Adoption of single agent anticancer therapy for advanced hepatocellular carcinoma and impact of facility type, insurance status, and income on survival: Analysis of the national cancer database 2004-2014.

BACKGROUND: This study analyzes the pattern of use of single agent anticancer therapy (SAACT) in the treatment and survival of advanced hepatocellular carcinoma (aHCC) before and after sorafenib was FDA approved in 2007. METHODS: Adult patients diagnosed with HCC and treated with only ACT from 2004 - 2014 were identified in NCDB database. Patients were analyzed during three time frames: 2004-2006 (pre-sorafenib (PS)), 2007-2010 (early sorafenib (ES)) and 2011-2014 (late sorafenib (LS)). Cox proportional hazards models and Kaplan-Meier method were used for analyses. RESULTS: The NCDB contained 31,107 patients with HCC diagnosed from 2004-2014 and treated with ACT alone. Patients were generally men (78.0%), >50 years of age (92.5%). A significant increase in the rate of adaption of SAACT was observed over time: 6.2% PS, 15.2% ES, and 22.2% LS (p < 0.0001). During this later period, the highest proportion of SAACT is among academic and integrated network facilities (23.3%) as compared to community facilities (17.0%, p < 0.0001). The median overall survival of patients with aHCC treated only with SAACT improved significantly over time from 8.0 months (m) (95% CI: 7.4-8.8) to 10.7 m (10.4-11.2) to 15.6 m (15.2-16.0, p < 0.001). Multivariate analysis indicates worse outcomes for patients treated at community cancer programs (HR 1.28, (5% CI: 1.23-1.32), patients without insurance (HR 1.11, 1.06-1.16) and estimated household income of <$63,000 (HR 1.09, 1.05-1.13). CONCLUSION: aHCC patients treated only with ACT have experienced an overall improvement in survival, but significant differences exist between facility type, insurance status, and income.

Kinetic characterization of protein arginine deiminase 4: a transcriptional corepressor implicated in the onset and progression of rheumatoid arthritis.

Protein arginine deiminase 4 (PAD4) is a Ca(2+)-dependent enzyme that catalyzes the posttranslational conversion of arginine to citrulline (Arg --> Cit) in a number of proteins, including histones. While the gene encoding this enzyme has been implicated in the pathophysiology of rheumatoid arthritis (RA), little is known about its mechanism of catalysis, its in vivo role, or its role in the pathophysiology of RA; however, recent reports suggest that this enzyme can act as a transcriptional corepressor for the estrogen receptor. Herein, we report our initial kinetic and mechanistic characterization of human PAD4. Specifically, these studies confirm that PAD4 catalyzes the hydrolytic deimination of Arg residues to produce Cit and ammonia. The metal dependence of PAD4 has also been evaluated, and the results indicate that PAD4 activity is highly specific for calcium. Calcium activation of PAD4 catalysis exhibits positive cooperativity with K(0.5) values in the mid to high micromolar range. Evidence indicating that calcium binding causes a conformational change is also presented. Additionally, the steady-state kinetic parameters for a number of histone H4-based peptide substrates and benzoylated Arg derivatives have been determined. K(m) values for these compounds are in the high micromolar to the low millimolar range with k(cat) values ranging from 2.8 to 6.6 s(-)(1). The ability of PAD4 to catalyze the deimination of methylated Arg residues has also been evaluated, and the results indicate that these compounds are poor PAD4 substrates (V/K