Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study

Introduction: The aim of this study was to characterize anti-citrullinated peptide antibody (ACPA) serostatus in pre-clinical rheumatoid arthritis (RA) with and without Human Leukocyte Antigen-Shared Epitope (HLA-SE) alleles. Methods: We identified 192 women in the Nurses’ Health Study cohorts with blood samples obtained 4 months to 17 years prior to medical record-confirmed RA diagnosis. Three controls were selected matched on age, cohort, menopausal status and post-menopausal hormone use. Reactivities to 18 ACPAs were measured using a custom BioPlex platform. We used conditional logistic regression to calculate the relative risk (RR) of RA for any ACPA-positive and peptide-specific ACPA-positive and examined RRs by time between blood draw and RA onset. Measures of multiplicative and additive interaction between any ACPA-positive and HLA-SE were calculated. Results: All ACPAs by peptide groups were significantly associated with RA risk, RRs ranged from 4.7 to 11.7. The association between ACPA and RA varied over time with the strongest association in those with blood draw less than 5 years before onset (RR 17.0 [95% CI 5.8 to 53.7]) and no association 10 or more years prior to onset (RR 1.4 [95% CI 0.5 to 4.3]). Individuals with both HLA-SE and any ACPA-positive had the highest risk of RA. HLA-SE-positive RA cases showed reactivity to more ACPA types than HLA-SE negative (χ2 test for trend, P = 0.01). Conclusions: There is increasing ACPA reactivity up to 10 years before RA onset with the strongest association within 5 years of RA onset. The magnitude of the response to ACPAs, in combination with the presence of HLA-SE, is most important for identifying those individuals with the highest risk of RA

The disposition and metabolism of tiazofurin in rodents, rabbits, and dogs.

The pharmacokinetics and metabolism of tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) have been examined in the mouse, rat, rabbit, and dog using tritiated drug as a marker. In all four species, tiazofurin, given as a single bolus iv injection, is removed from the circulation in a triphasic manner, with a generally prolonged terminal half-life. In all cases, the mean concentration of unchanged drug prevailing during this terminal phase was well within the cytotoxic range (IC50 vs. P388 cells is 2 microM in vitro). Urinary excretion accounted for between approximately 40 and 90% of the administered dose in all four species, with only minor quantities (less than 3%) of drug-derived radioactivity detected in the feces. The metabolism of tiazofurin was examined in mice and rats: although no evidence was uncovered for hydroxylation of tiazofurin at carbon atom 5 of the thiazole ring, phosphorylation of the drug at its 5\u27-hydroxyl was demonstrable in nearly every organ of both species, but, liver, striated muscles, and kidney were the only tissues catalyzing the synthesis of thiazole-4-carboxamide adenine dinucleotide to any prominent degree. This synthesis did not appear to be a saturated process, even at doses as high as 8000 mg/m2. Since rodent skeletal muscle accumulated high concentrations of tiazofurin phosphates in vivo, it is suggested that musculature may serve as a reservoir for the drug, and contribute to its rather protracted terminal half-life in plasma

An investigation of fludarabine as a potential radiation sensitizer of human prostate cancer cells in vitro

Aim: Patient relapse following radiotherapy for prostate cancer is of major concern to oncologists. As chemotherapeutic agents have shown promise as radiation sensitizers, we investigated the use of fludarabine monophosphate as a radiation enhancement agent in human LNCaP-LN3, PC3 and LNCaP prostate carcinoma cell lines with different sensitivities to fludarabine and ionizing radiation. Methods: Cells were treated with non-cytotoxic doses of fludarabine for 16 h pre-irradiation or 5 days post-irradiation; survival fractions were determined by clonogenic assay. Cell cycling was also assessed. Results: LNCaP-LN3 cells incubated with 1 μmol/L fludarabine for 5days post-irradiation were slightly sensitized (1.18 times, P =0.029), whilst 16 h pre-incubation had no effect on the radiation response. PC3 cells incubated with 10μmol/L fludarabine for 16h pre-irradiation were sensitized to ionizing radiation (1.61 times, P < 0.0001), but treatment for 5days post-irradiation with fludarabine had no effect on their radiosensitivity. Neither fludarabine incubation had any effect on the sensitivity of LNCaP cells to ionizing radiation. A characterization of the cell cycle following 16h exposure to fludarabine demonstrated that enhanced radiosensitivity of PC3 cells is independent of cell cycle. Conclusion: PC3, but not LN3 or LNCaP cells, were sensitized to ionizing radiation by pre-incubation with 10 μmol/L fludarabine for 16h (1.61 times, P < 0.0001) but not by post-irradiation exposure to the drug. The enhanced radiosensitivity of PC3 cells is independent of cell cycle. Further studies are required to elucidate the mechanism of fludarabine mediated sensitization in these cells. © 2008 The Authors Journal Compilatio