly decreased. Moreover, Gram-negative (G-) bacteria were prevalent in NAFLD (p = 0.008). Furthermore, a significant correlation with metabolic markers was revealed for disturbed microbiota in NAFLD. This novel study indicated that intestinal dysbiosis was associated with nonobese NAFLD and might increase the risk of NAFLD progression.

The Effect of Probiotic Treatment on Patients Infected with the H7N9 Influenza Virus.

BACKGROUND: A novel avian-origin influenza A (H7N9) virus emerged and spread among humans in Eastern China in 2013. Prophylactic treatment with antibiotics and probiotics for secondary infection is as important as antiviral treatment. This study aims to assess the ability of probiotic treatment to restore internal homeostasis under antibiotic pressure and to reduce/ameliorate the risk of secondary infections resulting from infection with the H7N9 virus. METHODS: This is a retrospective study in archival samples. Between April 1 and May 10, 2013, 113 stool, sputum, and blood specimens were collected and analyzed by denaturing gradient gel electrophoresis (DGGE) to determine the composition of the patient microbiomes. Microbial diversity was calculated using Gel-Pro analyzer and Past software. Cluster analysis of DGGE pattern profiles was employed to create a phylogenetic tree for each patient, and multidimensional scaling (MDS) and principal component analysis (PCA) were performed to visualize relationships between individual lanes. RESULTS: Five patients had secondary infections, including Klebsiella pneumonia, Acinetobacter baumanii and Candida albicans infection. The DGGE profiles of fecal samples obtained at different time points from the same individual were clearly different, particularly for patients with secondary infections. Shannon's diversity index and evenness index were lower in all infected groups compared to the control group. After B. subtilis and E. faecium or C. butyricum administration, the fecal bacterial profiles of patients who had not been treated with antibiotics displayed a trend of increasing diversity and evenness. C. butyricum failed to reduce/ameliorate secondary infection in H7N9-infected patients, but administration of B. subtilis and E. faecium appeared to reduce/ameliorate secondary infection in one patient. CONCLUSION: H7N9 infection might decrease intestinal microbial diversity and species richness in humans. C. butyricum failed to reduce/ameliorate secondary infection in H7N9-infected patients. B. subtilis and E. faecium may also play a role in reducing/ameliorating secondary infection in these patients.

A modified prognostic score for critically ill patients with cirrhosis: An observational study.

BACKGROUND AND AIMS: It is controversial whether patients with cirrhosis benefit from the intensive care unit (ICU) management. To identify the patients in whom ICU care may offer recovery, this study aimed to determine specific risk factors and to establish a novel prognostic score for 3-month mortality in critically ill patients with cirrhosis. METHODS: An observational study was performed from August 2008 to May 2014, encompassing 349 critically ill patients with cirrhosis during their ICU stay (a 70% training and 30% validation set). RESULTS: The overall 3-month mortality rate was 68.1% in training cohort. Prothrombin time, serum bilirubin, use of vasopressors, hepatic encephalopathy, and systemic inflammatory response syndrome at admission were identified as being strongly correlated with the 3-month prognosis. Based on these five variables, a modified score for critically ill cirrhosis (MSCIC) was developed. An increasing MSCIC was significantly correlated with a reduction in the rate of survival (P < 0.001). Moreover, excellent predictive power was found when the MSCIC was used (area under the receiver operating characteristic curve: 0.856 ± 0.047), which was significantly better than the prognostic efficiency of Acute Physiology and Chronic Health Evaluation II (P < 0.001), Model for End-stage Liver Disease (P = 0.02), Simplified Acute Physiology Score (P = 0.023), and the Child-Turcotte-Pugh score (P = 0.01); the MSCIC score was slightly better than that of Chronic Liver Failure-Sequential Organ Failure Assessment (P = 0.068). The similar result was obtained in validation set. CONCLUSIONS: The MSCIC is an easily adopted tool with a high prognostic efficacy for patients with advanced cirrhosis; MSCIC may act as a supplement to the clinical judgment of physicians when considering the prognosis.

Clinical, virological, and histopathological manifestations of fatal human infections by avian influenza A(H7N9) virus.

BACKGROUND: Systematic analysis of histopathological and serial virological changes of fatal influenza A(H7N9) cases is lacking. METHODS: Patients with A(H7N9) infection admitted to our intensive care unit during 10-23 April 2013 were included. Viral loads in the respiratory tract, as inferred from the cycle threshold (Ct) value of reverse transcription polymerase chain reaction (RT-PCR), and the serum hemagglutination inhibition (HAI) antibody titer, were analyzed. Postmortem biopsies of the lung, liver, kidney, spleen, bone marrow, and heart were examined. RESULTS: Twelve patients (6 deaths, 6 survivors) were included. Median viral load was higher in sputa than the nasopharyngeal swabs for fatal cases (median Ct, 23 vs 30.5; P = .08). RT-PCR for A(H7N9) was positive in stool samples (4/6 [67%]) of fatal cases and (2/6 [33%]) of survivors, but was negative in the cerebrospinal fluid, urine, or blood of all patients. Nosocomial bacterial infections were more common in patients who died than in survivors (83% vs 50%). HAI titers increased by ≥4-fold in those with convalescent sera. Postmortem biopsy for 3 patients showed acute diffuse alveolar damage. Patient 1, who died 8 days after symptom onset, had intra-alveolar hemorrhage. Patients 2 and 3, who died 11 days after symptom onset, had pulmonary fibroproliferative changes. Reactive hemophagocytosis in the bone marrow and lymphoid atrophy in splenic tissues were compatible with laboratory findings of leukopenia, lymphopenia, and thrombocytopenia. Hypoxic and fatty changes of kidney and liver tissues are compatible with impaired renal or liver function. CONCLUSIONS: Fatal A(H7N9) infection was characterized by viral and secondary bacterial pneumonia with 67% having positive RT-PCR in stool.