Uveitis Reactivation in Children Treated With Tumor Necrosis Factor Alpha Inhibitors.

PURPOSE: To evaluate reactivation of pediatric uveitis during/following treatment with tumor necrosis factor alpha inhibition (anti-TNFα). DESIGN: Retrospective cohort study. METHODS: We assessed the incidence of uveitis reactivation in children ≤18 years who had achieved uveitis quiescence under anti-TNFα. Survival analysis was used to calculate reactivation rates while still on (primary outcome), and following discontinuation of (secondary outcome), anti-TNFα. Potential predictive factors were assessed. RESULTS: Among 50 children observed to develop quiescence of uveitis under anti-TNFα, 39 met criteria to be "at risk" of the primary (19 for the secondary) outcome. 60% were female, ∼half had juvenile idiopathic arthritis, and most were treated with infliximab. Overall, the estimated proportion relapsing within 12 months was 27.8% (95% confidence interval [CI]: 15.9%-45.8%); the estimated probability of reactivation was higher following (63.8% [95% CI: 38.9%-87.7%]) vs before (21.6% [95% CI: 10.8%-40.2%]) anti-TNFα discontinuation. Among those who discontinued anti-TNFα, the likelihood of reactivation was higher for those treated with adalimumab vs infliximab (hazard ratio [HR] 13.4, P = .01, 95% CI: 2.2-82.5) and those with older age at uveitis onset (HR 1.3, P = .09, 95% CI: 1.0-1.7). The duration of suppression, on medication, did not significantly affect the likelihood of reactivation when quiescence was maintained for ≥1.5 years. CONCLUSIONS: Approximately 75% of children remaining on anti-TNFα following achievement of uveitis quiescence remain quiescent at 1 year. However, most reactivate following anti-TNFα discontinuation. These results suggest that infliximab more often is followed by remission, off medication, than adalimumab. The data do not suggest that maintenance of suppression for more than 1.5 years decreases the reactivation risk.

Identification of survival genes in human glioblastoma cells by small interfering RNA screening.

Target identification and validation remain difficult steps in the drug discovery process, and uncovering the core genes and pathways that are fundamental for cancer cell survival may facilitate this process. Glioblastoma represents a challenging form of cancer for chemotherapy. Therefore, we assayed 16,560 short interfering RNA (siRNA) aimed at identifying which of the 5520 unique therapeutically targetable gene products were important for the survival of human glioblastoma. We analyzed the viability of T98G glioma cells 96 h after siRNA transfection with two orthogonal statistical methods and identified 55 survival genes that encoded proteases, kinases, and transferases. It is noteworthy that 22% (12/55) of the survival genes were constituents of the 20S and 26S proteasome subunits. An expression survey of a panel of glioma cell lines demonstrated expression of the proteasome component PSMB4, and the validity of the proteasome complex as a target for survival inhibition was confirmed in a series of glioma and nonglioma cell lines by pharmacological inhibition and RNA interference. Biological networks were built with the other survival genes using a protein-protein interaction network, which identified clusters of cellular processes, including protein ubiquitination, purine and pyrimidine metabolism, nucleotide excision repair, and NF-kappaB signaling. The results of this study should broaden our understanding of the core genes and pathways that regulate cell survival; through either small molecule inhibition or RNA interference, we highlight the potential significance of proteasome inhibition.