RESUMO
INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC), a malignancy with a very dismal prognosis, has drawn a lot of attention, particularly in East Asia, where morbidity and mortality are higher. Although new information about the role of fatty acids (FAs) in HCC is constantly being discovered, it is still vital to investigate how FA metabolism affects the prognosis, immune microenvironment, and responsiveness of HCC to immunotherapy as a whole. MATERIALS AND METHODS: To determine the significance of FA metabolism in HCC immunotherapy, we first evaluated HCC samples from the single-cell dataset GSE151530. The TCGA-LIHC cohort and GSE140901 were further studied to identify the impact of FA metabolism on prognosis, immune microenvironment, drug sensitivity, and immunotherapy response by developing a fatty acid prediction index (FPI). The heterogeneity and similarity of the involvement of FA metabolism in pan-cancer is also investigated. RESULTS: Combining single-cell and bulk analyses, we confirmed that FA metabolism regulates tumor malignancy, prognosis, immune microenvironment, drug sensitivity, and immunotherapy response in patients with HCC. Moreover, it can have a considerable impact on the physiological activities of hepatocellular cancer. In addition, we demonstrate that FA metabolism has a comparable or same role in many malignancies. CONCLUSIONS: Our investigation shows the crucial regulatory role of FA metabolism in HCC and suggests a potential therapeutic method for HCC patients, which may improve their survival.
RESUMO
Background: Although accumulating literature has validated that necroptosis plays a prominent role in the tumorigenesis and progression of various malignant cancer, its mechanism in hepatocellular carcinoma (HCC) is poorly understood. Therefore, in the present study, we want to study the impact of necroptosis-related genes on the prognosis and microenvironment-infiltrating immunocytes and the effect of immunotherapy on patients with HCC. Methods: The necroptosis-related genes were obtained by reviewing the available published literature; we then evaluated the effects of the prognostic genes on the relative abundance of microenvironment infiltrated immunocytes. After construction of the Risk Score Signature, we evaluated the prognostic value and the effects on immune cells infiltrating the tumor microenvironment (TME). Combining the available data on immunotherapy, we also investigated the impact on anti-PD-L1-based immunotherapy. Results: A comprehensive study of the published literature confirmed that 22 genes are related to necroptosis. Among them, 10 genes were related to the prognosis of the HCC cohort in The Cancer Genome Atlas (TCGA) and had a multifaceted influence on TME. We obtained the Risk Score Signature by Lasso regression. Furthermore, we also corroborated the correlation between the Risk Score Signature and tumor-infiltrating immune cells in the TME. Next, in the study of the correlation between the Signature and immunotherapy, we found that the Signature was significantly correlated with the reactivity of anti-PD-L1 immunotherapy. We also confirmed that the Risk Score Signature is a reliable and efficient independent prognostic marker of HCC. Conclusion: We established a novel and effective prognostic model for patients with HCC, which is markedly related to the TME and immune infiltration in HCC and can also predict immunotherapeutic response and prognosis.
RESUMO
BACKGROUND: For liver transplant (LT) recipients, the liver CYP3A5 metabolic enzymes are determined by the donor's genes, whereas the intestinal enzymes are encoded by the recipient's genes. This combinational form confuses the metabolism of tacrolimus (Tac) in vivo. This retrospective study was conducted to investigate the combined effects of donor-recipient CYP3A5 genotype on tacrolimus pharmacokinetics in Chinese LT adult patients. METHODS: Three hundred seventy-three LT patients from two Chinese organ transplant centers were enrolled, and both recipients and donors were genotyped for CYP3A5. Patients were divided into four groups (RNDN, REDN, RNDE, REDE) according to CYP3A5*3 allele expressers (E) and non-expressers (N) in recipients (R) and donors (D). The dose-adjusted trough levels (C/D ratio) of tacrolimus were assessed for six months among the four groups. Multiple linear regression analysis was performed to assess the effects of the CYP3A5 genotype and several clinical variables on the C/D ratio. RESULTS: The RNDN group consistently had the largest C/D ratio throughout the entire study period, whereas the REDE group had the smallest C/D ratio, and the REDN/RNDE group had an intermediate (RNDN > REDN/RNDE > REDE) ratio. The C/D ratio in the RNDN and RNDE groups was higher than that in the REDN and REDE groups within three months, respectively; the ratio in the RNDN group was higher than that in the RNDE group, and the ratio in the REDN group was higher than that in the REDE group at six months. The effect of the donor CYP3A5 genotype on C/D values was observed throughout the timeline, and the recipient's genetics correlated only in the first three months. Among non-genetic factors, hemoglobin (HGB) and albumin (ALB) were correlated with Tac C/D values at a few time points. CONCLUSIONS: To predict the initial dose of tacrolimus in LT patients, both donor and recipient CYP3A5 genotypes must be taken into account; during the maintenance phase of targeted blood concentration, the donor's CYP3A5 genotype may be of prime importance, especially at three months after transplantation.