Gene variation profile and it's potential correlation with clinical characteristics in HBV-associated HCC patients of Sichuan Han nationality in China.

OBJECTIVE: To explore the correlation between hepatocellular carcinoma (HCC) gene variation profile and clinical characteristics in Han nationality with HBV infection in Sichuan province. METHODS: The clinical data and HCC tissues were obtained from the enrolled patients. Whole exome sequencing and bioinformatics analysis were performed on formalin-fixed and paraffin-embedded samples from HCC. Tumor mutational burden (TMB) was measured by an algorithm developed in-house. RESULTS: Sixteen high-frequency mutated genes with differential expressions were identified by WES. SMG1 gene variation could be positively correlated with satellite lesions. AMY2B and RGPD4 gene mutation seemed to have a greater chance of vascular invasion. The patients with TATDN1 variation have bigger diameters and greater chances of vascular and microvascular invasion (all P < 0.05). Univariate analysis indicated patients with gene TATDN1 variation had worse prognoses both in disease free survival (DFS) and overall survival (OS). In addition, the enrichment analysis showed many pathways, including the cell cycle pathway, viral oncogene pathway, MAPK pathway, PI3K-AKT pathway, etc., may be associated with HCC. CONCLUSION: This study explores the gene variation profile of HCC patients with HBV infection in Han nationality of Sichuan Province for the first time, which confirmed the existence of some high-frequency mutated genes and the possibility that the gene variations are involved in the tumorigenesis of HCC through multiple signal pathways. Also, patients with TATDN1 wild type showed a trend of better prognosis both in DFS and OS.

Structure-cardiac activity relationship of C19-diterpenoid alkaloids.

Thirty three C19-diterpenoid alkaloids, twenty-two prepared from known C19-diterpenoid alkaloids and eleven isolated from Aconitum and Delphinium spp. were evaluated for their cardiac activity in the isolated bullfrog heart assay. Among them, eleven compounds exhibited cardiac activity, with average rate of amplitude increase in the range of 16-118%. Compound 7, mesaconine (17), hypaconine (25), and beiwutinine (26) exhibited strong cardiac activities relative to the reference drug. The structure-activity relationship data acquired indicated that an alpha-hydroxyl group at C-15, a hydroxyl group at C-8, an alpha-methoxyl or hydroxyl group at C-1, and a secondary amine or N-methyl group in ring A are important structure features necessary for the cardiac activities of the aconitine-type C19-diterpenoid alkaloids without any ester groups. In addition, an alpha-hydroxyl group at C-3 is also helpful for the cardiac activity of these alkaloids.

Studies on the relative reactivity of three hydroxyl groups in aconitine.

The relative reactivity of three hydroxyl groups in aconitine toward acetylation, chlorination, sulfonylation, and oxidation has been studied in this paper. The reduction of C-3 ketone and C-15 ketone derivatives of aconitine was also investigated. It was found that (1) the relative reactivity of three hydroxyl groups toward acetylation, chlorination, and sulfonylation is 3-OH>13-OH>>15-OH; (2) 3-OH is much more reactive than 15-OH toward oxidation; and (3) reduction of the carbonyl group at C-3 with NaBH(4) generated a pair of C-3 epimers, while the reduction products of the carbonyl group at C-15 depend largely on the specific reducing agent and the absolute configuration of 16-OCH(3). When the substrate has 16ß-OCH(3), its carbonyl group at C-15 can be reduced with NaBH(4) to yield exclusively the 15α-OH-containing product. Upon replacement of reducing agent NaBH(4) with LiAlH(4), the C-15 carbonyl group can be reduced to yield a pair of C-15 epimers. On the other hand, when the substrate has 16α-OCH(3), C-15 carbonyl group can only be reduced to generate 15α-OH-containing product.

Conversional synthesis and cytotoxic evaluation of novel taxoid analogs.

Four novel taxoid analogs were conversionally synthesized from the C(19)-diterpenoid alkaloid deltaline, and their cytotoxic activities were evaluated against a small panel of cancer cell lines.