Transcatheter arterial chemoembolization plus apatinib with or without camrelizumab for unresectable hepatocellular carcinoma: a multicenter retrospective cohort study.

BACKGROUND: The evidence of transcatheter arterial chemoembolization (TACE) plus tyrosine kinase inhibitor and immune checkpoint inhibitor in unresectable hepatocellular carcinoma (HCC) was limited. This study aimed to evaluate the role of TACE plus apatinib (TACE + A) and TACE combined with apatinib plus camrelizumab (TACE + AC) in patients with unresectable HCC. METHODS: This study retrospectively reviewed patients with unresectable HCC who received TACE + A or TACE + AC in 20 centers of China from January 1, 2019 to June 31, 2021. Propensity score matching (PSM) at 1:1 was performed to reduce bias. Treatment-related adverse events (TRAEs), overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were collected. RESULTS: A total of 960 eligible patients with HCC were included in the final analysis. After PSM, there were 449 patients in each group, and the baseline characteristics were balanced between two groups. At data cutoff, the median follow-up time was 16.3 (range: 11.9-21.4) months. After PSM, the TACE + AC group showed longer median OS (24.5 vs 18.0 months, p < 0.001) and PFS (10.8 vs 7.7 months, p < 0.001) than the TACE + A group; the ORR (49.9% vs 42.5%, p = 0.002) and DCR (88.4% vs 84.0%, p = 0.003) of the TACE + AC group were also higher than those in the TACE + A group. Fever, pain, hypertension and hand-foot syndrome were the more common TRAEs in two groups. CONCLUSIONS: Both TACE plus apatinib and TACE combined with apatinib plus camrelizumab were feasible in patients with unresectable HCC, with manageable safety profiles. Moreover, TACE combined with apatinib plus camrelizumab showed additional benefit.

Single Nucleotide Polymorphisms in Key One-Carbon Metabolism Genes and Their Association with Blood Folate and Homocysteine Levels in a Chinese Population in Yunnan.

OBJECTIVE: One-carbon metabolism (OCM) is essential for DNA synthesis and methylation. Single nucleotide polymorphisms (SNPs) within OCM genes may affect folic acid (FA) metabolism, disrupt homocysteine (Hcy) homeostasis, and increase the risk of disease. This study investigated the relationship between SNPs in key OCM genes and their association with blood FA and Hcy levels in a healthy population in Yunnan, China. METHODS: Six SNPs within five key OCM genes (MTHFR C677T, MTHFR A1298C, MS A2756G, MTRR A66G, CBS T833C, and SHMT C1420T) were genotyped in 300 healthy volunteers (148 males and 152 females) using polymerase chain reaction/restriction fragment length polymorphism. Blood folate [serum FA (SFA) and red blood cell folate (RBC FA)] and Hcy levels were determined by chemiluminescence immunoassays and enzymatic assays. RESULTS: Subjects with the MTHFR 677TT genotype had significantly higher Hcy levels and RBC FA concentrations compared with those harboring the MTHFR 677CC/CT genotypes (p < 0.01). Both Hcy and blood FA concentrations were also increased in subjects with MS 2756AA, as well as those within CBS 833TT, when compared with those with MS 2756AG/GG (p < 0.05) and CBS 833TC/CC (p < 0.05) genotypes, respectively. Subjects harboring the combined genotype of MTHFR 677TT and MS 2756AA had a higher Hcy concentration than those carrying other MTHFR and MS combinations (p = 0.002). Similarly, subjects harboring the combination of CBS 833TT with MTHFR 677TT had higher Hcy concentrations than those harboring other CBS and MTHFR combinations (p = 0.011). CONCLUSIONS: The genotypes involving the MTHFR C677T, MS A2756G, and CBS T833C polymorphisms, including combinations of these genotypes, were the most important factors associated with blood FA and Hcy levels of the investigated SNPs in the OCM genes.

Response of MiRNA-22-3p and MiRNA-149-5p to Folate Deficiency and the Differential Regulation of MTHFR Expression in Normal and Cancerous Human Hepatocytes.

BACKGROUND/AIMS: Folic acid (FA) is a core micronutrient involved in DNA synthesis/methylation, and the metabolism of FA is responsible for genomic stability. MicroRNAs may affect gene expression during folate metabolism when cellular homeostasis is changed. This study aimed to reveal the relationship between FA deficiency and the expression of miR-22-p/miR-149-5p and the targeted regulation of miR-22-3p/miR-149-5p on the key folate metabolic gene Methylenetetrahydrofolate reductase (MTHFR). METHODS: Normal (HL-7702 cells) and cancerous (QGY-7703 cells) human hepatocytes were intervened in modified RPMI 1640 with FA deficiency for 21 days. The interaction between MTHFR and the tested miRNAs was verified by Dual-Luciferase Reporter Assays. The changes in the expression of miR-22-3p/miR-149-5p in response to FA deficiency were detected by Poly (A) Tailing RT-qPCR, and the expression of MTHFR at both the transcriptional and translational levels was determined by RT-qPCR and Western blotting, respectively. RESULT: MiR-22-3p/miR-149-5p directly targeted the 3'UTR sequence of the MTHFR gene. FA deficiency led to an upregulation of miR-22-3p/miR-149-5p expression in QGY-7703/HL-7702 cells, while the transcription of MTHFR was decreased in QGY-7703 cells but elevated in HL-7702 cells. Western blotting showed that FA deficiency resulted in a decline of the MTHFR protein in QGY-7703 cells, whereas in HL-7702 cells, the MTHFR protein level remained constant. CONCLUSION: The results suggested that miR-22-3p/miR-149-5p exert different post-transcriptional effects on MTHFR under conditions of FA deficiency in normal and cancerous human hepatocytes. The results also implied that miR-22-3p/miR-149-5p might exert anticancer effects in cases of long-term FA deficiency.