Comparative cardiovascular risk in users versus non-users of xanthine oxidase inhibitors and febuxostat versus allopurinol users

OBJECTIVES: The aim of this study is to determine major adverse cardiovascular events (MACE) and all-cause mortality comparing between xanthine oxidase inhibitors (XOIs) and non-XOI users, and between allopurinol and febuxostat. METHODS: This is a retrospective cohort study of gout patients prescribed anti-hyperuricemic medications between 2013 and 2017 using a territory-wide administrative database. XOI users were matched 1:1 to XOI non-users using propensity scores. Febuxostat users were matched 1:3 to allopurinol users. Subgroup analyses were conducted based on colchicine use. RESULTS: Of the 13 997 eligible participants, 3607 (25.8%) were XOI users and 10 390 (74.2%) were XOI non-users. After propensity score matching, compared with non-users (n = 3607), XOI users (n = 3607) showed similar incidence of MACE (hazard ratio [HR]: 0.997, 95% CI, 0.879, 1.131; P>0.05) and all-cause mortality (HR = 0.972, 95% CI 0.886, 1.065, P=0.539). Febuxostat (n = 276) users showed a similar risk of MACE compared with allopurinol users (n = 828; HR: 0.672, 95% CI, 0.416, 1.085; P=0.104) with a tendency towards a lower risk of heart failure-related hospitalizations (HR = 0.529, 95% CI 0.272, 1.029; P=0.061). Concurrent colchicine use reduced the risk for all-cause mortality amongst XOI users (HR = 0.671, 95% 0.586, 0.768; P<0.001). CONCLUSION: In gout patients, XOI users showed similar risk of MACE and all-cause mortality compared with non-users. Compared with allopurinol users, febuxostat users showed similar MACE and all-cause mortality risks but lower heart failure-related hospitalizations

PIN1 is over-expressed in hepatocellular carcinoma (HCC) and correlates with an increased beta-catenin and cyclin D1 protein levels

INTRODUCTION: In hepatocellular carcinoma, the expression of beta-catenin and cyclin D1 is increased, which may be of pathogenetic significance. As mutations of the beta-catenin gene are only found in around 20% of cases, other factors are involved in the accumulation of beta-catenin and cyclin D1. PIN1, a peptidyl-proplyl-isomerase, has been shown to stabilize both beta-catenin and cyclin D1, and to up-regulate cyclin D1 gene expression. We hypothesize that the beta-catenin and cyclin D1 accumulation in some of the HCC is contributed by PIN over-expression. METHODS: The expression of PIN1 in 23 paired-samples of neoplastic and non-neoplastic liver tissues was examined by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry and Western blot analysis. Immunohistochemistry was also performed on another 28 paired archival samples of HCC to detect PIN1, beta-catenin and cyclin D1 expression. RESULTS: Compared with paired non-neoplastic liver tissues, 12 of 23 (52%) HCC samples showed an increase in PIN1 expression by semi-quantitative RT-PCR. These cases also showed beta-catenin accumulation, and sequencing of exon 3 of the beta-catenin gene did not show any mutation. Together with the archival materials, PIN1 was found to be over-expressed by immunohistochemistry and Western blot analysis in 26 of 45 tumors (58%), all of which had concomitant accumulation of beta-catenin. Another 5 cases had beta-catenin accumulation without PIN1 over-expression, so that the overall frequency of beta-catenin over-expression was 68% (31/45). In 3 cases with beta-catenin accumulation but no PIN1 over-expression, 2 cases showed mutation in the exon 3 of the beta-catenin gene. Finally, 19 of 26 cases with PIN1 over-expression also had increase in cyclin D1 expression. CONCLUSION: PIN1 expression is increased in a significant proportion of HCC. There is a positive correlation between PIN1, and beta -catenin and cyclin D1 expression, which suggests that PIN1 may be critically involved in hepatocarcinogenesis