Incidence, survival, and diagnostic trends in GCA across seven decades in a North American population-based cohort.

OBJECTIVES: To analyze trends in the incidence and use of diagnostic modalities for GCA in a population-based cohort over the past seven decades. To explore survival trends in patients with GCA compared with the general population. METHODS: A population-based cohort of patients diagnosed with GCA was extended with new incident cases from 2010 to 2019. Three time periods were compared: Period One (1950-1979), Period Two (1980-1999), and Period Three (2000-2019). Cases were classified as: Diagnostic Group One, temporal artery biopsy (TAB) positive; Diagnostic Group Two, TAB-negative or not done with positive large-vessel imaging; or Diagnostic Group Three, clinical diagnosis of GCA. Survival was evaluated by comparing Kaplan-Meier estimated mortality rates for cases of GCA against expected mortality rates from Minnesota life tables RESULTS: Age- and sex-adjusted incident rates per 100,000 ≥ 50 years of age (95% CI) were 13.5 (10.1, 16.9) in Period One, 21.0 (17.1, 25.0) in Period Two, and 15.0 (12.4, 17.5) in Period Three. The percent of patients in Diagnostic Group One decreased over the three time periods (89%, 86%, and 72%) while the patients in Diagnostic Group Three increased (11%, 14%, and 17%). Standardized mortality ratios (95% CI) were 1.03 (0.79, 1.32), 1.11 (0.91, 1.34), and 0.82 (0.64, 1.04) across Periods 1-3, respectively. CONCLUSIONS: Incidence of GCA in females in the population declined, resulting in a decreasing overall incidence. More patients have been identified by large-vessel imaging and fewer by positive TABs. No significant difference in survival between patients with GCA and the general population was observed.

SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Improved treatments for advanced HCC are urgently needed. The recently identified human sulfatase 1 enzyme (SULF1) desulfates cell surface heparan sulfate glycosaminoglycans and down-regulates cell growth signaling in HCC cells in vitro. While investigating the epigenetic regulation of SULF1, we discovered that histone H4 acetylation is up-regulated by SULF1 in HCC cells. Histone deacetylase (HDAC) inhibitors reprogram cellular gene expression through the acetylation of nucleosomal histones and promote cell growth arrest and apoptosis. Hence, they are a promising modality for cancer treatment. METHODS: To explore the interaction between SULF1 expression and HDAC inhibitor action, we examined the effects of SULF1 expression on HCC cells and xenografts treated with HDAC inhibitors. RESULTS: (1) Forced expression of SULF1 significantly delayed the growth of Huh7 and Hep3B xenografts in nude mice in vivo. (2) SULF1 increased histone H4 acetylation by modulation of cellular HDAC and histone acetyltransferase activities. (3) SULF1 enhanced the induction of apoptosis by the HDAC inhibitors apicidin and scriptaid. (4) SULF1 enhanced the inhibition of tumor growth, migration, and angiogenesis by HDAC inhibitors. We also demonstrate that knockdown of SULF1 with shRNA constructs up-regulates phosphorylation of AKT and Erk and attenuates apicidin-induced apoptosis. The interaction between SULF1 and apicidin was confirmed in vivo in Huh7 and Hep3B xenografts. CONCLUSIONS: These results show that SULF1 promotes histone H4 acetylation, potentiates the effects of HDAC inhibitors, and inhibits HCC tumorigenesis.