Intricate effects of post-translational modifications in liver cancer: mechanisms to clinical applications.

Liver cancer is a significant global health challenge, with hepatocellular carcinoma (HCC) being the most prevalent form, characterized by high incidence and mortality rates. Despite advances in targeted therapies and immunotherapies, the prognosis for advanced liver cancer remains poor. This underscores the urgent need for a deeper understanding of the molecular mechanisms underlying HCC to enable early detection and the development of novel therapeutic strategies. Post-translational modifications (PTMs) are crucial regulatory mechanisms in cellular biology, affecting protein functionality, interactions, and localization. These modifications, including phosphorylation, acetylation, methylation, ubiquitination, and glycosylation, occur after protein synthesis and play vital roles in various cellular processes. Recent advances in proteomics and molecular biology have highlighted the complex networks of PTMs, emphasizing their critical role in maintaining cellular homeostasis and disease pathogenesis. Dysregulation of PTMs has been associated with several malignant cellular processes in HCC, such as altered cell proliferation, migration, immune evasion, and metabolic reprogramming, contributing to tumor growth and metastasis. This review aims to provide a comprehensive understanding of the pathological mechanisms and clinical implications of various PTMs in liver cancer. By exploring the multifaceted interactions of PTMs and their impact on liver cancer progression, we highlight the potential of PTMs as biomarkers and therapeutic targets. The significance of this review lies in its potential to inform the development of novel therapeutic approaches and improve prognostic tools for early intervention in the fight against liver cancer.

The impact of Karnofsky performance status on prognosis of patients with hepatocellular carcinoma in liver transplantation.

BACKGROUND: Functional performance as measured by the Karnofsky Performance Status (KPS) scale has been linked to the outcomes of liver transplant patients; however, the effect of KPS on the outcomes of the hepatocellular carcinoma (HCC) liver transplant population has not been fully elucidated. We aimed to investigate the association between pre-transplant KPS score and long-term outcomes in HCC patients listed for liver transplantation. METHODS: Adult HCC candidates listed on the Scientific Registry of Transplant Recipients (SRTR) database from January 1, 2011 to December 31, 2017 were grouped into group I (KPS 80-100%, n = 8,379), group II (KPS 50-70%, n = 8,091), and group III (KPS 10-40%, n = 1,256) based on percentage KPS score at listing. Survival was compared and multivariable analysis was performed to identify independent predictors. RESULTS: Patients with low KPS score had a higher risk of removal from the waiting list. The 5-year intent-to-treat survival was 57.7% in group I, 53.2% in group II and 46.7% in group III (P < 0.001). The corresponding overall survival was 77.6%, 73.7% and 66.3% in three groups, respectively (P < 0.001). Multivariable analysis demonstrated that KPS was an independent predictor of intent-to-treat survival (P < 0.001, reference group I; HR 1.19 [95%CI 1.07-1.31] for group II, P = 0.001; HR 1.63 [95%CI 1.34-1.99] for group III, P < 0.001) and overall survival(P < 0.001, reference group I; HR 1.16 [95%CI 1.05-1.28] for group II, P = 0.004; HR 1.53 [95%CI 1.26-1.87] for group III, P < 0.001). The cumulative 5-year recurrence rates was higher in group III patients (7.4%), compared with 5.2% in group I and 5.5% in group II (P = 0.037). However, this was not significant in the competing regression analysis. CONCLUSIONS: Low pre-transplant KPS score is associated with inferior long-term survival in liver transplant HCC patients, but is not significantly associated with post-transplant tumor recurrence.

Exploring the role of m7G modification in Cancer: Mechanisms, regulatory proteins, and biomarker potential.

The dysregulation of N(7)-methylguanosine (m7G) modification is increasingly recognized as a key factor in the pathogenesis of cancers. Aberrant expression of these regulatory proteins in various cancers, including lung, liver, and bladder cancers, suggests a universal role in tumorigenesis. Studies have established a strong correlation between the expression levels of m7G regulatory proteins, such as Methyltransferase like 1 (METTL1) and WD repeat domain 4 (WDR4), and clinical parameters including tumor stage, grade, and patient prognosis. For example, in hepatocellular carcinoma, high METTL1 expression is associated with advanced tumor stage and poor prognosis. Similarly, WDR4 overexpression in colorectal cancer correlates with increased tumor invasiveness and reduced patient survival. This correlation underscores the potential of these proteins as valuable biomarkers for cancer diagnosis and prognosis. Additionally, m7G modification regulatory proteins influence cancer progression by modulating the expression of target genes involved in critical biological processes, including cell proliferation, apoptosis, migration, and invasion. Their ability to regulate these processes highlights their significance in the intricate network of molecular interactions driving tumor development and metastasis. Given their pivotal role in cancer biology, m7G modification regulatory proteins are emerging as promising therapeutic targets. Targeting these proteins could offer a novel approach to disrupt the malignant behavior of cancer cells and enhance treatment outcomes. Furthermore, their diagnostic and prognostic value could aid in the early detection of cancer and the selection of appropriate therapeutic strategies, ultimately enhancing patient management and survival rates. This review aims to explore the mechanisms of action of RNA m7G modification regulatory proteins in tumors and their potential applications in cancer progression and treatment. By delving into the roles of these regulatory proteins, we intend to provide a theoretical foundation for the development of novel cancer treatment strategies.

Impact of Donor Age on Liver Transplant Outcomes in Patients with Acute-on-Chronic Liver Failure: A Cohort Study.

Background/Aims: Liver transplantation is the most effective treatment for the sickest patients with acute-on-chronic liver failure (ACLF). However, the influence of donor age on liver transplantation, especially in ACLF patients, is still unclear. Methods: In this study, we used the data of the Scientific Registry of Transplant Recipients. We included patients with ACLF who received liver transplantation from January 1, 2007, to December 31, 2017, and the total number was 13,857. We allocated the ACLF recipients by age into group I (donor age ≤17 years, n=647); group II (donor age 18-59 years, n=11,423); and group III (donor age ≥60 years, n=1,787). Overall survival (OS), graft survival, and mortality were compared among the three age groups and the four ACLF grades. Cox regression was also analyzed. Results: The 1-, 3-, and 5-year OS rates were 89.6%, 85.5%, and 82.0% in group I; 89.4%, 83.4%, and 78.2% in group II; and 86.8%, 78.4%, and 71.4% in group III, respectively (p<0.001). When we analyzed the different effects of donor age on OS with different ACLF grades, in groups II and III, we observed statistical differences. Finally, the cubic spline curve told us that the relative death rate changed linearly with increasing donor age. Conclusions: Donor age is related to OS and graft survival of ACLF patients after transplantation, and poorer results were associated with elderly donors. In addition, different donor ages have different effects on recipients with different ACLF grades.

The interaction of T2DM and BMI with NASH in recipients of liver transplants: an SRTR database analysis.

BACKGROUND: NASH-related liver transplants are increasing because of the obesity epidemic, but the influence of T2DM on various levels of BMI among NASH recipients is unclear. RESEARCH DESIGN AND METHODS: We analyzed data retrieved from SRTR on 4,515 patients. We divided patients by BMI into five groups: normal weight; overweight; class 1 obesity; class 2 obesity; and class 3 obesity. Statistical analysis was done. RESULTS: Patients in the NASH group with T2DM had a lower patient and graft survival than patients without T2DM (5-year patient and graft survival: 77.5% vs. 79.8%; P = 0.001 and 76.4% vs. 78.2%; P = 0.002, respectively). Multivariate Cox proportional regression showed an independent association between T2DM and decreased patient and graft survival (HR, 1.170; P = 0.015 and HR, 1.133; P = 0.048, respectively). In the lean and the class 3 obesity NASH groups, patients with T2DM had lower patient and graft survival than the patients without T2DM. In the class 3 obesity NASH group, T2DM was independently associated with decreased patient survival (HR, 1.581; P = 0.027). CONCLUSION: Our research reveals that the focus of the post-transplantation treatment should be different for different BMI patients.

Impact of donor diabetes mellitus status on liver transplant outcomes in patients with acute-on-chronic liver failure.

BACKGROUND: Liver transplantation (LT) is the most effective way to save patients with acute-on-chronic liver failure (ACLF). However, the impact of donor diabetes mellitus (DM) on LT outcomes in patients with ACLF has not been fully investigated. RESEARCH DESIGN AND METHODS: We retrospectively analyzed data from the Scientific Registry of Transplant Recipients (SRTR) between January 1st, 2008 to December 31st, 2017 in this study. All the patients were divided into donors with DM and without DM group (DM: 1,394; non-DM: 11138). We compared the overall survival (OS) and graft survival (GS) across different estimated ACLF (estACLF) grades between two groups. RESULTS: There were 25.10% estACLF-3 patients in the entire cohort. And in estACLF-3 patients, 318 patients had DM donors. The estACLF-3 associated 5-year OS rate in the non-DM group was 74.6%, significantly better than that in the DM group, with corresponding survival rate at 64.9% (P < 0.001). Donor DM was an independent predictor for OS in the entire cohort as well as in estACLF-3 patients. CONCLUSIONS: Donor DM was associated with inferior outcomes of LT in patients with estACLF-3. However, the differences were not obvious in recipients with other estACLF grades.